Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Intravenous acetylcysteine improved survival in paracetamol-induced hepatic failure

ACP J Club. 1992 Mar-April;116:47. doi:10.7326/ACPJC-1992-116-2-047


Source Citation

Keays R, Harrison PM, Wendon JA, et al. Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial. BMJ. 1991 Oct 26;303:1026-9.


Abstract

Objective

To determine whether intravenous acetylcysteine improves outcome in patients with fulminant hepatic failure after paracetamol (acetaminophen) overdose.

Design

Randomized placebo-controlled trial.

Setting

Liver failure unit of the Institute of Liver Studies, King's College Hospital, London, England.

Patients

50 patients with fulminant hepatic failure due to paracetamol overdose, not previously treated with acetylcysteine. Mean age was 34 years, 58% were women, mean time from overdose to presentation at hospital was 30 hours, and mean time from overdose to admission to the liver failure unit was 55 hours. 35 patients met at least 1 of the 3 criteria that defined a poor prognosis.

Intervention

Conventional intensive liver care, with and without intravenous acetylcysteine, 150 mg/kg body weight in 200 mL 5% dextrose over 15 min, followed by 50 mg/kg in 500 mL 5% dextrose over 4 h, and then 100 mg/kg in 1 L over 16 h. The final infusion rate was continued until death or recovery from encephalopathy.

Main outcome measures

Survival; occurrence of cerebral edema, hypotension, or renal failure; severity of liver decompensation.

Main results

The survival rate was higher in patients treated with acetylcysteine than in those treated with placebo (48% vs 20%, P = 0.04). {This absolute benefit increase of 28% means that 4 patients would need to be treated (NNT) with intravenous acetylcysteine (compared with placebo) to have 1 additional patient survive, 95% CI 2 to 56; the relative benefit increase was 140%, CI 5% to 485%.}* Survival rates for patients meeting at least 1 criterion for poor prognosis were 29% and 6% for the acetylcysteine and control groups, respectively (P = 0.06). The severity of liver failure as assessed by prolongation of prothrombin time and grade of encephalopathy was similar in the 2 groups, but there was a lower rate of cerebral edema with acetylcysteine (40% vs 68%, P = 0.047) {absolute risk reduction (ARR) 28%, relative risk reduction (RRR) 41%, CI 0.6% to 67%, NNT 4, CI 2 to 269}*. Among patients with cerebral edema, 2 of 10 patients who received acetylcysteine and none of 17 in the control group survived. Fewer patients treated with acetylcysteine required inotropic support to maintain mean arterial pressure (48% vs 80% P = 0.02) {ARR 32%, RRR 40%, CI 8% to 64%, NNT 4, CI 2 to 18}*. Among patients with hypotension, 2 of 12 patients receiving acetylcysteine and none of 20 patients from the control group survived. There were no instances of hypersensitivity reactions.

Conclusion

Intravenous acetylcysteine with conventional intensive liver care improved survival compared with conventional intensive liver care alone in patients with fulminant hepatic failure after paracetamol overdose.

Source of funding: Sterling Research Laboratories.

Address for article reprint: Dr. R. Williams, Institute of Liver Studies, King's College School of Medicine and Dentistry, London SE5 8RX, United Kingdom.

*Numbers calculated from data in article.


Commentary

This well-executed study demonstrates the efficacy of intravenous acetylcysteine* in the management of fulminant hepatic failure induced by paracetamol (acetaminophen). This group of investigators has previously reported on other aspects of fulminant hepatic failure induced by paracetamol including improvement in hemodynamics and oxygen transport brought about by acetylcysteine.

Acetylcysteine has shown beneficial protective effect on other tissues such as gastric mucosa (1) and the myocardium (2). Acetylcysteine is known to activate and generate sulfhydryl compounds (1) that have a cytoprotective effect possibly because of oxygen free-radical scavenging.

The main determinants of mortality in this study seem to be the occurrence of cerebral edema and hypotension. The severity of cerebral edema was not evaluated by measuring intracranial pressure, although the authors have experience in measuring intracranial pressure in cases of fulminant hepatic failure (3). We are not informed as to how many patients with cerebral edema were treated with thiopentone. In their previous study (3), the authors reported a 38% (5 of 13) survival as a result of thiopental infusion; 11 of 13 patients had fulminant hepatic failure due to paracetamol. Because survival of patients with cerebral edema in the present study (even in the acetylcysteine group) was very low, it is possible that acetylcysteine and thiopentone given together may have a deleterious effect.

It is reassuring to learn that acetylcysteine given even 55 hours after paracetamol overdose was effective in lowering mortality.

Nirmal S. Mann, MD, DSc
Texas A&M UniversityTemple, Texas, USA


References

1. Mann NS, Brawn PN. Am J Gastroenterol. 1988;83:1035.

2. Unverferth DV, Jagadeesh JM, Unverferth BJ, et al. J Natl Cancer Inst. 1983;71:917-20.

3. Forbes A, Alexander GJ, O'Grady JG, et al. Hepatology. 1989;10:306-10.

*Acetylcysteine is only approved for oral use in the U.S.A. Patients with acetaminophen overdose and intractable vomiting would need to be transported to an FDA-approved center for treatment. The Editor.