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Pharmacokinetic/Pharmacodynamic Modeling of Anesthetics in Children

Therapeutic Implications

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Abstract

Modeling the pharmacokinetics and pharmacodynamics of anesthetics in children is performed as a response to the clinical need for safe and efficacious administration of drugs with a low therapeutic index. Rates and concentrations of these drugs, which are the primary parameters used by anesthesiologists, depend on physiologic parameters that are markedly affected by development.

Volatile anesthetics have been used for >50 years in pediatric patients. The pharmacokinetics of inhalation agents are context sensitive, but little difference between age groups has been described. These agents are not only eliminated unchanged by the lung but they are also metabolized by the liver. Halothane has Michaelis-Menten kinetics, with up to 40% of the administered dose metabolized by the liver. For volatile anesthetics, the effect measured is the minimum alveolar concentration (MAC) that leads to movement of the limb in response to skin incision in 50% of the patients studied. The MAC is higher in infants than in children and adults. Infants aged 6 months have a MAC 1.5–1.8 times the MAC observed in adults aged 40 years.

Children have a greater clearance and volume of distribution of propofol than adults. In order to achieve similar plasma concentrations, children require three times the initial dose used in adults. In adults, an increased sensitivity to propofol has been demonstrated with aging, but nothing is known about the effects in children. However, it is clear that equipotent doses of propofol induce marked deleterious hemodynamic effects in infants compared with children.

Regional anesthesia is used in pediatrics, both in combination with general anesthesia during surgery or alone for postoperative analgesia. A marked decrease in protein binding has been described in infants. In the postoperative period, a rapid increase in binding because of inflammation decreases the free fraction, but the free drug concentration remains constant because of the resulting decrease in total clearance. A low clearance because of liver function immaturity has been observed during the first year(s) of life for bupivacaine and ropivacaine.

Pharmacodynamic interactions between general anesthesia and regional anesthesia need to be modeled. This is one of the future tasks for pharmacokineticists. Methods such as the Dixon up-and-down allocation and the isobolographic technique are promising in this field.

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References

  1. Verotta D, Sheiner LB. Semiparametric analysis of non-steady-state pharmacodynamic data. J Pharmacokinet Biopharm 1991; 19: 691–712

    PubMed  CAS  Google Scholar 

  2. Bailey JM. Context-sensitive half-times: what are they and how valuable are they in anaesthesiology? Clin Pharmacokinet 2002; 41: 793–9

    Article  PubMed  Google Scholar 

  3. Anderson BJ, McKee AD, Holford NH. Size, myths and the clinical pharmacokinetics of analgesia in paediatric patients. Clin Pharmacokinet 1997; 33: 313–27

    Article  PubMed  CAS  Google Scholar 

  4. West GB, Woodruff WH, Brown JH. Allometric scaling of metabolic rate from molecules and mitochondria to cells and mammals. Proc Natl Acad Sci U S A 2002; 99Suppl. 1: 2473–8

    Article  PubMed  Google Scholar 

  5. White CR, Seymour RS. Mammalian basal metabolic rate is proportional to body mass2/3. Proc Natl Acad Sci U S A 2003; 100: 4046–9

    Article  PubMed  CAS  Google Scholar 

  6. Brett CM. Cardiovascular physiology in pediatrics. In: Gregory GA, editor. Pediatric anesthesia. 2nd ed. New York: Churchill Livingstone, 1995: 30–1

    Google Scholar 

  7. Rolan PE. Plasma protein binding displacement interactions: why are they still regarded as clinically important? Br J Clin Pharmacol 1994; 37: 125–8

    Article  PubMed  CAS  Google Scholar 

  8. Benet LZ, Hoener BA. Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther 2002; 71: 115–21

    Article  PubMed  CAS  Google Scholar 

  9. Mazoit JX, Denson DD, Samii K. Pharmacokinetics of bupivacaine following caudal anesthesia in infants. Anesthesiology 1988; 68: 387–91

