the challenges of hyponatremia

7/30/2019 The Challenges of Hyponatremia

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6 J uly, 20106 J uly, 2010 ESIM 13, BrightonESIM 13, Brighton

The challenges ofThe challenges ofhyponatremiahyponatremia

Runolfur Palsson, MD, FACP, FASNRunolfur Palsson, MD, FACP, FASNDivisionDivision ofof NephrologyNephrology

LandspitaliLandspitali University HospitalUniversity HospitalUniversity of IcelandUniversity of Iceland


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TreatingTreating hyponatremiahyponatremia:: damneddamned ifif wewe dodo

andand damneddamned ifif wewe dondonttThomasThomas BerlBerl

HyponatremiaHyponatremia placesplaces thethe treatingtreating physicianphysician

betweenbetween aa rockrock andand aa hardhard placeplace

RichardRichard SternsSterns


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LANDSPITALI UNIVERSITY HOSPITAL DIVISION OF NEPHROLOGY

Recognize how understanding of the physiology ofRecognize how understanding of the physiology of

water homeostasis and cell volume regulation provideswater homeostasis and cell volume regulation providesa foundation for prudent treatment ofa foundation for prudent treatment ofhyponatremiahyponatremia

Be able to distinguish between acute and chronicBe able to distinguish between acute and chronichyponatremiahyponatremia

UnderstandUnderstand howhow thethe choicechoice ofoftreatmenttreatment forforhyponatremiahyponatremia dependsdepends onon severityseverity,, raterate ofofonsetonset andandthethe clinicalclinical featuresfeatures

Be able to diagnose and aggressively manage lifeBe able to diagnose and aggressively manage life--

threateningthreatening hyponatremichyponatremic emergenciesemergencies Be able to administer therapies that reliably correctBe able to administer therapies that reliably correct

hyponatremiahyponatremia at an appropriate rateat an appropriate rate

Learning objectivesLearning objectives


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Hyponatremia is defined as serum Na


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Hyponatremia is a disorderof water balance!


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Difference between intake and excretion of waterDifference between intake and excretion of waterresults in alteration of body fluid tonicityresults in alteration of body fluid tonicity

The body senses and regulates serumThe body senses and regulates serum osmolalityosmolality

(not serum Na) which is kept constant at ~285(not serum Na) which is kept constant at ~285mOsmmOsm/kg by matching water excretion and intake/kg by matching water excretion and intake

Serum Na is a surrogate marker for serumSerum Na is a surrogate marker for serum

osmolalityosmolality SerumSerum osmolalityosmolality is regulated by water balanceis regulated by water balance

(not sodium balance)(not sodium balance)

Water homeostasis: key conceptsWater homeostasis: key concepts


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OsmolalityOsmolality is equal in allis equal in allbody fluid compartmentsbody fluid compartments

SerumSerum osmolalityosmolality can becan becalculated:calculated:

OsmolalityOsmolality = 2 x serum Na += 2 x serum Na +

glucose + ureaglucose + urea EffectiveEffective osmolalityosmolality = 2 x= 2 x

serum Naserum Na

OsmolalityOsmolality of the body fluidsof the body fluids


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SumitKumar & Tomas Berl

ExcretionExcretion of fof freeree waterwater by the kidneyby the kidney


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ActionAction ofofargininearginine vasopressinvasopressin onon

thethe renalrenal principalprincipal cellcell



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Increased plasma

osmolality

Decreased effectivecirculating volume

VasoconstrictionRenal water

reabsorption

Decreased plasma

osmolality

Expanded plasmavolume

AVPAVP

++

V1a receptors V2 receptors

Regulation of vasopressin secretionRegulation of vasopressin secretion


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OsmoticOsmotic andand nonosmoticnonosmotic regulationregulation

ofofvasopressinvasopressin secretionsecretion



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Accumulation of water rarely occurs unless the abilityAccumulation of water rarely occurs unless the ability

to excrete water is impairedto excrete water is impaired The capacity of the kidneys to excrete water isThe capacity of the kidneys to excrete water is

