Clinical Pharmacokinetics

, Volume 35, Issue 1, pp 37–47 | Cite as

Clinical Pharmacology of Midazolam in Infants and Children

  • Jeffrey L. Blumer
Review Article Special Populations

Abstract

Midazolam is a parenteral benzodiazepine with sedative, amnesic, anxiolytic, muscle relaxant and anticonvulsant properties. The drug exerts its clinical effect by binding to a receptor complex which facilitates the action of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Midazolam has a faster onset and shorter duration of action than other benzodiazepines such as diazepam and lorazepam. The most serious adverse events associated with midazolam in children include hypoventilation, decreased oxygen saturation, apnoea and hypotension. It is water soluble in the commercially prepared formulation but becomes lipid soluble at physiological pH and can then cross the blood brain barrier. It is metabolised in the liver by the cytochrome P450 system, and its chief metabolite is 1-hydroxymethyl midazolam. The latter is conjugated to the glucuronide form, and it has only minimal biological activity. Midazolam is excreted primarily by the kidney. Its half-life in children over 12 months is reported to be 0.8 to 1.8 hours, with a clearance of 4.7 to 19.7 ml/min/kg. Doses given to children must be calculated on a mg/kg basis. For children 6 months to 5 years of age the initial dose is 0.05 to 0.1 mg/kg. A total dose up to 0.6 mg/kg titrated slowly may be necessary to achieve the desired endpoint. For children 6 to 12 years of age the initial dose is 0.025 to 0.05 mg/kg with a total dose up to 0.4 mg/kg to achieve the desired end-point.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Reves JG, Glass PS, Lubarsky DA. Nonbarbiturate intravenous anesthetics. In: Miller RD, editor. Anesthesia. 4th ed. New York: Churchill-Livingstone, 1994: 247–89.Google Scholar
  2. 2.
    Zorumski CF, Isenberg KE. Insights into the structure and function of GABA-benzodiazepine receptors: ion channels and psychiatry. Am J Psychiatry. 1991; 148: 162–73.PubMedGoogle Scholar
  3. 3.
    Kehlet H. Surgical stress: the role of pain and analgesia. Br J Anaesth. 1989; 63: 189–95.PubMedCrossRefGoogle Scholar
  4. 4.
    Kehlet H. The stress response to surgery: release mechanisms and the modifying effect of pain relief. Acta Chir Scand 1989; Suppl. 550: 22–8.Google Scholar
  5. 5.
    Ryder W, Wright PA. Dental sedation: a review. Br Dent J. 1988; 165: 207–16.PubMedCrossRefGoogle Scholar
  6. 6.
    Carrougher JG, Kadakia S, Shaffer RT, et al. Venous complications of midazolam versus diazepam. Gastrointest Endosc. 1993; 39: 396–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Ginsberg GG, Lewis JH, Gallagher JE, et al. Diazepam versus midazolam for colonoscopy: a prospective evaluation of predicted versus actual dosing requirements. Gastrointest Endosc. 1992; 38: 651–6.PubMedCrossRefGoogle Scholar
  8. 8.
    Bianchi Porro G, Baroni S, Parente F, et al. Midazolam versus diazepam as premedication for upper gastrointestinal endoscopy: a randomized, double-blind, crossover study. Gastrointest Endosc. 1988; 34: 252–4.PubMedCrossRefGoogle Scholar
  9. 9.
    Bardhan KD, Morris P, Taylor PC, et al. Intravenous sedation for upper gastrointestinal endoscopy: diazepam versus midazolam. BMJ. 1984; 288: 1046.PubMedCrossRefGoogle Scholar
  10. 10.
    Lloyd-Thomas AR, Booker PD. Infusion of midazolam in paediatric patients after cardiac surgery. Br J Anaesth. 1986; 58: 1109–15.PubMedCrossRefGoogle Scholar
  11. 11.
    Morselli PL, Principi N, Tognoni G, et al. Diazepam elimination in premature and full term infants, and children. J Perinat Med. 1973; 1: 133–41.PubMedCrossRefGoogle Scholar
