Serum Acetaminophen Concentration Research Articles

Evaluation of Serum Acetaminophen Concentration Utility for Closure of Patent Ductus Arteriosus.

Acetaminophen for patent ductus arteriosus (PDA) closure has gained popularity over the last decade; however, therapeutic drug monitoring for this indication remains uncertain. The exact timing and goal trough serum acetaminophen concentration ranges are not well defined. The purpose of our study is to evaluate the impact of therapeutic drug monitoring on both PDA closure rates and identify real-world risk of hepatotoxicity. Retrospective single-center chart review of neonates admitted to the neonatal intensive care unit (NICU) between April 2016 and August 2022 with at least 1 serum acetaminophen concentration to monitor for PDA closure. Acetaminophen was initiated at 15 mg/kg administered intravenously every 6 hours and a trough serum concentration was obtained prior to the sixth or seventh dose. PDA closure was confirmed radiographically with corresponding provider documentation. Associations of efficacy to closure were -analyzed using descriptive statistics. Thirty-eight neonates were included in the analysis, of which 18 (47%) achieved PDA closure. First serum acetaminophen trough concentration was obtained before the seventh dose [IQR, 6-8] and ranged from undetectable (< 5 mg/L) to 30.8 mg/L. Subgroup analysis of first concentrations revealed therapeutic trough, defined as 10 to 20 mg/L, did not correlate to PDA closure (no closure median concentration = 14.7 [IQR, 13-15.6] vs closure median concentration = 15.4 [IQR, 11.4-18.5], p = 0.42), or duration of treatment. No neonate experienced acetaminophen-associated toxicity. PDA closure did not correlate to serum acetaminophen trough concentration. The regimen of 15 mg/kg every 6 hours appears safe as no neonate experienced acetaminophen toxicity or discontinued treatment early.

Patterns of acetaminophen toxicity among patients with low-risk serum concentrations.

In 2012, the Commission on Human Medicines mandated lowering the acetaminophen toxicity nomogram treatment threshold in the UK to 100 µg/ml at 4 h post-ingestion. The present study aim was to evaluate biochemical and liver toxicity patterns in patients who presented with acetaminophen overdose and had low serum acetaminophen concentrations (<150 µg/ml). Patients admitted to the emergency department with a clear history of acute acetaminophen overdose with or without other medication or ethanol were consecutively enrolled into this retrospective cohort study. Patients with serum acetaminophen concentration >150 µg/ml or an unknown ingestion time were excluded. Data were extracted from electronic medical records and are presented as mean ± SD or median (interquartile range). A total of 103 patients were included (median age, 17 [4-21] years) and 80 (78%) were female. The median ingested acetaminophen dose was 5000 (2850-7650) mg. At baseline, the median serum acetaminophen concentration was 42 (4.5-64.8) µg/ml, and median alanine aminotransferase and aspartate aminotransferase levels were 22 (17-28) and 27 (16-45) IU/L, respectively. Twenty patients were treated with acetylcysteine, with none developing adverse reactions. No patient developed hepatotoxicity, including patients with initial multiple product ingestion or other risk factors. Patients presenting with an acute acetaminophen overdose with acetaminophen level <150 µg/ml, including patients with other risk factors, are at low risk of hepatotoxicity.

Comparative Analysis of Machine Learning Algorithms Evaluating the Single Nucleotide Polymorphisms of Metabolizing Enzymes with Clinical Outcomes Following Intravenous Paracetamol in Preterm Neonates with Patent Ductus Arteriosus.

