1.1

1.2

1.3

1.4

1.5

2.1

2.1.1

2.1.2

2.1.3

2.1.4

2.1.5

2.1.6

2.1.7

2.1.8

2.1.9

2.1.10

2.1.11

2.1.12

2.2

2.2.1

2.2.1.1

2.2.1.2

2.2.2

2.2.2.1

2.2.2.2

2.2.2.3

2.2.2.4

2.2.2.5

2.2.2.6

2.2.2.7

2.2.2.8

2.2.2.9

2.2.3

2.2.3.1

TableofContentsAboutPartOne

DownloadPartOne

HowtoPass

TheSAQ

TheViva

Curriculum

ResearchMethodsandStatistics

Evidence-BasedMedicine

StudyTypes

ClinicalTrialDesign

DataTypes

BiasandConfounding

FrequencyDistributions

SampleSizeCalculation

StatisticalTests

StatisticalTerms

RiskandOdds

SignificanceTesting

DrugDevelopment

Pharmacology

Pharmaceutics

Additives

Isomerism

Pharmacokinetics

Modeling

Absorption

Distribution

MetabolismandClearance

Elimination

BolusandInfusionKinetics

DrugMonitoring

EpiduralandIntrathecal

TIVAandTCI

Pharmacodynamics

ReceptorTheory

2

2.2.3.2

2.2.3.3

2.2.3.4

2.2.4

2.2.4.1

2.2.4.2

2.2.4.3

2.2.4.4

2.2.4.5

2.2.5

2.2.5.1

2.2.5.2

2.2.5.3

2.3

2.3.1

2.3.2

2.3.3

2.3.4

2.3.5

2.3.6

2.4

2.4.1

2.4.1.1

2.4.1.2

2.4.1.3

2.4.2

2.4.3

2.4.3.1

2.4.3.2

2.4.3.3

2.4.3.4

2.4.3.5

2.4.3.6

2.4.3.7

2.4.3.8

2.4.4

2.4.4.1

2.4.4.2

2.4.5

2.4.5.1

ReceptorTypes

Dose-ResponseCurves

MechanismsofAction

VariabilityinDrugResponse

AdverseEffects

DrugInteractions

AlterationstoResponse

Pharmacogenetics

DrugsinPregnancy

Toxicology

GeneralManagement

TCAOverdose

Organophosphates

CellularPhysiology

TheCellMembrane

Organelles

ExcitableCells

TransportAcrossMembranes

FluidCompartments

CellHomeostasis

RespiratorySystem

RespiratoryAnatomy

AirwayandAlveolus

ChestWallandDiaphragm

VariationsinAnatomy

ControlofBreathing

MechanicsofBreathing

Respiration

Compliance

Time-Constants

Resistance

Surfactant

VolumesandCapacities

Spirometry

WorkofBreathing

DiffusionofGases

OxygenCascade

DiffusingCapacityandLimitation

V\QRelationships

West'sZones

3

2.4.5.2

2.4.5.3

2.4.5.4

2.4.6

2.4.6.1

2.4.6.2

2.4.7

2.4.7.1

2.4.7.2

2.4.7.3

2.4.7.4

2.4.7.5

2.4.7.6

2.4.7.7

2.4.7.8

2.4.7.9

2.4.7.10

2.4.8

2.4.8.1

2.5

2.5.1

2.5.1.1

2.5.1.2

2.5.1.3

2.5.2

2.5.2.1

2.5.3

2.5.3.1

2.5.3.2

2.5.3.3

2.5.3.4

2.5.3.5

2.5.4

2.5.4.1

2.5.4.2

2.5.4.3

2.5.4.4

2.5.4.5

2.5.5

2.5.5.1

BasicsofV\QMatching

DeadSpace

Shunt

GasTransport

OxygenStorage

CarbonDioxide

AppliedRespiratoryPhysiology

PositivePressureVentilation

Hypoxia

HypoandHypercapnea

PositionandVentilation

Humidification

CoughReflex

Non-RespiratoryFunctions

AltitudePhysiology

RespiratoryChangeswithObesity

NeonatesandChildren

RespiratoryPharmacology

Anti-AsthmaDrugs

CardiovascularSystem

StructureandFunction

CardiacAnatomy

CoronaryCirculation

CardiacCycle

ElectricalProperties

CardiacActionPotential

CardiacOutput

DeterminantsofCardiacOutput

VenousReturn

MyocardialOxygenSupplyandDemand

Pressure-VolumeRelationships

CardiacReflexes

PeripheralCirculation

StarlingForces

VariationsinBloodPressure

PulmonaryCirculation

CerebralBloodFlow

HepaticBloodFlow

CirculatoryControl

Baroreceptors

4

2.5.5.2

2.5.5.3

2.5.5.4

2.5.6

2.5.6.1

2.5.6.2

2.5.6.3

2.6

2.6.1

2.6.1.1

2.6.1.2

2.6.1.3

2.6.1.4

2.6.1.5

2.6.1.6

2.6.1.7

2.6.2

2.6.2.1

2.6.2.2

2.7

2.7.1

2.7.2

2.7.3

2.8

2.8.1

2.8.2

2.8.3

2.8.4

2.8.5

2.8.6

2.8.7

2.8.8

2.8.9

2.8.9.1

2.8.9.2

2.8.9.3

2.8.9.4

2.8.9.5

2.8.9.6

2.8.9.7

ValsalvaManoeuvre

CVSChangeswithObesity

CVSEffectsofAgeing

CardiovascularPharmacology

Inotropes

Adrenoreceptors

Antiarrhythmics

RenalSystem

RenalPhysiology

FunctionalAnatomyandControlofBloodFlow

GlomerularFiltrationandTubularFunction

HandlingofOrganicSubstances

MeasurementofGFR

EndocrineFunctionsoftheKidney

Acid-BaseBalance

Dialysis

FluidsandElectrolytes

SodiumandWater

Potassium

Acid-BasePhysiology

PrinciplesofAcid-BasePhysiology

Compensation

Buffers

NervousSystem

Blood-BrainBarrier

CSF

SpinalCordAnatomy

IntracranialPressure

IntraocularPressure

Sleep

Pain

AutonomicNervousSystem

Neuropharmacology

Neurotransmitters

Anticonvulsants

LocalAnaesthetics

NeuraxialBlockade

AcetylcholineReceptors

Opioids

InhalationalAnaesthetics

5

2.9

2.9.1

2.9.2

2.9.3

2.9.4

2.9.5

2.9.6

2.9.7

2.9.8

2.9.9

2.10

2.10.1

2.10.2

2.10.3

2.11

2.11.1

2.11.2

2.11.3

2.11.4

2.11.5

2.11.6

2.12

2.12.1

2.13

2.13.1

2.13.2

2.13.3

2.13.4

2.14

2.14.1

2.14.2

2.14.3

2.15

2.15.1

2.15.2

2.15.3

2.15.4

2.16

2.16.1

2.16.2

Endocrine

ABriefOverviewofHormones

Insulin,Glucagon,andSomatostatin

ControlofBloodGlucose

HypothalamusandPituitary

Thyroid

AdrenalHormones

CalciumHomeostasis

Histamine

Prostanoids

MusculoskeletalSystem

SkeletalMuscleStructure

SkeletalMuscleInnervation

NeuromuscularBlockers

Nutrition&Metabolism

BasalMetabolicRate

FatMetabolism

CarbohydrateMetabolism

ProteinMetabolism

RequirementsandStarvation

AnaerobicMetabolism

Thermoregulation

RegulationofBodyTemperature

Immunology

Inflammation

InnateImmunity

AdaptiveImmunity

Hypersensitivity

Microbiology

ClassificationofMicroorganisms

AntimicrobialResistance

Antiseptics

Obstetrics&Neonates

RespiratoryChanges

CardiovascularChanges

FoetalCirculation

ThePlacenta

GastrointestinalSystem

Oesophagus

GastricSecretions

6

2.16.3

2.16.4

2.16.5

2.16.6

2.16.6.1

2.16.6.2

2.16.6.3

2.17

2.17.1

2.17.2

2.17.3

2.17.4

2.17.5

2.17.6

2.17.7

2.18

2.18.1

2.18.2

2.18.3

2.18.4

2.18.5

2.18.6

2.18.7

2.18.8

2.18.9

2.18.10

2.18.11

2.18.12

2.18.13

2.18.14

2.18.15

2.18.16

2.18.17

2.18.18

2.18.19

2.18.20

2.18.21

2.18.22

2.18.23

2.18.24

ControlofGastricEmptying

Swallowing

PhysiologyofVomiting

LiverPhysiology

FunctionsoftheLiver

LaboratoryAssessmentofLiverFunction

Bile

Haematology

Erythrocytes

IronHomeostasis

Platelets

Transfusion

Haemostasis

HaemostaticRegulation

CoagulopathyTesting

EquipmentandMeasurement

SIUnits

ElectricalSafety

WheatstoneBridge

NeuromuscularMonitoring

PressureTransduction

PressureWaveformAnalysis

Non-InvasiveBloodPressure

CardiacOutputMeasurement

PulseOximetry

OxygenAnalysis

End-TidalGasAnalysis

BloodGasAnalysis

GasFlow

PrinciplesofUltrasound

TemperatureandHumidity

Electrocardiography

Humidifiers

SupplementalOxygen

BispectralIndex

MedicalGasSupply

Vapourisers

BreathingSystems

CircleSystem

Scavenging

7

2.18.25

2.18.26

2.19

2.19.1

2.19.2

2.19.3

2.19.4

2.19.5

3.1

3.1.1

3.1.1.1

3.1.2

3.1.2.1

3.1.2.2

3.2

3.2.1

3.2.2

3.2.3

3.2.3.1

3.2.3.2

3.2.3.3

3.2.3.4

3.2.4

3.2.5

3.3

3.3.1

3.3.2

3.3.3

3.3.3.1

3.3.3.2

3.3.3.3

3.3.3.4

3.3.3.5

3.3.3.6

3.3.3.7

3.3.4

3.3.4.1

Diathermy

Lasers

ProceduralAnatomy

SubclavianVein

InternalJugularVein

IntercostalCatheter

AntecubitalFossa

Tracheostomy

Pharmacopoeia

Toxicology

RecreationalDrugs

ToxicAlcohols

Antidotes

Naloxone

Flumazenil

Respiratory

Oxygen

Helium

Bronchodilators

BetaAgonists

Antimuscarinics

PhosphodiesteraseInhibitors

LeukotrieneAntagonists

Corticosteroids

PulmonaryVasodilators

CardiovascularPharmacology

AdrenergicVasoactives

Non-adrenergicVasoactives

Antihypertensives

CentrallyActingAgents

CalciumChannelBlockers

DirectVasodilators

ACEInhibitors

AngiotensinReceptorBlockers

NeprilysinInhibitors

PotassiumChannelActivators

Antiarrhythmics

SodiumChannelBlockers

8

3.3.4.2

3.3.4.3

3.3.4.4

3.3.4.5

3.3.4.6

3.3.4.7

3.3.4.8

3.4

3.4.1

3.4.2

3.5

3.5.1

3.5.2

3.5.3

3.5.4

3.5.5

3.5.6

3.5.7

3.5.8

3.5.9

3.5.10

3.5.11

3.5.12

3.6

3.6.1

3.6.2

3.6.3

3.6.4

3.7

3.7.1

3.7.2

3.8

3.8.1

3.8.2

3.8.3

3.8.4

3.9

3.9.1

3.9.2

3.9.3

Beta-Blockers

Amiodarone

Sotalol

Digoxin

Adenosine

Magnesium

Atropine

Renal

Diuretics

IntravenousFluids

Neuropharmacology

Propofol

Barbiturates

Ketamine

Dexmedetomidine

LocalAnaesthetics

Benzodiazepines

Antidepressants

Antipsychotics

Anticonvulsants

GABAAnalogues

InhalationalAnaestheticAgents

NitrousOxide

Analgesics

Opioids

COXInhibitors

Tramadol

Paracetamol

Autonomic

Anticholinesterases

Antimuscarinics

Neuromuscular

DepolarisingNMBs

Non-DepolarisingNMBs

Dantrolene

Sugammadex

Haematological

Anticoagulants

DirectThrombinInhibitors

Antifibrinolytics

9

3.9.4

3.10

3.10.1

3.10.2

3.10.3

3.10.4

3.10.5

3.10.6

3.11

3.11.1

3.11.1.1

3.11.1.2

3.12

3.12.1

3.12.2

3.13

3.13.1

3.13.2

3.14

3.14.1

4.1

4.2

4.3

4.4

Antiplatelets

Antimicrobials

Penicillins

Glycopeptides

Aminoglycosides

Lincosamides

Metronidazole

Antifungals

Endocrine

Hypoglycaemics

Insulin

OralHypoglycaemics

Obstetric

Oxytocics

Tocolytics

Gastrointestinal

AcidSuppression

Antiemetics

OtherDrugs

IVContrast

Appendices

Definitions

KeyGraphs

LawsandEquations

StructuresforSAQs

10

PartOnePartOneisareferencefortraineespreparingfortheCICMandANZCAPrimaryExams.

PartOneis:DesignedtocovertheassessedsectionsoftheCICMandANZCAcurriculainenoughdetailtopassAroughguidefortheexpecteddepthofknowledgerequiredonatopicAtooltocorrectyourwrittenanswersAsourceofinformationyoumightfinddifficulttofindelsewhere

PartOneisnot:AtextbookThedefinitiveguidetotheprimaryexamAcompletereferenceTherewillbebothomissionsanderrors.Ifyoufindany,pleaseletmeknow.

Layout

Thebookisdividedintothreesections:

CurriculumCoversstatistics,physiology,equipmentandmeasurement,andanatomy.

Pagesarelaidoutusingthesectiontitle,topictitles,andorderfromtheCICMcurriculumAgreyblockindicatesatopicisfromtheCICMcurriculumORbothcurricula

WhenatopicisonlyexaminableintheANZCAcurriculum,ithasbeenslottedinsomewheresensibleApurpleblockindicatesatopicisONLYfromtheANZCAcurriculum

Topicscoveredbythepagearelistedatthebeginningofeachpage

PharmacopoeiaCoversdrugs.

Forthesakeofconsistency,thegeneralprinciplesofpharmacologyarecoveredinthecurriculum,whilstthespecificsofdifferentagentswillbefoundinthepharmacopoeia.Iflost,usethesearchbox.

AppendicesIncludesthekeydefinitions,graphs,andequationsyoushouldknow,aswellassamplestructuresforSAQs.

Acknowledgements+TechnicalStuff

PartOneisbuiltwithanumberofopen-sourcetools:

WritteninJohnGruber'selegantMarkdownBuiltandmadeprettybytheGitBooktoolchainWithpluginsfrom:

BenLauforautomatictimestampsMichaelJergerforcollapsiblechaptersRishabhGargfortopnavigation

EquationswritteninLATEXGraphshavebeen:

WritteninPGF/Tikzusingtexworks

AboutPartOne

11

ConvertedtovectorgraphicswithdvisvgmRefinedwithsvgo(Somegraphshavebeentakenfromopen-sourcesitessuchasWikimediaCommons.Thesehavebeencreditedwhereused.)

Additionally,chemicalstructureshavebeenbuiltinMarvinSketch

AbouttheAuthor

JakeBarlowisanAnaestheticandIntensiveCareRegistrarfromMelbourne,Australia.Interestedinallthingscriticalcare(withaparticularfascinationforphysiology),aswellasbiotech,physicalcomputing,teaching,analytics,andoutcomepredictioninintensivecare.Sendallcomments,criticism,andcomplaintsaboutPartOnetohimhere.

Copyright+Legal

Copyright©2015-2019C.JakeBarlow

ThisworkislicensedunderaCreativeCommonsAttribution-NonCommercial-ShareAlike4.0InternationalLicense.

Lastupdated2019-11-09

AboutPartOne

12

DownloadPartOne

PartOneisalsoprovidedwith:

APDFversionforofflineuseNotethat:

TheimagequalityofgraphsisreducedinthePDFversionThePDFversionisautomaticallybuiltwheneverthesiteisupdatedTherefore:

ThedownloadlinkwillalwayslinktothemostrecentversionThispagewillappearinthePDFversion

Acompanionsetofflashcards,madeinAnki

Lastupdated2018-07-16

DownloadPartOne

13

HowtoPassThefirstpartexamis:

PainfulTheknowledgedemandedishuge,andcannotbeavoided.EminentlyachievableRemember,itisnotimpossible-everybodybeforeyouhascompletedit.

PlanforSuccess

Thisisnotanexamyouwanttohavetositmorethanonce-trytogiveyourselfthebestchanceofsuccessthefirsttimeround:

CommityourselfearlyDecidewhenyouaregoingtosit:

Pickadate~9monthsinadvance6monthsisprobablypushingit9monthsisachievable12monthsisalmosttoolong-youwilllosemotivationandknowledgewillfade.

AcceptthatthetimebetweennowandtheexamisnotgoingtobethebesttimeofyourlifeConsiderpayingthemoneyassoonaspossible-lockyourselfinYourfamilyandfriendswillforgiveyou,eventually

Don'tlosefaithTherewillbetimesthatyouquestionwhyyouhavetolearnthisThoseareverylegitimatefeelingsAcceptthatpartofthisexamisanacademichazingyoumustpassthroughonyourpathtofellowship

BeStrategicThecurriculumprovidedisoverwhelming,andprobablynotachievableformostofus.Haveaplanabouthowyouwillapproachit:

HaveatimetableContenttocovereachweek

Ifoundsettingaweeklygoalwouldallowmetoplanaroundday-to-dayvariations(finishinglate,gooddays,baddays,etc)Adailytimetablewasoftenmangledbylife,creatingunnecessarystress

TimetostartvivapracticeAimtostartbeforethewritten.

Topicsthatyoucan'texplain,youprobablydon'tunderstandfullyThismaynotbeapparentuntilyoutryandexplainit.

KnowtheenemySyllabusReadthroughitsoyouappreciatethebreadthofknowledgerequired.KnowthestyleThisallowsyoutogiveanswersefficiently-thekeymetricforboththevivasandtheSAQsismarksperunittime.

StyleofexamquestionsIncludingthestyleofanswers-seetheSAQ.

HowtoPass

14

StyleofvivasDopracticevivas

Recordyourself,soyouknowyourticsDoadressrehearsalMakesureyoursuitstillfitsbeforetheday.

GraphsBeabletodrawthemwhiletalkingaboutthem.

DopastquestionsIcannotstressthisenough.Thisisthekeytopreparingforthisexam.

Pastquestions:TeachyouappropriatestructureTeachyoutowritetotimeEnsureyoulearnthecontentinthewayitwillberecalledEnsureyoudon'twastetimelearningthingsthatareunlikelytobeexaminedWhenIsattheCICMexam,Ihaddonealmostallthepastquestions,whichcovered~60%ofthecurriculum.Therewas1(outof24)oftheSAQsonatopicIhadnotansweredanSAQonbefore.

DoquestionstotimeKeepingtotimeisvital.

Itisalmostimpossibletowriteaperfectanswerin10minutesInmanycasesyouwillneedtomoveontothenextquestiondespitestillhavingthingstosayRememberthatthemarkingfollowsasigmoiddistribution

Thefirst30%ofmarksforaquestionareeasytogetThelast30%ofmarksareverydifficulttogetTherefore,themostefficientuseofyourtimeistoaimtoget~60-70%ofmarksforeachquestion.

Rememberthepassmarkis50%YouarenotexpectedtoknoweverythingBreadthtendstoberewardedoverdepthItisnormaltosittheexamandhaveaquestionyouhavenotthoughtaboutbefore

SuggestedApproach

Therearemanyequallyvalidwaystoapproachtheseexams.ThisishowIwoulddoit,ifIhadtodoitagain:

1. ReadageneralphysiologyandpharmacologytextbookThiswillhelpyouunderstandthescopeoftheundertaking.Iwouldrecommendspending2-3weeksreading:

ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.Inmyopinion,thisisthegeneralphysiologytext.Ibelievethatifyoukneweverythinginthisbook,youwouldpassthephysiologycomponentofbothexams.PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.Thefirstfewchaptersareagoodintroductiontopharmaceuticsandpharmacokinetics,whichwillhelpyouputlaterinformationfrommorecompletetextsintocontext.

2. Startdoingpracticequestions:Thisisthekeytotheexam.Isuggest:

StartdoingonequestionatatimeInthebeginning,youwillnotknowenoughtowritefor10minutes.

Afterdoingthequestion,checkyouransweragainstavailablepastanswersThisforcesactivelearning,andisfarmoreefficientthanreading.Lookat:

StructureHowdidyoustructureyouranswer?Whatwastheexamplestructure?

HowtoPass

15

ContentWhatdidyoumiss?Arethenumbers/graphsyouusedcorrect?

Thenstudythecurriculumareasthatquestioncovered,andmakenotesThiswouldtakeme~1-2hoursforanewcurriculumarea.

Onceyoustartdoingquestionswhichyouknowsomethingabout(havingansweredonesimilarpreviously),moveuptothreequestionsin24minutes.Thisteachesyoutokeeptime,whichisvitalforsuccessintheSAQ.

Stillcheckeachanswerafterwards,lookoverthatareaofthecurriculum,andreviseandrefineyournotesWhenyoufindyourselfrunningoutoftimebeforeyourunoutofthingstowrite,giveyourself9minutesperquestionIwouldsuggestnotgoingbeyondthis-youneedtoallocateyourtimestrategicallyontheday,andwritingtotimeiscritical.Asthisgetseasier,startdoing6ormorequestionsatatimetotrainyourwritinghandDooneortwofullexamstotimebeforegameday

3. DoalotofflashcardsFlashcardsarelessdemandingthandoingquestions,andasimpleformofrevision.

Theyaretheabsolutebestwayofrotelearningfacts(inmyopinion)Iusedanki,butusewhateverworksforyouMyankideckisavailablehere

4. DopracticevivasStartbeforethewritten.Thereisalotofcrossoverofskillsbetweenthevivaandthewritten.Bothrequireastructuredapproach,andgoodcontentknowledge.

Remembertotakeabreakafterthewrittenexams,itisexhausting

TheBottomLine

Pickadate,andcommittoitWorkoutwhichtimesworkbestforyouwithrespecttostudyDifferenttimeswillbebetterfordifferentthings.Ifound:

Daysoff(includingweekends)werebestforlearningnewcontentWorkdayswereforrevisingPostnightshiftwasawrite-off

MaintainapositiveattitudeStudygroupsaregoodforthis-sharethesuffering!SplitlargetopicsintomanageablechunksDon'tloseyourheadSetasidetimeforrelaxation,anddon'tfeelguiltyaboutit.Youdon'thavetoknoweverythingThepassmarkis50%

ReferencesThisisbasedonatalkIgaveatthe2016VPECCCourse,stillrawfromtheCICMprimary

Lastupdated2019-08-01

HowtoPass

16

HowtoPass

17

TheSAQAgoodresponsetoashort-answerquestionisconstructedfromtwothings:

StructureDevelopingastructuredapproachtoansweringSAQsisessentialtosucceedinginthissectionoftheexam.Astructuredapproach:

IseasilydigestedbytheexaminerReducestheamountoffilleryouneedtowrite,meaningyoucanwritemorefactsTypicallylendsitselftobulletpointsratherthanparagraphsAllowsyoutorecallmoreinformationthanyouwouldotherwiseEspeciallyifyoulearntitinthesameformat.Thisisparticularlyimportantforpharmacology.

KnowledgeObviously.

Additionally,agoodresponsewill:

AnswerthequestionThisisstatedrepeatedlyinexaminerreports.Ifthequestionasksforadiscussionoftherespiratorychangesofpregnancy,nomarkswillbeawardedforcardiovascularchanges.BelegibleNotbeperfectThisisoften-overlooked.

Examinerreports(andsomemodelanswers),assumeaperfectresponseThisnotfeasiblegiventhetimeallowedItisalsonotactuallyexpected-rememberthatthepassmarkis50%

Thebottomline:

AgoodresponsewillcoverthemajorpointsinreasonabledetailWillgenerallyfocusonprinciplesratherthanspecificsMarksbecomeprogressivelyhardertoacquire:

ThefirstoneortwomarksonaquestionshouldbeeasyGoingfroman8/10toa10/10willrequiretimewhichyoulikelycannotspare

AnsweringtheQuestion

Youhaveexactly10minutesperSAQYoushouldpracticeto8-9minutesperSAQInmanycases,thelastquestion(orquestions)goesunanswered.Thisdemonstratespoortimemanagement,aseasymarkswerethrownawaybycandidatesreachingforhardermarksonearlierquestions.

Duringreadingtime,youshouldevaluateeachquestionto:

DecidewhatpartofthecurriculumitisassessingWorkoutthecontext,ifanyDecidewhatstructurewouldbemostappropriate

Lastupdated2017-08-14

TheSAQ

18

TheSAQ

19

TheVivaThevivaisthepartoftheexammostcandidatesseemmoststressedabout.However:

Ifyoumakeitthroughthewritten,youwillmostlikelypassVeryfewpeoplesucceedinthewrittenexamstofailattheviva.

TheknowledgeisthereExaminerswantyoutopassTheywillredirectyouifyou'reofftrack.

Thismakesiteasiertomakeupmarksthanonthewritten,whereyoucaneasilygooffdowntherabbithole,haemorrhagingtimeandmarks

UnderstandingtheViva

Todowellattheviva:

UnderstandthevivaisaperformancepieceThevivaisaritualisedconversation.Successrequiresyoutoknowandunderstandthelanguageandstructureused,justliketheSAQ.StructureyouranswerAswiththeSAQ,categoriseyouranswer.

HaveagoodopeningstatementDon'tanswermorethanisasked.StartbroadOftenthevivawillgointodepthononlyoneortwoareasofatopic.Ifyoustartgoingintodetailononlypartsofatopic,itmakesithardfortheexaminertoredirectyouandscoresyounomarks.

BeconfidentEnjoyitifyoucan.LearntothinkonyourfeetThevivaassessesknowledgeinadifferentwaytotheSAQs.

Theknowledgewillbethere,butitmayrequireadifferentapproachtoaccessitThisrequirespractice.Thisisalsoimportantfordeliveringasoundanswerbasedonincompleteknowledge

It'sokaytosay"Idon'tknow"Butprobablynotonthefirstquestion.

Ifyoudon'tknowimmediately,canyouworkitoutfromfirstprinciples?Don'tgetangry

WithyourselfWiththeexaminerDon'targue.

Don'tapologiseApologies:

MakeyouloseconfidenceDon'tgetyoumarksRemember,marksperunit-time.

Don'ttalkovertheexaminerTheyareinterruptingyoubecausewhatyouaresayingisgainingnomarks.Ifyoukeeptalking,youwill:

NotbegettingmarksIrritatethem

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Potentiallylosingfuturemarks.

Lastupdated2019-11-02

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Evidence-BasedMedicineDescribethefeaturesofevidence-basedmedicine,includinglevelsofevidence(e.g.NHMRC),meta-analysis,andsystematicreview

WhatisEvidence-BasedMedicine?

Evidence-basedmedicine(EBM)is"theconscientious,explicit,andjudicioususeandappraisalofcurrentbestevidenceinmakingdecisionsaboutthecareofindividualpatients."ThepurposeofEBMistoprovideaframeworkforacquiringknowledgeandmakingoptimaldecisionsaroundmedicalcare.Itmeansintegratingindividualclinicalexpertisewiththebestavailableexternalclinicalevidencefromsystematicresearch."

TherearefivestagesofEBM:

1. Askananswerablequestion2. Search3. Criticallyappraisetheevidence4. Integratetheevidencewiththepatientsuniquecircumstancesandvalues5. Evaluatetheresult

LevelsofEvidence

Levelsofevidencegradestudiesonlikelihoodofbiasandinternalvalidity.TheNHMRCdefines6levelsofevidence,gradedfromI-IV(withthreelevelIIIsubtypes).

Ingeneral:

LevelIisevidencefromasystematicreviewofRCTsLevelIIisevidencefromatleastonegoodRCTLevelIII-1isevidencefromapseudo-RCTLevelIII-2isevidencefromacomparativestudywithconcurrentcontrols,suchasacohortorcase-controlstudyLevelIII-3isevidencefromacomparativestudywithoutconcurrentcontrols,suchasacohortstudywithhistoricalcontrolsLevelIVisevidencefromacase-series

NotethatexpertopinionisnotpartofNHMRClevelsofevidence,thoughitisincludedontheOxfordCentreforEvidenceBasedMedicinesystem,usedbytheNHS.

Level Intervention DiagnosticAccuracy Prognostic Aetiology Screening

IAsystematicreviewoflevelIIstudies

AsystematicreviewoflevelIIstudies

AsystematicreviewoflevelIIstudies

AsystematicreviewoflevelIIstudies

AsystematicreviewoflevelIIstudies

II Arandomisedcontrolledtrial

Astudyoftestaccuracywith:anindependent,blindedcomparisonwithavalidreferencestandard,amongconsecutivepersonswithadefinedclinicalpresentation

Aprospectivecohortstudy

Aprospectivecohortstudy

Arandomisedcontrolledtrial

Astudyoftestaccuracy

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III-1Apseudorandomisedcontrolledtrial

with:anindependent,blindedcomparisonwithavalidreferencestandard,amongnon-consecutivepersonswithadefinedclinicalpresentation

Allornone AllornoneApseudorandomisedcontrolledtrial

III-2

Acomparativestudywithconcurrentcontrols

AcomparisonwithreferencestandardthatdoesnotmeetthecriteriarequiredforLevelIIandIII-1evidence

Analysisofprognosticfactorsamongstpersonsinasinglearmofarandomisedcontrolledtrial

Aretrospectivecohortstudy

Acomparativestudywithconcurrentcontrols

III-3

Acomparativestudywithoutconcurrentcontrols

Diagnosticcase-controlstudy

Aretrospectivecohortstudy

Acase-controlstudy

Acomparativestudywithoutconcurrentcontrols

IV

Caseserieswitheitherpost-testorpre-test/post-testoutcomes

Studyofdiagnosticyield(noreferencestandard)

Caseseries,orcohortstudyofpersonsatdifferentstagesofdisease

Across-sectionalstudyorcaseseries

Caseseries

Gradesofevidence

Evidenceisgradedto"indicatethestrengthofthebodyofevidenceunderpinningarecommendation"(e.g.inaclinicalguideline).TheNHMRCgradesrecommendationsfromAtoDasfollows:

A:BodyofevidencecanbetrustedtoguidepracticeB:Bodyofevidencecanbetrustedtoguidepractice,inmostsituationsC:Bodyofevidenceprovidessomesupport,butcareshouldbetakeninitsapplicationD:Bodyofevidenceisweakandrecommendationmustbeappliedwithcaution

Studytypes:SystematicReviewsandMeta-analyses

SystematicReview

Processofevaluatingallofthe(quality)literaturetoansweraspecificclinicalquestion.Doesnotnecessarilyinvolvestatisticalanalysis.Ifitinvolvesquantitativeanalysisofmultipletrials,itisknownasameta-analysis.

Meta-analysis

Mathematicaltechniqueofcombiningtheresultsofdifferenttrialstoderiveasinglepooledestimateofeffect.Canbedoneby:

PoolingtheresultsofeachtrialPoolingalloftherawdataandconductingareanalysis

Meta-analysesusuallyuserandom-effectsmodels,whichassumestherewillbeavarietyofsimilartreatmenteffectsIndividualtrialsaresummarisedwithanoddsratio,andweighted,usuallybysamplesize

Stagesofa[meta-analysis]andsystematicreview:

1. Inclusionandexclusioncriteriaarepredefined2. Search:includingonlinedatabases,referencelists,citations,andexperts3. Validationofpotentiallyeligibletrials(critiqueofintervalvalidity,i.e.trialquality)

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4. [HeterogeneityAnalysis]5. [Meta-analysis]6. Reliabilityofresultdetermined

i.e.Consistencyacrossstudies,statisticalsignificance,largeeffectsize,biologicalplausibility.7. Sensitivityanalysis

Repeatingtheanalysiswithanalternativemodel,excludingborderlinetrialsoroutliers.Iftheresultisunchanged,thenthefindingsarerobust.

Heterogeneity

Forthepoolingofresultstobevalid,thetrialsneedtobesimilar.Differencesbetweentrialsiscalledheterogeneity,andisimportantbecause:

Heterogeneityanalysisaffectsthetypeofmodelthatcanbeused(fixedormixedeffects)Highlyheterogenousdataisnotappropriateformeta-analysis.

Heterogeneityisdividedinto:

StatisticalHeterogeneityTheeffectsoftheinterventionaremoredifferentthanwouldbeexpectedtooccurthroughchancealone.ClinicalHeterogeneityDuetotrialdesignitwouldbeinappropriatetopooltheresults.

E.g.,conductingameta-analysisontheeffectsofthesamedruginapaediatricandadultpopulationmaybeinappropriate,asthesetwotrialshaddifferentinclusioncriteria.

MethodologicalHetreogeneityWherethemethodsusedindifferenttrialsaretoodifferenttoallowpoolingofthedata.

ForestPlots

Resultsofmeta-analysesarepresentedinablobbogram,ormoreboringly,aForestPlot.

Where:

Thex-axisplotstheoddsratio,rememberingthatanORof1indicatesnodifferenceThey-axisliststhestudiesincluded,andtheoverallsummarystatisticThedot(orsquare)indicatesthepointestimate(fromitsx-location)andtheweightgiventothestudy(byitssize)ThehorizontallineindicatestheupperandlowerboundsoftheconfidenceintervalThediamondindicatestheoverallpointestimateand(byitswidth)theconfidenceintervalforthepointestimateTheresultoftheheterogeneitytestshouldalsobedisplayedP<0.1indicatessignificantheterogeneity.

FunnelPlots

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Funnelplotsareagraphicaltooltodetectpublicationbias.

Duetostatisticalpower,largerstudiesshouldbeacloserrepresentationofthetrueeffectTherefore,whenevaluatingannumberofstudies,onewouldexpectthatlargestudiesclusteraroundthe'trueeffect',andsmallerstudiestoscatterfurtherAgraphisthenplottedofORonthex-axis,andstandarderroronthey-axis

PublicationbiasissuggestedwhenresultsclusterononesideofthefunnelplotNoevidenceofpublicationbiaswouldhavestudiesclusteredaroundthetrueeffect

Strengthsandweaknessesofmeta-analyses

Strengths Weaknesses

Enhancedprecisionofestimatesofeffect Publicationbias

Usefulwhenlargetrialshavenotbeendoneorarenotfeasible Duplicatepublication

Generateclinicallyrelevantmeasures(NNT,NNH) Heterogeneity

Inclusionofoutdatedstudies

Becauseoftheseweaknesses:

Positivemeta-analysesshouldbeconsideredlargelyhypothesis-generating,andshouldbeconfirmedby(alarge)RCTNegativemeta-analysescanprobablybeaccepted

References

1. SacketDL,RichardsonWS,RosenbergW,HaynesRB.Evidence-basedMedicine:HowtopracticeandteachEBM.ChurchillLivingstone,London1997.

2. SackettDavidL,RosenbergWilliamMC,GrayJAMuir,HaynesRBrian,RichardsonWScott.Evidencebasedmedicine:whatitisandwhatitisn'tBMJ1996;312:71.

3. NHMRC.NHMRCadditionallevelsofevidenceandgradesforrecommendationsfordevelopersofguidelines.NationalHealth&MedicalResearchCouncil.2009.

4. MylesPS,GinT.Statisticalmethodsforanaesthesiaandintensivecare.1sted.Oxford:Butterworth-Heinemann,2001.5. LalkhenAG,McCluskeyA.StatisticsV:Introductiontoclinicaltrialsandsystematicreviews.CEACP2008.

Lastupdated2019-07-18

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StudyTypesDescribethefeaturesofevidence-basedmedicine,includinglevelsofevidence(e.g.NHMRC),meta-analysis,andsystematicreview

RandomisedControlTrial

Aprospectiverandomisedcontrolledtrialisthegoldstandardofexperimentalresearch.

Itinvolvesallocatingpatientsrandomlytoeitheraninterventionorareference(control)group,andmeasuringtheoutcomeofinterest.Allocationcanbeperformedinthreeways:

SimpleIndividualsallocatedrandomly.Thismayleadtounevengroupsizes.BlockAllocationisperformedwithinblockssuchthatgroupsizeswillremaincloseinsizeStratifiedGroupsarerandomisedwithinacategory(i.e.menandwomenarerandomisedseparately).

Strengths

OnlystudydesignwhichcanestablishcausationEliminatesconfoundingRandomisationcontrolsforbothknownandunknownconfoundingfactors,astheseshouldberandomlyallocatedbetweengroups.BlindingcanbeperformedinastandardisedfashionDecreasesselectionbias

Weaknesses

CostlyTime-consumingNotappropriateforallstudydesigns

Ethicalconcernse.g.AdrenalineinALSPracticalconcernsSmallpatientpopulationoruncommondiseasemaycauserecruitmentdifficulties

SystematicReviewTheprocessofevaluatingallofthe(quality)literaturetoansweraspecificclinicalquestion.This:

DoesnotnecessarilyinvolvestatisticalanalysisIfitinvolvesstatisticalanalysisofmultipletrialstogenerateacombinedestimateofeffect,itisknownasameta-analysis.

Meta-analysis

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Mathematicaltechniqueofcombiningtheresultsofdifferenttrialstoderiveasinglepooledestimateofeffect.Canbeperformedby:

PoolingtheresultsofeachtrialCombiningalloftherawdataandconductingareanalysis

Meta-analysesusuallyuserandom-effectsmodels,whichassumestherewillbeavarietyofsimilartreatmenteffectsIndividualtrialsaresummarisedwithanoddsratio,andweighted,usuallypredominantlybysamplesize

Stagesofa[meta-analysis]andsystematicreview:

1. Inclusionandexclusioncriteriaarepredefined2. Search:includingonlinedatabases,referencelists,citations,andexperts3. Validationofpotentiallyeligibletrials(critiqueofintervalvalidity,i.e.trialquality)4. [HeterogeneityAnalysis]5. [Meta-analysis]6. Reliabilityofresultdetermined

i.e.Consistencyacrossstudies,statisticalsignificance,largeeffectsize,biologicalplausibility.7. Sensitivityanalysis

Repeatingtheanalysiswithanalternativemodel,excludingborderlinetrialsoroutliers.Iftheresultisunchanged,thenthefindingsarerobust.

Heterogeneity

Forthepoolingofresultstobevalid,thetrialsneedtobesimilar.Differencesbetweentrialsisknownasheterogeneity.Heterogeneitycanbeeither:

Statistical;wheretheeffectsoftheinterventionaremoredifferentthanwouldbeexpectedtooccurthroughchancealone.Heterogeneityanalysisaffectsthetypeofmodelthatcanbeused(fixedormixedeffects)andhighlyheterogenousdataisnotappropriateformeta-analysis.Clinical;where,duetotrialdesign,itwouldbeinappropriatetopooltheresults.Forexample,conductingameta-analysisontheeffectsofthesamedruginapaediatricandadultpopulationwouldbeinappropriate,asthesearetwodifferentpopulations.Methodological;Wherethemethodsusedindifferenttrialsaretoodifferenttoallowpoolingofthedata.

ForestPlots

Resultsofmeta-analysesarepresentedinablobbogram,ormoreboringly,aForestPlot.

Where:

Thex-axisplotstheoddsratio,rememberingthatanORof1indicatesnodifferenceThey-axisliststhestudiesincluded,andtheoverallsummarystatistic

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Thesquareindicatesthepointestimate(fromitsx-location)andtheweightgiventothestudy(byitssize)ThehorizontallineindicatestheupperandlowerboundsoftheconfidenceintervalThediamondindicatestheoverallpointestimateand(byitswidth)theconfidenceintervalforthepointestimateTheresultoftheheterogeneitytestshouldalsobedisplayed.P<0.1indicatessignificantheterogeneity.

FunnelPlots

Agraphicaltooltodetectpublicationbias.Duetostatisticalpower,largerstudiesshouldbeacloserrepresentationofthetrueeffect.Whenevaluatingannumberofstudies,onewouldexpectthatlargestudiesclusteraroundthe'trueeffect'andsmallerstudiestohavemorescatter.

Strengthsandweaknessesofmeta-analyses

Strengths Weaknesses

Enhancedprecisionofestimatesofeffect Publicationbias

Usefulwhenlargetrialshavenotbeendoneorarenotfeasible Duplicatepublication

Generateclinicallyrelevantmeasures(NNT,NNH) Heterogeneity

Inclusionofoutdatedstudies

Becauseoftheseweaknesses,positivemeta-analysesshouldbeconsideredlargelyhypothesis-generating,andshouldbeconfirmedby(alarge)RCT.Negativemeta-analysescanprobablybeaccepted.

References

1. MylesPS,GinT.Statisticalmethodsforanaesthesiaandintensivecare.1sted.Oxford:Butterworth-Heinemann,2001.

Lastupdated2019-07-18

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ClinicalTrialDesignDescribethestagesindesignofaclinicaltrial

1. Determineresearchquestion2. Determinetargetpopulation3. Specifyoutcomes4. Determinerequirementforcontrolgroup5. Samplesizeestimation6. Controlforconfounding7. Controlforbias8. Datahandling9. Statisticalanalysisplan(pre-specified)

References

1. PSMyles,TGin.Statisticalmethodsforanaesthesiaandintensivecare.1sted.Oxford:Butterworth-Heinemann,2001.

Lastupdated2017-09-12

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DataTypesDescribethedifferenttypesofdata

Dataareaseriesofobservationsormeasurements.Canbeeitherqualitativeorquantitative.

QualitativeData

Usingwordsasdataratherthannumbers,evaluatingmeaningandprocess.Commoninthesocialsciences.

QuantitativeData

Usesnumbers,orcanbecodednumerically.Dividedintomultipletypes,eachwithmultiplesubtypes.

CategoricalDataexistindiscretecategorieswithoutintrinsicorder.

e.g.Medicalspecialty(intensivecare,emergencymedicine,orthopaedics,cardiology)Descriptivestatisticsforcategoricaldatacanbereportedusingtheabsolutenumberforeachcategory,percentages,orproportions

OrdinalDataexistsindiscretecategorieswithanintrinsicorder,e.g.agegroups(0-5,6-10,11-15...)

Descriptivestatisticsforordinaldataarethesameforcategoricaldata,buttheycanalsobesummarisedbythemedianandtherange(e.g.medianagegroup,agegrouprange).

NumericalDataisanactualnumber.Canbesubdividedintodiscreteorcontinuous:

DiscreteCanonlyberecordedasaninteger(wholenumber),e.g.numberofhospitaladmissions.

Dichotomousorbinarydata,whichoccurswhenthereareonlytwocategoriesContinuousWheredatacanassumeanyvalue(includingfractions),e.g.whitecellcount.

Continuousdatacanbefurthersubdividedintointervalorratiodata:RatiodataAreexpressedwithreferencetoarationalzero,whichiswherezeromeansnomeasurement.

e.g.Temperaturein°Kisaratiovariable,whilsttemperaturein°CisnotThisisbecause0°Kmeansnotemperature,whilst0°Cdoesnot;e.g.50°Kishalfthetemperatureof100°K,but50°Cisnothalfthetemperatureof100°C.Ratiovariablescan(unsurprisingly)beexpressedasratios,whilstintervalvariablescannot

IntervaldataDonothavearational0-thisisjustanotherpointontheline(e.g.temperaturein°C).

References

1. MylesPS,GinT.Statisticalmethodsforanaesthesiaandintensivecare.1sted.Oxford:Butterworth-Heinemann,2001.

Lastupdated2019-07-18

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BiasandConfoundingDescribebias,typesoferror,confoundingfactorsandsamplesizecalculations,andthefactorsthatinfluencethem

Bias

Biasisasystematicdeviationfromtruth,andcausesastudytolackinternalvalidity.

Inaresearchstudy,anobserveddifferencebetweengroupsmaybedueto:

AtruedifferencebetweengroupsAnerrorErrorcanbedueto:

Normalrandomvariation,i.e.chanceAsystematicdifference,i.e.biasUnlikeerrorduetochance,theeffectofbiascannotbereducedbyincreasingthesamplesize.

TypesofBias

Typeofbias Description Prevention

Selection Wheresubjectallocationresultsintreatmentgroupsthataresystematicallydifferent,apartfromintheinterventionbeingstudied Randomisation

Detection Wheremeasurementsaretakendifferentlybetweentreatmentgroups Blinding

Observer Wherethedatacollectorisabletobesubjectiveabouttheoutcome Blinding,Hardoutcomes

Publication Whennegativestudiesarelesslikelytobesubmittedorpublishedthanpositiveones Clinicaltrialregistries

Recall Alteredreportingofsymptomsbypatientsdependingonwhichgrouptheyhavebeenallocatedto Blinding

Response Whenpatientswhoenrollforatrialdifferfromthepopulation,limitinggeneralisability Randomsampling

Hawthorneeffect Whentheprocessofactuallydoingthestudyimprovestheoutcome

Controlgroup,maskingstudyintentfrompatientsandobservers

ConfounderAconfounderis"avariablethat,ifremoved,resultsinachangeintheoutcomevariablebyaclinicallysignificantamount."Itisatypeofbiaswhichwillresultinadistortionofthemeasuredeffect.

Aconfoundingfactormustbe:

AssociatedwiththeexposurebutnotaconsequenceofitAconfoundingfactorcannotbeonthecausalpathwaybetweenexposureanddiseaseItmustbepresentunevenlybetweengroupstocausedistortionofthemeasuredeffect

AnindependentpredictorofoutcomeTheconfoundingfactormustalsobeariskfactorforthedisease,butindependentlyfromexposure.

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Controllingforconfounding

ByDesign

RandomisationAllconfounders(knownandunknown)aredistributedevenlybetweengroups.RestrictionRestrictsparticipantstoremoveconfounders.

ResultsinreducedgeneralisabilityanddoesnotcontrolallfactorsMatchingPairingofsimilarsubjectsbetweengroups.

Mayintroduceadditionalconfounding,andmatchingbymultiplecharacteristicsisdifficult

ByAnalysis

StandardisationAdjustfordifferencesbytransformingdata.StratificationAnalysethedatainsubgroupsforeachpotentialconfoundingfactor.

References1. Sackett,D.L.(1979).Biasinanalyticresearch.JournalofChronicDiseases32(1–2):51–63.2. PSMyles,TGin.Statisticalmethodsforanaesthesiaandintensivecare.1sted.Oxford:Butterworth-Heinemann,2001.3. StatsnotesfrommyMPh(UniversityofSydney).ProbablyaTimothySchlublecture,circa2014.

Lastupdated2019-07-18

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FrequencyDistributionsandMeasuresofCentralTendencyDescribefrequencydistributionsandmeasuresofcentraltendencyanddispersion

FrequencyDistributions

Frequencydistributionsareamethodoftabulatingorgraphicallydisplayinganumberofobservations.

TheNormalDistribution

Thenormaldistributionisagaussiandistribution,wherethemajorityofvaluesclusteraroundthemean,andwhilstmoreextremevaluesbecomeprogressivelylessfrequent.

Thenormaldistributioniscommoninmedicinefortworeasons.

MuchofthevariationinbiologyfollowsanormaldistributionWhenmultiplerandomsamplesaretakenfromapopulation,themeanofthesesamplesfollowsanormaldistribution,evenifthecharacteristicbeingmeasuredisnotnormallydistributedThisisknownasthecentrallimittheorem.

Itisusefulbecausemanystatisticaltestsareonlyvalidwhenthedatafollowanormaldistribution

Theformulaforthenormaldistributionisgivenby:

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Fromthis,itcanbetseenthetwovariableswhichwilldeterminetheshapeofthenormaldistributionare:

μ(mu):Themeanσ(sigma):Thestandarddeviation

TheStandardNormalDistribution

Thestandardnormaldistributionisanormaldistributionwithameanof0andastandarddeviationof1.Theequationforthestandardnormaldistributionismuchsimpler,whichiswhyitisused.

Anynormaldistributioncanbetransformedtofitastandardnormaldistributionusingaztransformation:

Thevalueofzthengivesastandardisedscore,i.e.thenumberofstandarddeviationsformthemeaninastandardisedcurve.Thiscanthenbeusedtodetermineprobability.

Binomialdistribution

Whereobservationsbelongtooneoftwomutuallyexclusivecategories,i.e.:

If then

Ifthenumberofobservationsisverylargeandtheprobabilityofaneventissmall,aPoissondistributioncanbeusedtoapproximateabinomialdistribution.

MeasuresofCentralTendencyAsnotedaboveinthenormaldistribution,resultstendtoclusteraroundacentralvalue.Quantificationofthedegreeofclusteringcanbedoneusingmeasuresofcentraltendency,ofwhichtherearethree:

ModeThemostcommonvalueinthesample.MedianThemiddlevaluewhenthesampleisrankedfromlowesttohighest.

ThemedianisthebestmeasureofcentraltendencywhenthedataisskewedArithmeticmean

Theaverage,i.e:Themeaniscommonandreliable,thoughinaccurateifthedistributionisskewed.

MeasuresofDispersion

Measuresofvariabilitydescribethedegreeofdispersionaroundthecentralvalue.

BasicMeasuresofDeviation

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Range:ThelowestandhighestvaluesinthesampleHighlyinfluencedbyoutliersPercentiles:Rankobservationsinto100equalparts,sothatthemedianbecomesthe50%percentile.Bettermeasureofspreadthanrange.Interquartilerange:The25thto75thcentileAbox-and-whiskerplotgraphicallydemonstratesthemean,25thcentile,75thcentile,and(usually),the10thand90thcentiles.

OutliersarerepresentedbydotsOccasionallytherangeisplottedbythewhiskers,andtherearenooutliersplotted

VarianceandStandardDeviation

Varianceisabettermeasureofvariabilitythantheabovemethods.Variance:

Evaluateshowfareachobservationisfromthemean,andpenalisesobservationsmorethefurthertheyliefromthemeanSumsthesquaresofeachdifferenceanddividesbythenumberofobservationsi.e:

isused(insteadof )becausethemeanofthesampleisknownandthereforethelastobservationcalculatedmusttakenonaknownquantity

Thisisknownasadegreesoffreedom,whichisamathematicalrestrictionusedwhenusingonestatisticaltestinordertoestimateanotherItisaconfusingtopicbestillustratedwithanexample:

Youhavebeengivenasampleoftwoobservations(say,agesoftwoindividuals),andyouknownothingaboutthemThedegreesoffreedomistwo,sincethoseobservationscantakeonanyvalue.Alternatively,imagineyouhavebeengiventhesamesample,butthistimeItellyouthatthemeanageofthesampleis20Thedegreesoffreedomisone,sinceifItellyouthevalueofoneoftheobservationsis30,youknowthattheothermustbe10Therefore,onlyoneoftheobservationsisfreetovary-assoonasitsvalueisknownthenthevalueoftheotherobservationisknownaswell.

Differentstatisticaltestsmayresultinadditionallossesindegreesoffreedom.

StandardDeviation

Thestandarddeviationisthepositivesquarerootofthevariance.

Inasampleofnormaldistribution:

1SDeithersideofthemeanshouldinclude~68%ofresults2SDeithersideofthemeanshouldinclude~95%ofresults3SDeithersideofthemeanshouldinclude~99.7%ofresults

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StandarderrorandConfidenceIntervals

Standarderrorofthemeanis:

AmeasureoftheprecisionoftheestimateofthemeanCalculatedfromthestandarddeviationandthesamplesizeAsthesamplesizegrows,theSEMdecreases(astheestimatebecomesmoreprecise).Givenbytheformula:

Usedtocalculatetheconfidenceinterval

ConfidenceInterval

Theconfidenceinterval:

GivesarangeinwhichthetruepopulationparameterislikelytolieThewidthoftheintervalisrelatedtothestandarderror,andthedegreeofconfidence(typically95%):

Isafunctionofthesamplestatistic(inthiscasethemean),ratherthantheactualobservationsHasseveralbenefitsoverthep-value:

IndicatesmagnitudeofthedifferenceinameaningfulwayIndicatestheprecisionoftheestimateThesmallertheconfidenceinterval,themoreprecisetheestimate.AllowsstatisticalsignificancetobecalculatedIftheconfidenceintervalcrosses1,thentheresultisinsignificant.

References

1. "Normaldistribution".LicensedunderAttribution3.0Unported(CCBY3.0)viaSubSurfWiki.2. MylesPS,GinT.Statisticalmethodsforanaesthesiaandintensivecare.1sted.Oxford:Butterworth-Heinemann,20013. Coursenotesfrom"IntroductiontoBiostats",UniversityofSydney,SchoolofPublicHealth,circa2013.

Lastupdated2019-07-18

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SampleSizeCalculationDescribebias,typesoferror,confoundingfactorsandsamplesizecalculations,andthefactorsthatinfluencethem

Samples

Asampleisasubsetofapopulationthatwewishtoinvestigate.Wetakemeasurementsonoursamplewiththeaimtomakeinferencesonthegeneralpopulation.Anoptimalsample(inquantitativeresearch)willberepresentative,thatis,ithasthesamecharacteristicsofthepopulationitisdrawnfrom.

SamplingError

Duetochance,thesamplemeanwillnotequalthepopulationmean.Thisiscalledsamplingerror,andisaformofrandomerror.Alargersamplewillmorecloselyapproximatethepopulationmean,reducingrandomerrorleadingtomoreaccuratepointestimatesandnarrowerconfidenceintervals.

Thisiswhylargesamplesizesaredesirableinresearch.However,largerstudiesarealsomorecostlyandtimeconsumingtorun.Sample-sizecalculationsareperformedtofindahappymedium.

SampleSizeCalculation

Allsamplesizecalculationsdependon:

AcceptableriskofTypeIerror(α),typicallysetat0.05Asmallerα(lowerfalsepositiverisk)requiresalargersamplesize.AcceptableriskofTypeIIerror(β),typicallysetat0.20Asmallerβ(lowerfalsenegativerisk)requiresalargersamplesize.ExpectedeffectsizeAsmallereffectsizerequiresalargersamplesize,asthedifferencebetweengroupswillbesmallerandhardertodetect.PopulationvarianceAlargerpopulationvariancerequiresalargersamplesize,asthereismore'noise'inthesample.StudydesignCertaintrialdesigns(e.g.multiplearms)requirealargersamplesizeforagiveneffectsizeandpower.Practicalconsiderations

CostIncreasingsamplesizeincreasesthecostofastudy.ParticipantavailabilitySamplesizeislimitedwhenthenumberofeligibleparticipantsforastudyissmall(e.g.rarediseases)

Differentformulasforsamplesizecalculationsexistfordifferentstudies,andcanbeadjustedforparticularstudydesigns,suchasmultipleorunequalgroups.

References

1. MylesPS,GinT.Statisticalmethodsforanaesthesiaandintensivecare.1sted.Oxford:Butterworth-Heinemann,2001.2. Coursenotesfrom"IntroductiontoBiostats",UniversityofSydney,SchoolofPublicHealth,circa2013.

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Lastupdated2017-09-22

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StatisticalTestsDescribetheappropriateselectionofnon-parametricandparametrictestsandteststhatexaminerelationships(e.g.correlation,regression)

ParametricTests

Parametrictestsareusedwhendatais:

ContinuousandnumericalNormallydistributed

Rememberthatduetothecentrallimittheorem-largedatasets(n>100)aretypicallyamenabletoparametricanalysis,assamplemeanswillfollowanormaldistributionNon-normaldatacanbetransformedsothattheyfollowanormaldistribution

SamplesaretakenrandomlySampleshavethesamevarianceObservationswithinthegroupareindependentIndependentresultsarethosewhenonevalueisnotexpectedtoinfluenceanothervalue.

Acommonexampleisrepeatedmeasures:whenserialmeasuresaretakenfromapatientorahospital,theresultscannotbetreatedasindependentPairedtestsareusedwhentwodependentsamplesarecomparedUnpairedtestareusedwhentwoindependentsamplesarecompared

Testsmaybeone-tailedortwo-tailed:

Atwo-tailedtestevaluateswhetherthesamplemeanissignificantlygreaterorlessthanthepopulationmeanAone-tailedtestonlyevaluatestherelationshipinonedirectionThisdoublesthepowerofthetesttodetectadifference,butshouldonlybeperformedifthereisaverygoodreasonthattheeffectcouldonlyoccurinonedirection.

Commonparametrictestsinclude:

Ztest

Usedtotestwhetherthemeanofaparticularsample(x̄)differsfromthepopulationmean(μ)byrandomvariation.

Assumptions:

Largesamplen>100.DataisnormallydistributedPopulationstandarddeviationisknown

Student'sTTest

ThisisavariantoftheZtest,usedwhenthepopulationstandarddeviationisnotknown.

TheresultsfromTtestapproximatetheresultsoftheZtestwhenn>100

FTest

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Comparestheratioofvariances( )fortwosamples.IfFdeviatessignificantlyfrom1,thenthereisasignificantdifferenceingroupvariances.

AnalysisofVariance(ANOVA)

ANOVAtestsforsignificantdifferencesbetweenmeansofmultiplegroups,inamoreefficientmannerthanmultiplecomparisons(doinglotsofTtests).

ThereareseveraltypesofANOVAtestsusedindifferentsituations.

Non-ParametricTests

Non-parametrictestsareusedwhentheassumptionsforparametrictestsarenotmet.Non-parametrictests:

DonotassumethedatafollowsanyparticulardistributionThisisrequiredwhen:

Non-normalityisobviouse.g.Multipleobservationsof0Possiblenon-normalityTypicallysmallsamplesizes.Dataisordinal

Arenotaspowerfulasparametrictests(alargersamplesizeisrequiredtoachievethesameerrorrate)Aremorebroadlyapplicablethanparametrictestsastheydonotrequirethesameassumptions

Non-parametrictestsstillrequirethatdata:

IscontinuousorordinalWithin-groupobservationsareindependentSamplesaretakenrandomly

Ingeneral,non-parametrictests;

TakeeachresultandrankthemCalculationsarethenperformedoneachranktofindtheteststatistic

Commonnon-parametrictestsinclude:

Mann-WhitneyUTest/WilcoxonRankSumTest

AlternativetotheunpairedT-testfornon-parametricdata.

Process:

Datafrombothgroupsarecombined,ordered,andgivenranksTieddataaregivenidenticalranks,wherethatrankisequaltotheaveragerankofthetiedobservations

ThedataarethenseparatedintotheiroriginalgroupRanksineachgroupareaddedtogiveateststatisticforeachgroupAstatisticaltestisperformedtoseeifthesumofranksinonegroupisdifferenttoanother

WilcoxonSignedRanksTest

AlternativetothepairedT-testfornon-parametricdata.

Process:

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Asabove(fortheWilcoxonRankSumTest),exceptabsolutedifferencebetweenpairedobservationsarerankedThesign(i.e.positiveornegative)ispreserved.ThesumofpositiveranksisthencomparedwiththesumofnegativeranksIfthereisnodifferencebetweengroups,wewouldexpectthenetvaluetobe0

References1. MylesPS,GinT.Statisticalmethodsforanaesthesiaandintensivecare.1sted.Oxford:Butterworth-Heinemann,2001.

Lastupdated2017-09-22

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StatisticaltermsUnderstandthetermssensitivity,specificity,positiveandnegativepredictivevalueandhowtheseareaffectedbytheprevalenceofthediseaseinquestion

Describebias,typesoferror,confoundingfactorsandsamplesizecalculations,andthefactorsthatinfluencethem

Allthesetermsrefertocharacteristicsofdiagnostictests.Theeasiestwaytoapproachthisisviaa2x2table,andhasbeenrecommendedinpreviousexamsasanapproachtoquestionsonthistopic.

TypesofErrorDrawa2x2tableofdiseasestateversustestoutcome:

DiseasePositive DiseaseNegative Total

TestPositive TruePositives FalsePositives AllTestPositives

TestNegative FalseNegatives TrueNegatives AllTestNegatives

Total AllDiseasePositives AllDiseaseNegatives

TrueorfalsereferstowhetherthetestwascorrectPositiveornegativereferstothetestresult

ATypeIerrorisafalsepositive,whenweincorrectlyrejectthenullhypothesisThetypeIerrorratecanbedecreasedbydecreasingα

ATypeIIerrorisafalsenegative,whenweincorrectlyacceptthenullhypothesisThetypeIIerrorratecanbedecreasedbydecreasingβ,usuallyexpressedasincreasingpowerPoweristhechanceofdetectingadifferenceifitexists.Powerisequalto1-β.

SensitivityandSpecificity

Sensitivity

Sensitivityistheprobabilitythosewiththediseasetestpositive,i.e.thetruepositiverate,andexpressedmathematicallyas:

ItreferstotheabilityofatesttodetecttheconditionAhighlysensitivetestwilllikelybepositiveiftheconditionispresentTherefore,anegativeresultonasensitivetestgivesahighlikelihoodthediseaseisnotpresent

ThemnemonicforthisisSNOUT-Sensitive,Negative,ruleOUT

Specificity

Specificityistheprobabilitythosewithoutthediseasetestnegative,i.e.thetruenegativerate,andexpressedmathematicallyas:

ItreferstotheabilityofatesttodetectabsenceoftheconditionAhighlyspecifictestwilllikelybenegativeiftheconditionisnotpresent

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ThereforeapositiveresultonaspecifictestgivesahighlikelihoodthediseaseispresentThemnemonicforthisisSPIN-Sensitive,Positive,ruleIN

PositiveandNegativePredictiveValues

PositiveandnegativepredictivevaluesdescribetheproportionoftestresultswhicharetrueAhighvalueindicatesaccuracyofthetestBecauseofhowtheyarederived,theyaredependentonpopulationprevalenceofthedisease

PositivePredictiveValue(PPV)istheprobabilitythatthediseaseispresentwhenthetestispositive:

NegativePredictiveValue(NPV)istheprobabilitythatthediseaseisabsentwhenthetestisnegative:

RememberingtheDifference

RotelearningtheseformulasishardRememberthat:

SensitivityandspecificityarethesameforanygivenprevalenceofdiseaseThereforetheylookatcolumns(diseasepositiveordiseasenegative).PPVandNPVarenotThereforetheylookatrows(testpositiveortestnegative).

LikelihoodRatiosTheweaknessofPPVandNPVastoolsofevaluatingtheutilityofatestinclinicalpracticeisthattheydonottakeintoaccountthepopulationprevalence,i.e.thepriorprobability,ofacondition.

AclassicexampleistheurinebHCG,whichhasahighpositivepredictivevalueforpregnancy.Testedonanexclusivelymalegrouphowever,thetruepositiveratewillbe0(sincetherearenopregnancies),andsoalltestpositiveswillbefalsepositives.

Therefore:

TheactualutilityofatestindecisionmakingisdependentuponthepriorprobabilityofthediseasebeingpresentLikelihoodRatiosrelatethepre-testoddstothepost-testoddsTheyareusefulbecause(unliketheabovevalues)theydonotassumethatthepatientyouareapplyingthemtoisidenticaltothesamplefromwhichthestatisticwasderived.Thelikelihoodratiomultipliedbythepre-testoddsgivesthepost-testoddsofthediseasebeingpresent

Apositivelikelihoodratioisusedwhenthetestispositive:

Anegativelikelihoodratioisusedwhenthetestisnegative:

References

StatisticalTerms

44

1. MylesPS,GinT.Statisticalmethodsforanaesthesiaandintensivecare.1sted.Oxford:Butterworth-Heinemann,2001.2. Coursenotesfrom"IntroductiontoBiostats",UniversityofSydney,SchoolofPublicHealth,circa2013.

Lastupdated2019-11-02

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RiskandOddsUnderstandtheconceptsofriskandOddsRatio

Risk

AbsoluteRiskistheriskofaneventoccurringintheexposedgroupRelativeRisk(orriskratio)istheriskofaneventoccurringintheexposedgrouprelativetotheunexposedgroup.

AbsoluteRiskReductionisthedecreaseinriskprovidedbyanexposure:

Isaclinicalusefulmeasureofthevalueofanintervention,howeverisbetterexpressedas:NumberNeededtoTreat(NNT)isthenumberofindividualswhomustreceiveatreatmenttopreventoneevent:

RelativeRiskReductionisthedecreaseinincidenceprovidedbytreatment.Itisnotasusefulameasureofthevalueofanintervention,butdrugcompanieslikeitbecausethenumbersarebiggerthanabsoluteriskreduction.

Odds

Oddsaretheprobabilityofaneventhappeningcomparedtotheprobabilityofitnothappening,usuallyexpressedasafractionTheOddsRatioistheratiooftheoddsoftheoutcomeoccurringintheexposedcomparedtotheoddsofitoccurringintheunexposed

AnOR<1suggeststheriskislowerintheexposedgroupAnOR>1suggeststheriskishigherintheexposedgroupAnOR=1suggeststhatthegroupsareequivalent

Ingeneral,theORoverstatesriskcomparedtotheRR.ItisapproximatelyequaltotheRRwhentheoutcomeisrare(<10%)Itisusedwhen:

Thedenominatorisuncertain,i.e.:Inretrospectivedesigns,suchascase-controlstudieswhenpatientswiththediseasewereidentified,andthenexposuresascertained

Whenitstatisticallyappropriate(ORsaremucheasiertouseinstatisticaltests),i.e.:MultivariateregressionSystematicReviews

RiskversusOdds

RiskandOdds

46

RelativeRiskandOddsRatiosarebothmethodsofcomparingthelikelihoodofanoutcomeoccurringbetweentwogroups.Thedifference,andparticularlytheconceptofoddsratios,arecommonlyconfused.Relativerisktendsbemuchmoreintuitivethanoddsratios.Imagineatrialhasbeenperformed,wheregroupAwasexposedgroup:

IngroupA,themortalitywas50%IngroupB,themortalitywas25%

Therelativeriskisintuitive:

Theoddsratioisnot:

ARRof2isintuitive,buttheORof3isnot.Now,imagineanothertrialwhere:

IngroupA,themortalitywas90%IngroupB,themortalitywas10%

Therelativeriskis9,buttheORis81!

Sowhyuseoddsratiosatall?Oddsratiosare:

RequiredwhenresearchsubjectsareselectedonthebasisofoutcomeratherthanthebasisofexposureUsedbymanystatisticaltestsbecausethelogoddsratioisnormallydistributed,whichisamathematicallyusefulproperty

RelativeRiskhasaweaknessaswell-itisdependentonhowthequestionisframed.Usingthefirsttrialabove,wecalculatedthatRRfordeathwas2andtheORwas3.Ratherthancalculatingmortality,analternativemethodcouldbetolookatsurvival:

IngroupA,thesurvivalwas50%IngroupB,thesurvivalwas75%

Notethattherelativeriskisnot0.5(asyoumayinitiallyassume),howevertheoddsratioisjusttheinverseofthepreviousvalue.

References

1. MylesPS,GinT.Statisticalmethodsforanaesthesiaandintensivecare.1sted.Oxford:Butterworth-Heinemann,2001.2. Coursenotesfrom"IntroductiontoBiostats",UniversityofSydney,SchoolofPublicHealth,circa2013.3. SimonS.Oddsratiovs.relativerisk."Steve'sAttempttoTeachStatistics(StATS)".Children'sMercyHospital,2006.4. BlandJM,AltmanD.BlandJMartin,AltmanDouglasG.Theoddsratio.BMJ2000;320:1468.

Lastupdated2019-07-18

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RiskandOdds

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SignificanceTesting'Understandconceptofsignificanceandtestingofsignificance

Significancetestingis:

Theprocessofdeterminingwhetheradifferencebetweengroupsinastudyisduetoarealdifference,orchancealonePerformedusingp-valuesDoesnotimplyclinicalsignificanceForaresulttobestatisticallysignificant,theremustbea'real'differencebetweengroups.

Thisdifferencedoesnothavetobeclinicallymeaningfule.g.Adrugmayreliablycausea5mmHgdecreaseinSBP-thisisunlikelytocauseameaningfuldropincardiovascularmortalitybutmaybestatisticallysignificant

PValuesThep-valueistheprobabilityofobtainingasummarystatistic(e.g.amean)equaltoormoreextremethantheobservedresult,providedthenullhypothesisistrue.

Thep-valueiscommonly(mis)usedinfrequentistsignificancetesting.

Priortoperforminganexperiment,asignificancethreshold(α)isselectedTraditionally0.05(5%)or0.01(1%)Thesevaluesdefinethe"false-positiverate".

Whenmultipletestsarebeingperformedononesetofdata,thechanceofafalse-positivewillincreaseToreducethechanceofafalsepositiveoccurring,thesignificancethresholdforeachtestcanbereduced.OnemethodofthisistheBonferronicorrection,whereαisdividedbythenumberoftestsbeingperformed.

Thentheexperimentisperformed,andavalueforpiscalculatedIfp<α,itsuggeststhattheresultsareinconsistentwiththenullhypothesis(atthatsignificancelevel),anditshouldberejected.

ProblemswithP-values

P-valuesare,whenemployedcorrectly,areuseful.However,theydohaveseveralweaknesses:

AssumethenullhypothesisistrueThep-valueassumesthatthereisnorealdifferencebetweengroups.

ThismaynotbethecaseNotallhypothesesarecreatedequalTheremaybesignificantpriorevidencesupporting(orrefuting)H -thiswillbeignoredwheninterpretingap-value.

Anystudywithsignificantresultsmustthereforebeinterpretedinthecontextof:BiologicalplausibilityofthoseresultsThepreviousevidenceonthetopic

Itisacommonmisconceptionthatthep-valueestimatesthechancethattheresultistrueThisisnotthecase.Thep-valuemeasureshowinconsistenttheobservedresultsarewiththenullhypothesis.

Athresholdof0.05isnotalwaysappropriateThecostofbeingwrongmustbeincludedwheninterpretingap-value.Ifthisisatrueresult,whatarethepotentialbenefits?Ifthisisafalsepositive,whatarethepotentialharms?

VulnerabletomultiplecomparisonsConductingrepeatedanalyseswilleventuallyfinda'significant'result.Atanαof0.05,wewouldexpect1/20analysestobe

A

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afalsepositive.Conducting20analyseswouldthereforegenerateonefalsepositiveresult.

DoesnotquantifyeffectsizeAsignificantp-valuesimplysuggestsadifferenceexists,itdoesnotmeasurehowbigthisdifferenceis.

Aresultmaybestatisticallysignificantbutclinicallyunimportant,e.g.anantihypertensivemedicationcausingadecreaseinSBPby2mmHgmaybestatisticallysignificant,butclinicallyunimportant.

Relatedtosamplesizep-valuesareaffectedbysamplesize:Alargeeffectsizemaybehiddenbyaninsignificantp-valueifsamplesizeissmallSimilarly,atinyeffectsizemaybedetected(i.e.asignificantp-value)ifsamplesizeislarge

DoesnotaccountforbiasLikeotherstatisticaltest,thep-valuecannotaccountforbiasorconfounding.

References

1. WassersteinRL,LazarNA.TheASA'sStatementonp-Values:Context,Process,andPurpose.TheAmericanStatistician.2016vol:70(2)pp:129-133.

Lastupdated2019-07-18

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DrugApprovalandDevelopmentDescribetheprocessesbywhichnewdrugsareapprovedforresearchandclinicaluseinAustralia,andtooutlinethephasesofhumandrugtrials(PhaseI-IV)

DrugApproval

TheTherapeuticGoodsAdministration(TGA)approvesmedicineforbothresearchandclinicaluseinAustralia.

Research

Drugtrialsareapprovedforresearchpurposesundertwoschemes:

1. ClinicalTrialsExemptionDrugsmustbeevaluatedbyanexpertcommitteetoevaluateallaspectsofpharmacology,toxicology,mutagenicity,teratogenicity,organdysfunction,andotherside-effects.

2. ClinicalTrialsNotificationAdrugwhichhasbeenapprovedinanothernationwithsimilarlystringentrequirements(NewZealand,Netherlands,UK,Sweden,US)maybeusedinatrialwithoversightbyalocalethicscommittee.

ClinicalUse

TheTGAclassifiesmedicinesinto:

RegisteredMedicinesAssessedbytheTGAforquality,safety,andefficacy.

Allprescription(high-risk)medicines.Assessedon:Quality

CompositionofdrugsubstanceBatchconsistencyStabilitydataSterilitydata(ifapplicable)Impurities

Non-clinicalPharmacologydataToxicologydata

ClinicalEfficacy:resultsofclinicaltrials

MostOTC(low-risk)medicinesSomecomplementarymedicines

ListedMedicinesAssessedbytheTGAforquality,safety,butnotefficacy.

SomeOTCmedicinesMostcomplementarymedicines

PhasesofDrugDevelopment"Phase0"

Pre-clinicalR&D

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InvitroandanimaltestingPhaseI

FirstadministrationinhumansBasicpharmacokineticandtoxicologydata20-100humansubjects

PhaseIIAdministrationtoselectpatientgroupsAimtoestablishdose-responsecurveEvidenceofefficacy

PhaseIIIFull-scaleevaluationofbenefits,potentialrisksandcostsanalysis2000-3000patients,usuallytreatedingroupsofseveralhundredforrelativelyshortdurations(3-6months),regardlessofthelengthoftimethedrugwillbeusedinpracticeMaynotrevealuncommonorlong-termrisks

PhaseIVPost-marketingsurveillance

References1. PSMyles,TGin.Statisticalmethodsforanaesthesiaandintensivecare.1sted.Oxford:Butterworth-Heinemann,2001.2. MedicinesandTGAclassifications.TherapeuticGoodsAdministration.Availableat:https://www.tga.gov.au/medicines-and-

tga-classifications3. ChrisAnderson.PharmaceuticalAspectsandDrugDevelopment.ICUPrimaryPrep.

Lastupdated2017-09-16

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AdditivesDescribethemechanismsofactionandpotentialadverseeffectsofbuffers,anti-oxidants,anti-microbialandsolubilizingagentsaddedtodrugs

Additivesarecomponentsofadrugpreparationwhichdonotexertthepharmacologicaleffect.

Additivesinclude:

PreservativesBenzylalcohol

Antimicrobialwhen>2%Canbeusedasasolventwhen>5%Toxic

AntioxidantsSulfites

HypersensitivityNeurotoxicifgivenintrathecally

SolventsWaterAppropriatefordissolvingpolarmolecules.Non-aqueoussolventsUsedtodissolvenon-polarmolecules,ortoproducemorestablepreparationsofsemi-polarmolecules.Examplesinclude:

PropyleneglycolHypotensionArrhythmiaWithrapidinjection.PainoninjectionThrombophlebitis

MannitolDiuresis

SoybeanoilPainoninjectionAllergy

EmulsionFormedwhendropsofaliquidaredispersedthroughoutanotherliquidinwhichitisimmiscible.Emulsionsare:

UnstableEmulsifiersareusedtoenhancestability.PronetocontaminationDuetothewatercomponent.PronetorancidityDuetotheoilcomponent.

BuffersMaintainpHinaparticularrangeinorderto:

MaximisestabilityPreserveshelflife.Maintainsolubility

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Maximisepreservativefunction

References1. MacPhersonRD.Pharmaceuticsfortheanaesthetist.Anaesthesia.2001Oct;56(10):965-79.2. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.

Lastupdated2019-07-18

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IsomerismDescribeisomerismandprovideexamples

Isomerismdescribesgroupsofcompoundswhichhavethesamechemicalformulabutdifferentchemicalstructures.Isomerismisrelevantbecausedifferentisomersmayhavedifferentenzymaticandreceptoraffinities,alteringtheirpharmacokineticandpharmacodynamicproperties.

TypesofIsomerism

Isomerscanbedividedinto:

StructuralIsomersIdenticalchemicalformulabutdifferentarrangementofatoms.Structuralisomerismissubdividedinto:

StaticFurthersubdividedinto:

ChainisomerThecarbonskeletonvaries,butpositionoffunctionalgroupsisstatic.PositionisomerThecarbonskeletonisstatic,butthepositionoffunctionalgroupsvaries.

e.g.Isofluranevs.enfluraneDynamic(alsoknownastautomer)Themoleculeexistsinadifferentmolecularstructuresdependingontheenvironment.

e.g.MidazolamhaspHdependentimidazoleringopening.WhenthepHislessthan4theringremainsopen,maintainingwatersolubility.MidazolamissuppliedatpHof3.5,andsoiswatersolubleoninjectionbut(duetoitspKaof6.5)becomes89%unionisedatphysiologicalpHthereforeabletocrosslipidmembranes.

StereoisomersAtomsareconnectedinthesameorderineachisomer,butdifferentorientationoffunctionalgroups.Stereoisomersarenotsuper-imposable,meaningthedifferentisomerscan'tberotatedsothattheylookthesame.Stereoisomersaredividedinto:

GeometricIsomersHaveachemicalstructure(e.g.acarbon-carbondouble-bond)preventsfreerotationofgroups,sodifferentlocationsofchemicalgroupswillcreateanisomer.Geometricisomersareknownascis-ortrans-dependingonwhetherthesubgroupsareonthesameoroppositesides(respectively)ofthechemicalstructure.

e.g.AtracuriumOpticalIsomersOpticalisomersarechiral.Thismeanstheyhavenoplaneofsymmetry.Opticalisomers:

Wereinitiallynamedbasedonhowtheyrotatedunderpolarisedlight:(NotethisisdifferentfromD-andL-molecules,wheretheD-isomerreferstothemoleculesynthesisedfrom(+)glyceraldehyde).

Dextrorotatory(d-or(+)isomers)moleculesrotateclockwiseunderpolarisedlight.Levorotatory(l-or(-)isomers)moleculesrotatecounter-clockwiseunderpolarisedlight.

Unfortunately,differentmoleculeswerefoundtorotateindifferentdirectionsdependingonthetemperature.Therefore,adifferentclassificationscheme(R/S)isalsoused:

Basedonchemicalstructure"Priority"isassignedtoeachatominthestructureHighestpriorityisusuallythosewiththehighestmolecularweight,butotherrulesexistforambiguousorvery

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55

largemoleculesThemoleculeisarrangedinspacesuchthatthelowestpriorityatomisfacing"away"Anarrowisthendrawnfromthehighestprioritytothelowerpriorityatoms:

IfthisarrowtravelsclockwiseitistheR(Rectus)isomerIfthisarrowtravelscounter-clockwiseitistheS(Sinister)isomer

Opticalisomersaredividedinto:EnantiomersPossessonechiralcentre.

e.g.levobupivacaineislesscardiotoxicthanracemicbupivacaine.DiastereoisomersPossessmultiplechiralcentres,andmayhavemultiplestereoisomers.Sincenotallaremirrorimages,thesearenotenantiomers.

Foramoleculewithnchiralcentresupton isomersarepossible,thoughsomeofthesemaybeduplicates.

Preparations

Drugscanbeprovidedas:

RacemicsolutionsAracemicsolutionisonewhichwherethedifferentenantiomersarepresentinequalproportions.

EnantiopurepreparationsAdrugproducedwithasingleisomer,whichmaybemoreefficaciousorlesstoxic(anddefinitelymoreexpensive)thantheracemicpreparation.

References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. CICM.TheMockExam.3. ChemGuide.Geometricisomerism4. ChEBI.Misoprostol.EuropeanMolecularBiologyLaboratory.5. ANZCAJuly/August20006. DayJ,ThomsonA,McAllisterT.GetThroughPrimaryFRCA:MTFs.2014.Taylor&FrancisLtd.

Lastupdated2019-07-18

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ModelingExplaintheconceptofpharmacokineticmodelingofsingleandmultiplecompartmentmodels.

Pharmacokineticsdescribeswhatthebodydoestoadrug.Pharmacokineticmodelsaremathematicalconceptsusedtopredictplasmaconcentrationsofdrugsatdifferenttimepoints.

BasicPharmacokineticTerms

Keyconceptsinpharmacokineticsinclude:

Volumeofdistribution,VThevolumeofdistributionisdefinedasthetheoreticalvolumeintowhichanamountofdrugwouldbedistributetoproducetheobservedplasmaconcentration.

Unitsareml.kg

Itisawaytodescribewhatproportionofadrugisconfinedtoplasma,andwhatproportiondistributestoothertissuesItdoesnotcorrespondtoanyparticularvolume,howeveraV of:

Lessthan40ml.kg indicatesadrugisconfinedtoplasmaUpto200ml.kg indicatesadrugisconfinedtotheECFUpto600ml.kg indicatesadrugisdissolvedintotheTBWGreaterthan1L.kg indicatesadrugishighlyproteinboundorlipophilicAgentswhichcrossthebloodbrainbarriertypicallyhaveaV of1-2L.kg .

SubtypesofthevolumeofdistributionareusedtodescribedrugdistributionatdifferenttimesorwithdifferentmodelsTheseinclude:

VVolumeofcentralcompartment.V ssVolumeofdistributionatsteadystate.V peVolumeofdistributionatpeakeffect.

Whichvolumetousedependsonthepharmacologicalquestione.g.IntubatingdoseforopioidshoulduseavolumebetweenV (verysmall)andV ss(verylarge)-V peisidealasitwillallowatargetconcentrationtobeselectedforthetimeatwhichintubationwilloccurrelativetodrugadministration

Half-life(t )Thetimeittakesforaprocesstobe50%complete.Withrespecttodrugclearance,itisthetimeittakesforconcentration(typicallyinplasma)tofallby50%.

Aprocessisconsideredtobecompleteafter4-5half-livesConcentrationwilldecreaseby50%aftereachhalf-life,soafter5half-livesconcentrationwillbe3.125%ofitsstartingvalue.

Thisalsoappliestowashin-itwilltake~4-5eliminationhalf-livesofadrugforaconstant-rateinfusiontoreachitsfinalconcentration

Half-lifeismathematicallyrelatedtomanyotherkeypharmacokineticterms:

,where:isthetimeconstant

D

-1

D-1

-1-1

-1

D-1

1

D

D

1 D D

1/2

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istherateconstantforelimination

isthevolumeofdistribution

istheclearanceVarioustypesofhalf-lifearedescribed:

t αdescribestherapidityofthedistributionphasefollowingdrugadministrationt βdescribestherapidityoftheeliminationphaseoccurringafterdrugdistributionequilibriumThisonlyevaluatesclearancefromplasma,andsoisacompositeofbothexcretionfromthebody(e.g.renalandhepaticclearance)andongoingdistributiontoperipheraltissues.

Theeliminationhalf-lifeisgenerallynotusefultopredictdrugoffset,asthisisaffectedbymanyfactorsHowever,itdoessetanupperlimitonhowlongitwilltakeplasmaconcentrationtofallby50%.

Time-constant( )Thetimetakenforaprocesstocompleteifitcontinuedatitsinitialrateofchange.Timeconstantsarerelatedtohalf-life,butarebettersuitedwhenmodelingchangeinexponentialprocesses.

TimeconstantsarediscussedinmoredetailunderrespiratorytimeconstantsEliminationwillbevirtuallycompleteafterthreetimeconstants

Atimeconstantistheinverseoftherateconstantforelimination,i.e.Illustrationoftherelationshipbetweenhalf-lifeandtimeconstant:

ClearanceTheclearanceisvolumeofplasmacompletelyclearedofadrugperunittime.

Inaonecompartmentmodel,thiscanbeexpressedas: inml.min .

Asthetimeconstantistheinverseofk,clearancecanalsobeexpressedas:

Since and areconstants,clearanceisalsoaconstantTotalclearanceisasumoftheclearanceofeachindividualclearanceorgan

RateofeliminationAmountofdrugremovedbythebodyperunittime.

Rateofeliminationistheproductoftheclearanceandthecurrentconcentration:

,inmg.minThisisnottherateconstantforelimination

CompartmentalModeling

Thesimplestmodelimaginesthebodyasingle,well-stirredcompartment.

1/21/2

-1

-1

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Inaonecompartmentmodel,theconcentrationofadrug( )attime isgivenbytheequation:

Where:

istheconcentrationattime0Asdrugcanonlybeeliminatedfromthecompartment,thisisalsothepeakconcentration.kistherateconstantforeliminationThisisthefractionoftheVdfromwhichthedrugisremovedperunittime.Therateconstantdeterminestheslopeofthecurve.

Ahighrateconstantforeliminationresultsinasteepcurveandthereforeashorttimeconstant

Steadystate

Atsteadystate,inputisequaltooutput.Thereforeconcentrationatsteadystateis:

ProportionaltotheconcentrationoftheinfusionandinfusionrateInverselyproportionaltotheclearance:

ConcentrationofdrugcanthereforebedeterminedbytheamountinfusedandtheclearanceNotesteadystaterequiresperipheralcompartmentstobesaturated,andsowillonlyoccurafteraninfusionofmanyhours

MultipleCompartmentModels

ModelswithmultiplecompartmentshaveabetterfitwithexperimentaldatathansinglecompartmentmodelsThree-compartmentmodelsaretypicallyused,asadditionalcompartmentstypicallyoffernoextrafidelitybutaremathematicallymorecomplexAthree-compartmentmodelcanbeconceptualisedasaplasma(orcentral)compartment,awell-perfusedcompartment,andapoorly-perfusedcompartmentThisdoesn'tmeanthattheyshouldbethoughtofinthisway-theyareamathematicaltechniqueusedtocalculateplasmaconcentrationatagiventime.

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Plasmaconcentrationinmulti-compartmentmodelsis:

PredictedthroughtheneteffectofseveralnegativeexponentialequationsxThisiscoveredundertwo-compartmentmodelsbelow.Dependentontheeffectsof:

DistributionDistributiondescribesthemovementofdrugfromthecentralcompartment(V )totheperipheralcompartment(s).

RapidfallinplasmaconcentrationofadrugafteradministrationisgenerallyduetodistributionDistributionisanimportantmethodfordrugoffsetinshort-actingdrugs.

RedistributionRedistributionreferstothemovementofdrugfromtheperipheralcompartment(s)backintoplasma.

DrugswhichhavealargeV inaperipheralcompartmenttendtodistributequicklyalongthisconcentrationgradient,andredistributeslowlybackintoplasmaDrugswhichtendtodistributeslowlytendtoredistributequicklyonceadministrationhasceased

ExcretionExcretionistheremovalofdrugfromthebody.

ClearanceinTwo-CompartmentModels

Removalofdrugintwo-compartmentmodelsisvia:

DistributionfromthecentraltotheperipheralcompartmentEliminationfromthecentralcompartmentThisproducesabi-exponentialfallinplasmaconcentrationConsistsoftwophases:

PhaseαDistributionphase:Arapiddeclineinplasmaconcentrationduetodistributiontoperipheraltissues.PhaseβEliminationphase:Slowdeclineinplasmaconcentrationdueto:

EliminationfromthebodyRedistributionintoplasma

1

D

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Thiscurveisgivenbytheequation ,where:

istheconcentrationofdruginplasma

isthey-interceptofthedistributionexponentUsedtocalculatedistributionhalf-life.

isthey-interceptoftheeliminationexponentUsedtocalculateeliminationhalf-life.istherateconstantfordistribution

Thevalueof isdependentontheratioofrateconstantsfordistributionandredistribution(i.e. ).Ifdistributiongreatlyexceedsredistribution,thegradientof willbeverysteepandplasmaconcentrationwillfallrapidlyafteradministration

istherateconstantforelimination

Notethatthedistributionandeliminationcurvesappearstraightbecausethey-axisislog-transformedIfplasmaconcentrationwasplottedonthey-axis,theneachofthesecurveswouldbeanegativeexponential(wash-outcurve)

EffectSite

Pharmacokineticmodelstypicallydisplaytheplasmaconcentration.

Clinicallyhowever,weareinterestedindrugconcentrationsatthesiteofaction(e.g.thebrain)Concentrationattheeffectsite(alsoknownasbiophase)isgivenbyCe

Thiscannotbemeasured,andsoisacalculatedvalueEffectsiteconcentrationbedifferentfromplasmaconcentration(Cp)priortoreachingsteadystateThedelaybetweenplasmaandeffectsiteconcentrationsisanexampleofhysteresis.

Theeffectsitecanbemodeledasanadditionalcompartmentinthree-compartmentmodelsTheeffectsiteismodeledasacompartmentofnegligiblevolumecontainedwithinV ,butdoeshaverateconstants

EffectsitevolumechangesasV changesThek istherateconstantfordrugdiffusionfromplasmaintotheeffectsiteThek istherateconstantforeliminationofdrugfromtheeffectsiteThisisatheoreticaleliminationpathway-drugisnotusuallymetabolisedattheeffectsite.

Thet ke0describestheeffect-siteequilibrationtimeItdescribeshowrapidlytheeffectsitereachesequilibriumwithplasma.

Alargeke0(rapiddrugflow)givesashortt ke0Afteronet ke0,50%ofthefinaleffectsiteconcentrationwillbereachedprovidedplasmaconcentrationremainsconstant

Ashortert ke0indicatesthatthattheeffectsiteconcentrationwillreachequilibriumwithplasmamorerapidly,andthereforeamorerapidclinicaleffectfollowingadministrationisseenNotethat:

Thet ke0isnotthetimetopeakeffectNeitherisk

Foraninfusionrunatconstantplasmaconcentrationthepeakeffectwillbeseenat3-5xthet ke0Thetimetopeakeffectisafunctionofbothplasmakineticsandthet ke0

e.g.adenosinehassuchashorteliminationt

11

e1e0

1/2

1/21/2

1/2

1/2e0

1/21/2

1/2theeffectsiteconcentrationwillreachitspeakrapidlyregardlessoftheke0

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Non-CompartmentalModels

Compartmentmodelsarenotappropriatefordescribingthebehavioursofalldrugs.Non-compartmentalmodelsareusedwhendrug:

Clearanceisorgan-independentEliminationdoesnotoccursolelyfromthecentralcompartment

ThesemodelsuseAUC,whichiscalculatedbymeasuringtheplasmaconcentrationofadrugatdifferenttimeintervals,andplottingtheareaunderthecurve(AUC).Thiscanbeusedto:

Determineclearance

DetermineBioavailabilityDifferencebetweentheAUCofthesamedoseofdrugadministeredIVandviaanotherroute.

Footnotes

Theformulaforhalf-lifecanbederivedfromtheequationforawash-inexponentialasfollows:

Washinexponentialisgivenby:

canthenbesubstitutedandtheequationsolvedfor asfollows:

References

Pharmacokinetics

62

1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. PlasmaVolume.Mosby'sMedicalDictionary,8thedition.2009.3. StanskiRD,ShaferSL.TheBiophaseConceptandIntravenousAnesthesia.4. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.

Lastupdated2019-07-18

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AbsorptionDescribeabsorptionandfactorsthatwillinfluenceit.

Absorptionisdependentontherouteofadministration.Routesofadministrationareselectedbasedon:

EffectsiteofthedrugDrugfactors

BioavailabilityAvailablepreparations

PatientfactorsAbilitytotakeorabsorboralmedicationsPreference

KeyConceptsBioavailabilityistheproportionofdruggivenwhichreachesthesystemiccirculationunchanged,comparedtotheIVform.Itisaffectedby:

FormulationPhysicochemicalInteractionsInteractionswithotherdrugsandfood.PatientFactors

MalabsorptionsyndromeGastricstasis

First-passmetabolism

First-pass(pre-systemic)metabolismistheextenttowhichdrugconcentrationisreducedafteritsfirstpassagethroughanorgan,priortoreachingthesystemiccirculation.Firstpassmetabolismis:

Typicallyusedwhenreferringtopassageoforally-administereddrugsthroughtheliverMayalsorefertometabolismbythe:

LungsFirstpassofintravenouslyinjecteddrugspriortoenteringthearterialsideofthecirculation,e.g.fentanyl.Vascularendothelium

Relevantin:UnderstandingdifferencesbetweenPOandIVdosing

AlternativeroutesofadministrationfordrugswithlowPObioavailabilityDeliveryofprodrugsviaPOmechanismsIncreasesactivedrugconcentration.UnderstandingenzymeinteractionsUnderstandingtheeffectsofhepaticdisease

Porto-systemicshuntsdecreasefirstpassmetabolismAlteredbioavailabilityofdrugswithhighhepaticextractionratios

Routesofadministration

Intravenous

RapidOnset

Absorption

64

100%bioavailabilitySomedrugsmaystillundergometabolisminthepulmonarycirculation,suchasfentanyl,lignocaine,propofol,andcatecholamines.

Oral

Absorptionisthroughgutmucosa,througheither:TransportmechanismsUnionised(lipidsoluble)

AcidicdrugsareabsorbedmorerapidlyinthestomachThesmallbowelabsorbsbothacid(despitebeingionised)andalkalinedrugsduetohighsurfacearea

Lowestbioavailabilityofanyroutedueto:First-passmetabolismGutmetabolismofdrugsBacterialmetabolismofdrugs

Drugsmustbelipidsolubleenoughtocrosscell-membranesandwatersolubleenoughtocrossinterstitium

FactorsaffectingGITAbsorption

DrugFactorsMolecularWeightConcentrationGradientLipidSolubility

pHandpKaPharmaceuticalPreparationPhysiochemicalInteractions

FoodOtherdrugs

PatientFactorsGITbloodflowSurfaceArea

SmallbowelhasthelargestsurfaceareaofanyGITorganpHMotilityDigestiveEnzymesGITbacteriaandsubsequentmetabolismDisease

CriticalIllnessBowelObstructionEmesis/Diarrhoea

Epidural

MaybeviabolusorinfusionOnsetdeterminedbyproportionofunioniseddrugavailableLignocainehasamorerapidepiduralonsetthanbupivacaineasithasapKaof7.9(comparedto8.4)andthereforeagreaterunionisedportionatphysiologicpH.

Additionalfactorsincludeadditivesandintrinsicvasoactivepropertiesofthedelivereddrug

Subarachnoid/Intrathecal

Absorption

65

VerysmalldosingMinimalsystemicspreadExtentofsubarachnoidspreadisdependentonvolumeandtypeofsolutionAppropriatepositioningofthepatient,withhigher-specificgravitysolutions,isrequiredtoavoidsuperiorspreadoftheblockAdditionalfactorsincludeadditivesandintrinsicvasoactivepropertiesofthedelivereddrug

Inhalation

SystemicabsorptiondependentonparticlesizeLargeparticlesreachthebronchioles<1microndiameterparticlesmayreachthealveolus

Rapiddiffusiontocirculationduetohighsurfaceareaandnofirst-passmetabolism

Transdermal

Systemicabsorptiondependenton:Doserequirement

LargedoserequirementscannotbeeffectivelygiventransdermallyFickPrinciple

AmountofdruggivenAmountofdruginskin

RegionalbloodflowHistaminerelease

SurfaceAreaSkinthicknessLipidsolubility

pHofskinandemulsionpKaofdrug

MolecularweightAdvantages

ConvenientPainlessNofirstpassmetabolismSteadyplasmaconcentrationonceestablished

DisadvantagesSlowonsetVariableplasmaconcentrationinitiallyOverdoseandabusepotentials

Subcutaneous

Absorptiondependentonregionalbloodflow

Sublingual

RapidonsetBypassportalcirculation(drainsintoSVC)

Rectal

Variableabsorption

Absorption

66

DistalrectalabsorptionbypassesportalcirculationProximalrectalabsorptiondoesnotandmayresultinhepaticfirstpassmetabolismSmallsurfaceareaforabsorption

Intramuscular

Bioavailabilitycloseto1AbsorptiondependentonregionalbloodflowPotentiallocalcomplications:

AbscessHaematoma

References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. ChongCA,DennyNM.Localanaestheticandadditivedrugs.3. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.

Lastupdated2019-07-18

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DistributionDescribefactorsinfluencingthedistributionofdrugs.

Drugdistributionisdependentonmanyfactors,allofwhichcanberelatedtoFick'sLawofDiffusion:

Concentrationgradient

Tissuemass

MolecularWeightLargermoleculesarelessabletocrosscellmembranes,andsoagreaterportionwillremaininthecompartmenttheyaredeliveredto.

LipidSolubility

IonisationIoniseddrugsarepolar,andsoarelesslipidsoluble.

Ionisationisafunctionof:pKaThepKaisthepHatwhichaweakacidorweakbasewillbe50%ionised.

AssolventpHchanges,theproportionofionisedvs.unioniseddrugwilldifferHowdependsonwhetherthedrugisanacidorbase:

BasesareionisedBelowtheirpKaAcidsareionisedAbovetheirpKa

pHIncombinationwithpKa,affectstheionisedportion.

Unioniseddrugs:CrosscellmembranesmorereadilythantheionisedformAretypicallyhepaticmetabolisedAretypicallynotrenallyeliminated

Ioniseddrugs:AretypicallyrenallyexcretedwithoutundergoingmetabolismArepoorlylipidsolubleanddonotcrosscellmembranesreadilyMaybeiontrappedThisoccurswhenanunioniseddrugmovesacrossamembraneandbecomesionisedduetoachangeinpH.Thenow-insolubledrugistrappedinthenewcompartment.Thisisrelevantin:

PlacentaFoetalpHislowerthanmaternalpH,whichcantrapbasicdrugs(e.g.LA,opioids)infoetus.

ThisbecomesmoresignificantwithagreaterdivergenceofpH(e.g.placentalinsufficiency)RenaleliminationUrinaryalkalinisationisusedtoaccelerateeliminationofacidicdrugs,astheybecomeionisedandtrappedinurine.

Distribution

68

ProteinbindingProteinsanddrugsmaybeboundtogetherbyweakbonds.Theseincludeionicbonds,vanderWaal'sforces,andhydrogenbonds.

Drugsmaybindtoproteinsin:Plasma

AlbuminBindsacidandneutraldrugs.

HighcapacityTwomajorbindingsites(sixtotal)

SiteI(warfarin)SiteII(diazepam)

α1-acidglycoproteinBindsbasicdrugs.

SinglebindingsiteLowcapacityTypicallyresultsinlowertotalbinding(comparedtoalbumin)ofalkalinedrugs,despiteitsincreasedaffinity.

LipoproteinForlipidsolubledrugs.

TissueReceptor

Proteinbindingisimportantas:Onlyunbounddrugsareableto:

CrosscellmembranesInteractwithreceptorsUndergometabolismReducedproteinbindingincreasesclearanceofdrugswithlowextractionratios.Befilteredbythekidney

Highlytissuebounddrugs:HavealongdurationofactionHaveahighvolumeofdistribution,prolongingtheireliminationMaybuildupintissues,leadingtoadverseeffectse.g.Cornealdeposition,lungfibrosis.

Proteinbindingisaffectedby:Affinityofdrugforprotein

IoniseddrugsdonotbindtoproteinpH.Competitionbetweendrugsforbindingsites

AmountofproteinDisease

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69

Dueto:HypoalbuminaemiaNegativeacutephasereactant.Increasedα1-acidglycoproteinAcutephasereactant.

CompetitionSourceofpharmacokineticinteractions.

Proteinbindingtypically:CorrelateswithlipidsolubilityIsimportantonlywhenitisveryhighResultsinadecreasedV whenplasmabindingishighResultsinanincreasedV whentissuebindingishighIsimportantindurationofactionasitalsorelatestoaffinityfortissueproteins

RegionalbloodflowAffectsconcentrationgradientsbetweenbloodandtissue,andisaffectedbycardiacoutput.Regionsinclude:

VesselRichGroupBrainHeartLiverKidneys

VesselPoorGroupConnectivetissue

BonesLigamentTeethHair

MusclegroupsFat

References

1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.

Lastupdated2019-07-18

DssDss

Distribution

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MetabolismDescribethemechanismsofdrugclearanceandmetabolism.

Removalofdrugfromthebodyrequireseither:

MetabolismofactivedrugtoaninactivesubstanceTypicallybytheliver,butotherorgans(kidney,lungs)alsometabolisesomesubstances.ExcretionofactivedrugOftenbythekidneys,butmayalsobeinbile,orexhaled.

Removalofdrugsfromthebodyisachievedpredominantlythroughrenalexcretionofwater-solublecompoundsAsmanydrugsarelipophilic,metabolismtowatersolublecompoundsisrequiredtocleardrugsfromthebody

ClearanceClearancedescribestheeliminationofdrugfromthebody.Clearanceis:

ThevolumeofplasmacompletelyclearedofadrugperunittimeMeasuredinml.min .

DiscussedfurtherinmodelingDoesnotincluderedistributionIscalculatedfromtheareaundertheconcentrationtimecurve:

Totalclearanceisthesumofclearancesfromindividualorgans,e.g.:

,where:

,where:

isurineconcentrationinmmol.LFunctionofglomerularfiltration,reabsorption,andsecretion.

istheurineflowinml.min

istheplasmaconcentrationinmmol.L

,where:

isthehepaticbloodflowinml.min

istheextractionratio

Kinetics

Drugclearancecanfolloweitherfirstorderorzero-orderkinetics:

First-orderKineticsAconstantproportionofthedruginthebodyiseliminatedperunittime.

Mostdrugsareeliminatedbyfirstorderkinetics,asthecapacityoftheeliminationsystemexceedstheconcentrationofdrug

-1

-1

-1

-1

-1

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Zero-orderkineticsAconstantamountofdrugiseliminatedperunittime,independentofhowmuchdrugisinthebody.

OccurswhenthereissaturationofenzymesystemsItisalsoknownassaturationkineticsforthisreason.

e.g.Phenytoinfollowsfirstorderkineticsatlowerdoses,butzero-orderkineticsatdoseswithinthetherapeuticrangeThisisclinicallyrelevantasthenarrowtherapeuticindexmeansthattoxiclevelsmayoccurrapidlywithasmallincreaseindose.e.g.Ethanolalsofollowszero-orderkineticswithinthe"therapeuticrange",asitisaveryweak(dosesareingrams)positiveallostericmodulatoroftheGABA receptor

Zero-orderkineticsisconcerningas:PlasmaconcentrationswillrapidlyincreasewithonlymodestdoseincreaseThereisessentiallynosteadystate:ifdruginputexceedsoutput,plasmalevelswillcontinuetorise

Michaelis-Menten

TheMichaelis-Mentenequationdescribesthetransitionfromfirstordertozeroorderkineticsasdrugconcentrationincreases:

Metabolismincreasesproportionallywithconcentrationaslongastheconcentrationofdrugleavingtheorganofmetabolism(e.g.inthehepaticvein)islessthanhalfofthemaximalconcentrationofdrugthatorgancanmetabolise

A

rd

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Thisis~1/3 ofthemaximalrateofmetabolism

HepaticMetabolism

Theprincipleorganofdrugmetabolismistheliver.Hepaticmetabolism:

Usuallydecreasesthefunctionofadrug,though:ProdrugshaveincreasedpharmacologicallyactivityafterlivermetabolismSomedrugshaveactiveortoxicmetabolites

Canbedividedintotwophases

PhaseI

Phaseonereactions:

OccurintheendoplasmicreticulumImprovewatersolubilitybyexposingafunctionalchemicalgroupTypicallyoccurpriortophaseIIreactionsformostdrugsInclude:

OxidationLossofelectrons.

MainphaseIreactionCYP450driven

ReductionGainofelectrons.

CYP450drivenHydrolysisAdditionofawatermolecule,whichmayresultintwonewcompounds.

EsterasedrivenThereforerapid,highcapacity,organ-independentelimination.

ButylcholinesteraseNon-specificplasmacholinesteraseRBCesterase

CYP450System

CYP450enzymesare:

AsuperfamilyofenzymesvitalindrugmetabolismNamedafterthewavelengthoflighttheyabsorbwhen:

ReducedCombinedwithCO

Locatedin:LiverEndoplasmicreticulumofhepatocytes.LungsKidneyGutBrain

Over1000enzymes,with~50functionallyactiveClassifiedbythedegreeofsharedamino-acidsequenceinto:

Families

rd

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73

CYP1,CYP2,CYP3...SubfamiliesCYP1A,CYP1B...IsoformsCYP1A1,CYP1A2...

CYP2B6 CYP2C9 CYP2C19 CYP2D6 CYP2E1 CYP3A4 CYP3A5

PropofolPropofol,Parecoxib,Warfarin

Diazepam,Omeprazole,Clopidogrel,Phenytoin

Codeine,Metoprolol,Flecainide

Volatileanaestheticagents,paracetamol

Commonbenzodiazepines,Fentanyl,Alfentanil,Lignocaine,Vecuronium

Diazepam

KeyCYPenzymesinclude:

CYP2E1Metabolisesvolatilesandparacetamol.CYP3A4Responsiblefor60%ofmetabolicactivity.CYP2D6

Importantbecausegeneticpolymorphismleadstosignificantinter-patientvariabilityMayresultinsignificantover-orunder-metabolismofdrugs,andthereforesignificantinter-individualvariabilityinresponse.

5-10%ofthepopulationarepoormetabolisers2-10%areintermediatemetabolisers1-2%areultra-rapidmetabolisersBulkofthepopulation(70-90%)areextensivemetabolisers

ClinicaleffectwilldependonthetypeofdrugPro-drugs

Extensive/ultra-rapidmetaboliserswillconvertmoredrugtotheactiveform,andseeagreatereffectMayleadtooverdose.Poormetaboliserswillexcretemorepro-drugpriortometabolism,andseeareducedclinicaleffect

ActivedrugExtensive/ultra-rapidmetaboliserswillinactivatemoredrug,andseeareducedeffectPoormetaboliserswillseeaprolongedclinicaleffect

Clinicaleffectmaybealteredbyenzymeinteractionse.g.Oxycodoneusebyanultra-fastmetaboliser,incombinationwithaCYP3A4inhibitor(e.g.diltiazem)willresultinasignificantincreaseintheclinicaleffectofoxycodone

DrugsmetabolisedbyCYP2D6include:Analgesics

Codeine(prodrug)Oxycodone(metabolisedtothesignificantlymorepotentoxymorphone)MethadoneTramadol(metabolisedtoformwithgreaterMOPselectivity)

PsychiatricdrugsSSRIsTCAsHaloperidol

CardiovasculardrugsAmiodaroneFlecainideMexiletine

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PhaseII

PhaseIIreactions:

Involveconjugationwithanothercompound,producingahighlypolarmetaboliteThisincreaseswatersolubilityandthereforerenalelimination.TypicallyoccurinthehepaticendoplasmicreticulumInclude:

GlucuronidationAdditionofglucuronicacid.SulfationAdditionofasulfagroup.AcetylationAdditionofanacetylgroup.

Alsooccursinthelungandspleen.MethylationAdditionofamethylgroup.

ExtractionRatio

Extractionratioistheproportionofadrugthatisclearedfromcirculationduringeachpassthroughtheorgan,typicallytheliver:

Extractionratioisdependenton:

BloodflowHepatocyteuptakeEnzymecapacityDescribedbytheMichaelisConstant:Theconcentrationofasubstratewhichcausesanenzymetoworkat50%ofitsmaximumcapacity.

Drugscanhaveeitherahighorlowextractionratio:

HighextractionratioThesedrugshavearapiduptakeandhighcapacity,soeliminationisperfusiondependent.

Freedrugisrapidlyremovedfromplasma,bounddrugisreleasedfromplasmaproteinsandaconcentrationgradientismaintainedMetabolismofdrugswithahighextractionratiois:

IndependentofproteinbindingDependentonliverflowTypicallydoublingliverbloodflowwilldoublehepaticclearance.

ThereisahighvariabilityinplasmaconcentrationbetweenindividualsduetothevariationinliverbloodflowDrugswithhighextractionratiosaregenerallyindependentofenzymeactivity-decreasingenzymeactivityfrom99%to95%hasaminimaleffectonhepaticclearance

Thekeyexceptionisfirstpassmetabolism,astheabovechangewillresultinafive-folddifferenceindosereachingthesystemiccirculationThereforedrugswithahighextractionratiohavelowPObioavailability.

LowextractionratioEliminationiscapacity-dependent.

AmountoffreedrugavailableformetabolismisgreatlyaffectedbythedegreeofproteinbindingMetabolismis:

Largelyindependentofflow

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DrugshavegoodPObioavailability.Dependentonhepatocytefunctionandproteinbinding

FactorsAffectingHepaticMetabolism

DrugFactors PatientFactors

Lipidsolubility Age

Ionisation Obesity

Proteinbinding Pregnancy

Enzymecompetition Genetics:Slowvs.fastacetylators

Hepaticflow/ExtractionRatio

EnzymeInhibition/Induction

Hepaticdisease

Smoking,ETOH

OrganIndependentMetabolism

Mechanismsoforganindependentmetabolisminclude:

HofmannDegradationSpontaneousdegradationormetabolismofsubstancesoccurringinplasma.

e.g.CisatracuriumundergoesHofmanndegradationPlasmaEsterasesPlasmaesterasesarenon-microsomalenzymeswhichhydrolyseesterbonds.They:

AretypicallysynthesisedintheliveranderythrocytesHaveahighcapacityThis,combinedwiththeorgan-independentelimination,meansdrugsmetabolisedbyplasmaesteraseshaveareliableoffset.e.g.Suxamethoniumishydrolysedbyplasmaesterases

References

1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. EssentialpharmacologyfortheANZCAprimaryexam3. Birkett,DJ.Pharmacokineticsmadeeasy9:Non-linearpharmacokinetics.1994.AustralianPrescriber.

Lastupdated2019-07-18

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EliminationDescribethemechanismsofdrugclearanceandmetabolism.

Drugscanbeeliminatedin:

UrineBileSweatBreastmilkTearsExhaledgas

RenalEliminationDrugscanbe:

FilteredattheglomerulusFiltereddrugsare:

NotproteinboundOnlyfreedrugpresentinfilteredplasmawillbeexcreted.

ConcentrationoffiltereddrugwillbethesameasinunfilteredplasmaHighlyproteinbounddrugsarepoorlyfilteredThereisonlyaweakconcentrationgradientfavouringdissociationfromplasmaproteins.

SmallSubstanceslessthan7,000DaarefreelyfilteredSubstancesgreaterthan70,000Daareessentiallyimpermeable

Hydrophilic/lipophobicLipophilicdrugsmaybefilteredattheglomerulusbutwillbefreelyreabsorbedduringtheirpassagedownthetubule,suchthatonlytrivialamountsareeliminatedinurine.

SecretedinthetubulesActiveprocessallowssecretionagainstconcentrationgradientsSeparatemechanismsforacidicandalkalinedrugs

SaturatableprocessSaturationmayoccurofabasictransporterwhilststillallowingexcretionofacidicdrugs,andviceversa.

ReabsorbedinthetubulesPassivediffusiondownaconcentrationgradient.

HydrophilicmoleculescanonlybereabsorbedbyaspecialisedtransportmechanismAcidicdrugswillbebecomeionisedinanalkalineurine(andviceversa),reducingtheirsolubilityThisisthephysiologicaljustificationforurinaryalkalinisation.

HepaticElimination

Biliaryeliminationoccursfordrugsunabletobefilteredbytheglomerulus.Thesearetypically:

LargeGreaterthan30,000dalton.Lipidsoluble

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77

Enterohepaticrecirculation

Drugsexcretedinbilemay:

BehydrolysedinthesmallbowelbybacteriaandthenreabsorbedThenpassthroughtheportalcirculationandgetmetabolisedagainThisprocessmayoccurmanytimes

References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.

Lastupdated2019-07-18

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BolusandInfusionKineticsExplaintheconceptsofintravenousbolusandinfusionkinetics.Todescribetheconceptsofeffect-siteandcontextsensitivehalftime.

ContinuousInfusions

PlasmaconcentrationsofanIVinfusionareinfluencedby:

DistributionMetabolismElimination

OnsetofContinuousRateInfusions

Withoutaloadingdose,theconcentrationofdruginfusedataconstantincreasesinanegativeexponentialfashion:

PlasmaconcentrationinitiallyrisesrapidlyDistributionintoperipheralcompartmentsisthemainmethodfordrugstoleaveplasmaThisisbecauseatthestartofaninfusionthereisalargeconcentrationgradientbetweenplasmaandperipheralcompartments.EliminationbecomesmoreimportantinprolongedinfusionsAsperipheralcompartmentsfilltheconcentrationgradientbetweenplasmaandcompartmentsfalls,andredistributionbecomesrelativelylessimportant.Steadystateisachievedwhenconcentrationsincompartmentsareequal,andinputisequivalenttoclearance

Concentrationatsteadystateisdeterminedbytheratioofinfusionratetoclearance:Therefore,atsteadystatewithdrugswith100%bioavailability:

Fordrugsgivenbyaroutewithlessthan100%bioavailability:

Ifthedosingisgivenintermittently,then:

VolumeofdistributionatsteadystateistermedV ssandistheapparentvolumeintowhichadrugwilldisperseduringaprolongedinfusion,andisthesumofallcompartmentvolumesinthemodel.

ContinuousRateInfusionswithBolusDosing

Asseen,abovestartinganinfusionattheraterequiredtomaintainsteadystateisinefficient:

Foranydesiredplasmaconcentration,itwilltakethreetimeconstants(4-5half-lives)foracontinuousinfusiontoreachthisconcentration

Ifthehalf-lifeislong,thenachievingatherapeuticlevelwilltakesometimeAbolusdoseaimedtofilltheV willallowsteady-statetobereachedimmediately:

D

D

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79

StoppinganInfusion

Forabi-exponentialmodel(i.e.onlyoneperipheralcompartment),declineinplasmaconcentrationcanbemodeledbythe

equation .Inthismodel:

isthetime-constantforredistribution

isthetime-constantforterminalelimination(Providedtheinfusionhasreachedsteady-state).

Neither or correspondtoanyindividualrateconstant

Factorsaffectingrateofoffsetofaninfusioncanbeclassifiedintopharmacokinetic,pharmacodynamic,andotherdrugfactors:

PharmacokineticfactorsDistribution

VHighV willdecreaseclearancefromcentralcompartment.FactorsaffectingV include:

IonisationIontrappingcancausedrugtobesequestered.ProteinbindingLipidsolubilityAffectedbybodyfat.

SpeedofdistributionCOAffectsorganbloodflow.

RedistributionDuringaninfusion,peripheralcompartmentsbecomesaturatedwithdrug.Whenaninfusionceases,drugisredistributedcentralcompartment.

Thisisrelatedtocontext-sensitivehalftime(seebelow)Metabolism

RouteofclearanceOrgan-dependent

OrganfailuresExtractionratioOrganbloodflow

Organ-independentSaturatablekineticsZero-orderkinetics.

PresenceofactivemetabolitesEliminationRouteofexcretionofactivedrugoractivemetabolites.

DD D

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OrganfailuresPharmacodynamicFactors

AgeSensitivityDoserequiredforeffectanddoserequiredforrecovery.

OrganfailuresPregnancy

OtherdrugfactorsPharmacokineticinteractions

Enzymeinhibition/inductionPharmacodynamicinteraction

DrugtolerancesTachyphylaxis

DrugactionDrugswhichaltergeneorreceptorexpression,orbindirreversibly(e.g.clopidogrel)mayshowongoingeffectsevenafterthedrughasleftthesystem.

Context-SensitiveHalf-Time

Context-sensitivehalftimeis:

DefinedasthetimeforplasmaconcentrationtofalltohalfofitsvalueatthetimeofstoppinganinfusionAmethodtodescribethevariabilityinplasmaconcentrationsafterceasinganinfusionThe"context"isthedurationofinfusion.Usedbecauseterminaleliminationhalf-lifehaslittleclinicalutilityforpredictingdrugoffsetHalf-livesareoftenmisleadingwhendiscussingdruginfusions.Dependenton:

DurationofinfusionDuringaninfusion,drugsdistributeoutofplasmaintotissues.Whentheinfusionceases,drugisclearedfromplasmaandtissuedrugredistributesbackintoplasma.

Thelongeraninfusion,themoredrughasdistributedoutoftissues,andthelongertheredistributionphaseThelongestcontext-sensitivehalftimeoccurswhenaninfusionisatsteady-state

RedistributionThemaximalCSHTreacheddependsonthe:

V ssDrugswithalargerV sshavealongerCSHT,asonlyasmallproportionofthedruginthebodywillbeinplasmaandabletobecleared.RateconstantforeliminationDrugswithasmallerrateconstantforeliminationhavealongerCSHT.

Drugswithlongercontext-sensitivehalf-timeswillwearofflesspredictably.

DD

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RemifentanilhaslittleredistributionandasmallVd,andsohasaveryshortcontext-insensitivehalftimeItwearsoffreliablyandquicklyfollowingcessationofinfusion.

Context-SensitiveDecrementTime

DescribethetimeittakesforadrugleveltofalltoaparticularpercentageofitsstartingvaluefollowingcessationofaninfusionTheyareusedbecausethehalf-timesdonotdescribemono-exponentialdecayi.e.Thetimetakenfordrugconcentrationtoreach25%ofitsstartingvalueisnottwicethecontextsensitivehalf-time.Thecontext-sensitivehalf-timecouldalsobedescribedasthe50%context-sensitivedecrementtime

References

1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. HillSA.PharmacokineticsofDrugInfusions.ContinEducAnaesthCritCarePain(2004)4(3):76-80.

Lastupdated2019-07-18

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DrugMonitoringExplainclinicaldrugmonitoringwithregardtopeakandtroughconcentrations,minimumtherapeuticconcentrationandtoxicity

Drugmonitoring:

DescribestheindividualisationofdosingbymaintainingplasmadruglevelswithinatargetrangeIsimportantinadjustingdosetoaccountforinter-patientvariabilityinresponseVariabilitycanbe:

PharmacokineticAdjustingdrugdosebymonitoringplasmalevelsreducespharmacokineticvariability.PharmacodynamicDrugdoseisadjustedbyevaluatingtheclinicaleffect.

Druglevelsaremeasuredtoensuretheconcentrationisabovetheminimumtherapeuticconcentrationbutbelowtoxiclevels:

MinimumtherapeuticconcentrationTheED ,i.e.thedoserequiredtohaveaneffectin50%ofthepopulation.

DeterminesdesiredtroughlevelsMinimumtoxicconcentrationTheLD ,orthedosewhichislethalin50%ofthepopulation.

Determinestheacceptablepeaklevels

Fromtheselevelstworelatedtermsarederived:

Therapeuticrange(alsoknownasthetherapeuticwindow)Differencebetweentheselevels.TherapeuticindexRatiobetweentheselevels,i.e.

Ahighertherapeuticindexgivesagreatermarginforsafety

IndicationsDrugsaremonitoredinorderto:

AvoidtoxicityAdjustdosingforefficacyMonitorcomplianceordeterminefailureoftherapy

50

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Drugsthattypicallyrequiremonitoringhavea:

NarrowtargetrangeSignificantpharmacokineticvariabilityRelationshipbetweentheconcentrationinplasmaandclinicaleffectsDeterminedconcentrationrangeValidatedmonitoringassay

Drugswheretheeffectcanbemeasuredclinically(e.g.antihypertensives)tendtobeadjustedbasedonobservedeffects.Thisisnotpossiblewhen:

Theclinicalresponseistheabsenceofacondition,e.g.antiepilepticsThedrughasanarrowtherapeuticrange

DrugscommonlymonitoredintheICUsettinginclude:

Drug TherapeuticRange

Digoxin 0.8-2microgram/L

Vancomycin 10-20mg/L*

Tacrolimus 5-20microgram/L

Serolimus 5-15microgram/L

Phenytoin 10-20mg/L

*Trough

Timingofsamples

SamplingfortoxicityshouldoccurattimesofpeakconcentrationThisrequiresaccountingforabsorptionanddistribution

e.g.Digoxinlevelsshouldbeperformed>6hoursfollowingadosetoallowtimefordistributiontooccurIfsymptomatic,samplestakenatthistimemaydemonstratetoxicconcentrations

Samplingformonitoringshouldideallyoccuratsteadystatei.e.after4-5eliminationhalf-livesFordrugswithverylonghalf-lives(suchasamiodarone),samplingtendstooccurearliertoensuretoxiclevelshavenotbeenreached,assteadystatemaytakemonthstoachieve

Fordrugswithshorthalf-lives,troughlevels(i.e.pre-doselevels)shouldbetakenThisistheleastvariablepointinthedosinginterval.Fordrugswithlonghalflives,timingofsamplingislessimportant

InterpretationInterpretationofdruglevelsisdependenton:

TimingofsampleDurationoftreatmentatthecurrentdoseanddosingscheduleIndividualcharacteristicsthatmayaffectthepharmacokinetics

AgePhysiologyComorbidities(hepatic,renal,cardiac)

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DruginteractionsGeneticsEnvironmental

ProteinbindingAssaysmeasureboundandunbounddrugOnlyunbounddrugispharmacologicallyactive.Ifbindingischangedbydiseaseordisplacementbyotherdrug,theproportionofunbounddrugmaychangeandtargetedlevelsmayneedtobeadjustedaccordingly

ActivemetabolitesActivemetabolitesarenotmeasuredbutwillcontributetotheresponse.

References1. BirkettDJ.Therapeuticdrugmonitoring.AustPrescr1997;20:9-11.2. GhiculescuRA.Therapeuticdrugmonitoring,whichdrugs,why,when,andhowtodoit.AustPrescr2008;31:42-4.

Lastupdated2018-09-21

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EpiduralandIntrathecalDescribethepharmacokineticsofdrugsintheepiduralandsubarachnoidspace

Inbothspaces,speedofonsetisdeterminedbyFick'sLaw.

EpiduralSpace

Factorsimportanttoepiduraladministration:

DosegivenVolumegivenIncreasedvolumeincreasesareaofsubarachnoidthatthedrugisincontactwith,increasingrateofdiffusion.SolubilityAffectedby:

pKaandpHDeterminesunionisedportionavailabletocrossintoCSF.ProteinbindingDeterminesfreedrugportionabletocrossintoCSF.Lipidsolubility

CSFflowAltersconcentrationgradientbetweenepiduralandsubarachnoidspace.

IntrathecalFactorsimportanttointrathecaladministration:

DoseMuchsmallerdosesrequired.VolumeAffectsextentofspread.BaricityAffectsdirectionofspread:

Hyperbaricsolutionswillsinkwithgravitye.g.Heavybupivacaine(0.5%bupivacainewith8%dextrose)Hypobaricsolutionswillriseagainstgravity

References

1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. ANZCAFebruary/April20073. Factorsinfluencingdistributionofbupivacaineafterepiduralinjection-DiazNotes.

Lastupdated2017-09-17

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TotalIntravenousAnaesthesiaandTarget-ControlledInfusion

Describethepharmacologicalprinciplesofandsourcesoferrorwithtargetcontrolledinfusion

TotalintravenousanaesthesiainvolvesusingIVagentsalonetoachievehypnosis,analgesia,andmusclerelaxation.TIVA:

AdvantagesAvoidsadverseeffectsofanaestheticagents

Nausea/vomitingPollutionIncreasedcerebralbloodflow

DisadvantagesDrugmustbemetabolisedPotentialincreasedlikelihoodofawareness

LikelyrelatedtopoorapplicationoftechniqueratherthanthetechniqueitselfMostlyrelatedtodisconnectionofinfusionwithoutEEGmonitoring

Variableplasmaconcentration

TargetControlledInfusionTCIistheuseofpharmacokineticmodels(typicallycombinedwithmicroprocessor-controlledinfusionpumps)toachieveatargetconcentrationofdruginaparticularbodycompartment.

TCI-systems:

Areopen-loopEffectsofdrugarenotmeasured(unlikewithend-tidalgasmonitoring),whichintroducesavulnerabilitythatcanleadtoawareness.

e.g.Comparedtoinhalationalanaesthetics,wheretheloopisclosedbyusingend-tidaldrugmonitoringFollowstheBET(Bolus,Elimination,Transfer)principle:Aloadingdoseisgiventosaturatethevolumeofdistributiontoachievetargetconcentration

Infusionrateisthensettomaintainatargetplasmaconcentration:

Ratecompensatesfor:DrugeliminationDrugdistribution(transfer)

Target canbeadjusted:Forahigherconcentration:

AsmallbolusisgivenInfusionrateisincreased

Foralowerconcentration:InfusionispauseduntildesiredlevelisreachedInfusionraterestartsatalowerrate

Modelscantargeteither:

Plasmaconcentration,

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Willnotapproximate untilsteadstateisreached.Therefore:

Increase duringinduction,sothat willrisemorequickly

shouldbeadjustedtothelevelofthesurgicalstimulus

Effect-siteconcentration,Over-pressureoccursautomatically,sothereisnorequirementtoincreasetargetduringinduction.

TCIModelsforPropofol

TheBristolModel:

FirstpharmacokineticmodelBasedonthree-compartmentmodelofhealthpatientsAssumes:

PremedicationwithtemazepamFentanyl3μg.kg oninductionInhaledN O

Atargetplasmaconcentration( )of3μg.mlThemodel:

1mg.kg inductionbolus10-8-6maintenance:

10mg.kg .hr for10minutes8mg.kg .hr for10minutes6mg.kg .hr thereafter

MarshandSchniderModels:

ThesearecomputercontrolledmodelsBothwerederivedonverysmallgroupsofpatients(18and24respectively)Themodelsdiffermostlyinthefirst10minutesafterinduction,andprogressivelyconverge

-1

2-1

-1

-1 -1-1 -1-1 -1

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Theinitialbehaviourofthemodeliskeyindecidingwhichmodeltoapplytoanyparticularpatient.

