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Abstract

Acetaminophen is a frequently used over-the-counter or prescribed medication in the United States. Exposure to acetaminophen can lead to acute liver cytolysis, acute liver failure, acute kidney injury, encephalopathy, and coagulopathy. This retrospective cohort study (1/1/2012 to 12/31/2017) investigated the clinical outcomes of intentional and unintentional acetaminophen exposure using the National Poison Data System data. The frequency of outcomes, chronicity, gender, route of exposure, the reasons for exposure, and treatments as described. Binary logistic regression was used to estimate the prognostic factors and odds ratios (OR) with 95% confidence intervals (CI) for outcomes. This study included 39,022 patients with acetaminophen exposure. Our study demonstrated that the likelihood of developing severe outcomes increased by aging (OR = 1.12, 95% CI: 1.08–1.015) and was lower in females (OR = 0.88, 95% CI: 0.78–0.99). Drowsiness/lethargy (OR = 1.48, 95% CI: 1.22–1.82), agitation (OR = 1.66, 95% CI: 1.11–2.50), coma (OR = 23.95, 95% CI: 17.05–33.64), bradycardia (OR = 2.29, 95% CI: 1.22–4.32), rhabdomyolysis (OR = 8.84, 95% CI: 3.71–21.03), hypothermia (OR = 4.1, 95% CI: 1.77–9.51), and hyperthermia 2.10 (OR = 2.10, 95% CI: 1.04–4.22) were likely associated with major outcomes or death. Treatments included intravenous N-acetylcysteine (61%), oral N-acetylcysteine (10%), vasopressor (1%), hemodialysis (0.7%), fomepizole (0.1%), hemoperfusion (0.03%), and liver transplant (0.1%). In conclusion, it is important to consider clinical presentations of patients with acetaminophen toxicity that result in major outcomes and mortality to treat them effectively.

Keywords

Acetaminophen APAP poisoning toxicity exposure overdose outcome

Introduction

Acetaminophen (APAP) is frequently used as an antipyretic and analgesic medication available over-the-counter in the United States.¹ The safe dosage of acetaminophen in adults is 325–650 mg every 4–6 h with a daily maximum of 4 g.²

Despite its safety when administered at the recommended dose, acetaminophen exposure can lead to severe liver failure and death.³ Acetaminophen poisoning is one of the most common causes of acute liver failure (ALF) in the United States.⁴ Although most patients have mild-to-moderate outcomes, 29% of those who develop acute liver failure due to acetaminophen exposure undergo a liver transplant, with a 28% mortality rate.⁵ Nevertheless, in the early stages of acetaminophen exposure, nonspecific symptoms, including abdominal pain, malaise, nausea, and vomiting, are common, whereas specific symptoms (i.e., hepatotoxicity, encephalopathy, and nephrotoxicity) are rarely reported.⁶ Additionally, several reports of renal failure due to acetaminophen overdoses.^7,8 O’riordan et al. observed that patients with acute kidney injury caused by acetaminophen had poorer outcomes than those with normal renal function, with a 25% overall mortality.⁹ According to the National Poison Data System (NPDS) of the American Association of Poison Control Centers (AAPCC) in 2019, acetaminophen alone and acetaminophen-containing product exposures were defined as the fifth and tenth most prevalent causes of drug-related mortality, respectively.¹⁰ The total annual cost to manage acetaminophen exposure has been estimated at around 86.9 million dollars in the United States.¹¹

Acetaminophen overdose may arise from intentional or unintentional exposure. For example, older age, accidental overdose, alcohol abuse, and chronic liver disease contribute to in-hospital mortality.¹²

Predicting the outcomes of acetaminophen exposure continues to be a challenge. The prognosis prediction of patients with acetaminophen exposure presenting with characteristic symptoms significantly impacts their management and follow-up. Given the growing concerns regarding acetaminophen-related adverse events, we designed this study to determine the clinical manifestations and laboratory findings that attribute favorable versus severe outcomes of acetaminophen exposure, as well as the treatments that are most commonly used based on the outcomes of acetaminophen exposure in the United States using the NPDS database.

Methods and materials

Study design and patients

This retrospective cohort study is based on human ingestion calls reported in the NPDS database.

The AAPCCs maintains the NPDS, which collects self-reported information callers during the management of poison calls, and information calls operated by the country’s poison control centers. Additional exposures may not be reported to the PCC. NPDS data should not reflect the total US exposure to a particular substance.

Exposures do not necessarily indicate poisoning or overdose, and the AAPCC does not confirm the accuracy of any report. Results from NPDS data do not reflect AAPCC views. Patients, health professionals, or caregivers voluntarily report cases to the poison center.

Data was obtained with generic codes for acetaminophen. Trained toxicologists systematically collected the data, and cases were followed until the results were determined.

No institutional review board was authorized because this study did not fulfill the criteria for human research CFR 45 46.102 45 (f) (2), according to the Colorado Multi-Institutional Review Board for Human Protection instructions.

