European Journal of Clinical Pharmacology

, Volume 37, Issue 3, pp 267–272 | Cite as

The pharmacokinetics of midazolam in paediatric patients

  • K. Payne
  • F. J. Mattheyse
  • D. Liebenberg
  • T. Dawes


A serum concentration profile study on midazolam in children was done. Fifty six children aged 3–10 years took part. The routes investigated were intravenous, intramuscular, rectal and oral at 0.15 mg·kg−1, and the oral at 0.45 mg·kg−1 and 1 mg·kg−1. Serum concentration levels for 5 h were studied using gas liquid chromatography.

The volume of distribution, Vss, was 1.29 l·kg−1, the elimination half-life 1.17 h and the serum clearance 9.11 ml·kg−1·min−1. Peak serum concentrations for the intramuscular, rectal and oral routes were at 15 min, 30 min and 53 min respectively. Bioavailability was 87%, 18%, 27% respectively at a dose of 0.15 mg·kg−1. The oral route bioavailability halved to 15% at the two higher doses.

Bioequivalence was present between the 0.15 mg·kg−1 intramuscular dose and the 0.45 mg·kg−1 oral dose from 45 to 120 min.

Key words

midazolam pharmacokinetics children 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Greenblatt DJ, Lochniskar A, Ochs RH, Lauven PM (1981) Automated gas chromatography for studies of midazolam pharmacokinetics. Anesthesiology 55: 176–179Google Scholar
  2. 2.
    Dundee JW, Samuel IO, Toner W, Howard PJ (1980) Midazolam a water soluble benzodiazepine. Anaesthesia 35: 454–459Google Scholar
  3. 3.
    Reves JG, Frazen RJ, Vinik H, Greenblatt DJ (1985) Midazolam, pharmacology and uses. Anesthesiology 62: 310–324Google Scholar
  4. 4.
    Greenblatt DJ, Arendt RM, Abernathy DR, Giles HG (1983) In vitro quantiation of benzodiazepine lipophilicity. Br J Anaesth 55: 985–989Google Scholar
  5. 5.
    Whitwam JG (1987) Benzodiazepines — editorial. Anaesthesia 42: 1255–1257Google Scholar
  6. 6.
    Crevoisier C, Ziegler WH, Eckart M, Heijmann P (1983) Relationship between plasma concentration and effect of midazolam after oral and intravenous administration. Br J Clin Pharmacol 16: 51–61Google Scholar
  7. 7.
    Crevoisier C, Eckert M, Heijmann P, Thurneysen D (1981) Relation entre 1 effect clinique et al pharmacocinetique due midazolam après 1 administration IV et IM. Arzneimittelforsch 31: 2211–2215Google Scholar
  8. 8.
    Rita L, Seleny FL, Majurek A, Robins S (1985) Intramuscular midazolam for paediatric premedication sedation. Anesthesiology 63: 528–531Google Scholar
  9. 9.
    Payne KA, Heydenrych JJ, Kruger TC, Samuels G (1986) Midazolam premedication in paediatric anaesthesia. South Afr Med J 70: 657–659Google Scholar
  10. 10.
    Corman HH, Hornick EJ, Kritchman M, Terestman N (1958) Emotional reactions of surgical patients to hospitalization, anaesthesia and surgery. Am J Surg 21: 330–337Google Scholar
  11. 11.
    Padfield NL, Twohig M, Frazer AC (1986) Temazepam and trimeprazine compared with placebo as premedication in children. Br J Anaesth 58: 487–493Google Scholar
  12. 12.
    White PF (1986) Pharmacologic and clinical aspects of preoperative medication. Anesth Analg 65: 963–974Google Scholar
  13. 13.
    Fee JPH (1988) Premedication. Acta Anaesthesiol Scand 32: 1–5Google Scholar
  14. 14.
    Kretz FJ, Liegl M, Heinemeyer G, Eyrich K (1985) Die rektale Narkoseeinleitung bei Kleinkindern mit Diazepam und Midazolam. Anästhesiol Intensivmed 10: 343–346Google Scholar
  15. 15.
    Saint-Maurice C, Meistelman C, Rey E, Estene C, De Louture D, Olive G (1986) The pharmacokinetics of rectal midazolam for premedication in children. Anesthesiology 65: 536–538Google Scholar
  16. 16.
    Brown TCK, Fisk GC (1979) Preoperative preparation including premedication. In: Anaesthesia for children. Brown TCK, Fisk GC (eds) Blackwell Scientific Publications, Oxford, pp 103–108Google Scholar
  17. 17.
    De Roubaix JAM (1985) Premedikasie feite en fiksie. South Afr J Cont Med Educ 3: 7–19Google Scholar
  18. 18.
    Haagensen RE (1985) Rectal premedication in children. Anaesthesia 40: 956–959Google Scholar
  19. 19.
    Cote C, Goudsouzian NG, Letty M, Lin MD, Dedrick C (1982) Assessment of the risk factors related to acid aspiration syndrome in paediatric patients. Anesthesiology 56: 70–72Google Scholar
  20. 20.
    Yildiz F, Tryba M, Kuehn K, Hausdoerfer J (1984) Reduction in gastric acid secretion. Anaesthesia 39: 314–318Google Scholar
  21. 21.
    Harper KW, Collier PS, Dundee JW, Elliott P, Halliday NJ, Lowry KG (1985) Age and nature of operation on the pharmacokinetics of midazolam. Br J Anaesth 57: 866–871Google Scholar
