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acetaminophen poisoning

In acute acetaminophen overdose, the main site of injury is the liver. 1-10% of patients treated only with supportive care with suffer acute renal failure in conjunction withsevere hepatic failure. Etiology: 1) toxicity occurs when the amount of acetaminophen ingested exceeds the liver's capacity of glucuronidation &sulfation 2) metabolism of acetaminophen by hepatic microsomal enzymes results in a reactive intermediate which overwelmsthe detoxification capacity of glutathione S-transferase 3) risk factors a) 2.6 g/day may be toxic in a poorly nourished alcoholic b) fasting reduces glutathione stores c) critically illness d) malnutrition e) liver disease f) chronic kidney disease g) vegetarians [1] Epidemiology: 1) 1/2 of overdoses are unintentional [2] 2) individuals taking multiple acetaminophen-containing medications & elderly at risk [2] 3) female (80%) [1] Pathology: 1) hepatitis begins in phase 2 2) hepatic necrosis occurs in phase 3 3) complete resolution of hepatic dysfunction in phase 4 unless irreversible injury has occurred 4) pyroglutamic acidosis Clinical manifestations: 1) phase 1 - may begin shortly after ingestion - duration 12-24 hours - nausea, vomiting, anorexia, diaphoresis - most patients will be asymptomatic [6] 2) phase 2 - 24-72 hours after ingestion - right upper quadrant pain, nausea/vomiting, tachycardia, hypotension 3) phase 3 - 72-96 hours - resembles severe viral hepatitis - hepatic encephalopathy 4) phase 4 - 4 days to 2 weeks - resolution Laboratory: 1) abnormal liver function tests (phase 2) - serum ALT may be > 6000 U/L - levels < 300 U/L suggest another diagnosis 2) serum acetaminophen levels a) serum levels > 200 ug/mL obtained at least 4 hours after ingestion mandate N-acetylcysteine administration b) average levels - 840 ug/mL with intentional overdose [2] - 160 ug/mL with unintentional overdose [2] c) for other labs, see acetaminophen 3) elevated pyroglutamate in urine Management: 1) gastric decontamination a) ipecac: beneficial only within 2 hours of ingestion b) gastric lavage - performed prior to administration of charcoal - 34-40 French orogastric tube (adults) - 150-200 mL aliquots of warm water or normal saline - 5-10 liters total - beneficial only within 2 hours of ingestion c) activated charcoal - with & without sorbitol - beneficial within 4 hours of ingestion 2) antidote: N-acetylcysteine a) maximum benefit with 8 hours, but useful up to 24 hours after ingestion - start prior to serum acetaminophen results if presentation >= 8 hours after suspected ingestion [6] - 12 hours of treatment sufficient [5] b) oral - load 140 mg/kg PO or NG, then - 70 mg/kg q 4h X 17 - may be mixed in water or soda c) intravenous: - 140 mg/kg infused into a peripheral IV over 1 hour using an in-line 0.2-m millipore filter - maintenance doses q4h of 70 mg/kg infused into a peripheral IV over 1 hour using an in-line 0.2-m millipore filter - IV solution made by diluting a 20% solution of acetylcysteine to 3% with D5W - modified acetylcysteine regimen - infusion of a total dose of 300 mg/kg over 12 hours, vs roughly 20 hours - lower initial dose (100 mg/kg over 2 hours, vs 150 mg/kg over 15 minutes in the U.K. & 1 hour in the U.S.) - less vomiting or the need for rescue antiemetics within 2 hours [4] d) average length of treatment is 48 h e) treatment may be stopped after 5 initial doses of acetylcysteine (20 hours) when: - acetaminophen level is undetectable - ALT, AST & PT (INR) are normal [3] 3) sodium bicarbonate 4) once severe hepatic toxicity has occurred, treatment is supportive

Related

acetaminophen (Tylenol, Paracematol, Panadol, Tempra, Datril, APAP, non-Aspirin) acetylcysteine (Mucomyst, Mucosol, Acetadote)

General

toxicity; poisoning; overdose

References

  1. Medical Knowledge Self Assessment Program (MKSAP) 11, 17, 18. American College of Physicians, Philadelphia 1998, 2015, 2018.
  2. Larson AM et al, Acetaminophen-induced acute liver failure: Results of a United States multicenter, prospective study. Hepatology 2005 Dec; 42:1364 PMID: 16317692
  3. Betten DP, Cantrell FL, Thomas SC, Williams SR, Clark RF. A prospective evaluation of shortened course oral N-acetylcysteine for the treatment of acute acetaminophen poisoning. Ann Emerg Med. 2007 Sep;50(3):272-9. Epub 2007 Jan 8. PMID: 17210206 - Dart RC, Rumack BH. Patient-tailored acetylcysteine administration. Ann Emerg Med. 2007 Sep;50(3):280-1. Epub 2007 Apr 5. PMID: 17418449
  4. Bateman DN et al Reduction of adverse effects from intravenous acetylcysteine treatment for paracetamol poisoning: a randomised controlled trial. The Lancet, Early Online Publication, 28 November 2013 PMID: 24290406 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)62062-0/abstract - Park K et al Treatment of paracetamol overdose: room for improvement? The Lancet, Early Online Publication, 28 November 2013 PMID: 24290402 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)62303-X/fulltext
  5. Wong A, McNulty R, Taylor D et al. The NACSTOP trial: A multicenter, cluster-controlled trial of early cessation of acetylcysteine in acetaminophen overdose. Hepatology 2019 Feb; 69:774. PMID: 30125376 https://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/hep.30224
  6. Windle ML Fast Five Quiz: Acetaminophen Medscape. July 22, 2021 https://reference.medscape.com/viewarticle/954960_2