Muscle Relaxants in Muscle Relaxants in ChildrenChildren

Chan Saysana, M.D.Chan Saysana, M.D.Indiana UniversityIndiana University

Department of AnesthesiaDepartment of AnesthesiaSection of Pediatric Anesthesia and Critical CareSection of Pediatric Anesthesia and Critical Care

Neuromuscular BlockersNeuromuscular Blockers

Facilitate endotracheal Facilitate endotracheal intubationintubation

Provide surgical relaxationProvide surgical relaxation Facilitate controlled mechanical Facilitate controlled mechanical

ventilation (both OR and ICU)ventilation (both OR and ICU) Decrease metabolic demandDecrease metabolic demand Prevent shiveringPrevent shivering Improve chest wall complianceImprove chest wall compliance

NMB in childrenNMB in children

Growth and development NM Growth and development NM junctionjunction

Age-related pharmacologic Age-related pharmacologic characteristics of NMB agentscharacteristics of NMB agents Change in dose-response Change in dose-response

relationshiprelationship Duration of neuromuscular Duration of neuromuscular

blockadeblockade

NMB in childrenNMB in children

NM junction mature physically and NM junction mature physically and biochemicallybiochemically

Contractile properties of skeletal Contractile properties of skeletal muscle changemuscle change

Amount of muscle in proportion to Amount of muscle in proportion to body weight increases as agebody weight increases as age

Change in apparent VdChange in apparent Vd Change in redistribution/ excretionChange in redistribution/ excretion Change in rate metabolismChange in rate metabolism

Neuromuscular blockade in Neuromuscular blockade in childrenchildren Immaturity of neuromuscular system Immaturity of neuromuscular system

Ach receptor change in function and distributionAch receptor change in function and distribution Lower values of TOF, post-tetanic facilitation, and marked Lower values of TOF, post-tetanic facilitation, and marked

fade during prolonged tetanic stimulationfade during prolonged tetanic stimulation Longer elimination half-life of relaxantsLonger elimination half-life of relaxants General VGeneral VDD for most relaxants is about the same size as for most relaxants is about the same size as

the ECF volume (larger in infants than in older children or the ECF volume (larger in infants than in older children or adults)on weight basisadults)on weight basis

ED95 proportional to Vd/and concentration of blocker at ED95 proportional to Vd/and concentration of blocker at effector siteeffector site

Presence of greater number of fast muscles in ventilatory Presence of greater number of fast muscles in ventilatory musculaturemusculature

More liable for fatigueMore liable for fatigue Slow twitch fibers increase several fold in first 6 moSlow twitch fibers increase several fold in first 6 mo

Closing volume w/i tidal volumeClosing volume w/i tidal volume Airway closure occurs at end expirationAirway closure occurs at end expiration Aggravate hypoxemia/acidosis-potentiate relaxantAggravate hypoxemia/acidosis-potentiate relaxant

Neuromuscular blockade in Neuromuscular blockade in childrenchildren Higher doses are required to block Higher doses are required to block

diaphragm vs. adductor pollicisdiaphragm vs. adductor pollicis If TOF of adductor is near normal, then can If TOF of adductor is near normal, then can

assume diaphragm is fully recoveredassume diaphragm is fully recovered Laryngeal adductors are less sensitive than Laryngeal adductors are less sensitive than

adductor pollicis to NDNMB, respose similar in adductor pollicis to NDNMB, respose similar in intensity and time course to orbicularis oculiintensity and time course to orbicularis oculi

Clinical signs antagonism differentClinical signs antagonism different Ability flex arm, lift leg, and return of abdominal Ability flex arm, lift leg, and return of abdominal

muscle tonemuscle tone Requirement neostigmine lower in childrenRequirement neostigmine lower in children

With twitch response present, 20mcg/kg With twitch response present, 20mcg/kg neostigmine and 5mcg/kg glycopyrrolateneostigmine and 5mcg/kg glycopyrrolate

Factors which affect Kinetic Factors which affect Kinetic and dynamics of relaxantsand dynamics of relaxants

