We have used estimated hepatic blood flow (Qhep) as an aid to evaluate clearance (CL) values in animals and to predict clearance in man of five anaesthetic agents: fentanyl, alfentanil, methohexitone, thiopentone and ketamine. The disposition of methohexitone was determined in rats and that of ketamine in rats, rabbits and pigs. Further data were compiled from the literature and supplemented experimentally as needed. Allometric interspecies scaling, according to three different methods, was used to estimate blood clearance and unbound clearance (CLu) in man. The results of scaling according to the three different methods were evaluated in relation to estimated hepatic extraction ratio (CL/Qhep) of the drugs. In most animals the clearance of the drugs were comparable with or lower than estimated Qhep. However, ketamine showed extensive extrahepatic clearance in rabbits. Prediction of clearance in man was successful by at least one method for all five drugs, while prediction of CLu generally failed. Estimates of CL/Qhep gave no indication as to the choice of the best method. Volume of distribution at steady state could be predicted for alfentanil, thiopentone and ketamine. Comparison of clearance with Qhep should be used to evaluate clearance data in animals, however estimation of hepatic extraction ratios appears to be of little use for allometric scaling. The use of ketamine as an anaesthetic agent in rabbits is questionable, while the use of fentanyl in pigs, methohexitone in rats and ketamine in rats and pigs is well supported by the pharmacokinetic data.
Carbon dioxide pneumoperitoneum does not enhance the activation of coagulation and fibrinolysis associated with laparoscopic cholecystectomy. The coagulation and fibrinolytic systems are activated during and after gasless as well as conventional laparoscopic cholecystectomy.
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.
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