Muscle Relaxants in Children Chan Saysana M D

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 n Provide surgical relaxation n Facilitate controlled mechanical ventilation (both OR and ICU) n Decrease metabolic demand l Prevent shivering l Improve chest wall compliance l

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

NMB in children n n n 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 n Immaturity of neuromuscular system l l n n 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 l n ED 95 proportional to Vd/and concentration of blocker at effector site Presence of greater number of fast muscles in ventilatory musculature l l n Ach receptor change in function and distribution Lower values of TOF, post-tetanic facilitation, and marked fade during prolonged tetanic stimulation More liable for fatigue Slow twitch fibers increase several fold in first 6 mo Closing volume w/i tidal volume l l Airway closure occurs at end expiration Aggravate hypoxemia/acidosis-potentiate relaxant

Neuromuscular blockade in children n Higher doses are required to block diaphragm vs. adductor pollicis l l n Clinical signs antagonism different l n 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 Ability flex arm, lift leg, and return of abdominal muscle tone Requirement neostigmine lower in children l With twitch response present, 20 mcg/kg neostigmine and 5 mcg/kg glycopyrrolate

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

Neuromuscular Junction n n 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 1 st month of life Infants < 2 mo have lower TOF ratios as well as increased fade l Rate of Ach released during repeated nerve stimulation is limited in infants

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

Depolarizing Muscle Relaxant n Succinylcholine Only depolarizing relaxant in use l Effective dose that cause 95% depression of twitch response (ED 95) decreases with age l Infants have larger ECF volume l n Birth- 45% (0. 62 mg/kg) n 2 mo- 30% (0. 73 mg/kg) n 6 yr- 20% (0. 42 mg/kg) n Adult- 16 -18% (0. 29 mg/kg)

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

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

Succinylcholine Side Effects n Jaw stiffness l l n Arrhythmias l l n l l l Increase in serum creatine kinase especially in patients with neuromuscular disease Myoglobinemia to myoglobinuria Increased Intraocular pressure l n 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 l n Mild, transient increase HR Bradycardia- vagal in origin, prior atropine decreases incidence Hyperkalemia l n Increased masseter muscle tone ? Association between increased masseter tone and trismus in pt with MH 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) n Gold standard for most rapid onset and brief duration of action of all muscle relaxants n

Short-Acting Relaxant n Mivacurium l Benzylisoquinolinium n Potential for histamine release l l Rapidly hydrolyzed by plasma cholinesterase n Rare prolonged neuromuscular blockade in pt with plasma cholinesterase deficiency l l l Flushing, rarely hypotension heterozygous (15 -20 min duration) homozygous (considerable)- reversal considered with evidence of muscle activity 0. 3 mg/kg provides intubating condition in 1. 3 minutes

Intermediate-Acting Relaxants n Atracurium Imidazole compound l ED 95 0. 1 -0. 17 mg/kg l n Intubating dose two to three times provide intubating conditions w/i 2 min - complete recovery w/i 40 to 60 min l Spontaneous decomposition n By nonspecific esterases n Nonenzymatic hydrolysis (Hofmann elimination) n Inactive metabolites (laudanosine)

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

Cisatracurium n n One of ten stereoisomers of atracurium 3 x more potent than atracurium l n n Slower onset (lower dosage) Hofmann degradation Histamine release minimal even at 5 X ED 95 Lower plasma laudanosine level than atracurium Duration of action in renal failure patients not significantly prolonged

Vecuronium n n n 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 <1 yr age significantly more sensitive than older children l l Infant larger VD – lower plasma concentration Residual weakness after discontinuation of long-term administration in patients with renal impairment

Rocuronium n n n n Mono quaternary steroidal compound Low potency- therefore higher dose requirement and faster onset Primarily eliminated by the liver and the kidney excretes ~10% ED 95 0. 18 -0. 3 mg/kg 0. 6 mg/kg produce 90 -100% neuromuscular block in 0. 8 -1. 3 min Mean recovery 25%- 28 min, 90%-46 min Similar speed of onset in infants vs succinylcholine l 1. 2 mg/kg provided intubating conditions similar to 1. 5 -2 mg/kg succinylcholine w/I 30 sec. l Time to recovery 25% twitch response ~4075 min Peak effect at laryngeal adductor occur faster than on the adductor pollicis

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

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

Doxacurium n n n Benzylisoquinolinium ED 95 30 mcg/kg Duration of action similar pancuronium No side effect at doses up to 3 x ED 95 Long term administration may lead to residual weakness, decreased coordination for several days to weeks

Pipecuronium Steroidal compound n Analog of pancuronium n No cardiovascular side effects l Duration similar pancuronium l ED 95 80 mcg/kg children, 60 mcg/kg adult n Excreted by kidneys n Infants require less and recover more quickly n

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