The Case

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ACEP Now: Vol 37 – No 07 – July 2018

ILLUSTRATION: Chris Whissen & shutterstock.com

The patient is a 17-year-old non-English-speaking Bengali female with no past medical history who presented to the pediatric emergency department at 12:30 a.m. with complaints of abdominal pain, vomiting, and headache that began earlier that evening. She is accompanied by her mother, younger sister, and a male neighbor who was asked to come to help translate. She describes the abdominal pain as diffuse in nature without localization, with more than 15 episodes of non-bloody, non-bilious emesis. There is no food exposure to account for her symptoms as she has not had anything to eat that day. Her last menstrual period was about 20 days prior to ED visit and was normal. She denies recent travel, fever, chills, urinary symptoms, diarrhea, sick contacts, or taking medications for her symptoms.

On exam, she appears pale and uncomfortable, with dry mucous membranes. However, she is awake, alert, and oriented, with a Glasgow Coma Scale score of 15. The abdominal exam reveals mild diffuse abdominal tenderness without radiation, rigidity, or guarding. IV access is obtained, and blood work is sent at 1 a.m. Her complete blood count, complete metabolic panel, lipase, urinalysis, and urine human chorionic gonadotropin are all within normal limits. She is treated with a 1 L normal saline bolus, Zofran 4 mg IV, Pepcid 20 mg IV, and ketorolac 30 mg IV, and her symptoms improve.

In the setting of normal blood work and no clear reason for the vomiting, a bedside ultrasound is performed to evaluate the right upper quadrant. The bedside ultrasound is negative for any acute biliary pathology. The patient at this point has changed into a hospital gown and is noted to have self-mutilation marks on her left forearm in the shape of an “M.” When asked about these marks on her arm, she states that she cut herself while cooking. It becomes obvious that there is more to the story. The family and neighbor are asked to step out of the room, and CyraCom translation service is brought to the bedside. The patient is not very cooperative with questioning, but when asked if she took any medications, she admits to taking 27 650 mg Tylenol tablets at 2:30 p.m., about 10 hours prior to arrival. She states she took the pills because she was feeling sad because her boyfriend, whose name begins with “M,” broke up with her.

About one hour into the ED visit, an overdose panel is sent including acetaminophen, aspirin, and alcohol levels, plus a urine toxicology screen. The acetaminophen level is 143.1 ug/mL. A medical toxicologist is consulted, and N-acetylcysteine (NAC) is initiated. Initial aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are 40 U/L and 37 U/L, respectively. Within 24 hours, her AST and ALT peak at 4,453 U/L and 4,843 U/L, respectively, before starting to trend downward. The repeat acetaminophen level, drawn about eight hours after the initial level, goes from 143.1 ug/mL to 36.5 ug/mL. By hospital day two, the acetaminophen level is <10 ug/mL. The patient remains stable throughout the hospital course and is discharged on hospital day five.

Acetaminophen Overdose

Acetaminophen overdoses are a common cause of hepatotoxicity in both pediatric and adult patients. The availability of the drug and perception of its safety are likely factors in the large number of overdoses, both intentional and unintentional, seen. The metabolism of acetaminophen involves multiple enzymatic pathways. Glucuronidation accounts for the majority of metabolism, with normal dosing accounting for up to 42 percent to 67 percent. A secondary mechanism, sulfonation, is more active in the pediatric population and accounts for up to 20 percent to 46 percent. Both of the aforementioned pathways result in water-soluble metabolites that are renally excreted. Additional mechanisms responsible for the metabolism of acetaminophen are the cytochrome P-450 (CYP) hepatic isoenzymes. Of particular importance is hepatic isoenzyme 2E1, which results in the formation of a reactive metabolite NAPQI. When an overdose is taken, glucuronidation and sulfonation are saturated, resulting in increased metabolic activity of hepatic isoenzyme 2E1. The increased generation of NAPQI would normally be conjugated to glutathione to form an adduct. However, when glutathione levels decrease to approximately 30 percent, hepatotoxicity occurs, evidenced by an elevation in AST and ALT.

During stage I of the clinical course of toxicity, hepatic injury has not yet occurred, and even patients who will go on to develop hepatotoxicity may be asymptomatic, highlighting the importance of getting an acetaminophen level. Mild symptoms such as nausea, vomiting, pallor, and malaise may be present. A latent period may follow where the patient may have fewer symptoms or even appear clinically well. However, as glutathione stores deplete and NAPQI builds, hepatotoxicity ensues. Stage II represents the onset of hepatic injury, and signs and symptoms may vary with severity of hepatic injury. Most patients will develop elevations of AST and ALT within 24 hours of ingestion. By convention, acetaminophen-induced hepatotoxicity is defined as a peak ALT concentration above 1,000 IU/L.

