Abstract
Dear Editor,
Although proven to be an effective antidote for paracetamol (acetaminophen) overdose, N-acetylcysteine is associated with high risks of unpleasant anaphylactoid reactions. In this retrospective analysis, we studied the characteristics of anaphylactoid reactions among paracetamol-poisoned patients managed with N-acetylcysteine who presented to X Hospital from January 2018 to December 2021.
Demographics of paracetamol poisoning and characteristics of anaphylactoid reactions.
aE.g. Panadeine (paracetamol/codeine), Anarex (paracetamol/orphenadrine), Paracetamol extra (paracetamol/caffeine) or Ultracet (paracetamol/tramadol).
22 patients were given antihistamines and 10 were administered corticosteroids – only four had relatively mild reactions that did not require pharmacological intervention. N-acetylcysteine was prematurely terminated in seven patients with anaphylactoid reactions – in five because serial paracetamol levels were subtoxic, and in the other two because of the severity of the adverse reactions.
Seven patients ultimately developed paracetamol-induced hepatotoxicity (defined as aspartate or alanine-aminotransferase > 1000 IU/L) despite N-acetylcysteine but none of them had anaphylactoid reactions. One patient claimed to have overdosed only 4 hours prior to presentation but had already developed mild transaminitis on arrival (which would be inconsistent with her history). Interestingly, this patient would have remained consistently under the nomogram based on patient-reported timings, although her paracetamol-multiplication product (113 × 139 = 15,707) was already elevated at presentation and would have clued in to the severity of her overdose. This case exemplifies how the accuracy of the Rumack-Matthew nomogram depends on the reliability of the alleged time of ingestion.
The remaining six other patients all presented late with florid transaminitis at presentation; two in fact presented so late that serum paracetamol levels were undetectable at presentation. Two patients received extended N-acetylcysteine therapy (36 h, 84 h). One patient subsequently developed multiorgan failure (nephrotoxicity, coagulopathy, fulminant liver failure) and demised after being deemed a poor candidate for liver transplant; the other six had resolution of transaminitis on discharge.
Female gender, asthma, allergy and lower serum paracetamol levels have been reported in existing literature to increase risks of N-acetylcysteine-related anaphylactoid reactions. 1 Indeed, incidence of anaphylactoid reactions was higher in females (25.6%, vs 14.6%) in this study; while mean serum paracetamol levels were also significantly lower in patients who had anaphylactoid reactions (96.1 mcg/ml) compared to those who did not (111.6 mcg/ml) (Table 1). However, no increase in anaphylactoid reactions was noted among asthmatics (21.0%, vs 21.6%) or patients with prior drug allergy (22.7%, vs 21.3%) (Table 1).
Sandilands and Bateman noted the incidence of N-acetylcysteine-related anaphylactoid reactions in published studies varied widely, 2 for which there are several plausible explanations. While nausea and vomiting from N-acetylcysteine is particularly common, 2 many acutely-poisoned patients do present with these non-specific symptoms as well. Of note, this study deliberately excluded gastrointestinal symptoms to minimize confounding. This non-uniform definition of anaphylactoid reaction could explain why the 21.5% incidence rate found in this study is comparable to but slightly lower than that reported in Tan et al (24.4%). 3
Reported incidence rates were also nearly double in prospective studies (up to 48%) compared to retrospective studies (up to 23%). 2 Finally, the discrepancy in incidence rates in various studies could be attributed to differing treatment thresholds and administration protocols for N-acetylcysteine, because N-acetylcysteine-related anaphylactoid reactions appear to be concentration-dependent. 4
The traditional three-bag regimen adopted by most countries was first proposed by Prescott in 1974 and remained virtually unchanged for nearly four decades from 1970s to 2010s. 5 This regimen delivered half of the total dose over the initial 15 min as patients were postulated to be glutathione-depleted at presentation. 6 In addition, Prescott stretched the protocol over 20 h as this would represent five times the theoretical elimination half-life of paracetamol of 4 h. 6 Interestingly, however, no dose-ranging studies were performed to optimize this empirically-derived regimen 4 until 2005, when Kerr et al extended the loading dose duration from 15 min to an hour and found a non-statistically-significant reduction in infusion-related adverse events. 4
In 2013, the Scottish and Newcastle Anti-emetic Pretreatment (SNAP) protocol proposed by Thanacoody et al simplified the dosing regimen from three to two bags and compressed treatment from 20 to 12 h. 7 Pettie et al demonstrated that SNAP reduced the incidence of vomiting and antiemetic use (from 65% to 36%) and severe anaphylaxis (from 31% to 5%) while proving non-inferior in efficacy. 8 Since 2020, SNAP has been accepted as standard of care by National Health Service Greater Glasgow and Clyde, while Campbell et al have also reported successful patient-centric outcomes in this pilot as well. 9 Indeed, not only is SNAP shorter in duration (faster patient turn-around time) and simpler to prescribe (lower risk of prescription and administration errors), SNAP permits “personalized dosing” because it allows more N-acetylcysteine to be given as an extended dose in the initial 24-h period for massive overdoses – all while reducing harm as it is associated with less anaphylactoid reactions. 10
This study is challenged by several limitations. Retrospective outcome assessment was limited by missing data for several variables (for instance asthma and atopy history) and the robustness of documentation in the electronic medical records. Some patients with mild self-limiting side-effects like rash may not have highlighted their reactions. Co-ingestion of antihistamines in some mixed overdose cases may also skew assessment for anaphylactoid reactions.
In summary, the high incidence of anaphylactoid reactions associated with the traditional three-bag N-acetylcysteine dosing regimen warrant consideration for the adoption of other newer dosing regimens with superior side effect profiles such as SNAP.
Footnotes
Author contributions
MN was involved in data retrieval, data analysis and drafting of the final manuscript. MN also researched literature. RP conceptualized the study and was involved in critical revision of the manuscript. All authors reviewed and edited the manuscript and approved the final version of the manuscript.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethical statement
Informed consent
Permission was sought and granted by the SingHealth Centralized Institutional Review Board for waiver of informed consent as this was a large retrospective observational cohort study. All data retrieved from the electronic medical records (EMR) registry had personal information deidentified and anonymized prior to analysis.
Data Availability Statement
The datasets analysed during the current study are available from the corresponding author for scrutiny upon request.