David Nicholas Bateman

Paracetamol (acetaminophen) poisoning is common, and many publications describe various outcomes and treatments. As internationally agreed definitions are non-existent to describe patterns of paracetamol overdose (acute, repeated supratherapeutic, chronic, or staggered), it is difficult to analyze outcomes between studies. The Clinical Toxicology Recommendations Collaborative was tasked to provide guidance on the management of paracetamol poisoning and formed the Paracetamol Workgroup. The Workgroup concluded that an agreed set of terms was needed to perform the systematic review and categorize the evidence. A modified Delphi process was employed to establish uniform definitions to categorize various patterns of paracetamol overdose. Group consensus was reached for each one of the following standard definitions for each pattern of poisoning: acute, staggered, repeated supratherapeutic ingestions, and chronic for use in their upcoming systematic review. "Acute" ingestion represents an excessive amount of paracetamol ingested over a total time (from first paracetamol dose ingested to last paracetamol dose ingested) of less than 8 h. "Staggered" ingestion involves an excessive amount of paracetamol ingested over a total time period of between 8 h and 24 h. "Repeated supratherapeutic ingestion" describes ingestions exceeding the recommended daily dose for more than 24 h, and "chronic" ingestion includes both staggered or repeated supratherapeutic ingestions. "High-risk overdoses" are defined by either an ingested dose, that is greater than 500 mg/kg or 30 g (whichever is less), or an initial serum or plasma paracetamol concentration of greater than 300 mg/L (1,985 µmol/L) at 4 h on the Rumack-Matthew nomogram line. The definitions established by the Paracetamol Workgroup will structure the upcoming systematic review, ensuring consistent categorization of studies within each ingestion pattern to enable clearer comparisons of treatments and outcomes. We encourage researchers to define overdose patterns and patients at increased risk of hepatotoxicity consistently and to include these definitions in publications to improve research reliability and comparability.

Fifty years ago, basic scientific studies and the availability of assay methods made the assessment of risk in paracetamol (acetaminophen) poisoning possible. The use of the antidote acetylcysteine linked to new methods of risk assessment transformed the treatment of this poisoning. This review will describe the way in which risk assessment and treatments have developed over the last 50 years and highlight the remaining areas of uncertainty. A search of PubMed and its subsidiary databases revealed 1,166 references published in the period 1963-2023 using the combined terms "paracetamol", "poisoning", and "acetylcysteine". Focused searches then identified 170 papers dealing with risk assessment of paracetamol poisoning, 141 with adverse reactions to acetylcysteine and 114 describing different acetylcysteine regimens. To manage the extensive literature, we focused mainly on contributions made by the authors during their time in Edinburgh and Denver. The key relationship between paracetamol dose and toxicity risk was established in 1971 and led to the development of the Rumack-Matthew nomogram from data collected in Edinburgh. A series of papers on the mechanisms of toxicity were published in 1973, and these showed that paracetamol hepatotoxicity was caused by the formation of a toxic intermediate epoxide metabolite normally detoxified by glutathione but which, in excess, was bound covalently to hepatic enzymes and proteins. An understanding of the relationship between the rate of paracetamol metabolism, paracetamol concentration, and toxic hazard in humans soon followed. These discoveries were followed by the testing of a range of sulfhydryl-donors in animals and "at risk" patients. Acetylcysteine was developed as the lead intravenous antidote in the United Kingdom. The license holder in the United States refused to make an intravenous formulation. Thus, oral acetylcysteine became the antidote trialed in the United States National Multicenter Study. Intravenous acetylcysteine regimens used initially in the United Kingdom and subsequently in the United States used loading doses of 150 mg/kg over 15 minutes or one hour, 50 mg/kg over four hours, and 100 mg/kg over 16 hours. These regimens were associated with adverse drug reactions (nausea, vomiting and anaphylactoid reactions) and hence, treatment interruption. Newer dosing regimens now give loading doses more slowly. One, the Scottish and Newcastle Anti-emetic Pretreatment protocol, using an acetylcysteine regimen of 100 mg/kg over two hours followed by 200 mg/kg over 10 hours, has been widely adopted in the United Kingdom. A cohort comparison study suggests this regimen has comparable efficacy to standard regimens and offers opportunities for selective higher acetylcysteine dosing. No dose-ranging studies with acetylcysteine were done, and no placebo-controlled studies were performed. Thus, there is uncertainty regarding the optimal dose of acetylcysteine, particularly in patients ingesting very large overdoses of paracetamol. The choice of intervention concentration on the Rumack-Matthew nomogram has important consequences for the proportion of patients treated. The United States National Multicenter Study used a "treatment" line starting at 150 mg/L (992 µmol/L) at 4 hours post overdose, extending to 24 hours with a half-life of 4 hours, now standard there, and subsequently adopted in Australia and New Zealand. In the United Kingdom, the treatment line was initially 200 mg/L (1,323 µmol/L) at 4 hours (the Rumack-Matthew "risk" line). In 2012, the United Kingdom Medicines and Healthcare products Regulatory Agency lowered the treatment line to 100 mg/L (662 µmol/L) at 4 hours for all patients, increasing the number of patients admitted and treated at a high cost. Risk assessment is a key issue for ongoing study, particularly following the development of potential new antidotes that may act in those at greatest risk. The development of biomarkers to assess risk is ongoing but has yet to reach clinical trials. Even after 50 years, there are still areas of uncertainty. These include appropriate acetylcysteine doses in patients who ingest different paracetamol doses or multiple (staggered) ingestions, early identification of at-risk patients, and optimal treatment of late presenters.

