Background: Acetaminophen is the most widely used pharmaceutical analgesic and antipyretic agent in the United States and the world; it is contained in more than 100 products. As such, acetaminophen is one of the most common pharmaceuticals associated with both intentional and accidental poisoning.

Acetaminophen-induced hepatotoxicity is well recognized. Acetaminophen also is known as paracetamol and N-acetyl-p-aminophenol (APAP). It is found in the United States as 325-mg and 500-mg immediate-release tablets and as a 650-mg extended-release preparation. Various children's chewable, suspension, and elixir formulations of acetaminophen also are available. Furthermore, acetaminophen is found as a component of combination drugs such as propoxyphene-acetaminophen (eg, Darvocet) and oxycodone-acetaminophen (eg, Percocet).

Pathophysiology: The maximum daily dose of APAP is 4 g in adults and 90 mg/kg in children. The toxic dose of APAP after a single acute ingestion is 150 mg/kg or approximately 7 g in adults, although the at-risk dose may be lower in persons with alcoholism and other susceptible individuals. When dosing recommendations are followed, the risk of hepatotoxicity is extremely small.

Acetaminophen is rapidly absorbed from the stomach and small intestine and metabolized by conjugation in the liver to nontoxic agents, which then are eliminated in the urine.

In acute overdose or when maximum daily dose is exceeded over a prolonged period, the normal pathways of metabolism become saturated. Excess APAP is then metabolized in the liver via the mixed function oxidase P450 system to a toxic metabolite, N-acetyl-p-benzoquinone-imine (NAPQI). NAPQI has an extremely short half-life and is rapidly conjugated with glutathione, a sulfhydryl donor, and removed from the system. Under conditions of excessive NAPQI formation or reduced glutathione stores, NAPQI is free to covalently bind to vital proteins and the lipid bilayer of hepatocytes; this results in hepatocellular death and subsequent centrilobular liver necrosis.

The antidote for APAP poisoning is N-acetylcysteine (NAC). NAC is theorized to work by a number of protective mechanisms. Early after overdose, NAC prevents the formation and accumulation of NAPQI. NAC increases glutathione stores, combines directly with NAPQI as a glutathione substitute, and enhances sulfate conjugation. NAC also functions as an anti-inflammatory and antioxidant and has positive inotropic and vasodilating effects, which improve microcirculatory blood flow and oxygen delivery to tissues. Vasodilating effects decrease morbidity and mortality once hepatotoxicity is well established.

NAC is most effective when administered within 8 hours of ingestion. When indicated, however, NAC should be administered regardless of time since the overdose. Therapy with NAC has been shown to decrease mortality rates in late-presenting patients with fulminant hepatic failure (in the absence of acetaminophen in the serum).

Frequency:

• In the US: Acetaminophen is one of the most common agents in overdose reported to the American Association of Poison Control Centers. APAP toxicity is the most common cause of hepatic failure requiring liver transplantation in the United States and Great Britain.

Mortality/Morbidity: The majority of patients with APAP overdose survive with supportive care in conjunction with antidotal therapy. If correctly treated in a timely manner, most patients do not suffer significant sequelae.

• Case series report that fewer than 4% of patients who suffer severe hepatotoxicity develop hepatic failure; fatalities or liver transplantation occur in less than one half of these patients.

• Patients with malnutrition, AIDS, chronic ethanol abuse, or anorexia nervosa may be at increased risk for morbidity because of deficient glutathione stores and inadequate detoxification of NAPQI. Patients with enhanced ability to make NAPQI because of induction of the P450 system, specifically cyp2E1, may be at increased risk of morbidity; these patients include those taking agents known to induce this enzyme activity, such as rifampin, phenobarbital, isoniazid, phenytoin, carbamazepine, or patients with chronic ethanol abuse.

• Pediatric patients younger than 5 years appear to fare better than adults after APAP poisoning, perhaps owing to a greater capacity to conjugate acetaminophen, enhanced detoxification of NAPQI, or greater glutathione stores. However, since no controlled studies have supported any alternative pediatric therapy, treatment in children should not be different than in adults.

