Acute Acetaminophen Ingestion Research Articles

Acute ingestion of acetaminophen improves cognitive and repeated high intensity short-term maximal performance in well-trained female athletes: a randomized placebo-controlled trial

This study examined the effect of acute acetaminophen (ACTP) ingestion on physical performance during the 5 m shuttle run test (5mSRT), attention, mood states, and the perception of perceived exertion (RPE), pain (PP), recovery (PRS), and delayed onset of muscle soreness (DOMS) in well-trained female athletes. In a randomized, placebo-controlled, double-blind, crossover trial, fifteen well-trained female athletes (age 21 ± 2 years, height 165 ± 6 cm, body mass 62 ± 5 kg) swallowed either 1.5 g of ACTP or 1.5 g of placebo. The profile of mood states (POMS) and digit cancellation (DCT) were assessed 45 min postingestion, and 5mSRT was performed 60 min postingestion. The RPE and PP were determined immediately after each 30-s repetition of the 5mSRT, and the PRS and DOMS were recorded at 5 min and 24 h post-5mSRT. For the 5mSRT, ACTP ingestion improved the greatest distance (+ 10.88%, p < 0.001), total distance (+ 11.33%, p = 0.0007) and fatigue index (+ 21.43%, p = 0.0003) compared to PLA. Likewise, the DCT score was better on the ACTP (p = 0.0007) than on the PLA. RPE, PP, PRS, and DOMS scores were improved after ACTP ingestion (p < 0.01 for all comparisons) compared to PLA. POMS scores were enhanced with ACTP ingestion compared to PLA (p < 0.01). In conclusion, this study indicates that acute acetaminophen ingestion can improve repeated high intensity short-term maximal performance, attention, mood states, and perceptions of exertion, pain, recovery, and muscle soreness in well-trained female athletes, suggesting potential benefits for their overall athletic performance and mood state.

Using a decision tree algorithm to distinguish between repeated supra-therapeutic and acute acetaminophen exposures

BackgroundThis study aimed to compare clinical and laboratory characteristics of supra-therapeutic (RSTI) and acute acetaminophen exposures using a predictive decision tree (DT) algorithm.MethodsWe conducted a retrospective cohort study using the National Poison Data System (NPDS). All patients with RSTI acetaminophen exposure (n = 4,522) between January 2012 and December 2017 were included. Additionally, 4,522 randomly selected acute acetaminophen ingestion cases were included. After that, the DT machine learning algorithm was applied to differentiate acute acetaminophen exposure from supratherapeutic exposures.ResultsThe DT model had accuracy, precision, recall, and F1-scores of 0.75, respectively. Age was the most relevant variable in predicting the type of acetaminophen exposure, whether RSTI or acute. Serum aminotransferase concentrations, abdominal pain, drowsiness/lethargy, and nausea/vomiting were the other most important factors distinguishing between RST and acute acetaminophen exposure.ConclusionDT models can potentially aid in distinguishing between acute and RSTI of acetaminophen. Further validation is needed to assess the clinical utility of this model.

383 What Aminotransferase Values Are Clinically Important After Acetaminophen Poisoning?

Acute acetaminophen ingestion management includes plotting an acetaminophen concentration on the population-based Rumack-Matthew Nomogram. Nomogram implementation reflects an estimate of probability of hepatotoxicity (defined as aspartate or alanine aminotransferase >1,000 IU/L) based on ingestion time and acetaminophen concentration. Similarly, patients with unknown or repeated supratherapeutic acetaminophen exposure are treated with acetylcysteine to mitigate liver injury. Antidote efficacy is time sensitive, however, once hepatotoxicity is identified patients often have extended hospital courses and acetylcysteine administration.

Contralateral fatigue during severe-intensity single-leg exercise: influence of acute acetaminophen ingestion.