Introduction: Acetylcysteine is the only effective and licensed therapy for paracetamol poisoning. However, acetylcysteine loses efficacy if treatment is delayed 8-12 hours after paracetamol ingestion, and there is also uncertainty as to whether the dose should be increased in high-risk paracetamol ingestions. Studies have identified potential therapeutic targets, including enzymes that metabolize paracetamol; the pathways causing mitochondrial toxicity via c-Jun N-terminal kinases or superoxide generation; and other specific targets, such as nuclear factor-erythroid factor 2-dependent gene induction and autophagy. With this range of potential additional therapies, how should the speciality of clinical toxicology approach the development of new antidotes for this common poisoning? Historical background: When the first treatments for paracetamol toxicity were developed, the clinical trial and ethical basis of practice were different from today. Acetylcysteine was never subjected to placebo-controlled studies, even by the United States Food and Drug Administration, as it was presumed that the toxicity of high paracetamol concentrations was so evident that placebo-controlled studies were unethical. Thus, the absolute benefit of acetylcysteine remains unknown. In addition, no dose-ranging studies of acetylcysteine in patients were ever done. The weakness of assessing the efficacy of additional antidotes in small groups of patients with moderate poisoning is illustrated by the use of cimetidine in paracetamol poisoning. Current approaches to drug (and antidote) development: The approach required by regulatory authorities today relies on several important steps. First, a clear target for therapeutic effect is sought, normally in a laboratory model. Next, a 'proof of principle' study is required to demonstrate that the target is 'druggable'. Finally, clinical studies to confirm proof of principle applies in humans, followed by a controlled trial with matched patient groups with sufficient power to demonstrate the clinical outcome being sought. Such patient studies can be expensive to conduct, and non-commercial groups suffer the risk of not being funded. Fomepizole: Fomepizole prevents paracetamol-induced hepatic toxicity in mice by inhibiting cytochrome P4502E1, thereby preventing the conversion of paracetamol to its toxic metabolite. Fomepizole also inhibits c-Jun N-terminal kinases, a key pathway in the downstream toxicity on the mitochondria. The present evidence of efficacy in humans is based on small case series with no control groups. The availability of a licensed indication has facilitated off-label use of fomepizole in an unproven indication. Conclusions: Paracetamol poisoning is common, and randomized, controlled clinical trials are possible. The benefit of fomepizole can only be shown by such a study. As clinical trials using fomepizole as an added therapy to acetylcysteine are recruiting in the United States, these should be supported by all clinical toxicologists. In the interim, the publication of small case series using fomepizole should be discouraged by journals.

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Paracetamol poisoning continues to be a worldwide problem and despite the availability of an effective antidote, acetylcysteine (NAC), the optimal way to use this antidote, particularly following very large doses of paracetamol, has not been established. Recent case series have shown an increased toxicity from paracetamol, even in those receiving prompt NAC therapy, at high doses of paracetamol, particularly in patients above the 300 mg/L nomogram treatment line. Clinical trial evidence supporting shorter NAC dosing now allows the possibility for intensifying treatment without the risk of very high rates of ADRs. New biomarkers also show the possibility of early identification of patients at risk of liver injury who might also benefit from increased intensity treatment. This article discusses these data and proposes a logical therapy for increasing NAC dosing which now requires clinical trial testing.

Dear EditorWe believe the article by Link et al. [1] carries several erroneous messages.We accept that there is experimental evidence from rodents indicating that fomepizole is a potential treatmen...

(2020). Comment on fomepizole as an adjunctive treatment in severe acetaminophen ingestions. Clinical Toxicology. Ahead of Print.

Mullins et al. made a comment on our article (DOI: ; 10.1039/C9TX00002J) stating they noticed the omission of the one-bag, standard concentration protocol which is shared by several centers in North America when we discussed IV acetylcysteine protocols. In this reply we clarify that we did not include this methodology as it is a technical adaption of the way in which a 2-bag NAC regimen in administered and there is insufficient comparative data with other regimens.