N-acetylcysteine in non-acetaminophen acute liver failure

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Lee WM, et al. "Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure". Gastroenterology. 2009. 137(3):856-64.
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Clinical Question

In patients with non-acetaminophen acute liver failure, does intravenous N-acetylcysteine improve transplant-free survival?

Bottom Line

Intravenous NAC improves transplant-free survival in patients with early stage non-acetaminophen-related acute liver failure. Patients with advanced coma grades do not benefit from NAC and typically require emergency liver transplantation.

Major Points

Acute liver failure is a relatively rare syndrome associated with a high mortality rate and frequent need for liver transplantation. Since the 1950s, trials of therapies to limit further damage or improve hepatic regeneration have failed to show evidence of benefit. In recent years, acetaminophen poisoning, either intentional or unintentional, has become the most common etiology of acute liver failure identified both in Europe and in the United States. When given within the first 24 hours after ingestion, N-acetylcysteine (NAC) effectively can prevent or minimize liver damage caused by acetaminophen, even after massive overdoses.

Treatment with NAC may benefit patients with other forms of acute liver failure, either by improving systemic hemodynamics, tissue oxygen delivery, or via other favorable effects on the acutely injured liver. No clinical trials using NAC for patients with non-acetaminophen acute liver failure have been performed. In 1998, the Acute Liver Failure Study Group, funded by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, began a registry at 24 participating sites around the United States to better characterize and understand mechanisms of acute liver failure. A prospective, randomized, double-blind, placebo-controlled trial of NAC for patients of acute liver failure not caused by acetaminophen was initiated in late 1998, ending in 2006. This article summarizes the outcomes of this trial.

Guidelines

The findings have been adopted by the American Association for the Study of Liver Diseases in their Position Paper on The Management of Acute Liver Failure: Update 2011[1]

  • N-acetylcysteine may be beneficial for acute liver failure due to drug-induced liver injury
    • Rationale: For patients whose disease appears to be caused by etiologies other than acetaminophen, N-acetylcysteine may improve outcomes. In a randomized, controlled trial, NAC appeared to improve spontaneous survival when given during early coma stages (grades I and II) in the setting of non-acetaminophen acute liver failure including, for example, drug-induced liver injury.

Design

  • Prospective, randomized, double-blind, placebo-controlled trial
  • N=173
    • NAC (n=81)
    • Placebo (n=92)
  • Setting: 24 participating sites around the United States
  • Enrolment: September 1998 to November 2006
  • Mean follow-up: Medical histories and clinical and laboratory findings were recorded on case report forms through death, transplantation, or 3 weeks after study admission and at long-term follow-up visits 1 and 2 years after study entry.
  • Analysis: Intention-to-treat
  • Primary outcome: Overall survival at 3 weeks
  • Secondary outcomes:
    • Transplant-free survival
    • Rate of transplantation
    • Length of hospital stay
    • Composite of the number of organ systems failing, using specific definitions for hepatic encephalopathy, evidence for cerebral edema, use of vasopressor or ventilatory support, serum creatinine level (≥300 μmol/L) or bacteremia

Population

Inclusion Criteria

  • Evidence of acute liver failure (any degree of encephalopathy and coagulopathy: international normalized ratio [INR] ≥1.5) due to an illness of less than 24 weeks duration
  • Age 18-70 years

Exclusion Criteria

  • Known or suspected acetaminophen overdose
  • Previously received NAC
  • Liver failure due to pregnancy, cancer, or ischemia
  • Refractory hypotension or septic shock
  • Those expected to undergo transplantation imminently (i.e., in less than 8 hours)
  • Age >70 years

Baseline Characteristics

Comparisons are placebo vs. NAC.

