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Importance: The US and Canada currently have no formal published nationwide guidelines for specialists in poison information or emergency departments for the management of acetaminophen poisoning, resulting in significant variability in management., Objective: To develop consensus guidelines for the management of acetaminophen poisoning in the US and Canada., Evidence Review: Four clinical toxicology societies (America's Poison Centers, American Academy of Clinical Toxicology, American College of Medical Toxicology, and Canadian Association of Poison Control Centers) selected participants (n = 21). Led by a nonvoting chairperson using a modified Delphi method, the panel created a decision framework and determined the appropriate clinical management of a patient with acetaminophen poisoning. Unique to this effort was the collection of guidelines from most poison centers in addition to systematic collection and review of the medical literature. Comments from review by external organizations were incorporated before the guideline was finalized. The project began in March 2021 and ended in March 2023., Findings: The search retrieved 84 guidelines and 278 publications. The panel developed guidelines for emergency department management of single or repeated ingestion of acetaminophen. In addition, the panel addressed extended-release formulation, high-risk ingestion, coingestion of anticholinergics or opioids, age younger than 6 years, pregnancy, weight greater than 100 kg, and intravenous acetaminophen use. Differences from current US practice include defining acute ingestion as an ingestion presentation from 4 to 24 hours after overdose was initiated. A revised form of the Rumack-Matthew nomogram was developed. The term massive ingestion was replaced with the term high-risk ingestion and denoted by a specific nomogram line. Other recommendations include specific criteria for emergency department triage, laboratory evaluation and monitoring parameters, defining the role of gastrointestinal decontamination, detailed management of acetylcysteine treatment, associated adverse effects, and stopping criteria for acetylcysteine treatment, as well as criteria for consultation with a clinical toxicologist. Finally, specific treatment considerations, including acetylcysteine dosing, fomepizole administration, and considerations for extracorporeal elimination and transplant evaluation, were addressed., Conclusions and Relevance: This qualitative study provides a consensus statement on consistent evidence-based recommendations for medical, pharmacy, and nursing education and practice to optimize care of patients with acetaminophen poisoning.

Background: Acetaminophen (APAP) is the most common cause liver injury following alcohol in US patients. Predicting liver injury and subsequent hepatic regeneration in patients taking therapeutic doses of APAP may be possible using new 'omic methods such as metabolomics and genomics. Multi'omic techniques increase our ability to find new mechanisms of injury and regeneration., Methods: We used metabolomic and genomic data from a randomized controlled trial of patients administered 4 g of APAP per day for 14 days or longer with blood samples obtained at 0 (baseline), 4, 7, 10, 13 and 16 days. We used the highest ALT as the clinical outcome to be predicted in our integrated analysis. We used penalized regression to model the relationship between genetic variants and day 0 metabolite level, and then performed a metabolite-wide colocalization scan to associate the genetically regulated component of metabolite expression with ALT elevation. Genome-wide association study (GWAS) analyses were conducted for ALT elevation and metabolite level using linear regression, with age, sex, and the first five principal components included as covariates. Colocalization was tested via a weighted sum test., Results: Out of the 164 metabolites modeled, 120 met the criteria for predictive accuracy and were retained for genetic analyses. After genomic examination, eight metabolites were found to be under genetic control and predictive of ALT elevation due to therapeutic acetaminophen. The metabolites were: 3-oxalomalate, allantoate, diphosphate, L-carnitine, L-proline, maltose, and ornithine. These genes are important in the tricarboxylic acid cycle (TCA), urea breakdown pathway, glutathione production, mitochondrial energy production, and maltose metabolism., Conclusions: This multi'omic approach can be used to integrate metabolomic and genomic data allowing identification of genes that control downstream metabolites. These findings confirm prior work that have identified mitochondrial energy production as critical to APAP induced liver injury and have confirmed our prior work that demonstrate the importance of the urea cycle in therapeutic APAP liver injury., (© 2023. American College of Medical Toxicology.)

