Emergency Medicine

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Acetaminophen Poisoning

• Emergency Medicine
• Lin Chiu-Mei

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Key points

• Acetaminophen (APAP), when taken in overdose, may
  cause hepatotoxicity.
• The overdose itself may be clinically subtle the
  hepatotoxicity is manifested in 1 to 4 days.
• The antidote for APAP poisoning is
  N-acetylcysteine (NAC).
• All overdose patients should be screen for APAP.

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History

• Acetaminophen (N-acetyl-para-aminophenol, or
  APAP), marketed since 1950, is a nonnarcotic
  analgesic and antipyretic agent.
• APAP may cause hepatic toxicity, less frequent
  renal toxicity.
• The first case of APAP toxicity is reported in
  1966.

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Pharmacology

• Its antipyretic activity involves the inhibition
  of hypothalamic prostaglandin synthetase and
  cutaneous vasodilation.
• APAP is available in liquid, tablet, caplet, and
  suppository formulations.
• The therapeutic dose is 15 to 30 mg/kg every 4 to
  8 h in children and 325 to 1000 mg every 4 to 6 h
  in adults.

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Pharmacology (cont.)

• The maximum recommended daily dose is 80 mg/kg in
  children and 3.5 g in adults.
• APAP are rapidly and completely absorbed from the
  GI tract 0.5 to 1 h, peak serum concentrations
  occur 1/2 to 2 h following a therapeutic dose.
• Therapeutic levels are 10 to 20 ug/dl, effects
  generally maintain 6 to 8 h.

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Pathophysiology

• A highly reactive metabolite of APAP,
  N-acetyl-para-benzoquioneimine (NAPBQI), formed
  during its metabolism by the P450-MFO pathway.
• The minimal dose of APAP capable of causing liver
  toxicity following acute ingestion is estimated
  to be 140 mg/kg in children and 7.5 g in adults.

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Pathophysiology (cont.)

• N-acetyl-benzoquinoneimine (NAPQI), a strong
  oxidizing, there is not sufficient glutathione
  (30) available, bonds with cellular protein
  would produce hepatocellular centrilobular
  necrosis and renal injury.
• Chronic intoxication hepatotoxicity occur in
  adult ingesting 10 to 15g/day and chronic
  alcoholics ingesting 3 to 4g/day for a few days.

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Pathophysiology (cont.)

• Chronic alcoholism enhance APAP toxicity,marked
  elevated transaminases and sometimes prothrombin
  time
• Eating disorders deplete glutathione such as
  anorexia nervosa or starvation
• chronic use of phenytoin, phenobarbital etc.
  induce the cytochrome P450 produce an increase in
  APAPs toxic metabolite, NAPQI

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Clinical presentation 4 stages

• Stage I few hours to 24 h, malaise, diaphoresis,
  nausea,vomiting, and drowsiness
• Stage II24 to 48 h, abdominal pain, liver
  tenderness, elevated hepatic enzyme, oliguria
• Stage III 72 to 96h, peak liver dysfunction ,
  the degree of elevated hepatic enzymes is not
  related with outcome, definite hepatotoxicity is
  GOTgt1000 S/S hypoglycemia, coagulopathy,
  altered consciousness
• Stage IV 4 days to 2 weeks, resolution or
  extensive damage

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Different diagnosis

• Patient screen every present in a coma or has
  taken an intentional ingestion
• Hepatotoxins Amanita phalloides mushroom,
  halogenated hydrocarbons etc.
• Infectious hepatitis, shock liver, Reyes syndrome

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Laboratory analysis

• Methods radioimmunoassay, high pressure liquid
  chromatography (HPLC), and gas chromatography
  (GC)
• Cross reactions salicylate, salicylamide,
  diflunisal, and methyldopa
• Use of the level modified Rumack-Matthew (RM)
  nomogram, determinated no sooner than 4 h after
  ingestion, assess potential toxicity

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Rumack-Matthew nomogram

• Used in United States, probable hepatic toxicity
  risk line and a lower possible hepatic toxicity
  line
• US toxicologists recommend the antidote NAC
  (Mucomyst) be administered if the intersecting
  concentrations and time coordinates are above the
  lower line and that the course of therapy be
  completed even if the subsequent values fall
  below the toxic zone however English ones dont.

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Rumack-Matthew nomogram (cont.)

• Limitation of the nomogram 1. for children never
  has been proved,2. concomitantly ingested drugs
  or carbohydrate-rich foods may change the gastric
  emptying time and the peak time, 3. 2 to 4 h
  after the initial 4-h level may be greater than
  20 ug/ml or more, delayed toxic APAP
  concentration would be reported

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Laboratory analysis (cont.)

• Liver enzyme elevation increase as early as 4 h
  after ingestion and as late as 36 h
• Monitor liver and renal profiles bilirubin,
  prothrombin time, serum amylase, coagulation
  tests, and blood glucose, CBC, platelet count,
  phosphate, electrolytes, HCO3, ECG, and urinalysis

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Laboratory analysis (cont.)

• Prognostic laboratory values the following
  factors in predicting mortality in the patients
  with fulminant hepatic failure (HHF)1. Blood
  pHlt7.3, 2. Grade III coma, Cr.gt3.3, 3. Factor
  Vlt10, Factor VIII/Vgt30 4. IN PT ratio rises
  gt3.0, 5. The total bilirubin has been identified
  as a marker for survival(gt4).

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Management

• GI decontamination emesis is best avoided,
  gastric lavage has been questioned, administered
  activated charcoal (AC) and a cathartic to adult
  patients the administration of activated
  charcoal does not interfere with NAC multiple
  doses of AC?

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Management (cont.)--NAC

• N-Acetylcysteine(NAC), patients were treated only
  if presented within 24 h, is used for hepatoxic
  overdose on the basis of nonrandomized trial
  carried in UK using a 200 treatment line and in
  North America using a 150 treatment line
• Mechanism of action glutathione precursor that
  provides protective levels of a glutathione
  todetoxify the hepatotoxic reactive metabolite
  NAPQI

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Management (cont.)--NAC

• Controversy exists over the route of
  administration. Theoretically, oral
  administration results in more availability of
  the antidote at the site of injury via the portal
  circulation and avoid anaphylactoid reactions,
  the i.v. route avoids the risk of treatment
  failure by vomiting

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Management (cont.)--NAC

• Oral NAC in US, loading dose of 140 mg/kg
  followed by 70 mg/kg q4h for 17 additional
  maintenance doses, a total of 1330 mg/kg over 72
  h the complication of oral NAC is vomiting due
  to rotten odor- primperan or zofran used
• Intravenous (i.v.) NAC in Europe and Canada
  about 20 years but is not approved in US

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Variations in the duration of NAC therapy

• Intravenous NAC protocol for 20 h 20-h regimen
  of 300 mg/kg administered as 150 mg/kg i.v. in
  200 ml D5W over 15 min followed by 50 mg/kg in
  500 ml D5W over 4 h then 100 mg/kg in 1000 ml D5W
  over 16 h
• Intravenous NAC protocol for 48 h loading dose
  140 mg/kg of 0.2 g/ml NAC( diluted to 3
  solution made by 15 NAC and D5W) over 1 h
  followed by 12 maintenance doses of 70 mg/kg over
  1 h every 4 h over 48 h

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Management (cont.)--NAC

• Pregnancy the same
• Fulminant hepatic failure(FHF) NAC therapy,
  liver transplant PTgt50 s, metabolic acidosis and
  encephalopathy but prognosis is not documented
• Dialysis renal failure persists more than 48 h,
  reduces the half-life of APAP, but does not alter
  the clinical course