Is there any evidence for using N-acetylcysteine in acute liver failure due to shock (i.e., hypotension due to septic on pressors after cardiac arrest)?

Is there any evidence for using N-acetylcysteine (acetadote) in acute liver failure due to shock (ie hypotension due to septic on pressor - Shocked liver, or shock after cardiac arrest)?

Comment by InpharmD Researcher

Evidence supporting the use of N-acetylcysteine (NAC) in shock liver is limited, primarily consisting of case reports and observational studies, with mixed findings regarding clinical benefit. No standardized recommendations exist for NAC in this context. In non–acetaminophen-induced acute liver failure (NAI-ALF), individual studies report conflicting outcomes, but pooled data suggest NAC may improve overall survival. Common NAI-ALF etiologies include drug-induced liver injury, autoimmune hepatitis, and viral hepatitis, with less frequent causes such as hypoperfusion (from infection or sepsis), Wilson’s disease, and pregnancy-related ALF. These etiologies have also been clarified in the summaries and tables below. Notably, several studies specifically excluded patients with hepatic ischemia (shock liver) and septic shock, and the evidence for NAC in these populations remains largely limited to case reports. Despite some uncertainty, guideline societies recommend NAC for NAI-ALF, and no major safety concerns have been identified. We apologize for the limited legibility of the tables and have made our best attempts to ensure they are readable. In some cases, tables may appear small depending on screen resolution or zoom level.

Background

Per 2017 American Gastroenterological Association Institute (AGA) guidelines for the diagnosis and management of acute liver failure, no dosing recommendations were given for patients presenting with non-acetaminophen-associated acute liver failure, as the panel recommends N-acetyl cysteine (NAC) be used only in the context of clinical trials. The recommendation was based on two randomized controlled trials (RCTs) which demonstrated no effect on overall mortality with NAC when compared to placebo in 228 patients with non-acetaminophen-associated acute liver failure; the direct references for those 2 RCTs were not provided within the guidelines. In cases of acute liver failure of indeterminate cause, NAC can be considered given that those indeterminate cases may be related to acetaminophen overdose. [1]

As opposed to the 2017 AGA guidelines, the 2011 American Association for the Study of Liver Disease (AASLD) guidelines concluded that NAC may be beneficial for acute liver failure secondary to non-acetaminophen-related-drug-induced liver injury based on Lee et al.’s double-blinded RCT (N= 173; summarized in Table 3) in which intravenous NAC appeared to improve spontaneous survival when administered early during grades I and II coma stages. The study administered IV NAC infusion for 72 hours (initial loading dose of 150 mg/kg over 1 hour, followed by 12.5 mg/kg/h for 4 hours and continuous infusion of 6.25 mg/kg/h for remaining 67 hours). However, no maximum recommended dose was provided within the AASLD guidelines. [2]

According to the 2011 American Association for the Study of Liver Diseases (AASLD) guidelines, acute liver failure (ALF) is defined as the rapid onset of hepatic dysfunction—marked by an INR ≥1.5 and any degree of encephalopathy—in a patient without preexisting cirrhosis, occurring within 26 weeks of symptom onset. Non–acetaminophen-induced ALF encompasses cases arising from causes other than acetaminophen toxicity, including drug-induced liver injury, viral hepatitis, autoimmune hepatitis, and hepatic hypoperfusion, with approximately 15% of cases having no identifiable etiology. In contrast to the 2017 AGA guidelines, the AASLD guidelines concluded that N-acetylcysteine (NAC) may provide clinical benefit in ALF secondary to non–acetaminophen-related drug-induced liver injury, based on a double-blind randomized controlled trial conducted by Lee et al. (N=173; summarized in Table 3). In this study, a 72-hour IV NAC regimen—administered as a 150 mg/kg loading dose over 1 hour, followed by 12.5 mg/kg/h for 4 hours, and then 6.25 mg/kg/h for 67 hours—was associated with improved spontaneous survival when initiated early in patients with grade I–II hepatic encephalopathy, although the AASLD guidelines did not specify a maximum recommended dose. [2]

A 2021 updated meta-analysis included prospective, retrospective, and RCTs of NAC use in non-acetaminophen-related acute liver failure to analyze the American Association for the Study of Liver Diseases (AASLD) suggestion that NAC may be beneficial for non-acetaminophen-related-drug-induced liver injury. Participants ranged from neonates to adults (median age ~22 years), and etiologies of acute liver failure included drug-induced liver failure (n= 102), viral hepatitis (n= 213), autoimmune (n= 32), metabolic (n= 45), and other (e.g., infection, undetermined, pregnancy-related [n= 284]). [3]

NAC was well tolerated, with overall odds of survival in 7 studies (N= 883) being 1.77 times higher in those who received NAC (95% confidence interval [CI] 1.3 to 2.41; p<0.001), with favorable results also seen with NAC use for post-transplant and transplant-free survival. The study authors noted that due to the representation of multiple causes for acute liver failure for those awaiting transplants, findings suggest a potential role of NAC for other causes than acetaminophen-induced liver injury. However, this meta-analysis did not provide an agreed-upon/consistent dosage regimen of NAC among included studies, except that the route of administration was intravenous in 6 studies and oral in 1 study. [3]

International consensus statements recommend intravenous N-acetylcysteine (NAC) for all patients with non–acetaminophen-induced acute liver failure. The suggested regimen is a 150 mg/kg loading dose in 250 mL of 5% dextrose over 1 hour, followed by 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours; the 16-hour infusion may be repeated until encephalopathy and INR normalize. This guidance is based on three randomized trials evaluating NAC in non–acetaminophen-induced ALF, though only one trial demonstrated a statistically significant mortality benefit. A post hoc analysis of the largest trial (Lee et al.) found significantly improved transplant-free survival in patients with grade I/II encephalopathy (52% vs 30%; p=0.01), supporting NAC’s potential utility, particularly in virus- and drug-induced cases. In this study, the most common ALF etiologies were drug-induced liver injury, autoimmune hepatitis, and hepatitis B virus. [4], [5], [6]

An abstract published in 2024 describes a study that evaluated the use of NAC in ALF from cardiogenic shock (CS) between 2017 and 2022. A total of 69 patients were included in the study, 23 of whom received NAC, and 46 of whom did not receive NAC. Significantly more patients receiving NAC required mechanical ventilation (82.6% vs. 47.8%; p= 0.009), continuous renal replacement therapy or intermittent hemodialysis (69.6% vs. 21.7%); p<0.001), venoarterial extracorporeal membrane oxygenation (V-A ECMO; 34.8% vs. 6.5%; p= 0.005), and 2 or more temporary mechanical circulatory support devices (34.8% vs. 8.7%; p= 0.015) compared to patients who did not receive NAC. The NAC group, however, experienced a greater reduction in alanine aminotransferase (ALT) levels at 24 hours (13.5% vs. 4.2%: p= 0.03) and 72 hours (80.3% vs. 43.6%; p= 0.03); this persisted at 24 hours after adjusting for V-A ECMO (p= 0.04). Despite the reduction in ALT, the NAC group had a longer intensive care unit stay (16 vs. 5 days; p= 0.009), and there was no mortality benefit with the use of NAC (65.1% vs. 58.7%; p= 0.79). [7]

Literature Review

A search of the published medical literature revealed 12 studies investigating the researchable question:

Is there any evidence for using N-acetylcysteine (acetadote) in acute liver failure due to shock (ie hypotension due to septic on pressor - Shocked liver, or shock after cardiac arrest)?