Eligibility criteria

The inclusion criteria were any human exposure to acetaminophen alone or estimated to be the major involved toxicant from 1 January 2012 to 31 December 2017. Also, exclusion criteria were medical outcomes, duplicate data, or incomplete demographic data. Collected variables were gender, age, route of exposure, reason of exposure, duration of exposure, medical results, signs, and symptoms associated with exposure. In addition, treatments were collected at the initial call as part of routine data gathering of the poison center. We used the worst/highest biological parameters in each record to define the different observed complications and outcomes.

To determine the outcomes, follow-up was conducted unless the first call to the regional poison center happened satisfactorily long enough after the exposure that there was rational certainty that the clinical effect(s) would not get worse. Symptomatic patients were followed to the point where symptoms had completely or nearly got better unless the symptoms were predicted to be permanent or long-term.

Definition of terms

Only symptoms classified as “Related to the exposure” were included for analysis. Medical outcomes were classified as none, minor, moderate, or serious outcomes (major outcomes or deaths), based on standardized national classifications by the NPDS at the initial call.¹⁰ Reasons for the exposure were (1) intentional overdose, (2) unintentional overdose, (3) adverse reaction, (4) other, or (5) unknown. Route of exposure was categorized as ingestion and other. Chronicity of exposure was classified as (1) acute, (2) acute-on-chronic, and (3) chronic (supra-therapeutic repeated ingestion). Acute exposure was characterized as a single, repeated, or continuous exposure lasting less than 8 h.¹⁰ Acute-on-chronic was defined as a single exposure followed by a constant, repetitive, or intermittent exposure that lasted longer than 8 h.¹⁰ A continuous, repetitive, or intermittent exposure for more than 8 h was described as chronic.¹⁰ Patients were divided into two categories, major outcome or death and mild or moderate exposure. For laboratory assessments, blood samples were obtained during hospitalization. NPDS determines a cutoff of 100 and 1000 for liver tests. So, aspartate aminotransferase (AST), alanine aminotransferase (ALT) levels of more than 1000 U/L, and AST, ALT of between 100 and 1000 U/L were considered a score for liver damage. Other definitions used in this study included the following:

Hypotension: systolic blood pressure >90 mmHg or less than 15 mmHg less than the patient’s usual systolic blood pressure in adults.

Tachycardia: heart rate >100 beats per minute in adults.

Bradycardia: heart rate <60 beats per minute in adults.

Conduction disturbance: Impaired cardiac conduction as demonstrated by the following:

A QRS interval of more than 110 msec, or 20 msec longer than the patient’s base level as established by serial monitoring or QTc interval >470 msec for females or QTc interval >450 msec for males) or PR interval >200 msec or 40 msec longer than the patient’s baseline value as established by serial monitoring or any degree of heart block.

Arrhythmia: cardiac rhythm disturbance except for ventricular tachycardia, ventricular fibrillation, asystole, bradycardia, and tachycardia.

Abdominal pain: Pain in the abdominal region.

Anorexia: Loss of appetite.

Diarrhea: Frequent bowel evacuation or the passing of feces that is unusually soft or watery.

Vomiting: The reflex action of ejecting stomach contents through the mouth.

Nausea: The feeling of being about to vomit.

Hematemesis: Bloody nasogastric tube returns or bloody emesis (ranging from guaiac positive, blood-tinged to massive exsanguination)

Bilirubin increase: Increased bile pigments in the blood.

Coagulopathy: Consider prolonged bleeding times or prolonged partial thromboplastin time or other clinical or laboratory evidence of coagulopathy but disseminated intravascular coagulation was excluded.

Prothrombin time (PT) prolongation: Abnormally slow blood clotting, as indicated by an abnormally delayed time with a patient-to-control ratio greater than 1.2. International Normalized Ratio (INR) abnormalities (values greater than 1.1) were also coded here.

Dizziness/vertigo: A debilitating feeling in which the affected individual believes that he or his surroundings are always moving. Lightheadedness and other non-vertiginous dizziness symptoms were included.

Drowsiness/lethargy: Minor levels of the central nervous system (CNS) depression, fatigue, or sleep that a trigger can wake; however, proper sleep such as naps were not included here.

Agitated/irritable: Hyperactivity, anxiety, anxiousness, combativeness, or excessive restlessness were included.

Coma: All CNS depression and unconsciousness levels in which the patient cannot be awakened with a stimulus were included.

Tremor: An alternate rhythmical movement that can affect any region of the body.

Confusion: Patient’s incapacity to think with normal speed and clarity or disturbed orientation.

Seizure: Convulsion, a violent involuntary contraction, or series of contractions of the voluntary muscles.

Creatinine increase: increased creatinine of >133 μmol/L or >1.5 mg/dL.

Renal failure: acute and chronic renal failure resulting in clinically severe azotemia and renal function loss were included.

Urine color change: Only unusual color changes (blue, red, brown); however, normal fluctuations in urine concentration were not included.

Rhabdomyolysis: Muscle injury that leads to the leakage of muscle cell contents into the circulation; typically characterized as the presence of myoglobinuria or/and creatine kinase levels of more than 500 IU/L.

