Stage III represents the time of maximal hepatotoxicity occurring between 72 and 96 hours after ingestion. Patients can progress to fulminant hepatic failure, which clinically manifests as development of encephalopathy, coma, cerebral edema, coagulopathy, and gastrointestinal bleeding. Most deaths occurring from hepatic failure occur three to five days following acetaminophen overdose.¹

Patients who survive this period reach stage IV, defined as the recovery phase. Survivors have complete hepatic regeneration, and the rate of recovery varies, but in most cases, most lab values normalize within seven days.²

Acetaminophen level, for those who present within 24 hours of a single acute ingestion, can be plotted on the Rumack-Matthew nomogram to determine the patient’s risk of hepatotoxicity (see Figure 1). For single ingestions, indications to treat with NAC include a four-hour level of ≥150 mg/L for a witnessed ingestion or a level of >10 mg/L in an unwitnessed event with unknown time of ingestion. NAC can be administered via the oral or intravenous routes.

Credit: Merlin Cyrstal [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0], from Wikimedia Commons

There are several variations in treatment protocols; however, the most common are a 21-hour intravenous infusion and a 72-hour oral-dosing protocol. The variation in treatment exists because treatment theoretically should be initiated when the patient is suspected to be at risk for hepatotoxicity, continue while the patient remains at risk, and cease once the risk or toxicity is gone. Studies have shown equal efficacy in preventing toxicity between the intravenous and oral routes.2 The recommended dose of intravenous NAC is 150 mg/kg IV x 1 over 60 minutes followed by 50 mg/kg IV x 1 over four hours followed by 100 mg /kg IV x 1 over 16 hours for both pediatrics and adults.

Specific indications for intravenous NAC include fulminant hepatic failure, inability to tolerate oral NAC, and acetaminophen poisoning in pregnancy. The major adverse effect associated with intravenous NAC can be a severe anaphylactoid reaction; however, this is rare. The recommended dose of oral NAC is a 140 mg/kg loading dose either orally or via enteral tube. Starting four hours after the loading dose, 70 mg/kg should be given every four hours for an additional 17 doses. The main disadvantage of oral NAC is the high incidence of vomiting, which, in turn, can delay care.² This is most beneficial if treatment is initiated within eight hours after ingestion.¹ Therefore, it is important to assess the patient’s risk for hepatotoxicity, and at times, it may be necessary to initiate treatment with NAC prior to laboratory studies in order not to delay care.