Acetaminophen: hidden complexities of a simple overdose

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LEARNING OBJECTIVES

Upon completion of this article, the reader will be able to:

1. describe the testing for drugs-of-abuse to include the settings, techniques and matrices used;
2. discuss acetaminophen use and misuse to include data for the use, indications, and antidote, for the acetaminophen overdose.;
3. describe the clinical effects and treatment for acetaminophen overdose;
4. list and discuss laboratory assessment of acetaminophen excess; and
5. explain acetaminophen urinary elimination kinetics.
   

Acetaminophen is the most commonly administered medication in the U.S., with more than 28 billion doses purchased by U.S. consumers in 2005.¹ The recent rise in the use and abuse of prescription narcotics (many of which contain acetaminophen) suggests that this number is increasing.² Acetaminophen is the most common pharmaceutical compound taken in intentional overdoses.³ Acetaminophen is widely available as single component and combination products. The ease of access and possible errors in dosing of various products (drops, suspensions, and tablets all in different strengths) marketed for multiple indications (fever reduction, general and targeted condition pain relief, cough and cold preparations) led the U.S. Food and Drug Administration (FDA) to consider a number of steps to decrease the frequency of unintentional acetaminophen overdose.

In July 2009, the FDA Advisory Committee recommended eliminating acetaminophen from combination narcotic products. Although this step was not taken, the FDA did request that all manufacturers limit the amount of acetaminophen to 325 mg per unit dose in all prescription combination medications. This action was taken in January 2011, largely based on data indicating that nearly one-half of all significant overdoses of acetaminophen were in the form of prescription combination pain-relief products.⁴ Additionally, manufacturers have accepted the FDA panel recommendation to standardize the concentration of over-the-counter (OTC) acetaminophen available in liquid products intended for pediatric use.

In May 2011, the Consumer Healthcare Products Association, which is the trade association representing OTC industry, indicated it would voluntarily standardize liquid preparations at 160mg/5mL. Labeling and dosing tools will also improve; labeling will include weight-based dosing information (rather than age only), and dosing markings on syringes for infants and dosing cups for 2- to 12-year-olds will be standardized and improved.⁵ A standardized concentration is an important safety step away from the current variability of 80 mg/0.8mL, 120mg/5mL, or 160mg/5mL. This threefold difference in concentration can lead to significant overdoses, particularly in situations of repetitive dosing, or when other acetaminophen products are used concurrently, or the patient is at increased risk of acetaminophen toxicity, as described later.

In addition to possible dosing errors, patients taking acetaminophen may not recognize that acetaminophen exhibits a “ceiling effect” in terms of analgesia. Thus, with continued pain, more acetaminophen may be consumed. Although there is no increased extent of pain relief, the risk of hepatic injury is substantially increased. One study (using an intravenous formulation of acetaminophen now available for post-operative patients) has suggested that this ceiling effect on analgesia may occur at lower levels than currently recommended dosing for acetaminophen.⁶

In cases of intentional overdose, many patients are unwilling or unable to accurately identify the medications they have taken. Acetaminophen overdose, although eminently treatable if detected early, has no characteristic symptoms following overdose until many hours or even days later, when symptoms associated with hepatic failure present. Treatment is much less effective at this late stage.

A six-year review of the dosing experience at one adult hospital demonstrates some of these issues. Two hundred thirteen cases of confirmed acetaminophen poisoning were admitted. Another 24 cases had a suspicion of acetaminophen-related hepatotoxicity, but there was diagnostic uncertainty regarding this or other responsible toxic compounds. Of the 213 confirmed cases, 179 (84%) were suicide attempts, 13 (6%) were secondary to excessive therapeutic use of acetaminophen, and 17 (8%) were accidental. The time of presentation to the emergency department (ED) following the last acetaminophen dose ranged from one to 14 hours in this particular sample. All of the patients who presented within eight hours of ingestion had a benign hospital course with minimal, if any, elevation of transaminases, and were discharged within two to three days. Those who presented later after their ingestion had more significant transaminase elevation despite treatment with the commonly recognized antidote, acetylcysteine. Some late presenters had a course complicated by fulminant hepatic failure and acute renal failure, requiring up to two weeks’ hospitalization. This experience is similar to the findings of multicenter studies that led to the adoption of early treatment with acetylcysteine to prevent or limit hepatic injury.⁷