normally very large or up to 15normally very large or up to 15--20 L/day20 L/day

Thus, enormous water intake is required to causeThus, enormous water intake is required to causehypotonichypotonic hyponatremiahyponatremia under normal conditionsunder normal conditions If renal water handling is impaired, then modest waterIf renal water handling is impaired, then modest water

intake can causeintake can cause hypotonicityhypotonicity Impaired water excretion leading toImpaired water excretion leading to hyponatremiahyponatremia,,

almost invariably results from the inability to suppressalmost invariably results from the inability to suppressthe secretion of vasopressinthe secretion of vasopressin

How doesHow does hyponatremiahyponatremia develop?develop?


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IsotonicIsotonic hyponatremiahyponatremia ((pseudohyponatremiapseudohyponatremia))

A laboratory artifactA laboratory artifact causedcaused byby severesevere hypertriglyceridemiahypertriglyceridemia oror

paraproteinemiaparaproteinemia thatthat isis rarelyrarely encounteredencountered todaytoday duedue totowidespreadwidespread useuse ofofionion--specificspecific electrodeelectrode forfor serumserum NaNameasurementmeasurement

HypertonicHypertonic hyponatremiahyponatremia ((translocationaltranslocational)) Caused by hyperglycemia or hypertonicCaused by hyperglycemia or hypertonic mannitolmannitol therapy resulting intherapy resulting in

osmotic shift of water from ICF to ECF, thereby diluting serum Nosmotic shift of water from ICF to ECF, thereby diluting serum Naa

Serum Na tends to decrease ~1.7Serum Na tends to decrease ~1.7 mmolmmol/L for every 5.6/L for every 5.6 mmolmmol/L (100/L (100mg/mg/dLdL) serum glucose is above its normal value) serum glucose is above its normal value

HypotonicHypotonic hyponatremiahyponatremia ((dilutionaldilutional))

By far the most common type and is caused by water retentionBy far the most common type and is caused by water retentionresulting in water excess in relation to sodium stores, which caresulting in water excess in relation to sodium stores, which cann

be decreased, normal or increasedbe decreased, normal or increased

ClassificationClassification ofofhyponatremiahyponatremia


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Impaired renal water excretionImpaired renal water excretion Decreased extracellular fluid volumeDecreased extracellular fluid volume

Increased extracellular fluid volumeIncreased extracellular fluid volume-- Heart failureHeart failure

-- CirrhosisCirrhosis

-- Advanced renal failureAdvanced renal failure

Normal extracellular fluid volumeNormal extracellular fluid volume-- ThiazideThiazide diureticsdiuretics-- Syndrome of inappropriate secretionSyndrome of inappropriate secretion

ofofantidiureticantidiuretic hormone (SIADH)hormone (SIADH)

-- Adrenal insufficiencyAdrenal insufficiency

-- HypothyroidismHypothyroidism-- Low dietary solute intakeLow dietary solute intake

Excessive water intakeExcessive water intake PsychogenicPsychogenic polydipsiapolydipsia

Associated with prolonged exerciseAssociated with prolonged exercise

CNS disorders (includingCNS disorders (includingacute psychosis)acute psychosis)

CancerCancer

MedicationsMedicationsSSRISSRIss

TricyclicTricyclicantidepressantsantidepressants

NSAIDNSAIDss

Pulmonary diseasePulmonary disease

MiscellaneousMiscellaneous Postoperative statePostoperative state

PainPain

Severe nauseaSevere nausea

Causes ofCauses ofhyponatremiahyponatremia


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Healthy individuals on a normal diet excrete 600Healthy individuals on a normal diet excrete 600--900900

mosmolesmosmoles of solute in the urine dailyof solute in the urine daily If minimum urineIf minimum urine osmolalityosmolality is 60is 60 mOsmmOsm/kg, then maximum/kg, then maximum

urine output will be 10urine output will be 10--15 L15 L

Poor dietary intake can lower the daily urinary solute excretionPoor dietary intake can lower the daily urinary solute excretionto below 250to below 250 mosmolesmosmoles, resulting in significant reduction in, resulting in significant reduction inurine volumeurine volume

