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Three Part Question

In [patients with acute hepatic failure not caused by paracetamol] does [N-acetylcysteine] [improve morbidity or mortality]

Clinical Scenario

A pleasant elderly gentleman presents to the emergency department following a recent return from the Indian subcontinent. He is nauseated, feels tired and is clearly jaundiced. His blood tests confirm a hepatitis, and further tests confirm that this is secondary to a viral hepatitis infection. There is NO evidence of paracetamol overdose. A few hours later, you are called to see him as he has become increasingly confused. He is encephalopathic, and repeat bloods show he is developing a coagulopathy. You diagnose acute liver failure, and institute supportive measures. Your colleague states that you should start him on N-acetylcysteine (Parvolex), but you tell him not to be silly, as there is no paracetamol involved. However, he insists that N-acetylcysteine will still be beneficial. You wonder if there is any evidence behind his words.

Search Strategy

PUBMED Medline 1966 - 2006 Week 2
OVID Medline 1966 - 2006 Week 2
OVID Embase 1980 - 2006 Week 10
(N-acetylcysteine OR acetylcysteine) AND (liver failure OR acute liver failure OR hepatic failure OR acute hepatic failure)

Search Outcome

PUBMED search revealed 135 papers, of which 7 were deemed relevant. OVID search revealed 416 papers, of which 3 were relevant, but these were duplicates of those found in the PUBMED search. Thus overall 7 papers were assessed.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Janes, SE et al. August 2005 United Kingdom	15-month-old boy who developed fulminant hepatic failure after ingesting 10 ml of clove oil. Treated with IV N-acetylcysteine.	Case report	ALT	Initially >13,000, fell to 10,000 within 6 hours of commencing N-acetylcysteine	Single patient studied, results may not be applicable to a wider population with other causes of liver failure. Difficult to ascertain whether clinical improvement would have occurred even if N-acetylcysteine was not used
			Liver synthetic function	Improved steadily over 4 days following treatment with N-acetylcysteine
Eisen, JS et al. 2004 Canada	3-month-old female who developed fulminant hepatic failure after ingesting less than 8 mL of clove oil. Treated with intravenous N-acetylcysteine (N-AC) according to a protocol used for acetaminophen poisoning	Case report	Liver synthetic function	Improved steadily over 72 hours following treatment with N-acetylcysteine	Single patient studied, results may not be applicable to a wider population with other causes of liver failure. Difficult to ascertain whether clinical improvement would have occurred even if N-acetylcysteine was not used
Ben-Ari, Z et al. June 2000 Israel	7 patients with non-paracetamol induced liver failure. N-acetylcysteine administered at presentation.	Case reports	Mortality	4 patients recovered fully, 2 required orthotopic liver transplantation, 1 patient died	Only small number of patients studied, may not be representative of a larger population. Difficult to ascertain whether clinical improvement would have occurred even if N-acetylcysteine was not used
			Mean peak prothrombin time, serum factor V, aspartate aminotransferase and alanine aminotransferase levels	Significantly improved in the 4 patients that recovered fully
Ritter, C et al. October 2004 Brazil	Male Wistar rats, given carbon tyetrachloride to create an animal model of severe hepatic failure. The beneficial effects of N-acetycysteine and/or deferoxamine on these rats was then studied.	Prospective, randomized, controlled experiment	Survival rate	5% in untreated rats. 25% in rats treated with N-acetycysteine alone. 35% in rats treated with deferoxamine alone. 80% in rats treated with both N-acetycysteine and deferoxamine.	Experiment conducted in rats. No evidence that these results will apply to other species, namely humans. Hepatic failure induced by carbon tetrachloride may not be representative of all of the many varied causes of hepatic failure seen in reality.
			Hepatic/CNS oxidative damage, ALT, bilirubin, PT time	Significantly lower in rats treated with N-acetycysteine and deferoxamine compared to untreated rats or those rats treated with just one compound.
			Hepatocellular necrosis and inflammatory infiltration	Significantly lower in rats treated with N-acetycysteine and deferoxamine compared to untreated rats or those rats treated with just one compound.
Harrison, PM et al. June 1991 UK	20 patients with acute liver failure (12 paracetamol induced, 8 due to other causes) given acetylcysteine. Physiological parameters measured before acetylcysteine given and 30 minutes after treatment started.	Prospective, controlled experimental trial	Mean oxygen delivery	Increased from 856 to 975 ml/min/m2 (P=0.0036) in patients with liver failure caused by paracetamol. Similar results seen in patients with non-paracetamol acute liver failure	Trial shows an increase in physiological parameters with acetylcysteine, but no evidence that this translates to a decrease in clinical morbidity or mortality in patients with non-paracetamol acute liver failure. Only small numbers of patients studied, not all of which had non-paracetamol acute liver failure.
			Mean arterial pressure	Increased from 88 to 95 mm Hg (P=0.0054) in patients with liver failure caused by paracetamol. Similar results seen in patients with non-paracetamol acute liver failure
			Oxygen consumption	Increased from 127 to 184 ml/min/m2 in patients with liver failure caused by paracetamol. Similar results seen in patients with non-paracetamol acute liver failure
Devlin, J et al. February 1997 UK	Fifteen patients with hepatic dysfunction, either post transplant or during acute or acute-on-chronic liver failure. Patients given prostacyclin infusion, then wahout period, then N-acetylcysteine infusion. Physiological parameters pre- and post-infusions measured and compared.	Prospective, controlled experimental trial	Baseline oxygen delivery (DO2)	Increased from 667 +/- 154 to 751 +/- 166 ml/min/m2 following N-acetylcysteine (P<0.01). Only moderate improvement seen with prostacyclin.	Trial shows an increase in physiological parameters with acetylcysteine, but no evidence that this translates to a decrease in clinical morbidity or mortality in patients with non-paracetamol acute liver failure. Only small numbers of patients studied, not all of which had non-paracetamol acute liver failure.
			Oxygen consumption (VO2)	Improved from 150 +/- 30 to 169 +/- 25 ml/min/m2 following N-acetylcysteine (P<0.01). No improvement seen with prostacyclin.
			Indocyanine green clearance	Improved from 7.3 +/- 4.2% to 11.8 +/- 4.0% following N-acetylcysteine (P=0.002). No improvement seen with prostacyclin.
Walsh, TS et al. May 1998 UK	Patients with severe fulminant hepatic failure. 11 patients given N-acetylcysteine infusion, 7 given placebo infusion. Effects of infusions on haemodynamic parameters compared.	Prospective, controlled experimental trial	Oxgen delivery	No significant improvements seen with N-acetylcysteine compared to placebo	Trial looks for a change in physiological parameters with acetylcysteine, but no evidence that this translates to a change in clinical morbidity or mortality in patients with non-paracetamol acute liver failure. Only small numbers of patients studied, not all of which had non-paracetamol acute liver failure.
			Oxygen consumption	No significant improvements seen with N-acetylcysteine compared to placebo
			Base excess and whole blood lactate levels (a marker of tissue hypoxia)	No significant improvements seen with N-acetylcysteine compared to placebo