Property Marsh Schnider

Targets

Typicallytargetplasmaconcentration,butcantargeteffectsite.

EffectsitetargetingisusuallydonewiththemodifiedMarshmodel,duetothelargebolusdosinggivenbythestandardMarshmodel.

Typicallyeffectsite,butcantargetplasmaconcentration.

Plasmatargetinggivesinconsistentresults,asthefixedsizeofV meansanyincreaseindesiredplasmaconcentrationresultsinthesamesizebolusbeinggiven,irrespectiveofpatientparameters.

Requiredvariables

TBW(overestimatesinduction(butnotmaintenance)inobesepatients,considerusingIBW),Age(butnotusedincalculation)

Age,height(tocalculateleanbodymass),TBW

Values VariablecompartmentsizesbutbiggerV FixedV (4.27L)andV ,variableV andK

Other

The'modifiedMarsh'modelusesak of1.2L.min

insteadof0.26L.min ,whichdecreasesthe

requiredtoachievethetarget quickly.ThemodifiedMarshisthereforepreferableinpatientsathigherriskofoverdose.

LimitsBMIto<42formalesand<35forfemales,topreventabsurdcompartmentsizesbeingcalculatedfromthemethodusedtocalculateleanbodymass

Overall FasterinductionduetolargerV ,whichresultsinalargerloadingdose

Reducedrateofadverseevents.Overalllesspropofolused.

References

1. AbsalomAR,ManiV,DeSmetT,StruysMM.Pharmacokineticmodelsforpropofol--definingandilluminatingthedevilinthedetail.BrJAnaesth.2009Jul;103(1):26-37.

2. NaidooD.TargetControlledInfusions.DepartmentofAnaesthetics,UniversityofKwazulu-Natal.2011.3. EngbersFH,SutcliffeN,KennyG,SchraagS.Pharmacokineticmodelsforpropofol:Definingandilluminatingthedevilin

thedetail.BrJAnaesth.2010Feb;104(2):261-2;authorreply262-4.4. FRCA-TargetControlledInfusionsinAnaestheticPractice

Lastupdated2019-07-20

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eo-1

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ReceptortheoryToexplaintheconceptofdrugactionwithrespectto:receptortheory

Todefineandexplaindose-effectrelationshipsofdrugs,includingdose-responsecurveswithreferenceto:therapeuticindex,potencyandefficacy,competitiveandnon-competitiveantagonists,partialagonists,mixedagonist-antagonistsandinverseagonists

ToexplaintheLawofMassActionanddescribeaffinityanddissociationconstants

Areceptorisacomponentofacellwhichinteractswithadrugandinitiatesasequenceofeventsleadingtoanobservedchangeinfunction.

Existenceofreceptorsisinferredfromtheresponseoftissuestodrugs,genomesequencing,andmolecularbiology.Adrugbindstoareceptorformingareceptor-drugcomplex,whichinitiatesacascadeofeventstoexertapharmacologicaleffect.

DissociationConstantsInteractionbetweenareceptorandadrugisbaseduponthelawofmassaction,whichstatestherateofachemicalreactionisproportionaltothemassesofreactingsubstances.Thiscanbeexpressedas:

Theratiooftherateconstantfortheforwardsreaction(K )andthebackwardsreaction(K )isthedissociationconstant.Thisistheconcentrationofdrugwhen50%ofreceptorsareoccupied:

AlowK valueindicatesthatalowerconcentrationofdrugisrequiredtooccupy50%ofthereceptor,indicatingthatthedrughasahighaffinityforthereceptor.

PhysiologicalfactorswhichaffectthedissociationconstantaredeterminedbytheArrheniusequation:

,where:

isaconstant

istemperatureinkelvin

istheactivationenergyrequired,whichmaybeloweredbyacatalyst

isthegasconstant

PropertiesofDrugs

Keypropertiesofdrugsinclude:

PotencyTheamountofdrugrequiredtohaveaneffect.

Givenbythe(typicallytheE 50)ThisrelatestoBowman'sprinciple,whichstatesthattheleastpotentanaestheticagentshavethequickestonsetThisisbecausetheyareadministeredinhigherdoses(astheyarelesspotent,moreisrequiredtogetaneffect),which

association dissociation

D

D

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resultsinahighconcentrationgradientandarapiddistributionintotissues.

EfficacyThemaximaleffectthatadrugcangenerate.

IntrinsicactivityThesizeofeffectadrughaswhenbound,whichisgradedfrom0to1.

Thisisalsoknownasactivity

Drug-ReceptorInteractionsDrugscanbeclassifiedbythewaytheyinteractwithreceptorsinto:

AgonistsPartialagonistsInverseagonists

AntagonistsIndirectantagonists

AllostericModulatorsMixedAgonist-Antagonists

Agonists

Anagonistwillgenerateamaximalresponseatthereceptorsite.Anagonisthashighaffinityandanactivityof1.Agonistscanbecomparedby:

Relativepotencyimpliesthatiftwoagonistsareequallyefficacious,asmallerdoseofoneisrequiredtogetaneffectRelativeefficacyimpliesthatthemaximaleffectofoneagonistisgreaterthantheother

Partialagonist

Apartialagonistgeneratesasubmaximalresponseatthereceptor.Apartialagonisthasahighaffinityandanactivitybetween0and1.Apartialagonistcanactasaneffectiveantagonistinthepresenceofafullagonist,asitwillpreventmaximalbindingatareceptor,evenwithahighagonistconcentration.

Inverseagonist

Adrugwhichhasanegativeactivity(between0and-1)producingtheoppositeresponse(comparedtotheendogenousagonist)atreceptor.

Occursduetolossofconstitutiveactivityatthatreceptor

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Antagonist

Anantagonistproducesnoresponseatthereceptorsite,andpreventsotherligandsbinding.Antagonistshavehighaffinityandanactivityof0.

Antagonistswiththesepropertiesarealsoknownasdirectantagonists,whichcanbeeither:

CompetitiveantagonistsDisplaceotherligandsfromabindingsite.Competitiveantagonistscanbe:

ReversibleTheeffectcanbeoverriddenbyincreasingthedoseofagonist.IrreversibleDrugcannotbeoverriddenbyincreasingdoseofagonist.Dose-responsecurveappearssimilartothatofthenon-competitiveantagonist.

Non-competitiveantagonistsCreateaconformationalchangeinthereceptor.Theycannotbeoverriddenbyincreasingthedoseofagonist.

IndirectAntagonist

Indirectantagonistsreducetheclinicaleffectofadrug,butdosoviameansotherthanreceptorinteraction.Theyinclude:

ChemicalantagonistsWherethedrugbindsdirectlytoanother.Examplesincludeprotamineandheparin,andsugammadexandrocuronium.PhysiologicantagonistsAcounteringeffectisproducedbyagonismofotherpathways.

AllostericModulator

Adrugwhichbindstoanallostericsiteonthereceptorandproducesconformationalchangethatalterstheaffinityofthereceptorfortheendogenousagonist.

Allostericmodulatorscanbe:

PositiveIncreasesaffinityforendogenousagonist.

e.g.BenzodiazepinesarepositiveallostericmodulatorsattheGABA receptorNegativeDecreasesaffinityforendogenousagonist.

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MixedAgonist-Antagonist

Adrugwhichhasdifferenteffectsondifferentreceptors.

References

1. PinnockC,LinT,SmithT.FundamentalsofAnaesthesia.2ndEd.CambridgeUniversiyPress.2003.2. EncyclopaediaBritannica.Availableat:https://www.britannica.com/science/law-of-mass-action3. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.

Lastupdated2019-07-20

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ReceptorTypesToexplaintheconceptofdrugactionwithrespectto:receptortheory,enzymeinteractions,andphysicochemicalinteractions.

Toexplainreceptoractivitywithregardto:ionicfluxes,secondmessengersandGproteins,nucleicacidsynthesis,evidenceforthepresenceofreceptors,regulationofreceptornumberandactivity,structuralrelationships.

ReceptorTypes

Areceptorisaprotein,usuallyinthecellularmembrane,towhichaligandmaybindtogeneratearesponse.

IntracellularreceptorsMaybeeithercytoplasmicorintra-nuclear.

Intranuclearreceptorsareactivatedbylipidsolublemolecules(suchassteroidsandthyroxine)toalterDNAandRNAexpressionThisresultsinanalterationofproductionofcellularproteins,sotheeffectstendtobeslowacting.

Enzyme-linkedreceptorsAreactivatedbyaligandandcauseenzymaticactivityontheintracellularside.Theycanbeeither:

MonomersDimersWheretwoproteinsjoin,ordiamerise,onbindingofaligand.

Ion-channelreceptors(inotropic)Createachannelthroughthemembranethatallowselectrolytestoflowdowntheirelectricalandconcentrationgradients.Theycanbeeither:

Ligand-gatedchannelsUndergoconformationalchangewhenaligandisbound.Therearethreeimportantfamiliesofligandchannels:

PentamericfamilyConsistoffivemembranespanningsubunits.Include:

NicotinicAChreceptorGABA receptor5-HT receptor

InotropicglutamatereceptorsBindglutamate,aCNSexcitatoryneurotransmitter.Include:NMDAreceptor

1

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HighCa permeabilityInotropicpurinergicreceptorsFormcationicchannelsthatarepermeabletoCa ,Na ,andKActivatedbyATP

Voltage-gatedchannelsOpenwhenthethresholdvoltageisreached,facilitatingelectricalconductioninexcitabletissues.

Intheirnormalphysiologicalstate,voltagegatedchannelsdonotgenerallybehaveasreceptorsforaligand,howeversomedrugs(e.g.localanaesthetics)willbindtovoltagegatedchannelstoexerttheireffectHaveacommon4-subunitstructure(eachwith6transmembranesegments)surroundingacentralporeThisporeisselectivefortheparticularion,whichinclude:

NaLocatedinmyocytesandneuronsImportantingeneratingandtransmittinganactionpotentialbypermittingsodiuminfluxintocellsInhibitedbylocalanaesthetics,anti-epileptics,andsomeanti-arrhythmics

CaDividedintosubtypes,including:

LMuscularcontraction.TCardiacpacemaker.N/P/QNeurotransmitterrelease.KLocatedinmyocytesandimportantinrepolarisationfollowinganactionpotential.

UndergoaconformationalchangewhenthethresholdpotentialisreachedThisissensedbytheS4helix,whichactstoopenandclosethechannel.Existinoneofthreefunctionalstates:

RestingPoreisclosed.ActivePoreisopen,andionscanpass.InactiveTransientrefractoryperiodwheretheporeisopen,butionscannotpass.Thiscreatestheabsoluterefractoryperiodofacell.

G-proteincoupled(metabotropic)receptors:G-proteinsareagroupofheterotrimeric(containingthreeunits;α,β,γ)proteinswhichbindGDP.Whenstimulated,theGDPisreplacedbyGTPandtheα-GTPsubunitdissociatestoactivateorinhibitaneffectorprotein.Theeffectdependsonthetypeofα-subunit:

G proteinsArestimulatorly.These

IncreasecAMP,leadingtoabiochemicaleffectG proteinsAreinhibitory.These:

Inhibitadenylylcyclase,reducingcAMPG proteinsHaveavariableeffect,dependingonthecell.These:

ActivatephospholipaseCThisaffectstheproductionof:

Inositoltriphosphate(IP )

2+

2+ + +

+

2+

+

s

i

q

3

2+

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StimulatesCa fromtheSR,affectingenzymaticfunctionorcausingmembranedepolarisation.Diacylglycerol(DAG)ActivatesproteinkinaseC,whichhascell-specificeffects.

ActivateintracellularsecondmessengerproteinswhenstimulatedSecondmessengersystems:

Resultinbothtransmissionandamplificationofastimulus,asasingleactivatedreceptorcanactivatemultipleproteinsandeachactivatedproteinmayactivateseveralotherintermediateproteins

ThisisknownasaG-proteincascade

Enzymeinteraction

Drugscaninteractwithenzymesbyantagonismorbybeingafalsesubstrate.

Enzymeantagonism

Mostdrugswhichinteractwithenzymesinhibittheiractivity.Thisresultsin:

IncreasedconcentrationofenzymaticsubstrateDecreasedconcentrationoftheproductofthereaction

Drugscanbecompetitive,non-competitive,orirreversibleinhibitorsofenzymaticactivity.Examplesinclude:

Ramiprilisacompetitiveinhibitorofangiotensin-convertingenzyme.Aspirinisanirreversibleinhibitorofcyclo-oxygenase.

Falsesubstrates

Falsesubstratescompetewiththeenzymaticbindingsite,andproduceaproduct.Examplesinclude:

Methyldopaisafalsesubstrateoftheenzymedopaminedecarboxylase.

PhysicochemicalDrugswhosemechanismofactionisduetotheirphysicochemicalproperties.Examplesinclude:

MannitolreducesICPbecauseitincreasestonicityoftheextracellularcompartment(andisunabletocrosstheBBB),drawingfreewaterfromtheintracellularcompartmentasaconsequence.Aluminiumhydroxidereactswithstomachacidtoformaluminiumchlorideandwater,reducingstomachpH.

References

1. Anderson,C.Pharmacodynamics2.ICUPrimaryPrep.2. LawofMassAction.EncyclopaediaBritannica.3. ANZCAAugust/September20014. CatterallWA.StructureandFunctionofVoltage-GatedIonChannels.Annu.Rev.Biochem.1995.64:493-531.

Lastupdated2019-07-18

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Dose-ResponseCurvesTodefineandexplaindose-effectrelationshipsofdrugs,includingdose-responsecurveswithreferenceto:gradedandquantalresponse.

StandardDose-ResponseCurves

Adose-responsecurveisagraphofconcentrationagainstthefractionofreceptorsoccupiedbyadrug.

Log-DoseResponseCurves

Itisdifficulttocomparedrugsusingstandarddose-responsecurves.Therefore,doseiscommonlylog-transformedtoproducealog-doseresponsecurve.

Thiscurve:

Compareslog-doseversusclinicaleffectDemonstratesthatthebluedrughasgreaterpotencythanthereddrug,thoughbotharefullagonists

Responsescanbeeithergradedorquantal:

GradedresponsesdemonstrateacontinuousincreaseineffectwithdoseE.g.Bloodpressureandnoradrenalinedose

QuantalresponsesdemonstratearesponseonceacertainproportionofreceptorsareoccupiedExamplesinclude:

EDMediandoseofneuromuscularblockerrequiredtoproducea95%lossoftwitchheight.MACMeanalveolarconcentrationofagentrequiredtopreventmovementinresponsetoasurgicalstimulus.

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References

1. AndersonC.Pharmacodynamics1.ICUPrimaryPrep.Availableat:https://icuprimaryprep.files.wordpress.com/2012/05/pharmacodynamics-1.pdf

Lastupdated2017-10-04

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MechanismsofActionDrugscanactinfourways:

ReceptorsGPCRIntracellular

CytoplasmicIntranucleare.g.Steroids,whichalterRNAexpression.

IonChannelsBlockadeAllostericmodulation

EnzymeinteractionAnenzymeisabiologicalcatalyst,increasingthespeedofreaction.Enzymeinteractioncanbe:

Irreversibleinhibitione.g.Aspirin,whichirreversiblyinhibitsplateletthromboxaneproduction.

ReversibleinhibitionCompetitiveantagonism

e.g.ACE-I.Non-competitiveantagonism

PhysicochemicalOsmotic

e.g.mannitol.Acid-base

e.g.antacids.ChelationRedoxreactions

References

1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.

Lastupdated2019-07-18

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AdverseeffectsClassifyanddescribeadversedrugeffects.

Anadverseeffectis:

Anoxiousorunintendedeffectassociatedwithadministrationofadrugatthenormaldosei.e.,notanoverdoseOccur:

Mainlyinyoungandmiddle-agedindividualsTwiceascommoninwomenMaybeexacerbatedbyasthmaandpregnancy.

Distinctfromanadverseevent,whichisanuntowardoccurrenceduringtreatmentthatdoesnotnecessarilyhaveacausalrelationshiptodrugadministration

Adverseeffectscanbeclassifiedbymechanismasfollows:

TypeAAdverseReactions

Thesearerelatedtothepharmacologicalactionofthedrug.Theyare:

CommonRelatedtodose(dose-responserelationship)TemporallyassociatedwithdrugadministrationReproduciblePharmacologicallypredictablebasedonunderstandingofthedruginquestion

e.ghypokalaemiasecondarytodiureticuse

Theytypicallyresultin:

Organ-selectiveinjuryMorepronouncedwithlong-termuseandinriskgroups:

ExtremesofagePregnancyRenalfailure

HighmorbiditybutlowmortalityTreatmentistodecreasedose.

TypeBAdverseReactions

Thesearepatient-specificoridiosyncraticreactions.Theyare:

RarePotentiallygenetic,butpoorlyunderstood.Independentofdose

OccurwithlowdosesDonothaveadose-responserelationship

NotpharmacologicallypredictableImportantcausesinclude:

AcetylatorstatusCYP450variants

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ReceptorabnormalitiesEnzymealterations/deficiencies

e.g.SuxamethoniumapnoeaNotnecessarilyreproducible

Theytypicallyresultin:

Immuno-allergicreactionsPseudo-allergyIdiosyncraticreactionLowmorbiditybuthighmortality

e.g.Stevens-JohnsonSyndromeoranaphylaxisfollowingpenicillinadministration

Treatmentistoceasethemedication.

TypeCAdverseReactions

Theseare'statisticaleffects'associatedwithmonitoring.Theyare:

TypicallyanincreasedfrequencyofbackgrounddiseasethatisdetectedduetoincreasedscreeningAtypicalforadrugreactionandnotpharmacologicalpredictableNoidentifiabletemporalrelationshipNotreproducible

References

1. RHBMeyboom,MLindquist,ACGEgberts.AnABCofDrug-RelatedProblems.DrugSafety2000;22:415-23.2. PirmohamedM,BreckenridgeAM,KitteringhamNR,ParkBK.Adversedrugreactions.BMJ.1998Apr25;316(7140):1295-

8.OpenAccessReview.3. LazarouJ,PomeranzBH,CoreyPN.Incidenceofadversedrugreactionsinhospitalizedpatients—ameta-analysisof

prospectivestudies.JAMA1998;279:1200-5.

Lastupdated2019-07-18

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DrugInteractionsClassifyanddescribemechanismsofdruginteraction.

Druginteractionsoccur"whentheactionofonedrugmodifiesthatofanother".

MechanismsofDrugInteraction

Druginteractionsarebestclassifiedintothreecategories:

PhysicochemicalPharmacokineticPharmacodynamic

Physicochemical

Physicochemicalinteractionsoccurbecauseofanincompatibilitybetweenchemicalstructures.

e.g.Thiopentoneandsuxamethoniumprecipitateoutofsolutionifpreparedtogetherordeliveredtogetherinthesameline

Pharmacokinetic

Pharmacokineticinteractionscanbesub-classifiedintothoseaffectingabsorption,distribution,metabolism,orelimination.

Absorption

Fororalmedications,absorptionmaybeaffectedbydrugswhichalter:

GastricpHGastricemptyingtime

Metoclopramideresolvesgastricstasisandimprovesabsorptionoforallyadministereddrugs

Distribution

Distributionmaybeaffectedby:

CompetitionforplasmaproteinbindingLossofalbuminandα1-acidglycoproteinMedicationswhichaltercardiacoutputDisplacementfromtissuebindingsitesThistypicallyoccursduetoalterationofmetaboliccapacityofonedrugbytheother.ChelationofdrugfromtissuesChelatingagentsbindtoxicelementsandpreventtissuedamage

Phenytoinisusuallyhighly(90%)proteinbound.Areductioninproteinbindingto80%willdoublethefreephenytoinlevel.Fordrugswithfirst-orderkinetics,metabolismwillincreaseproportionallyhoweverphenytoinrapidlysaturatestheenzymesystem,leadingtozero-orderkineticsandahighplasmalevel.

β-blockersreducecardiacoutputandwillprolongthetimetofasciculationofsuxamethonium.

Metabolism

MetabolismmaybeaffectedbychangestotheCYP450enzymes:

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EnzymeinductionBarbituratesPhenytoinCarbamazepine

EnzymeinhibitionAmiodaroneAmiodaroneinhibitsmetabolismofS-warfarinbyCYP2C9,enhancingit'seffect.DiltiazemVerapamilCiprofloxacinMacrolidesMetronidazoleGrapefruitjuice

Elimination

Renaleliminationcanbeaffectedby:

ChangesinurinarypHCompetitionforactivetubulartransportmechanisms

SodiumbicarbonateincreasesurinarypHandenhancesexcretionofweakacidssuchasaspirin.

Pharmacodynamic

Pharmacodynamicinteractionscanbedirect,duetointeractiononthesamereceptorsystem;oraindirect,whentheyactondifferentreceptorsystem.Theseinteractionscanbeclassifiedaseither:

AdditiveWhentheeffectssummate.

e.g.Administeringmidazolamwithpropofolreducestheamountofpropofolrequiredtogenerateaneffect.AntagonisticWhentheeffectsopposeeachother.

e.g.NeostigmineindirectlyantagonisestheeffectofNDMRsbyincreasingthelevelofAChattheNMJ.SynergisticWhenthecombinedeffectisgreaterthanwouldbeexpectedfromsummationalone.

e.g.Co-administrationofremifentanilandpropofolhasasynergisticeffectinmaintenanceofanaesthesia.

Thesethreeinteractionscanbegraphicallydemonstratedusinganisobologram,whichdrawsalineofequalactivityversusconcentrationoftwodrugs.

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References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. KhanS,StannardN,GreijnJ.Precipitationofthiopentalwithmusclerelaxants:apotentialhazard.JRSMShortReports.

2011;2(7):58.

Lastupdated2019-07-18

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AlterationstoDrugResponseDefinetachyphylaxis,tolerance,addiction,dependenceandidiosyncrasy

Therearefourmechanismswhichresultinvariableresponsetodrug:

AlterationindrugthatreachesthereceptorThisistypicallyduetopharmacokineticfactors.RelativedifferenceinpresenceofexogenousandendogenousligandsAntagonistswillhaveagreatereffectinthepresenceofhighendogenousligandconcentration.VariationinreceptorfunctionandnumberUp-regulationanddown-regulationofreceptorsmayoccurasaconsequenceofprolongedstimulus.Alterationinfunctiondistaltothereceptor

KeyTermsTachyphylaxisistherapiddecreaseinresponsetorepeateddosingoverashorttimeperiod,usuallyduetodepletionoftransmitter

Desensitisationisthelossinresponseoveralongtimeperiod,usuallyduetochangeinreceptormorphologyorlossinreceptornumbers

Withdrawalisapathologicalresponsewhenadrugisceased

Duringadministrationreceptorsmaybe:Up-regulatedinthecontinuedpresenceofanantagonistDown-regulatedinthecontinuedpresenceofanagonist

LossofreceptornumbersmayprecipitatewithdrawalwhentheagonistorantagonistisceasedAddictionisabehaviouralpatterncharacterisedbycompulsiveuseandfixationonacquiringandusingadrug

IdiosyncrasyisanindividualpatientresponsetoadrugTypicallymediatedbyareactivemetaboliteratherthanthedrugitself.

Tolerance

Toleranceistherequirementforalargerdosetoachievethesameeffect,duetoalteredsensitivityofthereceptorstothestimulant.Mechanismscanbeclassifiedinto:

PharmacokineticAltereddrugmetabolismMetabolismmaybeincreasedordecreased:

EnzymaticinductionandincreaseddrugmetabolismIncreasedhepaticenzymepathwaycapacityincreasesmetabolismandlowersplasmaconcentration.DecreasedmetabolismDecreasedmetabolismofaprodrugcanresultinareducedeffect.

PharmacodynamicChangeinreceptormorphologyCanoccurwithion-channelreceptorsandGPCRs:

Ion-channelreceptorsbindtheligandbutdonotopenthechannelGPCRbecome'uncoupled'-phosphorylationofthereceptormakesitunabletoactivatesecondmessengercascade,thoughitcanstillbindtheligand.

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Receptordown-regulationProlongedexposuretoagonistscausestransmembrane(typicallyhormone)receptorstobecomeinternalised.Thisoccursmoreslowlythanuncoupling.Receptorup-regulationProlongedexposuretoantagonistscausesanup-regulationofreceptor.

Canleadtoreboundeffectswhenadrugisceased(e.g.hypertensionwithcessationofclonidine)ExhaustionofmediatorsSimilartotachyphylaxis-depletionofamediatingsubstancedecreasestheeffect.PhysiologicaladaptationActionsofadrugmaybecounteredbyacompensatoryhomeostaticresponse.Activeremovalofthedrugfromthecell

AlterationsinDrugResponse:PatientFactors

Pharmacokineticsandpharmacodynamicsareaffectedinpregnancyandatextremesofage.

Pregnancy

AbsorptionDecreasedgastricemptyingNauseaandvomitingIncreasedcardiacoutput

IncreasesIMandSCabsorptionVolatiles:

IncreasedonsetduetoincreasedMVandreducedFRCDecreasedonsetduetoincreasedCO

DistributionIncreasedV dueto:

IncreasedTBWIncreasedplasmavolumeIncreasedfatmass

Decreasedalbuminandα -glycoprotein

MetabolismNochangetoHBFProgesteroneinducesenzymesOestrogencompetesforenzymesDecreasedplasmacholinesteraseactivity

EliminationIncreasedRBFIncreasedGFR

PharmacodynamicDecreasedMACIncreasedLAsensitivityduetodecreasedα -glycoprotein

Foetus

Drugsthatcrosstheplacentacanbeteratogenictothefoetus,besidesexertingtheirusualpharmacologicaleffects.

Pharmacokineticfactorspredominantlyaffectplacentaltransfer,andinclude:

D

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LipidsolubilityLipidsolubledrugsdiffusemorerapidly.MolecularsizeDrugswithamolecularweight>1000daltoncrosstheplacentaslowly.ProteinbindingPlacentaltransportersSomemedicationsareactivelyremovedfromfoetalcirculation.PlacentalmetabolismTheplacentacanmetabolisesomemedications,althoughinsomecasesresultsintoxicmetabolites.

Maternalpharmacodynamicfactorspredominantlyaffecttheuterusandbreast,butmajororgansystemsarenotsignificantlyaffected.

Drugsthatcrosstheplacentacanhavedramaticeffectsinthefoetus.Theseinclude:

TeratogenesisAdrugwhichadverselyaffectsfoetaldevelopmentcausingapermanentabnormality.Multifactorialmechanismsthatarenotwellunderstood.

Neonates

At<1yearofage,pharmacokineticsaresignificantlyaltered:

AbsorptionDelayedgastricemptying,increasingabsorptionofdrugsmetabolisedinthestomachDecreasedsecretionofpancreaticenzymesandbilesaltsimpairsabsorptionoflipidsolublemedicationsSmallermusclemassandhigherrelativemusclebloodflowincreasesIMonsetIncreasedV :FRCratioincreasesonsetofvolatiles

DistributionTBWis70-75%(comparedto50-60%foranadult),andextracellularwateris40%(comparedto20%),whichtypicallyincreasesVPreterminfantshavereducedbodyfatGreaterproportionofcardiacoutputgoestohead,increasingonsetofcentrallyacting(e.g.anaesthetic)drugsDecreasedalbuminandα -glycoproteinImmatureBBBincreasesuptakeofpartiallyioniseddrugs

MetabolismEnzymaticcapacityofallpathwaysisreduced,whichprolongseliminationhalf-livesandreducesclearance.

HepaticallymetaboliseddrugsmustbedoseadjustedaccordinglyTheglucuronidepathwaymaynotmatureuntilage4

ExcretionGFRisproportionallyloweranddosenotreachadultequivalenceuntil6-12months

GFRisfurtherreducedinpre-terminfantsGFRisincreasedin1-3yearolds

PharmacodynamicSmallerAChreservesincreasesensitivitytoNMBsIncreasedMACbutmorerapidonsetNSAIDscauseclosuresofductusarteriosus

Geriatric

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Thoughthereisalineardecreaseinfunctionalcapacityofmajorsystemsbeginningat45,alterationsarepredominantlyaconsequenceofpolypharmacyanddruginteractions.

AbsorptionLaxativesandprokineticincreasegastricemptyingandreduceabsorptionoforalagents

DistributionThereisaproportionalincreaseinfatThereisaproportionaldecreasein:

LeanbodymassTotalbodywaterAlbumin

Metabolism↓Hepaticbloodflow↓EnzymaticactivityPhaseI>PhaseII.

EliminationLossofnephronnumberwithagereducesrenalclearance

PharmacodynamicIncreasedsensitivitytosedatives,opioids,andhypnoticsDecreasedsensitivitytoβ-agonistsandantagonistsDecreasedMACPolypharmacyincreasespotentialfordruginteractions

AlterationsinDrugResponse:DiseaseFactors

CardiacDisease

AbsorptionDecreasedcardiacoutputdecreasesPOabsorptionduetodecreasedgradient

DistributionDecreasedCOprolongsarm-braincirculationtimeIncreasedα -glycoproteinincreasingbindingofbasicdrugsDecreasedV

MetabolismLow-cardiacoutputstatesreducehepaticflowandwillreducemetabolismofdrugswithahighextractionratioHigh-outputstateshavetheoppositeeffect

EliminationDecreasedrenalbloodflow

HepaticDisease

AbsorptionPorto-cavalshuntingDecreasedfirstpassmetabolism.

DistributionImpairedsyntheticfunctionreducesplasmaproteinsandincreasesunboundfractionIncreasedV duetofluidretention

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Metabolicacidosischangesionisedfraction

MetabolismImpairedphaseIandIIreactionsReducedplasmaesteraselevels

EliminationReducedbiliaryexcretion

PharmacodynamicsHepaticencephalopathyincreasessensitivitytosedativesandhypnotics

RenalDisease

AbsorptionUraemiaprolongsgastricemptying

DistributionIncreasedV duetofluidretentionMetabolicacidosisadjustsionisedfraction

MetabolismBuildupoftoxicmetabolitesmayinhibitdrugtransportersUraemictoxinsinhibitenzymesanddrugtransporters

EliminationReducedclearanceofactivemetabolites/activedrugclearedrenally

Obesity

Absorption:DelayedgastricemptyingDecreasedsubcutaneousbloodflowPracticaldifficultywithIMadministration

Distribution:IncreasedV oflipidsolubledrugs

Dosingoflipid-solubledrugsbyactualbodyweightDosingofwater-solubledrugsbyleanbodyweight

IncreasedCOIncreasedα -glycoproteinIncreasedbloodvolumeGreaterlipidbindingtoplasmaproteins,increasingfreedrugfractions

Metabolism:IncreasedplasmaandtissueesteraselevelsNormalorincreasedhepaticenzymes

EliminationIncreasedrenalclearanceduetoincreasedCO

Non-SpecificAlterationstoDrugResponse

Absorption:

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Drugsgivencentrallywillactfasterthanthosegivenintoperipheralveins.RateofadministrationFasterrateofadministrationwillincreaserateofonset.

Pharmacodynamic

DrugtoleranceIncreaserequirementofdrug.e.g.inductionanaestheticagentsinpatientstoleranttoCNSdepressants.

DruginteractionMaybe:SynergisticAdditiveAntagonistic

References

1. AndersonC.VariabilityinDrugResponse1.ICUPrimaryPrep.2. RangHP,DaleMM,RitterJM,FlowerRJ.RangandDale'sPharmacology.SixthEdition.ChurchillLivingstone.3. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.4. CICMExaminerReport:Sep/Nov20125. AlfredAnaestheticDepartmentPrimaryExamTutorialSeries

Lastupdated2019-07-18

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PharmacogeneticsOutlinegeneticvariability.

Explainthemechanismsandsignificanceofpharmacogeneticdisorders(egmalignanthyperpyrexia,porphyria,atypicalcholinesteraseanddisturbanceofcytochromefunction).

Geneticpolymorphismoccurswhenseveralfunctionallydistinctgenesexistwithinapopulation.Geneticpolymorphismis:

CommonImportantindetermininganindividualssusceptibilitytoadversedrugreactionsAgoalofpersonalisedmedicineAimstoadjustdrugtherapiesforinterpatientvariability.

Pharmacogeneticdisorders

Pseudocholinesterase

Aconditionwhereplasmacholinesteraseisunabletobreakdownsuxamethonium,prolongingitsdurationofaction.Thisdisease:

MaybecongenitaloracquiredCongenitalisautosomalrecessiveHasfouralleles

UsualAtypical(dibucaine-resistant)Silent(absent)Fluoride-resistance

AcquiredisduetoalossofplasmacholinesterasePregnancyOrganfailure

HepaticRenalCardiac

MalnutritionHyperthyroidismBurnsMalignancyDrugs

OCPKetamineLignocaineandesterlocalanaestheticsMetoclopramideLithium

HasbeentraditionallymeasuredusingthedibucainenumberDibucaineis:

AnamidelocalanaestheticwhichinhibitsplasmacholinesteraseDifferentformsareinhibitedtodifferentextents,withgreaterinhibitionindicatingalessseveremutation.

Percentageinhibitioncorrelateswithdifferentgenotypes,e.g.:Normal(Eu:Eu)hasadibucainenumberof80(80%inhibited)

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Dibucaineresistant(Ea:Ea)hasadibucainenumberof20(20%inhibited)Notethatacquireddiseasewillhaveanormaldibucainenumber,astheenzymeitselfisworkingcorrectly,howeverdoesnotexistinalargeenoughquantitytometabolisesuxamethoniumrapidly

G6PD

Acommonx-linkedrecessiveconditionthatmaycausehaemolysisfollowingadministrationofoxidativedrugs.Theseinclude:

AspirinSulfonamidesSomeantibiotics

MalignantHyperthermia

Autosomaldominantdeficiencyintheskeletalmuscleryanodinereceptorgeneresultinginadefectofintracellularcalciumregulation.Thismutation:

Causesmassivecalciumreleasefromsarcoplasmicreticuluminthepresenceofvolatileanaestheticagents(andpotentiallysuxamethonium)Leadsto:

IncreasedmuscleactivityRapidincreaseinbodytemperatureandlacticacidosisHighmortalityfromhyperthermia,hyperkalaemia/rhabdomyolysis,leadingtoventriculararrhythmiaandcardiacarrest

Mutationpresentin1:5,000-1:50,000Presentswith:

Initially:TachycardiaMasseterspasmHypercapneaArrhythmia

Intermediate:HyperthermiaSweatingCombinedmetabolicandrespiratoryacidosisHyperkalaemiaMusclerigidity

Late:Rhabdomyolysis

MyoglobinuriaElevatedCK

CoagulopathyCardiacarrest

Managementconsistsof:Ceaseadministrationofvolatile

StartTIVAGivedantrolene

2.5mg.kg incrementsupto10mg.kg20mgvialsreconstitutedwith60mlsterilewater

3gmannitolasadditiveHighlyalkaline

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Damagingifextravasationoccurs.Treatcomplications:

HyperkalaemiaHyperthermiaAcidosisArrhythmiasRenalfailure

Porphyria

Autosomaldominantdeficiencyinthefirststepofhaemesynthesis.Thesemutations:

ResultinapartialdeficiencyofenzymesLeadtoaccumulationofporphyrinprecursorsMaybeprecipitatedbymanydrugs:

KetamineClonidineKetorolacDiclofenacPhenytoinErythromycinBarbiturates

References

1. RangHP,DaleMM,RitterJM,FlowerRJ.RangandDale'sPharmacology.SixthEdition.ChurchillLivingstone.2. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.3. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.

Lastupdated2019-07-18

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DrugsinPregnancyTheTherapeuticGoodsAdministrationclassifiesdrugsforsuitabilityinpregnancybasedonthepotentialofadrugtocause:

BirthdefectsDetrimentaleffectsatbirthProblemsinlaterlife

Theclassificationsystemis:

ValidonlyforthedoseandrouteofadministrationlistedDoesnotapplyinoverdose

Nothierarchical'B'drugsarenotsaferthan'C'drugs

Categories

CategoryATakenbylargenumberofwomenwithoutdetrimentaleffects.

CategoryBSubclassifiedinto:

CategoryB1TakenbyalimitednumberofwomenwithoutdetrimentaleffectAnimalstudiesshownoevidenceofdetrimentaleffecttothefoetus

CategoryB2TakenbyalimitednumberofwomenwithoutdetrimentaleffectAnimalstudiesareinadequateorlacking,butavailabledatashowsnoevidenceofdetrimentaleffecttothefoetus

CategoryB3TakenbyalimitednumberofwomenwithoutdetrimentaleffectAnimalstudiesshowevidenceoffoetaldamage,butthesignificanceofthisinhumansisunknown

CategoryCDrugswhichhavecaused(orasuspectedtocause)detrimentalfoetaleffects,butwithoutmalformationsTheseeffectsmaybereversible

CategoryD

Drugswhichhavecaused(oraresuspectedtocause)anincreasedincidenceoffoetalmalformationsordamageMayalsohavedetrimentaleffects

CategoryX

DrugswhichhaveahighriskofcausingpermanentdamageShouldnotbeusedinpregnancy,orwhenpregnancyispossible

References

1. Australiancategorisationsystemforprescribingmedicinesinpregnancy.TherapeuticGoodsAdministration.

Lastupdated2017-09-23

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GeneralManagementofPoisoningUnderstandingofthegeneralprinciplesofpoisoninganditsmanagement.

Principlesofmanagementofpoisoning:

"Recognition-Resus-RSI-DEAD"

RecognitionDegreeofemergencyGettingseniorhelpApplicationof100%oxygenearly

ResuscitationA:ControlinanypatientwithsignificantlyimpairedconsciousstateB:Oxygenifnotpreviouslyapplied.Mechanicalventilationifrequired.C:Intravenousaccessisalwaysrequired.Centralvenousaccessmayberequired.D:Glucoselevel.Controlseizures.E:Controlhypothermia

RiskassessmentHistoryincludingtiming,amount,co-administereddrugs,currentpatientstatus.

SupportivecareInvestigations

ECGInvasivemonitoringmayberequiredifhaemodynamicsareunstable.Druglevels

DecontaminationActivatedcharcoalmaybeappropriateifrecentingestion(<1hour)andtheairwayissecured

EnhancedEliminationUsedinseverepoisoningwhensupportivecareislikelytobeinadequate.Includes:

UrinaryalkalinisationFiltration

AntidotesE.g.naloxoneforopiates

Disposition

FootnotesLITFLhasafantasticsectionontheapproachtothepoisonedpatientifyouwantmoreinformation.

References1. Nickson,C.ApproachtotheAcutePoisoning.LITFL.2. LeslieRA,JohnsonEK,GoodwinAPL.DrPodcastScriptsforthePrimaryFRCA.CambridgeUniversityPress.2011.

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TricyclicAntidepressantOverdoseTricyclicantidepressantsareweakbasestypicallyusedfordepressionandasanadjunctforanalgesia.Theyhaveacomplexmechanismofaction,competitivelyinhibitingnoradrenalineandserotoninreuptake,andalsoblockingmuscarinicreceptors,histaminergicreceptors,α-adrenoreceptors,GABA-areceptors,andfastsodiumchannels.

Toxicity

Inoverdose,toxicityispredominantlyduetocardiacandcentraleffects,thoughthereareeffectsonmostofthemajororgansystems.

Cardiactoxicity

Cardiactoxicityisduetoantagonismofα-adrenoreceptorsuse-dependentblockadeoffastsodiumchannels.

α-antagonismresultsinvasodilatationandsubsequenthypotension.Hypotensionmayalsobeduetomyocardialdepressionfromsodiumchannelblockade.

BlockadeoffastsodiumchannelsoccursintheHis-Purkinjesystem,aswellastheatrialandventricularmyocardium.Thisresultsindecreasedmyocardialimpulseconduction.Theyblockchannelsintheinactivatedstate,resultinginause-dependentblockadesuchthattheeffectisgreateratfasterheartrates.Thisresultsinanincreaseddepolarisationandrepolarisationtime.ECGfindingsareconsistentwiththisandareessentiallypathognomonic:

WidenedQRSRightaxisdeviationoftheterminalQRS⩾3mmterminalRwaveinaVR.

AdditionalECGfindingsinclude:

TachycardiaAnydegreeofheartblockVentriculararrhythmias

Centraltoxicity

Centraltoxicityispredominantlyduetoanticholinergiceffects,thoughantihistaminiceffectscontribute.

Anti-cholinergiceffectstendtooccurpriortocardiaceffects,andinclude:

ConfusionAgitationSeizuresPupillarydilatationandblurredvision

Antihistaminiceffectsincludeobtundation.

Management

Standardmanagementofpoisoningapplies.TCAsarenotdialysableandastheyareweakbasesarenotamenabletourinaryalkalinisation.

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Cardiactoxicity

NaHCO andhyperventilationtoapH>7.5isusedtomanagecardiactoxicity.Thereareanumberofproposedmechanismsofactionforthebenefitofalkalinisation:

PlasmaalkalosisresultsinlessioniseddrugandincreasesdistributionintotissuesPlasmaalkalosisincreasesproteinbindingofdrugIntracellularalkalosisresultsinlessboundintracellulardrug,favouringitsmovementoutofcellsExtracellularalkalosisresultsinreducedH /K exchange,increasingintracellularpotassiumandhypopolarisingthecell.

Inadditiontothealkalinisingeffects,sodiumloadfromtheNaHCO improvesthesodiumconcentrationgradientintocells

α-adrenoreceptorantagonismcanbecounteredwithuseofanα-agonistsuchasnoradrenaline.

Arrhythmiasshouldbemanagedwithdrugsthatdonotprolongtheactionpotential-soamiodaroneandbeta-blockersarecontraindicated.InitialmanagementshouldbeusingNaHCO ,thoughMgSO andlignocainecanbeconsideredinrefractorycases.

Centraltoxicity

Seizuresshouldbemanagedwithbenzodiazepines,phenytoin,propofol,andphenobarbital.AvoidagentswhichresultinQRSprolongation.

References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. RangHP,DaleMM,RitterJM,FlowerRJ.RangandDale'sPharmacology.6thEd.ChurchillLivingstone.3. CICMJuly/September20074. SalhanickSD,TraubSJ,GrayzelJ.TricyclicAntidepressantPoisoning.In:UpToDate,Post,TW(Ed),UpToDate,Waltham,

MA,2017.5. Nickson,C.ToxicologyConundrum22.LITFL.6. Nickson,C.TricyclicAntidepressantToxicity.LITFL.7. UpToDate.Tricyclicantidepressantpoisoning

Lastupdated2019-07-20

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OrganophosphatePoisoningOrganophosphatesaresubstancesbindirreversiblytoacetylcholinesterase,causingcholinergicexcess.Examplesincludefertilisersandsaringas.

Toxicity

Effects(asexpected)aresignsofmuscarinicandnicotinicover-activation.Thiscanberememberedby'BLUDGES'forthemuscariniceffects:

Bradycardia(andsubsequenthypotension)LacrimationUrinationDefecationGITupsetEmesisSweatingandSalivation

and'M'forthenicotiniceffects:

Muscularspasm

Management

ManagementisaimedatreducingAChburden:

AtropineCompetitiveantagonisesAChatthemuscarinicreceptor.

AtropineispreferredoverglycopyrrolateasitwillcrossthebloodbrainbarrierandtreatcentralAChtoxicityPralidoximeReactivatesacetylcholinesterasebyluringtheorganophosphateawayfromtheenzymewithatantalisingoximegroup.

PralidoximemustbeusedwithinthefirstfewhoursofpoisoningAfterwhichtheorganophosphate-enzymegroup'ages'andisnolongersusceptible.Doesnotcrosstheblood-brainbarrierandsocannottreatcentraleffects

References

1. CICMMarch/May20092. RangHP,DaleMM,RitterJM,FlowerRJ.RangandDale'sPharmacology.6thEd.ChurchillLivingstone.

Lastupdated2019-07-18

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TheCellMembraneDescribethecellmembraneandcellularorganellesandtheirproperties.

Cellmembranesare:

FormedbyaphospholipidbilayerSeparatestheintracellularandextracellularfluid.Semi-permeableLeadstodifferentionicconcentrations(andthereforeelectricalcharge)oneithersideofthemembrane.

Alterationinchargemeansthemembraneactsasacapacitor,withmostcellshavingarestingpotential70-80mVlowerthanextracellularfluid

IonPermeabilityAtrest,thecellis:

PermeabletopotassiumPotassiumflowsoutdownitsconcentrationgradientThismakestherestingpotentialbecomesmorenegative.

Thisnegativechargeopposesthefurthermovementofpotassiumandsoanequilibriumisestablishedbetweenopposingelectricalandchemicalgradients

ImpermeabletoothercationsThemembraneisnotperfectlyimpermeabletosodium,andNa willleakindownitsconcentrationgradient.

The3Na -2K ATPasepumpsthreesodiumionsoutsideinexchangefortwopotassiumionsinordertomaintainthesegradientsAsthereisanunequalexchangeofcharge,thispumpiselectrogenic.

Ion [Intracellular] [Extracellular]

Na 15 140

K 150 4.5

Cl 10 100

References

1. BarrettKE,BarmanSM,BoitanoS,BrooksHL.Ganong'sReviewofMedicalPhysiology.24thEd.McGrawHill.2012.2. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.

Lastupdated2018-06-25

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OrganellesDescribethecellmembraneandcellularorganellesandtheirproperties

Organellesarespecialisedfunctionalsubunitswithinacell,typicallycontainedwithintheirownlipidbilayer.

Keyorganellesinclude:

MitochondriaEndoplasmicreticulumGolgiapparatus

Mitochondria

Mitochondria:

ProduceATPviaaerobicmetabolismOnlymethodofaerobicmetabolisminthebody.

MitochondriaexistingreaternumbersinmoremetabolicallyactivecellsConsistoftwomembranes(outerandinner),whichcreatethreespaces,

CytoplasmOutsidetheoutermembrane.IntermembranespaceBetweenthemembranes.

Outermembraneseparatesmitochondriafromcytoplasm,butcontainsporesallowingsomesubstances(pyruvate,aminoacids,fattyacids)topassInnermembrane:

Isolatestheelectrontransportchainfromtheintermembrane(spacebetweeninnerandoutermembranes)space.ProteinsontheinnermembraneconducttheredoxreactionsimportantforATPproductionElectrontransportchainpumpshydrogenionsintotheintermembranespace

InnermitochondrialmatrixContentsimportantinmanymetabolicprocesses:

CitricacidcycleFattyacidmetabolismUreacycleHaemesynthesis

References

1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.

Lastupdated2019-07-18

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ExcitableCellsExplainthebasicelectro-physiologyofneuraltissue,includingconductionofnerveimpulsesandsynapticfunction.

MembranePotential

Atrest,membranesare:

PermeabletopotassiumImpermeabletoothercations

Generationofmembranepotential:

IntracellularpotassiumconcentrationismuchhigherthanextracellularpotassiumconcentrationDuetotheactionoftheNa -K pump.Asthemembraneispermeabletopotassium,potassiumwillattempttodiffusedownthisgradient,generatinganegativeintracellularchargewhichopposesfurtherdiffusionAtsomepoint,anelectrochemicalequilibriumisreachedbetween:

TheconcentrationgradientdraggingpotassiumoutofthecellNegativeelectricalchargepullingitin

ThisequilibriumistherestingmembranepotentialRMPisdeterminedby:

PermeabilityofthemembranetodifferentionsRelativeionicconcentrationsoneithersideofthemembrane

ImpermeableionsdonotcontributetotherestingmembranepotentialAlteringmembranepermeabilitycausesaflowofionsandachangeinvoltage.

NernstEquation

ThepotentialdifferencegeneratedbyapermeableioninelectrochemicalequilibriumwhentherearedifferentconcentrationsoneithersideofthecellcanbecalculatedviatheNernstEquation:

,where:

istheequilibriumpotentialfortheion

isthegasconstant(8.314J.deg .mol )

isthetemperatureinKelvin

isFaraday'sConstantistheionicvalency(e.g.+2forMg ,-1forCl )

Goldman-Hodgkin-KatzEquation

TheNernstequationdescribestheequilibriumpotentialforasingleion,andassumesthatthemembraneiscompletelypermeabletothation.

However,calculationofmembranepotentialrequiresexaminingtheeffectsofmanydifferentionswithdifferentpermeability.ThiscanbeperformedwiththeGoldman-Hodgkin-Katzequation:

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,where:

isthepermeabilityconstantfortheion,

Ifthemembraneisimpermeableto ,then .

Notethat:

ThismodeldoesnotconsidervalencyTheconcentrationsofnegativeionsarereversedrelativetopositiveions

ActionPotential

Excitablecellscanrespondtoastimulusbyachangingtheirmembranepotential.Thismaybemediated:

Chemicallye.g.AChreceptorscausingNa channelstoopen.PhysicallyPressurereceptorsphysicallydeformingandopeningNa channels.

StimulatinganexcitablecellincreasesNa permeabilityThisincreases(i.e.makeslessnegative)membranepotentialIfseveralstimuli,oralargeenoughstimuliraisesthemembranepotentialabovethethresholdpotential,thenanactionpotentialwillbegeneratedThisisduetofastNa channels

Alsoknownasvoltage-gatedNa channelsOpenwhenmembranepotentialexceedsthresholdpotentialThresholdpotentialistypically-55mV.Fastsodiumchannelsgeneratetheall-or-nothingresponse:

StimulibelowthethresholdpotentialdonotgenerateanactionpotentialStimuliabovethresholdpotentialgenerateanactionpotentialThesizeofthestimulusdoesnotaffectthemagnitudeoftheactionpotential,asthisisdeterminedbythefastsodiumchannels.

KeyPlayersintheActionPotential

FastNa channelsareresponsiblefordepolarisation.Theyexistinthreestates:

ClosedImpermeabletoNa .OpenPermeabletoNa .Occurswhenthemembranepotentialreachesthresholdpotential.

Differentvoltage-gatedchannelsmayhaveslightlydifferentopening(threshold)potentialsInactivatedImpermeabletoNa .Occursshortlyaftertheopenstate,andlastsuntilthemembranepotentialfallsbelow-50mV.

Voltage-gatedK channels:

ArevitalforrepolarisationOpenslowlywithdepolarisationThisincreasespotassiumpermeabilityandreducesmembranepotential.

PhasesoftheActionPotential

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Thisdescribestheperipheralnerveactionpotential.Theheartiscoveredunderthecardiacactionpotential.

1. RisingPhaseAstimuluswhichrisesabovethethresholdpotentialopensfastNa channels,increasingNa influx.

AdditionalNa hasapositivefeedbackeffect,causingadditionalNa channelstoopenandfurtherdepolarisationThisdrivesthemembranepotentialtowardstheNernstequilibriumforNa

2. PeakPhaseInactivationoffast-channelsanddelayedactivationofK channelsslowsdepolarisation.

Membranepotentialpeaksat30mV3. FallingPhase

Aspotassiumexitsthecell,membranepotentialcontinuestofall.Voltage-gatedK channelsstarttocloseat-50mVInactivationoffastsodiumchannelsdefinestheabsoluterefractoryperiodNoNa canbeconducted,regardlessoftheintensityofthestimulus,andsoanactionpotentialcannotbegenerated

Theabsoluterefractoryperiodlasts~1ms4. Hyperpolarisation

Aspotassiumchannelscloseslowly,themembranepotentialslightlyundershootsrestingpotential,causingslighthyperpolarisationofthecell.

ThisistherelativerefractoryperiodAlargeenoughstimulusmayovercometheadditionalhyperpolarisationandgenerateasecondactionpotential.

Therelativerefractoryperiodlasts10-15ms5. Resting

Cellisstableatrestingmembranepotential.

PropagationoftheActionPotential

AnincreaseinNa inoneregionwilldiffusedownthecell,raisingthemembranepotentialabovetherestingpotentialintheadjacentmembraneThiscauseslocalfastNa channelstoopen,andthecelldepolarisesThisresultsinapropagatingwaveofdepolarisationandrepolarisation

RegionsofanervecellcoveredbyamyelinsheathdonothaveionchannelsInthesecells,propagationissaltatoryThisdescribesthe"jumping"oftheactionpotentialbetweengapsinthemyelinsheath.

ThesegapsareknownasnodesofRanvierIonchannelsgenerateanactionpotentialatthenodesintheusualmanner.Betweennodes,conductionisvialocalelectricalcurrents

Myelination:IncreasesconductingvelocityReducesenergyexpenditureViareductionintotalionflux.

ClassificationofNerveFibres

Classifiedontheirdiameterandconductionvelocity:

TypeAMyelinated,12-20μmindiameter,conductat70-120m.s .Subdividedinto:

AαMotorfibres.AβTouchfibres.

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AγIntrafusal(proprioceptive)musclefibre.AδPainfibres.

TypeBMyelinated,<3μm,conductat4-30m.s .Innervatepre-ganglionicneurons.TypeCUnmyelinated,1μm,conductat0.5-2m.s .Painfibres.

References1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.

Lastupdated2019-07-18

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TransportAcrossCellMembranesExplainmechanismsoftransportofsubstancesacrosscellmembranes,includinganunderstandingoftheGibbs-Donnaneffect.

Substancescancrosscellmembranesbydiffusion,activetransport,andexo-orendocytosis.

Diffusion

Thereareseveraltypesofdiffusion:

SimplediffusionMoleculespassthroughthecellmembraneorviaachannel.Thisprocessispassive,andoccursdownaconcentrationgradient.

Onlylipidsolublemolecules(gases,steroids)canpassdirectlythroughthelipidbilayerwithoutaspecialisedchannelVoltage-gatedandligand-gatedchannelsfacilitatesimplediffusion

Facilitateddiffusion(uniporters)Moleculesbindtoacarrierprotein,andmovetogetherthroughthelipidbilayer,beforeseparatingontheotherside.Facilitateddiffusionisconcentrationgradient-dependent,andlimitedbytheamountofcarrierproteinavailable..

Therateandextentofdiffusionisaffectedby:

HydrostaticpressuregradientsConcentrationgradientsElectricalgradients

ActiveTransport

Substancesthataremovedagainstaconcentrationgradientrequireactivetransport,andrequiresenergyintheformofATP.Activetransportmechanismsmaybe:

PrimaryactivetransportThesubstanceitselfismoved.SecondaryactivetransportThesubstancemovesagainstaconcentrationgradientwithanothermoleculethathadagradientestablishedbyactivetransport.

Thismoleculeistypicallysodium

Co-transporters(symporters)Usescarrierproteinsandmovestwosubstances(e.g.sodiumandanaminoacid)acrossamembrane.

Thisprocesswillbepassiveiftheenergygainedmovingonesubstancedownitsconcentrationgradientisgreaterthantheenergyrequiredtomovetheothersubstanceupitsconcentrationgradient

Counter-transporters(antiporters)Usecarrierproteinsandmovestwosubstancesinoppositedirectionsacrossthemembrane.

Maybeactiveorpassive

Keytransportersinclude:

TheNa -K ATP-asepumpThismovesthreesodiumionsoutofacellandtwopotassiumionsin,cleavingoneATPintheprocess.Thispumphasmanyfunctions:

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Maintenanceofcellularvolume(whichwouldotherwiseburstfromtheinfluxofwaterwithchangingECFtonicities)bynetlossofosmolesMaintenanceofthepotentialdifferenceacrossthemembraneEstablishmentofchemicalgradientstobeusedinsecondaryactivetransportmechanism

e.g.ReabsorptionofglucoseinthekidneyviatheS-GLUTtransporter

Exo-andEndocytosis

Theseprocessesdescribetheformationofavesicle(typicallyfrommembranephospholipid)totransportsubstances:

ExocytosisVesiclecontainingasubstancetobesecretedfuseswiththecellmembranewhenactivatedbycalcium,depositingthesubstanceoutsidethecell.

EndocytosisThecellmembraneinvaginatesaroundthesubstance,absorbingthesubstanceintothecell.Avesicle(orvacuole)mayormaynotbecreated.Endocytosismaybesubdividedinto:

Phagocytosis,whereleukocytesengulfbacteriaintoavacuolePinocytosis,wheresubstancesareendocytosedbutnotintoavacuole

Gibbs-DonnanEffectDescribesthetendencyofdiffusableionstodistributethemselvessuchthattheratiosoftheconcentrationsareequalwhentheyareinthepresenceofnon-diffusableions.

TheGibbs-DonnanEffect:

Occurswhen:Asemi-permeablemembraneseparatestwosolutionsAtleastoneofthosesolutionscontainsanon-diffusableion

Thedistributionofpermeablechargedionswillbeinfluencedbyboththeirvalenceandthedistributionofnon-diffusableions,suchthatatequilibriumtheproductsoftheconcentrationsofpairedionsoneachsideofthemembranewillbeequal:

Alterstonicityoneithersideofthecellmembrane,causingmovementofwaterwhichthenupsetstheGibbs-DonnaneffectThisresultsinno'steady'stablestate.

ThetwomaincontributorstotheGibbs-Donnaneffectinthebodyaresodiumandprotein.Thisoccursbecausecellmembranes:

AreimpermeabletoproteinIntracellularproteinconcentrationishigh.EffectivelyimpermeabletosodiumDuetotheNa -K ATP-asepump.

ChangingGibbs-Donnanequilibriumsalsochangethetonicityoneachsideofthecellmembrane,causingmovementofwaterwhichthenupsetstheGibbs-Donnaneffect-thereforethereisnostablestate.

TheGibbs-DonnanEffectisimportantfor:

MaintenanceofcellvolumeNa actsasaneffectiveosmole,reducingcellularswelling.PlasmaoncoticpressureIncreasedplasmaionconcentrationincreasesoncoticpressure.

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RestingMembranePotential

References1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. EatonDC,PoolerJP.Vander'sRenalPhysiology.6thEd(Revised).McGraw-HillEducation-Europe.2004.

Lastupdated2018-09-21

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FluidCompartmentsTodescribethecompositionandcontrolofintracellularfluid~andthemechanismsbywhichcellsmaintaintheirhomeostasisandintegrity~

Onaverage,thehumanbodyis~60%water.Distributionofwatercontentcanbedividedconceptuallyinto:

IntracellularfluidComposes2/3 oftotalbodywater.ICFis:

NotacontiguousfluidspaceUsefulasthecompositionofcellularcontentsisrelativelyuniform:

PotassiumisthedominantintracellularcationSodiumconcentrationsarelow.ThedominantanionisproteinChlorideconcentrationisrelativelylow.Lowinmagnesium

ExtracellularfluidComposestheremaining1/3 oftotalbodywater,andisfurtherdividedinto:

IntravascularfluidComposes~20%ofECF.Thisreferssolelytoplasmavolume(asthevolumeofbloodfromcellularcomponentsisICF).TheICFis:

Vitalfortransportingnutrients,waste,andchemicalmessengersbetweentheplasmaandcellsTranscellularfluidComposes~7%ofECF,anddescribesthevolumeofCSF,urine,synovialfluid,gastricsecretions,andaqueoushumor.InterstitialfluidComposesthebulkofECFvolume,anddescribesthefluidthatoccupiesthevolumebetweencells.

VariationsActualtotalbodywatercontentvariespredominantlywithfatcontent.Thisleadstodifferencesconcentrationsin:

Neonates~75-80%.Elderly~50%bytheageof60,duetoincreasedadiposity.WomenTypically~55%.

MeasuringVolumesofFluidCompartments

Allmethodsrelyontheindicator-dilutionmethod:

Aknownamount(i.e.knownvolumeofaknownconcentration)ofindicatorwithaffinitytoaparticularcompartmentisgivenandallowedtoequilibrateTheconcentrationoftheindicatoristhenmeasuredThedifferencebetweenthemeasuredconcentrationandtheinitialconcentrationisproportionaltothevolumeofthecompartment

Indicatorsusedforcalculationof:

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PlasmavolumeAcolloidthatwillberetainedinthevascularcompartment;e.g.radio-labeledalbumin.ECFvolumeAsubstancewhichcanentertheinterstitiumbutnotcells;e.g.thiosulfate.Totalbodywater

Asubstancewhichcanenterallcompartmentsfreely;e.g.heavywater( ).ICFvolumeCanbemeasuredbythedifferencebetweencalculatedECFvolumeandTVW.

References1. Brandis,K.FluidCompartments.AnaesthesiaMCQ.2. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.

Lastupdated2019-07-18

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CellHomeostasisTodescribethe~compositionandcontrolofintracellularfluidandthe~mechanismsbywhichcellsmaintaintheirhomeostasisandintegrity

CellularrespirationdescribestheproductionofATPthroughaseriesofredoxreactions.Oxygenisusedastheoxidisingagent,whilstthecatabolicfuelmaybeglucose,fat,orprotein.

Cellularrespirationcanbebrokendowninto:

Glycolysis/Lipolysis/ProteolysisCitricAcidCycleElectronTransportChain

Glycolysis

Glycolysis,ortheEmbden-Meyerhofpathway,describestheproductionofpyruvatefromglucose.Glycolysis:

OccursinthecytoplasmBeginswiththephosphorylationofglucosetoglucose-6-phosphateProduces:

2ATP2Pyruvate2NADH

NotethatoxygenisnotconsumedandcarbondioxideisnotproducedInaerobicconditions:NADHexchangeselectronsacrossthemitochondrialwall,regeneratingNAD andallowingglycolysistocontinueInanaerobicconditions:NAD isregeneratedthroughtheproductionoflactate

Whenaerobicconditionsarerestored,lactatecanbeoxidisedbacktopyruvateandentertheCACTransportedtotheliverandconvertedbacktopyruvate(andentertheCAC),orproduceglucose(Coricycle)

CitricAcidCycle/Kreb'sCycle

TakesplaceinthemitochondriaComplicatedCantakemanyvarioussubstrates:

AcetylCoAProducedbyβ-oxidationoffattyacidsandpyruvate.PyruvateKetoacids

Doesnotconsumeoxygenbutalsodoesn'tfunctionunderanaerobicconditions,duetoitsrequirementonfreshNADfromtheETCProduces:

NADHFADHCO

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ElectronTransportChain

Finalstageofcarbohydrate,fat,andproteincatabolismETCconsistsoffiveproteincomplexesElectronsarepassedalongthechainandcombinewithoxygen,releasingenergywhichstimulatesthemovementofhydrogenionsEachtimeahydrogenioncrossesthemitochondrialmatrix,anATPisproduced

ThisiscalledcoupledphosphorylationUncoupledphosphorylationallowshydrogenionstotraveldowntheirgradientwithoutgeneratingATP,whichproducesexcessheatinstead

36-38ATPareproducedbyaerobicglycolysisSourcesdisagreeonexactlyhowmuchATPisproduced.

2fromtheEmbden-Meyerhofpathway34-36fromtheCACandETC

References

1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.

Lastupdated2019-07-18

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AirwayandAlveolarAnatomyDescribethefunctionandstructureoftheupper,lowerairwayandalveolus.

UpperAirway

Theupperairwayconsistsofthe:

MouthNasalcavity

HairsfilterlargeparticlesOlfactoryreceptorsdetectharmfulgasespriortoinhalation

PharynxLarynx

Breathingcanbeoralornasal.Nasalbreathingoffers:

Goodhumidificationandfiltrationofinhaledparticlesbecausetheseptumandturbinateshave:HighmucosalsurfaceareaHighmucosalbloodflowGenerateturbulentflow

HighresistancetoflowAtahighminuteventilation,oralbreathingisfavoured.

Structures

PharyngealdilatormusclesIncludinggenioglossusandlevatorpalati.Preventpharyngealcollapseduringnegative-pressureventilationandduringsleep.

LarynxImportantforairwayprotection,speech,andeffortclosure.

PreventsaspirationduringswallowingbyelevatingtheepiglottisandoccludingofthearyepiglotticfoldsPhonationisachievedbyadjustingtension(andthereforeresonance)ofthevocalcordsbyactionofthecricothyroidDuringinspiration,cricoarytenoidmusclesrotatethearytenoidcartilageandabductthevocalcordstoreduceresistancetoairflowDuringexpiration,thethyroarytenoidmusclesadductthecordsandincreaseresistance,providingintrinsicPEEP

3-4cmH OofPEEPisgeneratedMaintainspatencyofsmallairwaysPreventsalveolarcollapseandthereforemaintainsFRC.

Effortclosureistighterocclusionofthelaryngealinlet,inwhichthearyepiglotticmusclescontractstronglytoactasasphincter,allowingtheairwaytowithstandupto120cmH Oofpressure.

LowerAirwayThelowerairwayconsistsofthetracheobronchialtree:

Fromtracheatoalveolus,theairwaysofthelungsdivide23timesThetracheobronchialtreeisdividedintotwozones,basedonwhethertheycontainalveoliandthereforeareabletoparticipateingasexchange:

Theconductingzoneisthefirst16divisions

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Therespiratoryzoneisthelast7divisions

ConductingZone

Thefirst16divisionsconstitutetheconductingzone:

Anatomically,theconductingzoneconsistsof:Trachea

Meandiameterof1.8cmandalengthof11cmD-shapedcrosssectionCurvedcartilagesanteriorlyandlongitudinalmuscle(trachealis)posteriorly.Externalpressureof40cmH Oissufficienttooccludetheextrathoracictrachea.Flowistypicallyturbulentinthetracheaandlargeairways

BronchiComprisethefirstfourdivisionsofthetracheaRightmainbronchusiswideranddeviateslessfromtheaxisofthetrachea(theleftmainbronchushasatighterturnovertheheart),whichiswhyforeignbodieswilltendtotherightsideThetwomainbronchidivideintoatotalof5lobarbronchi,whichinturndivideintoatotalof18segmentalbronchi

Cross-sectionalareaoftherespiratorytractislowestatthethirddivisionThesebronchiwillcollapsewhenintrathoracicpressureexceedsintraluminalpressureby~5cmH O.SegmentalbronchitravelwithbranchesofthepulmonaryarteryandlymphaticsThesearethebronchithatdemonstrateperibronchialcuffingandperihilarhazeinearlypulmonaryoedema.Flowistypicallytransitionalinthesmallerbronchiandbronchioles

BronchiolesEmbeddedinthelungparenchymaDonothavecartilageintheirwallstomaintainpatency-areheldopenbylungvolumeResistancetoflowtendstobenegligibleduetolargecrosssectionalarea,unlessthereisspasmofhelicalmusclebandsinbronchialwall

TerminalbronchiolesFlowmaybecomelaminarinthesmallestbronchiolesasflowdecreases

FlowintheconductingzoneduringinspirationisfastandturbulentNogasexchangeoccursintheconductingzoneThevolumeoftheconductingzonethereforecontributestoanatomicdeadspace.Bloodsupplytotheconductingzoneisviathebronchialcirculation

MucousissecretedbygobletcellsinthebronchialwallstotrapinhaledparticlesCiliainthebronchialwallsmoverhythmicallytodrivethemucociliaryelevator,drivingmucousuptotheepiglottis,whereitisthenswallowedorexpectorated

RespiratoryZone

Theremaining7divisionsmakeuptherespiratoryzone.Thisregion:

MakesupthemajorityoflungvolumeAllnon-anatomicaldeadspacevolumeisintherespiratoryzone,andis~30ml.kg (FRC)atrestBloodsupplyisviathepulmonarycirculation

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Gasflowintheterminalrespiratoryzoneisslowduetotheexponentialincreaseincross-sectionalareawitheachairwaydivision

Diffusionisthepredominantmechanismofgasmovement

Alveolus

Thealveolusisoptimisedforgasexchange:

SphericalshapemaximisessurfaceareatovolumeratioTotalsurfaceareaoflungalveoliis50-100mAlveolarwallsareextremelythin(0.2-0.3μm)Consequently,theyarefragileandcanbedamagedbyincreasesincapillarypressureAlveolarwallscontainadensemeshofcapillaries7to10μmthick,whichisjustlargeenoughforanerythrocytetopassthroughThealveolar-capillarybarrierconsistsofthreelayers:

TypeIpneumocytesExtracellularmatrixPulmonarycapillaryendothelium

Alveoliarecomposedofthreetypesofcells:

TypeIpneumocytesThin-walledepithelialcellsoptimisedforgasexchange.

Form~90%ofthealveolarsurfacearea

TypeIIpneumocytesSpecialisedsecretorycells.

SecretesurfactantAlveoliareinherentlyunstable,andsurfacetensionofalveolarfluidfavourscollapseofthealveoli.Surfactantreducessurfacetension,allowingthealveolitoexpand.Form~10%ofalveolarsurfacearea

AlveolarmacrophagesAlveolihavenocilia-inhaledparticlesarephagocytosedbyalveolarmacrophagesinalveolarseptaandlunginterstitium.

References1. LumbA.Nunn'sAppliedRespiratoryPhysiology.7thEdition.Elsevier.2010.2. WestJ.RespiratoryPhysiology:TheEssentials.9thEdition.LippincottWilliamsandWilkins.2011.3. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.

Lastupdated2019-07-18

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ChestWallandDiaphragmDescribethestructureofthechestwallanddiaphragmandtorelatethesetorespiratorymechanics.

Thechestwallisformedbytheribsandintercostalmuscles:

RibsSlopeantero-inferiorly,andareconnectedbytheexternal,internal,andinnermostintercostalmuscles.Intercostalmuscles

Externalintercostalsslopeantero-inferiorlyInternalandinnermostintercostalsslopeinfero-posteriorly

DiaphragmComplexdome-shapedmembranousstructure,consistingofacentraltendonandperipheralmuscles

PerformsthemajorityofinspiratoryworkofbreathingAbletodramaticallyincreaseintraabdominalpressure,soisessentialin:

CoughingVomitingSneezing

RoleinmaintainingloweroesophagealsphinctertoneIthasthreeperforations:

T8forthevenacava(eightletters)T10fortheoesophagus(tenletters)T12fortheaorta,thoracicduct,andazygosvein

Inspiration

Duringinspiration,thediaphragmandexternalintercostalmusclescontractDiaphragmpushestheintraabdominalcontentsdown,increasingthoracicvolumeandgeneratinganegativeintrathoracicpressure

DiaphragmissuppliedbythephrenicnervesfromC3/4/5.Externalintercostalspulltheribsantero-superiorly,whichincreasesthecross-sectionalareaofthechest,furtherincreasingthoracicvolume(andnegativepressure)

IntercostalmusclesaresuppliedbyintercostalnervesfromthesamespinallevelParalysisoftheexternalintercostalsdoesnothaveadramaticeffectoninspiratoryfunctionprovidedthediaphragmisintact

Accessorymusclesincludesternocleidomastoidandthescalene,whichelevatethesternumandfirsttworibsrespectively.Theyareactiveinhyperventilation.

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Expiration

ExpirationispassiveduringquietbreathingaselasticrecoilofthelungwillreturnthemtoFRCWhenminuteventilationishigh,expirationbecomesananactiveprocess:

Abdominalwallmuscles(rectusabdominis,internaloblique,externaloblique,transversusabdominis)contract,raisingintraabdominalpressureandforcingthediaphragmupInternalandinnermostintercostalscontract,pullingtheribsdownwardsandinwards,furtherdecreasingthoracicvolume

RespiratoryMechanicsinSpinalInjury

Paralysisoftheabdominalwallmuscles(e.g.spinalinjury)hassignificantaffectonrespiratorymechanics:Intheinitialphasesofinjury,spinalshockresultsinaflaccidparalysisoftheabdominalwall

Intraabdominalpressureislow,andsothediaphragmmovesinferiorlyThisresultsinahigherFRCbutlimitstidalvolumes,ascontractionofthediaphragmonlyincreasethoracicvolumebyasmallfraction.Nursinginasupinepositioncausestheabdominalcontentstopushthediaphragmsuperiorly,causing:

LowerFRCGreaterproportionalexpansionwithrespiration,improvingtidalvolumes

Oncespasticparalysisensues,theabdominalwallisrigidandthepatientcanbesatup

References

1. WestJ.RespiratoryPhysiology:TheEssentials.9thEdition.LippincottWilliamsandWilkins.2011.

Lastupdated2019-07-18

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VariationsinUpperAirwayAnatomyUnderstandthedifferencesencounteredintheupperairwayforneonates,childrenandadults.

NeonatesandChildren

Changesaremostobviousbelow1yearofage.Theytypicallyresolveby~8yearsofage.

HeadandneckchangesObligatenosebreathersNasalobstructionmaysignificantlyimpairrespiration.ProportionallyenlargedheadandocciputOptimalintubatingpositionisneutralratherthanramped.ProportionallyshortneckFavoursairwayobstructionwhenflexed.

LaryngealchangesDisproportionatelylargetonguethatcomplicateslaryngoscopyEpiglottisisu-shaped,longer,andstifferLarynxliesatC4(ratherthanC6inadults)NarrowestpartoftheupperairwayisthetransversediameterofthevocalcordsNotatthecricoid.

IntrathoracicchangesIntrathoracictracheaisalsoshorterMaybeonly4cmlong,sothereislittlemarginforerrorintubeplacement.Leftandrightbronchiariseatsimilarangles,soendobronchialintubationmayoccuroneithersideAirwaysthemselvesarenarrower,andhaveahigherresistancetoflow.

References

1. Nickson,C.PaediatricAirway.LITFL.2. Anderson,C.AnatomyoftheRespiratorysystem..ICUPrimaryPrep.3. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.4. TobiasJD.Pediatricairwayanatomymaynotbewhatwethought:implicationsforclinicalpracticeandtheuseofcuffed

endotrachealtubes.PaediatrAnaesth.2015Jan;25(1):9-19.

Lastupdated2019-11-02

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ControlofBreathingDescribethecontrolofbreathing

Ventilationiscontrolledbyafeedbackloopinvolving:

InputsIntegrationandcontrolcentresEffectors

InputsInputstotherespiratorycentrecomesfromanumberofsensors:

ChemoreceptorsChemoreceptorsactsynergistically.Chemoreceptorsaredividedinto:

PeripheralCentral

MechanoreceptorsOthereffects

PeripheralChemoreceptors

Peripheralchemoreceptorsaredividedinto:

ThecarotidbodyLocatedatthebifurcationofthecommoncarotidartery,andareinnervatedbytheglossopharyngealnerve(CNIX).TheaorticbodyLocatedintheaorticarch,andinnervatedbythevagus(CNX).

Peripheralchemoreceptorsarestimulatedby:

LowPaOPeripheralchemoreceptorsarestimulatedbylowO tension

HighPaCOPeripheralreceptorshavearapid(~1-3s)butweaker(~20%ofresponse)tochangesinCO ,comparedtocentralchemoreceptors

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Acidaemia(Carotidbodiesonly)Hypotension

CentralChemoreceptors

Centralchemoreceptorsarelocatedontheventralmedulla,andarestimulatedbyafallinCSFpHH andHCO areionised,andcannotcrosstheBBBbydiffusionBecauseofthis,centralchemoreceptorsrespondindirectlytochangesinarterialPaCO

CarbondioxideislipidsolubleandfreelydiffusesintoCSFInCSF,carbondioxidecombineswithwater(catalysedbycarbonicanhydrase)toformH andHCO

Thisgivesthecentralchemoreceptorsanumberofspecialproperties:IncreasedsensitivityIncreasedrelativetoplasmaduetominimalbuffering(asthereislessproteininCSF)RespondtorespiratoryacidosisFixedaciddoesnotcrossthebloodbrainbarrierandsohaveaminimalresponseonCSFpH.CerebralhypoxiaincreasesCSFlactate,whichwillstimulaterespiration.

MechanismofCO Retention

Prolongedrespiratoryacidosis(i.e.prolongedCSFacidosis)stimulatesactivesecretionofbicarbonateintotheCSFWhenpHnormalises,thestimulationofcentralchemoreceptorsceases

Similarly,renalabsorptionofbicarbonateincreases,whichnormalisesarterialpHandreducesperipheralchemoreceptorstimulation

Mechanoreceptors

Stretchreceptorsinbronchialmusclearestimulatedbyoverinflation,andstimulatetheapneusticcentretoreduceinspiratoryvolumes.ThisistheHering-Breuerreflex.

OtherStimulants

Otherinputswhichstimulaterespirationinclude:

Juxtacapillaryreceptors(J-receptors)Receptorsinalveolarwalls,potentiallystimulatedbyoedemaandemboli.IrritantreceptorsInhalationofnoxiousgasesstimulatesrespiration.PainreceptorsThalamus

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Increasedcoretemperaturestimulatesrespiration.LimbicsystemEmotionalresponses.CerebralcortexConsciouscontrolofbreathing.MusclespindlesVentilatoryresponsetoexercise.

IntegrationandControl

Therespiratorycentreislocatedinthemedullaandthepons.Itconsistsoffourgroups:

DorsalRespiratoryGroup(DRG)Controlsthediaphragm,andissoonlyinvolvedwithinspiration.VentralRespiratoryGroup(VRG)Controlstheintercostalmuscles,andsoisinvolvedininspirationandexpiration.ApneusticCentreModulatesDRGfunctiontopreventover-expansion.Lossofthisareacausesapneusis-long,deepbreaths.PneumotaxicCentreAlsomodulatestheDRG,increasingRRanddecreasingV tomaintainMV.

References

1. CICMFebruary/April20152. CICMMarch/May20093. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.4. BrandisK.ThePhysiologyViva:Questions&Answers.2003.

Lastupdated2019-07-18

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RespirationDescribetheinspiratoryandexpiratoryprocessinvolvingthechestwall,diaphragm,pleuraandlungparenchyma

Explainthesignificanceoftheverticalgradientofpleuralpressureandtheeffectofpositioning

Changeinlungvolumeoccursduetochangeinintrapleuralpressures.Therefore,respirationreliesonthethoraciccavitybeingairtight,withthetracheabeingtheonlymethodgascanenterorexitthechest.

Intrapleuralpressure(P )Intrapleuralpressureisthepressureinthespacebetweenthevisceralandparietalpleura,or(physiologically)betweenthelungsandthechestwall.

Usuallynegative,typically-5cmH OatrestBalancebetweenthe:

OutwardsrecoilofthechestwallInwardsrecoilofthelungs(P )

VarieswithverticaldistanceinthelungGravitypullsthelungparenchymainferiorlyIntrapleuralpressureistherefore:

MorenegativeintheapexTypically-10cmH OatFRCLessnegativeinthebaseTypically-3cmH OatFRC

ThischangesthedegreeofinflationatFRCApicalalveoliaremaximallyinflatedBasalalveoliarerelativelydeflated

Duringinspiration,thepleuralpressurechangesevenlythroughoutthelung,howeverthebasalalveoliarebetterventilatedbecausetheircomplianceisincreased(duetolowerrestingvolume)

Inspiration

Diaphragmaticandexternalintercostal/accessorymusclecontractioncausesanincreaseinthevolumeofthethoraxIntrapleuralpressurebecomesmorenegative,typicallyto-8cmH OWhenP >P ,thelungsexpandsAlveolarpressure(P )becomessub-atmospheric,andinspirationoccursAtendinspiration:

P =PP =P

Expiration

MuscularrelaxationcausesthechestwalltopassivelyreturntotheirrestingpositionThoracicvolumefallsP fallsto-5cmH OTheelasticrecoilofthelungcausesittocollapseuntilP =P

Pl

2

el

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2

2pl el

A

pl elA atmospheric

pl 2A atmospheric

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References1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.

Lastupdated2019-07-18

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ComplianceDefinecompliance(static,dynamicandspecific),itsmeasurement,andrelatethistotheelasticpropertiesoftherespiratorysystem.

ComplianceisthechangeinvolumeforagivenachangeinpressureComplianceismeasuredinml.cmH O .ItoccursduetothetendencyofatissuetoresumeitsoriginalpositionafterremovalofanappliedforceItistheinverseofelastance,whichistheforceatwhichthelungrecoilsforagivendistensionAdecreasedcompliancemeansthetranspulmonarypressuremustchangebyagreateramountforagivenvolume,whichincreaseselasticworkofbreathing

ComplianceoftheRespiratorySystem

Complianceoftherespiratorysystemisafunctionofbothlungandchestwallcompliance:

.

ThecurveisnotlinearascompliancevarieswithlungvolumeInthenormalrangehowever,(-5to-10cmH O)complianceofthelungandchestwallindependentlyistypicallystatedas~200ml.cmH O .

Complianceoftherespiratorysystemasawholeistherefore~100ml.cmH O

MeasurementofLungandChestWallCompliance

Lungcomplianceiscalculatedformthealveolar-intrapleuralpressuregradientChest-wallcomplianceiscalculatedfromtheintrapleural-ambientpressuregradientTotalcomplianceiscalculatedfromthealveolar-ambientgradient

Measuringambientandalveolarpressureisstraightforward,asiscalculatingcomplianceoftherespiratorysystemAlveolarpressureismeasuredbytakingaplateaupressure

SeparatinglungandchestwallcompliancerequiresmeasurementofintrapleuralpressureThisisperformedbymeasuringoesophagealpressure(usingaballoon)withanopenglottis,asoesophagealpressureapproximatesintrapleuralpressure.

Measurementofcomplianceofeachsystemindividuallydetermineswhatproportionofplateaupressureisdistributedtoeach

Ifthelungissignificantlylesscompliantthanthechestwall,agreaterpressureisrequiredtodistendthelungTherefore,thealveolar-intrapleuralgradientwillbemuchgreaterthantheintrapleural-ambientgradientThiscanbeexpressedbytheequation:

StaticCompliance

StaticcomplianceisthecomplianceofthesystematagivenvolumewhenthereisnoflowThereforethereisnopressurecomponentduetoresistanceAstaticcompliancecurveismadebymeasuringthepressureacrossarangeoflungvolumes,withpatienttakingincrementalbreathsStaticcomplianceisafunctionof:

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ElasticrecoilofthelungSurfacetensionofalveoli

DynamicCompliance

Dynamiccomplianceisthecompliancemeasuredduringrespiration,usingcontinuouspressureandvolumemeasurementsTherefore,dynamiccomplianceincludesthepressurerequiredtogenerateflowbyovercomingresistanceforces

ThismeansitisalsoabitofmisnomerDynamiccomplianceisalwayslessthanstaticcompliance,astherewillalwaysbeadegreeofairwayresistanceDynamiccomplianceisafunctionofrespiratoryrateInnormallungsatnormalrespiratoryratesitapproximatesstaticcompliance.Reducedininlungunitswithunequaltimeconstantsathighrespiratoryrates

Duetoincompletefillingofalveoli-theportionofpressurethatisusedtoovercomeairwaysresistanceisthereforeproportionallygreater

SpecificComplianceSpecificcomplianceisthecomplianceperunitvolumeoflung,expressedas:

Specificcomplianceisusedtocomparedifferentlungs

Hysteresis

Ingeneral,hysteresisreferstoanyprocesswherethefuturestateofasystemisdependentonitscurrentandpreviousstateSpecifictothelung,itmeansthecomplianceofthelungisdifferentininspirationandexpiration

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Thereishysteresisinbothstaticanddynamiccurves:Indynamiccompliancecurves:Airwaysresistanceisafunctionofflowrate.Flowrate(thereforeresistance)ismaximalatthebeginningofinspirationandend-expiration.Instaticcompliancecurves:Thereisnoresistivecomponent.Hysteresisisduetoviscousresistanceofsurfactantandthelung.

ChangesinCompliance

Respiratorysystemcompliancecanbeaffectedbychangestoeitherlungorchestwallcompliance,andcanbeincreasedordecreased.

IncreasedLungCompliance

NormalageingAsthmaattackEmphysema

DecreasedLungCompliance

AlterationsinlungvolumeandconsolidationComplianceisreducedatextremesoflungvolume.ItishighestatFRC.

ChildrenPneumonectomy/lobectomyAtelectasis/collapsePneumoniaARDS

Increasedpulmonarybloodvolume/venouscongestionAPO

IncreasedsurfacetensionReducedsurfactant

HyalineMembraneDiseaseImpairedparenchymalcompliance

Pulmonaryfibrosis

IncreasedChestWallCompliance

Collagendisorders

DecreasedChestWallCompliance

Chestwallrestriction/structuralabnormalitiesObesitySpasticparalysisofchestwallmusculatureOssificationofcostalcartilagesKyphosis/scoliosisScarring/constriction(e.g.circumferentialburns)

PositionProne(60%reducedcompliance)/supineThisisduetotheeffectofpositiononlungvolume.

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References1. BarrettKE,BarmanSM,BoitanoS,BrooksHL.Ganong'sReviewofMedicalPhysiology.24thEd.McGrawHill.2012.2. KennyJE.Heart-LungInteractionLectureSeries.Fromheart-lung.org.

Lastupdated2019-07-20

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Time-ConstantsExplaintheconceptsoftimeconstants

ARefresheronTimeConstants

Thetime-constantis:

ThetimethataprocesswouldtaketocompleteifitsinitialrateofchangeremainedconstantRelevantwhenmodelingaprocessusingexponentialfunctions

Rememberanexponentialfunctionisacurvewheretherateofchangeisproportionaltothecurrentvalue

Foraquantitythatdecreases overtime,thegeneralcaseis:

,where:

isthevalueof at

istherateconstant( plotsacurvethatgrows)

istime

Importantly:

isthereciprocalofthetimeconstant,

Inanegativeexponential,time-constantisthetimeitwouldtakefor toreach0iftheoriginalrateofchangewasmaintained.Otherfunfactsaboutthetimeconstant(foranexponentialdecay)include:

After1 , willbe37%( )ofitsinitialvalue

After2 , willbe13.5%( )ofitsinitialvalue

After3 , willbe5%( )ofitsinitialvalue

After5 , willbe1%( )ofitsinitialvalue

PhysiologicalSignificance

Thetime-constantisusedinrespiratoryphysiologyin:

TiminginspirationandexpirationEliminationofinhalationalanaestheticsThechangeinPaO andPaCO afterchangesinventilation

Inventilation:

Thetimeconstantisaffectedby:ComplianceResistanceInflationpressureAtaconstantinflationpressure,thetimeconstantisequaltotheproductofresistanceandcompliance,i.e.

1

2 2

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151

.

FortwolungunitsofequalcomplianceandresistanceInflationwilloccuraspertheexponentialgrowthfunctionTime-constantsofeachlungunitwillbeequalNoredistributionofgaswilloccuratend-inspirationasthepressureandvolumeofeachunitisthesame

Fortwolungunits,whereonehashalfthecompliancebuttwicetheresistanceThetimeconstantsareequal,thereforebothreachpeakfillingatthesametime

However,thepoorlycompliantunitwillonlyreachhalfthevolumeNoredistributionofgaswilloccuratend-inspirationasthepressureandvolumeofeachunitisthesame

Fortwolungunits,whereonehastwicetheresistanceoftheotherThetime-constantsareunequalTheresistantunitwillfillathalftherateoftheother

IfinspirationisprolongedbothwillreachthesamevolumeIfinspirationhishaltedearly,andexpirationprevented,therewillbeapressuregradientbetweentheunits(ascomplianceisthesame),andgaswillredistributefromthelow-resistantunittothehigh-resistantunit

FortwolungunitswhereonehashalfthecomplianceThetimeconstantsareunequalThepoorlycompliantunitwillfillathalftherateoftheother

IfinspirationisprolongedtheywillbothreachthesamepressureThevolumeinthepoorlycompliantunitwillbehalfthatofthemorecompliantunit.

Duringinspiration,thepressurerisesmorerapidlyinthepoorlycompliantunit,andifinspirationisstoppedandexpirationprevented,thiswillresultinredistributionintothemorecompliantunituntilpressuresareequal

Ingeneral:

RateoffillingisdeterminedbytimeconstantsHigh-resistancelungunitshavelongertimeconstantsandtakelongertofill

Finalvolume(assuminganindefiniteinspiration)isafunctionofcompliancePoorlycompliantunitswithemptyandfillrapidlyThiscreatestheconceptoffastandslowalveoli,dependingontheirtimeconstants.

Atasustainedinflationpressure:Alow-resistanceunitshowsinitialgreatervolumechangebutrapidlyapproachesequilibriumvolumeAhigh-complianceunittakesagreateroverallvolumeoveralongerperiod

Atend-inspiration:Pressureinunitswithashortertime-constantrisesmorerapidlyandifabreathisheldwillresultinredistributiontothoseunitswithalongertime-constant.

ClinicalSignificance

Iftime-constantsareequal:

ThepressureineachunitisidenticalthroughoutinspirationanddistributionTherefore,dynamiccompliancewillbeindependentofrespiratoryrate.

Iftime-constantsareunequal:

Long-timeconstantunitsmaystillbeinhalingwhilsttherestofthelunghasstopped,orbegunexhalationThisiscalledpendelluft.Inpendelluft,distributionofinspiredgasisdependentonrespiratoryrate

Asrespiratoryrateincreases,theproportionofthetidalvolumethatisdeliveredtotheregionwithalongtime-constantdecreasesFastalveoliarepreferentiallyinflated,causingV/Qscatterorshuntintheunventilatedslowalveoli.

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Dynamiccompliancewilldecreaseasrespiratoryraterisesandbemarkedlydifferentfromstaticcompliance

Footnotes

.Foracurvethatgrowsovertime,thetimeconstantisthetimeitwouldtakefor toreach63%ofitsfinalvalue,i.e.

.↩

References1. LumbA.Nunn'sAppliedRespiratoryPhysiology.7thEdition.Elsevier.2010.

Lastupdated2019-07-18

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ResistanceExplaintherelationshipbetweenresistanceandrespiratorygasflow

Describethefactorsaffectingairwayresistance,anditsmeasurement

Resistance(measuredincmH O.L .sec )comprisestheenergylostasfrictionalandinertialimpedancetogasflow,whereenergyislostasheat.Flowisafunctionofpressuregradient,resistance,andtypeofflow.

TypesofFlowFlowcanbeeitherlaminarorturbulent.Inlaminarconditionsflowisproportionaltodrivingpressure,whilstinturbulentconditionsflowisproportionaltothesquarerootofdrivingpressure.

Reynolds'Number

TypeofflowcanbepredictedbyReynolds'sNumber,adimensionlessindexwhere:

,where:

=Radius

=Gasdensity=Velocity

=Gasviscosity

AReynolds'Numberof<2000ispredominantlylaminarflow,whilst>4000ispredominantlyturbulent.

LaminarFlow

Inlaminarflow:

GasmovesinaseriesofconcentriccylinderswhichslideoveroneanotherGasinthecentremovestwiceasfastcomparedtotheoutside,whereitisalmoststationary

Gasappearsincross-sectionasanadvancingconeGasmayreachtheendofthetubewhenthevolumeofflowislessthanthevolumeofthetube.

Thisisthemechanismofalveolarventilationwhentidalvolumesarelessthananatomicaldeadspacevolume

Inastraightunbranchedtube,flowcanbequantifiedbytheHagen-PoiseuilleEquation:

,where:

=Flow

=Drivingpressure=Radius

=Length

=Viscosity

However,asinlaminarconditionsflowisproportionaltothedrivingpressureandinverselyproportionaltoresistance,flowcanbesubstitutedandtheequationsolvedforresistance:

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Thiscanbeusedtodescribethefactorsaffectingresistance:

LengthFixedconstant.ViscosityVarieswiththeparticulargasmixturebeingused.RadiusMaindeterminant.Maybedividedinto:

ExtraluminalfactorsCompression:

Haemorrhage,tumour,dynamichyperinflation,atelectasiscompressingairways,etc.Lungvolume:

Airwayradiusincreaseswhenlungvolumeexpandsduetoradialtractiononairways(untildynamichyperinflationoccurs,atwhichpointairwaysarecompressedagain)

LuminalconstrictionBronchospasm,bronchoconstriction.IntraluminalobstructionSputumplugging,aspiration.

Notethatairwayresistance:

Peaksatthe5 generationRapidlydecreaseswitheachairwaydivisionthereafterThisisduetothetotalcross-sectionalareaincreasingdramatically.

Reduceswithincreasinglungvolume,asradialtensiondistendsairways,increasingtheircrosssectionalarea

TurbulentFlow

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Highflowratesandbranchingofairwaysdisruptdisciplinedlaminarflow.Turbulentflow:is:

Dominantintheupperairway(wherevelocityishigh)Dominantinearly-generationairwaysduetoregularbranching,changesindiameter,andsharpanglesReducesafterthe11thgenerationbronchiolesProportionaltothesquarerootofthedrivingpressureTherefore,resistanceishigherinturbulentflowthaninlaminarflow.

Drivingpressureisproportionaltogasdensity,andindependentofviscosity

Resistanceinturbulentflowismanagedbymakingflowlessturbulent:

AchievedbyreducingReynoldsnumberHeliummixturesreducegasdensityOfgreaterbenefitinupperairwaythanlowerairwaydisease.

TransitionalFlow

Transitionalflowoccursatbranchesandanglesintheairways,asoccurinmostofthebronchialtree.

References

1. LumbA.Nunn'sAppliedRespiratoryPhysiology.7thEdition.Elsevier.2010.

Lastupdated2018-04-24

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SurfactantDescribetheproperties,productionandregulationof,surfactantandrelatethesetoitsroleininfluencingrespiratorymechanics

SurfaceTension

SurfacetensiondescribesthetendencyofafluidtominimiseitssurfaceareaItisrelatedtotheattractionbetweenparticlesinthefluidrelativetoparticlesoutsidethefluidSurfacetensioniswhy:

WaterscatteredonasurfaceformsroundeddropletsWhymultipledropletswilltendtocoalesceintoasinglelargerdroplet

ThisrelationshipisdescribedbyLaPlace'sLaw

,where:

ispressure

issurfacetensionisradius

AlveoliobeyLaplace'sLawHighsurfacetensioncausesthreeproblemswithalveoli

CompliancefallswhenthealveolusisemptyAstheradiusfalls,thepressurerequiredtoopenit(atagivensurfacetension)willbeincreased.Thisincreasesworkofbreathing.SmalleralveoliwillpreferentiallyemptyintobiggeralveoliSmalleralveolirequiregreatertransmuralpressurestoremaininflated.Thiscausessmalleralveolitoemptyintolargerones.FluidtransudationSurfacetensiondrawsfluidfrominterstitialspacesandcontributestopulmonaryoedema.

Overall,highsurfacetensionisdetrimentaltothelungs

Surfactant

SurfactantisasubstancewhichsubstantiallyreducesworkofbreathingbyreducingalveolarsurfacetensionSurfactantisproducedbytypeIIalveolarcellsinresponsetolunginflationandrespirationItiscomposedof:

85%phospholipid5%neutrallipid10%protein

SurfactantisamphipathicEachcomponenthasahydrophobicandhydrophilicend.

Thiscausesthemoleculestoorientthemselvesalongtheair-liquidinterface,disruptingtheattractivebondsbetweenwatermoleculesSurfacetensionisreducedinproportiontotheconcentrationofmolecules

TheconcentrationofsurfactantchangesthroughouttherespiratorycycleDuringexpirationalveolicollapseThedecreaseinalveolarradiusisoffsetbytheincreaseinsurfactantconcentration,sothefallinradiusismitigatedby

Surfactant

157

thedropinsurfacetension.

References1. CICMSeptember/November20122. LumbA.Nunn'sAppliedRespiratoryPhysiology.7thEdition.Elsevier.2010.

Lastupdated2019-07-18

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VolumesandCapacitiesExplainthemeasurementoflungvolumesandcapacities,andfactorsthatinfluencethem

Statethenormalvaluesoflungvolumesandcapacities

Defineclosingcapacityanditsclinicalsignificanceandmeasurement

Thelunghasfourvolumesandfour(main)capacities:

AvolumeismeasureddirectlyAcapacityisasumofvolumes

Volumes

Tidalvolume(V )Volumeofairduringnormal,quietbreathing.

Normalis7ml.kg ,or500ml

Inspiratoryreservevolume(IRV)Volumeofairthatcanbeinspiredabovetidalvolume.

Normalis45ml.kg ,or2500ml

Expiratoryreservevolume(ERV)Volumeofairthatcanbeexpiredfollowingtidalexpiration.

Normalis15ml.kg ,or1500ml

Residualvolume(RV)Volumeofairinthelungsfollowingamaximalexpiration.

Normalis15-20ml.kg ,or1500ml

Capacities

FunctionalResidualCapacity(FRC)FRC=RV+ERV.

Normalis30ml.kg or3000mlFRCdecreases20%whensupine,andafurther20%undergeneralanaesthesia

VitalCapacity(VC)VC=ERV+V +IRV.

Normalis4500ml

T

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InspiratoryCapacity(IC)IC=V +IRV.

Normalis3000ml

TotalLungCapacity(TLC)TLC=RV+ERV+V +IRV.

Normalis6000ml

FunctionalResidualCapacity

TheFRChasmanyimportantphysiologicalfunctions:

GasexchangeTheFRCallowsbloodinthepulmonarycirculationtobecomeoxygenatedthroughouttherespiratorycycle(iftherewasnoFRC,thenatexpirationthelungswouldbeemptyandnooxygenationwouldoccur).

OxygenReserveFRCistheonlyclinicallymodifiableoxygenstoreinthebody,andallowscontinualoxygenationofbloodduringapneicperiods.

MinimiseWorkofBreathingWorkofbreathingisafunctionoflungresistanceandcompliance.

ThelungsitsonthesteepestpartofthecomplianceoccursatFRCComplianceisoptimisedas:

AlveoliareopenandminimallydistendedBelowFRC,somealveolicollapseandthevolumeoflungavailabletoreceivethetidalvolumedecreasesRe-expansionofcollapsedalveolirequiresmoreworkthanexpandingopenalveoli.AboveFRC,somealveoliwillbecomeoverdistendedandtheircompliancewillfall

Airwayresistancedecreasesasairwayradiusincreasesaslungvolumeincreases

MinimiseRVAfterloadPVRisminimalatFRC.

AboveFRC,compressionofintra-alveolarvesselsoccursandPVRincreasesBelowFRC,extra-alveolarvesselscollapseandPVRincreases

MaintainlungvolumeaboveclosingcapacityIfclosingcapacity(seebelow)exceedsFRC,thenshuntwilloccur.

FactorsaffectingFRC:

FRCisreducedby:SupinepositioningFallsby~20%.AnaesthesiaFallsby~20%.Raisedintra-abdominalpressureImpairedlungandchestwallcompliance

FRCisincreasedby:PEEP

ExtrinsicIntrinsic(gastrapping)

PEEPEmphysemaAcuteasthmaAge

T

T

VolumesandCapacities

160

Mayincreaseslightly.

MeasurementofLungVolumesandCapacities

ERV,V ,andIRVcanallbemeasureddirectlyusingspirometryAspirometerisaflowmeter

ThepatientexhalesasfastaspossiblethroughtheflowmeterAflow-timecurveisproducedThiscurvecanbeintegratedtofindvolume

Anycapacitywhichisasumofthese(IC,VC)canthereforebecalculated

RVcannotbemeasuredbyspirometry,asitcan'tbeexhaledThereforeFRCandTLCcannotbecalculated

RVcanbemeasuredusing:GasdilutionBodyplethysmography

GasDilution

Gasdilutionreliesontwoprinciples:ConservationofMassHeliumhaspoorsolubilityandwillnotdiffuseintocirculation

Limitationsofgasdilution:Onlygascommunicatinggascanbemeasured-willunderestimateFRCingas-trapping

Method:Patienttakesseveralbreathsfromagasmixturecontainingaknownconcentrationofhelium(givingtimeforequilibration)TheconcentrationofexpiredheliumisthenmeasuredFromthelawofconservationofmass:

isequaltothevolumeofthegasmixturethepatientwasbreathingfrom( )andthepatientsFRCTherefore:

BodyPlethysmography

Bodyplethysmographyrelieson:Boyle'slaw

Pressureandvolumeareinverselyproportionalataconstanttemperature,i.e.( ).

Method:Patientisplacedinaclosedbox,withamouthpiecethatexitstheboxThepatientinhalesagainstaclosedmouthpiece:

Whenthepatientinhales,thevolumeofgasintheboxdecreases(thepatienttakesupmorespace)andthereforethepressureincreasesThechangeinvolumeoftheboxisgivenby:

T

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161

,where:

isthechangeinboxvolume,orTherefore:

As istheonlyunknownvalue,itcanbecalculated.

Thechangeinvolumeofthelungmustbethesameasthevolumeofthebox( )

Inthecaseofthelung,theinitialvolume( )isFRCTherefore:

ClosingCapacity

ClosingcapacityisvolumeatwhichsmallairwaysbegintocloseClosingcapacityisthesumofresidualvolumeandclosingvolume.

Becausedependentlungiscompressedbygravity,dependent(typicallybasal)airwaysareofsmallercalibrethannon-dependent(typicallyapical)airwaysDuringexpiration,theseairwaysarecompressedfirstAlveoliconnectedtotheseairwaysareisolated,andV/Qscatterorshuntoccurs.IfclosingcapacityexceedsFRC,thenairwayclosureoccursduringnormaltidalbreathingThisoccurswhen:

FRCisdecreasedCCisincreased

IncreaseswithageCCexceedsFRCinthesupinepatientat44CCexceedsFRCintheerectpatientat66

Thisisclinicallyrelevantduringpreoxygenation,asitwilllimitthedenitrogenationthatcanoccur

MeasurementofClosingCapacity

ClosingcapacityismeasuredusingFowler'sMethod,andiscoveredunderDeadSpace.

References

VolumesandCapacities

162

1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.

Lastupdated2019-07-18

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SpirometryDescribethepressureandflow-volumerelationshipsofthelung,chestwallandthetotalrespiratorysystem

Describethemeasurementandinterpretationofpulmonaryfunctiontests,includingdiffusioncapacity.

Pulmonaryfunctiontestsareperformedwithaspirometer,whichmeasureseithervolumeorflow(integratedfortime)toquantifylungfunction.

Basicspirometrycanbeusedtoquantify:

LungvolumesandcapacitiesAllexceptresidualvolume(andthereforeFRCandTLC).Dynamicmeasurements

FEVVolumeofairforciblyexhaledinonesecond.FVCForcedvitalcapacity.PEFRPeakexpiratoryflowrate.Flow-volumeloop

Additionaltestingcanbeperformedtomeasure:

ResidualvolumeFRCandTLCcanthereforebecalculated.Diffusioncapacity

BasicSpirometry

Basicspirometryincludes:

ForcedspirometryPatientforciblyexhalesavitalcapacitybreath,producingaexponential(wash-in)curve.Thiscalculates:

PEFRfromthegradientattime0(assumingmaximaleffort)FEV isthevolumeexpiredin1sNormalis>80%ofpredicted.FVCisthetotalvolumeexhaled.TheFEV /FVCratioNormalis>0.7.Thesevaluesalsoquantifydiseaseseverity:

Inobstructiveairwaysdisease:FEV <80%predictedFEV /FVCratio

Restrictivedisease:FEV <80%predictedFVCFEV/FVCratio>0.7TheratioisnormalastheFEV andFVCfallproportionally.

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Volume-TimeGraph(alsoknownasaspirographorspirogram)Quantifiesstaticlungvolumesbyhavingapatientperform:

NormaltidalbreathingVitalcapacitybreathVitalcapacityexhalation

Flow-VolumeLoopsNormal

Peakexpiratoryflowof~8L.sInitialflowishighestastheincreasedlungvolumeincreasesthecalibreoflungairways,reducingairwaysresistance.

ThisiscalledtheeffortdependentpartofthecurveFlowtailsofflaterinexpiration

Lungscollapse,andairwaycalibrefallsSmallairwaysarecompressedAnyincreaseinexpiratorypressurewillincreaseairwayresistanceproportionally.

Thisiscalleddynamicairwayscompression,andresultsinauniformflowratethatisindependentofexpiratoryeffort*Thisisthereforelabeledtheeffortindependent**partofthecurve.

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165

ObstructivelungdiseaseRVandTLCareincreasedduetogastrappingPeakflowislimitedEffort-independentportionbecomesconcave

RestrictivelungdiseaseTLCisreduced,butresidualvolumeisunchangedPeakflowmaybereduced(asseenhere)However,thisreductionisproportionaltothedecreaseinvolume,suchthattheFEV :FVCratioisnormal.Ifpeakflowispreserved,theFEV :FVCratiowillbeincreased.Effortindependentpartislinear

FixedupperairwayobstructionDescribesanupperairwayobstructionthatdoesnotchangecalibreduringtherespiratorycycle.

Peakinspiratoryandexpiratoryflowratesarelimitedbythestenosis

VariableextrathoracicobstructionVariableastheobstructionchangesduringtherespiratorycycle:

During(negativepressure)inspirationthelesionispulledintotrachea,reducinginspiratoryflowDuringexpirationthelesionispushedoutofthetracheaThewaytorememberthisisanextrathoracicobstructionimpedesinspirationThereverseeffectoccursinpositivepressureventilation

11

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VariableintrathoracicobstructionTheoppositetoextrathoracicobstruction.

DuringinspirationtheairwaycalibreincreasesandinspiratoryflowisunimpededDuringexpirationtheairwaycalibrefallsandexpiratoryflowisreduced

References1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.

Lastupdated2019-07-18

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WorkofBreathingDescribetheworkofbreathinganditscomponents

Workofbreathingistheenergyusedbythemusclesforrespiration.Itisdefinedas:

,measuredinJoules.

ThisgivestheworkforasinglerespiratorycycleEnergyexpenditureovertimeisbetterdescribedasthe"powerofbreathing".ItdoesnottakeintoaccountrespiratoryrateorflowrateThesefactorshaveasignificanteffectonenergyrequirement.

Thiswouldbegivenbytherateofwork,orpower,where:

,measuredinWatts.Tidalbreathingisefficientanduses<2%ofBMR

Theoxygenrequirementofbreathingatrestis~2-5%ofVO ,or~3ml.min

DeterminantsofWorkofBreathingWorkofbreathingisdividedinto:

ElasticworkAbout65%oftotalwork,andisstoredaselasticpotentialenergy.Energyrequiredtoovercomeelasticforces:

LungelasticrecoilSurfacetensionofalveoli

ResistiveworkAbout35%oftotalwork,andislostasheat.Thisisduetotheenergyrequiredtoovercomefrictionalforces:

BetweentissuesIncreasedwithincreasedinterstitiallungtissue

BetweengasmoleculesIncreasedathighflowratesIncreasedwithturbulentflow

HighrespiratoryratesUpperairwayobstructionIncreasedairwaydensity

HyperbaricDiving

IncreasedwithdecreasedairwayradiusLowlungvolume

InadequatePEEPDecreasedrespiratorymuscletone

BronchoconstrictionDynamicairwaycompressionEffort-independentexpiration.Apparatus

EndotrachealTubeHMEfilters

Airwayresistancevariesdependingonairwaydivision:Resistancepeaksatthe3rdairwaydivision(lobarbronchi)

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Fallswithincreasingairwaydivisionsduetoincreasedcross-sectionalarea

GraphingWorkofBreathing

Workofbreathingcanbeevaluatedwithadynamiclungcompliancecurve:

Iftherewerenoresistiveforces,thenthiscurvewouldbeastraightlineThetriangularareaistheelasticworkdone

Theresistiveworkofbreathingcausesthedeviationoftheinspiratoryandexpiratorylines:TheareabetweenthecompliancelineandtheinspiratorylineisadditionalresistiveinspiratoryworkdoneTheareabetweenthecompliancelineandexpiratorylineisadditionalresistiveexpiratoryworkdone

ThisworkistypicallydonebyelasticrecoilofthelungsIfthisareafallswithintheareaofelasticworkofbreathing,itisapurelypassiveprocess,usingthestoredelasticpotentialenergyofinspirationIfpartofthisareafallsoutsidetheareaofelasticworkofbreathing,itdemonstratesadditionalactiveworkofexpirationwhichmayoccurinobstructivelungdiseaseorwhenminuteventilationishigh

Activeexpiratorywork:

MinimisingWorkofBreathing

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169

Workofbreathingcanbeminimisedbyoptimisingthedeterminants:

ElasticworkPEEPKeeplungvolumeatFRCandmaximisenumberofventilatedalveoli.PositioningOptimiselungvolume.SurfactantMinimisingsurfacetension.OptimiserespiratoryrateElasticworkofbreathingtypicallydecreaseswithincreasedrespiratoryrate.

ResistiveworkDecreaserespiratoryrateRespiratoryrateisdirectlyproportionaltoresistivework.IncreaselaminarflowLaminarflowismoreefficientthanturbulentflow.Laminarflowcanbeincreasedby:

ReducinggasdensityHeliox.

IncreaseRadiusIncreaselungvolumeBronchodilators

Derivation

Workisdefinedas:

,where:

=WorkinJoules

=ForceinNewtons

=DistanceinMetres

Additionally,pressureisdefinedas:

,where:

=PressureinPascal

=AreainMeterssquared

Therefore:

Substituting:

,where:

=Volume

Therefore:

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170

References

1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.2. LumbA.Nunn'sAppliedRespiratoryPhysiology.7thEdition.Elsevier.2010.

Lastupdated2019-07-18

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OxygenCascadeDescribeandexplaintheoxygencascade

Theoxygencascadedescribesthetransferofoxygenfromairtomitochondria.

IneachstepofthecascadethePaO fallsItdemonstratesthatoxygendeliverytotissuesreliesonthepassivetransferofgasdownpartialpressuregradients.Thestepsofthecascadeare:

DryatmosphericgasHumidifiedtrachealgasAlveolargasArterialbloodMitochondriaVenousblood

Remember:

PartialpressuredeterminesrateandextentofgastransferOxygencontentiswhatisimportantforcellularfunction

AtmosphericGas

AtmosphericpartialpressureofoxygenisafunctionofbarometricpressureandtheFiO :

,where:

is760mmHg

is0.21

Therefore, =160mmHg

2

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HumidifiedTrachealGas

GasishumidifiedduringinspirationGasintheproximaltracheaisheatedto37°Candhas100%relativehumidityThesaturatedvapourpressureofwaterat37°Cis47mmHgTherefore:

,where:

and areasabove

is149mmHg

AlveolarGas

IdealalveolarPO iscalculatedusingthealveolargasequation:

,where:

isthealveolarpartialpressureofoxygen

istheinspiredpartialpressureofoxygen

isthearterialpartialpressureofcarbondioxide

istherespiratoryquotient,whereRisusedinthealveolargasequationtocorrectforthechangeininspiredrelativetoexpiredvolumeAsgenerallylessCO isproducedthanO consumed,expiredvolumesaretypicallylessthaninspiredvolumesRisdependentonthemetabolicsubstratesusedformetabolism:

Purefat≈0.7Pureprotein≈0.9Purecarbohydrate≈1ThenormalvalueforaWesterndietisquotedas0.8

isacorrectionfactor,usuallyequalto~2mmHg,andisgivenby

Alveolaroxygenisthereforedependenton:

PiO ,whichisafunctionof:FiOAirpressure

Alveolarventilation

As .

ArterialBloodThedifferenceinpartialpressureofoxygenbetweenalveolarandarterialbloodiscalledtheA-agradient:

AnormalA-agradientis

2

2 2

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NormalarterialPO is100mmHgItoccursdueto:

Shunt/VQscatterAsmallshuntisnormalduetobloodfromthebronchialcirculationandthebesianveins.Diffusionabnormality

Mitochondria

PO varieswithmetabolicactivity,buttypicallyquotedas5mmHgThePasteurpointisthepartialpressureofoxygenatwhichoxidativephosphorylationceases,andis~1mmHg

VenousBlood

PO isgreaterthanmitochondrialPOMixedvenousbloodtypicallyquotedas40mmHg.Higherthanmitochondriaasnotallarterialbloodtravelsthroughcapillarybeds

References1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.2. BrandisK.ThePhysiologyViva:Questions&Answers.2003.

Lastupdated2019-07-18

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DiffusingCapacityandLimitationExplainperfusion-limitedanddiffusion-limitedtransferofgases

Definediffusingcapacityanditsmeasurement

Describethephysiologicalfactorsthatalterdiffusingcapacity

RateofdiffusionofgasesisgivenbyFick'sLaw:

,where:

isthepressuregradientacrossthemembrane

istheareaofthemembraneisthesolubilityofthesubstance

isthethicknessofthemembrane

isthemolecularweightofthesubstance

Thesecanbedividedintopressure,lungfactors,andsubstancefactors:

PressuregradientInthelung,thisisafunctionof:

PartialpressureofthegasinthealveolusThisisaffectedby:

AtmosphericpressureVentilationAlveolarhypoventilationwill:

IncreasePACODecreasePAO

PartialpressureofthegasinbloodThisisaffectedby:

SolubilityofthegasinbloodCO is~20timesassolubleasO inblood.Bindingofgastoprotein:

ParticularlyhaemoglobinAffectstherateofuptakeofO andCO,andiswhycalculatedDL iscorrectedforhaemoglobin.

Theshapeoftheoxy-haemoglobindissociationcurveallowsalargevolumeofoxygentobeboundbeforePaO beginstorisesubstantially.

FormationofcarbaminocompoundsAnaestheticagentstoplasmacontentse.g.albumin,cholesterol.

LungfactorsSurfaceAreaAffectedby:

ParenchymavolumeBodysizePathologyManylungdiseaseswillreducesurfaceareaforgasexchange.

V/QmismatchBothshuntanddeadspacereducethesurfaceareaavailableforgasexchange.

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PulmonarybloodvolumeVasculardistensionandrecruitmentalsoaffectssurfacearea.Factorsaffectingpulmonarybloodvolumeinclude:

CardiacoutputIncreasedrecruitmentofvasculatureinhighoutputstatesDecreasedrecruitmentandincreasedV/Qmismatchinshockstates.

PostureIncreasedsurfaceareawhensupinerelativetosittingorstanding.

ThicknessIncreasingalveolar-capillarymembranethicknessimpedesgasexchange.Causesofthisinclude:

Pathologye.g.Pulmonaryoedemaandcardiacfailure.

SubstancefactorsSolubilityMoresolublesubstanceswilldiffusemorequickly.MolecularweightSmallersubstanceswilldiffusemorequickly.

DiffusionandPerfusionLimitation

Limitationreferstowhatprocesslimitsgasuptakeintoblood:

Gaseswhicharediffusionlimitedfailtoequilibrate,i.e.thepartialpressureofasubstanceinthealveolusdoesnotequalthatinthepulmonarycapillary

e.g.CarbonMonoxideGaseswhichareperfusionlimitedhaveequalalveolarandpulmonarycapillarypartialpressures,sotheamountofgascontenttransferredisdependentonbloodflow

e.g.Oxygen

Oxygen

Oxygendiffusiontakes~0.25sPulmonarycapillarytransittimeis0.75sTherefore,undernormalconditionsoxygenisaperfusionlimitedgasHowever,oxygenmaybecomediffusionlimitedincertaincircumstances:

Alveolar-capillarybarrierdiseaseDecreasestherateofdiffusion.

DecreasedsurfaceareaIncreasedthickness

Highcardiacoutput

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Decreasespulmonarytransittime.AltitudeDecreasesPAO .

CarbonDioxide

Carbondioxideisventilationlimited,ratherthandiffusionorperfusionlimitedThisisbecauseitis:

20xmoresolubleinbloodthanoxygenRapidlyproducedfrombicarbonateandcarbaminocompoundsPresentinfargreateramountsthanoxygen1.8L.kg existinthebody(though1.6L ofthisareinboneandotherrelativelyinaccessiblecompartments).

Impairmentofdiffusioncapacitycausestype1respiratoryfailureasoxygenisaffectedtoamuchgreaterextentthancarbondioxide

OtherGases

CarbonmonoxideDiffusionlimiteddueto:

HighaffinityforhaemoglobinContinualuptakeintoHbresultsinalowpartialpressuresinblood.

NitrousoxidePerfusionlimitedasequilibriumbetweenalveolusandbloodisrapidlyreachedasitis:NotboundtohaemoglobinRelativelyinsoluble

DiffusionCapacity

MeasurementoftheabilityofthelungtotransfergasesMeasuredasDL ordiffusingcapacityofthelungforcarbonmonoxideCarbonmonoxideisusedasitisadiffusionlimitedgas.Process:

Vitalcapacitybreathof0.3%COHeldfor10sandexhaledInspiredandexpiredCOaremeasuredDifferenceistheamountofCOwhichisnowboundtoHbDL iscorrectedfor:

AgeSexHb

DL isdecreasedin:Thickenedalveolar-capillarybarrier

InterstitiallungdiseaseReducedsurfacearea

EmphysemaPELobectomy/pneumonectomy

DL isincreasedin:ExerciseRecruitmentandcapillarydistension.Alveolarhaemorrhage

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HbpresentwithinthelungbindsCO.Asthma(maybenormal)Potentiallyduetoincreasedapicalbloodflow.Obesity(maybenormal)Potentiallyduetoincreasedcardiacoutput.

References1. BrandisK.ThePhysiologyViva:Questions&Answers.2003.2. LumbA.Nunn'sAppliedRespiratoryPhysiology.7thEdition.Elsevier.2010.3. ANZCAMarch/April19994. DerangedPhysiology-CarbonDioxideStorageandTransport

Lastupdated2017-10-04

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West'sZonesDescribeWest'szonesofthelungandexplainthemechanismsresponsibleforthem

West'sZonestakeintoaccounttheeffectofalveolarpressureonpulmonarybloodflow.Thelungisdividedintofourzones:

WestZone1:P >P >PAlveolarpressureexceedsarterialpressure.

Thealveoluscompressesthecapillary,andnobloodflowoccursAsthereisventilationbutnoperfusion,thiscanalsobethoughtofasdeadspaceThisoccurswhen:

AlveolarpressureishighPEEP

ArterialpressureislowShock

Hypovolaemia

WestZone2:P >P >PArterialpressureexceedsalveolarpressure,whichexceedsvenouspressure.

BloodflowoccursintermittentlyduringthecardiaccycleAlveolarpressureactsasaStarlingresistorFlowisproportionaltotheP -P gradient.

WhenP fallsbelowP (e.g.indiastole),thennobloodflowwilloccur

WestZone3:P >P >PArterialpressureexceedsvenouspressurewhichexceedsalveolarpressure.

BloodflowoccursthroughoutthecardiaccycleFlowisproportionaltotheP -P gradient.ForanaccuratemeasureofPCWP,aPACmustbeplacedinWestZone3(sothereisacontinualcolumnofblood)Thistendstohappennaturallyasthemajorityofpulmonaryflowistothisregion

WestZone4:P >P >P >PInterstitialpressureactsasaStarlingresistorforpulmonarybloodflow.

Itisseenwheninterstitialpressureishigh(e.gduetopulmonaryoedema).

References1. BrandisK.ThePhysiologyViva:Questions&Answers.2003.2. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.

Lastupdated2018-07-09

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BasicsofV/QMatchingOptimalgasexchangeoccurswhenregionsoflungareventilatedinproportiontotheirperfusion,i.e.V/Q=1

Unevendistributionofventilationandperfusioncausesinefficientgasexchange:ExcessiveventilationcausesexcessiveworkInadequateventilationcausesinadequategasexchange

DistributionofVentilation

TherightlungisslightlybetterventilatedthantheleftInanerectpatientthebasesofthelungarebetterventilatedTheweightoflungabovecompressesthelungbelow,improvingthecomplianceofdependentlungwhilststretchingthenon-dependentlung.

ThisisonlysignificantatlowinspiratoryflowratesTheV/Qratiointhebasesis~0.6TheV/Qratiointheapicesis>3

Inalateralposition:ThedependentlungisbetterventilatedinaspontaneouslybreathingpatientThenon-dependentlungisbetterventilatedinaventilatedpatient

DistributionofPerfusion

ThepulmonarycirculationisalowpressurecirculationGravitythereforehasasubstantialeffectonfluidpressureConsequently,thedistributionofbloodthroughoutthelungsisuneven:

ThebasesperfusedbetterthantheapicesThisisaffectedbylungvolume,withtheeffect:

BecomingmorepronouncedatTLC(withapicalperfusionfallingprecipitously)ReversingslightlyatRV

V/QRatios

TheglobalV/Qratiofornormalrestinglungis0.9TheglobalV/Qratioimprovesto1.0duringexercise

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V/QMismatchandEtymology

V/QmismatchoccurswhenV/Q≠1:V/Q>1(DeadSpace)Ventilationinexcessofperfusion.

However,pulmonarybloodispassingventilatedalveoliandPaO isnormal

V/Q0to1(V/Qscatter)Perfusioninexcessofventilation.

IncreasinginPAO willincreasePaOThisiscommonlyreferredtobythegeneraltermofV/Qmismatch

V/Q=0(Shunt)Mixedvenousbloodenteringthesystemiccirculationwithoutbeingoxygenatedviapassagethroughthelungs.PaOfalls.

References

1. WestJ.RespiratoryPhysiology:TheEssentials.9thEdition.LippincottWilliamsandWilkins.2011.2. LumbA.Nunn'sAppliedRespiratoryPhysiology.7thEdition.Elsevier.2010.

Lastupdated2017-10-04

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DeadSpaceDeadspaceistheproportionofminuteventilationwhichdoesnotparticipateingasexchange.

TypesofDeadSpace

Deadspacecanbedividedinto:

ApparatusdeadspaceDeadspacefromequipment,suchastubesventilatorcircuitry.Someapparatusdeadspacemayactuallyreducetotaldeadspace,asanETTbypassesthemajorityofanatomicaldeadspaceofthepatient(nasopharynx).

PhysiologicaldeadspaceDeadspacefromthepatient.Physiologicaldeadspaceisdividedinto:

AnatomicaldeadspaceThevolumeoftheconductingzoneofthelung.Anatomicaldeadspaceisaffectedby:

SizeandAge3.3ml.kg intheinfant,fallsto2.2ml.kg intheadultPostureDecreaseswhensupine.PositionoftheneckandjawIncreasedwithneckextension.LungvolumesIncreasesby~20mlperlitreofadditionallungvolume.AirwaycalibreBronchodilationincreasesairwaydiameterandthereforeV .

Pathological/AlveolarDeadSpaceDeadspacecausedbydisease.Causesofpathologicaldeadspaceinclude:

ErectpostureDecreasedpulmonaryarterypressure/impairedpulmonarybloodflow

HypovolaemiaRVfailure/IncreasedRVafterload:

HPVMI

PEIncreasedalveolarpressureIncreasesWestZone1physiology.

PEEPCOAD

CalculationofDeadSpaceTwomethodsexisttoallowdeadspacevolumestobecalculated:

PhysiologicaldeadspacemaybemeasuredwithBohr'smethodAnatomicaldeadspacemaybemeasuredbyFowler'smethodPathologicaldeadspacemaybecalculatedbysubtractinganatomicaldeadspace(Fowler'smethod)fromphysiologicaldeadspace(Bohr'sMethod)

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Fowler'sMethod

Fowler'sMethodisasingle-breathnitrogenwashouttest,usedtocalculateanatomicaldeadspaceandclosingcapacity.

Method:

Attheendofanormaltidalbreath(atFRC)avital-capacitybreathof100%oxygenistakenThepatientthenexhalestoRVExpirednitrogenconcentrationandvolumeismeasured.Aplotofexpirednitrogenconcentrationbyvolumeisgenerated,producingagraphwithfourphases:

Phase1(PureDeadSpace)Gasfromtheanatomicaldeadspaceisexpired.Thiscontains100%oxygen-nonitrogenispresent.Phase2Amixofanatomicaldeadspaceandalveolar(lungunitswithshorttimeconstants)isexpired.Themidpointofphase2(whenareaA=areaB)isthevolumeoftheanatomicaldeadspace.Phase3Expirednitrogenreachesaplateauasjustalveolargasisexhaled(lungunitswithvariabletimeconstants).Phase4Suddenincreaseinnitrogenconcentration,whichindicatesclosingcapacity.Thisincreaseoccursbecause:

BasalalveoliaremorecompliantthanapicalalveoliTherefore,duringinspirationbasalalveoliinflatemorethanapicalalveoliThesingle100%oxygenbreaththereforepreferentiallyinflatesthebasalalveoli.Attheendofthevitalcapacitybreath,theoxygenconcentrationinbasalalveoliisgreaterthanthatofapicalalveoli.Inexpiration,theprocessisreversed:

BasalalveolipreferentiallyexhaleAtclosingcapacity,smallbasalairwayscloseandnowonlyapicalalveoli(withahigherconcentrationofnitrogen)canexhaleMeasuredexpirednitrogenconcentrationincreases

Bohr'sMethod

PhysiologicaldeadspaceismeasuredusingtheBohrequation.Thiscalculatesdeadspaceasaratio,orproportionoftidalvolume:

TheBohrequationisbasedontheprinciplethatallCO exhaledmustcomefromventilatedalveoli.