Clinical effects and treatment of acetaminophen excess

When taken in overdose, acetaminophen is a major potential hepatotoxin.^8-10 Poisoning with this common agent may cause transient rises in hepatic transaminases, or lead to fulminant hepatic failure, metabolic acidosis, renal failure, cerebral edema, and death. Acetaminophen excess is currently the most etiology for hepatic transplant evaluation.¹¹ Transplant outcomes may vary based on etiology of the acetaminophen toxicity (accidental with or without underlying medical conditions vs. intentional).^12-14 Although it is clear that acetylcysteine is an effective antidote for acetaminophen poisoning,^15-18 specific criteria defining those at risk for hepatotoxicity or even attributing enzyme abnormalities to acetaminophen are not clear. A common approach in the U.S. is to treat all patients whose acetaminophen blood concentration falls above a line on the Rumack-Matthews nomogram,¹⁸ which begins at an acetaminophen concentration of 150 mcg/mL at four hours post ingestion and declines with a four-hour half life thereafter. The choice of this “150 line” derives from an arbitrary 25% “safety factor” reduction of the original parallel line which began at 200 mcg/mL at four hours post ingestion. Although it is customary in this country to treat patients above the “150 line,” the standard approach in many other parts of the world is to use the “200 line” as a criteria for treatment. The area of the nomogram between the 150 and the 200 lines is known as the “possible toxicity” region. There has never been prospective evaluation of whether patients in this area of the nomogram require treatment. Accumulated clinical and published experience suggests that these individuals are not at risk for serious hepatotoxicity or death.^19-21 There may be, however, some individuals who are at increased risk of severe toxicity from acetaminophen.²² This would include those with underlying liver disease, chronic alcoholism, generally poor nutrition, particular genetic polymorphisms, especially in the setting of chronic acetaminophen ingestion.²³

Laboratory assessment of acetaminophen excess

In order to avoid missing an acetaminophen overdose, it is common practice to obtain a serum acetaminophen determination by serum enzymatic colorimetric assay technique in all potential intentional overdose patients.^24,25 The serum acetaminophen concentration, when obtained between four and 24 hours after the ingestion, can be interpreted to determine the need for N-acetylcysteine treatment using the Rumack-Matthew nomogram.¹⁸ This screening approach requires obtaining blood from patients, many of whom are asymptomatic and would not otherwise require venipunture.

The 2003 National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines report that 84% of 300 serum acetaminophen determinations obtained at one hospital during a six-month period were below the detection limit of 1 mg/L, suggesting that approximately 500 unnecessary laboratory serum blood tests are performed annually.²⁴ Given that no other testing option was clinically available, this high negative rate has been accepted as necessary to prevent hepatotoxicity, liver transplantation, or death from an unrecognized acetaminophen overdose.

Although urinary drug immunoassays exist for common drugs of abuse, a simple, specific urinary immunoassay acetaminophen screen has only recently been marketed.²⁶ While there has been a suggestion that implementation of urine point-of-care testing in the emergency department can decrease central laboratory utilization in general²⁷ and with regard to acetaminophen specifically,^28,29 the medical community still relies on serum determinations to establish the ingestion of acetaminophen. Demonstrating the reliability of a non-invasive urine screen to facilitate detection or elimination of the diagnosis of acetaminophen overdose in an asymptomatic patient would prove very useful.

Prior to the modern-day immunoassays and automated analyzers, urinary screens for acetaminophen relied on indophenol colorimetric methods. The technique was plagued with multiple laboratory steps, long turnaround times and false negatives. These techniques have been abandoned for more than 25 years. While high-performance liquid chromatography (HPLC) is a reliable reference method for acetaminophen and metabolite determination, it does not have any significant use in hospital clinical settings.

Most hospitals use a colorimetric enzyme assay for acetaminophen determination in blood. Although not designed for application to urine as a matrix, this concept has been investigated. Some documented interferences (e.g., high bilirubin concentrations seen in many patients with established hepatic injury or even hematuria) may limit the utility of this test.^30,31

Perrone, et al,³² evaluated the utility of a qualitative urine acetaminophen screen in 88 adult patients seen in an ED following intentional ingestions. The authors compared serum acetaminophen concentrations to urinary thin layer chromatography (manufacturer limit of detection value of >= 5 mg/L). A negative urinary screen would potentially have eliminated the need for 76% of serum acetaminophen determinations.
A negative urine acetaminophen screen was highly predictive of negative serum acetaminophen levels (negative predictive value of 100%). Although promising, this tool has not been validated yet, and the limits of detection of the urine screen (by thin layer chromatography) have not been reproduced. A study of discard urine from 21 (blood) acetaminophen-positive patients out of nearly 200 overdose patients provided similar sensitivity and specificity measurements using the Triage TOX Drug Screen urine acetaminophen immunoassay testing device (BioSite, San Diego, CA).²⁹

Currently, most urine screens for common drugs of abuse are rapid, semi-quantitative immunoassays indicating the presence of a drug or metabolite above an established reporting threshold. A negative screen indicates that the drug/metabolite is either not present or beneath the detection or reporting threshold. A negative result from a specific urine screen for acetaminophen and/or metabolites would allow earlier disposition of patients without the cost or risks involved in obtaining blood samples from otherwise asymptomatic patients. An acetaminophen urine screen should be highly sensitive so as to identify the presence of even a low level of the drug because some patients may present either very early or very late following an overdose. Positive assays would require confirmatory quantitative serum determinations to evaluate the need for antidotal therapy with acetylcysteine.