Pharmacogenomics has been identified to play a crucial role in determining drug response. The present study aimed to identify significant genetic predictor variables influencing the therapeutic effect of paracetamol for new indications in preterm neonates. Paracetamol has recently been preferred as a first-line drug for managing Patent Ductus Arteriosus (PDA) in preterm neonates. Single Nucleotide Polymorphisms (SNPs) in CYP1A2, CYP2A6, CYP2D6, CYP2E1, and CYP3A4 have been observed to influence the therapeutic concentrations of paracetamol. The purpose of this study was to evaluate various Machine Learning Algorithms (MLAs) and bioinformatics tools for identifying the key genotype predictor of therapeutic outcomes following paracetamol administration in neonates with PDA. Preterm neonates with hemodynamically significant PDA were recruited in this prospective, observational study. The following SNPs were evaluated: CYP2E1*5B, CYP2E1*2, CYP3A4*1B, CYP3A4*2, CYP3A4*3, CYP3A5*3, CYP3A5*7, CYP3A5*11, CYP1A2*1C, CYP1A2*1K, CYP1A2*3, CYP1A2*4, CYP1A2*6, and CYP2D6*10. Amongst the MLAs, Artificial Neural Network (ANN), C5.0 algorithm, Classification and Regression Tree analysis (CART), discriminant analysis, and logistic regression were evaluated for successful closure of PDA. Generalized linear regression, ANN, CART, and linear regression were used to evaluate maximum serum acetaminophen concentrations. A two-step cluster analysis was carried out for both outcomes. Area Under the Curve (AUC) and Relative Error (RE) were used as the accuracy estimates. Stability analysis was carried out using in silico tools, and Molecular Docking and Dynamics Studies were carried out for the above-mentioned enzymes. Two-step cluster analyses have revealed CYP2D6*10 and CYP1A2*1C to be the key predictors of the successful closure of PDA and the maximum serum paracetamol concentrations in neonates. The ANN was observed with the maximum accuracy (AUC = 0.53) for predicting the successful closure of PDA with CYP2D6*10 as the most important predictor. Similarly, ANN was observed with the least RE (1.08) in predicting maximum serum paracetamol concentrations, with CYP2D6*10 as the most important predictor. Further MDS confirmed the conformational changes for P34A and P34S compared to the wildtype structure of CYP2D6 protein for stability, flexibility, compactness, hydrogen bond analysis, and the binding affinity when interacting with paracetamol, respectively. The alterations in enzyme activity of the mutant CYP2D6 were computed from the molecular simulation results. We have identified CYP2D6*10 and CYP1A2*1C polymorphisms to significantly predict the therapeutic outcomes following the administration of paracetamol in preterm neonates with PDA. Prospective studies are required for confirmation of the findings in the vulnerable population.

Predicting serum acetaminophen concentrations in acute poisoning for safe termination of N-acetylcysteine in a resource-limited environment

Purpose: The Prescott nomogram has been utilized to forecast hepatotoxicity from acute acetaminophen poisoning. In developing countries, emergency medical centers lack the resources to report acetaminophen concentrations; thus, the commencement and cessation of treatment are based on the reported dose. This study investigated risk factors that can predict acetaminophen detection after 15 hours for safe treatment termination.Methods: Data were collected from an urban emergency medical center from 2010 to 2020. The study included patients ≥14 years of age with acute acetaminophen poisoning within 15 hours. The correlation between risk factors and detection of acetaminophen 15 hours after ingestion was evaluated using logistic regression, and the area under the curve (AUC) was calculated.Results: In total, 181 patients were included in the primary analysis; the median dose was 150.9 mg/kg and 35 patients (19.3%) had acetaminophen detected 15 hours after ingestion. The dose per weight and the time to visit were significant predictors for acetaminophen detection after 15 hours (odds ratio, 1.020 and 1.030, respectively). The AUCs were 0.628 for a 135 mg/kg cut-off value and 0.658 for a cut-off 450 minutes, and that of the combined model was 0.714 (sensitivity: 45.7%, specificity: 91.8%).Conclusion: Where acetaminophen concentrations are not reported during treatment following the UK guidelines, it is safe to start N-acetylcysteine immediately for patients who are ≥14 years old, visit within 15 hours after acute poisoning, and report having ingested ≥135 mg/kg. Additional N-acetylcysteine doses should be considered for patients visiting after 8 hours.

Population Pharmacokinetic Modeling and Dose Optimization of Acetaminophen and its Metabolites Following Intravenous Infusion in Critically ill Adults.