Muscle weakness: any degree of partial loss of motor responsiveness, including subjective patient complaints of weakening

Hyperglycemia: Glucose levels more than 150 mg/dL that are not due to pre-existing diabetes.

Hypothermia: Body temperature reduction to less than 95°F (35°C).

Dehydration: Water deficiency in bodily tissues. It might be mild, moderate, or severe.

Fever/hyperthermia: Temperature equal to or greater than 100.4° F (38°C)).

Edema: Atypically high quantities of fluid in the intercellular tissue spaces. This definition includes both diffuse and localized edema.

Hyperventilation/tachypnea: Breathing at a rate of more than 20 breaths per minute in adults.

Mydriasis: Pupil dilation.

Pupil (s) non-reactive: Pupils do not respond to light.

Anion gap increase: (Na⁺ - (Cl⁻ + HCO₃⁻)) > 12 mEq/L.

Electrolyte abnormality: An electrolyte imbalance in any of the electrolytes (magnesium, potassium, chloride, sodium, calcium, phosphate, and bicarbonate) are all included.

Cytopenia: Insufficiency of at least one type of blood cells. Include anemia, pancytopenia, neutropenia and/or thrombocytopenia. Including absolute lymphocyte count of less than 1500/μL, Hemoglobin <14 gm/dL for males, and less than 12 gm/dL for females, Hematocrit <39% for males and less than 35% for females, Neutrophil concentration <2500/μL, Platelet concentration <150,000/μL, and White blood count <4500 μL (Caucasians) or <3900 (African-Americans).

Anemia: Hemoglobin< 14 g/dL males, <12 g/dL females; Hematocrit <39% males, <35% females.

Acidosis: Elevated lactic acid (lactate) levels, pH < 7.35, bicarbonate <20 mEq/L.

Alkalosis: pH > 7.45 or bicarbonate >28 mEq/L.

Minor effects: Symptoms that patient presented with, were minimally bothersome, resolved rapidly, and often involved skin or mucous membrane manifestations. The patient had returned to a pre-exposure state of well-being with no complications maintained.

Moderate effects: Symptoms that patient presented with, were not life-threatening, prolonged, pronounced, or more of a systemic nature than minor symptoms and might have led to taking treatment. The patient had returned to a pre-exposure state of well-being with no complications maintained.

Major effects: Symptoms that patient presented with, were life-threatening or led to significant complications or death.

Statistical analysis

Descriptive statistics included frequency (percentage) for qualitative data and mean ± SD and median (interquartile range) required for quantitative data. The Chi-square and Fisher exact tests were used to compare frequencies between categories as appropriate. Logistic regression models were used to assess the severity of the exposure. We utilized univariate logistic regression models to evaluate the severity of exposure analyses. Multivariate analyses were carried out on the variables, which were significant in the univariate analysis (p < .2). Variables in the final model with a p-value <.05 were considered statistically significant. Analyses were performed using SPSS version 26 (IBM, Armonk, NY). Variable importance was done using the varImp function in the caret R package. All reported p-values are two-sided, and p < .05 was considered statistically significant.

Results

Demographic characteristics

The frequency of baseline characteristics is presented in Table 1. The study population included 39,022 patients without missing data. All patients ingested acetaminophen as an involved major toxicant in the observed toxicity. Minor-to-moderate outcomes were frequently observed among this population (n = 35,519, 91%). Ingestion was recognized as a common route of exposure in the study population (n = 38,777, 99.4%). Intentional overdoses caused the majority of acetaminophen toxicity (n = 32,098, 82.3%). Unintentional overdose was the second most common cause of acetaminophen exposure (n = 5877, 15.1%). Another cause of acetaminophen toxicity was an adverse reaction to acetaminophen (n = 476, 1.2%). Although acetaminophen toxicity was frequently found in women compared to men (n = 27,269, 69%), they were 12% less likely to develop major outcomes (OR = 0.88, 95% CI: 0.78–0.99). The majority of patients experienced acute exposure to acetaminophen (n = 31,512, 80.8%), followed by chronic (n = 4520, 11.6%), and acute-on-chronic exposure (n = 2990, 7.7%). However, our model results showed that patients who experienced acute and acute-on-chronic exposure to acetaminophen were 18% (OR = 1.18, 95% CI: 1.02–1.37) and 34% (OR = 1.34, 95% CI: 1.09–1.63) more likely to develop serious outcomes, respectively.

Table 1.

Baseline characteristics of patients with acetaminophen exposure.