    Article  PubMed  CAS  Google Scholar 

  10. Booker PD, Taylor C, Saba G. Perioperative changes in α1-acid glycoprotein concentrations in infants undergoing major surgery. Br J Anaesth 1996; 76: 365–8

    Article  PubMed  CAS  Google Scholar 

  11. Dale O. The interaction of enflurane, halothane and the halothane metabolite trifluoroacetic acid with the binding of acidic drugs to human serum albumin: an in vitro study. Biochem Pharmacol 1986; 35: 557–61

    Article  PubMed  CAS  Google Scholar 

  12. Johansson JS, Zou H, Tanner JW. Bound volatile general anesthetics alter both local protein dynamics and global protein stability. Anesthesiology 1999; 90: 235–45

    Article  PubMed  CAS  Google Scholar 

  13. Burch PG, Stanski DR. Decreased protein binding and thiopental kinetics. Clin Pharmacol Ther 1982; 32: 212–7

    Article  PubMed  CAS  Google Scholar 

  14. Kingston HG, Kendrick A, Sommer KM, et al. Binding of thiopental in neonatal serum. Anesthesiology 1990; 72: 428–31

    Article  PubMed  CAS  Google Scholar 

  15. Mazoit JX, Samii K. Binding of propofol to blood components: implications for pharmacokinetics and for pharmacodynamics. Br J Clin Pharmacol 1999; 47: 35–42

    Article  PubMed  CAS  Google Scholar 

  16. Hines RN, McCarver DG. The ontogeny of human drug-metabolizing enzymes: phase I oxidative enzymes. J Pharmacol Exp Ther 2002; 300: 355–60

    Article  PubMed  CAS  Google Scholar 

  17. McCarver DG, Hines RN. The ontogeny of human drug-metabolizing enzymes: phase II conjugation enzymes and regulatory mechanisms. J Pharmacol Exp Ther 2002; 300: 361–6

    Article  PubMed  CAS  Google Scholar 

  18. de Wildt SN, Kearns GL, Leeder JS, et al. Cytochrome P450 3A: ontogeny and drug disposition. Clin Pharmacokinet 1999; 37: 485–505

    Article  PubMed  Google Scholar 

  19. Lejus C, Fautrel A, Malledant Y, et al. Inhibition of cytochrome P450 2E1 by propofol in human and porcine liver microsomes. Biochem Pharmacol 2002; 64: 1151–6

    Article  PubMed  CAS  Google Scholar 

  20. Lejus C, Le Roux C, Legendre E, et al. Fluoride excretion in children after sevoflurane anaesthesia. Br J Anaesth 2002; 89: 693–6

    Article  PubMed  CAS  Google Scholar 

  21. Sorbo S, Hudson RJ, Loomis JC. The pharmacokinetics of thiopental in pediatric surgical patients. Anesthesiology 1984; 61: 666–70

    Article  PubMed  CAS  Google Scholar 

  22. Paus T, Zijdenbos A, Worsley K, et al. Structural maturation of neural pathways in children and adolescents: in vivo study. Science 1999; 283: 1908–11

    Article  PubMed  CAS  Google Scholar 

  23. Wodey E, Pladys P, Copin C, et al. Comparative hemodynamic depression of sevoflurane versus halothane in infants: an echocardiographic study. Anesthesiology 1997; 87: 795–800

    Article  PubMed  CAS  Google Scholar 

  24. Carpenter RL, Eger II EI, Johnson BH, et al. Pharmacokinetics of inhaled anesthetics in humans: measurements during and after the simultaneous administration of enflurane, halothane, isoflurane, methoxyflurane, and nitrous oxide. Anesth Analg 1986; 65: 575–82

    Article  PubMed  CAS  Google Scholar 

  25. Bailey JM. Context-sensitive half-times and other decrement times of inhaled anesthetics. Anesth Analg 1997; 85: 681–6

    PubMed  CAS  Google Scholar 

  26. Yasuda N, Lockhart SH, Eger II EI, et al. Comparison of kinetics of sevoflurane and isoflurane in humans. Anesth Analg 1991; 72: 316–24

