title: A risk quantification instrument for acute acetaminophen overdose patients treated with N-acetylcysteine.
abstract: OBJECTIVE
  The risk of hepatotoxicity after acute acetaminophen overdose varies with timed serum acetaminophen concentration and delay to treatment. The ability to accurately predict hepatotoxicity is needed to reduce confusion about the optimal treatment regimen for individual patients and the effects of risk modifiers such as ethanol. We quantitatively estimate the risk of hepatotoxicity based on the degree and duration of pretreatment exposure to supratherapeutic concentrations of acetaminophen.
  
  
  METHODS
  We examined all hospitalizations for acute acetaminophen overdose within a retrospective multicenter Canadian registry. We used a previously developed composite measure incorporating timed serum acetaminophen concentration and time to N-acetylcysteine treatment into a single parameter. We then modeled hepatotoxicity on this parameter, as well as age, sex, and ethanol use. Hepatotoxicity was defined as peak aminotransferase level of 1,000 IU/L or greater at 24 hours or longer.
  
  
  RESULTS
  Of 1,270 admitted patients treated mostly with intravenous N-acetylcysteine for less than 24 hours, our model accurately identified the 94 patients who developed hepatotoxicity (discriminatory index 0.93). Hepatotoxicity occurred in none of the 313 patients (95% confidence interval [CI] 0% to 1.0%) above the traditional 150 mug/mL treatment line who were classified as low risk (<1%) using our instrument. After adjustment for severity of exposure, the risk of hepatotoxicity was considerably higher in the absence of coingested ethanol (median hepatotoxic dose 16.5 mmol/L x hour [95% CI 8.74 to 31.0 mmol/L x hour] versus 27.1 mmol/L x hour [95% CI 11.1 to 66.3 mmol/L x hour]), particularly among alcoholics (4.79 mmol/L x hour [95% CI 2.13 to 10.8 mmol/L x hour]).
  
  
  CONCLUSIONS
  Our risk prediction instrument identifies a large group of low-risk patients for whom 20-hour intravenous N-acetylcysteine therapy is sufficient. Our results suggest that acute and chronic ethanol use dramatically influences acetaminophen toxicity. This work may facilitate the evaluation of individualized treatment strategies for higher-risk patients.
authors.affiliation: Department of Emergency Medicine, Queen's University, Kingston, Ontario, Canada. sivilotm@meds.queensu.ca
authors.forename: Marco L A
authors.initials: ML
authors.lastname: Sivilotti
authors.forename: Mark C
authors.initials: MC
authors.lastname: Yarema
authors.forename: David N
authors.initials: DN
authors.lastname: Juurlink
authors.forename: Angela M
authors.initials: AM
authors.lastname: Good
authors.forename: David W
authors.initials: DW
authors.lastname: Johnson
mesh_terms: D000082:Acetaminophen / Q000097:blood / Q000506:poisoning*; D000111:Acetylcysteine / Q000627:therapeutic use*; D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000428:Alcohol Drinking / Q000009:adverse effects; D018712:Analgesics, Non-Narcotic / Q000506:poisoning*; D056486:Chemical and Drug Induced Liver Injury; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D062787:Drug Overdose / Q000097:blood / Q000150:complications / Q000188:drug therapy; D004635:Emergency Medicine / Q000295:instrumentation*; D005260:Female; D006801:Humans; D008107:Liver Diseases / Q000175:diagnosis*; D016015:Logistic Models; D008297:Male; D008962:Models, Theoretical; D010043:Outcome and Process Assessment, Health Care; D012189:Retrospective Studies; D018570:Risk Assessment / Q000379:methods; D012307:Risk Factors; D000637:Transaminases / Q000097:blood
chemical_list: D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen; D000637:Transaminases; D000111:Acetylcysteine