Outcomes	N (%)
Mild or moderate outcomes	35,519 (91.0)
Major outcomes and death	3503 (9.0)
Chronicity
Acute	31,512 (80.8)
Acute-on-chronic	2990 (7.7)
Chronic	4520 (11.6)
Gender
Female	27,269 (69.9)
Male	11,753 (30.1)
Route of exposure
Ingestion	38,777 (99.4)
Other	245 (0.6)
Reason of exposure
Intentional	32,098 (82.3)
Unintentional	5877 (15.1)
Adverse reaction	476 (1.2)
Other	19 (0.05)
Unknown	561 (1.4)

Moreover, aging was shown to be an independent risk predictor of serious outcomes. For every decade increase in age, the odds of serious outcome 12% increased (OR = 1.12, 95% CI: 1.08–1.015). Based on the logistic regression analysis, we determined the ORs for increased risk of severe outcomes (Table 2). The time duration of acetaminophen exposure is also shown in Table 3. Most of the patients were exposed to acetaminophen for less than 8 h.

Table 2.

Univariate and multivariate logistic regression analysis of the risk of severe outcomes in patients following acetaminophen exposure.

Variables	Univariate logistic odds ratio (95% CI)	Multivariate logistic odds ratio (95% CI)
Sociodemographic
Age	1.4 (1.38–1.43)	1.12 (1.08–1.015)
Gender (female)	0.75 (0.7–0.8)	0.88 (0.78–0.99)
Chronicity
Acute	2.33 (2.09–2.6)	1.18 (1.02–1.37)
Acute-on-chronic	2.87 (2.63–3.13)	1.34 (1.09–1.63)
Chronic
Gastrointestinal manifestations
Abdominal pain	1.98 (1.84–2.12)	1.41 (1.25–1.59)
Nausea	0.85 (0.8–0.91)	0.82 (0.73–0.93)
Vomiting	0.82 (0.76–0.87)	1.05 (0.93–1.2)
Diarrhea	1.82 (1.40–2.37)	0.93 (0.61–1.41)
Anorexia	4.56 (3.02–6.87)	1.61 (0.79–3.26)
Hematemesis	8.04 (6.12–10.57)	1.76 (1.01–3.06)
Hyperbilirubinemia	41.50 (36.6–47.04)	6.08 (5.08–7.28)
Neurological manifestations
Dizziness/vertigo	0.69 (0.512–0.95)	0.63 (0.36–1.11)
Drowsiness/lethargy	2.17 (1.95–2.42)	1.48 (1.22–1.82)
Coma	23.84 (19.2–29.64)	23.95 (17.05–33.64)
Seizures	6.99 (3.24–15.07)	1.37 (0.36–5.27)
Agitation	3.40 (2.77–4.18)	1.66 (1.11–2.50)
Confusion	8.34 (7.15–9.75)	1.28 (0.93–1.75)
Tremor	3.02 (1.8–5.05)	0.8 (0.28–2.30)
Cardiovascular manifestations
Hypotension	3.07 (4.43–3.86)	2.40 (1.63–3.51)
Bradycardia	6.05 (4.3–8.5)	2.29 (1.22–4.32)
Tachycardia	2.62 (2.36–2.92)	1.12 (0.89–1.39)
Arrhythmia	13.22 (5.8–30.14)	0.13 (0.01–1.14)
Conduction disturbances	5.74 (4.26–7.74)	1.44 (0.75–2.76)
Renal manifestations
Renal failure	147.8 (87.5–250.3)	9.89 (4.82–20.31)
Elevated creatinine	34.34 (29.02–46.6)	1.81 (1.37–2.38)
Urine color change	11.87 (7.96–17.73)	1.36 (0.67–2.77)
Coagulation manifestations
PT/INR prolonged	49.77 (45.4–54.5)	9.09 (8.03–10.29)
Coagulopathy	17.16 (15.1–19.5)	1.62 (1.34–1.96)
Musculoskeletal manifestations
Rhabdomyolysis	29.01 (16.7–50.5)	8.84 (3.71–21.03)
Muscle weakness	5.02 (3.24–7.78)	0.82 (0.38–1.75)
Endocrinology manifestations
Hyperglycemia	61.5 (37.30–101.6)	0.72 (0.30–1.72)
Constitutional manifestations
Hypothermia	37.5 (23.09–60.85)	4.1 (1.77–9.51)
Dehydration	8.47 (3.66–19.62)	0.70 (0.16–3.14)
Fever/hyperthermia	8.11 (5.57–11.82)	2.10 (1.04–4.22)
Edema	2.66 (1.56–4.54)	1.45 (0.43–4.91)
Respiratory manifestations
Hyperventilation/tachypnea	8.57 (6.75–10.87)	0.94 (0.55–1.56)
Ophthalmology manifestations
Mydriasis	3.92 (2.47–6.23)	1.75 (0.69–4.45)
Non-reactive pupils	203.9 (27.36–1520.56)	22.86 (1.12–466.56)
Elevated anion gap	9.6 (8.16–11.30)	1.18 (0.83–1.69)
Electrolyte abnormality	8.3 (7.35–9.31)	0.89 (0.70–1.20)
Cytopenia	66.5 (36.17–122.31)	0.55 (0.23–1.28)
Acidosis	17.77 (15.13–20.60)	2.77 (2.13–3.60)
Alkalosis	40.64 (8.63–191.49)	2.49 (0.055–113.21)
AST, ALT >1000 U/L	54.23 (49.49–59.61)	20.89 (18.49–23.61)
100 U/L<AST, ALT<1000 U/L	1.94 (1.78–2.12)	1.93 (1.69–2.20)

AST: Aspartate aminotransferase; ALT: Alanine transaminase; INR: international normalized ratio; PT: prothrombin time. p-value < .05 is considered as significant.

