 |
Acetaminophen
poisoning can cause gastroenteritis within hours and hepatotoxicity
1 to 3 days after ingestion. Severity of hepatotoxicity after a
single acute overdose is predicted by serum acetaminophen levels.
Treatment is with N-acetylcysteine to prevent or minimize hepatotoxicity.
Acetaminophen is contained in > 100 products sold OTC; they include many children's preparations in liquid, tablet, and capsule form and many cough and cold preparations. Many prescription drugs also contain acetaminophen . Consequently, acetaminophen overdose is common.
The principal toxic metabolite of acetaminophen , N-acetyl-p-benzoquinone imine (NAPQI), is produced by the hepatic cytochrome P-450 enzyme system; glutathione stores in the liver detoxify this metabolite. An acute overdose depletes glutathione stores in the liver. As a result, NAPQI accumulates, causing hepatocellular necrosis and possibly damage to other organs (eg, kidneys, pancreas). Theoretically, alcoholic liver disease or undernutrition could increase risk of toxicity because hepatic enzyme preconditioning may increase formation of NAPQI and because undernutrition (also common among alcoholics) reduces hepatic glutathione stores. However, whether the risk is actually increased is unclear. Acute alcohol ingestion may be protective because hepatic P-450 enzymes preferentially metabolize ethanol and thus cannot produce toxic NAPQI.
To cause toxicity, an acute overdose must total ≥ 150 mg/kg (about 7.5 g in adults) within 24 h.
Chronic excessive use or repeated overdoses cause hepatotoxicity in a few patients. Usually, chronic overdose is not an attempt at self-injury but instead results from taking inappropriately high doses to treat pain.
Symptoms,
Signs, and Diagnosis
Single acute
overdose:
Mild poisoning may not cause symptoms, and when present, symptoms are usually minor until ≥ 48 h after ingestion. Symptoms, which occur in 4 stages (see
Table 5: Poisoning: Stages of Acetaminophen Poisoning ), include anorexia, nausea, vomiting, and right upper quadrant abdominal pain. AST, ALT, and, if poisoning is severe, bilirubin and INR may be elevated. AST levels > 1000 IU/L are more likely to result from acetaminophen poisoning than from chronic hepatitis or alcoholic liver disease. Renal failure and pancreatitis may occur, occasionally without hepatic failure. After > 5 days, hepatotoxicity resolves or progresses to multiple organ failure, which can be fatal.
|
Table 5
|
| | |
|
Stages of Acetaminophen
Poisoning
|
|
Stage
|
Time Post-ingestion
|
Description
|
|
I
|
0 to 24 h
|
Anorexia, nausea, and vomiting
|
|
II
|
24 to 72 h
|
Right upper quadrant abdominal pain (common); AST, ALT, and, if poisoning is severe, bilirubin and PT (usually reported as the INR) sometimes elevated
|
|
III
|
72 to 96 h
|
Vomiting and symptoms of hepatic failure; AST, ALT, bilirubin, and INR peak; sometimes renal failure and pancreatitis
|
|
IV
|
> 5 days
|
Resolution of hepatotoxicity or progression to multiple organ failure (sometimes fatal)
|
|
Acetaminophen overdose should be considered in all patients with nonaccidental ingestions that may be attempts at suicide because acetaminophen overdose is common. Also, it often causes minimal symptoms during the early stages, is potentially lethal but is treatable, and may not be reported by suicidal or obtunded patients.
Likelihood and severity of hepatotoxicity can be predicted by the amount ingested or, more accurately, by the serum acetaminophen level. If the time of ingestion is known, the Rumack-Matthew nomogram (see Fig. 1: Poisoning: Rumack-Matthew nomogram for single acute acetaminophen poisoning. ) is used to estimate likelihood of hepatotoxicity; if the time is unknown, the nomogram cannot be used. For a single acute overdose of traditional acetaminophen or rapid-relief acetaminophen (which is absorbed 7 to 8 min faster), levels are measured ≥ 4 h after ingestion and plotted on the nomogram. A level ≤ 150 μg/mL (≤ 990 μmol/L) and absence of toxic symptoms indicate that hepatotoxicity is very unlikely. Higher levels indicate possible hepatotoxicity. For a single acute overdose with extended-relief acetaminophen (which has 2 peak serum levels about 4 h apart), acetaminophen levels are measured ≥ 4 h after ingestion and 4 h later; if either level is above the Rumack-Matthew line of toxicity, treatment is required.