Major organ failureMajor organ failure Up regulation Ach receptorsUp regulation Ach receptors Poor nutritionPoor nutrition Electrolyte/acid-base Electrolyte/acid-base

abnormalitiesabnormalities HypothermiaHypothermia Muscle atrophyMuscle atrophy

Neuromuscular JunctionNeuromuscular Junction

Incompletely developed at birthIncompletely developed at birth Conduction velocity of motor nerves Conduction velocity of motor nerves

increase throughout gestation as nerve increase throughout gestation as nerve fibers are myelinatedfibers are myelinated

Increase number of slow twitch fibers by 6 Increase number of slow twitch fibers by 6 momo

Diaphragm and intercostal muscles Diaphragm and intercostal muscles increase percentage of slow muscle fibers increase percentage of slow muscle fibers in 1in 1stst month of life month of life

Infants < 2mo have lower TOF ratios as Infants < 2mo have lower TOF ratios as well as increased fadewell as increased fade Rate of Ach released during repeated nerve Rate of Ach released during repeated nerve

stimulation is limited in infantsstimulation is limited in infants

Ach ReceptorAch Receptor

AdultAdult epsilon subunitepsilon subunit Agonists depolarize less easilyAgonists depolarize less easily Competitive agents block more easilyCompetitive agents block more easily

Fetal Fetal gamma subunitgamma subunit Agonists depolarize more easilyAgonists depolarize more easily Competitive agents block less easilyCompetitive agents block less easily

Depolarizing Muscle RelaxantDepolarizing Muscle Relaxant

SuccinylcholineSuccinylcholine Only depolarizing relaxant in useOnly depolarizing relaxant in use Effective dose that cause 95% Effective dose that cause 95%

depression of twitch response depression of twitch response (ED(ED9595) decreases with age) decreases with age

Infants have larger ECF volumeInfants have larger ECF volume Birth- 45% (0.62mg/kg)Birth- 45% (0.62mg/kg) 2mo- 30% (0.73mg/kg)2mo- 30% (0.73mg/kg) 6yr- 20% (0.42mg/kg)6yr- 20% (0.42mg/kg) Adult- 16-18% (0.29mg/kg)Adult- 16-18% (0.29mg/kg)

SuccinylcholineSuccinylcholine

Repeated administration and Repeated administration and continuous infusion results in continuous infusion results in tachyphylaxistachyphylaxis Phase II block (TOF<50%)Phase II block (TOF<50%)

Effective when given intramuscularlyEffective when given intramuscularly Short duration of action due to rapid Short duration of action due to rapid

hydrolysis by plasma cholinesterase hydrolysis by plasma cholinesterase (butyrylcholinesterase)(butyrylcholinesterase) Synthesized by liverSynthesized by liver Hydrolyzes several other compounds Hydrolyzes several other compounds

Cocaine, chloroprocaine, remifentanil, Cocaine, chloroprocaine, remifentanil, esmolol, mivacuriumesmolol, mivacurium

Succinylcholine ConcernsSuccinylcholine Concerns

Decreased plasma Decreased plasma cholinesterase activity cholinesterase activity Little change in activity between Little change in activity between

3mo and 12yr age3mo and 12yr age Plasma Cholinesterase Plasma Cholinesterase

deficiencydeficiency Heterozygous occurs ~4% Heterozygous occurs ~4% Homozygous 1:2000-3200Homozygous 1:2000-3200

Succinylcholine Side EffectsSuccinylcholine Side Effects Jaw stiffnessJaw stiffness

Increased masseter muscle toneIncreased masseter muscle tone ? Association between increased masseter tone and trismus in pt ? Association between increased masseter tone and trismus in pt

with MHwith MH ArrhythmiasArrhythmias

Mild, transient increase HRMild, transient increase HR Bradycardia- vagal in origin, prior atropine decreases incidenceBradycardia- vagal in origin, prior atropine decreases incidence

HyperkalemiaHyperkalemia Small change in normal children (clinically insignificant)Small change in normal children (clinically insignificant) Life-threatening arrhythmia in burn injury, paraplegia, encephalitis, or Life-threatening arrhythmia in burn injury, paraplegia, encephalitis, or

neuromuscular disease(Duchenne or Becker muscular dystrophy)neuromuscular disease(Duchenne or Becker muscular dystrophy) rhabdomyolysisrhabdomyolysis