Level of evidence

D - Case reports or unreliable data Read more→

Please see Tables 1-12 for your response.

N-acetyl Cysteine Use in the Treatment of Shock Liver
Design	Case report
Case presentation	A 79-year-old male with atrial fibrillation and chronic lymphocytic leukemia presented with worsening dyspnea and cold symptoms. He was found to be hypotensive (80/40 mmHg) and tachycardic (heart rate 158 bpm) with atrial fibrillation with rapid ventricular response (RVR). Initial labs showed elevated liver enzymes (aspartate aminotransferase [AST] 1,216 units/L, alanine aminotransferase [ALT] 736 units/L), lactic acidosis (9.4 mmol/L), and coagulopathy (INR 1.93), which worsened significantly. Repeat liver function test trended up (AST 5,028 units/L and ALT 2,328 units/L). He was admitted to the intensive care unit (ICU) for severe sepsis with multiorgan dysfunction, acute liver failure, and renal failure. Treatment included intravenous (IV) diltiazem, IV fluids, a 72-hour N-acetylcysteine (NAC) protocol, and antibiotics. Over 48-72 hours, his blood pressure and acidosis improved, HR stabilized, and liver enzymes trended downward. Workup for alternative liver injury causes was negative. He tolerated NAC without side effects. With improved mental status and stable vitals, he was transferred to a step-down unit and later discharged on oral antibiotics with outpatient follow-up.
Study Author Conclusions	A beneficial role for NAC in non-acetaminophen-induced liver failure has been established in several randomized controlled trials and prospective studies. However, its use in severe sepsis, a life-threatening condition, has been not been thoroughly reported. This case report highlights the use of NAC in liver failure secondary to severe sepsis. Further research is needed to establish guidelines for this intervention.

References:

Parvataneni S, Vemuri-Reddy S. N-acetyl Cysteine Use in the Treatment of Shock Liver. Cureus. 2020;12(2):e7149. Published 2020 Feb 29. doi:10.7759/cureus.7149

Role of N-Acetylcysteine Treatment in Non-Acetaminophen-Induced Acute Liver Failure: A Prospective Study
Design	Hospital-based prospective randomized case-control trial N= 80
Objective	To determine the effect of N-acetylcysteine (NAC) on the mortality of non-acetaminophen-induced acute liver failure (NAI-ALF) patients, as well as to evaluate the safety and efficacy of NAC use
Study Groups	NAC (n= 40) Control (n= 40)
Inclusion Criteria	Above the age of 18 years, confirmed NAI-ALF. *ALF was defined as biochemical evidence of ALF with INR of ≥1.5 and any degree of encephalopathy caused by illness of duration <8 weeks (fulminant hepatic failure).
Exclusion Criteria	Acetaminophen-induced ALF (on the basis of detailed history), ALF during pregnancy, acute or chronic liver failure, prior exposure to NAC, hepatic ischemia (shock liver).
Methods	NAC group received intravenous NAC infusion for 72 hours (initial loading dose of 150 mg/kg over 1 hour, followed by 12.5 mg/kg/h for 4 hours and continuous infusion of 6.25 mg/kg/h for remaining 67 hours), whereas the control group received placebo (5% dextrose). Patients were followed until discharge or death in hospital.
Duration	Between September 2011 to September 2013.
Outcome Measures	Survival, mortality, inpatient hospital stay.
Baseline Characteristics		NAC group (n= 40)	Control group (n= 40)	p-Value
	Age, years	30.60 ± 11.64	38.48 ± 20.11	0.035
	Male	17 (42.5%)	24 (60%)	0.122
	Hepatic encephalopathy Grade I Grade II Grade III Grade IV	10 (25%) 13 (32.5%) 7 (17.5%) 10 (25%)	21 (52.5%) 8 (20%) 7 (17.5%) 4 (10%)	0.054
	Fever	19 (47.5%)	10 (25%)	0.041
	Vomiting	12 (30%)	10 (25%)	0.618
	INR Bilirubin, mg/dL AST, mg/dL ALT, mg/dL Albumin, g/dL Creatinine, mg/dL	2.87 ± 1.19 21.12 ± 8.94 1,726 ± 983.4 1,050.78 ± 717.46 2.83 ± 0.55 1.45 ± 0.81	2.51 ± 0.78 20.67 ± 9.54 1,462 ± 678.8 1,055.80 ± 569.04 2.90 ± 0.75 1.35 ± 0.65	0.114 0.827 0.166 0.972 0.635 0.555
	Interval between jaundice and encephalopathy, days	22 ± 11.4	28 ± 18.2	0.081
	MELD score	31.83 ± 6.74	30.48 ± 5.04	0.313
	Etiology of ALF Acute hepatitis E Acute hepatitis A Acute hepatitis B Drug-induced ALF Undetermined etiology Others*	7 (17.5%) 5 (12.5%) 4 (10%) 10 (25.0%) 13 (32.5%) 1 (2.5%)	7 (17.5%) 3 (7.5%) 4 (10%) 5 (12.5%) 17 (42.5%) 4 (10.0%)	1 0.460 1 0.399 0.359 0.393
	* One patient of Wilson-induced ALF in each group. Control group comprised one patient each of autoimmune, cytomegalovirus (CMV), and herpes simplex virus (HSV)
Results	Endpoint	NAC group	Control group	p-Value
	Survival	29/40 (72.5%)	19/40 (47.5%)	0.025
	Survival stratified by etiology Undetermined (n= 30) Drug (n= 15) Viral (n= 30) Hepatitis E virus (HEV) (n= 14)	13 (42.3%) 10 (66.7%) 16/30 (53.3%) 7/14 (50%)	17 (56.7%) 5 (33.3%) 14/30 (46.7%) 7/14 (50%)	0.318 0.049 0.303 0.602
	Mortality	27.5%	52.5%	Adjusted odds ratio (4.650; p=0.010)
	Duration of hospital stay of survived patients, days	8.241 ± 2.115	10.737 ± 3.106	0.002
Adverse Events	No adverse effects were noted in patients that could have been attributed to NAC administration.
Study Author Conclusions	The findings of the study recommend the use of NAC along with conventional treatments in patients with NAI-ALF in non-transplant centers while awaiting referrals and conclude the use of NAC as safe.
InpharmD Researcher Critique	Significant between-study group heterogeneity in regard to the grade of encephalopathy, age, and fever. The authors noted that the exclusion of acetaminophen-induced ALF was on the basis of history rather than biochemical confirmation which was not available in the hospital.