    Article  PubMed  CAS  Google Scholar 

  27. Yasuda N, Lockhart SH, Eger II EI, et al. Kinetics of desflurane, isoflurane, and halothane in humans. Anesthesiology 1991; 74: 489–98

    Article  PubMed  CAS  Google Scholar 

  28. Carpenter RL, Eger II EI, Johnson BH, et al. The extent of metabolism of inhaled anesthetics in humans. Anesthesiology 1986; 65: 201–5

    Article  PubMed  CAS  Google Scholar 

  29. Cahalan MK, Johnson BH, Eger II EI. Relationship of concentrations of halothane and enflurane to their metabolism and elimination in man. Anesthesiology 1981; 54: 3–8

    Article  PubMed  CAS  Google Scholar 

  30. Vermeulen PM, Kalkman CJ, Dirksen R, et al. Predictive performance of a physiological model for enflurane closed-circuit anaesthesia: effects of continuous cardiac output measurements and age-related solubility data. Br J Anaesth 2002; 88: 38–45

    Article  PubMed  CAS  Google Scholar 

  31. Hendrickx JF, Van Zundert AA, De Wolf AM. Sevoflurane pharmacokinetics: effect of cardiac output. Br J Anaesth 1998; 81: 495–501

    Article  PubMed  CAS  Google Scholar 

  32. Lerman J. Sevoflurane in pediatric anesthesia. Anesth Analg 1995; 81: S4–10

    Article  PubMed  CAS  Google Scholar 

  33. Brandom BW, Brandom RB, Cook DR. Uptake and distribution of halothane in infants: in vivo measurements and computer simulations. Anesth Analg 1983; 62: 404–10

    PubMed  CAS  Google Scholar 

  34. Gallagher TM, Black GW. Uptake of volatile anaesthetics in children. Anaesthesia 1985; 40: 1073–7

    Article  PubMed  CAS  Google Scholar 

  35. Lerman J, Sikich N, Kleinman S, et al. The pharmacology of sevoflurane in infants and children. Anesthesiology 1994; 80: 814–24

    Article  PubMed  CAS  Google Scholar 

  36. Eger II EI, Saidman LJ, Brandstater B. Minimum alveolar anesthetic concentration: a standard of anesthetic potency. Anesthesiology 1965; 26: 756–63

    Article  PubMed  Google Scholar 

  37. LeDez KM, Lerman J. The minimum alveolar concentration (MAC) of isoflurane in preterm neonates. Anesthesiology 1987; 67: 301–7

    Article  PubMed  CAS  Google Scholar 

  38. Mapleson WW. Effect of age on MAC in humans: a meta-analysis. Br J Anaesth 1996; 76: 179–85

    Article  PubMed  CAS  Google Scholar 

  39. Lerman J, Robinson S, Willis MM, et al. Anesthetic requirements for halothane in young children 0–1 month and 1–6 months of age. Anesthesiology 1983; 59: 421–4

    Article  PubMed  CAS  Google Scholar 

  40. Murray DJ, Mehta MP, Forbes RB, et al. Additive contribution of nitrous oxide to halothane MAC in infants and children. Anesth Analg 1990; 71: 120–4

    Article  PubMed  CAS  Google Scholar 

  41. Murray DJ, Mehta MP, Forbes RB. The additive contribution of nitrous oxide to isoflurane MAC in infants and children. Anesthesiology 1991; 75: 186–90

    Article  PubMed  CAS  Google Scholar 

  42. Liu M, Hu X, Liu J. The effect of hypothermia on isoflurane MAC in children. Anesthesiology 2001; 94: 429–32

    Article  PubMed  CAS  Google Scholar 

  43. Neelakanta G, Miller J. Minimum alveolar concentration of isoflurane for tracheal extubation in deeply anesthetized children. Anesthesiology 1994; 80: 811–3

