Pharmacokinetics and dynamics of atracurium infusions after paediatric orthotopic liver transplantation

Abstract

We examined the pharmacokinetics and pharmacodynamics of atracurium besylate and its metabolites in children after orthotopic liver transplantation (OLT), as a suitable model for critically ill children. Ten children were studied after OLT on return to the intensive care unit (ICU). The mean (range) age was 36 (7-78) months, and weight 6-24.2 kg. Atracurium was started at induction of anaesthesia and adjusted in the ICU according to clinical need. Neuromuscular block was measured using accelerometry (TOFguard) and the train-of-four (TOF) ratio or count. Arterial plasma samples for atracurium and metabolites taken before, 12-hourly during, and at frequent intervals after the infusion were analysed by HPLC. The mean (range) maximum infusion rate during steady-state conditions was 1.44 (0.48-3.13) mg kg(-1) h(-1) and the duration of infusion 36.9 (22.5-98.4) h. Tachyphylaxis was not observed. The mean terminal half-life (t1/2) for atracurium was 18.8 (12-32.3) min. The steady-state plasma clearance (CLss) was 13.9 (7.9-20.3) ml min(-1) kg(-1) and the terminal volume of distribution (Vz) 390 (124-551) ml kg(-1); both were higher than in adults after successful OLT. The maximum concentration (Cmax) of laudanosine was 1190 (400-1890) ng ml(-1) and t1/2 was 3.9 (1.1-6.7) h. The renal clearance of laudanosine was 0.9 (0.1-2.5) ml min(-1) kg(-1) and increased with urine flow, but there was no significant relationship with serum creatinine. EEG spikes were confirmed in one child only; the corresponding laudanosine Cmax was 720 ng ml(-1). Monoquaternary alcohol Cmax was 986 (330-1770) ng ml(-1) and t1/2 42.9 (30-57.7) min. Mean recovery time on stopping the atracurium infusion to a TOF ratio >0.75 was 23.6 (12-27) min. Atracurium is an effective and safe neuromuscular blocking agent in this population. Laudanosine concentrations are not excessive if graft function is satisfactory.