title: Outcomes from massive paracetamol overdose: a retrospective observational study.
abstract: 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 (APAPpl) and treatment nomogram thresholds at those time points (APAPt) provides a useful assessment tool.
  
  
  
  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 APAPpl:APAPtratio (based on a treatment line through 100 mg l-1at 4 h), and time to acetylcysteine.
  
  
  
  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 APAPpl:APAPt≥ 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.
  
  
  
  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 APAPpl:APAPt≥ 3. Novel biomarkers of incipient liver injury and abbreviated acetylcysteine regimens require validation in this patient cohort.
authors.affiliation: Department of Clinical Toxicology, Guy's and St Thomas' NHS Foundation Trust and King's Health Partners, London, UK.|Department of Clinical Pharmacology, University College London, London, UK.
authors.forename: Daniel J B
authors.initials: DJB
authors.lastname: Marks
authors.affiliation: Department of Clinical Toxicology, Guy's and St Thomas' NHS Foundation Trust and King's Health Partners, London, UK.|Faculty of Life Sciences and Medicine, King's College London, London, UK.
authors.forename: Paul I
authors.initials: PI
authors.lastname: Dargan
authors.affiliation: Department of Clinical Toxicology, Guy's and St Thomas' NHS Foundation Trust and King's Health Partners, London, UK.|Faculty of Life Sciences and Medicine, King's College London, London, UK.
authors.forename: John R H
authors.initials: JRH
authors.lastname: Archer
authors.affiliation: Department of Clinical Pharmacology, University College London, London, UK.
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Davies
authors.affiliation: Department of Clinical Toxicology, Guy's and St Thomas' NHS Foundation Trust and King's Health Partners, London, UK.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Dines
authors.affiliation: Department of Clinical Toxicology, Guy's and St Thomas' NHS Foundation Trust and King's Health Partners, London, UK.|Faculty of Life Sciences and Medicine, King's College London, London, UK.
authors.forename: David M
authors.initials: DM
authors.lastname: Wood
authors.affiliation: Austin Toxicology Service and Victorian Poisons Information Centre, Austin Hospital, Victoria, Australia.
authors.forename: Shaun L
authors.initials: SL
authors.lastname: Greene
mesh_terms: D000082:Acetaminophen / Q000097:blood / Q000506:poisoning*; D000111:Acetylcysteine / Q000627:therapeutic use; D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D018712:Analgesics, Non-Narcotic / Q000097:blood / Q000506:poisoning*; D000931:Antidotes / Q000627:therapeutic use; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers; D001778:Blood Coagulation Disorders / Q000139:chemically induced / Q000453:epidemiology / Q000628:therapy; D056486:Chemical and Drug Induced Liver Injury / Q000453:epidemiology / Q000628:therapy; D003404:Creatinine / Q000097:blood; D062787:Drug Overdose / Q000150:complications / Q000188:drug therapy* / Q000453:epidemiology; D005260:Female; D006801:Humans; D008297:Male; D015995:Prevalence; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D018712:Analgesics, Non-Narcotic; D000931:Antidotes; D015415:Biomarkers; D000082:Acetaminophen; D003404:Creatinine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000111:Acetylcysteine
keywords: acetylcysteine; coagulopathy; hepatotoxicity; overdose; paracetamol