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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