From the EM Model
17.0 Toxicologic Disorders
17.1 Drugs and Chemical Classes

A recent study revealed that each year acetaminophen-associated overdoses account for 56,000 emergency department visits and 26,000 hospitalizations.¹ Despite readily available therapies, more than 450 Americans die annually from acetaminophen-associated toxicities, and approximately 100 of those are unintentional.

Case Presentation

A 24-year-old obese woman presents complaining of abdominal pain, vomiting, and malaise. She describes the pain as a constant, nonradiating, dull ache in her right upper quadrant that has been getting progressively worse over the past 48 hours. She has never had this pain before, and there are no alleviating or exacerbating factors. She has no significant past medical or surgical history, takes no medications, and has no known drug allergies.

Her initial vital signs are blood pressure 100/60, pulse rate 110, respiratory rate 18, temperature 36.4°C (97.5°F), and oxygen saturation 99% on room air. The patient is diaphoretic with mild epigastric and right upper quadrant abdominal tenderness and no rebound or guarding; Murphy sign is negative. Laboratory findings include an AST 1,250, ALT 1,140, alkaline phosphatase 160, total bilirubin 1.5, lipase 62, and WBC 14.5; the rest of the CBC and basic metabolic panel results are within normal limits. Fairly certain of a diagnosis of gallbladder disease, the emergency physician performs bedside ultrasonography, which, to his surprise, reveals a thin-walled gallbladder without stones or pericholecystic fluid.

On further questioning, the patient tearfully confides that she has been depressed and under considerable stress since losing her job and has made suicide attempts by intentionally overdosing on acetaminophen. Her initial ingestion was 3 days prior when she took approximately 20 of the 500-mg tablets. When she did not experience any symptoms by the following day she ingested an additional 40 tablets. She denies any co-ingestants and now denies active suicidal ideation.

Most acetaminophen (85%) is conjugated by the liver and excreted by the kidneys. Approximately 5% to 10% is oxidized by the cytochrome P450 system to form a toxic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI). Under normal conditions NAPQI is rapidly metabolized by glutathione to a nontoxic compound. When patients ingest toxic doses of acetaminophen, the normal conjugation pathways become saturated, and the P450 pathway plays a more prominent role. Eventually, glutathione stores are depleted, and excess NAPQI causes hepatotoxicity.

The presentation of acetaminophen poisonings can be very nonspecific; acetaminophen toxicity should be considered in patients who present with mild gastrointestinal complaints. Rumack et al described four separate clinical stages.² Stage I occurs before any hepatic injury is apparent. Nonspecific symptoms include nausea, vomiting, malaise, and pallor and can easily be mistaken for a viral illness or any number of disease processes. Some patients will even be asymptomatic in this stage. Stage II occurs within 24 to 72 hours and marks the beginning of hepatic injury. Symptoms, if present from stage I, may resolve, leading the patient or emergency physician to believe that the patient is improving. Symptoms can be similar to those of other forms of hepatitis and accompanied by elevated liver enzymes. Stage III occurs 72 to 96 hours after ingestion and marks maximum hepatotoxicity. Synthetic functions of the liver are affected, as evidenced by abnormal PT/INR, glucose, bilirubin, phosphate, ammonia, and lactate levels. Those who survive stage III will progress to recovery, stage IV. Most patients will have normalization of liver enzymes by day 7, although this may be delayed in severe poisonings.

CRITICAL DECISION

What is a toxic acetaminophen level?

In general, acetaminophen toxicity occurs after a dose of more than 150 mg/kg. For patients who present after a single overdose with a known time of ingestion, the Rumack nomogram is a sensitive predictor of toxicity.³ The original nomogram defines a 4-hour toxic acetaminophen level as greater than 200 mcg/mL. Patients with acetaminophen levels higher than this have a 60% risk of hepatotoxicity (arbitrarily defined as AST >1,000 IU/mL), 1% risk of renal failure, and 5% risk of mortality.

To enhance sensitivity and provide a layer of safety, the United States uses a modified Rumack nomogram with a 4-hour toxic level defined as levels above 150 mcg/mL. This modified nomogram was prospectively validated in 11,195 patients with acute acetaminophen overdose.⁴ Patients with an acetaminophen level below 150 mcg/mL have a 1% risk of hepatotoxicity; their symptoms will resolve spontaneously without treatment, and there is a 0% risk of mortality. Any patient with a single acute overdose with a known time of ingestion should have an acetaminophen level checked and plotted on the modified nomogram to predict toxicity.

The Rumack nomogram has its limitations, however. The nomogram has no role in delayed presentations or chronic ingestions. Because it is the metabolites of acetaminophen that are toxic, a therapeutic or negative acetaminophen level does not guarantee patient safety. Patients with delayed presentations or chronic ingestions should have liver enzymes measured along with an acetaminophen level. In 2004, Daly et al demonstrated that patients with delayed presentations (more than 24 hours after ingestion) or chronic ingestions who had an acetaminophen level of less than 10 mcg/mL and an AST below 50 IU/mL had a 0% risk of developing hepatotoxicity.⁵ Patients suspected of chronic, repeated ingestions and with detectable serum acetaminophen levels (>10 mcg/mL) or elevated liver enzymes should be presumed to have acetaminophen toxicity.

CRITICAL DECISION

Which patients require N-acetylcysteine for acetaminophen toxicity?