Acetaminophen (paracetamol) is a ubiquitously administered drug in critically ill patients. Considering the dearth of literature, we evaluated the population pharmacokinetics of intravenous acetaminophen and its principal metabolites (sulfate and glucuronide) in this population. Critically ill adults receiving intravenous acetaminophen were included in the study. One to three blood samples were withdrawn per patient for the estimation of acetaminophen, and its metabolites (acetaminophen glucuronide and acetaminophen sulfate). High-performance liquid chromatography was used for measuring serum concentrations. We used nonlinear mixed-effect modeling for estimating the primary pharmacokinetic parameters of acetaminophen and its metabolites. The effect of covariates was evaluated followed by dose optimization using Monte Carlo simulation. Patient factors such as demographic information, liver and renal function tests were used as covariates in population pharmacokinetic analysis. The therapeutic range for serum acetaminophen concentration was considered to be 66-132μM, while 990μM was considered as the threshold for toxic concentration. Eighty-seven participants were recruited. A joint two-compartment acetaminophen pharmacokinetic model linked to glucuronide and sulfate metabolite compartments was used. The central and peripheral volume distributions were 7.87 and 8.87 L/70kg, respectively. Estimated clearance (CL) was 0.58L/h/70 kg, while intercompartmental clearance was 44.2L/h/70 kg. The glucuronide and sulfate metabolite CL were 22 and 94.7L/h/70 kg, respectively. Monte Carlo simulation showed that twice-daily administration of acetaminophen would result in a relatively higher proportion of patient population achieving and retaining serum concentrations in the therapeutic range, with reduced risk of concentrations remaining in the toxic range. A joint pharmacokinetic model for intravenous acetaminophen and its principal metabolites in a critically ill patient population has been developed. Acetaminophen CL in this patient population is reduced. We propose a reduction in the frequency of administration to reduce the risk of supra-therapeutic concentrations in this population.

Do Propylene Glycol, Benzyl Alcohol, and Ethanol in Concomitant Drugs Influence Clinical Outcomes Following Intravenous Acetaminophen in Critically Ill Neonates?

Propylene glycol (PG) and benzyl alcohol (BA) have been shown to inhibit the metabolizing enzyme for acetaminophen in the liver. Ethanol has unpredictable effects on acetaminophen metabolism. Critically ill neonates commonly receive drug formulations containing PG, BA, and ethanol as excipients. Until now, there have been no reports on the influence of BA, PG, and ethanol as excipients in patients undergoing concomitant acetaminophen therapy. We devised the present study to evaluate whether any significant differences in plasma acetaminophen concentrations, liver function tests, and serum creatinine exist between neonates receiving excipients containing drugs compared to those without. We included neonates that were administered intravenous acetaminophen with at least one concomitant drug containing either BA, PG, or ethanol as excipients. Plasma acetaminophen concentrations and levels of liver function were evaluated using tests. The doubling of alanine aminotransferase levels was considered to be a marker of hepatotoxicity. Elevation of serum creatinine &gt;1.5 times higher than the baseline value was considered to be indicative of an acute kidney injury. Fifty-seven neonates were recruited in the study. No significant differences in the serum acetaminophen concentrations, liver and renal function tests, and rates of successful closure of ductus arteriosus were observed between the groups. No significant changes in the serum acetaminophen levels and the clinical outcomes were observed due to the presence of BA, PG, or ethanol in concomitant drugs as excipients. Probably, drugs containing these excipients can be safely administered, and even formulations containing these excipients with acetaminophen are likely to be safe for critically ill neonates.

Ocular penetration of oral acetaminophen in horses.

Acetaminophen (paracetamol) is increasingly used to treat painful conditions in horses but its ocular penetration has not been studied. To determine whether orally administered acetaminophen penetrates the aqueous humour of the normal equine eye and report an aqueous humour:serum acetaminophen concentration ratio in horses. In vivo experiment. Six privately owned horses with normal ophthalmic examinations weighing 568 ± 65 kg (mean ± standard deviation) and aged 11 ± 4 years were given 20 mg/kg acetaminophen orally every 12 h for a total of six doses. Physical exam parameters were recorded prior to, during, and after the dosing period. One hour after the final dose, horses were sedated and simultaneous aqueous humour and serum samples were collected and analysed for acetaminophen concentrations and selected eicosanoids. An aqueous humour:serum acetaminophen concentration ratio was calculated. A second aqueous humour sample was taken and analysed for eicosanoid concentrations 3 months after acetaminophen dosing. Physical exam data were compared between time points using a mixed model analysis (significance p < 0.05). Acetaminophen was detected in both serum and aqueous humour of all horses and mean ± standard deviation aqueous humour:serum acetaminophen concentration ratio was 44.9 ± 15.9%. No significant changes in physical exam parameters occurred during or after dosing. Eicosanoids were not detected in aqueous humour at any sampling point. Presence of acetaminophen in the aqueous humour may not relate to clinical effect. A therapeutic level of acetaminophen has not been determined in horses, and the absence of ocular inflammation does not reflect conditions in which acetaminophen may be used. Acetaminophen readily penetrates the aqueous humour of the normal equine eye after consecutive oral dosing. Further study is required to determine whether acetaminophen is useful in the treatment of ocular pain and inflammation.