Notethat:

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isthemixed-expiredcarbondioxidePartialpressureofCO inanexpiredtidalbreath.TheBohrequationrequiresalveolarPCO tobemeasuredAsthisisimpractical,theEnghoffmodificationistypicallyused,whichassumesthatPACO ≈PaCO .Theequationthenbecomes:

Anormalvalueforphysiologicaldeadspaceduringnormaltidalbreathingis0.2-0.35

PhysiologicalConsequencesofIncreasedDeadSpace

Indeadspace:

TheV/QratioapproachesinfinityasalveolarperfusionfallsThisresultsinariseinPaCOInaspontaneously-ventilatingindividual,thisstimulatestherespiratorycentretoincreaseminuteventilationtoreturnalveolarventilation(andthereforeCO )tonormalThereisminimaleffectonPaO ,asinpuredeadspaceallbloodispassingthroughventilatedalveoliandthereforeundergoesgasexchange

RelationshipbetweenAlveolarVentilationandPaCO

AtmosphericaircontainsnegligibleCO .AsMVincreases,PaCO willfall,aswillthegradientforfurtherCO diffusion.Thiscanbeexpressedbytheequation:

Notethatthisgraph:

DescribesthechangeinPaCO forachangeinalveolarventilationAdoublingofalveolarventilationwillhalvePaCO .DoesnotdescribethechangeinventilatorydriveforagivenchangeinPaCOThisiscoveredunderremovalofCO .

Footnotes

NotethatWestZone1(wherePA>Pa>Pv)physiologyisincreaseddeadspace.

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ThePaCO -ETCO differenceisaconsequenceofdeadspace,asdeadspacegasdilutesalveolargas.

References1. LumbA.Nunn'sAppliedRespiratoryPhysiology.7thEdition.Elsevier.2010.2. WestJ.RespiratoryPhysiology:TheEssentials.9thEdition.LippincottWilliamsandWilkins.2011.

Lastupdated2019-07-18

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ShuntExplaintheconceptofshuntanditsmeasurement

Shuntisbloodreachingthesystemiccirculationwithoutbeingoxygenatedviapassagethroughthelungs.

FactorsContributingtoShunt

NormalshuntAnatomicalshunt

Thebesianveins,whichdraindirectlyintotheleftcardiacchambersBronchialcirculations,whichdrainintothepulmonaryveins

FunctionalshuntBlooddrainingthroughalveoliwithaV/Qbetween0and1.

Thismaynotbetrueshunt,asbloodmayhavesomeoxygencontentbutnotbemaximallyoxygenatedPathologicalshuntPathologicalshuntingcanbeanatomical(e.gcongenitalcardiacmalformations),orphysiological(e.g.pneumoniacausingalveolarconsolidation).

Intra-cardiace.g.VSDExtra-cardiace.g.PulmonaryAVM,PDA

CalculationofShunt

ShuntcannotbedirectlymeasuredThisisbecausewecannotseparatetrueshunt(V=0)fromV/Qscatter(V/Q<1)whensamplingbloodenteringtheleftheartVenousadmixtureisusedinsteadVenousadmixtureistheamountofmixedvenousbloodthatmustbeaddedtopulmonaryend-capillarybloodtogivetheobservedarterialoxygencontent.Venousadmixture:

Isacalculated,theoreticalvalueAssumesthatalveolihaveeithercompleteshunt(noventilationatall,i.e.V/Q=0)ornoshunt(V/Q=1)Isexpressedasaratio,orshuntfraction:

,where:

=Shuntbloodflow

=Cardiacoutput

=Pulmonaryend-capillaryoxygencontent,assumedtohaveanoxygentensionequaltoPAO (withthecorrespondingoxygensaturation)

=Arterialoxygencontent

=Mixedvenousoxygencontent

PhysiologicalConsequencesofShunt

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NoCO candiffusefromshuntedbloodThereforePaCO mightbeexpectedtorise,however:

InaspontaneouslybreathingpatienttheincreasedPaCO increasesrespiratorydrive,andalveolarventilationincreasesTherefore,shuntdoesnottendtoincreasePaCO unless:

TheshuntfractionislargeandThepatientisunabletoincreasetheiralveolarventilationtocompensate

Additionally,thesteepnessoftheCO dissociationcurveatthearterialpointmeansthatalthoughCO contentincreases,theincreaseinPaCO issmall

EffectonOxygen

PaO fallsproportionallytoshuntfractionAsshuntedalveoliareperfusedbutnotventilated,trueshuntissaidtobeunresponsivetoanincreaseinFiOThisiswheretechnicaldefinitionsbecomeimportanttoavoidconfusion.

ForanalveoliwithaV/Qbetween0-1(V/QmismatchorV/Qscatter,butnottrueshunt):Thereisperfusion,butrelativelylessventilationThereforebloodpassingthroughthisalveoliwillbepartiallyoxygenatedIncreasingPAO willimproveoxygenation(assumingnodiffusionlimitation):

AdministrationofsupplementaloxygenHyperventilationAsperthealveolargasequation

ForanalveoliwithaV/Qof0(trueshunt)Thereisnoventilation.RegardlessoftheincreaseinPAO ,PaO willnotimprove.

TheIsoshuntDiagram

IsoshuntdiagramplotstherelationshipbetweenFiO andPaO againstasetof'virtualshuntlines'These'shuntfractions'arecalculatedfromtheaboveequationandsoareactuallyV/Qadmixturefractions

References

1. LumbA.Nunn'sAppliedRespiratoryPhysiology.7thEdition.Elsevier.2010.2. WestJ.RespiratoryPhysiology:TheEssentials.9thEdition.LippincottWilliamsandWilkins.2011.3. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.

Lastupdated2019-07-18

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OxygenStorageDescribetheoxygenandcarbondioxidestoresinthebody

Thestandardtextbook70kgmalecontains~1.5Lofoxygen,splitbetween:

~850mlinbloodThereis20.4mlofoxygenper100mlofblood,dividedupas:

20.1mlboundtohaemoglobin0.3mldissolved

~250mlboundtomyoglobin~450mlcontainedinFRC(21%of2.4L)Thisiswhypreoxygenationincreasessafeapnoeatimes,asthenitrogenwashoutincreasesthevolumeofoxygenstored.

Oxygen-HaemoglobinDissociationCurveThesigmoidshapeoftheoxygen-haemoglobindissociationcurveoffersmanyphysiologicaladvantages:

BufferingincaseoflowPaOTheplateauallowsoxygencontenttoremainhigh,evenifthePaO fallsMaintenanceofdiffusiongradienttotissuesThesteepsectionallowsalargeamountofoxygentobedeliveredwithonlyasmalldropinPaO ,whichallowstherateofoxygendeliverytobemaintained(astheblood-tissuepartialpressuregradientissteep)withanincreaseinoxygendemand.

ThesigmoidshapeexistsduetocooperativebindingEachoxygenwhichbindstoHbcausesconformationalchangeswhichallowitbindadditionaloxygenmoleculesmoreeasily.

Whenthefourthoxygenmoleculehasbound,Hbissaidtobeintherelaxedconformation(Rstate)Whennooxygenisbound,Hbissaidtobeinthetensestate(Tstate)

Thecurvecanberightorleft-shiftedbychangesintemperature,pH,CO ,and2-3DPG

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Notethatthemixedvenouspointisnotonthearterialcurve(unlikehowitisdisplayedabove),asthevenousdissociationcurveisright-shiftedrelativetothearterialcurve

HaemoglobinSpecies

Haemoglobinisafour-tetramermolecule,anditsspeciescanbephysiologicalorpathological:

PhysiologicalHbA

Mostcommon2alphaand2betasubunits(α β )

HbALesscommon2alphaand2deltasubunits(α δ )

HbFFoetalHbHigheraffinityforoxygenduetolackof2,3-DPG2alphaand2gammasubunits(α γ )

PathologicalHbSSickle-celldisease.

AbnormalbetasubunitUnabletodeformastheypassthroughcapillaries

Increasesbloodviscosity,thrombus,andischaemiathroughcapillaryocclusionOftencausessplenicinfarction

Reducedredcelllifespanto10-20days

MetHbMethaemoglobinaemia.

Ferrousiron(Fe )isoxidisedtoferriciron(Fe )Cannotbindoxygen,andleft-shiftstheoxyHbcurvefornormalHbwhichreducesoxygenoffloadingattissuesNormallypreventedby:

GlutathioneinredcellreducesoxidisingagentsMethaemoglobinreductaseenzymeusesNADHtoreduceMetHb

Occursdueto:Oxidisingagentsoverwhelmcapacityofglutathionesystem,e.g.:

SNPNOAmidelocalanaesthetics

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SulfonamidesFailureofthemethaemoglobinaemiareductaseenzyme

G6PD

COHbCarboxyhaemoglobin.

Haemoglobinbindscarbonmonoxidewithgreateraffinitythanoxygen

CyanoHbHaemoglobinirreversiblybindscyanidemolecules,causingafunctionalanaemiaCyanideinhibitscytochromeoxidaseintheelectrontransportchain,preventingoxidativephosphorylationoccurring

OxygenSaturation

OxygenSaturationcanbedefinedintwoways:

FunctionalSaturation

However,additionalhaemoglobinspeciesexistinvaryingamounts,andthisdefinitionmaydeceptivelyimplygoodoxygendeliverywhenthisisnotthecase.

FractionalSaturation

Fractionalsaturationincludescarboxy-andmet-haemoglobin,andsoisamoreaccurateestimatorofoxygensaturation.

Notethatpulseoximetrydoesn'tmeasureeitheroftheseandisdependentonthecalibration,butwilltypicallymeasurefunctionalsaturation.

Myoglobin

MuscleishighlymetabolicallyactiveandhasalargeO demand.MyoglobinservesasanO storeformuscle.ItissimilartoHbinthatitisalargeO -bindingiron-containingproteinmyoglobin,andisdifferentbecauseit:

Containsoneglobinchainandonehaemegroup(bindingoneO molecule),andsodoesnotexhibitcooperativebindingThemyoglobindissociationcurvethereforehasarapidupstrokeandanearlyplateau.HasaP of2.7mmHgThisallowsittotakeupoxygenfromhaemoglobin(asthepartialpressuregradientfavoursdiffusionintothecell),andunloaditintothecell(soitcanactuallybeused).Isfoundinskeletalandcardiacmuscle

References

1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.2. BrandisK.ThePhysiologyViva:Questions&Answers.2003.

Lastupdated2019-07-18

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CarbonDioxideDescribetheoxygenandcarbondioxidestoresinthebody

DescribethecarbondioxidecarriageinbloodincludingtheHaldaneeffectandthechlorideshift

Explainthecarbondioxidedissociationcurve

Describethemovementofcarbondioxidefrombloodtotheatmosphere

CO isproducedinthemitochondriaduringthecitric-acidcycleasaproductofmetabolism.

Thereis~120LofcarbondioxideinthebodyAtotalof1.8L.kg ,1.6L.kg ofwhichisinrelativelyinaccessiblecompartments.Normalelimination(and,atsteadystate,production)ofcarbondioxideis200ml.min

CarbonDioxideinBlood

Inblood,CO isstoredas:

Bicarbonate(90%)DissolvedgasCarbaminocompounds

Form ArterialBlood AdditionalCO invenousblood

Bicarbonate 90% 60%

Dissolved 5% 10%

Carbaminocompounds 5% 30%

Bicarbonate

CO diffusesfreelyintoerythrocytes,whereitcanbecatalysedbycarbonicanhydrasetoproducebicarbonate:

Tomaintainbicarbonateproduction,theproducts(H andHCO )arethenremoved:H ionsarebufferedtohaemoglobin

IntracellularHCO isthenexchangedwithextracellularCl-viatheBAND3membraneproteinThisiscalledtheHamburger,orChlorideShiftChlorideenteringthecelldrawswaterinalongitsosmoticgradient,increasingthehaematocritofvenousbloodrelativetoarterialblood

DissolvedGas

AsperHenry'sLaw,theamountofcarbondioxidedissolvedinbloodisproportionaltothePaCOAscarbondioxideis20xassolubleasoxygeninwater,dissolvedcarbondioxidecontributesmuchgreaterproportionofcarbondioxidecontentthandissolvedoxygendoestooxygencontent

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CO canbinddirectlytoproteins(predominantlyhaemoglobin),whichdisplacesaH ion:

TheH ionisthenbufferedbyanotherplasmaprotein(alsopredominantlyhaemoglobin)

BoundCO doesnotcontributetothepartialpressuregradientCarbaminocompoundsareonlyasmallcontributortooverallCO carriage,butcontributeaboutonethirdofthearterio-venousCO differenceduetotheHaldaneeffectTheHaldaneeffectstatesthatdeoxyHbbindsCO moreeffectivelythanoxyHb.Thisisbecause:

DeoxyHbisabetterbufferofHpKaofdeoxyHbis8.2,comparedtothatofoxyHbwhichis6.6.

Enhancedbufferingcontributes~30%oftheHaldaneeffectDeoxyHbformscarbaminocompoundsmoreeasilyDeoxy-Hbhas3.5xtheaffinityforCO thanOxy-Hb.

Thisforms~70%oftheHaldaneeffect

CO DissociationCurve

ThiscurveplotsPCO againstbloodCO contentinml.100ml .

Keypoints:

MixedvenousCO contentis52ml.100ml ,ataPCO of46mmHgArterialCO contentis48ml.100ml ,ataPCO of40mmHgApproximately50%ofthearterial-mixedvenousdifferenceoccursduetotheupwardsshiftofthecurve,whichisduetotheHaldaneeffectThisisthemechanismforchangesinPO affectingtheCO dissociationcurve.

RemovalofCO

CO dissolvesfrompulmonaryarterialbloodintothealveolusdownaconcentrationgradient.AsinspiredCO isnegligible,PACO isafunctionofalveolarventilationandCO output,givenbytheequation:

Simplified,PaCO isinverselyproportionaltoalveolarventilation:

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DistributionofCarbonDioxide

CO inthebodycanbeconsideredasathree-compartmentmodel:

Well-perfused(blood,brain,kidneys)Moderately-perfused(restingmuscle)Poorly-perfused(bone,fat))

Eachofthesetissueshasadifferenttime-constant,suchthatamismatchofventilationwithmetabolicactivitymaytake20-30minutestoequilibrateacrosscompartments

ThereforehypoventilationandhyperventilationhavedifferenteffectsonPCO :HyperventilationcausesarapiddecreaseinPCO inblood,subsequent(slower)redistributionfromperipheralcompartmentsHypoventilationcausesariseinPaCO ,therateofwhichisdeterminedbothbyproductionanddistributionintoplasma

Withnoventilation,PCO risesat3-6mmHg.minDuetotheHaldaneeffectthePaCO willrapidlyincreaseduringpassagethroughthepulmonarycapillary(despitethefactthatcarbondioxidecontentisunchanged)astheproportionofOxyHbincreases

Therefore:PaO ismoresensitiveatdetectingearlyhypoventilationprovidedPAO isnormalSteady-statePCO givesthebestindicationofadequacyofventilation

Inacutehypoventilation,producedCO ispreferentiallystoredintissues,decreasingCO eliminationInacutehyperventilation,CO ismobilisedfromtissuesresultinginincreasedCO elimination

CO Cascade

Region Value(mmHg)

MixedVenous 46

Alveolar 40

(Arterial) 40

Mixed-expired 27

VenousCO diffusesintothealveolus,reachingequilibriumwitharterialPCOAlveolarCO isthendilutedbydeadspacegas,resultinginalowerME'CO

References

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1. LumbA.Nunn'sAppliedRespiratoryPhysiology.7thEdition.Elsevier.2010.2. FRCA:AnaesthesiaTutorialoftheWeek-RespiratoryPhysiology

Lastupdated2018-04-24

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PositivePressureVentilationDescribethephysiologicalconsequencesofintermittentpositivepressureventilationandpositiveend-expiratorypressure.

Physiologicaleffectsofpositivepressureventilationaremostlyrelatedtotheincreasedmeanairwaypressure.Thisisafunctionof:

VentilationmodeTidalvolumeandpeak(andplateau)airwaypressureRespiratoryrateI:EratioPEEPPEEPhasamuchlargereffectthantheotherfactors.

PEEPisdefinedasapositiveairwaypressureattheendofexpirationPEEPisdistinctfrompositiveairwaypressure(whichisnotconfinedtoaphaseoftherespiratorycycle)andCPAP(whichisamodeofventilation)iPEEPreferstointrinsicPEEP,autoPEEPordynamichyperinflationiPEEPisPEEPgeneratedbythepatient,andoccurswhenexpirationstopsbeforethelungvolumereachesFRC.

ApplicationofexternalPEEPmaylimitthegenerationofiPEEPbymaintainingairwaypatencyinlateexpiration

RespiratoryEffectsDecreasedworkofbreathing

DecreasedVOMoreimportantwhenworkofbreathingishigh.

Alterationinanatomical/apparatusdeadspaceIntubationtypicallyreducesdeadspace,astheadditionalapparatusdeadspaceisofsmallervolumethantheanatomicaldeadspaceitreplacesNon-invasiveventilationmaskscausealargeincreaseindeadspace

Increaseslungvolume(andFRC,forPEEP)byanamountproportionaltothecomplianceofthesystemImprovesoxygenationviaalveolarrecruitmentImproveslungcomplianceviaalveolarrecruitment,reducingworkofbreathingElevatedairwaypressuresmayincreasetheproportionofWestZone1physiologyandalveolardeadspace

Inhealthylungsanincreaseinthe ratioisseenwhenPEEPexceeds10-15cmH O.ReducesairwayresistanceAirwayresistancedecreasesaslungvolumeincreases.

CardiovascularEffectsAlterationincardiacoutput

PEEPandIPPVgenerallydecreaseCOviadecreasingVRduetotheincreaseinintrathoracicpressure.LeadstoreductioninRVfillingpressure,LVfilling,andCO.

ThisisthepredominantreasonwhyCOfallswiththeapplicationofPEEPInawellpatient,COfallsby:

10%withIPPVandZEEP18%withIPPVand9cmH OofPEEP36%withIPPVand16cmH OofPEEP

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Thesechangesare:MoremarkedinhypovolaemiaChangesarereversedwithvolumeexpansion.LessseverewithpoorlungcomplianceReducedcompliancegreatlyreducestheeffectofPEEPandIPPVonthevasculature,asthechangeinintrapleuralpressureisreduced.

LVpreloadmayalsobereducedduetoincreasedRVafterloadIncreasedRVafterloadmayincreaseRVEDV,displacingtheinterventricularseptumintotheLVThebulgingseptumdecreasesLVEDV,causingLVdiastolicfunctionandreducedLVfillingThisisanexampleofventricularinterdependence.

ReducedLVafterloadduetoreducedLVtransmuralpressureInsomecases,IPPVaugmentscirculatoryfunctionbyreducingLVafterloadtoagreaterextentthanpreload.

Effectsinawellpatientareminimal,asPEEPisrelativelysmallinmagnitudecomparedtosystemicarterialpressuresInpatientsgeneratinghighlynegativeintrathoracicpressures,theLVtransmuralpressurecanincreasemarkedly,increasingLVafterloadandreducingcardiacoutput

ReductioninMAPMAPdecreasesasPEEPincreases.

ChangestooxygenfluxPEEPwilltendtoimprovePO whilstreducingCO.

ChangestopulmonaryvascularresistanceandRVafterloadIflungvolumeislowerthanFRC,thenPVRwillreduceasPEEPstretchesopenextra-alveolarvessels

Alveolarrecruitmentwillreducehypoxic-pulmonaryvasoconstriction,furtherreducingPVRIflungvolumeishigherthanFRC,thenPVRwillincreaseasPEEPcompressesalveolarvesselsTherefore,PEEPhasvariableeffectsonRVafterloaddependingonhowitchangeslungvolumewithrespecttoFRC

End-OrganEffects

Reducedurineoutputdueto:ReducedCOandrenalbloodflowADHreleaseasaconsequenceofreducedatrialstretchandANPreleaseMayworsenoedemainpatientswithprolongedperiodsofventilation.

Reducedhepaticbloodflowdueto:IncreasedCVPanddecreasedCOloweringthepressuregradientforhepaticflow

Mayresultincirculationonlyintermittentlythroughoutthecardiaccycle

References

1. LumbA.Nunn'sAppliedRespiratoryPhysiology.7thEdition.Elsevier.2010.2. LueckeT,PelosiP.Clinicalreview:Positiveend-expiratorypressureandcardiacoutput.CriticalCare.2005;9(6):607-621.

doi:10.1186/cc3877.3. Yartsev,A.PositiveEnd-ExpiratoryPressureandit'sconsequences.DerangedPhysiology.4. Yartsev,A.PositivePressureandPEEP.DerangedPhysiology.5. Yartsev,A.IndicationsandContraindicationsforPEEP.DerangedPhysiology.6. Yartsev,A.EffectsofPositivePressureandPEEPonAlveolarVolume.DerangedPhysiology.7. Yartsev,A.[PEEPandIntrinsicPEEP}(http://www.derangedphysiology.com/main/core-topics-intensive-care/mechanical-

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ventilation-0/Chapter%202.1.6/peep-and-intrinsic-peep).DerangedPhysiology.

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HypoxiaExplainthephysiologicaleffectsofhyperoxia,hypoxaemia,hypercapnia,hypocapnia,andcarbonmonoxidepoisoning.

HypoxaemiaisalowpartialpressureofoxygeninbloodHypoxiaisanoxygendeficiencyatthetissues,dueto:

ImpairedoxygendeliveryImpairedoxygenextraction

Oxygendeliveryisgivenbytheequation:

,where:

1.34isHüfner'sconstantThisistheoxygencarryingcapacityofhaemoglobin,inml.g (ofHb).

Thetheoreticalmaximumis1.39Invivoitis1.34duetotheeffectofcarboxyhaemoglobinandmethaemoglobincompounds,whichlimitO binding

0.03isthesolubilitycoefficientofO inwaterat37ºC,inmls.mmHgCanalsobeexpressedas0.003mls.dL .mmHg (mlsperdeciliterpermmHg).Differenttextsusedifferentvalues,dependingonwhetherhaemoglobinisreporteding.L org.100ml .

ClassificationsandCausesofHypoxia

Hypoxiacanbecategorisedintofourtypes:

HypoxichypoxiaAnaemichypoxiaIschaemichypoxiaHistotoxichypoxia

HypoxicHypoxia

Hypoxichypoxia,orhypoxaemia,ishypoxiaduetolowPaO (andthereforelowSpO ),typicallydefinedasaPaO <60.

CausesofhypoxaemiacanbefurtherclassifiedbasedontheirA-agradient:

CausesofhypoxaemiawithanormalA-agradient:LowPiODecreasedalveolarventilation

CausesofhypoxaemiawitharaisedA-agradient:DiffusionlimitationShunt(Increasedoxygenextraction)

LowFiO

HypoxaemiaoccursathighaltitudeswhenthePO isdecreased.

Decreasedalveolarventilation

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Afallinalveolarventilation( )causesariseinPACO ,andthereforedecreasesPAO .DecreasedV canoccurwith:

Respiratorycentredepression:DrugsHeadinjury(RaisedICP,closedheadinjury)EncephalopathyFatigue

Nervedysfunction:SpinalcordinjuryGBSMND

NMJdysfunction:ParalysisMG

Musculardysfunction:MyopathyFatigueMalnutritionDystrophy

Chestwallabnormalities:KyphoscoliosisAnkylosingSpondylitisPleuralfibrosis

DiffusionLimitation

ImpaireddiffusionofO acrossthemembraneresultsinaloweredPaO .Diffusionlimitationoccursdueto:

DecreasedalveolarsurfaceareaIncreasedalveolarcapillarybarrierthickness

PulmonaryfibrosisARDS

Shunt

Shuntoccurswhenbloodreachesthesystemiccirculationwithoutbeingoxygenatedviapassagethroughthelung.Asthealveolusisperfusedbutnotventilated,thustheV/Qratiois0.

Administrationof100%O haslesseffectonPaO asshuntfractionincreasesOxygencontentofshuntedalveoliisidenticaltomixedvenouscontentOxygencontentofnon-shuntedalveolidoesnotincreaseappreciablyathighpartialpartialpressuresashaemoglobinisalreadyfullysaturated

Shuntphysiologyisexploredinmoredetailundershunt.

IncreasedOxygenExtraction

Increasedoxygenextraction(VO )willnottypicallycausehypoxiaThisisbecause:

NormalVO is250ml.minNormalDO is1L.min

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Maximaloxygenextractionratiois~70%(thoughitvariesbetweenorgans)ThereforeVO canincreaseuntilitreaches70%oftheDO ,apointcalledcriticalDO .

However,itmayworsenhypoxiainthepresenceofasupply-side(DO )pathology

AnaemicHypoxia

ImpairedoxygendeliveryduetolowHbTypicallyasymptomaticatrestbutlimitsexercisetolerance

Compensationoccursbyincreasinglevelsof2,3-DPG,causingaright-shiftintheHb-O dissociationcurvetofavouroxygenoff-loadingattissues

CarbonMonoxidePoisoning

COpoisoningisclassifiedasasubsetofanaemichypoxiaascarboxyhaemoglobinreducestheeffectiveamountofhaemoglobininsolutionCOhas210timestheaffinityforHbthanO

COrapidlydisplacesO fromHbandisliberatedslowlyCOpoisoningcausesheadacheandnausea,butnoincreasedrespiratorydrivesincethePaO isunchanged

IschaemicHypoxia

Ischaemichypoxiaisduetoimpairedcardiacoutputresultinginimpairedoxygendelivery

HistotoxicHypoxia

Histotoxichypoxiaisduetoimpairedtissueoxidativeprocesses,preventingutilisationofdeliveredoxygenMostcommoncauseofhistotoxichypoxiaiscyanidepoisoning,whichinhibitscytochromeoxidaseandpreventsoxidativephosphorylationManagedbyusingmethyleneblueornitrites,whichformmethaemoglobin,inturnreactingwithcyanidetoformthenon-toxiccyanmethaemoglobin

EffectsofHypoxia

WithanormalPaCO ,PaO mustfallto50mmHgbeforeanincreaseinventilationoccursWitharisingPaCO ,afallinPaO below100mmHgwillstimulateventilationviaactiononcarotidandaorticbodychemoreceptors

Theeffectsofeachstimuliaresynergistic,andgreaterthanwhatisseenwitheithereffectalone

Prolongedhypoxaemiawillalsoleadtocerebralacidosis(viaanaerobicmetabolism),whichwillstimulatecentralpHreceptorsandstimulateventilation

Acid-BaseChanges

Hypoxiaresultsinbothfixedandvolatileacid-basedisturbancesAnaerobicmetabolismresultsinlactateproductionProductionoffixedacidresultsinabasedeficit,andalowbicarbonateHypoxiaandmetabolicacidosisstimulateventilationandhypocarbia

CO retention

InchronichypercarbiatheCSFpHnormalises(asbicarbonateissecretedintoCSF),witharaisedCO

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FallinPaO becomesthepredominantstimulusforventilation

References1. WestJ.RespiratoryPhysiology:TheEssentials.9thEdition.LippincottWilliamsandWilkins.2011.2. BarrettKE,BarmanSM,BoitanoS,BrooksHL.Ganong'sReviewofMedicalPhysiology.24thEd.McGrawHill.2012.3. CICMJuly/September20074. ICUBasicBook.

Lastupdated2019-07-18

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HypoandHypercapneaExplainthephysiologicaleffectsofhyperoxia,hypoxaemia,hypercapnia,hypocapnia,andcarbonmonoxidepoisoning

Carbondioxideislipidsolubleandcanrapidlycrossmembranes,allowingitaffectacid-basestatusinanycompartment.

Hypercapnea

RespiratoryEffects

IncreasedrespiratorydriveviachemoreceptorstimulationCVSeffects

PeripheralvasodilationMaycausetachycardiafromsympatheticstimulation

PulmonaryvasoconstrictionMyocardialdepressionIntracellularacidosis.Arrhythmogenic

CNSeffectsIncreasedCBFIncreasedICPsecondarytoincreasedCBFSNSactivationCNSdepressionWhenPaCO >100mmHg

HypocapneaRespiratoryEffects

Left-shiftofoxyhaemoglobindissociationcurveRespiratorydepression

CVSeffectsMyocardialdepressionIntracellularalkalosis.

CNSeffects

DecreasedcerebralbloodflowElectrolyteeffects

DecreasedserumKDecreasedserumCaLeadstoparesthesiasandtwitches.

Ca bindstoH bindingsiteonalbumin

References

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1. BrandisK.ThePhysiologyViva:Questions&Answers.2003.

Lastupdated2019-07-18

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PositionandventilationExplaintheeffectofchangesinpostureonventilatoryfunction

AlteredpatientpositioncancausesignificantchangestoV/Qmatching.

LateralDecubitus

Inthelateralpositioninaspontaneouslyventilatingpatient:

Dependentlungventilationimprovesby~10%Duetoimpairedcomplianceofthenon-dependentlung(ithyperinflates)andimprovedcomplianceofthedependentlung(itislessexpanded).

DependentlungcorrespondsmoretoWestZone3Non-dependentlungcorrespondsmoretoWestZone2

Dependentlungperfusionimprovesby~10%Duetotheeffectofgravity.

Inthelateralpositioninapositive-pressureventilatedpatient:

Themajority(~55%)ofthetidalvolumeisdeliveredtothenon-dependentlungThemajorityofpulmonarybloodflowisdeliveredtothedependentlungThecomplianceofthedependentlungfallsduetocompressionfromthe:

MediastinumAbdominalorgansThesemovecephaladinaparalysedpatient.

ThedependentlungtypicallyreceivesgreaterbloodflowduetotheeffectofgravityThismayworsenV/QmatchingBloodflowisalsoaffectedby:

HPVAnatomicalfactorsBloodflowisgreaterincentralthanperipheralportions.LungvolumeAlterationsisextra-alveolarandintra-alveolarpressuresatFRCmayalterregionalbloodflow.

Whenbothlungsarebeingventilated,V/QmatchingcanbeimprovedwithselectiveapplicationofPEEPtothedependentlung,whichimprovescompliance

ThoracotomyOpeningofanon-dependenthemithoraxcauses:

IncreasedcomplianceandFRCofthenon-dependentlungReducedcomplianceandFRCofthedependentlung

References1. Dunn,PF.PhysiologyoftheLateralDecubitusPositionandOne-LungVentilation.ThoracicAnaesthesia.Volume38(1),

Winter2000,pp25-53.

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2. GraphfromBenumofJL,ed.Anesthesiaforthoracicsurgery.2nded.Philadelphia:WBSaundersCompany,1995.3. ANZCAAugust/September2015

Lastupdated2017-09-20

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HumidificationDefinehumidityandgiveanoutlineoftheimportanceofhumidification

Humidificationdescribestheamountofwatervapourpresentinair:

AbsoluteHumidityistheamountofwatervapourinagivenvolumeofair(g.m )RelativeHumidityistheratiobetweentheamountofwatervapourinasampleofair(absolutehumidity)andtheamountofwaterrequiredtofullysaturatethatsampleatitscurrentpressureandtemperature

Moistureisthewaterproducedbycondensationwhenrelativehumidityexceeds100%.

Humidificationofinspiredairisimportanttoavoiddryingoutmucosaandsputum,whichleadstotissuedamageandfailureofthemucociliaryelevatorOptimalfunctionrequiresarelativehumidityofgreaterthan75%

MechanismThenoseis:

OptimisedforhumidificationTheseptumandturbinatesincreasecontactofairwithmucosalsurfacesby:

IncreasingsurfaceareaGeneratingturbulentflow

ThepreferredorificeforbreathingunlessairwaysresistancebecomesasignificantlylimitingfactorThisisrelevantin:

Airwayobstruction(e.g.polyps)Athighminuteventilations(>35L. )

Humidifiesinspiredgasto90%,comparedto60%forthemouth

Methodofhumidification:

FluidliningtheairwayactsasaheatandmoistureexchangerIninspiration:

RelativelydryairisevaporateswaterfromtheairwayliningRelativehumidityisincreasedto90%inthenasopharynxand100%BTPSbythesecondgenerationofbronchiThisgivesawatervapourpressureof47mmHgatBTPS,withanabsolutehumidityof44g.m .

Inexpiration:AircoolsintheupperairwayAscoolerairhasalowersaturatedvapourpressure,moisturecondensesontheairway.MoistureisreabsorbedThisreducespotentialwaterlossesfromtheairwayfrom300ml.day to150ml.day .

References1. LumbA.Nunn'sAppliedRespiratoryPhysiology.7thEdition.Elsevier.2010.2. WeatherFaqs.AbsoluteandRelativeHumidity.3. CICMSeptember/November2012

Lastupdated2018-09-21

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CoughReflexExplainthepathwaysandimportanceofthecoughreflex

Coughing:

IsanairwayprotectionreflexInvolvesdeepinspirationfollowedbyforcedexpirationagainstaclosedglottisThesuddenopeningofthecordscausesaviolentrushofairat>900km.h ,removingirritantsandsecretionsfromtheairways.

SensationVagusafferentshaveexquisitelysensitivelighttouchandcorrosivechemicalreceptorsinthelarynx,carina,terminalbronchioles,andalveoli.

IntegrationVagalafferentssynapseinthemedulla,whichcoordinatestheeffectorresponse.

EffectorAseriesofprocessesoccurinthreephases:

InspiratoryphaseAclosetovitalcapacitybreathistaken.CompressivephaseEffortclosureoftheepiglottistosealthelarynx,followedbyaviolentcontractionofabdominalmusculatureandinternalintercostals,causingarapidriseinintrapleuralpressureto>100mmHg.ExpulsivephaseWide-openingofthecordsandepiglottis,causingaviolentexpiration.

Compressionofthelungscausesnarrowingofthenoncartilaginousairwaysandincreasesturbulentflow,removingadherentmaterialfromthetracheobronchialtree

References

1. BarrettKE,BarmanSM,BoitanoS,BrooksHL.Ganong'sReviewofMedicalPhysiology.24thEd.McGrawHill.2012.

Lastupdated2019-07-18

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Non-RespiratoryFunctionsOutlinethenon-ventilatoryfunctionsofthelungs

Thelungsareauniqueorganas:

TheentirecardiacoutputpassesthoughthepulmonarycirculationTheyhaveahugecapillarybedwhichbloodisincontactwithTheyhavealargeinterfacewiththeexternalenvironment

Consequentlytheyareadaptedtoanumberofnon-respiratoryfunctions,whichinclude:

FiltrationImmunedefenceBloodresevoirMetabolismDrugDelivery

(Takingupdrugs)InhalationalAnaesthetics

SyntheticEndocrine

FiltrationTheentirecardiacoutputpassesthroughthe7μmpulmonarycapillaries,whichactasaneffectivesieveforparticulatematter.Thisfunctionmaybeimpairedbyintra-cardiacshunting(e.g.PFO)orpre-capillaryanastomoses.

Complementingthisrole,thelungsareabletoclearthrombimorerapidlythanotherorgansaspulmonaryendotheliumhasahighconcentrationofplasminactivatorandheparin.

Metabolism

Thepulmonaryendotheliumhasavarietyofeffectsondrugsandendogenoushormones:

Class Activated Inactivated

Amines 5-HT,Noradrenaline

Peptides AngiotensinI(viaACE) Bradykinin,ANP

Arachidonicacidderivatives Arachidonicacid Manyprostaglandins

OtherDrugs Lignocaine,fentanyl

BloodReservoir

Thehighlycompliantpulmonarycirculationcontainsaresevoirof~500mlofbloodwhichactsasavolumereservefortheLV.

Defence

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Thelargesurfacearearequiredforgasexchangeleavesthelungvulnerabletoinvasionbyairbornsubstances.Thisisattentuatedby:

MucousAmucouslayerprotectslargeairways,aslarge(>8μm)particlesimpactintothemucous.

MucousisexocytosedbygobletcellsinresponsetonoxiousstimuliincludingchemicalirritationaswellasinflammatoryandneuronalstimulationTheefficacyofthemucous-ciliasystemisenhancedbybronchoconstriction,whichreducesflowvelocityandcausesparticulatemattertosettle

CiliaCiliaareprojectionsfromepitheliumwhichbeatrhythmicallyat~12Hztopropelmucousoutoftheairwayatarateof~4mm.min .

Ciliaryfunctioncanbeimpededbypollutants,smoke,andinfectionCiliaryfunctionisstimulatedbyanaestheticagents

Inhaledparticleswhichreachtherespiratoryzonearenottrappedbymucous,butinsteadphagocytosedbyalveolarmacrophagesBronchoconstrictionreducesflowvelocityandcausesparticulateparticlestosettleinthemucous

DrugDelivery

Thesamepropertiesthatoptimisethelungforgasexchangeoptimiseitfordeliveryofinhaledagents.Drugsabsorbedinthepulmonarycirculationare:

LipophilicAlkaline(pKa>8)

EndocrineImportantendocrinefunctionsofthelunginclude:

Releaseofinflammatorymediatorssuchashistamine,endothelin,andeicosanoidsReleaseofnitricoxidetoregulatesmoothmuscleACEmetabolisesangiotensinItoangiotensinII

References

1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.2. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.

Lastupdated2019-07-18

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AltitudePhysiologyAltitudecausesanumberofphysiologicaleffects,relatedto:

ReduceatmosphericpressureReducedtemperatureReducedrelativehumidityIncreasedsolarradiation

PressureEffects

ReducedairpressureresultsinaproportionaldecreaseinPO :

At3,000m,alveolarPO is60mmHgAt5,400m,consciousnessislostinunacclimatisedindividualsAt10,400m,airpressureis187mmHgWith47mmHgofwatervapourandanalveolarPCO of40,breathing100%O givesanalveolarPO of100mmHg.At14,000m,consciousnessislostdespite100%OAt19,200m,theambientpressureissolowthattheboilingpointofwateris37°CThisistheArmstronglimit.

Respiratory

FallinPaO iscompensatedbyincreasingminuteventilation,whichdecreasesPACO andthereforeincreasesPAOLimitsofcompensationarereachedon100%oxygenat13,700m

Effectivecompensationislimitedbytherespiratoryalkalosis,thisisknownasthebrakingeffect:PeripheralchemoreceptorsdetecthypocapneaCentralchemoreceptorsdetectalkalosis

ThesubsequentrespiratoryalkalosisgeneratesacompensatorymetabolicacidosisThisacidosisrelaxesthebrakingeffectandallowsfurtherhyperventilation,andisthereforeamimportantpartofacclimatisation.

Thereisaninitialleft-shiftoftheoxygen-haemoglobindissociationcurveduetoalkalosisThisstimulatesacompensatoryincreasein2,3-DPGtoright-shiftthecurveandimproveoxygenoffloadingatthetissues

Cardiovascular

PVRincreasesduetoHPVHeartrateincreasesduetoincreasedSNSoutflow

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Strokevolumefalls(cardiacoutputremainsthesame)duetodecreasedpreload:Plasmavolumefallsdueto:

PressurediuresisInsensiblelossesfromhyperventilationandreducerelativehumidity

MyocardialworkincreasesIncreasedHRIncreasedviscosityofbloodduetohighhaematocritIncreasedRVafterloadfromhighPVRIncreasedpulmonarycapillaryhydrostaticpressuresleadtofluidtransudationandpulmonaryoedema

Haematological

IncreasedriskofthromboticeventstodueincreasedhaematocritIncreasedredcellmassduetoEPOsecretion

References1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.

Lastupdated2019-07-18

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RespiratoryChangeswithObesityDiscusstheeffectofmorbidobesityonventilation

Obesityisamultisystemdisorderdefinedbyanelevatedbodymassindex(BMI):

Normal:BMI<25Overweight:BMI25-30Obese:BMI>30MorbidlyObese:

ObesityrelateddiseaseandaBMI>35BMI>40

Characteristicsofobesityinclude:

ComplexgeneticandenvironmentalcausesIncreasedcaloricintakeIncreasedmetabolicrate(normalforBSA)

Morbidobesitycausesseveralchangestotherespiratorysystem:

AirwayIncreasedriskofOSAIncreasedriskofGORDandaspirationIncreasedriskofdifficultbag-maskventilationIncreasedriskofdifficultylaryngoscopy

ChangestorespiratorypatternIncreasedminuteventilation

SecondarytoincreasedVO andVCODuetotheincreaseinLBWandadiposity.IncreasedairwayreactivityCentraladiposityincreasescirculatingcytokines,includingTNF-α,IL-6,leptin.

ChangestovolumesandcapacitiesReducedrespiratorysystemcompliance

DecreasedchestwallcomplianceDuetoabdominalandchestwallfat.

FatdistributionmaybemoreimportantthanabsoluteBMIDecreasedlungcomplianceBasalatelectasisduetoabdominalcompressionandreducedrespiratorycompliance.

DecreasedERVandFRCNotethatRVisgenerallyrelativelyunchanged

IncreasedairwayresistanceDuetodecreasedairwayradiusatlowerlungvolumes.IncreasedworkofbreathingDuetoreducedrespiratorycomplianceandincreasedairwayresistance.ClosingcapacityencroachesonFRCAsFRCfalls,closingcapacitybecomesclosertoFRC.

Ifclosingvolumeexceedsexpiratoryreservevolume,thensmallairwayswillcollapseduringnormaltidalbreathing,causingshunt

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IncreasedA-agradientOccurswhenclosingcapacityexceedsFRC.

ChangestorespiratorycirculationPVRincreasesduetoreducedFRCcausingincreasedHPVMayleadtosecondaryPHTNandrightheartdysfunction.

References

1. AlvarezA,BrodskyJ,LemmensH,MortonJ.MorbidObesity:Peri-operativeManagement.Cambridge:CambridgeUniversityPress.2010.

2. LotiaS,BellamyMC.Anaesthesiaandmorbidobesity.ContinEducAnaesthCritCarePain2008;8(5):151-156.

Lastupdated2017-09-21

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RespiratoryChangesinNeonatesandChildren

TransitionatBirth

Transitionfromplacentalgasexchangetopulmonarygasexchangeoccurswithin20safterbirth:

CompressionofthethoraxthroughthevaginalcanalexpelsfoetallungwaterElasticrecoil,combinedwithcoolingoftheskinandmechanicalstimulation(whichstimulatetherespiratorycentre),facilitatefirstbreath

Therapiddropinpulmonaryvascularresistancewithspontaneousbreathingdrivesthechangesinthecardiaccirculation

ThefirstthreebreathsestablishfunctionalresidualcapacityLargechangesinintrathoracicpressureinthefirstthreebreathspressuredrivealveolaramnioticfluidintothecirculation,andestablishFRC.

NeonatesandChildrenComplianceNeonatalchestwallsarehighlycompliantrelativetotheirlungs(duetobothareducedlungcomplianceandincreasedchestwallcompliance),ascomparedtoadultswherelungandchestcomplianceisequal.Thereforeelasticworkofbreathingislargelydeterminedbythelungs.

OxygenationO consumptionis~10ml.kg .min inneonates,and6ml.kg .min inchildrenThereisa~10%shuntafterbirthwhichcontributestoagreaterA-agradient

VentilationObligatenosebreathersIncreasedCO productionduetohighermetabolicrateIncreasedminuteventilation,whichisduetoincreasedrespiratoryrate(25-40breathsperminute)

NeurologicalcontrolofbreathingRespiratorypatternschangefollowingbirth,andcompletechangetoadultrespiratorypatternsmaytakesomeweeks.Patternsinclude:

PeriodicbreathingisaslowlyoscillatingrespiratoryrateandVPeriodicapnoeaisintermittentapnoeainterspersedwithnormalbreathing.

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Closingcapacityisincreasedrelativetoadults,causingshuntFunctionalresidualcapacityisunchangedTidalvolumeanddeadspaceareunchanged

LaryngealanatomyLargeheadLargetongueLarge,stiff,U-shapedepiglottisElevatedlarynxGlottisisatC-3C4(C6inadults).Upperairwayisnarrowestatthecricoidring(ratherthantheglottis).Tracheaisshorterandnarrower4-5cmlong,6mmdiameterintheneonate.

SmallairwaysReducedbronchialsmoothmusclesobronchospasmisuncommonBronchiolescontribute50%ofairwaysresistanceBronchiolitismuchmoredistressinginneonatesandchildren.

References1. LumbA.Nunn'sAppliedRespiratoryPhysiology.7thEdition.Elsevier.2010.2. CICMMarch/May2013

Lastupdated2018-07-14

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Anti-AsthmaDrugsDescribethepharmacologyofanti-asthmadrugs.

OxygenIncreasesFiO andimprovessaturation.HelioxReducesspecificgravityofinhaledgasmixtures,improvinglaminarflow.β -agonistsActsonaG-proteincoupledreceptorto↑cellularlevelsofadenylylcyclase,↑cAMP,whichresultsinsmoothmusclerelaxationandbronchodilatation.CorticosteroidsGlucocorticoidsaresteroidhormonesthatbindtospecificintracellularreceptorsandtranslocateintothenucleus,wheretheyregulategeneexpressioninatissue-specificmanner.Theyareusedinasthmaastheycause:

BronchodilatationbyincreasingbronchialsmoothmuscleresponsetocirculatingcatecholaminesDecreasedairwayoedemabydecreasinginflammatoryresponsesandtransudateproduction

MuscarinicantagonistsAnti-muscarinicsaresyntheticquaternaryammoniumcompoundswhichcompetitivelyinhibitM3muscarinicreceptorsonbronchialsmoothmuscle,antagonisingthebronchoconstrictoractionofvagalimpulses.MethylxanthinesMethylxanthinesarephosphodiesteraseinhibitors,reducinglevelsofcAMPhydrolysisandincreasedintracellularlevelsofcAMP(viaadifferentmechanism,sotheyaresynergisticwithβ agonists)andcausingsmoothmusclerelaxation.KetamineIncreasessympatheticoutflowandrelaxesbronchialsmoothmuscle.VolatileAnaestheticAgentsVolatileanaestheticagentsreducesbronchialsmoothmuscleconstrictionwherethisispreexisting(suchasasthma).LeukotrieneAntagonistsSelectivelyinhibitsthecysteinylleukotrienereceptor,increasedactivityofwhichisinvolvedinairwayoedemaandbronchialsmoothmuscleconstriction.

References

1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.

Lastupdated2019-07-18

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CardiacAnatomyDescribetheanatomyoftheheart,thepericardiumandcoronarycirculation

EchocardiographicAnatomy

Theleftventricleis:

DividedintofourpartsFrombasetoapex,inequalthirdsalongthelongaxisoftheventricle:

BasalMid-cavityIdentifiedbypresenceofthepapillarymuscles.ApicalApexTipoftheventricle,beyondwherethecavityends.

EachpartisdividedintosegmentsTotalofseventeensegmentsbetween:

6basalandmid-cavitysegmentsInferiorMid-cavitycontainsthepostero-medialpapillarymuscle.InferoseptalInferolateralAnteriorAntero-septalAntero-lateralMid-cavitycontainstheanterolateralpapillarymuscle.

4apicalsegmentsInferiorAnteriorLateralSeptal

Apicalcap

CoronarySupply

Thesegmentsofthebasalandmid-cavitypartsaresuppliedbyallthreevessels:

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Intheapicalpart,the:

LADSupplies:

AnteriorSeptal

LCxSupplies:

LateralRCASupplies:

Inferior

TheapicalcapissuppliedbytheLAD.

References

1. AlfredAnaestheticDepartmentPrimaryExamTutorialSeries2. AHA17SegmentModel.PMOD.

Lastupdated2018-08-01

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CoronaryCirculationDescribetheanatomyoftheheart,thepericardiumandcoronarycirculation

VascularAnatomy

CoronaryArteryAnatomy

Theleftmaincoronaryartery:

ArisesfromtheposterioraorticsinussuperiortotheleftcoronarycuspoftheaorticvalveEddycurrentsproducedinthesinusesofValsalva(outpouchingsoftheaorticwall)preventthevalvesoccludingtheosoftheLMandRCAduringsystole,sotheyremainpatentthroughoutthecardiaccycle.Theleftmainis5-10mmlong,andbifurcatestoformtheLADandLCx

TheLAD:

CoursesalongtheanteriorinterventriculargroovetotheapexoftheheartHere,itanastomoseswiththeposteriordescendingarteryfromtheRCA.Suppliestheanterolateralmyocardiumandanterior2/3oftheinterventricularseptumBranchesoftheLADinclude:

DiagonalvesselsBranchesarenamedsuccessivelyfromproximaltodistal,i.e.LADD ,LADD ,etc.1 2

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Septalperforators

TheLCx:

CoursesalongtheleftatrioventriculargroovebetweentheLAandLVintheepicardialfatpadSuppliestheinferolateralwalloftheLVGivesoffthreeobtusemarginalbranches(OM ,OM )whichfollowtheleftmarginoftheheartRunsincloseapproximationwiththecoronarysinusformuchofitscourse

TheRCA:

Arisesfromtheanterioraorticsinus,superiortotherightcoronarycuspoftheaorticvalveCoursesverticallydownwardsintherightatrioventriculargrooveSuppliestheRAandRV

Theposteriordescendingartery:

ArisesfromeithertheLCxorRCAThesevesselstravelinoppositedirectionsaroundtheatrioventriculargroove.DescendsintheposteriorinterventriculargroovebeforecoursingalongthebasetoanastomosewiththeLADattheapexoftheheartIsalsoknownastheposteriorinterventricularartery

CoronaryDominance

CoronarydominancereferstowhichvesselgivesrisetothePDA:

Inaright-dominantcirculationthePDAissuppliedbytheRCAInaleft-dominantcirculationthePDAissuppliedbytheLCx

Additionally:

TheSAnodeissuppliedbytheRCAin60%ofindividualsTheAVnodeissuppliedbytheRCAin90%ofindividuals

VenousAnatomy

85%ofvenousdrainageoccursviathecoronarysinus,whichisformedfromthecardiacveins:ThegreatcardiacveinrunswiththeLADThemiddlecardiacveinfollowsthePDAThesmallcardiacveinrunswiththeRCATheobliqueveinfollowstheposteriorpartoftheLA

MostoftheremainderisviaanteriorcardiacveinswhichdraindirectlyintotheRAAsmallproportionofbloodfromtheheartisdrainedviathethebesianveinsdirectlyintofourthecardiacchambersMostintotherightatrium,andleastintotheleftventricle.Theportionofblooddrainingintotheleftsideofthecirculationcontributestophysiologicalshunt.

CoronaryBloodFlowCoronaryBloodFlow:

Normalis~250ml.min (~5%ofrestingCO)Mayincrease4xduringstrenuousexerciseMyocardialworkmayincreaseupto9x,thoughasmyocardialoxygenextractionisunchangedefficiencyisactuallyimprovedduringexercise.

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CBFisdependenton:

CoronaryvascularresistanceCoronaryperfusionpressureThedifferencebetweenaorticrootpressureandthegreaterofRAPorintracavitypressure:i.e.

NotethatthepressuregradientisusuallyAorta-CavityratherthanAorta-RAThisisbecausethepressureintheventricleactsasaStarlingresistor-coronaryflowisindependentofRAPwhilst

HeartrateLVCBFisaffectedinsystoleduetothechangesinperfusionpressure,andcompressionofintramuscularvessels(causinganincreaseinCVR).

RVCBFislessaffected,astheforceofcontractionissignificantlysmallerandapressuregradientismaintainedTachycardiareducesdiastolictimeandsubsequentlyLVCBF

ControlofCoronaryBloodFlow

CBFisautoregulated:

MyogenicautoregulationThisiscommontomanyorgansystems,andoccurswithinthecoronaries.

Increasingtransmuralpressureincreasestheleakinessofsmoothmusclemembranes,depolarisingthemResistanceincreasesproportionallytopressure,suchthatflowremainsconstant

MetabolicautoregulationAnaerobicmetabolismresultsinproductionofvasoactivemediatessuchaslactateandadenosine,whichstimulatevasodilationandthereforeincreaseflow(andoxygendelivery).

ThisisthepredominantmeansforautoregulationintheheartTypicalmyocardialoxygenextractionis70%andraisingthisfurtherisdifficultTherefore,increasingoxygensupplyrequiresanincreaseinbloodflow.

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Autonomicmechanismsalsocontrolsomeaspectsofcoronarybloodflow:

Directeffectsinclude:Parasympatheticandsympatheticinnervationofcoronaryvessels,withreleaseofAChorNAandAdecreasingorincreasingcoronarybloodflow

IndirecteffectsAremoreimportantthandirecteffectsArerelatedtoautoregulationoccurringwithchanginglevelsofmyocardialworkinresponsetoparasympatheticorsympatheticstimuli

References

1. Hall,JE,andGuytonAC.GuytonandHallTextbookofMedicalPhysiology.11thEdition.Philadelphia,PA:SaundersElsevier.2011.

2. CICMJuly/September20073. McMinn,RMH.Last'sAnatomy:RegionalandApplied.9thEd.Elsevier.2003.4. CoronaryArteryGraphbasedonCoronaryArterialCirculation-es.2/3/2013.(Image).ByAddicted04(Ownwork)CCBY

3.0,viaWikimediaCommons.

Lastupdated2019-07-18

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CardiacCycleDescribethenormalpressureandflowpatterns(includingvelocityprofiles)ofthecardiaccycle

Thecardiaccycle:

DescribessequenceofeventsthatoccurintheheartoveronebeatConsistsoftwophasesdividedintosixstagesTypicallyisdescriedasbeginninginlatediastolewhenthemyocardiumisrelaxedandtheventriclesarepassivelyfilling

Phasesofthecardiaccycle:

DiastoleIsovolumetricVentricularRelaxationRapidVentricularFillingSlowVentricularFilling(Thecyclebeginshere).AtrialContraction

SystoleIsovolumetricVentricularContractionEjection

PhasesoftheCardiacCycleEventsduringeachphaseofthecardiaccyclearerepresentedonWigger'sDiagram:

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SlowVentricularFilling(Diastasis)

Inslowventricularfilling:

TheAVvalvesareopenandthesemi-lunarvalvesareclosedTheventricleisrelaxedcompletelyandfillsslowlyTheventricleshavebeenmostlyfilledduringrapidventricularfillingandsothepressuregradientisreducing.

ThepressureineachventricleisalmostzeroArterialpressureisfalling,asitisend-diastoleCVPisslowlyrisingastheventricleandatriafillThisperiodoccursaftertheydescent.TheECGwillshowthebeginningsofaP-waveattheendofthisphase

AtrialContraction

Theatriacontract,andremainingbloodintheatriaisejectedintotheventricle.Thissupplies10%oftheventricularfillingatrest,butupto40%intachycardia.

Inatrialcontraction:

ArterialpressureisstillfallingTheCVPwaveformdemonstratestheawaveasatrialcontractionalsocausesbloodtorefluxintotheSVCTheECGwillshowthePRinterval

IsovolumetricVentricularContraction

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OncetheactionpotentialpassesthroughtheAVnodeandbundleofHis,ventricularcontractionbegins.

Inisovolumetriccontraction:

Ventricularpressurerises,andtheAVvalvescloseThisgivesrisetothefirstheartsound,S .

Asventricularpressureisstilllessthansystemicvascularpressure,thesemilunarvalvesremainclosedArterialpressureisstillfallingTheCVPwaveformshowstheC(closure)wave,asthetricuspidvalveherniatesbackintotheRAduringventricularcontractionThereisasimilarspikeinLApressureasthemitralvalvealsobulgesbackintotheLA.TheECGwillshowtheremainderoftheQRSorthestartoftheQTinterval

Atrialrepolarisationoccursatthisstage,butistypicallymaskedbyventriculardepolarisation

Ejection

Whenventricularpressureexceedsarterialpressure,thesemilunarvalvesopenandejectionoccurs.Initialejectionisrapid,butasventricularpressurefallsandsystemicpressurerisesthegradientfallsejectionbecomesslower.

Duringejection:

Arterialpressurerisesrapidly,andisslightlylessthanventricularpressureduringthisstageTheCVPwaveformshowsthexdescent,astheshorteningRVpullstheRAdown,rapidlyloweringCVPTheSTsegmentshowsontheECGastheventriclesarefullydepolarised,thoughtheTwavemayappearinlateejection

IsovolumetricRelaxation

Whencontractioniscomplete,theventriclesbegintorelax.Inertiameansthatejectioncontinuesforashorttime.

Duringisovolumetricrelaxation:

ThesemilunarvalvescloseThisgivesrisetothesecondheartsound,S ,andmarksthebeginningofisovolumetricrelaxation.

ThisoccurswhenventricularpressurefallsbelowvascularpressureArterialpressurebeginstofall,interruptedbythedicroticnotchwhichisabriefincreaseinarterialpressureasthesemilunarvalvescloseThevwaveisvisibleontheCVPwaveformDuetoatriafillingagainstclosedAVvalves.TheendoftheTwaveisvisibleontheECGasventricularrepolarisationoccurs

RapidVentricularFilling

Mostofventricularfillingoccursinthisphase.Thisisbecauseinearlyventriculardiastoletheventricleisstillrelaxingandsoapressuregradientismaintainedbetweentheatriaandventricle.

Duringrapidventricularfilling:

TheAVvalvesopenandventricularfillingoccursThisoccurswhenatrialpressureexceedsventricularpressure.ArterialpressureisfallingTheydescentoccurswhentheAVvalvesopen,causingarapiddropinCVPastheventriclesfillNoelectricalactivityisproduced-theECGshowstheTPinterval

1

2

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References

1. Hall,JE,andGuytonAC.GuytonandHallTextbookofMedicalPhysiology.11thEdition.Philadelphia,PA:SaundersElsevier.2011.

2. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.3. Wigger'sDiagram(withsomemodifictions)fromWigger'sDiagram.21/3/2012.(Image).ByDanielChangMD(revised

originalworkofDestinyQx);RedrawnasSVGbyxavax.CCBY3.0,viaWikimediaCommons.

Lastupdated2019-07-18

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CardiacActionPotentialExplaintheionicbasisofspontaneouselectricalactivityofcardiacmusclecells

Describethenormalandabnormalprocessesofcardiacexcitationandelectricalactivity

Anactionpotentialisapropagatingchangeinthemembranepotentialofanexcitablecell,usedincellularcommunicationandtoinitiateintracellularprocesses.Itiscausedbyalteringthepermeabilityofamembranetodifferentions.

PacemakerPotentialThispatternofelectricalactivityisseenintheSAandAVnodes.Ithasnorestingstate,andiscontinuallydepolarising.

PhasesofthePacemakerPotential

Phase0Beginsatthethresholdpotentialof-40mV,withapeakmembranepotentialof20mV.Drivenpredominantlybythevoltage-gatedL-type(long-lasting)Ca channelscausinganinfluxofcalciumions.Phase3Repolarisationphase,whichoccursasK channelsopenandCa channelsclose.Thenadiriscalledthemaximumdiastolicpotentialandis-65mV.Phase4Phase4consistsof:

ThefunnycurrentAsteadyinfluxofNa /K whichgraduallydepolarisesthecell.

Sympatheticstimulationincreasesthefunnycurrent,increasingtherateofdepolarisation.ParasympatheticstimulationincreasesK permeability,hyperpolarisingthecellandflattensthegradientofphase4.

2+

+ 2+

+ +

+

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CalciumcurrentInphase4,thisisthetransientcalciumcurrent,drivenbyT-typecalciumchannels.Theyopenwhenthemembranepotentialreaches~-50mV,alsocausingdepolarisation.

VentricularActionPotential

Topreventtetaniccontraction(whichwouldbebad)ventricularmusclehasalongplateaupriortorepolarisation,whichlengthenstheabsoluterefractoryperiodto250ms.Therelativerefractoryperiodis50ms.

PhasesoftheVentricularActionPotential

Phase0:DepolarisationAtthethresholdpotential,voltage-gatedfast-Na channelsopenbriefly,causingdepolarisation.Themembranepotentialpeaksat30mV.Phase1:PartialRepolarisationTheclosureofNa channelsresultsinK fleeingthecelldownitselectrochemicalgradient,causingaslightdropinvoltagecalledpartialrepolarisation.Phase2:PlateauL-typeCa channelsopen,causingaslowinwardCa currentwhichmaintainsdepolarisationandfacilitatesmusclecontraction.Phase3:RepolarisationMembranepermeabilitynormalises,andoutwardpotassiumcurrentreturnsthemembranepotentialtonormal.Phase4:RestingPotentialMembranepotentialreturnstoitsresting-85mV.

PropagationoftheCardiacActionPotentialPacemakercells:

+

+ +

2+ 2+

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AreresponsibleforautomaticityandrhythmicityoftheheartThefastestpacemakeristhefocusformyocardialconductionThisistypicallytheSAnode.

ShouldtheSAnodefail,thenextfastestpacemakerwilltakeoverThisprovidesanelementofredundancy

Conductionpathway:

AtrialConductionFromtheSAnode,theimpulsetravelsat~1m.s ,depolarisingtheatria.

CurrenttravelsdownBachmann'sBundle,whichconnectstherightatriumtotheleftatrium

AVnodeTheAVnodeistheonly(normal)siteofconnectionbetweentheatriaandventricles.AVnodalcells:

Transmitswithadelayof0.1sThisallowstimeforatrialcontractiontofinishbeforeventricularcontractionbegins.Haveaprolongedrefractoryperiodandcannotconductmorethan220impulsesperminute

Thisperiodisprolongedbyvagalstimulation,whichincreasespotassiumpermeabilityandhyperpolarisesthecellConversely,sympatheticstimulationincreasescalciumpermeabilityandallowsmorerapidtransmission

Conductsviathreepathways:BachmannPathwayAlsoconductstotheLA.WenckebachpathwayThorelpathway

VentricularConductionFromtheAVnode,thesignalpropagates:

InitiallyviatheBundleofHistotherightandleftbundlesSecondlyviathePurkinjefibreswhichconductat1-4m.sPurkinjefibreshavealongrefractoryperiod,andspontaneouslydepolarisewithanintrinsicrateof30-40bpm.Lastly,ventricularmuscleisdepolarisedEndocardium,papillarymuscleandseptumcontractfirst,followedbyapex,followedbythechambers.

AutonomicControlParasympatheticInnervation

SAnodebytherightvagusThereiscontinualPNSinput("Vagaltone")viainhibitoryAChGPCR,reducingtheSAnodefromitsintrinsicrateof90-120bpmtoamoresedate60-100bpm.AVnodebytheleftvagusTheatriaareinnervatedbyparasympatheticneurons,whilsttheventriclesareonlyminimallyinnervatedPNSstimulationthereforehaslittleeffectoninotropy,butdoesaffectchronotropy.

PNSstimulationmayhavenodirecteffectoninotropy,insteadactingindirectlyviachangesinchronotropy

SympatheticInnervationSNSactivitycausesreleaseofnoradrenaline(atpost-ganglionicsynapse)andadrenalinefromadrenalmedullawhichstimulatecardiacβ receptorscausing:

PositivechronotropyattheSAnodePositiveinotropyatventricularmusclePositivelusitropyShorteractionpotentialduration(duetoopeningofrectifyingK channelsIncreasedAVconduction

-1

-1

1

+

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CardiacTransplant

Thetransplantedhearthasnovagal/parasympatheticinnervationbutstillexpressesβ receptors,soit:

Defaultstoarestingheartrateof~100bpmBecomeshighlypreloaddependentasitcannotrespondquicklytochangesinSVRNotresponsivetoparasympatholytics(atropine,glycopyrrolate)orephedrine(asthisisindirectly-acting)toincreasechronotropy-isoprenalinemaybeusedGradualresponsetodemandsinexercise(lackslocalSNSinnervation,butwillstillrespondtocirculatingcatecholamines)Increasedsensitivitytocatecholaminesduetoincreasedexpressionofβ receptors

References1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.3. MatsuuraW,SugimachiM,KawadaT,SatoT,ShishidoT,MiyanoH,NakaharaT,IkedaY,AlexanderJJr,SunagawaK.

Vagalstimulationdecreasesleftventricularcontractilitymainlythroughnegativechronotropiceffect.AmJPhysiol.1997Aug;273.

Lastupdated2019-07-18

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DeterminantsofCardiacOutputDefinethecomponentsanddeterminantsofcardiacoutput

CardiacoutputafunctionofHeartRate(HR)andStrokeVolume(SV):

.

Heartrateisfairlyintuitive

StrokevolumeisdefinedasthedifferencebetweenESVandEDV,i.e.Strokevolumeisafunctionofthreefactors:

PreloadAfterloadContractility

PreloadandafterloadhavealmostasmanydefinitionsastherearetextbooksForthepurposeoftheexam,it'sgoodtohavebothalaboratoryandaclinicaldefinitionThesedefinitionsarethosewhichhaveappearedinoldexaminerreports,orgiventomebycardiacanaesthetists

Preload

Preloadisdefinedasthemyocardialsarcomerelengthjustpriortocontraction.

Asthisisnotmeasurablewithoutremovingtheheartandcuttingitintotinypieces,clinicallyitisusuallyapproximatedbyEDVor,lessappropriately,byEDP

EDVistypicallycalculatedonechocardiographyEDPistypicallymeasuredusingaCVCorPAC

CVP≈RVEDPPCWP≈LVEDP

DeterminantsofPreload

Preloadisafunctionof:

VenousReturnIntrathoracicPressureMSFP

VenouscomplianceAdecreaseinvenouscompliancewillincreaseLVEDP.Volumestate

VentricularcomplianceReducedindiastolicdysfunction.PericardialcomplianceValvulardisease

AVvalvediseasewillimpairpreloadSemilunarvalvediseasewillincreasepreload

AtrialkickWallthicknessIncreasedventricularwallthicknessdecreasespreload.

HOCM/Hypertrophy

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PreloadandtheRespiratoryCycle

NegativeintrathoracicpressurecausesRAPandPCWPtofallThisincreasesRAfilling,soandRVEDPandRVEDVincreaserelativetothepleuralpressure(thoughabsolutepressureisstilllow)LVeffectsaremorevariableNegativeintrapleuralpressures:

IncreaseLVtransmuralpressureThisimpairsejection.CausebowingoftheinterventricularseptumintotheLVThisreducesLVEDV.

Frank-StarlingMechanism

TheFrank-StarlingLawoftheHeartstatesthatthestrengthofcardiaccontractionisdependentoninitialfibrelengthAtacellularlevel,additionalstretchincreases:

ThenumberofmyofilamentcrossbridgesthatcaninteractMyofilamentCa sensitivity

ThislawisrepresentedbytheventricularfunctioncurvePlotofpreloadagainststrokevolume(orcardiacoutput,assumingaconstantheartrate).

RightshiftofthecurvedemonstratesnegativeinotropyLeftshiftofthecurvedemonstratespositiveinotropy

Thefailingventricle:

Incardiacfailure,theventriclebecomesoverstretchedThisreducesthenumberofoverlappingcrossbridges,reducingcontractility.Thisislimitedintheacutesettingbyconstrictionofthepericardium,whichpreventsexcessiveventriculardilation

Afterload

2+

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Afterloadisthesumofforces,bothelasticandkinetic,opposingventricularejection

Thisdefinitionisabitwordybutavoidsusingthewords"resistance"and"impedance",whicharestrictlydefinedinphysics(andcrudelyappliedinmedicine),andmaybeleaptonbythecruelexaminer

DeterminantsofAfterload

Afterloadisequaltoventricularwallstress,whichisgivenbytheequation:

,where:

isventricularwallstress

isventriculartransmuralpressureisventricularchamberradius

isventricularwallthickness

Eachofthesefactorsareinturninfluencedby:

VentriculartransmuralsystolicpressureTransmuralpressureisthedifferencebetweenintrathoracicpressureandtheventricularcavitypressureduringejection.

IntrathoracicPressureNegativeintrathoracicpressurewillincreaseafterload,astheventriclehastogenerateagreaterchangeinpressuretoachieveejection.

PEEPreducesLVafterloadNegative-pressureventilationwithahighworkofbreathingincreasesafterloadThisiswhyAPOdeteriorates-increasedworkofbreathingincreasesLVafterloadandworsensLVfailure,increasedpulmonaryoedema,causingincreasedworkofbreathing...

VentricularcavitypressureTofacilitateejection,theventriclemustovercome:

OutflowtractimpedanceValvulardisease

e.g.aorticstenosisHOCM

SystemicarterialimpedanceDeterminedbyresistance(SVR),inertia,andcompliance:

DeterminantsofresistancearestatedinthePoiseuilleEquation:

,where:η=ViscosityAffectedbyhaematocrit(e.g.increasedinpolycythaemia)l=VessellengthEssentiallyfixed.r=Vesselradius

GreatestdeterminantFunctionofdegreeofvasoconstrictionofresistancevessels

InertiaGivenbythemassofbloodinthecolumnAffectedbyheartrate

ArterialcomplianceDecreasedarterialcomplianceincreasesafterload.

Duringejection,theaortaandlargearteriesdistend,reducingpeaksystolicpressure(impedanceto

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furtherejection)Decreasedarterialcomplianceincreasesthechangeinpressureforanygivenvolume,increasingafterloadduringejectionDecreasedarterialcomplianceincreasesthespeedofpropagationofreflectedpressureswavesreturningtotheaorticroot

WavearrivalindiastoleaugmentscoronarybloodflowWavearrivalduringsystolefurtherincreasesafterload

Indiastolethearteriesrecoilandbloodpressureandflowaremaintained-theWindkesseleffect.

VentricularchamberradiusEnd-DiastolicVolumeIncreasedEDVincreasesventricularradiusandthereforewalltension.

MyocardialwallthicknessIncreasingwallthickness(seenclinicallyasventricularhypertrophy)decreasesafterloadbysharingwalltension(theproductofpressureandradius)betweenalargernumberofsarcomeres.

ContractilityContractilitydescribesthefactorsotherthanheartrate,preload,andafterloadthatareresponsibleforforchangesinmyocardialperformance.

DeterminantsofContractility

ContractilityisprimarilydependentonintracellularCa .Determinantsinclude:

DrugsDisease

IschaemiaReducedATPproductionsecondarytohypoxia,whichimpairssarcoplasmicreticulumCa function.Furtherexacerbatedbyintracellularacidosisfromanaerobicmetabolism.HeartFailureImpairedcontractilityreserve,i.e.minimalincreaseincontractilitywithsympatheticstimulation.

ReducedpeakCa andsarcoplasmicreticulumuptakeofCaAutonomicToneBowditchEffectContractilityimprovesatfasterheartrates.Thisisbecausethemyocardiumdoesnothavetimetoremovecalcium,soitaccumulatesintracellularly.AnrepEffectContractilityincreasesasafterloadincreases.

MeasuringContractility

Aswiththeotherdeterminantsofcardiacoutput,therehasbeensomedifficultyindevelopingmeasurableindicesforcontractilityAllmeasuresofcontractilityareaffectedbypreloadorafterloadtosomeextent

dP/dt ( )TherateofriseofLVP,assumingaconstantpreloadandafterload

ThisindexispreloaddependentbutafterloadindependentTypically,thedP/dt inisovolumetricventricularcontractionisused

2+

2+

2+ 2+

max

max

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AgreaterrateofriseindicatesamoreforcefulcontractionMeasurementrequiresLVcatheterisation

End-SystolicPressure-VolumeRelationshipUsestheventricularPressure-VolumeRelationshipLineplottedatthetangenttothecurvefromtheend-systolicpoint(whenisovolumetricventricularrelaxationbegins)

Thesteeperthegradientthegreaterthecontractility

EjectionFractionMostcommonmethodusedclinicallyisejectionfraction:

FootnotesTheuseofwallstressforpreloadandafterloadcomesfromtheCardiovascularHaemodynamicstext,butisnotusedintheCICMtexts

Thissitehasaniceoverviewofwalltension,andtherelationshipofpressuretoradius

Thisarticlediscussesthewallstressdefinitionforpreloadandafterload

Changeswithventilationaredescribedwithprettygraphshere

References1. BrandisK.ThePhysiologyViva:Questions&Answers.2003.2. DerangedPhysiology-Haemodynamicchangesduringmechanicalventilation3. AnwaruddinS,MartinJM,StephensJC,AskariAT.Cardiovascularhemodynamics:anintroductoryguide,contemporary

cardiology.NewYork:Springer;2013.p.29–51.4. NortonJM.TowardConsistentDefinitionsforPreloadandAfterload.AdvancesinPhysiologyEducationMar2001,25(1)

53-61.5. ANZCAJuly/September2006

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VenousReturnDefinethecomponentsanddeterminantsofcardiacoutput

Thevenoussystemhastwokeycardiovascularfunctions:

BloodreservoirContains65%ofbloodvolume.Conduitforreturnofbloodtotheheart

Venousreturnistherateatwhichbloodisreturnedtotheheart(inL.min ).Atsteadystate,venousreturnisequaltocardiacoutput,andcanbeexpressedas:

,where:

isvenousreturn

isthemeansystemicfillingpressureThisisthemeanpressureofthecirculationwhenthereisnoflow.Itisanindicatorofcirculatoryfilling,andisafunctionofcirculatingvolumeandvascularcompliance.

Normalmeansystemicfillingpressureis~7mmHg

istherightatrialpressureAnelevatedRAPreducesvenousreturn.

istheresistancetovenousreturn

Thisrelationshipcanbeexpressedgraphically:

Whenvenousreturnis0,themeasuredrightatrialpressureisanindicationofmeansystemicfillingpressure

Alterationstocirculatingvolumeandcomplianceaffectbothvenousreturnandmeansystemicfillingpressure

-1

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Alterationstotheresistancetovenousreturnaffectvenousreturnbutmeansystemicfillingpressureisunchanged

FactorsAffectingVenousReturn

Venousreturnwillbealteredbyanyofthevariablesintheaboveequation:

MSFPVolumee.g.Haemorrhage,resuscitation.Compliance

RAPRespiratorypumpNegativeintrathoracicpressurereducesRAP,improvingvenousreturn.PositivepressureventilationPericardialcompliance

ConstrictionTamponade

ResistancetoVenousReturnPostureVascularcompression

ObesityPregnancyLaparoscopy

OtherfactorsaffectingvenousreturnSkeletalmusclepumpContractionoflegmusclesincombinationwithanintactvenoussystempropelsbloodbacktowardstheheart.

InteractionbetweenVenousReturnandCardiacFunctionCurves

Guyton'scurvecanbesuperimposedonStarling'scurvetoexaminetheinteractionbetweenvenousandcardiacfunctionoverarangeofconditions:

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References1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.2. BrandisK.ThePhysiologyViva:Questions&Answers.2003.3. HendersonWR,GriesdaleDE,WalleyKR,SheelAW.Clinicalreview:Guyton-theroleofmeancirculatoryfillingpressure

andrightatrialpressureincontrollingcardiacoutput.CriticalCare.2010;14(6):243.doi:10.1186/cc9247.

Lastupdated2019-07-18

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MyocardialOxygenSupplyandDemandDescribemyocardialoxygendemandandsupply,andtheconditionsthatmayaltereach

MyocardialoxygensupplyisafunctionofcoronarybloodflowMyocardialoxygendemandisdeterminedbymyocardialworkMyocardialischaemiaoccurswhendemandexceedssupply

MyocardialOxygenSupply

Myocardialoxygensupplyisdependenton:CoronaryarteryflowOxygencontentofbloodOxygenextraction

Functionally,coronaryarteryflowisthedeterminant.Thisisbecause:OxygencontentinindividualswithoutpulmonarydiseaseismaximalRestingmyocardialoxygenextractionisnear-maximal(~70%)ThishighERmakestheheartlesstolerantofanaemiathanorganswithalowER.

ThereforecoronarybloodflowisthelimitingfactorCoronarybloodflowisgivenbytheequation:

AorticrootpressureisthedrivingpressureforcoronaryflowCavity(ventricular)pressureactsasaStarlingresistorforcoronaryflow

NotethatifRAPexceedscavitypressure,RAPwillbethepressureopposingcoronaryflow(duetodownstreampressureatthecoronarysinus)

Notethatcavityandaorticrootpressurechangethroughoutthecardiaccycle,therefore:TheflowtoeachventricleisdifferentduringthecardiaccycleTheleftventricleisbestperfusedindiastoleThereforeheartrateisanimportantdeterminantofcoronarybloodflow,astachycardiawilldecreasecoronarybloodflow

Flowtoeachventricleisafunctionofhowrelationshipschangeoverthecardiaccycle

LeftVentricularCoronaryBloodFlow:

RightVentricularCoronaryBloodFlow:

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MyocardialOxygenDemand

Normalmyocardialoxygenconsumption(MVO )is21-27ml.min .Thethreemajordeterminantsare:

HeartrateAchangeinheartratewillchangethenumberoftension-generatingcycles,causingaproportionalchangeinMVO .

Contractility

Referstotherateoftensiondevelopmentaswellasitsmagnitude.Changing willchangeMVO .

VentricularwalltensionVentricularwalltensionispressurework,ortheworkdonebytheventricletogeneratepressurebutnottoejectvolume.

WalltensionisgivenbytheLawofLaPlace

,where:

=Pressureduringcontraction=Radius

Walltensionisthereforeafunctionof:AfterloadIncreasingafterloadwillincreasethepressureduringcontraction.PreloadIncreasingpreloadwillincreaseradius,buttoalesserextentthanincreasingafterload.

Thisisbecausevolumeandradiusarenotdirectlyproportional

Minordeterminantsofmyocardialworkare:

ExternalworkExternalworkcanalsobethoughtofasvolumework,ortheenergyexpendedtoejectbloodfromtheventricle.

Thisisencompassedbytheareaenclosedbythepressure-volumeloopConversely,internalworkisdefinedastheworkrequiredtochangetheshapeoftheventricleandprepareitforejectionOnthepressure-volumeloopinternalworkisrepresentedbyatrianglebetweenthepointof0pressureandvolume,theendsystolicpoint,andthebeginningofrapidventricularfilling.

Thisisaminordeterminantbecausethemajorityofventricularworkisgeneratingthepressurerequiredtoejectblood,notactuallymovevolumeExternalworkisofgreaterimportanceathighCOExternalworkisusedtocalculatecardiacefficiency,givenbytheequation:

Basaloxygenconsumption

2-1

2

2

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Basaloxygenconsumption(~8ml.min .100g )comprises~25%ofMVO .

References1. GrossmanW,BaimDS.Grossman'sCardiacCatheterization,Angiography,andIntervention.7thEd(revised).2006.

LippincottWilliamsandWilkins.2. LeslieRA,JohnsonEK,GoodwinAPL.DrPodcastScriptsforthePrimaryFRCA.CambridgeUniversityPress.2011.3. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.4. MillerRD,ErikssonLI,FleisherLA,Weiner-KronishJP,CohenNH,YoungWL.Miller'sAnaesthesia.8thEd(Revised).

ElsevierHealthSciences.

Lastupdated2017-10-04

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Pressure-VolumeRelationshipsDescribethepressure-volumerelationshipsoftheventriclesandtheirclinicalapplications

LeftVentricularP-VLoop:

PlotofleftventricularvolumeversuspressureTimeisnotdirectlydemonstratedonthisgraph,butthestagesofthecardiaccyclecanbeinferred:

A-BisisovolumetricrelaxationVentricularpressureislessthanaorticpressurebutgreaterthanatrialpressure,sobothmitralandaorticvalvesareclosed.B-Cisrapidandslowventricularfilling,followedbyatrialsystoleAtrialsystoleissometimesdemonstratedbyasharp'bump'towardsC,asventricularpressurewillbrieflyriseoutofproportiontoventricularvolumeC-DisisovolumetriccontractionTheventriclecontracts.Asventricularpressureisgreaterthanatrialpressurebutlessthanaorticpressure,themitralvalvecloses(pointC)andtheaorticvalveremainsclosed.Pressureincreaseswithoutachangeinvolume.

ThisslopeofthislineisknownasthedP/dt ( ),andisanindexofcontractilityD-AisventricularejectionWhenventricularpressureexceedsaorticpressure,bloodisejectedintotheaortaandventricularvolumedecreases.

TheslopeofthelineB-CgivestheelastanceoftheventricleThisisalsoknownastheEnd-DiastolicPressureVolumeRelationship(EDPVR),andisoften(erroneously)referredtoasventricularcompliance.

ElastanceoftheventricleincreasesasitisfilledThisisdemonstratedbythedashedline.

TheventricleonlyoverfillsathighfillingpressuresIncreasedelastance(suchasindiastolicdysfunction)isdemonstratedbyanincreasedslopeofthisline,suchthatventricularpressurewillbehigheratanygivenvolumeBothventricularandarterialelastancearelowinnormalcircumstances(astateknownasventricular-arterialcoupling),asthisallowstheventricletoachieveawiderangeofvolumetransfersinejectionwithminimalchangeinfillingpressure.

ThehorizontaldistancebetweenpointB(ESV)andC(EDV)givethestrokevolumeEjectionfractioncanthenbecalculated.PreloadisgivenbytheEDVAfterloadis:

Technicallygivenbythepressure-volumerelationshipthroughouttheentiretyofejectioni.e.theslopeD-A.

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ThiscomesfromLaPlace'slaw:

UsuallyassumedtogivenbytheslopeofalinedrawnfromtheEDV(onthex-axis)totheend-systolicpoint(pointA)Thisisalsoknownasthearterialelastanceline.

ThegradientofthearterialelastancelinecanbeworkedoutfromtheloopsThisisdifferentfromtheaboveformulabecauseitonlyconsidersthepressure-volumerelationshipatend-systole,notthroughouttheentiretyofejection

isagoodsubstituteforafterloadbecauseitisrelativelyindependentofpreloadandcontractility,andwillvarywithchangesinafterload

i.e.Foragivenstrokevolume,anincreasein leadstoanincreaseinSBP.Similarly,iftheventricleisunable

tomaintainagivenstrokevolumeas increases,thenSBPwillfall.Contractilityisgivenbytheslopeoftheend-systolicpressurevolume-relationship

Alsoknownaselastanceatend-systole,or ,andisgivenbythetangenttothecurveatend-systole.Thismeasurementisnotentirelyindependentofotherfactors,asitisinfluencedbyafterload

BasicPressure-VolumeLoops

Theseloops:

ShowisolatedchangestoonefactoronlyArenotaccurateofreal-worldphysiologyInreality:

ChangingonefactorwillinfluenceotherfactorsThesevalueschangebeat-to-beat

LeftVentricularP-VLoop-IncreasedPreload:

EDVisincreased,bydefinitionTheslopeoftheESPVRremainsunchanged(ascontractilityisunchanged)

Theslopeoftheafterloadline( )isunchanged(asafterloadisunchanged),butitisright-shiftedduetotheincreasedend-diastolicvolumeESVisincreased,thoughlessthanEDV,suchthatstrokevolumeincreases

LeftVentricularP-VLoop-IncreasedAfterload:

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EDVisunchanged(aspreloadisunchanged)TheslopeoftheESPVRremainsunchanged(ascontractilityisunchanged)

Theslopeoftheafterloadline( )hasincreased,butitsx-interceptisunchangedNotethatthepressure-volumerelationshipthroughoutejectionisalsosteeper,anddiastolicpressurehasincreased.ESVisincreased,causingareductioninstrokevolume

LeftVentricularP-VLoop-IncreasedContractility:

EDVisunchanged(aspreloadisunchanged)

Theslopeandx-interceptoftheafterloadline( )isunchanged(asafterloadisunchanged)TheslopeoftheESPVRhasincreased,thoughitsx-interceptisthesameESVisdecreased,causinganincreaseinstrokevolume

AdvancedPressureVolumeLoopsTheeasiestwaytoapproachmorecomplicatedpressure-volumeloopsistoaddresseachofthebasicfactorsbeforetryingtodrawthecurve:

Howispreloadchanged?Howisafterloadchanged?Howiscontractilitychanged?Howareisovolumetriccontractionandisovolumetricrelaxationchanged?

Theseshowtheloopfortheprimaryphysiologicalchange,withoutcompensatoryresponses:

LeftVentricularP-VLoop-AorticStenosis:

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PreloadisincreasedduetothehigherESV,astheventriclestartsfillingfromahigherpointOutflowtractimpedanceincreasesventricularwallstressandthereforeafterloadThisleadstothedecreaseinstrokevolume.Contractilityisunchanged

LeftVentricularP-VLoop-AorticRegurgitation:

PreloadisdramaticallyincreasedastheventriclefillsfromboththeaortaandatriaduringdiastoleAfterloadisincreasedduetothegreaterwallstressduringejectionContractilityisunchangedThereisnotrueisovolumetricrelaxation,astheventriclewillbegintofillfromtheaortaatthecompletionofejectionDiastolicpressureisdecreasedandsotheperiodofisovolumetriccontractionisbrief

LeftVentricularP-VLoop-MitralStenosis:

PreloadisreducedduetotheincreasedgradientacrossthemitralvalveTheeffectofthisisheartratedependent,andwillworsenasheartrateincreases.AfterloadisunchangedAfterloadmayfallduetothereductioninventricularwallstress.

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ContractilityisunchangedESVdecreases(duetothereducedpreload),thoughlessthanEDV,suchthatstrokevolumeisreduced

LeftVentricularP-VLoop-MitralRegurgitation:

PreloadisincreasedastheregurgitantvolumeincreasesleftatrialpressureandthereforeventricularfillingpressureAfterloadisreducedasbloodisejectedintothelow-pressureatrialsystemContractilityisunchangedThereisnotrueisovolumetriccontractionphaseasbloodisejectedintotheatriawhileventricularpressureexceedsatrialpressureThereisnotrueisovolumetricrelaxationphase,asonceatrialpressureexceedsventricularpressuretheventriclewillbegintofillApparentstrokevolumeisincreasedduetothelargedifferencebetweenEDVandESV,howevereffectivestrokevolumeisreducedasonlyaportionofthisisforwardflow

RightVentricularP-VLoop:

TherightventricularcurveisverydifferenttotheleftventricularcurveRVpreloadisincreasedrelativetoLVpreloadNotethatstrokevolumeisthesame(asbothsidesshouldhavethesamecardiacoutput).RVafterloadisdramaticallyreducedduetothelow-resistancepulmonarycirculation

MuchoftheRVejectionoccursaftersystolicpressureisreachedTherightventricleisverysensitivetochangesinafterload

ContractilityisreducedRightheartcontractilityispartiallydependentoncoordinatedcontractionwiththeLV(particularlytheseptum),andthereforeisdecreasedwithLVsystolicfailureorconductingsystemdisease(suchasbundlebrachblock).

Footnotes

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TheKhanAcademyseriesChangingthePressure-VolumeLoopisafantasticintroductiontothetopic.

References1. BrandisK.ThePhysiologyViva:Questions&Answers.2003.2. Klabunde,RE.[VentricularPressure-VolumeRelationship(http://www.cvphysiology.com/Cardiac%20Function/CF024).

CardiovascularPhysiologyConcepts.2015.3. Desai,R.Arterialelastance(Ea)andafterload.KhanAcademy.4. Redington,AN.CardiopulmonaryandRight–LeftHeartInteractions.ThoracicKey.5. BorlaugBA,KassDA.Ventricular-VascularInteractioninHeartFailure.Heartfailureclinics.2008;4(1):23-36.

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CardiacReflexesDescribethecardiacreflexes

Cardiacreflexesarefast-actingreflexloopsbetweentheCVSandCNSwhichcontributetothemaintenanceofcardiovascularhaemostasis.

Theyinclude:

BaroreceptorreflexAorticarchandcarotidsinusreflexes.

BainbridgereflexAtrialstretchreceptorreflexes.

ChemoreceptorreflexDecreasedPaO <50mmHgordecreasedpHsensedbyperipheralchemoreceptorscausessubsequenttachycardiaandhypertension.

CushingreflexBrainstemcompressioncausesischaemiaofthevasomotorcentreleadingtoCushings'Triad:

HypertensionMayhaveawidepulsepressure.BradycardiaDuetobaroreceptorresponsefromhypertension.Irregularrespirations

Bezold-JarischreflexStimulationofCfibresofthevagusnerveinthecardiopulmonaryregion.

Thiscauses:SignificantbradycardiaHypotensionApnoea,followedbyrapidshallowbreathing.Thesefibrescanbestimulatedbyanumberofsubstances,including:

CapsaicinSerotoninThoseproducedinmyocardialischaemia

OculocardiacreflexPressureontheglobeortractiononocularmusclescausesadecreaseinheartrate.Thisismediatedbythe:

Trigeminalnerve(afferentlimb)Vagusnerve(efferentlimb)IncreasedvagaltonereducesSAnodalactivity.

References

1. CICMSeptember/November20132. BarrettKE,BarmanSM,BoitanoS,BrooksHL.Ganong'sReviewofMedicalPhysiology.24thEd.McGrawHill.2012.3. OpenAnaesthesia-Oculocardiacreflex:afferentpath

Lastupdated2019-07-18

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StarlingForcesDescribetheessentialfeaturesofthemicro-circulationincludingfluidexchange(Starlingforces)andcontrolmechanismspresentinthepre-andpost-capillarysphincters

Interstitialfluidisanultrafiltrateofplasma,withthenetfiltrationpressuredeterminedbytheneteffectofopposinghydrostaticandoncoticpressures:

ThesefourvariablesareknownasStarling'sforces.

Actualfluidmovementis(ofcourse)morecomplicated.Hydrostaticpressurefallsalongthecapillary,andmovementofsoluteandwaterareaffectedbyotherfactors.Someofthesearedescribedbythe:

Reflectioncoefficient(σ)Thisdescribesthefactthatasmallamountofproteinleaksfromthecapillary,slightlyincreasinginterstitialoncoticpressureandslightlydecreasingcapillaryoncoticpressure.Itisdependentontheinterstitialproteincontent,andhasavaluebetween0and1.

Filtrationcoefficient(Kf)Encompassesmembranepermeability(towater)andmembranesurfacearea.Variesbetweentissues:

TheStarlingEquationbecomes:

TypicalValuesforPressures(mmHg)

Arteriolarend Venousend

Capillaryhydrostaticpressure 25 10

Interstitialhydrostaticpressure -6 -6

Capillaryoncoticpressure 25 25

Interstitialoncoticpressure 5 5

Organ-SpecificValues

Intheglomerulus:

Reflectioncoefficientiscloseto1duetotheimpermeabilityoftheglomerulustoproteinKfishighduetobothhighpermeabilityandalargesurfacearea.HydrostaticpressureishighGlomerularoncoticpressureisessentially0

Intheliver:

Reflectioncoefficientiscloseto0inhepaticsinusoidsastheyareverypermeabletoprotein

Inthelungs:

Reflectioncoefficientof~0.5inthelungsduetosignificantleakofproteinProteinleakdecreasesasinterstitialoncoticpressurerises,limitingfurtheroedemaformation

Theoncoticpressuregradientissmall,andfavoursreabsorption

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Hydrostaticpressuregradientissmall,butfavoursextravasationoffluidInterstitialhydrostaticpressurebecomesmorenegativeclosertothehilum,drawingfluidintothepulmonarylymphatics

CausesofOedema

Oedemacanbelocalisedorgeneralised,andinbothcasescausedby:

IncreasedFiltrationPressureOccurswhencapillaryhydrostaticpressureexceedsinterstitialhydrostaticpressure.Causes:

IncreasedVenouspressureThisincludesanincreaseinCVP:

CCFTRIncreasedvenoconstrictionIncreasedMSFP

ImpairedvenousreturnObstructionRespiratorymusclepumpSkeletalmusclepump

Positioning

DecreasedOncoticPressureGradientDecreasedplasmaprotein

HepaticfailureCriticalIllness

IncreasedinterstitialoncoticpressureMannitol/starchextravasation

Increasedcapillarypermeability

InflammatoryproteinsSubstancePHistamineKinins

InadequateLymphFlow

References

1. BarrettKE,BarmanSM,BoitanoS,BrooksHL.Ganong'sReviewofMedicalPhysiology.24thEd.McGrawHill.2012.2. Brandis,K.Starling'sHypothesis.AnaesthesiaMCQ.3. ANZCAAugust/September2001

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VariationsinBloodPressureDescribethephysiologicalfactorsthatmaycontributetopulsevariationsinbloodpressure

Bloodpressureisnotuniformthroughoutthecirculation.Ventricularejectiongeneratestwowaves:

AbloodflowwaveTravelsat~20cm.s .AnarterialpressurewaveDistendstheelasticwallsofthelargearteriesduringsystole,whichthenrecoilduringdiastoletofacilitatecontinualbloodflow.ThisistheWindkesseleffect.

Thiswavetravelsat4m.sThisiswhatisfeltwhenpulsesarepalpated,andwhatisseenonthearteriallinewaveform

Keypressuresmeasuredare:

SystolicbloodpressureMaximalpressuregeneratedduringejection.

Determinedby:StrokevolumeSystolictimeArterialcomplianceReflectedpressurewave

Relevantfor:Bleeding

ClotdisruptionAneurysmalwallpressure

DiastolicpressurePressureexertedbythecirculationupontheaorticvalve.

Determinedby:CirculatorycomplianceCirculatingvolumeAorticvalve(in)competence

Relevantfor:Coronaryperfusion

MeanarterialpressureAveragepressureinthecirculationthroughoutthecardiaccycle,asmeasuredbytheareaunderthecurveofthearteriallinewaveform.

Determinedby:SystolicbloodpressureDiastolicbloodpressureHeartrateIncreasingHRwilltendtoincreaseMAP,asoverallsystolictime(andthereforetimespentathigherpressure)isincreased.Shapeofthearterialwaveform/diastolicrunoffTheslowdecreaseinpressureafterpeaksystolicpressurerepresentelasticrecoiloflargearteries,increasingthepressuredrivingbloodintotheperipheralcirculation.Alongerdiastolicrunoffperiodleadstoalargerareaunderthecurve,andahigherMAP.

Relevantfor:Organperfusion

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ChangesbySiteofMeasurement

Measuredpressurechangespredictablyatmoredistalsites:

AllgradientsareincreasedArterialupstrokeandfalloffarebothsteeper.TheSBPincreasesDBPdecreasesMAPisconstantThedicroticnotchoccurslaterandbecomeslesssharpThisoccursduetoreflectionsinarterialpressurewaves.

RespiratoryVariationVentilationcausesvariationinpeaksystolicpressureduetodynamicchangesincardiacloadingconditions:

Negativepressurerespiration(i.e.regularbreathing)generatesanegativeintrathoracicpressureduringinspirationLeadstoincreasedVR,butalsopoolingofbloodinthepulmonarycirculationandrelativeunderfillingoftheLV,leadingtoadecreaseinSVandpeaksystolicbloodpressure.PositivepressureventilationcausesthereverseIncreasedintrathoracicpressureduringinspirationresultsinadecreasedvenousreturnbutincreasesLVfillingviacompressionofthepulmonarycirculation.Whenthischangeis>10mmHg,itisknownaspulsusparadoxusThemagnitudeofthiseffectvarieswith:

MagnitudeofintrathoracicpressurechangeLargechangesinintrathoracicpressurecausecorrespondinglylargerchangesinventricularfilling.Otherfactorsaffectingcardiovascularfunction

PreloadVolumestate

CompliancePericardialcompliance

ConstrictionTamponade

CardiaccomplianceDiastolicdysfunction

AfterloadPERaisedintrathoracicpressure

PEEPTensionPTHx

Thesedifferencescanbemeasured:QualitativelyBylookingatrespiratoryswingonanarteriallineorplethysmograph;orbypalpation.QuantitativelyUsingpulsepressureorstrokevolumevariation.

PulsePressureVariation

Describesthevariationinpulsepressureoverthecourseofarespiratorycycle.Pulsepressurevariationis:

Mathematicallydefinedas:

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Therefore,itiscalculatedasapercentUsedasanindicatoroffluidresponsiveness

PatientshigherontheFrank-Starlingcurvewillhavelesschangeinstrokevolumewithanincreaseinpreload,andtherefore:

ReducedPPVBelessfluidresponsive

APPVof>12%suggestsvolumeresponsiveness.Notethatthisdoesnotnecessarilymeanafluidresponsivepatientneedsfluid.

Reliantonseveralassumptions:RegularsinusrhythmIrregularheartrates(particularlyAF)leadtosignificantalterationsinventricularfillingandthereforepulsepressure,independentoftherespiratorycycle.ControlledmechanicalventilationNospontaneousefforts.AdequatetidalvolumesMustbe>8ml.kg .NormalchestwallcomplianceRequiresaclosedchest.

StrokeVolumeVariation

SVVis:

Alternatelydefinedas:Thepercentchangeinstrokevolumeduringinspirationandexpirationovertheprevious20secondsVariationofbeat-to-beatSVfromthemeanvalueovertheprevious20seconds

CalculatedbyspecialiseddevicesfromaninvasivearterialwaveformCalculationincorporates:PulsepressureVascularcomplianceEstimatedfromnomogramsbasedonpatientage,gender,height,andweight.VascularresistanceEstimatedfromarterialwaveformshape.

AnalternativetoPPVinmeasuringfluidresponsivenessReliesonsimilarprinciples.ProbablylessspecificbutmoresensitivethanPPVforidentifyingfluidresponders

CirculatoryFactors

Changesincirculatoryfunction:

Inotropy

Therateofsystolicupstrokeisrelatedto ,andthereforecontractility.SVRThegradientbetweenthepeaksystolicpressureandthedicroticnotchgivesanindicationofSVR.E.g.,asteepdownstrokesuggestsalowSVR,asthepressureinthecirculationrapidlyfallswhenejectionceases.Preload

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Abeat-to-beatvariationisseenwiththerespiratorycycle,duetothechangeinpreloadoccurringwithchangesinintrathoracicpressure.

PathologicalChanges

Somepathologicalcausesinclude:

AorticStenosisCausesareductionin:

PulsepressureDuetoreducedstrokevolume.GradientofupstrokeDuetoreducedstrokevolume.

AorticRegurgitationWidepulsepressureCombinationof:

IncreasedSBPduetotheincreasedforceofejectionduetoincreasedpreload(StarlingsLaw),whichoccursduetohighESVDecreasedDBPduetopartofthestrokevolumeflowingbackintotheventriclethroughtheincompetentvalve

References

1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.2. Buteler,BenjaminS.Therelationofsystolicupstroketimeandpulsepressureinaorticstenosis.BritishHeartJournal.1962.3. Mark,JonathanB.Atlasofcardiovascularmonitoring.NewYork;Edinburgh:ChurchillLivingstone,1998.4. MarikPE.Techniquesforassessmentofintravascularvolumeincriticallyillpatients.JIntensiveCareMed.2009;24(5):329-

37.5. SolimanRA,SamirS,elNaggarA,ElDehelyK.Strokevolumevariationcomparedwithpulsepressurevariationand

cardiacindexchangesforpredictionoffluidresponsivenessinmechanicallyventilatedpatients.EgyptJCritCareMed.2015;3(1):9-16.doi:10.1016/J.EJCCM.2015.02.002

Lastupdated2019-07-18

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PulmonaryCirculationOutlinetheanatomyofthepulmonaryandbronchialcirculations

Describethephysiologicalfeaturesofthepulmonarycirculationanditsresistance

Understandthedifferencesbetweenthepulmonaryandsystemiccirculation

Thepulmonarycirculationis:

Alow-pressure,high-flow,high-pulsatilitycirculationSuppliedbythepulmonarytrunk(pressure25/8mmHg),drivenbytheRV(pressure25/0mmHg)

Arteriesandveinsrunwiththebronchiasfarastheterminalbronchioles,dividingatthesamepointsBeyondthis,theyformacapillarybedsothinitisessentiallysheetofflowingbloodpunctuatedbyalveoli

Thebronchialcirculation:

Arisesfromthesystemiccirculation,andsuppliesbloodtotheconductingzoneofthelungAthirddrainsbacktothesystemiccirculationTheremainderdrainsintothepulmonaryvessels-thisisaphysiologicshunt

Supplytotumoursispredominantlyfromthebronchialcirculation(ratherthanthepulmonarycirculation)asthesevesselsrespondtoangiogenicfactors.

DifferencesbetweenPulmonaryandSystemicCirculations

BloodPressure

Pulmonaryarterialpressureis25/8mmHg(MAP15mmHg)comparedto120/80mmHg(MAP100mmHg)inthesystemiccirculation.Thisisbecausethesystemiccirculationmust:

RegulateflowtodifferentorgansatdifferenttimesItthereforecontainsresistancevesselswhichallowittoallocatecardiacoutputaccordingly.Maintainflowtoorgansfarabovetheheart

Conversely,thepulmonarycirculationmust:

Accepttheentiretyofcardiacoutput,withlittlecapacitytoregulateflow(hypoxicvasoconstrictionbeingtheexception)Minimiseextravasationoffluid

AsperStarlingsLaw,fluidmovementoutofthecapillaryisgivenbythedifferenceinhydrostaticgradientsandoncoticgradientsThenetoncoticgradientissmall(butfavoursreabsorption),howeverthepulmonaryinterstitiumhasnohydrostaticpressureIncreasedpulmonarycapillarypressurethereforecausesextravasationoflargevolumesoffluid

Consequently,pulmonaryvesselsarethinwalledandcontainminimalsmoothmuscleThismakesthepulmonarycirculationhighlycompliant-thevolumeofbloodisabletochangesubstantiallywithminimalchangeinpressure

PulmonaryVascularResistance

VascularresistancefollowsOhmslaw,i.e.:

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Pulmonaryvascularresistanceis~1/10 thatofthesystemiccirculationThisisbecausethepressuredropacrossthepulmonarycirculationis10mmHg(MPAP-LAP),~1/10 thatofthesystemiccirculation,andflowisthesame

Determinantsofpulmonaryvascularresistanceare:

PulmonaryArteryPressureIncreasedPAPcausesadecreaseinPVR.Thisoccursbecause:

PreviouslyclosedpulmonarycapillariesarerecruitedwhentheircriticalopeningpressureisreachedThisismoreimportantwhenMPAPislow.VesselsdistendathigherpressuresThisismoreimportantwhenMPAPishigh.

LungvolumeLungvolumehasavariableeffectonPVR.

Atlargelungvolumes:Resistanceinlargeextra-alveolarvesselsdecreasesasthevesselsarepulledopeningbydistensionofelastictissuesResistanceinsmallintra-alveolarvesselsincreasesastheyarecompressedbythehighlungvolumes

Atsmalllungvolumes,thereverseoccurs

HypoxicPulmonaryVasoconstrictionLowPAO causesavasoconstrictioninthevesselssupplyingthatalveolus,increasingPVRanddirectingbloodtobetterventilatedalveoli.

LowalveolarPO istheprimarydeterminantLowmixedvenousPO alsocontributesConstrictionbeginswhenP O fallsbelow100mmHg,andbecomesdramaticbelow70mmHgThisisimportantin:

FoetalcirculationAlveolarconsolidation

PneumoniaCardiogenicpulmonaryoedema

thth

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RaisedLVEDPincreasespulmonaryvenouspressures.Basalalveoliaremoreaffected.HPVcausesconstrictionofbasalvessels,increasingbloodflowtoapicalalveoliandresultinginupperlobediversionseenonchestx-ray.

HighaltitudeHPVisattenuatedby:

ElevatedLAPGreaterthan25mmHg.HighCO

MinorfactorswhichaffectPVR:IncreasePVR:

HypercarbiaHypothermiaAcidaemiaPain

DecreasePVR:BronchodilatorsVolatiles

ResponsetoSubstances

Oxygen:

ThepulmonarycirculationconstrictswhenPO falls,whilstthesystemiccirculationdilates

CarbonDioxide:

ThepulmonarycirculationconstrictionswhenPCO rises,whilstthesystemiccirculationdilates

DistributionofPulmonaryFlowGravityhasasignificanteffectonpulmonarybloodflow:

Intheuprightlung,flowdecreasesalmostlinearlywithheightInthesupinelung,flowtoposteriorregionsexceedsthatofanteriorregionsThisoccursduetothelowdrivingpressureofthepulmonarycirculation,whichmeansgravityhasamuchmoresignificantaffectonpulmonarybloodflowthansystemicbloodflow.

West'sZones

Thelungisdividedintofourzones,basedontherelationshipbetweenalveolarandvascularpressures:

West'sZone1InWest'sZone1,PA>Pa>Pv.

Thisshouldnotoccurinnormalconditions,becauseanormalpulmonaryarterypressureisnormally(just)sufficientThisisbecauseintheuprightlung,thehydrostaticpressuredifferencewillbeabout30cmH O.However,ifalveolarpressureisraised(e.g.IPPV),orarterialpressurefalls(shock),theremaybearegionwherealveolarpressureexceedsarterialpressure

West'sZone2InWest'sZone2,Pa>PA>Pv.

Here,flowisdeterminedbythearterial-alveolarpressuregradientratherthanthearterial-venousgradientAlveolarpressureactsasaStarlingResistor,whereflowisindependentofdownstreampressure.

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West'sZone3Occurswhenalveolarpressurefallsbelowvenouspressure,i.e.Pa>Pv>PA.Flowisdependentonthearterial-venouspressuregradient.Capillarypressureincreasesalongtheirlength,increasingtransmuralpressureandmeanwidth.

West'sZone4Occursatlowlungvolumes,asextra-alveolarvesselscollapseandshuntoccurs.TheinterstitiumisactingasaStarlingresistor,whichcanbeexpressedas:Pa>Pint>Pv>PA.

HypoxicPulmonaryVasoconstriction

Asdiscussedabove,HPVallowsredirectionofbloodflowfrompoorlyventilatedregionsofthelung,andsoimproveV/Qmatching.HPVisrelevantindiseasestates,aswellasspecificphysiologiccircumstances:

Athighaltitude,thePAO isgloballyreduced,leadingtohighpulmonaryarterypressuresInutero,PAO isnegligible,andPVRisthereforeveryhighThisdivertsbloodfromthepulmonarycirculationintotheleftsideoftheheartviatheforamenovale.Whenthefirstbreathistaken,pulmonaryvesselsdilateandtheright-to-leftshuntisreversed.

References1. Dunn,PF.PhysiologyoftheLateralDecubitusPositionandOne-LungVentilation.ThoracicAnaesthesia.Volume38(1),

Winter2000,pp25-53.2. WestJ.RespiratoryPhysiology:TheEssentials.9thEdition.LippincottWilliamsandWilkins.2011.3. LumbA.Nunn'sAppliedRespiratoryPhysiology.7thEdition.Elsevier.2010.4. BrandisK.ThePhysiologyViva:Questions&Answers.2003.

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CerebralBloodFlowDescribethedistributionofbloodvolumeandflowinthevariousregionalcirculationsandexplainthefactorsthatinfluencethem,includingautoregulation.Theseinclude,butnotlimitedto,thecerebralandspinalcord,hepaticandsplanchnic,coronary,renalandutero-placentalcirculations

Withrespecttocerebralbloodflow:

Normalis~750ml.min or~15%ofrestingcardiacoutputNotethatthebrainmakesuponly~2%ofbodyweight.

Arelativelyhighbloodflowisrequiredduetothehighcerebralmetabolicrateforoxygen(CMRO )of50ml.minThebrainissensitivetointerruptionsinflowasithas:

AhighmetabolicrateNocapacitytostoreenergysubstrates

ThefactorsaffectingcerebralbloodflowcanbeclassifiedbythefactorsintheHagan-PoiseuilleEquation:

,where:

isthepressuredifferencedrivingflow,i.e.CPP

istheradiusofthebloodvessels

isthebloodviscosityThesearealsocalledrheologicfactors.

isthelengthofthetube,afixedquantity

FactorsAffectingPerfusionPressure{#cpp)

CerebralPerfusionPressureisthedifferencebetweenmeanarterialpressureandintracranialpressure:

AnormalCPPis~80mmHgInnormalindividuals,CBFisclassicallythoughttobeautoregulatedoveraCPPrangeof60-160mmHg

Thisoccursbymyogenicmeans,similartothekidneyInnormalcircumstances,thisisdependentonMAP(i.e.,withanormalICP<10mmHg,CBFisregulatedoveraMAPrangeof50-150mmHg).

NotethatmorerecentevidencewouldsuggestthatCBFisautoregulatedoveramuchnarrowerrangeofperfusionpressures,andhasagreatercapacitytobufferanincreasedratherthandecreasedperfusionpressure

Atthelowerlimit,thereducedperfusionpressuremeansflowcannotbemaintainedevenwithmaximalvasodilation

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Attheupperlimit,thehighperfusionpressureovercomesmaximalvasoconstrictionAdditionally,theincreasedCBFmayresultindamagetotheblood-brainbarrier

Thecurveisleft-shiftedinneonatesandchildren(duetolowernormalMAP)Thecurveisright-shiftedinchronichypertensionThecurveisprobablyinaccurateinthepathologicalconditionswhereitwouldotherwisebeuseful,suchasmalignancy,subarachnoidhaemorrhage,CVA,orTBI

Thismaybeduetodamagetoeitherthefeedbackmechanisms,ortheeffectors(vasculature)Flowmaybecomepressure-dependent,andsmallchangesinMAPcanhavelargechangesinCBF

FactorsAffectingVesselRadius

VasodilationandconstrictionaffectbothcerebralbloodflowandICP,asvasodilatationincreasescerebralbloodvolumeandthereforemayincreaseICPthroughtheMonroe-Kelliedoctrine.

Vesselcalibreisaffectedprimarilybyfourfactors:

CerebralmetabolismPaCOPaONeurohormonalfactorsTemperature

CerebralMetabolism

Cerebralmetabolism(typicallygivenbythecerebralmetabolicrequirementforoxygen,CMRO )hasalinearassociationwithcerebralbloodflow-thisisknownasflow-metabolismcoupling.Thisiscontrolledlocallythroughthereleaseofvasoactivemediators,suchasH ,adenosine,andNO.Determinantsofcerebralmetabolisminclude:

DrugsCerebralmetabolismmaybedecreasedbyuseofdrugssuchasbenzodiazepines,barbiturates,andpropofol.TemperatureCMRO decreaseslinearlyby~7%perdegreecentigrade,allowingprolongedperiodsofreducedCBFwithoutischaemiccomplications.

PaCO

Carbondioxideactsasacerebralvasodilator.

CBFisalmostlinearbetween20mmHgand80mmHgAbove80mmHg,thecirculationismaximallydilatedBelow20mmHg,thecirculationismaximallyconstrictedAdditionally,thealkalosiscausesaleft-shiftoftheoxyhaemoglobincurve.Thisreducesoffloadingofoxygen,causing

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hypoxiaandsubsequentvasodilation.Thereisaright-shiftinchronichypercapneaThemechanismofactioniscomplex,butinvolveslocalincreaseinH ions.ChangestoCBFwithCO aredependentoncurrentarteriolartone-vasodilatoryeffectsofCO aresignificantlyreducedwhentheperfusingpressureislow.

PaO

CBFincreasesrapidlywhenPaO fallsbelow60mmHgsothatcerebraloxygendeliveryismaintainedHypoxiacausesareleaseofadenosineandreducedcalciumuptake,withsubsequentvasodilation

Neurohormonal

Autonomiccontrolofcerebrovasculartoneislimited,thoughisresponsiblefortheright-shiftintheautoregulationcurvewithsustainedhypertension

FactorsAffectingBloodViscosityBloodviscosityisdependentonhaematocritReducedhaematocritisassociatedwithincreasedCBF,butreducedO -carryingcapacityTheoptimalhaematocritis~0.3-0.35,whichprovidesthebestbalancebetweenreductionofviscositytoimprovecerebralbloodflow,withoutreducingDO .

References1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. HillL,GwinnuttC.CerebralBloodFlowandIntracranialPressure.FRCAWebsite.

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3. WillieCK,TzengYC,FisherJA,AinsliePN.Integrativeregulationofhumanbrainbloodflow.JPhysiol.2014Mar1;592(5):841-59.

4. MuizelaarJP.CBFandmanagementofthehead-injuredpatient.In:NarayanRK,WilbergerJE,PovlishockJT,eds.Neurotrauma.NewYork:McGraw-Hill,1996:553–561.

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HepaticBloodFlowDescribethedistributionofbloodvolumeandflowinthevariousregionalcirculationsandexplainthefactorsthatinfluencethem,includingautoregulation.Theseinclude,butnotlimitedto,thecerebralandspinalcord,hepaticandsplanchnic,coronary,renalandutero-placentalcirculations

Theliverservesasabloodreservoir(30mlper100g,halfofwhichmaybemobilisedinhypovolaemia),andreceives25%ofcardiacoutputfromauniquedualbloodsupply:

Hepaticarterialsystem,whichsuppliesaboutone-thirdofblood,but40-50%ofOHepaticarterialbloodhasanSpO of~98%,aswouldbeexpected.Itisahigh-pressure,high-resistance,high-flowsystem(averagevelocity18cm.s ),withthecapacitytoautoregulate.

Portalvenoussystem,whichsuppliestheremainingtwo-thirdsofblood.Itisalow-resistance,low-pressure,low-velocitysystem(averageflow9cm.s ),withnocapacitytoautoregulate.TheSpO ofportalvenousbloodvariesdependingongutactivity:

Intherestinggut,SpO is~85%Intheactivegut,SpO is~75%

RegulationofFlow

Aswithotherorgans,bloodflowisautoregulatedviaintrinsicandextrinsicmechanisms,andmaybeaffectedbyexternalfactors.

IntrinsicAutoregulation

MyogenicautoregulationHepaticarterialbufferresponseThisisalsoknownasthe"hepaticartery-portalvenoussemi-reciprocalinterrelationship".

Hepaticarterialresistanceisproportionaltoportalvenousbloodflow,suchthatareductioninportalvenousflowcausesadecreaseinhepaticarterialresistanceandincreaseshepaticarterialflowThisisprobablymediatedbyadenosine.

ExtrinsicAutoregulation

AutonomicNervousSystemBoththehepaticandportalvasculaturehavesympatheticinnervation:

Thehepaticarteryhasdopaminereceptors,aswellasβ-andα-adrenoreceptorsTheportalveinhasonlyα-adrenoreceptorsActivationofthesereceptorscausesvenoconstriction,reducingthecomplianceofthehepaticvasculatureandmobilisingupto250mlofbloodintimesofsympatheticstress.

EndocrineandhormonaleffectsAnumberofsubstancesaffectportalflow:

Hormone PortalVeinEffect HepaticArteryEffect OverallEffectonFlow

Adrenaline Constriction Constriction(α),thendilation(β) Reduced

Glucagon Dilation - Increased

Secretin - Dilation Increased

AngiotensinII Constriction Constriction Reduced

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Vasopressin Constriction Constriction Reduced

PCO Constriction - Reduced

ExternalFactors

Flowinthehepaticveinisdependentonvenousreturn:

Increasedvenousreturn(e.g.negative-intrathoracicpressure)increaseshepaticflowDecreasedvenousreturn(e.g.positive-pressureventilation,tamponade,haemorrhage),reduceshepaticflow,andinextremecasesflowmayonlyoccurintermittentlythroughoutthecardiaccycle

Exercisereducesbothportalveinandhepaticarterialflow

Microvasculature

Hepaticarteriolesandportalvenulesformthehepatictriadwithabilecanaliculi.Hepaticarteriolesandvenulesanastomosetoformsinusoids,whichcreateaspecialisedlow-pressure(~2mmHg)capillarysystemwhichdrainsintothecentralveinsofthehepaticacinus.

Thisarrangement:

OptimiseshepaticO extractionIncreasedhepaticO demandismetbyincreasingO extraction,ratherthanbyincreasingflow(asoccursintheheart).Preventsshuntingandretrogradeflow

References1. CICMMarch/May20132. LeslieRA,JohnsonEK,GoodwinAPL.DrPodcastScriptsforthePrimaryFRCA.CambridgeUniversityPress.2011.3. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.4. KogireM,InoueK,SumiS,DoiR,YunM,KajiH,TobeT.Effectsofgastricinhibitorypolypeptideandglucagononportal

venousandhepaticarterialflowinconsciousdogs.DigDisSci.1992Nov;37(11):1666-70.

Lastupdated2019-07-18

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BaroreceptorsDescribethefunctionofbaroreceptorsandtorelatethisknowledgetocommonclinicalsituations.

Baroreceptorsarestretchreceptorswhichmonitorchangesinarterialpressure.Arterialpressureismonitoredbyreceptorsinthe:

AorticarchInnervatedbyCNX

CarotidsinusSmalldilationoftheICAatthelevelofthebifurcation.

InnervatedbyCNIXRememberthecarotidsinusisabaroreceptor,thecarotidbodyisachemoreceptor

Low-pressurestretchreceptors:

RespondtoincreasedvenousreturnAreinhibitedbypositivepressureventilationActbystretchandtypicallydescribedasvolumereceptorsArelocatedinthe:

AtrialwallsSVCandIVCPulmonarycirculation

BaroreceptorControlAfferentfibresfromCNIXandCNXtraveltotheNTSinthemedulla.EffectorneuronsfromtheRVLMareGABAergicandthereforeinhibitory,i.e.increasedbaroreceptordischargereducestonicsympathetictoneandincreasesvagaltone.

Increasedbaroreceptoractivitythereforeresultsin:

ArterialandvenousvasodilationHypotensionBradycardiaDecreasedcardiacoutputDecreasedrespiratoryrate

Conversely,increasedactivityoflow-pressurestretchreceptorsresultsinanincreaseratherthanadecreaseinheartrate.

BaroreceptorActivityBaroreceptorsare:

MoresensitivetopulsatilepressurethanconstantpressureAdecreaseinpulsepressurewithoutachangeinMAPwilldecreasebaroreceptorfiring.ActivethroughoutthecardiaccycleRapidcompensatoryresponsesarevitalintheshort-termcontrolofbloodpressure,e.g.withposture.Activeovertherangefrom50mmHgto200mmHg

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Thiscurveisleft-shiftedinchildrenandneonates,andright-shiftedinchronichypertension,thoughthisisreversible

Hormonalcontrol

Activationofatrial/ventricularstretchreceptorsstimulatesANP/BNPreleaserespectively,whichacttoreducebloodpressureinthefollowingways:

IncreasedGFRActtoconstricttheefferentarterioleanddilatesoftheafferentarteriole.ThissubsequentlyinhibitsreninsecretionthroughincreasedhydrostaticpressureattheJGAandincreasedNa andCl deliverytothemaculadensa.DecreasedaldosteroneViainhibitionofaldosteronesecretion.VasodilationCausesvasodilationofperipheralsmoothmuscle.

References1. BarrettKE,BarmanSM,BoitanoS,BrooksHL.Ganong'sReviewofMedicalPhysiology.24thEd.McGrawHill.2012.2. CICMSeptember/November20143. ANZCAJuly/August2000

Lastupdated2018-06-25

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ValsalvaManoeuvreExplaintheresponseofthecirculationtosituationssuchaschangesinposturehaemorrhage,hypovolaemia,anaemia,intermittentpositivepressureventilation,positiveend-expiratorypressure,andtheValsalvamanoeuvre.

AValsalvaisforcedexpirationagainstaclosedglottis.ThiscanbeachievedbyincreasingP to40mmHgfor15seconds.Thisincreaseinintrathoracicpressurealtersmanyhaemodynamicparameters.

Phases

AValsalvamanoeuvreconsistsoffourphases:

PhaseI

P isincreasedto40cmH O,withacorrespondingincreaseinPSBPandDBPincreasedueto:

CompressionoftheaortaIncreasedLVpreloadduetoejectionofbloodinthepulmonaryvasculature

PhaseII

VRfallsduetoincreasedPCOfallsduetodecreasedVRSBPandDBPfallduetodecreasedCO

BaroreceptorsareactivatedbythefallinBP,andSNSoutflowincreases,causing:

IncreasedHRIncreasedSVR

BPthereforestartstorecoverlateinPhaseII

PhaseIII

TheValsalvaceases,andP returnsto0cmH OPVRrapidlydropsasalveolarvesselsre-expandSBPandDBPrapidlyfalldueto:

DecreasedPVRcausingdecreasedLVpreloadLossofhighintrathoracicpressurecompressingtheaorta

PhaseIV

VRnormalisesCOnormalisesduetonormalVRandPVRSBPandDBPtransientlyincreaseduetoanormalCOenteringabaroreceptor-drivenhigh-SVRvascularbed

BaroreceptorsrespondtohighSBPanDBPbyincreasingvagaltone:

HRfalls(reflexbradycardia)BPfalls

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AbnormalResponses

Abnormalresponsesoccurincardiacfailureandautonomicneuropathy.

CCF

InCCFasquare-wavepattenisproduced:

IncreasingP resultinginasustainedincreaseinSBPandDBPThereisaslightdecreaseinSBPandDBPforthefewsecondsinphaseIIIwhenairwaypressureisreleased

Appearstobeduetotheincreasedcirculatingvolume,asthisdifferenceresolvesinvenesectedcardiacpatients,andisdemonstratedinnormalindividualswhoaretransfusedtoahighcirculatingvolume.

AutonomicNeuropathy

BaroreceptorresponsetotheValsalvaisminimalinbothphaseIIandIV:

InphaseII,thereisnocompensatoryincreaseinsympatheticoutflow,soBPcontinuestofalluntilP returnsto0mmHgInphaseIV,thereisnocompensatoryincreaseinvagaltoneandsoBPreturnstonormalwithoutovershooting

References

1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. JudsonWE,HatcherJD,WilkinsRW.BloodPressureResponsestotheValsalvaManeuverinCardiacPatientswithand

withoutCongestiveFailure.Circulation.1955;11:889-899.

Lastupdated2019-07-20

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CVSChangeswithObesityDescribethecardiovascularchangesthatoccurwithmorbidobesity

Obesityisamultisystemdisorderdefinedbyanelevatedbodymassindex(BMI):

Normal:BMI<25Overweight:BMI25-30Obese:BMI>30MorbidlyObese:

ObesityrelateddiseaseandaBMI>35BMI>40

Characteristicsofobesityinclude:

ComplexgeneticandenvironmentalcausesIncreasedcaloricintakeIncreasedmetabolicrate(normalforBSA)

Theeffectofobesityonthecardiovascularsystemiscomplex,andcanbeclassifiedinto:

HormonalchangesAbdominalvisceralfatisresponsibleforsecretingalargenumberofhormoneswhichaffectcardiovascularparameters:

IncreasedleptinContributestocardiacremodellingandLVH.AngiotensinogenLeadstosystemichypertensionandLVremodelling.

Smallamountsareproducedinadipocytes,whichincreasesasfatvolumeincreasesPlasminogenactivatorinhibitor-1ReducesfibrinolysisandpredisposestoVTE.InflammatoryadipokinesImpairendothelialfunction,leadingtoincreasedSVR.CatecholaminesIncreasedcontractility,SVR,andworsenendothelialfunction.

Releasedwith:HypoxiaHypercapneaNegativeintrathoracicpressureFragmentedsleepDuetoOSA.

ChangesinkeycardiovascularparametersIncreasedVODuetoincreasedLBMandfatmass.IncreasedBloodVolumeDuetoincreasedangiotensinIIandaldosterone.IncreasedStrokeVolumeDueto:

Increasedpreload(majorfactor)Increasedcontractility(minorfactor)Duetoincreasedcirculatingadrenalhormones.

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TomaintainDO .Initiallywithpreservedejectionfraction

CardiacchangesDiastolicdysfunctionDuetomyocardialfibrosisimpairingrelaxation.Fattyinfiltrationofmyocardiumandconductingsystem

PredisposestoarrhythmiasRiskisworsenedbychangeinmyocardialarchitecture,hypoxia,andincreasedcirculatingcatecholamines.

BiventricularhypertrophyasaresponsetoincreasedafterloadLVafterloadincreasedduetosystemichypertensionLVHismuchmorecommonthanRVH.

EccentrichypertrophyduetovolumeoverloadConcentrichypertrophyduetopressureoverloadorhormonalchanges

RVhypertrophydueto:LVdiastolicfailureIncreasedPVR

HypoxiaDueto:

EffectsofOSAIncreasedshuntthroughcollapsedlungbases

Acidosis

References

1. AlvarezA,BrodskyJ,LemmensH,MortonJ.MorbidObesity:Peri-operativeManagement.Cambridge:CambridgeUniversityPress.2010.

2. LotiaS,BellamyMC.Anaesthesiaandmorbidobesity.ContinEducAnaesthCritCarePain2008;8(5):151-156.

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CardiovascularEffectsofAgeingDescribethecardiovascularchangesthatoccurwithageing.

CVSeffectsofageingcanbedividedintocardiac,vascular,andautonomicchanges:

CardiacchangesDecreasedreceptordensityandnumberDecreasedmaximumheartrateDuetofibrosisoftheSAnodecausingreducedpacemakercellnumberandfunction,andreductionincatecholaminereceptordensity.

DecreasedinotropyMinor.IncreasedrelianceonatrialkickReducedventricularcomplianceincreasestherelianceonatrialkicktoachieveadequatepreload.Decreaseddiastoliccompliance

Duetohypertrophyfromincreasedafterload

VascularchangesReducedcomplianceDuetolossofelastictissueinthelargearteries.IncreasedSVRReducedcomplianceresultsinincreasedvascularresistance.Reducedendothelialcellfunction(decreasedNO)Impairstheabilityofthevasculartreetoadapttochangesinpressure/volumeleadingto:

ElevatedSBPReducedDBPReducedelasticrecoilcausesdiastolicrunoffandafallindiastolicbloodpressure.

ReducedcatecholaminereceptordensityReducedresponsivenessto(andincreasednumberof)circulatingcatecholamines.

AutonomicImpairedautonomicfunctionDuetodecreasedcatecholamineresponsiveness.ImpairedbaroreceptorresponseDecreasedexercisetoleranceRelianceonpreloadtomaintaincardiacoutput.

