Focus On: Acetaminophen Toxicity and Treatment
By Allan R. Mottram, MD & Alan M. Kumar, MD
After reading this article, the physician should be able to:
- Understand the pathophysiology of acetaminophen metabolism and how its metabolites harm the body.
- Explain the diagnostic treatment strategies in acetaminophen overdose.
- Discuss the therapeutic advantages of oral versus intravenous N-acetylcysteine.
The 2004 Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System indicated 133,125 exposures to acetaminophen and combination products containing acetaminophen. Of these, there were 218 deaths, almost half of which were due to ingestions of combination products.
This is certainly an underestimation of the morbidity and mortality related to acetaminophen overdose, but the number speaks to the magnitude of the problem.
Acetaminophen is a common pharmaceutical that is available to patients as a solitary agent and in combination with many other drugs. Patients may present with intentional, accidental, acute, and chronic ingestions. There are distinct diagnostic and therapeutic considerations for each of these presentations. The approval of intravenous N-acetylcysteine in the United States marketplace provides a useful alternative to traditional oral therapy. The recent development of shortened dosing protocols is a safe strategy to limit duration of hospitalization in specific cases.
Regardless of formulation, the time from ingestion to peak acetaminophen level is approximately 4 hours. Liquid formulations peak somewhat quicker, and even extended-release preparations are almost completely absorbed by 4 hours.
Acetaminophen is metabolized primarily through three hepatic mechanisms. Glucuronidation and sulfation account for the majority of acetaminophen metabolism. The remainder, approximately 5%-15%, is oxidized through the p450 system, predominantly CYP2E1. This oxidative step is responsible for production of N-acetyl-p-benzoquinoneimine (NAPQI). In therapeutic doses of acetaminophen, NAPQI is detoxified via conjugation with sulfhydryl groups donated from glutathione. With supratherapeutic ingestions of acetaminophen, glutathione becomes depleted, and NAPQI binds to hepatocellular proteins, causing toxicity.
The acetaminophen antidote N-acetylcysteine serves as a glutathione precursor and substitute and may augment nontoxic sulfation. This limits the formation of NAPQI and enables its detoxification. In critically ill patients N-acetylcysteine may attenuate multi-organ failure and improve cerebral edema.
Acute ingestions are single ingestions occurring within a 4-hour period. When this history is clear, the appropriate treatment protocol is straightforward. Serious sequelae are avoidable as long as therapy is begun within 8 hours of ingestion. A 4-hour acetaminophen level is obtained. An AST is obtained if hepatic injury is suspected, the acetaminophen level is above the Rumack-Matthew nomogram treatment line, or the time of ingestion is unclear.
N-acetylcysteine therapy is initiated if the acetaminophen concentration is on or above the nomogram treatment line, the AST is elevated, or the acetaminophen concentration is greater than 10 mcg/mL and the time of a suspected toxic ingestion is unknown.
By definition, chronic ingestions are multiple, occurring over more than 4 hours. Unfortunately, a clear history with distinct timelines and quantities is not often available. Strong consideration has to be given to the possibility of multiple ingestions over a prolonged period both in the accidental overdose and the unreliable historian.
Certain risk factors may place patients at higher risk for hepatotoxicity. These include malnutrition, chronic alcohol use, use of drugs that induce the CYP2E1 system, and, in children, an associated febrile illness. Laboratory evaluation is indicated for children at high risk if they have ingested more than 75 mg/kg within 24 hours. In children without criteria placing them at higher risk, ingestions of more than 150 mg/kg over 24 hours warrant laboratory evaluation. Adults who are at higher risk for hepatotoxicity and who have ingested more that 4 grams in 24 hours should have a laboratory evaluation, as well as those not at higher risk who have ingested more than 7.5 grams in 24 hours.
Acetaminophen concentration should be obtained at 4 hours from the time of last known ingestion, and the AST should be tested. Note that the Rumack-Matthew nomogram is not useful in chronic ingestion and that the acetaminophen concentration and AST are used in a different manner. Patients can be risk stratified based on these values and their clinical exam.
With normal use, acetaminophen concentration should never exceed 30 mcg/mL at peak levels and should rapidly decline to less than10 mcg/mL 4-6 hours after the last dose. High-risk patients should be admitted and treated. Outpatient management and follow-up can be considered for some low risk patients. However, caution is advised, especially with intentional ingestions, and one should err on the side of admission.
New Therapeutic Strategies
Treatment of acetaminophen overdose consists primarily of GI decontamination and supportive care. Activated charcoal is the mainstay of therapy, especially given that these patients are often unreliable, and multidrug ingestions are both unrecognized and common.
N-acetylcysteine therapy is necessary for any patient for whom hepatotoxicity is a consideration. New treatment modalities available to emergency physicians include intravenous dosing of N-acetylcysteine and shortened dosing protocols.
Intravenous N-acetylcysteine is a useful alternative and is indicated for patients with nausea and vomiting refractory to antiemetics, fulminant hepatic failure, pregnancy, and patients who require NPO status for any other reason. It is as effective as oral dosing, though it has a less favorable side effect profile.