Background: Several studies have suggested genetic variants associated with acetaminophen induced liver injury (DILI) following overdose. Genetic variation associated with acetaminophen-induced alanine aminotransferase elevation during therapeutic dosing has not been examined., Methods: We performed genetic analyses on patients that ingested therapeutic doses of 4 grams of acetaminophen for up to 16 days. We examined 20 genes previously implicated in the metabolism of acetaminophen or the development of immune-mediated DILI using the Illumina Multi-Ethnic Global Array 2. Autosomes were aligned and imputed using TOPMed. A candidate gene region analysis was performed by testing each gene individually using linkage disequilibrium (LD) pruned variants with the adaptive sum of powered scores (aSPU) test from the aSPU R package. The highest measured ALT during therapy, the maximum ALT, was used as the outcome., Results: 192 subjects taking therapeutic APAP were included in the genetic analysis. 136 (70.8%) were female, 133 (69.2%) were Caucasian race, and the median age was 34 years (IQR: 26, 46). Age > 50 years was the only clinical factor associated with maximum ALT increase. Variants in SULT1E1 , the gene responsible for Sulfotransferase Family 1E Member 1 enzyme production, were associated with maximum ALT. No single variant drove this association, but rather the association was due to the additive effects of numerous variants within the gene. No other genes were associated with maximum ALT increase in this cohort., Conclusion: Acetaminophen induced ALT elevation at therapeutic doses was not associated with variation in most genes associated with acetaminophen metabolism or immune-induced DILI in this cohort. The role of SULT1E1 polymorphism in acetaminophen-induced elevated ALT needs further examination.

Background: Drug induced liver injury (DILI) remains a prominent global issue and acetaminophen (APAP) overdose represents a common cause of hepatic injury and DILI. Transient alanine aminotransferase (ALT) elevations have been documented while adhering to recommended daily dosing. However, no metabolites have been identified in pre-treatment samples predicting which patients will develop these transient increases., Methods: This was a secondary analysis of samples collected from a parent study describing the course of ALT levels in subjects receiving therapeutic APAP dosing. Two hundred and four subjects recruited from Denver, Colorado received 4 g APAP/daily for at least 16 days. Subjects were grouped by ALT at any monitored time point above 60 units/L ( n  = 25) vs. no increase ( n  = 179). Serum samples from days 0, 7, 16, and 31 were run on ultra-high performance liquid chromatography mass spectrometry. We report the metabolomic results of samples analyzed prior to APAP administration and over time. Significant changes in metabolite and demographic variable expressions were explored using t -tests with false discovery rate correction, chi square, and partial least squares discriminant analyses., Results: Within pre-treatment day 0 samples, allantoate and ornithine were significantly elevated in subjects of the ALT elevation group ( p  = .032). Baseline ALT ( p  = .011) and alkaline phosphatase ( p  = .006) were also significant. These metabolites were significant independent of race, ethnicity, gender, or BMI., Conclusions: Allantoate and ornithine are directly involved in pathways related to nitrogen release and urea production. Further investigation into alterations in the glutathione metabolism and urea cycle pathways may lead to a greater understanding of the mechanisms associated with hepatic adaptation for a variety of pharmaceuticals.

Major depressive disorder (MDD) is a prevalent psychiatric disorder, and exposure to stress is a robust risk factor for MDD. Clinical data and rodent models have indicated the negative impact of chronic exposure to stress-induced hormones like cortisol on brain volume, memory, and cell metabolism. However, the cellular and transcriptomic changes that occur in the brain after prolonged exposure to cortisol are less understood. Furthermore, the astrocyte-specific contribution to cortisol-induced neuropathology remains understudied. Here, we have developed an in vitro model of "chronic stress" using human induced pluripotent stem cell (iPSC)-derived astrocytes treated with cortisol for 7 days. Whole transcriptome sequencing reveals differentially expressed genes (DEGs) uniquely regulated in chronic cortisol compared to acute cortisol treatment. Utilizing this paradigm, we examined the stress response transcriptome of astrocytes generated from MDD patient iPSCs. The MDD-specific DEGs are related to GPCR ligand binding, synaptic signaling, and ion homeostasis. Together, these data highlight the unique role astrocytes play in the central nervous system and present interesting genes for future study into the relationship between chronic stress and MDD., (© 2021. The Author(s).)

