1. Muscle Relaxants in Infants and Children- How They Differ From Adults? Mohamed Naguib, MD Department of Anesthesia College of Medicine University of Iowa

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

3. 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

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

5. Initial contacts are unspecialized, yet capable of rudimentary transmission

6. After encountering the muscle surface the motor axon: 1.stops its growth 2.begins its characteristic differentiation into a presynaptic terminal 3.inducing formation of a motor endplate on the muscle surface

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

8. MuSK = muscle-specific kinase MASC = MuSK-accessory specificity component ARIA = AChR-inducing activity

10.  Animals lacking either agrin or MuSK  no NMJs: 1.Generally immobile 2.Unable to breathe 3.Die at birth

11. NMJ 123123 Note stands of basal lamina stretching between the nerve terminal and postsynaptic membranes - rich in AChE Subsynaptic nuclei express a unique set of genes 50 nm

12. EM Analysis of nAChR Synapse Cytoplasm 43K

14. Changes in AChR properties during development AgeTurnoverSubunits Pre- innervation < 14 days I.U.Fast  NMJ 16 days I.U.Fast  birth Slow  2 weeks-adultSlow  Denervated extrajunctio nal Fast 

15. 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

16. 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

17. 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

18. Body Composition During Growth PrematureFull TermAdult TBW (% body wt)837360 ECF (% body wt) 62 4420 Blood Vol (ml/kg) 60 85-10570 ICW (% body wt)253340 Muscle Mass (% body wt) 152050 Fat (% body wt)31215

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

20. 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

21. 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”

22. Succinylcholine  In March 1995, the relative contraindication has been replaced with a boxed warning Warning Risk of Cardiac Arrest From Hyperkalemic Rhabdomyolysis

23. 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

24. Sch and Hyperkalemic Cardiac Arrest Management  Routine resuscitation measures are likely to be unsuccessful  I.V. calcium, insulin and glucose, bicarbonate, with hyperventilation

25. 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

26. 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

27. 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

28. 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

29. 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/m 2 )  Phase II block may develop (? Dose)

31. 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

32. 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

33. 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

34. 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)

39. 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

40. Our knowledge can only be finite, while our ignorance must necessarily be infinite Proceedings of the British Academy 1960, 46:69