The Australasian Clinical Toxicology Investigators Collaboration Randomized Trial of Different Loading Infusion Rates of N-Acetylcysteine

Study objective We determine whether the incidence of adverse events caused by intravenous N-acetylcysteine is significantly less when the initial dose is infused over a 60-minute period compared with the standard infusion period of 15 minutes. A secondary objective is to assess the efficacy of the 2 treatment arms. Methods This was a multicenter, randomized, prospective trial of patients who presented with acetaminophen poisoning and who were treated with N-acetylcysteine and had no history of hypersensitivity to N-acetylcysteine. Patients were randomly assigned to receive the initial dose of N-acetylcysteine over a 15-minute or 60-minute period. Baseline signs and symptoms and adverse events were serially evaluated before and during administration of N-acetylcysteine. Tests of liver injury and coagulation were collected at baseline and then at 12-hour intervals. Results The study was designed with an 80% power to detect a halving of the incidence of adverse events. Of 180 evaluable patients, 109 patients were randomized to the 15-minute group and 71 patients were randomized to the 60-minute group. The incidence of drug-related adverse events was 45% in the 15-minute group and 38% in the 60-minute group (95% confidence interval −8% to 22%). The study did not demonstrate a reduction of drug-related adverse outcomes with the 60-minute infusion. Incidence of maximum alanine aminotransferase levels indicating hepatotoxicity (serum level >1,000 IU/L) was 6.8% (5.6% for 15-minute, 8.7% for 60-minute). The difference did not attain statistical significance. Conclusion This study did not demonstrate a reduction of drug-related adverse outcomes with the 60-minute infusion. The study also confirmed that early treatment with N-acetylcysteine (within 8 hours of ingestion) is more effective than later treatment.