Table 3.

Exposure duration of patients.

Exposure duration	Acute	Acute-on-chronic	Chronic	Total
Single ingestion or less than 8 h	31,512	0	0	31,512
>8 h and ≤24 h	0	919	1051	1970
>24 h and ≤1 week	0	1133	1947	3080
>1 week and ≤1 month	0	242	529	771
>1 month and ≤3 months	0	40	89	129
>3 months	0	97	131	228
	31,512	2990	4,520	39,022

Clinical symptoms

Our results showed that there was no significant association between death and major outcomes with the following clinical symptoms: vomiting, diarrhea, alkalosis, anorexia, dizziness/vertigo, seizure, confusion, tremor, tachycardia, arrhythmia, conduction abnormality, change of urine color, muscle weakness, hyperglycemia, dehydration, edema, hyperventilation/tachypnea, mydriasis, elevated anion gap, electrolyte abnormality, and pancytopenia.

Regarding gastrointestinal symptoms, including findings related to hepatotoxicity, patients with abdominal pain were 41% more likely to experience severe effects than those without abdominal pain (OR = 1.41, 95% CI: 1.25–1.59). Patients with nausea were 18% less likely to develop serious outcomes than those who did not experience nausea (OR = 0.82, 95% CI: 0.73–0.93). Our results showed that acidosis (OR = 2.77, 95% CI: 2.13–3.60), hematemesis (OR = 1.76, 95% CI: 1.01–3.06), elevated levels of bilirubin (OR = 6.08, 95% CI: 5.08–7.28), prolonged PT/INR (OR = 9.09, 95% CI: 8.03–10.29), and coagulopathy (OR = 1.62, 95% CI: 1.34–1.96) were independent risk predictors of developing serious outcomes. Those individuals with AST, ALT levels more than 1000 U/L and AST, and ALT of between 100 and 1,000 U/L were 20.89 times (OR = 20.89, 95% CI: 18.49–23.61) and 93% (OR = 1.93, 95% CI: 1.69–2.20) more likely to develop serious outcomes, respectively.

Among patients with neurological manifestations, we found that drowsiness/lethargy (OR = 1.48, 95% CI: 1.22–1.82), agitation (OR = 1.66, 95% CI: 1.11–2.50), and coma (OR = 23.95, 95% CI: 17.05–33.64) independently predicted the prognosis of acetaminophen exposure.

Regarding cardiovascular symptoms, our results showed that the patients with hypotension and bradycardia were 2.40 (OR = 2.40, 95% CI: 1.63–3.51) and 2.29 (OR = 2.29, 95% CI: 1.22–4.32) times more likely to suffer serious outcomes compared to those without these symptoms.

The association between major outcomes and renal manifestations was significantly observed among patients with renal failure and elevated creatinine. In other words, severe effects were found to be 9.89 (OR = 9.89, 95% CI: 4.82–20.31) and 1.81 (OR = 1.81, 95% CI: 1.37–2.38) times greater in patients with renal failure and elevated creatinine levels, respectively.

Patients with other clinical findings, including non-reactive pupils, rhabdomyolysis, hypothermia, and fever/hyperthermia were 22.86 (OR = 22.86, 95% CI: 1.12–466.56), 8.84 (OR = 8.84, 95% CI: 3.71–21.03), 4.1 (OR = 4.11, 95% CI: 1.77–9.51), and 2.10 (OR = 2.10, 95% CI: 1.04–4.22) times more likely to end up developing serious outcomes.

The frequency of patients with significant clinical and laboratory manifestations who presented acute, acute-on-chronic, and chronic are shown in Table 4. Most patients developed abdominal pain, nausea, and elevated AST and ALT. Moreover, drowsiness/lethargy and PT/INR prolonged were also frequently seen among patients with an acute presentation. The rank order of the important variables of our study is presented in Figure 1.

Table 4.

Age and frequency of patients with the significant clinical and laboratory manifestations in logistics regression who presented acute, acute-on-chronic, and chronic.

