The presentation of acetaminophen poisonings can be very nonspecific; acetaminophen toxicity should be considered in patients who present with mild gastrointestinal complaints. Rumack et al described four separate clinical stages.² Stage I occurs before any hepatic injury is apparent. Nonspecific symptoms include nausea, vomiting, malaise, and pallor and can easily be mistaken for a viral illness or any number of disease processes. Some patients will even be asymptomatic in this stage. Stage II occurs within 24 to 72 hours and marks the beginning of hepatic injury. Symptoms, if present from stage I, may resolve, leading the patient or emergency physician to believe that the patient is improving. Symptoms can be similar to those of other forms of hepatitis and accompanied by elevated liver enzymes. Stage III occurs 72 to 96 hours after ingestion and marks maximum hepatotoxicity. Synthetic functions of the liver are affected, as evidenced by abnormal PT/INR, glucose, bilirubin, phosphate, ammonia, and lactate levels. Those who survive stage III will progress to recovery, stage IV. Most patients will have normalization of liver enzymes by day 7, although this may be delayed in severe poisonings.

CRITICAL DECISION

What is a toxic acetaminophen level?

In general, acetaminophen toxicity occurs after a dose of more than 150 mg/kg. For patients who present after a single overdose with a known time of ingestion, the Rumack nomogram is a sensitive predictor of toxicity.³ The original nomogram defines a 4-hour toxic acetaminophen level as greater than 200 mcg/mL. Patients with acetaminophen levels higher than this have a 60% risk of hepatotoxicity (arbitrarily defined as AST >1,000 IU/mL), 1% risk of renal failure, and 5% risk of mortality.

To enhance sensitivity and provide a layer of safety, the United States uses a modified Rumack nomogram with a 4-hour toxic level defined as levels above 150 mcg/mL. This modified nomogram was prospectively validated in 11,195 patients with acute acetaminophen overdose.⁴ Patients with an acetaminophen level below 150 mcg/mL have a 1% risk of hepatotoxicity; their symptoms will resolve spontaneously without treatment, and there is a 0% risk of mortality. Any patient with a single acute overdose with a known time of ingestion should have an acetaminophen level checked and plotted on the modified nomogram to predict toxicity.

The Rumack nomogram has its limitations, however. The nomogram has no role in delayed presentations or chronic ingestions. Because it is the metabolites of acetaminophen that are toxic, a therapeutic or negative acetaminophen level does not guarantee patient safety. Patients with delayed presentations or chronic ingestions should have liver enzymes measured along with an acetaminophen level. In 2004, Daly et al demonstrated that patients with delayed presentations (more than 24 hours after ingestion) or chronic ingestions who had an acetaminophen level of less than 10 mcg/mL and an AST below 50 IU/mL had a 0% risk of developing hepatotoxicity.⁵ Patients suspected of chronic, repeated ingestions and with detectable serum acetaminophen levels (>10 mcg/mL) or elevated liver enzymes should be presumed to have acetaminophen toxicity.

CRITICAL DECISION

Which patients require N-acetylcysteine for acetaminophen toxicity?

The use of N-acetylcysteine (NAC) for the prevention and treatment of hepatotoxicity in acetaminophen overdose has been established as both safe and effective. Although there are various oral and intravenous regimens, the most commonly used is the 20-hour intravenous NAC regimen. The initial loading dose is 150 mg/kg delivered over 15 minutes, followed by a 50 mg/kg dose delivered over 4 hours, followed by a 100 mg/kg dose delivered over 16 hours. The emergency physician must decide not only which patients might benefit from NAC but also when to begin administration.