Clinical Toxicology (2008) 46, 496–500 Copyright © Informa Healthcare USA, Inc. ISSN: 1556-3650 print / 1556-9519 online DOI: 10.1080/15563650701864760 LCLT ARTICLE Lower incidence of anaphylactoid reactions to N-acetylcysteine in patients with high acetaminophen concentrations after overdose Anaphylactoid reactions to NAC W. STEPHEN WARING, ALEXANDRA F. STEPHEN, OLIVER D. ROBINSON, MARGARET A. DOW, and JANICE M. PETTIE Scottish Poisons Information Bureau, The Royal Infirmary of Edinburgh, Edinburgh, United Kingdom Background. Mechanisms responsible for anaphylactoid reactions to N-acetylcysteine (NAC) are poorly understood, and acetaminophen itself may play an important role. The present study examined the relationship between serum acetaminophen concentrations and risk of anaphylactoid reactions. Methods. Prospective study of adverse reactions to NAC administered according to standardized clinical protocols in patients who present to hospital after acute acetaminophen overdose. Subgroups were defined by serum acetaminophen concentrations 0 to 100 mg/L, 101 to 150 mg/L, 151 to 200 mg/L, 201 to 300 mg/L, and >300 mg/L. Results. There were 362 patients, and anaphylactoid reactions occurred in 14.9%. Anaphylactoid reactions occurred less commonly in patients with high serum acetaminophen concentrations (p = 0.046 by Cochran-Armitage trend test) and high equivalent 4 h acetaminophen concentrations (p = 0.004). Discussion. High serum acetaminophen concentrations were associated with fewer anaphylactoid reactions, suggesting that these might in some way be protective. The biological basis needs further exploration so as to allow a better understanding of the mechanisms responsible for adverse reactions to NAC treatment. Keywords Acetaminophen; Adverse drug reaction; Overdose; Poisoning; Toxicity Introduction N-acetylcysteine (NAC) minimizes the risk of hepatotoxicity after acute acetaminophen overdose. However, a high propor- tion of patients experience adverse reactions to NAC, which are variably reported to occur in 5–15% of patients in retro- spective studies, and 40–56% in prospective studies [1–5]. Anaphylactoid reactions to NAC are characterized by erythema, urticaria, flushing, brochospasm, wheeze, and hypotension [6,7]. Around 15–30% of patients develop a dif- fuse erythematous or urticarial rash, which typically affects the upper trunk, neck, and face [8,9]. While the clinical pre- sentation is similar to true anaphylaxis, anaphylactoid reac- tions differ because prior exposure to NAC is not required, and treatment can normally be reintroduced without provok- ing a further reaction [7]. Features typically occur 20–60 min after commencing intravenous NAC, and subside quickly after the infusion is stopped [10]. Onset coincides with expected peak serum NAC concentrations during the standard intravenous loading regimen [11], and inadvertent adminis- tration of very high dosages is associated with severe anaphy- lactoid reactions [10]. Localized wheal and flare responses to NAC are concentration-dependent [12]. The incidence of anaphylactoid reactions may be reduced when the initial loading dose of NAC 150 mg/kg is administered over 60 or 90 min instead of the standard 15 min regimen [5, 13, 14]. For example, adverse reactions occurred in 49 of 109 (45%) after 15 min infusion, versus 27 of 71 (38%) after 60 min infusion, although the difference was not statistically significant [13]. Existing data suggest that anaphylactoid reactions are directly related to serum concentrations of NAC, and that risk is dose-dependent [5,13,14]. Nonetheless, the basic biologi- cal mechanisms of anaphylactoid reactions remain unclear. Histamine appears to be an important mediator, and wheal responses to localized NAC can be abolished by prior treat- ment with a selective histamine-1 receptor antagonist [12]. NAC is also capable of evoking endothelium-independent vasodilatation, possibly due to a direct relaxant effect on vas- cular smooth muscle [15]. Preliminary clinical data indicate fewer anaphylactoid reactions in patients with high serum acetaminophen concentrations, suggesting that acetami- nophen itself might be capable of conferring protective Received 16 August 2007; accepted 12 December 2007. Address correspondence to William Stephen Waring, Ph.D., F.R.C.P., The Royal Infirmary of Edinburgh, Scottish Poisons Information Bureau, 51 Little France Crescent, Edinburgh, EH16 4SA United Kingdom. E-mail: s.waring@ed.ac.uk Clinical Toxicology Downloaded from informahealthcare.com by Basildon Healthcare Library on 07/18/11 For personal use only.