PHARMACOKINETICS AND PHARMACODYNAMICS OF ATRACURIUM AND ITS METABOLITE LAUDANOSINE IN CARDIAC-SURGERY INVOLVING CARDIOPULMONARY BYPASS WITHINDUCED HYPOTHERMIA

The infusion velocity of the short-acting muscle relaxant atracurium h as to be reduced during hypothermic cardiopulmonary bypass to maintain a moderate degree of muscle relaxation. In the present study the exte nt of neuromuscular blockade and the plasma concentrations of atracuri um and its main metabolite, laudanosine, were assayed by high-performa nce liquid chromatography in 10 patients undergoing open heart surgery for coronary artery bypass. Anaesthesia was induced by an intravenous bolus injection of midazolam (10 to 15mg) and fentanyl (0.75 to 1.5mg ). Neuromuscular transmission was monitored at the adductor pollicis m uscle after supramaximal stimulation of the ulnar nerve over the wrist (train-of-four). Muscle relaxation was initiated with an intravenous bolus injection of 460 mu g/kg atracurium. Waning neuromuscular blocka de was enhanced by intravenous injection of constant maintenance doses of atracurium (100 to 200 mu g/kg) whenever the first twitch response of a train-of-four (T1) had attained 25% of its control. Plasma conce ntrations of atracurium and laudanosine were fitted to an open 2-compa rtment model where elimination of atracurium occurs from both the cent ral and peripheral compartments. For the pharmacodynamic component of the model the Hill equation was assumed. Pharmacokinetic and pharmacod ynamic parameters were estimated by means of the TOPFIT program and di fferences between normothermia and hypothermia were considered statist ically significant. The increase in neuromuscular blockade during hypo thermia was caused by a significantly (p < 0.05) decreased rate of the Hofmann-Elimination, the main metabolic pathway of atracurium, and by an increased sensitivity of neuromuscular junctions due to cooling.