  22. 22.
    Lloyd Thomas AR, Booker PD (1986) Infusion of midazolam in paediatrics after cardiac surgery. Br J Anaesth 58: 1109–1115Google Scholar
  23. 23.
    Payne KA, Heydenrych JJ, Martins M, Samuels G (1987) Caudal block for analgesia after paediatric inguinal surgery. South Afr Med J 72: 629–630Google Scholar
  24. 24.
    Nimmo WS (1984) Effect of anaesthesia on gastric motility and emptying. Br J Anaesth 56: 29–36Google Scholar
  25. 25.
    Nimmo WS, Heading RC, Wilson J, Tothill P, Prescott L (1975) Inhibition of gastric emptying and drug absorption by narcotic analgesics. Br J Clin Pharmacol 2: 509–513Google Scholar
  26. 26.
    Kanto J, Aaltonen L, Himberg J (1986) Midazolam as an intravenous induction agent in the elderly. Anesth Analg 65: 15–20Google Scholar
  27. 27.
    Benet LZ, Galeazzi RL (1979) Non-compartmental determination of the steady state volume of distribution. J Pharm Sci 68: 1071–1074Google Scholar
  28. 28.
    Gibaldi M (1984) Non-compartmental pharmacokinetics. In: Gibaldi M (ed) Biopharmaceutics and clinical pharmacokinetics, 3rd edn. Lea and Febiger, Philadelphia, pp 17–28Google Scholar
  29. 29.
    Metzler CM (1974) Bioavailability — a problem of equivalence. Biometrics 30: 309–317Google Scholar
  30. 30.
    Westlake WJ (1975) Statistical problems in interpreting comparative bioavailability trials. Int J Clin Pharmacol 11: 342–345Google Scholar
  31. 31.
    Langman MJS (1986) Towards estimation and confidence intervals. Br Med J 292: 716Google Scholar
  32. 32.
    Gardner MJ, Altman DG (1986) Confidence intervals rather than P values. Br Med J 292: 746–750Google Scholar
  33. 33.
    Rothman KJ (1978) A show of confidence. N Engl J Med 14: 1362–1363Google Scholar
  34. 34.
    Persson P, Nilsson A, Hartvig P, Tamsen A (1987) Pharmacokinetics of midazolam in total IV anaesthesia. Br J Anaesth 58: 548–556Google Scholar
  35. 35.
    Hull CJ (1984) General principles of pharmacokinetics. In: Prys-Roberts C, Hug CC (eds) Pharmacokinetics of anaesthesia. Blackwell Scientific Publications, Oxford, pp 1–24Google Scholar
  36. 36.
    Schwilden H, Stoeckel H, Schuttler J, Lauven P (1986) Pharmacological models and their use in clinical anaesthesia. Eur J Anaesthesiol 3: 175–208Google Scholar
  37. 37.
    Greenblatt DJ, Abernethy DR, Lochniskar A, Harmatz J, Limjuco RA, Shader RI (1984) Affects of age, gender and obesity on midazolam kinetics. Anesthesiology 61: 27–35Google Scholar
  38. 38.
    Harper KW, Collier PS, Dundee JW, Elliott P, Holliday NJ, Lowry KG (1985) Age and natuare of operation influence the pharmacokinetics of midazolam. Br J Anaesth 40: 956–559Google Scholar
  39. 39.
    Aaltonen L, Himberg J, Kanto J, Vuori A (1985) The usefulness of gas liquid chromatography in pharmacokinetic studies on midazolam. Int J Clin Pharmacol 23: 247–252Google Scholar
  40. 40.
    Greenblatt DJ, Lochniskor A, Scavone M (1986) Absence of interaction of cimetidine and ranitidine with intravenous and oral midazolam. Anesth Analg 65: 176–180Google Scholar
  41. 41.
    Bornemann LD, Min BH, Crews T, Rees MM (1985) Dose dependant pharmacokinetics of midazolam. Eur J Clin Pharmacol 29: 91–95Google Scholar
  42. 42.
    Gerecke M (1983) Chemical structure and properties of midazolam. Br J Clin Pharmacol 16: 11–16Google Scholar
  43. 43.
    Reinhart K, Dallinger G, Dennhardt R, Heinemeyer G, Eyrich K (1985) Comparison of midazolam, diazepam and placebo as I.M. premedication. Br J Anaesth 57: 294–299Google Scholar
  44. 44.
    Ziegler WH, Schalch E, Leishman B, Eckert I (1983) Comparison of the effects of IV administration of midazolam and the hydroxy metabolites. Br J Clin Pharmacol 16: 635–695Google Scholar
  45. 45.
    Kanto J (1983) Midazolam, the first water soluble benzodiazepine derivative. Drugs Today 19: 221–227Google Scholar

Copyright information

© Springer-Verlag 1989

Authors and Affiliations

  • K. Payne
    • 1
  • F. J. Mattheyse
    • 2
  • D. Liebenberg
    • 3
  • T. Dawes
    • 4
  1. 1.Department of AnaesthesiaUniversity of StellenboschParowvallei, TygerbergSouth Africa
  2. 2.Department of PhysiologyUniversity of StellenboschParowvallei, TygerbergSouth Africa
  3. 3.Department of Pharmacology, Medical SchoolUniversity of StellenboschParowvallei, TygerbergSouth Africa
  4. 4.Tygerberg HospitalParowvallei, TygerbergSouth Africa

Personalised recommendations