Comparison of two-bag and three-bag acetylcysteine regimens in the treatment of paracetamol poisoning: a systematic review and meta-analysis.

Introduction: Worldwide, paracetamol poisoning is a common cause of acute liver failure and referral to transplant centers. Acetylcysteine has long been the mainstay of treatment, but recent literature suggests that a simplification of the "three-bag" method may decrease adverse effects. Our primary hypothesis is that a simplified dosing regimen (two-bag regimen) is non-inferior to the three-bag method in preventing liver injury. Our secondary hypothesis is that a simplified regimen will have lower rates of adverse effects.

Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we searched Medline/PubMed, Google, Google Scholar, Cochrane Library, Embase and Toxnet on May 23, 2022. The Medical Subject Headings terms were NAC, acetaminophen toxicity, acetyl-cysteine, N-acetylcysteine, paracetamol, APAP, 2-bag, and 3-bag. The Embase terms were acetylcysteine, NAC, 2-bag, two bag, 3-bag, three bag, simplified dosing, acetaminophen, Tylenol^®, paracetamol, APAP, drug overdose, poisoning, and overdose. Studies included both non-United States Food and Drug Administration-approved and United States Food and Drug Administration-approved acetylcysteine regimens. Case reports, review articles, and animal studies were excluded. Two authors independently reviewed each study using Rayyan QCRI to determine if the studies met search criteria while blinded to the selections of each other. The two authors discussed until reaching a consensus. We used a primary outcome of non-inferiority of hepatotoxicity. We used secondary outcomes of non-allergic anaphylactoid reactions and adverse events. We conducted a fixed-effect meta-analysis using R package meta. To visually summarize the meta-analysis results, we also produced forest plots. We used Cochran's Q test and I² statistical analysis to assess heterogeneity between the studies.

Results: Our search resulted in 657 total citations, which were reduced to unique citations. Of the 643 studies, 46 met the criteria for full text review, and eight met the study criteria. Of the eight studies investigating a simplified acetylcysteine regimen, four studies utilized some form of a modified two-bag infusion regimen, varying in duration or dosing of infusions, and four studies shared the same "common" two-bag treatment, a regimen that delivers acetylcysteine 200 mg/kg over 4 h, followed by 100 mg/kg acetylcysteine over 16 h. The six studies comparing a two-bag dosing regimen to the three-bag technique were utilized for our random effect model meta-analysis. We found no significant heterogeneity amongst the six studies for either hepatotoxicity (Q(5) = 1.11; P = 0.95; I² = 0%; 95% CI: 0%-74.6%) or non-allergic anaphylactoid reactions and adverse events (Q(5) = 10.15; P = 0.07; I² = 50.7%; 95% CI: 0%-80.4%). Compared to the traditional three-bag dosing regimen, the two-bag method did not demonstrate a difference in relative risk for hepatotoxicity (OR: 0.88; 95% CI: 0.72-1.08; P = 0.23) but did demonstrate a significantly decreased likelihood of non-allergic anaphylactoid reactions and other adverse events (OR: 0.24; 95% CI: 0.17-0.35; P <0.0001).

Discussion: The two-bag method is a safe and effective treatment for acute paracetamol poisoning. The two-bag regimen is correlated with a significant reduction in non-allergic anaphylactoid reactions, compared to the three-bag method, and is non-inferior with respect to hepatotoxicity. While we feel this information is practice changing for many, further research in the form of a randomized control trial would be beneficial to compare even more abbreviated methods such as a "single bag method."

Conclusion: Two-bag acetylcysteine dosing regimens appear to be non-inferior to the three-bag method with respect to hepatotoxicity, and result in fewer anaphylactoid, cutaneous, and gastrointestinal reactions.