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Effect of infusion rate on thiopental dose-response relationships. Assessment of a pharmacokinetic-pharmacodynamic model.

Publication ,  Journal Article
Gentry, WB; Krejcie, TC; Henthorn, TK; Shanks, CA; Howard, KA; Gupta, DK; Avram, MJ
Published in: Anesthesiology
August 1994

BACKGROUND: The rate of administration of an intravenous anesthetic induction agent is an important variable determining the total dose required to reach a given endpoint, such as loss of consciousness (LOC). The influence of infusion rate on the dose-response relationship has not been described rigorously. In this study we characterized the effect of different thiopental infusion rates on the times and doses required to reach a clinical (induction) endpoint. METHODS: Fifty-six healthy, non-premedicated men, aged 19-59 yr, were randomly assigned to receive one of seven different thiopental infusion rates (40, 60, 75, 150, 300, 600, and 1,200 mg/min). The infusion was continued until the patient dropped a held object, indicating LOC. The infusion rates were selected using a simulation which predicted the relationship between the rate of administration and cumulative dose administered at the time of LOC. Average population pharmacokinetic parameters from a three-compartment thiopental model were combined with an effect-site rate constant for thiopental equilibration of 0.58 min-1 and a median effect-site concentration of 13.8 mg/l from previously published pharmacokinetic and pharmacodynamic models for thiopental. This derived model was used to predict the total amount of thiopental required, at each infusion rate, to produce LOC. RESULTS: The observed median effective doses for infusion rates of 40-150 mg/min were similar and ranged from 296 to 318 mg. Dose requirements increased significantly with increasing infusion rates greater than 150 mg/min; median effective doses for infusion rates of 300, 600, and 1,200 mg/min were significantly different from each other (436, 555, and 711 mg, respectively). The original simulation underestimated the observed thiopental doses at all but the lowest infusion rate. A new simulation was performed using a recently developed combined pharmacokinetic-pharmacodynamic model. This model incorporated a four-compartment thiopental pharmacokinetic model with quantal dose-response data to derive an effect-site rate constant for thiopental equilibration of 0.29 min-1 and a median effect-site concentration for LOC of 11.3 mg/l. The median thiopental doses predicted by this new simulation under the extreme conditions of a 30-fold range of infusion rates were within 13% of the observed doses. CONCLUSIONS: In this study we quantified the relationship between the rate of thiopental administration and the resultant cumulative thiopental dose necessary to produce LOC. This study validated a novel pharmacokinetic-pharmacodynamic model based on a four-compartment pharmacokinetic model and infusion quantal dose-response data. Finally, we demonstrated that thiopental dose-response relationships are dependent on drug administration rate, and found that the ability to predict this dependence accurately is influenced by the pharmacokinetics, pharmacodynamics, and median effect-site concentration used to simulate the dose-response relationships.

Duke Scholars

Published In

Anesthesiology

ISSN

0003-3022

Publication Date

August 1994

Volume

81

Issue

2

Start / End Page

316 / 324

Location

United States

Related Subject Headings

  • Unconsciousness
  • Thiopental
  • Reference Values
  • Models, Biological
  • Middle Aged
  • Male
  • Infusions, Intravenous
  • Humans
  • Dose-Response Relationship, Drug
  • Anesthesiology
 

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Gentry, W. B., Krejcie, T. C., Henthorn, T. K., Shanks, C. A., Howard, K. A., Gupta, D. K., & Avram, M. J. (1994). Effect of infusion rate on thiopental dose-response relationships. Assessment of a pharmacokinetic-pharmacodynamic model. Anesthesiology, 81(2), 316–324.
Gentry, W. B., T. C. Krejcie, T. K. Henthorn, C. A. Shanks, K. A. Howard, D. K. Gupta, and M. J. Avram. “Effect of infusion rate on thiopental dose-response relationships. Assessment of a pharmacokinetic-pharmacodynamic model.Anesthesiology 81, no. 2 (August 1994): 316–24.
Gentry WB, Krejcie TC, Henthorn TK, Shanks CA, Howard KA, Gupta DK, et al. Effect of infusion rate on thiopental dose-response relationships. Assessment of a pharmacokinetic-pharmacodynamic model. Anesthesiology. 1994 Aug;81(2):316–24.
Gentry, W. B., et al. “Effect of infusion rate on thiopental dose-response relationships. Assessment of a pharmacokinetic-pharmacodynamic model.Anesthesiology, vol. 81, no. 2, Aug. 1994, pp. 316–24.
Gentry WB, Krejcie TC, Henthorn TK, Shanks CA, Howard KA, Gupta DK, Avram MJ. Effect of infusion rate on thiopental dose-response relationships. Assessment of a pharmacokinetic-pharmacodynamic model. Anesthesiology. 1994 Aug;81(2):316–324.

Published In

Anesthesiology

ISSN

0003-3022

Publication Date

August 1994

Volume

81

Issue

2

Start / End Page

316 / 324

Location

United States

Related Subject Headings

  • Unconsciousness
  • Thiopental
  • Reference Values
  • Models, Biological
  • Middle Aged
  • Male
  • Infusions, Intravenous
  • Humans
  • Dose-Response Relationship, Drug
  • Anesthesiology