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

2. 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

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

4. 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

5. 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

6. 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

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

8. 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

9. 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

11. 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 % (0.29mg/kg)

12. 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

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

14. 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

15. 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

16. 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

17. Intermediate-Acting Relaxants
Atracurium
Imidazole compound
ED mg/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)

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

19. 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

20. 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

21. Rocuronium Mono quaternary steroidal compound
Low potency- therefore higher dose requirement and faster onset
Primarily eliminated by the liver and the kidney excretes ~10%
ED mg/kg
0.6mg/kg produce % neuromuscular block in min
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

22. 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

23. 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

24. 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

25. 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

26. 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