• 
• 

Three Part Question

[In children less than 18-year-old with non-acetaminophen acute liver failure] (patients), does [N-acetylcysteine (intervention) compared with placebo or standard treatment (comparison)] [improve survival (with or without liver transplantation) and morbidities (outcomes)]?

Clinical Scenario

A 14 year old boy is seen in the Emergency Department for exertional heat stroke that was subsequently complicated by multiorgan failure including acute liver failure (ALF). You wonder if N-acetylcysteine (NAC) which is used routinely in acetaminophen-induced ALF will be useful in the management of this teenager in the Children’s Intensive Care Unit (CICU).

Search Strategy

A literature search was performed using PubMed, Embase, CINAHL and clinicatrials.gov.
A further web search on google scholar was done.
[Liver failure, acute] AND [Acetylcysteine] AND [Child]

Search Outcome

A literature search, performed using PubMed, Embase and CINAHL using the keywords ‘(Liver failure, acute) AND (Acetylcysteine) AND (Child)’ yielded 77 articles. A search on clinicaltrials.gov did not reveal any additional relevant articles. A further web search on google scholar was done which yielded 1 additional article. For this evidence-based medicine review, we only included articles in the English language.
All 78 abstracts of potential articles were obtained and reviewed. 5 articles were unavailable and attempts made to contact the authors were unsuccessful. 4 articles were excluded as they were in a foreign language. 12 articles were found to be relevant.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Arit Parkas et al 2016 Pakistan	32 patients (5.5 – 9.5 years) with ALF of viral etiology were randomly divided into 2 groups: treatment with NAC and no treatment with NAC	Quasi experimental study	Hospital’s Lenth of stay	Shorter LOS for those treated with NAC (14.4 ± 6.7 vs. 23.8 ± 4.1 days; p = 0.001).	Non-blinded study with no placebo. Small sample size. Duration of treatment not known.
			Survival status	No difference in survival in both groups
Christine Kortsalioudaki et al 2008 United Kingdom	170 children with non-acetaminophen-induced ALF. Group 1 (1989-1994) (n =59, age range 0.003-15.8 years) received standard care. Group 2 (1995-2004) (n=111, 0.005-17.4 years) received NAC	Retrospective review	Overall survival	10 year survival was longer in those treated with NAC (75 vs. 50%, p =0.009).	Retrospective study design. Duration of NAC treatment varied [median 5 (range: 1 -77) days]
			Survival with native liver	More children survived with native liver in those treated with NAC (43 vs 22%, p = 0.005)
			Death without transplantation	No difference in death without transplantation
			Rate of re-transplantation	No difference in rate of re-transplantation
			Survival after transplantation	Survival after transplantation greater in group that received NAC ( 84 vs. 61%, p =0.02)
M P Senanayake et al June 2013 Sri Lanka	7 patients (6 months- 12 years) with dengue hemorrhagic fever/Dengue shock syndrome with ALF	Case series	Clinical (encephalopathy,survival, neurodevelopmental damage) outcome	All patients made complete recovery without residual hepatic or neuro-developmental damage	Retrospective study design. Small study size.
			Biochemical outcomes (platelet counts, international normalized ratio, liver transaminase levels, albumin)	Biochemical profiles improved from the first dose in all 7 patients
Robert H Squires et al April 2013 North America, United Kingdom	184 children (birth to 17 years) with non- acetaminophen ALF. 92 patients received continuous intravenous infusion of NAC and 92 patients received placebo	Adaptively allocated, double-masked, placebo-controlled study	1-year survival	No difference in 1-year survival between NAC and placebo groups (73% vs. 82%, p=0.19
			Survival without liver transplantation	One-year liver-transplant-free survival lower in those who received NAC vs placebo (35 vs. 53%, p =0.03)
			ICU and hospital length of stay, maximum degree of HE, number of organ systems failing.	No difference in ICU and hospital LOS, type or number of organ systems failing, or maximum grade of HE
Grabhorn E et al 2013 Germany	5 children (1-10 years) with fulminant hepatic failure secondary to severe Amanita Phalloides poisoning	Case series	Course of disease, Survival	All patients survived with no neurological sequelae	1 patient did not receive NAC. Small sample size.
Norberto Sotelo et al October-December 2009 Mexico	12 patients (ages 5-17 years) with ALF secondary to hepatitis A were treated with oral NAC	Case series	Description of clinical course	Laboratory values normalized in 8 days for half the patients, 10-15 days for 4 patients and 30 days for 2 patients	Small sample size.
Ali Faisal Saleem et al 2015 Pakistan	40 children (mean ages 80 ± 40 months) with ALF secondary to viral hepatitis received NAC	Retrospective review	Effectiveness in preventing mortality and morbidity by measuring change in laboratory and clinical parameters.	Statistically significant difference in Alanine aminotransferase, Aspartate aminotransferase and prothrombin time on admission comparing to discharge (p <0.001)	Small sample size. Lack of comparison group without NAC.