Massive warfarin overdose management in an adolescent patient

Introduction Warfarin is a widely used oral anticoagulant with established reversal guidelines in the setting of a supratherapeutic international normalized ratio (INR). Limited literature exists on managing acute warfarin overdoses in patients who are not chronically anticoagulated. Case A 15-year-old male, with no indication for anticoagulation, presented to a pediatric emergency department after an acute 1,000 mg warfarin ingestion. He had no significant complaints upon presentation aside from a mild intermittent headache. His past medical history was significant for anxiety, depression, Tourette syndrome, attention deficit hyperactivity disorder, and polysubstance misuse. Computed tomography of his head was unremarkable and serum acetaminophen, salicylate, and ethanol concentrations were negative. Approximately 16 h post-ingestion, his INR was 1.9 with an increase to 3.3 by 26 h. The regional poison center was consulted and recommended, consistent with the CHEST guidelines, holding treatment with vitamin K until INR was >10 or if signs or symptoms of bleeding occurred. The patient was admitted for monitoring and by hospital day (HD) #4, his INR had risen to >11.8 at which point oral vitamin K 10 mg was administered. On HD #7, the patient was deemed stable for transfer to inpatient psychiatry after repeat INRs of 2.9 and 3.4. Discussion Case reports have demonstrated early administration of vitamin K can temporarily lower INR and prevent detection of rebound. The CHEST warfarin reversal guidelines describe the risks and benefits with respect to bleeding and thrombosis in the non-intentional overdose patient. Application and extrapolation of these guidelines to acute overdose in patients who lack an indication for anticoagulation may or may not be warranted. Conclusion While established clinical guidance exists on reversing a supratherapeutic INR in patients chronically anticoagulated with warfarin, the risks and benefits of extrapolating this approach are unclear in those who lack an indication for anticoagulation.

A Basis for the Decision to Rule in or out Acetaminophen Toxicity: Assessment of the Serum Level Within 4 Hours Post Overdose

Background: Acetaminophen is a popular antipyretic and analgesic medication worldwide; however, its therapeutic window is narrow, which may lead to overdose or toxicity. This study was conducted to assess the correlation between the serum acetaminophen levels before and 4 hours after the acute toxicity with this drug. The objective of this study was to test the validity of the serum level to arrive at a clinical decision on the toxicity with acetaminophen. Methods: This cross-sectional study was performed on patients hospitalized and treated with a diagnosis of acute acetaminophen overdose during one year (Sept. 2018 to Sept. 2019) at the Toxicology Department of Imam Reza Hospital, Mashhad, Iran. Patients were analyzed for demographics, time of ingestion, their first and second serum acetaminophen concentrations. Results: A total of 204 patients (106 male &amp; 98 female) were included in this study. The average dose of acetaminophen ingestion by these patients was 14.5±3.50 g and all patients were treated successfully with N-Acetyl-Cysteine (NAC). The variables of age (P=0.293), serum acetaminophen levels at 1-2 h (P=0.679), and at 2-3 h (P=0.126) did not have significant relationships with the serum acetaminophen level on the fourth hour. However, the serum acetaminophen levels tested between 3-4 h and acetaminophen intoxication dosage had significant relationships with the acetaminophen level on the fourth hour. Conclusion: In patients with acute acetaminophen toxicity, the data on the serum levels obtained before a 4-hour timepoint from the ingestion were not useful to decide on the need for the rescue treatment with N-acetyl-cysteine.

Evaluation of urinary acetaminophen metabolites and its association with the genetic polymorphisms of the metabolizing enzymes, and serum acetaminophen concentrations in preterm neonates with patent ductus arteriosus