Outcomes	Chronicity
Outcomes	Acute N (%)	Acute-on-chronic N (%)	Chronic N (%)	p-value
Age (median (IQR))	19 (13)	32 (26)	37 (28)	<.001
Gender (female)	22,357 (70.9)	1964 (65.7)	2948 (65.2)	<.001
Abdominal pain	7892 (25.0)	996 (33.3)	1521 (33.7)	<.001
Nausea	14,238 (45.2)	1284 (42.9)	1824 (40.4)	<.001
Hematemesis	142 (0.5)	22 (0.7)	49 (1.1)	<.001
Hyperbilirubinemia	795 (2.5)	212 (7.1)	422 (9.3)	<.001
Drowsiness/lethargy	2376 (7.5)	169 (5.7)	182 (4.0)	<.001
Coma	320 (1.0)	28 (0.9)	37 (0.8)	.42
Agitation	412 (1.3)	43 (1.4)	44 (1.0)	.11
Hypotension	328 (1.0)	57 (1.9)	102 (2.3)	<.001
Bradycardia	119 (0.4)	13 (0.4)	11 (0.2)	.31
Renal failure	106 (0.3)	34 (1.1)	81 (1.8)	<.001
Elevated creatinine	392 (1.2)	120 (4.0)	231 (5.1)	<.001
PT/INR prolonged	2099 (6.7)	332 (11.1)	748 (16.5)	<.001
Coagulopathy	638 (2.0)	159 (5.3)	257 (5.7)	<.001
Rhabdomyolysis	45 (0.1)	8 (0.3)	12 (0.3)	.06
Hypothermia	76 (0.2)	8 (0.3)	13 (0.3)	.82
Fever/hyperthermia	79 (0.3)	13 (0.4)	19 (0.4)	.04
Non-reactive pupils	16 (0.1)	4 (0.1)	1 (0.0)	.11
Acidosis	749 (2.4)	133 (4.4)	238 (5.3)	<.001
AST, ALT>1000 U/L	3091 (9.8)	635 (21.2)	1288 (28.5)	<.001
100 U/L<AST, ALT<1000 U/L	3389 (10.8)	786 (26.3)	1414 (31.3)	<.001

AST: aspartate aminotransferase; ALT: alanine aminotransferase; INR: International Normalized Ratio; PT: Prothrombin time.

Figure 1.

Logistic regression variable importance.

Management

The frequency of treatments used to manage patients is shown in Table 5. Patients with either major or mild-moderate outcomes were often treated with intravenous N-acetylcysteine (NAC, n = 23,964), whereas hemoperfusion (n = 10) was less commonly used to treat patients. Of the patients treated, 0.1%, 0.7%, 1%, and 10% had liver transplants, hemodialysis, vasopressors, and oral NAC, respectively. Notably, 0.8% of the patients with major outcomes were treated with fomepizole.

Table 5.

Treatments used to manage acetaminophen-exposed patients who developed major versus mild-to-moderate outcomes.

Treatment	Major events or death	Mild-to-moderate events	p-value
Liver transplant	N (%)	N (%)	p-value
Yes	31 (0.9)	2 (0.005)	<.001^a
No	3472 (99.1)	35,517 (99.995)	<.001^a
Hemodialysis
Yes	234 (6.7)	29 (0.1)	<.001
No	3269 (93.3)	35,490 (99.9)	<.001
Hemoperfusion
Yes	8 (0.2)	2 (0.005)	<.001^a
No	3495 (99.8)	35,517 (99.995)	<.001^a
NAC, IV
Yes	3193 (91.2)	20,771 (58.5)	<.001
No	310 (8.8)	14,748 (41.5)	<.001
NAC, PO
Yes	395 (11.3)	3479 (9.8)	.006
No	3108 (88.7)	32,040 (90.2)	.006
Vasopressor
Yes	313 (8.9)	73 (0.2)	<.001
No	3190 (91.1)	35,446 (99.8)	<.001
Fomepizole
Yes	29 (0.8)	13 (0.04)	<.001
No	3474 (99.2)	35,506 (99.96)	<.001

IV: intravenous; PO: per os (by mouth); NAC, N-acetylcysteine.

^aFisher’s exact test is used.

Discussion

Using a large cross-sectional retrospective cohort from the NPDS, we investigated the clinical outcomes of intentional and unintentional acetaminophen exposures. The toxic metabolite of N-acetyl-p-benzoquinone imine produced by hepatic cytochrome P450 subfamilies can cause liver damage.^1,13 In addition, Damage Associated Molecular Patterns formed by necrotic hepatocytes facilitate cytokine production, leading to the activation of innate immune cells.¹⁴ Serper et al. performed a study similar to ours to investigate the results of patients with ALF following acetaminophen consumption alone or in combination with opioids and diphenhydramine.¹⁵

Our results showed that the odds of serious outcome 12%-increase for every decade increase with age. Moreover, we found that acute and acute-on-chronic exposures were more likely to result in major outcomes. In addition, females were less likely to develop severe consequences compared to males. Perneger et al. revealed that chronic exposure to acetaminophen raised the risk of developing an end-stage renal disease in residents of Maryland, Virginia, West Virginia, and Washington, DC.¹⁶ Schmidt et al. reported that older age was accompanied by an increased risk of developing hepatic failure and death following acetaminophen intoxication.¹⁷ According to a study done by Castanares-Zapatero et al., patients with hepatotoxicity due to high doses of acetaminophen who had poor outcomes were older than other cases.¹⁸ In contrast to our findings, Rubin et al. reported that hepatic failure induced by acetaminophen was common in women. In addition, they were more likely to need critical care than men.¹⁹ The explanation might be related to the combination of sedatives and acetaminophen-containing medications, as well as the belief that women are more prone to developing drug-induced liver failure.²⁵