  12. 12.
    Kanto JH. Midazolam: the first water-soluble benzodiazepine. Pharmacology, pharmacokinetics, and efficacy in insomnia and anesthesia. Pharmacotherapy. 1985; 5: 138–55.PubMedGoogle Scholar
  13. 13.
    Reves JG, Fragen RL, Vinik R, et al. Midazolam: pharmacology and uses. Anesthesiology. 1985; 62: 310–24.PubMedCrossRefGoogle Scholar
  14. 14.
    Booker PD, Beechey A, Lloyd-Thomas AR. Sedation for children requiring artificial ventilation using an infusion of midazolam. Br J Anaesth. 1986; 58: 1104–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Tolia V, Brennan S, Aravind MK, et al. Pharmacokinetic and pharmacodynamic study of midazolam in children during esophagogastroduodenoscopy. J Pediatr. 1991; 119: 467–71.PubMedCrossRefGoogle Scholar
  16. 16.
    Hartwig S, Roth B, Theisohn M. Clinical experience with continuous intravenous sedation using midazolam and fentanyl in the pediatric intensive care unit. Eur J Pediatr. 1991; 150: 784–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Versed Product Information. Nutley, New Jersey: Roche Laboratories, 1997.Google Scholar
  18. 18.
    McNabb AT, Levine M, Glick N, et al. Midazolam following open heart surgery in children: haemodynamic effects of a loading dose. Paediatr Anaesth. 1996; 6: 387–97.CrossRefGoogle Scholar
  19. 19.
    Kumar SP. Adverse drug reactions in the newborn. Ann Clin Lab Sci. 1985; 15: 195–203.PubMedGoogle Scholar
  20. 20.
    Baziel GM, Gimbriere JS, Booy LH. Benzodiazepine withdrawal reaction in two children following discontinuation of sedation with midazolam. Ann Pharmacother. 1993; 27: 579–81.Google Scholar
  21. 21.
    Bergman I, Steeves M, Buckart G, et al. Reversible neurologic abnormalities associated with prolonged intravenous midazolam and fetanyl administration. J Pediatr. 1991; 119: 644–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Hughes J, Gill A, Leach HJ, et al. A prospective study of the adverse effects of midazolam on withdrawal in critically ill children. Acta Paediatr. 1994; 83: 1194–99.PubMedCrossRefGoogle Scholar
  23. 23.
    Baziel GM, Gimbrere JS. Benzodiazepine withdrawal syndrome in two children following discontinuation of high dose midazolam [abstract]. Intensive Care Med. 1990; 16: 5119.Google Scholar
  24. 24.
    Garland DS, Dunne WM, Havens P, et al. Peripheral intravenous catheter complications in critically ill children: a prospective study. Pediatrics. 1992; 89: 1145–50.PubMedGoogle Scholar
  25. 25.
    Brown WJK, Buist NR, Gipson HT, et al. Fatal benzyl alcohol poisoning in a neonatal intensive care unit [letter]. Lancet. 1982; I: 1250.CrossRefGoogle Scholar
  26. 26.
    Kumar SP. Adverse drug reactions in the newborn. Ann Clin Lab Sci. 1985; 15: 195–203.PubMedGoogle Scholar
  27. 27.
    Gershank J, Boeder B, Ensley H, et al. The gasping syndrome and benzyl alcohol poisoning. N Engl J Med. 1982; 307: 1384–8.CrossRefGoogle Scholar
  28. 28.
    Kearns GL, Reed MD. Clinical pharmacokinetics in infants and children. A reappraisal. Clin Pharmacokinet. 1989; 17 Suppl. 1: 29–67.CrossRefGoogle Scholar
  29. 29.
    Burtin P, Jacqz-Aigrain E, Girard P. Population pharmacokinetics of midazolam in neonates. Clin Pharmacol Ther. 1994; 56: 615–25.PubMedCrossRefGoogle Scholar
  30. 30.
    Greenblatt DJ, Ehrenberg BL, Scavone JM, et al. Effect of infusion rate on the kinetic-dynamic relationship for intravenous midazolam [abstract]. Clin Pharmacol Ther. 1993; 53: 218.CrossRefGoogle Scholar
  31. 31.