The serotonergic system in the human brain modulates several physiological processes, and altered serotonergic neurotransmission has been implicated in the neuropathology of several psychiatric disorders. The study of serotonergic neurotransmission in psychiatry has long been restricted to animal models, but advances in cell reprogramming technology have enabled the generation of serotonergic neurons from patient-induced pluripotent stem cells (iPSCs). While iPSC-derived human serotonergic neurons offer the possibility to study serotonin (5-HT) release and uptake, particularly by 5-HT-modulating drugs such as selective serotonin reuptake inhibitors (SSRIs), a major limitation is the inability to reliably quantify 5-HT secreted from neurons in vitro. Herein, we address this technical gap via a novel sensing technology that couples 5-HT-specific DNA aptamers into nanopores (glass nanopipettes) with orifices of ~10 nm to detect 5-HT in complex neuronal culture medium with higher selectivity, sensitivity, and stability than existing methods. The 5-HT aptamers undergo conformational rearrangement upon target capture and serve as gatekeepers of ionic flux through the nanopipette opening. We generated human serotonergic neurons in vitro and detected secreted 5-HT using aptamer-coated nanopipettes in a low nanomolar range, with the possibility of detecting significantly lower (picomolar) concentrations. Furthermore, as a proof of concept, we treated human serotonergic neurons in vitro with the SSRI citalopram and detected a significant increase in extracellular 5-HT using the aptamer-modified nanopipettes. We demonstrate the utility of such methods for 5-HT detection, raising the possibility of fast quantification of neurotransmitters secreted from patient-derived live neuronal cells., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Bipolar disorder (BD) is characterized by cyclical mood shifts. Studies indicate that BD patients have a peripheral pro-inflammatory state and alterations in glial populations in the brain. We utilized an in vitro model to study inflammation-related phenotypes of astrocytes derived from induced pluripotent stem cells (iPSCs) generated from BD patients and healthy controls. BD astrocytes showed changes in transcriptome and induced a reduction in neuronal activity when co-cultured with neurons. IL-1β-stimulated BD astrocytes displayed a unique inflammatory gene expression signature and increased secretion of IL-6. Conditioned medium from stimulated BD astrocytes reduced neuronal activity, and this effect was partially blocked by IL-6 inactivating antibody. Our results suggest that BD astrocytes are functionally less supportive of neuronal excitability and this effect is partially mediated by IL-6. We confirmed higher IL-6 in blood in a distinct cohort of BD patients, highlighting the potential role of astrocyte-mediated inflammatory signaling in BD neuropathology., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Therapeutic acetaminophen (APAP) ingestion causes asymptomatic drug-induced liver injury in some patients. In most cases, elevations in alanine aminotransferase (ALT) are transient and return to the normal range, even with continued APAP ingestion, though ALT elevation persists in some patients unpredictably. The etiology of this liver injury or adaption is unclear. Our objective was to identify new pharmacogenomic variants associated with elevated ALT or elevated protein adduct concentrations in patients receiving therapeutic acetaminophen., Methods: We performed genome-wide sequencing analysis on eight patients using leftover blood samples from an observational study that administered four grams of acetaminophen for up to 16 days to all patients. Two patients with ALT elevations > two times the upper limit of normal, two patients with no adduct formation, and four control patients were sequenced. The genomes were aligned with the GRCh38 reference sequence, and variants with predicted low, moderate, or high impact on the subsequent proteins were first manually curated for biologic plausibility, then organized and examined in the REACTOME pathway analysis program., Results: We found 394 variants in 107 genes associated with elevated ALT. Variants associated with ALT elevation predominantly involved genes in the immune system (MHC class II complex genes), endoplasmic reticulum stress response (SEC23B and XBP1), oxidative phosphorylation (NDUFB9), and WNT/beta-catenin signaling (FZD5). Variants associated with elevated adducts were primarily in signal transduction (MUC20) and DNA repair mechanisms (P53)., Conclusions: While underpowered, genetic variants in immune system genes may be associated with drug-induced liver injury at therapeutic doses of acetaminophen.