|
Fig. 1
|
| | |
|
Rumack-Matthew nomogram for single acute acetaminophen poisoning.
|
 |
|
Semilogarithmic plot of plasma acetaminophen levels vs time. Cautions for use of this chart: (1) The time coordinates refer to time of ingestion. (2) Serum levels drawn before 4 h may not represent peak levels. (3) The graph should be used only in relation to a single acute ingestion. (4) The lower solid line 25% below the standard nomogram is included to allow for possible errors in acetaminophen plasma assays and estimated time from ingestion of an overdose. (Adapted from Rumack BH, Matthew H: Acetaminophen poisoning and toxicity. Pediatrics 55(6): 871–876, 1975; reproduced by permission of Pediatrics.)
|
|
Chronic overdose:
Symptoms may be absent or may include any of those that occur with acute overdose. The Rumack-Matthew nomogram cannot be used, but likelihood of clinically significant hepatotoxicity can be estimated based on AST, ALT, and serum acetaminophen levels. If AST and ALT are normal (< 50 IU/L) and the acetaminophen level is < 10 μg/mL, significant hepatotoxicity is very unlikely. If AST and ALT are normal but the acetaminophen level is ≥ 10 μg/mL, significant hepatotoxicity is possible; AST and ALT are remeasured after 24 h. If repeat AST and ALT are normal, significant hepatotoxicity is unlikely; if they are high, significant hepatotoxicity is assumed. If initial AST and ALT are high, regardless of the acetaminophen level, significant hepatotoxicity is assumed.
Prognosis
With appropriate treatment, mortality is uncommon. Poor prognostic indicators at 24 to 48 h postingestion include pH < 7.3 after adequate resuscitation, INR > 3, serum creatinine > 2.6, hepatic encephalopathy grade III (confusion and somnolence) or grade IV (stupor and coma), hypoglycemia, and thrombocytopenia. Acute acetaminophen toxicity does not predispose patients to cirrhosis.
Treatment
Activated charcoal is given if acetaminophen is likely to still remain in the GI tract.
N- Acetylcysteine is an antidote for acetaminophen poisoning. This drug is a glutathione precursor that decreases acetaminophen toxicity by increasing hepatic glutathione stores and possibly via other mechanisms.
For acute poisoning, N- acetylcysteine is given if hepatotoxicity is likely based on acetaminophen dose or serum level. The drug is most effective if given within 8 h of acetaminophen ingestion.
For chronic poisoning, N- acetylcysteine is given for the 1st 24 h if hepatotoxicity is possible (if AST and ALT are normal and acetaminophen level is initially elevated). If repeat AST and ALT (after 24 h) are normal, N- acetylcysteine is stopped; if repeat levels are high, they are remeasured daily, and N- acetylcysteine is continued until levels are normal. If hepatotoxicity is likely (especially if initial AST and ALT are high), a full course of N- acetylcysteine is given.
N- Acetylcysteine is equally effective given IV or po. IV therapy is given as a continuous infusion. A loading dose of 150 mg/kg in 200 mL of 5% D/W given over 15 min is followed by maintenance doses of 50 mg/kg in 500 mL of 5% D/W given over 4 h, then 100 mg/kg in 1000 mL of 5% D/W given over 16 h. For children, dosing may need to be adjusted to decrease the total volume of fluid delivered; consultation with a poison control center is recommended.
The loading dose of oral N- acetylcysteine is 140 mg/kg. This dose is followed by 17 additional doses of 70 mg/kg q 4 h. Oral acetylcysteine is unpalatable; it is given diluted 1:4 in a carbonated beverage or fruit juice and may still cause vomiting. If vomiting occurs, an antiemetic can be used; if vomiting occurs within 1 h of a dose, the dose is repeated.
Hepatic failure is treated supportively. Patients with fulminant hepatic failure may require liver transplantation.
Last full review/revision November 2005
Content last modified November 2005
| |
