Treatment

Treatment for acetaminophen toxicity consists of GI decontamination, the timely use of the antidote— ^-acetylcysteine (NAC)—and supportive care. For most cases of acetaminophen poisoning, adequate GI decontamination consists of the early administration of activated charcoal orally or through nasogastric tube. Emesis induced by administering syrup of ipecac is undesirable because it delays the administration of the antidote, NAC. In addition, more aggressive forms of decontamination such as orogastric lavage or whole bowel irrigation, are unnecessary because of the rapid GI absorption of acetaminophen and the great success of treating acetaminophen poisoning with NAC. However, aggressive GI decontamination should be considered in cases of polydrug overdose in which a coingestant is likely to be life-threatening (e.g., a cyclic antidepressant or a sustained-release calcium-channel blocker).

The mainstay of treatment for acetaminophen toxicity is the administration of the antidote, NAC. Although its mechanisms of action are not fully understood, NAC is thought to have two important beneficial effects. In early acetaminophen toxicity (less than 8 h after ingestion), NAC prevents toxicity by inhibiting the binding of the toxic metabolite NAPQI to hepatic proteins. NAC may act as a glutathione precursor or substitute, act as a sulfate precursor, or it may directly reduce NAPQI back to acetaminophen. In late acetaminophen toxicity (more than 24 h after ingestion), NAC diminishes hepatic necrosis by nonspecific mechanisms. NAC may act as an antioxidant, decrease neutrophil proliferation, improve microcirculatory blood flow, and increase tissue oxygen delivery and extraction.

The standard 72-h oral NAC regimen used in the United States is a loading dose of 140 mg/kg followed by maintenance doses 70 mg/kg every 4 h for 17 doses. If treatment is initiated within 8 h of acetaminophen ingestion, NAC is nearly 100 percent effective in preventing the development of hepatotoxicity, as defined by an AST level of greater than 1000.8 The longer NAC therapy is delayed past 8 h after ingestion, the greater is the risk of developing hepatotoxicity. Even by 24 h after acetaminophen ingestion, however, NAC treatment is associated with a lower risk of hepatotoxicity than are historical controls 7 (Fig, 165-6).

The major complications of oral NAC therapy are nausea and vomiting due to its foul odor and taste of rotten eggs. To hide these disagreeable characteristics, the standard 10% or 20% NAC solution should be diluted to a 5% concentration in a chilled beverage such as fruit juice or a soft drink prior to administration. NAC's disagreeable odor may be further minimized by having the patient sip the drink through a straw from a covered cup or by administering the dose by nasogastric or duodenal tube. Some patients with persistent nausea and vomiting may require concomitant antiemetic treatment with intravenous (IV) metoclopramide (Reglan), 0.1 mg/kg up to 1.0 mg/kg, ondansetron (Zofran), 0.15 mg/kg, or granisetron (Kytril), 0.01 mg/kg, to prevent vomiting and to administer NAC successfully.

Alternative IV NAC regimens have been used successfully in other countries for over 20 years but remain experimental in the United States. 9i0 These regimens possess potential limitations. IV NAC administration may be less effective for the treatment of acetaminophen overdoses in patients arriving more than 10 h after ingestion and is also associated with anaphylactoid reactions.11 At this time, the clinical experience of IV NAC usage in the United States remains too limited to recommend it as a replacement for the traditional oral NAC regimen used for early acetaminophen poisoning. However, IV administration of NAC may be required for patients with refractory vomiting and for patients with contraindications to oral therapy (e.g., caustic ingestions). IV NAC may also be preferable to oral NAC for the treatment of acetaminophen-induced fulminant hepatic failure.12

Currently, there is no IV NAC formulation available in the United States. If it is to be used, the oral NAC formulation, which is sterile, can be made into an IV formulation. Clinical experience suggests that patients with poor glutathione reserves have similar excellent clinical outcomes when the standard treatment guidelines are applied to their care. Thus, the dosage of NAC should not be modified for these patients.

In many clinical situations, NAC therapy is often started in close temporal proximity to the administration of activated charcoal. Although NAC is adsorbed by activated charcoal, there is no evidence that activated charcoal inhibits the clinical effectiveness of NAC. 13 Most authorities believe that NAC dosing is probably excessive. NAC dosing is based on a patient's weight and bears no relationship to the dose of acetaminophen ingested. In addition, NAC appears to be equally effective in preventing hepatotoxicity following the largest acetaminophen overdose.14 Separating the first dose of NAC and activated charcoal by 1 to 2 h, when possible, is a reasonable method to minimize potential NAC and activated charcoal interaction.

There are no data on which order is superior, and there is no evidence that administration of activated charcoal and NAC in a closer time frame is a problem.

Finally, the weight of clinical evidence suggests that NAC therapy is safe to use during pregnancy and that the approach to treating a pregnant patient following an acetaminophen overdose should remain the same. An ovine model demonstrated that NAC was unable to cross the placenta.15 Finally, fetal demise and malformations have been described when NAC treatment was delayed for acetaminophen overdose in first-trimester pregnant women.15

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