Agent Linked to Survival of Children with Acute Liver Failure

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Agent Linked to Survival of Children with Acute Liver Failure

By Gever, Staff Writer, MedPage TodayPublished: January 04, 2008Reviewed by Zalman S. Agus, MD; Emeritus Professor University of Pennsylvania School of Medicine.

LONDON, Jan. 4 -- More children with acute liver failure not related to acetaminophen poisoning survived after N-acetylcysteine therapy was made routine, researchers here said.

Ten-year actuarial survival among 111 children with non-acetaminophen acute liver failure treated with N-acetylcysteine was 75%, compared with 50% for 58 children getting other treatment (P=0.009), Anil Dhawan, M.D., of King's College Hospital, and colleagues, reported in the January issue of Liver Transplantation.

But in an accompanying commentary, a University of Cincinnati group dismissed out of hand any conclusion that N-acetylcysteine therapy was the cause of the improved actuarial survival.

The London results emerged from the King's College Hospital's experience with children from 1989 through 2004. In addition to improved actuarial survival, the group also found that N-acetylcysteine therapy was linked to shorter hospital stays (19 days versus 25 days, P=0.05) and fewer deaths after transplantation (16% versus 39%, P=0.02).

N-acetylcysteine is used routinely to treat acute liver failure resulting from acetaminophen overdose. Some hospitals have also adopted it as standard therapy for other cases of acute liver failure, which are rare but often fatal.

The drug is thought to benefit these patients by increasing hepatic tissue oxygenation and reducing inflammation, promoting liver cell survival. At King's College Hospital, it was given by continuous IV infusion at 100 mg/kg/day until liver function normalized or the patients underwent a liver transplant.

However, systematic evidence that the drug is safe and effective in these patients has been lacking. In the accompanying commentary, Mike A. Leonis, M.D., Ph.D., and F. Balistreri, M.D., of the University of Cincinnati, insisted the evidence remains lacking.

The King's College investigators compared outcomes in 59 children hospitalized with non-acetaminophen-related acute liver failure from 1989 through 1994, when N-acetylcysteine was not used, with outcomes in 111 children treated later when the hospital had made N-acetylcysteine therapy routine in such cases.

But other aspects of care also changed during the study period, and the two groups of children differed in some respects.

Dr. Dhawan and colleagues reported that jaundice and ascites were more common in the earlier group children. Blood tests including normalized prothrombin ratio, bilirubin, and white cell counts also suggested that the earlier patients had suffered more liver damage by the time they reached the hospital.

In addition, supportive care and inotropic medication were more common in children treated later.

Dr. Dhawan and colleagues also compared outcomes among children treated with N-acetylcysteine from 1995 through 1999 with those treated from 2000 through 2004.

No children treated in the most recent period died after a liver transplant, whereas post-transplant mortality among those receiving N-acetylcysteine earlier was 25% (P=0.0002). Significantly more of the later patients survived with their native livers (58% versus 32%, P=0.01).

In consideration of these factors, Dr. Dhawan and colleagues reached the modest conclusions that N-acetylcysteine appears to be safe in non-acetaminophen-related acute liver failure, and it "may have a positive effect on the outcome."

Drs. Leonis and Balistreri interpreted the findings more harshly, saying they suggest the improvement in outcome was not due to N-acetylcysteine treatment at all. The best they could say for the drug was that it appeared to do no harm, and a role in the improved outcomes could not be ruled out.

Two randomized trials of N-acetylcysteine for acute liver failure unrelated to acetaminophen toxicity are now underway, one in children and the other in adults. Both groups of scientists agreed that these trials should provide solid evidence on the drug's usefulness in this group of patients.

No research funding sources or conflicts of interest were disclosed.

Primary source: Liver TransplantationSource reference:Kortsalioudaki C, et al "Safety and efficacy of N-acetylcysteine in children with non-acetaminophen-induced acute liver failure" Liver Transplantation 2008; 14: 25-30. Additional source: Liver TransplantationSource reference: Leonis M, Balistreri W, "Is there a NAC to treating acute liver failure in children?" Liver Transplantation 2008; 14: 7-8.

http://www.medpagetoday.com/Gastroenterology/GeneralHepatology/tb/7855