Muscle Relaxants in Infants and Children- How They Differ From Adults?

Mohamed Naguib, MDDepartment of Anesthesia

College of MedicineUniversity of Iowa

Structural and functional development of NMJ Postnatal maturation of NMJ Pharmacokinetic considerations Succinylcholine in pediatric anesthesia Nondepolarizing neuromuscular blocking

drugs in pediatric anesthesia

1. Starts at 8 weeks of gestation 2. Myoblasts arise from the somite, motor axons from somata

in the neural tube, and Schwann cells from the neural crest3. All three cells travel to meet at the NMJ

1. Myoblasts fuse to form myotubes

2. Myotubes are approached by motor axons

3. Followed by Schwann cells

Initial contacts are unspecialized, yet capable of rudimentary transmission

After encountering the muscle surface the motor axon:

1. stops its growth 2. begins its characteristic differentiation

into a presynaptic terminal3. inducing formation of a motor endplate

on the muscle surface

Formation of the NMJ depends on a series of reciprocal inductive interactions between the motor neuron and the muscle cell

MuSK = muscle-specific kinaseMASC = MuSK-accessory specificity componentARIA = AChR-inducing activity

Animals lacking either agrin or MuSK no NMJs:

1. Generally immobile2. Unable to breathe3. Die at birth

NMJ

123

Note stands of basal lamina stretching betweenthe nerve terminal and postsynaptic membranes -rich in AChE

Subsynapticnuclei expressa unique set of genes

50 nm

EM Analysis of nAChRSynapse

Cytoplasm

43K

Changes in AChR properties during development

Age Turnover SubunitsPre-innervation

< 14 days I.U.

Fast

NMJ 16 days I.U. Fast

birth Slow

2 weeks-adult

Slow

Denervated extrajunctional

Fast

Structural and Functional Development

Type I fibers: slow, high oxidative “Marathon-fibers”More sensitive to NDMRsIn the diaphragm, it constitutes:

14% in premature26% in full-term neonates55% in adults

The diaphragm is more active than the peripheral muscles during NM block in neonates

Structural and Functional Development

In neonates• NM transmission is immature until the age of

2 months• Response to tetanic stimulation and the rate

of muscle contraction < older children• Greater individual variability to MRs

Body Composition During Growth

In neonates:

• Total body water, ECF volume, and blood volume are relatively larger on a weight basis than they are in older patients

• Muscle mass is smaller

• MRs are distributed to a volume that mirrors ECF compartment

Body Composition During Growth

Premature Full Term AdultTBW (% body wt)

83 73 60

ECF (% body wt)

62 44 20

Blood Vol (ml/kg) 60 85-105 70

ICW (% body wt)

25 33 40

Muscle Mass (% body wt)

15 20 50

Fat (% body wt) 3 12 15

Some NDMRs and/or their metabolites are excreted in the urine, or in the bile

1. Neonatal hepatic enzyme systems are incompletely developed or absent

2. The ability to oxidize or reduce drugs is deficient in neonates, but increase to adult levels within a few days of life

3. Conjugative processes are severely limited at birth but mature by 3 months of age

4. The ability to hydrolyze substrates is as effective as in adults

Succinylcholine

In November 1994, FDA mandated the change in the Sch package insert. To quote:

“ Except when used for emergency tracheal intubation or in instances where immediate securing of the airway is necessary, Sch is contraindicated in children and adolescent patients”

Succinylcholine In March 1995, the relative contraindication has

been replaced with a boxed warning

Warning

Risk of Cardiac Arrest From Hyperkalemic Rhabdomyolysis

Sch and Hyperkalemic Cardiac Arrest

A healthy appearing infant or child < 9 yr Undiagnosed myopathy (Duchenne’s

Dystrophy) Peaked T waves, ventricular dysrhythmias Cardiac arrest and death

Sch and Hyperkalemic Cardiac Arrest

Management Routine resuscitation measures are likely to

be unsuccessful I.V. calcium, insulin and glucose,

bicarbonate, with hyperventilation

Sch and Incomplete Jaw Relaxation

This phenomenon has been described in children who were anesthetized with halothane and paralyzed with Sch

It has also been called ‘masseter muscle rigidity’ (MMR), ‘masseter spasm’, or ‘trismus’

MMR or masseter spasm may be regarded as an early sign of MH

Sch and Incomplete Jaw Relaxation

Most existing studies are retrospective and lack agreement on the magnitude and incidence of this phenomenon

The reports suggested that the incidence of MMR in children receiving succinylcholine is 1%

Other studies report a 50% association between MMR and susceptibility to malignant hyperthermia

Sch and Incomplete Jaw Relaxation

This means that either the susceptibility to MH is much greater than is generally believed, or the diagnosis of “masseter spasm” was incorrectly made in normal patients

Sch and Incomplete Jaw Relaxation

It is probable that the high incidence of MMR reported by some investigators was the result of inadequate doses of succinylcholine administered to children

In the most recent prospective study, the incidence of MMR was reported to be 0.2%

Anesthesiology 1994; 81:99-103

Succinylcholine

When dosage is calculated on a weight basis: infants > children > adults

No difference when Sch is given on a surface area basis (40 mg/m2)

Phase II block may develop (? Dose)

Succinylcholine

PCHE conc. in neonates are about the half those of the adults

Fasciculations are rarely seen in neonates The intensity of the NM block after Sch is

increasing throughout childhood

NDMRs

Increased sensitivity in neonates and infants and relative resistance in children due to changes in drug distribution and muscle mass in these age groups

NDMRs The fat compartment

increases by 2-3 times during the first year of life

diminishes towards puberty The muscle compartment

decreases during the first year of life increases 2-3 times by the end of

active growth phase

NDMRs

Adults have more fat and less muscle tissue than children

When we give a MR on a body weight basis, the greatest dose may be needed by children (they have the least fat and the most muscle tissue compared with other age groups)

Conclusions

Developmental changes occur in the human NM junction for a least several months after birth

Onset of paralysis is more rapid in infants > children > adults

Recovery is dependent on the characteristics of NM blocker used

Our knowledge can only be finite,

while our ignorance

must necessarily be infinite

Proceedings of the British Academy 1960, 46:69