Dosage of N-Acetyl Cysteine in Acute Liver Failure Not Related to Acetaminophen

We thank Dr Saurabh for his interest in the article INASL-Consensus Statement on Acute Liver Failure (Part-2)-Management of Acute Liver Failure¹ and for pointing out the printing error.

The use of N-acetyl cysteine (NAC), a glutathione precursor, was initially introduced in the 1970s for the treatment of acetaminophen-induced ALF, and its safety/efficacy is well established in this fatal condition.^2,3 NAC has also been shown to provide beneficial effect in non-Acetaminophen ALF (NA-ALF).⁴ Various prospective studies and meta-analyses have also shown a beneficial effect of NAC in improving overall survival (OS), transplant-free survival (TFS) or even post-transplant survival (PTS).⁵ A few studies have, however, failed to show significant improvement in overall survival when compared to placebo.^2,6 In a recent meta-analysis of seven studies, the use of NAC was associated with improvement in OS, TFS, and PTS in patients with NA-ALF.⁷ There was a significant reduction in the duration of hospital stay. In this meta-analysis, the most common etiology of ALF was acute viral hepatitis. It was concluded that NAC should be used in all patients with NA-ALF especially in nontransplant centers and for optimal outcomes it is preferable to initiate treatment in the early stages of ALF.

NAC is available as Intravenous (200 mg/mL, 10 mL ampoule) and oral liquid formulation (10% and 20%) of NAC.⁸ Traditionally dosage protocol for NAC for acetaminophen-induced ALF includes a 21-h intravenous protocol, which includes (a) 150 mg/kg of NAC 20% in 200 mL 5% dextrose over 60 min followed by (b) 12.5 mg/kg/hour in 500 mL 5% dextrose for 4 h and then (C) 6.25 mg/kg/hour in 1000 mL 5% dextrose for 16 h). Instead of 5% dextrose, 0.9% normal saline can also be used.⁹ For children less than 12 years a body weight of more than 20 kg, the recommended volumes of 5% dextrose are 100 mL, 250 mL, and 500 mL for three dosages, respectively. In children with a body weight of less than 20 kg, the diluting volumes of 5% dextrose at 3 mL/kg, 7 mL/kg, and 14 mL/kg, respectively, have been used. At the end of 21 h infusion, it has been suggested that infusion be continued till encephalopathy resolves and INR normalizes.¹⁰

In the older studies, NAC has been used either by intravenous route or orally in patients with NA-ALF. The intravenous route has been preferred by many.¹¹ A systemic review comparing oral and intravenous NAC showed a similar level of hepatotoxicity in rats with acetaminophen overdose, and the route of dosing did not make much difference.⁷ One fears that oral NAC may have impaired absorption in, poor tolerance (due to nausea and vomiting), delayed gastric emptying and intestinal failure in the setting of ALF.¹¹ A prospective study that included the sick patients with ALF failed to show any significant benefit (in terms of OS and duration of hospital stay) using NAC by oral route.³ Therefore intravenous administration of NAC was preferred over the oral route by the INASL consensus document. INASL has recommended the dosage used by most of the studies.^5,12,13 The safety and tolerability of NAC is well established and minor adverse events reported include allergic reactions (Bronchospasm, rash), cardiac arrhythmias and peripheral edema.⁷ A summary of these studies have been provided in Table 1.^1,3,5,12, 13, 14, 15, 16, 17

Table 1.

Various Dosage Schedules for the Use of NAC for Non-acetaminophen Acute Liver Failure.

Study reference	Etiology of ALF	NAC regimen used	Route of administration
Kortsalioudaki et al, 200814	Infective/AIH/Metabolic/DILI/Indeterminate	100 mg/kg/24 h infusion until normalization of INR, death or LT. Median duration of treatment-5 (1–77) days	Intravenous
Lee et al, 20095	DILI/AIH/HBV/Indeterminate	150 mg/kg body weight followed by 12.5 mg/kg/hour over 4 h and then 6.25 mg/kg/hour over 16 h. Continued for remaining 67 h	Intravenous
Kumarasena et al, 201015	Dengue infection	150 mg/kg body weight followed by 12.5 mg/kg/hour over 4 h and then 6.25 mg/kg/hour up to72 h	Intravenous
Mumtaz et al, 20093	Infective/DILI/AFLP	140 mg/kg, followed by 70 mg/kg, for a total of 17 doses, 4 h apart starting within 6 h of admission.	Oral
Soteolo et al, 200916	HAV	100 mg/kg every 4 h × 16 h, followed by 100 mg/kg every 6–8 h depending on clinical/laboratory improvement	Oral
Parkash et al, 201617	HAV/HEV/Non-A to E	100 mg/kg/24 h continuous infusion till normalization of INR or death, median duration of treatment-15.5 days	Intravenous
Darweesh et al 201712	Infective/DILI/Pregnancy related	150 mg/kg infusion over 30 min followed by 70 mg/kg over 4 h, then 70 mg/kg over 16 h Afterwards 150 mg/kg/24 h till 2 INR reports are normal	Intravenous
Nabi et al, 201713	Infective/DILI/AIH	150 mg/kg body weight followed by 12.5 mg/kg/hour over 4 h and then 6.25 mg/kg/hour over 16 h, continued for remaining 67 h	Intravenous
INASL Consensus recommendation1	ALF all etiologies	(a) 150 mg/kg body weight in 250 mL of 5% dextrose over 1 h followed by (b) 50 mg/kg over 4 h and then (c) 100 mg/kg over 16 h. The latter dose, i.e. 100 mg/kg over 16 h, may be repeated till encephalopathy and INR normalize.	Intravenous

Note: ALF, acute liver failure; NAC, N-acetyl cysteine; AIH, autoimmune hepatitis; DILI, drug-induced liver injury; HBV, hepatitis B virus; HAV, hepatitis A virus; AFLP, acute fatty liver of pregnancy.

INASL consensus document for ALF, after due deliberation, recommended that NAC be administered intravenously in all patients with NA-ALF. The recommended regimen should read (a) 150 mg/kg body weight in 250 mL of 5% dextrose over 1 h followed by (b) 50 mg/kg over 4 h and then (c) 100 mg/kg over 16 h. The latter dose, i.e., 100 mg/kg over 16 h, may be repeated till encephalopathy and INR normalize. The time period of 16 h was wrongly printed as 6 h. We duly acknowledge this unintentional printing mistake, which may be corrected. An erratum has also been requested to be published in the upcoming issue of the journal.

Conflicts of interest

The authors who have taken part in this study declare that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.