Abbreviations
- GRADE
Grades of Recommendation Assessment, Development and Evaluation
- NAC
N-acetylcysteine
- UW
University of Wisconsin
Key Messages
Evidence on the clinical utility and cost-effectiveness of point-of-care devices could not be identified.
Two evidence-based guidelines recommend a 2-bag regimen of N-acetylcysteine, consisting of both a loading dose and maintenance dose, administered by IV for patients with acute acetaminophen overdose.
Context and Policy Issues
Acetaminophen, also called paracetamol or N-acetyl-p-aminophenol, is a popular drug used to temporarily reduce pain and fever.1 It is available in different strengths and forms, and for a wide range of populations, from children to elderly people.1 The maximum amount of acetaminophen allowed per day is 4,000 mg for adults and children aged 12 years and older.1 Although acetaminophen is safe when used as directed, long-term use and exceeding the maximum recommended daily dose can cause acetaminophen toxicity and liver damage.1
Due to the popularity and accessibility of acetaminophen, the risk of acetaminophen overdose, either by accident or on purpose, is relatively common and it is the leading cause of acute liver failure in Canada and around the world.1 Approximately 4,500 individuals are hospitalized each year in Canada due to acetaminophen overdose, and about 6% of patients hospitalized for acetaminophen overdose develop liver injuries including acute liver failure that may require a liver transplant or lead to death.1
The diagnosis of liver toxicity is based on serum levels of acetaminophen and other laboratory tests including liver function tests and a coagulation profile.2 The Rumack-Matthew nomogram, based on large data of patients not treated with antidote, plots acetaminophen concentration against time of ingestion as a predictor of hepatotoxicity and mortality.2,3 When the serum concentration of acetaminophen is above the curve at 200 mg/L at 4 hours and 25 mg/L at 16 hours, patients would have 60% incidence of severe hepatotoxicity and 5% rate of mortality.3 With 300 mg/L serum acetaminophen concentration at 4 hours and 37.5 mg/L at 16 hours, the incidence of severe hepatotoxicity would be up to 90%, and the rate of mortality would be up to 24%.3 Using this approach, patients with serum acetaminophen concentration greater than 140 mg/L at 4 hours after ingestion are considered having possible risk of hepatotoxicity, and treatment with N-acetyl-cysteine (NAC) is required.2,3 NAC has been indicated in Canada as an acetaminophen poisoning antidote.4
Several analytical methods for determining acetaminophen levels in human serum/plasma have been reported in the literature including high-performance liquid chromatography,5 UV-visible spectrophotometry,6 spectrofluorometric,7 and gas chromatography-mass spectrometry.8 When a patient is admitted to hospital or emergency department with actual or suspected acetaminophen overdose, blood samples are taken and sent to central laboratory for analysis of acetaminophen levels in the blood, and the diagnosis is delayed while waiting for the laboratory results. Point-of-care tests, also called bed-side tests or near-patient tests, are quick screening tests that could potentially improve the management of these patients. Several point-of-care tests for acetaminophen detection are reported in the literature,9,10 however, their clinical utility compared with laboratory-based diagnostic tests is unclear.
This report aims to review the clinical utility and cost-effectiveness of point-of-care devices that measure acetaminophen toxicity for patients with suspected overdose. The report also summarizes the recommendations from evidence-based guidelines regarding the administration of IV N-acetylcysteine for patients with acute acetaminophen overdose.
Research Questions
What is the clinical utility of point-of-care devices that measure acetaminophen toxicity for patients with suspected overdose?
What is the cost-effectiveness of point-of-care devices that measure acetaminophen toxicity for patients with suspected overdose?
What are the evidence-based guidelines regarding the administration of IV N-acetylcysteine for patients with acute acetaminophen overdose?
Methods
Literature Search Methods
A limited literature search was conducted by an information specialist on key resources including MEDLINE, the Cochrane Database of Systematic Reviews, the international HTA database, the websites of Canadian and major international health technology agencies, as well as a focused internet search. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were acetaminophen, overdose, and n-acetylcysteine. CADTH-developed search filters were applied to limit retrieval to health technology assessments, systematic reviews, meta-analyses, or network meta-analyses; randomized controlled trials, controlled clinical trials, or any other type of clinical trial; economic studies; and guidelines. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2016 and June 15, 2021.
Selection Criteria and Methods
One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in .
Exclusion Criteria
Articles were excluded if they did not meet the selection criteria outlined in , they were duplicate publications, or were published before 2016. Guidelines with unclear methodology were also excluded.
Critical Appraisal of Individual Studies
The included publications were critically appraised by 1 reviewer using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument11 for guidelines. Summary scores were not calculated for the included studies; rather, the strengths and limitations of each included publication were described narratively.