  • Females: 68 vs. 47%
  • Caucasian: 55 vs. 56%
  • Admit coma grade I–II: 62 vs. 73%
  • Age: 17 - 71 years
  • Weight: 38 - 178 kg
  • Symptom to Coma (days): 17 vs. 15
  • Jaundice to Coma (days): 12 vs. 7
  • Bilirubin (mg/dL): 20.3 vs. 22.3
  • Creatinine (mg/dL): 1.0 vs. 1.3
  • INR: 2.9 vs. 2.4
  • ALT (IU/L): 756.5 vs. 999
  • MELD: 33 vs. 32

Interventions

  • Randomization was stratified by the standard hepatic encephalopathy (coma) categories (I–II vs III–IV)
  • After randomization, infusion of either 5% dextrose (placebo) or 5% dextrose with N-acetylcysteine was begun, with an initial loading dose of 150 mg/kg/h of NAC over 1 hour, followed by 12.5 mg/kg/h for 4 hours, then continuous infusions of 6.25 mg/kg NAC for the remaining 67 hours.
  • Response to treatment was recorded carefully, including vital signs, progression of coma grade, and the use of other supportive measures such as mannitol, need for intubation, increase in intracranial pressure in patients with an intracranial monitor inserted, and assessment of adverse events.
  • Medical histories and clinical and laboratory findings were recorded on case report forms through death, transplantation, or 3 weeks after study admission and at long-term follow-up visits 1 and 2 years after study entry.

Outcomes

Comparisons are placebo vs. NAC.

Primary Outcomes

Overall survival at 3 weeks
66% vs. 70% (P=0.283)

Secondary Outcomes

Transplant-free survival
27% vs. 40% (P=0.043)
Overall transplantation rates
45% vs. 32% (P=0.093)
Length of hospital stay (days)
13 vs. 9 (P=0.056)

Subgroup Analysis

Overall survival at 3 weeks by coma category at randomization
I-II: 75% vs. 79% (OR 1.28; 95% CI 0.53-3.07; P=0.292)
III-IV: 53% vs. 48% (OR 0.82; 95% CI 0.29-2.34; P=0.645)
Transplant-free survival by coma category at randomization
I-II: 30% vs. 52% (OR 2.46; 95% CI 1.14-5.30; P=0.010)
III-IV: 22% vs. 9% (OR 0.33; 95% CI 0.06-1.74; P=0.912)
Transplantation rate by coma category at randomization
I-II: 46% vs. 28% (OR 0.44; 95% CI 0.20-0.96; P=0.037)
III-IV: 42% vs. 43% (OR 1.08; 95% CI 0.37-3.10; P=0.891)
Overall survival according to etiology
Drug-induced liver injury: 65% vs. 79%
Autoimmune hepatitis: 67% vs. 64%
HBV: 50% vs. 76%
Indeterminate: 69% vs. 60%
Transplant-free survival according to etiology
Drug-induced liver injury: 27% vs. 58%
Autoimmune hepatitis: 27% vs. 9%
HBV: 17% vs. 40%
Indeterminate: 23% vs. 40%

Adverse Events

Nausea and vomiting
4% vs. 14% (P=0.031)
Any infection
20% vs. 20% (P=0.975)
Any rash
2% vs. 2% (P=>0.999)
Any bronchospasm
1% vs. 1% (P=>0.999)
Any arrhythmia
10% vs. 9% (P=0.796)
Any other
9% vs. 11% (P=0.594)

Criticisms

  • To determine if unrecognized acetaminophen toxicity might have caused some of the indeterminate patients illnesses, sera from 113 patients (those with available samples) were analyzed after the conclusion of the trial using a highly sensitive and specific assay for acetaminophen adducts in serum. However, low or absent levels of the parent compound, acetaminophen, do not rule out hepatotoxicity since the time of ingestion may be relatively remote or unknown, especially when overdose may have been unintentional or occurred over several days.

Funding

  • Grant from National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
  • Grant from the Orphan Products Division, United States Food and Drug Administration.
  • Additional funding was provided by the Stephen Tips Fund of the Northwestern Medical Foundation
  • Additional funding was provided by Jeanne Roberts and Rollin and Mary Ella King Funds of the Southwestern Medical Foundation
  • The N-acetylcysteine used in the trial was supplied initially by Apothecon/Geneva Pharmaceuticals (Princeton, NJ), a division of Bristol Myers Squibb, and after April 2003 was supplied by Cumberland Pharmaceuticals (Nashville, TN).

Further Reading

  1. AASLD Position Paper. 2011.