    Klotz U, Reimann IW. Chronopharmacokinetic study with prolonged infusion of midazolam. Clin Pharmacokinet. 1984; 9: 469–74.PubMedCrossRefGoogle Scholar
  32. 32.
    Payne K, Matteyse FJ, Liebenberg D, et al. The pharmacokinetics of midazolam in paediatric patients. Eur J Clin Pharmacol. 1989; 37: 267–72.PubMedCrossRefGoogle Scholar
  33. 33.
    Wandel C, Böcker R Bönrer H, et al. Midazolam is metabolized by at least three different cytochrome P450 enzymes. Br J Anesth. 1994; 73: 658–61.CrossRefGoogle Scholar
  34. 34.
    Slaughter RL, Edwards DJ. Recent advances: the cytochrome P450 enzymes. Ann Pharmacother. 1995; 29: 619–24.PubMedGoogle Scholar
  35. 35.
    Schuetz JD, Beach DL, Guzelian PS. Selective expression of cytochrome P450 CYP3A mRNAs in embryonic and adult human liver. Pharmacogenetics. 1994; 4: 11–20.PubMedCrossRefGoogle Scholar
  36. 36.
    Zeigler WH, Schalch E, Leishman B, et al. Comparison of the effects of intravenously administered miazolam, triazolam, and their hydroxy metabolites. Br J Clin Pharmacol 1983; Suppl. 1: 63S–69S.CrossRefGoogle Scholar
  37. 37.
    Paine MF, Shen DD, Kinze KL, et al. First-pass metabolism of midazolam by the human intestine. Clin Pharmacol Ther 1996: 60(1): 14–24.PubMedCrossRefGoogle Scholar
  38. 38.
    Thummel KE, O’shea D, Paine MF, et al. Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism. Clin Pharmacol Ther. 1996; 59(5): 491–502.PubMedCrossRefGoogle Scholar
  39. 39.
    Arendt RM, Greenblatt DJ, Liebisch DC, et al. Determinants of benzodiazepine brain uptake: lipophilicity versus binding affinity. Psychopharmacology. 1987; 93: 72–6.PubMedCrossRefGoogle Scholar
  40. 40.
    Greenblatt DJ. Clinical pharmacokinetics of oxazepam and lorazepam. Clin Pharmacokinet. 1981; 6: 88–105.CrossRefGoogle Scholar
  41. 41.
    Jones RD, Visram AR, Chan MM, et al. Acomparison of three induction agents in paediatric anaesthesia — cardiovascular effects and recovery. Anaesth Intensive Care. 1994; 22: 545–55.PubMedGoogle Scholar
  42. 42.
    Rey E, Delaunay L, Pons G, et al. Pharmacokinetics of midazolam in children: comparative study of intranasal and intravenous administration. Eur J Clin Pharmacol. 1991; 41(4): 355–7.PubMedCrossRefGoogle Scholar
  43. 43.
    Jacqz-Aigrain E, Wood C, Robieux I. Pharmacokinetics of midazolam in critically ill neonates. Eur J Clin Pharmacol. 1990; 39(2): 191–2.PubMedCrossRefGoogle Scholar
  44. 44.
    Jacqz-Aigrain E, Daoud P, Burtin P, et al. Pharmacokinetics of midazolam during continuous infusion in critically ill neonates. Eur J Clin Pharmacol. 1992; 42(3): 329–32.PubMedCrossRefGoogle Scholar
  45. 45.
    Hughes J, Gill AM, Mulhearn H, et al. Steady-state plasma concentrations of midazolam in critically ill infants and children. Ann Pharmacother. 1996; 30: 27–30.PubMedGoogle Scholar
  46. 46.
    Patel IH, Soni PP, Fukuda EK, et al. The pharmacokinetics of midazolam in patients with congestive heart failure. Br J Clin Pharmacol. 1990; 29: 565–9.PubMedCrossRefGoogle Scholar
  47. 47.
    Pentikainen PJ, Valisalmi L, Himberg JJ, et al. Pharmacokinetics of midazolam following intravenous and oral administration in patients with chronic liver disease and in healthy subjects. J Clin Pharmacol. 1989; 29: 272–7.PubMedGoogle Scholar
  48. 48.
    Trouvin JH, Farinotti R, Haberer JP, et al. Pharmacokinetics of midazolam in anaesthetised cirrhotic patients. Br J Anaesth. 1988; 60: 762–7.PubMedCrossRefGoogle Scholar
  49. 49.
    Driessen JJ, Vree TB, Guelen PJM. The effects of acute changes in renal function on the pharmacokinetics of midazolam during long-term infusion in ICU patients. Acta Anaesthesiol Belg. 1991; 42: 149–55.PubMedGoogle Scholar
