When an overdose case is seen within one hour, gastric lavage is recommended. If seen within 4 hours, activated charcoal should be given (1g/kg up to 50 g as a slurry with 60-90 ml water). It will not adversely affect subsequent NAC absorption. The treatment of choice is N-acetylcysteine (NAC). Since it is safe and free of adverse effects, treatment should be initiated after 4 hours following acetaminophen ingestion (up until 48 hours), when blood levels exceed the threshold for risk (150 mg/ml at 4 hours and 20 mg/ml at 16 hours), or when there is a delay in obtaining acetaminophen blood levels. The nomogram for predicting risk of toxicity is not useful in accidental poisoning (e.g., therapeutic doses in alcoholics). NAC is usually given orally diluted about 1:3 with cola or citrus juice. Start with a loading dose of 140 mg/kg followed by 70 mg/kg every four hours for 17 additional doses. If the patient vomits within 1 hour, repeat the dose or use NG tube. Intravenous dosing may soon be available and can be given over 20 or 48 hours. Close monitoring for anaphylaxis is needed for the first hour after the i.v. loading dose.

The efficacy of NAC is superb when initiated in the first 10 hours but remains better than historical controls even from 16-24 hours after acetaminophen ingestion. The mechanism of action is believed to be as a cysteine prodrug, either being hydrolyzed to cysteine or reacting with plasma cystine to liberate cysteine. Increased cysteine availability to the liver drives the synthesis of glutathione which then can keep up with the production of toxic metabolite for its specific detoxification. Other benefits of NAC, such as improved tissue perfusion, are more controversial. In patients who develop acute liver failure (ALF) or with grade III or IV encephalopathy due to acetaminophen, overall mortality is about 30%, which is lower than ALF from other causes. The sudden severe insult to the liver, although profound, because of its discrete temporal occurrence, can rapidly reverse making this situation different from the more gradual and progressive nature of the pathogenesis of other forms of ALF. Thus, the timing and decision to transplant is quite uncertain. The King's College retrospective analysis however demonstrated objective criteria that point to a very high mortality (>90%) justifying transplantation: metabolic acidosis (pH<7.31) on day 2+ or combination of protime >100 secs (INR >6.5), serum creatinine >3.9 mg/l, and grade III to IV encephalopathy. Patients who meet these criteria should be transplanted expeditiously.