References

1. ANZCAFebruary/April20162. CheitlinMD.Cardiovascularphysiology-changeswithageing.AmJGeriatrCardiol.2003Jan-Feb;12(1):9-13.

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InotropesUnderstandthedetailedpharmacologyofinotropesandvasopressors

Inotropesareagentswhichaltermyocardialcontractility.

PositiveinotropesincreasecontractilityNegativeinotropesdecreasecontractility

ClassesofPositiveInotrope

Classes ClassI:IncreaseIntracellularCalcium

ClassII:CalciumSensitisers ClassIII:Metabolic/Endocrine

Examples Adrenaline,milrinone,glucagon,digoxin Levosimendan T3,Insulin

GeneralMechanismofAction

IncreaseintracellularCa byavarietyofdifferentpathways

IncreasesensitivityofactomyosintoCa

Variable.T3potentiatestheeffect(orincreasesexpressionof)cardiacβreceptors

References1. LeslieRA,JohnsonEK,GoodwinAPL.DrPodcastScriptsforthePrimaryFRCA.CambridgeUniversityPress.2011.2. TielensET,ForderJR,ChathamJC,MarrelliSP,LadensonPW.AcuteL-triiodothyronineadministrationpotentiates

inotropicresponsestoP-adrenergicstimulationintheisolatedperfusedratheart.CardiovascularResearch32(1996)306-310.

Lastupdated2017-09-18

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AdrenoreceptorsUnderstandthepharmacologyofadrenoreceptorblockingdrugs.

Thiscoversthepharmacologyofadrenoreceptors.Theproductionandmetabolismofendogenouscatecholaminesiscoveredunderadrenalhormones.Detailedinformationonspecificsympathomimeticagents,includingstructure-activityrelationships,isinthepharmacopeia.

Adrenoreceptorsareclassifiedbytheirvaryingsensitivitytodifferentcatecholamines.Additionally:

AlladrenoreceptorsareGprotein-coupledreceptorsEachreceptorcontainsseventransmembraneα-helicalsubunits,threeextracellularloops,andthreeintracellularloops

AlphareceptorshavedifferentsubunitsandmechanismsofactionAllbetareceptorsare:

G coupledActivateadenylatecyclaseincreasingcAMP,leadingtoincreasedNa/K<sup+ATPaseactivityandhyperpolarisation

AdrenoreceptorSubtypes

α -receptors:

ArepresentinsmoothmuscleAgonismcausesvasoconstriction,relaxationofGITmuscle(viapresynapticreceptors),andcontractionofGUmuscle.Theyare:

G coupledPhospholipaseCactivatedincreasesIP ,increasecalcium

α -receptors:

ArepresentintheCNS,arterioles,pancreasAgonismcausessedation,analgesia,vasodilatation,andinhibitionofinsulinrelease.Theyare:

G coupledInhibitsadenylatecyclase,decreasingcAMP

β -receptors:

ArepresentincardiacmuscleandtheJGACardiacagonismincreasesinotropy,chronotropy,anddromotropyJGAagonismincreasesreninrelease

IncreaseincAMPincreasesintracellularcalcium

β -receptors:

Arepresentinskeletalvascularandbronchialsmoothmuscle,theliver,andoncellmembranesAgonismcauses:

VasodilationandbronchodilationHepaticglycogenolysisIncreasesactivityoftheNa -K ATPasepump,increasingintracellularpotassium

IncreaseincAMPincreasesNa /K ATPaseactivityandhyperpolarisation

β -receptors:

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Agonismcauseslipolysisandthermogenesis.

References1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.2. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.3. BarrettKE,BarmanSM,BoitanoS,BrooksHL.Ganong'sReviewofMedicalPhysiology.24thEd.McGrawHill.2012.

Lastupdated2018-05-27

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AntiarrhythmicsUnderstandthepharmacologyofantiarrhythmicdrugs

AntiarrhythmicdrugsaretypicallyclassifiedusingtheVaughanWilliamsclassificationsystem,whichdividesdrugsintofourclassesbasedontheireffectonthecardiacactionpotential.Manydrugswillactviamultiplemechanisms.

ClassI:Blockvoltage-gatedNachannelsClassIa:IntermediatedissociationClassIb:FastdissociationClassIc:Slowdissociation

ClassII:β-BlockersClassIII:Prolongtheactionpotential(UsuallyviaK channelblockade)ClassIV:Ca antagonists

Thisclassificationisnotablyincomplete,assomedrugs(suchasamiodarone)fitintomultiplecategories,andothers(suchasdigoxin,adenosine,andmagnesium)fitintonone.

ClassINa -channelblockadeinhibitsactionpotentialprolongationbyblockingactiveandrefractorysodiumchannelsinause-dependentfashionThisinhibitstachyarrhythmiaswhilstallowingnormalconductionExtentofblockdependsontheheartrate,membranepotential,andthesubclassofdrugSodiumchannelblockadeincreasespacingthresholdanddefibrillationenergyrequirement

ClassIa

ClassIadrugshavemixedpropertiesofIbandIc,andalsohaveClassIIIeffectsAstheyprolongtheAVconductionandprolongtheactionpotentialtheyincreasebothQRSdurationandtheQTintervalExamplesincludeprocainamide

Pro-arrhythmiceffectsmayresultbecauseAVnodalconductionmaybeincreased,sodespitedecreasedatrialactivityincreasedventricularconductanceresultsinapotentiallyfatalshorteningofdiastolictime

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ClassIb

ClassIbdrugsbindtoopensodiumchannel,andwillassociateanddissociatefromasodiumchannelinthecourseofanormalbeatTachyarrhythmiasarepreventedbecausedissociationoccurstooslowlyforafurtheractionpotentialtobegeneratedClassIbdrugswillbindselectivelytorefractorychannels,suchasoccursinischaemiaAstheyhavelittleeffectonnormalcardiactissuetheyhavelittleeffectontheECGExamplesofclassIbagentsincludeincludephenytoinandlignocaine

ClassIc

ClassIcdrugsassociateanddissociateslowlycreatingasteady-statelevelofblockThiscausesindiscriminateblockadeandgeneralreductioninexcitabilityClassIcagentsareusedtosuppressunidirectionalorintermittentconductionpathwaysAstheymarkedlyslowconductionvelocitytheyincreaseQRSdurationExamplesofClassIcagentsincludeflecainide

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ClassII

Normalβ-adrenergicstimulationhasanumberofpro-arrhythmiceffects:

IncreasedpacemakerpotentialcurrentIncreasedslow-inwardCa currentIncreasedrepolarisingK andCl currentsIncreasedCa storedinthesarcoplasmicreticulum,whichmaybespontaneouslyreleasedcausingadelayed-after-depolarisationsReducedserum[K ]*

β-blockershaveanantiarrhythmiceffectbyantagonisingthesemechanisms.Theyareusefulfortreatmentofarrhythmiasoccurringwithsympatheticover-activation,suchaspostMI.

ClassIIIBlockingofoutwardK channelsslowscardiacrepolarisation,whichincreasesthecardiacrefractoryperiod.Thishasanumberofbeneficialeffects:

DecreasedautomaticityDecreasedectopyReduceddefibrillationenergyrequirementIncreasedinotropy

Duetotheprolongedrepolarisation,theywillalsocausealongQT(thoughinthecaseofamiodaronethisisnotassociatedwithanincreasedriskofTPD).

ClassIV

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ClassIVdrugsinhibitL-typeCa channels,inhibitingtheslowinwardcalciumcurrent,which:

SlowsSAandAVnodalconductionAVblockadeslowstransmissionofsupra-ventriculararrhythmias.ReducesinotropyPreventsafter-depolarisationsThissuppressesectopybyreducingcalciumleakfromsarcoplasmicreticulum.

AlternativestoVaughanWilliamsAstheVaughanWilliamsclassificationsystemdoesnotneatlydivideagents,andsomeagentsdonotfitintoanycategory,theymayalsobeclassifiedbytheiruses:

Indication Examples

SVT Digoxin,adenosine,verapamil,β-blockers

VT Lignocaine,mexiletine

SVT/VT Amiodarone,flecainideprocainamide,sotalol

Digoxintoxicity Phenytoin

References

1. RangHP,DaleMM,RitterJM,FlowerRJ.RangandDale'sPharmacology.6thEd.ChurchillLivingstone.2. BruntonL,ChabnerBA,KnollmanB.GoodmanandGilman'sThePharmacologicalBasisofTherapeutics.12thEd.

McGraw-HillEducation-Europe.2011.3. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.

Lastupdated2019-07-18

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FunctionalAnatomyandControlofRenalBloodFlowDescribethefunctionalanatomyofthekidneysandrenalbloodflow.

FunctionalAnatomy

Thefunctionalunitofthekidneyisthenephron.Nephrons:

Arecomposedoftheglomerulus,proximaltubule,loopofHenle,distaltubule,andcollectingductAredividedbytheirlocationinto:

SuperficialcorticalnephronsHaveshortloopsofHenle.JuxtamedullarynephronsHavelongloopsofHenle,andtheefferentarterioleformsthevasarectaforthekidney.Mid-corticalnephronsMayhaveeitherlongorshortloops.

ControlofRenalBloodflow

Thekidneys:

Receive22%ofcardiacoutputatrestExtractonly10%ofdeliveredOHaveahighrenalbloodflowexceedsthatrequiredformetabolismHighflowisinsteadneededtoproducethelargevolumeofglomerularfiltrate(125ml.min )requiredforexcretionofwaste.

Autoregulation

Renalbloodflowisautoregulatedoverawiderangeofmeanarterialpressures(60-160mmHg)via:

MyogenicautoregulationTubuloglomerularfeedback

Myogenicautoregulation:

DescribestheintrinsicconstrictionoftheafferentarterioleinresponsetoanincreasedtransmuralpressureThisincreasesvascularresistanceinproportiontotheincreaseinpressure,keepingflowconstant

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Tubuloglomerularfeedbackismorecomplicated,anddescribestheconstrictionordilationoftheafferentarterioleinresponsetoadenosineorNO(respectively)releasefromthemaculadensa:

ThemaculadensaliesinthewalloftheascendinglimboftheloopofHenleItdetectschangeintubularflowrate(probablyviachangingNa fluxacrossitsmembrane)

Increasedflowintheloopindicatesanincreasedperfusionpressure,promptingreleaseofadenosineandconstrictionoftheafferentarterioleDecreasedflowindicatesadecreasedperfusionpressure,reducingadenosinereleaseandpromptingthereleaseofNOandrenin,whichcausestheafferentarterioletodilate

Notably,flowtojuxtamedullarynephronsisnotautoregulated.Highbloodpressureincreasesjuxtamedullaryflow,increasingGFRandimpairingrenalconcentration,resultinginapressurediuresis.

NeuronalControl

Thekidneysareinnervatedbynoradrenergicsympatheticnerves,whichcauses:

AfferentandefferentarteriolarconstrictionThisincreasescapillaryhydrostaticpressure(increasingfiltration)andalsoincreasescapillaryoncoticpressure(decreasingfiltration).

ThisleadstoanoverallslightreductioninGFR

HormonalControl

Renin:

Isreleasedfromthejuxtaglomerularapparatusbyβ stimulationCatalysestheproductionofangiotensinIfromcirculatingangiotensinogenAngiotensinIisthenconvertedintoAngiotensinIIbycirculatingACE.

TheactionsoftheRAASaredescribedinmoredetailintheendocrinefunctionsofthekidney.

References

1. BarrettKE,BarmanSM,BoitanoS,BrooksHL.Ganong'sReviewofMedicalPhysiology.24thEd.McGrawHill.2012.2. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.3. Hall,JE,andGuytonAC.GuytonandHallTextbookofMedicalPhysiology.11thEdition.Philadelphia,PA:Saunders

Elsevier.2011.

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GlomerularFiltrationandTubularFunctionDescribeglomerularfiltrationandtubularfunction.

Glomerulus

TheglomerulusisasetofcapillarieswhichinvaginateBowman'scapsuleFluidfiltersoutofthecapillarybedintoBowman'sspacebasedonStarlingforces:

MembranepermeabilityHydrostaticpressuregradientsOncoticpressuregradient

Reflectioncoefficient

GlomerularFiltrationRate

GlomerularFiltrationRateis:

ThevolumeofplasmafilteredbytheglomeruluseachminuteNormalrenalbloodflowis1.1L.min ,howeverrenalplasmaflowisless(600ml.min foranormalhaematocrit).Therefore,thenormalfiltrationfraction(proportionofrenalbloodflowwhichisfiltered)is~20%.Typically125ml.min

Decreaseswithage(partiallyduetolossofnephronnumber)

GFRcanbeexpressedastheproductofNetFiltrationPressureandthecombinationofmembranepermeabilityandmembranesurfacearea,designatedK (thefiltrationcoefficient):

NetFiltrationPressureisgivenbyopposingStarlingForcesacrosstheglomerularmembrane:

Asproteinisnotfilteredinnormalstates,theoncoticpressureinBowman'sSpaceisusuallyassumedtobe0mmHg.TheaveragecapillaryNFPis~17mmHgHydrostaticpressureDeterminedbyrenalbloodflowandtherelativeconstrictionoftheafferentandefferentarterioles.Hydrostaticpressuredecreasesalongthecapillary.Affectedby:

MAPCatecholaminesLocalautoregulation

MyogenicTubuloglomerularFeedbackHormones

AngiotensinIIconstrictstheefferentarteriolemorethantheafferentarteriole,causinganincreaseinrenalresistancewithonlyasmalldecreaseinGFR.ProstaglandinE2dilatestheafferentarteriole,increasingGFR

OsmoticpressureIncreasesalongthecapillary,asproteinfree-fluidisfilteredleavingahigherconcentrationofproteinwithinthecapillary.Thischangeincapillaryoncoticpressureisproportionaltothefiltrationfraction-agreaterfiltrationfractionwillcauseahigheroncoticpressureoffluidinthecapillary.

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MembranepermeabilityOverallpermeabilityis:

Afunctionof:Membranepermeability,inturnaffectedby:

CapillaryendotheliumBasementmembraneNegativelychargedmoleculeshavereducedfiltrationasthebasementmembraneisalsonegativelychargedwhichopposesmovementoutofthecapillary.FootprocessesofpodocytesMoleculeslessthan7000Daltonarefreelyfiltered,whilstlargermoleculesarefilteredless.

MembraneSurfaceAreaTypicallyveryhighforwaterandsolutes.Affectedby:

GlomerulonephritisChangeinbasementmembraneorpodocytefootprocesses

AngiotensinIIcausingcontractionofmesangialcells

TubularFunction

ProximalTubule

Theproximaltubulereabsorbs60%ofglomerularfiltrate.Itreabsorbsbasicallyeverything,includingprotein,andsecretesH ,organicions(suchasuricacidandsalicylates),ammonium,andupto60%offilteredureaload.

LoopofHenle

TheloopofHenleconsistsofathindescendinglimbandathickascendinglimb;

ThedescendinglimbreabsorbswateronlyThethickascendinglimb:

Reabsorbscommonions(Na ,K ,Cl )andHCOExcretesH

ThefunctionoftheloopistoconcentrateurineinstatesofwaterdeprivationThisisdoneviathecountercurrentmechanism.

CountercurrentMultiplier

Thecountercurrentconcentratingsystemis:

FormedfromtheloopofHenleandcollectingductsDrivenentirelybytheremovalofNaClfromtheascendinglimbMosteasilyunderstoodinstages:

NaClisactivelytransportedoutofthethickascendinglimb,increasinginterstitialosmolalityatthatlevelIncreasedinterstitialosmolalityresultsinwaterreabsorptionfromthedescendinglimb,increasingtubularosmolalityatthatlevelThismoreconcentratedtubularfluidthenflowstoadeeper,moreconcentratedlevel,andmorewaterisreabsorbedTheeffectisprogressiveconcentrationoftubularandinterstitialfluid,butwithalowandstableenergycostastherelativegradientsthateachtransportpumpworksagainstissmallTheendresultisadiluteurineleavingtheascendinglimb,butahighlyconcentratedmedullaryinterstitium

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Thevasarectaareperitubularcapillariesthat:

SurroundtheloopofHenleofjuxtamedullarynephronsFollowtheloopintothemedullaHavetypicallylowbloodflowThisprevents"washout"ofthecountercurrentmultiplier,astheslowbloodflowallowssoluteconcentrationstoequaliseateachleveloftheloop.

Inhypovolaemicsituations,renalbloodflowfallsandvasarectaflowdecreases,furtherreducingwashoutWhenrenalbloodflowishigh,vasarectaflowincreasesThiswashesoutpartofthemedullaryconcentrationgradientandreducestheconcentratingabilityofthekidney.

Distaltubules

Fluidenteringthedistaltubulehasaboutone-thirdtheosmolarityofplasma.Thedistaltubule:

Reabsorbs:Na ,Cl ,HCO ,CaSecretes:K ,H

CollectingDucts

Thecollectingductslieintheinterstitium(concentratedbytheloopofHenle)Intheabsenceofaquaporins,thecollectingductsareimpermeabletowater

Osmolalitycanfallaslowas50mmol.L duetocontinuedreabsorptionofsoluteInthepresenceofaquaporins,waterflowsdowntheosmoticgradientintotheconcentratedinterstitium,resultinginahighlyconcentratedurineADHalsoincreasescollectingductpermeabilityofurea

Ureamovesviasolventdragwithwater

References1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. GregerR,WindhorstU.ComprehensiveHumanPhysiology:FromCellularMechanismstoIntegration.Springer-Verlag

BerlinHeidelberg.1996.3. CICMMarch/May2010

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HandlingofOrganicSubstancesDescribetheroleofthekidneyinthehandlingofglucose,nitrogenousproductsanddrugs

Broadlyspeaking,thekidney:

ReabsorbsimportantsubstancesFiltersandsecreteswasteproducts

MethodsofReabsorptionReabsorptionfromtubuletobloodcanoccurviatwomechanisms:

TranscellularreabsorptionSubstanceisabsorbedintotubularepitheliumandthensecretedintoblood.Thisistypicallyachievedbysymporters,whichrelyonthelowintracellularsodiumconcentrationtomovesubstancesoutofthetubuleagainsttheirconcentrationgradient.ParacellularreabsorptionSubstancepassesthroughthematrixoftightjunctionsbetweenepithelialcells.

RateLimitation

Therearefunctionalupperlimitsontherateofreabsorptionofsubstancesfromthetubule.Therearetwolimits:

TubularMaximum(T )LimitedSaturationoftransportersoccur,soafurtherincreaseinsoluteconcentrationdoesnotincreasetherateofsubstancereabsorption.

ThemaximumsoluteconcentrationforaT systemisafunctionofthetransporter.

GradientLimitedLeaksinthetightjunctionswillresultinsolutemovingfromtheinterstitiumbackintothetubuleifthetubularconcentrationfallstoolow.

Themaximumsoluteconcentrationforagradientlimitedsystemisrelatedtothepermeabilityofthetightjunctions.

GlucoseGlucoseis:

FreelyfilteredattheglomerulusCompletelyreabsorbedviathetranscellularrouteintheproximalconvolutedtubuleundernormalcircumstancesActivelytransportedviatheSGLUT(Sodium-dependentGlucosesymporter)transmembraneprotein

Secondaryactivetransport(downtheestablishedSodiumgradient)TherearetwosubtypesoftheSGLUTprotein:

Low-affinity,high-capacityRapidlyreabsorbsglucose,butisineffectivewhenglucoseconcentrationislow.ItislocatedearlyinthePCT,andreabsorbs~90%offilteredglucose.High-affinity,low-capacitySlowlyreabsorbsglucose,butremainseffectiveevenwhenglucoseconcentrationislow.ItislocatedlateinthePCT,whereglucoseconcentrationislower(havingalreadybeenreabsorbedbythehigh-capacitytransporter),andreabsorbs~10%offilteredglucose.

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AsGFRincreases,glucosefiltrationandthereforeglucoseabsorptionincreaseAsglucoseisco-transportedwithNa ,absorptionofNa andH OalsoincreaseThisphenomenonisknownasglomerulo-tubularbalance

GlucosereabsorptionisaT system,andisoverwhelmedwhenfilteredglucoseexceeds300mg.min or16mmol.minThistypicallyoccurswhenplasma(andthereforefiltered)glucoseconcentrationsexceed12mmol.L

ConsequencesofGlycosuria

GlycosuriaoccurswhenfilteredglucoseexceedsthecapacityofthePCTtoreabsorbit,andcauses:

IncreasedurinevolumeGlucoseactsasanosmoticdiureticby:

ReducingNa reabsorptioninthePCTAssomeglucoseisnotabsorbed,thesodiumthatwouldnormallybereabsorbedwith(tubuloglomerularbalance)isremaininginthetubule.ReducingwaterandsaltreabsorptionintheLoopofHenleDuetohightubularflowrates.

Impairstheformationofthemedullaryconcentrationgradient,limitingconcentratingcapacityStimulatesADHrelease

ElectrolytederangementsHypokalaemiadueto:

ReducedK reabsorptionduetohightubularflowratesAldosteronereleaseduetohypovolaemia,increasingNa reabsorptionandK secretion

ADHreleaseinresponsetohypovolaemiaLossofsubstrateforATPgenerationIncreaseriskofurinaryinfections

NitrogenousProducts

Aminoacidsarereabsorbedbyamino-acidtransportersThesearenot(entirely)selective,andreabsorbseveralstructurallysimilaraminoacids.

ThesesharedpathwayscreatecompetitionforbindingsitesbetweenaminoacidsExcessofonesubstancewillleadtobothexcretionofthissubstanceinurine,aswellasinappropriateexcretionofrelatedsubstances

Largerproteins(suchasalbumin)areinfactfilteredattheglomerulus(thoughinverysmallamounts)Reuptakeoccursinseveralstages:

EndocytosisattheluminalmembraneThisisanenergy-dependentprocess,requiringproteintobindtomembranereceptors.Degradationofproteinintoindividualaminoacids

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Reuptakeacrossthebasolateralmembrane

Smallerproteinsandpeptides(e.g.insulin,angiotensinII)arecompletelyfilteredCatabolismoccursinthetubularlumenbymembrane-surfacepeptidasesAminoacidsarereabsorbedbystandardamino-acidtransporters

Urea

Ureaisasmall,watersolublemoleculeproducedintheliverfromammoniaasamethodforeliminatingnitrogenouswaste.

Ureaexcretioniscomplex,asithasanimportantroleinthecountercurrentmultiplier.Thismeansthatintheshortterm(hourstodays)eliminationmaynotmatchproduction,althoughoverweekstheywillbeequal.Ureais:

Freelyfiltered~50%offilteredloadisreabsorbedinthePCTbysolventdrag(withwaterreabsorption)Ureaconcentrationisslightlyincreasedasmorewaterisreabsorbedthanurea.TheureareabsorbedinthePCTisthensecretedintotheLoopofHenleviaUTuniporters

Luminalconcentrationofureaismuchhigherintheascendinglimbduetotheabsorptionofwater~50%isreabsorbed(again)inthemedullarycollectingductsHere,urinebecomessoconcentratedthatluminalconcentrationofureaexceedsmedullaryconcentration.

Overall,50%offilteredloadisexcreted

pHDependentDrugReabsorption

Manysubstances,suchasdrugs,areweakacidsorbasesReabsorptionofthesesubstancesispHdependent

WeakacidsareproportionallymoreionisedatapHabovetheirpKaWeakbasesareproportionallymoreionisedatapHbelowtheirpKaUnionisedsubstancesarelipidsoluble,andabletodiffuseintotubularcellsdownconcentrationgradientsIonisedsubstancesaretrappedwithinthelumen

References

1. EatonDC,PoolerJP.Vander'sRenalPhysiology.6thEd(Revised).McGraw-HillEducation-Europe.2004.

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MeasurementofGFRDescribetheprinciplesofmeasurementofglomerularfiltrationrateandrenalbloodflow

Renalclearanceofasubstancequantifiestheeffectivenessofkidneysinexcretingsubstances.Thedefinitionofclearanceisthevolume(typicallyofplasma)clearedofadrugperunittime.Renalclearancecanthereforebeexpressedas:

,where:

=Clearance

=Urineconcentration

=Urineflowrate

=Plasmaconcentration

ClearanceandGFR

Astheeliminationofmostsubstancesisdependentonglomerularfiltration,clearanceofasubstancecanbeusedtoestimateGFR.Methodsinclude:

InulinInulinisanaturallyoccurringpolysaccharide.

InulinclearanceaccuratelymeasuresGFRasitis:FreelyfilteredbytheglomerulusNotsecretedatthetubulesNotreabsorbed

However,inulinisnotproducedbythebodyandsomustbegivenbyIVinfusionThislimitsitsclinicalutility.

CreatinineCreatinineisabyproductofmusclecatabolism.

Creatinineisusedclinicallytomeasurerenalfunctionbecauseitis:ProducedatarelativelyconstantrateFactorsaffectingcreatinineproductioninclude:

RaceMusclemass

AgeSex

DietNotmetabolisedFreelyfilteredbytheglomerulusMinimallysecretedAsGFRfallstheproportionofcreatininesecretedbyrenaltubulesincreases,soplasmacreatininewilloverestimateGFRwhenGFRislow.Notreabsorbed

GFRcanbeapproximatedbycreatinineclearance

Thisisgivenbytheequation:

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SerumCreatinine

ThisformulademonstratesthatGFRisinverselyproportionaltoserumcreatinineconcentration.

Thisisonlytruewhenbothcreatinineproductionandglomerularfiltrationareatsteady-stateAsuddendropinglomerularfiltration(e.g.aorticcross-clamp)willnotresultinanimmediateriseincreatinine.

DuringacutechangesinGFR,serumcreatininewillunderestimateGFRuntilanewsteadystateisreachedCreatininemustbeproducedandnoteliminatedforittorise.

EstimatingCreatinineClearance

Usingtheaboveformularequiresmeasurementofurinevolume.Thisis:

Typicallyperformedbytakinga24hoururinecollectionTedious,andsocreatinineclearanceisoftenestimatedAcommonmethodistheCockcroft-Gaultformula,whichhasacorrelationof~0.83withcreatinineclearance:

,where:

=Clearance

=Age

=Sexcoefficient(Male=1,Female=0.85)

=Creatinineinµmol.L

AlternativeformulasareMDRDandCKD-EPI.TheseequationshavetwoadvantagesofCockcroft-Gault:

TheyarebetterpredictorsofGFRTheydonotrequireweight,andsocanbecalculatedbythelaboratoryautomaticallyOtherrequireddata(e.g.age)canbetakenfromhospitalrecords.

Theseestimateshavesimilarweaknessestotheabove:

Dependentonserumcreatinine,whichcanbehighlyvariable.Formulasarederivedfromaveragevaluesofdependentvariables,andsowillbeunreliableatextremesof:

AgeMusclemassCriticallyillMalignancyDiet

References

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1. Hall,JE,andGuytonAC.GuytonandHallTextbookofMedicalPhysiology.11thEdition.Philadelphia,PA:SaundersElsevier.2011.

2. CockcroftDW,GaultMH.PredictionofCreatinineClearancefromSerumCreatinine.Nephron1976;16:31-413. LeveyAS,StevensLA,SchmidCH,ZhangYL,CastroAF3rd,FeldmanHI,KusekJW,EggersP,VanLenteF,GreeneT,

CoreshJ;CKD-EPI(ChronicKidneyDiseaseEpidemiologyCollaboration).Anewequationtoestimateglomerularfiltrationrate.AnnInternMed.2009May5;150(9):604-12.

4. MDCalc-Cockcroft-GaultEquation.5. NIDDK.EstimatingGlomerularFiltrationRate(GFR)

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EndocrineFunctionsoftheKidneyOutlinetheendocrinefunctionsofthekidney

Thekidneyisinvolvedinanumberofendocrineprocessesandproducesormetabolisesanumberofhormones:

RAASVitaminDEPOProstaglandins

Renin-Angiotensin-AldosteroneSystemTheRAASisasignalingpathwayinvolvedinbloodpressurecontrol.Itinvolvesanumberofhormones:

Angiotensinogenisproducedbytheliverinresponseto:GlucocorticoidsThyroidhormonesOestrogensAngiotensinIIVariousinflammatoryproteins

Reninisaproteaseproducedbythekidneysinresponsetoβ stimulationorhypotension,andexiststocleaveangiotensinogentoangiotensinI

ACEcleavesangiotensinItoangiotensinII,andalsocleavesbradykininintoinactivemetabolites

AngiotensinIIincreasesbloodpressureviaanumberofmechanisms:Simulatesaldosteronereleasefromtheadrenalcortex,increasingsodiumandwaterretentionVasoconstrictionofefferentgreaterthantheafferentarteriolesResultsinslightdecreaseinGFRatalowerperfusionpressure,butincreasesfiltrationfraction.

NB:Differentsourcesquotedifferentchanges(increaseordecrease)inGFRThefinaleffectmayvarydependingonthecontributionofotherautoregulatoryprocesses.

ReducesK throughconstrictionofglomerularmesangialcellsIncreasedSNSactivityandcentralandperipheralvasoconstrictionIncreasesthirstviahypothalamicstimulationStimulatesADHrelease,reducingrenalwaterexcretionStimulatesreleaseofangiotensinogen

Aldosteroneactsonthedistalconvolutedtubuleto:IncreasereabsorptionofNa andwaterIncreaseeliminationofK andH

VitaminDVitaminDhasacomplexmetabolicpathwaywhichmeandersthroughanumberoforgansystems:

VitaminD maybeabsorbedindietorproducedinskinbytheactionofUVlighton7-dehydrocholesterolVitaminD isthenhydrolysedintheliverbyCYP450enzymestoform25-hydroxycholecalciferol(25-OHD )25-OHD isthenconvertedintheproximaltubuletocalcitriol-theactiveform

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Erythropoietin

ErythropoiesisisstimulatedbyEPOrelease:

Inadults,EPOisreleasedfromthe:Peritubularcapillaryfibroblasts(85%)Liver(15%)

EPOisreleasedinresponseto:HypoxiaHypotensionLowHct

Erythropoiesisisinhibitedby:HighredcellvolumeRenalfailureProductionofEPOisdecreasedinrenalfailure,whichiswhypatientswithend-stagerenaldiseaserequireexogenousEPO.

References1. BarrettKE,BarmanSM,BoitanoS,BrooksHL.Ganong'sReviewofMedicalPhysiology.24thEd.McGrawHill.2012.2. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.

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Acid-BaseBalanceDescribetheroleofthekidneysinthemaintenanceofacid/basebalance

Acidsproducedbythebodycanbe:

Volatile(CO )Bodyproducesandeliminates~13-20mol.dayRemovedbythelungs

Fixed(everythingelse)Includelactate,sulphate,phosphate,andketonesBodyproducesandeliminates10mmol.kg .dayEliminatedbythekidneyMechanismsforeliminationofacidinclude:

ReabsorptionofHCOThisisequivalenttotheremovalofthesameamountofH .

Asthereisusuallyanetproductionofacid,undernormalcircumstancesallfilteredHCO isreabsorbedNotethatremovalofanacidloadisassociatedwithgreaterHCO generationandreabsorption,notincreasedH secretion

BoundtofilteredbuffersAsammonium

TherateandextentofthesereactionsisdependentonECFpHandionconcentrations,whichgivesthekidneycontroloverionconcentrationsUrinarypHcanfallaslowas~4.4,beforetheactivetransportofH isinhibited

BicarbonateandtheKidneyBuffersystemsminimisechangesinpHuntilthekidneycaneliminateexcesshydrogen.

BicarbonateisthepredominantECFbuffersystem(seeAcid-Basephysiologyformoreonbuffers).ByadjustingthelevelofHCO thekidneyisabletoadjustpH,aspertheHenderson-Hasselbalchequation:

Where:

=6.1,thepKaofHCO

=24,thenormal[HCO ]inmmol.L

=1.2,thenormal[CO ]inmmol.L

Bicarbonateis:

Freelyfiltered4320mmol.day ofHCO isfiltered(24mmol.L x180L.day ,normalrangeis4-5mol.day )ReabsorbedinthePCT(90%),thickascendinglimb,DCT,andCT

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Adjustingrateofabsorptionallowscorrectionofanacidosisoralkalosis.AllHCO reabsorptionisequivalenttoalossofH .

ReabsorptionofBicarbonate

Reabsorptionofbicarbonateinvolvesseveralsteps:

H issecretedintothelumeninoneofthreeways:PrimaryH ATPaseinthePCTandDCTH -Na antiporterinthePCTandascendinglimbH -K ATPaseintheCT

SecretedH combineswithfilteredHCO toformCO andH OCO andH OdiffuseintothetubularcellCO andH OareconvertedbackintoHCO andH inthetubularcellHCO isreabsorbedintothecapillaryviatheHCO -Cl antiporter,andtheH ionisavailabletobesecretedintothetubule(inexchangeforK inthecollectingductsandNa intheproximaltubule)

ThiscomplicatedprocessallowsHCO tobemovedfromthetubuletothetubularcellandthentothecapillary.ThereisnoeliminationofH bythismethod-thepurposeofH secretionistofacilitatethereabsorptionofHCO intothetubularcell.

AmmoniaGlutamineprovidesamechanismforeliminationofalargenumberofH ions:

Thisisimportantin:EliminationofexcessmetabolicacidRenalcompensationforacidosis

Thisoccursvia:FilteredglutamineisabsorbedintoproximaltubularcellsandmetabolisedtoNH (ammonium)andHCOHCO diffusesintoblood,andtheNH issecretedintothetubuleviatheNH -Na antiporterandeliminatedinurine

The reactionhasapKaof9.2meaning:AmmoniacannotactasaneffectiveurinarybufferAmmoniaisnotatitratableacid,asitwillnotreleaseH ionsasurinarypHincreasesThismeansfilteredammoniadoesnotcontributetothelowerlimitofurinarypH(4.4),whichiswhyitissoimportantintherenalcorrectionofseveremetabolicacidosis.

BoundtoFilteredBuffers

SecretedH mayalsocombinewithafilteredbuffer(e.g.PO ).TheseH ionsarenotreabsorbed.About36mmolofH iseliminatedwithfilteredPO eachday,witheachPO bindingtwoH ions.

References

1. CICMSep/Nov20142. ANZCAFeb/April20123. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.4. Acid-BaseOnlineTutorial,UniversityofConneticut5. Brandis,K.RenalRegulationofAcid-BaseBalance,in'Acid-basepHysiology'.

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DialysisDialysisistheseparationofparticlesinaliquidbasedontheirabilitytopassthroughamembrane.

Indications

Failureofnormalrenalfunctions,i.e.:

AcidElectrolytederangementParticularlyhyperkalaemia.IntoxicationsOverloadUreamia

PhysicalMechanisms

Fluidandelectrolytescanberemovedbyfourdifferentmechanisms:

DiffusionDiffusionisthespontaneousmovementofsubstancesfromahigherconcentrationtoalowerconcentration,whererateofmovementisproportionaltotheconcentrationgradient(asperFick'sLaw).

UltrafiltrationMovementofwater,asdeterminedbyStarling'sForces.

Whenasolventpassesthroughamembrane,theprocessiscalledosmosis.Thefrictionalforcesbetweensolutesandwatermoleculeswillpulldissolvedsubstancesalong,aprocessknownasbulkfloworsolventdrag.

Implementation

HaemodialysisUsesdiffusion.

Bloodispumpedthroughanextracorporealcircuitthatcontainsadialyser.Dialysateflowiscountercurrent,whichmaximisesthegradientfordiffusion.Solutesmoveacrossamembranebetweenbloodanddialysate,asperFick'sLaw:

ConcentrationgradientbetweenbloodanddialysateFlowrateofbloodanddialysate

SolubilityofthesoluteMassChargeProteinbinding

DialysismembranepermeabilityThicknessPorositySurfacearea

HaemofiltrationUsesultrafiltration.

Bothapositivehydrostaticpressureinbloodandanegativehydrostaticpressureindialysateisgenerated,causing

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ultrafiltrationandremovalofsolutesviasolventdrag.

Eliminationviabulkflowisindependentofsoluteconcentrationgradientsacrossthemembrane.TransportisdependentonStarlingForces:

ThetransmembranepressuregeneratedThisisafunctionof:

BloodflowtothemembraneDetermineshydrostaticpressure.Oncoticpressuregradient

PorosityofthemembraneAdditionally,ahighfiltrationfractionwillcauseexcessivehaemoconcentration,andclottingofthefilterThefilteredfluid(ultrafiltrate)isdiscarded,andreplacedwithanotherfluiddependingonthedesiredfluidbalance.

Differences

RenalReplacementTherapy(RTT)canbevia:Peritonealdialysis(PD)Intermittenthaemodialysis(IHD)IHDcausesgreatercardiovascularinstabilitycomparedtoCRRTasthefluidandelectrolyteshiftsoccurmorerapidly.ContinuousRenalReplacementTherapy(CRRT)

ContinuousVeno-VenousHaemofiltration(CVVH)ContinuousVeno-VenousHaemodiafiltration(CVVHDF)

Methodchosendependsdesiredeffect:

Smallmolecules(<500Da)andelectrolytescanberemovedbyfiltrationordialysisMedium-sizedmolecules(500-5000Da)arebestremovedbyfiltrationLowmolecularweightproteins(5000-50000Da)areremovedbyfiltrationThisincludesremovalofinflammatoryproteins,whichmaybebeneficialinsepsis.Waterisbestremovedbyfiltration

PharmacokineticsofRRTPharmacokineticsareunpredictable,butarebroadlyaffectedby:

DrugfactorsFreedruginplasmaDrugswithasmallproportionoffreedruginplasmaare(unsurprisingly)poorlyremovedbyRRT(butmayberemovedviaplasmapheresis).Theseinclude:

Highly(>80%)proteinboundsubstancesExamplesincludedphenytoin,warfarin,andmanyantibiotics.

NotthatthismaynotapplyinoverdoseOnceproteinbindingsitesaresaturated,bothfreedrugfractionandefficacyofdialysisisincreased.

DrugswithaV greaterthan1L.kgSize/MolecularWeight

Smallmolecules(<500Da)aremoreeasilyclearedbydiffusivemethodsofRTTMolecules>15kDaarepoorlydialysedThisincludesproteins,heparins,andmonoclonalantibodies.

VolumeofdistributionDrugswithhighvolumesofdistributionarepoorlydialysed,asremovalofdrugfromplasmaonlyremovesasmallproportionoftotal-bodydrugcontent.

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Dose/FlowratesReducedflowrateswillreduceclearance.

Conventionalhigh-fluxhaemodialysishasmorerapidclearancecomparedtolower-fluxhaemoperfusionorCRRTMembranepermeabilityTimingDrugsgivenbetweenIHDorSLEDsessionswillnotbecleareduntilthenextsession.s

PatientfactorsResidualrenalfunctionPatientsresidualGFRwillalsoaffectpharmacokinetics.

AnIncompleteListofDrugs

DrugsRemovedonRRT DrugsnotremovedonRRT

Barbiturates Digoxin

Lithium TCAs

Aspirin Phenytoin

Sotalol/Atenolol Otherbeta-blockers

Theophylline Gliclazide

EthyleneGlycol Benzodiazepines

Methanol Warfarin

Aminoglycosides,metronidazole,carbapenems,cephalosporins,penicillins Macrolides,quinolones

References

1. JohnsonCA,SimmonsWD.DialysisofDrugs.NephrologyPharmacyAssociates.

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SodiumandWaterDescribethefunction,distribution,regulationandphysiologicalimportanceofsodium,chloride,potassium,magnesium,calciumandphosphateions

NormaltotalbodyNa is60mmol.kg ,70%ofwhichisexchangeable.TotalbodyNa isdistributedas:

50%inECFSodiumisthedominantextracellularcation.

TypicalECF[Na ]of140mmol.L .45%inbone5%inICFAminorintracellularcation.

ICF[Na ]varieswithcelltype,butistypically12-20mmol.L .Concentrationiskeptlowbytheactionofthe2Na -3K ATPaseexchangepumpandthelowpermeabilityofthecellularmembranetoNa

FunctionofSodiumRegulationofECFvolumePrincipalECFcation.Changesinsodiumlevelscausecompensatoryfluidshifts.Lossofsodiumcontentwillresultinhypotension/hypovolaemia,withconsequentbaroreceptorstimulationandactivationoftheRAAS.Baroreceptorswillactivatewitha7-10%changeinvolume.

OsmolarityChangesinsodiumconcentrationaffectosmoreceptorsandwillaffectADHandthirstmechanisms.Osmoreceptorswillactivatewitha1-2%changeinosmolality.

Acid-BasebalanceNa -H exchangepumpsinthekidneyarestimulatedinacidosis.

RestingMembranePotentialAlterationsinsodiumconcentrationwillaffectintracellularpotassiumtoasimilardegree,whichwillaltertheRMP.

RegulationofSodiumandWater

Regulationofanysystemistypicallyabalancebetweeninputandoutput:

SodiumintakeisessentiallyunregulatedTherefore,sodiumconcentrationisafunctionof:

SodiumeliminationSodiumreabsorptionWaterhomeostasisControloftotalbodywaterisamajormechanismtoregulatesodiumconcentration.

SodiumElimination

Sodiumiseliminatedin:

SweatandGITObligatoryandnotamenabletoregulation.

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Acclimatisationtohotenvironmentsimprovestheefficiencyofsweatingbyreducingitstonicity,reducingsodiumlossGITUrine

AdjustrenaleliminationisthemainmechanismtoregulatesodiumconcentrationCanbeperformedintwoways:

ChangesinGFRChangesinGFRduetohyperorhypovolaemiawill(indirectly)adjustsodiumelimination.IncreasedplasmavolumeincreasesGFR,andviceversa.ChangesinsodiumreabsorptionThisisthemainmechanismforcontrollingsodiumineuvolaemia,andismediatedprimarilybyaldosterone.

SodiumReabsorption

Giventhat:

Normalglomerularfiltrateis~180L.dayThedominantosmoleinglomerularfiltrateissodiumNormalurineoutputis~1.5L

Themajorityoffilteredsodiummustbereabsorbed.ThisiscalledbulkreabsorptionandoccursinthePCTandLOH:

60%oftotalreabsorptionisbytheNa -K ATPasepumpinthePCT30%oftotalreabsorptionisbytheNa -K -2Cl co-transporterintheLOH

Theremaining10%ofsodiumreabsorptionoccursintheDCTandCT.Asitisundertheinfluenceofaldosterone,itisthecomponentwhichisimportantinregulation.AldosteroneincreasesNa reabsorptionbyincreasingthenumberoractivityofthesepumps:

Na -Cl pumpsintheDCTNa -K ATPasepumpsinprincipalcellsoftheDCTNa -H pumpsinintercalatedcellsoftheCT

WaterHomeostasis

Bodywaterhomeostasisinvolves:

SensorsOsmoreceptorspresentinthe:

MaculadensaCircumventricularorgansSubfornicalorganandthevascularorganofthelaminaterminalis.

Changeincellularvolumesecondarytochangesinosmolalityalterhormonesecretion.EffectorsPredominantlyhormonal:

ADHRAASNatriureticpeptides

References

1. BrandisK.ThePhysiologyViva:Questions&Answers.2003.2. CICMSeptember/November2014

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3. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.4. NationalResearchCouncil.RecommendedDietaryAllowances.10thEd.1989.NationalAcademiesPress.

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PotassiumDescribethefunction,distribution,regulationandphysiologicalimportanceofsodium,chloride,potassium,magnesium,calciumandphosphateions.

Potassiumisthemajorintracellularcation,with90%oftotalbodypotassiumpresentintheICF.Afurther8%issequesteredinbone,with2%presentintheECF.

NormalECFconcentrationis3.5-5mmol.LNormalICFconcentrationis~150mmol.L

FunctionandDysfunctionPotassiumisimportantfor:

RegulationofintracellularpHControlofintracellularvolumeDNAandproteinsynthesisEnzymaticfunctionRestingmembranepotential

Therestingmembranepotentialisdeterminedbytheratioofintracellular:extracellularpotassium,aspertheNernstequation:

SmallchangesinextracellularionconcentrationproducelargechangesinvoltageThishassignificanteffectonexcitabletissues.RapidchangesinpotassiumconcentrationcausesymptomsatlowerlevelsthanchronicchangesSymptomsarerelatedtothechangeinactionpotentialgeneration.

VentricularActionPotentialinHyperkalaemia:

Hyperkalaemia

Hyperkalaemiacauses:

TherestingmembranepotentialtobecomelessnegativeAspertheNernstequation.

Thisresultsintherestingmembranepotentialbeingclosertothethresholdpotential,increasingirritabilitySeveralsymptoms,including:WeaknessParalysisParasthesiasECGfindingsarethoseofprolongeddepolarisationandrapidrepolarisation:

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Serum[K ](mmol/L) ECGFindings

5.5-6.5 TalltentedTwaves

6.5-7.5 LossofPwave,lengtheningPRinterval

7.5-8.5 WideningQRS

>8.5 Sine-waveQRS

Hypokalaemia

Hypokalaemia:

Causestherestingmembranepotentialtobecomemore-negativeThismakesitmoredifficultforastimulustoreachthethresholdpotential,andthereforeitishardertogenerateandpropagateactionpotential.ECGfindingsarethoseofrapiddepolarisationandprolongedrepolarisation,andinclude:

ProlongedPRLongQTFlatTwavesorTWIUwavesSTdepressionSeverehypokalaemiamayresultin:FrequentsupraventricularandventricularectopicsSupraventriculararrhythmiasVentriculararrhythmias

Regulation

Serumpotassiumisdependentonintake,sequestration,andelimination.

Intake

Dietaryintakemaybehighlyvariable.PotassiumiscompletelyabsorbedfromtheupperGItract.

Sequestration

Severalfactorsaffectpotassiumsequestration:

Insulinandβ -agonismresultsinincreaseactivityoftheNa -K ATPasepump,shiftingpotassiumintocellsfollowingamealandduringexerciseAcidosiscausesanextracellularshiftofpotassium,ashydrogenionsareexchangedforpotassiumionsThereverseoccursinalkalosis.CelllysismayreleasealargeamountofpotassiumintocirculationandcausesignificanthyperkalaemiaifalargenumberofcellsaredestroyedAldosteroneincreasesuptakeofpotassiumintocells

Elimination

Eliminationofpotassiumoccursviathekidneys,andisdependentonproductionoflargevolumesofglomerularfiltrateandsecretionbythedistalconvolutedtubuleandcollectingduct.

Innormalconditions:

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ThePCTandascendinglimbreabsorbthemajorityofabsorbedpotassiumThisisessentiallyfixed.

PCTabsorbs~55%Ascendinglimbabsorbs~30%

TheprincipalcellsoftheDCTandcollectingductsecretepotassiumAlteringpotassiumsecretionisthemainmethodbywhichthekidneyregulatesserumpotassium.

ThecollectingducthasamuchgreaterrolethantheDCTWithnormaldietaryintake,morepotassiumissecretedthanreabsorbedThischangesinconditionsofpotassiumdepletion.

ControlofTubularSecretion

Tubularpotassiumsecretionismainlyafunctionof:

Plasma[K ]Increasedplasma[K ]stimulatestheNa -K ATPasepumpintheprincipalcells,andalsostimulatesaldosteronereleasefromtheadrenalcortex.TubularflowrateMovementofpotassiumoutofprincipalcellsoccursdownapassiveconcentrationgradient.IncreasingtubularflowrateincreasestheconcentrationgradientforpotassiumAldosteroneAldosteroneincreasesproductionoftheNa -K ATPasepump,whichincreasespotassiumsecretionanduptakeintocells.

Minorcontributorsinclude:

SodiumandwatercontentHighsodiumcontentinhibitsaldosteronerelease,reducingpotassiumeliminationHighwatercontentinhibitsADHexcretionandreducessecretionofpotassium,howeverhighwatercontentalsoincreasesflowthroughtherenaltubule,whichindirectlyincreasestubularsecretionofpotassium.

AlkalosisAlkalosisincreaseseliminationofpotassiumastheNa -K ATPasepumpisstimulatedbylowH ionconcentration.

References

1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. Hall,JE,andGuytonAC.GuytonandHallTextbookofMedicalPhysiology.11thEdition.Philadelphia,PA:Saunders

Elsevier.2011.3. Nickson,C.Hyperkalaemia.LifeintheFastLane.4. ParhamWA,MehdiradAA,BiermannKM,FredmanCS.HyperkalemiaRevisited.TexasHeartInstituteJournal.

2006;33(1):40-47.

Lastupdated2017-10-04

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PrinciplesofAcid-BasePhysiologyExplaintheprinciplesunderlyingacid-basechemistry

Therehavebeenseveraldifferenttheoriesofacid-basechemistry.TheonemostrelevantfortheprimaryexamistheBrønsted–Lowrydefinition,whichdefines:

AnacidasaprotondonorAbaseasaprotonacceptor

pHStandsforthepowerofhydrogenIsameasureofhydrogenionactivityinasolution

Activitycanbeapproximatedbyconcentration

Therefore,pHcanbeexpressedasafunctionofhydrogenionconcentration:UsingpHratherthanconcentrationmakesiteasiertocomparedifferentsolutions.

pKaStrongacids(andbases)dissociatecompletelyinsolutionWeakacids(andbases)onlypartiallydissociateTheyhaveadissociatedstate(A-)andanundissociatedstate(HA)Theratioofconcentrationsoneachsidecanbeusedtocalculatetheaciddissociationconstant,Ka

Thisequationdescribesthestrengthofanacidbyindicatinghowreadilytheacidgivesupitshydrogen.SimilartopH,thisvalueisoftenlogtransformedtopKaproduceanindex,whichallowseasycomparisonofdifferentsubstances:

pKahasseveralusefulproperties:Anacidofbasewillbe50%ionisedwhenthepHofitssolutionequalsitspKaAcidsaremoreionisedabovetheirpKaBasesaremoreionisedbelowtheirpKaAnincreaseinpHof1abovethepKawillresultinthatsubstancebeingeither90%(foranacid)or10%(forabase)ionised

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SystemicEffectsofAcid-BaseDisorders

pHdisturbanceaffectsmanyorgansystems:

Respiratory

IncreasedPeripheralandcentralchemoreceptorsincreaseventilationinresponsetoafallinpH.Oxyhaemoglobin-DissociationCurve

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Right-shiftedbyafallinpH.BronchoconstrictionHypercapneacausesparasympathetically-mediatedbronchoconstriction.

CardiovascularInotropyInotropyfallsinacidosisduetoadirectmyocardialdepressanteffect.MaybeoffsetbyincreasedSNStoneinlow-gradeacidosis.Alkalosismayincreaseinotropybyincreasingresponsivenesstocirculatingcatecholamines.DecreasedresponsetocatecholaminesWhenpH<7.2.ArrhythmiasSecondarytoalteredSNStoneandelectrolytes.VasodilationDirectlyduetohypercapnea.

CNSH ionscannotcrosstheBBB,howeverCO can.FluidandElectrolyte

PlasmaK increasesby0.6mmol.L forevery0.1unitfallinpHThisisduetoimpairmentoftheNa /K -ATPaseH ionsbindtothesamesiteonalbuminascalcium,soionisedcalciumwillincrease

MSKBonesChronicmetabolicacidosisconsumesbonephosphatetobufferH ions,causingosteoporosis.

CellularEnzymefunctionDenaturationandfunctionalimpairment.MolecularionisationChangeinionisationmaychangeamoleculesabilitytocrosscellmembranes(e.g.reducingdoseofthiopentoneinacidosis),oraffecttheirfunctionRestingmembranepotentialChangeinionpermeabilitywillalterRMP,andthereforehoweasyitistogenerateanactionpotential.

ChangewithTemperature

pHistemperaturedependent:

pHincreasesby0.015forevery1°CfallintemperatureDuetodecreasedionicdissociationofwater.GassolubilityalmostalwaysincreaseswhentemperaturefallsDissolvingistypically(notalways)anexothermicreaction.Asthekineticenergycontentofamoleculefalls,itsabilitytodissociatefromsolutiondecreases.

AsCO dissolves,PaCO fallsAsbloodgasmachinesoperateat37°C,ameasurementerrorwilloccurifapatientisnotcloseto37°C

AhypothermicpatientwillhaveahigherpHandCO thanmeasured

TherearetwocommonmethodsformanagingpHofsignificantlyhypothermicpatients(e.g.,thoseonCPB):pH-statandalpha-stat.

pH-stat

CO isaddedtothecircuitsothatpHandPaCO arenormalwhencorrectedfortemperatureThistheoreticallyimprovesoxygendeliverybypreventingtheleft-shiftintheoxyhaemoglobindissociationcurveTheincreasedCO alsocausescerebralvasodilation,which:

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IncreasesspeedanduniformityofcerebralcoolingIncreasesriskofcerebralembolicevents

alpha-stat

pHandCO valuesaremaintainedat'normalfor37°C'Measuredvalueswillbedifferent,as:

pHwillbeincreasedCO willbedecreased

CellularautoregulationispreservedUnlikepH-stat,thisdoesnotcausecerebralvasodilation

References1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.2. ANZCAJuly/August19993. Chemlab.Solubility.FloridaStateUniversity.

Lastupdated2019-07-18

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CompensationExplaintheprinciplesunderlyingacid-basechemistry

MetabolicAcidosis

Compensationtometabolicacidosisincludes:

BufferingOccursoverminutestohours.Includes:

ECFbuffersBicarbonatePlasmaproteins

AlbuminICFbuffers

Includephosphate,proteinsLeadstohyperkalaemiaduetoH /K exchangeK increasesby0.6mmol.L per0.1unitfallinpH.

BoneExchangeofNa andCa inbone.

LeadstodemineralisationandreleaseofalkalinecompoundsRespiratorycompensationOccursinminutes.

RapidresponseCannotcompensatecompletely

RenalcompensationOccursoverdaystoweeks.Includes:

EliminationofH boundtofilteredbuffersIncludeammonium,phosphate

ReabsorptionofbicarbonateActivesecretionofH intheDCT/CTUndercontrolofaldosterone.

References

1. Diaz,A.Describehowthebodyhandlesmetabolicacidosis.PrimarySAQs.

Lastupdated2017-09-20

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BuffersDescribethechemistryofbuffermechanismsandexplaintheirrelevantrolesinthebody

Abufferisasolutionwhichconsistsofaweakacidanditsconjugatebase,thatcanresistachangeinpHwhenastrongeracidorbaseisadded.

Buffering:

Isakeypartofacid-basehomeostasisAllowscompensationforlargechangesinacidoralkaliloadwithminimalchangeinhydrogenionconcentration

Inoneexperiment,dogswereinfusedwith14,000,000nmol.L ofH ,withacorrespondingriseinH ofonly36nmol.L

Efficacyofabuffersystemisdeterminedby:

pKaofthebuffer80%ofbufferingoccurswithin1pHunitofthepKaofthesystem.pHofthesolutionAmountofbufferWhetheritisanopenorclosedsystemAnopenbuffersystemcanhavetheamountofchemicalatone(orboth)endsadjustedbyphysiologicalmeans.

Thisalterstheconcentrationofreactantsateitherendoftheequation,thusalteringthespeedofthereactionviatheLawofMassAction

BufferSystems

Importantbuffersystemsinclude:

BicarbonatebuffersystemProteinbuffersystem

HaemoglobinbuffersystemPhosphatebuffersystem

AllbuffersystemsareinequilibriumwiththesameamountofH .Thisisknownastheisohydricprinciple.

BicarbonateBufferSystem

Thebicarbonatebuffersystemis:

ThemostimportantECFbuffersystemBicarbonateisformedintheerythrocyteandthensecretedintoplasmaBicarbonatediffusesintotheinterstitiumandisalsothedominantfluidbufferininterstitialspace

FormedintheerythrocyteAbufferpairconsistingofbicarbonateandcarbonicacidCarbonicacidisexceedinglyshortlivedinanyenvironmentevenremotelycompatiblewithlifeanditrapidlydissociatestoHCO andH .

Hydrogenionsareconsumedorreleasedbythefollowingreaction:

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Carbonicanhydrase(presentinerythrocytes)isanenzymewhichallowsrapidconversionofH OandCO toH CO (andbackagain)EachstageofthereactionhasanindividualpKa:

AsthepKaofthe systemis6.1,thesesubstancespredominateatphysiologicalpHThepKaforthesecondstageofthereactionis9.3andsoessentiallynoCO existsinbloodClincicallythisreactioncanbeignored.

Inclinicalconditions,thereactionbecomes:

Additionofastrongaciddrivestheabovereactiontotheleft,forming(briefly)H CO beforeitdissociatestoCO andH O

CO isthenabletobeexhaled,whichpreventsequilibrationandallowsthesystemtobuffermoreacid

Bicarbonateisaneffectivebufferbecauseitis:

PresentinlargeamountsOpenatbothends

CO canbeadjustedbychangingventilationBicarbonatecanbeadjustedbychangingrenaleliminationThispreventsthebicarbonatebuffersystemfromequilibratingandallowsittoresistlargechangesinpHdespiteitslowpKaHowever,becauseitreliesheavilyonchangesinpulmonaryventilationitisunabletoeffectivelybufferrespiratoryacid-basedisturbances.

ProteinBufferSystem

AllproteinscontainpotentialbuffergroupsHowever,theusefuloneatphysiologicalpHistheimidazolegroupsofthehistidineresidues.Extracellularly,proteinshaveasmallcontributionwhichisentirelyduetotheirlowpKaIntracellularlyproteinshaveamuchgreatercontributionbecause:

IntracellularproteinconcentrationismuchgreaterthanextracellularconcentrationIntracellularpHismuchlower(~6.8)andclosertotheirpKa

HaemoglobinBufferSystem

Haemoglobinis:

AproteinbuffersystemQuantitativelythemostimportantnon-bicarbonatebuffersystemofbloodThisisbecausehaemoglobin:

Existsingreateramountsthanplasmaproteins(150g.L comparedto70g.L )Eachmoleculecontains38histidineresiduesThisresultsin1gofHb~3xthebufferingcapacityof1gofplasmaprotein.

Inthecell:

Haemoglobinexistsasaweakacid( )aswellasitspotassiumsalt( )Inacidosis:

AdditionalH ionsareboundtoHbmoleculesHCO diffusesdownitsconcentrationgradientintoplasmaElectroneutralityismaintainedthroughtheinwardsmovementofCl .DissolvedCO willalsoformcarbaminocompoundsbybindingtotheterminalaminogroups

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ThepKaofHbisvariabledependingonwhetherithasboundoxygen:DeoxyhaemoglobinhasapKaof8.2BecauseofitshigherpKa,deoxyhaemoglobinwillmorereadilyacceptH ionswhichmakesitabetterbufferofacidicsolutions.OxyhaemoglobinhasapKaof6.6BothareessentiallyequidistantfromnormalpH,andareequallyeffectivebuffersQuantitatively,permmolofoxyhaemoglobinreduced,~0.7mmolofH canbebufferedTherefore0.7mmolofCO canenterbloodwithoutachangeinpH.

ThisisthemechanismbehindtheHaldaneeffect,andwhyvenousbloodisonlyslightlymoreacidicthanarterialblood

PhosphateBufferSystem

Phosphoricacidis:

TribasicandcanthereforepotentiallydonatethreehydrogenionsHowever,onlyoneofthesereactionsisrelevantatphysiologicalpH,withapKaof6.8:

ThequantitativeeffectislowdespitetheoptimalpKaduetothelowplasmaconcentrationofphosphateAthigherconcentrations,suchasintracellularlyandinurine,itisasignificantcontributorInprolongedacidosis,CaPO canbemobilisedfrombonesandcanbeconsideredasanalkalireserve

Footnotes

1. AlexYartsevoffersanexcellentdiscussiononbufferinginhisexcellenttrademarkproseatDerangedPhysiology2. Brandis'sanaesthesiaMCQisrequiredreading

References

1. BarrettKE,BarmanSM,BoitanoS,BrooksHL.Ganong'sReviewofMedicalPhysiology.24thEd.McGrawHill.2012.2. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.

Lastupdated2019-07-18

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CerebrospinalFluidDescribethephysiologyofcerebrospinalfluid

CSFisatranscellularfluidintheventriclesandsubarachnoidspace.~150ml(2ml/kg)ofCSFexistinanormalindividual,dividedevenlybetweentheheadandspinalcolumn.

Functions

MechanicalProtectionDuetoitslowspecificgravity,CSFreducestheeffectiveweightofthebrain(byafactorof30)andthereforereducestraumacausedbytheaccelerationanddecelerationofthebrain.BufferingofICPCSFcanbedisplacedtothespinalsubarachnoidandhaveitsrateofreabsorptionincreasedinordertooffsetanincreaseinICPbyanotherspace-occupyinglesion.StableExtracellularEnvironmentNeuronsaresensitivetoionicchangesintheextracellularenvironment.IonicconcentrationsinCSFaretightlycontrolled,whichensuresstableneuronalactivity.Additionally,toxinsareactivelyremovedfromCSF.pHRegulationpHofextracellularfluidisimportantinthecontrolofrespiration,andisalsotightlyregulated.NutritionSupplyofO andsimplesugarsandaminoacids,andremovalofCO occursoccursinCSF.

Formation

CSFisproducedinthechoroidplexus(70%)andbraincapillaryendothelialcells(30%)atarateof0.4ml.min (500ml.day).Itisproducedbyacombinationofultrafiltrationandsecretionfromplasma:

Na isactivelytransportedDrivesflowofCl ionsandwater.Glucoseistransportedviafacilitateddiffusiondownitsconcentrationgradient

FactorsAffectingFormation

Formationisrelativelyconstantwithinnormalparameters(alteringtherateofabsorptionisthepredominantmeanstocontrolpressure),thoughitisreducedby:

DecreasedChoroidalBloodFlowCPP<70mmhgreduces=""CSFformation.

Contents

Content RelativeChange [CSF]

Na - 140mmol.L

Cl ↑ 124mmol.L

K ↓ 2.9mmol.L

Gluc ↓ 3.7mmol.L

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pH ↓ 7.33

PCO ↑ 50mmHg

Protein ↓ Variable*

Ca ↓ 1.12mmol.L

Mg ↑ 1.2mmol.L

*CSF[protein]isvariable:

HighestinthelumbarsacLowestintheventriclesAlwayslowerthanplasma[protein]ThismeansCSFisapoorbuffersolution,whichincreasesitssensitivitytoderangementsinrespiratoryacid-basestatus.

Insummary:

[Na ]isunchanged[Mg ]and[Cl ]areincreasedConcentrationsofeverythingelseisless

Circulation

CSFflowisdrivenbyrespiratoryoscillations,arterialpulsations,andongoingproductioninthechoroidalplexus.

ProductioninthechoroidalplexusinthelateralventriclesTothethirdventricleviatheForamenofMunroTothefourthventricleviatheAqueductofSylviusTothecisternamagnaviathetwolateralForaminaofLuschkaandthemidlineForamenofMagendieItmaynowpasseither:

Cranially,tothebasilarcisternsandviatheSylvianfissuretothecorticalregionsCaudally,tothespinalsubarachnoidspaceviathecentralcanal

Reabsorption

ReabsorptionofCSF:

Occursinthearachnoidvilli,whicharelocatedintheduralwallsofthesagittalandsigmoidsinuses85%ofreabsorptionoccursinintracranialarachnoidvilliRemainderbyspinalarachnoidvilli

IspredominantlyviapinocytosisandopeningofextracellularfluidspacesIspressure-dependent

ReabsorptionoccurswhentheCSFpressureis1.5mmHggreaterthanvenouspressureTypicallyanICP<7mmHgresultsinminimalCSFreabsorption.Abovethis,CSFabsorptionincreasesinalinearfashionupto22.5mmHg.

References1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. Hall,JE,andGuytonAC.GuytonandHallTextbookofMedicalPhysiology.11thEdition.Philadelphia,PA:Saunders

Elsevier.2011.

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Blood-BrainBarrierTheblood-brainbarrierisaphysiologicalbarrierwhichpreventssubstancesintheECFofthebodymovingfreelyintotheECFofthebrain.ThefunctionsoftheBBBare:

MaintainastableextracellularmilieuOptimisesneuronalfunctionbypreventingfluctuationsinplasmaK ,Na ,andH affectingcerebralcells.ProtectionofthebrainIsolatesthebrainfromtoxins.ProtectionofthebodyIsolatestherestofthebodyfromCNSneurotransmitters.

Anatomy

TheBBBoccursinthreelayers:

CapillaryendothelialcellsJoinedwithtightjunctions,preventingfreemovementofsolventandsolute.

SubstancesmustmovethroughcapillaryendotheliumtoreachthebrainCapillaryendothelialcellscontainhighnumbersofmitochondria,duetothehigherenergycostoftheactivetransportmechanisms.

BasementmembraneAstrocytesGlialcellwhichextendsfootprocessesaroundthebasementmembrane,andreducepermeabilityofendothelialcells.

Duetotheirfunction,severalimportantCNSstructuresmustexistoutsideoftheBBB.Theseareknownasthecircumventricularorgans,andinclude:

SensingstructuresChemoreceptortriggerzone(AreaPostrema)Identifiestoxinsinthesystemiccirculation,triggeringvomiting.HypothalamusOsmoreceptorsdetectsystemicosmolarity.SubfornicalorganRoleinCVSandfluidbalance.Organumvasculosum

SecretingstructuresPituitarySecreteshormones.PinealglandSecretesmelatonin.ChoroidplexusProducesCSFviasecretionandultrafiltrationofplasma.

MovementofSubstances

Substancescanmovevia:

DiffusionForlipidsolublemoleculesonly;e.g:

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COO

FacilitateddiffusionFormovementoflarger/lesssolublemoleculesdowntheirconcentrationgradient,e.g:

GlucoseWater

ActivetransportResponsibleformovementofmostsmallions;e.g:

NaClKMgCa

Othersubstancesarespecificallyexcluded:

CatecholaminesMetabolisedbyMAOincapillaryendothelium,preventingtheiractionasCNSneurotransmitters.AminoacidsPreventactionasneurotransmitters.AmmoniaMetabolisedinastrocytestoglutamine,limitingitsneurotoxiceffects.

References1. LawtherBK,KumarS,KrovvidiH.Blood–brainbarrier.ContinuingEducationinAnaesthesiaCriticalCare&Pain,Volume

11,Issue4,1August2011,Pages128–132.2. BrandisK.ThePhysiologyViva:Questions&Answers.2003.

Lastupdated2019-07-18

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SpinalCordAnatomyDescribethemajorsensoryandmotorpathways(includinganatomy)

SpinalCordAnatomy

Thespinalcordintransversesectionconsistsofacentralsectionofgreymattercontainingneuronalcellbodiesandsynapses,andaperipheralsectionofwhitemattercontainingmyelinatedascendinganddescendingpathways.Importantpathwaysare:

CorticospinaltractMotorfunction.Crossesatthebrainstem.DorsalcolumnLighttouchandproprioception.Crossesatthebrainstem.SpinothalamictractPainandtemperature.Crosseswithintwovertebralsegments.

SpinocerebellartractUnconsciousproprioception.Doesnotcross.

SpinalCordSyndromesLesionstocertainanatomicalregionsofthespinalcordproduceaparticularconstellationsoffindings.

CompleteTransection

Acompletetransectionresultsinlossofmovementandsensationbelowthelevelofthelesion.Initially,paralysisisflaccid(andothersigns,suchaspriapism,maybeabsentinthis'spinalshock'phase)becomesspasticafterafewweeks.Bowelandbladderfunctionislost.

LesionsaboveT10willresultinimpairedcoughintheinitialstageastheabdominalwallisunabletocontract(intercostalmusclefunctionmaybeimpairedaswell,butthisisoflessimportanceclinically).

CentralCordSyndrome

Centralcordsyndromeresultsinaflacidparalysisandlossofsensationoftheupperlimbsgreaterthanthelowerlimbs.

AnteriorCordSyndrome

Anteriorcordsyndromesparesthedorsalcolumnsonly,thereforemotorfunctionandpainandtemperaturesensationareaffectedbelowthelevelofthelesion.

Brown-SequardSyndrome

Hemisectionofthecordresultsin:

IpsilaterallossofmotorfunctionbelowthelevelofthelesionIpsilaterallossoflighttouchandproprioceptionbelowthelevelofthelesionContralaterallossofpainandtemperaturesensationbelowthelevelofthelesionIpsilaterallossofpainandtemperaturesensationatthelevelofthelesion

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CaudaEquina

CaudaEquinasyndromeresultsfromcompressionoflumbosacralnerverootsbelowtheleveloftheconusmedullaris.ItmayproduceacombinationofUMNandLMNsigns:

RadiculopathySacralsensorylossAsymmetricLMNweaknessandatrophyErectiledysfunctionandinabilitytoejaculateUrinaryretentionandoverflowincontinenceConstipationandoverflowincontinence

References1. GoldberS.ClinicalNeuroanatomyMadeRidiculouslySimple.3rdEd.Medmaster.2005.2. McMinn,RMH.Last'sAnatomy:RegionalandApplied.9thEd.Elsevier.2003.

Lastupdated2017-09-22

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IntracranialPressureExplainthecontrolofintra-cranialpressure

NormalICPis

P1isthefirstpeak,andrepresentsarterialpulsationP2isthesecondpeak,andrepresentsintracranialcomplianceIfP2>P1,thisissuggestiveofpoorintracranialcomplianceP3isthethirdpeak,andisadicroticwaverepresentingvalveclosure

Inaddition,asecondsetofLundbergwavesaredescribed:

Awavesarepathological,andconsistofsquare-waveplateausupto50mmHglasting5-20minutes.Theyaresuggestiveofherniation,andarealwayspathological.BwavesarevariablespikesinICPat30-120secondintervals,suggestiveofcerebralvasospasmCwavesareoscillationsthatoccur4-8timesperminute,andareabenignphenomenaoccurringwithrespiratoryandbloodpressurevariations

RaisedintracranialpressuremaycausefocalischaemiawhenICP>20mmHg,andglobalischaemiawhentheICP>50mmHg:

MonroeKellieDoctrine

Thisstatesthat:

Theskullisarigidcontainerofafixedvolume,containingapproximately8partsbrain,1partblood,and1partCSFAsithasnegligibleelastance,anyincreaseinvolumeofonesubstancemustbemetwithadecreaseinvolumeofanotherorariseinICP

ElastanceistechnicallycorrectaswearediscussingachangeinpressureforagivenchangeinvolumeComplianceisachangeinvolumeforagivenchangeinpressure.

PhysiologicalResponsestoanIncreaseinICP

DisplacementofCSFintothespinalsubarachnoidspaceCompressionofvascularbedIncreasedCSFreabsorption

TheCushingreflexmayoccurinbrainstemherniationThisisatriadofhypertension,bradycardia,andirregularrespirationsecondarytoSNSactivation,andisareflexiveresponsetomedullaryischaemia.

Hypertension

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ToimproveCPP.BradycardiaDuetoabaroreceptorresponse.IrregularrespirationDuetorespiratorycentredysfunction.

PhysiologicalBasisofTreatment

TreatmentcanbeclassifiedaspertheMonroeKelliedoctrine:

Brain

OsmoticagentssuchasmannitolandhypertonicsalineIncreaseplasmaosmolalityandexpandbloodvolume,creatinganosmoticgradientbetweenbrainparenchymaandbloodwitharesultingreductioninbrainoedemaandICP.Timelyevacuationofmasslesionsandintracranialhaemorrhage

CSF

ExternalVentricularDrainFacilitatesremovalofCSF.

Blood

ReducingcerebralmetabolicrateResultsinreducedbloodflowduetoflow-metabolismcoupling.Maybeachievedwith:

CNSdepressantssuchaspropofol,benzodiazepines,orbarbituratesHaveseveralbeneficialeffects:DepresscerebralmetabolismwhichreducesoxygenrequirementsReduceseizurerisk,whichisdetrimentalbecauseitgreatlyincreasescerebralO demandandimpairsvenousreturnImprovesventilatordyssynchrony,limitingcoughingandbearingdown,andsubsequentrisesinICPHypothermiaCausesareductionincerebralmetabolismandriskofseizures.PreventionofhypoxiaorhypercapneaHypoxiaandhypercapneabothcausevasodilatation,withasubsequentincreaseincerebralbloodvolume,bloodflow,andICP.

InducedhypocarbiaCausesvasoconstrictionandasubsequentreductionincerebralbloodflowandbloodvolume.Thisleadsto:

ReductioninICPReductionincerebraloxygendeliveryConsequently,alow-normalETCO targetisusedtoavoidtissuehypoxia.

References1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. CrossME,PlunkettEVE.Physics,Pharmacology,andPhysiologyforAnaesthetists:KeyConceptsfortheFRCA.2ndEd.

CambridgeUniversityPress.2014.3. StocchettiN,MaasAI.Traumaticintracranialhypertension.NEnglJMed.2014May29;370(22):2121-30.

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4. BarrettKE,BarmanSM,BoitanoS,BrooksHL.Ganong'sReviewofMedicalPhysiology.24thEd.McGrawHill.2012.

Lastupdated2019-07-18

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IntraocularPressureNormalintraocularpressureis~15mmHg,witharangeof12-20mmHg.Regulationofintraocularpressureisimportantfor:

VisionSustainedhigh(>25mmHg)canleadtoblindnessduetocompressionofaxonsoftheopticnerveandtheopticarteryattheopticdisc.

DeterminantsofIntraocularPressure

Astheglobehastypicallypoorcompliance,asmallincreaseinvolumecancausealargeincreaseinintraocularpressure.Factorsaffectingvolumeinclude:

VolumeofaqueoushumorAqueoushumorisaclearfluidthatfillstheanteriorandposteriorchambersoftheeye,andprovidesavasculartissueswithnutrientsandoxygenwhilststillallowinglighttopassfreelybetweenthelensandretina.Volumeofaqueoushumorisafunctionof:

ProductionAqueoushumorisproducedbysecretionandfiltrationfromcapillariesintheciliarybodyintheposteriorchamber,andcirculatesthroughintotheanteriorchamber.

Productionisacceleratedbyβ2 agonismProductionisinhibitedbyα agonismCarbonicanhydraseinhibitorsdecreaseaqueoushumorproductionprobablybydecreasingsodiumsecretionintotheeye

ReabsorptionAqueoushumorisreabsorbedintovenousbloodinthecanalofSchlemm.

ThetrabeculaemeshworkisthemainsourceofresistancetoreabsorptionIfthisisblocked,asignificantreductioninreabsorptioncanoccurandIOPwillincrease.Reabsorptionisaffectedby:

HaemorrhageBlockstrabecularmeshwork.MuscarinicantagonismDilatespupil,whichbringstheirisclosertocanalanddecreasesabsorption.α agonismDilatesthepupil,decreasingabsorption.PGFRelaxesciliarymuscle,increasingabsorption.

VolumeofbloodwithintheglobeAffectedby:

MAPVenousobstruction

ExternalfactorsOtherfactorsaffectingvolumeorcomplianceoftheglobe:

ExtraocularmuscletensionExtraocularcompression

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References

1. ANZCAJuly/August20002. Hall,JE,andGuytonAC.GuytonandHallTextbookofMedicalPhysiology.11thEdition.Philadelphia,PA:Saunders

Elsevier.2011.3. GoelM,PiccianiRG,LeeRK,BhattacharyaSK.AqueousHumorDynamics:AReview.TheOpenOphthalmologyJournal.

2010;4:52-59.

Lastupdated2019-07-18

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SleepDescribethephysiologyofsleep

Sleepisanaturallyoccurringstateofunconsciousnessfromwhichonecanbearousedbyanexternalstimuli.

Sleepisimportantin:

HomeostasisofmanyorgansystemsMemoryformationPreservationofcognitivefunction

StagesofSleep

StagesofsleepareclassifiedbasedonEEGchanges:

REMsleepCharacterisedbyEEGactivityresemblingthatofawakeindividuals.REMsleep:

Lastsfor5-30minutesEventfrequencydecreaseswithage.InREMsleep:

IrregulareyemovementsDreamingoccursIrregularHRandRRMusclecontractionoccurs(butmuscletoneisdecreased)

Non-REMsleepDeepsleep,characterisedbydepressionofHR,SVR,BP,RR,andmetabolicrate(~0.9METs)ItisdividedintofourstagesonEEG:

Stage1:4-6Hzθwavesreplaceα-wavesDosing,easilyroused.Stage2:Similartostage1withoccasionalhighfrequency50μVbursts(sleepspindles)Stage3:1-2Hzhigh-voltageδwavesappearStage4:LargeδwavesbecomesynchronisedDeepsleep.

PeriodsofREMsleepalternatewithnon-REMsleepduringthenight,withanaverageof4-5cyclesofREMsleeppernight.

RespiratoryEffects

GABAergicneuronsdepresstherespiratorycentre,leadingtorespiratorydepression:

DecreasedMVDecreasedVGreatestdecreaseoccursduringREMsleep,whereitfallsby~25%.UnchangedRR

IncreasedPaCODecreasedPOMorepronouncedinelderly.

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Duetoreducedtonicactivityofpharyngealmuscles.

References1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. LeslieRA,JohnsonEK,GoodwinAPL.DrPodcastScriptsforthePrimaryFRCA.CambridgeUniversityPress.2011.3. LumbA.Nunn'sAppliedRespiratoryPhysiology.7thEdition.Elsevier.2010.

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PainDescribethephysiologyofpain,includingthepathwaysandmediators

Keydefinitions:

PainPainisan"unpleasantsensoryoremotionalexperienceassociatedwithactualorpotentialtissuedamage,ordescribedinsuchterms."Paincanbebroadlyclassifiedby:

AetiologyNociceptivepainStimulationofnociceptorsbynoxiousstimuli.VisceralpainNeuropathicpainNervoussystemdysfunction.

DurationAcutepainPainduetosymptomsofcurrentpathology.ChronicpainPainoccurringafterthepathologicalprocesshasresolved.

HyperalgesiaIncreasedresponsetoanormallypainfulstimulus.

PrimaryhyperalgesiaLocalreductioninpainthreshold.SecondaryhyperalgesiaHyperalgesiaawayfromthesiteofinjuryduetoalterationinspinalcordsignaling.

AllodyniaPainfulresponsetoanormallypainlessstimuli.Occursduetopathologicalsynapsebetweensecond-orderneuronesinthespinalcord.

AnaesthesiadolorosaPaininanareawhichisanaesthetised.

PeripheralNociception

Nociceptorsarereceptorswhichrespondtoanoxiousstimulus.Nociceptors:

Canbestimulatedorsensitisedby:ChemicalsignalsSeetable.Mechanicalsignals

ShearstressThermalsignals

Hotnociceptorsactivateabove43°CColdnociceptorsactivatebelow26°C

StimulationinitiatesanervousimpulseSensitisationincreasesareceptorssensitivitytoastimulatingmediator

Keychemicalstimulatingandsensitisingmediatorsinclude:

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StimulatingMediators SensitisingMediators

H Prostaglandins

K Leukotrienes

ACh SubstanceP

Histamine NeurokininA

5-HT CalcitoninGRP

Bradykinin

Nociceptors

Impulsesareconductedbytwotypesofprimaryafferentfibres:

Aδfibres:Small(~2-5μmdiameter)MyelinatedConductsharppainatupto40m.sMediateinitialreflexresponsestoacutepainSynapseinlaminaeIinthedorsalhornSubstancePistheneurotransmitterattheNK1receptor.

Cfibres:<2μmdiameterUnmyelinatedConductdullpainat2m.sSynapseinlaminaeIIinthedorsalhornSubstancePistheneurotransmitterattheNK1receptor.

PainPathwayandSiteofActionofAnalgesicsTheresponsetoapainfulstimulusrequiresacascadeofprocesses:

ActivationofnociceptorsMembranedepolarisationinresponsetostimulus.Ifthestimulusisgreatenoughtoreachthethresholdpotential,anactionpotentialisgenerated.

NSAIDSreducenociceptormediatedinflammationOpiatesactonperipheralMOPreceptorsLocalanaestheticspreventsignalpropagation

SynapseinthedorsalhornInputfrombothAδandCfibres,anddescendinginterneurons.

DescendinginhibitoryinputreducesnociceptivetransmissionBasisof"gatecontrol"theory.Descendinginputincreasedwith:

TouchAβ'touch'fibresstimulateinhibitoryinterneuronsinthedorsalhorn,'closingthegate'byincreasingdescendinginhibitionandpreventsignalsfromperipheralCfibresfromrisingtothethalamus.ArousalOpioidreceptorsParticularlyMOP(pre-andpost-synaptically).

Opioidsactpre-synapticallytoreduceSubstancePandglutaminerelease.α receptors

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Clonidine,tricyclicantidepressants,noradrenaline-reuptakeinhibitors,andendogenouscatecholamines.Gabapentinandpregabalininhibitpresynapticneurotransmitterrelease

WidedynamicrangeneuronesReceiveafferentinputfromchemical,thermal,andmechanoreceptors.

TypicallymoredifficulttostimulateImportantinwind-upMediatedbyNMDAagonism.

KetaminereduceswindupandcentralsensitisationLeadtosecondaryhyperalgesiaLeadtoallodyniaViaadditionalsynapsestosensoryneuronesinlaminaIIIandIV.Interneuronsynapseswithasecond-orderneuronesfibreThesesecondaryafferents:

Crosswithin1-2vertebralsegmentsandascendsinthespinothalamictractReceivesinputfromdescendingfibresOpioidsactpost-synapticallytohyperpolarisesecond-orderneurones

Reflexarc

HighercentresPainperceptionoccursinthesomatosensorycortex.

NeuropathicPainPainduetoalesionofthesomatosensorysystem,ratherthanastimulusitself.Neuropathicpainisdividedinto:

CentralneuropathicpainFromCNSinjury,e.g.spinalcordinjury,CVA,multiplesclerosis.PeripheralneuropathicpainDamagefrom:

DiabetesIschaemiaofSchwanncellscausesdemyelination,causingtheexposedaxontogenerateactionpotentialsinappropriately.TraumaTransectedaxonsmayregrowwithendingsthatspontaneouslyfireorthathavealteredthresholdpotentials.

MechanismsofNeuropathicPain

NeuromaHealingofdamagednervesleadstoneuromaformation.Neuromas:

AremoresensitivetopainfulstimuliCausespontaneouspainMaysproutandinnervatelocaltissuesMovementofthesetissuesmayleadtopain.

WindupPhantomlimbpainNeuronsdamagedinremovalofalimbdevelopadditionalsynapses,leadingtophantomsensations.

FeaturesofNeuropathicPain

Neuropathicpainisassociatedwith:

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InjuryordiseasethatcausesnerveinjuryBurningorelectricalqualityReducedorabsentsensationPoorresponsetotypicalanalgesia

ChronicRegionalPainSyndrome

DamagetotheSNScanleadtoabnormalitiesinautonomicfunction:

ChangeintemperatureduetovasomotordysfunctionAlteredsweatingReducedhairgrowthOsteoporosisHyperalgesiaandallodynia

PainintheElderly

NervousSystemChanges:

PeripheralNervousSystemNervedeteriorationDecreasedmyelinationDecreasedconductionvelocityReducedrangeandspeedofANSresponsesIncreasedrestingsympathetictone

CentralNervousSystemDecreasedpainperceptionIncreasedsensitivitytoanaestheticandanalgesicsReachceilingeffectsmorerapidly.DegenerationofmyelinSubsequentcognitivedysfunctionduetoneuronalcircuitdysfunction.GeneralisedatrophyDecreasedneurotransmitterproduction

References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SchugSA,PalmerGM,ScottDA,HalliwellR,TrincaJ.AcutePainManagement:ScientificEvidence.4thEd.2015.

AustralianandNewZealandCollegeofAnaesthetistsandFacultyofPainMedicine.3. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.4. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.5. MerskeyH,BogdukN.ClassificationofChronicPain.2ndEd.1994.IASPTaskForceonTaxonomy.IASPPress,Seattle.6. HalaszynskiT.InfluencesoftheAgingProcessonAcutePerioperativePainManagementinElderlyandCognitively

ImpairedPatients.TheOchsnerJournal.2013;13(2):228-247.7. MelzackR,WallPD.Painmechanisms:anewtheory.Science.1965.19;150(3699):971-9.8. GibsonS.PathophysiologyofPain.

Lastupdated2019-07-18

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AutonomicNervousSystemDescribetheautonomicnervoussystem,includinganatomy,receptors,subtypesandtransmitters(includingtheirsynthesis,releaseandfate)

TheANSisthesectionofthenervoussystemwhichregulatesinvoluntaryandvisceralfunctions.Theseinclude:

HaemodynamicsDigestionUrinationanddefecationThermoregulationSexualfunction

Theautonomicnervoussystemcanbedividedinto

CentralANSControloccursinthehypothalamus,brainstem,andspinalcord.PeripheralANSDividedanatomicallyandfunctionallyintothe:

SympatheticnervoussystemParasympatheticnervoussystem

GRAPHFROMPAGE258ofGANONG

CentralControl

Thehypothalamuscontrolsautonomicfunctionsbyneuralandendocrinemechanisms.Itissubdividedanatomicallyintofourregions:

AnteriorhypothalamusControlsthePNSandthermoregulation.ItalsoreleasesADHinresponsetoincreasedplasmaosmolality,andoxytocin.MedialhypothalamusInhibitsappetiteinresponsetoincreaseinbloodglucose.LateralhypothalamusContainsthethirstcentreanddrivetoseekfood.PosteriorhypothalamusControlsvasomotorcentres,modulatingsympatheticvasoconstriction,aswellaspositiveandnegativeinotropyandchronotropy.Alsomodulateswakefulnessinresponsetosympatheticstimuli.

Signalsfromthehypothalamushaveatonicoutputto:

AllsmoothmuscleHeartExocrineorgansEndocrineorgansGITGU

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Inthegreymatterofthespinalcord,efferentnervessynapsewithtwoothernervesconnectedinseries.Thismaintainstonicautonomicoutflow.

FIGUREFROMPAGE67-POWERANDKAM

Efferentnervesexitthespinalrootanteriorly,andformtheventralroot.

Conversely,afferentnervesexitposteriorly,formingthedorsalrootandthendorsalrootganglion,beforesynapsinginthespinalcord.

SympatheticNervousSystem

Thesympatheticnervoussystemoptimisesthebodyforshort-termsurvival.

Sympatheticinnervationisfromthesympathetictrunks.These:

AreapairedbundleofsympatheticneuronswhichrunlateraltothevertebralbodiesfromT1toL2Thetrunkissubdividedintofourparts:

Thecervicalpartinnervatesthehead,neck,andpartofthethoraxThethoracicpartisfurthersubdividedinto:

UpperthoracicfromT1-T5,whichinnervatestheaorta,heart,andlungsLowerthoracicfromT6-T12,whichinnervatestheforegutandmidgut

ThelumbarpartformsthecoeliacplexusThepelvicpartinnervatethepelvicvisceralandlowerlimbvasculature

Containthesympatheticganglion,whichisasynapsebetweenthe:Shortpre-ganglionicfibreCellbodyislocatedinthelateralhornofthespinalcord,andconnectstothesympatheticganglion.

ReleasesAChtostimulatethepost-ganglionicfibre.Longpost-ganglionicfibreCellbodyislocatedinthesympatheticganglion,andstimulatestheeffectsite.

HasanicotinicAChreceptorReleasesNAattheeffectsiteSensitivity(forACh)andactivity(forNArelease)ismodulatedbyanumberofothersubstances:

EnkephalinNeuropeptideYDopamineAdrenalineProstaglandinGABANeurotensin

Therearethreeexceptionstotheabovestructure:

Theadrenalglandisamodifiedsympatheticganglion.Itis:DirectlyinnervatedbypreganglionicneuronsreleasingACh

Sweatglandshavemuscarinicreceptors,andarestimulatedbyAChratherthannoradrenalineSkeletalmusclearteriolesalsohavemuscarinicAChreceptors,andarestimulatedbyACh

Effect

Sympatheticstimulationhasanumberofeffectsbyeitherdirectneuralinnervationoradrenalinerelease.Theyareconsistentwitha'fightorflight'response,andoptimisethebodyforshort-termstressconditions.

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Organ Innervation Response

Eye Cervical Pupillarydilatation

Lungs Thoracic Bronchodilation

Heart Thoracic ↑↑↑Chronotropy,↑↑↑inotropy,↑↑↑lusitropy,↑↑dromotropy

Vasculature Sacral Constriction

MSK Sacral Sweating,contraction,lipolysis

Endocrine Lowerthoracic Adrenalineandnoradrenalinerelease

GIT Thoracic,lumbar DecreasedsalivationandGITmotility,increasedsphinctertone,gluconeogenesis

GU Pelvic Detrusorrelaxation,sphinctercontraction,↑uterinetone

ParasympatheticNervousSystem

Parasympatheticinnervationarisesfromthe:

CranialnervesFromCNIII,VII,IX,and(mostly)X.

Thevagusisthemajorcranialparasympathetic,innervatingthe:Heartviathecardiacplexus

TheSAnodeisinnervatedbytherightvagusTheAVnodeisinnervatedbytheleftvagusTheventriclesarealsosparselyinnervatedfromtheleftvagus.

LungsviathepulmonaryplexusStomach,liver,spleen,andpancreas,andgutproximaltothesplenicflexureviathegastricplexus.

HypogastricplexusArisesfromS2-S4,andinnervatesthebladder,uterus,andgutdistaltothesplenicflexure.

Theparasympatheticnervoussystemgangliasiteclosetothetargetorgan.Thismeansthatthe:

Pre-ganglionicfibreislongPreganglioniccellbodysitswithinthebrainstem(cranialnerves)orsacralgreymatter(hypogastricplexus)ReleasesAChtostimulatethepost-ganglionicneuroneatanicotinicAChreceptor

Post-ganglionicfibreisshortReleasesAChtostimulatethetargetorganatamuscarinicAChreceptor

Effect

EffectorOrgan ParasympatheticInnervation Response

CNS CNIIIviatheEdinger-Westphalnucleus,CNVII Pupillaryconstriction(CNIII),lacrimation(CNVII)

Lungs CNX Bronchoconstriction,increasedmucousproduction

Heart CNX

↓↓↓Chronotropy,↓↓↓dromotropy,↓inotropy,↓lusitropy(↓ininotropyandlusitropyisgreaterintheatriathantheventricles)

CNVII(submaxillaryandmandibularsalivaryglands),CNIX

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GIT (parotidgland),CNX(stomachtoproximaltwo-thirdsofthetransversecolon),hypogastricplexus(distalone-thirdofthetransversecolontorectum)

Salivation,decreasedsphinctertone,increasedmotility

GU Hypogastricplexus Detrusorcontraction,erection

GanglionBlockadeBlockadeoftheganglion(atthenicotinicAChreceptor)blockstransmissionandreducessympatheticandparasympatheticimpulsetransmission.ClinicaleffectofganglionblockadedependsonwhichpartoftheANSisdominantinthatorgansystem:

SNSdominantorgansystemsEffectivesympatholysis:

VasculatureVasodilation,hypotension.SweatglandsAnhydrosis.

PNSdominantorgansystemsEffectiveparasympatholysis:

HeartTachycardia.IrisMydriasis.GITDecreasedton.BladderUrinaryretention.SalivaryReducedsecretions.

EntericPlexus

TheentericplexusisasystemofautonomicnervesintheGITwhichisfreeofCNScontrol.Itconsistsofsensoryandintegrativeneuronsaswellasexcitatoryandinhibitorymotorneuronswhichgeneratecoordinatedmuscularactivity.

References1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. BarrettKE,BarmanSM,BoitanoS,BrooksHL.Ganong'sReviewofMedicalPhysiology.24thEd.McGrawHill.2012.3. Klabunde,RE.NeuralActivationoftheHeartandBloodVessels.Accessed2016.

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AnticonvulsantsAnunderstandingofthepharmacologyofanti-depressant,anti-psychotic,anti-convulsant,andanti-Parkinsonianmedication

Anticonvulsantsworkviaanumberofdifferentmechanisms:

SodiumChannelBlockers

Sodiumchannelblockers:

Stabilisetheinactivestateofthechannel,preventingreturntotheactivestateandpreventgenerationoffurtheractionpotentialsThishaltspost-tetanicpotentiationandlimitsthedevelopmentofseizureactivity.MayalsohaveClassIantiarrhythmicpropertiesDuetoNa blockingeffects.Include:

PhenytoinCarbamazepineLamotrigine

GABAMediatorsGABAisthekeyinhibitoryneurotransmitterintheCNS.GABAmediators:

EnhancetheeffectofGABAMultiplepotentialmechanisms:

DirectGABA-receptoragonistse.g.Benzodiazepinesandphenobarbital.Positiveallostericmodulatione.g.Propofolandthiopentone.GABAreuptakeinhibitione.g.Tiagabine.GABAtransaminaseinhibitione.g.Vigabatrin.IncreaseGABAsynthesise.g.SodiumValproate.

GlutamateBlockers

GlutamateisanimportantCNSexcitatoryneurotransmitter.Glutamateantagonists:

Aregenerallyavoidedduetotheirsideeffectprofile,whichincludespsychosisandhallucinationsIncludetopiramate

OtherAgentsGabapentinandpregabalin:

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DonotappeartomediateGABAInhibitofexcitatoryα δvoltage-gatedcalciumchannelsintheCNSThisgivesthemanticonvulsantproperties.

References1. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.2. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.3. Medscape-AntiepilepticDrugs.AccessedDecember2015.

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NeurotransmittersDescribethemajorneurotransmittersandtheirphysiologicalrole,withparticularreferencetoGABA,excitatoryandinhibitoryaminoacids,acetylcholine,noradrenaline,dopamineandserotoninandNMDAreceptor

GABA

GammaaminobutyricacidisthemajorinhibitoryCNSneurotransmitter.GABAreceptorshavethreesubtypes:

GABAInotropicreceptorimportantfortheactionofmanydrugs.

Pentamericstructure2αBindGABA.2β1γ

Affectedbymanydifferentdrugs:BenzodiazepinesPositiveallostericmodulationatattheα/γinterface.GeneralanaestheticagentsIncludingpropofol,barbiturates,halogenatedvolatiles,andetomidate.

ActattheβsubunitCauseaconformationalchangewhichincreasesCl openingtime,hyperpolarisingthecell.

GABAMetabotropicreceptor.GABAInotropicreceptorlocatedonlyintheretina.

NMDA

N-methylD-aspartatereceptorisaninotropicreceptorthatis:

AgonisedbyglutamateGlycineisco-agonist

VoltagedependentCentralporeusuallyblockedbyanMg ionBecomesunblockedwhenpartiallydepolarised

ImportantintheactionofdrugswhichdonotactattheGABA receptorAntagonisedby:

KetamineXenonN O

References1. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.

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LocalAnaestheticsUnderstandingofthepharmacologyoflocalanaestheticdrugs,includingtheirtoxicity

Localanaestheticdrugscreateause-dependenttemporaryblockadeofneuronaltransmissionbyblockingthevoltage-gatedsodiumchannelinthecellmembrane,preventingdepolarisation.

MechanismofAction

Actionisdependentonblockadeofthesodiumchannel.Twotheoriesexist:

Unioniseddrugpassesthroughthecellmembrane,andthenbecomesionisedintracellularlyTheioniseddrugisthenabletobindtotheopensodiumchannel,andpreventconductionofsodiumandthereforegenerationofanactionpotential

LocalanaestheticsalsodisplayreducedaffinityforK andL-typeCa channelsThistheoryexplainsuse-dependentblockade,assodiumchannelscanonlybeblockedintheiropenstate

Analternativesuggestedmechanismofactionisthedrugentersthecellmembraneandmechanicallydistortsthechannel,renderingitineffective

OnsetisinverselyproportionaltothesizeofthefibreFromfastesttoslowest:

PainTemperatureTouchDeeppressureMotor

ChemicalStructureofLocalAnaestheticsAlllocalanaestheticsareweakbasesconsistingof:

AhydrophiliccomponentAlipophilicaromaticringAnamideoresterlinkconnectingthetwo

Chemicalstructureinfluencespharmacologicalbehaviour:

HydrophilicportionTypicallythetertiaryamine.

Determinesionisation3bonds:Lipidsoluble4bonds:Watersoluble

LipophilicportionTypicallyaromaticring.

Determineslipidsolubility,andthereforepotency,toxicity,anddurationofactionEstervs.amide

AmidesHepaticallymetabolised(hydroxylationandN-de-alkylation)Thisisslower,thereforethereisagreaterriskofsystemictoxicity.Stableinsolution

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EstersHeat-sensitiveCannotbeautoclaved.RapidlyhydrolysedinplasmaOrganindependentelimination.HaveagreaterincidenceofallergyDuetotheinactivemetabolitePABA.

AminegrouplengthPotencyandtoxicityincreaseascarbon-chainincreasesToxicity(butnotpotency)continuestoincreasebeyond10carbons

IsomerismAltersbehaviour:

LevobupivacaineislesstoxicR-ropivacaineislesspotentandmoretoxic

KeyCharacteristicsofLocalAnaesthetics

Characteristicsarerelatedtochemicalstructure.Theseinclude:

PotencyPotencyisexpressedwiththeminimumeffectiveconcentrationoflocalanaesthetic(C )ThisistheconcentrationofLAthatresultsincompleteblockofanervefibrein50%ofsubjectsinstandardconditions.MorepotentagentshavealowerC .Potencyisafunctionof:

LipidsolubilityPotency(andalsotoxicity)increaseswithgreaterlipidsolubility.VasodilatorpropertiesIngeneral,localanaestheticscausevasodilationinlowconcentrations,andvasoconstrictionathighconcentrations(exceptcocaine,whichcausesvasoconstrictionatallconcentrations).

DurationofactionDurationofactionisafunctionof:

DrugfactorsVasodilatorpropertiesVasoconstrictionincreasesthedurationofblock.UseofadditivesAdditionofadrenalinetolignocaineincreasesdurationofblock.LipidsolubilityIncreasedlipidsolubilityincreasesdurationofaction,asagentremainsinthenerveforlonger.

PotencythereforehasapositivecorrelationwithdurationofactionDurationofactionisincreasedwhenpHincreases,astheionisedportionfalls

ProteinbindingHighlyproteinboundagentshaveanincreaseddurationofactionduetoincreasedtissuebinding.

ProteinbindingdecreaseswithdecreasingpH,increasingthefractionofunbounddrugThisiswhyagentssuchasbupivacainearemorecardiotoxicinacidoticpatients.Localanaestheticsarepredominantlyboundtoα-1-acidglycoprotein(AAG)AAGisreducedinpregnancy,increasingthefreedrugfractionandthereforereducingthetoxicdoseofLAinpregnantpatients.

PatientfactorsTissuepHDecreaseddurationofblockwhentissuepHislow.

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MetabolicimpairmentHepaticfailureincreasesdurationofactionofaminosteroidsButylcholinesterasedeficiencyincreasesdurationofesterlocalanaesthetics

SiteofadministrationWellvascularisedtissue(e.g.intercostalarea)willhavegreatersystemicuptakeofdrugthanvesselpoortissue.

OnsetSpeedofonsetisrelatedto:

DrugfactorsDoseIncreasingthedoseincreasesthespeedofonset,asperFick'sLaw.

IncreasedconcentrationwillincreasespeedofonsetandblockdensityIncreasedvolume(withoutincreasingdose,resultingindecreasedconcentration)willdecreasespeedofonset

LipidsolubilityAnincreasedlipidsolubilityincreasesthespeedatwhichthelocalanaestheticentersthenerve.However:

LipidsolubilityalsocorrelateswithpotencyTherefore,inpractice,morelipidsolubleagentsareadministeredinlowerdoses,andsohaveareducedspeedofonsetThisisknownasBowman'sPrinciple.

IonisedportionOnlyunioniseddrugcancrosscellmembranes.Ionisationisafunctionof:

pKaTissuepH

Thisisalsowhyanaestheticsareineffectiveinanaesthetisinginfectedtissue,asthelowpHmakesthemajorityoftheLAionisedandunabletocrossthecellmembrane.

PatientfactorsNerveactivityLocalanaestheticsproduceafrequencydependentblockade,meaningnervesfiringfrequentlywillbeblockedmorerapidlythanquiescentnervesNervefibresizeLargernervesrequireanincreasedconcentrationoflocalanaesthetictoachieveblockadethansmallernerves.NervetypeDifferentnervefibresareaffectedatdifferentspeeds,whichismostly(thoughnotentirely)afunctionofcriticallength.

Aγ(proprioceptive)areaffectedfirstSmallmyelinatedAδ(sharppain,cold)fibresareaffectedsecondLargemyelinatednervesareaffectedthirdTheseincludeAα(motor)andAβ(touch)fibres.UnmyelinatednervesareaffectedlastTheseincludeC(dullpain,heat)fibres.

HyperkalaemiaReducesonsetofaction.

Toxicity

Localanaestheticsare:

ToxictoboththeCNSandCVSToxicityoccurswhenthereisanexcessplasmaconcentrationThisoccurswhentherateofdrugenteringthesystemiccirculationisgreaterthanthedrugleavingthesystemiccirculationduetoredistributionandmetabolism.

Toxicityisrelatedtothe:

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DrugfactorsDrugusedAgentsarecomparedusingtheCC/CNSratio,whichistheratioofthedoseofdrugrequiredtocausecardiovascularcollapse(CC)comparedtothedoserequiredtocauseseizure.Itisacrudealternativetothetherapeuticindex.DoseusedContinuousinfusionsaremorelikelytocauseadelayedonsetoflocalanaesthetictoxicity.

BlockfactorsSiteofadministrationThisaffectstherateofuptakeintothesystemiccirculation,andthelikelihoodofinadvertentintravascularinjection.Ranked(fromhighesttolowest):

Intravascular(obviously)ThisisthemostcommoncauseofLAtoxicity.

Siteisalsorelevanthere:aninjectionintothecarotidarterywillcausetoxicityatalowerdosethanifinjectedintoaperipheralvein.

IntercostalCaudalEpiduralBrachialplexusSubcutaneous

UseofadjunctsAdrenalineVasoconstrictorpropertiesreducesystemicabsorptionofLA.

TechniqueFrequentaspirationTestdoseUseofultrasound

PatientfactorsAnythingthatincreasespeak[plasma]canleadtoanincreasedriskofLAtoxicity.

Bloodflowtoaffectedareaα1-acidglycoproteinLowlevelsofthisproteinincreasefreedrugfraction.

NeonatesandinfantshavehalfthelevelofAAGthanadults.HepaticdiseaseReducesclearanceofamides,whichmaycausetoxicitywithrepeateddosesoruseofinfusions.AgeOrganbloodflow(andthereforeclearance),aswellaspharmacokineticinteractionsmayaffectclearanceofLA.BothchildrenandtheelderlyhavereducedclearanceofLA.AcidosisIncreasesunionisedportion.HypercarbiaIncreasescerebralbloodflow.

CardiacToxicity

Cardiactoxicityoccursdueto:

BlockingofthecardiacNa channel(K andCa channelsmayalsobeinvolved)Severityoftoxicitywillvarydependingonhowlongtheagentbindstothechannel,withlesstoxicitycausedbyagentsspendinglesstimebound:

Lignocaine

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Spendstheshortesttimeboundtothechannel,socausestheleastamountoftoxicity.Thisisalsowhylignocainecanbeusedasanantiarrhythmic,butotheragentscannot.BupivacaineTakes10xaslongtodissociateaslignocaine.Thiscanleadtore-entrantarrhythmias,andthenVF.Theriskofthisisincreasedintachycardiaduetouse-dependentblockade.RopivacaineDissociatesmorerapidlyfromcardiacchannelsthanbupivacaine.

DirectmyocardialdepressanteffectsReducescAMPlevelsbydisruptingmetabotropicreceptors.

Cardiactoxicityistriphasic:

InitialphaseHypertensionTachycardia

Intermediatephase:HypotensionMyocardialdepression

Terminalphase:SeverehypotensionVasodilationVariousarrhythmias

SinusbradycardiaVariabledegreeheartblockVTVFAsystole

CNSToxicity

LocalanaestheticsintheirunionisedstatecancrosstheBBBandinterferewithCNSconduction.CNStoxicityisbiphasic:

Initially,inhibitoryinterneuronsareblockedThiscausesexcitatoryeffects:

PerioraltinglingSlurredspeechVisualdisturbancesTremulousnessDizzinessConfusionConvulsionsTypicallysignifiestheendoftheexcitatoryphase.

Secondly,thereisageneraldepressionofallCNSneuronsThiscausesinhibitoryeffects:

ComaApnoea

Treatment

ToxicityismanagedwithanABCapproach,thoughdefinitivemanagementusesIntralipidemulsion:

Intralipidisanemulsionofsoyaoil,glycerol,andeggphospholipids.Mechanismofactioninuncertain,buttheoriesinclude:

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LipidsinkILEbindsunionisedLA,causingittodistributeoffreceptorsites.FattyacidmetabolismCardiacfattyacidmetabolismisinterruptedbyLA.ILEprovidesasourceoffattyacidstoallowmetabolismtocontinue.CompetitiveantagonismILEmaydirectlyinhibitLAbinding.

DosingofIntralipid20%:Bolusof1.5ml.kg over1minuteInfusionat15ml.kg .hr

ComplicationsincludepancreatitisNotethatILEinterfereswithamylaseandlipaseassays,andsothesewillbeunreliable.

Notethatwhilstpropofolcanbeusedtotreatseizures,theamountoflipidcontainedinpropofolisinadequatetobindLA

References

1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. ChristieLE,PicardJ,WeinbergGL.Localanaestheticsystemictoxicity.ContinuingEducationinAnaesthesiaCriticalCare

&Pain,Volume15,Issue3,1June2015,Pages136–142.3. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.4. BeckerDE,ReedKL.EssentialsofLocalAnestheticPharmacology.AnesthesiaProgress.2006;53(3):98-109.

Lastupdated2019-07-18

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NeuraxialBlockadeDescribethephysiologicalconsequencesofacentralneuraxialblock

Centralneuraxialblockadereferstoblockadeoffibresinthespinalcordbyadministrationofintrathecalorepidurallocalanaesthetic.

RespiratoryResponses

Anincreasinglevelofblockwillleadtogreatereffects:

ThoracicImpedimenttoactiveexpirationandexpectorationduetoblockadeofintercostalsandabdominalwallmusculatureLossofvitalcapacityLossofsomeaccessorymuscleuse

CervicalImpedimentduetodiaphragmaticblockade.

CardiovascularResponsesOccurduetoblockadeofsympatheticchainfibresinthethoracolumbarregion.

Anincreasinglevelofblockwillleadtogreatereffects:

SacralParasympatheticblockadeonly.MinimalCVSeffects.Lowerthoracic/lumbarArteriolarandvenousvasodilationinlowerabdomenandlowerlimbs,causingafallinSVR,BP,andGFR.UpperthoracicLossofcardioacceleratorfibresaboveT5,causingareductioninheartrateandcontractility,compoundinghypotensionduetofallinSVR.CranialNervesVagalblockadewillreducePNStoneandattenuatesomeofthelossofSNStone.BrainstemInhibitionofvasomotorcentrewithprofoundfallinCVSparameters.

CNSResponsesAnincreasinglevelofblockwillleadtogreatereffects:

CervicalHorner'ssyndrome(miosis,anhydrosis,ptosis)duetolossofsympathetictrunks.CranialnervePupillarydilationduetoCNIIIblockade.BrainstemandCerebralCortexAnaesthesiaduetoblockadeofthereticularactivatingsystemandthalamus.

References

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1. Diaz,A.CardiovascularResponsetoCentralNeuraxialBlockade.PrimarySAQs.2. ANZCAJuly/August2007

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AcetylcholineReceptorsUnderstandingofthepharmacologyofanticholinesterasedrugs.

Describetheadverseeffectsofanticholinesteraseagents.

ThiscoversthepharmacologyofacetylcholinereceptorsandtheproductionandmetabolismofACh.Detailedinformationonspecificagentsisinthepharmacopeia.

Acetylcholineisaneurotransmittervitalfornormalfunctionof:

CNSANSMusclecontraction

Synthesis,Release,andMetabolismAChisproducedisthenervecytoplasmbyacetyltransferasefrom:

CholineFromdietandrecycledACh.Acetyl-coenzymeAProducedintheinnermitochondrialmatrix.

Oncesynthesised,AChisthenpackagedintovesicles(eachcontaining~10,000AChmolecules),whicharereleasedinresponsetocalciuminfluxoccurringattheculminationofanactionpotential.

Acetylcholineismetabolisedbyacetylcholinesteraseonthepost-junctionalmembrane.AChE:

Hastwobindingsites:AnionicbindingsiteBindsthepositivelychargedquaternaryammoniummoiety.EsteraticbindingsiteBindstheestergroupofACh.

Oncebound,AChisacetylatedAcetylated-AChisthenhydrolysedtoproduceaceticacid

AChReceptorSubtypes

TherearetwotypesofAChreceptor:

NicotinicAChreceptorsInotropicLinkedtoanionchannel.

Non-specific-mayallowNa ,K ,orCa tocrossConsistsoffivesubunits:

TwoαBindACh.OneβOneδOneγ

Locatedin:

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Post-synapticNMJPreganglionicautonomicnervoussystemAntagonismcausesganglionblockade.Brain

KnownasnicotinicbecausenicotineagonisesthisreceptorActivation:

2AChmoleculesmustbindtoactivatethereceptorOncebound,receptorundergoesaconformationalchangewhichopensthecentralionporePermeabilitytoNa (andtoalesserextent,K andCa )increases,leadingtodepolarisation

MuscarinicAChreceptorsMetabotropicG-proteincoupled.KnownasmuscarinicbecausemuscarinealsoagonisesthisreceptorSubdividedinto:

M (Gq)SecretoryglandsandCNS.M (Gi)Heart.M GqBronchialandarteriolarsmoothmuscle.M (Gi)andM (Gq)CNS.

References

1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.

Lastupdated2019-07-18

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OpioidsKeydefinitions:

Opiatesareallnaturally-occurringsubstanceswithmorphine-likepropertiesOpioidsisageneraltermforsubstanceswithanaffinityforopioidreceptorsOpiumisamixtureofalkaloidsfromthepoppyplant

ClassificationofOpioids

NaturallyoccurringEndogenousopioids

EndorphinsEnkephalinsDynorphins

OpiumderivativesPhenanthrenes

MorphineCodeine

SemisyntheticSimplemodificationstomorphine.

DiacetylmorphineBuprenorphineOxycodone

SyntheticPhenylpiperidines

FentanylAlfentanilRemifentanilPethidine

DiphenylpropylaminesMethadone

OpioidReceptorClassification

AllopioidreceptorsareGireceptors.Activation:

Inhibitsadenylylcyclase,reducingcAMPPre-synapticallyinhibitsvoltage-gatedCa channels

DecreasesCa influxReducesneurotransmitterrelease

Post-synapticallystimulatesactivatesK channelsCausesK effluxLeadstomembranehyperpolarisation

Receptor Actions NotableProperties

MOPAnalgesia(spinalandbrain),euphoria,meiosis(viastimulationoftheEdinger-Westphalnucleus),nauseaandvomiting(viaCTZ),sedation,bradycardia,inhibition

Onlyopioidreceptortocause

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ofgutmotility,urinaryretention,physicaldependence nausea/vomiting

KOP Analgesia(predominantlyspinal),sedation,meiosis,dysphoria Lessrespiratorydepression

DOP Analgesia,respiratorydepression,urinaryretention,physicaldependence Minimalconstipation

NOP Anxiety,depression,changeinappetite

Hyperalgesiaatlowdoses,analgesicathighdoses

Mechanismofeffects:

RespiratorydepressionDecreasescentralchemoreceptorsensitivitytoCO .ConstipationStimulationofopioidreceptorsinthegut.

Normallyactivatedbylocalendogenousopioids(usedasneurotransmitters)Agonismofthesereceptors(µ,k,andtoasmallerextent,δ)reducesGITsecretionsandperistalsis

References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. KatzungBG,TrevorAJ.BasicandClinicalPharmacology.13thEd.McGraw-HillEducationEurope.2015.3. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.

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InhalationalAnaestheticsStructure-activityrelationshipsofinhalationalagents

Describetheuptake,distributionandeliminationofinhalationalanaestheticagentsandthefactorswhichinfluenceinductionandrecoveryfrominhalationalanaesthesiaincludingthe:-Conceptsofpartitioncoefficients,concentrationeffectandsecondgaseffect-Relationshipsbetweeninhaledandalveolarconcentration-Significanceofthedistributionofcardiacoutputandtissuepartitioncoefficientsonuptakeanddistributionofvolatileagents

DescribetheconceptandclinicalapplicationofMACinrelationtoinhaledanaestheticagents

Describehowthepharmacokineticsofdrugscommonlyusedinanaesthesiainneonatesandchildrendifferfromadultsandtheimplicationsforanaesthesia

Propertiesofanidealinhalationalanaestheticagent

Inhaledanaestheticsarechemicalswithgeneralanaestheticpropertiesthatcanbedeliveredbyinhalation.Theycanbedividedinto:

VolatileanaestheticagentsVolatilityreferstothetendencyofaliquidtovapourise.Volatileagentsinclude:

SevofluraneIsofluraneDesfluraneMethoxyfluraneEnfluraneHalothaneEther

AnaestheticgasesNitrousoxideXenon

KeyPrinciplesofInhalationalAgents

Keyprinciples:

TheclinicaleffectofaninhalationalagentisdependentonitspartialpressurewithintheCNSAtequilibrium,thepartialpressureintheCNS(P )equalsthepartialpressureinblood(P ),andinthealveoli(P )Reachingequilibriumisrarelyachievedinpracticeasittakesmanyhours.Rateofonsetandoffsetofaninhalationalagentaredependentonbothphysiologicalandpharmacologicalfactorsaffectingthetransferofagent:

IntothealveoliFromthealveoliintobloodFrombloodintotheCNS

MinimumAlveolarConcentration(MAC)

MACisdefinedastheminimumalveolarconcentrationatsteadystatewhichpreventsamovementresponsetoastandardsurgicalstimulus(1cmforearmincision)in50%ofapopulation.

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Notethatthisdefinition:

DoesnotreflectlackofawarenessDoesreflecttheactionofanagentonspinalcordreflexesThisiswhy1MACisadequateforthemajorityofpatients,asawarenessandrecallaresuppressedatlowerMACvaluesthanarerequiredforimmobility.ConsciousnessisbetterestimatedbyMAC-awakeEnd-tidalconcentrationofagentthatpreventsappropriateresponsestoaverbalcommandin50%ofapopulation.

Notethatthistechnicallymeasuresawarenessratherthanmemory.MAC-awakeistypicallyone-thirdofMACforcommonly-usedagents

Isonlyvalidatsea-levelTheclinicaleffectofanagentisdependentonitspartialpressurenotconcentration.

At1atm,thesearealmostthesame1atm≃100kPa;therefore2%sevofluraneis≃2kPaAsaltitudeincreases,theactualpartialpressurewillfallforanygivenconcentrationi.e.2%sevofluraneat0.5atmis≃1kPaofsevoflurane.

MACis:

Ameasureofpotency(i.e.theEC oftheagent,wheretheoutcomeismovement)TheMACofanagentisinverselyproportionaltopotency;i.e.morepotentagentsrequiresmalleralveolarconcentrationstoproduceanaesthesia.

ThisgivesrisetotheMeyer-Overtonhypothesis,whichsuggeststhatanaesthesiarequiresasufficientnumberofmoleculestodissolveintotheneuronalcellmembrane.

Ifthiswastrue,theproductoftheoil:gaspartitioncoefficientandMACwouldbeconstant,whichisnotthecase.AdditiveTheMACsofdifferentagentsusedsimultaneouslyareadditive.Normally-distributedNotallpatientswillbeunresponsiveat1MAC.

Thestandarddeviationis0.1,so95%ofpatientswillnotmoveinresponsetoastimulusat1.2MACEstimatedclinicallyusingend-tidalgasmeasurementMACisnotbasedonarterialpartialpressure(F )ofagent.

Thisisanimportantdifference,becauseevenatsteady-state,F ≠FThisoccursdueto:

V/QmismatchShuntedalveoliwillnotabsorbanaestheticagent,andunperfusedalveoliwillcontainagentthatisnotbeingabsorbed.

ThisisworsenedbytheeffectsofanaesthesiaVolatileagentsareheavyandhavefinitediffusibility

However,thedifferencebetweenF andF foranyagentisthesameatsteadystate(andinabsenceofnitrousoxide)Thismeansthat,atsteady-state,MACwillbeproportionalto,andanaccuratemeasureof,P .

Oneofseveralrelatedterms:MACawakeConcentrationrequiredtopreventresponsetoaverbalstimuliinabsenceofnoxiousstimuli.

Typically~1/3 ofMACformostagents(sevoflurane,isoflurane,desflurane)Notablyhigherfornitrousoxide(MAC-awake~2/3 ofMAC)MAC-awakeistypicallylessthanMAC-asleepas:

HysteresisbetweenalveolarandeffectsiteconcentrationsDuringinduction,alveolarconcentrationishigherthaneffectsiteconcentration,andsooverestimateseffect.Duringwashout,alveolarconcentrationislessthaneffectsiteconcentration,andthereverseeffectoccurs."Neuralinertia"Intrinsicresistanceofnervecellstoachangeintheirstate.

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MAC-BARMinimumalveolarconcentrationrequiredtoblockadrenergicresponse,i.e.topreventariseinHRorBPfollowingskinincision.MACTheMACrequiredtopreventamovementresponsetoastandardsurgicalstimulusin95%ofthepopulation.MAC.hrTheamountoftimeapatientisexposedto1MACofanagent.Usedtocomparedifferentagents.

FactorsAffectingMAC

DecreasesMAC IncreasesMAC

Age(~6%/10years↑)andneonates Youth

Hypothermia Hyperthermia

Hypocapnea Hypercapnea

Hyponatraemia Hypernatraemia

Hypothyroidism Hyperthyroidism

AcutealcoholandotherCNSdepressantintoxication ChronicETOHandCNSdepressantabuse

Chronicamphetamineintake Acuteamphetamineintake

Hypovolaemia/Hypotension

Lithium

Hypoxia

Anaemia

Pregnancy

SNSactivationandanxiety

IncreasedP

Notethatadditionofotheragents(e.g.opioids)willaffectdifferentMACsubtypes(e.g.MAC vsMAC )differently.

PartitionCoefficients

Apartitioncoefficientdescribestherelativeaffinityofanagentfortwophases,andisdefinedastheratiooftheconcentrationofagentineachphase,whenbothphasesareofequalvolumeandthepartialpressuresareinequilibriumatSTP.

Theblood:gaspartitioncoefficientdescribesthesolubilityoftheagentinbloodrelativetoair,whenthetwophasesareofequalvolumeandinequilibriumatSTPAlowblood:gaspartitioncoefficientindicatesarapidonsetandoffset.Thisisbecause:

PoorlysolubleagentsgenerateahighP ,whichcreatesasteepgradientbetweenP andP ,givingarapidonsetofactionConversely,solubleagentsdissolveeasilyintopulmonarybloodwithoutsubstantiallyincreasingPThiscausesleadstoaslowonsetdueto:

AlargefallinP astheagentleavesthealveolus,decreasingthegradientforfurtherdiffusionAsmallgradientbetweenP andP

Theoil:gaspartitioncoefficientdescribesthesolubilityoftheagentinfatrelativetoair,whenbothphasesareofequalvolumeandinequilibriumatSTPAhighoil:gaspartitioncoefficientindicatesagreaterpotency,andthereforealowMAC.

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PharmacokineticsofInhalationalAgents

AchievingtherequiredP requiresmaintainingP atahighenoughlevel.ByincreasingP ,thepressuregradientfordiffusionintoblood,andthereforeCNS,isincreased.

Asdiscussedabove,rateofonsetofaninhalationalagentisdependentonrateofuptake:

IntothealveoliFromthealveoliintobloodFrombloodintotheCNS

Factorsaffectingalveolarconcentrationofagent:

InspiredconcentrationAhighinspiredconcentration(F )willincreasetherateofincreaseofalveolarconcentration(F ).Inspiredconcentrationisdependenton:

DeliveredconcentrationinfreshgasFreshgasflowIncreasingFGF(andtheconcentrationofagentintheaddedgas)increasesF .VolumeofthebreathingsystemAlowercircuitvolumewillincreasetherateatwhichthepatientreachesequilibriumwiththecircuit,andthereforeincreaseF .CircuitabsorptionAbsorptionofagentbythecircuitwilldecreaseF .

VIncreasedalveolarventilationincreasesF ,asitreplenishesagentthathasbeentakenupintothevasculature.

Similarly,increaseddeadspacewillprolonginduction,asanaestheticgaswillbedeliveredtonon-perfusedalveoliFRCAlargeFRCwilldilutetheamountofagentinspiredwitheachbreath,andsoreduceF .

ThisismeasuredwiththeV /FRCratioIncreasedratioincreasesspeedofonset.

Normalinadults:1.5:1Normalinneonates:5:1

SecondgaseffectUseofN OwithanotheragentwillincreasetheP ofthatagent.Thisisbecause:

N Ois20xassolubleinbloodaseitherbloodornitrogen,andisadministeredinhighconcentrations,soitisrapidlyabsorbedfromalveoliIfnitrousoxideisdeliveredathighconcentrations,it'srapidabsorptionmeansthatalveoliwillshrink,causing:

AnincreaseinthefractionalconcentrationofallothergasesThisisknownastheconcentrationeffect,andincreasesthepressuregradientdrivingdiffusionintoblood,increasingspeedofonset.

TheconcentrationeffectisthecauseofthesecondgaseffectTheconcentrationeffectismorepronouncedasFiN OincreasesTheconcentrationeffectismoreprofoundinlungunitswithmoderatelylowV/Qratios,causinginalargeincreaseinFThisresultsinalargervalueofF foranygivenF ,evenatsteadystate.

AugmentedventilationasmoreinhalationalagentisdrawninthealveolifromdeadspacegasThesecondgaseffectalsocausesdiffusionhypoxiaWheninspiredN Oisreduced,N Owillleavebloodandenterthealveolus,displacingothergasesinthealveolus.

ThiscancauseareductioninPAO ,andthereforehypoxaemiaDiffusionhypoxiaisavoidedbydelivering100%oxygen,whichmaintainsanadequatePAO asN Oisremoved

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NotethatN Oreachesahigherratiofasterthandesflurane,despiteitslowerblood:gaspartitioncoefficient,duetotheconcentrationeffect

Factorsaffectingdruguptakefromthelungs:

Blood:gaspartitioncoefficient

Agentswithalowblood:gaspartitioncoefficientreach equilibriummorerapidly.Theblood:gascoefficientisaffectedby:

TemperatureBlood:gaspartitioncoefficientsdecreaseastemperatureincreases.HaematocritVariableeffect,whichdependsontheparticularagentsaffinityforredcellsorplasma(andserumconstituents,e.g.albumin).

Anagentthatislesssolubleinredcells(e.g.isoflurane)willhaveadecreasedblood-gaspartitioncoefficientinanaemia.

FatBlood:gaspartitioncoefficientincreasesfollowingfatingestion.

AlveolarbloodflowIncreasedalveolarbloodflowincreasesuptakeanddeliverytotissues,includingtheCNS.

However,theincreaseduptakecausesareductioninPTherefore,rateofonsetisreducedwhenalveolarbloodflowishigh.

Thiseffectismorepronouncedwithagentswithahighblood:gaspartitioncoefficientAlveolarbloodflowisafunctionof:

CardiacoutputShunt

Alveolar-VenouspartialpressuregradientThedifferenceinpartialpressureofagentinthealveolusandvenousbloodisduetotheuptakeofdrugintissues.Tissueuptakeisdependenton:

TissuebloodflowAstheCNShasahighbloodflow,itwillequilibratemorequickly.Blood:tissuesolubilitycoefficients

Musclehassimilaraffinitytoblood,butequilibratesmoreslowlythantheCNSduetolowerbloodflowFathasamuchhigheraffinityforanaestheticthanmuscle,butequilibratesveryslowlyduetotheverylowbloodflowThisisofgreaterimportanceintheobese,especiallyduringprolongedanaesthesia,astheyhavealongerequilibrationtimeandthereforeprolongedemergence.

Wash-outofInhalationalAgents

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Recoveryisdependentonhowquicklyaninhalationalagentcanbeeliminatedfromtheeffectsite,andcanbegraphedbytheF /F ratioovertime:

Washoutcanbedividedinto:

RapidwashoutOfagentincircuitandFRC.

Thetimeconstantforremovalofagentfromthecircuitisafunctionofcircuitvolumeandfreshgasflow,i.e.

SlowwashoutOfagentinpatient.

ThetimeconstantforremovalofagentfromthepatientisafunctionofFRCandminuteventilation,i.e.

Factorsaffectingvolatilewashout:

Brain-BloodandTissue-BloodTissue:BloodcoefficientofagentDurationanddepthofanaesthesiaImportantforhighlysolubleagentsusedinlongcases.