References:

Nabi T, Nabi S, Rafiq N, et al. Role of N-acetylcysteine treatment in non-acetaminophen-induced acute liver failure: A prospective study. Saudi J Gastroenterol. 2017;23(3):169-175. doi:10.4103/1319-3767.207711

Intravenous N-Acetylcysteine Improves Transplant-Free Survival in Early Stage Non-Acetaminophen Acute Liver Failure
Design	Prospective, double-blind, multicenter, randomized, controlled trial N= 173
Objective	To determine if N-acetylcysteine (NAC) increases the overall survival rate of patients with non-acetaminophen-related acute liver failure.
Study Groups	NAC (n= 81) Placebo (n= 92)
Inclusion Criteria	Age 18 years and older, evidence of acute liver failure (any degree of encephalopathy and coagulopathy; international normalized ratio [INR] ≥ 1.5) due to an illness of < 24 weeks duration
Exclusion Criteria	Known or suspected acetaminophen overdose, previously received NAC, hepatic ischemia (shock liver), liver failure caused by pregnancy or cancer, refractory hypotension, septic shock, expected transplantation < 8 hours, age >70 years old
Methods	Prospective data including serum, tissue, and DNA were collected on all patients eligible for the study. Patients were stratified by site and coma grade (I-II vs III-IV) and were randomly assigned to receive 5% dextrose with NAC IV infusion or placebo (5% dextrose) infusion at an initial loading dose of 150 mg/kg/hour of NAC over 1 hour followed by 12.5 mg/kg/hour for 4 hours, then continuous infusions of 6.25 mg/kg NAC for the remaining 67 hours.
Duration	1998-2006
Outcome Measures	Primary Outcome: overall survival at 3 weeks (21 days) Secondary Outcomes: transplant-free survival and transplantation rate
Baseline Characteristics		NAC (n= 81)	Placebo (n= 92)
	Age, years (range)	42 (17-69)	40.5 (18-71)
	Female	47%	68%
	Caucasian	56%	55%
	Coma grade I-II on admission	73%	62%
	Creatinine level, mg/dL	1.3 (0.2-6.6)	1.0 (0.5-9.5)
	INR	2.4 (1.4-20.1)	2.9 (1.1-14)
	ALT level, IU/L	999 (13-10,153)	756.5 (31-13,100)
	Etiolgy of liver failure Drug induced liver injury Autoimmune hepatitis Hepatitis B virus Indeterminate	23% 14% 31% 32%	28% 16% 13% 28%
Results	Endpoint	NAC (n= 81)	Placebo (n= 92)	p-Value	Odds ratio (95% confidence interval)
	Overall survival at 3 weeks Coma category I-II Coma category III-IV Total	79% 48% 70%	75% 53% 66%	.292 .645 .283	1.28 (0.53 to 3.07) 0.82 (0.29 to 2.34)
	Transplant-free survival Coma category I-II Coma category III-IV Total	52% (n= 58) 9% (n= 23) 40%	30% (n= 56) 22% (n= 36) 27%	.010 .912 .043	2.46 (1.14 to 5.30) 0.33 (0.06 to 1.74)
	Transplantation rate Coma category I-II Coma category III-IV Total	28% 43% 32%	46% 42% 45%	.037 .891 .093	0.44 (0.20 to 0.96) 1.08 (0.37 to 3.10)
Adverse Events	Common Adverse Events: nausea and vomiting (14% NAC patients vs. 4% placebo patients, p=.031)
	Serious Adverse Events: arrhythmia (9% NAC vs. 10% placebo, p= 0.796)
	Percentage that Discontinued due to Adverse Events: N/A
Study Author Conclusions	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.
InpharmD Researcher Critique	This study did not include an equal number of patients with early and late coma grade patients; 114 patients with coma grade I-II were enrolled vs. 59 with grade III-IV.

References:

Lee WM, Hynan LS, Rossaro L, et al. Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure [published correction appears in Gastroenterology. 2013 Sep;145(3):695. Dosage error in article text]. Gastroenterology. 2009;137(3):856-864.e1. doi:10.1053/j.gastro.2009.06.006

Non-Acetaminophen 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 Hospital
Design	Quasi-experimental study N= 32
Objective	To determine the role of N-acetylcysteine (NAC) in acute liver failure (ALF) secondary to viral etiology in children
Study Groups	Child with NAC in treatment (n= 16) Child without NAC in treatment (n= 16)
Inclusion Criteria	Children of either sex, between the ages of 5 to 13 years, presenting with non-acetaminophen induced ALF of viral etiology, admitted to the pediatric unit of NICH.
Exclusion Criteria	Children presenting with acetaminophen-induced ALF or other etiologies like autoimmune hepatitis and Wilson disease.
Methods	Children treated with NAC were included in group A and children not given NAC were enrolled in group B. NAC was administered as a continuous intravenous infusion (100 mg/kg/24 hours) until normalization of the INR or death.
Duration	December 2013 to December 2014.
Outcome Measures	Length of hospital stay, mortality.
Baseline Characteristics		Child with NAC in treatment (n= 16)	Child without NAC in treatment (n= 16)	p-Value
	Age, years	7.5±1.366	7.6±1.232	0.615
	Male	10 (62.5%)	12 (75%)	0.4456
	Etiologies of ALF HAV Non A-E HBV Co-infection HAV & HEV	10 (62.5%) 3 (18.8%) 2 (12.5%) 1 (6.25%)	13 (81.3%) 2 (12.5%) 1 (6.25%) 0	-
	Hepatic encephalopathy I II III IV	5 (15.6%) 7 (22%) 3 (9.4%) 1 (3.1%)	6 (18.7%) 4 (12.5%) 4 (12.5%) 2 (6.2%)	0.709
	Investigations Total bilirubin, mg/dL Direct bilirubin, mg/dL AST ALT Prothrombin time Albumin Serum potassium, mEq/L Serum creatinine, mg/dL Platelets, /ul	7.9±5.2 6.1±4.3 1360.4±540.2 1401.9±612.0 55.00±14.41 2.744±0.333 3.819±0.617 0.969±0.679 224813±123934	7.9±4.5 6.6±4.2 1405.6±467.6 1446.2±526.8 61.56±14.21 2.650±0.398 3.85±0.637 1.2±0.792 203938±151615	0.892 0.334 0.422 0.442 0.2779 0.5636 0.908 0.419 0.701
Results	Endpoint	Child with NAC in treatment (n= 16)	Child without NAC in treatment (n= 16)	p-Value
	Mean length of hospital stay, days	14.4±6.7	23.8±4.1	0.001
	Survival	11 (68.75%)	7 (43.75%)	0.154
	All 16 patients received NAC for a median duration of 15.5 days. Further analysis for survival status according to the grade of encephalopathy demonstrated statically significant evidence in patients with hepatic encephalopathy grade 1 & 2, that who received NAC had higher survival than Non-NAC group. Results from above studies indicates that NAC augments recovery in some earlier stages of encephalopathy beyond that perhaps significant irreversible damages to body organ occur that have less response to this drug that may be evaluated in further studies.
Adverse Events	N/A
Study Author Conclusions	There was no significant difference in the overall survival of patients treated with NAC and without NAC. There was a significant improvement in survival observed in patients with early-stage of encephalopathy grades 1& 2 treated with N-Acetylcysteine.
InpharmD Researcher Critique	The study is limited in that it is a single-center study conducted in Pakistan with a small number of patients. This is a quasi-experimental study with non-probability consecutive sampling. The secondary survival analysis stratified by encephalopathy grade is merely exploratory.