  50. 50.
    Jacqz-Aigrain E, Daoud P, Burtin P, et al. Placebo-controlled trial of midazolam sedation in mechanically ventilated newborn babies. Lancet. 1994; 344: 646–50.PubMedCrossRefGoogle Scholar
  51. 51.
    Allonen H, Ziegler G, Klotz U. Midazolam kinetics. Clin Pharmacol Ther. 1981; 30: 653–61.PubMedCrossRefGoogle Scholar
  52. 52.
    Olkkola KT, Aranko K, Luurila H, et al. A potentially hazardous interaction between erythromycin and midazolam. Clin Pharmacol Ther. 1993; 53: 298–305.PubMedCrossRefGoogle Scholar
  53. 53.
    Backman JT, Olkkola KT, Aranko K, et al. Dose of midazolam should be reduced during diltiazem and verapamil tretments. Br J Clin Pharmacol. 1994; 37: 221–5.PubMedCrossRefGoogle Scholar
  54. 54.
    Klotz U, Ziegler G, Ludwig L, et al. Pharmacodynamic interaction between midazolam and a specific benzodiazepine antagonist in humans. J Clin Pharmacol. 1985; 25: 400–6.PubMedGoogle Scholar
  55. 55.
    Shannon M, Albers G, Burkhart K. Safety and efficacy of flumazenil in the reversal of benzodiazepine-induced conscious sedation. The flumazenil pediatric study group. J Pediatr. 1997; 131: 582–6.PubMedCrossRefGoogle Scholar
  56. 56.
    Hickey PR, Wessel DL, Streitz SL, et al. Transcatheter closure of atrial septal defects: hemodynamic complications and anesthetic management. Anesth Analg. 1992; 74: 44–50.PubMedCrossRefGoogle Scholar
  57. 57.
    Tolia V, Fleming SL, Kauffman RE. Randomized, double-blind trial of midazolam and diazepam for endoscopic sedation in children. Dev Pharmacol Ther. 1990; 14: 141–7.PubMedGoogle Scholar
  58. 58.
    Bahal-O’Mara N, Nahata MC, Murray RD, et al. Sedation with meperidine and midazolam in pediatric patients undergoing endoscopy. Eur J Clin Pharmacol. 1994; 47: 319–23.PubMedGoogle Scholar
  59. 59.
    Sandler ES, Weyman C, Conner K, et al. Midazolam versus fentanyl as premedication for painful procedures in children with cancer. Pediatrics. 1992; 89: 631–4.PubMedGoogle Scholar
  60. 60.
    Friedman AG, Mulhern RK, Fairclough D, et al. Midazolam premedication for pediatric bone marrow aspiration and lumbar puncture. Med Pediatr Oncol. 1991; 19: 499–504.PubMedCrossRefGoogle Scholar
  61. 61.
    Sheridan RL, McEttrick M, Bacha G, et al. Midazolam infusion in pediatric patients with burns who are undergoing mechanical ventilation. J Burn Care Rehabil. 1994; 15: 515–8.PubMedCrossRefGoogle Scholar
  62. 62.
    Rosen DA, Rosen KR. Midazolam for sedation in the paediatric intensive care unit. Intensive Care Med. 1991; 17: S15–S19.PubMedCrossRefGoogle Scholar
  63. 63.
    Salonen M, Kanto J, Iisalo E, et al. Midazolam as an induction agent in children: a pharmacokinetic and clinical study. Anesth Analg. 1987; 66: 625–8.PubMedCrossRefGoogle Scholar
  64. 64.
    Ilkhanipour K, Juels CR, Langdorf MI. Pediatric pain control and conscious sedation: a survey of emergency medicine residencies. Acad Emerg Med. 1994; 1: 368–72.PubMedCrossRefGoogle Scholar
  65. 65.
    Shane SA, Fuchs SM, Khine H. Efficacy of rectal midazolam for the sedation of preschool children undergoing laceration repair. Ann Emerg Med 1994 24: 1065–73.PubMedCrossRefGoogle Scholar
  66. 66.
    Kuman A, Bleck TR. Intravenous midazolam for the treatment of refractory status epilepticus. Crit Care Med. 1992; 20: 483–8.CrossRefGoogle Scholar

Copyright information

© Adis International Limited 1998

Authors and Affiliations

  • Jeffrey L. Blumer
    • 1
  1. 1.Division of Pediatric Pharmacology and Critical Care, Rainbow Babies and Children’s HospitalCase Western Reserve University, ChiefClevelandUSA

Personalised recommendations