Blood-AlveolusBlood:gascoefficientofagentHighlysolubleagentswillhaveanincreasedamountofdrugdissolvedintissue,soalargereservoirofdrugexiststhatwillhavetoberemoved.AlveolarCardiacoutputDecreasedcardiacoutputincreaseselimination.

ShuntDecreaseselimination.

Alveolus-AirMV /FRCIncreasedalveolarventilationincreaseselimination.

OtherfactorsMetabolismofagentAgentsundergoingmetabolismareeliminatedmorerapidly.AbsorptionofagentintocircuitPercutaneousloss

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Lossofagentbydiffusionfromtissuesintoexternalenvironment.

AlterationtoPharmacokinetics

Increasedrateofinductioninchildrendueto:

IncreasedV /FRCratioIncreasesP .LoweralbuminandcholesterolReducedblood-gassolubilitycoefficientsforsomeagents.

Increasedrateofinductioninelderlydueto:

LowerMACrequirementLoweralbuminReducesblood-gassolubilitycoefficientsforsomeagents.LowercardiacoutputP andthereforeP isestablishedmorerapidly.

Alteredrateofinductioninpregnancydueto:

IncreasedV /FRCratioIncreasedminuteventilationThisisofgreaterimportanceinspontaneousventilation,asthisiscontrolledbytheanaesthetistduringcontrolledventilation.DecreasedFRCIncreasesP ,increasingP andspeedofonset.

LoweralbuminReducesblood-gassolubilitycoefficientsforsomeagents.IncreasedCOReducesrateofriseofP ,reducingP andthereforespeedofonset.ReducedMACrequirementProgesteronehassomesedativeproperties.

AlterationtoPharmacokineticswithSpecialMethodsofAdministration

Intarget-controlledanaesthesia,FGFandagentF arecontrolledbythemachinetoreachthetargetF rapidlyatlowconcentrations.Thiscauses:

Aninitialover-pressureofF ,inordertofilltheFRCandreachthedesiredFAmorerapidinduction,asthetargetF isreachedmorerapidly

Inliquidinjection,anaestheticagentisinjectedintothebreathingsystem.Thiscauses:

AverylargedegreeofoverpressureInthiscircumstance,therateofriseofend-expiredagentconcentrationisidenticalfordifferentagents.

i.e.Onsetisindependentoftheblood:gascoefficient

MechanismofActionofInhaledAnaestheticAgents

Mechanismsofactioncanbedividedinto:

MacroscopicAtthelevelofthebrainandspinalcord.

Inthespineby:

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DecreasingtransmissionofnoxiousafferentsignalsatthethalamusInhibitionofspinalefferents,decreasingmotorresponses

Inthebrainby:GlobaldepressionofCBFandglucosemetabolism

MicroscopicSynapsesandaxonsby:

Inhibitingpre-synapticexcitatoryactivity:ACh5-HTGlutamine

Augmentingpost-synapticinhibitoryactivity:GABA

MolecularAnaestheticagentsmayalterthefunctionofmoleculeswithintheCNS.Theseinclude:

Alterationofα-subunitsoftheGABA receptorThisprolongsthetimeitspendsopenonceactivated,prolongingtheinhibitoryCl currentandincreasingthedegreeofhyperpolarisation.Enhancetheactivityoftwo-poreK channelsIncreasestherestingmembranepotentialofbothpre-synapticandpost-synapticCNSneurons.

IncompleteTheoriesoftheMechanismofActionofGeneralAnaestheticAgents

Meyer-OvertonHypothesis:

PotencyofanaestheticsrelatestotheirlipidsolubilityAnaestheticmoleculesdissolveintoCNSmembranes,disruptingtheireffectFlaws:

NotalllipidsolubledrugshavegeneralanaestheticaffectsOtherfactorsdisruptcellmembraneswithoutcausinganaesthesia

VolumeExpansion,PressureReversal(Mullin'sCriticalVolumeHypothesis):

CNScellmembranesexpandwithgeneralanaestheticagentsThisdistortschannelsresponsibleformaintainingmembranepotentialandgeneratingactionpotentials.IncreasedambientpressurereversesgeneralanaesthesiaFlaws:

Doesnotaccountforstero-selectivityofdrug-receptorinteractionsI.e.receptorsselectforonestereoisomeroverothers.

Structure-ActivityRelationshipsofInhaledAnaesthetics

Chemicalstructuresofdifferentvolatileanaestheticsarecoveredinthepharmacopeia.

Differentchemicalandphysicalpropertiesaltertheeffectofinhalationalagents:

PhysicalMolecularweightAdecreaseinmolecularweightdecreasesboilingpointandthereforeincreasesSVP.

ChemicalH contentGreaterhydrogencontent:

IncreasesflammabilityIncreasespotency

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F contentGreaterfluoridecontent:

DecreasesflammabilityDecreasesoxidativemetabolismThisdecreasestoxicity.Decreasespotency

Cl contentIncreasedchlorideincreasespotency.-CHF (Di-fluor-methylgroup)

ProducesCOinthepresenceofdrysodalime

TheIdealInhaledAnaestheticAgent

Fromthepropertiesdiscussedabove,wecanconstructthefollowingidealagent:

PhysicochemicalLiquidatroomtemperatureHighSVPLowspecificheatcapacityLongshelf-lifeLightstableHeatstableDoesnotreactwiththecomponentsinthebreathingcircuit

RubberMetalPlasticSodalime

Notflammable/explosiveSmellsnicePreservativefreeEnvironmentallyfriendlyCheap

PharmacokineticHighoil:gaspartitioncoefficientLowMAC.Lowblood:gaspartitioncoefficientRapidonsetandoffset.NotmetabolisedNon-toxic

PharmacodynamicDoesnotcauselaryngospasmorairwayhyperreactivityNoeffectonHDxparametersAnalgesicHypnoticAmnesticAnti-epilepticNoincreaseinICPSkeletalmusclerelaxationAnti-emeticNotocolyticeffects

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NotteratogenicorotherwisetoxicNodruginteractions

References1. KhanKS,HayesI,BuggyDJ.PharmacologyofanaestheticagentsII:inhalationanaestheticagents.ContinuingEducationin

AnaesthesiaCriticalCare&Pain,Volume14,Issue3,1June2014,Pages106–111.2. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.3. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.4. LeslieRA,JohnsonEK,GoodwinAPL.DrPodcastScriptsforthePrimaryFRCA.CambridgeUniversityPress.2011.5. MillerRD,ErikssonLI,FleisherLA,Weiner-KronishJP,CohenNH,YoungWL.Miller'sAnaesthesia.8thEd(Revised).

ElsevierHealthSciences.6. ZhouJX,LiuJ.Theeffectoftemperatureonsolubilityofvolatileanestheticsinhumantissues.AnesthAnalg.2001

Jul;93(1):234-8.7. HendrickxJ,PeytonP,CaretteR,DeWolfA.Inhaledanaestheticsandnitrousoxide:Complexitiesoverlooked:thingsmay

notbewhattheyseem.EurJAnaesthesiol.2016Sep;33(9):611-9.8. AranakeA,MashourGA,AvidanMS.Minimumalveolarconcentration:ongoingrelevanceandclinicalutility.Anaesthesia.

2013May;68(5):512-22.doi:10.1111/anae.12168.9. LermanJ,GregoryGA,WillisMM,EgerEI2nd.Ageandsolubilityofvolatileanestheticsinblood.Anesthesiology.1984

Aug;61(2):139-43.

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HormonesAhormoneisachemicalmessengerproducedbyaductlessglandwhichhasitsactionatadistanttargetcellviaaspecificreceptor.

Lipidhormones,dividedinto:SteroidsSteroidsaresynthesisedfromcholesterol,andarereleasedastheyareproduced(theyarenotstored).Theyarehighlylipidsolubleandactoncytoplasmicandintra-nucleicreceptors.

AldosteroneTestosteroneOestrogenCortisol

EicosanoidsEicosanoidsareformedfromcellmembranephospholipid.

ProstaglandinsThromboxanesLeukotrienes

PeptidehormonesPeptidehormonesarestoreingranulesandreleasedbyexocytosis.Theyaredividedinto:

Short-chainInsulinADHOxytocinACTH

Long-chainGHProlactin

GlycopeptidesProteinswithcarbohydrategroups.

LHFSHTSH

MonoaminederivativesDerivedfromasingleaminoacid.

CatecholaminesStoredingranulesandactatmembranereceptors.

AdrenalineNoradrenaline

SerotoninThyroxine

References

1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.

Lastupdated2017-09-17

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Insulin,Glucagon,andSomatostatinDescribethephysiologyofinsulin,glucagonandsomatostatin.

Insulin

Insulinisapolypeptidehormone,andis:

SynthesisedfromproinsulinintheroughendoplasmicreticulumofBcellsintheIsletsofLangerhansExcretedviaexocytosisinresponsetoanincreaseinintracellularCaMinimallyproteinboundwithatinyvolumeofdistributionV 0.075L.kg ,increasedto0.146L.kg indiabetics.Metabolisedinliver,muscle,andkidneybyglutathioneinsulintranshydrogenase,withrenaleliminationofinactivemetabolitesCirculatoryhalf-lifeof~5min.

ActionsofInsulin

Insulinbindstoaspecificinsulinreceptor(amembrane-spanningproteincomposedofαandβsubunits)onthecellmembrane.Thecomplexisinternalised,anditseffectsaremediatedbytyrosinekinase.

Seconds Minutes Hours

Muscle Increasedglucose,aminoacid,ketone,andK uptake Increasedanabolism,decreasedcatabolism

Fat Increasedglucose(viaGLUT4),aminoacid,andK uptake Increasedglycerolphosphatesynthesis Increasedfatty

acidsynthesis

Liver

Decreased:gluconeogenesis,ketogenesis.

Increased:glycogensynthesis,glycolysis,proteinsynthesis,lipidsynthesis

General Increasedcellgrowth

GlucoseTolerance

Hyperglycaemiaoccursindiabetesduetodecreasedperipheralutilisationasglucoseuptakeisreducedduetoabsenceoforresistancetoinsulin.Inaddition,thesuppressiveeffectofinsulinonhepaticgluconeogenesisisabsentorreduced.

GlucagonGlucagonisapolypeptidehormone,andis:

SynthesisedintheAcellsofthepancreasHasacirculatinghalf-lifeof~5minMetabolisedpredominantlyintheliverSecreteddirectlyintotheportalvein,andundergoesfirst-passmetabolismresultinginlowcirculatinglevels.

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Liver Glycogenolysis,gluconeogenesis,glucoserelease,ketoneformation

CVS Inotropy

Fat Lipolysis

Metabolic Increasedmetabolicrate,GHrelease,somatostatinrelease,insulinrelease

Secretionofglucagonisinfluencedbyanumberoffactors:

StimulateRelease InhibitRelease

Hypoglycaemiaandstarvation Somatostatin

Aminoacids Secretin

Physiologicalstress:Exercise,infection FreeFattyAcids

β-agonists α-agonists

Cortisol Insulin

ACh Ketones

Theophylline GABA

SomatostatinSomatostatinisapolypeptidehormonethat:

Inhibitssecretionofotherhormonesincluding:GlucagonInsulinOtherpancreaticpeptides

MayfunctionasaneurotransmitterintheCNS

References

1. BarrettKE,BarmanSM,BoitanoS,BrooksHL.Ganong'sReviewofMedicalPhysiology.24thEd.McGrawHill.2012.2. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.

Lastupdated2019-07-18

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ControlofBloodGlucoseExplainthecontrolofbloodglucose

Normalbloodglucoseinthenon-diabeticis4-6mmol.L ,thoughwillriseafterconsumptionofcarbohydrate.Glucoseregulationcanbedividedinto:

Short-termRegulationviasecretionorinhibitionofinsulinandglucagonfromthepancreaticislets.Long-termRegulationviabothneuronal(SNSactivation)andhormonal(cortisol,GH)mechanisms.

HormonalMechanisms

ShortTerm

GlucoselevelsaresenseddirectlyinthepancreasandwillresultininsulinreleasewhentheBGLis>5.6mmol.L .PancreaticBcellsresponddirectlytoglucosebysecretinginsulininabiphasicfashion:

Aninitial,rapidincreaseinreleaseGlucoseentersviatheGLUT-2transporter,andisconvertedtopyruvatewhichentersthecitricacidcycleandproducesATPATPinhibitsATP-sensitiveK channels,reducingK effluxandcausingdepolarisationDepolarisationcausesCa release,resultinginexocytosisofinsulingranules

Aprolonged,slowincreaseinreleaseGlutamateisproducedasaby-productofthecitricacidcycleGlutamatestimulatesmaturationofotherinsulingranulesReleaseofthesegranulescausesthesecondphaseofinsulinrelease

Conversely,alowglucoselevelstimulatessecretionofglucagon.Thisistypicallylessimportantthantheeffectofinsulinunlessinsituationsofstarvationorseverephysiologicalstress.

LongTerm

Sustainedhypoglycaemiaincreasesfatutilisationanddecreasesglucoseutilisation(limitingfurtherdropsinbloodglucose),viastimulatingreleaseof:

GHCortisol

NeuronalMechanismsHypoglycaemiadirectlystimulatesthehypothalamus,causing:

IncreasedSNStoneAdrenalinereleaseinturnstimulateshepaticglucoserelease.

OrganEffects

Glucoselevelsareinfluencedbythe:

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LiverInsulinandglucagonactonthelivertocontinuallyadjusttherelativeratesofglycogenolysisandglycogenesis,allowingittofunctionasaneffectivebufferofbloodglucose.

Hepaticdiseasesignificantlylimitstheefficacyofthissystem,andresultsinawidely-fluctuatingbloodglucoselevelKidney

Atransientglycosuriamaybeseenashyperglycaemiadecreasesrenalabsorptionofglucose

PhysiologicalResponsestoHypoglycaemia

BSL(mmol.L ) Symptoms EndocrineResponse

4.6 Insulinsecretioninhibited

3.8 Autonomicdysfunction Glucagon,adrenaline,andGHsecretion

2.8 CNSdysfunction

2.2 Lethargy,Coma

1.7 Convulsions

0.6 Permanentbraindamage,Death

References1. BarrettKE,BarmanSM,BoitanoS,BrooksHL.Ganong'sReviewofMedicalPhysiology.24thEd.McGrawHill.2012.2. Hall,JE,andGuytonAC.GuytonandHallTextbookofMedicalPhysiology.11thEdition.Philadelphia,PA:Saunders

Elsevier.2011.

Lastupdated2019-07-18

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HypothalamusandPituitaryDescribethecontrol,secretionsandfunctionsofthepituitaryandthehypothalamus

Hypothalamus

Thehypothalamusisacircumventricularorganthatregulatesalargenumberofautonomicprocesses:

ThermoregulatoryIntegratesthermoreceptorinputandcontrolsactivityofheatlossandheatgainmechanisms.SatietyFeelingsofhungeraremodulatedbyglucose,CCK,glucagon,andleptin.Waterbalance

ContainsosmoreceptorswhichcontrolADHreleasefromtheposteriorpituitaryAngiotensinIIstimulatesthirstandADHreleaseviathesubfornicalorganandorganumvasculosum

CircadianrhythmsBalancebetweenanteriorandposteriorhypothalamicstimulationcontrolssleep-wakecycle.Pituitarycontrol

Anteriorpituitarybyhormonesecretionintothelongportalvein.Secretedhormonesinclude:GnRH,stimulatesFSHandLHreleaseCRH,stimulatesACTHreleaseGHRH,stimulatesGHreleaseTRH,stimulatesTSHreleaseSomatostatin,inhibitsGHandTSHreleaseDopamine,inhibitsprolactinrelease

PosteriorpituitarybyneuronalinnervationBehaviourPunishmentandrewardcentres.Sexualfunction

Pituitary

Thehypothalamic-pituitaryaxisdescribesthecomplexfeedbackloopsbetweentheseendocrineorgans:

Short-loopfeedbackdescribesnegativefeedbackfromthepituitaryonthehypothalamus,e.g.GHinhibitingGHRHreleaseLong-loopfeedbackdescribesnegativefeedbackfromapituitarytargetgland(i.e.thyroid,adrenal,gonads)onthehypothalamus,e.g.cortisolinhibitingCRH(aswellasACTH)release.

Theseaxesarealsonamedwithtargetgland,e.g.hypothalamic-pituitary-adrenalaxis

PituitaryHormones

Thepituitaryglandsecreteseighthormonesfromtwolobes:

AnteriorPituitarySecretessixhormonesinresponsetohypothalamicendocrinestimulus.Theseareclassifiedas:

Stimulatinghormones,whichactatanothergland:ACTHShort-chainpeptidethatstimulatescortisolreleasefromthezonafasciculata.ReleaseisstimulatedbyCRH,andinhibitedbycortisol.

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TSHGlycoproteinthatstimulatessynthesisandreleaseofT andT .ReleaseisstimulatedbyTRH,andinhibitedbyT .FSHGlycoproteingonadotropin.ReleaseisstimulatedbyGnRH,andinhibitedbycirculatingsexsteroids.Hasdifferenteffectsdependingonsex:

Females:Stimulatesoestrogensynthesisandovarianfollicledevelopment.Males:Stimulatesspermmaturation.

LHGlycoproteingonadotropinwithdifferenteffectsdependingonsex:

Females:Rapidincreasestimulatesovulationandcorpusluteumdevelopment.Males:Stimulatestestosteronesynthesis.

Directactinghormones:GHLong-chainpeptidereleasedinapulsatilefashion.ReleaseisstimulatedbyGHRHandistypicallyhighwithexercise,hypoglycaemia,andstress.ReleaseisinhibitedbysomatostatinandIGF-1.GHhasgenerallyanaboliceffects:

Directlystimulateslipolysis,increasingcirculatingFFAIndirectlystimulatesIGF-1release,promotingcellgrowthanddevelopment

ProlactinLong-chainpeptidewhichpromotesbreastdevelopmentduringgestation,andlactationafterdelivery.

PosteriorpituitarySecretestwohormones:

ADHShort-chainpeptidewhichis:

ReleasedinresponsetoosmoreceptorsinthecircumventricularorgansdetectingachangeinosmolalityADHreleaseis:

Reducedwhenosmolalityis<275mosm.l-1</sup>Increasedwhenosmolalityis>290mOsm.L

Effectiveat:V receptorsinvascularsmoothmuscle,causingvasoconstrictionV receptorsinkidneycollectingductstoincreasewaterreabsorption,andonendotheliumtoincreasevWFandfactorVIIIreleaseV receptorsinthepituitarytostimulateACTHrelease

OxytocinShort-chainpeptide,structurallysimilartoADH,whichcauses:

UterinecontractionLet-downreflexStimulatesmilkreleaseonsuckling.PsychologicalPairbonding.

References

1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.2. Nickson,C.Vasopressin.LITFL.

Lastupdated2019-07-18

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ThyroidDescribethecontrol,secretionsandfunctionsofthethyroid.

Thethyroidgland:

ProducesandsecretestwohormonesinresponsetoTSH:T (thyroxine,93%)T (tri-iodothyronine,7%)

Secretionsarecontrolledviaanegative-feedbacklooponthehypothalamic-pituitary-thyroidaxisIncreasedTSHresultsin:

IncreasediodineuptakeIncreasediodinationtoformT andTIncreasedproteolysisofthyroglobulin,whichreleasesT andT

SecretionsaredecreasedwithdecreasediodineuptakePerchlorateBlocksNa /I symporter.Wolff-ChaikoffeffectAreductioninthyroidhormoneproductionduetoahighcirculating[iodide].

SynthesisThyroidhormonesare:

SynthesisedinfolliclesAfollicleisformedofasinglelayerofcuboidalepitheliumaroundacentrallumen(follicularcavity)containingthyroglobulin.

IodideistransportedintofollicularcellsviaasecondaryactivetransportmechanismNa /I co-transporter.IodideisthenoxidisedtoiodineThyroglobulinissynthesisedintheendoplasmicreticulumofthefollicularcellandexcretedintothefollicularcavityIodineisexcretedintothefollicularcavityusingachlorideexchangepumpInthefollicularcavity:

Thyroidperoxidasecatalysestheiodinationofthyroglobulin,formingmono-iodotyrosineanddi-iodotyrosineThesearesubsequentlyoxidised,formingT andT respectively

Insummary:

Iodideistakenintothethyroidfolliclesbysecondaryactivetransport,andoxidisedtoiodineThyroglobulinissynthesisedinthefollicle,andexcretedintothefollicularcavityIodineissecretedintothefollicularcavity,whereitcombineswiththyroglobulintoproduceT andT

SecretionandMetabolism

Thyroidhormonesare:

SecretedinvesiclesviaendocytosisintothesurroundingcapillariesColloidentersthyroidcellviapinocytosisattheapicalmembraneVesiclesthenfusewithlysosomes

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ThyroidhormonecleavedfromthyroglobulinbyproteasesFreeT andT diffusethroughthebaseofthethyroidcellintosurroundingcapillaries

Highlyproteinboundtoalbuminandthyroxine-bindingglobulinT hasat of7daysT hasat of24hoursBotharedeiodinatedintheliver,kidney,andmuscle

55%ofT willbefirstdeiodinatedtoT

PhysiologicalEffects

Thyroidhormones:

ActonthyroidreceptorsinthecellnucleusIncreasinggenetranscription,proteinsynthesis,andmitochondriasizeandnumber.T is3-5xmoreactivethanT

Effectsofthyroidhormonearepredominantlymetabolic:

System Effect

Resp ↑MVdueto↑CO production

CVS ↑HR,↑inotropy,↑CO,↓SVR,↓DBP

CNS ↑Excitability:Seizures,tremor

MSK ↑Osteoblasticactivity

GU Impotence(men),oligomenorrhoea(women)

GIT ↑GITmotility

Metabolic↑BMRupto100%,↑carbohydratemetabolism(↑glucoseuptake,↑glycolysis,↑gluconeogenesis),↑fatmetabolism(↑lipolysis,↑non-shiveringthermogenesis,↓plasmacholesterol,↓plasmaphospholipids,↓triglycerides),↑proteinmetabolism(↑anabolismatphysiologicallevels,↑catabolismathighlevels)

References

1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. CICMSeptember/November2008

Lastupdated2019-07-18

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AdrenalHormonesDescribethecontrol,secretionsandfunctionsofrenalandadrenalhormones

Thiscoverstheproductionofadrenalhormones.Informationspecifictocatecholaminesreceptorfunctioncanbefoundunderadrenoreceptors,whilstdetailedinformationonspecificagents,includingstructure-activityrelationships,isinthepharmacopeia.

Theadrenalglandsarepairedtriangularglandsatthesuperiorpoleofthekidney.Theglandcanbedividedinto:

AdrenalcortexConsistsofthreelayerswhichproducesteroidhormones(AgoodmnemonicisGFRforthelayers,andACT(H)forhormones)

ZonaGlomerulosaPredominantlyproducesmineralocorticoids(aldosterone).ZonaFasciculataPredominantlyproducesglucocorticoids(cortisol).ZonaReticularisPredominantlyproducessexsteroids(testosterone).

AdrenalmedullaProducescatecholamines.

SteroidHormones

Mineralocorticoids

Aldosteroneisthekeymineralocorticoidhormone,accountingfor95%ofmineralocorticoidactivity:

Releaseisstimulatedby:IncreasedserumKIncreasedAngiotensinII

HypovolaemiaDecreasedosmolarity

IncreasedACTHDecreasedserumpH

Actstoincreasesodiumandwaterretention(andremovalofpotassium),via:IncreasedexpressionandactivationofNa /K pumpsonthebasolateralmembraneofDCTandCTcells,causingincreasedNa (andwater)reabsorptionandK eliminationStimulationoftheNa /H pumpinintercalatedcellsontheDCT

Glucocorticoids

Cortisol(hydrocortisone)istheprimaryglucocorticoidinthebody,accountingfor95%ofendogenousglucocorticoideffect.Cortisolis:

Producedat~15-30mg.dayReleasedinresponsetoACTHACTHisreleasedinresponsetoCRH,whichis:

ReleasedinresponsetostressModulatedbycircadianrhythms,anddemonstratesdiurnalvariation:

CRHpeaksjustbeforewakingCRHtroughsduringsleep

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Cortisolhaseffectsonmanyorgansystems,andinphysiologicalamountscause:

CVSIncreasedsensitivitytocatecholaminesIncreasesfluidretention

Metabolic(Essentiallyanti-insulineffects):

GluconeogenesisToprovidesubstrates,italsostimulates:

ProteolysisLipolysis

Decreasedglucoseuptake

Catecholamines

Naturallyoccurringcatecholaminesinclude:

AdrenalineNoradrenalineDopamine

Synthesisofcatecholaminesoccursintheadrenalmedulla,whichisamodifiedsympatheticganglioncomposedofchromaffincells.

SynthesisandreleaseisdependentonAChreleasebythepresynapticneuronUnlikemanyotherhormones,catecholaminesecretionisnotanegative-feedbackloop.

Processofcatecholaminesynthesis:

TyrosineisconcentratedintheadrenalmedullaTyrosineishydroxylatedtoDOPAbytyrosinehydroxylaseThisistherate-limitingstep,andisprobablythebestenzymetoremember.DOPAisdecarboxylatedtodopamineDopamineisconvertedtonoradrenalineNoradrenalineisconvertedtoadrenalinebyPNMT(PhenylethanolamineN-methyltransferase)Thismayonlyoccurintheadrenalmedulla.

Plasmahalf-livesofnoradrenalineandadrenalinearesmallasaconsequenceoftheirmetabolismandelimination.

Extraneuronaluptakeinthelungs,liver,kidney,andGITNeuronaluptakebysympatheticnerveendingsInactivationbyMAOinnervecytoplasmInactivationbyCOMTintheliverandkidney

References

1. BrandisK.ThePhysiologyViva:Questions&Answers.2003.2. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.

Lastupdated2018-06-25

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CalciumHomeostasisDescribethefunction,distribution,regulationandphysiologicalimportanceofsodium,chloride,potassium,magnesium,calciumandphosphateions

Describethecontrolofplasmacalcium.

Calciumisabivalentcation.Almostall(99%)ofcalciumislocatedinbone,withtheremainderinplasmaandsofttissues.Normalplasmalevelsare2.2-2.55mmol.L ,which(inplasma)maybe:

Ionised(free)calcium(50%)Normalrange1.1to1.3mmol .Boundtoalbumin(40%)Ascalciumcompounds(10%)

FunctionsofCalcium

CellSignalingCalciumhasanumberofrolesincellsignaling:

AffectscellsodiumpermeabilityandthereforetheRMPofexcitablecellsCalciumtriggersexocytosisofneurotransmittervesiclesCalciumisanimportantsecondmessengerforsomeGproteins

BoneCalciumhastwofunctionsinbone:

PhysicalstructureAlkalireserveCalciumphosphatecanbemobilisedtobufferacidosis.

EnzymaticcofactorCalciumisanimportantcofactorinenzymaticpathways,includingthecoagulationcascade.Clinicalhypocalcaemiadoesnotcausecoagulopathyhowever,ascalciumlevelslowenoughtopreventcoagulationarenotcompatiblewithlife.

RegulationofCalcium

Calciumisregulatedtomaintainastableionisedcalciumlevel.Threehormonesareinvolvedintheregulationofcalcium:

ParathyroidHormoneProteinhormonesecretedbythefourparathyroidglands,locatedontheposteriorsurfaceofthethyroid,inresponsetoafalliniCa levels,andactstoincreaseplasmacalcium:

IncreasecalciumreabsorptioninthePCTandlateDCTIncreaseosteoclasticactivityinboneIncreasevitaminDactivationintheintestine,whichinturnincreasesintestinalabsorptionofdietarycalcium

VitaminD/CalcitriolOnceconvertedtocalcitriolinthekidney(viastimulationfromPTH),vitaminDactsto:

IncreasecalciumreabsorptionfromkidneyandgutIncreasebonecalcification

CalcitoninPeptidehormonesecretedbytheCcellsofthethyroidgland,inresponsetoariseiniCa greaterthan2.4mmol.L .

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Calcitoninactsto:DecreaseabsorptionofcalciumfromgutandkidneyDecreaseosteoclasticactivityofbone

References1. BrandisK.ThePhysiologyViva:Questions&Answers.2003.2. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.

Lastupdated2017-09-08

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HistamineDescribethephysiologyofhistamineandserotonin

Histamineisanendogenousamineproducedbydecarboxylationofhistidine.Histamineis:

PresentinalltissuesParticularlyabundantinthoseexposedtotheoutsideenvironment:

LungsGutSkin(lungs,gut,skin)

Producedinandreleasedby:MastcellsReleasedbyexocytosisduringinflammatoryandallergicreactions.BasophilsHistaminocytesinthestomachHistaminergicneuronsintheCNS

Metabolisedby:HistaminaseImidazoleN-methyltransferase

HistamineReceptorsandEffectsHistamineactson:

H receptorsGqreceptorinvolvedbroadlyininflammationandvasodilation.H receptorsGsreceptorinvolvedingastricacidsecretion.H receptorsGipresynapticreceptorintheCNS.H receptorsGireceptorlocatedinbonemarrowandothersolidhaematologicalorgans(spleen,liver,thymus).

System H H H H

Resp Bronchoconstriction Bronchodilation

CVS↑Vasodilation(endothelialeffect),coronaryvasoconstriction,↓AVnodalconduction

↑HR,↑inotropy,coronaryvasodilation,↑capillarypermeability

CNSPresynapticinhibitionofneurotransmission

MSK Wealduetolocalvasodilation,itch,↑nociception

GIT ↑Peristalsis ↑Gastricacidsecretion

HaemeAlterIL-16release

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References

1. ParsonsME,GanellinCR.Histamineanditsreceptors.BritishJournalofPharmacology.2006;147(Suppl1):S127-S135.doi:10.1038/sj.bjp.0706440.

2. RangHP,DaleMM,RitterJM,FlowerRJ.RangandDale'sPharmacology.6thEd.ChurchillLivingstone.3. BowenR.Histamine.Vivo.ColoradoState.

Lastupdated2017-09-17

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ProstanoidsProstanoidsareadiversefamilyofeicosanoids(20-carbonmolecules),producedfromarachidonicacid,andinclude:

ThromboxaneProstacyclinProstaglandins

Synthesis

Arachidonicacidisconvertedinto:

LeukotrienesbyLOXCyclicendoperoxidasesbyCOXenzymesTheseundergofurthermetabolismtoproduce:

ThromboxanesThromboxaneA

ProstacyclinsPGI

ProstaglandinsPGE

EPEPEP

PGFPGD

Effects

Receptor Receptor Respiratory Vascular GIT GU Other

ThromboxaneA Gq Vasoconstriction Platelet

aggregation

PGI Gs BronchodilationVasodilation(renalandpulmonary)

PGE EP Gq Bronchoconstriction Increasedcontraction

Renalvasodilation

PGE EP Gs BronchodilationClosureofductusarteriosus

Decreasedcontraction

Renalvasodilation

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PGE EP Gi

Gastricmucousproduction,GITcontraction

Uterinecontraction

PGF Gq Bronchoconstriction Vasoconstriction Uterinecontraction

PGD Gs Renalvasodilation

Promotessleep

References

1. RicciottiE,FitzGeraldGA.ProstaglandinsandInflammation.Arteriosclerosis,thrombosis,andvascularbiology.2011;31(5):986-1000.doi:10.1161/ATVBAHA.110.207449.

Lastupdated2019-07-18

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SkeletalMuscleDescribetheanatomyandphysiologyofskeletal,smooth,andcardiacmuscle

Describethemechanismofexcitation-contractioncoupling

Skeletalmusclehasanumberoffunctions:

FacilitatemovementPostureViatoniccontractionofantagonisticmusclegroups.SofttissuesupportAbdominalwallandpelvicfloorsupportviscera.VoluntarysphinctercontrolHeatproduction

StructureandContents

Skeletalmuscleconsistsoflongtubularcells,knownasmusclefibres,whichrunthelengthofthemuscle.Skeletalmusclecells:

Areundervoluntarycontrolfromthesomaticnervoussystemviaα-motorfibresα-motorfibresmaycontrolmultiplemyofibres,formingamotorunit.Are10-100μmindiameterContainseveralhundredperipheralnucleiContainmultiplemitochondria

Slowoxidativefibres(redfibres)Containmultiplemitochondria,producesustainedcontraction,andareresistanttofatigue.Fastglycolyticfibres(whitefibres)Containlownumbersofmitochondriaandlargeamountsofglycogen,andproducestrongcontractionsbutaremoreeasilyfatigued.

ContainsarcoplasmicreticulumContainlargeamountsofglycogen~200gtotal.ContainmyoglobinAppearstriatedmicroscopicallyduetothearrangementofmyofibrils

MyofibrilsaremultiplemyofilamentsarrangedinparallelMyofilamentsareformedfrommultiplesarcomeresarrangedinseriesAsarcomereisthefunctionalunitofmuscle

Musclefibresaresurroundedbylayersofconnectivetissue:

EndomysiumThinlayerwhichsurroundseachmusclefibre.PerimysiumSurroundsbundlesofmusclefibres.EpimysiumThicklayerwhichsurroundsanentiremuscle.

Theselayersofconnectivetissuejoinattheendofamuscletoformatendonoraponeurosis.

Sarcomere

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Thesarcomereisthefunctionalcontractileunitofmuscle.Averagesarcomerelengthis2.5μm.

Thesarcomerecontainstwomainproteins:

Myosin(thick)filamentsMyosinisalargeproteinwithtwoheads,whichbindactinandATP.Themyosinheadflexesonitsneckduringcontraction.Actin(thin)filamentsActinisasmallerproteinthanmyosin,andpotentiatestheATPaseofmyosin.Actinfilamentshaveagroovewhichcontainsanotherproteincalledtropomyosin,towhichtroponinattachesto.

Troponinhasthreesubunits:TroponinT-bindstroponintotropomyosinTroponinI-preventsmyosinbindingtoactinbyphysicallyobstructingthebindingsiteTroponinC-BindsCa whichinitiatescontraction

Theseproteinsarearrangedtoformthreebandsandtwolines:

A-bandThemyosinfilaments.H-bandThesectionofmyosinfilamentsnotoverlappingwithactinfilaments.I-bandThesectionofactinfilamentsnotoverlappingwithmyosinfilaments.Z-lineEachendofthesarcomere.ActinfromadjacentsarcomeresareconnectedattheZline.M-lineBandofconnectionsbetweenmyosinfilaments.

Excitation-ContractionCoupling

Musclecontractionnormallyrequiresthecoordinationofelectrical(signaling)eventswithmechanicalevents.

InresponsetoAChstimulatingnicotinicreceptors,theNa andK conductanceoftheend-plateincreasesandanend-platepotentialisgeneratedMusclefibresundergosuccessivedepolarisationandanactionpotentialisgeneratedalongTtubulesThesedelivertheAPdeepintothecell,andclosetothesarcoplasmicreticulum.Ca isreleasedfromsarcoplasmicreticulumThisprocessinvolves:

DihydropyridineReceptorSpecialisedvoltage-gatedL-typeCa channel,activatedbyT-tubulardepolarisation.ResponsibleforasmallamountofCa transport.RyanodineReceptor

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AsecondCa channelwhichisattachedto,andactivatedby,thedihydropyridinereceptor,causingamuchlargerreleaseofCa .

Ca isreleasedfromtheSR(increasingintracellularCa 2000x)andbindstotroponinC,weakeningthetroponinI-actinlinkanduncoveringmyosin-bindingsitesonactinCross-linkagesformbetweenactinandmyosin,whichreleasesADPThereleaseofADPtriggersapowerstroke,whichisaprocessofattachment,pulling,anddetachmentEachcycleshortensthesarcomereby~10nm:

Themyosinheadrotatesonits'neck',movingtoanewactinbindingsiteATPbindstothe(nowfree)bindingsiteonthemyosinATPishydrolysedtoADP,intheprocess"re-cocking"themyosinheadThisprocesscausesthethickandthinkfilamentstoslideoneachother,withthemyosinheadspullingtheactinfilamentstothecentreofthesarcomere.Therefore,overthecourseofapowerstroke:

TheA-bandisunchangedTheH-bandshortensTheI-bandshortens

PowerstrokescontinueaslongasthereisATPandCa available

Inrelaxation:

Ca ispumpedbackintothesarcoplasmicreticulumThisisanATP-dependentprocess,andiswhymusclerelaxationisactive.TroponinreleasesCaBindingsitesareoccludedbytroponin,andnofurthercontractionoccurs

References

1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. BarrettKE,BarmanSM,BoitanoS,BrooksHL.Ganong'sReviewofMedicalPhysiology.24thEd.McGrawHill.2012.3. Slomianka,L.Muscle.UniversityofWesternAustralia-SchoolofAnatomyandHumanBiology.

Lastupdated2019-07-18

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SkeletalMuscleInnervationExplaintheconceptofmotorunits

Describetherelationshipbetweenmusclelengthandtension

Describethemonosynapticstretchreflex,singletwitch,tetanusandtheTreppeeffect

MotorUnitsAmotorunitconsistsofanα-motorneuronandthegroupofmusclecellsthatitinnervates

AnactionpotentialinthisneuronwillcausecontractionofallthemyocytesintheunitLargemuscleshavemanymyocytesperunitSmall,precisemuscles(e.g.extraocular)havefewmyocytesperunit

ForceofContractionMuscletensionisdependentonthreefactors:

InitialmyocytefibrelengthOptimalstretchmaximisesthenumberofoverlappingactinandmyosinfilaments.NumberofcontractingmyocytesRecruitmentofadditionalmotorunitsincreasestheforceofcontraction.FrequencyofActionPotentialsHighfrequencyactionpotentialscauseaccumulationofcalciuminthecytoplasm(theBowditchorTreppeeffect),increasingforceofcontraction.

Astheabsoluterefractoryperiodofskeletalmuscleisshorterthancardiacmuscle,tetany,orsustainedmusclecontraction,canoccur

Proprioception

Proprioceptionistheabilityofthebodytodetermineit'spositioninspace.Therearetwokeyproprioceptivesensors:

MusclespindlesGolgitendonorgans

MuscleSpindles

Musclespindlessensechangesinmusclelength.They:

Areaspecialisedmusclefibre,knownasintrafusalfibresRunparalleltomyocytes(alsoknownasextrafusalfibres)Consistoftwoelements:

Central,non-contractileportionwhichsensestensionContractileendsThisallowsthemusclespindletoadjustitslengthwithitsmuscle,sothataconstanttensioninthenon-contractileportioncanbemaintainedoverarangeofmusclelengths.

Musclespindleshavebothafferentandefferentinnervation:

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AfferenttypeIafibresadjusttheirelectricaloutputtosignalbothcurrentfibrelengthandrateofchangeAfferenttypeIIfibresonlysignalfibrelengthEfferentγneuronsinnervatethecontractileelements

Voluntarymusclecontractionresultsincontractionofbothmotorunits(α1neurons)andintrafusalfibres(γ-motorneurons).

Tonicinnervationofγ-motorneuronsincreasesmuscletonebystretchingthenon-contractileportions,increasingIafiringandsubsequentα-motorunitfiring.

GolgiTendonOrgans

Golgitendonorgansarestretchreceptorslocatedbetweenmuscleandtendon.They:

RuninseriestomyocytesSensestretchCausereflexivemusclerelaxation,intendedtopreventmuscledamage

Reflexes

Areflexisaninvoluntary,predictablemovementinresponsetoastimulus.Therearetwotypes:

Monosynaptic:MotorneuronsynapsesdirectlywiththesensoryneuronMonosynapticreflexesarerapid,butonlygeneratesimpleresponses.Therearefivecomponentstoamonosynapticreflex:

SensoryreceptorTypicallymusclespindles.AfferentneuronTypeIaafferentsrelaysignalfrommusclespindletoventralhornviathedorsalroot.SynapsebetweenafferentandefferentneuronIntheventralhornEfferentneuronα-motorneurontravelsfromtheventralhornandinnervatesthemotorunit.EffectormuscleInnervatedmotorunitcontractsinresponse.

Polysynaptic:MotorneuronisseparatedfromthesensoryneuronbyoneormoreinterneuronsinthedorsalhornThisallowsmodulationofsignal.Responsesareslowerbutmorecomplex,e.g.withdrawalofalimbfromahotobject.

TwitchandTetany

Atwitchistheresponseofamuscletoasinglestimulus(actionpotential)Atetaniccontractiondescribesthesustainedcontractionproducedbyrepetitivestimulationbeforerelaxationcanoccur

Thisstimulationmustbecausingaboveacriticalfrequency,whichisdependentontheactionpotentialdurationforacellRepetitivestimulationcausesrepeatedSRdepolarisation,leadingtosustainedhighintracellularCa levelsasCaentryexceedsCa exitForcefromtetaniccontractionisupto4xgreaterthanthatofatwitch

References1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.2. ANZCAMarch/April2000

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NeuromuscularBlockersUnderstandingofthepharmacologyofneuromuscularblockingdrugs

Theneuromuscularjunctionisachemicalcommunicationbetweenthemotorneuronandthemusclecell.VesiclescontainingACharereleasedwhenactivatedbyCa ,andinfluxofwhichoccurswhentheactionpotentialreachesthenerveterminal.

NicotinicAChreceptorssitontheshouldersofjunctionalfoldsofmusclecells,whilstacetylcholinesteraseisburiedintheclefts.

FactorsAffectingNeuromuscularBlockade

PatientFactors

Factor Effect Mechanism

HepaticDisease Prolongeddurationofaminosteroidsandsuxamethonium

Decreasedmetabolism,decreasedproductionofpseudocholinesteraseinseveredisease

Pseudocholinesterasedeficiency Prolongeddurationofsuxamethonium Decreasedmetabolism

Age Increasedsensitivityinneonates,particularlyprematureinfants IncompletematurationofNMJ

Hypokalaemia Potentiatesnon-depolarisingblockade,reducesdepolarisingblockade

Increasesmagnitudeofstimulusrequiredtodepolarisecell

Hyperkalaemia Potentiatedepolarisingblockade,reducenon-depolarisingblockade

Decreasesmagnitudeofstimulusrequiredtodepolarisecell

Hypermagnesaemia Potentiatesblockade DecreasesAChrelease,decreasessensitivityofpost-synapticmembrane

Hypocalcaemia Potentiatesblockade DecreasespresynapticACHrelease,decreasessensitivityofpost-synapticmembrane

Respiratoryacidosis Potentiatesblockade EnhanceseffectofNMBagents

Hypothermia Potentiatesblockade Reduceshepaticmetabolism,renalelimination,Hoffmandegradation

Hypovolaemia Slowsrateofonsetandenhancesduration Prolongedcirculationtime

MyastheniaGravis Increasedsensitivitytonon-depolarisingagents

Autoimmuneblockadeofreceptorsgivespre-existinglevelofblock

Eaton-LambertSyndrome IncreasedsensitivitytoallNMBs Autoimmunedestructionofvoltage-gatedCa

channelspreventAChvesicleexocytosis

DrugFactors

Drugs Effect Mechanism

FrusemidePotentiatesblockadeatlowdose,reducesblockadeathighdose

Inhibitsproteinkinases(reducingAMP/ATPsynthesis)atlowdose,inhibitsPDEathighdoseswhichincreasesAChrelease

Inhalationalanaesthetics Potentiatesblockade

Stabilisepost-junctionalmembrane,blockadeofpresynapticAChreceptors

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Antibiotics Potentiateblockade Variable.Aminoglycosidesandtetracyclinesprolongblockade

Localanaesthetics Potentiateblockade ReduceAChreleaseandstabilisepost-junctionalmembrane

Anticholinesterases Reducesblockade IncreaseACHlevelsattheNMJbydecreasingbreakdown

OCP Potentiatesdepolarisingblockade Competesforbindingsitesonplasmacholinesterases

Ca -channelblockers Potentiateblockade InhibitCa dependentAChrelease

Lithium Potentiatesblockade AugmentsactionofNMBs

AdditionalFactorsAffectingOnsetofNeuromuscularBlockade

MostofthesecanberelatedtoFick'sLaw:

Factor Effect Mechanism

Potency

Lowpotencydecreasestimetoonset

Bowman'sprinciple:Lesspotentdrugsmustbeadministeredinhigherdoses,andsohaveagreaterconcentrationgradientdrivingdiffusiontotheeffectsite

Dose

Increaseddosedecreasestimetoonset

Greaterconcentrationgradient

CardiacOutput

Highoutputdecreasestimetoonset

Increaseddrugdelivery

Musclegroupflow

Highmuscularflowdecreasestimetoonset

Increaseddrugdelivery

PrimingPrinciple

(May)decreasetimetoonset

A'priming'doseofnon-depolarisingblockeristoanawakepatientgivenpriortoinduction.Thisoccupieslessthan70%ofreceptors,sodoesnotcausesignificantneuromuscularblockade.Afterinduction,aseconddoseisgiventooccupytheremainingreceptorsandcompleteblockade.

References1. SterlingE,WinsteadPS,FahyBG.GuidetoNeuromuscularBlockingAgents.2007.AnesthesiologyNews.2. ICUAdelaide.NeuromuscularBlockers.3. PinoRM.RevisitingthePrimingPrincipleforNeuromuscularBlockers:UsefulnessforRapidSequenceInductions.AustinJ

AnesthesiaandAnalgesia.2014;2(5):1030.4. ANZCAFebruary/April2011

Lastupdated2019-07-18

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BasalMetabolicRateDescribebasalmetabolicrateanditsmeasurement

Outlinethefactorsthatinfluencemetabolicrate

BasalMetabolicRateistheenergyoutputrequiredtosustainlifeatrest.

'Resting'isdefinedasanindividualwhois:Fastedfor12hoursInacomfortableexternalenvironmentAtmentalandphysicalrest

Normalvaluesare:100W.day70kcal.hr

Metabolicrateistheactualenergyconsumptionofanindividual,andisgreaterthanBMRduetoanumberoffactors.

FactorsAffectingMetabolicRateMetabolicRateisaffectedby:

AgeBMRdecreasesasageincreases.

NeonateshaveaBMRtwicethatofanadultChildrenhaveanincreasedBMRrelativetothatofanadultBMRdeclinesby2%foreachdecadeoflife

BodyCompositionLeanmusclehasagreaterenergyrequirementthanfat.

HigherbodyfatpercentageresultsinalowerBMRFemaleshavealowerBMRforthisreason-whenadjustedforleanmassthereisnodifference

DietDigestionincreasesBMRby~10%duetotheenergyrequiredtoassimilatenutrientsThisisknownasthespecificdynamicactionoffood.

Protein>carbohydrate>fatNotethattheSpecificDynamicActionforeachmacromoleculeisnotrelatedtotherespiratoryquotientforthatfoodtype.

StarvationdecreasestheBMRExercise

SkeletalmuscleisthelargestandmostvariablesourceofenergyconsumptionEnvironment

CoolerenvironmentsincreaseBMRTemperateenvironmentsdecreaseBMRupto10%

PhysiologicalstatesPregnancyincreasesBMRupto20%in2ndand3rdtrimesterLactationincreasesBMRCatecholaminesincreaseBMRCorticosteroidsincreaseBMR

DiseasestatesMalignancyincreasesBMR

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SepsisincreasesBMRHyperthyroidismincreasesBMR

MeasurementofBMRusingIndirectCalorimetry

BMRismeasuredusingindirectcalorimetry,whichcalculatesheatproductionviameasurementofVO andVCO .Anumberofmethodsexistsdependingonwhetherthepatientisintubatedornot,orwhethertheyarerequiringsupplementaryoxygen.

Ingeneral:

PatientsshouldberelaxedandfastedFiO needstobecalculated(ortakenfromtheventilatorsettings),andE CO andE O mustbemeasuredSteady-stateshouldbeachievedacrossafiveminuteperiod

TheaverageMVO andMVCO changesby<10%

Therespiratoryquotient( )changeby<5%Thisratiowillvarydependingonthesubstancesmetabolised:

Carbohydrates=1Protein≈0.8Fat≈0.7

RestingEnergyExpenditureisgivenbytheabbreviatedWeirequation:

inWattsperunittimeofmeasurement.

ErrorsinIndirectCalorimetry

AirleaksandmeasurementerrorsMeasuresconsumption(ratherthanrequirements)Pointestimateofadynamicprocess

Footnotes

Therespiratoryquotientisthevalueof atsteady-state,whilsttherespiratoryexchangeratioisaffectedbymetabolicrate.

References

1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. ANZCAFeb/April20063. LITFL-IndirectCalorimetry

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FatMetabolismDescribethephysiologyandbiochemistryoffat,carbohydrateandproteinmetabolism

Digestion

Triglyceridesarethemainconstituentofbodyfatinanimalsandvegetables,andthereforeindietaryfat.Theyconsistofthreefattyacidmoleculesjoinedbyaglycerolmolecule.

Asfatsarenotwatersoluble,theytendtoclumptogetherinchymeandarehardtodigestduetothelowsurfacearea:volumeratio.Emulsificationspeedsupthedigestiveprocess,andoccursviatheactionof:

BilesaltsManybilesaltshaveahydrophobicandahydrophilicend,whichgiveadetergentaction.Bilesaltsboundtofattyacidsformamixedmicellewhichcanbefurtherdigestedbyenzymesordirectlyabsorbed.PartiallydigestedfatsMechanicalactionofthestomach

Onceemulsified,triglyceridescanbehydrolysedbylipaseintofattyacidsandmonoacylglycerol.

Absorption

Absorptionoccursinanumberofstages:

Mixedmicelles,freefattyacids,monoacylglycerol,andcholesterolsareabsorbedviafacilitateddiffusionintotheenterocyteFromtheenterocyte:

Short-chainfattyacids(thosewith<12carbonatoms)entertheportalveinandtraveldirectlytotheliverLong-chainfattyacidsarere-esterifiedandpackagedwithalayerofproteinandcholesteroltoformachylomicronRe-esterificationmaintainstheconcentrationgradientfordiffusionoffattyacids,allowingfurtheruptaketooccur.

ChylomicronsareejectedfromthecellintothelymphaticsandtraveltothesystemiccirculationChylomicronsareremovedfromcirculationbylipoproteinlipaseLipoproteinlipaseisfoundoncapillaryendotheliumandboundtoalbumin.LipoproteinlipasebreaksdowntriglycerideinchylomicronsandVLDLtofreefattyacidsandglycerolThisreactionusesheparinasacofactor.Freefattyacidsandglycerolarethenfreetoenteradiposetissue

StorageFatisstoredastriglycerides,andformsthebulkofenergystorageofthebody.

Triglyceridesaresynthesisedbytheliver:

OccurswheninsulinlevelsarehighandglycogenstoresarefullFromexcesscarbohydrateandaminoacidsTheseareconvertedtofattyacidsandglycerol,andthenesterifiedtoformtriglyceride.Thisisknownaslipogenesis.

Metabolism

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Freefattyacidscanbeabsorbedbyadipocytesforstorage,orbeβ-oxidisedtoacetylCoAintheliver,whichcanenterthecitricacidcycletoproduceATP.

References1. ChaneyS.OverviewofLipidMetabolism.UniversityofNorthCarolinaSchoolofMedicine.2005.2. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.3. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.

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CarbohydrateMetabolismDescribethephysiologyandbiochemistryoffat,carbohydrateandproteinmetabolism

Storage

Carbohydratesarestoredinliverandmuscleasglucosepolymersknownasglycogen.

Thelivercontains~100gofglycogenThiscanmaintainplasmaglucosefor~24hours.Skeletalmusclecontains~200gofglycogenThiscannotbereleasedintocirculation,andisforuseonlybythemuscle.

Productionofglycogenisstimulatedbyinsulin,whichisreleasedasplasmaglucoselevelsrisefollowingcarbohydrateingestion.Whenplasmaglucoselevelsfall,thereleaseofglucagonandadrenalinestimulatesglycogenolysis.

GlycolysisGlycolysis:

DescribestheprocessofconvertingglucoseintopyruvateThisisknownastheEmbden-Meyerhofpathway.OccursinthecytoplasmDoesnotconsumeoxygenorproducecarbondioxideProduces2ATPGlycolysisallowsproductionofATPinanaerobicconditions.

Gluconeogenesis

Gluconeogenesisistheproductionofglucosefromothermolecules.Gluconeogenesis:

RequiresATPtoperformSomeorgans(heart,brain)relyonglucoseforATPHasmanypotentialsubstrates:

LactatePyruvateGlycerolAminoacidsCAC-intermediates

IsstimulatedbyglucagonIsinhibitedbybiguanides(metformin)

References1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.

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ProteinMetabolismDescribethephysiologyandbiochemistryoffat,carbohydrateandproteinmetabolism

Essentialaminoacidscannotbeproducedbytransamination-theymustbesuppliedinthediet.

Metabolism

Proteincatabolisminvolvesthedeaminationofaminoacids.Deaminationcanoccurinoneoftwoways:

OxidativedeaminationHepaticdeamination,removingtheaminogrouptocreateaketoacidandammonia.Ammoniaproducedintheliverenterstheureacycleandbecomesurea,whichrequires3ATP.TransaminationAminogroupistransferredbyaminotransferasestoanotheraminoacidoraketoacidtoproduce:

Ketoacids,which:EnterthecitricacidcycleandproduceATPGetconvertedtoglucoseorfattyacids

AminogroupsEntertheureacycleandbecomeurea

FootnotesAmmoniacanalsobeproducedinthekidneybythedeaminationofglutamateinthekidney.Inthisinstance:

ItiseliminateddirectlyinurineasammoniumDoesnotentertheureacycle

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References

1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.

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RequirementsandStarvationDescribethenormalnutritionalrequirements

Fasting

Fastingisthemetabolicstateachievedaftercompletedigestionandabsorptionofameal.

Fastingcanbedividedinto:

EarlyfastingLessthan24hours.

PlasmaglucosefallsduetoconsumptionLeadstohormonalchanges:

Insulinreleasedecreases,causing:Liver

DecreasedglycogenesisIncreasedgluconeogenesis

MuscleDecreasedglucoseutilisationDecreasedglycogenesisDecreasedproteinsynthesis

FatDecreasedlipogenesisDueto:

DecreasedglucoseuptakeDecreasedTGuptake

IncreasedlipolysisAdrenalinereleaseincreases,causing:

DecreasedinsulinreleaseIncreasedlipolysisIncreasedmuscleFFAuseIncreasedhepaticglycogenolysisandgluconeogenesis

GlucagonreleaseincreasesCellularmetabolismalters:

Decreasedglucoseuptakebynon-obligateglucoseconsumerse.g.Muscle.IncreasedFFAandketonebodyuseβ-oxidationofFFAstomeetATPrequirements,leadingtoformationofketonebody.

SustainedfastingGreaterthan24hours.Seestarvationbelow.

Starvation

Starvationisthefailuretoabsorbsufficientcaloriestosustainnormalbodyfunction,requiringthebodytosurviveonendogenousstores.

Days:

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EnergyisconservedthroughreductioninmovementHormonalchanges

Increasedgluconeogenesis,usingglycerol,lactate,andaminoacidsInsulinconcentrationsfallfurtherCortisollevelsincreaseGlucagonlevelspeakat4days

MetabolicchangesGlucoseusecontinuestofall,andFFAuseincreasesFurtherfallinmuscleproteinsynthesis

Weeks:Tissuesadapttometaboliseketones(withplasmalevelsrisingupto7mmol.L ,andgluconeogenesisfalls

Thebrainstillrequires100gofglucoseperdayBMRfallsAllbutlife-savingmovementceasesDeathtypicallyoccursafter30-60days,whenmusclecatabolismweakenstherespiratorymusclessuchthatsecretionscannolongerbecleared,andpneumoniaoccurs

RefeedingSyndrome

Refeedingsyndromeisaderangedmetabolicstatethatoccurswithfeedingafteraperiodofprolongedfasting,typically>5days.

Therearethreepathogenicmechanisms:

Alargespikeininsulincausesincreasedcellularuptake(andlowplasmalevels)of:GlucoseMagnesiumPhosphatePotassium

Sodiumandwaterretentionoccurs,whichmayprecipitatecardiacfailureIncreasedcarbondioxideproductionincreasesminuteventilationandworkofexhaustedrespiratorymuscles

Managementisbyslowinstitutionoffeedingandaggressiveelectrolytemanagement.

References

1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.2. ANZCAAugust/September2001

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AnaerobicMetabolismDescribetheconsequencesofanaerobicmetabolismandketoneproduction

Lactate

TheEmbden-Meyerhofpathway:

Describestheconversionofglucosetopyruvate(andtwoATP)DoesnotconsumeO orproduceCOThereforeitoccursinbothanaerobicandaerobicconditions.ConsumestwoNAD andproducestwoNADH

Inanaerobicconditions(intheerythrocyte,andinthesettingofcellularhypoxia):

ThereisnooxygenavailabletoallowfurtherATPproductionviatheelectrontransportchainThereisalsonoregenerationofNAD intheETC.Inorderforglycolysistocontinue,NAD isregeneratedviaproductionoflactate

About1400mmoloflactateisproducedperday.Lactateiseither:

OxidisedinthecellThisrequiresrestorationofNAD ,e.g.resolutionofcellularhypoxia.CirculatedtotheliverLactateisthen:

OxidisedtopyruvateConvertedtoglucoseThisprocessisknownastheCoricycle.

Ketones

Ketones:

β-oxidationoffattyacidsintheliverproducesacetyl-CoAAcetyl-CoAusuallyentersthecitricacidcycletoproduceATPWhenlargeamountsofacetylCoAareproduced,theymayinsteadcondensetoformacetoacetate,whichcanthenbereducedtoβ-hydroxybutyrateThesesubstancesareknownasketones

Ketonescanonlybeproducedbytheliver,andonlyusedasasubstratebythekidney,aswellasskeletalandcardiacmuscle

Productionofketonesisacceleratedbyglucagonandadrenaline

References

1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. ANZCAAugust/September2011

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RegulationofBodyTemperatureOutlinethemechanismsforheattransferbetweenthebodyanditsenvironment.

Definethethermoneutralzone,anddescribethemechanismsbywhichnormalbodytemperatureismaintained.

Regulationofbodytemperatureisdonebybalancingheatlossandheatproduction,predominantlythroughbehaviouralmechanismsandskinThebodyisabletomaintainarelativelyconstantcoretemperatureunderawiderangeofenvironmentalconditions

Thethermoneutralzoneistherangeacrosswhichthebasalrateheatproduction(andoxygenconsumption)isbalancedbytherateofheatloss

Foranadultitistypically27-31°CInneonatesitishigher,typically32-34°C.

PrinciplesNetfluxofheatisdeterminedbythebalanceofmetabolicheatproductionandthecontributionoffourmechanismsofheatloss:

RadiationConductionConvectionEvaporation

Radiative

Radiativeheatexchange:

DescribesthelossofheatthroughEMRbyallobjectsabove0°KRadiativeheatlossisproportionaltotemperatureRadiativeheatlossdoesnotrequireatransfermedium

Makesup~45%ofheatlossunderthermoneutralconditions.Dependsonthetemperaturedifferentialbetweenanindividualandtheirenvironment

Acoldenvironment(e.g.operatingtheatre)causesalargeradiantheatlossTheheatlossfromthepatientisgreaterthantheheatgainfromthesurroundingenvironment.

Conduction

Conductionisthetransferofheat(askineticenergy)bydirectcontactfromahighertemperatureobjecttothelowertemperatureone.Conduction:

RequiresphysicalcontactbetweenbodiestoconductheatSolidsconductheatbetterthangasesThereisnoconductioninavacuum

HeatlossviaconductionisminimalinairbutisamajorcauseofheatlossinimmersionAsarteriesandveinstypicallyrunnexttoeachother,arterialheattendstobetransferredtothe(cooler)veins,limitingfurtherheatlossThisissimilartocounter-currentexchangeinthekidney.

Asfatisapoorerconductorofheatthanmuscle,increasedbodyfatwillslowheatlossbyconduction

Convection

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Convectionislossofheatbyconductionbyamovingobject.Convectionis:

ThepredominantmechanismofheatlossinthenakedhumanEffectsaregreatereffectsathigherwindspeeds.

Evaporation

Evaporativelossesdescribethelossofheatenergyduetothelatentheatofvapourisationofwater.Evaporationof100mlofwaterwillreducebodytemperatureby~1°C.

TemperatureSensationandRegulation

Temperaturesensorsarecentralandperipheral,whilstregulationoccurscentrally.

CentralSensation

Centraltemperaturesensorsexistinthe:

AbdominalvisceraSpinalcordHypothalamusAnteriorhypothalamusisthemostimportantcentralthermoreceptor,andrespondstobothincreasedanddecreasedtemperaturesbyalteringtheirrateofdepolarisation,elicitinganarrayofneuronalandhormonalresponses.Brainstem

Theinter-thresholdrangeistherangeofcoretemperaturesnottriggeringaresponse.

Normalis0.2to0.4°C.Widensunderanaesthesiato~4°C

PeripheralSensation

Peripheraltemperaturesensorsare:

FreenerveendingsExtremelysensitiveAltertheirratesoffiringbyordersofmagnitudeinresponsetotemperaturechange.Dividedinto:

ColdreceptorsLiebeneaththeepidermis,andareexcitedbycooling(inhibitedbywarming),activefrom10-40°C,withastaticmaximaat25°C.WarmreceptorsLiedeeptothedermis,areexcitedbywarming(andinhibitedbycooling),activefrom30-50°C,withastaticmaximaat44°C.

Regulation

Temperaturesensationrunsfromcutaneousreceptorsviathespinothalamictractsandmedullatothehypothalamus.Corticalinputisreceivedviathethalamocorticalrelay,whilstprimitiveresponsesareeffectedviathemidbrain.

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Increaseheatloss Reduceheatloss/Increaseheatgain

CNS Removeclothing,sprawl,reduceactivity. Huddle,seekshelter,addclothing

Cardiovascular IncreaseperipheralvasodilationandAVshunting,andcardiacoutputtoimproveflowtocutaneoustissues

Vasoconstriction,peripheralcirculatoryshutdown

Musculocutaneous Sweating Piloerection,Shivering

Metabolic IncreasedBMR,non-shiveringthermogenesis

Vascularchangesaretheleastmetabolicallycostlyandcanresultindramaticincreases(upto60%ofcardiacoutput)inskinbloodflowWhenenvironmentaltemperatureexceedsbodytemperature,conductionandconvectionresultinheatgain-evaporativecoolingviasweatingistheonlywaytoreducebodytemperatureEfficacyofsweatingisrelatedtorelativehumidity

Piloerection(hairstandingonend)trapsalayerofwarmairclosetothebodytoactasaninsulatorThisisofmoreimportanceinotherprimatesthaninman,astheyhaveenoughbodyhairtomakeiteffective.

Increasingbasalmetabolicrateand'waste'heatproductionisessentialtomaintaintemperatureincoldenvironments.Thiscanbethrough:

ShiveringThesimultaneouscontractionofagonisticandantagonisticmuscles.Non-shiveringthermogenesis:

HormonalLevelsofthyroidhormoneandadrenalineincrease,raisingmetabolicrateinallcellsBrownfatBrownfatproducesheatthroughuncoupledoxidativephosphorylation,whichusestheelectrontransportchaintoproduceheatratherthanATP.Brownfatis:

Avitalmechanismforheatproductionintheneonate(theyhaveanimmatureshiveringresponse),andforms~5%ofneonatalmassLocatedin:

NeckSupraclavicularInterscapularSuprarenal

SympatheticallyinnervatedContainslargenumbersofβ receptors

EffectofAnaesthesia

Generalanaesthesiacausesa1-3°Cdropincorebodytemperature,whichoccursinthreephases:

RapidreductionCoretemperaturefallsby1-1.5°Cinthefirst30minutes.

Predominantlyduetovasodilation,whichisdueto:ReductioninSVR,withgeneralisedvasodilationandincreasedskinbloodflowHeatredistributionisthemajorinitialfactor(ratherthanheatloss),asvasodilationleadstoincreasedheatcontentofperipheries.ImpairsthermoregulatoryvasoconstrictiveresponsesInter-thresholdrangeiswidenedto4°C(upfrom0.4°C)

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GradualreductionFurtherdropincoretemperatureof1°Coverfollowing2-3hours.

DuetoheatlossexceedingheatproductionNon-shiveringthermogenesisistheonlyresponseavailabletoparalysed,anaesthetisedpatient.

PlateauOncecorebodytemperaturefallsfarenough,thermoregulatoryresponsesareactivatedandfurtherheatlossisattenuatedbyincreasedmetabolicheatproduction.

Neuraxialanaesthesia:

HypothermiaislessextremeasthermoregulationisonlyaffectedinareascoveredbytheblockadePlateaudoesnotoccurasvasoconstrictiveresponsesareinhibitedbytheblockade

References

1. Auerbach.WildernessMedicine.SixthEdition.Chapter4:Thermoregulation.2. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.3. DiazA.Define"thermoneutralzone".Brieflyexplainhowthebodyregulatestemperaturewhentheambienttemperature

exceedsthethermoneutralzone.PrimarySAQs.4. BuggyDJ,CrossleyAW.Thermoregulation,mildperioperativehypothermiaandpostanaestheticshivering.BrJAnaesth.

2000May;84(5):615-28.

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InflammationDescribethefactorsinvolvedintheprocessofinflammationandtheimmuneresponse,includinginnateandacquiredimmunity

Inflammationisanon-specificresponsetriggeredbyapathogenortissueinjury,whichaimstolimitfurthertissuedamage.

Inflammationisclassicallycharacterisedby:

PainHeatRednessSwellingLossoffunction

Thisisaconsequenceof:

VasodilationIncreasesbloodflowtoarea,whichincreasessupplyofimmunecellsandresourcesforcellularrepair.IncreasedvascularpermeabilityIncreasesextravasationofproteinandimmunecells.MigrationofphagocytesRemovepathogensandcellulardebris.

ProcessofInflammation

TissuedamageTraumacausesmechanicaldisruptionofvasculatureandmastcelldegranulation,causinglocalinflammationandactivationofhaemostaticmechanismsInfectionstimulatesdegranulationoflocalmacrophages,releasinginflammatorycytokinesandtriggeringmastcelldegranulation

LocalinflammatoryresponseHistaminecausesarteriolarandpost-capillaryvenuledilatationandsubsequentextravasationReleaseofchemotacticmoleculesattractscirculatinginflammatorycells

SystemicinflammatoryresponseSevereinflammationmayleadtocytokinesinthesystemiccirculation,causing:

FeverNeutrophilrecruitmentfrombonemarrowReleaseofacute-phaseproteinsfromliver

References1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.

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InnateImmunityDescribethefactorsinvolvedintheprocessofinflammationandtheimmuneresponse,includinginnateandacquiredimmunity

Theinnateimmunesystemconsistsofprotectivemechanismswhicharepresentlife-long,andtypicallyformsthefirstlineofdefenceagainstpathogens.

Keyfeaturesofinnateimmunityinclude:

ImmediacyNon-specificresponseNotmodifiedbyrepeatexposures

Theinnateimmunesystemconsistsofthreecomponents:

PhysicochemicalbarriersHumoralmechanismsCellularMechanisms

PhysicochemicalBarriers

Theseinclude:

SkinMucousmembranes

MucousMucociliaryelevator

GastricacidUrinationOptimisedbyhighflowratesandlowresidualbladdervolumes.

InnateHumoralMechanisms

Humoralmechanismsdescribestheroleofinflammatoryproteinsininnateimmunity:

ComplementThecomplementsystemisacomplexgroupofabout25plasmaproteinsimportantinbothinnateandadaptiveimmunity.

Thecomplementsystemisactivatedby:Antigen-antibodycomplexesThe'classicalpathway.'SubstancesinthebacteriacellwallThe'alternativepathway.'

Complementhasanumberofinflammatoryfunctions:DestructionofbacteriaSeveralcomplementproteinscometogethertoformamembraneattackcomplex,whichcreateslargeporesincellmembranes,causingwatertodiffuseinandbacteriatoburst.OpsonisationofbacteriaBoundcomplementactsasabindingsiteforphagocytes.ActivationofmonocytesandphagocytesChemotaxis

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Attractsleucocytes.MastcelldegranulationAugmentsinflammation.

Acute-PhaseProteinsInflammatoryproteinswithanumberofeffects:

OpsonisationInflammatorymediatorsIncreasebloodflowanddeliveryofinflammatorycellsviathreemechanisms:

DilatationandincreasedcapillarypermeabilityEndothelialactivationincreasingleukocyteadhesionAttractionofneutrophilsandmonocytes

ProteolyticenzymesBactericidalenzymeslocatedinsaliva,tears,respiratorymucous,andneutrophils.

InnateCellularMechanismsCellularcomponentsoftheinnateimmunesysteminclude:

MastcellsExistinlooseconnectivetissueandmucosa,andcontainmanyintracellulargranulesofheparinandhistamine.

LeukocytesNeutrophils(60%ofallleukocytes)Phagocytosebacteriaandfungi(15-20perneutrophil).Thisprocessconsistsofanumberofsteps:

ExitcirculationbymarginatingalongcapillaryborderwhenactivatedMigrateviachemotaxistowardsthetissueinsultPhagocytoseopsonisedbacteriaandfungiKillorganismswitharespiratoryburst:Agranulecontaininghydrogenperoxide,hydroxylandoxygenradicalsfuseswiththetargetcellmembrane,destroyingboththetargetandtheneutrophil.

MonocytesBecomemacrophageswhentheyleavecirculationandentertissue.Macrophageshavealifespanof2-4months,andcanphagocytoseupto100bacteriabeforeitdies.Functionsinclude:

PhagocytosisanddestructionofpathogenEspeciallyintracellularpathogens(listeria,mycobacteria),parasites,andfungi.BreakdownofdamagedbodycellsPresentantigentoT-helpercellsSecretionofinflammatorymediators

EosinophilsKillmulticellularparasites.BasophilsContainheparinandhistamine.LymphocyteSubtypeofleukocyteimportantinadaptiveimmunity.Include:

NaturalKillercellsActiveagainstviralandtumourcells.BcellsTcells

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References

1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.

Lastupdated2019-07-18

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AdaptiveImmunityDescribethefactorsinvolvedintheprocessofinflammationandtheimmuneresponse,includinginnateandacquiredimmunity

Theadaptiveimmunesystemrespondstoanexposure,demonstratingspecificityandmemory,withimprovedefficacyonrepeatexposure.

Adaptiveimmunitymaybe:

ActivePrimaryimmuneresponsegeneratedbyexposuretoantigen.

InfectionVaccinationAninactive(butstillforeignandthereforeantigenic)proteincomponentofapathogenisgiventothepatient,resultinginanimmuneresponse.Subsequentexposuretothewholepathogentriggersasecondaryimmuneresponse.

PassivePreformedantibodyisgiventothepatient.Thiswillprovidetreatment/coverageforthelifeoftheantibody,butimmunitywillbelostwhentheantibodybreaksdownorsuppliesareexhausted.

TransplacentalColostrumAdministrationofserum

Componentsoftheactiveimmunesysteminclude:

CellularPredominantlyTlymphocytesHumoralIncludingcomplementandantibody.

AdaptiveCellularImmunity

Lymphocytesaredividedintotwotypes:

BlymphocytesAreproducedinthebonemarrow,andmigratetolymphoid(nodes,spleen,MALT)wheretheyarerenamedplasmacellsandproduceantibody.Functionsinclude:

ProductionofantibodyagainstspecificantigensPresentationofantigentoT-cellstoactivethemProliferationtoformmemorycells

TlymphocytesAreproducedinthebonemarrowandmigratetothethymuswheretheymature.Tcellswhichexpressantibodytohostproteinapoptose,resultinginonly2%ofimmatureTcellssurviving.MatureTcellsthenspreadtolymphoidtissue.TherearefivetypesofTcells,ofwhichtwoaremostimportant:

HelperT-cells2/3 ofT-cellsarehelpercells,areareidentifiedbytheirCD4membraneprotein.Functionsinclude:

CytokineproductionBlymphocytestimulationMacrophageactivation

CytotoxicT-cells

rds

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AreidentifiedbytheirCD8membraneprotein.Functionsinclude:DestructionofvirallyinfectedandtumourcellsAllcellsexpressproteinsthattheyareproducingonmembraneMHCImolecules,forinspectionbyimmunecells.Infectedortumourcellswillexpressforeignproteins,andcauseactivationofcytotoxicTcells:

InduceapoptosisinthetargetcellRapiddivisionofcytotoxicTcell,whichtheninspectsothercellsforinfection

Transformationtomemorycells

AdaptiveHumoralImmunity

AntibodiesY-shapedimmunoglobulinswhich:

AreproducedinresponsetoapathogenArespecifictothatpathogen

Antibodyfunctionsinclude:

OpsonisationAgglutinationEachantibodycanbindmultiplepathogens,increasingtargetsizeforleukocytes.InactivationofpathogenAntibodybindingmaydisablethepathogen.ActivationofcomplementAntibody-antigencomplexescausecomplementactivation.

PrimaryImmuneResponse

Theprocessofinvasionofanewpathogentoantibodyproductiontakes~5days,andoccursinanumberofsteps:

APCphagocytoseapathogenAPCsincludemacrophagesanddendriticcells.APCexpressantigen(bitsofpathogen)oncellsurfaceAPCtraveltolymphoidtissueandpresentittoBandTcellsWhenanAPCfindsaBandTcellwithareciprocalantibody:

ThelpercellbecomesactivatedbyAPCThelpercellrapidlyproliferates('clonalexpansion')

ProportionbecomememorycellsBcellsareactivatedbyboththeAPCandaT-helpercell(requiresboth)Bcellsrapidlyproliferate

ProportionbecomememorycellsProportionbecomeplasmacells

Plasmacellsproduceantibodyatarateof2000moleculespersecond,whichoverridesnormalcellularhomeostasis,causingdeathwithinaweek.AntibodyproducedinaprimaryimmuneresponseisIgM,withsomeIgGproducedlateron.

SecondaryImmuneResponse

Repeatinvasionbythesamepathogenismetwithamuchmorerapidandaggressiveimmuneresponse:

APCsphagocytoseapathogenAPCsexpressandpresentantigenMemoryTandMemoryBcellsformedduringtheprimaryresponseareactivated,andbeginrapidlydividingandproducingantibody

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References

1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.

Lastupdated2019-07-18

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HypersensitivityExplaintheimmunologicalbasisandpathophysiologicaleffectsofhypersensitivity,includinganaphylaxis.

Understandthepharmacologyofthedrugsusedinthetreatmentofanaphylaxis.

Hypersensitivityreactionsareexaggeratedimmuneresponsesthatcausehostinjury.

ClassificationofHypersensitivityReactionsTheGelandCoombssystemclassifieshypersensitivityreactionsbythemechanism.Itiscommonlyusedbutfailstoclassifymorecomplexdiseases.

Type Timing Mediator Pathophysiology Diseaseexample(s)

TypeI-Immediatehypersensitivity

Secondstominutes

IgE BasophilandmastcelldegranulationAnaphylaxis(systemic),Atopy(local)

TypeII-Cellularhypersensitivity

5-8hours IgM,IgG

Antibodybindingtocellsurfaceantigen,resultingincelldeathviacomplementmembraneattackcomplexes,orphagocytosisbymacrophages

Transfusionreactions,hyperacuteallograftrejection

TypeIII-Immune-complexdeposition

2-8hours

IgM,IgG,IgA

TissuedepositionofAb-Agcomplexes.AccumulationofPMNs,macrophages,andcomplement.

SLE,necrotisingvasculitis,post-StrepGN

TypeIV-Delayedhypersensitivity

24-72hours T-cell T-cellinducedmononuclearcellaccumulation.

Releaseofmonokinesandlymphokines.

TB,Wegener'sGranulomatosis,Granulomatousvasculitis

TypeIHypersensitivity

AntigensimulatesaBlymphocytetoproduceaspecificIgEagainstitThisIgEthenbindstoFcreceptorsonmastcells,sensitisingthemtothisexposureOnre-exposuretheantigenbinds(cross-links)IgEonmastcells,causingdegranulation:

Histamine,leukotrienes,andprostaglandinsarereleasedThismaycauselocalorsystemiceffects,dependingonmethodofexposure:

Asystemicreactioniscalledanaphylaxis,andmanifestsasacombinationof:HypotensionBronchospasmLaryngealoedemaRashes

Localreactionsdependontherouteofexposure,andincludeAsthmaInhaled.AllergicrhinitisNasopharyngealmucosa.

Non-immuneanaphylaxis(alsoknownasanaphylactoid)reactionsarecharacterisedbyaimmediategeneralisedreactionclinicallyindistinguishablefromtrueanaphylaxis,buttheimmunenatureisunknown,ornotduetoatypeIhypersensitivity

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reaction

ManagementofAnaphylaxis

Adrenalineisthedrugofchoice,asittreatscardiovascularcollapse,bronchospasm,anddecreasesoedemaformation.Inadults,0.3-0.5mgIMQ5-15minInchildren,0.01mg/kgIMQ5-15min

Glucagonmaybeusedinβ-blockedpatientsresistanttoadrenaline.Inadults,1-5mgIVover5minutes,followedbyinfusionat5-15microg/minInchildren,20-30mcg/kgupto1mgover5minutes

Non-pharmacologicalmanagementincludesearlyintubationtoprotectagainstairwayobstructionduetoangioedema.Adjunctsincludeantihistaminesandsteroids.Theyaresecondlineastheydonotattenuatecardiovascularcollapse,resolveairwayobstruction,orhavestrongevidencebehindtheiruse.Theyinclude:

Diphenhydramine25-50mgIV(Children:1mg/kgupto40mg)upto200mgin24/24Salbutamol,forbronchodilationMethylprednisolone1-2mg/kg,ostensiblytoprotectagainstreboundanaphylaxis(thoughthereisminimalevidence)

TypeIIHypersensitivity

AntibodiesbindtocellsurfaceantigenAntibody-AntigencomplexactivatescomplementComplementgeneratesaninflammatoryresponseCelldeathoccursvia:

ComplementmembraneattackcomplexPhagocytosis

Clinicalpicturedependsonaffectedorgans.Examplesinclude:

HyperacuteallograftrejectionTransfusionreactionsandhaemolyticdiseaseofthenewbornGoodpasture'ssyndromeAutoimmunecytopaeniasMyastheniaGravis

TypeIIIHypersensitivity

Immune-complexreactionwhereAb-AgcomplexesareformedanddepositedintissuesSubsequentcomplementactivationcausesinflammationandneutrophilsactivation,leadingtotissuedamageTherearetwosubtypesoftypeIIIreactions:

Formationofcomplexesincirculationandsubsequentdepositionintissuese.g.Serumsickness

FormationofcomplexesintissuesSmallamountsaretypicallyremovedbythereticuloendothelialsystem,butinthiscasetherearetoomany,ortheyaretoosmall,tobeclearedeffectively.

e.g.TheArthusreaction(alocalisedvasculitis,whichmaybenecrotising)

TypeIVHypersensitivity

AntigenispresentedtoTlymphocyteswhichproliferateandbecomesensitisedT-cellsthenreleasecytokines,attractingmacrophagesandleadingtolocalinflammationDuringprolongedexposure,macrophagesmayfusetoformgiantcellsandformagranuloma.Examplesinclude:TB

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Granulomatousvasculitis

References

1. CICMJuly/September20072. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.

Lastupdated2019-07-18

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ClassificationofMicroorganismsDescribetheclassificationofmicro-organisms,includingviruses,bacteria,protozoaandfungi

Microorganismscanbeclassifiedasprokaryotes(bacteria),viruses,oreukaryotes(whichincludefungi,helminths,andprotozoa).

Bacteria

BacteriaareprokaryoticorganismsMostclinicallyrelevantbacteriacanbeclassifiedbyGramstainandshape

GramstainseparatesbacteriaaccordingtotheircellwallcompositionItcannotbeusedonorganismsthatlackacellwall,suchasmycoplasma.

Acrystalvioletfollowedbyaniodinesolutionisappliedtotheslide,whichisthenwashedwithasolventGram+veorganismswillretainthestainduetotheirthickpeptidoglycancellwall,whilstgramnegativeorganismsbecomecolourless

Asafraninpinkstainisthenapplied,whichstainsthegram-vebacteriapinkBacteriacanalsobeclassifiedbyshapeinto:

CocciAppearroundonmicroscopy.Rods

Combiningofthesetwosystemsclassifiesalargeproportionofmicrobes:

Examples: GramPositive GramNegative

Cocci StaphylococcusAureus,StreptococcusPneumoniae N.Meningitidis,N.Gonorrhoea

Rods Listeria,Clostridiumdifficile EscherichiaColi,Pseudomonasaeruginosa

BacterialSubclassification

Additionaltestingcanbedonetofurtherclassifybacteria:

CatalasetestingisperformedonGrampositivecocciHydrogenperoxideisaddedtoabacterialsample,andinthepresenceofcatalasewillproduceoxygen.

CatalasepositiveindicatesStaphylococciCatalasenegativeindicatesStreptococci(andenterococci)

CoagulasetestingisperformedonStaphylococcalspeciesCoagulaseisanenzymewhichcleavesfibrinogentofibrin.Thestaphylococcalcolonyisaddedtorabbitplasmaandincubated.Inthepresenceofcoagulase,fibrinisformed.

CoagulasepositivestronglysuggestsS.AureusCoagulasenegativeexamplesincludeS.epidermidisorS.saprophyticus

HaemolytictestingisperformedonStreptococcalspeciesBacterialcoloniesareaddedtobloodagar,andthecolourchange(duetohaemolysis)isnoted.

αhaemolyticorganismsproducedarkgreenagar,asmethaemoglobinisproducedbyhydrogenperoxideproducedbytheseorganisms.Examplesinclude:

Strep.pneumoniaeStrep.viridans

β-haemolyticorganismsproduceyellowagarfromcompletehaemolysis.Examplesinclude:

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Strep.pyogenesStrep.agalactiae

γ-haemolyticorganismsleavetheagarunchanged.Examplesinclude:E.faecalisE.faecium

Additionally,gramnegativerodsshouldbefurtherclassifiedintopseudomonalandnon-pseudomonalorganisms

Viruses

VirusesconsistofmoleculesofeitherDNAorRNAshieldedinaproteincoat.Theyrequiretheuseofhostcellstructuresforreproductionandarethereforeobligateintracellularparasites.Theycanbeclassifiedbyfiveproperties:

1. DNA/RNADNAvirusesreplicateinthecellnucleususingahostpolymerase.

2. Double-strandedorsingle-strandedi. MostDNAvirusesaredouble-stranded(dsDNA)ii. MostRNAvirusesaresingle-stranded(ssRNA)

3. Negative-senseorpositive-sense(RNAvirusesonly)i. Positive-sensegenomesmaybetranslateddirectlyintomRNAii. Negative-sensegenomesrequireanRNA-dependentRNApolymerasetotranslatethemtoapositive-sensestrandprior

totranslation.4. CapsidSymmetry

Theproteincoatmaybeeithericosahedralorhelical5. Envelopedornon-enveloped

Inadditiontoaproteincoat,virusesmayhavealipidmembrane(acquiredfromthehostcell)aroundtheirproteincoat.

EukaryoticOrganismsEukaryoticorganismsincludefungi,protozoa,andhelminths,aswellasplantsandanimals.Theydifferfromprokaryoticorganismsinanumberofways:

Property Prokaryotes Eukaryotes

Chromosomes Single,circular Multiple

NucleusandOrganelles None Membraneboundnucleusandorganelles

Cellwall Usually Inplants

Ribosome 70S 80Sincell,70Sinorganelles

Size 0.2-2mm 10-100mmm

Fungitypicallyfeedondead/decomposing/theimmunocompromisedandproducespores.Theyaresubclassifiedinto:YeastsYeastsareunicellular.Theyaredividedinto:

CandidaAlbicansNon-albicansMoredifficulttotreat.

CryptococcusMouldsMouldsarearefilamentous.

Aspergillus

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PenicilliumDimorphousHavecharacteristicsofbothyeastsandmoulds.

Histoplasma

Protozoaareparasiticsingle-celledeukaryotes.Theycanbeintracellularorextracellular.

Helminthsareparasiticmulti-celledeukaryotes.Theycanbeintracellularorextracellular.Theyaresubdividedintotapeworms(cestodes),flukes(trematodes),androundworms(nematodes).

Footnotes.Thisclassificationdoesnotcapturespirochetes,mycoplasmas,chlamydias,andotherlesscommonlyencounteredorganisms.Amorecompleteclassificationusessixproperties:↩

1. CellWallStructurei. Flexible(e.g.Spirochetes)ii. Rigidiii. Non-existent(e.g.Mycoplasmaspp.)

2. Morphologyi. Unicellularii. Filamentous

3. GrowthLocationi. Extracellularii. Obligateintracellularparasites(e.g.Chlamydiaspp.)

4. GramStaini. Grampositiveii. Gramnegative

5. Shapei. Cocciii. Rods

6. O tolerancei. Aerobesii. Anaerobes(e.g.Clostridiumspp.)

References1. HarveyRA,CornelissenCN,FisherBD.LippincottIllustratedReviews:Microbiology(LippincottIllustratedReviews

Series).3rdEd.LWW.2. CICMSeptember/November2008

Lastupdated2019-07-20

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AntimicrobialResistanceDescribetheprinciplesofanti-microbialresistance

Resistanceoccurswhenthemaximalleveloftheagenttoleratedisinsufficienttoinhibitgrowth.

Resistancecanoccurbroadlyviatwomechanisms:

GeneticAlterationSpontaneously,throughmutationandsubsequentnaturalselectionofresistantorganismsTransferalofresistancegenesfromorganismtoorganismviaplasmids

ProteinExpressionIncreasingordecreasingexpressionofproteinswithsubsequentchangeinefficacyofantimicrobials.

MechanismsSpecificmechanismsofresistance(whichmaybegeneticalterationsorchangesinproteinexpression)include:

PreventaccesstotargetDecreasepermeability

Narrowingofporinchannelse.g.StreptococcalresistancetopenicillinstypicallyoccursbyreducingaccesstoPBPs.Lossofnon-essentialtransporterchannelse.g.Anaerobeshavenooxygen-transportchannelwhichpreventspenetrationbyaminoglycosides.

ActiveeffluxofagentIncreasedefficiencyorexpressionofeffluxpumps.Canbe:

RemovedfromcellTrappedbetweencellwalllayerse.g.GlycopeptideresistanceinVRSA.

AlterantibiotictargetsiteChangesinbindingsiteproteinwillincreaseresistancetoagentswithlowaffinityOver-expressionoftargetproteinSynthesisoftarget-protectingproteins

ModificationorInactivationofDrugMetabolismofdruge.g.β-lactamaseshydrolyseβ-lactamrings

ModificationofMetabolicPathwaysDevelopmentofmetabolicpathwaystobypasssiteofactionofantibiotice.g.ResistancetoTrimethoprim-Sulfamethoxazolebyallowingbacteriatosynthesisorabsorbfolicacid.

References

1. HarveyRA,CornelissenCN,FisherBD.LippincottIllustratedReviews:Microbiology(LippincottIllustratedReviewsSeries).3rdEd.LWW.

2. CICMSeptember/November20083. BlairJM,WebberMA,BaylayAJ,OgboluDO,PiddockLJ.Molecularmechanismsofantibioticresistance.NatRev

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Microbiol.2015Jan;13(1):42-51.doi:10.1038/nrmicro3380.4. Microrao-MechanismsofAntimicrobialResistance

Lastupdated2019-07-18

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AntisepticsOutlinethepharmacologyofantisepticsanddisinfectants

KeyDefinitions

Relevantdefinitionsforantisepticsinclude:

CleaningPhysicalremovalofforeignmaterial.

Usedfornon-criticalitems,whichcomeintocontactwithhealthyskinbutnotmucousmembranes(e.g.bloodpressurecuff)

DecontaminationDestructionofcontaminantssuchthattheycannotreachasusceptiblesiteinsufficientnumbertocauseharm.DisinfectionEliminationofallpathologicalorganisms,excludingspores.

Usedforsemi-criticalitems,whicharethosethatcontactmucousmembranesbutdonotbreakthebloodbarrier(e.g.endoscopes,laryngoscopes)

SterilisationEliminationofallformsofmicrobiallife,includingspores.

Usedforcriticalitems,whicharethosethatentersterileorvasculartissueandposeahighriskofinfection(e.g.surgicalinstruments,vascularandurinarycatheters)

AntisepticAgents

Drug IsopropylAlcohol Chlorhexidine Povidoneiodine

PharmaceuticsTypically60-90%-requiressomewatertodenatureprotein.Flammable.

Maybeaqueousorcombinedwithisopropylalcohol.

Iodinecombinedwithapolymer(povidone)toenhancewatersolubility

AntiviralProperties Poorantiviral Poorantiviral Goodantiviral

AntibacterialProperties Broadspectrumantibacterial

Broadspectrumantibacterialandantifungal

Broadspectrumincludingfungi,spores(unlikeiodine),andtuberculosis

Toxic Irritantonmucousmembranesandopenwounds Hypersensitivity Hypersensitivity

Other Persistentantisepticeffect

Requirescontinualreleaseofiodinetoachieveeffect.Inactivatedbyorganicsubstances.Stains.

References

1. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.2. SabirN,RamachandraV.Decontaminationofanaestheticequipment.ContinuingEducationinAnaesthesia,CriticalCareand

Pain.(2004).4(4),103–106.

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RespiratoryChangesofPregnancyExplainthephysiologicalchangesduringpregnancy,andparturition

Respiratorychangesinpregnancyareafunctionoftwothings:

AnatomicalcompressionofthechestIncreasedVO andVCO

AnatomicalChangesDiaphragmpushedupwardsby~4cmIncreasedAPandtransversediameterofthechestwall(~2-3cm)Largeairwaydilation,reducingairwayresistanceby~35%

VolumesandCapacitiesFromconceptionuntilterm:

V increasesby40%Inspiratorycapacityincreasesby10%Expiratorycapacitydecreasesby30%Totallungcapacitydecreasesby5%Vitalcapacityisunchanged

From~20weeksuntilterm:

ERVdecreasesRVdecreasesFRCdecreases

By20%erectBy30%supine

Ventilation

Progesteronestimulatesrespiratorycentres,shiftingtheO andCO responsecurvestotheleftwhichcauseshyperventilationandarespiratoryalkalosis.Fromconceptionuntilterm:

MVincreasesby50%10%increaseinRR40%increaseinV

PCO fallsto~26-32mmHg,withacompensatorydropinplasma[HCO ]to18-21mmol.L

LabourandPostpartumDuringlabour:

MVincreases70%duetopainandincreasedoxygendemandThiscauseshypocapnea,socessationofuterinecontractions(andtheassociatedpainandoxygendemand)arefollowedbya

2 2

T

2 2

T2 3

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hypoventilatoryperiodproducingdesaturation

FRCandRVreturntonormalwithin48hoursofdelivery.

References

1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.

Lastupdated2019-07-18

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CardiovascularChangesofPregnancyExplainthephysiologicalchangesduringpregnancy,andparturition

Physiologicalconsequencesofchangesinpostureduringpregnancy

Pregnancyisatimeofincreasedmetabolicdemand,whichcardiovascularchangesreflect.Thesechangesinclude:

IncreasedintravascularvolumeOccursviatwomechanisms:Increasedoestrogencausesanincreasedplasmavolume

Thisdecreasescapillaryoncoticpressure,predisposingtooedemaThismaybeexacerbatedbythegraviduteruscompressingtheIVC,especiallynear-term

IncreasedEPOcausesanincreasedredcellvolumeIncreasedvenousreturnDuetoincreasedintravascularvolumeandMSFP.

ThegraviduterusmaycompresstheIVCandimpairVR,hencepregnantwomenarepositionedwithaleftlateraltilttodisplacetheuterusofftheIVC

IncreasedVRcausesanincreaseinCO(withbothanincreaseinHRandSV,aswelladecreaseinSVR)DecreasedSVRresultsinSBP,DBPandMAPdropping(despitetheincreaseinCO)

MagnitudeofChangesbyTrimester

Parameter Direction FirstTrimester

SecondTrimester

ThirdTrimester Notes

Plasmavolume ↑ 35% 45% 50% Peaksbetween32-36 week,decreases

slightlythereafter

Bloodvolume ↑ 5% 15% 20% Increaseslessthanplasmavolume,

resultinginthefallinhaematocritto33%

HR ↑ 15% 18% 25% Increasesprogressivelythroughout

SV ↑ 20% 25% 30% Increasesprogressivelythroughout

CO ↑ 20% 40% 45% Increasesthroughoutanddramaticallyinlabour

ChangesDuringLabour

Uterinecontractionboluses~300mlofbloodintothematernalcirculationCausesanincreaseinCObyupto30%duringtheactivephaseand45%duringejection.

AssociatedwithcorrespondingincreaseinSBPandDBPby10-20mmHg

Post-partumCOisupto80%ofpre-labourvaluesduetoautotransfusion,andreturnstonormalwithin2weeksofdelivery

References

1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.

Lastupdated2018-03-04

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FoetalCirculationExplainthephysiologicalchangesduringpregnancy,andparturition

InUtero

Thefoetalcirculationhasanumberofstructuraldifferences:

TwoumbilicalarteriesTheumbilicalarteryreturnsdeoxygenatedbloodtotheplacenta.

PO of18mmhg(SpO 45%)Over50%ofthecombinedoutputofbothfoetalventriclesenterstheplacenta

OneumbilicalveinTheumbilicalveinsuppliesoxygenatedbloodtothefoetus.

HasaPaO of28mmHg(SpO 70%)60%ofbloodfromtheumbilicalveinenterstheIVC40%ofbloodenterstheliver

Twoducts:DuctusvenosusShuntsbloodfromtheumbilicalveintotheIVC.DuctusarteriosusShuntsbloodfromthepulmonarytrunktothedescendingaorta.

AforamenovaleShuntsbloodfromtherightatriumtotheleftatrium.ImmaturemyocardiumFoetalmyocardiumdoesnotobeyStarlingsLaw,anddoesnotadjustcontractilityforanygivenpreload.Therefore:

SVisfixedCOisHRdependentNormalHRattermis110-160bpm.

Thesestructuraldifferencealterthepathwayofbloodcirculation:

Oxygenatedbloodreturnsviatheumbilicalvein40%flowstotheliver60%isreturnedtotheIVC

OxygenatedbloodintheIVCisdirectedviatheEustachianvalvethroughtheforamenovaleBloodreturningfromtheSVCisdirectedintotheRV,andthenintothedescendingaortabytheductusarteriosus

~10%ofRVoutputflowsthroughthepulmonarycirculation

Thisarrangementhasseveralfeatures:

BloodwiththemostoxygenisdeliveredtothearchvesselstosupplythebrainBloodwiththeleastoxygenisdeliveredtotheumbilicalarteriesforgasexchangeBoththeRVandtheLVejectintosystemiccirculations,andareofsimilarsizeandwallthickness

ChangesatBirth

Severalchangeshappenatbirth:

Placentalcirculationislost

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Thereisatransitionfromcirculationinparalleltocirculationinseries.AnFRCisestablishedReversalofhypoxicpulmonaryvasoconstrictionresultsinarapiddropinPVR.ThecordisclampedThesystemicvascularbedvolumefalls,andSVRincreasesduetothelossofthelow-resistanceplacentalcirculation.

ThefallinPVRlowersRVafterloadRAPfallsduetothelossofhypoxicpulmonaryvasoconstriction.

TheriseinSVRincreasesLVafterloadLAPrisesastheLVmovesuptheStarlingcurve.WhenLAPexceedsRAP,theforamenovaleclosesAdegree(~10%)ofresidualshuntremains.Shuntis:

BidirectionalLeft-to-rightshuntisunconcerningRight-to-leftshunthasusuallyonlyminoreffectsonsystemicSpOWillbeincreasedwith↑PaCO ,excessivePEEP,↓pH.

BewareembolicmaterialDon'tforgetthebubbles.

IncreasedleftsidedafterloadcausesflowreversalintheductusarteriosusThereisprogressiveclosureoftheductusoverhourstodays,undertheinfluenceofprostaglandinsandoxygenatedbloodflowingthroughtheduct.

Theductusvenosusprogressivelyfibrosesoveraperiodofdaystoweeks

References

1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.3. BrandisK.ThePhysiologyViva:Questions&Answers.2003.

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ThePlacentaOutlinethefunctionsoftheplacenta,anddeterminantsofplacentalbloodflow.

Theplacentaisanorganofmaternalandfoetaloriginwhichsupportsthedevelopingfoetus.

PhysiologicalProperties

Theplacentahasthreebroadfunctions:

InterfacebetweenfoetusandmotherfornutrientexchangeImmunologicalbarrierEndocrine

NutrientandWasteExchangeFunctions

Theprimarypurposeoftheplacentaisdiffusionofnutrientsandoxygen,andremovalofwaste.

Aswiththelung,diffusionisdependentonFick'sPrinciple,i.e.:

,where:

=Flowofsubstanceacrossthemembrane

=Areaofthemembrane

=Diffusionconstantforthesubstance,whereMolecules<600Dainsizemorereadilydiffusedownconcentrationgradients

=ConcentrationdifferenceacrossthemembraneMaternalplacentalflowis~600mL.min atterm-doublethatoffoetalflow-whichimprovesdiffusionbyincreasingtheconcentrationgradientforsolutes

=Thicknessofthemembrane

O Diffusion

Attheendofpregnancy,PO forfoetalblood:

Enteringtheplacentaviatheumbilicalarteryis18mmHg(SpO245%)Leavingtheplacentaviaumbilicalveinis28mmHg(SpO270%)

ThefoetusisabletohaveadequatedeliveryofO despitethelowPO forfourreasons:

HighCardiacIndexIncreasedcardiacoutputincreasesDO .

FoetalHbContainstwogammasubunitsinsteadofbetasubunits.Thesepreventthebindingof2,3-DPG,whichresultinaleft-shiftedOxy-Haemoglobindissociationcurve,favouringoxygenloadingatalowPaO .

Foetal[Hb]is50%greaterthanmaternal[Hb]

TheDoubleBohreffect:

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TheBohreffectstatesthatanincreaseinPaCO right-shiftstheoxyhaemoglobindissociationcurve.Conversely,theaffinityofHbforO increasesinalkalaemia.ThedoubleBohreffectdescribesthishappeninginoppositedirectionsinthefoetalandmaternalcirculations,favouringtransferofO tothefoetus:

Intheplacenta,foetalCO diffusesintomaternalblooddownitsconcentrationgradientThismakesfoetalbloodrelativelyalkaline,andmaternalbloodrelativelyacidic.Therefore:

O unloadingofmaternalbloodisfavouredO loadingoffoetalbloodisfavoured

CO Diffusion

CO isextremelylipidsoluble,andsopasseseasilyacrossmembranes.FoetalPaCO is~50mmHg,andintervillousPCO is~37mmHg.CO offloadingisfavouredinthefoetusby:

AhighFoetal[Hb]increasestheamountofCO thatcanbecarriedascarbaminohaemoglobinTheDoubleHaldaneeffect:TheHaldaneeffectstatesthatdeoxygenatedHbbindsCO withmoreaffinitythanoxygenatedHb.ThedoubleHaldaneeffectdescribesthishappeninginoppositedirectionsinthematernalandfoetalcirculations,favouringCO transfertothemother:

AsmaternalbloodreleasesO ,thisfavoursmaternalloadingofCO withoutanincreaseinmaternalPCO (Haldaneeffect)ThereleaseofCO fromthefoetalHbfavoursO loading,whichinturnfavoursfurthermaternalO release.

NutrientDiffusion

Inlatepregnancy,foetalcaloricrequirementsarehigh(approximatelythesameasthemother).Facilitateddiffusionofglucoseviacarriermoleculesoccursintrophoblasts.

Activetransportoccursforaminoacids,Ca ,Fe,folate,andvitaminsAandC.Othertransportersactivelyremovesubstancesfromfoetalcirculation.

ImmunologicalFunction

TheplacentaisselectivelypermeabletoIgGviapinocytosis,whichallowsmaternalantibodiestoprovidepassiveimmunitytothefoetus.

EndocrineFunction

Synthesises:

βHCGhPLOestriol

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Progesterone

Development

Theplacentadevelopssimultaneouslyfromfoetusandmother:

Fromtheuterinewall,themotherproducesbloodsinusesaroundthetrophoblasticcordsTheseinturnsendoutplacentalvilli

Thiscreatesasinusofmaternalbloodinvaginatedbymultiplefoetalvilli

Foetalvilliaresuppliedbytwoumbilicalarteriesandasingleumbilicalvein

MaternalsinusesarefilledfromtheuterinearteriesThematernalsinusesaresuppliedbyspiralarteries

PropertiesoftheDevelopingPlacenta

Thick(er)membraneimpairspermeabilityPlacentalmembranepermeabilityissmallinearly-to-midpregnancy,reachingmaximumat~34weeksSmallersurfacearea

PropertiesoftheMaturePlacenta

Thickmembrane-improvedpermeabilitySurfaceareaof14mWeightof~500gBloodflowof600mL.min attermFlowisreducedduringcontractionsduetoincreaseduterinepressureandalsowithα-adrenergicstimulation.

References

1. Hall,JE,andGuytonAC.GuytonandHallTextbookofMedicalPhysiology.11thEdition.Philadelphia,PA:SaundersElsevier.2011.

2. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.

Lastupdated2019-07-18

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GastricSecretionsDescribethecomposition,volumesandregulationofgastrointestinalsecretions

TheGITproducesaanumberofsubstanceswhichcanbeclassifiedbyregionandfunction:

SalivaH O(98%)Digestiveproteins

AmylaseLipaseMucinHaptocorrinBindsVitaminB12.

ImmunologicalproteinsLysozymeLactoferrinIgA

GastricDigestive

HClGastrinPepsinIntrinsicFactor

MucosalProtectionMucousHCO

SmallBowelDigestive

PancreaticLipaseAmylaseTrypsinogen

EndocrineSecretinSomatostatin

ControlofSecretionsSecretionoccursinthreephases:

CephalicThought/sight/taste/smelloffood,resultinginvagal-mediatedstimulustoreleasegastrin.Accountsfor~30%ofproduction.GastricStretchofthestomachstimulatesHClsecretionandgastrinrelease.Accountsfor~50%ofproduction.IntestinalAdropinpHoftheproximalduodenumreleasessecretintostimulatetheexocrinepancreas.

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SalivarySecretions

Approximately1Lofsalivaisproducedbytheparotid,submandibular,andsublingualglandseachday.

Salivahasfourmainfunctions:

LubricationMucin

DigestionAmylaseLipaseParticularlyimportantinneonateswhoproducelittlepancreaticlipase.

NeutralisationofacidForprotectionpriortovomiting.Antibacterial

GastricSecretions

Thestomachproduces~2Lofsecretionsperday:

AcidsecretionParietalcellscontainanH -K exchangepump.

H isproducedbycarbonicanhydraseonCO andwater,with'waste'HCO removedfromthecellinexchangeforCl .

HighlevelsofacidproductionresultinlargeamountsofbicarbonatebeingsecretedintobloodThiscreatesanalkalinetideasportalvenouspHincreasesdramaticallyRespiratoryquotientofthestomachmaybecomenegativeduetoconsumptionofCO

ThispumpisactivatedinresponsetoincreasedlevelsofintracellularCa fromstimulationby:AChHistamine(H )Gastrin

Inhibitedby:LowgastricpHSomatostatin

GastricGastinisapeptidefamilysecretedfromantralGcells.

Secretionisstimulatedby:Neural(vagal)stimulationinthecephalicphaseofdigestionMainmechanism.ProteinandaminoacidsinthestomachDrugs

AlcoholCaffeine

Secretionisinhibitedby:LowpHSecretinGlucagon

Gastrinhasanumberofpro-digestiveeffects:StimulatesgastricacidsecretionStimulatespancreaticsecretion

+ ++

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StimulatesbiliarysecretionIncreasesgastricandintestinalmotility

PepsinogensChiefcellssecretepepsinogenIandisreleasedbyAChorβstimulation.Pepsinogeniscleavedtopepsininthegastriclumen,andbreaksdownprotein.

IntrinsicFactorParietalcellsproduceintrinsicfactor,whichformsacomplexwithB whichfacilitatesitslaterabsorptionintheterminalileum.

MucousNeckcellsproducemucopolysaccharide,glycoprotein,andHCO inresponsetostimulusbyprostaglandins,whichprotectsmucosaandlubricatesfood.

PancreaticSecretionsExocrinepancreaticsecretionsareproducedbytheacinarandductalcells,attherateof1.5Lperday.

Releaseisstimulatedby:CCKSecretinAChViavagalstimulation.

Consistof:HCOToalkalinisegastriccontents.

PancreaticbicarbonateproductionlowersvenouspH,andneutralise'sthealkalinetideofthestomach.WaterEnzymes

TrypsinogenProteolysis.AmylaseHydrolysisofglycogen,starch,andcomplexcarbohydrate.LipaseHydrolysisofdietarytriglycerides.

EndocrineFunctionCholecystokinin(CCK)isapeptidefamilysecretedbyintestinalenteroendocrinecells(Icells)inthemucosaoftheduodenumandjejunum.Cholecystokinin:

RegulatessatietyRegulatesleptinreleasefromfatStimulatessecretionsfromthegallbladderandduodenum

Secretinstimulatespancreaticrelease.Secretinis:ReleasedbytheproximalduodenuminresponsetolowpH

Motilinstimulatesthemigratingmotorcomplex.Motilinis:ReleasedcyclicallyfromMcellsinthesmallbowel

References

1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.

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OesophagusDescribethecontrolofgastrointestinalmotility,includingsphincterfunction.

Theoesophagusisamusculartubeconnectingthepharynxtothestomach.Theoesophagushas:

SkeletalmuscleinitsupperthirdSmoothmuscleinitslowerthird

LowerOesophagealSphincterTheLoSis:

Themostdistal2-4cmoftheoesophagusMacroscopicallyindistinguishablefromtherestoftheoesophagus

HoweverithasahigherconcentrationofnervecellsandisabletoconstrictatahigherpressureTonicallyinnervatedbythevagusImportantinthepreventionofrefluxCompetencyoftheLoSisrequiredtopreventreflux

Barrierpressureisthepressuredifferencebetweenthepressureattheloweroesophagealsphincterandthepressureinthestomach,andistypically~15-25mmHgBarrierpressureisaffectedby:

ChangesinloweroesophagealsphincterpressureSwallowingBarrierpressuredecreasesduringswallowing,andtransientlyincreasesimmediatelyafterwards.Anatomical

AgeSphinctertoneisdecreasedinneonatesandtheelderly.DiaphragmAnexternalsphincterisformedbythediaphragmaticcrura,andexertsapinch-cockactionontheoesophagus.StomachAfoldinthestomachwalljustdistaltotheGOJcreatesaflapvalve,whichoccludestheGOJwhengastricpressurerises.OesophagusTheoesophagusentersthestomachatanobliqueangle,limitingretrogradeflow.

HormonalGastrin,motilin,α-agonismincreaseLoStoneProgesterone,glucagon,vasoactiveintestinalpeptide(VIP)decreaseLoStone

DrugsETOH,IVandvolatileanaestheticagents,andanticholinergicsdecreaseLoStoneSuxamethonium,metoclopramide,andanticholinesterasesincreaseLoStone

ChangesingastricpressureRaisedintraabdominalpressure

ObesityPregnancy

DiseaseHiatusherniaGOJmovesintothethorax,causing:

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Lossofpinch-cockactionNegativeintrathoracicpressurereducesLoSpressureandthereforebarrierpressure

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References

1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.2. ANZCAJuly/August19993. KahrilasPJ,PandolfinoJE.Hiatushernia.GIMotilityonline.2006.4. ANZCAAugust/September2015

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ControlofGastricEmptyingDescribethecontrolofgastrointestinalmotility,includingsphincterfunction.

Gastricemptyingisaneurallyandhormonallymediatedprocesswhichaimstopresentfoodtothesmallbowelinacontrolledmanner.Differentdrugs,hormones,andphysiologicalstatescaneitherencourageorinhibitgastricemptying.

DeterminantsofGastricEmptying

Rateofgastricemptyingisafunctionof:

AntralpressureMaindeterminantaspyloricresistancetendstobelow,andisaffectedby:

StomachDuodenumSystemicfactorsDrugs

Pyloricresistance

Stomach

GastricdistensionVagalexcitationfromgastricstretchcausesreleaseofgastrin,increasingperistalticfrequency.Compositionofchyme:

LiquidsemptyfasterthansolidsLiquidshaveahalf-timeof~20minutes,andemptyinanexponentialfashionSolidshaveahalf-timeof~2hours,withadwelltimeof~30minutes,andemptyinalinearfashion

Proteinindependentlystimulatesgastrinrelease

Duodenum

Theduodenumhashormonalmechanismswhichhaveanegativefeedbackongastricemptying.Theseinclude:

DuodenaldistensionHypoosmolarandhyperosmolarchymeAcidicchymeInresponsetoacidtheduodenumreleasessecretinandsomatostatin:

SecretindirectlyinhibitsgastricsmoothmuscleSomatostatininhibitsgastrinrelease

FatandproteinFatandproteinbreakdownproductsstimulatereleaseofcholecystokinin,whichinhibitsgastrin.

Carbohydrate-richmealsemptyfasterthanprotein,whichemptyfasterthanfat.

Systemic

Motilinreleasedbythesmallbowelenhancesthestrengthofthemigratingmotorcomplex,aperistalticwaveofcontractionthroughthewholeGITwhichoccursevery60-90minutesSympatheticinputfromthecoeliacplexusinhibitsgastricemptyingPregnancyhasanumberofeffectsongastricemptying:

ProgesteronerelaxessmoothmuscleandinhibitsgastricsmoothmuscleresponsetoAChandgastrin,aswellascreating

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incompetenceoftheLoSleadingtoGORDGastrinproductionincreasesSomegastrinisproducedbytheplacenta.Gastricacidproductionisincreasedduringthethethirdtrimester

Parasympatheticinputenhancesgastricmotility

Effectofdrugs

Drugswhichincreasegastricemptyinginclude:

MetoclopramideErythromycin

Drugswhichinhibitgastricemptyinginclude:

OpioidsAlcoholAnticholinergicagents

References

1. CICMJuly/September20072. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.

Lastupdated2019-07-18

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SwallowingDescribethecontrolofgastrointestinalmotility,includingsphincterfunction

Swallowingisdividedintothreephases:

OralPhaseVoluntaryFoodispushedagainsthardpalatebytongue

PharyngealPhaseInvoluntaryCoordinatedbymedulla.ClosureofnasopharynxAdductionofvocalcordsHyoidelevationanddeflectionofepiglottisPharyngealcontractionPropelsfoodbolustowardsoesophagus

OesophagealphaseInvoluntaryClosureofUoSRestingbarrierpressure100mmHg.RelaxationofLoSRestingbarrierpressure20mmHg,whichisabalancebetween:

LoSpressure(30mmHg)Antralpressure(10mmHg)

Oesophagealperistalsis

Impairmentofanyoftheseprocessesincreasesriskofaspiration:

ObtundationReducedcoughreflex.MuscularweaknessImpairedmedullarycoordination

References

1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.

Lastupdated2019-07-18

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PhysiologyofVomitingDescribethecontrolofgastrointestinalmotility,includingsphincterfunction

Vomitingistheactive,forcefulexpulsionofgastriccontentsfromthestomach.Itisdifferentfromregurgitationwhichisapassiveprocess.

ItisamechanismtoexpeltoxicsubstancesfromtheGIT.

StimulationStimulantstovomitingcanactcentrally,ordirectlyinthebowel:

CentralstimulationCentralstimulimayactdirectlyonthevomitingcentre.OthersactviatheCTZ,whichispartoftheareapostremalocatedoutsideoftheblood-brainbarrier,andsoitcanbestimulatedbycirculatingsubstances.Centralvomitingstimuliinclude:

Direct:EmotionPainOlfactoryVisual

ViatheCTZ:Vestibularactingon:

HACh

Drugs/Toxinsactingon:5-HTDμ-opioidreceptors

GITstimulationGITstimulitravelSNSandPNSafferentstothevomitingcentre.TheCTZisnotinvolvedandsoanti-emeticswhichactherearenotusefulinthistypeofvomiting.

GITvomitingstimuliincludedistensionandtoxins.Neurotransmittersinclude:

5-HT inmucosalstretchreceptorsAChinNTSafferentsH inNTSafferents

PostoperativeNauseaandVomiting

Centralstructuresinvolvedinclude:

ChemoreceptortriggerzoneNTSMultiplepathwaysexist(similartothosedescribedabove),andneurotransmittersinvolvedinclude:

5-HTDNKHmACh

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RiskfactorsPatientfactors

FemaleNon-SmokerYoungageHistoryofPONVormotionsickness

AnaestheticfactorsVolatileuseNitrousoxideuseRelativeriskof1.4.OpioiduseAnaesthesiaduration

SurgicalfactorsGynaecologicalsurgeryLikelynotanindependentriskfactor,andsimplyconfoundedbyfemalegender.Strabismussurgeryinchildren

Processofvomiting

Vomitingconsistsofasetofprocessescoordinatedbythevomitcentreinthemedullaoblongata,andisdividedintothreephases:

Pre-ejectionphaseProdromalnauseaSalivationRetrogradeintestinalcontractionwhichforcesintestinalcontentsintothestomach

RetchingPhaseDeepinspirationandbreath-holdingtosplintthechestEpiglotticclosureElevationofthesoftpalate(preventsnasalsoiling)

ExpulsivephaseRelaxationofoesophagealsphinctersPyloriccontractionViolentcontractionofthediaphragmandabdominalmuscles

References

1. BrandisK.ThePhysiologyViva:Questions&Answers.2003.2. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.3. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.4. PierreS,WhelanR.Nauseaandvomitingaftersurgery.ContinuingEducationinAnaesthesiaCriticalCare&Pain,Volume

13,Issue1,1February2013,Pages28–32.

Lastupdated2019-07-18

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FunctionsoftheLiverDescribethestorage,synthetic,metabolicandexcretoryfunctionsoftheliver

Storage

Theliverisimportantinstorageandreleaseof:

CarbohydratesasglycogenTheadultliverstores~100gofglycogen.FatastriglyceridesAllfat-solublevitamins(A,D,E,K)ManywatersolublevitaminsincludingfolicacidandBIronCopper

Synthetic

Syntheticfunctionsinclude:

BileproductionPlasmaproteinsincluding:

ClottingfactorsAlbuminproduction120-300mg.kg ofalbuminisproducedperday,dependentonnutritionalstatus,plasmaoncoticpressure,andendocrinefunction.

MetabolicMetabolicfunctionsinclude:

CarbohydrateFatProteinBilirubinmetabolismDrugsandToxins

Carbohydrates

MonosaccharidesanddisaccharidespassivelydiffuseintohepatocytesGradientismaintainedbyconvertingglucosetoglucose-6-phosphatewhichisusedtoproduceglycogen.Thismaintainsthegradientfordiffusion.Glycogeniseithersynthesised(glycogenesis)orbrokendown(glycogenolysis)dependingonplasmaglucoseandinsulin:

Increasedbloodglucosestimulatesinsulinrelease,increasingtheformationofglycogenthroughactivationofglycogensynthetaseDecreasedbloodglucosestimulatesglycogenolysisandgluconeogenesisfromaminoacids.

Lipids

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Fatcanbe:StoredastriglyceridesHydrolysedtoglycerolandfattyacids,whichisusedforATPproduction

ProteinsandUrea

Aminoacidsareabsorbedfrombloodtobeusedforgluconeogenesisandforproteinsynthesis.InordertoproducesubstratesfortheCAC,Aminoacidsmaybe:

TransaminatedDeaminatedDecarboxylated

Thenitrogenousscrapofthesereactionsisurea,whichisproducedinseveralstages:

AvarietyofmetabolicprocessesconvertaminoacidstoglutamateGlutamateisconvertedtoammoniabyglutamatedehydrogenaseAmmoniathenenterstheureacycletoproduce(surprisingly)urea,atthecostof3ATP

Anormaldietof100gproteinperdayproduces~30gofurea,and1000mmolofhydrogenions

Endocrine

ProducesangiotensinogenProducesIGF-1ConvertsT4toT3

Immunoprotective

KupffercellsTissuemacrophagesofthehepaticreticuloendothelialsystem.Theyphagocytoseharmfulsubstancesincluding:

EndotoxinsBacteriaVirusesImmunecomplexesThrombinFibrincomplexesTumourcells

Acid-BaseBalance

Mayproduceorconsumelargenumbersofhydrogenions:

CarbondioxideproductionMetabolismoforganicacidanions

LactateKetonesAminoacids

AmmoniumProductionofplasmaproteinsNotablyalbumin

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References1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.3. BrandisK.ThePhysiologyViva:Questions&Answers.2003.

Lastupdated2019-07-18

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LaboratoryAssessmentofLiverFunctionDescribethelaboratoryassessmentofliverfunction

SyntheticFunction

Measuresofsyntheticfunctioninclude:

AlbuminMainplasmaprotein.

Normalrange28-58g.LHalf-life~20daysImportantin:

MaintenanceofplasmaoncoticpressureBinding

CalciumDrugs

Decreasedinliverdysfunctionandmalnutrition

CoagulationAssaysClottingfactorsareproducedbytheliver.Hepaticimpairmentmayresultinreducedproductionandabnormalityofclottingassays,althoughfunctionalclottingfunctionmaybenormal(aspro-coagulantproteinsareaffectedtoasimilarextent).

INRTestoftheextrinsicpathway.APTTTestofintrinsicpathway.

MetabolicFunctionTransaminasesarereleasedwhenliverparenchymaisdamaged,andareusedtoevaluatemetabolicfunction:

ALTNormalrange<54U.L .ASTNormalrange<35U.L .

ObstructiveTests

ALP(AlkalinePhosphatase)Enzymeinvolvedindephosphorylationofmanycompounds.ALPisfoundinallcells,butparticularlyintheliver,bileduct,bone,kidney,andplacenta.

Normalrangeis30-120U.LGGTEnzymefoundinbiliaryduct.

Normalrange:Males:11-50U.LFemales:7-30U.L

Bilirubin

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Byproductofhaemoglobinmetabolism.Maybemeasuredastotal,orasconjugatedandunconjugatedbilirubin.

References1. Diaz,A.Outlinetheclinicallaboratoryassessmentofliverfunction.PrimarySAQs.

Lastupdated2019-07-18

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BileDescribethephysiologyofbileanditsmetabolism

Bileisadarkgreensolutionproducedbythelivertofacilitateabsorptionoffatandfat-solublevitamins(ADEK)throughemulsification.Bileis:

Producedbytheliverattherateof1LperdayConcentratedinthegallbladderImportantintheabsorbanceoflipidandfat-solublevitaminsFormedfrom:

WaterProteinBilirubinBilesaltsThesodiumandpotassiumsaltsofbileacids.Bileacids:

AreareproducedfromcholesterolAreamphipathic,andactasemulsifiersoflipidBreakuplargefatglobulesintosmallermicelles,whichcanthenbeabsorbed.Majorbileacidsinclude:

CholicacidChenodeoxycholicacid

Areabsorbedintheterminalileum,andrecycledbytheportalcirculationLipidsElectrolytes

References1. Hall,JE,andGuytonAC.GuytonandHallTextbookofMedicalPhysiology.11thEdition.Philadelphia,PA:Saunders

Elsevier.2011.2. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.

Lastupdated2019-07-18

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ErythrocytesOutlinethephysiologicalproductionofbloodanditsconstituents

Erythrocytes:

Are7.5μmindiameterAre2umthickHavealifespanof120daysHave:

NonucleusMaximisescellvolumeavailableforHb.NomitochondriaCannotperformaerobicmetabolism-allATPisgeneratedviaglycolysis.NoribosomesIncapableofproducingprotein

HaveabiconcavediscshapeThismaximisessurfacearea(optimisinggastransfer)andmakesthecellsflexibleenoughtopassthroughcapillarybeds(whicharenarrowerthanthecell).Areimportantin:

DeliveringO tothetissuesanddeliveringCO tothelungsAcid-BasebalanceMetabolismofsomedrugs

Carry~29pgofhaemoglobinComprise40-50%ofbloodvolume

ProductionErythrocyteshaveamyeloidprogenitorwhichdifferentiatesintothemyeloidline.EPO(seeendocrinefunctionsofthekidneystimulatesmyeloidprogenitorcellsto:

DifferentiateProliferate

ProerythroblastsbeginsynthesisofHb,withongoingproductionoccurringuntilthecellismatureFurtherdifferentiationresultsinsuccessivelossoforganelles,increasingHbcontentThelossofribosomesandnucleusofthereticulocytearethefinalstageoferythropoiesisTheentireprocesstakes~7-10days

FunctionGasCarriageAcid-BaseBuffering

ProductionofHCOBindingofH toHb

MetabolismEsterases(andother-ases)inerythrocytesmetabolisemanydrugs,including:

RemifentanilSNP(reactswithHbtoformNO,CN,andMet-Hb)Esmolol

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Elimination

Oldredcellsareremovedfromcirculationvia:

Phagocytosisbymacrophagesin:SpleenMajormechanism.LiverBonemarrow

Haemolysis~10%ofredcellbreakdownoccursincirculation,wheretheHbdimersarethenboundtohaptoglobinbyhaemopexin.

Thisisimportanttopreventglomerularfiltrationofhaeme,andlossofiron

HaemoglobinMetabolism

Haemoglobinisbrokendowninto:

GlobinBrokendownintoconstituentaminoacids.IronRe-entershaemoglobinsyntheticpathway.HaemeComplexmetabolicpathway,notableasitistheonlymetabolicprocessthatproducescarbonmonoxide:

MetabolisedtobiliverdinbysplenicmacrophagesinthereticuloendothelialsystemofthespleenCirculatingerythrocytesarephagocytosedbysplenicmacrophagesHaptoglobinbindscirculatingHb,theHb-Haptoglobincomplexisthenphagocytosedbysplenicmacrophages

BiliverdinisreducedtounconjugatedbilirubinThisisfatsoluble,andbindstoalbumin.UnconjugatedbilirubinisconjugatedinthelivertoconjugatedbilirubinConjugatedbilirubinissecretedinbilebyactivetransportThisisimpairedduringhepaticdisease,leadingtoincreasedbilirubinlevelsinplasma.SecretedconjugatedbilirubinismetabolisedtourobilinogenbygutbacteriaUrobilinogenmayhaveanumberoffates:

Enterohepaticrecirculationandeliminationinbile(again)FurthermetabolismbygutbacteriatostercobilinogenandthentostercobilinEnterohepaticrecirculationandurinaryexcretion,whereitisoxidisedtourobilin

InDisease

Blood Urine Faeces

Prehepaticdisease ↑Unconjugatedbilirubin ↑Urobilinogen,

bilirubinnotpresent Normal

Intrahepaticdisease

↑Conjugatedbilirubin,↑Unconjugatedbilirubin Bilirubinpresent Maybepaleduetodecreased

urobilinogenexcretedinbile

Posthepaticdisease ↑Conjugatedbilirubin ↓Urobilinogen,

bilirubinpresent Pale

References

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1. BarrettKE,BarmanSM,BoitanoS,BrooksHL.Ganong'sReviewofMedicalPhysiology.24thEd.McGrawHill.2012.

Lastupdated2019-07-18

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IronHomeostasisDescribethenormalnutritionalrequirements

Approximately3-5gofironisfoundinthebodyas:

Oxygen-carryingglobinmoleculesHaemoglobin(~70%)andmyoglobin(~5%).Catalystforbiologicalreactions(~25%)Catalase,peroxidase,andcytochromesallrequireiron.

AbsorptionDietaryironcomesintwoforms:

HaemegroupsDirectlyabsorbedviaspecialisedtransportproteins.Dietaryironsalts

Ferrous(Fe )ironissoluble,andisabsorbedviafacilitateddiffusionacrosstheenterocytemembraneReducedacidityofthestomachwillreducetheabsorptionofferrousiron

Ferric(Fe )ironprecipitateswhenpH>3,andsocannotbeabsorbedindependentlybythesmallbowel.Apathwaymayexistforabsorptionofferricironfromsolublechelates

Onceintheenterocyte,ironcanbe:Stored,boundtoferritinTransportedviaferroportinoutoftheenterocyte,whereitisthenoxidisedtoferrousironandboundtotransferrin

RegulationExcretionisuncontrolledRegulationofironlevelsisonlybyabsorptionHepcidinisaliverproteinwhichinhibitstheactionofferroportin

HighhepcidinpreventsirontransportfromtheenterocyteHepcidinisdeficientinhaemochromatosis

References

1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.

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PlateletsOutlinethephysiologicalproductionofbloodanditsconstituents

Describetheprocessandregulationofhaemostasis,coagulationandfibrinolysis

Plateletsaresmallcellfragmentswhicharevitalinhaemostasisviaformingaplateletplug.They:

Havealifespanof7-10daysAreremovedbythereticuloendothelialsysteminthespleenandliver

Production

Plateletsare:

Anuclearcirculatingcellbodies,whichbudfrommegakaryocytesAsthemegakaryocytecellvolumeincreases,thecellmembraneinvaginatesandsmallplateletsbudoff.