References:

Parkas A, Asghar M, Haider N. Non-acetaminophen 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 hospital. Infect Dis J Pakistan. 2016;25:11–14.

Impact of Duration of N-Acetylcysteine in Non-Acetaminophen-Induced Acute Liver Failure
Design	Retrospective cohort study N= 63
Objective	To compare differences in patient outcomes based on intravenous (IV) N-acetylcysteine (NAC) duration
Study Groups	Standard duration NAC (≤72 hr) (n= 40) Extended duration NAC (>72 hr) (n= 13)
Inclusion Criteria	Age ≥ 18 years, admitted to the medical ICU during a defined period, received IV N-acetylcysteine for the diagnosis of non-acetaminophen–induced acute liver failure (NAI-ALF)
Exclusion Criteria	Etiology of ALF was attributed to acetaminophen overdose, hypoxic hepatitis, or alcohol-associated hepatitis.
Methods	Eligible patients were divided into cohorts based on the duration of IV NAC. There was no standard dosing regimen regarding the dose of IV NAC. If patients were receiving IV NAC outside of the hospital, only the administration within the institution was considered for total duration of therapy.
Duration	Between January 2008 and December 2018.
Outcome Measures	Primary outcome: Time to normalization of INR to less than 1.3 or less than 1.5. Secondary outcomes: All-cause mortality, transplant-free survival at 3 weeks.
Baseline Characteristics		Standard duration NAC (≤72 hr) (n= 40)	Extended duration NAC (>72 hr) (n= 13)	p-Value
	Age, years	52.2 ± 15.5	52.2 ± 13.2	0.99
	Female	28 (70%)	9 (69.2%)	1.0
	Weight, kg	89.7 ± 23.9	69.3±18.2	<0.01
	Etiology of NAI-ALF Viral hepatitis Autoimmune hepatitis Drug-induced liver injury Amanita mushroom Hemophagocytic lymphohistiocytosis Wilson disease Rhabdomyolysis Other^a Unknown	7 (17.5%) 1 (2.5%) 6 (15%) 2 (5%) 4 (10%) 3 (7.5%) 3 (7.5%) 6 (15%) 8 (20%)	3 (23.1%) 0 3 (23.1%) 5 (38.5%) 0 0 1 (7.7%) 0 1 (7.7%)	0.79
	Median coma grade^b on day of N-acetylcysteine initiation	2 (2-3)	2 (1–3)	0.35
	INR on day of NAC initiation, median (IQR)	3 (2.2–3.7)	2.5 (1.8–7)	0.8
	Bilirubin on day of NAC initiation, mg/dL, median (IQR)	7.3 (3.6–15.7)	4.7 (1.6–7.6)	0.08
	Serum creatinine on day of NAC initiation, mg/dL, median (IQR)	2.2 (1.3–3.7)	1 (0.6–2.2)	0.05
	Total duration of NAC, hr, median (IQR)	32.6 (21–51.3)	106.3 (84.5–142.6)	<0.01
	Total dose in mg/kg received, median (IQR)	330 (300–452.9)	753.7 (697–1,003.6)	< 0.01
	Total cost of NAC therapy, U.S. dollars^d, median (IQR)	1,396.61 (1,121.46–1,755.63)	2,430.90 (2,003.89–3,111.94)	< 0.01
	^aOther etiologies include cholestasis (n = 2), Budd-Chiari (n = 1), congestive hepatopathy (n = 2), sickle cell (n = 1). ^bPer West Haven criteria. ^dBased on average wholesale price of $8.62 per 200 mg/mL vial.
Results	Endpoint	Standard duration NAC (≤72 hr) (n= 40)	Extended duration NAC (>72 hr) (n= 13)	p-Value
	Time to INR < 1.5, days, median (IQR)	4 (2–10)	4 (2–6)	0.61
	Proportion achieving INR < 1.5, median (IQR)	21 (52.5%)	11 (84.6%)	0.04
	Time to INR < 1.3, days, median (IQR)	4 (3–10)	4 (3–6)	0.84
	Proportion achieving INR < 1.3, median (IQR)	20 (50%)	11 (84.6%)	0.04
	Liver transplant	11 (27.5%)	3 (23%)	1.0
	Transplant-free survival^a	12/29 (41.4%)	10/13 (76.9%)	0.03
	All-cause mortality at 3 wk^a	7/29 (24.1%)	0/13 (0%)	0.08
	ICU length of stay (LOS) (survivors), days, median (IQR)	8 (3–11)	8 (7–11)	0.92
	Hospital LOS (survivors), days, median (IQR)	16 (10–22)	12 (10–17)	0.47
	^aExcludes those who died within the first 72 hr (n = 11).
Adverse Events	Common Adverse Events: N/A
Study Author Conclusions	Patients with NAI-ALF who received extended duration N-acetylcysteine were found to have significantly higher transplant-free survival than patients who received standard duration, although there was no significant difference in time to normalization of international normalized ratio or overall survival. A prospective, randomized, multicenter study is warranted to identify subpopulations of patients with non-acetaminophen-induced acute liver failure who could benefit from extended treatment duration as a bridge to transplant or spontaneous recovery.
InpharmD Researcher Critique	This study is subject to the limitations inherent to a retrospective analysis. Selection bias may have influenced the results. Due to its retrospective nature, the study was unable to account for any potential increased adverse effects of extended duration IV NAC, such as hypotension and flushing. The point estimate of effect suggests no major difference between the groups with respect to the primary outcome.