Exhaustive single-leg exercise has been suggested to reduce time to task failure (Tlim) during subsequent exercise in the contralateral leg by exacerbating central fatigue development. We investigated the influence of acetaminophen (ACT), an analgesic that may blunt central fatigue development, on Tlim during single-leg exercise completed with and without prior fatiguing exercise of the contralateral leg. Fourteen recreationally active men performed single-leg severe-intensity knee-extensor exercise to Tlim on the left (Leg1) and right (Leg2) legs without prior contralateral fatigue and on Leg2 immediately following Leg1 (Leg2-CONTRA). The tests were completed following ingestion of 1-g ACT or maltodextrin [placebo (PL)] capsules. Intramuscular phosphorus-containing metabolites and substrates and muscle activation were assessed using 31P-MRS and electromyography, respectively. Tlim was not different between Leg1ACT and Leg1PL conditions (402 ± 101 vs. 390 ± 106 s, P = 0.11). There was also no difference in Tlim between Leg2ACT-CONTRA and Leg2PL-CONTRA (324 ± 85 vs. 311 ± 92 s, P = 0.10), but Tlim was shorter in Leg2ACT-CONTRA and Leg2PL-CONTRA than in Leg2CON (385 ± 104 s, both P < 0.05). There were no differences in intramuscular phosphorus-containing metabolites and substrates or muscle activation between Leg1ACT and Leg1PL and between Leg2ACT-CONTRA and Leg2PL-CONTRA (all P > 0.05). These findings suggest that levels of metabolic perturbation and muscle activation at Tlim are not different during single-leg severe-intensity knee-extensor exercise completed with or without prior fatiguing exercise of the contralateral leg. Despite contralateral fatigue, ACT ingestion did not alter neuromuscular responses, muscle metabolites, or exercise performance.

Acute acetaminophen ingestion improves performance and muscle activation during maximal intermittent knee extensor exercise

AimAcetaminophen is a commonly used medicine for pain relief and emerging evidence suggests that it may improve endurance exercise performance. This study investigated some of the physiological mechanisms by which acute acetaminophen ingestion might blunt muscle fatigue development.MethodsThirteen active males completed 60 × 3 s maximum voluntary contractions (MVC) of the knee extensors with each contraction separated by a 2 s passive recovery period. This protocol was completed 60 min after ingesting 1 g of maltodextrin (placebo) or 1 g of acetaminophen on two separate visits. Peripheral nerve stimulation was administered every 6th contraction for assessment of neuromuscular fatigue development, with the critical torque (CT), which reflects the maximal sustainable rate of oxidative metabolism, taken as the mean torque over the last 12 contractions. Surface electromyography was recorded continuously as a measure of muscle activation.ResultsMean torque (61 ± 11 vs. 58 ± 14% pre-exercise MVC) and CT (44 ± 13 vs. 40 ± 15% pre-exercise MVC) were greater in the acetaminophen trial compared to placebo (both P < 0.05). Voluntary activation and potentiated twitch declined at a similar rate in both conditions (P > 0.05). However, the decline in electromyography amplitude was attenuated in the acetaminophen trial, with electromyography amplitude being greater compared to placebo from 210 s onwards (P < 0.05).ConclusionThese findings indicate that acute acetaminophen ingestion might be ergogenic by increasing CT and preserving muscle activation during high-intensity exercise.

The Poisoned Pediatric Patient.