Thetimefromstemcelltoplateletis~10days,andisstimulatedbythrombopoietinNewplateletsareheldinthespleenfor36hoursuntiltheymature

Contentsα-granulesContainfibronectin,fibrinogen,vWF,PDGF,andThrombospondin,plateletfactor4.δ-granulesContain5-HT,ATP,ADP,andCa .ContractileproteinsFacilitateplateletdeformationwhenactivated.

ActivationPlateletsareactivatedby:

CollagenExposedbydamagedendothelium.AdrenalineADPThrombin

Activationresultsinseveralevents:ExocytosisofgranulesActivationofmembranephospholipaseA toformthromboxaneADeformationfromadisctoaspherewithlongprojectionsPromotionofthecoagulationcascadeChangeinglycoprotein(GP)expressionbytheactionofADP:ADPantagonists(e.g.clopidogrel)preventexpressionoftheGPIIb/IIIacomplex.

GPIb/IIb/IIIafacilitateplateletattachmenttovWFvWFalsobindstosub-endothelialconnectivetissue.GPIIb/IIIaarealsoreceptorsforfibrinogen,whichencouragesplateletaggregation

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References

1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. KraftsK.ClotorBleed:APainlessGuideforPeopleWhoHateCoag.PathologyStudent.

Lastupdated2019-07-18

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TransfusionUnderstandingtheadverseconsequencesofbloodtransfusion,includingthatofmassivebloodtransfusion

ProductionandStorageofBloodProducts

Redcells,platelets,andFFPhavedifferentstoragerequirements.

RedBloodCells

Storedblooddecaysovertime-thisisknownasastoragelesionPreservativesareusedtoextendthetimebloodcanbestored:

Keptat~4°C(balancebetweenfreezingandbeingtoowarm)ReducescellularmetabolicrequirementInhibitsbacterialgrowth

CollectedinanasepticfashionStoredinspecialsolutions:

SAGMiscurrentlyusedbytheAustralianRedCross:SalineAdenineSubstrateforATPsynthesisGlucoseSubstrateforRBCglycolysisMannitol

CPDA1(citrate-phosphate-dextrose-adenine)wastraditionallyusedCitratebindscalcium,preventingclottingPhosphateactsasabufferandphosphatesourceformetabolismDextroseAdenine

Astoragelesiondescribesthechangesthatoccurinstoredblood:Lossof2,3DPGLessofafactorinCPDA1blood.HaemolysisHyperkalaemiaTypicallynotclinicallyrelevantaspotassiumistakenupintoredcellswhenmetabolismresumes.AcidaemiaHyponatraemiaNotclinicallysignificant.

Bloodcanbestoredforupto35days,whichcorrespondsto70%survival

Platelets

Plateletsrequireparticularstorageconditionstoremainfunctional:

Temperature~22°CBelowthis,plateletsdeformandbecomenon-functionalGasexchangePlateletsarestoredinabagwhichallowsgasexchangetooccur,minimisinglacticacidandcarbondioxideproduction

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AgitationPlateletsarestoredonanagitatorwhichpreventsclottingandensurestheplateletsarewellmixed,whichmaximisesthediffusiongradientforgasexchangepHcontrolpHiskeptbetween6.2to7.8topreventdegranulation.

Asplateletsdonotcontainantigen,thereisnotastrictrequirementforplateletstobetypematched.However:

Rh(+)plateletsshouldbeavoidedinRh(-)patientsThesmallamountofcontaminatingredcellsmayprecipitaterhesusdisease.Plasmaincompatibilityshouldbeavoidedasthismayleadtohaemolysisofrecipientredcells

Childrenareatgreaterriskduetotheirproportionallysmallerbloodvolume

FreshFrozenPlasma

FreshFrozenPlasmais:

Preparedeithervia:SeparationfromwholebloodApheresisRemovalofalargevolume(typically800ml)ofplasmafromasinglepatient,withreturnofredcellstothedonor.

Oncecollected,itisfrozenandre-thawedinawaterbathpriortouse

Cryoprecipitate

CryoprecipitateispreparedbyremovingtheprecipitatefromFFPwhichformsat1–6°C.Cryoprecipitatecontainspredominantly:

FibrinogenFibronectinvWFFactorVIIIFactorXIII

WholeBlood

Wholebloodundergoesadditionalchanges:

Whitecellsbecomenonfunctionalwithin4-6hoursofcollection,thoughantigenicpropertiesremainPlateletsbecomenon-functionalwithin48hoursofstorageat4°CFactorlevelsdecreasesignificantlyafter21days

BloodGroups

Bloodgroupsrefertotheexpressionofsurfaceantigensbyredbloodcells,aswellasanyantibodyinplasma.Bloodgroupscanbedividedintothreetypes:

ABORhesusOtherantibodiesTheseareadditionalantibodiesthatapatientmayexpressinplasma,andincludeKell,Lewis,Duffy,etc.

ABO

TheABObloodgroupis:

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Acomplexcarbohydrate-basedantigensseriesThesemaybeeitherAorBantigen,andpatientsmayexpressone,both,orneither,givingfourbloodgroups(A,B,AB,O).ExpressedontheH-antigenstemofRBCs,andonthesurfaceoftissuecells.

TheBombayBloodGroup(orhhorOhgroup)describesindividualswhodonotexpresstheHantigenTheseindividuals:

Don'texpressA-orB-antigen(asthereisnoH-antigenstem)andare'universaldonors'ExpressH-antibodyCanonlyreceivebloodfromotherindividualswiththeBombayphenotype

IndividualsexpressIgMantibodytoforeignbloodgroupsThisdevelopswithin6monthsofbirth,likelyduetoenvironmentalexposuretosimilarantigens.AssociatedwithaseverehypersensitivityreactionifanABO-mismatchoccurs

Group RBC Plasma

A A-antigen B-antibody

B B-antigen A-antibody

O - A-antibodyB-antibody

AB A-antigenB-antigen -

Rhesus

TheRhesusbloodgroupisthenextmostimportantgroupafterABO.TheRhesussystem:

Consistsof~50differentantigens,themostimportantofwhichisDRhesusstatusisthereforeexpressedaspositive(D-85%ofthepopulation)ornegative(anything-but-D).RhesusantibodydoesnotnaturallyoccurinRh(-)individuals

ThisisrelevantinRhesusdiseaseARh(-)motherexposedtoRh(+)bloodwilldevelopAnti-Dantibody,whichcancrossplacentaandinduceabortioninafutureRh(+)foetus.Thiscanoccurwith:

IncompatibletransfusionFoetal-maternalhaemorrhage

CompatibilityTestingDonorbloodmustbetestedwithrecipientbloodtoavoidatransfusionreaction.Thisinvolvesthreeprocesses:

BloodTyping(ABO/Rh)Bloodistypedbymixingitinvitrowithplasma(andplasmawitherythrocytes)ofknowngroups(containingIgMantibody(Anti-A,Anti-B,Anti-AB)),andobservingforagglutination.AntibodyScreenForotherantibodies.

TestingissimilartoABOscreening,exceptplasmaismixedwithredcellscontainingknownantigen(e.g.Kell,Duffy),andmonitoredforagglutination.

Cross-matchInvolvestwoprocesses:

SalinetestErythrocytesaresuspendedinsalineandmixedwithantibodiesatroomtemperature,monitoringforagglutination.

ThisconfirmsABOtypeIndirectCoombs'test

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IdentifiesIgGantibodyinhostplasmawhichwouldcausehaemolysisoftransfusedredcells.Thisistypicallynolongerdone,asitoffersnegligibleextrasafetyovertheaboveprocesses.Doingitinvolves:

IncubatingBindsIgGAbtoantigenonRBCmembrane.WashingRemovesserumandunboundIgG.TestingwithanantibodytoIgG,knownasantiglobulinserum.

Apositivetestwillcauseclumpingofredcells,aseachantiglobulinserumwillbindtwoIgGmolecules,whichhaveinturnbeenboundtoredcellsAnegativetestwillcausenoagglutination,astheIgGhasnotbeenboundtoredcells

Ifnegative,theantiglobulinserumisre-usedonacontrolsampletoensurethatitisnotafalsenegative

TransfusionReactions

Transfusionreactionscanbeclassifiedaseitheracute(<24hours)ordelayed(>24hours),andasimmunologicalornon-immunological.

ImmunologicalAcuteReactions

Reaction Incidence Mechanism

ABOMismatch 1:40,000 ABOincompatibilitycausingrapidintravascularhaemolysis,whichmaycausechest

pain,jaundice,shock,andDIC.RhD-reactionstendtocauseextravascularhaemolysis.

Haemolytic(acute)

1:76,000(1:1.8millionfatal)

Immunologicaldestructionoftransfusedcells(TypeIIhypersensitivity).Presentswithfever,tachycardia,pain,progressingtodistributiveshock

Febrile,non-haemolytic

~1:100Cytokinereleasefromstoredcellscausingamildinflammatoryreaction,withtemperaturerisingto≥38ºCor≥1ºCabovebaseline(if>37ºC).Benign-butrequiresexclusionofahaemolyticreaction.

Urticaria 1:100 Hypersensitivitytoplasmaproteinsinthetransfusedunit

Anaphylaxis 1:20,000 TypeIhypersensitivityreactiontoplasmaproteinintransfusedunit

TRALI Variable DonorplasmaHLAactivatesrecipientpulmonaryneutrophils,causingfever,shock,andnon-cardiogenicpulmonaryoedema

Non-ImmunologicalAcuteReactions

Reaction Incidence Mechanism

MassiveTransfusionComplications Variable Seebelow

Non-immunemediatedhaemolysis Rare DuetophysicochemicaldamagetoRBCs(freezing,devicemalfunction).

Mayleadtohaemoglobinuria,haemoglobinaemia,tachycardiaandfevers.

Sepsis

1:75,000(platelets),1:500,000(RBC)

Contaminationduringcollectionorprocessing.Mostcommonorganismsarethosewhichuseironasanutrientandreproduceatlowtemperatures,e.g.YersiniaPestis.

TransfusionRelatedCirculatoryOverload(TACO)

<1:100Rapidincreaseinintracellularvolumeinpatientswithpoorcirculatorycomplianceorchronicanaemia.MayresultinpulmonaryoedemaandbeconfusedwithTRALI.

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DelayedImmunologicalReaction

Reaction Incidence Mechanism

Delayedhaemolytictransfusionreaction 1:2,500 Developmentofsensitisationwiththereactionoccurring2-14days

afterasingleexposure.TypicallyKidd,Duffy,Kellantibodies.

Post-transfusionPurpura Rare AlloimmunisationtoHumanPlateletAntigencausingsuddenself-

limitingthrombocytopenia

TA-GVHD Rare TransfusedlymphocytesrecognisehostHLAaspositivecausingmarrowaplasia,withmortality>90%

Alloimmunisation1:100(RBCantigens),1:10(HLAantigens)

Previoussensitisationleadingtoantibodyproductiononre-exposure.

Transfusion-relatedImmuneModulation

Notknown Transientimmunosuppressionfollowingtransfusionpotentiallyduetocytokinereleasefromleukocytes

DelayedNon-ImmunologicalReaction

Reaction Incidence Mechanism

IronOverload

Chelationafter10-20units,organdysfunction50-100units

EachunitofPRBCcontains~250mgofiron,whilstaverageexcretionis1mg.day .

ComplicationsofMassiveTransfusion

Amassivetransfusionisonewhere:

Greaterthanone-halfofcirculatingvolumein4hoursWholecirculatingvolumein24hours

Riskofcomplicationfromamassivetransfusionisinfluencedby:

NumberofunitsRateoftransfusionPatientfactors

Complication Mechanism

Airembolism Inadvertentinfusion

Hypothermia Cooledproducts

Hypocalcaemia Consumptionwithcoagulopathyandboundtocitrateaddedtotransfusedunits

Hypomagnesaemia Boundtocitrateintransfusedunits

Citratetoxicity Citrateisaddedtostoredunitsasananticoagulant

Lacticacidosis Hyperlactataemiaduetoanaerobicmetabolisminstoredunits

Hyperkalaemia Potassiummigratesfromstorederythrocytesintoplasmawhilstinstorage

References

-1

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1. BloodService.Classification&IncidenceofAdverseEvents.AustralianRedCross.2. NationalBloodAuthority.PatientBloodManagementGuidelines.AustralianRedCross.3. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.

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HaemostasisDescribetheprocessandregulationofhaemostasis,coagulationandfibrinolysis

Haemostasisdescribesthephysiologicalprocessesthatoccurtostopbleeding.Itinvolvesthreeprocesses:

VesselconstrictionDecreasesflow,whichlimitsfurtherhaemorrhageandreducestheshearstresseswhichbreakupformingclotPlateletplugformationorPrimaryHaemostasisPlateletsadheretothedamagedvesselwallandaggregateFibrinformationorSecondaryHaemostasisFibrinisformedfromfibrinogen(viathecoagulationcascade),whichstabilisestheplateletplug

PrimaryHaemostasisFollowingavascularinjury,theexposureofsubendothelialproteinsstimulatesplateletstoformanocclusiveplugviaseveralprocesses:

AdhesionExposedcollagenbindstoGPIareceptoronplatelets.vWFalsobindstoplatelets.

ActivationMetabolicactivation,increasingPhospholipaseA andPhospholipaseC,increasingplateletintracellularCa andinitiatingatransformationfromadisctoaspherewithlongprojections.

Metabolicactivationisstimulatedby:CollagenAdrenalineADPThrombin

Additionally,plateletsreleaseADPandthromboxaneA fromtheiralphagranulesanddensebodies,amplifyingfurtherplateletaggregationandadhesion

AggregationWithotherplatelets-heldtogetherbyfibrin-formingaplug.

ContractionAftersometimeplateletscontract,retractingtheclotandsealingthewall.

SecondaryHaemostasis

Thecoagulationcascadeisanamplificationmechanismwhichactivatesclottingfactorsinordertoproducefibrin.

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Participatingfactorsinthecoagulationcascadecanbeeitherenzymesorcofactors:

Enzymescirculateintheirinactiveform,andbecomeactive(e.g.VII⇒VIIa)whenhydrolysedbytheirprecursorfactorCofactorsamplifythecascade

Pathways

Thecascadeisdividedintotheintrinsicpathwayandextrinsicpathway,whichjointoformthecommonpathway.Invitro,theintrinsicandextrinsicpathwaysoperateseparately.Thisisanartifactoflabmeasurement-invivothepathwaysareco-dependent.

ExtrinsicPathway

Theextrinsicpathwaycontainstwofactors,andtheprocessofactivationoccursinseconds:

TissueFactorMembraneproteinonsub-endothelialcells,whichisexposedwhenthevesselisdamaged(itisfoundinafewotherplacesaswell).ItbindstofactorVIItoformVIIa,andthusactivatestheextrinsicpathway.FactorVII

IntrinsicPathway

Theintrinsicpathwayisactivatedoverminutes,andcontains:

ContactfactorsOnlyimportantinvitrowhenconductinglabtesting-deficiencyofthesefactorsdoesnotcauseacoagulopathy.

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HMWKHMWKactivatesfactorXII.FactorXIIFactorXIIaactivatesfactorIX,asdoesthrombin.

FactorXIFactorIXFactorVIIIFactorVIIIcirculatesinacomplexwithvWF,preventingitfromdegradation.Whenactivatedbythrombin,itactsasacofactorforfactorIXatoactivatefactorX.

Theintrinsicpathwayisactivatedby:

ThrombinMainactivatoroftheintrinsicpathwayinvivo.CollagenGlassInvitro.

CommonPathway

Thecommonpathwaycontains:

FactorXFactorVCofactor(similartofactorVIII),whichwhenactivatedbythrombinallowsfactorXatoconvertprothrombinintothrombin.FactorII(prothrombin)Hasseveralkeyroles:

CleavesfibrinogentofibrinActivatesfactorXIIIFactorXIIIastabilisesclotbyformingcross-bridgesbetweenfibrininaplateletplug.AmplificationoftheclottingcascadebyactivatingfactorsVandVIIIActivatesproteinCThrombinbindswiththrombomodulintoformacomplexwhichinhibitscoagulation.

FactorI(fibrinogen)

TheCell-BasedModelofCoagulation

Thecascademodel(above)accuratelydescribestheprocessofclottinginvitro,butnotinvivoThecell-basedmodelhasseveralchanges,notingthecentralroleoftheplatelet:

InitiationphaseCoagulationbeginswithtissuefactorbeingexposed,whichalsoactivatesplatelets.AmplificationphaseApositivefeedbackloopoccurs:

ProductionofXacausesproductionofthrombin(IIa),primingthesystemThrombinthenactivatesfactorsV,VIII,andIX,acceleratingXaproductionandfurtherthrombingeneration

PropagationphasePlateletsbindactivatedclottingfactors,causinghighratesofthrombinformationaroundthem.

References

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1. KraftsK.ClotorBleed:APainlessGuideforPeopleWhoHateCoag.PathologyStudent.2. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.3. ClottingCascade22/4/2007.(Image).ByJoeD(Ownwork).CCBY3.0,viaWikimediaCommons.

Lastupdated2019-07-18

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HaemostaticRegulationDescribethemechanismsofpreventingthrombosisincludingendothelialfactorsandnaturalanticoagulants

Haemostasismustbecontrolledtopreventrampantclottingofthevasculartree.Thisinvolvesbothendothelialfactorsandproteins.

EndothelialRegulation

Intactendotheliumandtheglycocalyxpreventclottinginanumberofways:

MinimisestasisHighbloodflowEspeciallywhereflowisturbulent(largearteries).MaximiselaminarflowGlycocalyxsmoothsflow.

InhibitionofplateletadhesionandactivationNO,prostacyclin,andectonucleotidases(whichdegradeADP)inhibitplateletactivation.

Membrane-boundanticoagulantproteinsHeparan(notheparin)ActivatesantithrombinIII.ThrombomodulinBindsthrombin,preventingcleavageoffibrinogentofibrin.Thethrombin-thrombomodulincomplexactivatesproteinC(whichinturninactivatesfactorsVaandVIIIa).

PreventexposureofprocoagulantproteinCollagenvWFTissueFactor

tPAsecretion(see'ClotLysis')

ClotRegulation

EffectofbloodflowDilutesclottingfactorsActivatedclottingfactorsarewashedawayandmetabolisedbytheRES.LaminarflowCausesaxialstreamingofplatelets,minimisingendothelialcontactandchanceofactivation.fa

ActivationofanticoagulantfactorsTissueFactorPathwayInhibitorInhibitsVIIa,antagonisingtheactionoftissuefactorAntithrombinIIIInhibitstheserineproteases,i.e.thenon-cofactorfactorsinallthreepathways-IIa,VIIa,IXa,Xa,XIa,XIIa.ProteinCInactivatesproteinVaandVIIIa,andisactivatedbythrombin.ProteinSCofactorwhichhelpsproteinC.

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ClotLysis

Clotbreakdownisperformedby:

TissuePlasminogenActivator(tPA)Bindstofibrin,andthencleavesplasminogentoplasmin.Thiskeepstheplasminformationinthevicinityoftheclot,limitingitssystemicspreadof.

PlasmincleavesfibrinintofibrindegradationproductsFDPsconvenientlyinhibitfurtherthrombinandfibrinformation.

References

1. KraftsK.ClotorBleed:APainlessGuideforPeopleWhoHateCoag.PathologyStudent.2. VanHinsberghVWM.Endothelium—roleinregulationofcoagulationandinflammation.SeminarsinImmunopathology.

2012;34(1):93-106.

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CoagulopathyTestingOutlinethemethodsforassessingcoagulation,plateletfunctionandfibrinolysis

CoagulationFactors

Allthesetestsmeasurehowlongittakestomakefibrin.Theyevaluatedifferentpartsofthecoagulationcascade,whichhelplocalisewhereacoagulopathymaybeoccurring.

Inthesetests:

CitrateisaddedtobloodBindscalciumandpreventsclotting.SampleiscentrifugedPlasmadecantedCalcium(toreplacethecalciumlostbybindingtocitrate)andareagentisaddedTimetakentoclotmeasured

ProthrombinTime/INR

Theprothrombintimemeasurestheextrinsicpathway.Tissuefactorhastobeaddedtothesampleinorderstartclotting-thisiswhyitisknownastheextrinsicpathwayasasubstanceextrinsictothesamplemustbeadded.AsthePTvariessignificantlybetweendifferentlabs,theINRisusedtoallowvaluestobecompared.

AnydisorderoftheextrinsicorcommonpathwayswillprolongthePT,i.e.deficiencyorinhibitionof:

FactorVIIFactorXFactorII(prothrombin)FactorVFactorI(fibrinogen)

Althoughwarfarinaffectsfactorsinallthreepathways,itsclinicaleffectsaremeasuredusingINR.Thisisbecause:

FactorVIIhastheshortesthalf-lifeoftheclottingfactorsaffectedbywarfarinThereforesoitslevelswillfallthequickest.ThereforeafallinFactorVIIlevelsistheearliestindicationofchangesincoagulationstatusduetowarfarinAsfactorVIIisonlyintheextrinsicpathway,thePT/INRaretheonlytestswhichcanevaluateitsfunction

(Activated)PartialThromboplastinTime

Thepartialthromboplastintimemeasurestheintrinsicpathway,whichbeginsproducefibrinwhenactivatedbytheadditionofphospholipidtothesample(phospholipidiscontainedinplatelets,andsoisnottechnically"extrinsic").Theactivatedpartialthromboplastintimeisthesametest,exceptanactivatingagentisaddedtospeedupthereaction.

AnydisorderoftheintrinsicorcommonpathwayswillprolongtheAPTT,i.e.deficiencyorinhibitionof:

FactorXIFactorIXFactorVIIIFactorXFactorV

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FactorII(prothrombin)FactorI(fibrinogen)

Heparinaffectsbothsidesofthepathway(IIa,IXa,Xa,XIa)howevertypicallyaffectsintrinsicfactorsmorethanextrinsic.

Inaddition,anti-phospholipidantibodieswillalsoprolongtheAPTTbybindingtheaddedphospholipid.

ActivatedClottingTime

ActivatedClottingTimeisusedtoforthedosingandreversalofheparinincardiopulmonarybypassandotherextracorporealcircuits.

Freshwholebloodisaddedtoatubewithanactivator(e.g.glassbeads)tostimulatetheintrinsicpathway.Thetimeuntilclotformationismeasuredinseconds.Differentactivatorswillhavedifferentnormalranges,andtargetrangesforthecircuitinuse.

PlateletFunction

EvaluatehowwellplateletsaggregateinresponsetofactorslikeADP,collagen,arachidonicacid,andadrenaline(i.e.,endogenousstimulatorsofplateletaggregation).

Inthistest,theaggregatingagentisaddedtoatubeofplatelets,andthechangeinturbiditymeasured.Differentpatternsofresponse(ornon-response)canbediagnosticofdifferentplateletfunctiondisorders.

PointofCareTestingPointofcarecoagulationtesting:

InvolvestestingofwholebloodTraditionaltestingusesplasmaonly.

Thereforeincludesthecell-basedmodelofcoagulationMaybetterrepresentactualclottingfunctioncomparedwithtraditionalcoagulationfactortesting.

Providesinformationonallphasesofclotting

ViscoelasticMethods

Include:

Thromboelastography(TEG)Continuousmeasurementanddisplayofviscoelasticpropertiesofabloodsamplefrominitialfibrinformationtoclotretraction,andultimatelyfibrinolysis.Involves:

Aknownvolume(typically0.36ml)ofwholebloodaddedtoactivatorsintwodisposablecuvettes(cups)heatedto37°CContactactivators(suchaskaolin)areaddedtothebloodtoaccelerateclottingAheparinasecuvetteisalsocommonlyusedsoclottingfunctioncanbemeasuredduringfullanticoagulation(e.g.CPB)

PinattachedtotorsionwireimmersedintobloodTorsiononthepinisconverted(byatransducer)intoaTEGtracing.Cuvetterotatesthrough4°45′inalternatedirectionsEachrotationtakes10s.Pininitiallyremainsstationaryasitrotatesthroughtheun-clottedbloodThisisrepresentedbyastraightlineonthetracing.Asbloodclots,cuprotationexertstorqueonthepinThestrongerthebloodclot,thegreaterthetorqueexertedonthepin

RotationalThromboelastometry(ROTEM)

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ModifiedversionofTEG:ApinfixedtoasteelaxisisrotatedinbloodviamovementofaspringThecuvetteremainsstationary.Twosamplesareused:

Tissuefactorisaddedtomeasuretheextrinsicpathway(knownastheENTEMcuvette)Contactactivatorisaddedtomeasuretheintrinsicpathway(INTEMcuvette)

Impedancetorotationisdetectedbyanopticalsystem:LEDMirroronthesteelaxisElectroniccamera

UsesdifferentreferencerangesandnomenclaturetoTEG

AdvantagesandDisadvantagesofTEG/ROTEM

Advantages Disadvantages

Rapidcomparedwithtraditionaltesting Stillmeasurescoagulationinartificialconditions

Useswholeblood,providingamorecompletepictureofplasma-RBC-plateletinteraction

Doesnotmeasurecontributionofendotheliumandthereforeconditionsaffectingplateletadhesion(e.g.vonWillebrand'sdisease)

Real-timedisplayofclotevolution HardertoinstituteQAoutsideoflaboratory

Reducesnon-evidence-basedtransfusion Measurementmethodologyisnotyetstandardisedbetweeninstitutions

Predictiveofpost-operativehypercoagulablestates Baselinemeasurementdoesnotpredictpost-operativebleeding

Verysensitivetoheparineffect Doesnotmeasureeffectofhypothermia

Requirestrainingandcompetencyofnon-labstaff

Moreexpensivethantraditionaltesting

InterpretingTEG/ROTEM

Notethatreferencerangesarenotincludedhere,andwillvarydependingonthe:

Technique(TEG/ROTEM)usedActivatorusedAdjuvantsaddede.g.Citratedvs.recalcifiedsamples.

Parameter(TEG)

Parameter(ROTEM) Definition Relevance

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R(reaction)time

CT(clottingtime)

Timeuntil2mmamplitude

Timeuntilinitialfibrinformation,dependentonplasmaconcentrationofclottingfactors

KtimeCFT(clotformationtime)

Timeforamplitudetoincreasefrom2-20mm

Measurementofclotkinetics(clotamplification),dependentonfibrinogen

αangle αangle

Anglebetweenthetangenttothetracingat2mmandthemidline

Rapidityoffibrinformationandcross-linking.Alternatemeasureofclotkinetics,dependentonfibrinogen

MA(maximumamplitude)

MCF(maximumclotthickness)

GreatestamplitudeIndicatespointofmaximalclotstrength,dependentpredominantlyonplatelets(80%)andfibrinogen(20%),bindingviaGPIIb/IIIa.TreatmentwithplateletsorDDAVP.

CL30(clotlysis30)

LY30Percentdecreaseinamplitude30minutesafterMA

Clotstability,dependentonfibrinolysis.ReducedCL30canbetreatedwithanantifibrinolytic,suchasTXA

References

1. KraftsK.ClotorBleed:APainlessGuideforPeopleWhoHateCoag.PathologyStudent.2. ActivatedClottingTime-PracticalHaemostasis.3. SrivastavaA,KelleherA.Point-of-carecoagulationtesting.ContinEducAnaesthCritCarePain.2013;13(1):12-16.

Lastupdated2019-07-18

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SIUnitsTheInternationalSystemofUnits(SI,orSystèmeInternationald'Unités),isasetofmeasurementstandardswhichdefines(almost)allstandardsintermsofuniformnaturalphenomena,andformthebaseofthemetricsystem.

BaseSIUnits

TherearesevenbaseSIunits,withmanyderivedunitsmadefromcombinationsofthese.BaseSIunitsaremutuallyindependent.Theyconsistof:

Quantity Unit Abbreviation Definition

Time Second sDurationof9,192,631,770periodsoftheradiationcorrespondingtothetransitionbetweentwohyperfinelevelsofthegroundstateofanatomofCs-133

Length Metre m Distancethatlighttravelsinavacuumin1/299,792,458 ofasecond

Current Ampere ATheconstantcurrentthatwouldproduceaforceof2x10 Newtonbetweentwoconductorsofinfinitelengthandnegligiblecrosssectioninavacuum

Temperature Kelvin °K1/273.16 ofthetriplepointofwater.Thetriplepointisthetemperatureatwhichasubstanceexistsinequilibriuminallthreephases(solid,liquid,gas).

Amount Mole mol Theamountofsubstancewhichcontainsasmanyelementaryentitiesasin0.012kgofCarbon12

LuminousIntensity Candella cd Luminousintensityofasourcewhichemitsmonochromaticradiation

at540x10 Hzatradiantintensityof1/683wattspersteradian

Mass Kilogram kg WeightoftheInternationalPrototypeKilogram(IPK)

DerivedUnits

Quantity Unit Abbreviation ConversiontoBaseSIUnits Definition

Area Squaremetre m

Velocity MetreperSecond m.s

Acceleration MetreperSecondperSecond m.s

Force Newton N Forcerequiredtoaccelerate1kgat1m.s

Pressure Pascal Pa Forceperarea

Energy/Work/QuantityofHeat Joule J Energyconvertedwhen1Nis

appliedto1kgover1m

DoseEquivalence Sievert Sv Radiationdosepermass

th

-7

th

12

2

-1

-2

-2

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Power Watt W second

ElectromotiveForce Volt V Measureofelectricalpotentialenergy

References

1. PhysicalMeasurementLaboratory.NationalInstituteofStandardsandTechnology.Andvarioussubpages

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ElectricalSafetyUnderstandtheconceptsofpatientsafetyasitappliestomonitoringinvolvingelectricaldevices

ElectricalPrinciples

ChargeisthepropertyofasubatomicparticlewhichcausesittoexperienceaforcewhenclosetootherchargedparticlesChargeismeasuredincoulombs(C).

CurrentistheflowofelectronsthroughaconductorCurrentismeasuredinamps(A).

VoltageisthestrengthoftheforcethatcausesmovementofelectronsBytradition,voltagesarequotedrelativetoground(orearth).Ifapotentialdifferenceexists,acurrentwillflowfromthatobjecttotheearthviathepathofleastresistance.Ifthispathcontainsaperson,anelectricalinjurymayresult.

ResistancedescribestowhatextentasubstancereducestheflowofelectronsthroughitResistanceismeasuredinohms(Ω).

SubstanceswithhighresistanceareinsulatorsSubstanceswithlowresistanceareconductors

Inductanceisthepropertyofaconductorbywhichachangeincurrentinducesanelectromotiveforceintheconductor,andanynearbyconductors

CapacitanceistheabilityofanobjecttostoreelectricalchargeMeasuredinFarads(F),whereonefaradiswhenonevoltacrossthecapacitorstoresonecoulombofcharge.

Acapacitorisanelectricalcomponentconsistingoftwoconductorsseparatedbyaninsulator(calledadielectric)Whenadirectcurrentflows,electrons(anegativecharge)buildupononeoftheseconductors(calledaplate),whilstanelectrondeficit(positivecharge)occursontheotherplate

CurrentwillflowuntilthebuildupofchargeisequaltothevoltageofthepowersourceCurrentcanberapidlydischargedwhenthecircuitischanged

Analternatingcurrentcanflowfreelyacrossacapacitor,andcausesnobuildupofcharge

ImpedancedescribestowhatextenttheflowofalternatingcurrentisreducedwhenpassingthroughasubstanceImpedancecanbethoughtofas'resistanceforACcircuits',andisacombinationofresistanceandreactance.

Reactanceisafunctionoftwothings:InductionofvoltageinconductorsbythealternatingmagneticfieldofACflowCapacitanceinducedbyvoltagesbetweentheseconductors

ElectricalInjury

Potentialelectricalinjuriescanbedividedinto:

VentricularFibrillationLikelihoodisafunctionof:

CurrentdensityFrequencyLowestcurrentdensityrequiredisat50Hz.

BurnsFunctionofcurrentdensity.Burnstypicallyoccurattheentryandexitpointasthisiswherecurrentdensityishighest.

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TetanicContractionFlexorsarestrongerthanextensors,whichmaymaintaingriponlivewire.DeathmayresultfromeitherVForasphyxiationfromsustainedrespiratorymusclecontraction.

ElectricalShock

Electricalshocksaredividedintotwotypes,basedontheirabilitytoinduceVF:

MicroshockCurrentrequiredtoinduceVFwhenapplieddirectlytomyocardium.

Typicalcurrentis0.05-0.1mAThisrequiresskinbreachPotentialcauses:

GuidewirePacingleadColumnofconductingfluidCVCPICC

MacroshockCurrentrequiredtoinduceVFfromsurfacecontact.

Typicalcurrentis100mAThisismuchhigherbecausemostofthiscurrentisnotgoingtotheventricle,andsothetotalcurrentmustbegreatertoachievesufficientcurrentdensityinthemyocardiumtoinduceVF

Otherdetrimentaleffectsseenatlowercurrentsinclude:

Current(mA) Effect

1 Tingling

5 Pain

8 Burns

15 Skeletalmuscletetany

50 Skeletalmuscleparalysis&respiratoryarrest

PrinciplesofElectricalSafety

Powerpointscontainthreewires:

Active240V.MeasuringvoltageforACcurrentisnotintuitive,asthevoltagewillbenegativehalfthetime.Therootmeansquare(RMS)isusedinstead-eachvalueforthevoltageissquared(givingapositivenumber),andthendividedbythenumberofsamplestogiveanaverage.Neutral0V,relativetoground.EarthDirectpathwayintoground.

Anelectricalcircuitiscompletedbetweenanapplianceandthepowerstationbyreturningcurrenttothestationviatheearth.Thisisanearthreferencedpowersupply.

ElectricalDangers

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ActivewireshortstoequipmentcasingPrincipleofearthwire,whichprovidespathofleastresistanceforcurrenttotravelifanindividualtouchesthecase

HighcurrentdrainthroughawiregeneratesheatandstartsafirePrincipleoffuseswhichtriggerwhencurrentdrainis>15A

MethodsofElectricalSafety

InsulationConductorsarecoatedbyahigh-resistancesubstance,preventingcurrentflowingwhereitshouldn't.

FusesSafetydeviceswhichceaseallcurrentflowwhencurrentexceedsacertainthreshold(typically20A).Ifthereisafaultwhichgreatlylowersresistance(i.e.insulationbreaks,causingadevicetobecomeliveanddrainviatheearthwire),ahighcurrentwillflowandthefusewillbetriggered.

Afaultrequires:AfaultthatcausesahighcurrentflowThefusetoworkcorrectly

ResidualCurrentDevicesAnRCDmeasuresthecurrentdifferencebetweentheactiveandneutrallines.

Inannon-faultsituation,thesewillbeequalInafaultsituation,currentwillbebeingdeliveredbytheactivelinebutnotreturnedviatheneutralCurrentwillinsteadflowtogroundviafaultyequipment/throughthepatient.

TheRCDwilldetectifthereisa>10mAdifferencebetweentheactiveandneutrallines,anddisconnectpowerwithin10msifitdoesso

Afaultrequires:CurrenttoflowAsinglefaultwillturnoffthecircuit

Pros:SafeCons:Willshutoffpowertothedevice,whichisbadforECMO/CPB/ventilatorswithoutbatterybackup

LineIsolationSupply,withalineisolationmonitorAlineisolatedsupplyisa'transformer'withanequalnumberofwindings,suchthatthevoltageproducedisthesameoneachside.However,thepowerpointisnotphysicallyconnectedtothesupply,creatinganearth-referencedfloatingsupply.

Afaultrequires:TwofaultsThismakesafailurewithpotentialforshockmuchlesslikely.

ActivewiremustbeconnectedtogroundNeutralwiremustbeconnectedtogroundAcircuitthenexists:activewire-ground-neutralwire,andacurrentcouldflow

AlineisolatedsupplyispairedwithalineisolationmonitorThismonitorstateshowmuchcurrentcouldflow,ifasecondfaultcompletedthecircuit.

ThisiscalledaprospectivehazardcurrentThelineisolationmonitorcontinuouslychecksthehazardcurrentbyevaluatingtheimpedancebetweentheactivewireandground,andtheneutralwireandground

Inano-faultsituation,bothimpedancesshouldbethesameandclosetoinfinite(Impedancewon'tbeabsolutelyinfiniteastherewillalwaysbeasmallcurrentleakfromdevices).Inasingle-faultsituation,thecalculatedimpedancefortheaffectedlinewillbesignificantlylower,andthereforetheprospectivehazardcurrentwillincrease

Analarmwillsoundwhentheprospectivehazardcurrentexceeds20mAPros:Asinglefaultisnotdangerousandwillnotresultinapowerloss(importantforvitalequipment)

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Cons:Twoormorefaultsaredangerous,andwillstillnotresultinapowerloss

EquipotentialearthingThisistheonlymethodwhichpreventsmicroshock.

Ultra-lowresistanceearthcablesareattachedtoelectricaldevicesandthepatientsbedThesecablesarethenattachedtospecialwallearthconnectorsThisensuresallequipmentisreferencedtoacommonground,minimisingtheriskofleakagecurrentsbetweendevicesandthepatient

ClassificationofElectricallySafeEquipment

Theseclassificationsaredesignedtolimitmacroshock:

ClassI:EarthedAnypartthatcancontacttheuserisearthedtoground.

Ifafaultdevelopssuchthatpartsofthedevicethattheusercantoucharelive,thenthereisariskofshockIfthecaseisearthed,thepathofleastresistanceshouldbeviatheearthwireThiswillcausealargecurrenttoflow,andshouldblowafuse,ceasingcurrentflow.

ClassII:Double-insulatedAllpartsofthedevicethattheusercantouchhavetwolayersofinsulationaroundthem,reducingthechanceofthedevicebecominglive.

ClassIII:Low-voltageDeviceoperatesatlessthan40VDC/24VAC,limitingtheseverityofshockadevicecandeliver.

ClassificationofElectricallySafeAreas

Bareas:ProtectionagainstmacroshockResidualCurrentDevicesLineIsolationSupply

BFareas:Cardiac(microshock)protectionEquipotentialEarthingAlldevices,andthepatient,areearthedtoeachotherbythickcopper(i.e.low-resistance),suchthatanypotentialdifferencebetweendeviceswillbeequalisedviathepathofleastresistance(thewire,notthepatient).

Zareas:Noparticularprotections

ElectricalDeviceswhichAttachtoPatients

DevicessuchasECGandBISrequireanelectricalconnectiontothepatient.Riskofelectrocutionbythesedevicesisreducedby:

Highresistancewires

References1. ElectricityandElectricalHazards.2. AlfredAnaesthesiaPrimaryExamTutorialProgram3. AstonD,RiversA,DharmadasaA.EquipmentinAnaesthesiaandIntensiveCare:AcompleteguidefortheFRCA.Scion

PublishingLtd.2014.

Lastupdated2019-07-18

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WheatstoneBridgeTheWheatstonebridgeisanelectricaldeviceusedtoaccuratelymeasureverysmallchangesinelectricalresistance.TheWheatstonebridgeis:

Usedinmanyothermedicaldevices(e.g.invasivepressuremonitoring)AdevicewithinfinitegainAnulldeflectiongalvanometerNotanamplifierAsitdoesnotincreasecurrentamplitude.

Mechanism

TheWheatstonebridgeconsistsof:

BatteryFourresistors

and areknownandfixed

isknownandadjustable

isunknownGalvanometer

TheWheatstonebridgereliesontheratioofresistancesbetweentheknown( )andunknown( )legs:

When )equalcurrentflowsdowneitherlimbandthereisnocurrentflowacrossthegalvanometerAtthispointthebridgeissaidtobebalanced.

Theequationcanthenbere-arrangedtosolvefor :

Verysmallchangesin leadtoacurrentflowacrossthebridge

canthenbeadjusteduntilthebridgeisbalanced,andthevalueof calculated

References

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1. AlfredAnaestheticDepartmentPrimaryExamTutorialSeries

Lastupdated2017-10-02

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NeuromuscularMonitoringDescribetheconceptofdepthofneuromuscularblockadeandexplaintheuseofneuromuscularmonitoring

Describetheclinicalfeaturesandmanagementofinadequatereversalofneuromuscularblockade

Thedegreeofneuromuscularblockadecanbeassessed:

ClinicallyCrudecomparedtoelectricalassessment.Testsinclude:

Sustainedheadlift>5secondsSuggests<30%blockade.V >10ml.kgTongueprotrusion

ElectricallyUsinganervestimulator.Canbe:

Visual/tactileMonitoringoftwitchheightbyanaesthetist.ElectricalMonitoringoftwitchheightbyadevice:

Accelerometer

Accelerationisproportionaltoforceforanygivenmass( ),thereforeanaccelerometertapedtothethumbcanbeusedtoassessforceofcontraction.MechanicalforcetransducersMuscletensionismeasuredusingastraingauge.Requirescontrolpriortoadministration.ElectromyographyEMGresponseismeasuredusingelectrodesoverthemuscle.TheAUCoftheresponsecurvecanbeusedtocalculatedegreeofblockade.

NerveStimulator

Anervestimulator:

Consistsoftwoelectrodes,apowersupply,andsomebuttonsforcontrolProducesamonophasic,squarewaveatconstantcurrent,lastingnomorethan0.3msGeneratesasupra-maximalstimulusEnsureseverynervefibreisdepolarised,whichmeansaconsistentlyreproducibleresponsewillbegenerated.Asupra-maximalstimulusis25%greaterthanthemaximumrequiredtodepolariseallnervefibres.AllowsassessmentofdifferentmusclegroupsNotallmusclegroupsareaffectedequallybyneuromuscularblockade.

TypicallysmallermusclegroupsaremoresensitiveThepositive(red)leadisplacedproximalUlnarnerveElectrodesareplacedalongtheulnarborderofthewristattheflexorcrease,andthumbadductionisassessed.FacialnerveThepositiveelectrodeisplacedattheoutercanthus,andthenegativeelectrodeisplacedanteriortothetragus.Eyebrowtwitchingisassessed.PosteriortibialnerveElectrodesareplacedposteriortothemedialmalleolus,andplantarflexionisassessed.

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StimulationPatterns

Therearefivecommonstimulationpatterns:

TrainofFourFoursingletwitches(0.1ms)deliveredat2Hz(i.e.1.5sforall4).

NumberofobservedtwitchesgivesanindicationofreceptoroccupancyWithincreasingblockade,theamplitudeandnumberofobservedtwitchesdecreases.

FadeisthereductionoftwitchheightwithrepeatedstimuliduringapartialneuromuscularblockOccursduetotheeffectofnon-depolarisingagentsonthepresynapticmembrane,reducingAChproduction.Numberofobservedtwitchesdependsonthedegreeofblockade:

Notwitches≈100%blockadeOnetwitch≈90%blockadeTwotwitches≈80%blockadeThreetwitches≈75%blockadeReversalagentsshouldnotbegivenwithaToFcount<3.Fourtwitches≈<75%blockade

TheratiooftheamplitudeofT toT (ToFratio)canalsobeusedasameasureofblockade:ToFratio>90%isadequateforextubationToFratio>70%suggestsadequaterespiratoryfunction

Shouldnotberepeatedfasterthanevery10s

TetanicstimulationHighfrequency(50-200Hz)supramaximalstimulusfor5seconds.

NormalmusclewillexhibittetaniccontractionPartiallyparalysedmuscleexhibitsfadeDegreeoffadeisproportionaltodegreeofblockade,andisverysensitive.

Post-tetaniccount(PTC)UsedindeepblockadewhenthereisnoresponsetoToF.Atetanicstimulusisgiven,followed3slaterbysingletwitchesat1Hz.

NoresponsemaybeseeninverydeepblockadeHowever,twitchesmaybeseenpriortothereturnofaToFresponse.Thisiscalledpost-tetanicfacilitation,andoccursduetothetetanicstimulusmobilisingAChvesiclesintothepre-junctionalarea.

Typically,aToFof1willoccurwhenthePTC≈9Shouldnotberepeatedfasterthanevery6minutesDuetoresidualpost-tetanicpotentiation.

DoubleburstTwo0.2ms50Hz(tetanic)stimuliareapplied750msapart.

TwoidenticalcontractionsoccurinnormalmuscleAmplitudeofthesecondburstisreducedinpartiallyparalysedmuscleDBratioissimilartotheToFratio,butiseasiertoassessclinically.Aratio>0.9isrequiredforadequatereversal

SingletwitchAsinglestimuluslasting~0.2msisapplied.

>75%blockadecausesadepressedresponseAtwitchmustbeassessedpriortoblockadesoabaselinecanbeestablished

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References

1. LeslieRA,JohnsonEK,GoodwinAPL.DrPodcastScriptsforthePrimaryFRCA.CambridgeUniversityPress.2011.2. Saenz,AD.PeripheralNerveStimulator-TrainofFourMonitoring.2015.Medscape.3. McGrathCD,HunterJM.Monitoringofneuromuscularblock.ContinuingEducationinAnaesthesiaCriticalCare&Pain,

Volume6,Issue1,1February2006,Pages7–12.

Lastupdated2019-07-18

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PressureTransductionDescribetheprinciplesofmeasurement,limitations,andpotentialsourcesoferrorforpressuretransducers,andtheircalibration

Describetheinvasiveandnon-invasivemeasurementofbloodpressureandcardiacoutputincludingcalibration,sourcesoferrorsandlimitations

Atransducerconvertsoneformofenergytoanother.Pressuretransducersconvertsapressuresignaltoanelectricalsignal,andrequireseveralcomponents:

CatheterTubingStopcockFlushTransducer

Thissystemmustbecalibratedintwoways:

StaticcalibrationCalibratestoaknownzero.DynamiccalibrationAccuraterepresentationofchangesinthesystem.

StaticCalibration

Staticcalibrationinvolves:

Levelingthetransducer(typicallytothelevelofthephlebostaticaxisattherightatrium,ortheexternalauditorymeatus)Achangeintransducerlevelwillchangethebloodpressureduetothechangeinhydrostaticpressure(incmH O).Zeroingthetransducer

OpeningthetransducertoairZeroingthetransduceronthemonitorAchangeinmeasuredpressurewhenthetransducerisopentoairisduetodrift,anartifactualmeasurementerrorduetodamagetothecable,transducer,ormonitor.

DynamicCalibration

Dynamiccalibrationensurestheoperatingcharacteristicsofthesystem(ordynamicresponse)areaccurate.Dynamicresponseisafunctionof:

DampingHowrapidlyanoscillatingsystemwillcometorest.

DampingisquantifiedbythedampingcoefficientordampingratioDescribestowhatextentthemagnitudeofanoscillationfallswitheachsuccessiveoscillationCalculatedfromtheratiooftheamplitudesofsuccessiveoscillationsinaconvolutedfashion:

,where:

2

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ResonantFrequencyHowrapidlyasystemwilloscillatewhendisturbedandleftalone.

Whendampingislow,itwillbeclosetothenaturalfrequency(orundampedresonantfrequency)

Dampingandnaturalfrequencyareused(ratherthanthephysicalcharacteristics)astheyarebotheasilymeasuredandaccurateindescribingthedynamicresponseThesepropertiesareactuallydeterminedbythesystemselasticity,mass,andfriction,butitisconceptuallyandmathematicallyeasiertousedampingandresonance

PressureWaveformsandDynamicResponse

ThedynamicresponserequiredisdependentonthenatureofthepressurewavetobemeasuredAccuratelyreproducinganarterialwaveformrequiresasystemwithagreaterdynamicresponsecomparedtoavenouswaveform

Anarterialpressurewaveformisaperiodic(repeating)complexwave,thatcanberepresentedmathematicallybyFourieranalysisFourieranalysisinvolvesexpressingacomplex(arterial)waveasthesumofmanysimplesinewavesofvaryingfrequenciesandamplitudes

Thefrequencyofthearterialwave(i.e.,thepulserate)isknownasthefundamentalfrequencyThesinewavesusedtoreproduceitmusthaveafrequencythatisamultiple(orharmonic)ofthefundamentalfrequency

Increasingthenumberofharmonicsallowsbetterreproductionofhigh-frequencycomponents,suchasasteepsystolicupstroke

Accuratereproductionofanarterialwaveformrequiresupto10harmonics-or10timesthepulserateAnarterialpressuretransducershouldthereforehaveadynamicresponseof30Hz

Thisallowsaccuratereproductionofbloodpressureinheartratesupto180bpm(180bpm=3Hz,3Hzx10=30Hz)

Resonance

Ifhighfrequencycomponentsofthepressurewaveformapproachthenaturalfrequencyofthesystem,thenthesystemwillresonateThisresultsinadistortedoutputsignalandasmallovershootinsystolicpressure.

Damping

Apressuretransductionsystemshouldbeadequatelydamped:

Anoptimallydampedwaveformhasadampingof0.64.Itdemonstrates:Arapidreturntobaselinefollowingastep-change,withoneovershootandoneundershoot

Acriticallydampedwaveformhasadampingcoefficientof1.Itdemonstrates:

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Themostrapidreturntobaselinepossiblefollowingastep-changewithoutovershootingAnover-dampedwaveformhasadampingcoefficientof>1.Itdemonstrates:

Aslowreturntobaselinefollowingastep-changewithnooscillationsSlurredupstrokeAbsentdicroticnotchLossoffinedetail

Anunder-dampedwaveformhasadampingcoefficientcloseto0(e.g.0.03).Itdemonstrates:Averyrapidreturntobaselinefollowingastep-changewithseveraloscillationsSystolicpressureovershootArtifactualbumps

Optimallydampedwaveformsareaccurateforthewidestrangeoffrequencyresponses:

TestingDynamicResponse

Dynamicresponsecanbetestedbyinducingastep-changeinthesystem,whichallowscalculationofboththenaturalfrequencyandthedampingcoefficient.Clinically,thisisperformedbydoingafast-flushtest.

Fastflushvalveisopenedduringdiastolicrunoffperiod(minimisessystemicinterference)Thepressurewaveproducedindicatesthenaturalfrequencyanddampingcoefficientofthesystem:

ThedistancebetweensuccessiveoscillationsshouldbeidenticalandequaltothenaturalfrequencyofthesystemTheratioofamplitudesofsuccessiveoscillationsgivesthedampingcoefficient

OptimisingDynamicResponse

Thelowerthenaturalfrequencyofamonitoringsystem,thesmallertherangeofdampingcoefficientswhichcanaccuratelyreproduceameasuredpressurewave.Therefore,theoptimaldynamicresponseisseenwhenthenaturalfrequencyisashighaspossible.Thisisachievedwhenthetubingis:

ShortWideStiffFreeofairIntroducinganairbubblewillincreasedamping(generallygood,sincemostsystemsareunder-damped),howeveritwilllowerthenaturalfrequencyandisdetrimentaloverall.

Footnotes

FundamentalsofPressureMeasurement

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Pressureexertedbyastaticfluidisduetotheweightofthefluid,andisafunctionof:

Fluiddensity(inkg.L )Acceleration(effectofgravity,inm.s )Heightofthefluidcolumn

Thiscanbederivedasfollows:

,thereforeCombiningtheaboveequations:

Thisisusuallyexpressedas:

NotethatthisexpressiondoesnotrequirethemassorvolumeoftheliquidtobeknownThisiswhypressureisoftenmeasuredinheight-substanceunits(e.g.mmHg,cmH O)

References

1. BrandisK.ThePhysiologyViva:Questions&Answers.2003.2. AlfredAnaestheticDepartmentPrimaryExamProgram3. Miller,RD.ClinicalMeasurementofNaturalFrequencyandDampingCoefficient.In:Anesthesia.5thEd.Churchill

Livingstone.

Lastupdated2019-07-18

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PressureWaveformAnalysisDescribetheinvasiveandnon-invasivemeasurementofbloodpressureandcardiacoutputincludingcalibration,sourcesoferrorsandlimitations

Analysisofarterialpulsecontouris:

Real-timeandcontinuousUsedtoestimatecardiacoutputLessaccuratebutalsolessinvasive(e.g.thermodilution)ortechnicallydemanding(e.g.echocardiography)thanothermethods.

Thereforealsocalculate(andoftendisplay)strokevolumevariationandpulsepressurevariation

PrinciplesAllmodelsrecognisethattheamplitudeofthesystolicupstrokeis:

DirectlyproportionaltostrokevolumeInverselyproportionaltoarterialcompliance

Otherprinciplesusedbysome(butnotall)devicesinclude:

Three-elementWindkesselmodelCharacterisesthearterialtreeashavingthreemajorfeatures:

AorticImpedanceArterialCompliancePredictedusingpatientcharacteristics.SystemicVascularResistance

ConservationofMass

Devices

Devicescanbeclassifiedbasedonwhethertheyare:

Calibrated/UncalibratedCalibratedInitialestimationisrefinedusingadilutiontechnique.

Dilutionsmaybeby:Thermodilution

ColdsalineinjectedintoSVCUsinganIJVorSCVCVC.Temperaturechangedmeasuredatthefemoralartery

LithiumdilutionSmallamountsoflithiumchlorideinjectedintoacentralveinChangeinlithiumconcentrationmeasuredinradialarteryCObycalculatedStewart-Hamiltonequation

PeriodicallyrecalibratedtocorrectfordriftUncalibratedNotcorrectedforameasured'true'cardiacoutput.

Inaccurateforshorttermchangesinarterialproperties

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Notvalidatedin:ShockARDSHepaticsurgeryDuetochangesinarterialtone.Cardiacsurgery

Invasive/Non-invasiveInvasiveRelyona(usuallyfemoral)arterialcatheter.Non-invasiveRelyonthevolumeclampmethod:

InflatablecuffwrappedaroundfingerPlethysmographestimatesbloodvolumeinthedigitalarteriesCuffinflatesanddeflatesthroughoutthecardiaccycle,keepingthevolumeofthearteriesconstantArterialpressureisproportionaltocuffpressure.Inaccuratein:

PeripheraloedemaVasoconstrictedstates

CommonDevicesinUse

PiCCO/VolumeView/FloTracCalibratedInvasive3-elementWindkesselMechanism:

CalculatesareaundersystolicpartofthearterialcurveDividescalculatedareabyaorticcomplianceComplianceestimatedbyproprietaryalgorithmeachtimethedeviceiscalibrated.

SVRiscontinuouslyestimatedfromcalculatedCOandmeasuredBPLiDCO

CalibratedInvasiveConservationofmassComplianceinferredfrombiometricdata

Clearsight/CNAPUncalibratedNon-invasive

T-LineCalibratedProprietary,non-validatedauto-calibratingalgorithm.Non-invasiveUsesradialapplanationtonometry

References1. JozwiakM,MonnetX,TeboulJ-L.PressureWaveformAnalysis.AnesthAnalg.2017.2. Francis,SE.ContinuousEstimationofCardiacOutputandArterialResistancefromArterialBloodPressureusingaThird-

OrderWindkesselModel.MIT.2007.

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Non-InvasiveBloodPressureDescribetheinvasiveandnon-invasivemeasurementofbloodpressureandcardiacoutputincludingcalibration,sourcesoferrorsandlimitations

Non-invasivebloodpressuremeasurementsisperformedwitheithera:

DeviceforIndirectNon-invasiveAutomaticMeanArterialPressure(DINAMAP)Automaticbloodpressurecuff.VonRecklinghausen'soscillotonometer"Manual"bloodpressurecuff.

Usestwocuffs,andthereforetwotubes

DINAMAPComponents:

OnecuffPerformsbotharterialocclusionandmeasurement.TubingDeviceforinflatingtheocclusivecuffandgraduallydeflatingitPressuretransducerDisplay

Method:

CuffisinflatedaboveSBPCuffdeflatesatarateof2-3mmHg.sWhencuffpressureequals:

SBPTurbulentflowoccurspastthecuff,creatingpressureoscillations.ThepressureatwhichthesearefirstdetectedistheSBP.MAPThepressureatwhichamplitudeofoscillationsismaximal.

DBPiscalculatedfromMAPandSBP

Cons

RequiresanappropriatelysizedcuffCuffshouldbe~20%greaterthanarmdiameter.

Cuffsthataretoosmallwillover-readCuffsthataretoowidewillunder-read

RequiresaregularrhythmInaccurateatextremesofbloodpressureInaccuratewhenusedmorefrequentlythanonceperminuteInaccuratewhenthevesselisincompressible

HeavilycalcifiedvesselsWhenappliedtoforearm/foreleg

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VonRecklinghausen'sOscillotonometer

Components:

TwocuffsOcclusivecuffMeasurementcuff

TubingDeviceforinflatingtheocclusivecuffandgraduallydeflatingitAneroidbarometerfortransducingpressureDisplay

Process:

CuffisinflateduntiltheradialpressureisnolongerpalpableThisisapproximatesSBP.Cuffisdeflated,andre-inflatedto20mmHgabovetheestimatedSBPCuffisdeflatedatarateof2-3mmHg.s whilstauscultatingthebrachialarteryWhencuffpressureequals:

SBPTurbulentflowoccurspastthecuff,turbulentflowcausesthefirstoftheKorotkoffsounds(cleartappingpulsations)tobeheard.DBPThecuffnolongercompressesthevesselatall,sonoturbulentflowoccursandnothingisauscultated.

References

1. ANZCAJuly/August20002. AstonD,RiversA,DharmadasaA.EquipmentinAnaesthesiaandIntensiveCare:AcompleteguidefortheFRCA.Scion

PublishingLtd.2014.3. LeslieRA,JohnsonEK,GoodwinAPL.DrPodcastScriptsforthePrimaryFRCA.CambridgeUniversityPress.2011.

Lastupdated2019-07-18

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CardiacOutputMeasurementDescribetheinvasiveandnon-invasivemeasurementofbloodpressureandcardiacoutputincludingcalibration,sourcesoferrorsandlimitations

Explainthederivedvaluesfromcommonmethodsofmeasurementofcardiacoutput(i.e.measuresofvascularresistance)

Cardiacoutputmeasurementcanbeperformed:

InvasivelyPulmonaryArteryCatheter

ThermodilutionFickPrinciple

TOEArterialwaveformanalysis

PiCCOVigileo

Non-invasivelyTTEMRIThoracicimpedance

Thermodilution

Thermodilutionremainsthegoldstandardofcardiacoutputmeasurement.

Thistechnique:

RequiresapulmonaryarterycatheterVariousdifferentdesignsexist.ForCOmeasurement,theyrequire:

AproximalportattheRA/SVCAtemperatureprobeatthetipTypicallyasiliconoxidethermistor.AballoonatthetipTofloatitintoposition.Adistal(PA)portisrequiredformeasuringPAPandthePCWP,butisnotrequiredforCOcalculation

MethodforIntermittentCardiacOutputMeasurementbyThermodilution

Aknownvolumeof(typicallydextrose)ataknowntemperature(classicallycooled,butthisisnotrequired)isinjectedintotheproximalportThetemperatureofbloodismeasuredatthetipThisproducesatemperature-timecurve.Theareaunderthecurvecanbeusedtocalculatecardiacoutput,asperthemodifiedStewart-HamiltonEquation:

,where:

=Cardiacoutput

=Volumeofinjectate

=Temperatureofblood

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=Temperatureofinjectate

=DensityconstantRelatestothespecificheatandspecificgravityofbothinjectateandblood.

=ComputationconstantAccountsforcatheterdeadspaceandheatexchangeduringinjection.

=Areaunderthechangeintemperature-timecurve

ErrorsinThermodilution

NaturalvariabilityCardiacoutputvariesupto10%withchangesinintrathoracicpressureduringrespiration.Therefore:

Ameanof3-5measurementsshouldbetakenMeasurementsshouldbetakenatend-expiration

IncorrectvolumeofinjectateToomuchunderestimatesCOToolittleoverestimatesCO

WarmfluidThecloserthetemperatureofinjectateistoblood,thegreaterdegreeoferrorintroducedtothemeasurement.

Colderinjectateismoreaccurate,butcarriestheriskofinducingbradyarrhythmiasPoorlypositionedPACThePACmustbepositionedinWest'sZone3forbloodflowtooccurpastthetip,andforthemeasuredtemperaturetobeaccurate.TricuspidregurgitationResultsinretrogradeejectionofinjectatebackpastthevalve.Arrhythmia

FickPrinciple

CardiacOutputcanalsobemeasuredusingtheFickPrinciple.Thistechnique:

UsestheFickPrincipleTheflowofbloodtoanorganisequaltotheuptakeofatracersubstancedividedbythearterio-venousconcentrationdifference.

Inthiscase,thetracersubstanceisoxygenThe'organ'isthewholebody

Thisproducestheequation: ,where:

isCardiacOutput

isthepatientsoxygenconsumptionTypicallyestimatedas3.5ml.kg .min

isarterialoxygencontent

ismixedvenousoxygencontentReliesonmixedvenousbloodsampledfromthepulmonaryartery,andarterialbloodsampledfromaperipheralarterialline

References

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1. Moise,S.F.,Sinclair,C.J.andScott,D.H.T.(2002),Pulmonaryarterybloodtemperatureandthemeasurementofcardiacoutputbythermodilution.Anaesthesia,57:562–566.

2. Nishikawa,T.&Dohi,S.Errorsinthemeasurementofcardiacoutputbythermodilution.CanJAnaesth(1993)40:142.

Lastupdated2019-07-18

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PulseOximetryDescribetheprinciplesofpulseandtissueoximetry,co-oximetryandcapnography,includingcalibration,sourcesoferrorsandlimitations

Pulseoximetryreliesonseveralprinciples:

OxygenatedanddeoxygenatedhaemoglobinabsorblightofdifferentwavelengthstodifferentextentsLightof660nmand940nmisused.

Deoxyhaemoglobinhasagreaterabsorbanceofred(660nm)lightthanoxyhaemoglobinOxyhaemoglobinhasagreaterabsorbanceofinfrared(940nm)lightthandeoxyhaemoglobinTherelativeabsorbanceofeachallowsdeterminationoftheproportionsofoxygenatedanddeoxygenatedhaemoglobin

TheBeer-LambertLaw(s):Absorptionoflightpassingthroughasubstanceisdirectlyproportionaltoboththedistanceittravelsthroughthesubstanceandtheconcentrationofattenuatingspecieswithinthesubstance.Itisacompositeof:

Beer'sLawAbsorptionoflightisproportionaltotheconcentrationof"attenuatingspecies"Lambert'sLawAbsorptionisproportionaltothethicknessofthesolution,ormoreprecisely,thateachlayerofequalthicknessabsorbsanequalproportionofradiationthatpassesthroughit

Bloodflowispulsatile

Method

Apulseoximeterconsistsof:

TwodiodesofthedesiredwavelengthsPhotocellMicroprocessor

Duringpulsatileflow,theexpansionandcontractionofthebloodvesselsaltersthedistanceandhaemoglobinconcentrations,changingtheabsorptionspectraofblood(aspertheBeer-LambertLaw).

Non-pulsatileelementsareduetotissuesandvenousblood

Thesearesubtractedfromthetotal,leavingthepulsatileelementwhichrepresentsthearterialcomponentTheratioofabsorbanceofthepulsatileelementsandthenon-pulsatileelementsiscalledR,andiscalculatedas:

RiscomparedwithasetofstandardisedvaluestodeliveracalculatedSpO

AnRof1givesanSpO of85%AnRof0.4givesanSpO of100%AnRof2givesanSpO of50%

TheIsobesticPoint

TheisobesticpointisthewavelengthatwhichlightisabsorbedequallybybothhaemoglobinspeciesLightabsorptionisthereforeindependentofsaturation,andisinsteadafunctionofhaemoglobinconcentrationThiscanbeusedtocorrectforhaemoglobinconcentrationTherearetwoisobesticpointsforoxygenatedanddeoxygenatedhaemoglobin,at590nmand805nm

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Limitations

RequiresdetectablepulsatileflowLimitedbypoorperipheralperfusion(shock,hypotension,hypothermia)andnon-pulsatileflow(ECMO,CPB)Bodymovementsconfoundreadings(shivering,seizing)

LowsaturationsInaccuratebelow70%,andcompletelyunreliablebelow50%.

VenouspulsationDetectedaspulsatileflow,anderroneouslyinterpretedbythemicroprocessorasarterialflow.

ConfoundedbyambientlightThediodesarecycledatseveralhundredtimespersecondwhichallowsthedetectortocompensatefortheeffectofambientlight(thevalueswhenthediodesareoffgivetheeffectofambientlight).

Absorptionspectraconfoundedby:Haemoglobinopathies

Carboxyhaemoglobincausesthepulseoximetertoreadartificiallyhighduetoasitalsoabsorbs660nmlightMethaemoglobinaemiacausestheSpO totrendtowards85%,asthoughitabsorbs660nmlightisalsoabsorbs940nmlighttoagreaterdegree

DyesMethylenebluewillcausetheSpO toread<65%forseveralminutesIndocyaninegreenwillalsocauseadecreasedSpO

References1. DavisPD,KennyD.BasicPhysicsandMeasurementinAnaesthesia.5thEd.Elsevier.2003.2. MardirossianG,SchneiderRE.LimitationsofPulseOximetry.AnesthProg39:194-1961992.3. CICMMarch/May20144. TremperKK,BarkerSJ.Pulseoximetry.Anesthesiology.1989Jan;70(1):98-108.5. WilliamsGW,WilliamsES.BasicAnaesthesiologyExaminationReview.OxfordUniversityPress.2016.

Lastupdated2019-07-18

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OxygenAnalysisDescribetheprinciplesofmeasuringoxygenconcentration

Asoxygenisamoleculecontainingtwosimilaratoms,itspartialpressurecannotbedeterminedusinginfraredtechniques(unlikeCO ).Oxygencontentofagasisinsteaddeterminedusing:

ParamagneticanalysesFuelCells

ParamagneticAnalysisPrinciplesofparamagneticanalysis:

OxygenisparamagneticThismeansitisattractedbymagneticfields,butdoesnotpropagatethefield.

Thisisbecauseitstwounpairedvalentelectronshavethesamespin.Manyothergasesweaklyrepelledbymagneticfields(diamagnetic)

Theattractionofagasmixturetoamagneticfieldisthereforeproportionaltoitsoxygencontent

Manydifferentmethodsexistwhichusethispropertytodetermineoxygencontent

PressureMethod

GastestedflowsintoatubeAreferencegasflowsintoaparalleltubeBothgasesthenpassthrough:

FlowrestrictorsMagneticfieldThisisbeingturnedonandoffat~100Hz.

ThegasescombineinthemagneticfieldThegreatertheoxygencontentofthegas,themoreitwillmoveintothemagneticfieldThismovementcreatesanegativepressurebehindthegas.Thepressuredifferencebetweenthetestedgasandthereferencegasisproportionaltotheoxygencontentofthetestgas.

TemperatureMethod

Usedinmanymoderndevices.

Gasflowsthroughamagneticfield,causingtheparticlestoalignThischangesthethermalconductivityoftheoxygenmolecules.ThechangeinthermalconductivityofthegasmixtureisproportionaltotheoxygencontentThisisdetectedbymeasuringcurrentpassingthroughaheatedwire

Pros

AccurateRapidresponsetimeModernanalyserscanidentifybreath-to-breathvariationinFiO .Don'trequireregularcalibration

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Cons

WatervapourreducesaccuracyInterferencefromotherparamagneticgases

NitricoxideEffectisminimalasnitricisdeliveredinfarsmallervolumesthanoxygen,andisonlyweaklyparamagnetic.

FuelCells

Fuelcellsrelyonreductionofoxygentomeasureoxygenpartialpressure.Theyconsistof:

OxygenpermeablemembraneKOHsolutionThiscontains:

LeadanodeLeadisconsumedasthefuelcelloperates.Goldcathode

Method

OxygendiffusesacrossthemembraneintothepotassiumhydroxidesolutionAtthecathode:

Attheanode:

Theoxygenconsumptionisproportionaltothecurrentgenerated,whichismeasuredwithanammeter

Pros

NopowerrequiredSmallAccurate

Cons

WillaccumulatenitrogeninthepresenceofN OResultsinanunder-readingofPO .Mustbereplacedafter6-12monthsRequiresregulartwo-pointcalibration21%and100%oxygenareused.Relativelyslowresponsetimecomparedtoparamagneticanalysers~20s.

References1. AstonD,RiversA,DharmadasaA.EquipmentinAnaesthesiaandIntensiveCare:AcompleteguidefortheFRCA.Scion

PublishingLtd.2014.

Lastupdated2019-07-18

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OxygenAnalysis

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End-TidalGasAnalysisDescribetheprinciplesofpulseandtissueoximetry,co-oximetryandcapnography,includingcalibration,sourcesoferrorsandlimitations

Principles

SeveralmechanismsforE CO measurementexist:

InfraredSpectroscopyColourimetricMethodsRaymanScatteringGasChromatography

InfraredSpectroscopy

Infraredspectroscopyreliesonthefactthat:

GaseswithtwoormoredifferentatomswillabsorbinfraredradiationDifferentgasesabsorbingdifferentwavelengthstodifferentdegreesMeasuringtheabsorbedwavelengthsandcomparingwiththelikelycompositionofamixture,asystemcanbedesignedusingaspecificwavelengthtomeasuregasconcentrationsandavoidinterference

End-tidalgasanalysisusinginfraredlightisusedinthemeasurementof:

COCapnographyisthecontinuousmeasurementandgraphicaldisplayofthepartialpressureofCO inexpiredgas.ThisisthemostcommonmethodtomeasureE CO .Anaestheticagents

MeasurementofCOComponents:

SapphiresamplingchambercontaininggassampleCO absorbsinfraredradiationatapeakwavelengthof4.28μmThesapphirelensonlyallows4.28μmlightthrough

EmitterDetectorMicroprocessorDisplay

Method:

LightisemittedandpassesthroughthesamplingchamberAlensisusedtofocusemittedlight.LevelsofradiationaremeasuredontheothersideofthechamberLevelscorrespondtotheamountofgaspresentinthesampleThelessradiationthatreachesthedetector,themoregasthereisinthesampleabsorbingit

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EquipmentErrors

Errorscanbeclassifiedinto:

SpecifictotechniqueThecollisionbroadeningeffectIntermolecularforcesvarydependingontheirproximitytoothermoleculesinthegasmixture.Achangeinintermolecularforcesmayaltertheirbond-energyandthefrequenciesatwhichtheyabsorbradiation.Itcanbeovercomeby:

CorrectingforthepresenceofothergasesManuallyadjustingtheobtainedvalues

CrossoverwithothergasmixturesCO andN Ohavesimilarabsorbancespectra,andmayleadtoerrorwhenadeviceisnotdesignedtomeasurebothwavelengths.

FailureofequipmentThesecanbeovercomebyuseofdouble-beamcapnometer.ThisusesareferencechamberwhichcontainsCO -freeair,andthesameemitter-detectorsystem.Allabsorptionfromthissystemmustoccurduetoartifact(asnoCO ispresent).Theartifactualcomponentisthensubtractedfromthevaluedetectedinthemainchamber.Thiscorrectsfor:

VariableamountofinfraredradiationreleasedVariablesensitivityofthedetectorVariableefficacyofthecrystalwindowandlenssystem

RelatingtotypeofcapnometerusedE CO maybeeitherside-streamorin-line.

Side-streamCO involvesalengthofnarrowtubingdrawinggasfromtheexpiratorylimbofthebreathingcircuit(typicallyfromtheHMEfilter)tothecapnograph

Side-streamrequiresaflowof150ml.minHasa(prettyinsignificant)delay(<1s)inmeasurementMaybeblockedbywatervapour,andrequireuseofawatertraptoremovecondensation

In-linesystemshaveasamplingchamberattachedin-linewiththeETTThesamplingchamberslightlyincreasesthedead-spaceofthecircuitMayberelevantinchildrenorverydifficulttoventilatepatients.AddsweighttopatientendofthebreathingcircuitRequireheatingto41°Ctoavoidcondensation

NormalE CO Waveform

Thenormaltraceconsistsoffourcomponents:

1. ThebaselineThisconsistsof:

Inspiratorytime

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Earlydead-spaceexhalationThisistheperiodimmediatelybeforephase2,wheresomegaswithaPCO of0isexhaled.

2. Alveolarexhalation,wherePCO risesrapidly3. Alveolarplateau,wherePCO flattens

Thehighest-pointofthiscurveislabeledE CO .4. Inspiration,wherePCO returnsto0

E CO WaveformVariations

Airwayobstruction:

Occursduetounevenemptyingofalveoliwithdifferenttime-constants

Hyperventilation:

LowerE CO withshorterbaselinePlateauphasemaynotoccuratveryhighrespiratoryrates

Rebreathing:

BaselineincreasesasinspiredCO ismeasuredfromgasanalyser

ChangesinE CO

NormalE CO is32-42mmHg,whilstnormalPaCO is35-45mmHg.

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HighE CO

Thismaybefrom:

DecreasedventilationDecreasedRRDecreasedVIncreasedV andthereforeagreaterV :V ratio

IncreasedproductionofCOIncreasedmetabolicrate

SepsisTourniquetreleaseROSCfollowingarrest

IncreasedinspiredRebreathing(i.e.equipment/ventilatormalfunction)ExternalsourceofaddedCO

LowE CO

RapidLossofE CO

FailureofventilationCircuitdisconnectAirwayobstructionBronchospasm

FailureofcirculationCardiacarrestShock

GradualLossofE CO

IncreasedV (i.e.increasedMV)DecreasedCO production

HypometabolicstateHypothermia

IncreasedV ,i.e.V/QmismatchIncreasedWestZoneIphysiology:

HypotensionIncreasedRVAfterload:

PEHighPEEP

SamplingerrorAirentrainmentintothesamplechamberInadequateV

DiscrepancybetweenE CO ,PACO ,andPaCO

ThenormalgradientbetweenPaCO andE CO is0-5mmHg.Healthyandawakeindividualsshouldhaveessentiallyno(<1ml)alveolardeadspace,andsoessentiallynogradient.Thisgradientisincreasedinpatientswith:

V/QmismatchE CO willunderestimatearterialCO asgasfromun-perfusedalveoli(withnegligibleCO )willdiluteCO expiredgas

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ColourimetricMethods

Litmuspaperwhichchangescolourwhenexposedtohydrogenions(producedbyCO )canbeusedtoconfirmendo-trachealintubation,thoughtheymaygeneratefalse-positiveresultsduetogastricpH.

References

1. CrossME,PlunkettEVE.Physics,Pharmacology,andPhysiologyforAnaesthetists:KeyConceptsfortheFRCA.2ndEd.CambridgeUniversityPress.2014.

2. DavisPD,KennyD.BasicPhysicsandMeasurementinAnaesthesia.5thEd.Elsevier.2003.3. LeslieRA,JohnsonEK,GoodwinAPL.DrPodcastScriptsforthePrimaryFRCA.CambridgeUniversityPress.2011.

Lastupdated2019-07-18

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BloodGasAnalysisDescribethemethodsofmeasurementofoxygenandcarbondioxidetensioninbloodandbloodpH

Bloodgasmachinesdirectlymeasurethreevariablesandcalculatetheremainder.Measuredvariablesare:

POCOpH

Calculatedvariablesinclude:

BicarbonateUsingthepH,CO andtheHenderson-Hasselbalchequation.BaseExcessCalculatedusingtheHenderson-HasselbalchandSiggaard-Andersonequation.Canbeexpressedintwoways:

BaseExcessTheamountofalkalithatmustbeaddedtothesampletoreturnittoanormalpH,atatemperatureof37°CandaPaCO of40mmHg.StandardisedBaseExcessAsbaseexcess,butcalculatedforbloodwithaHbconcentrationof50g.L .ThisisthoughttobetterrepresenttheECFasawhole.

OxygenTensionOxygentensionismeasuredwithaClarkeelectrode.Thisconsistsof:

AchamberforthebloodsampleAchambercontainingapotassiumchloridesolution,which:

Isseparatedfromthebloodchamberbyanoxygen-permeablemembraneThispreventsbloodbeingindirectcontactwiththecathode,whichwouldleadtoproteindepositiononthecathodeandincorrectmeasurement.ContainsaplatinumcathodeContainsasilver/silverChlorideanode

Abatteryapplying0.6Vacrosstheelectrodes

Method

Avoltageof0.6Visappliedacrosstheelectrodes,causingthesilvertoreactivewithchlorideinthesolutiontoproduceelectrons:

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Thispotentialdifferenceisrequiredtostartthereaction0.6Vischosenbecauseitisenoughtostartthereactionbutwillhaveminimaleffectonmeasuredcurrentflow

Atthecathode,oxygencombineswithelectronsandwatertoproducehydroxylions:

Foreachoxygenmoleculepresentatthecathode,fourelectronscanbeconsumedIncreasingtheoxygenavailableatthecathodeincreasesthenumberofelectronsconsumed,andthereforeincreasescurrentflow

OxygenwillmovefromthesamplechambertothemeasuringchamberaccordingtoitspartialpressureMeasuredcurrentflowisthereforeproportionaltooxygentensioninblood

Calibration,Limitations,andAccuracy

CalibrationisperformedwithstandardgasmixturesRequiresregulartwo-pointcalibration.CathodemustbekeptcleanfromproteinandnotdamagedCathodemustbekeptat37°CMayreadfalselyhighwithhalothane

pHMeasurement

pHisameasureofthehydrogenionconcentration insolution,andisdefinedasthenegativelogarithmtothebase10ofthe[H ]:

ApHof7.4isa[H ]of40nmol.L at37°CAchangeinapHunitof1isequivalenttoa10-foldchangeinthe[H ]AchangeinpHof0.3isequaltodoublingorhalvingthe[H ]

ThepHelectrodeconsistsof:

AchamberforthebloodsampleAmeasuringchamber,separatedfromthesamplebyH -permeableglass,whichcontains:

AbuffersolutionAsilver/silverchloridemeasuringelectrode

Areferencechamber,alsoseparatedfromthechamberbyH -permeableglass,whichcontains:AKClsolutionHasnobufferingproperties.

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Amercury/mercurychloridereferenceelectrode

Method

ReliesontheprinciplethattwosolutionswithdifferentH activitieswilldevelopapotentialdifferencebetweenthem(proportionaltotheconcentrationgradient)H passesthroughtheglassalongaconcentrationgradient:

Avariablepotentialdifferenceisgeneratedinthemeasuringchamber,asH ionsarebufferedandtheconcentrationgradientismaintainedAconstantpotentialdifferenceisgeneratedinthereferencechamber,asthereisnobufferofH ionsintheKClsolution

OnceH hasequilibratedbetweenbloodandtheKClsolution,thepotentialdifferencebetweenthemeasuringandreferenceelectrodesisproportionaltotheH concentrationinblood

Calibration,Limitations,andAccuracy

Calibrationisperformedwithtwophosphatebuffersolutionscontainingtwodifferent(known)[H ]Mustbekeptat37°CHypothermiaincreasessolubilityofCO andthereforelowersPaCOAreducedpartialpressureofCO isrequiredtokeepthesamenumberofmoleculesdissolved(asperHenry'sLaw)

Therefore,asbloodcoolsitspHwillincreaseElectrodesmustbekeptcleanfromproteinandnotdamaged

CarbonDioxideTension

CarbondioxidetensionismeasuredwithaSeveringhauselectrode,whichisbasedonthepHelectrode,asPaCO2isrelatedto[H ].TheSeveringhauselectrodeconsistsof:

Achamberforthebloodsample,separatedfromthebicarbonatechamberbyaCO permeablemembraneAchambercontainingbicarbonatesolutioninanylonmesh,andseparatedfromboththemeasuringandreferencechambersbyH -permeableglassAmeasuringchambercontaining:

AbuffersolutionAsilver/silverchloridemeasuringelectrode

Areferencechambercontaining:AKClsolutionAmercury/mercurychloridereferenceelectrode

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Method

CO diffusesfrombloodintothebicarbonatechamberCO reactswithwaterinthebicarbonatechambertoproduceH ionsFromhere,theprocessisidenticaltothepHelectrode,exceptbicarbonatetakestheplaceofblood:

H ionsdiffuseintothereferencechamberuntiltheH ionconcentrationhasequilibratedH ionscontinuallydiffuseintothemeasuringchamber(astheyarebuffered)

ThisestablishesaconstantpHgradientThisgradientisproportionaltheH ionconcentrationinthebicarbonatechamber,whichisproportionaltotheCO contentofblood.

Calibration,Limitations,andAccuracy

CalibrationisperformedwithsolutionsofknownCO concentrationMustbekeptat37°CHypothermiadecreasessolubilityofCO andthereforedecreasespHElectrodesmustbekeptcleanfromproteinandnotdamagedSlowresponsetimerelativetopHelectrodeduetotimetakenforCO todiffuseandreactThiscanbeacceleratedwithcarbonicanhydrase

Footnotes

.TechnicallypHisdefinedastheactivityofH inasolution.Clinically,activityisidenticaltoconcentration,soinmedicinethesedefinitionsarefunctionallythesame.↩

References1. LeslieRA,JohnsonEK,GoodwinAPL.DrPodcastScriptsforthePrimaryFRCA.CambridgeUniversityPress.2011.

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2. (FRCA-MeasurementofpO2,pCO2,pH,pulseoximetryandcapnography)[http://www.frca.co.uk/article.aspx?articleid=100389]

3. AstonD,RiversA,DharmadasaA.EquipmentinAnaesthesiaandIntensiveCare:AcompleteguidefortheFRCA.ScionPublishingLtd.2014.

Lastupdated2018-09-21

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GasFlowDescribethemeasurementofflow,pressureandvolumeofgases

TypesofFlow:

LaminarflowFluidmovinginasteadymannerwithoutturbulence.TurbulentflowIrregularfluidmovementinradial,axial,andcircumferentialaxes.

Laminarflowismoreefficientthanturbulentflow,asitrequiresasmallerpressuregradienttogeneratethesameflowFortwofluidsmovingatthesamespeed,thevelocityofindividualparticlesinlaminarflowwillbebothhigherandlower

TransitionalflowMixtureoflaminarandturbulentflow.Flowistypicallyturbulentinthecentre,andlaminarattheedges.

Devicesusedtomeasuregasflowinclude:

Variable-OrificeFlowmetersFixed-OrificeFlowmetersPneumotachograph.Hotwireflowmeter

NoteorificebasedflowmetersrelyontheHagan-PoiseuilleEquation:

Viscosity( )andlength( )arefixedbybothdevicesFixedorificeflowmetersalsofixradius( ),suchthatthechangeinpressuremustthereforebeproportionaltoflow:

,where isaconstant

Variableorificeflowmetersalsofixpressure( ),suchthatflowcanbecalculatedfromtheradius:

Flowmeters

Constantpressure,variableorificeflowmetersarefoundonwallandcylindergases.Theyconsistof:

Aninverseconicaltube(i.e.narroweratthebottom,andwideratthetop)AneedlevalveAbobbinMayhaveagroovewhichcausesthebobbintospin,confirmingitisnotstuck.

Method:

GasflowsfromthebottomtothetopofthetubeThebobbinobstructsflowThereforethereisapressuredifferenceacrossit.

Remember:

Atequilibrium,thepressureexertedbythebobbinontheflowofgas( )

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isequaltothepressureexertedbythegasonthebobbin

Asflowisincreased,thebobbinispushedfurtheruptheflowmeterduetotheincreasedpressureThebobbinwillreachanewequilibriumpositionwhentheorificeoftheflowmeterhasbecomewideenoughforthepressureonthebobbintoequalthepressureofgravity

Flowmetersarecalibratedforindividualgasesas:

Laminar(typicallylowflows)flowisproportionaltoviscosityTurbulent(typicallyhighflows)flowisproportionaltodensity

Pros

CheapNoadditionalpowersupplyrequiredAccurateReadingsmaybealteredby:

ChangeintemperatureaffectsviscosityanddensityofgasChangeinpressureaffectsdensityofgas

Cons

MustbeverticalBobbinscanbecomestuck

PneumotachographsConstantorifice,variablepressureflowmeter.Severaldifferentdesignsexist,andinclude:

FleischpneumotachographConsistsofseveralfineboreparalleltubesplacedinthegascircuitDecreasedradiusandincreasedresistancereducesgasflowvelocity,improvinglaminarflow.AdifferentialpressuretransducerisplacedateitherendofthetubesThepressuredropacrossthetubingisdirectlyproportionaltoflow

PitottubesConsistsoftwotubesplacedintothegascircuit:

OnefacesintothegasflowTheotherfacesawayfromthegasflow

Thepressuredifferencebetweentubesisproportionaltoflow

Pros

AccurateContinualmeasurementAllowcalculationofvolumes

Cons

IncreasedresistanceIncreaseddeadspaceRequirelaminarflow

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Inaccuratewhen:FlowsarehigherthanwhatthesystemisdesignedforAlterationingasdensity

ChangeingasmixtureAlterationingastemperature

HotWireFlowmeter

Components:

TwofineplatinumwiresinthegascircuitOneheatedto180°CatOL.minOneat0°C

Ammeter

Method:

Asgasflows,thewirecoolsRateofheatdissipationisproportionaltogasflowTheamountofcurrentrequiredtoreturnthewireto180ismeasured,andisproportionaltoflow

Pros

AccurateFast

Cons

Fragile

References

1. AstonD,RiversA,DharmadasaA.EquipmentinAnaesthesiaandIntensiveCare:AcompleteguidefortheFRCA.ScionPublishingLtd.2014.

Lastupdated2019-07-18

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PrinciplesofUltrasoundDescribethephysicalprinciplesofultrasoundandtheDopplerEffect.

Ultrasoundisanimagingtechniquewherehigh-frequencysoundwaves(2-15MHz)areusedtogenerateanimage.Anultrasoundwaveisproducedbyaprobeusingthepiezoelectriceffect:

CertaincrystallinestructureswillvibrateataparticularfrequencywhenacertainvoltageisappliedacrossthemTheconversionofelectricalenergytokineticenergyishowtheultrasoundprobecreatesanultrasoundwave.Similarly,theycangenerateavoltagewhenavibrationisinducedinthemThisishowtheprobeinterpretsreflectedwaves.

BasicPrinciplesSpatialresolutionHowclosetwoseparateobjectscanbetoeachotherandstillbedistinguishable.Itisdividedinto:

Axialresolution,howfaraparttwoobjectscanbewhenoneisabovetheother(inthedirectionofthebeam)Lateralresolution,howfaraparttwoobjectscanbewhensideside-by-side

Contrastresolutionishowsimilartwoobjectscanappear(inechogenicappearance)andstillbedistinguishable

Higherfrequencysettingsoffergreaterspatialresolutionbutdecreasedpenetration

LowerfrequencysettingsofferreducedspatialresolutionbutincreasedpenetrationTheyareusedforvisualisingdeepstructures.

AffectofTissuesonUltrasoundAttissueinterfaces,thewavemaybe:

AbsorbedSoundislostasheat,andincreaseswithdecreasedwatercontentoftissues.ReflectedSoundbouncesbackfromthetissueinterface,andreturnstotheprobe.

Reflectionisdependentonthe:DifferenceinsoundconductionbetweenthetwotissuesAngleofincidence(closeto90°improvesreflection)Smoothnessofthetissueplane

Theamplitudeofsoundreturningtotheprobedeterminesechogenicity,orhowwhitetheobjectwillbedisplayedThetimetakenforthesoundtoreturndeterminesdepth

Thetimetakenforawavetoreturnisproportionaltotwicethedistanceoftheobjectfromtheprobe

Depthcanbecalculatedusing ,where:

isDepthisthespeedofsoundintissue,andisassumedtobe1540ms

tisTimeTransmittedSoundpassesthroughthetissue,andmaybereflectedorabsorbedatdeepertissues.ScatteredSoundisreflectedfromtissuebutisnotreceivedbytheprobe.

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Attenuationdescribesthelossofsoundwavewithincreasingdepth,andisafunctionoftheabovefactors.AttenuationismanagedbyincreasingthegainGainreferstoamplificationofreturnedsignal.Time-gaincompensationreferstoamplificationofsignalswhichhavetakenlongertoreturn,whichamplifiessignalsreturnedfromdeeptissues

Modes

Ultrasoundmodesinclude:

B-Mode(brightnessmode)Thestandard2Dultrasoundmode,andplotsthemeasuredamplitudeofreflectedultrasoundwavesbythecalculateddepthfromwhichtheywerereflected.M-Mode(movementmode)Selectsasingleverticalsectionoftheimageanddisplayschangesovertime(i.e.depthonthey-axis,andtimeonthex-axis).

DopplerEffect

Thedopplereffectisthechangeinobservedfrequencywhenawaveisreflectedoff(oremittedfrom)amovingobject,relativetothepositionofthereceiver.Inmedicalultrasound,thisisthechangeinfrequencyofsoundreflectedfromamovingtissue(e.g.anerythrocyte).Itisgivenbytheequation:

where:

=Velocityofobject

=Frequencyshift=Speedofsound(inblood)

=Frequencyoftheemittedsound

=Anglebetweenthesoundwaveandtheobject

Reflectedfrequenciesarehighertowardstheprobeandloweraway.

CalculationofCardiacOutput

Remember, .

HeartrateismeasuredStrokevolumeiscalculatedby:

Measuringthecross-sectionalareaoftheleftventricularoutflowtractObtainedbymeasuringthediameterusingultrasound.MeasuringthestrokedistanceObtainedviaintegratingthevelocity-timewaveformfortimeacrosstheleftventricularoutflowtract(LVOTVTI).

Theintegralofflow(m.s andtime(s))fortime(s),producesadistance(m)MultiplyingtheLVOTcross-sectionalarea(m )bythestrokedistance(m),producesavolume(m )Thisisthestrokevolume.

References

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1. CrossME,PlunkettEVE.Physics,Pharmacology,andPhysiologyforAnaesthetists:KeyConceptsfortheFRCA.2ndEd.CambridgeUniversityPress.2014.

2. CICMJuly/September2007.

Lastupdated2019-07-18

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TemperatureandHumidityDescribethemeasurementoftemperatureandhumidity

Temperatureisthetendencyofabodytotransferheatenergytoanotherbody,andismeasuredindegrees.Itisdistinctfromheat,whichisthekineticenergycontentofabody,andismeasuredinJoules.Thetwoarerelatedbythespecificheatcapacity,whichdescribeshowmuchenergy(J)mustbeappliedtoabodytoraiseitstemperaturefrom14°Cto15°C,withoutachangeinstate.

Humiditymaybeeitherabsoluteorrelative:

AbsoluteHumidityisthemassofwatervapourinavolumeofairRelativeHumiditymeasuresthepercentagesaturationofairatcurrenttemperature,ormoreformally:

MeasurementofTemperature

Temperatureismeasuredbyanumberofmethods:

LiquidExpansionThermometry

Thisisusedinmercurythermometers.Theseconsistof:

Agraduatedevacuatedcapillaryofnegligiblevolume,attachedtoAmercuryreservoir,ofmuchgreatervolume,separatedbyAconstrictionringPreventstravelofmercuryupthecapillarybygravity.

Mechanism:

Whenheated,thekineticenergyofthemercuryincreasesanditexpands,forcingitupthecapillaryAsthethermalexpansioncoefficientforallliquidsisverysmall,thecapillarymustbeofaverysmallvolumetocreateausabledevice.Thespeedthatthisoccursisrelatedtothetime-constantofthesystemThisistypically30seconds.Measurementthereforetakes~4time-constants,or2minutes.

Pros

EasytouseAccurateReusableSterilisableCheap

Cons

SlowresponseOnlyaccurateonceithasreachedthermalequilibrium.GlasscanbreakMaycausereleaseofmercuryoralcohol.Inaccurateat:

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LowtemperatureswithmercuryFreezesat-38.8°C.HightemperatureswithalcoholBoilsat78.5°C.

Electrical

Electricalmethodsinclude:

ResistancethermometerPlatinumwireincreaseselectricalresistancewithincreasingtemperature.

ThereforethevoltagedropacrossthewirewillcorrespondtothetemperatureofthewireChangeinresistanceislinearacrossthetemperaturerangeHowever,theseareexpensive.

ThermistorMetal(e.g.SiO )semiconductorwhichchangesitsresistanceinapredictablynon-linearfashion(run-awayexponent)withtemperature.

CanbemanufacturedsothatchangeislinearovertheclinicalrangeMuchcheaperthanwireresistancemethodsThedegreeofvoltagedropisusuallyverysmall,howeverthiscanbeamplifiedusingaWheatstonebridge

ThermocoupleAtthejunctionoftwodissimilarmetals,apotentialdifferencewillbeproducedproportionaltotheirtemperature.ThisisknownastheSeebeckeffect.

Non-linear(washinexponent)Degradeovertime

MeasurementofHumidity

Humiditycanbemeasuredbyanumberofmethods:

HairHygrometerHair(actualhair)changeselasticitydependingonthehumidityofair.Changesinelasticitycanberelatedtochangesinhumidity.

WetandDryBulbThissystemmeasuresbothtemperatureandrelativehumidity.

TwothermometersareusedOneiswrappedinawick,whichisattachedtoawaterreservoirThisisthewetthermometer.Thedrythermometergivesameasurementofsurroundingairtemperature

ThewetthermometeriscooledduetoevaporativecoolingfromthewickHighenergywatermoleculesbecomevapour,leavingonlylowenergymoleculesbehind.Thetemperaturedifferencebetweenthethermometersisafunctionof:

LatentheatofvapourisationofwaterHowmuchevaporativecoolingisoccurringThisisfunctionofhumidity.

At100%relativehumidity,noevaporativecoolingwilltakeplaceandthetemperatureswillbeequalAshumiditydecreases,evaporativecoolingwillcoolthewetthermometer,andthetemperaturedifferenceallowshumiditytobedetermined

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References

1. AstonD,RiversA,DharmadasaA.EquipmentinAnaesthesiaandIntensiveCare:AcompleteguidefortheFRCA.ScionPublishingLtd.2014.

2. AlfredAnaestheticDepartmentPrimaryExamTutorialSeries

Lastupdated2019-07-18

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ElectrocardiographyDescribetheprinciplesbehindtheECG

TheECGisagraphicalrepresentationoftheelectricalactivityoftheheart,asmeasuredbythesumofelectricalvectorsatthepatientsskin.

Components

AnECGconsistsof:

ElectrodesDisposable,stickycomponentswhichactasconductorsduetoasilver/silverchloridecoating.Toreduceelectrodeimpedance,skinshouldbe:

HairlessDryClean

CablesShieldedtopreventcurrentsbeinginducedandelectrocutingthepatient.ProcessorMonitor

ECGLeads

ECGleadsarecreatedbytakingthepotentialdifferencebetweentwoelectrodes,whichvariesby0.5-2mVthroughthecardiaccycleasmyocardiumdepolarises.ECGleadsaredividedinto:

LimbleadsPotentialdifferencebetweenlimbelectrodes:

I:RAtoLAII:RAtoLLIII:LAtoLL

AugmentedleadsPotentialdifferencebetweentheaverageofthelimbleads(calledtheindifferentelectrode)andeachindividuallimblead.

AugmentedleadsareofmuchlowervoltageandmustbeamplifiedThreeaugmentedleadsexist(oneforeachlimbelectrode)

PrecordialleadsPotentialdifferencebetweentheindifferentelectrodeandoneofthesixadditionalelectrodesplacedonthechestwall.

TherelationshipbetweenelectrodesandleadsisdescribedwithEinthoven'sTriangle:

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Method

Asthemyocardialmembranepotentialchangesacrossthecardiaccycle,apotentialdifferencecanbemeasuredattheskin.Adepolarisationwavetravelingtowardsthepositiveelectrode(orarepolarisationwavetravelingaway)willcauseanupwarddeflectionintheECG

Thesepotentialdifferencesareverysmall,andthereforeneedtobe:DistinguishedfrombackgroundinterferenceSeveraltechniquesexist:

CommonmoderejectionIdenticalelectricalactivityoccurringinmultipleelectrodesislikelyduetointerferenceratherthancardiacactivity,andisremovedfromthemeasuredsignal.

AgroundelectrodeistypicallyusedforthispurposeECGmodesECGscanbesettovaryinglevelsofsensitivity.

DiagnosticmodeRespondstohigherrangeoffrequencies,butisatgreaterriskofinterference.MonitormodeECGrespondstoalowerrangeoffrequencies,reducinginterferencebutalsoresolution.Thisiscommonon3-leadECG.

HighinputimpedanceMinimisessignalloss.

AmplifiedFrequenciesinthedesiredsignalrangeareamplified.

SourcesofError

ImprovesignaldetectionGoodadherenceOptimalskincontactEnsuredryandhairless.

MinimiseexternalelectrostaticforcesEarthedDiathermyShivering

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Risks

ECGelectrodescanactasanexitelectrodeforsurgicaldiathermy

References

1. AstonD,RiversA,DharmadasaA.EquipmentinAnaesthesiaandIntensiveCare:AcompleteguidefortheFRCA.ScionPublishingLtd.2014.

2. CICMFebruary/April2016

Lastupdated2019-07-18

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HumidifiersHumidifiersaddwatervapourtoinspiredgas,takingtheplaceofnormalbodymechanismswhicharebypassedorimpededbyinvasiveandnon-invasiveventilation.Maintainingadequatehumidityofinspiredgasisimportantin:

ReducingmetabolicloadHumidificationofinspiredgasaccountsfor~15%ofbasalheatexpenditure.MaintainingfunctionofthemucociliaryelevatorInspirationofdrygasincreasesviscosityofmucous.ReducingwaterlossWaterwillbeabsorbedfrommucosatohumidifygas.

Humidifierscanbeclassifiedintoactiveorpassive.

PassiveHumidifiersPassivehumidifiers:

DonotrequirepowerDonotrequirewater

TheHeatandMoistureExchange(HME)filteristheclassicpassivehumidifier:

PlacedbetweenthepatientandthepatientY-pieceConsistsof:

AmoistureexchangelayerPleated,hygroscopicallycoatedfoamorpaper.

Expiredgascoolsasitpasses,condensingontothefoam,withcondensationpromotedbyhygroscopiccoating(usuallythisisNaCl)Thelatentheatofvapourisationresultsinadecreasedtemperatureofexpiredgas

AfilterlayerTypicallyaelectrostaticorhydrophobicmaterial.

ExpiredgasiscooledanddriedInspiredgasisthenheatedandhumidifiedAnHMEtakesupto20minutestobefullyeffective,andcanachievearelativehumidityupto70%Efficacydependsuponthepatient'scoretemperatureandtheconditionoftheairway

Pros

CheapLightweightStraightforwardMaycontainanti-bacterialfilter

Cons

MaybeblockedwithvomitandsecretionsIncreaseairwayresistanceIncreasedeadspaceNotaseffectiveaspoweredactivesystemsOnlylast24hours

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Takes15-20minutestobecomefullyeffective

ActiveHumidifiers

ActiveHumidifiers:

Requireeither:PowerUnpoweredhumidifiersaretypicallylesseffective,andonlyoperatewellatlowerflowrates.Water(Orboth)

Consistof:AwaterbathTypicallysterilewater.AheatingelementToheatthewaterbath.AgaspipeInspiredgasesarebubbledthroughthewaterbathtohumidifythem.AwatertrapTotrapcondensedwater.Shouldbechangedregularlytominimiseinfectionrisk.

Pros

GreaterhumidificationAppropriateforlong-termventilation

Cons

BulkyExpensiveRequirepowerInfectionriskfromwaterbath

References

1. McNultyG,EyreL.Humidificationinanaesthesiaandcriticalcare.ContinuingEducationinAnaesthesiaCriticalCare&Pain,Volume15,Issue3,1June2015

Lastupdated2019-07-18

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SupplementalOxygenDescribedifferentsystemstodeliversupplementaloxygenandtheadvantagesanddisadvantagesofthesesystems

Devicesfordeliveryofoxygencanbeclassifiedinto:

VariableperformancedevicesFixedperformancedevices

VariablePerformanceDevicesVariableperformancedevices:

DonotdeliverafixedFiOThisisbecauserespiratoryflowisnon-uniformAlthoughminuteventilationmaybe5-6L.min ,peakinspiratoryflowsaresubstantiallyhigher.DeliveredFiO isdependentonoxygenflowandinspiratoryflow

IncreasingoxygenflowratewillincreaseFiO ,buttheeffectwillvarydependingonthedevice(volume,seal)andthepatient

Include:NasalCannulaeProngsdeliveringgasat1-4L.min .

Higherflowsmaydrymucosa,andleadtoepistaxisNasopharynxactsasanoxygenreservoir,somewhatincreasingFiOWelltolerated

Alloweating,drinking,andtalkingHudsonMaskSimpleunsealedmask,allowinggasflowupto15L.min .

CheapLesswelltoleratedRebreathingmayoccur

Non-RebreatherMaskModifiedversionoftheHudsonmask,containingareservoirbag.

ReservoirbagisfilledduringexpirationGasisdrawnfromthereservoirbagduringinspiration,increasingFiOSomeairisentrainedfromaroundthemaskandsoFiO is<1.

FixedPerformanceDevices

Fixedperformancedevices:

TheoreticallydeliverafixedFiOTheseareusuallyflowlimitedaswell,andsoFiO maydecreaseathigherinspiratoryflows.Include:

VenturiConsistsofaconethroughwhichoxygenflows.Aperturesonthesideoftheconeentrainroomair.

Airisentrainedvia:FrictionaldragofmoleculesTheventurieffect(thoughthisiscontroversial)

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Thewideningoftheconeleadstoanincreaseinfluidvelocityandthereforeadecreaseinpressure,asperthe

Bernoulliprinciple.Entrainedairisproportionaltoflowrate,sotheratioofoxygentoairisconstantforanygivenaperturesizeThisisknownastheentrainmentratio.WilldeliverthespecifiedFiO providedoxygenflowisabovetheminimumrateThereforebecomevariableperformancedeviceswheninspiratoryflowgreatlyexceedsoxygenflow.

References1. AstonD,RiversA,DharmadasaA.EquipmentinAnaesthesiaandIntensiveCare:AcompleteguidefortheFRCA.Scion

PublishingLtd.2014.

Lastupdated2019-07-18

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BispectralIndexDescribetheprinciplesbehindtheBIS

BispectralIndex(BIS)isaproprietarysignal-processedEMGandEEGmonitorusedtoestimatedepthofanaesthesia.

TheBISoutputsfourvalues:

BISDimensionlessindexbetween0and100where:

0representscorticalelectricalsilence85-100representsnormalawakecorticalactivity40-60isconsistentwithgeneralanaesthesia

SignalQualityIndex(SQI)Dimensionlessindexbetween0and100whichgivesanindicationoftheaccuracyoftheBISvalue.ElectromyographyGivesanindicationoftheinfluenceofmuscleactivityonBISvalues.SuppressionRatio(SR)Percentageofprevious63secondswhereEEGisisoelectric.

Method

Proprietary,butinvolves:

MultivariatelogisticregressionofEEGfeaturesthatcorrelatewithclinicallevelsofsedationInitialvalidationonacohortofhealthyvolunteers,notundergoingsurgeryUseoffourfrontotemporalEEGmonitors

Analytictechniques:

CompressedSpectralArrayThesignaloverashortperiod(e.g.5-10seconds)ofEEGrecordingsareanalysedtogetherEachperiodisknownasanepoch.AFouriertransformationisperformedThisbreakstheEEGsignaldownintothesinewavesusedtoproduceit.AhistogramofeachfrequencyisplottedAsanaesthesiadeepens,lowerfrequenciesbegintodominateThespectraledgefrequencyisthefrequencygreaterthan95%ofthefrequenciesinthecompressedspectralarrayItisanindicatorofanaestheticdepth,butnotofdrugconcentration.

CoherenceUnderanaesthesia,theelectricalactivityindifferentsectionsofthebrainfallsoutofphase.

Pros

ReducedanaestheticawarenessinhighriskpatientgroupsTrauma,GAcaesariansection,cardiacsurgery.Non-invasiveUseappearstoresultinreducedanaestheticuseandmorerapidemergence

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Cons

ProprietaryalgorithmExpensiveMaybeinaccuratewith:

HypothermiaHypercarbiaHypoxiaMusclerelaxantsBISmayfallinappropriately.Non-GABAergicagents(e.g.ketamine,nitrousoxide)Maynotfallappropriately.

References

1. AstonD,RiversA,DharmadasaA.EquipmentinAnaesthesiaandIntensiveCare:AcompleteguidefortheFRCA.ScionPublishingLtd.2014.

Lastupdated2019-07-18

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MedicalGasSupplyDescribethesupplyofmedicalgases(bulksupplyandcylinder)andfeaturestoensuresupplysafetyincludingpressurevalvesandregulatorsandconnectionsystems

Production

FractionalDistillation

Oxygenisproducedontheindustrialscalebyfractionaldistillationofatmosphericair.Thisprocess:

ReliesonthefactthatdifferentgaseshavedifferentboilingpointsByliquefyingairandthenheatingitgradually,eachgascanberemovedseparatelyasitboils.Occursinstages:

AtmosphericairisfilteredRemovesdustandothercontaminants.Airiscompressedto6atmandthencooledtobelowambienttemperatureWatervapourcondensesandisremoved.CompressedairpassedthroughazeolitesievewhichremovesCOCompressedairisallowedtore-expandAsitdoessoitlosesheatenergyasperGay-Lussac'sLaw,andliquefies.

AirmustbecooledbelowtheboilingpointofthedesiredgasesThisrequiresgettinggasesverycold,andsotheprocessmaybemechanicallyassistedusingaturbine,and/oraheatexchanger.Keyboilingpoints(at1atm):

Nitrogen:77°KOxygen:90°KHelium:4°KHeliumcanbeproducedbyfractionaldistillation,butliquefyingitisunderstandablydifficultgiventhevery,verylowboilingpoint.Heliumcanalsobemined,asheliumproducedbyalphadecayofradioactivematerialsmaybetrappedingaspocketsundertheearth.

LiquidairisthenfractionallydistilledTemperatureofliquidairisraisedslowly.

Astheboilingpointofeachgasisreached(e.g.77°Kfornitrogen),thatgaswillbegintovapourisefromtheliquid,andcanbecollectedTheremainingliquidcanthenbefurtherheated,untiltheboilingpointforthenextgasisreachedThisprocesscanberepeateduntilallthedesiredgaseshavebeenseparated

OxygenConcentrator

Oxygenconcentrators:

Produceupto95%oxygenfromairbyremovingnitrogenBuiltusingtwozeolitelattices

PressurisedairisfilteredthroughonelatticeNitrogenandwatervapourareretainedinthelatticeOxygenandargonareconcentratedProducesa95%oxygen/5%argonmixture.

Theunusedcolumnisheatedtoreleasetheboundnitrogenandwater

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Pros

CheapReliableAvoidneedforoxygendelivery

Cons

ResultinanaccumulationofargonwhenusedatlowflowsonacirclesystemRequirecontinuouspowerFireandexplosionrisk

Storage

MedicalGasCylinders

Gascylindersare:

MadefromchromiummolybdenumoraluminiumUsedas:

BackupforapipedsupplyWhenapipedsupplyisnotavailable(transports)Whenthegasisuncommonlyused(e.g.nitricoxide)

ThecommoncylinderusedinhospitalisCDThiscontains460Lofoxygenat15°Cand137bar.

Cylindersarenotcompletelyfilled,toreduceriskofoverpressureandexplosionsifthetemperaturerisesThefillingratioistheweightofliquidinafullcylindercomparedtotheweightofwaterthatwouldcompletelyfillthecylinder

Incoolclimates,thefillingratiois~0.75Inwarmerclimates,thefillingratioisreducedto~0.67

Cylindersaretestedforsafetyevery5-10yearsTestsinclude:

EndoscopicexaminationTensiletests1%ofcylindersaredestroyedtoperformtestingonthemetal.

Pros

PortableReusable

Cons

HeavyLimitedsupply

CylinderManifolds

Cylindermanifoldsareformedofsetsoflargegascylindersusedinparallel.

Allcylindersinagroupareusedtogether

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Whenthepressurefallsbelowasetlevel,apressurevalvewillswitchandgaswillbedrawnfromanothercylindergroupThefirst(nowempty)cylindergroupisexchangedforfullcylinders

Pros

CheapUsefulasabackupsupply

Cons

LesscapacitythanaVIEFireandexplosionrisk

VacuumInsulatedEvaporator

TheVIE:

StoresliquidoxygenItisvacuuminsulatedasitmustkeepoxygenbelowitscriticaltemperature(-119°C).TheVIEtypicallystoresoxygenbetween-160°Cand-180°C,andat700kPa.

ThegasisstoredbelowitscriticaltemperatureandaboveitsboilingpointTheamountofoxygenremainingiscalculatedfromitsmass

DoesnotrequireactivecoolingInsteaditiscooledby:

InsulationEvaporationHeatenteringtheVIEcausesliquidoxygentoevaporate.OxygenvapourisdrawnofftheVIEtothepipelinesupply,sotheVIEremainscoolandatasteadypressureprovidedoxygenisbeingdrawnfromit.

HasapressurereliefvalvetopreventexplosionsifoxygenisnotbeingusedHasanevaporatortoevaporatelargevolumesofoxygenrapidlyifdemandishigh

Thisissimplyanuninsulatedpipeexposedtotheoutsidetemperature

Pros

CheapestoptionforoxygendeliveryandstorageStoringoxygenasaliquidismuchmoreefficientthanasagasDoesnotrequirepower

Cons

Set-upcostsareexpensiveRequiresaback-upsetupWillwastelargevolumesofoxygenifnotbeingusedcontinuouslyFireandexplosionrisk

SafetyinMedicalGasSupply

Manysystemsexisttoensuresafety:

ColourcodingofcylindersandhosesOxygeniswhiteNitrogenisblack

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AirisblackwithwhiteshouldersNitrousoxideisblueHeliumisbrown

HelioxisbrownwithwhiteshouldersCarbondioxideisgrey-green

LabelingofconnectionsThepinindexsystemUsedtopreventthewronggasyokebeingconnectedtoacylinder.

PinsprotrudefromthebackoftheyokeHolesexistonthevalveblockPinsandholesmustlineupforthecylindertobeconnectedTherearesixpositions,dividedintotwogroupsofthreeCommoncombinationsinclude:

Oxygen:2-5Air:1-5Nitrousoxide:3-5

SleeveIndexSystemUsedinAustraliawhenconnectingpipelinegases.

WallblockcontainsasleevewhenpreventsfittingtheincorrectgashosetothewallScrewthreadisidenticalinallcases

Non-InterchangeableScrewThread(NIST)Used(butnotinAustralia)whenconnectingpipelinegases.

NISTconnectorshaveaprobeandanutProbediameterisgas-specific,preventingthewronggasfrombeingconnected

TestingMustdemonstrate

CorrectoxygenconcentrationsAbsenceofcontaminationDeliveryofadequatepressurewhenseveralothersystemsonthesamepipelineareinuse

Testingmustbeperformedtwiceonanewinstallation:FirstbyengineersSecondbyamedicalofficerIntheatres,thisshouldbethedirectoroftheanaestheticdepartmentortheirdelegate,whoshouldholdfellowshipofANZCA.

References

1. AstonD,RiversA,DharmadasaA.EquipmentinAnaesthesiaandIntensiveCare:AcompleteguidefortheFRCA.ScionPublishingLtd.2014.

2. ANZCAAugust/September20163. TheEssentialChemicalIndustryOnline-Oxygen,Nitrogen,andtheraregases.4. Thompson,C.TheAnaestheticMachine-GasSupplies.UniversityofSydney.

Lastupdated2019-07-18

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VapourisersDescribetheprinciplesandsafeoperationofvapourisers

Deliveryofgasthatisfullysaturatedwithanaestheticagentwouldresultinlethaldosesbeingadministered.Theuseofavapouriserallowsasafedoseofanaestheticagenttobegiven.Vapouriserscanbedividedinto:

VariablebypassvapourisersAirthatisfullysaturatedwithgasismixedwitha'bypass'streamofgas,dilutingthedeliveredconcentration.Furthersubdividedinto:

PlenumRequiressupra-atmosphericpressuretooperate.

MoreaccurateDraw-overDrivenbythepatientsinspiratoryeffort.

Portable

VariableBypassVapouriserVariablebypassvapourisersaimtodeliverthesameconcentrationofanaestheticagentoverarangeofflows.Theyachievethisby:

FlowmanagementBafflesandwicksincreasethesurfaceareaoftheliquid/gasinterface,increasingtherateofvapourisation.

ExcessivelyhighflowratesmayresultingasnotbeingfullysaturatedwithagentwhenitexitsthevapouriserstreamThesearelesseffectiveindraw-overvapourisers,asresistancemustbeminimised

TemperaturemanagementTheSVPofvolatileagentsincreasesnon-linearlyastemperatureincreases.Temperaturechanges:

Occurthrough:ChangesinambienttemperatureLossthroughlatentheatofvapourisationLiquidagentfromthevapouriserwillcooloverthecourseofananaesthetic.

Aremanagedwith:TemperaturestabilisationUseofmaterialswithbothahighthermalconductivityandspecificheatcapacity,allowingthevapourisingchambertobufferchangesinsurroundingtemperature.TemperaturecompensationAdjustsflowintoeitherthevapourisingchamberorbypasschambertoaccountforchangesinenvironmentaltemperature.Methodsinclude:

BimetallicstripMetalstripwhichbendsinresponsetoenvironmentaltemperature,adjustingtheamountofgasenteringthevapourisingchamber.AneroidbellowsConnecttoaconeintheopeningofthebypasschamber.Astemperaturedecreases,thebellowscontractandtheconepartiallyobstructsthebypasschannel.

DifferenceBetweenPlenumandDraw-OverVapourisers

Plenumvapourisersare:

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MoreaccurateDesignedtodeliveraccurateagentconcentrationsoverawiderange(0.25-15L.min )offlowrates

Below250ml.min theresistanceoftheflowsplittingvalvebecomesmoresignificant,causingtheamountofgasinthebypassstreamtobehigherthanintendedAbove15L.min gasmaynotbefullysaturated

HeavierTypicallybuiltofmetalssuchascoppertomaximisethermalstability.Highinternalresistance

Mustbeusedout-of-circleMustbeusedwithpositive-pressure

Draw-OverVapourisersare:

LessaccurateLessuseofbafflesandwickstominimiseinspiratoryresistance

LessthermallystableOxfordMinatureVapouriserdoesnothaveabimetallicstripOxfordMinatureVapouriserusesglycolasathermalbuffer

MeasuredFlowVapourisersMeasuredflowvapourisershaveaseparatestreamofagent-saturatedgasthatisaddedtothegasflow.Thisrequiresthedeviceto:

MeasurefreshgasflowrateAdjustvapour-gasflowratesothedesiredconcentrationisdelivered

Thissystemisusedforthedeliveryofdesflurane,asdesflurane:

HasaveryhighSVPRequireshighbypassflowratetodilutetoaclinicallyusefulconcentration.HasalowboilingpointIntermittentlyboilsatroomtemperature,whichwillcauselargefluctuationsindelivery:

ExcessiveagentdeliveryduringboilingThiswillleadtocoolingduetothelatentheatofvapourisation.CooleddesfluranewillhaveamuchlowersaturatedvapourpressureSignificantunder-deliverywillthenoccur.

TheTec6vapouriser:

Heatsdesfluraneto39°CSVPofdesfluraneatthistemperatureis1500mmHg.GaseousdesfluraneisthenaddedtothefreshgasflowTheamountaddeddependson:

DesiredconcentrationFreshgasflowrateAsflowincreasestheresistancetoflowofdesfluranevapourdecreases.

GeneralSafetyFeaturesofVapourisersAgentspecificity:

KeyindexedfillingPinindexedsafetysystemconnectors

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Colourcodingofunitandagentcontainers

Singleagentadministration:

InterlockmechanismPreventsmultiplevapourisersbeingturnedon.Singlecartridgeslot(Aladdinsystem)

Tippingandoverfilling:

LongvapourisationchamberinflowHeavyconstructionTransportmodesSidefillingandoverflowports

Anti-pumping:

Checkvalvesandlongvapourisationchamberinflowprevententrainmentofvapourisergasintheinflowofthebypasschannel

Agentdepletion:

FillinggaugesLowpressurealarms(Tec6)

OtherFactorsAffectingVapourisers

CarrierGasComposition:

NitrousoxideandairaremoreviscousthanoxygenThisleadstodecreasedflowthroughthevapourisingchamberwhenFiO islowThiseffectisnotclinicallysignificant.

Altitude:

ClinicaleffectofvolatileagentisafunctionoftheirpartialpressureintissuesAsSVPisindependentofatmosphericpressure,thisisunchangedataltitudeAvapourisersetat2%willdeliver4%gasat0.5atmpressure,howeverastheatmosphericpressureisreducedthesamepartialpressureofvapourisdelivered

Thedeliveredconcentrationofanagentataltitudeisgivenbytheequation:

,where:

istheconcentrationofagentinthegasdeliveredtothepatientThismustbemultipliedbytheatmosphericpressuretofindthepartialpressureofagentdeliveredtothepatient.

istheconcentrationdialeduponthevapouriser

istheatmosphericpressurewherethevapouriserwascalibrated

istheatmosphericpressurewherethevapouriserisbeingused

References

1. MillerRD,ErikssonLI,FleisherLA,Weiner-KronishJP,CohenNH,YoungWL.Miller'sAnaesthesia.8thEd(Revised).

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ElsevierHealthSciences.2. BoumphreyS,MarshallN.Understandingvapourizers.ContinuingEducationinAnaesthesiaCriticalCare&Pain.Volume

11,Issue6,1December2011,Pages199–203,

Lastupdated2019-07-18

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BreathingSystemsThisprovidesageneraloverviewofanaestheticbreathingsystems.Thecirclesysteminparticulariscoveredelsewhere.

Classifications:

OpenAnaestheticgasesnotconfinedtothecircuit.

LimitedcurrentpracticalapplicationExpensive,environmentalcontamination.e.g.Ethermasks

Non-rebreathingNoexpiredgasisre-inspired;requiresaone-wayvalve.

LimitedpracticalapplicationRequiresalow-resistancedraw-overvapourisere.g.Tri-serviceapparatus

RobustInexpensive

RebreathingsystemsExpiredgasisre-inspired.

AbsorptionsystemsRequiresmethodforCO absorption.

CircleCommonanaestheticcircuit,coveredindetailunder.Canbe:

VapouriserOut-of-CircuitCommonsystem,coveredindetailundercirclesystem.

Vapouriserin-circuitUncommonsystem.

Inaspontaneousventilationmode,thepatientwillincreaseagentconcentrationasminuteventilation↑Thismeansthatassurgicalstimulus↑,depthofanaesthesiaalso↑.

WatersMaplesonBorCwithaCO absorptioncanisterbetweenbagandFGF.

Non-absorptionRebreathingexpiredgasispartofcircuitdesign.MaplesonSystems

MaplesonSystemProperties:

RebreathingofexpiredgasdoesnotnecessarilyequatetoCO retention,providedtheFGFisaboveacertainmultiple(circuitdependent)ofthepatientsMV

PaCO isafunctionofFGFandCO productiononlyIncreasingMVwithoutincreasingFGFwillresultinre-breathingofCO andunchangedPaCO .

Inanyspontaneousventilationmode,patientswillhyperventilateifFGFisinadequate

Types:

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MaplesonASetup

APLvalveclosetomaskTubingbetweenbagandmaskFGFclosetobag

Flowrequirements

Spontaneousventilation:APLvalveissetlow.Initialexhalation(whichismostlydeadspace,andnotcontainingCO )willfillbaguntilbagpressureexceedsAPLvalveopeningpressure.ProvidedtheAPLvalveissetlow,themajorityofCOcontainingexhalationwillexitthroughtheAPLvalve,andFGFrequiredtoclearCO fromthecircuitislow.

Controlledventilation:APLvalveissethigh.Moreoftheexhalationwillfillthebag,andsoagreaterFGFisrequiredtopreventre-breathing.

MaplesonB&CSetupAPLvalveandFGFaresituatedclosetothemask.

MaplesonBhaslongtubingbetweenthemaskandbagMaplesonChasshorttubingbetweenthemaskandbag

Flowrequirements

Spontaneousandcontrolledventilationaresimilar,at .MaplesonD

SetupFGFisisclosetomaskValveisclosetobagTubingbetweenFGFandAPLvalveCo-axialversionsexist,butarefunctionallysimilar.

FlowrequirementsOverall,generallythebestcircuittomaximiseefficiencyacrossbothspontaneousandcontrolledventilation.

Spontaneousventilation:

Controlledventilation:Bestcircuitforcontrolledventilation.

MaplesonE/Ayre'sT-pieceSetup

T-shapedcircuitwithnovalveorbagMaplesonF/Jackson-ReesmodificationtotheAyre'sT-piece

SetupBag(withhole)addedtothestemoftheTofaMaplesonEAllowsmonitoringofventilation,andoccludingtheholeofthebagallowscontrolledventilation.FunctionallyidenticaltoaMaplesonD,withanoperator-controlledAPLvalve

FlowrequirementsAsperMaplesonD.

Spontaneousventilation:

Controlledventilation:

References1. Westhorpe,R.PaediatricBreathingSystems.RCHAnaestheticTutorialProgram.2019.

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CircleSystemThiscoversthecirclebreathingsystem.Ageneraloverviewofanaestheticbreathingsystemsiscoveredunderanaestheticcircuits.

Thecirclebreathingsystemisahighlyefficientsystemwhich:

HasseveralkeyadvantagesPreservesanaestheticgasesmakingvolatileanaesthesiacost-effectivePreservesmedicalgases(oxygen)whichisusefulinresource-limitedsettings(e.g.prehospital)PreservesheatandmoistureReducesfireriskParticularlywitholderagents.

Requiresre-breathingofexpiredgasesCO isactivelyremoved.Isaclosed-circuitsystem

Theonlygaseswhichmustbereplacedarethose:Consumedbythepatient

OxygenAbsorbedandmetabolisedvolatileagents

Lostvialeak

PrinciplesAcirclecircuitconsistsof:

AY-piece,connectingthecircuittothepatientExpiratoryandinspiratoryvalves,ensuringunidirectionalflowAmeansofgeneratingpressureInmostsystemsthisconsistsofbothaventilatorandareservoirbagwithAPLvalveattached,withabag/ventswitchtoswapbetweencircuits.

ThesearetypicallyplacedontheexpiratorylimbsothatgascanberemovedviascavengingpriortopassagethroughsodalimeThisreducessodalimeconsumption,assomeCO willbescavenged.

SodalimeToabsorbCO .Freshgasflow

Includesoxygen,airandnitrousoxideOxygenenterstheback-barlastWhenthevapouriserisout-of-circuit,allfreshgasflowwillpassthroughthevapouriserpriortoenteringthecircle

Aseparatehigh-pressurehigh-flowoxygenflush,whichbypassesthevapouriser

SodaLime

Sodalime:

Consistsofgranulesof:81%Ca(OH)4%NaOH15%H OSilicates

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Hardensgranules.

pHindicatorVisualrepresentationofuptakeofCO bysoda-lime.

PhenolphthaleinRedtowhite.EthylvioletWhitetopurple.

Granulesare4-8meshinsizeWillpassthroughameshwith4holespersquareinch,butnot8Balancebetweensurfacearea(speed/efficacyofreaction)andresistancetoflow

AbsorbsCO byfollowingreaction:

ThisincreasesthepHofthesodalime,causingthepHindicatortochangecolour100gofsodalimecanabsorb~26LofCO

Pros

CheapertooperateConservesgases,heat,andmoistureLowdeadspaceReducedgreenhouseeffects

Cons

GasmixturesettingsarenotdeliveredtothepatientSettingsaffectthefreshgasflowmixture,whilstthepatientrespiresgasfromthecircuit.Thesearenotidentical,especiallyatlowflows.Nitrogenmaybuildupinthecircuitduringlow-flowanaesthesia,andpotentiallyleadtodeliveryofahypoxicgasmixtureLessportablethanopen-circuitsystemsIncreasedcircuitresistanceRequiressodalime,whichcanbetoxic

ProducesCompoundA-EfromsevofluraneProducescarbonmonoxidefromdesflurane,isoflurane,andenfluraneDangerousifaspirated

References

1. AstonD,RiversA,DharmadasaA.EquipmentinAnaesthesiaandIntensiveCare:AcompleteguidefortheFRCA.ScionPublishingLtd.2014.

Lastupdated2019-07-18

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ScavengingDescribethehazardsofanaestheticgaspollutionandthemethodsofscavenginganaestheticgases

Scavengingistheremovalandsafedisposalofwasteanaesthesiagasesfromthebreathingcircuittoavoidcontaminationofthetheatreenvironment.Thisisimportantascontinuousexposureofstafftoanaestheticgaseshasbeenimplicatedin:

CognitiveimpairmentSpontaneousabortionInfertilityHaematologicalmalignancy

MethodsofScavengingAscavengingsystemconsistsof:

GascollectionassemblyConnectstotheAPLvalveandventilatorreliefvalveCollectsgasventedfromthecircuit.Usesa30mmconnectorPreventsaccidentalconnectiontothebreathingsystem.