: Acetaminophen is gaining importance as a first-line drug for treating patent ductus arteriosus (PDA) in neonates. Predominant metabolites of acetaminophen in preterm neonates vary from that of adults; and the drug is predominantly metabolized by conjugation and partly by Cytochrome P450 (CYP) enzymes. We carried out the present study to identify the principal urine metabolites of acetaminophen (glucuronide/sulphate) in preterm neonates with hemodynamically significant PDA receiving intravenous acetaminophen, and to evaluate the prevalence of single nucleotide polymorphisms (SNPs) in the key CYP enzymes (CYP1A2*3, CYP1A2*4, CYP1A2*1C, CYP1A2*1K, CYP1A2*6, CYP2D6*10, CYP2E1*2, CYP2E1*5B, CYP3A4*1B, CYP3A4*2, CYP3A4*3, CYP3A5*3, CYP3A5*7, and CYP3A5*11) and their effect on urinary metabolites and serum acetaminophen concentrations. Nineteen (32.8%) neonates had heterozygous CYP1A2*1C, two (3.3%) with heterozygous CYP1A2*1K, 15 (27.8%) and two (3.7%) had heterozygous and homozygous CYP2D6*10, two (3.7%) had heterozygous CYP2E1*5B, seven (12.3%) and three (5.3%) had heterozygous and homozygous CYP3A4*1B, and three (5.5%) had CYP3A5*7 amongst the study population. Acetaminophen sulphate predominated over glucuronide metabolite at all time points. Postnatal days of life was significantly associated with an increase in the urine acetaminophen metabolites with decreased serum acetaminophen concentrations. A significant prevalence of SNPs in the key CYP enzymes related to acetaminophen metabolism was observed in our neonatal population. Population pharmacokinetic-pharmacodynamic modeling incorporating genetic and metabolite data is urgently needed for implementation of precision medicine in this vulnerable population.

Clinical Experience, Characteristics, and Performance of an Acetaminophen Absorption Test in Critically Ill Patients.

Altered drug and nutrient absorption presents a unique challenge in critically ill patients. Performing an acetaminophen absorption test (AAT) has been used as a marker for gastric motility and upper small bowel absorption; thus, it may provide objective data regarding enteral absorptive ability in critically ill patients. What is the clinical experience with AAT when used as a surrogate marker for enteral absorption in critically ill patients? This single-center, retrospective, cohort study evaluated serum acetaminophen concentrations within 180 minutes following 1-time enteral administration of an AAT. Patients admitted to the surgical and medical intensive care units and medical intensive care units over a 7-year period were evaluated. Groups were defined as positive (acetaminophen concentration of ≥10 mg/L) or negative (acetaminophen concentration of <10 mg/L) AAT. The outcomes were to describe the clinical experience, characteristics, and performance of AAT. Forty-eight patients were included. Patients were 58.5 ± 14 years of age, mostly male (58.3%), and admitted to the surgical intensive care unit (66.7%). Median hospital length of stay was 47.5 (27-78.8) days. Thirty-four patients (70.8%) had a positive AAT [median concentration, 14 (12-18) mg/L]. Median time to first detectable concentration was 37 (33-64) minutes. AAT characteristics were similar between the groups including total dose, weight-based dose, time to first and second assays, drug formulation, and site of administration between groups. There were no independent risk factors identified on regression analysis for negative AAT. An acetaminophen dose of 15 mg/kg with 2 coordinated serum concentrations approximately 30 and 60 minutes after administration is a reasonable construct for AAT. Future research is needed to assess AAT utility, safety, and clinical outcomes for predicting patient ability to absorb enteral feeds and medications.

Intravenous acetaminophen (at 15 mg/kg/dose every 6 hours) in critically ill preterm neonates with patent ductus arteriosus: A prospective study.

Acetaminophen has been increasingly used in treating patent ductus arteriosus (PDA) in preterm neonates. Variations were observed in the dosing regimen of acetaminophen across the studies. There is hardly any data available for a relatively higher dose of intravenous acetaminophen (15mg/kg/dose every 6 hours) in the preterm population. We present here the results of a prospective study with this dose of intravenous acetaminophen for treating PDA in critically ill preterm neonates. Preterm neonates (≤37weeks of gestational age) with haemodynamically significant PDA were enrolled. Intravenous acetaminophen at 15mg/kg/dose every 6 hours was administered. Echocardiographic monitoring, liver and renal function tests were carried out. Standard definitions were adhered for defining acute kidney injury (AKI) and hepatotoxicity. Fifty-five neonates were recruited. Following the first dose, less than half had their serum acetaminophen concentrations in the therapeutic range. Extreme preterm neonates were less likely to have a sustained therapeutic acetaminophen concentration after the first dose. Following multiple doses and at steady state, 97.2% and 98.8% respectively were in the therapeutic range. Forty-three (78.2%) neonates had successful closure of the ductus arteriosus of which 22 were extreme preterm, 17 were very preterm and 4 were late preterm neonates; and considering their birthweights, 21 were extremely low, 16 were very low and 6 were low birthweight categories. Ten neonates had elevated alanine aminotransferase levels with three in the low-to-moderate risk of hepatotoxicity category. Eight neonates had altered renal function tests indicating AKI. Intravenous acetaminophen at 15mg/kg/dose every 6 hours was efficacious in 78.2% of the preterm neonates with PDA. We observed a lower incidence of hepatotoxicity, and AKI in the study population. No association was observed between the serum acetaminophen concentrations and PDA closure.