MyalgiasMyalgias Increase in serum creatine kinase especially in patients with Increase in serum creatine kinase especially in patients with

neuromuscular diseaseneuromuscular disease Myoglobinemia to myoglobinuriaMyoglobinemia to myoglobinuria

Increased Intraocular pressureIncreased Intraocular pressure Mechanism unclear-?contracture of extraocular muscle vs. Mechanism unclear-?contracture of extraocular muscle vs.

cycloplegic action of sch –outflow resistance of aqueous humorcycloplegic action of sch –outflow resistance of aqueous humor Malignant HyperthermiaMalignant Hyperthermia

SuccinylcholineSuccinylcholine

Routine use declined due to rare Routine use declined due to rare life-threatening complications life-threatening complications with MH and cardiac arrest in with MH and cardiac arrest in patients with undiagnosed patients with undiagnosed muscular dystrophy (1993)muscular dystrophy (1993)

Gold standard for most rapid Gold standard for most rapid onset and brief duration of onset and brief duration of action of all muscle relaxantsaction of all muscle relaxants

Short-Acting RelaxantShort-Acting Relaxant MivacuriumMivacurium

BenzylisoquinoliniumBenzylisoquinolinium Potential for histamine releasePotential for histamine release

Flushing, rarely hypotensionFlushing, rarely hypotension

Rapidly hydrolyzed by plasma Rapidly hydrolyzed by plasma cholinesterasecholinesterase

Rare prolonged neuromuscular blockade in Rare prolonged neuromuscular blockade in pt with plasma cholinesterase deficiencypt with plasma cholinesterase deficiency

heterozygous (15-20min duration)heterozygous (15-20min duration) homozygous (considerable)- reversal homozygous (considerable)- reversal

considered with evidence of muscle activity considered with evidence of muscle activity

0.3mg/kg provides intubating condition 0.3mg/kg provides intubating condition in 1.3 minutesin 1.3 minutes

Intermediate-Acting RelaxantsIntermediate-Acting Relaxants AtracuriumAtracurium

Imidazole compoundImidazole compound EDED9595 0.1-0.17mg/kg 0.1-0.17mg/kg

Intubating dose two to three times Intubating dose two to three times provide intubating conditions w/i provide intubating conditions w/i 2min- complete recovery w/i 40 to 60 2min- complete recovery w/i 40 to 60 minmin

Spontaneous decompositionSpontaneous decomposition By nonspecific esterasesBy nonspecific esterases Nonenzymatic hydrolysis (Hofmann Nonenzymatic hydrolysis (Hofmann

elimination)elimination) Inactive metabolites (laudanosine)Inactive metabolites (laudanosine)

AtracuriumAtracurium

Plasma laudanosine Plasma laudanosine concentrations tend to be higher concentrations tend to be higher in children with hepatic in children with hepatic impairmentimpairment CNS effectsCNS effects

Side effects consist of flushing, Side effects consist of flushing, anaphylactoid reactions or anaphylactoid reactions or bronchospasmbronchospasm

CisatracuriumCisatracurium One of ten stereoisomers of atracuriumOne of ten stereoisomers of atracurium 3x more potent than atracurium3x more potent than atracurium

Slower onset (lower dosage)Slower onset (lower dosage) Hofmann degradationHofmann degradation Histamine release minimal even at 5X Histamine release minimal even at 5X

EDED9595

Lower plasma laudanosine level than Lower plasma laudanosine level than atracuriumatracurium

Duration of action in renal failure Duration of action in renal failure patients not significantly prolonged patients not significantly prolonged

VecuroniumVecuronium Quaternary ammonium steroidal Quaternary ammonium steroidal

compoundcompound Absence adverse cardiovascular effects Absence adverse cardiovascular effects

even in high doseseven in high doses Metabolized by the liver and excreted in Metabolized by the liver and excreted in

bilebile Biphasic distribution of dose requirement Biphasic distribution of dose requirement

and duration of actionand duration of action Infants <1yr age significantly more Infants <1yr age significantly more

sensitive than older childrensensitive than older children Infant larger VInfant larger VDD – lower plasma – lower plasma

concentrationconcentration Residual weakness after discontinuation of Residual weakness after discontinuation of

long-term administration in patients with long-term administration in patients with renal impairmentrenal impairment