History: The course of acetaminophen toxicity generally is divided into 4 phases. Evidence of end-organ (hepatic, renal) toxicity often is delayed 24-48 hours postingestion.

• Because antidotal therapy is most efficacious when initiated within 8 hours postingestion, the clinician must attempt to obtain an accurate history of the time(s) of ingestion, the quantity and formulation of acetaminophen ingested, and any co-ingestants (eg, diphenhydramine, other anticholinergic drugs, opioids), which may delay absorption.

• However, as a patient's history often is inaccurate, the serum acetaminophen concentration is important for diagnosis and treatment, even in the absence of symptoms.

• Phase 1 (0-24 h)

• Asymptomatic

• Anorexia

• Nausea and vomiting

• Diaphoresis

• Malaise

• Phase 2 (18-72 h)

• Decreasing symptoms of phase 1

• Right upper quadrant abdominal pain and rising liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST])

• Phase 3 (72-96 h)

• Centrilobular hepatic necrosis with accompanying abdominal pain

• Jaundice
• Coagulopathy
• Hepatic encephalopathy

• Recurrence of nausea and vomiting

• Renal failure

• Fatality

• Phase 4 (4 d to 3 wk)

• Complete resolution of symptoms

• Complete resolution of organ failure

Physical: Physical examination findings vary, depending on the phase of toxicity.

• Phase 1

• Pallor

• Malaise

• Vomiting

• Diaphoresis

• Phase 2

• Right upper quadrant abdominal tenderness

• Tachycardia

• Hypotension possibly due to volume loss

• Phase 3

• Tender hepatic edge

• Jaundice

• Evidence of coagulopathy, including gastrointestinal (GI) bleeding

• Evidence of hepatic encephalopathy

• Phase 4: Resolution

Causes:

• Production of acetaminophen's toxic metabolite, NAPQI, in excess of an adequate store of glutathione necessary to conjugate it, leads to NAPQI-induced hepatocellular necrosis and hepatic failure.

• Additional mechanisms of acetaminophen-induced toxicity are postulated as well.

Lab Studies:

• Acetaminophen serum concentration

• A serum acetaminophen concentration drawn 4 or more hours after a single ingestion may be plotted on the Rumack-Matthew nomogram as a guide to recommended NAC therapy. Do not rely upon this nomogram following multiple acetaminophen ingestions, multiple ingestions such as those involving anticholinergics or opioids, extended release formulations, or chronic ingestions. Note that the Rumack-Matthew nomogram is a treatment nomogram and distinct from the Done nomogram, which serves to predict the severity of toxicity in salicylate poisoning.

• Determine serum acetaminophen concentration in any intentional overdose because the history of acetaminophen ingestion may not be elicited, and manifestations of toxicity may not become evident until after treatment should have been initiated. (See Special Concerns for information regarding extended-relief acetaminophen.)

• Transaminase levels

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) begin to rise within 24 hours postingestion and peak at 48-72 hours.

• Severe toxicity can be defined as AST or ALT greater than 1000 IU/L.

• Measures of hepatic function

• Serum glucose

• Prothrombin time (PT) and bilirubin

• Electrolytes and creatinine

• Look for anion gap acidosis to help rule out co-ingestion, metabolic disorder from vomiting, or liver failure (if subacute ingestion).

• Renal failure has been shown to coexist with or, rarely, be independent of liver toxicity in overdose. One study indicated that this is more likely to occur in alcoholic persons. Renal failure usually is not observed acutely but rather within 2-3 days of overdose.

• Human chorionic gonadotropin (HCG) in females of childbearing age

• Acetaminophen crosses the placenta, and the fetal liver is able to elaborate NAPQI by 14 weeks of gestation.

• Delay in treating pregnant patients with antidotal therapy is associated with fetal demise.

• A type and crossmatch should be drawn for the treatment of active bleeding in the face of coagulopathy.

