About one billion doses of acetaminophen are taken safely per annum, and 60 million people in the U.S. take acetaminophen on a weekly basis.^1,2 With such enormous popularity it is no surprise that each year there are 56,000 emergency department (ED) visits, 2,600 hospitalizations, and 500 deaths in the U.S. related to acetaminophen toxicity.² Some cases of acetaminophen toxicity are simple to recognize and manage, such as an intentional single recent ingestion of a large number of regular-release acetaminophen with no co-ingestions in an otherwise healthy patient. Unfortunately, most cases are not so simple, with half of them being unintentional overdoses, many with a delayed presentation; some with delayed-release formulations, combined formulations, or co-ingestions, and some in patients with co-morbidities—all factors that make recognition and management more challenging.³ In this EM Cases column, I endeavour to outline the top 10 clinical pitfalls in the recognition and management of acetaminophen toxicity.

Current recognition and management of acetaminophen toxicity involves eliciting the time of ingestion, amount of acetaminophen ingested, type of acetaminophen preparation, co-ingestions, and co-morbidities; it involves understanding how the typical symptoms of nausea, vomiting, diaphoresis, pallor, lethargy, and malaise in the first stage often become quiescent, only to be replaced by right upper quadrant (RUQ) pain and elevated liver transaminases in the second and third stages; and it involves timely administration of activated charcoal and N-acetylcysteine. In the massive overdose, it involves the additional consideration of 4-methylpyrazole (Fomepizole) and dialysis.

PITFALL 1

Failing to recognize the seriousness of an unintentional acetaminophen overdose in patients with pain syndromes or those taking cold preparations that contain acetaminophen

Most fatalities, which comprise one to two percent of overdoses, result from either a delayed presentation after deliberate overdose, or from excessive dosing for fever or pain over several days.⁴ It is incumbent upon the emergency physician to ask patients about specific analgesics and their quantities and dosages, and when in doubt, obtain an acetaminophen level. With half of cases being inadvertent there may be no obvious history of ingestion. Consider acetaminophen toxicity in patients presenting with unexplained hepatic injury or failure, hypoglycemia, lactic acidosis, or altered mental status.

PITFALL 2

Failing to recognize patient factors that may potentiate or augment acetaminophen toxicity including other medications, co-ingestions, chronic alcohol use, and malnutrition

All of these factors may increase the risk of liver damage after acetaminophen overdose and should be taken into account when interpreting the Rumack-Matthew nomogram and in deciding on N-acetylcysteine (NAC) antidote dosing.

PITFALL 3

Assuming that a patient with normal or near-normal transaminases has not taken a life-threatening overdose

It is important to understand that AST and ALT are typically unaffected and normal or near-normal in the first 12 hours after a supratherapeutic ingestion. Normal serum AST and ALT levels alone are not predictors of outcome. That being said, AST levels greater than 1,000 IU/L are more likely to result from acetaminophen poisoning than from chronic hepatitis or alcoholic liver disease, and evidence suggests that the acetaminophen level multiplied by the aminotransferase level (calculated at the time of presentation and after several hours of NAC) holds promise as a risk predictor following acetaminophen overdose.⁵ This calculation may be especially useful when the time of ingestion is unknown.

PITFALL 4

Failure to recognize the potential value of hyperphosphatemia and elevated arterial lactate in predicting death and the need for liver transplant^6,7

A prospective study looking at serum phosphate levels in patients with acetaminophen toxicity found that hyperphosphatemia was seen only in non-survivors, suggesting that it is a highly accurate predictor of death following acetaminophen overdose.⁸ A retrospective study of acetaminophen-poisoned patients found that when using a threshold of 3.5 mmol/L, arterial lactate drawn early had a positive likelihood ratio of 13, and negative likelihood ratio of 0.35 for death.⁹

PITFALL 5

Using the Rumack-Matthew nomogram to inform treatment with NAC in patients with delayed presentations, chronic overdoses, extended-release preparation overdose, or co-ingestions with drugs known to alter the metabolism of acetaminophen (e.g., opioids, phenytoin, carbamazepine, trimethoprimsulfamethoxazole)

The Rumack-Matthew nomogram should only be used in isolated, single, acute overdoses of regular-release acetaminophen within 24 hours of ingestion, which is the minority of patients. Use of the nomogram in other clinical scenarios may be misleading. In one study that looked at patients with significant liver injury as a result of acetaminophen overdose, only 17 percent could be appropriately risk stratified using the nomogram.¹⁰

PITFALL 6

Neglecting to administer NAC for late presentations in a timely manner

While it is true that NAC is most effective when given within eight hours of ingestion, a common pitfall is to assume more delayed ingestions do not benefit from administration of NAC.¹¹ There are often significant delays from the time of ordering NAC to the time that the infusion is started. NAC should be given immediately. Indications for NAC include “line crossers” on the Rumack-Matthew nomogram (after an isolated acute ingestion of regular-release acetaminophen within 24 hours) and those patients with elevated transaminases (even in the absence of elevated acetaminophen level) deemed to be as a result of acetaminophen toxicity. If the initial level is not above the nomogram line at the four-hour mark, then an eight-hour and 12-hour level should be drawn.

PITFALL 7

Using the same dosing protocol of NAC for all acetaminophen-toxic patients

In my opinion a toxicologist should be consulted for recommendations on NAC dosing as dosing adjustments should be made depending on a variety of complex factors including timing of ingestion, amount of acetaminophen, type of preparation, co-ingestions, and comorbidities.¹² Dose adjustments are also recommended for patients with massive overdose and those requiring dialysis.¹³

PITFALL 8

Failure to recognize massive acetaminophen overdose in patients with altered level of awareness who have normal transaminases

Massive acetaminophen overdose is defined as greater than 500 mg/kg.¹⁴ It typically presents with a very different toxidrome, characterized by early presentation, exceedingly high acetaminophen levels, coma and lactic acidosis, but with preservation of normal transaminases in this early stage. The reason that massive overdose is important to identify is because management of these patients requires consideration of fomepizole and dialysis in addition to a higher-than-usual dose of NAC. In addition, charcoal is indicated up to 4 hours in massive overdose (compared to 2 hours in  nonmassive overdose).¹⁵ Fomepizole 15 mg/kg given once can be considered as an adjunct to NAC.¹⁶ It is thought to halt the formation of N-acetyl-p-benzoquinone imine, and to inhibit cellular necrosis. The indications for fomepizole based on current evidence are unclear, as there have yet to be robust RCTs published. It is reasonable to consider fomepizole in the massive-overdose patient, those requiring hemodialysis, and those with evidence of significant hepatic injury. Typical indications for dialysis include altered mental status, metabolic acidosis, elevated lactate plus serum acetaminophen greater than 900 mg/L (5,960 mmol/L).¹⁶

Conclusions

Some patients with acetaminophen overdose are relatively straightforward to recognize and manage in the ED. But many present challenges, i.e., in recognition of the condition in unintentional ingestions or in the altered patient, in management due to factors that make the Rumack nomogram useless or misleading, or in dosing of NAC. Massive overdose patients require recognition of an entirely different toxidrome and specific management. Although common, acetaminophen toxicity is no simple matter.

A special thanks to Drs. Emily Austin and Margaret Thompson for their expertise on the EM Cases podcast that inspired this column.

Dr. Helman is an emergency physician at North York General Hospital in Toronto.

He is an assistant professor at the University of Toronto, Division of Emergency

Medicine, and the education innovation lead at the Schwartz/Reisman Emergency

Medicine Institute. He is the founder and host of Emergency Medicine Cases

podcast and website.

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