Delayed peaks of acetaminophen in overdose patients with concomitant abdominal trauma

Objective To present two cases of delayed acetaminophen absorption in abdominal trauma patients with concomitant acetaminophen overdose. Cases Case 1. A 25-year-old female arrived to the emergency department with multiple stab wounds. She had ingested an unknown amount of acetaminophen and was then stabbed by her boyfriend in a suicide pact. Initial acetaminophen concentration was 211.7 mcg/mL and the patient was started on N-Acetylcysteine (NAC) therapy. She was found to have injuries and was taken for operative repair. Acetaminophen concentrations were down trending and nearly undetectable until 58 h post-presentation when concentrations began to rise again. Case 2 A 41-year-old female ingested approximately 500 tablets of acetaminophen prior to jumping from a four-story building in a suicide attempt. She was found to have multiple traumatic injuries as well as an initial acetaminophen concentration of 225 mcg/mL and was started on NAC therapy. The patient underwent multiple interventions to treat her traumatic injuries. Despite receiving no acetaminophen while inpatient, the patient’s acetaminophen concentrations peaked a second time on her third hospital day. Conclusions In this case series, two patients with abdominal trauma and coexistent massive acetaminophen ingestions were described. Both cases demonstrated a delayed rise in serum acetaminophen concentrations and required extended NAC therapy.

Acetaminophen Serum Concentrations in Infants Treated Intravenously for Patent Ductus Arteriosus.

Although acetaminophen has emerged as a therapeutic option for treating hemodynamically significant patent ductus arteriosus (PDA) in preterm infants, limited data exist on pharmacodynamics. The objective of this research is to report serum acetaminophen concentrations at steady state in infants treated with intravenous acetaminophen for PDA and to examine associations with clinical outcomes. This retrospective study evaluated all infants admitted during the study period who received intravenous acetaminophen for the treatment of PDA. Acetaminophen dosing was 15 mg/kg every 6 hours. A serum acetaminophen concentration was obtained 4 hours after the eighth dose. Associations between serum concentrations and efficacy, assessed by ductal constriction on echocardiogram, and safety, assessed by serum creatinine and hepatic transaminases, were explored using simple linear regression. A total of 36 infants were included, with a median birth weight of 720 g (IQR 585-895 g) and a median gestational age of 25 weeks (IQR 24-26 weeks). The median acetaminophen concentration in the cohort was 12.3 mg/L (IQR 6.7-16.5 mg/L; range, 1.1-29.0 mg/L). Serum acetaminophen concentrations did not correlate with infant demographics, hepatic transaminases during treatment, or duct size at treatment completion. We observed ductal closure across a wide range of serum acetaminophen concentrations. We did not identify an association between acetaminophen serum concentrations following intravenous therapy and ductal response or hepatic toxicity.

Transaminase and Creatine Kinase Ratios for Differentiating Delayed Acetaminophen Overdose from Rhabdomyolysis.

IntroductionRhabdomyolysis and delayed acetaminophen hepatotoxicity may be associated with elevated serum transaminase values. Establishing the cause of elevated transaminases may be especially difficult because of limited or inaccurate histories of acetaminophen ingestion. We hypothesized that the comparative ratios of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatine kinase (CK) can differentiate acetaminophen hepatotoxicity from rhabdomyolysis.MethodsA retrospective chart review of patients in four hospitals from 2006 to 2011 with a discharge diagnosis of acetaminophen toxicity or rhabdomyolysis was performed. Subjects were classified into three groups: rhabdomyolysis, acetaminophen overdose (all), and acetaminophen overdose with undetectable serum acetaminophen concentrations [acetaminophen(delayed)]. Ratios of AST, ALT, and CK were compared using non-parametric statistical methods.Results1,353 subjects were identified and after applying our exclusion criteria there were 160 in the rhabdomyolysis group, 68 in the acetaminophen overdose (all) group, and 29 in the acetaminophen (delayed) group. The AST/ALT ratio for the rhabdomyolysis group was 1.66 (Interquartile range: 1.18–2.22), for the acetaminophen overdose (all) group was 1.38 (1.08–1.69, statistically lower than the rhabdomyolysis group, p = 0.018), and for the acetaminophen (delayed)group was 1.30 (1.06–1.63, p = 0.037). CK/AST ratios were 21.3 (12.8–42.2), 5.49 (2.52–15.1, p < 0.001), and 3.80 (1.43–13.8, p < 0.001) respectively. CK/ALT ratios were 37.1 (16.1–80.0), 5.77 (2.79–25.2, p < 0.001), and 5.03 (2.20–17.4, p < 0.001) respectively. Increasing CK to transaminase ratio cutoffs resulted in increasing test sensitivity but lower specificity.ConclusionAST/ALT, CK/AST and CK/ALT ratios are significantly larger in rhabdomyolysis when compared to patients with acetaminophen toxicity. This result suggests that the ratios could be used to identify patients with rhabdomyolysis who otherwise might have been diagnosed as delayed acetaminophen toxicity. Such patients may not require treatment with N-acetylcysteine, resulting in cost savings and improved resource utilization.

