Pharmacokinetics and Clinical Experience of 20-H Infusions of Methohexitone in Intensive Care Patients With Postoperative Pyrexia

Abstract

We have studied the pharmacokinetics of 20-h infusions of methohexitone in young patients with postoperative fever undergoing artificial ventilation of the lungs. The infusion rate was adjusted so that patients were unresponsive to vocal stimulation but reacted to tracheal suction. The mean steady state concentration of methohexitone required was 2.6 mg litre-1 (unbound 0.53 mg litre-1). The mean (SD) total clearance of methohexitone was 16.3 (4.2) ml min-1 kg-1, which is greater than that for volunteers or normal surgical patients. The unbound clearance correlated positively with body temperature during the infusion (r = 0.796, P = 0.017). The terminal half-life of methohexitone was 6.3 (3.8) h and that of the 4'-hydroxy metabolite 5.8 (2.1) h. There were no marked haemodynamic effects of the infusion, and no excessive sedation after the infusion. However, the clearance of methohexitone was high and variable, possibly as a direct effect of postoperative fever. Consequently, the need for individual titration of the rate of infusion is emphasized.

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

“…Previously, we have used the rabbit as an animal model to study the effects of pyrogen-induced fever on the pharmacokinetics of methohexitone (Redke & Bjo Èrkman 1994) and alfentanil (Bjo Èrkman & Redke 1996). A positive correlation of the clearance of methohexitone with body temperature resembled observations in patients with postoperative fever (Redke et al 1991). No similar in¯uence of endotoxin on the clearance of ketamine could be discerned.…”

“…Blood, plasma and plasma water concentrations of the drugs were determined by gas-liquid chromatography according to published methods: fentanyl, Bjo Èrkman & Stanski (1988); methohexitone, Redke et al (1991); ketamine and norketamine, Bjo Èrkman et al (1992).…”

“…The f u of fentanyl in plasma from eight pigs was determined by equilibrium dialysis against isotonic phosphate buffer at 37 C (Meuldermans et al 1982) at a total concentration of 15 ng mL À1 . The f u of methohexitone in plasma from 11 rats and 18 rabbits at concentrations of 0Á5 and 10 mg mL À1 was determined by ultracentrifugation (Redke et al 1991). The f u of ketamine was determined by equilibrium dialysis (as for fentanyl) in plasma from 10 rats and seven pigs at concentrations of 0Á3 and 6 mg mL À1 .…”

“…The literature data for man are shown in Table 2. In addition, literature values of l and f u in man were: fentanyl l 0Á97 and f u 16%, alfentanil l 0Á63 and f u 7Á9% (Meuldermans et al 1982), methohexitone f u 21% (Redke et al 1991), thiopentone l 1Á0, 0Á88 or 0Á95 (Morgan et al 1981;Jung et al 1982;Wada et al 1997) and f u 20% (Jung et al 1982). These data were used to calculate total blood clearance or unbound clearance (CL u ) from literature data on plasma clearance.…”