SEDATION & NEUROMUSCULAR

BLOCKADE

Pediatric Critical Care Medicine

Emory UniversityChildren’s Healthcare of

Atlanta

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Objectives• Definition• Signs & Symptoms• Categories• Shock physiology• Treatments

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Myths • Children don’t feel pain/anxiety; underestimation

of pain• Masking symptoms of progressing injury• Side effects: respiratory depression &

cardiovascular compromise• Addiction

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Truths - Pain• Pathophysiology of pain

Tissue damage release local mediators (bradykinin, substance P, prostoglandins, K+) heighten nociception facilitate the communication of painful sensations to the spinal cord & brain

Tissue injury release of histamine & serotonin increase pain sensitivity in areas surrounding the site of initial injury

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Truths - Pain• All nerve pathways for the conduction of painful

stimuli & awareness of pain are functional by 24 wk EGA

• Failure to manage painful stimuli increases perception of pain for future painful events

• Lack of pain control increases the stress responses

» Simons SH, van Dijk M. van Lingen RA et al: Randomized controlled trial evaluation effects of morphine on plasma adrenaline/noradrenaline concentration in newborns. Arch. Dis Child Fetal Neonatal Ed. 2005; 90: F36-F40

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Truths – Side Effects• Respiratory & hemodynamic compromises

– Potentiates with combination with other sedatives & analgesics

– Understanding the pharmacokinetics and effects of these agents

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Truths - Addiction• Definitions:

– Addiction– Tolerance– Dependence

• Dependence: – 1/3 pts who received tx>4wks– Continuous infusion: tolerance develops within days

» Riss, J.; Cloyd, J.; Gates, J.; Collins, S. (Aug 2008). "Benzodiazepines in epilepsy: pharmacology and pharmacokinetics.". Acta Neurol Scand 118 (2): 69–86. doi:10.1111/j.1600-0404.2008.01004

• Risk factors:– Dependent personality– Short acting benzo– Long-term use of benzo

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Sedation – A Continuum

• Analgesia• Minimal sedation• Moderate sedation• Deep sedation• General anesthesia

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Awake/ Drowsy/Gen. Anest.

Baseline AnxiolysisModerate Deepsedation sedation

Sedation – A Continuum

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Sedation Measurement Tools

• Modified Ramsey Score– 0 – unresponsive– 1 – responsive to noxious stimuli– 2 – responsive to touch or name– 3 – calm & cooperative– 4 – restless & cooperative– 5 – agitated– 6 – dangerously agitated & uncooperative

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Sedation Measurement Tools

• Bispectral Index (Bis)– Measure level of consciousness by algorithmic analysis of

EEG– Scale 0 (silent EEG) to 100 (fully awake)– Good tools to use for deep sedation/anesthesia, doesn’t

differentiate level of consciousness for moderate to deep sedation

– Mason KP et all: Value of bispectral index monitor in defferentiating between moderate and deep Ramsay Sedation Scores in children. Paediatr Anaesth. 2006 Dec; 16 (12):1226-31

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Sedative - Hypnotic• Sedation, motion control, and anxiolysis• NO analgesia• Classes

– Benzodiazepines– Barbiturates– Chloral hydrate– Diprivan– α –adrenergic agonists

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Sedation Neurotransmitters

• GABA: inhibitory neurotransmitter in the brain• Glycin: inhibitory neurotransmitter in the spinal

cord & brain stem• Glutamate: excitatory receptors

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Sedation - Benzodiazepines• Augment GABA & glycin transmission binding

to receptors influx Cl- hyper-polarization resistance to neuronal excitation

• BZD bind to receptor complex enhance GABA binding to its receptors increase in GABA efficiency

• BZD increase the frequency of Cl- channel opening increase GABA potency

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Sedation - Benzodiazepines• Effects: anxiolytic, amnestic, anti-convulsant,

hypnotic, sedative, skeletal muscle relaxant

• Decrease CMRO2 & CBF

• Impair anterograde amnesia,• Affect ventilatory response to both hypoxia &

hypercapnea• Potentiate effect with alcohol & narcotics• Decrease both pre & after-load decrease MAP

with min effect on CO

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Sedation - Benzodiazepines• Tolerance involves GABAA receptor

– Down regulation– Alterations to the subunit configuration– Uncoupling & internalizing of the BZD binding site– Change in gene expression

