Manini 8/4/05
Acetaminophen Poisoning
Intro/Scope:
 Other common names: paracetamol, N-acetyl-para-aminophenol (APAP)
 Most commonly reported potentially toxic agent
 Greatest absolute number of toxic fatalities in US
 Extremely common co-ingestant
 APAP is leading cause of admission to liver transplant units in US (2003 study).
What happens in Overdose?
 Sulfation and glucuronidation pathways become saturated
 APAP shunted to P450 pathway, resulting in NAPQI, a highly reactive and toxic intermediate.
 Increase in NAPQI depletes glutathione stores
 NAPQI binds nonspecifically to intracellular proteins, resulting in general cell dysfunction.
Signs and Symptoms:
 Stage I (30 min-24 hr): pallor, diaphoresis, n/v, abd pain, anorexia, malaise.
 Stage II (24-48 hr): Resolution of stage I sx/signs, RUQ pain, liver/renal dysfunction
 Stage III (72-96 hr): jaundice, peak LFTs, hepatic/renal failure, death.
 Stage IV (4 d – 2 wk): fulminant hepatic failure, coma, death OR resolution of
hepatotoxicity
Evaluation of Toxicity:
 150 mg/kg is potentially toxic dose
 Serum APAP level at 4 hours post-ingestion
 Send serum APAP in ALL CASES of toxic ingestion: 1/500 pts without a history of APAP
ingestion will have a toxic level.
 APAP treatment nomogram – cannot be applied to levels obtained before 4 hours. (see
Figure below)
Treatment:
 Consider orogastric lavage for co-ingestants – typically only for intubated pts
 Activated Charcoal (AC) – 1gm/kg for patients without contraindications (To wit:
decreased gut motility, perforated viscous, endoscopy planned, or not protecting airway).
If multi-dose AC is indicated for co-ingestants, stagger doses with PO NAC by 2 hrs to
avoid potential interference, although there is evidence this is not clinically significant.
 N-acetylcysteine (NAC) – administer this early (< 8 hrs): early NAC was equally
efficacious regardless of how high the serum APAP level was. (Smilkstein, 1988)
o PO Dosing (Mucomyst):
 72 hr protocol
 Load: 140 mg/kg
 Maintenance: 70 mg/kg q 4 hr x 17 doses
o IV Dosing (Acetadote):
 20 hr protocol
 Load: 150 mg/kg in 200 cc D5W over 15 min to 1 hr. Adverse effects are
probably rate related, so there is still disagreement on this. Label says 15
min is safe, but some experts think 1 hr is safer.
 Next 4 hr: 50 mg/kg in 500 cc D5W
 Next 16 hr: 100 mg/kg in 1L D5W
o IV vs PO NAC:
 IV NAC is used in all studies that demonstrate a benefit in hepatic failure.
 PO ass’d with emesis, which may cause aspiration.
 Co-ingestants may alter gut motility, favoring IV.
 IV protocol is shorter (20 hr vs 72 hr), saving 52 hr of hospital LOS.
 PO has fewer side effects than IV (rash, angioedema, anaphylactoid
reactions).
Manini 8/4/05
Fulminant Hepatic Failure:
 IV NAC dramatically improves survival if started before 8 hrs. Continue NAC until
recovery from encephalopathy or patient expires.
 King’s College Criteria (O’Grady, 1991):
o pH < 7.3 AND any of the following: PT >100, Creat > 3.0, Encephalopathy
o Patients meeting criteria have 15% survival rate if not transplanted.
 Other prognostic markers: lactate >3 (Bernal, 2002), low phosphate (Schmidt, 2002)
 Supportive Care: treat bleeding, cerebral edema, infections, multi-organ system failure
APAP Nomogram
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Study Questions
1. The toxic intermediate N-acetyl-p-benzoquinoneimine is formed via which pathway?
. . . . . a. Sulfation
. . . . . b. Glucuronidation
. . . . . c. Cytochrome P-450
. . . . . d. Glutathionation
2. True/False: An adolescent presents with an acute ingestion of acetaminophen 5 hours
prior. She is lethargic and is not responding appropriately. This clinical presentation is
due to the acetaminophen toxicity.
3. N-acetylcysteine is most effective if given within how many hours of the
acetaminophen ingestion?
4. Which is the first clinical stage that liver function tests may be abnormal?
. . . . . a. Stage I
. . . . . b. Stage II
. . . . . c. Stage III
. . . . . d. Stage IV
5. A patient arrives to the emergency department 7 hours after intentionally ingesting an
unknown amount of acetaminophen. What should be done?
. . . . . a. Directly admit the patient to the floor and await a psychiatric consult.
. . . . . b. Draw a stat acetaminophen level and await the result before further treatment.
. . . . . c. Give the patient syrup of ipecac if she has not vomited and then administer
activated charcoal.
. . . . . d. Draw a stat acetaminophen level and administer NAC.
Suggested Reading
1. Keays R, et al. Intravenous actetylcysteine in paracetamol induced fulminant
hepatic failure: a prospective controlled trial. Br Med J. 303:1026-1029.
2. O’Grady JG et al. Liver transplantation after paracetamol overdose. Br Med J
303:217-9, 1984.
3. Smilkstein MJ et al. Efficacy of oral N-acetylcysteine in the treatment of
acetaminophen overdose. Analysis of the National Multicenter Study. NEJM 319:
1557-62, 1988.
4. Bizovi KE, Parker SJ, Smilkstein MJ. Chapter 142 - Acetaminophen. In: Marx JA
(ed). Rosen's Emergency Medicine Concepts and Clinical Practice, fifth edition.
2002, St. Louis: Mosby Year Book, pp. 2069-2075.
5. Smilkstein MJ. Chapter 31 Acetaminophen. In Goldfrank LR, Flomenbaum NE,
Lewin NA, Weisman RS, Howland MA, Hoffman RS (eds). Goldfrank's
Toxicologic Emergencies, sixth edition. 1998, Stamford: Appleton & Lange; pp.
541-564.
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Answers to questions
1. c
2. False. Acute ingestion of acetaminophen does not cause altered mental status.
3. 8 hours
4. b
5. d