The use of N-acetylcysteine (NAC) for the prevention and treatment of hepatotoxicity in acetaminophen overdose has been established as both safe and effective. Although there are various oral and intravenous regimens, the most commonly used is the 20-hour intravenous NAC regimen. The initial loading dose is 150 mg/kg delivered over 15 minutes, followed by a 50 mg/kg dose delivered over 4 hours, followed by a 100 mg/kg dose delivered over 16 hours. The emergency physician must decide not only which patients might benefit from NAC but also when to begin administration.

For acute overdoses, in which an acetaminophen level is available within 8 hours of the time of ingestion, the emergency physician has the luxury of time. Smilkstein et al., demonstrated that NAC administration within the first 8 hours is essentially 100% effective at preventing hepatotoxicity.⁴ This does not imply that physicians should unnecessarily delay NAC administration; rather, this knowledge should reassure the clinician that an acetaminophen level can be checked and plotted on the nomogram without negative consequences.

Because patients are at greater risk of morbidity and mortality if they are not treated with NAC within 8 hours of ingestion, all patients with delayed presentations should be empirically treated with NAC prior to any laboratory evaluation. If the acute ingestion occurred within the past 24 hours, the acetaminophen level should be plotted on the nomogram. If the patient’s level is above the toxic level, NAC should be continued, and the patient should be admitted for further treatment.

Likewise, all patients with ingestions that occurred more than 24 hours before presentation and those with chronic or multiple ingestions should be empirically treated with NAC. These patients with acetaminophen levels of more than 10 mcg/mL or AST levels above 50 IU/mL should be presumed to have toxicity and should be admitted for continuation of treatment.⁵ Remember that patients who smoke and chronically consume alcohol, those who are fasting or debilitated, and those who take medicines that delay gastric emptying (opiates, anticholinergics) or induce liver enzyme activity (phenytoin, phenobarbital, carbamazepine, rifampin, and isoniazid) are more susceptible to acetaminophen toxicity.

Even patients who present in fulminant hepatic failure benefit from NAC.^6,7 Keays et al demonstrated that patients with fulminant hepatic failure who received NAC had improved survival rates (48% versus 20%), a lower incidence of cerebral edema (40% versus 68%), and fewer episodes of hypotension requiring pressor support (48% versus 80%).⁶

If there is any doubt, err on the side of caution and administer NAC until the case can be discussed with the local poison control center. Activated charcoal (1g/kg up to 50 grams) should be administered within 4 hours of an ingestion for decontamination.

CRITICAL DECISION

Which patients should be transferred to a liver transplant center following an acetaminophen overdose?

Although patients with fulminant hepatic failure still benefit from NAC administration, it is important to identify which patients will require a liver transplant for survival. The King criteria predict death from fulminant hepatic failure if the patient does not receive a liver transplant.^8-10 The King criteria are a serum pH below 7.3 after adequate fluid resuscitation; creatinine above 3.3 mg/dL; INR above 6.5, and grade III or IV encephalopathy. If any of the above criteria are met, serious consideration should be given to transferring the patient to a regional liver transplant center for definitive management.

Case Resolution

The young woman who attempted suicide with acetaminophen was treated with intravenous NAC and admitted to a monitored bed. The following morning, repeat liver enzymes showed improvement: AST of 540 and ALT of 616. The NAC was continued for an additional 20 hours, and the following day the patient’s liver enzymes had normalized. She was discharged from the hospital, and outpatient followup with a psychiatrist was scheduled.

Summary

Toxic exposures are a growing threat; it is essential that emergency physicians be able to diagnose and treat these patients effectively. Failure to recognize these subtle poisonings in the emergency department could lead to further morbidity and mortality.

References

1. Nourjah P, Ahmad SR, Karwoski C, Willy M. Estimates of acetaminophen (paracetamol)- associated overdoses in the United States. Pharmacoepidemiol Drug Saf. 2006;15(6):398-405.
2. Rumack BH, Peterson RC, Koch GG, Amara IA. Acetaminophen overdose. 662 cases with evaluation of oral acetylcysteine treatment. Arch Intern Med. 1981;141:380-385.
3. Rumack BH. Acetaminophen hepatotoxicity: the first 35 years. J Toxicol Clin Toxicol. 2002;40(1):3-20.
4. Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985). N Engl J Med. 1988;319(24):1557-1562.
5. Daly FF, O’Malley GF, Heard K, et al. Prospective evaluation of repeated supratherapeutic acetaminophen (paracetamol) ingestion. Ann Emerg Med. 2004;44(4):393-398.
6. Keays R, Harrison PM, Wendon JA, et al. Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial. BMJ. 1991;303(6809):1026-1029.
7. Harrison PM, Keays R, Bray GP, et al. Improved outcome of paracetamol-induced fulminant hepatic failure by late administration of acetylcysteine. Lancet. 1990;335(8705):1572-1573.
8. O’Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989;97(2):439-445.
9. Makin AJ, Wendon J, Williams R. A 7-year experience of severe acetaminophen-induced hepatotoxicity (1987-1993). Gastroenterology. 1995:109(6)1907-1916.
10. Anand AC, Nightingale P, Neuberger JM. Early indicators of prognosis in fulminant hepatic failure: an assessment of the King’s criteria. J Hepatol. 1997;26(1):62-68.