title: Changing the Management of Paracetamol Poisoning.
abstract: OBJECTIVE
  The management of paracetamol poisoning was revolutionized after use of acetylcysteine in the 1970s. The protocol used, 3 weight-related infusions, requires almost 24 hours in hospital. It is associated with adverse events in treated patients, particularly anaphylactoid reactions and vomiting. Present treatment nomograms were based on a small series of untreated patients: only 5 of 22 (23%) and 6 of 25 (24%) between the 100 to 200 mg/L and 200 to 300 mg/L nomogram lines, respectively, developed liver injury (alanine transaminase >1000 IU/L). Many patients treated today are unlikely to be at actual risk for major hepatotoxicity. This article discusses the background to future prospects in this area.
  
  
  METHODS
  The history behind approaches to the use of acetylcysteine is presented briefly. The rationale for, and key findings of, a new 12-hour antidote regimen for paracetamol poisoning are detailed. Newer markers of hepatotoxicity, such as miR-122, HMGB1, and necrosis K18, which predict patients at risk more reliably and earlier than existing tests, are discussed.
  
  
  RESULTS
  A 2-phase 12-hour acetylcysteine infusion protocol (100 mg/kg over 2 hours: 200 mg/kg over 10 hours) was studied in a formal factorial design against the traditional 3-phase 20.25-hour infusion protocol, with and without pretreatment with ondansetron or placebo. The 12-hour regimen was associated with very significant reductions in anaphylactoid reactions (odds ratio = 0.23; 95% CI, 0.12-0.43; P < 0.0001) and vomiting (odds ratio = 0.37; 95% CI, 0.18-0.79; P = .003) compared with the 20.25-hour infusion protocol. There were few withdrawals from the clinical trial, indicating the feasibility of conducting such studies in Europe.
  
  
  CONCLUSIONS
  Novel proteomic markers are better than existing standard tests (alanine transaminase and international normalized ratio) early in the course of paracetamol poisoning. Together with these new biomarkers of hepatotoxicity, a 12-hour acetylcysteine protocol offers clinicians and patients the possibility for better targeting of therapy, fewer adverse effects, a simpler dosing regimen, and shorter hospital stay.
authors.affiliation: Pharmacology, Toxicology and Therapeutics, University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom. Electronic address: nbateman@staffmail.ed.ac.uk.
authors.forename: D Nicholas
authors.initials: DN
authors.lastname: Bateman
mesh_terms: D000082:Acetaminophen / Q000506:poisoning*; D000111:Acetylcysteine / Q000008:administration & dosage* / Q000009:adverse effects; D018712:Analgesics, Non-Narcotic / Q000506:poisoning*; D000707:Anaphylaxis / Q000139:chemically induced*; D000931:Antidotes / Q000008:administration & dosage / Q000009:adverse effects; D000932:Antiemetics / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000209:etiology; D002985:Clinical Protocols; D016166:Free Radical Scavengers / Q000008:administration & dosage* / Q000009:adverse effects; D024243:HMGB1 Protein / Q000097:blood; D006801:Humans; D035683:MicroRNAs / Q000097:blood; D017294:Ondansetron / Q000627:therapeutic use; D014839:Vomiting / Q000139:chemically induced
chemical_list: D018712:Analgesics, Non-Narcotic; D000931:Antidotes; D000932:Antiemetics; D015415:Biomarkers; D016166:Free Radical Scavengers; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; C531907:MIRN122 microRNA, human; D035683:MicroRNAs; D000082:Acetaminophen; D017294:Ondansetron; D000111:Acetylcysteine
keywords: antidotes; paracetamol overdose; risk assessment