    Article  PubMed  CAS  Google Scholar 

  44. Katoh T, Ikeda K. Minimum alveolar concentration of sevoflurane in children. Br J Anaesth 1992; 68: 139–41

    Article  PubMed  CAS  Google Scholar 

  45. Inomata S, Kihara S, Yaguchi Y, et al. Reduction in standard MAC and MAC for intubation after clonidine premedication in children. Br J Anaesth 2000; 85: 700–4

    Article  PubMed  CAS  Google Scholar 

  46. Inomata S, Suwa T, Toyooka H, et al. End-tidal sevoflurane concentration for tracheal extubation and skin incision in children. Anesth Analg 1998; 87: 1263–7

    PubMed  CAS  Google Scholar 

  47. Yaguchi Y, Inomata S, Kihara S, et al. The reduction in minimum alveolar concentration for tracheal extubation after clonidine premedication in children. Anesth Analg 2002; 94: 863–6

    Article  PubMed  CAS  Google Scholar 

  48. Katoh T, Kobayashi S, Suzuki A, et al. Fentanyl augments block of sympathetic responses to skin incision during sevoflurane anaesthesia in children. Br J Anaesth 2000; 84: 63–6

    Article  PubMed  CAS  Google Scholar 

  49. Taylor RH, Lerman J. Minimum alveolar concentration of desflurane and hemodynamic responses in neonates, infants, and children. Anesthesiology 1991; 75: 975–9

    Article  PubMed  CAS  Google Scholar 

  50. Cranfield KA, Bromley LM. Minimum alveolar concentration of desflurane for tracheal extubation in deeply anaesthetized, unpremedicated children. Br J Anaesth 1997; 78: 370–1

    Article  PubMed  CAS  Google Scholar 

  51. Olofsen E, Dahan A. The dynamic relationship between end-tidal sevoflurane and isoflurane concentrations and bispectral index and spectral edge frequency of the electroencephalogram. Anesthesiology 1999; 90: 1345–53

    Article  PubMed  CAS  Google Scholar 

  52. Ropcke H, Rehberg B, Koenen-Bergmann M, et al. Surgical stimulation shifts EEG concentration-response relationship of desflurane. Anesthesiology 2001; 94: 390–9

    Article  PubMed  CAS  Google Scholar 

  53. Denman WT, Swanson EL, Rosow D, et al. Pediatric evaluation of the bispectral index (BIS) monitor and correlation of BIS with end-tidal sevoflurane concentration in infants and children. Anesth Analg 2000; 90: 872–7

    Article  PubMed  CAS  Google Scholar 

  54. McCann ME, Bacsik J, Davidson A, et al. The correlation of bispectral index with endtidal sevoflurane concentration and haemodynamic parameters in preschoolers. Paediatr Anaesth 2002; 12: 519–25

    Article  PubMed  Google Scholar 

  55. Avram MJ, Krejcie TC, Henthorn TK. The relationship of age to the pharmacokinetics of early drug distribution: the concurrent disposition of thiopental and indocyanine green. Anesthesiology 1990; 72: 403–11

    Article  PubMed  CAS  Google Scholar 

  56. Stanski DR, Maitre PO. Population pharmacokinetics and pharmacodynamics of thiopental: the effect of age revisited. Anesthesiology 1990; 72: 412–22

    Article  PubMed  CAS  Google Scholar 

  57. Gentry WB, Krejcie TC, Henthorn TK, et al. Effect of infusion rate on thiopental dose-response relationships: assessment of a pharmacokinetic-pharmacodynamic model. Anesthesiology 1994; 81: 316–24

    Article  PubMed  CAS  Google Scholar 

  58. Shanks CA, Avram MJ, Krejcie TC, et al. A pharmacokinetic-pharmacodynamic model for quantal responses with thiopental. J Pharmacokinet Biopharm 1993; 21: 309–21

    PubMed  CAS  Google Scholar 

  59. Monrigal C, Premel-Cabic A, Turcant A, et al. Pharmacocinétique du thiopental chez la mère et le nouveau-né. Ann Fr Anesth Reanim 1986; 5: 565–9