The in vivo net energy content of resistant starch (RS) has not been measured in humans so it has not been possible to account for the contribution of RS to dietary energy intake. We aimed to determine the in vivo net energy content of RS and examine its effect on macronutrient oxidation. This was a randomized, double-blind cross-over study. Eighteen healthy adults spent 24 h in a whole room indirect calorimeter to measure total energy expenditure (TEE), substrate oxidation, and postprandial metabolites in response to three diets: 1) digestible starch (DS), 2) RS (33% dietary fiber; RS), or 3) RS with high fiber (RSF, 56% fiber). The in vivo net energy content of RS and RSF are 2.74 ± 0.41 and 3.16 ± 0.27 kcal/g, respectively. There was no difference in TEE or protein oxidation between DS, RS, and RSF. However, RS and RSF consumption caused a 32% increase in fat oxidation ( p = 0.04) with a concomitant 18% decrease in carbohydrate oxidation ( p = 0.03) versus DS. Insulin responses were unaltered after breakfast but lower in RS and RSF after lunch, at equivalent glucose concentrations, indicating improved insulin sensitivity. The average in vivo net energy content of RS is 2.95 kcal/g, regardless of dietary fiber content. RS and RSF consumption increase fat and decrease carbohydrate oxidation with postprandial insulin responses lowered after lunch, suggesting improved insulin sensitivity at subsequent meals.

Disrupted serotonergic neurotransmission has long been implicated in major depressive disorder (MDD), for which selective serotonin reuptake inhibitors (SSRIs) are the first line of treatment. However, a significant percentage of patients remain SSRI-resistant and it is unclear whether and how alterations in serotonergic neurons contribute to SSRI resistance in these patients. Induced pluripotent stem cells (iPSCs) facilitate the study of patient-specific neural subtypes that are typically inaccessible in living patients, enabling the discovery of disease-related phenotypes. In our study of a well-characterized cohort of over 800 MDD patients, we generated iPSCs and serotonergic neurons from three extreme SSRI-remitters (R) and SSRI-nonremitters (NR). We studied serotonin (5-HT) biochemistry and observed no significant differences in 5-HT release and reuptake or in genes related to 5-HT biochemistry. NR patient-derived serotonergic neurons exhibited altered neurite growth and morphology downstream of lowered expression of key Protocadherin alpha genes as compared to healthy controls and Rs. Furthermore, knockdown of Protocadherin alpha genes directly regulated iPSC-derived neurite length and morphology. Our results suggest that intrinsic differences in serotonergic neuron morphology and the resulting circuitry may contribute to SSRI resistance in MDD patients.

Study Objective: We compare 3 methods of hands-only cardiopulmonary resuscitation (CPR) education, using performance scores. A paucity of research exists on the comparative effectiveness of different types of hands-only CPR education. This study also includes a novel kiosk approach that has not previously been studied, to our knowledge., Methods: A randomized, controlled study compared participant scores on 4 hands-only CPR outcome measures after education with a 25- to 45-minute practice-while-watching classroom session (classroom), 4-minute on-screen feedback and practice session (kiosk), and 1-minute video viewing (video only). Participants took a 30-second compression test after initial training and again after 3 months., Results: After the initial education session, the video-only group had a lower total score (compressions correct on hand placement, rate, and depth) (-9.7; 95% confidence interval [CI] -16.5 to -3.0) than the classroom group. There were no significant differences on total score between classroom and kiosk participants. Additional outcome scores help explain which components negatively affect total score for each education method. The video-only group had lower compression depth scores (-9.9; 95% CI -14.0 to -5.7) than the classroom group. The kiosk group outperformed the classroom group on hand position score (4.9; 95% CI 1.3 to 8.6) but scored lower on compression depth score (-5.6; 95% CI -9.5 to -1.8). The change in 4 outcome variables was not significantly different across education type at 3-month follow-up., Conclusion: Participants exposed to the kiosk session and those exposed to classroom education performed hands-only CPR similarly, and both groups showed skill performance superior to that of participants watching only a video. With regular retraining to prevent skills decay, the efficient and free hands-only CPR training kiosk has the potential to increase bystander intervention and improve survival from out-of-hospital cardiac arrest., (Copyright © 2018 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed antidepressants. They regulate serotonergic neurotransmission, but it remains unclear how altered serotonergic neurotransmission may contribute to the SSRI resistance observed in approximately 30% of major depressive disorder (MDD) patients. Patient stratification based on pharmacological responsiveness and the use of patient-derived neurons may make possible the discovery of disease-relevant neural phenotypes. In our study from a large cohort of well-characterized MDD patients, we have generated induced pluripotent stem cells (iPSCs) from SSRI-remitters and SSRI-nonremitters. We studied serotonergic neurotransmission in patient forebrain neurons in vitro and observed that nonremitter patient-derived neurons displayed serotonin-induced hyperactivity downstream of upregulated excitatory serotonergic receptors, in contrast to what is seen in healthy and remitter patient-derived neurons. Our data suggest that postsynaptic forebrain hyperactivity downstream of SSRI treatment may play a role in SSRI resistance in MDD.