Summary of Evidence
Quantity of Research Available
A total of 477 citations were identified in the literature search. Following screening of titles and abstracts, 467 citations were excluded and 10 potentially relevant report from the electronic search were retrieved for full-text review. One potentially relevant publication was retrieved from the grey literature search for full-text review. Of these potentially relevant articles, 9 publications were excluded for various reasons, and 2 publications met the inclusion criteria and were included in this report. These were both evidence-based guidelines. Appendix 1 presents the PRISMA12 flow chart of the study selection. Additional references of potential interest are provided in Appendix 5.
Summary of Study Characteristics
The detailed characteristics of the included guidelines by Chiew et al. (2020)13 and the University of Wisconsin (UW) Health (2019)14 are provided in Appendix 2 ().
Study Design
Both included guidelines13,14 were clinical practice guidelines, which were developed to provide recommendations on the use of NAC for the management of acetaminophen overdose. A systematic search of the literature was conducted, and the quality of evidence and the strength of recommendations were assessed and graded using the Grades of Recommendation Assessment, Development and Evaluation (GRADE) in both guidelines. The UW Health guideline14 rated the level of evidence from high to very low, and the recommendations as either strong or conditional. The wordings are presented in the footnotes of in Appendix 2. The guideline by Chiew et al, (2020)13 did not provide the rating scheme for the strength of the evidence and recommendations. Recommendations in both guidelines were developed by expert panels, and the guidelines were reviewed by external reviewers and were published either on their websites or peer-reviewed journals.
Country of Origin
The guidelines were conducted by authors from Australia and New Zealand,13 and the US.14
Patient Population
The target population of both guidelines13,14 are adult and pediatric patients with acetaminophen overdose. The intended guideline users were health care providers involved in the management of acute acetaminophen overdose.
Interventions and Comparators
The dosing regimens of NAC for treatment of acetaminophen overdose were considered in both guidelines.13,14
Outcomes
Both guidelines13,14 considered evidence based on efficacy and safety outcomes of NAC for the treatment of acetaminophen overdose for the development of the recommendations. The clinical efficacy outcomes of NAC included lowering acetaminophen plasma concentration, lowering liver enzyme levels, and therefore preventing liver toxicity.15 The common adverse events of IV NAC were anaphylactoid reactions, such as rash, pruritus, angioedema, bronchospasm, tachycardia, and hypotension.15
Summary of Critical Appraisal
The detailed quality assessments of the included guidelines13,14 () are presented in Appendix 3.
Both guidelines13,14 were explicit in terms of scope and purpose (i.e., objectives, health questions and populations), and had clear presentation (i.e., specific, and unambiguous recommendations, different options for management of the condition or health issue, and easy to find key recommendations). In terms of stakeholder involvement, both guidelines13,14 clearly defined target users and the development groups; however, it was unclear if the views and preferences of the patients were sought in the guideline by Chiew et al. (2020).13 For rigour of development, both guidelines13,14 reported systematic methods used to search for evidence, criteria for selecting evidence, explicit link between recommendations and the supporting evidence, and methods of formulating the recommendations. Both guidelines13,14 considered health benefits, side effects, and risks in formulating the recommendations, were peer-reviewed before publication, and provided a procedure for updating. Both guidelines13,14 used GRADE methodology to assess and grade their recommendations. For clarity, the recommendations in both guidelines13,14 are specific and unambiguous, provide different options for management of the condition, and are easily identifiable. For applicability, both guidelines13,14 were explicit in terms of facilitators and barriers to application (e.g., confirmed acetaminophen ingestion/management in a clinical setting, and seeking advice from a poisons information centre), advice and/or tools on how the recommendations can be put into practice (e.g., acetaminophen management flow charts), and resource implications (e.g., considering costs in recommendations). However, neither guideline13,14 presented monitoring and or auditing criteria for auditing or monitoring the use of the guideline. For editorial independence, competing interests of guideline development group members were reported, but it was unclear if the views of the funding body have influenced the content of the guidelines. Overall, both included guidelines13,14 were of good methodological quality.
Summary of Findings
The summary of guideline recommendations is presented in Appendix 4 (Table 4).
Clinical Utility of Point-of-Care Devices
No clinical utility studies of point-of-care devices that measure acetaminophen toxicity for patients with suspected overdose were identified; therefore, no summary can be provided.
Cost-Effectiveness of Point-of-Care Devices
No cost-effectiveness studies of point-of-care devices that measure acetaminophen toxicity for patients with suspected overdose were identified; therefore, no summary can be provided.