1. Michael S. Toce, MD, MS* 2. Michele M. Burns, MD, MPH*,† 1. *Harvard Medical Toxicology Program and 2. †Division of Emergency Medicine, Department of Medicine, Boston Children’s Hospital, Boston, MA * Abbreviations: AGMA: : anion gap metabolic acidosis ALT: : alanine aminotransferase APAP: : acetaminophen ASA: : acetylsalicylic acid AST: : aspartate aminotransferase Cl-: : chloride ECG: : electrocardiogram GI: : gastrointestinal GSH: : glutathione HCO3−: : bicarbonate IV: : intravenous K+: : potassium NAC: : N-acetylcysteine NAPQI: : N-acetyl-p-benzoquinoneimine NPDS: : National Poison Data System PO: : oral Poisonings remain a frequent source of morbidity and mortality in the pediatric age group. All pediatricians, whether in training or in practice, encounter these patients, yet toxicologic training is lacking in most pediatric residencies. After completing this article, readers should be able to: 1. Understand the epidemiology of pediatric poisonings and explain how developmental milestones influence behavior that may lead to a poisoning exposure. 2. Perform a focused toxicologic physical examination and describe the various toxidromes. 3. Explain the primary acid-base disturbance in salicylate toxicity. 4. Determine which patient requires treatment after acute acetaminophen ingestion. 5. Provide the differential diagnosis of an anion gap metabolic acidosis. 6. Identify which drugs can lead to QRS and QTc prolongation and the treatment for each abnormality. 7. Describe the toxicologic differential diagnosis for hypoglycemia and explain the physiologic reasons why pediatric patients are at increased risk for complications. This review focuses on the epidemiology and initial evaluation and treatment of the poisoned pediatric patient. We emphasize the diagnosis and treatment of acetaminophen and aspirin toxicity, identifying and treating prolonged QRS/QTc, and developing a differential diagnosis for an anion gap metabolic acidosis (AGMA) and hypoglycemia (Table 1). View this table: Table 1. Introduction to the Poisoned Patient Pediatric exposures and poisonings continue to be a significant cause of morbidity and mortality. According to the 2014 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS), 1,326,789 toxic exposures occurred in children younger than age 20 years in 2014, representing 1,595 exposures per 100,000 …

Drug-Induced Liver Injury

Drug-induced liver injury (DILI) can result from both idiosyncratic and intrinsic mechanisms. This article discusses the clinical impact of DILI from a broad range of medications as well as herbal and dietary supplements. Risk factors for idiosyncratic DILI (IDILI) are the result of multiple host, environmental, and compound factors. Some triggers of IDILI often seen in critical care include antibiotics, antiepileptic medications, statins, novel anticoagulants, proton pump inhibitors, inhaled anesthetics, nonsteroidal anti-inflammatory agents, methotrexate, sulfasalazine, and azathioprine. The mechanism of IDILI due to these medications varies, and the resulting damage can be cholestatic, hepatocellular, or mixed. The primary treatment of IDILI is to discontinue the causative agent. DILI due to acetaminophen is intrinsic because the liver damage is predictably aligned with the dose ingested. Acute acetaminophen ingestion can be treated with activated charcoal or N-acetylcysteine. Future areas of research include identification of mitochondrial stress biomarkers and of the patients at highest risk for DILI.

Acute acetaminophen ingestion does not alter core temperature or sweating during exercise in hot-humid conditions.

Acute acetaminophen (ACT) ingestion has been reported to reduce thermal strain during cycling in the heat. In this study, nine active participants ingested 20 mg of ACT per kg of total body mass (ACT) or a placebo (PLA), 60 min prior to cycling at a fixed rate of metabolic heat production (ACT: 8.3 ± 0.3 W/kg; PLA: 8.5 ± 0.5 W/kg), which was equivalent to 55 ± 6% VO2max , for 60 min at 34.5 ± 0.1 °C, 52 ± 1% relative humidity. Resting rectal temperature (Tre ; ACT: 36.70 ± 0.17 °C; PLA: 36.80 ± 0.16 °C, P = 0.24), esophageal temperature (Tes ; ACT: 36.54 ± 0.22 °C; PLA: 36.61 ± 0.17 °C, P = 0.50) and mean skin temperature (Tsk ; ACT: 34.00 ± 0.14 °C; PLA: 33.96 ± 0.20 °C, P = 0.70) were all similar among conditions. At end-exercise, no differences in ΔTre (ACT: 1.12 ± 0.15 °C; PLA: 1.11 ± 0.21 °C, P = 0.92), ΔTes (ACT: 0.90 ± 0.28 °C; PLA: 0.88 ± 0.23 °C, P = 0.84), ΔTsk (ACT: 0.80 ± 0.39 °C; PLA: 0.70 ± 0.46 °C, P = 0.63), mean local sweat rate (ACT: 1.02 ± 0.15 mg/cm(2) /min; PLA: 1.02 ± 0.13 mg/cm(2) /min, P = 0.98) and whole-body sweat loss (ACT: 663 ± 83 g; PLA: 663 ± 77 g, P = 0.995) were evident. Furthermore, ratings of perceived exertion and thermal sensation and thermal comfort were not different between ACT and PLA conditions. In conclusion, ACT ingested 60 min prior to moderate intensity exercise in hot-humid conditions does not alter physiologic thermoregulatory control nor perceived strain.

