Betten DP, Cantrell FL, Thomas SC, Williams SR, Clark RF. A prospective evaluation of shortened course oral N-acetylcysteine for the treatment of acute acetaminophen poisoning. Ann Emerg Med. In press. doi://10.1016/j.annemergmed.2006.11.010. Available at: http://www.annemergmed.com. (Reprinted by permission.)
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STUDY OBJECTIVE: Treatment with a shortened duration of oral N-acetylcysteine (20 to 48 hours) after acute acetaminophen poisoning is effective in the prevention of subsequent hepatic failure and death when administered to individuals meeting appropriate laboratory criteria. METHODS: Individuals with a potentially toxic acetaminophen ingestion according to serum acetaminophen levels were identified prospectively using a large statewide poison control system database throughout a 12-month period. N-acetylcysteine was administered for a minimum of 6 doses (20 hours), after which laboratory studies were obtained. Discontinuation of N-acetylcysteine was recommended by the poison center when 2 criteria were met: serum acetaminophen was undetectable (<10 μg/mL) and liver test results were normal (serum aminotransferase, international normalized ratio). A follow-up questionnaire was administered to individuals treated with N-acetylcysteine for 48 hours or less to ascertain the presence of symptoms consistent with progressive hepatotoxicity. RESULTS: Of 205 acutely poisoned individuals treated with N-acetylcysteine for 48 hours or less, 195 were successfully contacted after discharge, and 187 of 195 (95.9%) reported no symptoms consistent with hepatic failure. Eight individuals (4.1%) reported abdominal pain or vomiting; however, none received further N-acetylcysteine treatment or additional hospitalization. CONCLUSION: A shortened duration of treatment with N-acetylcysteine (20 to 48 hours) may be an effective treatment option in individuals considered to be at no further risk of developing liver toxicity according to the fulfillment of appropriate laboratory criteria before N-acetylcysteine discontinuation.
Acetaminophen is a commonly available drug contained in many over-the-counter medications. When taken in therapeutic doses, it is an effective antipyretic and analgesic medication. Unfortunately, in high doses, it is extremely dangerous and has the ability to cause fulminant hepatic failure. The incidence of accidental or purposeful acetaminophen overdose is larger than that of all other commonly available medications.1
The liver metabolizes acetaminophen in 2 major pathways. The first pathway, which accounts for 80%–90% of acetaminophen metabolism, involves glucuronidation and sulfination. This produces nontoxic metabolites. The second pathway involves the cytochrome P450 pathway. These enzymes produce a reactive intermediate, N-acetyl-p-benzoquinine imine (NAPQI), which is either detoxified by a glutathione-regulated pathway or reduced to an end product that causes hepatocellular destruction.
In an acetaminophen overdose, the pathway involving glucuronidation and sulfination becomes overwhelmed. To compensate, the liver shifts to produce more of the reactive metabolite, NAPQI, via the P450 pathway. Subsequently, as glutathione stores are exhausted, the liver experiences hepatocellular injury through the oxidation of NAPQI. An antidote for preventing injury is N-acetylcysteine (NAC), which not only replenishes glutathione stores but also is a free-radical scavenger that prevents oxidation.
NAC is approved for use in cases of acetaminophen overdose, with an oral loading dose of 140 mg/kg body weight and 17 subsequent doses of 70 mg/kg body weight every 4 hours. When this regimen is followed, acetaminophen poisoning has an impressively low overall mortality after a 72-hour course of medication.
The current standard of care specifies a total of 18 oral doses of NAC. Clinicians have questioned this protocol and have suggested shortened oral courses. Toxicology groups have cited the 72-hour rule as excessive and have studied the outcomes of patients on a shortened regimen of only 20 hours. In a study by Yip and Dart,2 33 patients were followed after presenting within 8 hours of an acetaminophen overdose. The patients had little to no elevation in their laboratory tests, with the maximum laboratory values for the international normalized ratio, aspartate aminotransferase, and alanine aminotransferase being 1.5, 41 IU/L, and 54 IU/L, respectively. All the patients were discharged in good condition after completing a 20-hour course of oral NAC.
