muscle relaxants in infants and children- how they differ from adults?
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Muscle Relaxants in Infants and Children- How They Differ From Adults?. Mohamed Naguib, MD Department of Anesthesia College of Medicine University of Iowa. Structural and functional development of NMJ Postnatal maturation of NMJ Pharmacokinetic considerations - PowerPoint PPT PresentationTRANSCRIPT
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