Chemical modifications of histones can mediate diverse DNA-templated processes, including gene transcription 1-3 . Here we provide evidence for a class of histone post-translational modification, serotonylation of glutamine, which occurs at position 5 (Q5ser) on histone H3 in organisms that produce serotonin (also known as 5-hydroxytryptamine (5-HT)). We demonstrate that tissue transglutaminase 2 can serotonylate histone H3 tri-methylated lysine 4 (H3K4me3)-marked nucleosomes, resulting in the presence of combinatorial H3K4me3Q5ser in vivo. H3K4me3Q5ser displays a ubiquitous pattern of tissue expression in mammals, with enrichment observed in brain and gut, two organ systems responsible for the bulk of 5-HT production. Genome-wide analyses of human serotonergic neurons, developing mouse brain and cultured serotonergic cells indicate that H3K4me3Q5ser nucleosomes are enriched in euchromatin, are sensitive to cellular differentiation and correlate with permissive gene expression, phenomena that are linked to the potentiation of TFIID 4-6 interactions with H3K4me3. Cells that ectopically express a H3 mutant that cannot be serotonylated display significantly altered expression of H3K4me3Q5ser-target loci, which leads to deficits in differentiation. Taken together, these data identify a direct role for 5-HT, independent from its contributions to neurotransmission and cellular signalling, in the mediation of permissive gene expression.

Objective: Medication organizers may help improve medication compliance; however, they may increase the risk of having an unintentional pediatric exposure. The objective of this study was to measure the association between a pediatric emergency department (ED) visit for an unintentional pharmaceutical ingestion and the use of a medication organizer in the household., Methods: This was a cross-sectional case control study at a tertiary care children's hospital ED. Cases included subjects <6 years of age who were evaluated in the ED for an unintentional pharmaceutical ingestion. The control group presented to the ED for a non-injury complaint and was matched using age and sex., Results: The unadjusted odds ratio (OR) of risk for unintentional pharmaceutical ingestion with use of a medication organizer was 2.0 (95% CI, 1.3, 2.9). After adjusting for the presence of prescription medications in the home, the OR of risk for ingestion remained statistically significant at 1.8 (95% CI, 1.1, 2.7). The child obtained the exposure medication from the medication organizer in 63% of cases where a medication organizer was present in the home. Cases were more likely to have knowledge of, and previous contact with poison control centers (PCC) than non-injury controls. Overall, a large number of caregivers (36%) did not have any knowledge of PCC. There were also differences in smoking and use of seat belts between cases and controls., Conclusions: The use of medication organizers may be a risk factor for unintentional pediatric pharmaceutical ingestions, even when controlling for the use of prescription medications in the home. Further research is needed to evaluate the specific role of medication organizers, and subsequently, improve prevention strategies.

