RESUMO
OBJECTIVE: To determine the pharmacokinetics and pharmacodynamics of the neuromuscular blocking agent atracurium besylate in patients with fulminant hepatic failure (FHF). DESIGN: Open study of patients receiving atracurium infusions to facilitate mechanical ventilation. SETTING: Intensive care unit in a tertiary referral university teaching hospital. PATIENTS: Ten encephalopathic patients with FHF requiring mechanical ventilation while awaiting orthotopic liver transplantation. Three patients died before transplantation could be performed, three died after transplantation, and four survived following successful transplantation. METHODS: Plasma, urine and dialysate fluid were analysed for atracurium and its metabolites using HPLC. Neuromuscular blockade was measured using transcutaneous ulnar nerve stimulation and an accelerometer. Electroencephalography and liver function tests were performed daily. RESULTS: Patients received atracurium infusions for a period ranging from 38 to 217 h. Six patients required continuous arteriovenous haemodiafiltration (CAVHD) to replace renal function. Atracurium mean steady state clearance was 8.6 ml/min/kg, and train-of-four recovery ratio to 75% took 63 min (range 32-108). Laudanosine clearance was markedly reduced in the non-survivors; the half-life was 38.5 hrs compared with 5.3 h in the 4 patients who underwent successful transplantation. Laudanosine accumulation could be observed in all patients before transplantation, but kinetics returned to normal after successful transplantation. The highest laudanosine level recorded was 6,860 ng/ml. There was no evidence of adverse central neurological effects attributable to laudanosine. CAVHD did not contribute significantly to clearance of atracurium or its metabolites. CONCLUSIONS: Atracurium kinetics and dynamics are near-normal even in patients with fulminant hepatic failure and renal failure; laudanosine accumulation will occur, but this is not associated with measurable central neurological effects. Implantation of a functioning liver graft results in clearance of laudanosine, which seems to be independent of renal function. Atracurium is an appropriate choice for producing neuromuscular blockade for periods of several days in patients with fulminant hepatic failure and renal impairment.