TransfertubingScavenginginterfaceThestructureofthescavenginginterfacedependsonthetypeofscavengingsystem.

OpeninterfaceActivescavengingsystemsuseapumptogenerateapressuregradientdrawinggastothedisposalassembly.Thescavenginginterfaceisopentoairtopreventthenegativepressurebeingtransmittedtothepatient.ClosedinterfacePassivescavengingsystemsuseaseriesofpositiveandnegativepressurereliefvalves.

Whengaspressureinthecollectionassemblyexceeds5cmH O,thepositivereliefvalveopensandgasentersareservoirbagWhengaspressureinthedisposalassemblyfallsbelow0.5cmH O,thenegativereliefvalveopensandgasentersthedisposalassembly

MoretransfertubingDisposalassembly

References

1. AstonD,RiversA,DharmadasaA.EquipmentinAnaesthesiaandIntensiveCare:AcompleteguidefortheFRCA.ScionPublishingLtd.2014.

Lastupdated2019-07-18

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DiathermyDiscusstheprinciplesofsurgicaldiathermy,itssafeuseandthepotentialhazards

Diathermyistheuseofanelectricalcurrenttocuttissueandcoagulatebloodvialocalisedheating.Diathermy:

Useshighfrequency,alternatingcurrentpassingbetweentwoelectrodesFrequenciesbetween300kHzand2MHzareused,whichhaveanegligibleriskofinducingarrhythmia.

Heatenergyproducedisproportionaltoelectricalpowerdissipated( )Reliesontheprincipleofcurrentdensity

AhighcurrentdensityattheelectrodecausestissuedamageAlowcurrentdensity(e.g.attheplateofaunipolarelectrode)causesheatingwithoutdamage

DiathermyTypesDiathermycanbeeither:

UnipolarConsistsofaprobecontainingoneelectrode,andalargeplate(placedelsewhereonthepatient)containingtheotherprobe.BipolarConsistsofapairofforcepswitheachpointcontainingaseparateelectrode.Minimisesthecurrentpassingbetweenprobes,andisusedwhenusingdiathermyonelectricallysensitivetissues(e.g.brain).

DiathermyModes

Diathermymodesinclude:

CuttingLow-voltagemodeproducingahighcurrentintheshapeofacontinuoussinewave.CoagulateHigh-voltagemodeproducingadampedsinewaveresponse.BlendedMixtureofcuttingandcoagulateondifferenttissues.

RisksBurnsFromincorrectlyappliedunipolarplate.ElectrocutionMayinjurepatient,staff,ordamageequipmentandimplants.ElectricalInterferenceMayinhibitpacingincertainpacemakers,ortriggerICDs.SmokeproductionRespiratoryirritant,disseminationofviralparticles,andmaybecarcinogenic.TissuedisseminationPotentialsourceofmetastaticseeding.

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References1. AstonD,RiversA,DharmadasaA.EquipmentinAnaesthesiaandIntensiveCare:AcompleteguidefortheFRCA.Scion

PublishingLtd.2014.

Lastupdated2017-09-16

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LasersDescribetheprinciplesofsurgicallasers,theirsafeuseandthepotentialhazards

Alaserisadeviceforlightamplificationbystimulatedemissionofradiation.Laserlightis:

Non-divegentAllphotonsmoveinparallel.CoherentAllphotonsareinphase.MonochromaticAllphotonshavethesamewavelength.

Lasersareusedclinicallyfor:

PreciseincisionsDestructionofcellsbylocalisedvapourisationofwater.DestructionofchemicalsTattoos,oncologicaldrugs.TissuedestructionwithoutheatingOpthalmology.

PrinciplesMethod:

Anenergysourceispassedthroughalasingmedium,housedinaresonatormadeofmirrorsAsthelasingmediumisexcited,electronsenterahigherenergylevelWhenmorethan50%ofelectronsareatahigherenergylevel,populationinversionhasoccurred.Aselectronsfallbacktotheirrestingstate,theyreleaseaphoton

AspontaneousemissionoccurswhenanelectronentersitsrestingstatespontaneouslyAstimulatedemissionoccurswhenanelectronentersitsrestingstateafterbeingstruckbyaphotonreleasedfromaspontaneousemission

StimulatedemissionsresultinamplificationoflightreleaseThemirrorsintheresonatingchamberensuremostlightisreflectedbackintothechamber,causingmorestimulatedemissionsTheexitfromthechambercanbebeadjustedsoonlycertainpolaritiesoflightareemittedAlensmaybeusedtofocusthelaserbeam

Lasersmaybe:PulsewaveUsesshortburstsoflaserlighttominimisecollateraldamage.ContinuouswaveMayleadtoexcessiveheating.

Pros

Precisesurgeryandhaemostasis

Lasers

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Cons

RequiremultiplesafetyprecautionsLasersafetyofficerEyeprotectionWarningsignsondoorsCovertheatrewindowsNon-combustibledrapesMattefinishonequipmenttominimisechanceofreflection

AdditionalrisksinairwaysurgeryUselowestFiO possibleAvoidN OConsideruseofhelioxUsespecialisedlasertubesNormalPVCETTsarecombustible.

References

1. AstonD,RiversA,DharmadasaA.EquipmentinAnaesthesiaandIntensiveCare:AcompleteguidefortheFRCA.ScionPublishingLtd.2014.

Lastupdated2019-07-18

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SubclavianVeinDescribetheanatomyrelevanttocentralvenousaccess(includingfemoral,internaljugular,externaljugular,subclavianandperipheralveins)

Thesubclavianvein:

IsacontinuationoftheaxillaryveinasitcrossestheuppersurfaceofthefirstribTravelsposteriortotheclavicle,separatedfromthesubclavianarterybytheanteriorscaleneJoinswiththeinternaljugularveintoformthebrachiocephalicvein

BordersAnteriorlybytheclavicle,subclaviusmuscle,andpectoralismajorPosteriorlybyanteriorscalenemuscleandsubclavianarteryInferiorlybyfirstribandlungapexSuperiorlybyskin,subcutaneoustissue,andplatysmaMediallybythebrachiocephalicveinLaterallybytheaxillaryvein

SurfaceAnatomyTheneedleisplacedinthedeltopectoralgroove,inferiorandlateraltothemiddlethirdoftheclavicle.Theneedleisinsertedatashallowangle,passingunderthemiddlethirdoftheclavicleaimingatthesternalnotch.

References1. McMinn,RMH.Last'sAnatomy:RegionalandApplied.9thEd.Elsevier.2003.

Lastupdated2019-07-18

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InternalJugularVeinDescribetheanatomyrelevanttocentralvenousaccess(includingfemoral,internaljugular,externaljugular,subclavianandperipheralveins)

Theinternaljugularvein:

OriginatesatthejugularbulbThisisadilatationformedbytheconfluenceoftheinferiorpetrosalsinusandthesigmoidsinus.ExitstheskullviathejugularforamenDescendslaterallytotheinternalcarotid(andlaterthecommoncarotid)inthecarotidsheathTerminatesbehindthesternalendoftheclavicle,whereitjoinswiththesubclavianveintoformthebrachiocephalicvein

BordersAnteriorlybySCMPosteriorlybythelateralmassofC1,scalenemuscles,andlungpleuraMediallybytheinternalcarotid

RelationshipsVagusnerveliesbehind/betweenthecarotidandIJVCervicalsympatheticplexusliesposteriortothecarotidsheathDeepcervicallymphnodeslieclosetotheveinExternaljugularcrossesthesternomastoidbellyofSCM,runningposteriorlyandmoresuperficialtotheIJV,laterperforatingdeepfasciatodrainintothesubclavianveinPleurarisesabovetheclavicle,andisclosetotheveinatitsterminationThoracicductpasseslateraltotheconfluenceoftheleftIJVandSCV,andmaybeinjuredduringleftIJVcannulation

TherightlymphaticductmaybeinjuredduringrightIJVcannulation,butduetoitssmallersizethisislesscommon

SurfaceAnatomyIdentifythetriangleformedbythetwoheadsofSCMandtheclavicle.Palpatetheartery,andensurethesiteofentryislateraltothecarotid.Aim:

Caudally,ata30angletothefrontalplaneParalleltothesagittalplaneTowardstheipsilateralnipple

UltrasoundAnatomy

IdentifytheveindeeptoSCM,notingthatitis(unliketheadjacentICA):

Non-pulsatileThinwalledCompressible

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Approaches

AnteriorAtthemedialborderofSCM,3-4cmabovetheclavicle.Requiresretractionofthecarotidmedially.CentralapproachAttheapexofthetriangleformedbyeachmusclebellyofSCMandtheclavicle.PosteriorapproachAttheposterioredgeofSCM,justsuperiortowheretheEJVcrossesthesternomastoid.

References

1. Lasts2. http://radiopaedia.org/articles/internal-jugular-vein3. http://www.frca.co.uk/article.aspx?articleid=1000304. Internaljugularveincatheterisation:PosteriorandCentralApproach

Lastupdated2019-07-18

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IntercostalCatheterDescribetheanatomyrelevanttotheinsertionofanintercostalcatheter

Anintercostalcatheterdrainstheintrapleuralspace.

SurfaceAnatomy

AnICCshouldbeplacedinthesafetriangle:

Thisisbordered:

AnteriorlybypectoralismajorPosteriorlybylatissimusdorsiToofarposteriorwillinjurethelongthoracicnerve.SuperiorlybythebaseoftheaxillaInferiorlybythe5 intercostalspaceToofarinferiorlyrisksplacementintheliverorspleen.

LayersofDissectionSkinSubcutaneoustissueExternalintercostalInternalandinnermostintercostalmusclesNotetheneurovascularbundlewhichsitsontheinferioraspectoftheribs,thereforeaimtoplacetheICCatthebottomoftheintercostalspace-"abovetheribbelow".Parietalpleura

References

1. LITFL-ChestDrain

Lastupdated2017-09-18

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IntercostalCatheter

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AntecubitalFossaDescribetheanatomyrelevanttocentralvenousaccess(includingfemoral,internaljugular,externaljugular,subclavianandperipheralveins)

Theantecubitalfossaisatriangularspaceontheanterioraspectoftheforearm.

Borders

Thetriangularbordersareformed:

MediallybypronatorteresLaterallybybrachioradialisSuperiorlybyanimaginarylinebetweenthemedialandlateralepicondyles

Theroofofthefossaisformedbysubcutaneoustissue

Thefloorisformedbybrachialisandsupinator

ContentsFrommedialtolateral:

MediannerveBrachialarteryBicepstendonandaponeurosisRadialandposteriorinterosseousnervesVeins

BasilicveinCephalicveinVenousvariations:

AmediancubitalveinconnectingthebasilicandcephalicveinsAmedianveinoftheforearm,whichdividesintoamedianbasilicandmediancephalicveinwhichdrainintothebasilicandcubitalveins

References1. FRCA-TheCubitalFossa

Lastupdated2019-07-18

AntecubitalFossa

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TracheostomyDescribetheanatomyrelevanttotheperformanceofanaso,orendo,trachealintubation,acricothyroidotomyortracheostomy

Trachea

Thetracheaisfibrocartilagenoustubewhich:

ExtendsfromthelarynxsuperiorlytothePlaneofLouisinferiorlyTerminatesbydivisionintotherightandleftmainstembronchiRunsat15degreesparalleltothesurfaceoftheneck,suchthatthedistaltracheaisdeeperthantheproximaltracheaHasaD-shapedcrosssection

Anteriorwallisformedby18-22incompletecartilaginousringswhichmaintaintrachealpatencyPosteriorwallofthetracheaisspannedbylongitudinalsmoothmuscleknownastrachealis

Istypically:10cmlong2.3cmwide1.8cminAPdiameter

Relationships

Lateraltothetracheaarethe:CarotidsheathsContainsthecarotidartery,internaljugularvein,andvagalnerves.Thyroidlobes(andinferiorthyroidarteries)Recurrentlaryngealnerves.

InferiortothethyroidisthmusliesthethyroidveinsPosteriortothetracheaarethe:

OesophagusVertebralcolumn

SurfaceAnatomy

Midlineneckstructuresarerelevantsurfaceanatomy:

LaryngealstructuresIncluding:Hyoid,thyroidcartilage,cricothyroidmembrane,cricoidcartilage.SternalnotchThyroidlobesLielateraltotrachea.

LayersofDissectionSkinSubcutaneousfatSuperficialandDeepPretrachealfasciaTrachealwall

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Ideallybetween1stand2ndrings

References1. McMinn,RMH.Last'sAnatomy:RegionalandApplied.9thEd.Elsevier.2003.

Lastupdated2019-07-18

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ToxicAlcoholsAlcoholsinclude:

EthanolMethanolEthyleneGlycol

Intoxicity:

AllpresentwithsymptomsofalcoholintoxicationAllcontributetotheosmolargapDifferenttoxicitiesoccurduetothedifferentmetabolites

Ethanol

Ethanolisaweakalcoholwithacomplicatedmechanismofactionsimilartovolatileanaestheticagents:

EnhancedGABA-mediatedinhibitionThisisreversiblewithflumazenil.InhibitionofCa entryInhibitionofNMDAfunctionInhibitionofadenosinetransport

Property Drug

Dosing Oneunitis~8g/10mlofpureethanol

Absorption RapidPOabsorption

Metabolism

Saturatablekineticsat>4mmol.L duetohighdosesrequiringextensiveNAD foroxidation,limitingmetabolismto~1unitperhour.Low(0.2)extractionratio,sohighportalveinconcentrationsfromrapidabsorption(e.g.shots)causesagreaterpharmacologicaleffect.Ethanolismetabolisedbyalcoholdehydrogenasetoacetylaldehyde,whichismetabolisedbyaldehydedehydrogenasetoacetylCoA.

Elimination 10%eliminatedunchangedinairandurine

Resp Respiratorydepression

CVS Vasodilatationincreasingheatloss,reducedcardiovasculardiseasemortalityduetoincreasedHDLandinhibitionofplatelets.Alcoholiccardiomyopathyinabuse.

CNS Slurredspeech,intellectualimpediment,motorimpediment,euphoria,dysphoria,increasedconfidence.Dementia,encephalopathy,peripheralneuropathy,andcerebellaratrophywithchronicuse.

Endocrine StimulatesACTHreleaseand'pseudo-Cushing'ssyndrome'.Inhibitstestosteronerelease.Maycauselacticacidosisandhypoglycaemiaintoxicity.

Renal InhibitionofADHrelease,causingdiuresis.Ethanolisosmoticallyactiveandcontributestotheosmolargap.

GIT Gastritis.Fattyliver,progressingtohepatitis,necrosis,fibrosisandcirrhosis

GU Tocolyticeffect

Haeme Inhibitionofplateletaggregation

Metabolic Highenergycontentcomparablewithfat(29kJ.g )

Other SynergisticwithotherCNSdepressants.Metabolicinteractionswithwarfarin,phenobarbitone,andsteroids

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Methanol

MetabolisedbyalcoholdehydrogenasetoformaldehydeandthenformicacidFormicacidisneurotoxicDamagesretinaandtheopticnerve.

EthyleneGlycol

Metabolisedbyalcoholdehydrogenasetoglycoaldehyde,and(viaseveralintermediatesteps)tooxalicacidOxalicacidbindscalcium,whichcauses:

HypocalcaemiaLongQT

Acuterenalfailure

References

1. RangHP,DaleMM,RitterJM,FlowerRJ.RangandDale'sPharmacology.6thEd.ChurchillLivingstone.2. HolfordNH.Clinicalpharmacokineticsofethanol.ClinPharmacokinet.1987Nov;13(5):273-92.3. LITFL-ToxicAlcoholIngestion

Lastupdated2019-07-18

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NaloxonePureMOPantagonistusedfor:

TreatmentofopioidoverdoseReducingconstipationIncombinationwithPOoxycodone.

Property Drug

Class μ-selectiveopioidreceptorcompetitiveantagonist

Uses Opioidoverdose,neuraxialopioidsideeffects(e.g.pruritus),preventionofconstipationincombinationwithoralopioids

Presentation Clear,colourlesssolutionat400mcg.ml

RouteofAdministration IV,IM,PO

Dosing 0.1-0.4mgQ5min,0.5mg.kg .hr byinfusion

Absorption Veryhighfirstpassmetabolismleadingto~2%PObioavailability

Distribution 50%proteinbound.V 2L.kg ,highlylipidsoluble.

Metabolism Rapidhepaticglucuronidation

Elimination Renalelimination

Resp Reversalofopioid-inducedrespiratorydepression(↑RR,↑V )

CVS ↑SVR&↑BP,arrhythmiadue↑inSNStone

CNS ↓Analgesia,↓sedation,↓miosis.Antanalgesicinopioidnaivepatients.Precipitationofopioidwithdrawal.

Otherconsiderations

Durationofactionis~30-40minutesisshorterthansomeopioids,whichmayleadtore-narcosisifnotgivensubsequentdosesorbyinfusion

References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.

Lastupdated2019-07-18

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FlumazenilCompetitiveantagonistandinverseagonistofthebenzodiazepinereceptor.

Property Action

Class Imidazo-benzodiazepine

Uses ReversalofBZD

RouteofAdministration IV

Dosing 0.1mgbolusesupto2mg

Onset Within2minutes

Distribution Moderatelipidsolubility,50%proteinbound.t β<1hour-mayrequireinfusion.

Metabolism Hepatictoinactivemetabolites

Elimination Renalofmetabolites

CNS MayprecipitateseizuresorBDZwithdrawalduetoinverseagonisteffect

GIT N/V

References

1. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.

Lastupdated2017-09-17

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Oxygen

Property Action

Class Naturallyoccurringgas

Uses ImproveFiO ,COpoisoning,hyperbaricO therapy

Pharmaceutics Clear,colourless,odourlessgasatSTP.Criticaltemperature-119°C,manufacturedbyfractionaldistillation.Highlyflammable.

RouteofAdministration Inhaled

Dosing 0.21-1.0FiO

Absorption Diffusionacrossthealveolarcapillarymembraneinproportiontomembraneareaandpartialpressuregradient,andinverselyproportionaltomembranethickness

Distribution BoundtoplasmaHb,anddissolvedinplasma

Metabolism MetabolisedinmitochondriaofcellsduringthecitricacidcycletoproduceATP,creatingCO

Elimination ExhalationasCO ,orcombinedwithH OtoproduceHCO andeliminatedinurine

Resp↓Respiratorydriveinallindividuals.Mayresultinafatal↓inthosedependentonhypoxicdrive.PulmonarytoxicityduetofreeradialformationwhenPiO >0.6bar-pneumonitis/ARDSduetolipidperoxidationofthealveolar-capillarymembrane.Absorptionatelectasis.

CVS ImprovementinallCVSparametersinthesettingofhypoxia.However,hyperoxia↓CO,↓PVR,↓PAP,andcausescoronaryvasoconstrictionwithprolongedadministration

CNSCNSO toxicity,typicallyatpressures>1.6barthoughthisisvariable.Presentswithavarietyofneurologicalsymptoms,progressingtodisorientationandseizure.RetrolentalfibroplasiainneonatesexposedtohighFiO .

Other Firerisk

References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. RAHAdvancedDivingMedicineCourseNotes:Chapter6OxygenandCarbonDioxideToxicity

Lastupdated2019-07-18

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HeliumHeliumisaninertgaswhichisusedtoreducethespecificgravityofinhaledgasmixtures.Itistypicallyprovidedasa0.79/0.21Helium-Oxygen(Heliox)mixture(thoughotherdilutionsexist).

Helium Heliox(0.79/0.21) Oxygen

SpecificGravity(ascomparedtoair) 0.18 0.34 1.09

ReducedspecificgravityresultsinaproportionalreductioninReynoldsNumber,improvinglaminarflowwithintheairways.

Property Action

Class InertGas

Uses Obstructivelungdisease,deepwaterdiving

Presentation Clear,colourlesssolution

RouteofAdministration Inhaled

Dosing TypicallyasHeliox:79%He/21%O

Absorption Diffusionacrossthealveolarcapillarymembraneinproportiontomembraneareaandpartialpressuregradient,andinverselyproportionaltomembranethickness

Distribution Distributesproportionallytosolubilityandtissuepartialpressures

Metabolism Notmetabolised

Elimination Respiratoryexhalationalongapressuregradient

Resp Significantlydecreasesthespecificgravityofinhaledgasmixtures

ToxicEffects HighPressureNeurologicSyndromeat>16atm

References

1. RAHAdvancedDivingMedicineCourseNotes:Chapter6OxygenandCarbonDioxideToxicity

Lastupdated2017-12-22

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BetaAgonistsThiscoverstheinhaledβ-agonistsusedforbronchodilation.Informationoncatecholaminesandsympathomimeticswithactivityonβ-receptorsiscoveredunderadrenergicvasoactives.

CommonFeatures

PharmacodynamicEffects β-agonists

Resp Bronchodilatation,↓HPVcausing↑shuntandpotential↓PaO ifO isnotco-administered.

CVS ↑HR(β withhigherdoses),↓BP(β withlowerdoses)

GU Tocolytic.

Metabolic Hypokalaemiafromβ stimulationofNa /K ATPase,hyperglycaemia.

Other Potentiatesnon-depolarisingmusclerelaxants

Differences

Property Salbutamol Salmeterol

Class Syntheticsympathomimeticamine Syntheticsympathomimeticamine

Uses Acuteasthma/bronchospasm,hyperkalaemia Nocturnalandexercise-inducedasthma

Presentation MDI(100µg),solutionat2.5-5mg.ml fornebulisation MDI

RouteofAdministration Inhaled,IV Inhaled

Dosing 1-2puffsviaMDI,5mgnebulised.0.5mcg.kg .min asIVinfusion.

Onset Rapid Slow

Distribution Lowproteinbinding

Metabolism Highfirstpasshepatictoinactivemetabolites,t β6hours. ExtensivehepaticviaCYP3A4

Elimination Urinaryeliminationofactive(30%)drugandinactivemetabolites Renalofmetabolites

References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.

Lastupdated2017-09-07

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Bronchodilators

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Antimuscarinics(Respiratory)AntimuscarinicswithpredominantlycardiaceffectsarecoveredatAntimuscarinics(Cardiac),whilstatropineiscoveredseparately.

TheseagentscompetitivelyantagoniseAChatM receptorsinbronchialsmoothmuscle,preventingparasympatheticmediatedbronchoconstriction.

Property Ipratropium Tiotropium

Class Muscarinicantagonist Muscarinicantagonist

Uses Bronchodilatation Bronchodilatation

Presentation MDIorsolutionfornebulisation MDI

RouteofAdministration Inhaled Inhaled

Dosing 18mcgMDI,500µgnebuliser

Absorption 5%bioavailabilityviainhaledroute

Metabolism Hepatictoinactivemetabolites

Elimination Equalrenalandfaecalelimination

Resp Bronchodilation Bronchodilation

GIT DecreasedGIsecretionsinlargedoses DecreasedGIsecretionsinlargedoses

CNS Mydriasisifdepositedineye Mydriasisifdepositedineye

References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.

Lastupdated2017-08-02

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PhosphodiesteraseInhibitors/MethylxanthinesMethylxanthinesnon-selectivelyinhibitphosphodiesterase,whichresultsinreducedlevelsofcAMPhydrolysisandthereforeincreasedintracellularcAMP,andsubsequentsmoothmusclerelaxation.Thiseffectissynergisticwithβ agonists,whichalsoincreasecAMPbyincreasingproduction.

Property Theophylline

Class Methylxanthine/Non-selectivephosphodiesteraseinhibitor

Uses AsthmaandCOAD

RouteofAdministration IVorPO

Dosing 4-6mg.kg IVload,thenat0.4mg.kg .hr targetingserumconcentrationof10mcg.ml

Absorption Highoralbioavailability

Distribution V 0.5L.kg ,40%proteinbinding.

Metabolism HepaticviaCYP450toactivemetabolites(caffeineand3-methylxanthine),lowhepaticextractionratio

Elimination Highlyvariableeliminationaffectedbyage,renaldisease,hepaticdisease

Resp Bronchodilation,↑Diaphragmaticcontractility

CVS ↑Inotropy,↑chronotropy.Narrowtherapeuticrangeduetoarrhythmogenic(VF)properties

CNS ↓Seizurethreshold

Renal Natriuresisandhypokalaemia

ToxicEffects Lowtherapeuticindex,withtoxicitymanifestedastachyarrhythmiasincludingVF,tremor,insomniaandseizures

References

1. Lexicomp.Theophylline:DrugInformation.In:UpToDate,Post,TW(Ed),UpToDate,Waltham,MA,2017.2. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.3. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.

Lastupdated2019-07-18

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LeukotrieneAntagonistsSelectivelyinhibitthecysteinylleukotrienereceptor,increasedactivityofwhichisinvolvedinairwayoedemaandbronchialsmoothmuscleconstriction.

Property Montelukast

Class LeukotrieneAntagonist

Uses Asthma,allergicrhinitis

RouteofAdministration PO

Dosing 10mgdaily

Absorption 64%PObioavailability

Distribution t 5hours,>99%proteinbound

Metabolism HepaticbyCYP3A4

Elimination Predominantlyfaecal

Resp Bronchodilatation

References

1. .Lexicomp.Montelukast:Druginformation.In:UpToDate,Post,TW(Ed),UpToDate,Waltham,MA,2017.

Lastupdated2017-09-20

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LeukotrieneAntagonists

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CorticosteroidsGlucocorticoidsareendogenous(hydrocortisone)andsynthetic(prednisolone,methylprednisolone,dexamethasone)steroidhormoneswithmetabolic,anti-inflammatory,andimmunosuppressiveeffects.Theybindtospecificintracellularreceptorsandtranslocateintothenucleus,wheretheyregulategeneexpressioninatissue-specificmanner.

Corticosteroidshavemultipleindicationsincluding:

Replacementinadrenalsuppressionorothercortisol-deficientstatesAutoimmunedisordersAnaphylaxisandatopicdisorders,includingasthmaHypercalcaemiaChemotherapyImmunosuppressionfollowingtransplantation

CommonFeatures

System Effect

Resp ↑Bronchialsmoothmuscleresponsetocirculatingcatecholamines,↓airwayoedema

CVS ↑Inotropy,↑vascularsmoothmuscleresponsetocirculatingcatecholamines(↑receptorexpression),↑BPsecondarytomineralocorticoideffects

CNS Moodchanges,sleepdisturbance,psychosis

MSK Atrophy,thinningofskin

Renal Glycosuria,Na andfluidretention(mineralocorticoideffect),hypokalaemia

GIT Gastriculceration

Metabolic ↑Gluconeogenesis,diabetes,↑proteincatabolism,fatredistribution,adrenalsuppression(negativefeedbackonACTH),↑lipolyticresponsetocirculatingcatecholamines

Immune ↓Transudateproduction,↓productionofinflammatorymediators,↓macrophagefunction,↓transportoflymphocytes,↓T-cellfunction,↓antibodyproduction,↑susceptibilitytoinfection,

ToxicEffects Relativesteroiddeficiencyinadrenalsuppressedindividualswithinfectionorsurgery

ComparisonofCorticosteroids

Property Hydrocortisone Prednisolone Methylprednisolone Dexamethasone

RouteofAdministration IV/PO PO PO/IV/IM IV

RelativeDoseEquivalents 100mg 25mg 20mg 4mg

Absorption 50%PObioavailability

100%PObioavailability

60%PObioavailability

Distribution

Variableproteinbindingdependingonconcentration,V 0.5L.kg

Variableproteinbindingdependingonconcentration,V0.5L.kg

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Metabolism Hepatic Hepatic Hepatic Hepatic

Elimination Eliminationt is2hours

Eliminationt is3hours

Eliminationt is3hours

Eliminationtis4hours

Relativemineralocorticoideffect

+++ ++ + +

References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.3. NiemanLK,LacroixA,MartinKA.Pharmacologicuseofglucocorticoids.In:UpToDate,Post,TW(Ed),UpToDate,

Waltham,MA,2017.4. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.

Lastupdated2019-07-18

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PulmonaryVasodilators

Property NitricOxide Iloprost Sildenafil

Class Inorganicgas Syntheticeicosanoidwithprostacyclinactivity

Uses ARDS,RVF,PHTN PHTNPHTN,erectiledysfunction

Presentation Aluminiumcylinderswith100/800ppmNO/N Syntheticanalogofepoprostenol

RouteofAdministration Inhaled Inhaled PO

Dosing 1-40ppm,viainspiratorylimbofventilator 20mgTDS

Absorption 40%PObioavailability

Distribution AvidlyboundtoHb95%proteinbound,V of100L

MetabolismMetabolisedtomethaemoglobinandnitritepriortoreachingsystemiccirculation-tof<5s

HepaticbyCYP450

Elimination Faecal

MechanismofAction

StimulatescGMPwhichreducesintracellularCa

StimulatescAMPwhichreducesintracellularCa andsmoothmusclegrowth

InhibitscGMP

Resp InhibitsHPV,improvesV/Qmatching

CVS↓vascularresistance,↓PVRinventilatedalveoliandimprovingV/Qmatching.↑Capillarypermeability.

↓BPwithcompensatory↑HR ↓PVR

CNS ↑CBF

Haeme Inhibitsplateletaggregation.MetHb Inhibitsplateletaggregation

Other ReboundpulmonaryHTNonabruptcessation

References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.

Lastupdated2019-07-18

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PulmonaryVasodilators

575

AdrenergicVasoactivesThiscoversthepharmacologyofspecificcatecholaminesandsympathomimetics.Thesynthesisofendogenouscatecholaminesiscoveredunderadrenalhormones,whilstspecificsofcatecholaminereceptorfunctioniscoveredunderadrenoreceptors.

Adrenergicdrugs:

Actvia:Dopamine(D)Adrenoreceptors(αandβ)

Canbe:Direct-actingStimulatethereceptor.Indirect-actingStimulatethereleaseofnoradrenalinetocauseeffects.

Classifiedaseither:Naturally-occurringcatecholaminesSyntheticcatecholaminesSyntheticsympathomimeticsDrugswhichactonadrenoreceptorsbutarenotclassifiedascatecholaminesduetotheirchemicalstructure.

ComparisonofCommonlyUsedAdrenergicAgents

Properties Noradrenaline Adrenaline Phenylephrine Metaraminol Ephedrine

Class NaturalCatecholamine

NaturalCatecholamine

Sympathomimeticphenylethylaminederivative

Syntheticsympathomimetic

Syntheticsympathomimetic

Uses ↑SVR

Cardiacarrest,anaphylaxis,inotropy,chronotropy,adjunctinlocalanaesthetics

↑SVR ↑SVR ↑SVRwithout↓inHR

Dosing Startat0.05µg/kg/min

Infusionstartsat:0.01µg/kg/min

Bolusstartat50-100mcg Bolus0.5-2mg 3-6mgbolus

Route IV IV/IM/ETT/SC IV/IM/SC IV IV

Presentation

Clear,colourless,light-sensitivesolution.Sodiummetabisulfiteasexcipient.

Aclear,colourlesssolutiontypicallyat0.1-1mg/ml

Clear,colourlesssolutionat100mcg/ml

Clear,colourlesssolutioninampouleat10mg/ml,typicallyreconstitutedto0.5mg/ml

Clear,colourlesssolutionin30mg/mlampoule

Absorption IVonlyVariableETTandSCabsorption

IMonset15minutes,durationupto1hour

IVonly IVorIM

t 2min.MetabolisedbymitochondrialMAOand

t 2min.MetabolisedbymitochondrialMAOand Someuptakeinto

Hepatic(notmetabolisedbyMAOandCOMT),givinga

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Metabolism COMTinliver,kidney,andbloodtoVMAandmetadrenaline.

COMTwithinliver,kidney,andbloodtoVMAandmetadrenaline.

HepaticbyMAO adrenergicnerveendings

longer(10-60minute)durationofactionandat βof3-6hours

Elimination

Pulmonaryuptakeofupto25%.Urinaryexcretionofmetabolites

Urinaryexcretionofmetabolites

Renalofmetabolites,t β2-3hours

50%unchangedinurine

Mechanismofaction α>>β

β>αatlowerdoses.Athighdosesα effectsdominate.

Directα

Directandindirect(via↑NArelease)αagonism

↑NArelease(indirectα )anddirectαandβagonism

Respiratory ↑MV,bronchodilation

↑MV,bronchodilation Bronchodilation

CVS

↑SVR,↑MyocardialOconsumption,↑Coronaryflow.

↑Inotropy,↑HR,↑SVRandPVR,↑BP,↑CO,↑myocardialOconsumption.Coronaryvasodilation.Arrhythmogenic.

↑SVRandBP,potentialreflexbradycardia.Notarrhythmogenic.

↑SVR/PVR,reflexbradycardia.Indirect↑incoronaryflow.

Directandindirect(viaNArelease)↑inHR,BP,andCO.Arrhythmogenic.

CNS ↑Painthreshold,↑MAC

↑MAC,mydriasis.

MSK Necrosiswithextravasation

Necrosiswithextravasation

Renal ↓RBF ↓RBFand↑insphinctertone ↓RBF ↓RBF ↓RBF

Metabolic

↑BMR,↑lipolysis,↑gluconeogenesisandBSL,↑Lactate.Initially↑insulinsecretion(β),then↓(α)

GU↓Uterinebloodflowandfoetalbradycardia

↓Uterinebloodflow

↓Uterinebloodflow

ComparisonofLessCommonAdrenergicAgents

Properties Dopamine Isoprenaline Dobutamine

Class NaturalCatecholamine SyntheticCatecholamine SyntheticCatecholamine

Uses Haemodynamicsupport Severebradycardia Stresstesting,increasingCO

Dosing Start1µg/kg/min Infusionfrom0.5-10µg/min 0.5-20µg/kg/min

Route IV IV IV

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CardiovascularPharmacology

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Presentation Clear,colourlesssolutionwith200mgor800mginwater

Clearsolutionat1mg/ml

250mgdobutaminein20mlwater

Metabolismt 3min.25%ofdoseconvertedtonoradrenaline.RemainderismetabolisedbyMAOandCOMTsimilartonor/adrenaline.

HepaticbyCOMT t 2min.COMTtoinactivemetabolites.

Elimination Renal,t β3minutesUrinaryexcretionofunchangeddrugandmetabolites

Mechanismofaction D ,D ;β>αatlowerdose β >β β >>β ,D

Respiratory Potentbronchodilation Bronchodilation

CVS ↑Inotropy,↑HR,↑CO,coronaryvasodilation.Athighdoses,↑SVRandPVR,↑VR.

↑SVR,potentialreflexbradycardia.Notarrhythmogenic.

↑HR,CO,contractility,andautomaticity.Βeffectsmay↓SVRandBP.

CNS Inhibitsprolactin.Nausea. Stimulant Tremor

MSK Necrosiswithextravasation

Renal

↑RBFand↑urinaryoutputwithnoimprovementinrenalfunction

GIT Mesentericvasodilation

Structure-ActivityRelationshipsofSympathomimetics

Catecholaminesconsistof:

AcatecholringAbenzeneringwithtwohydroxylgroupsinthe3and4position.

LosingonehydroxylgroupIncreaseslipidsolubilityanddecreasesthepotency10-fold

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PreventsmetabolismbyCOMT,prolongingdurationofactionLosingbothhydroxylgroupsdecreasesthepotency100-fold

Changingthehydroxylgroupstothe3and5positionincreasesbeta-2selectivitywhenthereisalsoalargesubstitutionpresentontheaminegroup

AnethylaminetailConsistsof:

BetacarbonThefirstcarbon.

AddingahydroxylgroupdecreaseslipidsolubilityandCNSpenetrationAddinganygroupincreasesalphaandbetaselectivity

AlphacarbonThesecondcarbon.

AddingagrouppreventsmetabolismbyMAO,prolongingdurationofactionMethylationincreasesindirectactivity

AminegroupTheterminalnitrogen.

AdditionofamethylgroupgenerallyincreasesbetaselectivityAsthechainlengthincreases,sodoesthebetaselectivity.

Dopamine

Dopamineistheprototypicalcatecholamine,towhichothersarecompared

Noradrenaline

CardiovascularPharmacology

579

Noradrenalinehasahydroxylgroupaddedtothebetacarbon,increasingitsalphaselectivity

Adrenaline

AdrenalineissimilartonoradrenalinewithanadditionalhydroxylgrouponthebetacarbonAdrenalinealsohasamethylgroupaddedtotheterminalamine,increasingbetaselectivity

Metaraminol

CardiovascularPharmacology

580

MetaraminolhasanadditionalhydroxylgrouponthebetacarbonMetaraminolhasonlyonehydroxylgrouponthephenolring,so:

ItisnolongerclassifiedasacatecholamineItisnotmetabolisedbyCOMT,prolongingitsdurationofactionIthasreducedpotency,requiringadministrationinhigherdoses

Metaraminolhasanadditionalmethylgrouponthealphacarbon,preventingmetabolismbyMAOandfurtherprolongingitsdurationofaction

Ephedrine

Likemetaraminol,ephedrinehasahydroxylgrouponthebetacarbonandamethylgrouponthealphacarbonEphedrinehasnohydroxylgroupsonthephenolring,furtherreducingitspotencyandincreasingitseliminationhalf-lifeEphedrinehasamethylgroupontheamine,increasingitsbetaselectivity

References1. BrandisK.ThePhysiologyViva:Questions&Answers.2003.2. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.3. YartsevA.DerangedPhysiology-StructureofSyntheticCatecholamines4. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.

Lastupdated2019-07-18

CardiovascularPharmacology

581

CardiovascularPharmacology

582

Non-AdrenergicVasoactivesKeynon-adrenergiccardiovasculardrugsincludevasopressin(anditsanalogues,terlipressinandornipressin),phosphodiesteraseIIIinhibitorssuchasmilrinone,andcalciumsensitiserssuchaslevosimendan.

Property Vasopressin(ADH) Milrinone Levosimendan

Class Naturalnonapeptide PhosphodiesteraseIIIinhibitor

Calciumsensitiserandphosphodiesteraseinhibitor

UsesHaemorrhage,DI,catecholamine-sparingvasopressor

RefractoryCCFandlowCOstates Severeacuteheartfailure

Dosing 5-10unitsIVbolus,upto4U/hrinfusion

Load12-24mcg/kgover10min,theninfusionat0.05-2mcg/kg/min

Route IV/SC/IM IV IV

Presentation Clearsolution Yellowsolutionat1mg/ml 2.5mg/mLin5ml&10mlvials

Distribution 70%proteinbound Veryhighproteinbinding>90%

Metabolismt 10minutes.Metabolisedbytissuepeptidasesandrenalelimination.

t 1-2.5hourst 1hour.Hepatictoactivemetabolitewithat~70hours

Elimination 80%ofdrugisexcretedunchanged

Mechanismofaction

V receptors(kidney,platelets)areadenylatecyclasemediated.V (vascularsmoothmuscle)andV receptors(pituitary)arephospholipaseC/inositoltriphosphatemediated

InhibitsphosphodiesterasebreakdownofcAMP,increasingintracellularCalevels.AlsoincreasesspeedofCa uptakeintocardiacmuscle,increasinglusitropy.

BindstotroponinCincreasingmyofilamentCa sensitivity.AlsoopensK channelscausingvasodilation.ItmayalsohavesomePDIIIinhibitioneffect.

CVS ↑SVRthroughvasoconstriction

Increasedinotropy,increasedlusitropy,decreasedSVRandPVR(PVRdecreasesmorethanSVR).Increaseddysrhythmias.

IncreasedCOwithoutincreasedO demand,vasodilation,prolongedQTcwithriskofarrhythmia

GIT GITsmoothmusclecontraction

Renal

↑Aquaporininsertionintotheapicalmembraneofcollectingductswhich↑waterreabsorption

Haematological↑Coagulationfactormobilisationand↑plateletaggregation

Metabolic Hyponatraemia

References

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1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.3. BruntonL,ChabnerBA,KnollmanB.GoodmanandGilman'sThePharmacologicalBasisofTherapeutics.12thEd.

McGraw-HillEducation-Europe.2011.

Lastupdated2019-07-18

Non-adrenergicVasoactives

584

CentrallyActingAnti-Hypertensives

Property Clonidine Methyldopa

Class Centralα -agonist(200:1α :α ) Phenylalaninederivative

Uses Analgesia,sedation,anti-hypertensive Antihypertensive(especiallyinpregnancy)

Presentation Clearcolourlesssolutionat150μg.mlTablets-notappropriateforurgentbloodpressurereduction

RouteofAdministration

PO/IVat10-200mcguptoQID.Canbeaddedtoneuraxialblockadeat1-2mcg.kg todecreaseopioidrequirement. PO/IV.

Dosing 50-200μgQID. 250-500mgPOBD/TDS.

Absorption 100%PObioavailabilitywithrapidabsorption HighlyvariablePObioavailability

Distribution 20%bound,V 2L.kg 50%proteinbound,V0.3L.kg

Metabolism 50%hepatictoinactivemetabolites,t β9-18hours Intestinalandhepatic

Elimination 50%renaleliminationunchanged 40%renaleliminationunchanged

MechanismofAction

Agonistofcentralα2receptor,↓SNStoneviadecreasedNAreleasefromperipheralnerveterminals.

Metabolisedtoα-methyl-noradrenalineintheCNS,whichagonisescentralα2receptors.

CVS

Initial↑inBPduetoα stimulation,evidentwithbolusdosing.Followedbyprolonged↓inBP,↑PR,↓AVconduction,↑baroreceptorsensitisation(lowerHRforagivenincreaseinBP).CessationmaycausereboundHTN.

↓SVRwithunchangedHRorCO

CNSSedation,analgesiadueto↓NAreleasewhich↓opioidrequirement.Adjunctinchronicpainandinopioidwithdrawal.Anxiolysisatlowdoses.Centralantiemeticeffect.

May↓MAC

Metabolic Stressresponsetosurgicalstimulusisinhibited

Renal DiuresissecondarytoinhibitionofADH

References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.

Lastupdated2017-09-12

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Antihypertensives

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CalciumChannelBlockersCa -channelblockers:

HaveaffinityforL-typecalciumchannelsL-typechannelsexistinmyocardium,nodal,andvascularsmoothmuscle.

Variableaffinityforeachcausesapreferenceforeithernodalandinotropic,orvasculareffectsPreventCa entryintocellsinause-dependentfashion

Class ChemicalStructure Drugs

ClassI Phenylalkylamines Verapamil

ClassII Dihydropyridines Nifedipine,amlodipine,nimodipine

ClassIII Benzothiazepines Diltiazem

ComparisonofCalciumChannelBlockers

Property Verapamil Amlodipine Diltiazem

Class Phenylalkylamine Dihydropyridine Benzothiazepine

Uses SVT,excludingAFwithWPW HTN,AnginaAngina,HTN,SVT,Raynaud's,migraine,oesophagealdysmotility

Presentation 20-240mgtablet,POsolution,IVat2.5mg.ml Tablet Tablet

IsomerismRacemicpreparation.TheD-isomeralsohassomelocalanaestheticactivity

RouteofAdministration PO/IV PO PO

Dosing 80-160mgBD/TDS 2.5-10mgdaily 30-120mgTDS

Absorption 20%bioavailability 60%bioavailability 40%bioavailability

Distribution 90%proteinbound 90%proteinbound,lipidinsoluble. 80%proteinbound

Metabolism Hepatictoactivenorverapamil Hepatictoinactivemetabolites Hepatictoactivemetabolites

Elimination Renaleliminationofactivemetabolites

Renalofinactivemetabolites

Renalofactivemetabolites.t2-7hours

CVS↓HRvia↓SAand↓AVnodalconduction,↓inotropy,↓SVR,↓BP,arrhythmiaincludingHB

↓SVR,↓BP,withreflexive↑HR,↑inotropy,↑CO

↓AVnodalconductionbuttypicallystableHR,↓SVR,↓CVR,↓MVO ,↑CO

CNS ↓Cerebralvascularresistance↓Cerebralvascularresistancewithnimodipine

GIT ↓LOStone

InteractionsContraindicatedwithconcurrentβ-blockeruseduetoprofound↓HR,↓

Contraindicatedwithconcurrentβ-blockeruseduetoprofound↓

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inotropy HR,↓inotropy

References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.3. RangHP,DaleMM,RitterJM,FlowerRJ.RangandDale'sPharmacology.6thEd.ChurchillLivingstone.

Lastupdated2019-07-18

CalciumChannelBlockers

587

DirectVasodilatorsDirectvasodilatorsinclude:

Ca channelblockers(seeCalciumChannelBlockers)NitratesIncreaseproductionofNO:

NOactivatesguanylatecyclase,increasingcGMPcGMPinhibitsCa uptakeintosmoothmuscleandenhancesitssequestrationintosmoothendoplasmicreticulumThedecreaseincytoplasmic[Ca ]causessmoothmusclerelaxationandvasodilation

HydralazineMultimodalmechanismofaction,including:

OpensK channels,hyperpolarisingvascularsmoothmuscleDecreasesintracellularCa invascularsmoothmuscleActivationofguanylatecyclase

Property SodiumNitroprusside GTN Hydralazine

Class InorganicNitrate OrganicNitrate Directvasodilator

Uses Afterload(withsomepreload)reduction Afterload&preloadreduction,angina HTN

Presentation Solutionat10mg.ml ,mustbeprotectedfromlight

Spray,tablets,patch,IVsolutionwhichisabsorbedintoPVC-requiresapolyethyleneadministrationset

20mgampouleorpowder.Shouldnotbereconstitutedwithdextrose.

RouteofAdministration IVonly IV,topical,sublingual PO,IV

Dosing 0.5-6µg.kg .min 10-200µg.min 5-20mgIV

Absorption <5%PObioavailability

30%bioavailabilityduetohighfirstpassmetabolism

Metabolism

Prodrug.ReactswithOxy-HbinRBCtoform1xNO,5xCN ,andMetHb.MetHbreactswithCNtoformcyanomethaemoglobin.CNismetabolisedintheliverandkidneytoformSCN,themajorityofwhichisexcretedinurine(thoughmaybere-convertedtoCN).

CNmayalsocombinewithhydroxocobalamin(vitaminB )toformcyanocobalamin,whichiseliminatedinurine.

Prodrug.MetabolisedtoNOandglyceroldinitrate(whichisthenalsoconvertedtoNO)intheliver.

N-acetylatedingutandliver

EliminationRenaleliminationofSCNandcyanocobalamin.ImpairedinrenalfailurewhichmayworsenCNtoxicity.t forSCNis2-7days

t 1-4mins.Urinaryexcretion

Dependentonacetylationrates

Resp Inhibithypoxicpulmonaryvasoconstrictionleadingto↑shunt Bronchodilation

Vasodilationpredominantlyof

Arteriolarvasodilation

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CVS ↓SVR>venodilation.↓SBPand↓preload,↑HRmaintainsCO,↓MVO

capacitancevessels,↓preload,↓VR,↓EDP,↓walltensionimprovingsubendocardialbloodflow,↓MVO

withcompensatorytachycardiaandincreasedCO

CNS ↑CBFfollowingcerebralvasodilatation↑CBFfollowingcerebralvasodilatation,whichmaycauseheadache

IncreasedCBF

Haematological Methaemoglobinemia Methanoglobinaemia

ToxicEffects Threemechanisms:hypotension,thiocyanatetoxicity,CNtoxicity.

MethaemoglobinaemiacanoccurwithGTN

GTNpatchesmayexplodeifleftonduringDCcardioversion.

NitrateToxicityNitratetoxicitycanberelatedto:

CyanideThiocyanateMethaemoglobinaemia

CyanideToxicity

CyanidetoxicityoccursonlywithSNP,asCN isproducedasabyproductofmetabolism.

KineticsRapidcellularuptakeSmallVHepaticallymetabolisedtothiocyanate,usingthiosulfateasasubstrate

MechanismCN bindstocytochromeoxidase,preventingoxidativephosphorylation.Thiscauseshistotoxichypoxia,andischaracterisedby:

RapidlossofconsciousnessandseizuresMetabolicacidosisLactataemiaArrhythmiaIncreasedMVOHypertensionDuetotachyphylaxistoSNP.

RiskofcyanidetoxicityfromSNPisrelatedto:InfusionrateInfusionduration

ManagementSupportivecare,includinginotropesCyanidechelatorsBindCN,removingitfromthecirculation.Include:

DicobaltedetateHydroxycobalamin(VitaminB )Sulfurdonors

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Provideadditionalsulfhydrylgroups,allowingfurtherhepaticmetabolismofCN toSCN.Include:

ThiosulfateNitritesConvertsOxy-HbtoMet-Hb,whichhasahigheraffinityforCN thancytochromeoxidase.Include:

SodiumnitriteAmylnitrite

ThiocyanateToxicity

ThiocyanteisproducedwithhepaticmetabolismofCN .Toxicityoccurswhenthiocyanateaccumulates,whichoccursin:

LongdurationSNPinfusions7-14days.PatientswithrenalfailureReducedclearance,mayoccurin3-6days.PatientsgiventhiosulfateformanagementofCN toxicity.

EffectsMultisystemic,including:

RashAbdominalpainWeaknessCNSdisturbance

TreatmentDialysis

Methaemoglobinaemia

MethaemoglobinaemiaoccurswhentheFe (ferrous)ioninhaemoglobinisoxidisedtotheFe (ferric)form,whichisunabletobindoxygen.

Duetothehighconcentrationofoxygeninerythrocytes,methaemoglobiniscontinuallybeingformedSeveralendogenousreductionsystemsexisttokeepMetHblevelsstableat~1%

Predominantlycytochrome-b reductaseNADPH-MHbreductaseThisreducesmethaemoglobinaemiainthepresenceofareducingagent,classicallymethyleneblue.ReducedglutathioneMoreimportantinpreventingoxidativestressinothercellsthantheRBC.

Diseaseoccursduetothelossinoxygen-carryingcapacityfromthelossofeffectivehaemoglobine.g.a20%MetHblevelgivesatheoreticaloxygencarryingcapacityof80%oftheactualhaemoglobinThereisinfactaslightleftshiftoftheoxyhaemoglobindissociationcurve,asoxygenbindsmoretightlytothepartially-oxidisedhaemoglobin.

References

1. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.2. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.3. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.4. CICMSeptember/November20085. LITFL-CyanidePoisoning

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6. ThomasC,LumbA.Physiologyofhaemoglobin.ContinuingEducationinAnaesthesiaCriticalCare&Pain,Volume12,Issue5,1October2012,Pages251–256.

7. WrightRO,LewanderWJ,WoolfAD.Methemoglobinemia:Etiology,Pharmacology,andClinicalManagement.AnnalsofEmergencyMedicine,Volume34,Issue5,1999,Pages646-656.

8. RusswurmM,KoeslingD.NOactivationofguanylylcyclase.TheEMBOJournal.2004;23(22):4443-4450.

Lastupdated2019-07-18

DirectVasodilators

591

AngiotensinConvertingEnzymeInhibitorsACEinhibitorspreventtheconversionofangiotensinItoangiotensinIIbyangiotensinconvertingenzyme(ACE)inthelungs,inturnreducingeffectsofangiotensinII.Theseeffectsinclude:

VasoconstrictionNoradrenalinereuptakeinhibitionThirstADHreleaseACTHreleaseAldosteronereleaseReducesKf,reducingGFR

Indications

HypertensionParticularlyininsulindependentdiabeteswithdiabeticnephropathyLesseffectiveforthisindicationintheblackpopulationContributetopost-operativehypertensionandmaybewithheldperioperatively

CardiacfailureAllgrades.

MIwithLVdysfunctionImprovedprognosis.

Classification

Canbedividedintothreegroupsbasedonpharmacokinetics:

ActivedrugwithactivemetabolitesCaptopril.ProdrugRamipril.NotmetabolisedandexcretedunchangedinurineLisinopril.

CommonFeaturesofACEInhibitors

Property Drug

Resp Bradykinincough

CVS ↓SVRandBP.UnaffectedHRandbaroreceptorresponse.

Endocrine Hypoglycaemiaindiabetics

Renal Withanormalrenalperfusionpressure,natriuresisresults.However,afallinrenalperfusionpressuremaycausepre-renalfailure(e.g.renalarterystenosis).

Haeme Agranulocytosis,thrombocytopenia

ACEInhibitors

592

Immune Angioedema

Metabolic ↑Reninrelease.

Interactions ↓Aldosteronerelease,which↑theefficacyofspironolactoneandmayprecipitatehyperkalaemia.PharmacodynamicinteractionwithNSAIDstodroprenalperfusionpressure.

References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.

Lastupdated2019-11-02

ACEInhibitors

593

AngiotensinReceptorBlockersAngiotensinreceptorantagonistsareverysimilartoACEinhibitors,except:

BradykinindoesnotaccumulateasitisstillbrokendownbyACEThereforethereisnocoughandpatientcomplianceisimproved.TheAT receptorincardiactissueismorecomprehensivelyblockedwhichmayimprovecardiacoutcomesTheAT receptorisnotblocked,whichmayalsoimprovecardiacoutcomes

References

1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.

Lastupdated2017-07-27

12

AngiotensinReceptorBlockers

594

PotassiumChannelActivatorsPotassiumchannelactivatorsstimulateATPsensitiveK channels,causinganincreaseinintracellularcGMPandsubsequentrelaxationofsmoothmuscleinthe:

HeartVenouscapacitancevesselsArterioles

Property Nicorandil

Uses HTN,angina,CHF

RouteofAdministration PO

Dosing 10-30mgBD

Absorption 80%PObioavailability

Distribution Negligibleproteinbinding

Metabolism Hepaticdenitration

Elimination Renaleliminationofactivedrugandmetabolites

CVS ↓Preload,↓afterload,↓BP,↑coronaryflow

CNS Headache,improveswithongoinguse

Haeme Inhibitionofplateletaggregation

References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.

Lastupdated2017-09-22

+

PotassiumChannelActivators

595

SodiumChannelBlockersSodiumchannelblockersinclude:

ClassIa:ProcainamideQuinidineDisopyramide

ClassIb:LignocaineMexiletine(lignocaineanalogue)

ClassIc:Flecainide

Ingeneral:

IVpreparationsaregivenforVTGoodPObioavailabilityandlowproteinbindingMetabolitesarerenallycleared

Property Procainamide Lignocaine Flecainide

Class ClassIaamide ClassIbamidelocalanaesthetic ClassIcamidelocalanaesthetic

Uses SVT/VT VT SVT/VT

Presentation Clearsolutionat10-20mg.ml (1-2%)

RouteofAdministration PO/IV IV PO/IV

Dosing 100mgIVload,followedbyinfusionat2-6mg.ml

Loadat1mg.kgfollowedbyinfusionat1-3mg.min

2mg.kg (upto150mg)loadover10-30minutes,followedbyinfusionat1.5mg.kg .hr ,aimingforlevelsof<0.9mg/ml

Absorption 75%bioavailability IVonlyforarrhythmia 90%orallybioavailable

Distribution 33%unionised,70%proteinbound 50%proteinbound

MetabolismHepatictoactivemetabolitesviaacetylation-slowacetylatorsatincreasedriskofsideeffects

Hepaticamidasestoinactivemetabolites Hepatictoactivemetabolites

MechanismofAction

Reducestherateofriseofphase0,raisesthethresholdpotential,andprolongstherefractoryperiodwithoutprolongingtheactionpotential

Reducestherateofriseofphase0oftheactionpotential.Repolarisationphaseisshortened.

Reducestherateofriseofphase0oftheactionpotential.Repolarisationisunchanged.

CVS↓HR,↓SVR,↓BP,↓CO,heartblock,may↑HRwhenusedforSVT,↑QTwithriskofTDP

AVblock,myocardialdepressioncausingunresponsive↓BP

Precipitatepre-existingconductiondisorders,↓inotropy,↑pacinganddefibrillationthreshold

CNS

Circumoraltingling,dizziness,parasthesia,confusion,seizures,coma

Dizziness,parasthesia,headache

-1

-1

-1

-1

-1

-1 -1

Antiarrhythmics

596

ImmuneLupoidsyndromein20-30%,reducesantimicrobialeffectofsulfonamides

InteractionsPharmacokineticinteractionswithdigoxin,propranolol,amiodarone

References

1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.

Lastupdated2019-07-18

Antiarrhythmics

597

Beta-Blockersβ-blockersarecompetitive(oftenhighlyselective)antagonistsofβ-adrenoreceptors.Theyaresub-classifiedintointoselectiveandnon-selectiveagents:

Selective(β antagonism)(BEAM)BisoprololEsmololAtenololMetoprolol

Non-selective(β andβ antagonism)PropranololSotalolTimolol

Non-selective(β&αantagonism)CarvedilolLabetalol

Indications

CardioAnginaArhythmia

Rate-controlinAFParoxysmalSVTSinustachycardiafrom↑catecholamines

CardiacFailureSecondarypreventionforMI

VascularHypertension(2 line)AlsousefulforaggressivecontrolofBP.HypotensiveanaesthesiaAttenuatehypertensiveresponsetolaryngoscopy

Non-CVSThyrotoxicosisGlaucoma(topically)AnxietyMigraineprophylaxis

CommonFeatures

Property Action

KineticsVariabilityprimarilyduetolipidsolubility.Poorlipidsolubilityconferspoorgutabsorptionandminimisesneedforhepaticmetabolism.LipidsolubleagentswillhaveCNSeffectsandbeexcretedinbreastmilk.

Respiratory Bronchospasm.

1

1 2

nd

Beta-Blockers

598

CVS ↓Inotropy,↓HR,↓MVO ,↓BP,↑SVR(β effect),worsenarrhythmia.

CNS Tiredness,nightmares,andsleepdisturbancewithlipidsolubleagents.↓IOP.

Metabolic ↓Insulinreleaseandbluntedhypoglycaemicresponse(β effect).

Interactions ContraindicatedwithcardioselectiveCa channelblockers.duetoextreme↓HR&↓inotropy.

ComparisonofBetaBlockers

Property Esmolol Metoprolol Atenolol Propranolol Labetalol

Class Cardioselective Cardioselective Cardioselective βnon-selective

Non-selectiveβ&selectiveα Ratioofβ:αantagonismis3:1afterPOand7:1afterIVadministration

Uses

Short-termtreatmentoftachyarrhythmiaandHTN

MI,HTN,migraine,thyrotoxicosis

HTN,angina,tachyarrhythmias,acuteMI

HTN,Angina,dysrhythmia,essentialtremor,anxietyHOCM,phaeochromocytoma,migraine,oesophagealvarices

HTN,MI

Presentation Clear,colourlesssolution

Clear,colourlesssolution,50mgTablet.

25/50/100mgtablets,syrup,colourlesssolution.

Tabletsandsolutionat1mg.ml

Tabletsandsolutionat5mg.ml

RouteofAdministration IV PO/IV PO/IV PO/IV PO/IV

Dosing 50-200μg.kg.min

IV:1mgbolusesPO:12.5-100mgBD

PO:50-100mgdailyIV:2.5mgIVupto10mg

PO:10-100mgBD/TDSIV:1mgbolusestitratedtoresponse

PO:100-800mgBDIV:10-20mgIVbolus,followedby20-80mgQ30minupto300mg.Alternativelybyinfusionat1-2mg.min

Absorption IVonly

50%bioavailability,improveswithregularuse

45%PObioavailability 30%bioavailability

Highlyvariablebioavailability:10-80%

Distribution 60%proteinbound

20%proteinbound.Lipidsoluble

5%proteinbound 95%proteinbound 50%proteinbound

Metabolism

RBCesterasestoaninactivemetaboliteandmethylalcohol.t of10minutes

Hepaticwithgeneticvariabilityint ofactivemetabolites

Minimalmetabolism-dosereduceinrenalfailure

Hepatictoactiveandinactivemetabolites

Considerablehepaticfirstpassmetabolismwithinactivemetabolites

Renal

2 2

22+

1

-1 -1

-1 -1

1/21/2

Beta-Blockers

599

Elimination Renaleliminationofactivedrug

Renaleliminationofmetabolites

eliminationofinactivemetabolites

CVS Venousirritant

↓SVR,↓BP.Doesnottendto↓HRor↓COwhengivenacutely.

CNS Orthostaticdizziness

References

1. LeslieRA,JohnsonEK,GoodwinAPL.DrPodcastScriptsforthePrimaryFRCA.CambridgeUniversityPress.2011.2. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.3. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.4. MacCarthyEP,BloomfieldSS.Labetalol:areviewofitspharmacology,pharmacokinetics,clinicalusesandadverseeffects.

Pharmacotherapy.1983.Jul-Aug;3(4):193-219.

Lastupdated2019-07-18

Beta-Blockers

600

AmiodaroneAmiodaroneisanantiarrhythmicagentwithacomplexmechanismofactionandmanyeffects.

K channelblockadeincardiacmyocytes,inhibitingtheslowoutwardcurrentandslowingrepolarisation(ClassIII)β-blocker-likeactivityonSAandAVnodes,decreasingautomaticityandslowingnodalconduction(ClassII)Ca channelblocker-likeactivityonL-typeCa channels,decreasingtheslowinwardCa current,increasingdepolarisationtimeanddecreasingnodalconduction(ClassIV)α-blocker-likeactivity,decreasingSVR

Property Amiodarone

Class ClassIIIantiarrhythmic,thoughexhibitsactionfromall4classes.

Uses VT/VF,resistantarrhythmia,ALS.

Presentation 100/200mgtablets,IV:150mgampouletobereconstitutedinD5W.

RouteofAdministration IV/PO.

Dosing IV:Loadwith5mg.kg over1/24,withafurther15mg.kg overthefollowing24/24PO:200mgTDSfor1/52,200mgBDfor1/52,200mgODthereafter.

Absorption PoorPOabsorptionwithbioavailability~50%.

Distribution HighlyproteinboundwithveryhighV of~70L.kg sduetoaccumulationinfatandmuscle.

Metabolism HepaticmetabolismwithinhibitionofCYP3A4,totheactivedesmethylamiodarone.

Elimination Verylongt ofupto~55days.Biliary,skin,andlacrimalelimination,with<5%ofdrugeliminatedrenally.Notremovedbydialysis.

Resp 10%3-yearriskofpneumonitis,fibrosis,pleuritis.

CVS ↓HR,↓BP,↓SVR,↑QTwithoutriskofTDP.Irritanttoperipheralveins.

CNS Mildblurringofvisionfromcornealdeposition,sleepdisturbance,vividdreams,peripheralneuropathy.

MSK Photosensitivity,greyskin.

Endocrine Hyperthyroidism(1%)andhypothyroidism(6%).

GIT Nausea,vomiting,cirrhosis,hepatitis,andjaundice.

Other

AmiodaronehaspotentialtocauseanumberofdruginteractionsduetoitsinhibitionofCYP3A4anditshighproteinbinding.Aselectioninclude:Digoxin,statins,warfarin,phenytoin,andotherantiarrhythmics.Contraindicatedinporphyria.

AmnemonicforsomeoftherarereffectsisBITCH:

BlueskinInterstitiallungdiseaseThyroidCornealHepatic

+

2+ 2+ 2+

-1 -1

D-1

1/2

Amiodarone

601

References

1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.Peckandhill

2. RangHP,DaleMM,RitterJM,FlowerRJ.RangandDale'sPharmacology.6thEd.ChurchillLivingstone.

Lastupdated2019-07-18

Amiodarone

602

SotalolTheD-isomerofsotalolisaclassIIIantiarrhythmic,whilsttheL-isomeralsohasclassIIactivity.

Property Action

Class ClassIIIantiarrhythmic

Uses Tachyarrhythmiaprophylaxis

Presentation Solutionat10mg.ml andtablets

Isomerism Racemicmixture

RouteofAdministration PO/IV

Dosing PO:40-160mgBDIV:50-100mgover20minutes

Absorption >90%bioavailability

Distribution Noproteinbinding

Metabolism Notmetabolised

Elimination Excretedunchangedinurine

Resp Bronchospasm

CVS Torsades(<2%)-morecommonwithhighdoses,longQT,andelectrolyteimbalances

CNS Maskingsymptomsofhypoglycaemia

GU Sexualdysfunction

References

1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.

Lastupdated2019-07-18

-1

Sotalol

603

DigoxinDigoxinisacardiacglycosideusedinthetreatofatrialarrhythmiasandincardiacfailureasapositiveinotrope.

Digoxinhasbothadirectandindirectmechanismofaction:

DirectInhibitscardiacNa /K ATPase,causing:

Increasingintracellular[Na ],increasingactivityoftheNa /Ca pumpIncreasedintracellularCa increasesinotropyDecreasedK resultsprolongsrefractoryperiodoftheAVnodeandbundleofHis

IndirectParasympathomimeticeffectsbyincreasingAChreleaseatcardiacmuscarinicreceptors.

SlowsAVnodalconductionandventricularresponseThisimprovescoronarybloodflow,increasingtimeforventricularfilling,andimprovingcardiacoutput.

Property Action

Class CardiacGlycoside

Uses Arrhythmia-particularlyAF/Flutter,andCCF

Presentation Tablets,elixir,clearcolourlesssolution

RouteofAdministration PO/IV

Dosing PO:62.5μg-250μg,IV:250-500μgload

Absorption >70%bioavailabilitythoughvarieswithformulation

Distribution 25%proteinbound.V 5-11L.kg ,dependentonleanmass

Metabolism Minimalhepaticmetabolism

Elimination Renaleliminationofactivemetabolitest 35hours-increasedinrenalfailure

CVS ↓HR,↑inotropy,arrhythmiasincluding;bigeminy,PVCs,1 /2 /3 degreeAVblock,SVT,VT

CNS Derangedred-greencolourperception,visualdisturbances,headache

Immune Eosinophiliaandrash

Metabolic Gynaecomastia

ToxicEffects NarrowTI.SeverearrhythmiawithDCcardioversion

Interactions

Interaction Drug

Increasedlevel Amiodarone,captopril,erythromycin,verapamil

Decreasedlevel Antacids,cholestyramine,phenytoin,metoclopramide

References

+ ++ + 2+

2++

D-1

1/2st nd rd

Digoxin

604

1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.

Lastupdated2018-09-21

Digoxin

605

AdenosineAdenosineactsviaA adenosinereceptorsintheSAandAVnode,whichwhenstimulatedopenK channelscausinghyperpolarisationandareductioninCa current,withsubsequentblockadeofAVnodalconduction.

Property Action

Class Naturallyoccurringpurinenucleoside

Uses SVT

Presentation Colourlesssolutionat3mg.ml

RouteofAdministration IV

Dosing 3mg/6mg/12mginincreasingdoses

Metabolism Rapidlydeaminatedinplasma.t <10s

Resp Bronchospasm,↑RRandV

CVS ↓↓AVnodalconduction,maycauseAF/lutter

ToxicEffects Contraindicatedinsick-sinussyndrome,2 /3 degreeAVblock

Interactions

Interaction Drug

Increasedeffect Dipyridamole

Decreasedeffect Methylxanthines,suchasaminophyllineandcaffeine

References

1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.

Lastupdated2017-07-27

1+

2+

-1

1/2

T

nd rd

Adenosine

606

MagnesiumMg isacationthatisimportantforneurotransmissionandneuromuscularexcitability.Magnesium:

InhibitsAChreleaseattheNMJActsacofactorinmultipleenzymesystemsIsimportantintheproductionof:

ATPDNARNA

Property Action

Uses HypoMg,arrhythmia,eclampsia,tocolysis,bariumpoisoning,asthma,tetanus,autonomichyperreflexia

Presentation 2mmol.ml ,madeupinto10mmolin100mlforperipheraladministration

RouteofAdministration PO/IV

Dosing IV:10-20mmol

Distribution 30%proteinbound

Elimination Significanturinaryexcretion,evenwhendeficient

Resp Bronchodilation

CVS ↓SVR,hypotension,↓HR

CNS CNSdepression,anticonvulsant

GU ↓Uterinetoneandcontractility

ClinicalEffectsofMagnesium

[Plasma] Effect

<0.7mmol.L Arrhythmia

4-6mmol.L Nausea,hyporeflexia,speechimpairment

6-10mmol.L Weakness,respiratorydepression,bradycardia

>10mmol.L Cardiacarrest

References1. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.2. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.3. RangHP,DaleMM,RitterJM,FlowerRJ.RangandDale'sPharmacology.6thEd.ChurchillLivingstone.

Lastupdated2017-09-20

2+

-1

-1

-1

-1

-1

Magnesium

607

Magnesium

608

AtropineNaturallyoccurringtertiaryaminewhichcompetitivelyantagonisesAChatthemuscarinicreceptor,causingparasympatholyticeffects.

Property Atropine

Class Naturallyoccurringtertiaryamine.Muscarinicantagonist.

Uses Bradycardia,organophosphatepoisoning,antisialagogue,treatmentofPDPH

Presentation Clear,colourlesssolutionat600μg.ml .Racemicmixture,withonlytheL-isomeractive

RouteofAdministration IV

Dosing 600μg-3mg

Distribution 50%proteinbound,V 3L.kg .CrossesBBB.

Metabolism Extensivehepatichydrolysis

Elimination Renaleliminationofmetabolitesandunchangeddrug

Resp Bronchodilation,↓secretions

CVS ↑HRdueto↑AVnodalconduction,peakswithin2-4minutesandlasts2-3hours

CNS Centralanticholinergicsyndrome,confusion,↑IOP,↑CSFsecretioninchoroid,cerebralvasoconstriction

MSK Inhibitssweating

GIT ↓LoStone

References

1. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.2. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.3. Mahmoud,AhmedAbdelaalAhmed,AmrZakiMansour,HanyMahmoudYassin,HazemAbdelwahabHussein,Ahmed

MoustafaKamal,MohamedElayashy,MohamedFaridElemady,etal.‘AdditionofNeostigmineandAtropinetoConventionalManagementofPostduralPunctureHeadache:ARandomizedControlledTrial’127,no.6(2018):6.

Lastupdated2019-07-18

-1

D-1

Atropine

609

DiureticsAnunderstandingofthepharmacologyofdiuretics.

Diureticsaredrugsthatactonthekidneytoincreaseurineproduction.Theycanbeclassifiedbytheirmechanismofactioninto:

ThiazidesLoopdiureticsPotassiumsparingAldosteroneantagonistsOsmoticCarbonicAnhydraseinhibitors

CommonFeaturesofDiuretics

Property Diuretics

Absorption Typicallypoorbioavailability(exception:acetazolamide)

Distribution Variableproteinbinding

Metabolism Generallynotmetabolised.Keyexceptions:Spironolactoneisextensivelymetabolisedwithactivemetabolites,andasmallamountoffrusemideismetabolisedtoglucuronide.

Elimination Renaleliminationofunchangeddrug

CVS Reducedintraandextravascularvolume

Renal

Anydiureticwhichinhibitssodiumreabsorptioncanprecipitatehypokalaemia(asagreaterintra-luminalconcentrationofsodiumresultsinexchangeofsodiumforpotassiumions),hyponatraemia(asthereisstillanetlossofsodium),andalkalosis(fromlossofhydrogenionsexchangedforsodium,ortheoverallraisedstrongiondifference).

ComparisonofDiuretics

Thiazides LoopDiuretics PotassiumSparing

Aldosteroneantagonists Osmotic

Example Hydrochlorothiazide Frusemide Amiloride Spironolactone Mannitol

Site Distaltubule LoopofHenle Distaltubule Distaltubule Glomerulus

Mechanismofaction

InhibitNa andClreabsorption,andincreaseCareabsorptionintheDCT

InhibitNKCC2,theNa /K /2.Cltransportproteininthethickascendinglimb,impedingthecounter-currentmultiplier.Thisreducesthehypertonicityofthemedulla,andsubsequentwaterreabsorptioninthecollectingsystem.

InhibitsNa /Kexchangepump.Weakeffect.

Competitivealdosteroneantagonist.AldosteronestimulatesNareabsorption,whichinturnstimulatesKsecretion.

Filteredattheglomerulusandnotreabsorbed,increasingfiltrateosmolarityandincreaseswaterexcretion.

+ -

2+

+ + -

+ ++

+

Renal

610

Resp

Cardiac

AntihypertensiveduetoreducedplasmavolumeandSVR

Arteriolarvasodilation,reducingSVRandpreload

Increasesintravascularvolume,increasingpreload.MayincreaseCOorresultincardiacfailure.

CNS ↓ICP

Renal ReducedrenalbloodflowandGFR

IncreasedrenalbloodflowandGFR

Increasedrenalbloodflow

Metabolic

Hypokalaemic,hypochloraemicalkalosis.Hyperglycaemia.

Hypochloraemia,hyponatraemia,hypokalaemia,hypomagnesaemia.Occasionalhyperuricaemiaprecipitatinggout.

Hyperkalaemia. Hyperkalaemia,hyponatraemia.

Miscellaneous Blooddyscrasias

Deafness,typicallyfollowinglargedoses.Morecommoninkidneyimpairmentandwithaminoglycosideuse.

Gynaecomastiaandmenstrualirregularityduetoanti-androgynismfromaldosteroneantagonism

References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. RangHP,DaleMM,RitterJM,FlowerRJ.RangandDale'sPharmacology.6thEd.ChurchillLivingstone.

Renal

611

3. Auerbach.WildernessMedicine.SixthEdition.

Lastupdated2019-07-18

Renal

612

IntravenousFluidsIntravenousfluidscanbeclassifiedinto:

CrystalloidsCanpassfreelythroughasemipermeablemembrane.Canbefurtherclassifiedinto:

ECFreplacementsolutionsHavea[Na ]similartoECF,suchthattheyareconfinedmostlytotheECF.MaintenancesolutionsDesignedtodistributethroughoutTBW.SpecialsolutionsThesesolutionsdon'tfitintotheabovetwocategories,andinclude:

HypertonicsalineMannitol8.4%SodiumBicarbonate

ColloidsSubstanceevenlydispersedthroughoutanothersolutioninwhichitisinsoluble.Canbeclassifiedinto:

NaturallyoccurringAlbuminHeat-treatedhumanalbumin.

ProducedatlowpHbutnottechnicallysterileUsewithin3hoursofopening.ContributestoplasmaoncoticpressureContributestodrugandendogenoussubstancebinding

SyntheticDextransHighmolecularweightsugarssynthesisedfromsucrosebybacteria.

InterferewithhaemostasisduetovWFinhibitionInterferewithbloodcrossmatchRiskofanaphylaxis

GelatinsHighmolecularweightproteinsproducedbycollagenhydrolysis.

GreatestanaphylaxisriskDonotinterferewithclotting

Hydroxyl-ethylstarchesRiskofanaphylaxisRiskofrenalimpairmentAccumulateinthereticuloendothelialsystem

ComparisonofCrystalloids

Contents(mmol.L ) 0.9%NaCl Hartmann's Plasmalyte

Na 154 130 140

Cl 154 109 98

K 4

Ca 3

+

-1

+

-

+

2+

2+

IntravenousFluids

613

Mg 1.5

Lactate 28

Acetate 27

Gluconate 23

pH 5.0 6.5 5.5

References

http://www.anaesthesiamcq.com/FluidBook/fl7_2.php

Lastupdated2019-07-18

2+

IntravenousFluids

614

PropofolPropofol(2-6di-isopropylphenol)isaphenolicderivativewitheffectsonmanyreceptorsincluding:

GABAPotentiatestheeffectofGABA,prolongingCl channelopeningandhyperpolarisingthecell.GlycineNicotinicAChD receptors

Property Action

Class Phenolicderivative

Uses Inductionofanaesthesia,sedation,TIVA

Presentation

Whiteoil-in-wateremulsionatapHof7-8.5containing:-10-20mg.ml propofol-10%Soybeanoil(solubilisingagent)-1.2%Purifiedeggphosphatide(emulsifier)-2.25%Glycerol(fortonicity)Bacteriostaticadditivesincluding:-Generics:Sodiummetabisulfite-Diprivan:Disodiumedetate(lessallergenic)Riskofbacterialcontaminationlimitsshelflife.Energycontentis1.1kcal.ml

pKa 11-almostallisunionised(andactive)atphysiologicpH

RouteofAdministration IVonly

Dosing Induction:1-2.5mg.kg Maintenance:4-12mg/kg/hr.Targetplasmaconcentrationof4-8μg.ml tomaintaingeneralanaesthesia

Distribution 98%proteinbound.VeryhighV at4L.kg .Rapidinitialdistribution:t α(fast)1-3minutes,intermediatedistributiont α(slow)30-70minutes.t

MetabolismHepaticandextra-hepaticmetabolismtoinactiveglucuronidesandsulphates;t β2-12hours.Clearanceof30-60ml.kg.min ,unaffectedbyrenalandhepaticdisease.Contextsensitivehalf-timepeaksat50minutesfollowinga9hourinfusion.

Elimination Tri-exponential.Renaleliminationofinactivemetabolites.

Resp Respiratorydepression,apnoea.Strongsuppressionoflaryngealreflexes.↓Responsetohypoxiaandhypercapnea.Bronchodilation.

CVS↓Arterialandvenousvasodilation(viastimulatingNOrelease)causing↓SVRand↓VR,with↓BP.↓Inotropyvia↓inSNStone,↓MVO .Depressesbaroreceptorreflex.Painoninjectionduetolipidemulsion.

CNSHypnosis.RapidLoC(within1arm-braincirculationtime).↓CMRO2,CBF,andICP.Anticonvulsant.↓IOP.Paradoxicalexcitatoryeffectsseenin~10%-dystonicmovementsofsubcorticalorigin.EEGdemonstratesnon-specificseizure-likeactivity.

MSK Painoninjectionintosmallveins

Renal Greenurine

GIT Anti-emetic.↓HepaticBloodFlow

Metabolic Fatoverloadsyndrome,lipaemiafollowingprolongedinfusion.Inhibitsmitochondrialfunction.

Propofolinfusionsyndrome:Acidosis,bradycardia,andMODSfollowingprolongedinfusion(>24

A-

2

-1

-1

-1 -1

D-1

1/21/2 1/2 </sub>of2.7min.ke0

1/2-1

2

-1 -1

Neuropharmacology

615

mitochondrialdefects.Believedduetoinhibitionofmitochondrialfunction.

References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. CICMJuly/September2007http://ceaccp.oxfordjournals.org/content/4/3/76.full.pdf

http://www2.pedsanesthesia.org/meetings/2007winter/pdfs/Morgan-Friday1130-1150am.pdf

Lastupdated2019-07-18

Neuropharmacology

616

BarbituratesThiopentoneisapositiveallostericmodulatoratGABA receptors(ataseparatesitetobenzodiazepines)intheCNS.Barbituratescause:

DecreasedrateofdissociationofGABAIncreasesthedurationofchannelopening,causingeffectivehyperpolarisationduetoincreasedCl conductance.

Clinicaleffectsdifferfrombenzodiazepinesasbenzodiazepinesincreasefrequencyofopening,whilstbarbituratesincreaseduration

Directactivationofthechannelathigherdoses

Property Thiopentone

Class Barbiturate

Uses Inductionofanaesthesia,statusepilepticus,controlofICPrefractorytoothermeasures

Presentation500mgofyellowpowderwithNaCO forreconstitutionasa2.5%solution.Containerusesnitrogenasafillergas(topreventHCO formationwhenCO combineswithwaterduringreconstitution,which↓pHandthereforewatersolubility).pHof11whenreconstituted-bacteriostaticsolution.

Isomerism Tautomer.pKaof7.6,suchthat60%isunionisedatpH7.4(i.e.watersolubilitydecreasesonceinjected).

RouteofAdministration IV

Dosing 3-7mg.kg .Consider75mgboluses,assessinghaemodynamicandneuronaleffects.

Distribution65-85%proteinbound.HighlipidsolubilityandCBFgivesarapid,reliableonset.Rapidoffsetduetoredistribution,withafastt αof8minutes.Prolongedeliminationhalflife(11hours)contributestolongCSHT.Increasedunionisedportioninacidosis.t

Metabolism CapacitydependentCYP450metabolism-saturatesathighdoses(longCSHTwithinfusion).Metabolisedto(active)pentobarbital,whichalsoincreasesthedurationofitsclinicaleffects.

Elimination Renalofmetabolites,<1%excretedunchanged

Resp Respiratorydepression,bronchospasm,laryngospasm

CVS Vasodilationandvenodilation(↓MSFP),↓inotropy,withcompensatorytachycardia(baroreceptorresponsepreserved)

CNS

Hypnosisandanaesthesiawithin40secondsofinjection,withreliablelossoflashreflex.Anticonvulsant.Dose-dependentflatteningoftheEEG(βαθδburstsuppressionisoelectric),causingprogressive↓CMRO (55%ofmaximalduringburstsuppression),↓CBF,and↓ICP.

Resolutionofinductiondosein5-10minutesduetoredistribution.

Endocrine ↓RBFcausing↓UO

GIT Hepaticenzymeinduction

Immune Anaphylaxis~1;20,000

Metabolic Mayprecipitateacuteporphyriccrisesandiscontraindicatedinthesepatients

Other

IntraarterialinjectioncausesprecipitationaswatersolubilitydecreasesatbloodpH.Microembolisationandischaemiaresult,whichshouldbetreatedwithintraarteriallocalanaesthesia,analgesia,anticoagulation,andsympatheticblockadeofthelimb.

Tissuenecrosisonextravasation.

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References

1. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.2. LITFL-Thiopentone3. Hill,SA.Pharmacokineticsofdruginfusions.ContinuingEducationinAnaesthesia.2004.

Lastupdated2019-07-18

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KetamineKetamineisaphencyclidinederivativeusedforinduction,sedation,analgesia,andasabronchodilatorinsevereasthma.

Ketamineactsvia:

Non-competitiveantagonistofNMDAandglutamatereceptorsintheCNSReducespresynapticglutamatereleaseSodiumchannelinhibitionLocalanaesthetic-likeeffect.Potentialmonoaminergic,muscarinic,andnicotinicantagonism

Property Action

Class Phencyclidinederivative

Uses Inductionofanaesthesia,sedation,analgesia,asthma

Presentation Clear,colourlesssolutionforminganacidicsolution(pH3.5-5.5)

Isomerism RacemicmixtureorthesingleS(+)enantiomer,whichis2-3xaspotentastheR(-)enantiomerbuthaslessbronchodilatoryproperties

RouteofAdministration IV,IM,PO,PR,PN,viaepidural(withpreservative-freesolution)

Dosing Induction:1-2mg.kg IV,5-10mg.kg IM,Sedation:0.2-0.5mg.kg IV

Distribution 25%proteinbound.t α10-15minutes

Metabolism HepaticmetabolismtoactivenorketaminebyCYP450andthentoinactivemetabolites,t β2-4hours

Elimination Renaleliminationofinactivemetabolites.Actionofnorketamineprolongedinrenalfailure.

Resp Bronchodilation,tachypnea,relativepreservationoflaryngealreflexes.Apnoeawithrapidinjection.PreservedcentralresponsetoCO .

CVS ↑Sympatheticoutflow:↑HR,↑BP,↑SVR,↑MVO .Actsdirectlyasamyocardialdepressant-bewaremaximallystimulatedpatient.Depressesbaroreceptorreflex.

CNS

Dissociation,analgesia,emergencephenomena(hallucinations,delirium)reducedbyconcurrentBDZadministration(increasingriskwithhigherdosesandrapidadministration).

Producesdissociativeanaesthesiawithin90secondsbydissociatingthalamocorticalandlimbicsystemsonEEG.Purposefulmovementsunrelatedtostimulusmayoccurevenduringsurgicalanaesthesia.

↑IOP.

Renal Cystitiswithlong-term,high-doseuse

GIT N/V

References

1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.3. CICMJuly/Sept2007

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DexmedetomidineDexmedetomidineisacentralα -agonist(α :α activity1600:1)usedforitssedationandanalgesicproperties.

Property Action

Class Imidazolederivative

Pharmaceutics D-stereoisomerofmedetomidine(theL-stereoisomerisinactive)

Uses Sedationwithoutrespiratorydepression

Presentation Clearcolourlesssolutionat10µg.ml

RouteofAdministration IVonly

Dosing 0.2-0.7µg.kg .hr

Distribution 95%proteinbound

Metabolism Hepatictoinactivemetabolites

Elimination Renalofmetabolites,t βof2hours

CVSInitialtransient↑SVRandBPduetoα effects,followedby↓MAP,↓HR.

Rebound↑BPwhenabruptlyceased.

CNSSedation,anxiolysisatlowdose(anxiogenicathighdose),amnesia.↓MAC.

↓SNSoutflow.

References

1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.3. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.

Lastupdated2017-09-16

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LocalAnaestheticAgentsLocalanaestheticdrugsdeliverause-dependent,temporaryblockadeofneuronaltransmissionUnioniseddrugpassesthroughthecellmembrane,andthenbecomesionisedintracellularlyTheioniseddrugisthenabletobindtotheionchannel,andpreventconductionofsodiumandthereforegenerationofanactionpotential

Alllocalanaestheticsconsistof:AhydrophiliccomponentAlipophilicaromaticringAnamideoresterlinkconnectingthetwo

CommonFeaturesofLocalAnaesthetics

Property Action

Class Amide(-NHCO-)orEster(-COOH-)

Pharmaceutics Amidesarestableinsolution,estersareunstableinsolution.Allareformulatedasahydrochloridesalttoensurewatersolubility.

pKa Allareweakbases,andhaveapKa>7.4

Onset

Onsetisrelatedtodose(Fick'sLaw)andpKa,withalowpKagivingafasteronsetasthereismoreunioniseddrugpresentandthereforemoredrugabletocrossthecellmembrane.Thisiswhylocalanaestheticsarepooratanaesthetisinginfectedtissues,asthetissuepHislowresultinginagreaterproportionofioniseddrug,andlessdrugreachingtheeffectsite.

DurationofAction

Durationofactionisrelatedtoproteinbinding,withgreaterproteinbindinggivingalongerdurationofaction

Potency Potencyisrelatedtolipidsolubility(higherlipidsolubilityincreasespotency)andvasodilatorproperties(weakervasodilatorshavinggreaterpotency)

AbsorptionSystemicabsorptionvarieswithsiteofentry(fromhighestabsorptiontolowest:IV,intercostal,caudalepidural,lumbarepidural,brachialplexus,subcutaneous),dose,andpresenceofvasoconstrictors

Distribution Amidesareextensivelyproteinbound,estersareminimallybound

Metabolism Amidesarehepaticallymetabolised,estersarehydrolysedbyplasmacholinesterases(givingamuchshortert )

CVSVasodilatationatlowconcentrations,vasoconstrictionathighconcentrations.InhibitionofcardiacNachannels,inhibitingmaximumrateofriseofphase0ofthecardiacactionpotential.Negativeinotropyproportionaltopotency.

CNSDoes-dependentCNSeffects:circumoraltingling,visualdisturbances,tinnitus,tremors,dizziness,slurredspeech,convulsions,coma,apnoea.PotentiatedbyotherCNSdepressantsandhypercarbia(dueto↑CBFand↓seizurethreshold).

ToxicEffects Estershaveahigherincidenceofallergyduetotheirmetabolitepara-aminobenzoicacid(PABA).LocalanaesthetictoxicityispredominantlyCNSandCVS.

ComparisonofLocalAnaesthetics

Property Lignocaine Bupivacaine Ropivacaine Cocaine

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Class Amide Amide Amide Ester

Uses Local/regional/epidural,ventriculardysrhythmia Local/regional/epidural Local/regional/epidural

Topicalanaesthesiaandvasoconstriction

Presentation

Clear,colourlesssolutionat0.5/1/2%withorwithoutadrenaline.Spray.Ointment.4%solution.

Clear,colourlesssolutionat0.25/0.5%

Clear,colourlesssolution

1-4%solution,Moffat'ssolution(8%cocaine,1%NaCO ,1:2000adrenaline)

pKa 7.9 8.1 8.1 8.6

RouteofAdministration SC,epidural,IV SC,epidural SC,epidural Topical

Onset/Duration Rapidonset,shortduration

Intermediateonset,longduration

Intermediateonset,longduration 20-30minutes

MaximumDose

Analgesia:4mg.kgwithoutadrenaline,7mg.kg withadrenaline

2mg.kg 3mg.kg 3mg.kg

Distribution 70%proteinbound Highlyproteinbound

Lowerlipidsolubilityreducesmotorblockcomparedtobupivacaine

Highlyproteinbound

Metabolism Hepaticwithsomeactivemetabolites

Hepatictoinactivemetabolites

Hepatictoactivemetabolites

Plasmaesterases,somehepaticmetabolism(unlikeotheresters)

Elimination Reducedinhepaticorcardiacfailure

Eliminationofactivedrugandinactivemetabolites

CC/CNSratio 7 3 5

Other

MosttoxicofLAagentsasittakeslongertodissociatefromthemyocardialNa channel.Levobupivacaineislesscardiotoxictheracemicmixture,possiblyasithasmoreintrinsicvasoconstrictiveproperties.

Maycause↑BP,↑HR,coronaryvasoconstriction,myocardialdepression,VF,↑temperaturedueto↑serotonin,dopamine,andnoradrenalinereuptake

LignocaineToxicity

Serumconcentration(µg.ml ) Phase Effect

2 Safe Antiarrhythmic.Maybegintohavelightheadedness,circumoraltingling,numbness

5 Excitatory Dysarthria

8 Excitatory Visualchanges

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10 Excitatory Seizures

12 Depressive Lossofconsciousness

20 Depressive Respiratorydepression

25 Depressive CVSdepression

PharmaceuticsofTopicalLocalAnaesthetics

EffectoftopicallocalanaestheticsisgovernedbyFick'sLaw.

Characteristic Effect

PharmaceuticFactors

Presentation Aerosolimprovesspeedofonsetbymoisturisingskin

Concentrationofactivecomponent Increasespeedofonset

Stability

pH ↑pHensuresmorelocalanaestheticisintheunionisedform,↑absorption.

Additives AffectpHandvasoconstrictoractivity

DrugFactors

Molecularweight Smallmoleculeswilldiffusemoreeasily

pKa Affectsionisationandthereforelipidsolubility

Lipidsolubility ↑lipidsolubilityimprovesspeedofonset.

Potency Determinesamountofdrugneededtoproduceaneffect

Vasoconstrictoractivity Willaffectbothspeedofonsetanddegreeofsystemicabsorption

PatientFactors

Site Degreeofvascularityofsite

Skin Skinthicknessandareawillaffectonset

References1. CICMMarch/May20092. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.3. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.4. OpenAnaesthesia.LocalAnaestheticsSystemicToxicity5. GadsdenJ.LocalAnaesthetics:ClinicalPharmacologyandRationalSelection.NYSORA.6. LeslieRA,JohnsonEK,GoodwinAPL.DrPodcastScriptsforthePrimaryFRCA.CambridgeUniversityPress.2011.7. ChristieLE,PicardJ,WeinbergGL.Localanaestheticsystemictoxicity.ContinuingEducationinAnaesthesiaCriticalCare

&Pain,Volume15,Issue3,1June2015,Pages136–142.

Lastupdated2017-09-20

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BenzodiazepinesBenzodiazepinesaredouble-ringedpositiveallostericmodulatorsoftheGABAreceptorsintheCNS.They:

Bindtotheα/γinterfaceofthereceptor,increasingaffinityofthereceptorforGABAThisleadstohyperpolarisationofthecellmembranesanddecreasedneuronaltransmissionThemechanismvariesbetweenreceptors:

GABA isaligandgatedpost-synapticCl ionchannelActivationincreasesCl conductanceviaincreasingfrequencyofchannelopening.GABA isapre-andpost-synapticG-proteincoupledreceptorActivationincreasesK conductance.

CommonFeaturesofBenzodiazepines

Property Action

Uses Sedation,anxiolysis,hypnotic,anticonvulsants,amnestic,musclerelaxation

Absorption

Distribution Highlylipidsolubleandproteinbound,verylowV

Metabolism Generallyactivemetabolites.

Elimination Renaleliminationofactiveandinactivemetabolites.

Resp ↓V ,↑RR,apnoea.

CVS ↓SVR,↓SBP,↓DBP,↑HR.TypicallystableCO.

CNS Hypnosis,sedation,anterogradeamnesia,anticonvulsant,↓CBF.↓MAC.

MSK Skeletalmusclerelaxation.

Metabolic ↓Adrenergicstressresponse.

ComparisonofBenzodiazepines

Property Midazolam Diazepam Clonazepam

Physicochemical

pKa6.5.StructureisdependentonsurroundingpH-atapH<4itsringstructureopensanditbecomeswatersoluble.

40%propyleneglycol.

RouteofAdministration PO/IV/IM. PO/IV/IM. PO.

Absorption 50%PObioavailability. GoodPObioavailability.

Distribution V 1.5L.kg ,95%proteinbound. 95%proteinbound.

MetabolismPartiallymetabolisedtooxazepamand1-α-hydroxy-midazolam.Clearance~7ml.kg .min .

Hepatictoallactivemetabolitesincludingoxazepam,temazepam,anddes-methyl-diazepam(hast βupto100hours).

Hepatictoinactivemetabolites.

Eliminationt β2-4hours,prolongedwithcirrhosis,CHF,obesityandinthe t β20-45hours.

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elderly.

References

1. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.2. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.3. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.4. RangHP,DaleMM,RitterJM,FlowerRJ.RangandDale'sPharmacology.6thEd.ChurchillLivingstone.

Lastupdated2019-07-18

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AntidepressantsSymptomsandmanagementofTCAoverdoseiscoveredunderTricyclicAntidepressantOverdose.

Antidepressantdrugsinclude:

TricyclicAntidepressants(TCAs)Mechanismofactionbymultipleeffects,including:

CompetitivelyinhibitreuptakeofNAand5-HTMuscarinicantagonismLeadstoanticholinergicsideeffects(drymouth,blurredvision,constipation,urinaryretention).H andH antagonismα antagonismNMDAantagonism

SelectiveSerotoninReuptakeInhibitors(SSRIs)Inhibitneuralreuptakeof5-HTPreferredoverTCAsas:

SimilareffectivenessBettersideeffectprofile

MonoamineOxidaseInhibitors(MAO-Is)Inhibitmonoamineoxidaseonexternalmitochondrialmembrane,increasingthelevelofamineneurotransmittersintheCNSandPNSTwoenzymesexist:

MAO-ADominantenzymeinCNSActsonserotonin,noradrenaline,adrenaline

MAO-BDominantinGITandplateletsResponsiblefor75%ofMAOactivityPreferentialmetabolismofnon-polaramines

MAO-IsclassifiedbytheirmechanismandselectivityNon-selective,irreversibleBindcovalentlytotheenzyme,permanentlyinactivatingit.

MayleadtohypertensivecrisiswhencatecholaminelevelsincreasedTyramineinfoodMetabolisedbyMAO-B.IndirectlyactingsympathomimeticsAbsolutelycontraindicated.

RiskofserotoninsyndromewithserotoninreuptakeinhibitorsInclude:

PhenelzineIsocarboxazidTranylcypromine

Enzymelevelswilltake2-3weekstorecoverfollowingcessationMAO-Aselective,reversible

HypertensivecrisisislesscommonMAO-Bunaffected-tyramineismetabolisedShortactingEnzymelevelsnormaliseafter24hoursofcessation.

Include:

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MoclobemideMAO-Bselective

MuchlowerriskofhypertensivecrisisInclude:

SelegilineDiscontinuationsyndromemayoccurifabruptlyceased

Property TricyclicAntidepressants SelectiveSerotoninReuptakeInhibitors

MonoamineOxidaseInhibitors

Example Amitriptyline Fluoxetine

Uses Depression,treatmentofchronicpainandtrigeminalneuralgia Depression,anxiety

Treatmentresistantdepression.Nowlargelysupersededduetoside-effectprofile

Absorption HighPObioavailability HighPObioavailability

DistributionHighlylipidsolublewithHighV .Veryhighlyproteinbound-leadstointeractionswithwarfarin,digoxin,andaspirin

Highlyproteinbound,highV

Metabolism Hepaticwithactivemetabolites.Largeinterpatientvariability

Hepaticwithnon-linearkinetics

VenlafaxinedoesnotaffectCYP450enzymes.

Elimination Unaffectedbyrenalimpairment

Resp Drymouth

CVS

Posturalhypotension,↑HR.QTprolongationandwideningQRSinoverdose,witharrhythmiamorelikelywhenQRSexceeds0.16s.

LesscardiotoxicthanTCAs,mayprecipitateserotoninsyndrome

CNSSedation,blurredvision,loweredseizurethreshold.Excitation,followedbyseizuresanddepressioninoverdose.

IdenticalantidepressanteffecttoTCAs.Lesssedation

Renal Urinaryretention

GU SexualdysfunctionGreaterincidenceofsexualdysfunctioncomparedwithTCAs

GIT ConstipationGreaterincidenceofN/VcomparedwithTCAs

Other

Multiplecomplexdruginteractions,includingarrhythmiasandvariableBPwithsympathomimetics,centralanticholinergicsyndrome,serotoninsyndrome,andseizures.

↑Sensitivitytocatecholamines-suggestavoiding:-Indirectlyactingsympathomimetics-Ketamine-Surgicalstress

Continueduringperioperativeperiodtoavoidriskofdiscontinuationsyndrome.

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SerotoninSyndrome

SerotoninsyndromeisexcessiveserotoninintheCNS,typicallyasaconsequenceofdruginteractions.Thesyndromemaybemild,moderate,orsevere,andpresentswithsomeorallof:

AlteredmentalstateConfusion

MotorchangesMyoclonusHyperreflexiaTremor

AutonomicinstabilityDiaphoresisShiveringFever

Serotoninsyndromeistypicallyself-limitingandresolveswithcessationofthedrug.

References

1. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.2. AltamuraAC,MoroAR,PercudaniM.Clinicalpharmacokineticsoffluoxetine.1994Mar;26(3):201-14.3. BromheadH,FeeneyA.Anaesthesia&PsychiatricDrugs-Antidepressants.AnaesthesiaTutorialoftheWeek(164).2009.

Lastupdated2019-07-18

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AntipsychoticsAntipsychoticsaredrugsusedforthemanagementofpsychosesandthoughtdisorders.Theyhaveacomplicatedmechanismofactionwitheffectsonmultiplereceptors:

Centraldopamine(typicallyD ,butvarieswithagent)antagonismResponsiblefortheantipsychoticproperties5-HT antagonism

Otherreceptorswhicharequantitativelylessimportant:H antagonismα antagonismMuscarinicAChantagonism

Basedontheiraffinitytovariousreceptors,theyare(loosely)classifiedaseither:

Typicalor1 generationantipsychoticsHigheraffinityforD receptors(subsequentlylessblockadeof5-HT ),causingagreatereffecton'positive'symptoms'andagreaterincidenceofextrapyramidalsideeffectsAtypicalor2 generation,whichtypicallyhavefewermotoreffectsHavegreatereffectonnegativesymptoms.

CommonFeaturesofAntipsychotics

Property Drug

Uses Behaviouralemergencies,schizophrenia/psychosis

CVS QTprolongation

CNS Apathy,↓initiative,↓responsetoexternalstimuli,↓aggression.Nolossofintellectualfunction.

Endocrine ↑Prolactin(typicalantipsychotics)

Haeme Leukopeniaandagranulocytosis(predominantlyclozapine,butcanbeall)

Metabolic Weightgain,diabetes,hypercholesterolaemia(allatypical>typical)

OtherToxicities Neurolepticmalignantsyndrome,EPSE

NeurolepticMalignantSyndrome

AntipsychoticMalignantSyndromeisrareandpresentssimilarlytoMH,witharapidriseinbodytemperatureandconfusion.Ithasahighmortality(upto20%).

Extra-PyramidalSideEffects

MotordisturbancesfromantipsychoticusearetermedEPSEs,andaredividedintotwomaintypes:

AcuteDystonicReactionsareinvoluntarymovementsandparkinsoniansymptoms.Theyare:

MorecommonwithtypicalagentsDeclinewithongoinguseReversiblewithcessationoftheagent

TardivedyskinesiaissimilartoADR,except:

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InvoluntarymovementsaremorepronouncedanddisablingItoccurswithlongtermuse(10-20years)Theyareirreversible,andworsenwhentherapyisstopped

ComparisonofAntipsychotics

Property Haloperidol Olanzapine Clozapine

Class Typical Atypical Atypical("3 gen")

Uses BehaviouralEmergencies BehaviouralEmergencies,Psychosis/Schizophrenia Treatmentresistantschizophrenia

Presentation Tablets,syrup,clearsolutionforinjectionat5mg.ml

Tablets,solutionforinjection Yellowtablet

RouteofAdministration PO/IM/IV PO/IM PO

Dosing 1-5mgIV,2-30mgIM,1-15mgPO IM5-10mg,PO5-20mg Mustbeprescribedbya

psychiatrist

Absorption 50%PObioavailability 60%PObioavailability Rapidabsorption

Distribution 92%proteinbound 93%proteinbound,V~14L.kg V 2L.kg

Metabolism Hepatictolargelyinactivemetabolites

Hepatictoinactivemetabolites

Mayobeyzero-orderkineticsattheupperlimitofthedoserange

Elimination Renalofmetabolites Renalofinactivemetabolites

Renalofactivedrug(~25%)andinactivemetabolites

CVS Hypotension Myocarditis(potentiallyfatal)

CNS Seizures

GIT Antiemetic Hepatitis

Haeme Agranulocytosis,thromboembolicdisease

ReferencesRangandDaleSmith,Scarth,SasadaCriticalCareDrugsManualhttp://lifeinthefastlane.com/book/critical-care-drugs/https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=8248https://www.ncbi.nlm.nih.gov/pubmed/8453823

Lastupdated2019-07-18

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AnticonvulsantsIngeneral,anticonvulsantsare:

WellabsorbedorallyHighlyproteinboundHepaticallymetabolisedbyCYP450enzymes,andinducetheirownmetabolism(aswellasthatofotherdrugs)RenallyeliminatedInteractwitheachother

Property Phenytoin SodiumValproate Carbamazepine Levetiracetam

UsesGTCS,partialseizures,trigeminalneuralgia,ventriculararrhythmias

PartialseizuresAntiepileptic,trigeminalneuralgia

GTCS,partialseizures,myoclonicseizures,seizureprophylaxis

Presentation

Capsules,syrup,solution.IVformulationincompatiblewithdextrose.

Tablets,syrup,solution

Tablets,suppositories,syrup

Tablets,oralliquid,IVliquid

RouteofAdministration PO,IV,IM PO,IV PO PO,IV(over15

minutes)

Dosing15-20mg.kg load,aimingplasmalevels10-20mcg.ml

300-1250mgBD 50-800mgBD

Typically1gloading,then500mgBDincreasingupto1.5gBD.Doseadjustedinrenalimpairment.

MechanismofAction

StabilisesNa channelsintheirinactivestate,inhibitinggenerationoffurtheractionpotentials.

StabilisesNachannelsintheirinactivestateandGABAergicinhibition

StabilisesNachannelsintheirinactivestateandpotentiatesGABA

Unknown,butdifferenttootherantiepilepticsandmayberelatedtoinhibitionofN-typeCa currents

Absorption SlowPOabsorption.PObioavailability90%

PObioavailability100%

95%PObioavailability

Near100%PObioavailability

Distribution Highlyproteinbound Highlyproteinbound

Highlyproteinbound

Nilsignificantproteinbinding,V ~0.5L.kg

Metabolism

Hepatichydroxylationwithhighlyindividualvariationindosing.Obeysfirst-orderkineticsinthetherapeuticrange,andzero-orderkineticsjustabovethetherapeuticrange.MetabolisedbyCYP450.Induceswarfarin,benzodiazepines,OCPmetabolism.Inhibitedbymetronidazole,chloramphenicol,isoniazid.Geneticpolymorphismresultsin

Hepatictoinactiveandactivemetabolites

HepaticHepatichydrolysistoinactivemetabolites

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reducedmetabolismin5-15%ofpatients.

EliminationRenaleliminationofinactivemetabolitesandactivedrug

Renaleliminationofmetabolitesandactivedrug

Renalelimination

Renalofactivedrug(majorroute)andmetabolite(minorroute)

CVS

↓BP,heartblock,andasystolewithrapidadministration,antiarrhythmicproperties

Antiarrhythmic

CNS

↑Seizurethreshold,paraesthesia,ataxia,nystagmus,slurredspeech,tremor,vertigo.

↑Seizurethreshold ↑Seizurethreshold

↑Seizurethreshold,anxiolytic.Minimal↓inseizurethresholdoncessation.

RenalWaterretentionfromADH-likeeffects

RarelyprecipitatesAKI

GITHepatotoxicity(idiosyncratic).Nauseaandvomiting.

Hepatotoxicity.

Haeme Aplasticanaemiaandotherblooddyscrasias

Thrombocytopenia,leukopenia(requiresregulartesting)

Thrombocytopenia

Immune Rash SJS

Metabolic Hyperammonaemia

Other

Requiresmonitoringduetonarrowtherapeuticwindowandsignificantpharmacokineticvariation.Gumhyperplasia.Teratogenic.Mayprecipitateporphyria.

Reducesefficacyofaminosteroids.Teratogenic.

References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.3. CICMMarch/May20104. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.5. Levetiracetam-DrugInformation.FDA.2009.

Lastupdated2019-07-20

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GABAAnaloguesGabapentinandpregabalin:

ArebothstructuralanaloguesofGABAHavenodirectactionontheGABA receptorActontheα δsubunitofvoltagegatedCa channelsintheCNS,inhibitingneurotransmitterreleaseMayhavesomeNMDAreceptoractivity

ComparisonofGABAAnalogues

Property Gabapentin Pregabalin

Uses Focalseizures,neuropathicpain Focalseizures,neuropathicpain,anxiety

RouteofAdministration PO

Dosing 100mgTDS,increasingupto1200mgTDS 50mgBD/TDS,upto600mgindivideddoses(BDorTDS)

Absorption PObioavailabilityof60%,decreaseswithincreasingdoseduetosaturationoftransporter

90%PObioavailability,delayedbyfoodbutunaffectedbydose

Distribution Minimallyproteinbound Minimallyproteinbound

Metabolism Notmetabolised Notmetabolised

Elimination Renaleliminationofactivedrug,t β6hours Renaleliminationofactivedrug,t β6hours

CNS Drowsiness,ataxia,psychiatricsymptoms Confusion,psychiatricsymptoms,drowsiness

GIT N/V

References

1. TaylorCP,AngelottiT,FaumanE.Pharmacologyandmechanismofactionofpregabalin:thecalciumchannelalpha2-delta(alpha2-delta)subunitasatargetforantiepilepticdrugdiscovery.EpilepsyRes.2007Feb;73(2):137-50.Epub2006Nov28.

2. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.

Lastupdated2019-07-18

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InhalationalAnaestheticAgentsDescribetheeffectsofinhalationalagentsonthecardiovascular,respiratoryandcentralnervoussystems

Describethetoxicityofinhalationalagents

Describethecomparativepharmacologyofnitrousoxide,halothane,enflurane,isoflurane,desflurane,sevoflurane,xenonandether

Thissectioncoversfeaturesandstructuresofinhalationalanaesthetics.Structure-activityrelationshipsarecoveredunderinhalationalanaesthetics.

CommonFeaturesofInhalationalAgents

Property Action

MetabolismHepaticCYP450(CYP2E1)metabolisesC-halogenbondstoreleasehalogenions(F ,Cl ,Br ),whichcanbenephrotoxicandhepatotoxic.TheC-FbondisminimallymetabolisedcomparedtotheC-Cl,C-Br,andC-Ibonds.Allagentsundergohepaticoxidation,exceptforhalothanewhichisreduced.

RespAllhalogenatedagents↓V and↑RR,withanoverall↓inMVandthereforecausePaCO to↑;and↓sensitivityofcentralrespiratorycentrestoCO .ImpairmentofHPVmayworsenV/Qmatchingand↑shunt.

CVS ↓MAP(predominantlyby↓inSVRduetoNOreleaseandCa channelblockade),↓inotropyduetoCa channelblockade.

CNS

Hypnosis.↓CMRO .Above1MACthereisuncouplingoftheCBF-CMRO relationship,andCBF↑despite↓CMRO duetocerebralvasodilation.ICPmaymirrorCBFchanges.

Allexcepthalothanehavesomeanalgesiceffect.↓EEGfrequencysuchthatθ-andδ-wavedominatetheEEGasdepth↑.Maycauseburstsuppression.

MSK MusclerelaxationviablockadeofCa channels.AdditionalaugmentationoftheeffectsofNMBDduetoskeletalmusclevasodilation.MayprecipitateMH.

Renal

Dosedependent↓inRBF,GFR,andUOsecondaryto↓inMAPandCO.

FluorinatedethersproduceF ionswhenhepaticallymetabolised,whichmayproducehigh-outputrenalfailureatserumconcentrations>50μmol/L.Thisisprobablyonlyaconcernwithmethoxyflurane(asithassignificant(>70%)hepaticmetabolism)whenusedatanaestheticdoses.

GIT ↓Hepaticbloodflow.

GU Tocolysis.

ToxicEffects Decreasedfertilityandincreasedriskofspontaneousabortioninoperatingtheatrepersonnel.

ComparisonofCommonInhalationalAgents

Property Sevoflurane Isoflurane Desflurane

Pharmaceutics

Minimallysoluble,lightstable,notflammable.Formulatedwith300ppmofH OtopreventformationofHFacidbyLewisacidsinglass.

Solubleinrubber,lightstable,notflammable.

Lightsensitive,flammableat17%.

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Structure

MolecularWeight 200.1 184.5 168.0

Boilingpoint 58.5°C 48.5°C 23.5°C

SVP(mmHg)at20°C 158 239 669

Blood:gascoefficient 0.7 1.4 0.42

Oil:gascoefficient 50 98 29

MAC 2 1.15 6.6

Metabolism

3-5%CYP2E1metabolismtohexafluoroisopropanolandinorganicF (whichmaybenephrotoxic)

0.2%hepatictonontoxicmetabolites

RespBronchodilation,↓MV.Smallest↓inV andthereforesmallest↑inPaCO

Bronchodilation,airwayirritability.↓MV(greaterthanhalothane)with↑inRR

Airwayirritabilitymanifestascoughingandbreath-holding,↑secretions

CVS

↑QT,↓SVRcausing↓MAPwithoutareflex↑HR.Inotropyunchanged.Smallest↓inBPofanyinhalationalagent.

Reflex↑HRdueto↓MAPfrom↓SVR.Small↓inotropyandCO,equivalenttosevofluranebutgreaterthandesflurane.Maycausecoronarysteal.

Minimal↓inotropy(leastofallinhalationalagents),butgreater↓inSVRandBPthansevoflurane.↑inHR,withabiggerincreaseat>1.5MAC.

Large↑inSNStonewithrapid↑indesfluraneconcentration.

CNS

↑Post-operativeagitationinchildrencomparedtohalothane.Smallest↑inCBFat>1.1MAC,withnoincreaseinICPupto1.5MAC.Cerebralautoregulationintactupto1.5MAC.

Bestbalanceof↓CMROfor↑inCBF.

ToxicEffects

SevofluraneinteractswithsodalimetoproduceCompoundA(aswellasBthroughE,whichareunimportant),whichisnephrotoxicinrats(butnot,itseems,inhumans).

-CHF groupmayreactwithdrysodalimetoproduceCO.

Desfluranehasmuchgreatergreenhousegaseffectsthansevofluraneorisoflurane.

ComparisonofUncommonInhalationalAgents

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Property Enflurane Halothane Xenon

Pharmaceutics

Structuralisomerofisofluranewithdifferentphysicalproperties

Lightunstable.Corrodessomemetalsanddissolvesintorubber.

Notflammable.Veryexpensivetoproduce.

Structure

MolecularWeight 184.5 197 131

Boilingpoint 56.5°C 50.2°C -108°C

SVP(mmHg)at20°C 175 243 -

Blood:gascoefficient 1.8 2.4 0.14

Oil:gascoefficient 98 224 1.9

MAC 1.7 0.75 71

Metabolism

~25%undergoesoxidativephosphorylationbyCYP450systems,producingtrifluoroaceticacid,whichbindstoproteinandcancauseaT-cellmediatedhepatitis,whichcanbefatalin~1/10,000anaesthetics.

Notmetabolised.

RespLargest↓inV ,thereforelargest↑inPaCO

↑InRR,↓inV withoverallunchangedPaCO

↓RR,↑inV suchthatMVisconstant.3xasdenseand1.5xasviscousasN O,whichincreaseseffectiveairwayresistance.Doesnotappeartocausediffusionhypoxia.

CVSGreatest↓ininotropy,HR,SVR,andMAP.Significant↑incatecholaminesensitivity.

MorestableMAP,↓HR

CNS

Produces3Hz"spikeandwave"EEGpatternathighconcentrations,resemblinggrandmalseizures

Greatest↑inCNSbloodflowat>1.1MAC Analgesic,↑PONV

MSK Musclerelaxationwhen>60%.DoesnottriggerMH.

Renal

Directnephrotoxicity,potentiallyrelatedtofluoride(thoughthisassociationisnotpresentwithotheranaestheticagents)

GU Leasttocolyticeffect

Toxiceffects ProducesF ions

Hepaticdamagemaybe:-Reversibletransaminitis-Fulminanthepaticnecrosis,witha

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mortalityof50-75%.

References

1. KhanKS,HayesI,BuggyDJ.PharmacologyofanaestheticagentsII:inhalationanaestheticagents.ContinuingEducationinAnaesthesiaCriticalCare&Pain,Volume14,Issue3,1June2014,Pages106–111.

2. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.3. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.4. MillerRD,ErikssonLI,FleisherLA,Weiner-KronishJP,CohenNH,YoungWL.Miller'sAnaesthesia.8thEd(Revised).

ElsevierHealthSciences.PeckandHill5. LeslieRA,JohnsonEK,GoodwinAPL.DrPodcastScriptsforthePrimaryFRCA.CambridgeUniversityPress.2011.6. LawLS,LoEA,GanTJ.XenonAnesthesia:ASystematicReviewandMeta-AnalysisofRandomizedControlledTrials.

AnesthAnalg.2016Mar;122(3):678-97.

Lastupdated2017-10-07

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NitrousOxideDescribethepharmacologyofnitrousoxide

Describethecomparativepharmacologyofnitrousoxide,halothane,enflurane,isoflurane,desflurane,sevoflurane,xenonandether

Property NitrousOxide

Pharmaceutics

Non-flammablebutsupportscombustion.Producedbyheatingammoniumnitrateto250°C.PotentialcontaminantsincludeNH ,N ,NO ,andHNO .

Storedasaliquid,suchthatthegaugepressureisonlyaccuratewhenallremainingN Oisinthegaseousphase.

ThefillingratioisthemassofN Ointhecylindercomparedtothemassofwateritcouldhold,andis0.75intemperateregions,and0.67inwarmerregions.

MolecularWeight 44

Boilingpoint -88°C

CriticalTemperature/Pressure 36.5°C/72bar

SVP(at20°C) 39,000mmHg

Blood:gascoefficient 0.47

Oil:gascoefficient 1.4

MAC 105(MACawake68)

MechanismofAction

Severaldifferentmechanisms,including:-Stimulatesdynorphinrelease(actsatKOPreceptor)-PositiveallostericmodulatoratGABA receptor-NMDAantagonist

Metabolism <0.01%hepaticreduction.

Resp Diffusionhypoxiaduetosecondgaseffect.Small↓inV ,↑inRRsuchthatMVisunchanged.

CVS ↑SNStone,mildmyocardialdepression.↑PVR-bewareinpulmonaryhypertension.

CNS Powerfulanalgesicwhen>20%,viaendorphinandenkephalinmodulation,andonopioidreceptors.↑CBF.Lossofconsciousnesscommonat80%.1.4xrelativeriskofPONV

GU Nottocolytic-usefuladjuvantinGAcaesariansectiontoreducevolatileanaestheticuse

GIT Expansion

Metabolic ↑Homocysteine.

ToxicEffects

MoresolublethanN meansitwillrapidlydiffuseintoair-filledcavities,increasingthevolumeofcompliantcavities(PTHx,bowel),andincreasingthepressureofnon-compliantcavities(middleear).

Prolongeduse(>6hours)oxidatescobaltioninvitaminB ,preventingitsactionasacofactorformethioninesynthetase,preventingDNAsynthesis.Thisleadsto:-Megaloblasticchangesinbonemarrow-Agranulocytosis-Peripheralneuropathy-Possibleteratogenicity-avoidinearlypregnancy

Greenhousegas.

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EntonoxEntonoxisa50/50mixtureofnitrousoxideandoxygen,usedasanalgesiainlaborandminorprocedures.

Property Entonox(50%O ,50%N O)

Pharmaceutics Thegasesdissolveeachotherandbehavedifferentlythanwouldbeexpectedfromtheirindividualproperties.ThisisthePoyntingeffect.

CriticalTemperature/Pressure

Pseudocriticaltemperatureof-6°C,belowwhichitwillseparateintoliquid50%N O(withsomedissolvedO ),andgaseousO .Thisismostlikelytooccurat117bar,andcanleadtodeliveryofahypoxicmixture.

Deliveryofahypoxicmixispreventedby:-Storingcylindershorizontally(↑areafordiffusion)-Storingcylindersattemperatures>5°C-Usingadiptubesothatliquid50%N Oisusedbeforethegaseousmixture

References

1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.3. ANZCAFebruary/April20064. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.5. EmmanouilDE,QuockRM.AdvancesinUnderstandingtheActionsofNitrousOxide.AnesthesiaProgress.2007;54(1):9-

18.doi:10.2344/0003-3006(2007)54[9:AIUTAO]2.0.CO;2.6. Hendrickx,J.,Peyton,P.,Carette,R.,&DeWolf,A.(2016).Inhaledanaestheticsandnitrousoxide.EuropeanJournalof

Anaesthesiology,33(9),611–619.7. BrownS,SneydJ.Nitrousoxideinmodernanaestheticpractice.2016.BJAEducation,16(3),87–91.

Lastupdated2019-07-18

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Opioids

CommonFeatures

Property Effect

Uses Analgesia,sedation,eliminationofsympatheticresponsetolaryngoscopy/surgicalstressresponse

Resp ↓CNSsensitivitytoCO causingrespiratorydepression(↓RR>↓V )-↑relianceonhypoxicdrive(thereforerespiratorydepressionmaybepotentiatedbyhighFiO )

CVS ↓HR.May↓BPduetohistaminerelease(lesswithsyntheticagents).↑PVR

CNS Sedation,euphoria.NauseaandvomitingduetoCTZstimulation.MeiosisduetostimulationoftheEdinger-Westphalnucleus.↓MACupto90%

Renal ↓RPF,↑ADH,↑uretericandsphinctertone

MSK Musclerigidity,pruritus(especiallywithintrathecaladministration)

Metabolic ↓ACTH,prolactin,gonadotrophichormonesecretion.↑ADHsecretion

GIT ↓PeristalsisandGITsecretionswithsubsequentconstipation

Immunological Impaired:chemotaxis,lymphocyteproliferation,andantibodyproduction

ComparisonofNaturallyOccurringOpioids

Property Morphine

Receptor MOP,KOP

RouteofAdministration SC/IM/IV/Intrathecal

pKa 8.0,23%unionisedatphysiologicpH.

Absorption Low(relative)lipidsolubility-sloweronsetandSCabsorption.POpreparationsabsorbedinsmallbowel,bioavailability30%-highfirstpassmetabolism.

Distribution ~35%proteinbinding.V 3.5L.kg

Clearance(ml.kg.min ) 15

Metabolism Hepaticglucuronidationto70%inactivemorphine-3-glucuronideand10%activemorphine-6-glucuronide,whichis13xaspotentasmorphine.t βof160minutes.

Elimination Renaleliminationofactivemetabolites-accumulationinrenalfailure

TimetoPeakEffect(IV) 10-30minutes

Duration(IV) 3-4hours

EquianalgesicDose(IV,to10mgIVmorphine) 10mg

ComparisonofSemisyntheticOpioids

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Property Oxycodone Buprenorphine

Receptor MOP,KOP,DOPPartialMOPagonist,KOPantagonist(antanalgesiceffect)

RouteofAdministration PO/IV Topical

pKa 8.5,<10%isunionisedatphysiologicpH.

Absorption PObioavailability60-80% Significant1stpassmetabolism

DistributionAslipidsolubleasmorphine,45%proteinbound,V 3L.kg .MorerapidonsetthanmorphinedespitehigherpKapotentiallyduetoactiveCNSuptake

Clearance(ml.kg.min ) 13

MetabolismHepaticdemethylationtonoroxycodone(80%,viaCYP3A)andthemorepotentandactiveoxymorphone(20%,viaCYP2D6).t β200minutes.

Hepatictoactivenorbuprenorphine

Elimination Renaleliminationofactivedrugandmetabolites70%biliary,30%renalelimination,t β40hours

TimetoPeakEffect(IV) 5minutes

Duration(IV) 4hours

EquianalgesicDose(IV,to10mgIVmorphine)

10mg.Note10mgPOoxycodoneis≈15mgPOmorphineduetohigherfirstpassmetabolismofmorphine

ComparisonofSyntheticOpioids

Property Fentanyl Alfentanil Remifentanil

Receptor MOP MOP MOP

RouteofAdministration SC/IM/IV/Epidural/Intrathecal/Transdermal IV

IV(containsglycine,socannotbeadministeredintrathecally)

pKa 8.4,<10%unionisedatpH7.4 6.5,90%unionisedatpH7.4conferringrapidonset

7.3means58%unionisedatphysiologicpH.

AbsorptionRapidonsetofaction(<30s,peakat5min)duetolipidsolubility(600xthatofmorphine).

90xmorelipidsolublethanmorphine,butmorerapidonsetthanfentanyl.Thisisdueto:1.LowpKameansagreaterproportionisunionisedatphysiologicalpH.2.Lowerpotencyofalfentanilcomparedtofentanylmeansagreaterdoseisrequired(Bowman'sPrinciple)

20xmorelipidsolublethanmorphine.

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Distribution600xaslipidsolubleasmorphineconferringalargerV (4L.kg ).85%proteinbound.

90xaslipidsolubleasmorphine,smallV of0.6L.kg .90%proteinbound

20xaslipidsolubleasmorphine,verysmallV of0.4L.kg .70%proteinbound.CSHTisconstantduetorapidmetabolism.

Clearance(ml.kg .min ) 13 6 40

Metabolism

Significantfirstpasspulmonaryendothelialuptake.Hepaticdemethylationtoinactivenorfentanyl.t βof190minutes,longerthanmorphineduetohigherlipidsolubilityandV .

Shortereliminationt βthanfentanyl(100minutes)despitelowerclearanceduetolowerV .ProlongedwithadministrationofmidazolamduetoCYP3A3/4competition.

Rapidmetabolismbyplasmaandtissueesterases-t β10minutes

Elimination Renaleliminationofinactivemetabolites Renaleliminationofmetabolites

Renalofinactivemetabolites

TimetoPeakEffect(IV) 5minutes 90seconds 1-3minutes

Duration(IV)

Variabledependingondoseanddistribution.Withdoses>3μg.kg tissuesbecomesaturatedandthedurationofactionissignificantlyprolonged

5-10minutesOffset5-10minutesfromceasinginfusion

EquianalgesicDose(IV,to10mgIVmorphine)

150mcg 1mg 50mcg

References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.3. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.4. ANZCAJuly/September20105. SchugSA,PalmerGM,ScottDA,HalliwellR,TrincaJ.AcutePainManagement:ScientificEvidence.4thEd.2015.

AustralianandNewZealandCollegeofAnaesthetistsandFacultyofPainMedicine.

Lastupdated2019-07-18

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COXInhibitorsCyclo-oxygenaseinhibitorsaretypicallyusedtotreatmildtomoderatepain.OralCOXinhibitorstypicallyhave:

RapidabsorptionHighproteinbindingLowV

MechanismofAction

Therearetwo(ish)isoenzymesofCOX:

COX-1Importantforhomeostaticfunction.COX-2Inducedwithtissuedamageandcontributestoinflammation.COX-2:

Existsinthevascularendotheliumwhereitsynthesisesprostacyclin(whichopposestheactionofthromboxanes)Inhibitionmayresultinarelativeabundanceofthromboxane,causingplateletaggregationandvasoconstriction

COX-3VariantofCOX-1whichexistscentrallyandmediatestheanalgesicandantipyreticeffectsofparacetamol.

Effectsoccurdueto:

DecreaseinendoperoxidasesInhibitedbyCOX.Increaseinotherarachidonic-acidderivedfactorsDuetothediversionofarachidonicaciddownotherpathways.

COXinhibitionhasdifferenteffectsindifferenttissues:

PreventssubsequentconversionofprostaglandinstothromboxaneA andPGIPeripherally,inhibitionofprostaglandinsynthesisisanti-inflammatoryCentrally,itisanti-pyreticInthestomach,itdecreasesmucousproductionandleadstomucosalulceration

Aspirin(anon-specificCOXinhibitor),preventsproductionofboththromboxaneA andPGIAsplateletshavenonucleus,theCOXinhibitionremainsfortheentiretyoftheplateletlifespanEndothelialcellswillproducenewCOXwithinhours,andsoitsanti-inflammatoryeffectsaretemporary

AdverseEffects

Asthma/BronchospasmSecondarytoincreasedleukotrienesynthesisduetoincreasedarachidonicacidlevels.Occursin20%ofasthmaticswithNSAIDuse.

