Massive paracetamol overdose: an observational study of the effect of activated charcoal and increased acetylcysteine dose (ATOM-2)

Abstract

Context: Paracetamol is commonly taken in overdose, with increasing concerns that those taking “massive” overdoses have higher rates of hepatotoxicity and may require higher doses of acetylcysteine. The objective was to describe the clinical characteristics and outcomes of “massive” (≥ 40 g) paracetamol overdoses.

Methods: Patients were identified through the Australian Paracetamol Project, a prospective observational study through Poisons Information Centres in NSW and Queensland, over 3 and 1.5 years, respectively, and retrospectively from three clinical toxicology unit databases (over 2.5 to 20 years). Included were immediate-release paracetamol overdoses ≥ 40 g ingested over ≤ 8 h. Outcomes measured included paracetamol ratio[defined as the ratio of the first paracetamol concentration taken 4–16 h post-ingestion to the standard (150 mg/L at 4 h) nomogram line at that time] and hepatotoxicity (ALT >1000 U/L).

Results: Two hundred paracetamol overdoses were analysed, reported median dose ingested was 50 g (interquartile range (IQR): 45–60 g) and median paracetamol ratio 1.9 (IQR: 1.4–2.9, n = 173). One hundred and ninety-three received acetylcysteine at median time of 6.3 h (IQR: 4–9.3 h) post-ingestion. Twenty-eight (14%) developed hepatotoxicity, including six treated within 8 h of ingestion. Activated charcoal was administered to 49(25%), at median of 2 h post-ingestion (IQR:1.5-5 h). Those receiving activated charcoal (within 4 h of ingestion), had significantly lower paracetamol ratio versus those who did not: 1.4 (n = 33, IQR: 1.1–1.6) versus 2.2 (n = 140, IQR: 1.5–3.0) (p < .0001) (paracetamol concentration measured ≥ 1 h after charcoal). Furthermore, they had lower rates of hepatotoxicity [unadjusted OR: 0.12 (95% CI: <0.001–0.91); adjusted for time to acetylcysteine OR: 0.20 (95%CI: 0.002–1.74)].

Seventy-nine had a paracetamol ratio ≥2, 43 received an increased dose of acetylcysteine in the first 21 h; most commonly a double dose in the last bag (100 to 200 mg/kg/16 h). Those receiving increased acetylcysteine had a significant decrease risk of hepatotoxicity [OR:0.27 (95% CI: 0.08–0.94)]. The OR remained similar after adjustment for time to acetylcysteine and paracetamol ratio.

Conclusion: Massive paracetamol overdose can result in hepatotoxicity despite early treatment. Paracetamol concentrations were markedly reduced in those receiving activated charcoal within 4 h. In those with high paracetamol concentrations, treatment with increased acetylcysteine dose within 21 h was associated with a significant reduction in hepatotoxicity.

Keywords:

• Paracetamol
• acetylcysteine
• overdose
• activated charcoal
• hepatotoxicity

Acknowledgements

The authors wish to thank the staff of the New South Wales and Queensland Poisons Information Centre staff for assisting with identifying patients who ingested “massive” paracetamol overdoses. And the many people who have contributed to the HATS, SEATS, and PAH databases.

Disclosure statement

All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Additional information

Funding

Geoff Isbister is funded by an NHMRC Senior Research Fellowship ID1061041. Colin Page is supported by an Emergency Medicine Research Foundation Research Fellowship. This research was partially supported by an NHMRC Program Grant 1055176.