Overdose patients are often admitted not only for NAC dosing but also for psychiatric evaluation after a suicide attempt. Many of these patients have very intricate psychosocial problems that require immediate attention and aggressive therapy. Proper psychiatric evaluation and treatment are often placed on hold until these patients are medically stable for discharge. Although it may be important to rapidly facilitate psychological treatment, patients who received NAC therapy spent an average of 2.66 days in the hospital.3 Conversely, a shorter course of treatment, when appropriate, can expedite other necessary treatments and proper disposition of these individuals. Until now, there has not been a large study exploring the safety of shortened courses of NAC for acetaminophen overdose.
Betten et al.4 completed a prospective, observational study of 205 low-risk patients with acute acetaminophen ingestion to evaluate the efficacy of a shortened oral course of NAC. Eligible patients included those presenting after an acute ingestion and for whom acetaminophen levels were available within 4–24 hours of the known time of ingestion. One hundred twenty-five of the patients had acetaminophen levels that corresponded to probable toxic ingestion, and 80 patients had levels indicating possible toxic ingestion according to the Rumack-Matthew nomogram. The patients were identified as low-risk by specific criteria. Early discontinuation was carried out only if: (1) the acetaminophen levels decreased to <10; (2) the international normalized ratio was ≤1.3; (3) and the aspartate aminotransferase and alanine aminotransferase levels were ≤60 IU/L, when all values were measured ≥20 hours after the initiation of NAC therapy. Theoretically, one would expect that NAC could be safely discontinued when low-to-undetectable acetaminophen levels are reached. At this point, no further NAPQI would be produced, as it is rapidly cleared because of its short half-life of 10 minutes.5
Patients were followed to evaluate their outcomes after receiving 6–10 doses of NAC. A follow-up phone call and a questionnaire 3 days after discharge were used to evaluate the patients' symptoms. Only 10 patients were lost to follow-up, and local organ registries and state death records were checked and showed no documented mortality. For the remaining 195 patients, there were no deaths or transplants, and only a minority (4%) reported transient symptoms such as abdominal pain or vomiting.
This cohort of patients is larger than that of any previous study reported on a shortened course of oral NAC; however, the results may not be universally applicable. The study lacks a control group that can provide an accurate comparator for patients following the shortened protocol. Also, with the low incidence of acetaminophen toxicity resulting in liver failure, this study is inadequately powered to show the safety of a shortened regimen in the general population. From the reported data, it is unclear what percentage of the total number of acetaminophen overdoses will be categorized as low-risk. Finally, the questionnaire used in the follow-up, applied 3 days after discharge, was not validated to show any clear association with acute liver failure.
In 2004, the Food and Drug Administration approved parenteral dosing of NAC, including a loading dose followed by 20 hours of a continuous intravenous infusion. The shortened course of parenteral therapy provides an alternative to the oral regimen. Intravenous therapy results in a shorter hospital stay, patient/doctor convenience, higher tolerability, and similar outcomes.6 The major distinction between oral therapy and intravenous therapy is a 100-fold difference in cost. After exploring prices within our medical institution, we found that a complete regimen of oral NAC costs about $60, whereas a complete regimen of intravenous NAC, including medication costs and the cost of infusion, totals approximately $6800. Both of these estimates exclude the cost of hospitalization. There are currently no head-to-head trials comparing parenteral NAC therapy and oral NAC therapy. A meta-analysis comparing intravenous therapy and oral therapy showed no differences in the overall mortality.6 The current indications for parenteral therapy include intolerance to oral intake, evidence of gastrointestinal bleeding or obstruction, and fulminant hepatic failure.
Oral NAC therapy needs to be studied further in larger comparative trials to evaluate whether earlier discontinuation is safe for those patients deemed low-risk from an acute acetaminophen overdose. This study shows that in the proper low-risk subset of patients, a shortened oral NAC course may be effective in preventing fulminant hepatic failure, liver transplantation, and mortality. Even though the intravenous regimen shortens the course to a 20-hour protocol, there may be a 100-fold difference in cost in comparison with the oral equivalent. Perhaps more important than cost, a shortened oral course can expedite the proper disposition of the patient. If patients can be appropriately risk-stratified into a low-risk group and complete a 20-hour oral NAC regimen, as practitioners we can safely facilitate their placement in psychiatric facilities for the proper treatment of their psychosocial problems.