    Article  PubMed  CAS  Google Scholar 

  60. Gaspari F, Marraro G, Penna GF, et al. Elimination kinetics of thiopentone in mothers and their newborn infants. Eur J Clin Pharmacol 1985; 28: 321–5

    Article  PubMed  CAS  Google Scholar 

  61. Westrin P, Jonmarker C, Werner O. Thiopental requirements for induction of anesthesia in neonates and in infants one to six months of age. Anesthesiology 1989; 71: 344–6

    Article  PubMed  CAS  Google Scholar 

  62. Jonmarker C, Westrin P, Larsson S, et al. Thiopental requirements for induction of anesthesia in children. Anesthesiology 1987; 67: 104–7

    Article  PubMed  CAS  Google Scholar 

  63. Turcant A, Delhumeau A, Premel-Cabic A, et al. Thiopental pharmacokinetics under conditions of long-term infusion. Anesthesiology 1985; 63: 50–4

    Article  PubMed  CAS  Google Scholar 

  64. Le Corre P, Malledant Y, Tanguy M, et al. Non linear disposition of thiopentone following long-term infusion. Eur J Drug Metab Pharmacokinet 1993; 18: 255–9

    Article  PubMed  Google Scholar 

  65. Russo H, Bressolle F, Duboin MP. Pharmacokinetics of high-dose thiopental in pediatric patients with increased intracranial pressure. Ther Drug Monit 1997; 19: 63–70

    Article  PubMed  CAS  Google Scholar 

  66. Schüttler J, Ihmsen H. Population pharmacokinetics of propofol: a multicenter study. Anesthesiology 2000; 92: 727–38

    Article  PubMed  Google Scholar 

  67. Murat I, Billard V, Vernois J, et al. Pharmacokinetics of propofol after a single dose in children aged 1–3 years with minor burns: comparison of three data analysis approaches. Anesthesiology 1996; 84: 526–32

    Article  PubMed  CAS  Google Scholar 

  68. Kataria BK, Ved SA, Nicodemus HF, et al. The pharmacokinetics of propofol in children using three different data analysis approaches. Anesthesiology 1994; 80: 104–22

    Article  PubMed  CAS  Google Scholar 

  69. Rigby-Jones AE, Nolan JA, Priston MJ, et al. Pharmacokinetics of propofol infusions in critically ill neonates, infants, and children in an intensive care unit. Anesthesiology 2002; 97: 1393–400

    Article  PubMed  CAS  Google Scholar 

  70. Bray RJ. Propofol-infusion syndrome in children. Lancet 1999; 353: 2074–5

    Article  PubMed  CAS  Google Scholar 

  71. Schnider TW, Minto CF, Shafer SL, et al. The influence of age on propofol pharmacodynamics. Anesthesiology 1999; 90: 1502–16

    Article  PubMed  CAS  Google Scholar 

  72. Westrin P. The induction dose of propofol in infants 1–6 months of age and in children 10–16 years of age. Anesthesiology 1991; 74: 455–8

    Article  PubMed  CAS  Google Scholar 

  73. Davidson JA, Macleod AD, Howie JC, et al. Effective concentration 50 for propofol with and without 67% nitrous oxide. Acta Anaesthesiol Scand 1993; 37: 458–64

    Article  PubMed  CAS  Google Scholar 

  74. Viviand X, Berdugo L, De La Noe CA, et al. Target concentration of propofol required to insert the laryngeal mask airway in children. Paediatr Anaesth 2003; 13: 217–22

    Article  PubMed  CAS  Google Scholar 

  75. Wodey E, Chonow L, Beneux X, et al. Haemodynamic effects of propofol vs thiopental in infants: an echocardiographic study. Br J Anaesth 1999; 82: 516–20

    Article  PubMed  CAS  Google Scholar 

  76. Burm AGL, Vermeulen NPE, Van Kleef JW, et al. Pharmacokinetics of lidocaine and bupivacaine in surgical patients following epidural administration: simultaneous investigation of absorption and disposition kinetics using stable isotopes. Clin Pharmacokinet 1987; 13: 191–203