References:

Bass SN, Lumpkin M, Mireles-Cabodevila E, et al. Impact of Duration of N-Acetylcysteine in Non-Acetaminophen-Induced Acute Liver Failure. Crit Care Explor. 2021;3(5):e0411. doi: 10.1097/CCE.0000000000000411

Effect of N-Acetylcysteine on Mortality and Liver Transplantation Rate in Non-Acetaminophen-Induced Acute Liver Failure: A Multicenter Study
Design	Prospective, multicenter, observational study N= 155
Objective	To study the value of intravenous NAC in reducing liver transplantation and mortality in non-acetaminophen-induced acute liver failure (NAI-ALF)
Study Groups	NAC (n= 85) Control (n= 70)
Inclusion Criteria	NAI-ALF patients, as evidenced by jaundice (bilirubin >25 µmol/L) and coagulopathy (elevated INR >1.5) with or without encephalopathy
Exclusion Criteria	Age below 18 or greater than 70 years, known or suspected acetaminophen intake 2–3 days before admission, liver failure due to cancer, previous intake of oral NAC, ischemic hepatitis due to severe heart failure, or heart surgery
Methods	NAC was given as an infusion of 150 mg/kg in 100 ml dextrose 5% over 30 min, followed by 70 mg/kg in 500 ml dextrose 5% over 4 h, then 70 mg/kg in 500 ml dextrose 5% over 16 h. Subsequently, a continuous infusion of 150 mg/kg in 500 ml dextrose 5% over 24 h was continued until two consecutive INR results of less than 1.3. The patient was then switched to oral NAC at a dose of 600 mg/day and was discharged 2–3 days after the change to oral NAC.
Duration	From January 2011 to December 2013
Outcome Measures	Primary outcome: Reduction in mortality or liver transplantation Secondary outcomes: Length of ICU and hospital stays, organ system failure, and hepatic encephalopathy
Baseline Characteristics		NAC (n= 85)	Control (n= 70)	p-Value
	Age, years	33.5 ± 11	34.8 ± 8.8	-
	Female	34 (40%)	28 (40%)	-
	Encephalopathy at admission	24 (28.2%)	25 (35.7%)	1.0
	Encephalopathy grade 0 I–II III–IV	61 (71.7%) 20 (23.5%) 4 (4.7%)	45 (64.2%) 19 (27.1%) 6 (8.5%)	0.7
	Cause of ALF Viral infection HAV HBV HEV CMV HAV + HEV EBV Drugs* Pregnancy With viral infection Pregnancy-related SLE	41 (46.7%) 12 11 6 8 3 1 (with INH) 31 (36.7%) 5 (6.7%) 5 (6.7%) 3 (3.3%)	40 (56.7%) 10 14 5 6 3 2 (with liver iron overload) 28 (40%) - - 2 (3.3%)	0.36
	SLE systemic lupus erythematosus, HBV hepatitis B virus, HAV hepatitis A virus, HEV hepatitis E virus, CMV cytomegalovirus, EBV Epstein-Barr virus *For example isoniazid (INH), weight loss herbal capsules, muscle building capsules
Results	Endpoint	NAC (n= 85)	Control (n= 70)	p-Value
	Recovered	82 (96.4%)	17 (23.3%)	<0.01
	Died	1 (3.3%)	16 (23.3%)	-
	Liver transplantation	2 (6.7%)	37 (53.3%)	-
	During hospital course after NAC Encephalopathy during course Hospital stay, days ICU admission Bleeding	28 (33.3%) 10.1 ± 3.89 28 (33.3%) 20 (23.3%)	44 (63.3%) 28.0 ± 5.32 47 (66.7%) 47 (66.7%)	0.02 <0.001 0.01 <0.01
	Liver function tests Se Bill, lmol/L (before^a) Se Bill, lmol/L (after^b) ALT, IU/L (before) ALT, IU/L (after) AST, IU/L (before) AST, IU/L (after) INR (before) INR (after)	91.27 ± 41.31 87.53 ± 33.77 3,144.00 ± 1,748.27 1,930.67 ± 1,285.93 3,951.33 ± 1,630.23 1,154.73 ± 539.04 2.39 ± 0.52 1.97 ± 1.04	101.43 ± 36.02 114.20 ± 50.63 2,993.33 ± 1,294.80 2,113.33 ± 1,106.01 3,956.33 ± 1,385.55 2,850.00 ± 1,320.85 2.25 ± 0.46 3.05 ± 1.13	0.314 0.02 0.706 0.558 0.990 <0.001 0.283 <0.001
	Se Bill: serum bilirubin, ALT: alanine transaminase, AST: aspartate transaminase, INR: international normalized ratio ^a Before NAC start ^b After NAC start
Adverse Events	Prolonged cholestasis (96.4% of NAC), fever (10%), allergic reaction (10%), dyspepsia (13.3%)
Study Author Conclusions	NAC is safe and leads to a greater degree of spontaneous recovery in NAI-ALF patients (especially with coagulopathy only), making it effective in saving this cohort from death, reducing the need for transplantation, and reducing other complications, especially when started as early as possible at a high intravenous dose. This is confirmed by greater improvements in all parameters of liver injury. However, the use of NAC should not prevent early contact with a transplant center for any patient demonstrating evidence of coagulopathy with any degree of encephalopathy, since referral ensures that these critically ill patients can undergo urgent transplantation, should it be needed.
InpharmD Researcher Critique	The historical control group was utilized rather than a concomitant control group due to an ethical reason of possibly depriving an ALF patient of potential NAC benefits. Prolonged cholestasis observed in 82 (96.4%) NAC patients was due to a steady but slow decrease over a period of 2-3 months.

References:

Darweesh SK, Ibrahim MF, El-Tahawy MA. Effect of N-acetylcysteine on mortality and liver transplantation rate in non-acetaminophen-induced acute liver failure: a multicenter study. Clin Drug Investig. 2017;37(5):473-482. doi: 10.1007/s40261-017-0505-4

