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

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

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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 crest
3. All three cells travel to meet at the NMJ

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1. Myoblasts fuse to form myotubes
2. Myotubes are approached by motor axons
3. Followed by Schwann cells

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Initial contacts are unspecialized, yet
capable of rudimentary transmission
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• After encountering the muscle surface the
  motor axon
• stops its growth
• begins its characteristic differentiation into a
  presynaptic terminal
• inducing formation of a motor endplate on the
  muscle surface

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Formation of the NMJ depends on a series of
reciprocal inductive interactions between the
motor neuron and the muscle cell
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MuSK muscle-specific kinase MASC
MuSK-accessory specificity component ARIA
AChR-inducing activity
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• Animals lacking either agrin or MuSK ? no NMJs
• Generally immobile
• Unable to breathe
• Die at birth

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NMJ
1 2 3
50 nm
Subsynaptic nuclei express a unique set of genes
Note stands of basal lamina stretching
between the nerve terminal and postsynaptic
membranes - rich in AChE
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EM Analysis of nAChR
Synapse
43K
Cytoplasm
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Changes in AChR properties during development
Age Turnover Subunits
Pre-innervation lt 14 days I.U. Fast a, b, g, d
NMJ 16 days I.U. Fast a, b, g, d
birth Slow a, b, g, d
2 weeks-adult Slow a, b, d, e
Denervated extrajunctional Fast a b, g, d
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Structural and Functional Development

• Type I fibers slow, high oxidative
  Marathon-fibers
• More sensitive to NDMRs
• In the diaphragm, it constitutes
• 14 in premature
• 26 in full-term neonates
• 55 in adults
• The diaphragm is more active than the peripheral
  muscles during NM block in neonates

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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 lt older children
• Greater individual variability to MRs

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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

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Body Composition During Growth
Premature Full Term Adult
TBW ( 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
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• Some NDMRs and/or their metabolites are
  excreted in the urine, or in the bile

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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

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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

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Succinylcholine

• In March 1995, the relative contraindication has
  been replaced with a boxed warning

Warning Risk of Cardiac Arrest From Hyperkalemic Rhabdomyolysis
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Sch and Hyperkalemic Cardiac Arrest

• A healthy appearing infant or child lt 9 yr
• Undiagnosed myopathy (Duchennes Dystrophy)
• Peaked T waves, ventricular dysrhythmias
• Cardiac arrest and death

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Sch and Hyperkalemic Cardiac Arrest

• Management
• Routine resuscitation measures are likely to be
  unsuccessful
• I.V. calcium, insulin and glucose, bicarbonate,
  with hyperventilation

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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

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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

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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

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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 8199-103

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Succinylcholine

• When dosage is calculated on a weight basis
  infants gt children gt adults
• No difference when Sch is given on a surface area
  basis (40 mg/m2)
• Phase II block may develop (? Dose)

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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

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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

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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

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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)

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Conclusions

• Developmental changes occur in the human NM
  junction for a least several months after birth
• Onset of paralysis is more rapid in infants gt
  children gt adults
• Recovery is dependent on the characteristics of
  NM blocker used

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Our knowledge can only be finite, while our
ignorance must necessarily be infinite
Proceedings of the British Academy 1960, 4669