Examples:Examples:

Beer drinkerBeer drinker

ss

potomaniapotomania

--

high water intake, low dietary proteinhigh water intake, low dietary protein

Tea and toastTea and toast hyponatremiahyponatremia -- a diet that is deficient in salt and proteina diet that is deficient in salt and protein

HyponatremiaHyponatremia develops if fluid intake is greater than thedevelops if fluid intake is greater than themaximum amount of urine output that can be generatedmaximum amount of urine output that can be generated

Low dietary solute intakeLow dietary solute intake


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Healthy individuals on a normal diet excrete 600Healthy individuals on a normal diet excrete 600--900900

mosmolesmosmoles of solute in the urine dailyof solute in the urine daily If minimum urineIf minimum urine osmolalityosmolality is 60is 60 mOsmmOsm/kg, then maximum/kg, then maximum

urine output will be 10urine output will be 10--15 L15 L

Poor dietary intake can lower the daily urinary solute excretionPoor dietary intake can lower the daily urinary solute excretionto below 250to below 250 mosmolesmosmoles, resulting in significant reduction in, resulting in significant reduction inurine volumeurine volume

Examples:Examples:

Beer drinkerBeer drinker

ss

potomaniapotomania

--

high water intake, low dietary proteinhigh water intake, low dietary protein

Tea and toastTea and toast hyponatremiahyponatremia -- a diet that is deficient in salt and proteina diet that is deficient in salt and protein

HyponatremiaHyponatremia develops if fluid intake is greater than thedevelops if fluid intake is greater than themaximum amount of urine output that can be generatedmaximum amount of urine output that can be generated

600600 mosmolesmosmoles 6060 mOsmmOsm/kg = 10 L/kg = 10 L

900900 mosmolesmosmoles 6060 mOsmmOsm/kg = 15 L/kg = 15 L

Low dietary solute intakeLow dietary solute intake


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Androgue & Madias, N Engl J Med 2000;342:1581-89

EffectsEffects ofofhyponatremiahyponatremia onon thethe brainbrain

andand adaptiveadaptive responsesresponses


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AcuteAcute hyponatremiahyponatremia (48 hrhr)) FrequentlyFrequently mildmild oror nono symptomssymptoms HeadacheHeadache RestlessnessRestlessness MuscleMuscle crampscramps NauseaNausea andand vomitingvomiting LethargyLethargy ConfusionConfusion andand disorientationdisorientation

Severe cerebral edemaSevere cerebral edema Risk of death fromRisk of death from

untreateduntreated hyponatremiahyponatremia

Adaptation minimizesAdaptation minimizes

brain swellingbrain swelling RiskRisk ofofinjuryinjury fromfromovertreatedovertreated hyponatremiahyponatremia

ClinicalClinical featuresfeatures ofofhyponatremiahyponatremia


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WaterWater intoxicationintoxication duedue toto compulsorycompulsoryexcessiveexcessive fluidfluid intakeintake PatientsPatients withwith severesevere psychosispsychosis

UseUse ofofecstasyecstasy (N(N--methylmethyl--3,43,4--methylenedioxyamphetamine)methylenedioxyamphetamine)

MarathonMarathon runnersrunners

Postoperative iatrogenicPostoperative iatrogenic hyponatremiahyponatremia

ClinicalClinical settingssettings ofof

acuteacute hyponatremiahyponatremia


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Normal brainHyponatremic brain edema

AcuteAcute hyponatremiahyponatremia and brain edemaand brain edema

in a marathon runnerin a marathon runner

Ayus et al, Ann IntMed 2000;132:711-14


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NoncardiogenicNoncardiogenic pulmonarypulmonary edemaedema

Ayus et al, Ann IntMed 2000;132:711-14


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A study of runners in the 2002 Boston Marathon:

488 out of 766 runners provided a blood sample at

the finish line

63 runners (13%) had hyponatremia (serumNa


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FrequentlyFrequently asymptomaticasymptomatic PatientsPatients withwith asymptomaticasymptomatic

hyponatremiahyponatremiahavehave beenbeen foundfound totohavehave aa numbernumber ofofproblemsproblems:: AttentionAttention impairmentimpairment

GaitGait instabilityinstability

FallsFalls

IncreasedIncreased riskrisk ofofbonebone fracturesfractures

ChronicChronic hyponatremiahyponatremia


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AlgorithmAlgorithm forfor thethediagnosisdiagnosis ofofhyponatremiahyponatremia

Rai et al, AmJ Nephrol 2006;26:579-89

DiagnosticDiagnostic criteriacriteria for SIADH:for SIADH:

DecreasedDecreased serumserum osmolalityosmolality(100 mOsmmOsm/kg/kg

ClinicalClinical euvolemiaeuvolemia

UrineUrine NaNa >40>40 mmolmmol/L/L withwith normalnormaldietarydietary saltsalt intakeintake

NormalNormal thyroidthyroid andand adrenaladrenalfunctionfunction

NoNo renalrenal diseasedisease NoNo recentrecent useuse ofofdiureticdiuretic agentsagents


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The rate of correction of the serum Na is determinedThe rate of correction of the serum Na is determined

by whetherby whether hyponatremiahyponatremia is acute or chronicis acute or chronic The definition of acute or chronic is largely based onThe definition of acute or chronic is largely based on

the severity of the clinical featuresthe severity of the clinical features

LifeLife--threatening acutethreatening acute hyponatremiahyponatremia requires rapidrequires rapidcorrection of serum Nacorrection of serum Na

In contrast, the treatment of chronicIn contrast, the treatment of chronic hyponatremiahyponatremia

should be cautious because too rapid correction ofshould be cautious because too rapid correction ofthe serum Na can result in dangerous osmoticthe serum Na can result in dangerous osmoticdemyelinationdemyelination injury of the brainsteminjury of the brainstem

Treatment ofTreatment ofhyponatremiahyponatremia

can be a dilemma!can be a dilemma!


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OsmoticOsmotic demyelinationdemyelination syndromesyndrome

Demyelination lesion

Sveinsson et al, Icelandic Med J 2008;94:665-71

Normal brain Central pontine myelinolysis


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Rapid elevation of the serum Na is necessary, particularlyRapid elevation of the serum Na is necessary, particularlyif the clinical manifestations are severeif the clinical manifestations are severe

RaisingRaising thethe serumserum NaNa 44--66 mmolmmol/L/L overover 22--33 hourshours appearsappears

enoughenough

toto

preventprevent

seriousserious

neurologicneurologic

complicationscomplications

Administer 3%Administer 3% NaClNaCl (513(513 mmolmmol/L), 1/L), 1--2 ml/kg IV per hour2 ml/kg IV per hour

Should elevate theShould elevate the serumserum NaNa approximately 1approximately 1--22 mmolmmol/L/Lper hourper hour

Subsequently, the rate of correction should be less than 10Subsequently, the rate of correction should be less than 10mmolmmol/L per 24 hours/L per 24 hours

Treatment of acuteTreatment of acute hyponatremichyponatremic

encephalopathyencephalopathy


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Androgue-Madias formula:

Change in serum Na = infusate Na serum Natotal body water + 1

Estimates the effect of 1 liter of any fluid infused on serum Na Assumes all of the infusate is retained; does not consider urine

losses of electrolyte or water

Adrogu et al. N Engl J Med. 2000;342:1581-89

HowHow muchmuch hypertonichypertonic salinesaline

shouldshould bebe administeredadministered??