Safety and Efficacy of N-Acetylcysteine in Children With Non-acetaminophen-induced Acute Liver Failure
Design	Single-center, retrospective chart review N= 170
Objective	To evaluate the safety and efficacy of N-acetylcysteine (NAC) in children with acute liver failure (ALF) not caused by acetaminophen poisoning
Study Groups	Standard care (n= 59) Standard care + NAC (n= 111)
Inclusion Criteria	Children presenting with non-acetaminophen-induced ALF (INR > 2 with abnormal liver function or INR > 1.5 accompanied by encephalopathy)
Exclusion Criteria	Acetaminophen-induced LAF
Methods	A continuous intravenous infusion of NAC 100 mg/kg/24 hours was given until normalization of the INR, death, or transplantation in the standard care + NAC group (1995 to 2004). Standard care treatment (1989 to 1994) was directed at maintaining normal tissue oxygenation and preventing and treating complications of ALF, which included continuous intravenous dextrose infusion to prevent hypoglycemia, broad-spectrum antimicrobial prophylaxis, and ranitidine and/or sucralfate administration for prevention of acute gastrointestinal bleeding. If children developed encephalopathy grade > 2, became hypoxic, or needed sedation, they were admitted to the pediatric intensive care unit (PICU). Hemofiltration was initiated if oliguria or renal failure developed, and fresh frozen plasma was given if an invasive procedure needed to be done. Persistent elevation of INR > 4 (with or without encephalopathy) prompted the child to be listed for transplantation.
Duration	Data collection period: 1989 to 2004
Outcome Measures	Primary outcome: overall survival, survival with the native liver, death without transplantation, transplantation, rate of retransplantation, survival after transplantation Secondary outcomes: length of intensive care unit and hospital stay, need for inotropic support, development of renal failure (serum creatinine > 2 times upper normal limit for age or anuria), raised intracranial pressure (intracranial pressure > 25 mmHg measured by an intracranial bolt or presence of clinical signs such as abnormal pupillary reflexes or hypertonia), development of other complications
Baseline Characteristics		Standard care (n= 59)	Standard care + NAC (n= 111)	p-value
	Median age, years (range)	3.02 (0.003 to 15.8)	3.51 (0.003 to 17.4)	Not significant
	Male	34 (58%)	57 (51%)	Not significant
	Etiology of ALF Metabolic disorders Infectious causes Autoimmune hepatitis Neonatal hemochromatosis Drug or toxin	11 (19%) 7 (12%) 6 (10%) 7 (12%) 4 (7%)	16 (14%) 14 (13%) 7 (6%) 7 (6%) 7 (6%)	Not significant Not significant Not signficant Not significant Not significant
	Presenting features Jaundice Encephalopathy Hepatomegaly Splenomegaly Ascites Fever Nausea Vomiting Diarrhea Poor feeding Abdominal pain Rash	55 (93%) 32 (54%) 44 (75%) 29 (49%) 17 (29%) 19 (32%) 6 (10%) 30 (51%) 12 (20%) 23 (39%) 15 (25%) 4 (7%)	84 (76%) 60 (54%) 84 (76%) 40 (36%) 10 (9%) 39 (35%) 19 (17%) 55 (50%) 14 (13%) 51 (46%) 30 (27%) 12 (11%)	0.006 Not significant Not significant Not significant 0.0008 - - - - - - -
	Laboratory values on admission Aspartate aminotransferase, IU/L Serum bilirubin, μmol/L Gamma glutamyltransferase, IU/L Alkaline phosphatase, IU/L Albumin, g/L Creatinine, μmol/L INR Hemoglobin, g/dL White cell count, 1 x 10⁹/L Platelet count, 1 x 10⁹/L	560 326 61 364 28 70 3.2 10.8 11 169	1,446 194 51 287 33 82 2.8 10.7 7.9 137	≤ 0.005 ≤ 0.05 - - ≤ 0.005 ≤ 0.05 ≤ 0.05 - ≤ 0.005 -
	It was not reported whether the laboratory parameters on admission were given as means or medians.
Results	Endpoint	Standard care (n= 59)	Standard care + NAC (n= 111)	p-value
	Overall survival	29 (49%)	82 (74%)	0.009
	Alive with native liver	13 (22%)	48 (43%)	0.005
	Death without transplantation	15 (25%)	21 (19%)	-
	Transplantation	32 (54%)	42 (38%)	-
	Retransplantation	8 (26%)	6 (15%)	-
	Survival after transplantation	44 (74.6%)	103 (92.8%)	0.02
	Median length of stay (range) PICU Hospital	6 (1 to 58) 25 (1 to 264)	5 (1 to 68) 19 (1 to 201)	- 0.05
	Inotropic support	12 (23%)	40 (37%)	< 0.05
	Renal failure	17 (29%)	28 (25%)	Not significant
	Intracranial hypertension	12 (24%)	22 (20%)	Not significant
	Other complications Infection Seizures Gastrointestinal bleeding Pulmonary bleeding Bone marrow failure	10 (17%) 6 (11%) 11 (20%) 6 (11%) 5 (9%)	24 (22%) 14 (13%) 16 (14%) 9 (8%) 10 (9%)	Not significant Not significant Not significant Not significant Not significant
Adverse Events	Common Adverse Events: Three patients in the standard care + NAC group experienced maculopapular rash, which resolved with no treatment. Cardiac reactions occurred in 3 children (bradycardia in 2, tachycardia in 1). Mild dizziness and peripheral edema occurred in 1 child. One child developed bronchospasm and a florid maculopapular rash after commencing NAC.
	Serious Adverse Events: N/A
	Percentage that Discontinued due to Adverse Events: N/A
Study Author Conclusions	The administration of NAC to children with ALF not caused by acetaminophen toxicity appeared to be safe and may be associated with a better outcome. The duration of hospital stay was shorter for children receiving NAC and they also appeared to have a higher incidence of native liver recovery and a better survival after LT.
InpharmD Researcher Critique	This study was conducted over a 15 year period, which most likely led to variation in "standard care" between physicians. This imminent confounding factor and the retrospective design limit the external validity of these results. Overall, the results show NAC has the potential to increase survival in children with non-acetaminophen-induced ALF.

References:

Kortsalioudaki C, Taylor RM, Cheeseman P, Bansal S, Mieli-Vergani G, Dhawan A. Safety and efficacy of N-acetylcysteine in children with non-acetaminophen-induced acute liver failure. Liver Transpl. 2008 Jan;14(1):25-30. doi: 10.1002/lt.21246. PMID: 18161828.