Our results showed that intentional overdose was more common among this population. In contrast to our findings, Larson et al. discovered that most patients with ALF in a multicenter prospective study in the United States were caused by unintentional acetaminophen overdoses.⁴ This might be attributed to suffering from chronic pain syndrome and a lack of awareness regarding the co-ingestion of acetaminophen with other substance abuse.⁴ Castanares-Zapatero et al. found that suicidal overdose resulted in poor outcomes and a higher mortality rate.¹⁸ In contrast to the previous study, Schiødt found that the morbidity and mortality rates of patients with acetaminophen exposure due to suicidal attempts were lower than those hospitalized for acetaminophen exposure related to intentional misuse.²⁰ In this regard, data from the Rochester Epidemiology Project, in which patients at Mayo Clinic are treated for excessive acetaminophen use, indicated that intentional overdose was responsible for 76.3% of acetaminophen exposure. As a result of this type of exposure, 66.7% of patients required liver transplants. Furthermore, this exposure was due to the treatment of chronic pain rather than suicidal attempts.²¹

We found that abdominal pain, nausea, acidosis, hematemesis, prolonged PT/INR, coagulopathy, elevated AST and ALT, and hyperbilirubinemia were associated with major outcomes or death. In this context, Murphy et al. reported a 19-year-old woman who presented with severe abdominal pain and vomiting who experienced life-threatening hepatic and renal toxicity following ingesting 11.5 g of acetaminophen.²² According to our results, Castanares-Zapatero et al. showed that patients with hepatotoxicity induced by acetaminophen who experience greater outcomes had higher ALT levels, elevated levels of bilirubin, acidosis and coagulopathy compared to patients who had a favorable outcome.¹⁸ Furthermore, Zyoud et al. reported that patients who developed hyperbilirubinemia, prolonged prothrombin time, and increased creatinine levels had poorer outcomes.²³

To put neurological manifestations into perspective, we found that coma, drowsiness, and agitation were more likely to be associated with serious outcomes. Ala et al. reported a 34-year-old woman who presented with non-hepatic coma, drowsiness, a Glasgow Coma Score of 9, elevated ALT, acidosis, and hypotension who underwent intravenous NAC, intubation, and ventilation.²⁴ Some studies showed that encephalopathy and coagulopathy are inversely related to survival, which confirms our findings.^25,26 Moreover, Kasmi et al. reported a 5-year-old girl who developed agitation, lethargy, jaundice, and abdominal pain due to acetaminophen toxicity caused by unintentional exposure, contributing to the development of fulminant hepatic failure.²⁷ Coma is one of the rare manifestations of acetaminophen overdose, the mechanism of which is not fully understood.²⁸ As we expected, our study demonstrated a great association between coma and the development of major outcomes.

Our results showed that renal manifestations, including renal failure and increased creatinine levels, lead to major outcomes. The outcomes and requirement for a liver transplant in patients with ALF caused by acetaminophen are strongly associated with serum creatinine concentration.²⁹ Larson et al. found that the creatinine level in half of the ALF patients caused by acetaminophen was greater than 2 mg/dL, with non-survivors having higher levels than survivors.⁴ However, Campbell et al. reported renal failure without hepatotoxicity in a 15-year-old woman who took 50–60 acetaminophen tablets (325 mg) and presented with mild abdominal pain and elevated creatinine.³⁰ Interestingly, Rexrode et al. discovered that taking 2500 or more acetaminophen tablets was not associated with either increased creatinine levels or decreased creatinine clearance among men who took part in the Doctors’ Health Survey’s Cohort study of analgesic usage with a 14-year follow-up.³¹

Moreover, our findings showed the association of bradycardia with serious outcomes in patients with acetaminophen overdose. Ralapanawa et al. conducted a cross-sectional study and found that around 21% of patients with acetaminophen toxicity developed bradycardia.³² Although some studies concluded that there was no decisive evidence of cardiotoxicity following acetaminophen overdose.^{33, 34} KhabazianZadeh et al. conducted a review study of cases with cardiotoxicity following acetaminophen overdose. They found that although the evidence is quite rare, acetaminophen toxicity might result in problems, including heart failure and dysrhythmias mostly secondary to hepatic failure.³⁵

Some studies reported rhabdomyolysis following acetaminophen overdose.^{36, 37} Although rhabdomyolysis is also rarely seen after high doses of acetaminophen and might be attributed to non-declared co-intoxicants, our study demonstrated that patients who developed rhabdomyolysis have 10 times more serious consequences without this symptom. Similarly, high doses of acetaminophen and rhabdomyolysis might result in transaminase elevation but with different patterns in these two different clinical settings.³⁸

Interestingly, our results also revealed the association between hypothermia and hyperthermia with serious outcomes. Contrary to our findings, hypothermia is thought to protect against hepatotoxicity following acetaminophen overdose by suppressing cytochrome P450 and reducing the formation of N-acetyl-p-benzoquinoneimine.³⁹ A similar finding was also shown in an animal study that hypothermia alleviated the liver damage caused by acetaminophen toxicity in mice by enhancing glycogen recovery and lowering hepatic congestion.³⁹

Although we asked NPDS for single-agent acetaminophen cases, we could not rule out some possible co-intoxicants such as ethanol or anxiolytic/sedative drugs or proarrhythmic co-ingestants such as propoxyphene that may have contributed to the reported features (especially the CNS or cardiovascular ones, respectively) and complications such as hypothermia and rhabdomyolysis.