Purpose: Opioid prescription fill rates and the time to fill after emergency department (ED) discharge were studied., Methods: Data were evaluated for all patients discharged from the ED between September 1, 2011, who were February 1, 2012, who were diagnosed with one of the following: dental pain, jaw pain, flank pain, abdominal pain, pelvic pain, back pain, neck pain, knee pain, headache, fracture, or sprain. Clinical information was abstracted via computer algorithm, and prescription filling within 100 days of prescription writing was determined by cross-referencing patient demographics with the state prescription drug monitoring program. Logistic regression analysis and a Cox proportional hazards model were used to determine if any clinical and demographic characteristics were associated with fill rates or the time to fill, respectively., Results: Of the 2243 patients who received an opioid prescription at ED discharge, 1775 (79%) filled it, with a median time to fill of 0 days. On adjusted analysis, characteristics associated with filling the opioid prescriptions included Caucasian race, being insured by the federal government or through a state indigent assistance program, a chief complaint of back pain, and a history of filling an opioid prescription within the past year. No characteristics were predictive of a prolonged time to filling., Conclusion: One in five patients who received an opioid prescription at discharge from an urban academic ED did not fill it. Several factors may be associated with a greater likelihood of filling, such as insurance status and history of filling an opioid prescription within the past year., (Copyright © 2016 by the American Society of Health-System Pharmacists, Inc. All rights reserved.)

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.

Study Objective: We examine the characteristics of clinical decision support alerts triggered when opioids are prescribed, including alert type, override rates, adverse drug events associated with opioids, and preventable adverse drug events., Methods: This was a retrospective chart review study assessing adverse drug event occurrences for emergency department (ED) visits in a large urban academic medical center using a commercial electronic health record system with clinical decision support. Participants include those aged 18 to 89 years who arrived to the ED every fifth day between September 2012 and January 2013. The main outcome was characteristics of opioid drug alerts, including alert type, override rates, opioid-related adverse drug events, and adverse drug event preventability by clinical decision support., Results: Opioid drug alerts were more likely to be overridden than nonopioid alerts (relative risk 1.35; 95% confidence interval [CI] 1.21 to 1.50). Opioid drug-allergy alerts were twice as likely to be overridden (relative risk 2.24; 95% CI 1.74 to 2.89). Opioid duplicate therapy alerts were 1.57 times as likely to be overridden (95% CI 1.30 to 1.89). Fourteen of 4,581 patients experienced an adverse drug event (0.31%; 95% CI 0.15% to 0.47%), and 8 were due to opioids (57.1%). None of the adverse drug events were preventable by clinical decision support. However, 46 alerts were accepted for 38 patients that averted a potential adverse drug event. Overall, 98.9% of opioid alerts did not result in an actual or averted adverse drug event, and 96.3% of opioid alerts were overridden., Conclusion: Overridden opioid alerts did not result in adverse drug events. Clinical decision support successfully prevented adverse drug events at the expense of generating a large volume of inconsequential alerts. To prevent 1 adverse drug event, providers dealt with more than 123 unnecessary alerts. It is essential to refine clinical decision support alerting systems to eliminate inconsequential alerts to prevent alert fatigue and maintain patient safety., (Copyright © 2015 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Medication history discrepancies have the potential to cause significant adverse clinical effects for patients. More than 40% of medication errors can be traced to inadequate reconciliation., Objective: The objective of this study was to determine the accuracy of electronic medical record (EMR)-reconciled medication lists obtained in an academic emergency department (ED)., Methods: Comprehensive research medication ingestion histories for the 48 h preceding ED visit were performed and compared to reconciled EMR medication lists in a convenience sample of ED patients. The reconciled EMR list of prescription, nonprescription, vitamins, herbals, and supplement medications were compared against a structured research medication history tool. We measured the accuracy of the reconciled EMR list vs. the research history for all classes of medications as the primary outcome., Results: Five hundred and two subjects were enrolled. The overall accuracy of EMR-recorded ingestion histories in the preceding 48 h was poor. The EMR was accurate in only 21.9% of cases. Neither age ≥ 65 years (odds ratio [OR] = 1.3; 95% confidence interval [CI] 0.6-2.6) nor sex (female vs. male: OR = 1.5; 95% CI 0.9-2.5) were predictors of accurate EMR history. In the inaccurate EMRs, prescription lists were more likely to include medications that the subject did not report using (78.9%), while the EMR was more likely not to capture nonprescriptions (76.1%), vitamins (73.0%), supplements (67.3%), and herbals (89.1%) that the subject reported using., Conclusions: Medication ingestion histories procured through triage EMR reconciliation are often inaccurate, and additional strategies are needed to obtain an accurate list., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: Acetaminophen-cysteine adducts (APAP-CYS) are a serum biomarker of acetaminophen exposure, formed when the oxidative metabolite of acetaminophen binds to cysteine residues of hepatic proteins. APAP-CYS adducts become elevated in cases of acute liver failure following acetaminophen overdose and have been proposed as a diagnostic tool to identify acetaminophen-induced acute liver failure when standard testing is inconclusive., Case Report: A 26-year-old female with history of unexplained, severe hepatitis presented with a second episode of severe hepatitis including coagulopathy and transaminase levels >10,000 U/L. The patient reported ingesting "only a couple" of acetaminophen tablets several days prior to her presentation. An acetaminophen concentration of 14 mcg/mL at presentation aroused suspicion that acetaminophen might have caused the patient's liver failure, despite her adamant denial of overdose. APAP-CYS adduct levels measured from serum obtained 4 days after her presentation and in two consecutive serum samples are reported alongside previously reported APAP-CYS levels., Discussion: The patient's APAP-CYS adduct levels were consistent with those seen in acute liver injury due to acetaminophen toxicity, even up to 1 week following presentation, and allowed for confirmation of acetaminophen toxicity as the cause of the her hepatitis. Overall, this case demonstrates the real-time application of APAP-CYS adducts as a biomarker to diagnose acetaminophen toxicity in patients with indeterminate acute liver failure.