Intravenous N-acetylcysteine in pediatric patients with nonacetaminophen acute liver failure: a placebo-controlled clinical trial
Design	Adaptively allocated, doubly masked, placebo-controlled trial N= 184
Objective	To determine if a continuous intravenous infusion of (N-acetylcysteine) NAC for up to seven days would improve overall survival compared to placebo one year following treatment allocation in non-acetaminophen (APAP) Pediatric Acute Liver Failure (PALF)
Study Groups	NAC (n= 92) Placebo (n= 92)
Inclusion Criteria	Age < 18 years old, absence of known chronic liver disease, biochemical evidence of acute liver injury, a liver-based coagulopathy, not corrected by parenteral vitamin K
Exclusion Criteria	Acute acetaminophen toxicity, prior exposure to N-acetylcysteine during the course of the presenting illness, pregnancy, malignancy, sepsis, signs of cerebral herniation, being on a liver support device, intractable hypotension
Methods	Patients were adaptively allocated within strata defined by age (less than 2 years of age or at least 2 years old) and hepatic encephalopathy (HE) (grade 0-1 or 2-4) to receive NAC (150 mg/kg/day) in 5% dextrose in water (D5W) or placebo. Study medications were infused over 24 hours for up to 7 days.
Duration	February 2001 to September 2009
Outcome Measures	Primary: one-year survival Secondary: survival without liver transplantation (LTx), lengths of ICU and hospital stay, maximum degree of HE, number of organ systems failing
Baseline Characteristics		NAC (n= 92)	Placebo (n= 92)
	Age, years (interquartile range [IQR]) Age < 2	3.7 (0.8 to 10.5) 33 (35.9%)	4.5 (1.0 to 9.5) 29 (31.5%)
	Male	47 (51.1%)	54 (58.7%)
	Caucasian	68 (73.9%)	65 (70.7%)
	Coma grade at randomization 0-1 2-4	65 (70.7%) 27 (29.3%)	68 (73.9%) 24 (26.1%)
	Diagnosis at hospital discharge Indeterminate Autoimmune Infection Metabolic Wilson’s disease Tyrosinemia Galactosemia Mitochondrial Glycosylation defect Niemann-Pick type C Other	55 (59.8%) 8 (8.7%) 9 (9.8%) 13 (14.1%) 7 1 2 1 1 1 7 (7.6%)	54 (58.7%) 11 (12.0%) 6 (6.5%) 5 (5.4%) 3 2 0 0 0 0 16 (17.4%)
Results	Endpoint	NAC (n= 92)	Placebo (n= 92)	p-Value
	One year survival*	73%	82%	0.19
	One year LTx free survival Age < 2 Age < 2 with HE grade of 0-1	35% 29% (n= 34) 25% (n= 20)	53% 58% (n= 31) 60% (n= 20)	0.03 0.03 0.0493
	*Subgroup analysis by age above and below 2 years, by HE grade 0–1 and grade 2–4, and the combinations of age and HE grade did not reveal significant differences within any sub-groups No significant difference between groups for length of ICU or hospital stay, type or number of organ systems failing, or maximum grade of HE recorded following treatment allocation.
Adverse Events	Common Adverse Events: infection (n= 11 NAC, n= 8 placebo), rash (n= 4, n= 2), bronchospasm (n= 1, n= 0), arrythmia (n= 1, n= 4)
	Serious Adverse Events: respiratory distress (NAC group, n= 1), Staphylococcus aureus bacteremia (NAC group, n= 1), bradycardiac episode (NAC group, n= 1), hypoglycemia (NAC group, n= 1), aplastic anemia + EBV post-transplantation lymphoproliferative disease + fever + chills + sinusitis (NAC group, n= 1), small intestine ulcerations (placebo, n= 1), fever, sensorineural hearing loss (placebo, n= 1), bigeminy (placebo, n= 1)
	Percentage that Discontinued due to Adverse Events: N/A
Study Author Conclusions	NAC did not improve 1-year survival in children with non-APAP acute liver failure. One year LTx-free survival was significantly lower in the NAC treated group, especially among children less than 2 years of age with HE grade 0–1. Although the difference in outcome by treatment arm was large in that small group, the interim analyses and small sample size reduced substantially the statistical power to find a large difference to be statistically significant. This study does not support the broad use of NAC in non-APAP PALF and it emphasizes the importance of conducting prospective pediatric drug trials, regardless of results in adults.
InpharmD Researcher Critique	The etiology of acute liver failure appears to differ between children and adults; the results of this trial showing that the likelihood of LTx-free survival was not improved by NAC (and possibly made worse) provides further evidence of this.

References:

Squires RH, Dhawan A, Alonso E, et al. Intravenous N-acetylcysteine in pediatric patients with nonacetaminophen acute liver failure: a placebo-controlled clinical trial. Hepatology. 2013 Apr;57(4):1542-9. doi: 10.1002/hep.26001. Epub 2013 Feb 4. PMID: 22886633; PMCID: PMC3509266.

Use of N-acetylcysteine in Children With Fulminant Hepatic Failure Caused by Acute Viral Hepatitis
Design	Single-center, retrospective study N= 40
Objective	To determine the efficacy of N-acetylcysteine (NAC) for the treatment of fulminant hepatic failure (FHF) secondary to acute viral hepatitis (AVH)
Study Groups	Children receiving NAC (N= 40)
Inclusion Criteria	Age one month to 16 years, admitted to the pediatric intensive care unit (PICU) with diagnosis of FHF (biochemical evidence of liver injury, no history of known chronic liver disease, coagulopathy not corrected by vitamin K, INR > 1.5 with encephalopathy or > 2 without encephalopathy
Exclusion Criteria	Children with FHF other than viral etiologies
Methods	Children received NAC intravenously as a 21-hour regimen in 3 doses with a cumulative dose of 300 mg/kg over 21 hours (initial loading dose of 150 mg/kg over one hour, followed by 50 mg/kg for 4 hours, then continuous infusion of 100 mg/kg over next 16 hours).
Duration	2007 to 2011
Outcome Measures	Efficacy of NAC: improvements of biomarkers, alteration of liver function tests (LFTs), and incidence of survival
Baseline Characteristics		Children receiving NAC (N= 40)
	Age, months	80 ± 40
	Male	25 (63%)
	Glasgow coma scale ≤ 8 at admission	11 (28%)
	Laboratory values at admission Alanine aminotransferase (ALT), IU/L Aspartate aminotransferase (AST), IU/L Prothrombin time (PT), seconds INR Serum bilirubin, mg/dL Albumin, g/L Hypoglycemia Positive blood culture	2,102 ± 1,509 2,495 ± 2,786 45 ± 35 4 ± 2.3 17 ± 14 2.8 ± 0.5 12 (30%) 9 (23%)
	Intensive care unit (ICU) therapy Mechanical ventilation Inotropic support Renal replacement therapy Length of ICU stay, days	24 (60%) 19 (48%) 5 (13%) 3.4 ± 2
	Include relevant baseline characteristics that will provide a general (big picture) view of the patients in the study.
Results	Endpoint	Pre-NAC	24 hours post-NAC	Before discharge/death	p-value
	ALT, IU/L	2,101 ± 1,529	1,019 ± 816	466 ± 495	< 0.001
	AST, IU/L	2,500 ± 2,005	528 ± 451	435 ± 431	< 0.001
	PT, seconds	43.5 ± 34	31.2 ± 30	28.3 ± 33	< 0.001
	INR	3.8 ± 2	3.3 ± 3	4.7 ± 9	0.51
	Serum bilirubin, mg/dL	17.6 ± 14	17 ± 12	14.6 ± 11	0.15
	Albumin, g/dL	2.8 ± 0.5	2.9 ± 0.51	2.9 ± 0.5	0.16
	A total of 15 (38%) patients died.
Adverse Events	Common Adverse Events: Not disclosed
	Serious Adverse Events: Not disclosed
	Percentage that Discontinued due to Adverse Events: N/A
Study Author Conclusions	N-Acetylcysteine use in FHF secondary to AVH is effective in developing countries without liver transplantations facilities. It shows improvement in LFTs and encephalopathy. Further studies, including pediatric randomized trials on FHF secondary to AVH, are needed before its routine use.
InpharmD Researcher Critique	This was a single-center, retrospective study, which has inherent limitations and biases. Additionally, this study was conducted in Pakistan, which may limit its generalizability to pediatric patients in the United States. With the absence of a control group, it is difficult to determine whether improvement in biomarkers and LFTs was due to the effects of NAC or spontaneous recovery over time.

References:

Saleem AF, Abbas Q, Haque AU. Use of N-acetylcysteine in children with fulminant hepatic failure caused by acute viral hepatitis. J Coll Physicians Surg Pak. 2015;25(5):354-8.