Surprisingly, we realized that some unproven treatments such as hemodialysis, hemoperfusion, and fomepizole had been used to treat severe acetaminophen poisoning. Our results suggested that patients who underwent liver transplants and hemodialysis, as well as those individuals who needed to use vasopressor and fomepizole, were almost the ones with severe outcomes. However, intravenous and oral NAC was frequently used to treat patients with mild or moderate outcomes. Fomepizole is a CYP2E1 inhibitor approved to treat methanol and ethylene glycol intoxications by suppressing alcohol dehydrogenase.⁴⁰ Besides, some studies reported the efficacy of fomepizole in treating acetaminophen exposure.^41–44 Hemodialysis is reported as an effective treatment in the severe acetaminophen exposure.^45,46 However, hemodialysis is generally not recommended to treat acetaminophen-poisoned patients.⁴⁷ Altogether, these studies showed a possible association between treatment with fomepizole and hemodialysis in severe acetaminophen-poisoned patients. However, we should bear in mind that these treatments are all exceptional unproven treatments. Although these therapies may be effective in some cases, they should not be used routinely.

The strength of our study is that the data came from a large sample, allowing us to consider the likelihood of experiencing mild-to-moderate outcomes versus major outcomes/death related to acetaminophen exposure. However, our study has some limitations that should be mentioned. First, since this was a retrospective cohort study focused on data from the NPDS, it restricts the interpretation of data compared to the prospective studies. Second, because the case records in this database are self-reported and the AAPCC cannot verify their reliability accurately, any exposures do not necessarily reflect a poisoning or overdose. Third, there is no available data regarding the follow-up of long-term outcomes and the dosage of acetaminophen. Fourth, the patients who presumably only took acetaminophen were included in this study; but we could not rule out possibly not-declared co-intoxicants that may have contributed to the observed features. Fifth, we could not collect data for increased intensity acetylcysteine. We suggest a future investigation to address this subject.

Nevertheless, most acetaminophen toxicity cases were caused using combined acetaminophen substances, including opioids.

Lastly, we provided the reported duration of exposure to acetaminophen; we could not provide details in acetaminophen exposure cases with late presentation or time to start NAC. We suggest a further study to address this topic.

Conclusion

Our results showed that symptoms, such as drowsiness/lethargy, agitation, coma, bradycardia, rhabdomyolysis, hypothermia, and hyperthermia, were associated with the development of major outcome or death, which have not received considerable attention previously. Furthermore, our study demonstrated that unproven treatments such as fomepizole administration, hemodialysis, and hemofiltration have been used to treat severe acetaminophen poisoning.

Footnotes

Acknowledgements

The authors want to express sincere thanks to the National Poison Data System for providing the poisoning data. In addition, the authors want to thank Professor Robert Hendrickson for reviewing the manuscript and valuable suggestions. Finally, we would also like to thank Mrs Heather Delva for her assistance in collecting the data and designing the study.

Author contributions

OM. designed the study. OM, FS, AH, BM, and CH contributed to writing the draft and revising the manuscript. All authors approved the final version of the manuscript.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Disclaimer

The American Association of Poison Control Center (AAPC) supports the National Poison Data System (NPDS), which houses de-identified case records of all self-reporting information obtained by callers during exposure management, and poison information calls managed by country poison control centers (PCCs). Even though NPDS is the only large database of exposures in the United States, it is worth mentioning that the exposures reported to the NPDS do not indicate all the exposures in the country. NPDS data do not display the total universe of exposure to a specific substance, as additional exposure to PCCs may be under-reported. Therefore, the NPDS data do not exactly reflect the incidence of exposure to acetaminophen. Therefore, NPDS data does not illustrate all exposures in the US. Moreover, investigation of the accuracy of each reported case to NPDS is complicated.

Data Availability Statement

The datasets which were analyzed during this study are available from the corresponding author upon any reasonable request with permission of National Poison Data System (NPDS) administrator.

ORCID iDs

Omid Mehrpour

Ali Hadianfar

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Prognostic factors of acetaminophen exposure in the United States: An analysis of 39,000 patients

Abstract

Keywords

Introduction

Methods and materials

Study design and patients

Eligibility criteria

Definition of terms

Statistical analysis

Results

Demographic characteristics

Clinical symptoms

Management

Discussion

Conclusion

Footnotes

Acknowledgements

Author contributions

Declaration of Conflicting Interests

Funding

Disclaimer

Data Availability Statement

ORCID iDs

References