A single-arm clinical trial of a 48-hour intravenous N-acetylcysteine protocol for treatment of acetaminophen poisoning

Introduction. Acetylcysteine prevents hepatic injury when administered soon after acetaminophen overdose. The most commonly used treatment protocols are a 72-hour oral and a 21-hour intravenous (IV) protocol. Between 1984 and 1994, 409 patients were enrolled in a study to describe the outcomes of patients who were treated using a 48-hour IV protocol. In 1991, an interim analysis reported the first 223 patients. The objective of this manuscript is to report the rates of hepatotoxicity and adverse events occurring during a 48-hour IV acetylcysteine protocol in the entire 409 patient cohort. Methods. This was a multicenter, single-arm, open-label clinical trial enrolling patients who presented with a toxic serum acetaminophen concentration within 24 h of acute acetaminophen ingestion. Patients were treated with 140 mg/kg loading dose followed by 70 mg/kg every 4 h for 12 doses. Serum aminotransferase activities were measured every 8 h during the protocol, and adverse events were recorded. The primary outcome was the percentage of subjects who developed hepatotoxicity defined as a peak serum aminotransferase greater than 1000 IU/L. Results. Four hundred and nine patients were enrolled, and 309 met inclusion for the outcome analysis. The overall percentage of patients developing hepatotoxicity was 18.1%, and 3.4% of patients treated within 10 h developed hepatotoxicity. One acetaminophen-related death occurred in a patient treated at 22 h. Adverse events occurred in 28.9% of enrolled subjects; the most common adverse events were nausea, vomiting, and flushing, and no events were rated as serious by the investigator. Conclusions. Acetaminophen-overdosed patients treated with IV acetylcysteine administered as 140 mg/kg loading dose followed by 70 mg/kg every 4 h for 12 doses had a low rate of hepatotoxicity and few adverse events. This protocol delivers a higher dose of acetylcysteine which may be useful in selected cases involving very large overdoses.

Acetaminophen-cysteine adducts during therapeutic dosing and following overdose

BackgroundAcetaminophen-cysteine adducts (APAP-CYS) are a specific biomarker of acetaminophen exposure. APAP-CYS concentrations have been described in the setting of acute overdose, and a concentration >1.1 nmol/ml has been suggested as a marker of hepatic injury from acetaminophen overdose in patients with an ALT >1000 IU/L. However, the concentrations of APAP-CYS during therapeutic dosing, in cases of acetaminophen toxicity from repeated dosing and in cases of hepatic injury from non-acetaminophen hepatotoxins have not been well characterized. The objective of this study is to describe APAP-CYS concentrations in these clinical settings as well as to further characterize the concentrations observed following acetaminophen overdose.MethodsSamples were collected during three clinical trials in which subjects received 4 g/day of acetaminophen and during an observational study of acetaminophen overdose patients. Trial 1 consisted of non-drinkers who received APAP for 10 days, Trial 2 consisted of moderate drinkers dosed for 10 days and Trial 3 included subjects who chronically abuse alcohol dosed for 5 days. Patients in the observational study were categorized by type of acetaminophen exposure (single or repeated). Serum APAP-CYS was measured using high pressure liquid chromatography with electrochemical detection.ResultsTrial 1 included 144 samples from 24 subjects; Trial 2 included 182 samples from 91 subjects and Trial 3 included 200 samples from 40 subjects. In addition, we collected samples from 19 subjects with acute acetaminophen ingestion, 7 subjects with repeated acetaminophen exposure and 4 subjects who ingested another hepatotoxin. The mean (SD) peak APAP-CYS concentrations for the Trials were: Trial 1- 0.4 (0.20) nmol/ml, Trial 2- 0.1 (0.09) nmol/ml and Trial 3- 0.3 (0.12) nmol/ml. APAP-CYS concentrations varied substantially among the patients with acetaminophen toxicity (0.10 to 27.3 nmol/ml). No subject had detectable APAP-CYS following exposure to a non-acetaminophen hepatotoxin.ConclusionsLower concentrations of APAP-CYS are detectable after exposure to therapeutic doses of acetaminophen and higher concentrations are detected after acute acetaminophen overdose and in patients with acetaminophen toxicity following repeated exposure.