• Others– Paradoxical reaction – disinbition usually in children or

older adults with h/o alcohol abuse or ones with underlying aggressive behavior

– Rebound insomnia & anxiety after only 7 days– Long lasting memory deficit with long term use – Worsening of depression

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Sedation - Benzodiazepines• Withdrawal syndrome

– Anxiety, insomnia, nightmares, seizures, psychosis, hyper-reflexia

– Post midazolam infusion phenomenon– Slow tapering to decrease withdrawal

T ½Hr

ProteinBinding

Active metab. Metabolism

Midazolam 1-4 94% alpha1-hydroxymidazola

m

P450Glucoronide conjugation

Lorazepam 14.5 91% None Hepatic glucuronidatio

n

Diazepam 46.6 97.8% Desmethyl diazepam (t½

48-96 hrs)

Liver

Sedation - Benzodiazepines

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BZD - Midazolam• Most commonly used sedative • Water soluble (less thrombophlebitis) less pain

with injection• IV, IM, PO, IN, PR, Buccal• Metabolized by P450 (CYP) enzymes & by

glucuronide conjugation• Side effects:

– Post midazolam infusion phenomenon– A “midazolam infusion syndrome”: delayed arousal hrs

to days after discontinuation, associated with high dose infusion

– “Hang over”: psychomotor & cognitive function impairment to the next day

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BZD - Lorazepam• Highly protein bound, extensively metabolized

into inactive forms• Lipophobic confine in the vascular space• IV, IM, PO, SL• Solvent: polyethylene & propylene glycol

hyperosmolar metabolic acidosis with prolonged infusion

• Injectable solution contains benzyl alcohol• Uses:

– Status epilepticus– Alcohol withdrawal syndrome, catatonia– Anti-emetic

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BZD - Diazepam• IV, IM, PO (100% bio-availability), PR (90%)• Highly protein bound, cross BBB & placenta,

excrete in stools• Lipophilic evenly distributed accumulative

effect with repeat doses• High risk of thrombophlebitis, pain with injection• P450 + glucuronidation in liver long t ½

metabolite • Uses: anxiety, insomia, seizure, muscle spasm,

restless leg syndrome, alcohol and BZD withdrawal

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Sedation - Barbiburates• GABAA receptor (different from BZD) increases duration

of Cl- channel opening increases GAGA efficacy• Block AMPA receptor (glutamate subtype)

• Decrease CMRO2 & CBF

• Side effects: myocardial depression, hypotension• Effects: CNS depressants (mild sedation anesthesia);

anxiolytic, hypnotic, anti-convulsants (except Methohexital)

• Uses:– Surgical anesthesia– Delirium tremens– Seizures– Insomnia

Sedation - Barbiburates

Types Names T ½

Long acting Phenobarbital 24-96 hrs

Medium acting

PentobarbitalSecobarbital

20-45 hrs

Ultra short acting

ThiopentalMethohexital

4-24 hours

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Sedation - Chloral Hydrate• Sedative & hypnotic: short term use for insomnia• Enhance GABA receptor complex• Tolerance with long term use• Overdose: N/V, convulsion, confusion, irregular

breathing, arrhythmias, coma– SV, junctional or ventricular arrhythmias including

torsades de pointes

• Side effects: rash, gastric discomfort, myocardial depression, hepatic failure– Hyperbilirubinemia: displace bilirubin from albumin sites

Chloral Hydrate Trichloroethanol (TCE)

Trichloroacetate (TCA) Glucuronidation

Alcohol dehydrogenase

T ½ 8-12hr45% protein bound30-60 min peak

T ½ 67 hrsInc. 3-4X in neonatesDisplace bili from albuminCNS depression

Sedation - Chloral Hydrate

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Sedation - Diprivan• 10% soybean oil, 2.25% glycerol, 1.2% egg

phosphatide• Protein bound; metabolized by conjugation in

liver + extra hepatic elimination

• Potentiate GABAA receptor activity slow the closing of the Cl- channels

• Rapid distribution to peripheral tissue ultra short effects

• T ½ 2-24 hrs

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Sedation - Diprivan• Adverse effects:

– Pain with injection, pro-bacterial growth, produce green urine

– Negative inotrope, potent vasodilitation, bradycardia– Potent respiratory depressant– Deplete trace element (Zinc) in prolonged infusion– “Propofol infusion syndrome”– “Gasping syndrome”

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Sedation - α-adrenergic Agonists• α-1 agonist: stimulates phospholipase C activity