Stage III represents the time of maximal hepatotoxicity occurring between 72 and 96 hours after ingestion. Patients can progress to fulminant hepatic failure, which clinically manifests as development of encephalopathy, coma, cerebral edema, coagulopathy, and gastrointestinal bleeding. Most deaths occurring from hepatic failure occur three to five days following acetaminophen overdose.¹

Patients who survive this period reach stage IV, defined as the recovery phase. Survivors have complete hepatic regeneration, and the rate of recovery varies, but in most cases, most lab values normalize within seven days.²

Acetaminophen level, for those who present within 24 hours of a single acute ingestion, can be plotted on the Rumack-Matthew nomogram to determine the patient’s risk of hepatotoxicity (see Figure 1). For single ingestions, indications to treat with NAC include a four-hour level of ≥150 mg/L for a witnessed ingestion or a level of >10 mg/L in an unwitnessed event with unknown time of ingestion. NAC can be administered via the oral or intravenous routes.

Credit: Merlin Cyrstal [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0], from Wikimedia Commons

There are several variations in treatment protocols; however, the most common are a 21-hour intravenous infusion and a 72-hour oral-dosing protocol. The variation in treatment exists because treatment theoretically should be initiated when the patient is suspected to be at risk for hepatotoxicity, continue while the patient remains at risk, and cease once the risk or toxicity is gone. Studies have shown equal efficacy in preventing toxicity between the intravenous and oral routes.2 The recommended dose of intravenous NAC is 150 mg/kg IV x 1 over 60 minutes followed by 50 mg/kg IV x 1 over four hours followed by 100 mg /kg IV x 1 over 16 hours for both pediatrics and adults.

Specific indications for intravenous NAC include fulminant hepatic failure, inability to tolerate oral NAC, and acetaminophen poisoning in pregnancy. The major adverse effect associated with intravenous NAC can be a severe anaphylactoid reaction; however, this is rare. The recommended dose of oral NAC is a 140 mg/kg loading dose either orally or via enteral tube. Starting four hours after the loading dose, 70 mg/kg should be given every four hours for an additional 17 doses. The main disadvantage of oral NAC is the high incidence of vomiting, which, in turn, can delay care.² This is most beneficial if treatment is initiated within eight hours after ingestion.¹ Therefore, it is important to assess the patient’s risk for hepatotoxicity, and at times, it may be necessary to initiate treatment with NAC prior to laboratory studies in order not to delay care.

The effects of delaying care are far worse than initiating treatment that may ultimately not be needed, in which case therapy can be stopped. Additional elimination techniques exist, including hemodialysis. Indications for hemodialysis include patients with exceedingly high acetaminophen levels (greater than 500 ug/mL) who are at high risk for hepatotoxicity despite NAC therapy as well as those with elevated lactic acid levels and metabolic acidosis. Hemodialysis also removes NAC, and subsequently, NAC infusion rates need to be doubled during dialysis.²

Patients can also present with chronic acetaminophen toxicity from repeated supratherapeutic doses. However, the incidence of serious acetaminophen toxicity is small following chronic ingestion and much more common in acute, massive dosing. Patients at greater risk for hepatotoxicity following repeated supratherapeutic ingestions have increased activity of CYP 2E1 leading to increased NAPQI formation or have decreased glutathione stores and turnover rate. In patients with suspected chronic ingestion with risk of hepatotoxicity, an acetaminophen level and liver function enzymes should be obtained. Patients with elevated liver enzymes and/or elevated acetaminophen level should be treated with NAC to prevent further liver damage.²

Discussion

The responsibility to provide the best care for patients is incumbent on emergency physicians, and they may have to overcome numerous barriers to fulfill that responsibility. Language barriers can have deleterious effects, and patients who face such barriers are less likely than others to have a usual source of medical care. In 1998, the Office for Civil Rights of the Department of Health and Human Services issued a memorandum that states that the denial or delay of medical care because of language barriers constitutes discrimination. Ad hoc interpreters including family members, friends, and untrained members of the support staff are commonly used in clinical encounters. However, they are more likely to commit errors that may have adverse consequences. Ad hoc interpreters are unlikely to have had training in medical terminology and confidentiality. Their presence may inhibit discussions regarding sensitive issues such as domestic violence, substance abuse, or mental illness, as illustrated in this case.³ Barriers such as these leave emergency physicians more vulnerable to medical error that could be harmful to their patients. For this reason, it is important to be knowledgeable about the potential pitfalls and to approach each patient with the same objectivity.

Dr. Peña is an emergency medicine resident at St. Joseph’s University Medical Center in Paterson, New Jersey.

Dr. Kashani is a medical toxicologist emergency medicine faculty at St. Joseph’s University Medical Center.

References

1. Algren DA. Review of N-acetylcysteine for the treatment of acetaminophen (paracetamol) toxicity in pediatrics. World Health Organization website. Accessed Feb. 10, 2018.
2. Hoffman RS, Howland MA, Lewin NA, et al. Goldfrank’s Toxicologic Emergencies. 10th ed. New York, NY: McGraw-Hill Education; 2014:447-458.
3. Flores G. Language barriers to health care in the United States. New Engl J Med. 2006;335(3):229-231.