Muscle Relaxants in Children Chan Saysana, M.D. Indiana University Department of Anesthesia Section of Pediatric Anesthesia and Critical Care

Neuromuscular Blockers Facilitate endotracheal intubation Provide surgical relaxation Facilitate controlled mechanical ventilation (both OR and ICU) Decrease metabolic demand Prevent shivering Improve chest wall compliance

NMB in children Growth and development NM junction Age-related pharmacologic characteristics of NMB agents Change in dose-response relationship Duration of neuromuscular blockade

NMB in children NM junction mature physically and biochemically Contractile properties of skeletal muscle change Amount of muscle in proportion to body weight increases as age Change in apparent Vd Change in redistribution/ excretion Change in rate metabolism

Neuromuscular blockade in children Immaturity of neuromuscular system Ach receptor change in function and distribution Lower values of TOF, post-tetanic facilitation, and marked fade during prolonged tetanic stimulation Longer elimination half-life of relaxants General VD for most relaxants is about the same size as the ECF volume (larger in infants than in older children or adults)on weight basis ED95 proportional to Vd/and concentration of blocker at effector site Presence of greater number of fast muscles in ventilatory musculature More liable for fatigue Slow twitch fibers increase several fold in first 6 mo Closing volume w/i tidal volume Airway closure occurs at end expiration Aggravate hypoxemia/acidosis-potentiate relaxant

Neuromuscular blockade in children Higher doses are required to block diaphragm vs. adductor pollicis If TOF of adductor is near normal, then can assume diaphragm is fully recovered Laryngeal adductors are less sensitive than adductor pollicis to NDNMB, respose similar in intensity and time course to orbicularis oculi Clinical signs antagonism different Ability flex arm, lift leg, and return of abdominal muscle tone Requirement neostigmine lower in children With twitch response present, 20mcg/kg neostigmine and 5mcg/kg glycopyrrolate

Factors which affect Kinetic and dynamics of relaxants Major organ failure Up regulation Ach receptors Poor nutrition Electrolyte/acid-base abnormalities Hypothermia Muscle atrophy

Neuromuscular Junction Incompletely developed at birth Conduction velocity of motor nerves increase throughout gestation as nerve fibers are myelinated Increase number of slow twitch fibers by 6 mo Diaphragm and intercostal muscles increase percentage of slow muscle fibers in 1st month of life Infants < 2mo have lower TOF ratios as well as increased fade Rate of Ach released during repeated nerve stimulation is limited in infants

Ach Receptor Adult Fetal epsilon subunit Agonists depolarize less easily Competitive agents block more easily Fetal gamma subunit Agonists depolarize more easily Competitive agents block less easily

Depolarizing Muscle Relaxant Succinylcholine Only depolarizing relaxant in use Effective dose that cause 95% depression of twitch response (ED95) decreases with age Infants have larger ECF volume Birth- 45% (0.62mg/kg) 2mo- 30% (0.73mg/kg) 6yr- 20% (0.42mg/kg) Adult- 16-18% (0.29mg/kg)

Succinylcholine Repeated administration and continuous infusion results in tachyphylaxis Phase II block (TOF<50%) Effective when given intramuscularly Short duration of action due to rapid hydrolysis by plasma cholinesterase (butyrylcholinesterase) Synthesized by liver Hydrolyzes several other compounds Cocaine, chloroprocaine, remifentanil, esmolol, mivacurium

Succinylcholine Concerns Decreased plasma cholinesterase activity Little change in activity between 3mo and 12yr age Plasma Cholinesterase deficiency Heterozygous occurs ~4% Homozygous 1:2000-3200

Succinylcholine Side Effects Jaw stiffness Increased masseter muscle tone ? Association between increased masseter tone and trismus in pt with MH Arrhythmias Mild, transient increase HR Bradycardia- vagal in origin, prior atropine decreases incidence Hyperkalemia Small change in normal children (clinically insignificant) Life-threatening arrhythmia in burn injury, paraplegia, encephalitis, or neuromuscular disease(Duchenne or Becker muscular dystrophy) rhabdomyolysis Myalgias Increase in serum creatine kinase especially in patients with neuromuscular disease Myoglobinemia to myoglobinuria Increased Intraocular pressure Mechanism unclear-?contracture of extraocular muscle vs. cycloplegic action of sch –outflow resistance of aqueous humor Malignant Hyperthermia