– Vasoconstriction, mydriasis– Use a vasopressrs, nasal decongestants, eye exam

• α-2 agonist: inhibits adenylyl cyclase activity– Reduce brainstem vasomotor center-mediated CNS

activation– Use: anti-hypertensive, sedative, opiate & alcohol

withdraw– α-2a: sedation, sleep, analgesia, sympatholysis– α-2b: vasoconstriction, anti-shivering, endogenous

analgesia

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Sedation - α-adrenergic Agonists• Clonidine: α-2: α-1 = 200:1

– Large volume of distribution, long T½ 12-24 hrs– Acts on receptors in the locus coeruleus (stress & panic)– Prevent pre-synaptic release of NE in the sympathetic

nervous system anti-hypertensive– Acts on peripheral α-2 vasoconstriction

• Dexmetomidine: α-2: α-1 = 1600:1 – T½ 1.5-3 hrs, ½ excrete unchanged in urine– Min respiratory depression, sedated yet easily aroused– Highly lipophilic, cross BBB– Effective in CV symptoms for cocaine intoxication– Reduce sympathetic activity decrease HR & BP– Rapid infusion hypertension due to activation of α-1

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Sedation - Ketamine• Dissociate anesthesia (similar in structure of PCP)

hallucigenic, analgesic, amnestic• NMDA (glutamate) antagonist analgesic; • Binds to opioid receptors (μ & sigma) in high dose

• Increases catecholamines release & cholinergic receptor stimulation bronchodilator, mucous production, increase SVR, HR, CO

• Increasse CBF & CRMO2

• Metabolized to Norketamine to excrete in urine

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Analgesia• Oucher Scale by Judy Beyer, modified by Wong: self

report with faces & numerical pain scale

• Pain physiological responses – observational pain scale (OPS)– HR & BP– Measuring level of adrenal stress hormone

• COMFORT score:– Behaviors: alertness, facial tension, muscle tone, agitation,

movement– Physiologic responses: HR, respiration, BP

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Analgesia• Anti-pyretic & non-opioid• Opiod• Methadone

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Analgesia – Antipyretic or Non-opioid

• Cyclo-oxygenase (COX) 1,2,3: inhibit prostaglandins production (peripheral & central)– Cox 1:protective prostaglandins preserve gastric

lining integrity; maintain normal renal function– Cox 2: inducible by pro-inflammatory cytokines & growth

factors; in both brain & spinal cord: nerve transmission for pain & fever

• Useful for inflammatory processes (bony or rheumatic)

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Analgesia – Antipyretic or Non-opioid

• Aspirin:– Alter platelet function; can cause gastric irritant

• Ketorolac– Platelet dysfuncion serious risk of GI bleeding

• Trilisate (choline magnesium trisalicylate; ASA like compound)– No SE on platelet– Use in post-op pain or cancer patients

• Paracetamone– Central Cox 3, no anti-inflammatory activity

• Naproxen– Cox 1 inhibitor

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Analgesia - Opioids• Terms:

– Agonist– Antagonist– Partial agonist

• Receptors: µΚδσ– Inhibit synaptic transmission in CNS and myenteric

plexus– Found in pre-synaptic, decrease release of excitatory

neurotransmitter for nociceptive stimuli– Coupling with G-protein, regulate trans-membrane signaling by

regulate cAMP

SUB-TYPE

PROTOTYPICDRUGS

ACTIONS

Mu1µ1

Opiates & most opiate peptides

Supraspinal analgesiaProlactin release

Acetylcholine turnover in brain

Mu2µ2

Morphine Respiratory depression; GI transitDopamine turnover in brain

Most CV effects

Deltaδ

Enkephalins Spinal analgesiaDopamine turnover

KappaΚ

Dynorphin Spinal analgesia; sedationInhibition of ADH

Sigmaσ

N-allynormetazocine Psychotomimetic effects

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Analgesia – Morphine• µ2 agonist: analgesia, sedation, euphoria, resp.

depression• K and δ agonist: spinal analgesia, miosis,

psychomimetic effects• Glucuronide metabolism M3G (exrete) & M6G

(active metabolites)• Poor lipid solubility, protein binding• SQ, IV, IT, epidural

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Analgesia – Morphine• Increase in sensory threshold for pain• Respiratory depression: decrease RR, MV & response to