Comment on “Acute Ethanol Coingestion Confers a Lower Risk of Hepatotoxicity after Deliberate Acetaminophen Overdose”

OBJECTIVES: Little is known about the clinical significance of acute ethanol coingestion around the time of acetaminophen (paracetamol) overdose. This study prospectively examined the effect of acute ethanol coingestion on risk of hepatotoxicity among patients admitted to hospital for N-acetylcysteine (NAC) therapy after deliberate acetaminophen overdose. METHODS: This was a prospective observational study and included sequential patients who presented within 24 hours of acute acetaminophen ingestion and required NAC therapy. Significant hepatotoxicity was defined by alanine transaminase > 1,000 U/L or the international normalized ratio > 1.3 after a standardized intravenous administration of 300 mg/kg NAC. RESULTS: There were 362 patients, including 178 (49.2%) who coingested ethanol acutely. The prevalence of hepatotoxicity was 5.1% (95% CI = 2.6% to 9.5%) in those who ingested ethanol, compared to 15.2% (95% CI = 10.7% to 21.2%) in those who did not (p = 0.0027 by chi-square proportional test). Acute ethanol intake conferred a lower risk of hepatotoxicity in patients who had acetaminophen concentrations above or below the "200-line" and was independent of the interval between ingestion and assessment. CONCLUSIONS: Acute ethanol intake is associated with a lower risk of hepatotoxicity after acetaminophen overdose. This apparent protective effect cannot be explained solely by lower exposure to acetaminophen in this group, nor differences in the interval between ingestion and initiation of treatment. Further work is required to establish mechanisms by which ethanol might confer protection against hepatotoxicity, so as to identify novel strategies for reducing risk after acute acetaminophen ingestion. Language: en

Acute Ethanol Coingestion Confers a Lower Risk of Hepatotoxicity after Deliberate Acetaminophen Overdose

Little is known about the clinical significance of acute ethanol coingestion around the time of acetaminophen (paracetamol) overdose. This study prospectively examined the effect of acute ethanol coingestion on risk of hepatotoxicity among patients admitted to hospital for N-acetylcysteine (NAC) therapy after deliberate acetaminophen overdose. This was a prospective observational study and included sequential patients who presented within 24 hours of acute acetaminophen ingestion and required NAC therapy. Significant hepatotoxicity was defined by alanine transaminase > 1,000 U/L or the international normalized ratio > 1.3 after a standardized intravenous administration of 300 mg/kg NAC. There were 362 patients, including 178 (49.2%) who coingested ethanol acutely. The prevalence of hepatotoxicity was 5.1% (95% CI = 2.6% to 9.5%) in those who ingested ethanol, compared to 15.2% (95% CI = 10.7% to 21.2%) in those who did not (p = 0.0027 by chi-square proportional test). Acute ethanol intake conferred a lower risk of hepatotoxicity in patients who had acetaminophen concentrations above or below the "200-line" and was independent of the interval between ingestion and assessment. Acute ethanol intake is associated with a lower risk of hepatotoxicity after acetaminophen overdose. This apparent protective effect cannot be explained solely by lower exposure to acetaminophen in this group, nor differences in the interval between ingestion and initiation of treatment. Further work is required to establish mechanisms by which ethanol might confer protection against hepatotoxicity, so as to identify novel strategies for reducing risk after acute acetaminophen ingestion.

