Acetaminophen Toxicity Treatment & Management

The management of patients with chronic ingestion, those with late presentation, and those who have ingested extended-release (ER) acetaminophen (APAP) is discussed.

Chronic ingestion

If a patient presents after multiple ingestions or chronic ingestion of supra-therapeutic doses of APAP over hours or days, evaluate for the presence of a persistent serum APAP concentration and laboratory indicators of hepatotoxicity.

Begin N -acetylcysteine (NAC) therapy if the patient has elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels or a measurable serum APAP concentration.

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

Late presentation

If a patient presents 8-24 hours or later after an acute ingestion, initiate NAC therapy and evaluate for laboratory evidence of hepatotoxicity. If evidence of hepatotoxicity exists, continue NAC therapy and consult a regional poison control center for guidance on a treatment regimen.

NAC administration in cases of hepatic failure has been associated with a decreased incidence of cerebral edema and improved survival. Therefore, NAC therapy should be initiated if concern exists for potential toxicity while awaiting confirmatory laboratory studies.

ER acetaminophen (Tylenol ER)

The Tylenol ER preparation became available in 1995. The tablet is composed of APAP 325 mg in immediate release (IR) form surrounding a matrix of APAP 325 mg formulated for slow release. Some alteration of the elimination kinetics of this preparation may affect the reliability of the Rumack-Matthew nomogram to predict potential hepatotoxicity and subsequent treatment based on serum APAP concentrations. Several studies show that the elimination of ER and IR APAP preparations is nearly identical after 4 hours. However, some case reports have documented APAP levels that are above the potential toxicity and treatment line on the nomogram as late as 11-14 hours after the ingestion of the ER preparation.

Recommended management includes the measurement of 4-, 6-, and 8-hour APAP concentrations. 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 APAP levels may be necessary if the patient has food in his or her stomach or co-ingestants that delay gastric emptying.

Consult a regional poison control center for guidance in the evaluation and optimal treatment regimen for these cases.

Before the patient arrives at the hospital, stabilize any immediate life-threatening conditions, and initiate supportive care. In the emergency department, continue supportive therapy, including intravenous (IV) fluids, oxygen, and cardiac monitoring.

Gastric decontamination

Oral activated charcoal (AC) avidly adsorbs acetaminophen (APAP) and may be administered if the patient presents within 1 hour of ingestion.

Oral AC may be of benefit longer than 1 hour after the ingestion if the ingestion involves an agent that delays gastric emptying or slows gastrointestinal (GI) motility. Oral AC administered with N -acetylcysteine (NAC) greater than 4 hours after ingestion has been shown in one case series to be effective in reducing the incidence of transaminitis after toxic APAP ingestion. However, it is well documented that the effectiveness of oral AC diminishes over time, especially beyond 60 minutes after an ingestion.

In summary, oral AC should only be administered if a potentially toxic amount of drug has been ingested and a patient presents within 1 hour of ingestion. AC should not be administered if the patient does not have an intact or protected airway.^[10]

More important than GI decontamination after APAP ingestion is the early administration of NAC. Early administration of NAC, within 8 hours of ingestion, is nearly 100% hepatoprotective. NAC should be administered while awaiting a serum APAP level if the patient presents close to or later than 8 hours after an acute ingestion or if the patient is pregnant.

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

For further information, see the American College of Emergency Physicians treatment guidelines for acetaminophen poisoning.^[11]

Hospitalization

Admit patients for NAC therapy if they have a serum APAP level that is associated with potential toxicity, as determined by the Rumack-Matthew treatment nomogram.

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

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

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

Outpatient guidelines

Patients who do not have a serum APAP level associated with potential toxicity, as determined by the Rumack-Matthew nomogram, may be discharged or transferred for psychiatric evaluation if indicated, when they are otherwise medically clear.

Outpatient treatment guidelines are available from the American Association of Poison Control Centers.^[12]

Early administration of N -acetylcysteine (NAC) is more important than GI decontamination with oral activated charcoal (AC) in cases of acetaminophen (APAP) ingestion. In vitro studies have shown that NAC is adsorbed to AC and the administration of AC reduced total NAC absorption by 39% in human volunteers, as measured by serum NAC levels. Prospective evaluation of patients treated with AC and NAC, however, indicated no adverse outcome associated with this treatment.

Despite binding to NAC, AC adsorbs APAP more avidly. Therefore, although the administration of AC may decrease the bioavailability of oral NAC, this decrease is clinically inconsequential. Importantly, AC administration may prevent significant APAP absorption from the GI tract and obviate the need for NAC.

“Super-loading” doses of oral NAC have not been shown to be of greater clinical benefit than the current recommended loading dose.

Administration considerations

Administer AC and draw a 4-hour serum APAP concentration if the patient presents within 1 hour of ingestion.

Draw a serum APAP level if the patient presents later than 4 hours after ingestion. Administer NAC if the presentation is close to 8 hours after the ingestion, or if the APAP level will not be available within 8 hours postingestion, and if the history is unclear, but a potentially toxic APAP ingestion is suspected.

Oral NAC administration may be staggered with AC administration if there is the rare need for multiple doses of AC for the treatment of a co-ingestant.^[13] Intravenous NAC administration is preferable in such a case.

For greatest hepatoprotective efficacy, administer NAC within 8 hours of an acute ingestion^[14] ; a later presentation should not preclude NAC administration if the history or presentation suggests potential toxicity.^[15] The failure to administer NAC because of late presentation could be considered medically and legally inappropriate.

Consider and evaluate for possible co-ingestants and consider the possible effects of decreased GI motility on the absorption of APAP; the predictive value of the treatment nomogram may be less reliable in these situations. Therefore, in the absence of good data on multidrug ingestions or co-ingestions involving APAP, administer NAC as early as possible and consult the regional poison control center for guidance on a treatment regimen.

Consultation with a medical toxicologist is recommended for patients who have a complicated or late presentation, hepatic or renal dysfunction, or a history of potentially toxic co-ingestants. Medical toxicologists are available through consultation with a regional poison control center.

A hepatologist should be consulted in the setting of hepatic dysfunction and liver failure.

Consult a transplant surgeon in the setting of clinical and laboratory indicators that are highly predictive of death unless urgent transplantation is undertaken. (see Prognosis.) The King's College Hospital criteria for the determination of the urgent need for transplantation after acetaminophen (APAP)-induced fulminant hepatic failure include the following:

• Arterial pH less than 7.3 (regardless of grade of encephalopathy) OR
• Grade III or IV encephalopathy
• Prothrombin time (PT) greater than 100 seconds
• Serum creatinine greater than 3.4 mg/dL