Guidelines
The Australia and New Zealand guideline by Chiew et al. (2020)13 recommends NAC administered as a 2-bag regimen. Initial loading dose is 200 mg/kg over 4 hours followed by 100 mg/kg over 16 hours; this is a strong recommendation based on low-level evidence. For patients with initial acetaminophen concentration greater than double the nomogram line, the second bag in the 2-bag regimen should be doubled (i.e., 200 mg/kg IV NAC over 16 hours). Patients with initial acetaminophen concentration that is greater than or equal to triple the nomogram line may benefit from higher NAC doses; this is a strong recommendation based on low-level evidence. NAC should be continued if the concentration of acetaminophen is greater than 10 mg/L (66 µmol/L) or alanine transferase is elevated and increasing (> 50 units/L); this is a strong recommendation based on low-level evidence.
The UW Health guideline14 recommends enteral NAC regimens be preferred over IV regimens because the enteral regimen is equally efficacious and less expensive, unless the patient is unable to tolerate an enteral regimen; this is a strong recommendation based on high-level evidence. For IV administration, the NAC dosing is 150 mg/kg load over 1 hour, followed by a continuous infusion at 12.5 mg/kg/hour for 20 hours or more; this is a conditional recommendation based on low-level evidence. NAC treatment may be discontinued when acetaminophen concentration is below 10 mg/L and aspartate aminotransferase has decreased to less than 1,000 units/L; this is a conditional recommendation based on moderate-level evidence.
Limitations
This review did not identify any clinical utility studies or economic evaluation studies of point-of-care devices that measure acetaminophen toxicity for patients with suspected overdose, therefore no conclusions can be formed on these research questions. There were no significant methodological limitations of both included guidelines. The recommendations from the Australia and New Zealand guideline by Chiew et al. (2020)13 were mostly based on low-level evidence. Both included guidelines were conducted in Australia and New Zealand, and the US, and it is unclear whether the recommendations could be generalized to the Canadian context.
Conclusions and Implications for Decision- or Policy-Making
This report identified 2 evidence-based guidelines13,14 regarding the administration of IV NAC for patients with acute acetaminophen overdose. No relevant evidence was identified regarding the clinical utility or cost-effectiveness of point-of-care devices that measure acetaminophen toxicity for patients with suspected overdose.
Both guidelines recommend a 2-bag NAC IV regimen for the management of acetaminophen overdose. The NAC dose and the length of infusion were slightly different between guidelines. For instance, the Australia and New Zealand guideline13 slows the loading dose of NAC (i.e., 200 mg/kg for 4 hours), while the UW Health guideline14 recommends a loading dose of 150 mg/kg over 1 hour. For continuous infusion, the guideline by Chiew et al. (2020)13 recommends 100 mg/kg over 16 hours, while the UW Health guideline14 recommends 12.5 mg/kg/hour for 20 hours or more. However, conditions for the discontinuation of NAC treatment in both guidelines were similar (i.e., acetaminophen concentration is below 10 mg/L or liver enzyme levels return to normal). For patients with acetaminophen concentration many times higher than the nomogram line, a threshold for acetaminophen toxicity in the Rumack-Matthew graph plotting serum acetaminophen concentration against hours after ingestion, the Australian and New Zealand guideline13 suggests an even higher doses of continuous infusion of NAC (i.e., 200 mg/kg for 16 hours, instead of 160 mg/kg for 16 hours). The UW Health guideline14 favours enteral NAC regimen over IV regimen, as the enteral regimen is equally efficacious and less expensive. The recommendations of 1 guideline13 were based on evidence the authors assessed as low quality, while those in the other guideline14 were based on a mix of evidence the authors assessed to be low to high quality.
CADTH previously published 2 Rapid Response reports: 116 on the clinical effectiveness and cost-effectiveness of point-of-care devices to measure acetaminophen toxicity, and the other17 on the evidence-based guidelines regarding the administration of IV NAC for patients with acute acetaminophen overdose in the pre-hospital setting. The first report16 identified 3 clinical studies on point-of-care tests, and no economic evaluations. The second report17 identified 1 guideline, which recommends NAC treatment for all patients experiencing acetaminophen overdose who were at risk of hepatotoxicity; however, this report did not include the strength of the recommendation, and it did not assess the strengths and limitations of the guideline. None of the previous CADTH reports examined the clinical utility of point-of-care devices that measure acetaminophen toxicity for patients with suspected overdose. Thus, there is a need for future research on the clinical utility and cost-effectiveness of point-of care devices for management of acetaminophen toxicity.
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Appendix 4. Main Study Findings and Authors’ Conclusions
Note that this appendix has been formatted for accessibility but has not been copy-edited.
Download PDF (104K)
Appendix 5. References of Potential Interest
Previous CADTH Reports
- 1.
- 2.
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