PlateletdysfunctionAconsequenceofCOX-1inhibitiononly,andmayresultinincreasedperioperativebleedingrisk(thoughdecreasedAMIandCVArisk).

Thromboticevents,includingMIandCVARiskisgreaterwithCOX-2inhibitors,duetoselectiveinhibitionofprostacyclin.withNNHfornon-fatalMIbeing500patient-years,andNNHforfatalMIbeing1000patient-years.

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ImpairedGFROccursasaconsequenceofuninhibitedafferentarteriolarconstriction.Worsewithconcurrenthypovolaemia,renalarterystenosis,orconcurrentACE-Iuse.

GastricerosionAconsequenceofimpairedmucosalsecretionthroughCOX-1inhibition.Thiscanresultinpain,anaemia,orfatalbleed.Ingeneral,riskofgastricerosionis(fromhighesttolowestrisk):

KetorolacDiclofenac/naproxenIbuprofen(<1.2g/day)COX-2Inhibitors

TransaminitismayoccurfollowingNSAIDuse

ComparisonofCOXInhibitors

Characteristic Aspirin Diclofenac Ketorolac Ibuprofen Celecoxib Parecoxib

MechanismofAction

Irreversibleinhibitionofplateletthromboxaneproduction.Asplateletsareanucleate,theyareunabletoregeneratethromboxane.

Non-selectiveCOXinhibitor

Non-selectiveCOXinhibition

Non-selectiveCOX-inhibition

COX-2inhibitor(30:1infavourofCOX-2)

COXinhibitor(61:1infavourofCOX

Uses

Preventionofarterialthromboembolism,MI,CVA,migraine,analgesia,others(e.g.Still'sdisease)

Mild-to-moderatepain

Potentanti-analgesic,minimalanti-inflammatoryproperties

Mild-to-moderatepain

Analgesia,particularchronicarthriticpain

Acuteinflammatorypain

Distribution

85%proteinbound.WeakacidwithapKaof3,unionisedinthestomachandionisedatphysiologicalpH

97%proteinbound

AbsorptionGastricabsorption(pKa3)leadstorapidonset.

Metabolism

Hepaticmetabolismtosalicyluricacidandglucuronides.Mayhavezero-ordereliminationinoverdose.

CYPtoinactivemetabolites

CYP2C9toinactivemetabolites

CYP2C9toinactivemetabolites

Elimination

Renal.Eliminationmaybeincreasedwithurinaryalkalinisation.

Low-dose(100mg

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Dose

daily)selectivelyinhibitsplateletCOX,whilstpreservingendothelialCOX,resultingindecreasedplateletaggregationwhilstmaintainingvasodilation.300-900mgforanalgesia/migraine.

50mgBD/TDS

15-30mgIM/IVQ6H

400-800mgTDS,or10mg/kg

100-200mgBD 20-40mgBD

Route PO PO/PR/IM/IVIM/IV(off-labelinAustralia)

PO/PR PO IV

Respiratory

Aspirinuncouplesoxidativephosphorylation,increasingOconsumptionandCO production.Italsomaystimulate,and(athigherdoses)depresstherespiratorycentre.Inoverdose,thesearesignificant,andmayresultinamixedrespiratoryandmetabolicacidosis.

CVSMIandCVAriskreduction.Increasedbleeding.

RiskofMIsimilartoCOX-2inhibitors.LocalthrombuswithIVinjection.

Lowerdosenotassociatedwithprothromboticevents.

UncleareffectonCVAandMI,butrecommendedtoavoiduseinIHD/CVD

UncleareffectonCVAandMI,butrecommendedtoavoiduseinIHD/CVD

Metabolic

Reye'ssyndromeismitochondrialdamage,hepaticfailure,andcerebraloedema(andencephalopathy)inchildren<12.Mortality40%.

References

PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.

Lastupdated2019-07-18

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TramadolTramadolisananalgesicagentwithacomplicatedmechanismofaction:

Actionatallopioidreceptors,butparticularlyMOP,causinganalgesiaaswellasnauseaandvomitingInhibits5-HTreuptakewhichprovidesdescendinginhibitoryanalgesiaInhibitsNAreuptakedescendinginhibitoryanalgesiaNMDAreceptorantagonist

Properties Tramadol

Class Cyclohexanolderivative.Racemicmixtureof(+)TramadolwhichhasgreaterMOPand5HTreuptakeeffects,and(-)Tramadol,whichmediatesNAreuptakeinhibition

Uses Analgesia

Presentation Racemicmixture-eachisomerhascomplementaryeffects.IVsolutionisclearat50mg.ml

RouteofAdministration PO/IV/Topical

Dosing 50-100mgQID.Potency1/5 thatofmorphine.

Absorption Bioavailability70%

Distribution V 4L.kg

Metabolism Hepatictoactiveandinactivemetabolites

Excretion Urinaryofpredominantlyinactivemetabolites,t β300minutes

Respiratory Minimalrespiratorydepression

CVS AvoidconcomitantMAO-IusegivenNAreuptakeinhibition

CNS IncreasedseizureriskinthosewithepilepsyorconcurrentSSRI/SNRI/TCAuse.Minimaladdictionpotential

GIT N/V

References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.

Lastupdated2019-07-18

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ParacetamolParacetamolananalgesicandantipyreticwhichistypicallyclassedasanNSAID,thoughitisuniqueandimportantenoughtogetitsownpage.Ithasanumberofmechanismsofaction:

Non-selectiveCOXinhibition,includingCOX-3ThisconferssomeoftheanalgesicpropertiesInhibitionofcentralprostaglandinsynthesisThisconferstheantipyreticeffectbyinhibitingprostaglandinEsynthesisintheanteriorhypothalamusinresponsetopyrogensSerotonergicinhibitionProvidessomeadditionalanalgesicactionCannabinoidinhibitionProvidessomeadditionalanalgesicactionviaendocannabinoidreuptakeinhibition.

Property Effect

Class NSAID,acetanilidederivative

Uses Analgesia,antipyretic

Presentation Tablets,capsules,syrup,clearcolourlesssolutionforIVadministration

RouteofAdministration PO/PR/IV

Dosing 10-15mg.kg Q4Hupto90mg.kg .day

Onset IV:5mins,peakat40minsPO/PR:40mins,peakat1hour

Absorption Rapidabsorption(viasmallbowel,thereforeproportionaltogastricemptying),variablebioavailability(upto90%)-greaterbyPRroute

Distribution 10%proteinbound,smallV :0.5-1L.kg (thoughlargerthanotherNSAIDs)

Metabolism Predominantlyhepaticglucuronidation.However,10%ismetabolisedtoNAPQIbyCYP2E1whichishepatotoxic.

Elimination Activesecretionintorenaltubules-considerdosereductioninrenalimpairment

Resp Mayexacerbateanalgesicasthmaduetoglutathionedepletion

CNS Excellentanalgesia.Synergisticwithotheranalgesics,resultinginagent-sparingeffectandreducedsideeffects

Metabolic Antipyretic

Haeme Cytopaenias(rare)

ToxicityParacetamolispartiallymetabolisedtothetoxicN-acetyl-p-amino-benzoquinoneimine(NAPQI)

InnormalcircumstancesthisrapidlyconjugatedwithglutathioneIntoxicity,glutathioneisexhaustedNAPQIthencovalentlybindstocriticalproteinsinhepatocytes,causingcentrilobularhepaticnecrosisandcelldeath

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Toxicdoses:>200mg.kg inasingleingestionRepeatedingestionof>150mg.kg .day fortwodays>100mg.kg .day forthreedays

Riskfactorsfortoxicity:Glutathionedeficiency

ExtremesofageMalnutritionHepaticdysfunction

Enzymeinducers:Anti-epileptics

CarbamazepinePhenytoinPhenobarbitone

RifampicinETOHOCP

FeaturesofOverdose

ConsciousNausea,vomiting,andepigastricpainHaemolyticanaemiaDistributiveshockHyperglycaemiaLate(>48hours)hepaticfailureLater(3-5days)coagulopathyFulminanthepaticfailure(3-7days)

TreatmentofOverdose

Activatedcharcoalwithtabletingestionifseenwithin1hourofingestion.

SerumparacetamolleveltodeterminerequirementforNAC(N-acetylcysteine)basedonthenomogramIVNACisusedasitisaglutathioneprecursor,replenishingdepletedglutathioneandfacilitatingfurtherconjugationofNAPQI

References1. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.2. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.3. ParacetamolPoisoning.RoyalChildren'sHospital.4. HinsonJA,RobertsDW,JamesLP.MechanismsofAcetaminophen-InducedLiverNecrosis.Handbookofexperimental

pharmacology.2010;(196):369-405.

Lastupdated2019-07-18

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650

Paracetamol

651

Antimuscarinics(Cardiac)AntimuscarinicsusedforbronchodilationarecoveredunderAntimuscarinics(Respiratory),whilstatropineiscoveredseparately.

Antimuscarinicsareascompetitive,reversibleantagonistsofAChatthemuscarinicreceptor.Theyaredividedinto:

NaturallyoccurringtertiaryaminesThesecancrosstheblood-brainbarrier,andhavecentraleffects.

AtropineHyoscine

SyntheticquaternaryaminesDonotcrosstheblood-brainbarrier.

Glycopyrrolate

Property Glycopyrrolate Hyoscine

Class Quaternaryamine.Muscarinicantagonist Tertiaryamine

Uses Bradycardia,antisialagogue Antisialagogue,motionsickness

Presentation Clear,colourlesssolutionat200μg.ml .Incompatiblewithdiazepamandthiopentone.

Racemic,onlyL-isomeractive

RouteofAdministration IV/IM PO,SC,IV/IM

Dosing 200-400μg 20-40mgIVslowpushorIM

Absorption MinimalPOabsorption-notusedviathisroute. <50%PObioavailability

Distribution CrossesplacentabutnotBBB,V 0.5L.kg V 2L.kg

Metabolism Minimalhepatichydrolysis Extensivemetabolismbyhepaticesterases

Elimination Renalof85%unchangeddrug Renalofmetabolites

Resp Bronchodilation,antisialagogue Bronchodilation,greatestantisialagogueeffect

CVSInitialbradycardiaduetopartialagonisteffect.Reversesvagalcausesofbradycardia,maycausetachycardiaindoses>200μg.HRpeaksat3-9minutesfollowingadministration.

Leastlikelyanticholinergictocausetachycardia

CNSMostlikelyanticholinergictocausecentralanticholinergicsyndrome

MSK Anhydrosis

GIT Reducedoralandgastricsecretions,andgastricmotility

Reducedoralandgastricsecretions,andgastricmotility.Increasesbiliaryperistalsis

GU Difficultmicturition

References

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Autonomic

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1. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.2. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.

Lastupdated2018-07-29

Autonomic

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AnticholinesterasesAnticholinesterasesantagoniseAChE,decreasingthebreakdownofAChandthereforeincreasingitsavailabilityatthe:

NicotinicreceptorIncreasesmusclestrength.

Reversalofnon-depolarisingneuromuscularblockadeMuscarinicreceptorIncreasesparasympathetictone.

Anticholinesterasescanbe:

ReversibleFormacarbamylatedenzymecomplexIrreversible

Property Neostigmine Organophosphates

Class Quaternaryamine,formscarbamylatedenzymecomplex Irreversibleanticholinesterase

Uses Reversalofnon-depolarisingNMB,myastheniagravis,analgesia Insecticides,pesticides,chemicalweapons

Presentation Clear,colourless,lightstablesolutionat2.5mg.ml

RouteofAdministration PO,IV,intrathecal Topical

Dosing 0.05mg.kg forreversal,15-30mgPOforMG

Absorption LowPObioavailability Rapidtopicalabsorptionduetohighlipidsolubility

Distribution DoesnotcrossBBB,V 0.7L.kg CrossesBBB

Metabolism Majoritybyplasmaesterasestoquaternaryalcohol,withsomehepaticmetabolism Notmetabolised

Elimination 55%unchangedinurine t αofweeks

Duration 50minutes UntilnewAChEissynthesised

Resp Bronchospasm,↑secretion Bronchospasm,↑secretion

CVS ↓HR(maybeprofound),↓CO ↓HR,↓CO

CNS N/Vandanalgesicwhenadministeredintrathecally,cerebralvasoconstriction Centralcholinergicsyndrome

MSK ReversalofNMB,↑fasciculations,↑sweating,maycauseparalysis Paralysis

GIT ↑Peristalsis,↑LoStone,N/V ↑Peristalsis,↑LoStone,N/V

Other Muscarinicreceptorsaffectedatlowdose,nicotinicreceptorsathighdose

Maybereversedininitialstages(beforeorganophosphate-AChEcomplexhas'aged')withpralidoxime

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References

1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. ANZCA2007Feb/April3. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.4. Mahmoud,AhmedAbdelaalAhmed,AmrZakiMansour,HanyMahmoudYassin,HazemAbdelwahabHussein,Ahmed

MoustafaKamal,MohamedElayashy,MohamedFaridElemady,etal.‘AdditionofNeostigmineandAtropinetoConventionalManagementofPostduralPunctureHeadache:ARandomizedControlledTrial’127,no.6(2018):6.

Lastupdated2019-07-18

Anticholinesterases

655

DepolarisingNMBsSuccinylcholinebindstothenicotinicAChreceptorcausingdepolarisation.ItcannotbehydrolysedbyacetylcholinesteraseintheNMJ,andsoremainsboundtothereceptor.This:

Producesasustaineddepolarisationwhichkeepsvoltage-gatedsodiumchannelsintheirinactivestatePreventsthepost-junctionalmembranefromrespondingtofurtherAChrelease

Property Succinylcholine

Class Depolarisingmusclerelaxant.

Uses Facilitatetrachealintubation.

Presentation ColourlesssolutionofpH3,at50mg.ml .Structurally,itistwoAChgroupsjoinedattheacetylgroups.

RouteofAdministration IV,IM.

Dosing 1-2mg.kg IV,3-4mg.kg IMupto150mg.

OnsetandDuration

IVonsetin30sto1minute,lasting2-3minutes,withoffsettypicallywithin10minutes.OffsetoccursduetodissociationofdrugoutofNMJintoplasma,asaconcentrationgradientisestablishedbydrugbreakdowninplasma.Prolongeddurationinpatientswithpseudocholinesterasedeficiency.IMonsetin2-3minutes.

Distribution 30%proteinbound.Nildistributionduetorapidmetabolism-V 0.25L.kg .Crossesplacentainverysmallamounts.

Metabolism Rapidhydrolysisbyplasmacholinesterasessuchthatonly20%ofadministereddosereachestheNMJ.

Elimination Minimalrenaleliminationduetorapidmetabolism.

Resp Apnoea,andsuxamethoniumapnoea.Maycausemasseterspasm.↑Salivationduetomuscariniceffects.

CVS ArrhythmiaduetoSAnodestimulation,aswellassecondarytohyperkalaemia.Bradycardia(duetomuscariniceffectswithsecond/largedoses,orinchildren).

CNS ↑ICP(duetocontraction),↑IOP(by10mmHg-thisissignificant)suchthatitiscontraindicatedinglobeperforation.

Metabolic MalignantHyperthermia.

MSK Myalgiaspostdepolarisation,particularlyinyoungfemales.Prolongedblockadewithpseudocholinesterasedeficiency.

RenalandElectrolyte

Hyperkalaemia(K ↑by~0.5mmol.L )duetodepolarisationcausingK efflux,↑inburns(>10%),paraplegia(first6months)andneuromusculardisordersincludingmusculardystrophyandmyopathies(includingcriticalillnessmyopathy).

GIT Intragastricpressure↑by10cmH O,matchedby↑inLoSpressure.

Immunological Anaphylaxis-highestriskofallNMBsat~11/100,000

AdverseEffectsTheadverseeffectsofsuxamethoniumcanberememberedasthreemajor,threeminor,andthreepressures:

Major

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AnaphylaxisSuxamethoniumApnoeaMalignanthyperthermia

MinorHyperkalaemiaMyalgiasBradycardia

PressureIOPICPIntragastricpressure

PhaseIandPhaseIIBlockade

InitialblockadeistermedPhaseI,whichisapartialdepolarisingblock.SustaineduseofsuxamethoniummaycausesaPhaseIIblockwhich:

Appearssimilartoanon-depolarisingblockMaybedueto:

PresynapticinhibitionofAChsynthesisandreleaseDesensitisationofthepost-junctionalreceptor

Keydifferencesinclude:

Property PhaseIBlock PhaseIIBlock

BlockAmplitude Reduced Reduced

Train-of-fourratio >0.7 <0.7

Post-tetanicpotentiation No Yes

Effectofanticholinesterases Blockaugmented Blockinhibited

MalignantHyperthermia

RareautosomaldominantgeneticconditionTriggeredbysuxamethoniumandvolatileanaestheticagentsMutationoftheryanodinereceptorcausesexcessiveamountsofcalciumtoleavethesarcoplasmicreticulum,causingcontinualmusclecontraction

Resultsingreatlyincreasedcarbondioxide,lactate,andheatproductionCelllysiswithmyoglobulinaemiaandhyperkalaemiaresults

SuxamethoniumApnoea

AdeficiencyofbutylcholinesterasecausessuxamethoniumtonotbemetabolisedMaybecongenital(genetic)oracquired(hepaticfailure)Canbetreatedwithfreshfrozenplasma

References

Neuromuscular

657

1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SuxamethoniumChlorideInjectionBPPRODUCTINFORMATION3. Appiah-AnkamJ,HunterJM.Pharmacologyofneuromuscularblockingdrugs.ContinuingEducationinAnaesthesiaCritical

Care&Pain,Volume4,Issue1,1February2004,Pages2–7.4. CookT,HarperN.Anaesthesia,Surgery,andLife-ThreateningAllergicReactions:ReportandfindingsoftheRoyalCollege

ofAnaesthetists'6thNationalAuditProject:PerioperativeAnaphylaxis.RoyalCollegeofAnaesthetists'.2018.

Lastupdated2019-07-18

Neuromuscular

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Non-DepolarisingNeuromuscularBlockersNon-depolarisingNMBsaremusclerelaxantsusedto:

FacilitatelaryngoscopyandtrachealintubationControlICPImproverespiratorysystemcomplianceImprovepatientsafetyontransportation

MechanismofactionisbycompetitiveantagonismofAChattheNMJ,preventinggenerationofend-platepotentials.Effectivepharmacodynamicresponserequires>70%receptoroccupation.

CommonFeaturesofNeuromuscularBlockers

Property Action

RouteofAdministration IV/IM

Distribution SmallV astheyarepolarandunabletocrosslipidmembranes

Elimination Reducedurinaryclearancewhichprolongsthemechanismofactionofaminosteroidsinrenalfailure

Resp Apnoea

MSK ↑Durationinhypothermia

Renal ↑Durationinacidosis,↑durationinhypokalaemia,↓durationinhyperkalaemia,↑durationinhypermagnesaemia

Metabolic CriticalIllnessMyopathyinpatientswithlong-termrelaxantuse

TheED is:

Thedoseofaneuromuscularblockingdrugrequiredtoproducea95%reductionintwitchheightin50%ofthepopulationAcommonly-usedtherapeuticend-pointforneuromuscularblockingdrugsTypically,inductiondosesusedare2-5xtheED .

ComparisonofNeuromuscularBlockers

Property Rocuronium Vecuronium Pancuronium Atracurium Cisatracurium

Class Aminosteroid AminosteroidBis-quaternaryaminosteroid

Benzylisoquinoliniumderivative

Benzylisoquinoliniumderivative

Presentation

Clear,colourlesssolutionat10mg.ml

10mgpowderforreconstitutioninwater.ContainsmannitolandNaOH.

Colourlesssolutionat2mg.ml ,whichmustbestoredat4°C

Colourlesssolutionat10mg.ml ,whichshouldbestoredat4°C.Mixtureofalltenextantdiastereoisomers.

R-Cis,R'-Cisisomerofatracurium,whichis15%ofatracuriumbyweightbutprovides50%ofitsNMBDaction.

Colourlesssolutionat2-5mg.ml ,whichshouldbestoredat4°C

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IntubatingDose

0.6-1.2mg.kg 0.1mg.kg 0.05-0.1

mg.kg 0.5mg.kg 0.15-0.2mg.kg

ED 0.3mg.kg 0.05mg.kg 0.07mg.kg 0.25mg.kg 0.05mg.kg

Onset 45-90s 90-120s 90-150s 90-120s 60-180s

Duration

~30minuteswithnormalrenalfunction,repeatdosesmaybemoreunpredictable

45-65minutes

60-100minutes 15-35minutes 25-30minutes

Metabolism

<5%hepaticdeacetylationtoinactivemetabolites

20%hepaticdeacetylationwithweaklyactivemetabolites

20%hepaticdeacetylationwithweaklyactivemetabolites

60%byesterhydrolysis,withremainderbyHofmannelimination.

Metabolisedtolaudanosine,whichcausesseizuresinhighconcentrations(relevantwhenadministeredbylonginfusion)

Hofmannelimination

Elimination

60%biliary,40%urinary.Prolongeddurationinhepaticandrenalfailure

70%biliary,30%urinary

80%biliary,20%urinary

RespSlightriskofbronchospasmwithrapidinjection

Slightriskofbronchospasmwithrapidinjection

CVS ↑HRathighdoses No↑HR

↑HRandMAPduetomuscarinicantagonism

Riskof↓BPwithrapidinjection

Riskof↓BPwithrapidinjection

Immune

Higherriskofanaphylaxis,~6/100,000.Anaphylaxisriskassociatedwithuseofpholcodineintheprevious3years.

NotablynoanaphylaxisrecordedinNAP6

Anaphylaxis~4/100,000.

OtherReversiblewithsugammadex

Reversiblewithsugammadex

References

1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.3. CrillyH,RoseM.Anaphylaxisandanaesthesia–cantreatingacoughkill?.AustPrescr.2014;37:74-6.

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4. Lexicomp.Rocuronium:Druginformation.In:UpToDate,Post,TW(Ed),UpToDate,Waltham,MA,2017.5. Lexicomp.Vecuronium:Druginformation.In:UpToDate,Post,TW(Ed),UpToDate,Waltham,MA,2017.6. Lexicomp.Pancuronium:Druginformation.In:UpToDate,Post,TW(Ed),UpToDate,Waltham,MA,2017.7. Lexicomp.Atracurium:Druginformation.In:UpToDate,Post,TW(Ed),UpToDate,Waltham,MA,2017.8. Lexicomp.Cisatracurium:Druginformation.In:UpToDate,Post,TW(Ed),UpToDate,Waltham,MA,2017.9. CookT,HarperN.Anaesthesia,Surgery,andLife-ThreateningAllergicReactions:ReportandfindingsoftheRoyalCollege

ofAnaesthetists'6thNationalAuditProject:PerioperativeAnaphylaxis.RoyalCollegeofAnaesthetists'.2018.

Lastupdated2019-07-20

Non-DepolarisingNMBs

661

DantroleneDantroleneisaryanodine(RYR1)receptorantagonist,whichpreventsreleaseofCa fromthesarcoplasmicreticulum,uncouplingtheprocessofexcitation-contraction.

Property Dantrolene

Uses MH,NMS,ecstasyintoxication,chronicmusclespasticity

Presentation Vialsoforangepowdercontaining20mgdantroleneand3gmannitol,reconstitutedwith60mlofH Otoformanalkalinesolution.

Dosing 2.5mg.kg IVevery10-15minutes,upto10mg.kg .Onceresolved,continuegiving1mg.kg every4-6hoursfor24hours.

Absorption IVonly,maycauseskinnecrosisifextravasates.

Distribution 85%proteinbound

Metabolism Hepaticmetabolismtoactive5-hydroxy-dantrolene

Elimination Renalofmetabolites,t βof12hours

Resp Respiratoryfailureduetoskeletalmuscleweakness

CVS Volumeoverloadduetolargevolumegivenwithadministration

MSK Skeletalmusclerelaxation

Renal Diuresis

GIT Hepaticfailure

References

1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.3. ANZCAAugust/September2011

Lastupdated2017-09-16

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Sugammadex

Property Sugammadex

Class Gammacyclodextrin.

Uses Reversalofneuromuscularblockinducedbyrocuroniumandvecuronium.

Presentation Clearcolourlesssolutionat100mg.ml .

Pharmaceutics Storebelow30°C.

RouteofAdministration IVonly.

Dosing2mg.kg ifToF>2.4mg.kg ifPTC>2.16mg.kg forreversalfollowingRSIdose.

Distribution V of11-14L.kg .

Metabolism Notmetabolised.

Elimination Renaleliminationofactivedrugandcomplex.

MechanismofAction Formsacomplexwithrocuroniumandvecuronium,causingreversalofneuromuscularblockade.

CVS Rarelymayprecipitatebradycardia-canresultincardiacarrest.

Immune Anaphylaxis.

Other

InteractswithOCP-treatasmissedpillShorteneddurationofrocuroniumandvecuroniumwhenusedwithin24hoursofsugammadexadministration.Onsetisdelayedupto5minutes,anddurationshortenedby10-15minutes.Thisperiodmaybeextendedinrenalfailure.

References1. SugammadexFullPrescribingInformation.FDA.

Lastupdated2019-07-20

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Anticoagulants

Property Warfarin Heparin Enoxaparin

Uses AF,DVT/PE,ProstheticValves AF,DVT/PE,Extra-corporealCircuitAnticoagulation DVTProphylaxis

Pharmaceutics

Marevanandcoumadinmaypotentiallyhavedifferentbioavailabilities(ithasnotbeenassessed)andsoshouldnotbesubstituted

Mucopolysaccharideorganicacidwhichoccursnaturallyintheliverandinmastcells,withahighlyvariablemolecularweight(between5,000and25,000Da)

Smallerfragmentsofheparin(preparedfromUFH),withameanmolecularweightof5,000Da

MechanismofAction

PreventsthereturnofvitaminKtoitsreducedform,andthereforethegamma-carboxylationofvitamin-Kdependentclottingfactors(II,VII,IX,X),aswellasProteinCandProteinS).

PotentiatestheeffectofATIII,rapidlyincreasingitsanti-IIaandanti-Xaeffect(1:1effect).

InhigherconcentrationsalsoinhibitsIXa,XIa,XIIa,andplateletaggregation.

PotentiatestheactionofATIII,increasinginhibitionofXaandIIa,but(unlikeUFH)ina4:1ratio.

MorepredictableeffectonXastandardisesdosingandjustifieslackofmonitoringrequirement.

Onset

8-12hours.Peakat72hoursduetothehalf-lifeofexistingclottingfactors,andthetotalbodystoresofvitaminK

ImmediateIVonset

Absorption 100%bioavailability IV,SC SConly

Distribution 99%proteinbound Lowlipidsolubility,highlyproteinbound

Doesnotbindtoheparin-bindingproteins

Metabolism

Completehepaticmetabolism.Significantpharmacokineticinteractionwithenzymeinducersandinhibitors.

Hepaticinteractionsduetoenzymaticinduction(ETOH,amiodarone,salicylates,NSAIDs)andinhibition(OCP,barbiturates,carbamazepine)

Renaleliminationofmetabolites

Elimination Faecalandrenaleliminationofmetabolites,t βof40hours Renalofinactivemetabolites

Renalofactivedrugandinactivemetabolites

CVS Microthrombi HypotensionwithrapidIVadministration

Metabolic Lessosteoporosisduetolessprotein(andthereforetissue)binding Osteoporosis

Renal Inhibitsaldosteronesecretion

GIT N/V

Haeme Haemorrhage Haemorrhage,HITTs

Haemorrhage,lowerriskofHITTsthanUFH.Lessthrombocytopaenia.

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664

Reversal-Waiting-VitaminK-FFP-Prothrombinex

Reversedwithprotamine(1mgper100U).

Incompletereversalwithprotamineasonlytheanti-IIaeffectisinhibited.

OtherTeratogenic.ComplicatedpharmacokineticsrequiringmonitoringusingINR.

RequiresmonitoringwithAPTTorATIIIlevels.LargeinterpatientvariabilityduetovariableamountsofATIII.

1unitistheamountofheparinrequiredtoprvent1mlofbloodclottingfor24hoursat0°C

Nomonitoringrequired.

HITTs

Heparin-InducedThromboticThrombocytopeniacomesintwoflavours:

TypeI:Isnon-immunemediatedOccurswithin4daysofanticoagulantdosesIsanisolatedthrombocytopeniawithoutclinicalsignificance

TypeII:IsimmunemediatedOccurswithin4-14daysIsassociatedwithseriousthrombosisandhighmortality(typicallyfromPE)andmorbidity(fromCVAandlimbischaemia)

Protamine

Protamineis:

Abasiccationicproteinderivedfromsalmonspermwhichcombineswiththeacidicanionicheparintoformastable,inactivesaltinsolutionClearedmorerapidlythanheparinReboundanticoagulationmayoccur.

Adverseeffectsfromprotamineinclude:

HistaminereleaseBronchospasmHypotension

PulmonaryhypertensionThiscanbeprofoundandresultinadramaticincreaseinRVafterloadandEDV,withacorrespondingfallinLVpreload(interventricularinterdependence),leadingtodramatichypotensionandarrest.

MediatedbythromboxanesDuetoprotamine-heparincomplexes,ratherthanprotaminealoneAdministrationofprotamineinabsenceofheparindoesnotleadtopulmonaryhypertension.

AnticoagulationWhengiveninexcess.

References

Haematological

665

1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.3. ANZCAAugust/September20114. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.

Lastupdated2019-07-18

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DirectThrombinInhibitorsDirectthrombininhibitorspreventcleavageoffibrinogentofibrin,andarethereforeveryeffectiveanticoagulants.

Property Dabigatran

Class NOAC

Uses VTEprophylaxis,AF

Presentation 75/110mgCapsules

RouteofAdministration PO

Dosing VTE:220mgdaily,AF:150mgBD

Absorption 6.5%bioavailability

Distribution 35%proteinbound

Metabolism Prodrug-activatedbyplasmaandhepaticesterases

Elimination Renaleliminationofactivedrug

Haeme Haemorrhage

Immune Allergy

Other Significantinteractionswithamiodarone,quinidine,St.John'sWort,aswellasotheranticoagulantandantiplateletagents.Dialysable.Potentiallyreversiblewithidarucizumab.

References

1. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.2. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.

Lastupdated2019-07-18

DirectThrombinInhibitors

667

AntifibrinolyticsAntifibrinolyticsincludeaprotinin,aminocaproicacid,andtranexamicacid.Allpreventthebreakdownoffibrin(!)byvariousmechanisms.TXAcompetitivelyinhibitsplasminogenactivator,reducingrateoffibrinolysis.

Property TranexamicAcid(TXA)

Class Antifibrinolytic

Uses Trauma(within3hours),cardiacsurgery,obstetricsurgery,andmenorrhagia

Presentation Tablets,syrup,clearcolourlesssolutionforinjection

RouteofAdministration IV,PO

Dosing 1gslowIV,whichmaybefollowedbyinfusionof1gover8hours

Absorption 50%bioavailability

Distribution Lowplasmaproteinbinding,V 9-12litres

Metabolism Minimalhepaticmetabolism

Elimination Renalofactivedrug-dosereduceinrenalimpairment

GIT Nausea,vomiting

Haematological Reducesfibrinolysis,possibleincreaseinDVT/PE

Immunological Allergicdermatitis

References

1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. LITFL-TranexamicAcid

Lastupdated2019-07-18

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AntiplateletsNoteaspirinisincludedunderCOXinhibitors.

ClassificationofAntiplateletAgents

Antiplateletagentscanbeclassifiedbywhichstageofplateletfunctiontheyaffect:

AdhesionvWFinhibitorse.g.Dextran70.

ActivationProstacyclinse.g.Epoprostenol.Phosphodiesteraseinhibitione.g.Dipyridamole.COXinhibitorsPreventthromboxaneA2production,e.g.aspirin.

AggregationADPreceptorantagonistsPreventactivationofGPIIb/IIIareceptors,e.g.clopidogrel.GPIIb/IIIareceptorantagonistsPreventplateletaggregationviafibrinlinkagesbetweenGPIIb/IIIareceptors,e.g.tirofiban.

ComparisonofCommonAntiplateletAgents

Property Clopidogrel Dipyridamole Tirofiban

Class ADPantagonist Phosphodiesteraseinhibitor GPIIb/IIaantagonists

Uses PVD,STEMI,NSTEMI,stentprophylaxis CVA UA,NSTEMI

RouteofAdministration POonly PO/IV IVonly

MechanismofAction

IrreversiblypreventsADPfrombindingtoitsreceptorontheplatelet,preventingactivationoftheIIb/IIIareceptor

Inhibitsplateletadhesiontowalls,potentiatesprostacyclinactivityandincreasesplateletcAMP,↓Ca andinhibitingplateletaggregationanddeformation.Alsoactsasacoronaryvasodilator.

ReversibleantagonismofIIb/IIIareceptor,preventingplateletaggregation

Dosing 300mgload,75mgdailythereafter 200mgBDforCVA

Load25mcg.kg ,maintenance15mcg.kg

Absorption Rapidabsorptionandonsetwithin2hours VariabledependingonoralintakeIVonly.Onsetwithin10minutes

Distribution Highlyprotein-bounddrugandmetabolites Highlyproteinbound 65%protein

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Metabolism

Prodrug.Majorityhydrolysedbyesterasestoinactivedrug,withasmallproportionhepaticallymetabolisedbyCYP450toactiveform.ProlongeddurationofactionduetoirreversibleADPblockaderatherthanlongeliminationhalf-life.

Partialhepatictoinactivemetabolites

Notmetabolised.

Elimination Urinaryandfaecal Renalandfaecal

Urinaryasunchangeddrug.Plateletaggregationreturnstobaselinewithin4-8hours

CVS VasodilatationmaydropCPPinASandrecentMI

Coronaryarterydissection

GIT Mucosalirritation

Haeme Haemorrhage Thrombocytopaeniaandhaemorrhage Haemorrhage

Other

Manypharmacokineticinteractions,includinggeneticvariability.Previouslythoughttokineticallyinteractwithomeprazole-morerecentlydisproved.

References

1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. RangHP,DaleMM,RitterJM,FlowerRJ.RangandDale'sPharmacology.6thEd.ChurchillLivingstone.

Lastupdated2019-07-18

Antiplatelets

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PenicillinsPenicillinsarebactericidalantibioticsthatpreventcell-wallsynthesisbypreventingcross-linkingofpeptidoglycansbyreplacingthenaturalsubstratewiththeirβ-lactamringPenicillinsbindtopenicillinbindingproteins(PBPs)inthebacterialwallPenicillinsonlyrarelyachievecompleteeradicationofsensitiveorganismswithoutadditionofasynergisticantibiotic(suchasgentamicin)

CommonFeatures

Property Effect

Absorption Typicallywellabsorbedorally.IMdosingtendtocauselocalisedpainandirritation.

Distribution Typicallyhavegoodtissuepenetration.Onlycrosstheblood-brainbarrierandenterboneifitisinflamed.Typicallylowproteinbinding(exceptionisflucloxacillin,whichis95%proteinbound).

Metabolism Typicallysmallproportionishepaticallymetabolised.

Elimination Majority(60-90%)iseliminatedunchangedinurinepredominantlybyactivetubularsecretion,withrenalclearanceproportionaltototalrenalplasmaflow.Asmallquantityissecretedinbile.

MechanismsofResistance

AlterationorprotectionofPBPsGramnegativebacteriamayhavealteredpermeabilityofporinsintheiroutermembrane,whichprotectsthePDP

Hydrolysisbyβ-lactamase-producingbacteriaClavulanicacidandtazobactaminhibitβ-lactamase,whichcanrenderotherwiseresistantbacteriasensitiveNotably,flucloxacillinhasamodifiedbeta-lactamringthatisnotsensitivetoβ-lactamases

ComparisonofPenicillins

Narrowspectrum,naturallyoccurring

Narrowspectrum,synthetic

Extended-spectrum Antipseudomonal

Examples Benzylpenicillin,phenoxymethylpenicillin Flucloxacillin Ampicillin,

amoxacillinPiperacillin,ticarcillin

Indications

Grampositivesandanaerobes,particularlystreptococciandmeningococci.Alsolisteria,Clostridia,andTreponema.

Grampositivecocci,particularlystaphylococcibutalsostreptococci.

Grampositive,particularlyenterococci.Somegramnegative.

Grampositive,gramnegativeincludingpseudomonas.

Otherbits Highlybactericidal

Lessactivethanbenzylpenicillinonorganismssensitivetoboth.

Canpenetratesomegram-negatives.

Gramnegativecover.

References

Antimicrobials

671

1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. BarzaM,WeinsteinL.Pharmacokineticsofthepenicillinsinman.ClinPharmacokinet.1976;1(4):297-308.3. BruntonL,ChabnerBA,KnollmanB.GoodmanandGilman'sThePharmacologicalBasisofTherapeutics.12thEd.

McGraw-HillEducation-Europe.2011.4. CICMJuly/September2007

Lastupdated2019-07-18

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GlycopeptidesNon-β-lactamagentsthatinhibitcellwallsynthesis.Theyare:

Activeagainstgram-positiveanaerobesandaerobesBacteriostaticagainstenterococciandstreptococciBacteriocidalagainststaphylococci

Property Vancomycin

Uses MRSA,C.difficile

Presentation Powderforreconstitution

RouteofAdministration PO,IV,Intrathecal

Dosing Peaklevelsdeterminedbydose,troughlevelsbydoseandinterval

Absorption Nooralbioavailability.PoorCSFpenetration

Distribution V 0.4-1L.kg .PoorCSFpenetrationevenwithinflamedmeninges-higherlevelsarerequiredforCNSpenetration.~50%proteinbound.

Metabolism Minimalhepaticmetabolism

Elimination 90%secretedunchangedinurine-significantlyprolongedinrenalimpairment

CVS Phlebitis,redmansyndrome(profoundnon-anaphylactichistaminereleasewithrapidinjection)

CNS Ototoxicity

Renal Nephrotoxicity,typicallytemporaryandresolvesoncessation

Haematological Thrombocytopenia

Immunological 'Redmansyndrome'duetohistaminereleasewithrapidinjection,withaccompanying↑HR↓BP.Neutropenia.

Other Synergisticactionwithcephalosporins,aminoglycosides,andrifampicin

References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. WellingtonICUDrugManual3. RybakMJ.Thepharmacokineticandpharmacodynamicpropertiesofvancomycin.ClinInfectDis.2006Jan1;42Suppl

1:S35-9.

Lastupdated2019-07-18

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AminoglycosidesBactericidalantimicrobialsthatpreventproteinsynthesisbyirreversiblebindingtothe30Sribosomalsubunit,preventingmRNAtranscription.

Astheyarelarge,polarmolecules,theymustbeactivelytransportedintothecellThisoccurswithanoxygendependenttransporterThereforetheyarenoteffectiveagainstanaerobes.

TransportisinhibitedbyincreasedCa ,Mg ,lowpH,andlowOAminoglycosidekillingisdependentonthepeakconcentrationoverMICTypicallypeakconcentrationmustbe8-10xMIC.

Exposuretoaminoglycosidescausesbacteriatodown-regulateaminoglycosideuptake,andthereforeincreasesMICThiseffectdisappearsafter~24hours,andisonejustificationfordailydosingofaminoglycosides.Additionaljustificationsinclude:

Allowslargersingledosestobeused,increasingbactericidaleffectAminoglycosidesexhibitapost-antibioticeffectOngoingbactericidalactivityevenafterconcentrationfalls.

Property Gentamicin

Uses/Spectrum Gramnegativeincludingpseudomonas,limitedgrampositive(staph,limitedstrep),synergisticeffectswithβ-lactamsandvancomycin.

RouteofAdministration IVonly.

Dosing 4-7mg.kg .

Distribution 70%proteinbound.VerysmallV of0.2L.kg ,whichmayresultinsignificantpharmacokineticchangeswithoedema.

Metabolism Notmetabolised.

Elimination Eliminatedunchanged,eliminationt prolongedupto70hoursinrenalimpairment.

CNS Ototoxicityduetoaccumulationinperilymph,andisusuallypermanent.Increasedriskwithconcomitantfrusemideuse.

MSK Muscleweakness.

Renal Nephrotoxicityduetoaccumulationintherenalcortex,typicallyreversible.

ToxicEffects Narrowtherapeuticindex,requiresmonitoringanddosereductioninrenalimpairment.

References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. StubbingsW,BostockJ,InghamE,ChopraIMechanismsofthepost-antibioticeffectsinducedbyrifampicinandgentamicin

inEscherichiacoli.JAntimicrobChemother.2006Aug;58(2):444-8.3. DerangedPhysiology-KillCharacteristicsofAntibioticAgents

Lastupdated2017-08-12

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Aminoglycosides

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LincosamidesInhibitproteinsynthesisbydisruptingthe50Sribosomalsubunit.Maybebacteriostaticorbacteriocidal,dependingontheconcentrationandtheparticularorganism.

Property Clindamycin

SpectrumofActivity

Grampositivecocci,anaerobes.Littleactionagainstgramnegativeaerobes.Alsoactiveagainstsomeprotozoa,suchasP.falciparum.

RouteofAdministration PO/IV

Dosing 150-300mgQ6H

Absorption 90%PObioavailability

Distribution Excellentbonypenetration

Metabolism Hepatictoactiveandinactivemetabolites

Elimination Renaleliminationofallmetabolites

MSK Maycauseneuromuscularblockadeinoverdose

GIT ReasonableincidenceofGITupset,withfatalpseudomembranouscolitisreported.DerangedLFTs

Immune Atopy,eosinophilia,DRESS

References

1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. Lexicomp.Clindamycin(systemic):DrugInformation.In:UpToDate,Post,TW(Ed),UpToDate,Waltham,MA,2017.

Lastupdated2019-07-18

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MetronidazoleMetronidazoleinterruptscellularmetabolismbypreferentialreduction,capturingelectronsthatwouldbeusuallytransferredtoothermolecules.Thisleadstoabuildupofcytotoxicintermediatemetaboliccompoundsandfreeradicals,thatresultinDNAbreakageandsubsequentcelldeath.

Property Drug

Class Nitroimidazole

Uses Anaerobesandprotozoa

RouteofAdministration PO/IV

Dosing 500mgBD

Absorption 100%bioavailability

Distribution CrossesBBB

Metabolism Hepatictoactivemetabolites

Elimination Renalofactivemetabolites

Metabolic Significantrash,nausea,vomiting,headache,flushing

GIT Nausea,vomiting,metallictaste

Immunological Hypersensitivityreactions

Interactions Disulfiram-likereactionwithETOH

References

1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. Lexicomp.Metronidazole(systemic):Druginformation.In:UpToDate,Post,TW(Ed),UpToDate,Waltham,MA,2017.

Lastupdated2019-07-18

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AntifungalsAntimicrobialagentstargetingeukaryoticandheterotrophicmicrobes.Canbedividedbyclassinto:

AzolesInhibitergosterolsynthesis.Subdividedinto:

TriazolesFluconazoleItraconazoleVoriconazolePosaconazole

ImidazolesKetoconazole

EchinocandinsInhibitglucansynthesis.

CaspofunginMicafunginAnidulafungin

PolyenesDisruptcellmembrane.

AmphotericinBNystatin

CommonFeatures

MechanismsofAntifungalResistance

Threebroadmechanisms:

IncreasedeffluxIncreasedexpressionoftransportproteinsremovingdrugfromcell.AlterationoftargetenzymeChangestoproteintargetpreventdrugbindingorinactivation.

TypicallyonlyrequireschangesinafewaminoacidsAlterationofdrugmetabolismReducedenzymeactivitypreventsaccumulationoftoxicproduct.

Amphotericinresistanceisrareinvivo,andistypicallyviadifferentmechanisms:

DecreasedergosterolcontentAlteredsterol:phospholipidratio

ComparisonofAntifungals

Drug Fluconazole Voriconazole Caspofungin AmphotericinB

Class Azole AzoleEchinocandins Polyenes

Candida(includingazoleresistant

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SpectrumofActivity

Candidaalbicans(mostotherspecies,especiallyC.glabrataandtoalesserextentC.kruseiareresistant),asresistancerapidlydevelops),cryptococcus,coccidioides,histoplasma,blastomyces,andsomeaspergillus(resistancemayalsodeveloprapidly).Atleastasgoodasamphotericininsusceptibleorganisms.

Asfluconazole,butbroaderspectrumofactivity

C.glabrataandC.kruseiandCandidabiofilms),aspergillus.Notablynoactivityagainstcryptococcus,fusarium,andtrichosporon.

Additionally,echinocandinstypicallyhavenocross-resistancewithotherantifungals

Effectiveagainstmanyfungi,withnotableexceptionsbeingChromoblastomycosis,Aspergillusterreus,Candidalusitaniae,Scedosporium,andsomeFusarium.

Pharmaceutics Poorwatersolubility Poorwatersolubility

Poorwatersolubility

Fourdifferentformulations,mostcommonisamphotericinBcolloidaldispersion(ABCD)

Dosing 100-800mgOD,adjustinrenalfailure

Typically70mgloadingdose,followedby50mgdaily;dosereducedinhepaticimpairment

Loadwith0.25-0.5kg.kg ,followedby0.25-1.5mg.day ,reducedinsevererenalimpairment

RouteofAdministration IVorPO IVonly(high

MW)IVforsystemicindications

Absorption

HighPObioavailability,POabsorptionatlowpH(interactionwithantacids,vitaminsupplements)

<5%PObioavailability

DistributionCrossesBBB-goodCSFpenetration.Verylowproteinbinding(~10%)

Notdialysableduetoveryhighproteinbinding,V .Goodtissuepenetration.

EssentiallynoCSFpenetration,97%proteinboundinserum

Rapiduptakebyreticuloendothelialsystem.Bindstoorganicaniontransportingpeptides(importantinhepatocytedrugbinding),importantinkeydruginteractions(suchastacrolimus)

Metabolism

MetabolisedbyandcausereversibleinhibitionofmultiplehepaticCYP450enzymes(including3A4,2C19,2C9),leadingtoincreasedconcentrationsofmanydrugs/metabolites

Asfluconazole

ExtensivehydrolysisandN-acetylationtoinactivemetabolites

Minimalmetabolism

Elimination 80%offluconazolerenallyeliminatedunchanged

Mostlyclearedvialiver.

Renalofmetabolites

Renalandfaecaleliminationofunchangeddrug

MechanismofInhibitergosterolsynthesis

Preventcellwallsynthesis Bindssterols,

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Action byinhibitingCYP450enzyme

Asfluconazole byblockingproductionofbeta-glucan

integrityofthecellmembrane

CVS HTN LongQT Histaminerelease

CNS Headache,visualdisturbances

Hallucinations,psychosis

Renal

AKIviaafferentarteriolarconstrictionanddirecttubulartoxicity,hypokalaemia,renaltubularacidosis

GIT HepatotoxicityMildhepatotoxicityinupto~15%

Haeme Thrombophlebitis,normocyticanaemia

References

1. AndersonJB.Evolutionofantifungal-drugresistance:mechanismsandpathogenfitness.NatRevMicrobiol.2005Jul;3(7):547-56.

2. DrewRH.PharmacologyofAmphotericinB.In:UpToDate,Post,TW(Ed),UpToDate,Waltham,MA,2018.3. AshleyED,PerfectJR.Pharmacologyofazoles.In:UpToDate,Post,TW(Ed),UpToDate,Waltham,MA,2018.4. LewisRE.Pharmacologyofechinocandins.In:UpToDate,Post,TW(Ed),UpToDate,Waltham,MA,2018.5. BekerskyI,FieldingRM,DresslerDE,LeeJW,BuellDN,WalshTJ.Pharmacokinetics,excretion,andmassbalanceof

liposomalamphotericinB(AmBisome)andamphotericinBdeoxycholateinhumans.AntimicrobAgentsChemother.2002Mar;46(3):828-33.

Lastupdated2019-07-18

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InsulinsInsulinsaresyntheticpolypeptidehormones.They:

HaveasimilarmechanismofactionandpharmacodynamicsofendogenousinsulinOneunitofinsulinisdefinedastheamountrequiredtomakeapreviouslyhealthy2kgrabbithypoglycaemic

TypesofInsulin

Differentinsulinsarecategorisedbytheirtimeofonset,peak,andduration,andareclassifiedaseither:

FastactingIntermediateactingLongacting

FastActing

FastactinginsulinsareusedforcontrollingBSLspikespostmeals,andforcontrolofhyperglycaemia.Administeredsubcutaneouslytheyhavehavean:

Onsetof5-15minutesPeakat1-2hoursLast4-6hours.

Fastactinginsulinsinclude:

InsulinAspart(Novorapid)InsulinLispro(Humalog)

IntermediateActing

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IntermediateactinginsulinsareusedforcontrolofBSLbetweenmealsasapseudo-basalbolus.Administeredsubcutaneouslytheyhavean:

Onsetof1-2hoursPeakat4-6hoursLast>12hours

Intermediateactinginsulinsinclude:

NPHProtophane

LongActing

Longactinginsulinsareusedforcreatingabaselineinsulinlevel.Administeredsubcutaneouslytheyhavean:

Onsetof1-1.5hoursPeakat5hoursLast24hours

Long-actinginsulinsinclude:

Insulinglargine(Lantus)Insulindetemir(Levemir)

PharmacokineticsofExogenousInsulinPreparations

Property Drug

Class Syntheticpolypeptidehormones

Uses Diabetes,hyperglycaemia,hyperkalaemia,β-blockertoxicity,Ca -blockertoxicity

Presentation Clearcolourlesssolutiontypicallyat100IU.ml

RouteofAdministration SC,IM,IV

Absorption Variable,asdescribedabove.Insuliniscomplexedwithdifferentsubstances(e.g.protamine,zinc),whichalteritsrateofabsorption

Distribution MinimalproteinbindingandminimalredistributionoutofECF-V 0.075L.kg

Metabolism Glutathioneinsulintranshydrogenase.Metabolismisconstant-durationofactionisentirelyduetodifferentratesofsubcutaneousabsorption.

Elimination Renalofinactivemetabolites

References

1. DiabetesEducationOnline.TypesofInsulin.UCSF.AccessedJanuary2016.2. Graphofinsulinactivityprofilesfrom:DiabetesEducationOnline.TypesofInsulin.UCSF.AccessedJanuary2016.3. MudaliarS,MohideenP,DeutschR,CiaraldiTP,ArmstrongD,KimB,ShaX,HenryRR.Intravenousglargineandregular

insulinhavesimilareffectsonendogenousglucoseoutputandperipheralactivation/deactivationkineticprofiles.DiabetesCare.2002Sep;25(9):1597-602.

4. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.

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OralHypoglycaemics

Class Biguanides Sulfonylureas Glitazones Gliflozins

Example Metformin Gliclazide Pioglitazone Dapagliflozin

Uses T2DM T2DM T2DM T2DM

MechanismofAction

Delayglucoseabsorption,increaseperipheralinsulinsensitivity,inhibithepaticgluconeogenesis

Increaseinsulinsecretionfrompancreaticβ-cells.Mayincreaseinsulinsensitivity

ActivatestheintranuclearPPARγreceptor,affectinggenetranslationandincreasinginsulinsensitivity

InhibitsglucosereabsorptionbytheS-GLUT co-transporterinthekidney,increasingglucoseeliminationinurine

Dosing 500mg-2gBD 40-160mgBD 15-30mgdaily 5-10mgdaily

Absorption Bioavailability60%

Bioavailability80%

Highbioavailability.DelayedonsetandlatepeakeffectgivenMoA

Bioavailability>75%

Distribution Minimallyproteinbound

Extensivelyboundtoalbuminbynon-ionicforces,suchthattheydonottendtodisplaceotherhighlyproteinbounddrugs

LowV(0.6L.kg )

Metabolism NotmetabolisedPartialhepatictoinactivemetabolites

ExtensivehepaticphaseItoinactiveandactivemetabolites

Extensivehepatictoinactivemetabolites

EliminationRenaleliminationofactivedrug

Renaleliminationofactivedrugandinactivemetabolites

RenalandGIeliminationofactiveandinactivemetabolites

Renalofinactivedrug

CVSMayprecipitatefluidretention

Renal

Contraindicatedinrenalimpairmentduetoincreasedriskoflacticacidosis

Contraindicatedinrenalimpairment(<60ml.min )asithasnobenefit

MSK Photosensitivity

Metabolic

↑Appetite,weightgain.Hypoglycaemia

Weightloss,reducedinsulinrequirements

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infasting.

Renal IncreasedUTIandthrushrisk

GIT Nausea,Diarrhoea Cholestasis

Toxic

Severelacticacidosissecondarytoinhibitionofoxidativeglucosemetabolism,especiallyinrenalfailureandalcoholics

Crossplacenta,causingfoetalhypoglycaemia.

Mayleadtoeuglycaemicdiabeticketoacidosisduetobluntedinsulinproductioninthefaceofstresshormones.ConsiderinpatientswithDKAsymptoms(drowsiness,abdominalpain,nausea/vomiting),elevatedketones,andmetabolicacidosisinthesettingofanormalBSL.

References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.3. DapaglifozinforType2Diabetes.2013.AustPrescr2013;36:174-9.4. KilovG,LeowS,ThomasM.SGLT2inhibitionwithdapagliflozin:Anovelapproachforthemanagementoftype2diabetes.

AmericanFamilyPhysician.Volume42,No.10,October2013Pages706-710.5. ANZCA.SevereEuglycaemicKetoacidosiswithSGLT2InhibitorUseinthePerioperativePeriod.2018.

Lastupdated2019-07-18

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OxytocicsOxytocicsareagentswhichincreasetheforceofuterinecontraction.

Property Oxytocin Ergometrine PGF(Dinoprost) Carboprost

Class

Endogenous(typicallysyntheticversionused)posteriorpituitaryhormone

Ergotalkaloid Prostaglandin

UsesAugmentationoflabour,increaseuterinetone(PPH)

PPH SeverePPH SeverePPH

Presentation Clearliquidat5-10U.mlClearliquidat250μg.ml ,upto8doses(2mg)

RouteofAdministration IV IV,IM Intramyometrial

injection,IM Intramyometrial,IM

Dosing 1.5-12mU.min250μgIM(IVinemergencyviaslowpush)

500μgIM

Metabolism Oxytocinasesinliverandkidney

MechanismofAction

OxytocinGPCRintheuterus,increaseCainflux.StructurallysimilartoADH.

Actsonαand5HT receptorsonuterineandvascularsmoothmuscle

Resp Bronchospasm(maybesevere)

Bronchospasm(severeifIVsothisrouteiscontraindicated)

Bronchospasm,APOdueto↑PVRwithsubsequenthypoxia

CVS ↑HR,↓BPfollowingboluses

↑SVR,↑BP(maycause,↓HR)coronaryvasoconstriction

↑SVR,↑BP ↑SVR,↑BP(usuallytransient)

CNS Headache,nausea,vomiting Headache,nausea Nausea,

vomiting Headache

Renal↓UOduetoADH-likeeffectswithprolongedinfusions

GU

↑Uterinetone(↑frequencyatlowdose,tetaniccontractionathighdose),foetaldistress,lactation

↑Uterinecontractionfrequencyandtone

↑Uterinecontractionfrequencyandtone

↑Uterinecontractionfrequencyandtone,contraindicatedinpelvicinflammatorydisease

Other

Maybemetabolisedbyoxytocinasesinbloodproductsifco-administeredonthesameline

Contraindicatedinpre-eclampsiaduetoHTN

Deprecatedbycarboprost,increasedbodytemperature

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References

1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.3. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.4. RoyalWomen'sHospita.PostpartumHaemorrhage-Carboprost.2017.

Lastupdated2019-07-18

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TocolyticsTocolyticsareagentswhichdecreaseuterinetone.Tocolyticsinclude:

β -agonistsCa -channelantagonistsCOXInhibitorsMgSONitratesVolatileanaestheticagents

Alltocolyticsarediscussedinmoredetailelsewhere-thiscoversjustthemechanismofactionoftheiruterineeffects.

Drug β -agonists Ca -channelantagonists COXInhibitors

Example Salbutamol,Terbutaline Nifedipine Indomethacin

MechanismofAction

ActivateGPCR,↑cAMP,whichactivatesproteinkinaseAandleadstoinhibitionofmyosinlightchainkinaseandrelaxation

BlockL-typeCa channels,causingrelaxation

Inhibitprostaglandinsynthesis,whicharevitalforuterinecontraction

References

1. Diaz,A.Describethemechanismofactionandsideeffectsofthreeclassesofdrugsthatareusedtoincreaseuterinetone,andthreeclassesofdrugsusedtodecreaseuterinetone.PrimarySAQs.

Lastupdated2019-07-18

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AcidSuppression

PropertyNon-

ParticulateAntacids

ParticulateAntacids ProtonPumpInhibitors H receptorantagonists

Example Sodiumcitrate

AluminiumHydroxide/Calciumcarbonate

Omeprazole Ranitidine

Uses Aspirationprophylaxis

Aspirationprophylaxis

Aspirationprophylaxis,GORD,pepticulceration

Aspirationprophylaxis,GORD,pepticulceration

Absorption

Rapidabsorptionduetohighwatersolubility

Lowerwatersolubilityresultsinslowerabsorptionandonsetbutnoriskofalkalosis

Absorbedinsmallbowel,highPObioavailability 50%PObioavailability

Distribution LowV of0.3L.kg 15%proteinbound

Metabolism

Prodrug,activatedwithinparietalcell.CYP450metabolised,inhibitsCYP2C19(reducing,amongotherthings,theantiplateleteffectofclopidogrel)

PartialhepaticbyCYP450

Elimination Renalofmetabolitesandactivedrug

Renalofmetabolitesandactivedrug

MechanismofAction

Basereactswithgastricacidtoproducesaltandwater

Basereactswithgastricacidtoproducesaltandwater

IrreversibleantagonismoftheparietalH /K ATPase

Competitiveantagonismofthe(Gs)H receptor,which↓cAMPproduction,↓intracellularCa ,and↓activityoftheH /K ATPase

Resp

Lowerriskofpneumonitisifaspirated

Greaterriskofpneumonitisifaspirated

Potentiallyincreasedseverityofpneumoniaifaspirationoccurs(riskwithmicro-aspirationinlong-termintubatedpatients)

Pneumonitis/pneumoniaasperPPI

CVS↓HR,↓BP,andarrhythmogenicwithrapidIVadministration

RenalPotentialmetabolicalkalosis

Noriskofalkalosis Interstitialnephritis

GIT ↑GastricpH ↑GastricpH ↑GastricpH(pH↑by~1),↓

volumeofsecretions

Other Tastebad

References1. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.2. ANZCAFeb/April2012

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3. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.OxfordUniversityPress.4thEd.2011.

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AntiemeticsAntiemeticdrugscanbeclassifiedbytheirmechanismofaction:

SerotoninantagonistsOndansetron

CorticosteroidsDexamethasoneHasadditionaleffectsonpostsurgicalpainandfatigue.

DopamineantagonistsPhenothiazines

ChlorpromazineProchlorperazine

ButyrophenonesDroperidol

BenzamidesMetoclopramide

AnticholinergicsHyoscineAtropine

AntihistaminesCyclizine

NK antagonistsAprepitant

OthersBenzodiazepinesCannabinoidsPropofol

ComparisonofAntiemeticDrugs

Property Ondansetron Droperidol Metoclopramide Cyclizine

Class SerotoninantagonistBenzamidedopamineantagonist

DopamineantagonistPiperazinederivative/Hantagonist

Uses

Nausea.Ineffectiveforvomitingduetomotionsicknessordopamineagonism

Antiemetic,sedation,behaviouralcontrol

Prokinetic,antiemetic

Antiemetic(includingmotionsicknessandradiationsickness)

PresentationTablet,wafer,clearsolutionforinjectionat4mg.ml

Clearsolutioninbrownglass,incompatiblewiththiopentoneandmethohexital

Clearsolutioninplastic

50mgtabletsor50mg.mllight-sensitivesolution

RouteofAdministration PO/SL/IV IV IV/PO PO/IV/IM

Dosing4-8mgTDSGiveoninductionfor

IVGiveatendofsurgeryfor

25-50mgIV(note10mghasnoantiemeticproperties

1mg.kg upto150mgperday

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PONV PONV

Absorption PObioavailability60% PObioavailability30-90%

PObioavailability80%

Distribution 75%proteinbound90%proteinbound,V2L.kg

Minimalproteinbinding,V ~3L.kg

Metabolism

Hepatictoinactivemetabolites.Dosereductioninhepaticimpairment.t3/24.

Extensivehepaticmetabolism Hepaticmetabolism

Hepatictoinactivemetabolites

Elimination Renaleliminationofinactivemetabolites

Renalandhepaticofdrugandmetabolites

Renalof20%unchangeddrugandremainderasmetabolites

Renalofmetabolites

MechanismofAction

Centralandperipheralantagonismof5-HTreceptors,reducinginputtothevomitingcentre

CentralDblockadeandpost-synapticGABAantagonism

AntiemeticactivityviacentralD antagonism,prokineticactivityviamuscarinicagonism,peripheralD antagonism

CompetitiveHantagonistandanticholinergicatM ,M ,Mreceptors

CVS

BradycardiawithrapidIVadministration,QTprolongation

QTprolongation,hypotensionsecondarytoαantagonism

↑/↓HR,↑/↓BP↑HRand↓BPduetoαantagonism

CNS Headache

Sedation(neurolepsis),extrapyramidalsymptomsin~1%

Extrapyramidalsymptoms,neurolepticmalignantsyndrome

Sedation

GIT Constipation Antiemetic Antiemetic,prokinetic IncreasedLoStone

Endocrine Hyperprolactinaemia

References

1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SébastienPierre,MD,RachelWhelan.NauseaandVomitingAfterSurgery.ContinEducAnaesthCritCarePain2013;13

(1):28-32.doi:10.1093/bjaceaccp/mks0463. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.

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IntravenousContrast

Intravenouscontrastmaybedividedinto:

X-rayContrastTheseagentsareallbasedonatri-iodinatedbenzenering,whichabsorbsx-rayradiation.Alterationstothisringaltertoxicity,lipophilicity,andelimination.

Agentsareclassifiedbythesestructuraldifferencesinto:IonicIonicsubstancesarestrongacidsandarewatersolubleduetoionisation.Theyarefurtherdividedinto:

MonomersTypicallyhighmolecularweight.Dimers

Non-IonicWatersolubleduetohydrophilicsidechains.Lowermolecularweightthanioniccontrastagents.

MonomerAgentofchoiceforangiography.

EasytoinjectWatersolubleatphysiologicpH

DimerHardertoinjectthanmonomersduetohigherviscosity.Typicallyusedforurography.

Allarerenallyeliminated,andmayberetainedinrenaldysfunctionGadoliniumContrastGd ,duetoitssevenunpairedelectrons,isparamagneticandwillaltersthemagneticfieldofanMRImachine.

FreegadoliniumisnephrotoxicandmustbechelatedThisincreasesitssolubilityandallowsittoberenallyeliminatedGadoliniumalsoattenuatesx-rays,butisnotusedasx-raycontrastasdosesrequiredwouldbetoxic

AdverseReactions

Adversereactionstolow-osmolarityagentsareuncommon(3%),withseverereactionsbeingveryrare(0.04%)andfatalreactionsbeingextremelyrare(1:170,000).

GeneralAdverseReactions

Adversereactionsinclude:

ChemotoxicityPlateletinhibitionIncreasedvagaltone

NegativeinotropyNegativechronotropy

IonictoxicityCellularmembranedysfunctionMayworsenmyastheniagravis.

OsmotoxicityPainEmesisIncreasedPAP

3+

OtherDrugs

693

DecreasedPVRHypersensitivityreactionTypicallyoccurwithin20minutesofinjection.

Riskfactorsinclude:

AsthmaoratopyCriticallyillCardiacdiseaseRenaldisease

ContrastNephropathy

Definedasanincreaseincreatinineby25%abovebaselinewithinthreedaysofIVcontrastadministration.

Itistheorisedthatosmoticstressanddirecttubulartoxiceffectsleadtorenaltubularinjury,andmaycauseacutetubularnecrosisTypicallyisbenign,withcreatininereturningtobaselinewithin10-14daysSignificantuncertaintyastowhethercontrastmediadocauseacutekidneyinjuryIFthisriskispresent,itisprobablyonlyrelevantinpatientswhohave:

ImpairedrenalfunctionArterialcontrast

Rehydrationandvolumecorrectionareeffectiveinpreventingariseincreatinine

References

1. DickinsonMC,KamPC.Intravasculariodinatedcontrastmediaandtheanaesthetist.Anaesthesia.2008Jun;63(6):626-34.2. TheRoyalAustralianandNewZealandCollegeofRadiologists.IodinatedContrastMediaGuideline.Sydney:RANZCR;

2016.

Lastupdated2019-07-18

OtherDrugs

694

DefinitionsThisappendixisalistofkeydefinitionsthatarecommontomanytopics.

A

AbsoluteHumidityMassofwatervapourinagivenvolumeofair.Measuredinmg.L .

AbsorptionTherateatwhichadrugleavesitssiteofadministrationandtheextenttowhichthisoccurs.

AccuracyTheabilityofameasuringdevicetomatchtheactualvalueofthequantitybeingmeasured.

AcidAprotondonor.

AcidaemiaArterialbloodpH<7.35.

AcidosisAprocesswhichleadstoanexcessofhydrogenions,andmayleadtoacidaemiaifthereisinadequatecompensation.Canbesubdividedinto:

Respiratoryacidosis:PaCO >45Metabolicacidosis:HCO <22

ActivityTheeffectiveconcentrationofasubstanceinareactingsystem.

AcutePainDefinedaspainof:

RecentonsetLimitedprobabledurationIdentifiablecausalandtemporalrelationshiptoinjuryordisease

AdiabaticAprocessthatoccurswithouttransferofheatormatter.Forexample,gasesheatupwhencompressed(greaterthantheenergyusedtocompressthem),andcoolwhenallowedtoexpand(adiabaticcooling).

AffinityAbilityofadrugtobindtoareceptor.

AfterloadSumofforces,bothelasticandkinetic,opposingventricularejection.

AgingNaturallyoccurring,physiologicaldeclineinthestructureandfunctionalreserveofallorgansystems.

AgonistDrugwhichproducesamaximalresponseatreceptorsite.

AlkalaemiaArterialbloodpH>7.45.

-1

23-

Definitions

695

AlkalosisAprocesswhichleadstoadeficitofhydrogenions,andmayleadtoalkalaemiaifthereisinadequatecompensation.Canbesubdividedinto:

Respiratoryalkalosis:PaCO <35Metabolicalkalosis:HCO >26

AllodyniaPaincausedbyapreviouslynon-painfulstimulus.

AllostericModulatorSubstancewhichbindsareceptordistanttotheligand-bindingsite,andmodifies(positivelyornegatively)theeffectoftheligand.Hasnoactivityinabsenceofaligand.

AnaesthesiaWithoutsensation.

AnalogueSignalWheretheoutputofthetransducervarieswiththeinputsignal.

AnionNegativelychargedion.

AnodeTheelectrodewhichconventionalcurrentflowsinto.

AnrepeffectMethodofmyocardialautoregulationinwhichanincreaseinafterloadcausesanincreaseincontractility.

AntagonistDrugwhichproducesnoresponseatthereceptor,butpreventsotherligandsbinding.

AutoregulationAbilityofanorgantomaintainhomeostasisinthepresenceofdynamicphysiologicalconditions.

AzeotropeAmixtureoftwosubstancesthatcannotbeseparatedbyfractionaldistillation,aseachcomponentsharessameboilingpoint.Thisistypicallytemperaturedependent.

B

BaseProtonacceptor.

BaseExcessAmountofacidthatmustbeaddedtoasolutiontoloweritspHto7.4,at37°CandwithaPaCO of40mmHg.

BathmotropyDegreeofmyocardialexcitability.Usedwitheitherpositiveornegativebathmotropy.

Bell-MagendieLawTheprinciplethatinthespinalcordthedorsalrootsaresensoryandtheventralrootsaremotor.

BiasThesystematicdistortionoftheestimatedinterventioneffectawayfromthe“truth”,causedbyinadequaciesinthedesign,conduct,oranalysisofatrial.

23-

2

Definitions

696

Black-bodyradiationElectromagneticradiationgivenoffbyallbodiesatgreaterthan0°K.Wavelengthofradiationemitteddependsonthetemperatureofthebody.

BohrEffectAnincreasein[H ]orPaCO decreasesHbaffinityforO2.

BoilingPointThetemperatureatwhichthevapourpressureofaliquidequalstheenvironmentalpressuresurroundingtheliquid.

Thereforeboilingpointdecreasesasenvironmentalpressurefalls,asthereislessexternalpressurekeepingmoleculesintheirliquidstateBoilingdiffersfromevaporationasmoleculesanywhereintheliquidmayenterthegaseousphase,whilstevaporationoccursonlyatthesurface

BowditchEffectIncreaseincontractilityseenwithanincreaseinHR.AlsoknownastheTreppeeffect.

Boyle'sLawPressureofagasisinverselyproportionaltovolume.

BufferSolutioncontainingaweakacidanditsconjugatebaseandwillresistachangeinpHwhenastrongeracidofbaseisadded.

C

CalibrationAprocessofcheckingamonitoringdeviceforlinearityofcorrelationbetweenactualandmeasuredvaluesoveragivenmeasurementrange.

CapacitanceAbilityofasystemtostoreelectricalcharge.MeasuredinFarads.

CentralBloodVolumeVolumeofbloodinheartandlungs.

CentralSensitisationIncreasedresponsivenessofnociceptiveneuronsinthecentralnervoussystem(i.e.,post-synaptic)totheirnormalorsubthresholdafferentinput.

ChemotaxisMovementofcellsalongagradientofincreasingconcentrationofanattractingmolecule.

ChronicPainPainthat:

PersistsbeyondthetimeoftissuehealingFrequentlyhasnoclearlyidentifiablecause

ClearanceVolumeofplasmacompletelyclearedofasubstanceperunittime.

CoronaryBloodFlowAtrestis~5%ofCO,or225ml.min ,andmayincrease3-4xduringexercise.

ColloidSubstanceevenlydispersedthroughoutanothersolutioninwhichitisinsoluble.

ColligativeProperties

+2

-1

Definitions

697

Thepropertiesofasolutionthatdependontheratioofsolutetosolvent,andnotonthetypeofmoleculespresent.These

include:VapourpressureBoilingpointFreezingpointOsmoticpressure

ComplianceDistensibilityofasystem.Expressedasthechangeinvolumeforagivenchangeinpressure.

ConcentrationEffectDescribesthedisproportionatelyrapidriseinFi/FAratioofnitrousoxide,asitsrapiddiffusionacrossthealveolarmembraneincreasestheconcentrationofalveolargas,andalsoaugmentsrespirationbydrawingindeadspacegas.

Context-SensitiveHalf-TimeTimetakenforplasmadrugconcentrationtofallto50%ofitsstartingvalueaftercessationofadruginfusionaimedtomaintainaconstantplasmaconcentration.Varieswiththecontext,orduration,ofdruginfusion.

ContractilityFactorsaffectingmyocardialperformance,independentofpreloadandafterload.

CriticalLengthThelengthofaxonwhichmustbeblockedinordertopreventactionpotentialtransmission.Itisdependentonmyelinationandfibrediameter.

CriticalPointThepointonaphasediagramwheretheliquidandgasphasesofasubstancehavethesamedensity,andarethereforeindistinguishable.

Thispointiswhereasubstanceisatbothitscriticaltemperatureandcriticalpressure

CriticalPressurePressurerequiredtoliquefyavapouratitscriticaltemperature.

CriticalTemperatureTemperatureabovewhichasubstancecannotbeliquified,irrespectiveofhowmuchpressureisapplied.

CriticalVolumeThevolumeoccupiedbyagivenamountofsubstanceatitscriticalpoint.

DDaltonUnitofmassequalto1/12 ofthemassofCarbon-12.

Dalton'sLawThepartialpressureofagasinamixtureisequaltothepressurethatgaswouldexertifitoccupiedthevolumealone.

DeadSpaceInspiredgasnotparticipatingingasexchange.Includes:

ApparatusdeadspaceGasintheventilatororbreathingcircuit.AnatomicaldeadspaceGasintheconductingzoneofthelung.AlveolardeadspaceAlveolargasnotparticipatingingasexchange.AlsoknownasWestZone1.

th

Definitions

698

PhysiologicaldeadspaceSumofalveolarandanatomicaldeadspace.

DensityMassperunitofvolume.

DependenceWhenacharacteristicwithdrawalsyndromeoccurswhenadrugiswithdrawn,oranantagonistadministered.

DiffusionPassivemovementofasubstancedownanactivitygradientbyBrownianmotion.

DiffusionHypoxiaFallinalveolarPAO duetodilutionofalveolargasbyN Odiffusingfrombloodtoalveoli.

DigestionProcessofbreakingdownmacromoleculesintoreadilyabsorbedcompounds.

DopplerEffectAlterationinfrequencyofasignalduetoarelativedifferenceinvelocitybetweentheemitterandobserver.Detectedfrequencieswillbe:

HigheriftheemitterismovingtowardtheobserverLoweriftheemitterismovingawayfromtheobserver

DownregulationDecreaseinreceptornumberduetochronicagonistexposure.

DriftAfixeddeviationfromthetruevalueatallpointsinthemeasuredrange.

DrugSubstanceadministeredtocauseachangeinaphysiologicalsystem.

DuplicatePublicationWherethesamesetofresultsarepublishedinmultiplejournals.Academicallyunethical,andwillcauseasystematicbiasinameta-analysesasthesamesetofpatientsareincludedtwice.

DyneForcerequiredtoaccelerate1gby1cm.sec .

E

EfficacyMaximaleffectproducedbyadrug.Analogoustointrinsicactivity.

ElectrocardiogramGraphicalrecordingofthevectorsumofcardiacelectricalactivity,asmeasuredbyelectrodesontheskin.

EmulsionAfinedispersionofminutedropletsofoneliquidinanotherinwhichitisnotsolubleormiscible.

EnzymeBiologicalcatalyst.

EutecticAmixtureofsubstanceswiththelowestpossiblemeltingpointthananyothermixtureofthesamesubstances(andlowerthanthatofeithersubstance).

2 2

-2

Definitions

699

ExcitabilityHowrapidlyanexcitablecelldepolarises.Givenbythegradientofphase0oftheactionpotential,andisdependentonthefunctionofvoltage-gatedsodiumchannels.

ExponentialFunctionMathematicalfunctionwheretherateofchangeisproportionaltothecurrentvalue.

ExternalValidityHowwellfindingsfromonesettingcanbeappliedtoanother.

FFahraeus-LindqvisteffectDecreaseinapparentviscositythatoccurswhenasuspension(e.g.blood)flowsthroughatubeofsmallerdiameter.

FastingMetabolicstateachievedaftercompletedigestionandabsorptionofamealpriortotheonsetofstarvation.

FickPrincipleBloodflowtoanorganequalstheuptakeofatracersubstancebythatorgan,dividedbythearterio-venousconcentrationdifference.

FlowQuantityoffluidpassingapointperunittime.

FourierAnalysisDeconstructionofacomplexwaveformbyseparatingitintoitsconstituentsinewaves.Theslowestcomponentisknownasthefundamentalfrequency.

FreeradicalExtremelyreactivemolecularconstituentcarryinganunpairedelectron.

FreezingpointTemperatureatwhichmolecularmovementbegins.

FunctionalResidualCapacityVolumeofgasinthelungsattheendofanormaltidalexpiration,whentherecoilpressureofthelungsequalstheexpansilepressureofthechestwall.

GGalvanometerDevicetomeasureelectricalcurrent,usuallyviadeflectionofawireinamagneticfield.

GasSubstanceaboveitscriticaltemperature.

GeneralanaesthesiaDruginduced,controlled,andreversibleproductionofunconsciousness.

Gibbs-DonnanEffectDescribesthetendencyofdiffusableionstodistributethemselvessuchthattheratiosoftheconcentrationsareequalwhentheyareinthepresenceofnon-diffusableions.

GrahamsLawThespeedofdiffusionofagasthroughamembraneisinverselyproportionaltothesquarerootofthemolecularweight.

Definitions

700

H

HaldaneeffectDeoxygenatedbloodformscarbaminocompoundsandbuffersH betterthanoxygenatedblood.

Half-LifeTimetakenfordrugconcentration(typicallyinplasma)tofallbyhalf.

HeatKineticenergycontentofabody,asmeasuredinjoules.

Henry'sLawAmountofgasdissolvedinasubstanceisdirectlyproportionaltothepartialpressureofgasatthegas-liquidinterface.

HeterometricautoregulationChangeinventricularfunctionbasedonmyocardialfibrelength.AlsoknownasStarling'sLaw.

HomeometricautoregulationMechanismswhichaltermyocardialperformanceindependentoffibrelength.

HormoneChemicalmessengersecretedbyaductlessglandandhasactiononadistanttargetcell.

HyperalgesiaGreaterthannormalamountofpainfromanoxiousstimulus.Maybe:

PrimaryOccurringintheregionoftissuedamage,e.g.inaninflamedareaaroundawound.SecondaryExtendingbeyondtheregionoftissuedamage.

HypoxaemiaWhenPaO islessthan60mmHg.

HypoxiaThepointatwhichinadequateoxygenationoftissuesresultsinanaerobicmetabolism.

HysteresisWhenthefuturestateofasystemdependsnotonlyonitscurrentstate,butonthestatesprecedingit.

I

IdealGasAgaswhichwillobeytheidealgaslaw.Anidealgasmusthave:

NegligibleintermolecularattractionAsmallmolecularvolumecomparedtothespacebetweenthemolecules

IdiosyncrasyAneffectofadrugaffectingonlyasmallnumberofpatients,typicallyduetotheactionofaparticularmetabolite.

InductancePropertyofaconductorbywhichachangeincurrentinducesanelectromotiveforceintheconductorandanynearbyconductors.

InotropeDrugwhichaltersmyocardialcontractility.

+

2

Definitions

701

IntrinsicActivityMaximaleffectproducedbyadrug.Analogoustoefficacy.

ImpedanceResistancetoalternatingcurrent.

InternalValidityWhereacausalrelationshipbetweenvariableshasbeenproperlydemonstrated,i.e.alackofbias.

IrritabilityHoweasilyanexcitablecellcanbestimulated.Givenbyhowclosetherestingmembranepotentialistothresholdpotential.

IsomerCompoundwiththesamechemicalformula,butdifferentchemicalstructureorarrangementofatoms.

IsothermLineofconstanttemperaturedrawnonapressure-volumegraphforagas,whichdescribestherelationshipbetweenpressure,temperature,andvolumeforaparticulargas.

J

JouleEnergytransferedtoanobjectwhenitisactedonby1Nfor1m.

L

LaminarFlowFlowoccurringsmoothlyandwithoutturbulence.

LocalAnaestheticDrugwhichreversiblypreventstheconductionofthenerveimpulseintheregiontowhichitisapplied,withoutaffectingconsciousness.

M

MACTheminimalalveolarconcentration(measuredin%of1atm)atsteadystatewhichpreventsamovementresponsetoastandardsurgicalstimulus(midlineincision)in50%ofapopulation.

ManometerDevicewhichmeasuresgaspressure.

MeanSystemicFillingPressureThepressuremeasuredanywhereinthesystemiccirculationwhenallflowofbloodisstopped.

MixedVenousBloodBloodfromtheIVC,SVCandcoronarysinus,whichhasbeenmixedbythepumpingactionoftheRVandistypicallysampledfromthepulmonaryartery.

MoleAmountofasubstancewhichcontainsasmanyrepresentativeparticlesasthereareatomsin12gofcarbon-12.

MolalityNumberofmolesofsoluteperkgofsolvent.

Definitions

702

MolarityNumberofmolesofsoluteperLofsolvent.Varieswith:

TemperatureSolventdensitySolutevolume

N

NaturalFrequencyFrequencyatwhichasystemwilloscillateatifdisturbedandleftalone.

NauseaUnpleasantsubjectivesensationassociatedwithurgetovomit.

NeuropathicPainPaincausedbyalesionordiseaseofthesomatosensorynervoussystem.

NociceptionNeuralprocessofencodinganoxiousstimulus.

O

OddsRatioEstimateofrisk,wheretheORistheratioofoddsofanoutcomeinthosetreatedvs.thosenottreated.OR=1suggestsnoeffect,≤1suggestsreducedrisk>1suggestsincreasedrisk.

OhmResistancewhichwillallowoneampereofcurrenttoflowpervoltofpotentialdifference.

OpiateNaturallyoccurringsubstancewithmorphine-likeproperties.

OncoticPressureProportionofosmoticpressureduetocolloid.

OpioidDescribesanysubstancewithactivityatopioidreceptors,andwhichcanbereversedbynaloxone.

OsmosisMovementofasolventacrossasemipermeablemembranetoanareaofgreatersoluteconcentration.

OsmoticPressurePressurethatmustbeappliedtoasolutiontopreventthemovementofasolventfromenteringasolutionwithhigherosmolality.

OxygenFluxVolumeofoxygendeliveredtothetissuesperminute.

P

p50Thepartialpressureatwhichanoxygen-carryingproteinis50%saturated.

Definitions

703

PainUnpleasantsensoryandemotionalexperienceassociatedwithactualorpotentialtissuedamage,orexpressedintermsofsuchdamage.

PartitionCoefficientDescribetherelativeaffinityofanagentfortwophases.Itisdefinedastheratiooftheconcentrationofagentineachphase,whenbothphasesareofequalvolumeandthepartialpressuresareinequilibriumatSTP.

PasteurPointPO atwhichoxidativephosphorylationceases.

PEEPSupra-atmosphericairwaypressureattheendofexpiration.

pHThepowerofhydrogen.Describestheactivityofhydrogenionsinasolution,andisexpressedas

.

PreloadLoadimposedonamusclebeforecontraction,andmeasuredastheaveragemyocardialfibrelengthattheonsetofsystole.MaybeapproximatedclinicallyusingEDV.

PrecisionTheabilityofameasurementdevicetoprovidereproducibleresultsuponrepeatedmeasurement.

Pseudo-criticaltemperatureTemperatureatwhichagasmixturewillseparateintoitsconstituentcomponents.

RRadiationTransferofenergyviaelectromagneticradiation.

ReceptorComponentofacellwhichbindstoaligandandresultsinachangeinfunction.

ReductionReactionwhichresultsinagainofanelectron.

ReflexUnconscious,predictableresponsetoastimulus.

RegurgitationPassivepassageofgastriccontentsintothemouth.

RelativeHumidityRatioofmassofwatervapourinagivenvolumeofair,tothemassrequiredtosaturatethatvolumeatthattemperature.Expressedasapercentage.

RespiratoryExchangeRatioRatioofCO producedtoO consumedatanygivenpoint.

RespiratoryQuotientRatioofCO producedtoO consumedatsteady-state.

ReynoldsNumberDimensionlessindexwhichpredictsthelikelihoodofturbulentflow.

2

2 2

2 2

Definitions

704

S

SaturatedVapourVapourwhichisinequilibriumwithitsownliquidstate,i.e.thereareasmanymoleculesenteringthevapourphaseastheretherearethosecondensingintotheliquidphase.

Asaturatedvapourcontainstheleastamountofenergypossiblewithoutcondensing

SaturatedVapourPressurePressureexertedbyavapourwhichisinequilibriumwithitsliquidstate.Increaseswithtemperature,sinceasthekineticenergy(heat)contentofmoleculesincrease,moreofthementerthevapourphase.

SecondGasEffectDisproportionatelyrapidriseinFA/Firatioseenwhenananaestheticagentisco-administeredwithnitrousoxide.

SeebeckeffectThegenerationofapotentialdifferenceatthejunctionoftwodissimilarmetals,withitsvaluedependentonthetemperatureofthejunction.

ShiveringInvoluntary,oscillatory,muscularactivitythataugmentsmetabolicheatproduction.

ShuntBloodenteringtheleftsideofthecirculationwithoutbeingoxygenatedviapassagethroughthelungs.

SpecificGravityDensityofaliquid,inmassperunitvolume.

SpecificHeatCapacityAmountofheatenergyrequiredtoraisethetemperatureof1kgofasubstanceby1°Kwithoutachangeinstate.

StandardBaseExcessThebaseexcesscalculatedforanHbof5g.L ,andwhichgivesabetterrepresentationofECFpH.

SurfaceTensionDescribesthetendencyofafluidtominimiseitssurfacearea.

SuspensionParticlesofanyphasedispersedinaliquid.

SynergismWhentwodrugsinteracttoproduceagreatereffectthanwouldbeexpected.

TTemperatureAbilityofabodytotransferheatenergytoanotherbody,asmeasuredindegrees.

ThirstConscioussensationofthephysiologicalurgetodrink.

TimeconstantTimeitwouldtakeforanexponentialfunctiontocompleteiftheinitialrateofchangecontinued.Aprocessis:

63%completeat1T86.5%completeat2T95%completeat3%

-1

Definitions

705

TonicityEffectiveosmolalityofasolution.Givenbytheosmolality,minustheconcentrationoffreelydiffusableosmoles(inplasma,theseareureaandglucose).

TonometerDevicewhichmeasurespressureofliquid.

TransducerDevicewhichchangesasignalfromoneenergyformtoanother.

TreppeEffectIncreaseincontractilitywithanincreaseinHR.AlsoknownastheBowditcheffect.

TurbulentFlowIrregularmovementinradial,axial,andcircumferentialaxes.

VValsalvaManoeuvreForcedexpirationagainstaclosedglottis.

VapourSubstanceinagaseousphasebelowitscriticaltemperature.

VapourpressurePressureexpertedbyavapour.

VenousadmixtureAmountofmixedvenousbloodthatmustbeaddedtopulmonaryend-capillarybloodtogivetheobservedarterialoxygencontent.

ViscosityDescribesthetendencyofafluidtoresistflow.

VoltPotentialdifferencewhichdissipates1Wofenergyper1Aofcurrent.

VolumeofDistributionApparentvolumeintowhichadrugisdistributedtoproducetheidentifiedplasmaconcentration.

Lastupdated2019-07-20

Definitions

706

KeyGraphsGraphs:

HelpyoutoconveyknowledgeandunderstandingefficientlyinthewrittenAreoftenafeatureofthevivaastheyallowexaminerstoassessdepthofunderstanding

Youwillbeaskedtodemonstratehowtheychangeunderdifferentphysiologicalstates

Itiseasytogetdistractedbythecurve,andforgetthebasics(especiallyinthewritten).Toavoidthis,approachtheminthesamewayeachtime:

AxisFirstdrawtheaxis.

Iftheaxisiscontinuous(e.g.PaO ),ensureyouplaceanarrowatthefarendIftheaxisendsatafixedpoint(e.g.SpO ),ensureyouplaceabarattheendtosignifyitdoesnotcontinueindefinitely

LabelsLabeleachaxiswithwhatitisrepresenting.UnitsGiveeachlabelappropriateunits.

Intheviva,youcanjustsaythisoutloudasyou'redrawingtheaxesCurveDrawthecurve.SpecialPointsIdentifythekeypointsofthecurveandlabelthesepoints.Theseinclude:

InterceptsInflectionpointsImportantvaluese.g.Themixedvenouspoint.

Pharmacology

Dose-Response:

Doseresponsecurveisawash-inexponentialDifficulttocomparedifferentdrugsusingthiscurve

Log -Response:

22

Dose

KeyGraphs

707

Log-transformofdoseallowsdifferentdrugstobecomparedBothredandbluedrugsarefullagonists(astheybothreach100%response),howeverthebluedrugismorepotentasithasalowerE 50

Agonists:

Partialagonistsdonotreach100%responseInverseagonistshaveanegativeresponse

Antagonists:

Non-competitiveantagonistspreventmaximalresponsebeingreachedCompetitiveagonistsrightshiftthecurve,astheycanbeovercomewithincreasingdoseofagonist

TherapeuticIndex:

D

KeyGraphs

708

CanbecalculatedfromtheratiooftheLD andED

Models

TheOne-CompartmentModel:

DrugisaddedtoandremovedfromthesinglecentralcompartmentThereisnodistributionpossible.V isequaltothevolumeofdistributionk istherateconstantforelimination

Three-CompartmentModel:

DrugisaddedtoandremovedfromthecentralcompartmentDrugwillalsodistributeto(andredistributefrom)theperipheralcompartmentsPlasmaconcentrationwilldependon:

RateofdrugdeliveryRateofdrugdistributionandredistribution

50 50

110

KeyGraphs

709

Rateofdrugelimination

Effect-Site:

DrugdistributestotheeffectsitefromthecentralcompartmentEffectsitehasnovolume,butdoeshaverateconstantst ke0isgenerallydrawnwithdrugbeingeliminatedfromtheeffectsite,howeverinrealitythisdoesnotoccurasdrugshouldonlybeeliminatedfromthecentralcompartment

Pharmacokinetics

Zero-orderkinetics:

AconstantamountofdrugiseliminatedperunittimeHalf-lifeisnotaconstantvalueHalf-lifeprogressivelyshortens,asthetimetakentogofrom50%to25%ishalfthetimeittooktogofrom100%to50%.

First-OrderKinetics:

AconstantproportionofdrugiseliminatedperunittimeHalf-lifeisaconstantvalue

1/2

KeyGraphs

710

Biexponentialelimination:

Notethatconcentrationhasbeenlog-transformedThisdescribestheeliminationofdrugfromatwocompartmentmodel

Pharmacodynamics

Isobologram:

Plotslinesofequalactivityversusconcentrationoftwodrugs

Plasma-SiteTargeting:

TCIgraphsareeasytodrawifyourememberthat:

Thepumpaimstoachievethetargetedconcentration:AsrapidlyaspossibleWithoutovershoot

KeyGraphs

711

EffectsiteconcentrationsfallslowerthanplasmasiteconcentrationsDrugcanonlyredistributebacktoplasmawheneffectsiteconcentrationisgreaterthanplasmaconcentration.

Thereforeinplasmasitetargeting:

PlasmaconcentrationrisesrapidlywithinitialbolusdoseDoesnotovershootEffectsiteconcentrationrisesmoreslowly

Exponentialwashincurveastheconcentrationgradientbetweenplasmaandeffectsitefallsovertime

Effect-SiteTargeting:

Plasmaconcentrationovershootseffect-sitetargetandthendeclinesrapidlyEffectsiteconcentrationrisesrapidly,andisachievedmorequicklycomparedwithplasma-sitetargetedmodel

Statistics

Boxplot:

Boxisdefinedbythe25 and75 centilesLineinthemiddleoftheboxisthemedian("50 centile")"Whiskers"eithersideoftheboxdefinethe10 and90 centiles

Thesemayalsorefertothe5 and95 centilesResultsoutsideofwhiskersaredefinedasoutliers,andarerepresentedbysingledots

Respiratory

Oxygen

OxygenCascade:

th ththth th

th th

KeyGraphs

712

GraphoflocationversusoxygenpartialpressureAtmospheric(dry)airhasaPO of160mmHgTracheal(humidified)gashasaPO of149mmHgReducedduetosaturatedvapourpressureofwater.AlveolargashasaPO of105mmHgReducedtothepresenceofCO ,asperthealveolargasequation.ArterialbloodhasaPO of~100mmHgReducedtotheAlveolar-arterialoxygengradient.TissueshaveaPO of~5mmHgMixedvenousbloodhasaPO of~40mmHgGreaterthantissuePO asnotalloxygeninblooddiffusesintoorisconsumedbytissues.

OxyhaemoglobinDissociationCurve:

GraphofPaO versusoxygensaturationNotethatPaO2 iscontinuous,andsoanarrowshouldbedrawnatthetipofthex-axis,whilstsaturationisfiniteandsothey-axisshouldbecappedat100%ThecurveisasigmoidshapeKeypoints:

At10mmHg,saturationis10%

22

22

2

22

2

22

KeyGraphs

713

Thep50isat27mmHgThemixedvenouspointisat40mmHg,wherehaemoglobinis75%saturatedNotethatduetotheHaldaneeffect,themixedvenouspointdoesnottechnicallyexistonthearterialcurve.Thisisasmallpointandisignoredinmostgraphs(includingthisone),butmaybeworthstatingifyou'refeelingconfidentintheviva.The"ICUpoint"(theupperinflection)isat60mmHgwherehaemoglobinis93%saturatedThearterialpointis97%saturatedat100mmHg

Thecurvemayberight-shiftedby:IncreasedHIncreasedPaCOIncreasedtemperatureIncreased2-3DPG

Theseshiftsaredefinedbyamovementofthep50

Double-BohrEffect:

ThedoubleBohreffectcaneasilybecomeconfusing,especiallywhenyouareunderpressureandonlyallowedonecolour(asinthewrittenexam)Hereisastraightforwardmethodwhichminimisestheconfusion:1. Drawanadultcurvewithap50of27mmHg2. Drawafoetalcurvewithap50of17mmHg3. Drawaright-shiftedadultcurve4. Drawaleft-shiftedfoetalcurve

PaO andMinuteVentilation:

+

2

2

KeyGraphs

714

ExponentialcurveMinuteventilationdoublesasPaO decreasesfrom100mmHgto60mmHgInflectionpointis~50-60mmHgBelowthisthereisalargeincreaseinventilation.HypercapnealeadstoagreaterminuteventilationforanygivenPaO

IsoshuntDiagram:

PlotstherelationshipbetweenPAO versusPaO fordifferent(fixed)shuntfractionsTheseareknownasisoshuntlinesKeyisoshuntlinesare:

At50%shunt,PaO2isessentiallyindependentofPAO2At30%shunt,PaO2willnotincreaseabove100mmHgon100%oxygenatatmosphericpressure

CarbonDioxide

CarbonDioxideDissociationCurve:

GraphofcarbondioxidecontentversuspartialpressureKeypointsonthiscurve:

2

2

2 2

-1

KeyGraphs

715

ArterialCO contentis48mls.100ml ofbloodat40mmHgMixedvenousCO contentis52.mls.100ml ofbloodat46mmHg

Notethatthemixedvenouscurveisup-shiftedduetotheHaldaneeffectRememberthat50%ofthedifferenceinCO contentisduetotheHaldaneeffect.Therefore:

ThemixedvenouscurveshouldbedrawnsuchthatCO contentis50mls.100ml at40mmHgThearterialcurveshouldbedrawnsuchthatCO contentis50mls.100ml at46mmHg

PaCO andMinuteVentilation:

GraphsthechangeinminuteventilationforprimarychangeinPaCORememberthatminuteventilationincreasesby~3L.min forevery1mmHgincreaseinPaCOFromthis,therelationshiptootherstatescanbederived:

Minuteventilationisreducedduringsleep,butthecentralresponsetoCO isonlyminimallyaffectedThecentralresponsetoCO isheavilyaffectedduringanaesthesiaMinuteventilationisincreasedforanygivenPaCO inthesettingofacidosis

AlveolarVentilationandPaCO :

GraphsthechangeinPaCO foraprimarychangeinminuteventilationExponentialcurveasPaCO isinverselyproportionaltominuteventilationMinuteventilationisincreasedforanygivenPaCO duringexercise

AnatomicalandPhysiologicalInteractions

ClosingCapacityandAge:

2-1

2-1

22

-1

2-1

2

2-1

2

22

2

2

22

2

KeyGraphs

716

NotethatalthoughFRCincreasesslightlywithage,thisisnotgenerallyshownonthisgraphClosingcapacityincreaseswithincreasingageKeyintersectionsare:

GreaterthanFRCwhensupineat44yearsofageGreaterthanFRCwhenerectat66yearsofage

DiffusionandPerfusionLimitation:

ClassicallydrawnaspartialpressureversusdistancealongthecapillaryTimealongcapillarymayalsobeused,howevernotethattotaltransittimewillchangewithcardiacoutput.Notethatatthebeginningofthecapillary,oxygenpartialpressurewillbeequaltothatofmixedvenousblood

Inperfusionlimitation,PaO willequalPAO beforetheendofthecapillaryIndiffusionlimitation,partialpressureswillnotbeequalattheendofthecapillaryInnormalcircumstances,PaO equalsPAO at~1/3 ofthedistancealongthecapillaryIftimeisbeinggraphedonthex-axis,thenthiswilloccurat~0.25s,astotalcapillarytransittimeis~0.75s.

Nitrousoxiderapidlydiffusesintobloodandisandnottypicallypresentinmixedvenousblood,sothiscurvebeginsattheoriginandPaN OwillrapidlyreachPAN O(inthisinstance100mmHg)CarbonmonoxidebindsavidlytohaemoglobinandsoPaCOincreasesslowly,resultingindiffusionlimitation

RegionalVentilationandPerfusion:

2 2

2 22

2 2

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GraphofalveolarventilationandalveolarbloodflowversusribnumberintheerectpersonBasalalveolarhavegreaterperfusionandventilationthanapicalalveoliNotetheperfusiongradientissteeperthantheventilationgradientNotethattheV/Qratiois:

~1atthe3 rib~3.3attheapex~0.63atthebase

AirwayResistanceandAirwayGeneration:

GraphofairwayresistanceversusairwaygenerationAirwaygenerationsarefrom1to23,andsothisgraphshouldnotextendoutsidethesevaluesAirwayresistanceismaximalatthe5 generationThishasthelowesttotalcross-sectionalarea.Airwayresistanceisnegligibleintherespiratoryzone,whichexistsafterthe15 generation

AirwayResistanceandLungVolume:

Airwayresistancedecreasesaslungvolumeincreasesasradialtensiondistendsairways,increasingtheircross-sectionalareaandloweringairwayresistance

rd

th

th

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PulmonaryVascularResistanceandPulmonaryArteryPressure:

PulmonaryvascularresistancedecreasesaspulmonaryarterypressureincreasesArterialpressurehasagreatereffectonPVRthanvenouspressure

LungandChestWallVolumeandPressureRelationships:

GraphoflungvolumeversusrecoilpressureExpressinglungvolumeasapercentageoftotallungcapacitymaymakeiteasiertorememberthekeypointsonthisgraphNotethatrecoilpressureisthepressuregeneratedbetweenthelungandthechestwallwhentheyaredistended,itisnotintrapleuralpressure

ThisgraphiscomplexanditiseasytodrawincorrectlyThisisanapproachtomakeitaseasyaspossible:1. Drawasigmoidgraphforthepressure-volumerelationshipoftherespiratorysystemasawhole

Asrecoilpressureis0atFRCthiswillbethey-interceptThegraphwillasymptoteatresidualvolume,asvolume(bydefinition)cannotbecomelowerthanthisvolume

2. Drawasteeprun-awayexponentialforthepressure-volumerelationshipofthechestwallRecoilpressureshouldbe~-5cmH OatFRCRecoilpressureshouldbe0cmH Oat~75%ofTLCRecoilpressureshouldnotexceed~5cmH OatTLC

3. Drawasteepwash-inexponentialforthepressure-volumerelationshipofthelungRememberlungvolumecannotfallbelowresidualvolumeRecoilpressureshouldbe~5cmH OatFRCThisshouldbeequalandoppositetotherecoilpressureforthechestwall,asthesumofthesemustbe0atFRC.Notethatthiscurveshouldslightlyexceedthecurvefortherespiratorysystemasrecoilpressureincreases

WorkofBreathing:

22

2

2

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Graphoflungvolume(aboveFRC)versusintrapleuralpressureNotethatintrapleuralpressurebecomesmorenegativealongthex-axis.Theareaunderdifferentsectionsofthiscurvegivetheworkofbreathing

ElasticinspiratoryworkofbreathingisgiventhebluetriangleResistiveworkofexpirationisgivenbytheredareaNotethatasthisisentirelycontainedwithintheareaofelasticinspiratorywork,expirationispassiveanddoesnotrequireadditionalenergyexpenditure.Resistiveworkofinspirationisgivenbythegreenarea

WorkofBreathing-ActiveExpiration:

Whenresistiveexpiratoryworkexceedselasticinspiratorywork,activeexpirationmustoccurInthisgraph,activeexpirationisgivenbytheredareanotcontainedwiththebluetriangle

NeonatalFirstBreath:

Thisgraphdescribesthepressure-volumechangesoftheneonateasittakesitsfirstbreathsandestablishesFRCThisgraphiseasytodrawprovidedyourememberthat:

Priortothefirstbreath,lungvolumeis0Asthelunginitiallyhasverypoorcompliance,theintrapleuralpressuremustbecomeverynegativemorelungvolume

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increasessubstantiallyAttheendofeachbreath,intrathoracicpressureiscloseto0Witheachsubsequentbreath:

LungcomplianceimprovesThereforethemagnitudeofpressureswingsisreduced.FRCincreasesLungvolumeatend-inspirationisincreased.

Spirometry

ForcedVitalCapacity:

Graphofexpiredvolume(vitalcapacity)overtime~80%oftotalvolumeisexpiredwithinthefirstsecond(FEV )TotalFVCis4.5Linthe70kgGuytonManThegradientofinitialexpirationisthepeakexpiratoryflowrate

Spirometry:

GraphoflungvolumeovertimeIncludesanormaltidalbreathandavitalcapacitybreath

Flow-VolumeLoops

Normalloop:

1

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Peakexpiratoryflowis~8L.sPeakinspiratoryflowis~6L.sEffortindependentexpirationoccursduringexpiration

ObstructiveDisease:

ResidualvolumeandtotallungcapacityareincreasedduetogastrappingPeakexpiratoryflowisreducedThereisscallopingoftheeffort-independentportionofthecurveAlsoknownasaconcavecurve.

RestrictiveDisease:

TotallungcapacityisreducedResidualvolumeisnormalPeakexpiratoryflowmaybereduced(asseenhere)HowevertheFEV :FVCratiowillbenormalinpurelyrestrictivelungdisease.Effort-independentexpirationislinearandwilljoinwiththenormalcurve

FixedUpperAirwayObstruction:

-1-1

1

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ObstructionthatdoesnotchangecalibrethroughouttherespiratorycyclePeakexpiratoryandinspiratoryflowratesarelimited

ExtrathoracicObstruction

Obstructionworsensduringinspirationasitis'pulledin'bynegativeintrathoracicpressure

IntrathoracicObstruction

Obstructionworsensduringexpirationasitiscompressedbydynamicairwayscompression

AnaestheticAgents

F /F :A I

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GraphofthealveolaroverinspiredagentfractionversustimeforvariousvolatileagentsIndicatestherelativespeedofonsetofdifferentagentsUptakeofagentisproportionaltosolubilityinblood,andthereforeisinorderoftheirblood:gascoefficients

Theexceptionisnitrousoxide,whichhasafasterrateofrisethandesfluranedespiteitsgreaterblood:gascoefficientduetotheconcentrationeffect

F /F :

GraphofalveolaragentfractionversustimeforavolatileagentNotethelogarithmicscaleonthey-axisExponentialwashoutcurveFunctionoftwoseparatewashoutcurves

RapidwashoutwithremovalofagentfromcircuitandFRCSlowwashoutduetodiffusionofagentfromtissuesintoblood,andthenalveolus

Cardiovascular

LeftVentricularCoronaryBloodFlow:

GraphofbloodflowtotheleftventricleovertimeSystoleshouldbeclearlyidentified.LeftventricularflowoccurspredominantlyindiastolePeakflowis~115ml.min .Thereisabriefperiodofflowreversalduringisovolumetriccontraction

RightVentricularCoronaryBloodFlow:

A A0

-1

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GraphofbloodflowtotherightventricleovertimeRightventricularflowoccursthroughoutthecardiaccycleThisisbecauseaorticrootpressureexceedscavitypressurethroughoutthecardiaccycle.Peakflowis~15ml.min

BaroreceptorResponse:

GraphofheartrateversussystolicbloodpressureNotethattheRRintervalisinverselyproportionaltoheartrate.Heartrateresponsesasymptoteatextremesofbloodpressure

StarlingCurve:

Typicallydrawnasagraphofstrokevolume(orcardiacoutput,assumingaconstantheartrate)versuspreload(typicallyestimatedasend-diastolicvolume,butmayalsobeend-diastolicpressure)GraphdoesnotcrosstheoriginasEDVisnever0ml

StarlingCurve-Failing:

-1

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Myocardiumthathasbeenoverloadedbyhighend-diastolicvolumesmayleadtoadecreaseintensiongeneratedbythemyocardium

VenousReturn:

GraphofvenousreturnversusrightatrialpressureThex-interceptisthepointofnoflowwithinthecirculation(asVR=CO),andthereforeisthemeansystemicfillingpressureThecurveflattenswhenRAPbecomesnegative,asexternaltissuesactasaStarlingresistorandpreventfurtherincreasesinflow

VenousReturn-ComplianceandVolume:

Decreasingvenouscomplianceorincreasingcirculatingvolumeresultsinanincreaseinmeansystemicfillingpressure(asforanygivencompliance,pressuremustincreaseifvolumeincreases)andanincreaseinvenousreturnforanygivenrightatrialpressureTheoppositeoccurswithadecreaseincirculatingvolumeoranincreaseinvenouscompliance

VenousReturn-ResistancetoVenousReturn:

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Alteringresistancetovenousreturn(e.g.duringpregnancy,orlaparoscopicsurgery)willaltervenousreturnwithoutchangingmeansystemicfillingpressure

CirculatoryFunctionCurve:

PlottingthevenousreturncurveandtheStarlingcurveonthesameaxesgeneratesthisgraphThisisonlyvalidatsteadystate,i.e.whenCO=VR

Notethatassteady-stateexistswhenCO=VR,theinterceptofthesetwocurvesistheoperatingpointofthecirculation

WiggersDiagram:

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WiggersdiagramisagraphicalrepresentationoftheeventsduringeachphaseofthecardiaccycleKeypointstonote:

AorticdiastolicpressureoccursjustpriortoaorticvalveopeningAcommonmistakeistolabeldiastolicpressureatthedicroticnotch.VentricularpressureexceedsaorticpressureduringejectionAorticpressurewillslightlyexceedventricularpressureduringthelastpartofejectionThisisduetotheinertiaofejectedbloodcausingongoingforwardflowdespitethepressuregradient.ThedicroticnotchoccursontheaorticpressurecurveAcommonmistakeistodrawthisontheventricularcurve.CVPslightlyexceedsventricularpressureduringventricularfillingTheCwaveoccursduringisovolumetriccontractionTheVwavebeginspriortotheTwave,butpeaksaftertheTwavehasfinishedElectricaleventsslightlyproceedventricularmechanicalevents

ActionPotentials

PacemakerPotential:

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Thepacemakerpotentialhasonlythreephases,andnotablyno'restingphase'Thisisduetothefunnycurrent.Maximaldiastolicpotentialis-65mVPeakmembranepotentialis~20mV

PacemakerPotential-IonFlux:

DemonstratesthetimingofelectrolytepassageacrossthecellmembraneFunnycurrentoccursthroughoutphase4andtheearlypartofphase0T-typecalciumcurrentbeginsinlatephase4andterminatespriortotheonsetofphase0L-typecalciumcurrentoverlapswiththeT-typecurrentandcontinuesthroughoutphase3Outwardrectifyingpotassiumcurrentbeginsduringphase3andcontinuesduringphase4,restoringmembranepotential

PacemakerPotential-AutonomicTone:

Alterationtoautonomictonealterstheslopeofthefunny-current(Somesourcesalsonoteachangetomaximaldiastolicpotential,althoughthisisnotshownhere).

VentricularActionPotential:

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Theventricularactionpotentialconsistsof5phases0:Rapiddepolarisation1:PartialrepolarisationDuetoinitialeffluxofpotassiumwithoutproportionalcalciuminflux.2:PlateauOutwardpotassiumcurrentismatchedbyinwardcalciumcurrent.3:RepolarisationNotethattheabsoluterefractoryperiodendswhenrestingmembranepotentialfallsbelow-50mV,whichtypicallyoccursat~250ms.4:RestingmembranepotentialNotethat:

RestingMembranePotentialistypically~-85mVTherelativerefractoryperiodendswhenthemembranepotentialisatitsrestingstate

VentricularActionPotential-Hyperkalaemia:

Inhyperkalaemia:Theventricleismoreirritableasrestingmembranepotentialislessnegative,bringingitclosertothresholdpotentialThedurationoftheactionpotentialisshorter,increasingthechanceforare-entrantarrhythmia

BasicPressure-VolumeLoops

Pressure-volumeloopsarecoveredindetailunderpressure-volumerelationships.

LeftVentricularP-VLoop:

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LeftVentricularP-VLoop-IncreasedPreload:

LeftVentricularP-VLoop-IncreasedAfterload:

LeftVentricularP-VLoop-IncreasedContractility:

Advanced-PressureVolumeLoops

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Whendrawingchangestomoreleft-fieldpressure-volumeloopswhichyoumaynothaveseenbeforeapproachtheminthefollowingway:

Howispreloadchanged?Howisafterloadchanged?Howiscontractilitychanged?Howareisovolumetriccontractionandisovolumetricrelaxationchanged?

Advancedpressure-volumeloopsarecoveredindetailunderpressure-volumerelationships.

RightVentricularP-VLoop:

LeftVentricularP-VLoop-AorticStenosis:

LeftVentricularP-VLoop-AorticRegurgitation:

LeftVentricularP-VLoop-MitralStenosis:

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LeftVentricularP-VLoop-MitralRegurgitation:

Antiarrhythmics

VentricularActionPotential-ClassIa:

Prolongtherateofriseofphase0Lengthenthemyocardialactionpotential

VentricularActionPotential-ClassIb:

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Prolongtherateofriseofphase0Shortenthemyocardialactionpotential

VentricularActionPotential-ClassIc:

Prolongtherateofriseofphase0Donotalterthelengthofthemyocardialactionpotential

PacemakerPotential-ClassII(Beta-Blockade):

Sympatholyticeffectreducesthemagnitudeofthefunnycurrent

VentricularActionPotential-ClassIII:

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Prolongdurationofphase3ofthemyocardialactionpotentialThisprolongstherefractoryperiodandreducesthechanceofare-entrycircuitoccurring,andthereforereducestachyarrhythmiasbutmayincreasetheriskoftorsadedepointesduetoanincreasedriskofafterdepolarisations.

PacemakerPotential-ClassIV(CalciumChannelBlockade):

Inthepacemakercell,reducethemagnitudeofT-typeandL-typecalciumcurrents,reducingtherateofriseofphase0ofthepacemakeractionpotential

CNSMonroe-KellieDoctrine:

Graphstheintracranialpressureversusthevolumeofacomponent(blood,brain,orCSF)inthecranialvaultNotethatoverallvolumeisnotcorrect,asthisisunchanged-ifoverallvolumeincreasedthepressurewouldreduce(e.g.suchasadecompressivecraniectomy).Notetheinitialperiodofcompensation,whichoccursduetodisplacementofCSFtothespinalsubarachnoid,decreasedcerebralbloodvolume,andadecreaseinCSFvolume.OncecompensatoryresponsesareexhaustedICPwillincreaserapidlyduetothepoorelastanceofthecranialvault

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FocalischaemiaoccurswhenICPexceeds20mmHgGlobalcerebralischaemiaoccurswhenICPexceeds50mmhg

CerebralBloodFlowandCerebralPerfusionPressure:

CerebralbloodflowisautoregulatedforaCPPof50-150mmHg(Notethatthisclassicrelationshipisprobablyincorrect,andthatCBFisprobablyonlyautoregulatedacrossanarrowrangeofbloodpressures).

CerebralBloodFlowandPaCO :

CBFincreasesby~3%forevery1mmHgincreaseinCOBelowaPaCO of20mmHg,CBFcannotdecreasefurtherasthereducedflowresultsintissuehypoxia,andmetabolicautoregulatoryresponsesAboveaPaCO of80mmHg,CBFcannotincreasefurtherasvesselsaremaximallydilated

CerebralBloodFlowandPaO :

AboveaPaO of60mmHg,CBFisessentiallyindependentofPaOBelowaPaO of60mmHg,CBFincreasesrapidly

CerebralBloodFlowandTemperature:

2

22

2

2

2 22

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Cerebralmetabolicratefallsby~6%per°CdecreaseintemperatureThisresultsinaconcomitantreductioninCBFThisisanalmostlinearresponse.

Renal&Acid-Base

IonisedpotentialvspH-Acids:

AcidsareionisedabovetheirpKa

IonisedpotentialvspH-Bases:

BasesareionisedbelowtheirpKa

GlomerularFiltrationandMeanArterialPressure:

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GFRisautoregulatedforaMAPbetween60and160mmHg

GlomerularFiltrationRateandSerumCreatinine:

Atsteady-state,GFRandserumcreatinineareinverselyproportionalFollowingastep-changeinGFR,itwilltake~48hoursbeforesteady-stateisachievedagainDuringthisperiod,estimatesofGFRusingserumcreatininewillbelessaccurate.

GlucoseFlux:

Asglucoseisfreelyfilteredattheglomerulus,filteredplasmaglucosewillbedirectlyproportionaltoserumglucoseThisrelationshipisgivenbythedottedblackline.Undernormalcircumstances,allfilteredglucosewillbereabsorbedThisrelationshipisgivenbytheoverlapoftheredanddottedblacklines.Whenglucosefiltrationexceedsglucosereabsorption,glucosewillbegintobeexcretedinurine.Thisisgivenbythedottedblueline.

Theserumconcentrationofasubstanceatwhichthisoccursisknownasthetransportmaximum,orTInreality,someglucosewillbefilteredbeforeT isreached.ThisisduetothedifferentaffinityofS-GLUTchannels,andisthecauseofthegentlecurvesseenontheplotsofreabsorptionandexcretion.

Theserumconcentrationatwhichglucosestartstoappearinurineisknownasthethresholdconcentration

maxmax

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ThedifferencebetweenthresholdconcentrationandT isknownassplay

Haematology

CoagulationCascade:

Thecoagulationcascadeiscoveredindetailunderclotting

Thromboelastography:

TEG/ROTEMcanbeusedtoguidecoagulopathytreatmentas:ProlongedRtimeIndicatesdecreasedclottingfactorconcentration;giveFFP.

max

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Decreasedα-angle/prolongedKtimeDecreasedrapidityoffibrinogencross-linking;givefibrinogen.DecreasedMA(maybeassociatedwithprolongedKtime)Decreasedmaximalclotstrength;giveplateletsorDDAVP.DecreasedCL30/CL60Fibrinolysis;giveantifibrinolytic.

Other

HeatLossUnderAnaesthesia:

Heatlossunderanaesthesiaoccursinthreephases:1. Rapidreduction:1-1.5°Cin30minutes2. Gradualreduction:1°Cover2-3hours3. Plateau:Furtherheatlossattenuatedbymetabolicheatreduction

Doesnotoccurinneuraxialanaesthesiaasvasoconstrictiveresponsesarepreventedbysympathectomy

Equipment&MeasurementEinthoven'sTriangle:

Einthoven'striangledemonstratestherelationshipbetweendifferentlimbleadsandaugmentedleadsontheECGUnderstandingthetrianglemeansonecanidentifymisplacedECGelectrodesbythechangesinECGmorphology

e.g.iftheRAandLAelectrodesareswitched:LeadIwillinvertitspolarity

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LeadIIandIIIwillbeswitchedLeadsaVLandaVRwillbeswitchedLeadaVFwillbeunchanged

DampingCoefficients:

Followingastep-change:Anoptimally-dampedwaveformwillreturntobaselinewithoneovershootandoneundershootAnunder-dampedwaveformreturnstobaselinerapidlybutovershootsandundershootsseveraltimesAcriticallydampedwaveformreturnstobaselineasfastaspossiblewithoutovershootingAnover-dampedwaveformreturnstobaselineslowerthanacriticallydampedwaveform,anddoesnotovershoot

WheatstoneBridge:

CoveredindetailunderWheatstonebridge

GasAnalysis

ClarkElectrode:

CoveredindetailunderOxygenTension

pHElectrode:

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CoveredindetailunderpHMeasurement

SeveringhausElectrode:

CoveredindetailunderCarbonDioxideTension

Capnography

Capnograph:

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Thecapnographwaveformconsistsoffourcomponents:1. Baseline

Inspirationandearlydead-spaceexpiration(containingnoCO ).2. Alveolarexhalation3. Alveolarplateau

HighestpointisdefinedasE CO .4. Inspiration

VariationsonthewaveformarecoveredunderE CO WaveformVariations

References

1. Wigger'sDiagram(withsomemodifications)fromWigger'sDiagram.21/3/2012.(Image).ByDanielChangMD(revisedoriginalworkofDestinyQx);RedrawnasSVGbyxavax.CCBY3.0,viaWikimediaCommons.

2. ClottingCascade22/4/2007.(Image).ByJoeD(Ownwork).CCBY3.0,viaWikimediaCommons.

Lastupdated2019-07-18

2

T 2

T 2

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LawsandEquationsThisappendixisalistofthekeylawsandequationscommontomanytopics:

GeneralLaws

Fick'sLawofDiffusionDiffusionofasubstanceacrossamembraneisgivenby:

,where:

=Areaofthesheet

=Diffusionconstant,whichisproportionaltothesolubilityofthegasandinverselyproportionaltothesquareroot

ofthemolecularweight,i.e.

=Thicknessofthesheet

Hagan-PoiseuilleEquationCalculatestheflowforagivenpressuredifferentofaparticularfluid.Mayalsoberearrangedtocalculatepressureorresistance.

Givenbytheequation:

,where:QistheflowPisthedrivingpressureηisthedynamicviscosityListhelengthoftubingristheradius

Hasseverallimitations:OnlymodelslaminarflowFluidmustbeincompressibleNottechnicallyvalidforair,butprovidesagoodapproximationwhenusedclinically.FluidmustbeNewtonianFluidmustbeinacylindricalpipeofuniformcross-section

ReynoldsNumberReynoldsNumberisadimensionlessindexusedtopredictthelikelihoodofturbulentflow.R<2000islikelytobelaminar,R>2000islikelytobeturbulent.Givenbytheequation:

,where:

visthelinearvelocityoffluidin

disthefluiddensityinristheradiusin

nistheviscosityin

CellPhysiology

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NernstEquationCalculatestheelectrochemicalequilibriumforagivenion:

,where:

istheequilibriumpotentialfortheion

isthegasconstant(8.314J.deg .mol )

isthetemperatureinKelvin

isFaraday'sConstantistheionicvalency(e.g.+2forMg ,-1forCl )

Goldman-Hodgkin-KatzEquationCalculatesthemembranepotentialforgivenvaluesofintracellularandextracellularionicconcentrations:

,where:

isthepermeabilityconstantfortheion,

Ifthemembraneisimpermeableto ,then .

Henderson-HasselbalchCalculatesthepHofabuffersolution:

,where:

isthepHofthesolution

isthepKaofthebuffer

istheconcentrationofbase

istheconcentrationofacid

RespiratoryLawsModifiedBohrEquationTheratioofdeadspacetotidalvolumeventilationequationsthearterial-mixed-expiredCO2difference,overthearterial

CO2.

LaPlace'sLawThelargerthevesselradius,thelargerthewalltensionrequiredtowithstandagiveninternalfluidpressure.Forathin-walled

sphere,WallTension(T)ishalftheproductofpressureandradius,i.e.

AlveolarGasEquationThealveolarPO2isequaltothePiO2minusthealveolarCO2/therespiratoryquotient,i.e.:

GasLawsBoyle'sLaw

,i.e.pressureandvolumeareinverselyrelatedatconstanttemperatureandpressure.

-1 -1

+2 -

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BoylesLawcanbeusedtoworkouthowmanylitresofgasareremainingingascylinder,e.g.:AstandardCcylinderis1.2LinsizeNormalcylinderpressureis~137bar,andatmosphericpressureis~1bar

Therefore,thecylindercontains~164LofoxygenThiscanbeusedtocalculatethevolumeofgasremaininginthecylinderduringuse,usingthevolumeofthecylinder(fixed)andthecurrentpressureasmeasuredattheregulator

Charle'sLaw

,i.e.volumeandtemperaturearelinearlyrelatedwhenpressureisconstant.

Gay-Lussac'sLaw/TheThirdGasLaw ,i.e.pressureandtemperaturearelinearlyrelatedwhenvolumeisconstant.

TheUniversalGasEquation

,i.e.combinationofBoyle's,Charle'slawcombiningeachvariableandtheuniversalgasconstant,R(8.13).

Henry'sLawThenumberofmoleculesofdissolvedgasisproportionaltothepartialpressureofthegasatthesurfaceoftheliquid

Graham'sLawofDiffusionDiffusionratesthroughorificesareinverselyproportionaltothesquarerootofthemolecularweight

Dalton'sLawofPartialPressuresInamixtureofgases,eachgasexertsthepressurethatitwouldexertifitoccupiedthevolumealone.

CardiovascularEquations

Fick'sPrincipleFlowofbloodthroughanorganequalstheuptakeofatracersubstancebytheorgandividedbytheconcentrationdifferenceofthesubstanceacrossit,i.e.:

Starling'sLawofFluidExchangeFlowoffluidacrossthecapillariesisproportionaltothehydrostaticpressuredifferenceandtheoncoticpressuredifference(timesthereflectioncoefficient),alltimesbythefiltraitoncoefficient,i.e.:

VenousAdmixtureCalculatestheshuntfractionbyidentifyinghowmuchmixedvenousbloodmustbeaddedtoidealpulmonarycapillaryblood

toproducetheidentifiedarterialoxygencontent.

Equipment

DopplerequationCalculatesthevelocityofanobjectbasedonthechangeinobservedfrequencywhenawaveisreflectedoff(oremittedfrom)

LawsandEquations

746

theobject:

where:

=Velocityofobject

=Frequencyshift=Speedofsound(inblood)

=Frequencyoftheemittedsound

=Anglebetweenthesoundwaveandtheobject

References1. Davis&Kenny.BasicPhysicsandMeasurementinAnaesthesia,5thEdition.2. Gorman.RAHDivingandHyperbaricMedicine.Chapter3:Thephysicsofdiving.

Lastupdated2019-07-18

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StructuresforSAQsStructuredanswersarevital:

StructureaidsbothlearningandrecallofinformationAstructuredformatiseasytofollowlesslikelytoirritatethedrunk/tired/hungovermindoftheexaminerYoumaygetmarksforincompleteanswersifyourstructuredemonstratesyouhaveanunderstandingofthetopic,evenifthedetailsarenotfilledin

Somequestionslendthemselvesmoreeasilytoaparticularstructurethanothers,butallquestionscanbemadetofitevenabasicstructure.

RegulationofPhysiologicalResponsesSensorIntegrationEffector

ChangeinLevelofaSubstanceIntakeDistributionElimination

CompareandContrast(Drugs)ClassPharmaceutics

UsesChemicalPresentationHeat/lightstabilityRoutesofadministrationDoses

PharmacokineticsAbsorptionDistributionMetabolismElimination

PharmacodynamicsMainActionModeofActionEffects(Seethephysiologicalapproach)SideEffectsToxiceffects

AllergicDose-dependentIdiopathic

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Druginteractions

DescribeWhyTwoDrugsareUsedinCombination

DefinitionBrief,ofeachdrug.

ConsiderthecomponentsofanaesthesiathateachprovidesPharmacokinetics

InteractionsRelativeonsetMetabolism

Noeffect/Induces/InhibitsElimination

PharmacodynamicsIsobologramSynergistic/additive/antagonistic.Thenlisttheeffectsofeachdrug,andhowtheyaremodifiedbytheother

e.g.ifdrugsaresynergistic,thendecreaseddoseswillberequiredIncreasesbeneficialeffectsDecreasesadverseeffects

DescribethePhysiologyof...

RespiratoryBronchodilation/constrictionVasodilation/constrictionVRRSecretionLaryngealreflexes

CVSPreloadContractility/Pumpeffects

InotropyChronotropy/rhythmDromotropyLusitropyBathmotropyNodaleffectsCoronaryBloodFlow

Afterload/PipeeffectsSBPDBPMAPSVRPVR

IntraarterialinjectionCNS

Sedation

T

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AnalgesiaPro/anticonvulsantAmnesticCerebralMetabolicRateCerebralBloodFlowICPIOP

MusculocutaneousBloodFlowNMJ

EndocrineGynaecomastiaHairBone

RenalandGURenalBloodFlowNephrotoxicityBladdertoneUterinetone

GITandHepaticHepatotoxicity/LFTsSecretionsGastricemptyingN/V/D/C

HaematologicalG6PDPorphyriasBonemarroweffects

ImmunologicalAnaphylaxisHistaminergicNeutrophilfunction

Metabolic

AnatomicalStructure

AnatomyofthestructureRelationshipsRelevantsurfaceanatomyLayersofdissection

PhysicsandMeasurement

DefinitionUsesPhysicalprinciplesComponentsCalibrationAdvantages/Disadvantages

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References

Dr.PodcastWisdomfromdrunk,tired,and/orhungoverexaminers.

Lastupdated2019-07-18

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