CO2• Miosis: pupillary constriction via oculomotor nucleus• Decrease stress hormones: ACTH, ADH, prolactin, GH & epi• Uncertain response to N/V: act on chemo-trigger zone +

depress vomiting center• Smooth muscle relaxation: directly or via vagus nerve• Increase biliary tract tone biliary colic• Urinary retention via increase tone in bladder detrusor

muscle or vesical sphincter• Histamine release bronchospasm or CV collapse

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Analgesia - Fentanyl• 100X >morphine• Strong agonist at the µ and K• Lipophilic: cross BBB rapid onset with short

duration 2/2 rapid redistribution• Block systemic & pulmonary hemodynamic effect of

pain• Prevent biochemical & endocrine stress (catabolic)• Adverse effects: N/V, constipation, dry mouth,

somnolence, confusion, anesthesia (weakness), sweatingSevere AE: glottic & chest wall rigidity with rapid infusion

(>5mcg/kg)

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Analgesia – Other Fentanyls

• Sufentanil– 5-10x > Fentanyl, most potent opioid in clinical practice– Smaller volume of distribution, faster recovery after

prolonged infusion

• Alfentanil– 5x < Fentanyl, short duration 5-10 min– Useful for RSI with ICP

• Remifentanil– Metabolized by plasma esterase with short t ½ – Potent µ with mild K & δ effects, potent respiratory

depression, no histamine release– Similar kinetics in neonates & adults– Very expensive

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Analgesia – Other Opioids• Meperidine

– K receptor agonist; strong opioidergic, anticholinergic and antispasmodic; Local anesthetic properties – surgical spinal analgesia

– Superior to Morphine for billiary spasm or renal colic– Metabolized to normeperidine - twice as toxic– “Serotonin syndrome” with CNS excitatory effects:

tremors, ms spasm, myoclonus, psychiatric changes & seizure

– Interact with MAOIs agitation, delirium, headache, convulsions, hyperthermia (Libby Zion Law)

– Contraindicated in liver, kidney disease, seizure disorder, enlarged prostate or urinary retention, hypothyroidism, asthma, Addison’s disease.

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Analgesia – Other Opioids• Codein

– Methylmorphine: analgesic, anti-tussive, anti-diarrheal– Alkaloid found in opium poppy (papaveraceae)– Convert to morphine in the liver by P450 and to active

metabolites– Prolonged use physical dependence & psychologically

addictive; mild withdrawal symptoms– Preserve pupillary signs

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Analgesia – Other Opioids• Tramadol (Ultram, Tramal)

– Weak µ agonist, release serotonin, inhibits reuptake of norepinephrine

– Therapy for most neuralgia and chronic pain– Hard to wean due to effects on opioid, serotonin/NE activity– Decrease seizure threshold

• Hydromorphone (Dilaudid)– Centrally acting opioid class on µ receptor, 8x > morphine– Water soluble with quick onset– Lack of toxic metabolite, lower dependency, less nausea– Brief but intense withdrawal

RELATIVE POTENCY

T½(Hr)

ACTIVEMETABOLITES

MORPHINE 1 2.2 MORPHINE-6-GLUCURONIDE

MEPERIDINE 0.1 3.2 NORMEPERIDINET1/2 15 HRS

FENTANYL 100 4 NONE

HYDROMORPHONE

7 NONE

SUFENTANIL 500 2.7 NONE

REMIFENTANIL N/A NONE

ALFENTANIL 10 1.2 NONE

METHADONE 1 19 NONE

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Analgesia – Opioid Antagonist

• Naloxone– Competitive antagonist with high affinity for µ receptor

in CNS rapid onset of withdrawal– IV with fast onset of action; T½ 30-81 min

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Analgesia – Other• Methadone

– Acts on opioid receptors without the euphoric effects prevent narcotic withdrawal syndrome

– Binds on NMDA (N-methyl-D-aspartate) antagonist against glutamate decrease craving for opioids & tolerance

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Analgesia – Withdrawal• Neurologic excitability: Sleep disturbances,

agitation, tremors, seizures, choreoartheroid movements

• GI disturbances: V/D• Autonomic dysfunction: hypertension,

tachycardia, tachypnea, fever, frequent yawning, sweating or goose flesh,

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Neuromuscular Blockade• Large highly charged water - soluble molecules at

physiologic pH can’t cross BBB, placenta, GI• Onset is more rapid & less intense at the

laryngeal muscle (vocal cord) & peripheral muscle

• Diaphragm is the most resistant to paralysis

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Neuromuscular Blockade• Types

– Depolarizing: mimic action of acetylcholine– Non-depolarizing: competitively block ACH receptors

