Systematic Review Of Outcomes, Including Hepatotoxicity, After Non-Intentional Supratherapeutic Ingestion of Paracetamol

P Acheampong1,3, SHL Thomas1,2. 1Wolfson Unit, Regional Drug and Therapeutics Centre / Royal Victoria Infirmary, Newcastle upon Tyne, UK, 2Newcastle University, Newcastle upon Tyne, UK, 3University of Liverpool, Liverpool, UK

Introduction: Accidental ingestion of excess paracetamol is very common; while most patients do not have sequelae, there have been a number of reports of severe hepatotoxicity arising from supratherapeutic use. Appropriate risk stratification is required to identify those at risk so that they can be treated with N-acetylcysteine (NAC). However, considerable uncertainty exists about the appropriate use of NAC under these circumstances, with international differences in guidance (1,2). We therefore carried out a systematic review of reported cases of unintended supratherapeutic paracetamol ingestions including the reported doses and the associated liver outcomes to inform management in the UK.

Methods: A systematic search of OVID Medline and EMBASE databases from 1946 and 1974 respectively to September 2013 was undertaken to identify case reports of non-intentional supratherapeutic ingestions of paracetamol excluding intentional overdoses. Cases were classified based on whether the ingested dose was above or below the amounts specified in US and Australasian guidance as being associated with hepatic injury (1); (e.g. >200 mg/kg or 10 g over one day in an adult).

Results: Ninety-seven cases from 38 publications met the selection criteria. Of these, 61 were less than 7 years old and 20 cases were treated with NAC. Twenty one cases, of which 13 reported ingested doses above the US/Australasian threshold, had additional risk factors for liver injury. Liver outcomes based on reported dose and NAC treatment are reported in Table 1.

Table 1: Liver outcome in reported supratherapeutic paracetamol ingestions

Hepatic injury (1000 > AST or ALT >2x upper limit of normal); hepatotoxicity (AST or ALT ≥1000); † death following liver failure; NAC – N-acetylcysteine

Serious liver outcomes involving hepatotoxicity, liver failure or death occurred in most reported cases. No cases were identified who had low or undetectable paracetamol concentrations and normal LFTs at admission (or point of suspicion) that subsequently developed a serious liver outcome although this information was only available in a minority of cases (36/97).

Conclusions: Most published cases of unintended supratherapeutic paracetamol ingestion resulting in serious liver outcomes involved children. Doses below current US/Australasian thresholds did not exclude a risk of severe outcomes, but there were no cases with low/negative paracetamol concentration and normal LFT on admission or point of suspicion who later developed serious liver outcomes. Our findings are limited by publication bias, as cases with severe outcomes are more likely to be reported.

(1) Daly FFS et al. (2008). Med J Aust 188: 296-301

(2) Toxbase® guidelines on management of therapeutic excess of paracetamol