Reliability of the reported ingested dose for predicting the requirement of N-acetylcysteine in paracetamol overdose patients

To the Editor:

I read with interest the study conducted by Duffull and Isbister published in your journal.¹ They showed that paracetamol overdose patients who presented late (serum paracetamol concentration taken between 7 and 16 h) had a higher rate of hepatotoxicity, were more likely to have a paracetamol concentration above the ‘150-line’ on the Rumack–Matthew nomogram and more likely to receive NAC. Also, they showed that the administration of single-dose activated charcoal (SDAC) reduced the probability of the paracetamol concentration being above the nomogram. A key finding is that the reported dose is a strong predictor of the paracetamol concentrations being above the nomogram line. As far as I know, at least three other studies^2–4 have confirmed the utility of the patient-reported dose of paracetamol for predicting the requirement for treatment based on the Rumack–Matthew nomogram. The present study has not mentioned any of them, yet they may be of interest for comparing results in other settings to assess generalizability. For instance, it is interesting to note that the other studies^2–4 reported cut-off dose values, and that these differed between the studies (8 and 12 g).

It is noted in the study by Duffull and Isbister that 143 patients (9%) with a paracetamol concentration below the ‘150-line’ had received NAC and in 37 patients (2.3%) the concentration was above this line but they were not administered NAC. Since it is possible that this deviation from the treatment protocol biased the results, I wonder if the authors explored this through a sensitivity analysis. Also, the reason for overtreatment is not discussed and other details relating to these exposures are not presented in the article.

Further clarification of other conclusions made by the authors may be helpful for physicians, in particular those who work at centres that cannot measure the serum paracetamol concentrations. First: If the patients present 7 h or more after overdose, NAC should be given before getting the paracetamol concentration. Interestingly, this is the accepted current practice in many centres. Second: It is not clear what definite “cut-off dose” the authors suggest for a “wait and watch approach” in the patients who present within 7 h post-ingestion. Third: The results show that the administration of SDAC reduced the probability of the paracetamol concentrations being above the treatment line. I note in Fig. 1 that there is minimal separation of the lines after 60 g, do the authors know why this is the case? Could it relate to saturation of the activated charcoal (the dose given is not stated in the article), the limited number of patients ingesting such doses and its impact on the model, or other factors? If this is considered a reliable observation, and since patients ingesting such a massive dose of paracetamol are prone to recurrent vomiting, would activated charcoal not be advised? Also, it would be interesting for the authors to elaborate as to why they believe that despite SDAC being a low-risk intervention it could not be given as a duty of care in such patients when it appears to be effective. Furth: Did the authors consider assessing whether the presence or absence of vomiting influenced the paracetamol concentration?