Has the Time Come to Give Oral N-acetylcysteine Intravenously?
Has the Time Come to Give Oral N-acetylcysteine Intravenously?
ABSTRACT & COMMENTARY
In a recent retrospective review, yip and colleagues evaluated 76 patients who received oral N-acetylcysteine (NAC) intravenously. While more than half of these patients had recurrent vomiting, other indications included gastrointestinal hemorrhage, refusal to take oral NAC, and co-ingestants. Patients were given a loading dose of 140 mg/kg diluted to 3% and run for more than one hour through a 0.2 micron (hyperalimentation) filter, followed by doses of 70 mg/kg every four hours. Overall, all patients did well with only four (5.3%) suffering minor allergic reactions, which occurred during the loading dose only.
Yip et al conclude that intravenous administration of the current oral preparation is generally safe. (Yip L, et al. Intravenous administration of oral N-acetylcysteine. Crit Care Med 1998;26:40-43.)
COMMENT BY ROBERT HOFFMAN, MD
Acetaminophen (APAP) overdose produces centrilobular hepatic necrosis through the formation of a cytochrome P450-generated toxic metabolite known as NAPQI. Small amounts of NAPQI that result from therapeutic doses of APAP are normally detoxified by glutathione. Hepatotoxicity only results following a large overdose when glutathione stores are depleted and NAPQI is allowed to bind to and destroy hepatocytes. NAC is the only antidote available for the treatment of APAP poisoning. In the early phases of an overdose, NAC serves both as a glutathione substitute and precursor and also promotes the elimination of APAP by providing substrate for the nontoxic sulfation pathway. Later, NAC may alter the inflammatory response and improve hemodynamics and hepatic oxygen extraction by mechanisms that are yet to be fully elucidated.
A well-designed, large, prospective study demonstrated that when the standard oral NAC regimen (a loading dose of 140 mg/kg followed by 17 doses of 70 mg/kg given every four hours) is initiated within eight hours of ingestion, even patients with massive APAP levels have outcomes that cannot be distinguished from nontoxic ingestions.1 Beyond eight hours, as the time from ingestion to the administration of NAC increases, both the incidence of hepatic dysfunction and mortality begin to increase. However, even when initiated more than 24 hours post-ingestion, the benefits of NAC can still be appreciated.2
Although NAC seems to be a "perfect" antidote, all of those who have used it know that this is far from true. NAC has a foul, sulfur-like smell and taste, which results in significant nausea and vomiting that lower the patient's ability to comply with a full 72-hour regimen. Tricks, such as diluting NAC in cold soda or juice and the use of nasogastric tubes and antiemetics, improve tolerability but often contribute to substantial delays in NAC administration. Furthermore, in some cases, co-ingestants such as caustics or corrosives contraindicate the use of any oral therapy, and many (unfounded) concerns have been expressed regarding the efficacy of oral NAC when multiple-dose activated charcoal therapy is required.
Most other "civilized" countries have solved this problem by using intravenous NAC therapy. Intravenous protocols range in duration from less that 24 hours to a standard 72-hour course. While all of these protocols seem to be equally efficacious when initiated early, the longer therapies seem superior when patients present later.3 Unfortunately, in this country, no product is approved for intravenous use.
This study is an essential contribution to the literature in that it gives support to a practice that many of us have been forced to adopt for years. In fact, it may even tempt some readers to make intravenous NAC administration part of their routine practice. I must, however, urge against the routine intravenous use of oral NAC. First of all, while severe reactions did not occur in the present study, bronchospasm has been reported, especially in patients with reversible airways disease. Second, although intuitively these regimens should be equally efficacious, oral NAC works well, and head-to-head studies have never been performed. Finally, readers must remember that short therapies appear to be less efficacious when the time to therapy is prolonged. In conclusion, this paper gives strong support for the intravenous use of oral NAC in select circumstances. When patients cannot or will not tolerate oral therapy or when there is concern for the integrity of the gastrointestinal tract, intravenous delivery of oral NAC is acceptable. In the best of both worlds, the patient should be informed and consented of this decision, consultation with a toxicologist or poison center should be obtained to support the decision, and the hospital formulary committee should be informed. In addition, a well written note should be placed in the chart supporting the decision. The loading dose should be diluted, administered slowly (at least for more than an hour) and given through a 0.2 micron filter. Even patients who tolerate intravenous therapy should be switched to oral therapy as soon as possible. Finally, at this point in time, I favor a full 72-hour course of treatment-especially when NAC is started beyond eight hours post-ingestion. Eventually, we will all probably be using shorter courses of therapy when uncomplicated patients present early.
References
1. Smilkstein MJ, et al. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose: Analysis of a national multicenter study (1976-1985). N Engl J Med 1988;319:1557-1562.
2. Keays R, et al. Intravenous acetaminophen in paracetamol-induced fulminant hepatic failure: A prospective controlled trial. Brit Med J 1991;303:1026-1029.
3. Smilkstein MD, et al. Acetaminophen overdose: A 48-hour intravenous N-acetylcysteine treatment protocol. Ann Emerg Med 1991;20:1058-1063.
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