Outcomes from massive paracetamol overdose: a retrospective observational study

Abstract

Linked article: This article is commented on by Bateman DN and Dear JW. Should we treat very large paracetamol overdose differently? Br J Clin Pharmacol 2017; 83: 1163-5. https://doi.org/10.1111/bcp.13279 AIMS: Treatment of paracetamol (acetaminophen) overdose with acetylcysteine is standardized, with dose determined only by patient weight. The validity of this approach for massive overdoses has been questioned. We systematically compared outcomes in massive and non-massive overdoses, to guide whether alternative treatment strategies should be considered, and whether the ratio between measured timed paracetamol concentrations (APAP_pl ) and treatment nomogram thresholds at those time points (APAP_t ) provides a useful assessment tool.

Methods: This is a retrospective observational study of all patients (n = 545) between 2005 and 2013 admitted to a tertiary care toxicology service with acute non-staggered paracetamol overdose. Massive overdoses were defined as extrapolated 4-h plasma paracetamol concentrations >250 mg l^-1 , or reported ingestions ≥30 g. Outcomes (liver injury, coagulopathy and kidney injury) were assessed in relation to reported dose and APAP_pl :APAP_t ratio (based on a treatment line through 100 mg l^-1 at 4 h), and time to acetylcysteine.

Results: Ingestions of ≥30 g paracetamol correlated with higher peak serum aminotransferase (r = 0.212, P < 0.0001) and creatinine (r = 0.138, P = 0.002) concentrations. Acute liver injury, hepatotoxicity and coagulopathy were more frequent with APAP_pl :APAP_t ≥ 3 with odds ratios (OR) and 95% confidence intervals (CI) of 9.19 (5.04-16.68), 35.95 (8.80-158.1) and 8.34 (4.43-15.84), respectively (P < 0.0001). Heightened risk persisted in patients receiving acetylcysteine within 8 h of overdose.

Conclusion: Patients presenting following massive paracetamol overdose are at higher risk of organ injury, even when acetylcysteine is administered early. Enhanced therapeutic strategies should be considered in those who have an APAP_pl :APAP_t ≥ 3. Novel biomarkers of incipient liver injury and abbreviated acetylcysteine regimens require validation in this patient cohort.

Keywords: acetylcysteine; coagulopathy; hepatotoxicity; overdose; paracetamol.

Figure 1

Correlations between reported dose of paracetamol ingested and (A) extrapolated 4‐h plasma paracetamol concentrations and (B) APAP_pl:APAP_t

Figure 2

Relationship between reported dose of paracetamol ingested and (A) serum aminotransferase concentration, (B) INR and (C) serum creatinine; (D) cumulative frequency of different grades of liver injury with reported dose

Figure 3

Relationship between APAP_pl:APAP_t and (A) serum aminotransferase concentration, (B) INR and (C) serum creatinine

Figure 4

Percentage of patients in each APAP_pl:APAP_t group with (A) no liver injury (serum aminotransferase concentrations <50 IU l⁻¹), (B) acute liver injury, (C) hepatotoxicity and (D) coagulopathy