• Urinalysis: Proteinuria and hematuria may be seen with acute tubular necrosis (ATN), usually in conjunction with hepatic failure.

• Arterial blood gas

• Poor prognosis is associated with an arterial pH less than 7.30 (which fails to correct with fluid administration) and serum creatinine greater than 3.4 mg/dL.

• An arterial blood gas (ABG) should be drawn in patients with clinical or laboratory evidences of toxic overdose or altered mental status.

Imaging Studies:

• CT scan of the head

• CT scan may reveal cerebral edema in patients with late presentation and encephalopathy.

• Consider in patients with altered mental status.

• Ultrasound

• Ultrasound may reveal mild hepatic enlargement in late presentation.

• If clinically indicated, this is usually an inpatient procedure.

Procedures:

• Gastric lavage

• Gastric lavage is controversial and has no proven efficacy in isolated acetaminophen overdose.

• Consider in early presentation (<1 h) following a multidrug ingestion with altered mental status or hemodynamic compromise.

Prehospital Care: Stabilize immediate life-threatening conditions and initiate supportive care.

Emergency Department Care:

• Supportive therapy, including IV fluids, oxygen, and cardiac monitor

• Gastric decontamination

• Oral activated charcoal avidly adsorbs acetaminophen and should be administered if the patient presents within 1-2 hours of ingestion or later, especially if a GI motility-inhibiting co-ingestant may have been involved.

• Administer oral activated charcoal if the time of ingestion is unknown, the patient ingested extended-relief acetaminophen, or possibility of a drug co-ingestion exists.

• Administer N-acetylcysteine, if indicated.

• Assess for evidence of other life-threatening co-ingestions.

Consultations:

• Medical toxicologist, available through consultation with a regional poison control center

• This consultation is recommended if using IV NAC.

• Consultation with a medical toxicologist also is recommended for patients who have a complicated or late presentation, hepatic or renal dysfunction, or a history of potentially toxic co-ingestants.

• If fulminant hepatic failure is present, consult a hepatologist and transplant surgeon.

Agents used in the treatment of acetaminophen poisoning include activated charcoal, N-acetylcysteine, and antiemetics.

Drug Category: GI decontaminants -- Emergency treatment in poisoning caused by drugs and chemicals. Network of pores present in activated charcoal adsorbs 100-1000 mg of drug per gram of charcoal. Does not dissolve in water.

Drug Category: Antidote -- May provide substrate for conjugation with the toxic metabolite of acetaminophen. Administer all doses, even if acetaminophen level has dropped below toxic range.

Drug Category: Antiemetics -- Emesis frequently is associated with acetaminophen toxicity and is a common consequence of activated charcoal and NAC administration. For these reasons, antiemetic therapy often is necessary to allow successful administration of NAC.

Antiemetics that do not decrease gastric motility or significantly alter mental status are the DOC; anticholinergic drugs, such as prochlorperazine (Compazine) are not considered beneficial, in part because of their propensity to cause both of these effects. Phenothiazines also may add to the toxicity associated with other anticholinergic drugs, which are often in APAP-containing formulations.

Further Inpatient Care:

• Admit patients for NAC therapy if they have an acetaminophen level associated with potential toxicity, as suggested by the Rumack-Matthew treatment nomogram.

• Unless coexisting toxicologic, medical, or psychiatric issues are present, patients with acetaminophen toxicity may be admitted and treated on a general medical floor.

• Admit patients to an ICU setting if they show signs of significant hepatotoxicity; hepatic failure; or other potentially life-threatening, coexisting, toxicologic, or medical issues.

Further Outpatient Care:

• Patients who do not have a suggestive history or acetaminophen level associated with potential toxicity, as determined by the Rumack-Matthew nomogram, may be discharged or transferred for psychiatric evaluation if indicated.

Transfer:

• Transfer patients with fulminant hepatic failure to a facility capable of intensive care monitoring and evaluation for potential transplantation.

Patient Education:

• Advise patients of the potential risk associated with the inappropriate use of acetaminophen, which commonly is considered an innocuous over-the-counter drug.