Figure 1: Urine APAP excretion following ingestion of 37.5 mg/kg in fasted state (unpublished volunteer study results) indicating persistence of detectable urine APAP at > 16hours with this 4-fold supratherapeutic dose.

Information on acetaminophen urinary kinetics

Some work has been done to assess the urinary presence of acetaminophen. Approximately 4% of a therapeutic acetaminophen dose is excreted unchanged in the urine in all age groups of patients with normal renal function, regardless of underlying morbidities, age, renal blood flow, and genetic predispositions.^33-39

The urinary excretion of acetaminophen and its metabolites in different age and ethnic groups is relatively well established.^40,41 Peak urinary excretion occurs within the first four hours. There are no major age-related differences in the overall rate of elimination of acetaminophen, but there are important differences in glucuronate and sulfate conjugates. Approximately 90% of a therapeutic dose (given as 10mg/kg) of acetaminophen and its conjugates is excreted within 14 hours of ingestion and excretion is almost complete within 26 hours (less than 1% remains to be excreted). Kinetic curves to identify a urinary threshold vs. dose and time, however, are not available.³¹ In addition, variability in dose, dose formulations, and early decontamination efforts in the setting of acetaminophen overdose^42-44 would be expected to alter some aspects of elimination kinetics.

A study by Retaco, et al,³⁹ provides basic information to allow for extrapolation to the overdose setting. This study indicated that the urinary excretion of acetaminophen following the ingestion of 500 mg of acetaminophen (7mg/kg to 10mg/kg) is approximately 0.2 to 0.4 mg/hour at the 12-hour mark. Considering that the normal urinary output is 0.5 mL to 1.0mL/kg/hour, the urinary concentration of acetaminophen is estimated to be approximately 2.8 to 11 mg/L at 12 hours in a 75 kg adult.

Following therapeutic doses, the concentration of acetaminophen is higher in urine than in plasma with a 10:1 ratio in individuals with normal renal function and 4:1 in patients with impaired renal function.³⁴ Following an overdose the normal metabolism of acetaminophen is affected. Enzymatic pathways become saturated, resulting in an increase in the excretion of unchanged acetaminophen to approximately 10% to 14%. It is, therefore, not surprising that urine determinations have been positive (even using the now-abandoned indophenol colorimetric method) in overdose cases with delayed presentation and no detectable serum or plasma acetaminophen.³⁵

Available data does not allow extrapolation to the urinary concentration of large doses of acetaminophen at 24 hours. We conducted a small (n = 5) volunteer study investigating the plasma and urinary kinetics following ingestion of 37.5 mg/kg acetaminophen (HH study protocol 122968; reference 45). Figure 1 shows these results; each line represents the serial measurements in a study participant, with the dotted line representing the minimum value of any subject at any time. These results (representing ~4 times therapeutic dosing) support the contention that detectable urinary concentrations (5mg/L) following a larger ingestion would persist for more than 24 hours. In the study, access to water was not limited or standardized. Thus, in a clinical patient encounter, the possible effect of urinary dilution by ethanol ingestion or intravenous fluid administration would need to be considered.

Conclusion

Acetaminophen is a commonly available OTC medication with a well-established mechanism and clinical presentation of toxicity in overdose or therapeutic excess. Still, there are a number of complexities present in the assessment and management of patients who may have taken acetaminophen, particularly in suicide attempts. Because of the widespread use of urine drug screens in this patient population to screen for abuse of illicit drugs, the incorporation of a urinary acetaminophen screen may have utility as a negative rule out. This would avoid the need for a serum test, while potentially identifying patients with hidden acetaminophen ingestion. The potential for this test to identify late-presenting acetaminophen patients at a time when their blood acetaminophen has cleared needs to be determined. At the same time, a urinary immunoassay may serve as a negative confirmatory test in those patients with non-acetaminophen-related hepatic injury with hyperbilirubinemia and a false-positive blood acetaminophen test by colorimetry.

Charles A. McKay, Jr., MD, F(ACMT), F(ACEP), ABIM, is section chief, Division of Medical Toxicology in the Department of Traumatology and Emergency Medicine at Hartford Hospital and associate medical director of the Connecticut Poison Control Center (CPCC) at the University of Connecticut (UCONN) School of Medicine, where he is an associate professor of Emergency Medicine.  An attending physician at Hartford Hospital since 1988, McKay is a graduate of Dartmouth College and Dartmouth Medical School in Hanover, NH, with an externship in anatomic and surgical pathology, residencies in internal medicine at Rhode Island Hospital and emergency medicine at Denver (CO) General Hospital, and medical toxicology training at Denver General Hospital and the New York Poison Control Center, New York City He is currently board-certified in these three areas, and is a member of the American College of Medical Toxicology Board of Directors. He runs a toxicology consult service at three hospitals and is active in teaching, research, and consultation. He is the director of the Medical Toxicology Fellowship program and is a member of the core faculty for the emergency medicine residency at UCONN.

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