Redefining APAP Overdose Management

Figure: APAP, overdose, management, poisoning, Rumack-Matthew nomogram, acetaminophen, N-acetylcysteine, NAC, MDCalc, Medscape, toxicity, guidelines, Delphi method, charcoal, high-risk lineFigureCases of acetaminophen overdose are so commonly seen in the emergency department that it is possible for physicians to be lulled into thinking they know everything about evaluating and managing these poisonings. But there are still nuances about APAP poisoning that have not been completely defined or parsed. It is generally known, for example, that using the Rumack-Matthew nomogram to determine which patients need treatment with the antidote N-acetylcysteine (NAC) is only appropriate when there has been a single acute ingestion. But what do we mean by single acute? I've never really seen a definitive answer to that question. We can end up more confused than when we started if we consult online decision aids. MDCalc states that a single acute ingestion is when the entire ingestion occurs within an eight-hour period. (https://tinyurl.com/29b44xmf.) Medscape notes that the nomogram applies to single acute ingestions but does not offer a clarifying definition. (https://tinyurl.com/ms7rurvp.) Neither does UpToDate. (https://tinyurl.com/yc8en9tj.) Trying to find the answer in textbooks is even more perplexing. Goldfrank's Toxicologic Emergencies states that “an acute overdose is somewhat arbitrarily defined as one in which the entire ingestion occurs within a single 4-hour period” without giving any reference to justify that conclusion. (11th ed., McGraw Hill: New York; 2019.) Rosen's Emergency Medicine claims that “an acute ingestion is a single ingestion or a series of ingestions that are arbitrarily defined to occur within an 8-hour period,” again without explaining how they arrived at that arbitrary definition. (8th ed., Elsevier Health Sciences: Philadelphia; 2013.) Tintinalli's Emergency Medicine notes that the nomogram only directly applies to a single oral exposure without specifying what exactly that means. (9th ed., McGraw-Hill Education: New York; 2020.) It is significant that despite abundant research and about a half-century of clinical experience with APAP toxicity, there is seemingly no agreement about one of the most important questions involved in managing these cases: When is it appropriate to apply the Rumack-Matthew nomogram to determine whether treatment with NAC is indicated? Surprisingly, the United States and Canada had not previously created standard guidelines laying out the details and nuances on how to treat patients with APAP poisoning. A recent publication attempts to correct that deficit. Management of Acetaminophen Poisoning in the US and Canada: A Consensus Statement Dart RC, Mullins ME, Matoushek T, et al. JAMA Network Open 2023;6(8):e2327739 https://tinyurl.com/2jyd89z7 The goal of this paper was to create a set of practice guidelines to be used by poison centers and emergency practitioners in the United States and Canada to manage APAP poisoning. The study established a panel of experienced clinicians suggested by leading toxicology groups from both countries and used a modified Delphi method to arrive at consensus recommendations. The authors noted that the original studies on using NAC as an antidote for APAP poisoning from the 1970s and 1980s considered an acute ingestion as occurring over a period of “less than 24 hours regardless of the ingestion pattern.” This definition was confirmed by the eponymous Barry Rumack, MD, who is an author on this current paper. When plotting the APAP level on the nomogram, the x-axis (time since ingestion) is calculated from the time the first pill or liquid was swallowed. The panel recommended that the nomogram not be used if the history was unreliable; that is, if it did not provide adequate detail, had conflicting statements, or was not consistent with the patient's presentation or laboratory results. Of course, even using this 24-hour definition of acute ingestion may require some nuanced clinical decision-making. Say a patient comes to the emergency department after taking four 500-mg tablets 22 hours previously and then an unspecified “handful” 30 minutes before arrival. It might be reasonable to ignore the earlier minor exposure and get a level four hours after the later ingestion. As always, some of these cases are not cut and dried, and the regional poison center is always available to consult on nuanced or complicated cases. The panel suggested adding a high-risk line to the Rumack-Matthew nomogram starting at 300 mcg/mL for a four-hour level and ending at 9 mcg/mL at 24 hours. (View the nomogram: https://tinyurl.com/2jyd89z7.) The panel defined a high-risk acute case as a clear history of ingesting more than 30 g of APAP in 24 hours or at a level above the high-risk line on the nomogram. The panel recommended considering giving activated charcoal in these cases even if more than four hours had elapsed since ingestion. They also recommended considering increasing the dose of NAC in consultation with a regional poison center or medical toxicologist. I'm not a big fan of suggesting “consideration” of a clinical intervention, but this irresolute recommendation indicates some disagreement among the panel members. The authors also noted that the patient's weight should be capped at a maximum of 100 kg when calculating the dose of NAC to administer on a milligram per kilogram basis. The panel also discouraged stopping NAC based solely on duration of treatment (for example, after a 21-hour IV protocol has been completed). They suggested the following criteria for stopping NAC: The APAP level is less than 10 mcg/mL; the INR is less than 2.0; the ALT/AST is back to the patient's baseline or decreased 25 percent to 50 percent from peak, and the patient is clinically well. There is much more in this paper, which is a must-read for medical toxicologists and emergency physicians who deal with APAP poisoning regularly. One may quibble with specific points, but the consensus statement does clear up some ambiguities that have been unresolved until now. DR. GUSSOW is a voluntary attending physician at the John H. Stroger Hospital of Cook County in Chicago, an assistant professor of emergency medicine at Rush Medical College, a consultant to the Illinois Poison Center, and a lecturer in emergency medicine at the University of Illinois Medical Center in Chicago. Follow him on X @poisonreview, and read his past columns at http://bit.ly/EMN-ToxRounds. Share this article on X and Facebook. Access the links in EMN by reading this on our website: www.EM-News.com. Comments? Write to us at [email protected].

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