• Classifications– Short: succinylcholine, mivacurium– Intermediate: atracurium, vecuronium, rocuronium,

cisatracurium– Long: pancuronium, doxacurium, pipecuronium

% of Blocka

de

Clinical Relaxation

Ventilation

0 None; TOF > 0.7

Tetanus sust. @ 50Hz

Normal

Inspiratory force > 50cm H2O

25 Poor; inadequate head lift & leg flexion

Slightly to moderate. Diminished VC

50 Fair Mod. to markedly diminished VCTV may be adequate

75 Good TV diminished

90 Good TV inadequate

95 Very good; adequate for tracheal intubation under light anesthesia

Some diaphragmatic motion

100 Excellent; very good for tracheal intubation

ApneaFurhman, 3rd Edition

Metab./excretion

Onset(min)

Duration

(min)

Dosage(mg/kg)

Infusion

Succinylcholine

Pseudo-cholinest.

1 3-4 IV- 1-2IM-3-4

Mivacurium PlasmaCholinester

.

1-3 9-12 0.2 10-14 mcg/kg/min

Atracurium Hoffmann 1-4 20-35 0.3-0.4 0.6-1.2 mg/kg/hr

Cisatracurium

Hoffmann 2-3 35-45 0.1-0.2 0.06-0.24 mg/kg/hr

Vecuronium LiverRenal exc.

1-3 30-40 0.1 0.06-0.15 mg/kg/hr

Rocuronium LiverRenal exc.

1 30-90 0.5-1 10-20 mcg/kg/min

Pancuronium

LiverRenal exc.

2-3 40-60 0.1 0.02-0.1 mg/kg/hr

Pipecuronium

LiverRenal exc.

Doxacurium Renal 5-11 30 0.03-0.05

6-12 mcg/kg/hr

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NMB: Depolarizing• Succinylcholine

– Stimulates all cholinergic receptors – Binds directly to the postsynaptic ACH receptors– Metabolized by pseudocholinesterase– Also binds to muscarinic receptors of SA node

negative inotrope and chronotrope– Short duration due to high volume of distribution– Prolonged & repeat exposure membrane can

repolarize but remain refractory to subsequent depolarization “Phase II block”, clinical resemblance to non-depolarizing agents.

– Prolonged effects in hepatic dysfunction, hyper-magnesia & pregnancy

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NMB: DepolarizingSuccinylcholineContraindications

– History of malignant hyperthermia (personal or family)– Neuromuscular disease involving denervation– Muscular dystrophy– Stroke over 72 hours old– Rhabdomyolysis– Burn over 72 hours old– Significant hyperkalemia

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NMB: Depolarizing

SuccinylcholineMalignant hyperthermia:

– Myopathic metabolic disorder– Autosomal dominant– Sympathetic hyperactivity, mucular rigidity acidosis and

hyperthermia– Uncontrolled increase in skeletal muscle oxidative

metabolism hypoxia, hypercapnea and hyperthermia– Treatment: dantrolene, cooling and sedation

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NMB: DepolarizingSuccinylcholine

Side effects– Trismus: masseter muscle spasm (can associate with

MH)– Fasciculations: via nicotinic activation – Bradycardia: via muscarinic activation at SA node

especially children; can occur in adults in repeated dose or infusion

– Rhabdomyolysis and muscle pain– Transient ocular hypertension: safe in open globe injury

if use in conjunction with sedation– Mild increase in intra cranial pressure

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NMB: Non-Depolarizing• Competitively inhibits the postsynaptic Ach

receptors of the neuromuscular motor endplate• Prevents depolarization & inhibits all muscle

function• Categories

– Benzylisoqyinolinium: atracurium, mivacurium» Histamine release» Can cause autonomic ganglionic blockade

– Aminosteroids: rocuronium, vecuronium, pancuronium

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NMB: Non-Depolarizing• Low plasma protein binding capacity• 4 routes of elimination: renal excretion, hepatic

excretion, biotransformation, tissue binding• Types

– Short: Mivacurium– Intermediate: atracurium, Vecuronium, Rocuronium,

cisatrocurium– Long: d-tubocurarine, pancuronium, pipecuronium,

doxacurium

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NMB: Non-Depolarizing reversal

• Abx, hypotension, hypothermia, acidosis & hypocalcemia prolong or potentiate NMB

• Duration of reversals are the same in all 3 classes• Neostigmine

– 25-70 mcg/kg

• Edrophonium– Faster acting– 125-250 mcg/kg