RocuroniumRocuronium Mono quaternary steroidal compoundMono quaternary steroidal compound Low potency- therefore higher dose requirement Low potency- therefore higher dose requirement

and faster onsetand faster onset Primarily eliminated by the liver and the kidney Primarily eliminated by the liver and the kidney

excretes ~10%excretes ~10% EDED9595 0.18-0.3mg/kg 0.18-0.3mg/kg 0.6mg/kg produce 90-100% neuromuscular block in 0.6mg/kg produce 90-100% neuromuscular block in

0.8-1.3min0.8-1.3min Mean recovery 25%- 28min, 90%-46minMean recovery 25%- 28min, 90%-46min Similar speed of onset in infants vs succinylcholineSimilar speed of onset in infants vs succinylcholine

1.2mg/kg provided intubating conditions similar 1.2mg/kg provided intubating conditions similar to 1.5-2mg/kg succinylcholine w/I 30 sec.to 1.5-2mg/kg succinylcholine w/I 30 sec.

Time to recovery 25% twitch response ~40-Time to recovery 25% twitch response ~40-75min75min

Peak effect at laryngeal adductor occur faster than Peak effect at laryngeal adductor occur faster than on the adductor pollicison the adductor pollicis

RocuroniumRocuronium

Infants clear rocuronium slower Infants clear rocuronium slower than childrenthan children

Infant larger VInfant larger VDD

Renal failure clearance is Renal failure clearance is decreased by 30 to 40%decreased by 30 to 40% Increased duration of action in Increased duration of action in

patient with hepatorenal diseasepatient with hepatorenal disease

Long-Acting RelaxantsLong-Acting Relaxants PancuroniumPancuronium Bisquaternary ammonium steroidal compoundBisquaternary ammonium steroidal compound Induces tachycardia (increase CO)-vagolyticInduces tachycardia (increase CO)-vagolytic

Increase systolic blood pressureIncrease systolic blood pressure Advocated for various cardiac surgical Advocated for various cardiac surgical

proceduresprocedures Vagolytic properties blunt vagotonic properties of Vagolytic properties blunt vagotonic properties of

narcoticsnarcotics No histamine releaseNo histamine release In neonate (NICU)In neonate (NICU)

Increase HR, BP, plasma Epi, NE levelsIncrease HR, BP, plasma Epi, NE levels ? Concern cerebral hemorrhage b/c increased ? Concern cerebral hemorrhage b/c increased

BP, increase CBF w/ less autoregulationBP, increase CBF w/ less autoregulation

DoxacuriumDoxacurium

BenzylisoquinoliniumBenzylisoquinolinium EDED9595 30mcg/kg 30mcg/kg Duration of action similar Duration of action similar

pancuroniumpancuronium No side effect at doses up to 3x EDNo side effect at doses up to 3x ED9595

Long term administration may lead to Long term administration may lead to residual weakness, decreased residual weakness, decreased coordination for several days to coordination for several days to weeksweeks

PipecuroniumPipecuronium

Steroidal compoundSteroidal compound Analog of pancuroniumAnalog of pancuronium

No cardiovascular side effectsNo cardiovascular side effects Duration similar pancuroniumDuration similar pancuronium

EDED9595 80mcg/kg children, 80mcg/kg children, 60mcg/kg adult60mcg/kg adult

Excreted by kidneysExcreted by kidneys Infants require less and recover Infants require less and recover

more quicklymore quickly

SummarySummary

Physiologic considerations Physiologic considerations based on age, weight, and based on age, weight, and underlying illnessunderlying illness

Pharmacodynamic differencesPharmacodynamic differences Pharmacokinetic differencesPharmacokinetic differences

Onset time, duration, side effects Onset time, duration, side effects Hypotension, hypothermia, Hypotension, hypothermia,

acidosis, hypoclacemiaacidosis, hypoclacemia Surgical procedureSurgical procedure