Ch i h i


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ClinicalClinical observationsobservations suggestsuggest thatthat thethe riskrisk ofofdemyelinationdemyelination injuryinjury of the brain is increased ifof the brain is increased ifthethe raterate ofofcorrectioncorrection ofofthethe serumserum NaNa is fasteris faster

thanthan 1212 mmolmmol/L/L inin thethe firstfirst 2424 hourshours andand 1818mmolmmol/L/L inin 4848 hourshours

ThisThis isis particularlyparticularly importantimportant inin patientspatients withwith

extremeextreme hyponatremiahyponatremia ((serumserum NaNa


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GoalsGoals

::

66--88 mmolmmol/L/L inin 2424 hourshours

1212--1414 mmolmmol/L/L inin 4848 hourshours

1414--1616 mmolmmol/L/L inin 7272 hourshours LimitsLimits::

LessLess thanthan 1010 mmolmmol/L/L inin 2424 hourshours

LessLess thanthan 1818 mmolmmol/L/L inin 4848 hourshours LessLess thanthan 2020 mmolmmol/L/L inin 7272 hourshours

SternsSterns

et al,et al,

SeminSemin

NephrolNephrol

2009;29:2822009;29:282

--9999

TreatmentTreatment ofofchronicchronic hyponatremiahyponatremia::

recommendedrecommended ratesrates ofofcorrectioncorrection


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EffectiveEffective inin correctingcorrecting hyponatremiahyponatremia causedcaused byby

volumevolume depletiondepletion Eliminates volume stimulus for vasopressin secretionEliminates volume stimulus for vasopressin secretion

Unpredictable onset of waterUnpredictable onset of water diuresisdiuresis

InIn SIADH,SIADH, isotonicisotonic salinesaline isis ineffectiveineffective andand maymay lowerlowerthe serum sodiumthe serum sodium

IfIfthethe sodiumsodium containedcontained inin aa literliter ofofsalinesaline isis excretedexcretedinin lessless thanthan aa literliter ofofurineurine;; thethe netnet effecteffect isis freefree waterwater

retentionretention ThusThus,, wewe reservereserve isotonicisotonic salinesaline forfor hyponatremichyponatremic

patientspatients whowho requirerequire treatmenttreatment forfor volumevolume depletiondepletion

IsotonicIsotonic salinesaline

T t tT t t ff t i dt i d l il i


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ConventionalConventional treatmenttreatment optionsoptions areare suboptimalsuboptimal

becausebecause ofoflimitedlimited efficacyefficacy andand poorpoor safetysafety andandtolerabilitytolerability IdentifyIdentify andand treattreat thethe underlyingunderlying causecause FluidFluid restrictionrestriction 0.50.5--1.0 L/1.0 L/dayday isis thethe mainstaymainstay butbut

poorlypoorly toleratedtolerated longlong--termterm DrugDrug therapiestherapies::

LoopLoop diureticsdiuretics plusplus increasedincreased saltsalt intakeintake

DemeclocyclineDemeclocycline 600600--1200 mg/1200 mg/dayday LithiumLithium 600600--900 mg/900 mg/dayday UreaUrea 30 g/30 g/dayday VasopressorVasopressor receptorreceptor antagonistsantagonists

TreatmentTreatment ofofsustainedsustained euvolemiceuvolemic

andand hypervolemichypervolemic hyponatremiahyponatremia

Wh tWh t l ll l ff fl idfl id t i tit i ti


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UNa + UKUNa + UK FluidFluid restrictionrestrictionSNaSNa

>1>1


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SchrierSchrier et al, Net al, N EnglEnglJJ MedMed 2006;355:20992006;355:2099--122122

Treatment hyponatremia with tolvaptan

Randomized controlled trial


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WhenWhen aa reversiblereversible causecause ofofwaterwater retentionretention isis correctedcorrected,,

vasopressinvasopressin levelslevels fallfall andand thethe excretionexcretion ofofdilutedilute urineurine causescausesserumserum NaNa toto riserise rapidlyrapidly

Maximally dilute urine increases the serum Na by >2Maximally dilute urine increases the serum Na by >2 mmolmmol/L/hr/L/hr

CanCan occuroccur whenwhen excessiveexcessive waterwater drinkingdrinking isis discontinueddiscontinued oror

impairedimpaired renalrenal waterwater excretionexcretion isis correctedcorrected Continued vigilance is essential:Continued vigilance is essential:

