Response to Letter: Identification of patients at risk of anaphylactoid reactions to N-acetylcysteine in the treatment paracetamol overdose

To the Editor:

We read with great interest the work by Schmidt that further delineated patients who are at high risk of developing anaphylactoid reactions to N-acetylcysteine (NAC). The results and corresponding figures demonstrate elegantly the direct correlation between the paracetamol concentration and the risk of developing an adverse reaction to NAC.¹ Several other studies have also shown a direct relationship between the incidence of adverse reactions and paracetamol concentrations, further demonstrating the protective effect of paracetamol concentrations.^2–4

The etiology of the anaphylactoid reaction is not entirely understood, and currently the data are conflicting. In vitro studies performed on mast cells have shown that NAC leads to mast cell degranulation and histamine release. In the same mast cells, if paracetamol was co-incubated, there was decreased release of histamine.⁵ This has not necessarily been carried over into human studies; in a prospective study of 169 patients who received NAC, 22 patients developed an anaphylactoid reaction, and none of those patients had an increase in their serum tryptase concentration, leading to a question of whether adverse reactions to NAC are in fact mast cell mediated.⁶ The anaphylactoid reactions also appear to be rate related, and giving the initial bolus over 60 min appears to lead to lower incidence of reactions.³

Given that there is a negligible risk of developing fulminant hepatic failure if the serum paracetamol concentration falls below the line on the Rumack–Matthew Nomogram that intersects 150 μg/mL at 4 h,⁷ and that there is as high as a 40% anaphylactoid reaction rate with a zero paracetamol concentration,¹ it may be reasonable to question why Danish medical practice has not adopted some minimum criteria to define patients at risk of hepatotoxicity. By doing so, they will decrease the incidence of adverse reactions to NAC and lower the cost of health care without sacrificing medical outcome.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.