Endotoxin-induced Fever Increases the Clearance of Methohexitone in Rabbits

Abstract

We have previously observed that the clearance of methohexitone, given by continuous infusion for sedation in the intensive care unit, was influenced by body temperature in patients with post-operative fever. The aim of the present study was to reproduce this finding in an animal model that can then be used to predict similar influences for other anaesthetic agents. Sixteen rabbits were infused for 2.0 h with methohexitone (8.4 +/- 0.5 mg kg-1 h-1 (mean +/- s.d.)) and in eight of them fever was induced with intravenous Escherichia coli endotoxin. Arterial blood samples were taken over 6 h and plasma concentrations of methohexitone were assayed by gas chromatography. The mean body temperatures of the rabbits over the periods of measurement varied between 38.5 and 41.8 degrees C, and the total clearance of methohexitone (mean 50.7 mL min-1 kg-1) was positively correlated with temperature (r = 0.545, P = 0.029). No significant correlations with temperature were found for other pharmacokinetic parameters. We conclude that these observations correspond to the findings in the clinical pharmacokinetic study, showing the validity of the animal model.

Ocular fluorescein kinetics before and after vitrectomy on swine

“…Other studies have revealed diminished volumes of distribution caused by decreased environmental and body temperature [14,20]. Previously vitrectomized swine were exposed to reduced ambient temperatures and kept on minimum standards for food supply during the 1-month residence period, factors that may have negatively influenced the apparent volumes of distribution for fluorescein.…”

Clearance of Fentanyl, Alfentanil, Methohexitone, Thiopentone and Ketamine in Relation to Estimated Hepatic Blood Flow in Several Animal Species: Application to Prediction of Clearance in Man

“…The pharmacokinetics of ketamine were determined in New Zealand White rabbits, using six control animals (2Á2±2Á6 kg) and seven animals (2Á1±3Á1 kg) pretreated with Escherichia coli endotoxin, as previously described for methohexitone (Redke & Bjo Èrkman 1994) and alfentanil (Bjo Èrkman & Redke 1996). The rate of infusion was 9Á7±11Á4 mg kg À1 h À1 for 2 h and blood sampling was at 5, 10,30,60,90,120,123,128,135,145,160,180,210,240,300 and 360 min after the start of the infusion.…”

Influence of Escherichia coli Endotoxin on the Pharmacokinetics and Respiratory Depressant Effect of Alfentanil in Rabbits

“…An increased V dss with an unchanged f u suggests increased drug binding in tissues. 30 In general, the rabbit model seems well able to mimic the effects of fever on the pharmacokinetics of several drugs in humans. Pretreatment of rabbits with bacterial endotoxin caused up to 2-fold increases in the volume of distribution of trimethoprim 14 and gentamicin.…”

“…This type of interaction has been reported previously. 30 Studies in other animal species have yielded less consistent findings. 15 Septicemia 19 or endotoxinemia 21 also raised the volume of distribution of several cephalosporins in rabbits.…”

“…30 Alfentanil was chosen as a representative of the opioid analgesics which has no (known) active metabolites and fast enough elimination kinetics to allow experiments to be fitted into the time frame of acute endotoxin effects. 30 Alfentanil was chosen as a representative of the opioid analgesics which has no (known) active metabolites and fast enough elimination kinetics to allow experiments to be fitted into the time frame of acute endotoxin effects.…”