Comment(s)

There is no doubt that N-acetylcysteine has saved countless lives in the management of paracetmol haepatotoxicty. In the first instance, this is due to the N-acetylcysteine acting replenishing stores of glutathione, which prevents hepatic damage by binding to a toxic metabolite of paracetamol. However, the effects of N-acetylcysteine seem to go beyond this, as there is evidence that continued infusion of N-acetylcysteine has beneficial effects in patients with established paracetamol induced hepatic damage, long after paracetamol has been cleared. Thus, the next logical step is to ask if N-acetylcysteine has a role in acute liver failure not caused by paracetamol. The papers discussed above have started the ball rolling in answering this, through several different approaches. Experimental evidence in rats (Ritter et al.) would suggest there is a benefit, and two out three investigations (Harrison et al. and Devlin at al.) show a beneficial effect of N-acetylcysteine on various physiological parameters in humans. These papers are however beset by the weaknesses described above. Perhaps more promising are the actual case reports of N-acetylcysteine playing a role in recovery from acute liver failure (Eisen et al., Janes et al., and Ben-Ari et al.). These are, however, just isolated reports. One must remember that there may have been many times when N-acetylcysteine has been used but has failed to provide any benefit in the clinical setting. Such cases may not have been reported, thus creating a skewed view in the literature of only successful cases.

Clinical Bottom Line

At present, there is no evidence that N-acetylcysteine improves mordity or mortality in non-paracetamol acute liver failure. There are enough reports in the literature, however, that would suggest that a multicentre randomized controlled trial in this area would be very worthwhile.

References

1. Janes SE, Price CS, Thomas D. Essential oil poisoning: N-acetylcysteine for eugenol-induced hepatic failure and analysis of a national database. European journal of paediatrics 2005 Aug;164(8):520-2
2. Eisen JS, Koren G, Juurlink DN, Ng VL. N-acetylcysteine for the treatment of clove oil-induced fulminant hepatic failure. Journal clinical toxicology 2004;42(1):89-92
3. Ben-Ari Z, Vaknin H, Tur-Kaspa R. N-acetylcysteine in acute hepatic failure (non-paracetamol-induced). Hepatogastroenterology 2000 May-Jun;47(33):786-9
4. Ritter C, Reinke A, Andrades M, Martins MR, Rocha J, Menna-Barreto S, Quevedo J, Moreira JC, Dal-Pizzol F. Protective effect of N-acetylcysteine and deferoxamine on carbon tetrachloride-induced acute hepatic failure in rats Critical Care Medicine 2004 Oct;32(10):2079-83
5. Harrison PM, Wendon JA, Gimson AE, Alexander GJ, Williams R. Improvement by acetylcysteine of hemodynamics and oxygen transport in fulminant hepatic failure New England journal of Medicine 1991 Jun 27;324(26):1852-7
6. Devlin J, Ellis AE, McPeake J, Heaton N, Wendon JA, Williams R. N-acetylcysteine improves indocyanine green extraction and oxygen transport during hepatic dysfunction Critical care medicine 1997 Feb;25(2):236-42
7. Walsh TS, Hopton P, Philips BJ, Mackenzie SJ, Lee A. The effect of N-acetylcysteine on oxygen transport and uptake in patients with fulminant hepatic failure. Hepatology 1998 May;27(5):1332-40.