The hepatoprotective effect of N-acetylcysteine with repeated toxic acetaminophen ingestions: a case report

We present a patient who presented 37 times after large acute acetaminophen ingestions without residual signs of liver dysfunction. The presentations were all very similar: witnessed ingestions of 25 g of acetaminophen presenting within 1 h. Due to a potentially toxic serum acetaminophen concentration, she received N-acetylcysteine 16 times within a 12-month period and 21 times overall. This case is an extreme real-life example regarding the absence of subsequent hepatic injury with repeated potentially toxic acetaminophen ingestions requiring repeated treatments with N-acetylcysteine despite a theoretical vulnerable time period immediately after acetaminophen overdose.

A Case of Opioid Overdose? Or Is It?

A 28-year-old man was found unresponsive at home by a roommate. When emergency medical services (EMS) arrived, he was found to have miosis and was cyanotic with respiratory depression. He was unresponsive to intranasal naloxone (2 mg) that was administered via mucosal atomizer twice. On admission to the emergency department, the patient had a systolic blood pressure of 95 mmHg, a diastolic blood pressure of 70, oxygen saturation was 84% on 100% nonrebreather mask, and respiration rate was 10 breaths/min. Physical examination showed pinpoint pupils. Per the roommate, this patient had been in a car accident a year prior and had been prescribed hydrocodone. After becoming addicted to hydrocodone, he was known to buy street drugs. His roommate explained that the previous night, he bought Norco® (hydrocodone and acetaminophen) from a drug dealer. A urine drugs of abuse screening panel was ordered, which included amphetamines, barbiturates, benzodiazepines, cocaine metabolite (benzoylecgonine), opiates, and tetrahydrocannabinol (THC) and was negative. The serum acetaminophen concentration obtained upon admission was <10 ug/mL. Because the patient's history and physical were consistent with an opioid toxidrome, the clinician gave intravenous naloxone (0.4 mg) and the patient woke up. The clinician called the laboratory for a toxicology consultation. He asked if there were any send-out tests that would detect …

Is it Adequate to Determine Acetaminophen Toxicity Solely on Patients&amp;apos; History? An Analysis on Clinical Manifestation of Intoxication Patients with Positive Serum Acetaminophen Concentrations

Purpose: Acute acetaminophen intoxication is a common occurrence that can cause lethal complications. In most domestic emergency departments, clinicians tend to treat acetaminophen intoxication based on patients' history alone, simply due to the lack of a rapid acetaminophen laboratory test. We performed a 20-month study of intoxication patients to determine the correlation between the history of patients and serum laboratory tests for acetaminophen. Methods: We took blood samples from 280 intoxication patients to evaluate whether laboratory findings detected traces of acetaminophen in the sample. Patients were then treated according to their history. Laboratory results came out after patients' discharge. Agreement between patients' history and laboratory results were analyzed. Results: Among the 280 intoxicated patients enrolled, 38 patients had positive serum acetaminophen concentrations; 18 out of 38 patients did not represent a history suggesting acetaminophen intoxication. One patient without the history showed toxic serum acetaminophen concentration. Among the patients with the history, two patients with toxic serum acetaminophen concentration did not receive N-acetylcysteine (NAC) treatment due to their low reported doses, while other 2 patients without significant serum acetaminophen concentration did receive NAC treatment due to their high reported doses. Conclusion: This study showed a good overall agreement between history and laboratory test results. However, some cases showed inconsistencies between their history and laboratory test results. Therefore, in treating intoxication patients, a laboratory test of acetaminophen with rapid results should be available in most domestic emergency departments.