N-acetylcysteine Therapy in Acute Viral Hepatitis
Design	Single-center, randomized, placebo-controlled trial N= 41
Objective	To investigate the effect of N-acetylcysteine (NAC) for treatment of acute viral hepatitis
Study Groups	NAC (n= 20) Placebo (n= 21)
Inclusion Criteria	Age 14 to 60 years, transaminase values > 10 times the upper limit of normal value (> 400 units/L), total bilirubin > 3 mg/dL and positive anti-HBc-IgM or antiHAV-IgM detected in serological examinations and negative serologic tests for hepatitis C virus, hepatitis D virus and human-immunodeficiency virus
Exclusion Criteria	Not explicitly stated
Methods	Patients were randomized to receive oral NAC 200 mg three times a day or oral placebo three times a day. Monitoring of biochemical markers continued until the level of total serum bilirubin reached 2 mg/dL and alanine aminotransferase (ALT) fell below 100 U/L.
Duration	Follow-up: 6 months after discharge.
Outcome Measures	Period for normalization of ALT to < 100 U/L and total bilirubin to < 2 mg/dL
Baseline Characteristics		NAC (n= 20)	Placebo (n= 21)	p-value
	Median age, years (range)	23 (15 to 48)	24 (16 to 52)	> 0.05
	Male	12 (60%)	16 (76%)
	Hepatitis A infection	4 (20%)	5 (23%)	-
	Hepatitis B infection	16 (80%)	16 (76%)	-
	Laboratory parameters ALT, U/L Aspartate aminotransferase, U/L Alkaline phosphatase, U/L Total bilirubin, mg/dL Direct bilirubin, mg/dL Activity of prothrombin, % Albumin, g/dL	1,730 ± 628 987 ± 545 488 ± 201 7.75 ± 4.36 5.29 ± 3.14 72.6 ± 22.7 3.95 ± 0.54	2,129 ± 1,278 1,397 ± 1,002 410 ± 149 10.1 ± 3.04 7.17 ± 3.26 74.1 ± 18.9 3.98 ± 0.4
Results	Endpoint	NAC (n= 20)	Placebo (n= 21)	p-value
	Time to ALT < 100 U/L, days	19.7 ± 6.9	20.4 ± 6.5	> 0.05
	Time to total bilirubin < 2 mg/dL, days	13.7 ± 8.5	16.9 ± 7.8	> 0.05
Adverse Events	Common Adverse Events: Not disclosed
	Serious Adverse Events: Not disclosed
	Percentage that Discontinued due to Adverse Events: Not disclosed
Study Author Conclusions	The use of NAC in acute viral hepatitis complicated by jaundice is no more effective than placebo. However, the use of NAC in AVH cases is not harmful.
InpharmD Researcher Critique	This study included a small sample size and took place in Turkey, which may limit the generalizability to patients in the United States. Overall, the use of NAC for treatment of acute viral hepatitis does not appear to be effective based on these results.

References:

Gunduz H, Karabay O, Tamer A, Ozaras R, Mert A, Tabak OF. N-acetyl cysteine therapy in acute viral hepatitis. World J Gastroenterol. 2003;9(12):2698-2700. doi:10.3748/wjg.v9.i12.2698

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, 2008	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, 2009	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, 2010	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, 2009	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, 2009	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, 2016	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 2017	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, 2017	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.

References:

Adapted from:
Praharaj DL, Anand AC, Acharya SK. Dosage of N-Acetyl Cysteine in Acute Liver Failure Not Related to Acetaminophen. J Clin Exp Hepatol. 2022;12(2):726-728. doi:10.1016/j.jceh.2022.01.002

Adult case studies on the treatment of NAI‑ALF with NAC
Cause of ALF	Reference	Case description	Study outcome
Cocaethylene	Hassen 2018	Middle-aged female presenting with cocaine and alcohol use leading to ALF.	Resolution of clinical and biochemical derangements.
Sickle cell hepatic crisis	Zhang 2019	Young male with sickle cell disease and frequent pain crisis, presenting with ALF.	Resolution of clinical and biochemical derangements.
Dengue hemorrhagic fever (DHF)	Abeysekera 2013	Middle-aged female with DHF, symptom onset 5 days ago, presenting with ALF.	Resolution of clinical and biochemical derangements.
	Manoj 2014	Middle-aged male with DHF, symptom onset 4 days ago, presenting with ALF.	Resolution of clinical and biochemical derangements.
	Dalugama 2017	Middle-aged male with DHF, symptom onset 4 days ago, presenting with ALF.	Resolution of clinical and biochemical derangements.
	Dissanayake 2021	Thirty adults with severe dengue fever leading to ALF.	Resolution of clinical and biochemical derangements.
Shock liver	Parvataneni 2020	Elderly male presenting with sepsis and atrial fibrillation with rapid ventricular response, leading to multi-organ failure, including ALF.	Improvement in clinical status and biochemical derangements, with eventual discharge.
Tyrosine kinase inhibitor - Crizotinib	Brown 2017	Middle-aged female with metastatic non-small cell lung cancer on crizotinib, presenting with acute liver injury, which progressed to ALF.	Worsening bilirubinemia, coagulopathy, and hepatic encephalopathy. The patient ultimately developed subarachnoid hemorrhage and supportive care was withdrawn.
Tyrosine kinase inhibitor - Crizotinib	Adhikari 2018	Middle‑aged male with ALK + metastatic non‑small cell carcinoma on crizotinib, presenting with ALF and multiorgan dysfunction.	Worsening bilirubinemia, coagulopathy, and hepatic encephalopathy despite improvement in transaminitis. The patient ultimately died from multi‑organ dysfunction.
Ifosfamide	Cheung 2011	Middle‑aged female with synovial sarcoma of the neck, treated with ifosfamide and doxorubicin leading to ALF.	Resolution of clinical and biochemical derangements. No further liver toxicity in subsequent chemotherapy cycles with doxorubicin alone.
Norfloxacin	Elliot 2016	Older female on treatment with norfloxacin treatment for 3 days presented with ALF.	Resolution of clinical and biochemical derangements.
Rifampin, isoniazid, pyrazinamide, ethambutol (RIPE)	Fox 2020	Young female with tuberculosis presenting with ALF after 4 days of RIPE treatment.	Resolution of clinical and biochemical derangements. Discharged on alternative tuberculosis medications.
Remdesivir (in context of COVID-19 infection)	Carothers 2020	Two patients developed ALF after 3-10 days of remdesivir treatment for COVID-19 pneumonia.	One patient fully recovered while the other died of presumed septic shock.

References:

Adapted from:
Jiang SX, Hussaini T, Yoshida EM. N-acetylcysteine for non-acetaminophen induced acute liver failure: A review. Saudi J Gastroenterol. 2022;28(2):85-91. doi:10.4103/sjg.sjg_406_21