Monitor urine output and measure serum Na frequentlyMonitor urine output and measure serum Na frequently

IfIfurineurine outputoutput suddenlysuddenly increasesincreases,, thenthen oneone shouldshould attemptattempt totocounteractcounteract thethe elevationelevation ofofserumserum NaNa AdministerAdminister 5%5% dextrosedextrose IVIV

AdministerAdminister desmopressdesmopressnn (DDAVP)(DDAVP) parenterallyparenterally

OvercorrectionOvercorrection ofofserumserum sodiumsodium

R lRe ersal fof i d t tinad ertent tio ercorrection


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PerianayagamPerianayagamet al,et al, ClinClinJJ AmAmSocSoc NephrolNephrol 2008;3:3312008;3:331--66

ReversalReversal ofofinadvertentinadvertent overcorrectionovercorrection

ofofhyponatremiahyponatremia


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A 67 year old female was brought to the emergencydepartment following a seizure that occurred in the setting of

progressive weakness for several days There was a history of recently diagnosed small cell lung

cancer

On physical exam she was lethargic and confused;

Wt 60 kg, BP 125/75 without orthostatic drop, P 90; lungswere clear and there was no edema

Laboratory studies Blood: Na 112 mmol/L, K 4.2 mmol/L, Cl 76 mmol/L, CO2 26

mmol/L, creatinine 80 mol/L (0.9 mg/dL), osmolality 234 mOsm/kg

Urine: Osmolality 660 mOsm/kg, Na 102 mmol/L, K 64 mmol/L

CT scan of the brain showed evidence for mild cerebraledema but no other abnormalities

Case PresentationCase Presentation


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How do you judge the volume status of the patient?

Euvolemic

What is a likely cause of the hyponatremia?

SIADH due to ectopic production of vasopressin by the lung

cancer

Is the hyponatremia acute or chronic?

Serious neurological signs and symptoms indicate acute

hyponatremia with brain edema Duration unknown, but probably a significant chronic

component

DiagnosisDiagnosis


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How should this patient be treated?

Hypertonic saline with close monitoring The goal is to raise the serum Na by ~5-6 mmol/L over 2-3

hours

How much hypertonic (3%) saline should be

administered? Concurrent furosemide therapy may be required to

increase free water clearance

Closely monitor the patients clinical status, urineoutput and and measure serum Na every 1-2 hours

Immediate managementImmediate management


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How should this patient be treated?

Hypertonic saline with close monitoring The goal is to raise the serum Na by ~5-6 mmol/L over 2-3

hours

How much hypertonic (3%) saline should be

administered? Concurrent furosemide therapy may be required to

increase free water clearance

Closely monitor the patients clinical status, urineoutput and and measure serum Na every 1-2 hours

Androgue-Madias formula:Change in serum Na = infusate Na serum Na total body water + 1Change in serum Na = 513 mmol 112 mmol/L 30 L + 1 = 12.9 mmol/LThus, 1 L of 3% saline will increase the serum Na by 12.9 mmol/L

6 12.9 = 0.465 L => 155 mL per hour will be needed

Immediate managementImmediate management


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Fluid restriction

How much? To get any meaningful improvement in serum Na,

would need to completely eliminate all p.o. or i.v.

electrolyte-free H2O Additional strategies:

Increase daily solute load (salt tablets, urea)

Furosemide

Tolvaptan

The patient needs continued close monitoring

LongLong--term managementterm management


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Fluid restriction

How much? To get any meaningful improvement in serum Na,

would need to completely eliminate all p.o. or i.v.

electrolyte-free H2O Additional strategies:

Increase daily solute load (salt tablets, urea)

Furosemide

Tolvaptan

The patient needs continued close monitoring

Estimation of electrolyte-free water excretion:Urine Na + Kserum Na166 112 = 1.4

>1 indicates that no free-water excretion is occurring

LongLong--term managementterm management

Th kThank ou ffor our tt tiattention!!


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ThankThank youyou forfor youryour attentionattention!!

the challenges of hyponatremia

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