Can a serum acetaminophen concentration obtained less than 4 hours post-ingestion determine which patients do not require treatment with acetylcysteine?

Context: The interpretation of acetaminophen concentrations obtained prior to 4 hours after an acute, single overdose remains unclear. Patient care decisions in the Emergency Department could be accelerated if such concentrations could reliably exclude the need for treatment.Objective: To determine the agreement between a serum acetaminophen concentration obtained less than 4 hours after an acute ingestion and the subsequent 4 + hour concentration, and the predictive accuracy of early concentrations for identifying patients with potentially toxic exposures.Methods: A secondary analysis of patients admitted for acetaminophen poisoning at one of the 34 hospitals in eight Canadian cities from 1980 to 2005. We examined serum acetaminophen concentrations obtained less than 4 hours post-ingestion, and again 4 or more hours post-ingestion. For the diagnostic accuracy analysis, we specified a cutpoint of 100 μg/mL (662 μmol/L) obtained between 2 and 4 hours and a subsequent 4 to 20 hour acetaminophen concentration above the nomogram treatment line of 150 μg/mL (993 μmol/L).Results: Of 2454 patients identified, 879 (36%) had a subsequent acetaminophen concentration above the nomogram treatment line. The 2–4 hour concentration demonstrated a sensitivity of 0.96 [95% CI; 0.94, 0.97] and a negative likelihood ratio of 0.070 [0.048, 0.10]. Coingested opioids reduced this sensitivity to 0.91 [0.83, 0.95], and antimuscarinics to 0.86 [0.72, 0.94]. Only very low to undetectable acetaminophen concentrations prior to 4 hours reliably excluded a subsequent concentration over the treatment line.Conclusions: Applying an acetaminophen concentration cutpoint of 100 μg/mL (662 μmol/L) at 2–4 hours after an acute ingestion as a threshold for repeat testing and/or treatment would occasionally miss potentially toxic exposures. Absorption of acetaminophen is only slightly delayed by coingested opioids or antimuscarinics. Our analysis validates the practice of not retesting when the first post-ingestion acetaminophen concentration is below the lower limit of quantification.

Acute hepatotoxicity associated with therapeutic doses of intravenous acetaminophen

Background: IV acetaminophen at 4 g per day is considered safe, producing no hepatic failure in more than 1400 cases. Oxidation of acetaminophen forms a reactive intermediate that binds to cellular proteins resulting in acetaminophen-protein adducts (APAP-CYS). Serum concentrations of APAP-CYS have been found to correlate with acetaminophen-induced hepatotoxicity. We report a case of hepatotoxicity associated with therapeutic doses of IV acetaminophen, with elevated serum APAP-CYS. Case details: The patient was a 92-year-old, 68 kg woman without known hepatic disease or ethanol abuse. On hospital day 3 she underwent laparoscopic reduction of internal hernias under general anesthesia. Surgery was uncomplicated and postoperatively she was treated with subcutaneous heparin and IV acetaminophen, 1 g every 6 h for almost 4 days (total dose = 13 g). At the start of therapy, transaminases were normal. On hospital day 5, she was noted to have marked transaminase elevations (AST: 4698 IU/L; ALT: 3914 IU/L) with increases in INR (1.68), ammonia (60 mcg/dL), and total bilirubin (1.8 mg/dL). Serum acetaminophen concentration was 15.3 mcg/mL 26 h after her last dose. Acetaminophen was discontinued and IV acetylcysteine was given and continued at the second maintenance dose rate for a second 16-hour infusion, at which time transaminases, INR, ammonia and total bilirubin were all improving. The patient was discharged 2 days later. Serum APAP-CYS concentrations in serum samples obtained during her hospitalization were elevated (peak = 4.81 μM on hospital day 5; expected range for therapeutic dosing <1.1 μM). Case discussion: We have identified a case of acute liver injury associated with therapeutic dosing of IV acetaminophen. The serum APAP-CYS concentrations are consistent with that seen in cases of hepatotoxicity following repeated supratherapeutic acetaminophen ingestion. Several factors that likely contributed to her susceptibility included advanced age, post-operative status, a likely catabolic state and multiple acetaminophen doses over several days. These uncommon circumstances limit the generalizability of risk. We believe the findings are most consistent with acetaminophen-induced liver injury. Conclusion: This case illustrates a potential hazard of IV acetaminophen and demonstrates the potential utility of APAP-CYS adducts in evaluating causality in acute liver injury.