Succinylcholine Routine use declined due to rare life-threatening complications with MH and cardiac arrest in patients with undiagnosed muscular dystrophy (1993) Gold standard for most rapid onset and brief duration of action of all muscle relaxants

Short-Acting Relaxant Mivacurium Benzylisoquinolinium Potential for histamine release Flushing, rarely hypotension Rapidly hydrolyzed by plasma cholinesterase Rare prolonged neuromuscular blockade in pt with plasma cholinesterase deficiency heterozygous (15-20min duration) homozygous (considerable)- reversal considered with evidence of muscle activity 0.3mg/kg provides intubating condition in 1.3 minutes

Intermediate-Acting Relaxants Atracurium Imidazole compound ED95 0.1-0.17mg/kg Intubating dose two to three times provide intubating conditions w/i 2min- complete recovery w/i 40 to 60 min Spontaneous decomposition By nonspecific esterases Nonenzymatic hydrolysis (Hofmann elimination) Inactive metabolites (laudanosine)

Atracurium Plasma laudanosine concentrations tend to be higher in children with hepatic impairment CNS effects Side effects consist of flushing, anaphylactoid reactions or bronchospasm

Cisatracurium One of ten stereoisomers of atracurium 3x more potent than atracurium Slower onset (lower dosage) Hofmann degradation Histamine release minimal even at 5X ED95 Lower plasma laudanosine level than atracurium Duration of action in renal failure patients not significantly prolonged

Vecuronium Quaternary ammonium steroidal compound Absence adverse cardiovascular effects even in high doses Metabolized by the liver and excreted in bile Biphasic distribution of dose requirement and duration of action Infants <1yr age significantly more sensitive than older children Infant larger VD – lower plasma concentration Residual weakness after discontinuation of long-term administration in patients with renal impairment

Rocuronium Mono quaternary steroidal compound Low potency- therefore higher dose requirement and faster onset Primarily eliminated by the liver and the kidney excretes ~10% ED95 0.18-0.3mg/kg 0.6mg/kg produce 90-100% neuromuscular block in 0.8-1.3min Mean recovery 25%- 28min, 90%-46min Similar speed of onset in infants vs succinylcholine 1.2mg/kg provided intubating conditions similar to 1.5-2mg/kg succinylcholine w/I 30 sec. Time to recovery 25% twitch response ~40-75min Peak effect at laryngeal adductor occur faster than on the adductor pollicis

Rocuronium Infants clear rocuronium slower than children Infant larger VD Renal failure clearance is decreased by 30 to 40% Increased duration of action in patient with hepatorenal disease

Long-Acting Relaxants Pancuronium Bisquaternary ammonium steroidal compound Induces tachycardia (increase CO)-vagolytic Increase systolic blood pressure Advocated for various cardiac surgical procedures Vagolytic properties blunt vagotonic properties of narcotics No histamine release In neonate (NICU) Increase HR, BP, plasma Epi, NE levels ? Concern cerebral hemorrhage b/c increased BP, increase CBF w/ less autoregulation

Doxacurium Benzylisoquinolinium ED95 30mcg/kg Duration of action similar pancuronium No side effect at doses up to 3x ED95 Long term administration may lead to residual weakness, decreased coordination for several days to weeks

Pipecuronium Steroidal compound Analog of pancuronium No cardiovascular side effects Duration similar pancuronium ED95 80mcg/kg children, 60mcg/kg adult Excreted by kidneys Infants require less and recover more quickly

Summary Physiologic considerations based on age, weight, and underlying illness Pharmacodynamic differences Pharmacokinetic differences Onset time, duration, side effects Hypotension, hypothermia, acidosis, hypoclacemia Surgical procedure