Comment(s)

Reports on the overall efficacy of NAC in non-acetaminophen ALF use in pediatrics have been inconsistent Till date, there is only one placebo-controlled clinical trial on 184 pediatric patients treated for non-acetaminophen ALF and this study did not show that NAC improved 1-year survival. Furthermore, one-year liver transplant-free survival was significantly lower with NAC, particularly among those less than 2 years old. The investigators postulated that this may be due to pathobiological mechanisms in non-acetaminophen ALF in children and that NAC may influence pathways involved in hepatic regeneration. In contrast, a retrospective review of 170 patients with non-acetaminophen induced- ALF demonstrated that NAC was safe and was associated with improved overall 10--year survival and higher incidence of native liver recovery without transplantation. Another retrospective study on 32 children with ALF secondary to various viral etiologies (most common etiology being Hepatitis A infection) demonstrated that children who were treated with NAC had a shorter length of stay but no difference in survival was shown between the groups. A smaller retrospective review of 40 children with fulminant hepatic failure, albeit one that only included ALF caused by hepatitis A infection showed that children who were treated with NAC had a significant improvement of liver enzymes and prothrombin time on admission compared to discharge. The level of evidence for the efficacy of NAC in non-acetaminophen induced ALF in children is low with only one small randomized trial conducted to date. Majority of studies that demonstrated positive results are retrospective in nature. Further prospective randomized controlled pediatric studies on the use of NAC will be required to address the impact of NAC in non-acetaminophen induced ALF in children.

Clinical Bottom Line

NAC use in children with non-acetaminophen liver failure does not improve 1-year survival (Recommendation: grade B).

References

1. Arit Parkas, Mohammad Asghar, Nighat Haider Non-acetaminphen Induced Acute Liver Failure of Viral Etiology: Treatment with and without N-acetylcysteine; comparing the length of hospital stay and survival status in children at the tertiary care Infectious Diseases Journal of Pakistan 2016. 25(01)
2. Christine Kortsalioudaki, Rachel M. Taylor, Paul Cheeseman, Sanjay Bansal, Giorgina Mieli-Vergani, Anil Dhawan Safety and Efficacy of N-acetylcysteine in Children with Non-Acetaminphen-Induced Acute Liver Failure Liver Transplantation 2008; 14;25-30
3. M P Senanayaki, M D C J P Jayamanne, I Kankananarachchi N-acetylcysteine in children with acute liver failure complicating dengue viral infection The Ceylon Medical Journal 2013; 58(2): 80-82
4. Robert H Squires, Anil Dhawan et al Intravenous N-acetylcysteine in Pediatric Patients with Non-Acetaminophen Acute Liver Failure: A Placebo-controlled Clinical Trial Hepatology 2013 April; 57(4): 1542-1549
5. Grabhorn E, Nielson D, Hillebrand G, Brinkert F, Herden U, Fischer L, Ganschow R Successful outcome of severe Amanita phalloides poisoning in children Pediatric Transplantation 2013; 17(6): 550-555
6. Norberto Sotelo, Maria de los Angeles Durazo, Alejandro Gonzalez, Nagasharmila Dhanakotti Early treatment with N-acetylcysteine in children with acute liver failure secondary to hepatitis A Annals of Hepatology 2009; 8(4): 353-358
7. Ali Faisal Saleem, Qalab Abbas, Anwar ul Haque Use of N-Acetylcysteine in Children with Fulminant Hepatic Failure Caused by Acute Viral Hepatitis Journal of the College of Physicians and Surgeons Pakistan 2015, 25(5): 354-358