Acute Acetaminophen Overdose Is Associated with Dose‐Dependent Hypokalaemia: A Prospective Study of 331 Patients

Hypokalaemia is a recognized complication of acute acetaminophen overdose. It is unclear whether this might be a pharmacological effect of acetaminophen, or due to association with confounding factors. The present study sought to better characterize the relationship between acetaminophen concentrations and risk of hypokalaemia. A prospective study of patients received N-acetylcysteine treatment within 15 hr of acute acetaminophen ingestion. Serum potassium concentrations were determined before and after N-acetylcysteine. Serum acetaminophen concentrations were used to indicate overall drug exposure by comparison to the Rumack-Matthew nomogram. Hypokalaemia was pre-defined by serum concentrations <3.5 mmol/l, and groups compared by Mann-Whitney tests. There were 331 patients. Median (95% confidence interval) fall in serum potassium concentration after N-acetylcysteine was 0.05 mmol/l (-0.11-0.30 mmol/l) if acetaminophen concentrations were below the 'high-risk' treatment line, 0.30 mmol/l (0.17-0.40 mmol/l) if between the 'high-risk' and 'normal' treatment lines (P = 0.0358), and 0.40 mmol/l (0.20-0.50 mmol/l) if above the 'normal' treatment line (P = 0.0136). A receiver operating characteristic showed that high acetaminophen concentrations were predictive of hypokalaemia (P = 0.0001 versus zero discriminatory line), and 4 hr acetaminophen concentration >156 mmol/l gave 81% sensitivity and 48% specificity. The risk of hypokalaemia after acute acetaminophen overdose depends on the extent of acetaminophen exposure, irrespective of N-acetylcysteine administration and independent of whether vomiting occurred. Acetaminophen appears to cause concentration-dependent hypokalaemia after overdose, and the pharmacological basis requires further consideration.

Population-based incidence and outcome of acetaminophen poisoning by type of ingestion.

1) To determine, in a population-based sample, the observed frequency of acetaminophen overdose-related ED evaluation and hospitalization. 2) To examine the relative frequency of hospitalization by pattern of ingestion, the outcome of each group, and the presence or absence of postulated risk factors. This study was a 46-month, retrospective chart review of all acetaminophen-related visits, by patients at least 10 years of age, to either of the two hospitals that serve a four-county region of central Virginia. Of 636 charts identified for review, only 137 involved acute or chronic acetaminophen overdose. One hundred twenty-six patients presented after an acute ingestion; 122 of these patients gave a history of a single, supratherapeutic ingestion of acetaminophen. Twenty-five patients were hospitalized for treatment. Eighteen of these were treated with N-acetylcysteine (NAC) based on the Rumack-Matthew nomogram; one suffered significant hepatic injury. The other seven presented at least 18 hours after ingestion, with no measurable serum acetaminophen. Two of these suffered significant hepatic injury. Four additional patients presented after multiple ingestions within 24 hours. Three were hospitalized, but none experienced significant injury. Only 11 patients were evaluated for chronic acetaminophen overmedication for pain (more than 6 g/day over a period of more than 24 hours). Four were admitted for treatment; three suffered significant hepatic injury. Thus, the observed incidence of acute acetaminophen ingestion in this region was 21.4/100,000/yr (95% CI = 17.7 to 25.2). The observed incidence of hospitalization for acute acetaminophen toxicity was 4.8/100,000/yr (95% CI = 3.0 to 6.5). The observed incidence of hospitalization for all acetaminophen poisoning was 5.5/100,000/yr (95% CI = 4.1 to 7.0). High ethanol consumption was present more frequently in those who suffered hepatic injury. Most patients evaluated for acetaminophen ingestion present early following acute single overdose. Relatively few of these patients require hospitalization and, for those hospitalized, the outcome is good. More significantly, acetaminophen overdose patients whose risk cannot be estimated using the Rumack-Matthew nomogram represented 44% of those hospitalized and 83% of those who suffered significant hepatic injury. Emergency physicians need to determine how they can impact the outcome of these patients. Efforts should be directed at further characterizing historical, physical, and biochemical markers of risk and at determining in which circumstances hospitalization for NAC or other therapies is justified.