• Educate parents of the proper acetaminophen dosing for children and the danger associated with misusing various acetaminophen preparations (eg, infant suspension vs pediatric elixir, pediatric vs adult suppositories). Because infant suspension (drops) is a more concentrated formulation than the elixir (100 mg/mL vs 32 mg/mL), this can be a potential source of therapeutic error. Parents always should be given clear dose and formulation instructions.

• Educate patients of the increased potential for renal toxicity associated with concurrent acetaminophen and NSAID analgesic use or chronic alcoholism.

Medical/Legal Pitfalls:

• NAC-activated charcoal interaction

• In vitro studies have shown that NAC is adsorbed to activated charcoal and the administration of activated charcoal reduced total NAC absorption by 39% in human volunteers, as measured by serum NAC levels. Prospective evaluation of patients treated with activated charcoal and NAC, however, indicated no adverse outcome associated with this treatment.

• Despite binding to NAC, activated charcoal adsorbs acetaminophen more avidly. Therefore, although charcoal may decrease the bioavailability of NAC, this decrease is clinically inconsequential.

• Finally, activated charcoal administration may prevent significant acetaminophen absorption and obviate the need for NAC.

• Super-loading doses of NAC have shown to be of no greater clinical benefit than the current recommended loading dose.

• Administer activated charcoal and draw a 4-hour serum acetaminophen concentration if the patient presents within 1-2 hours of ingestion, presents later after co-ingestion with a substance that could delay systemic absorption, or the history is unclear.

• Draw an acetaminophen level if the patient presents later than 4 hours after ingestion. Administer NAC if presentation is close to 8 hours postingestion or if the acetaminophen level will not be available within 8 hours postingestion.

• NAC may be staggered with activated charcoal if multiple doses of activated charcoal are necessary for treatment of a co-ingestant.

• For greatest efficacy, administer NAC within 8 hours of ingestion; however, a later presentation should not preclude its administration if the history or presentation suggests potential toxicity. Failure to administer NAC because of late presentation could be considered medically and legally risky.

• Failure to consider and evaluate for possible co-ingestants or to consider the effects of decreased GI motility on absorption of APAP; the treatment nomogram does not pertain to these situations. Therefore, in the absence of good data on multidrug or co-ingestions involving APAP, administer NAC as early as possible and consult the regional poison control center for guidance on a treatment regimen.

Special Concerns:

• Chronic ingestion

• If a patient presents with ingestion of supratherapeutic doses of acetaminophen over hours or days, evaluate for presence of hepatotoxicity and unmetabolized acetaminophen.

• Begin NAC therapy if the patient has elevated AST and ALT and a measurable acetaminophen concentration.

• Consult the regional poison control center for guidance on a treatment regimen.

• Late presentation

• If a patient presents 8-24 hours or longer postingestion, evaluate for ongoing hepatotoxicity and initiate NAC therapy if indicated.

• NAC administration in cases of hepatic failure has been associated with decreased incidence of cerebral edema and improved survival.

• Extended-relief acetaminophen (Tylenol ER)

• The Tylenol ER preparation became available in 1995. The tablet is composed of acetaminophen 325 mg in immediate release form with a matrix of acetaminophen 325 mg formulated for slow release. Some alteration of the elimination kinetics of this preparation may affect the ability of the Rumack-Matthew nomogram to guide treatment. Several studies show that eliminations of extended and immediate-release acetaminophen are nearly identical after 4 hours. However, some case reports have documented acetaminophen levels falling above the treatment nomogram line as late as 11-14 hours postingestion of the extended-release preparation.

• Check 4-, 6-, and 8-hour acetaminophen concentration levels. Begin NAC therapy if any level crosses above the nomogram treatment line. If the 6-hour level is greater than the 4-hour level, begin NAC therapy. More prolonged monitoring of levels may be necessary if the patient has food in the stomach or co-ingestants that delay gastric emptying. Consult the regional poison control center for guidance in evaluation and treatment regimen.

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