    Article  PubMed  CAS  Google Scholar 

  77. Emanuelsson BM, Persson J, Alm C, et al. Systemic absorption and block after epidural injection of ropivacaine in healthy volunteers. Anesthesiology 1997; 87: 1309–17

    Article  PubMed  CAS  Google Scholar 

  78. Thompson AH, Elliot HL, Kelman AW, et al. The pharmacokinetics and pharmacodynamics of lignocaine and MEGX in healthy subjects. J Pharmacokinet Biopharm 1987; 15: 101–15

    Google Scholar 

  79. Mazoit JX, Lambert C, Berdeaux A, et al. Pharmacokinetics of bupivacaine after short and prolonged infusions in conscious dogs. Anesth Analg 1988; 67: 961–6

    Article  PubMed  CAS  Google Scholar 

  80. Karmakar MK, Aun CS, Wong EL, et al. Ropivacaine undergoes slower systemic absorption from the caudal epidural space in children than bupivacaine. Anesth Analg 2002; 94: 259–65

    PubMed  CAS  Google Scholar 

  81. Lönnqvist PA, Westrin P, Larsson BA, et al. Ropivacaine pharmacokinetics after caudal block in 1–8 year old children. Br J Anaesth 2000; 85: 506–11

    Article  PubMed  Google Scholar 

  82. Iida H, Watanabe Y, Dohi S, et al. Direct effects of ropivacaine and bupivacaine on spinal pial vessels in canine: assessment with closed spinal window technique. Anesthesiology 1997; 87: 75–81

    Article  PubMed  CAS  Google Scholar 

  83. Ecoffey C, Desparmet J, Berdeaux A, et al. Pharmacokinetics of lidocaine in children following caudal anaesthesia. Br J Anaesth 1984; 56: 1399–402

    Article  PubMed  CAS  Google Scholar 

  84. Meunier JF, Goujard E, Dubousset AM, et al. Pharmacokinetics of bupivacaine after continuous epidural infusion in infants with and without biliary atresia. Anesthesiology 2001; 95: 87–95

    Article  PubMed  CAS  Google Scholar 

  85. Hansen TG, Ilett KF, Reid C, et al. Caudal ropivacaine in infants: population pharmacokinetics and plasma concentrations. Anesthesiology 2001; 94: 579–84

    Article  PubMed  CAS  Google Scholar 

  86. McCann ME, Sethna NF, Mazoit JX, et al. The pharmacokinetics of epidural ropivacaine in infants and young children. Anesth Analg 2001; 93: 893–7

    Article  PubMed  CAS  Google Scholar 

  87. Deng XM, Xiao WJ, Tang GZ, et al. The minimum local anesthetic concentration of ropivacaine for caudal analgesia in children. Anesth Analg 2002; 94: 1465–8

    PubMed  CAS  Google Scholar 

  88. Bosenberg A, Thomas J, Lopez T, et al. The efficacy of caudal ropivacaine 1, 2 and 3mg−1 for postoperative analgesia in children. Paediatr Anaesth 2002; 12: 53–8

    Article  PubMed  CAS  Google Scholar 

  89. Mazoit JX, Dalens BJ. Ropivacaine in infants and children. Curr Opin Anaesthesiol 2003; 16: 305–7

    Article  PubMed  Google Scholar 

  90. SourceForge.net [online]. Available from URL: http://wfn.sourceforge.net/ [Accessed 2006 Apr 30]

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Acknowledgments

The author received funding from the French Ministry of Education and Research and the association MAPAR (Mise Au Point en Anesthésie Réanimation). MAPAR received funding from AstraZeneca and Abbott Laboratories.

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  1. Département d’Anesthésie-Réanimation, AP-HP; Université Paris-Sud, Hôpital Bicêtre, Le Kremlin-Bicêtre, F-94275, France

    Jean-Xavier Mazoit

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Mazoit, JX. Pharmacokinetic/Pharmacodynamic Modeling of Anesthetics in Children. Pediatr-Drugs 8, 139–150 (2006). https://doi.org/10.2165/00148581-200608030-00001

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