When selecting which treatment to use, physicians should consider patient tolerance, stability, and safety. In the vomiting patient, a trial of antiemetic therapy is appropriate; if it fails, intravenous N-acetylcysteine should be given to avoid further delay in administration of the antidote. The effectiveness of N-acetylcysteine therapy is optimal when given within 8 hours of exposure, and every effort should be made to achieve this goal. Fulminant hepatic failure is often complicated by gastrointestinal bleeding, need for lactulose, and altered mental status, making intravenous formulations a logical choice.
In the pregnant patient, intravenous N-acetylcysteine has the theoretical advantage of increased delivery to the fetus, but this is controversial.
There are many oral and intravenous dosing strategies in the literature. The two that are used most commonly in practice are the 72-hour oral and the 20-hour intravenous protocols.
The standard oral protocol is a 140- mg/kg loading dose, followed by 70 mg/kg every 4 hours for an additional 17 doses. Adverse reactions to oral N-acetylcysteine are generally mild, and are mostly limited to nausea and vomiting. The most likely difficulty one may find is patient compliance with administration due to unpalatability. Oral formulations have the advantage of lower cost and a smaller risk of an anaphylactoid reaction.
The standard IV protocol is 150 mg/kg in 200 cc D5W infused over 15 minutes, immediately followed by 50 mg/kg in 500 cc D5W infused over 4 hours, then 100 mg/kg in 1,000 cc D5W infused over the remaining 16 hours.
In contrast to oral N-acetylcysteine, the intravenous formulation has an increased rate of adverse reactions. Asthmatic patients are more likely than nonasthmatic patients to experience side effects. The most significant of these is the anaphylactoid reaction that may result in flushing, urticaria, pruritus, bronchospasm, angioedema, hypotension, and tachycardia.
Anaphylactoid reactions are similar to anaphylactic reactions, but they differ in that they are not IgE mediated. Although approximately 1% of these reactions are severe, the majority are mild. They should be treated symptomatically, and the infusion should be held. Following resolution of symptoms, the infusion may be restarted at a slower rate. The recurrence rate is low.
The intravenous formulation may also shorten the duration of hospitalization. This is advantageous to both the patient and provider for many reasons.
Regardless of protocol utilized, therapy should be guided by patient condition, resolution of transaminase elevation, and completion of acetaminophen metabolism. At the anticipated completion of therapy, both AST and acetaminophen levels should be rechecked. This practice will detect late rises in AST and trigger longer therapy.
AST should be less than 100 IU/L, and acetaminophen less than 10 mcg/mL. If either is elevated, therapy should be continued. When therapy is extended, end points become normalization of INR, resolution of encephalopathy, and a decreasing AST (at least to a level less than 1,000 U/L).
In acute ingestions of acetaminophen, a 4-hour level should be obtained. Treatment is initiated if the level is above the treatment line on the Rumack-Matthew nomogram. For chronic ingestions, an AST should be measured in addition to an acetaminophen level 4 hours from the last known ingestion.
Treatment is indicated for any elevation of AST and for acetaminophen levels greater than 10 mcg/mL. Regardless of the duration of therapy, an AST and acetaminophen level should be tested prior to discontinuation. If the AST is greater than 100 IU/L or the acetaminophen level is greater than 10 mcg/mL, therapy should be continued.
Oral and intravenous NAC protocols are acceptable. The oral route has the advantage of far fewer anaphylactoid reactions and lower cost, and is ideally suited to the uncomplicated patient who presents early. The disadvantages are potential for longer duration of therapy, unpalatability, poorer patient compliance, nausea, and vomiting.
Intravenous formulations have the benefit of shortened duration of therapy and better patient tolerance. It is indicated in patients with:
- Refractory emesis despite antiemetics.
- Concomitant ingestion that requires continuous gastrointestinal decontamination that would interfere with NAC administration.
- Gastrointestinal bleeding/obstruction or caustic ingestion.
- Altered mental status/high aspiration risk.
- Patient refusal to take oral NAC, NG tube not an option.
- Neonatal APAP toxicity from maternal overdose.
- In utero exposure from maternal OD (i.e., pregnant patient).
Disadvantages are an increased rate of anaphylactoid reactions and increased cost.
Acetaminophen overdose can be a devastating event that may lead to liver failure, liver transplant, and even death. We are fortunate to have a remarkably effective antidote that is available in both oral and intravenous treatments.
Regardless of the route of administration and dosing protocol used, remember that it is most important to get the drug on board early, preferably within 8 hours of exposure, and complete an adequate duration of therapy.
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Dr. Allan R. Mottram is a third-year resident at the University of Chicago, Section of Emergency Medicine. Dr. Alan M. Kumar is an assistant professor of emergency medicine at the University of Chicago, and practices emergency medicine at Lutheran General Hospital in Park Ridge, Ill. Dr. Robert C. Solomon is an attending emergency physician at Trinity Health System in Steubenville, Ohio, and clinical assistant professor of emergency medicine at the West Virginia School of Osteopathic Medicine.
In accordance with the Accreditation Council for Continuing Medical Education (ACCME) Standards and American College of Emergency Physicians policy, contributors and editors must disclose to the program audience the existence of significant financial interests in or relationships with manufacturers of commercial products that might have a direct interest in the subject matter.
Dr. Mottram, Dr. Kumar, and Dr. Solomon have disclosed that they have no significant relationships with or financial interests in any commercial companies that pertain to this educational activity.
"Focus On: Acetaminophen Toxicity and Treatment" has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME).
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