Objectives: Case reports have described a syndrome of cyclic vomiting associated with chronic marijuana use, termed cannabinoid hyperemesis syndrome. The primary objective was to determine the prevalence of patients presenting with cyclic vomiting before and after the liberalization of medical marijuana in Colorado in 2009. The secondary objective was to describe the odds of marijuana use among cyclic vomiting visits in these same time periods., Methods: This was a cross-sectional study of cyclic vomiting visits to the emergency department (ED) before and after marijuana liberalization. ED visits with International Classification of Diseases, ninth revision, coding for cyclic vomiting or that met diagnostic criteria for cyclic vomiting by the Rome III criteria were included., Results: The authors reviewed 2,574 visits and identified 36 patients diagnosed with cyclic vomiting over 128 visits. The prevalence of cyclic vomiting visits increased from 41 per 113,262 ED visits to 87 per 125,095 ED visits after marijuana liberalization, corresponding to a prevalence ratio of 1.92 (95% confidence interval [CI] = 1.33 to 2.79). Patients with cyclic vomiting in the postliberalization period were more likely to have marijuana use documented than patients in the preliberalization period (odds ratio = 3.59, 95% CI = 1.44 to 9.00)., Conclusions: The prevalence of cyclic vomiting presentations nearly doubled after the liberalization of medical marijuana. Patients presenting with cyclic vomiting in the postliberalization period were more likely to endorse marijuana use, although it is unclear whether this was secondary to increased marijuana use, more accurate marijuana reporting, or both., (© 2015 by the Society for Academic Emergency Medicine.)

Currently, only 10% of board-certified medical toxicologists are pediatricians. Yet over half of poison center calls involve children < 6 years, poisoning continues to be a common pediatric diagnosis and bedside toxicology consultation is not common at children's hospitals. In collaboration with executive staff from Department of Pediatrics and Emergency Medicine, regional poison center, and our toxicology fellowship, we established a toxicology consulting service at our tertiary-care children's hospital. There were 139 consultations, and the service generated 13 consultations in the first month; median of 11 consultations per month thereafter (range 8-16). The service increased pediatric cases seen by the fellowship program from 30 to 94. The transition to a consult service required a culture change. Historically, call center advice was the mainstay of consulting practice and the medical staff was not accustomed to the availability of bedside medical toxicology consultations. However, after promotion of the service and full attending and fellowship coverage, consultations increased. In collaboration with toxicologists from different departments, a consultation service can be rapidly established. The service filled a clinical need that was disproportionately utilized for high acuity patients, immediately utilized by the medical staff and provided a robust pediatric population for the toxicology fellowship.

Objectives: The hepatic cytochrome 2D6 (CYP2D6) is a saturable enzyme responsible for metabolism of approximately 25% of known pharmaceuticals. CYP interactions can alter the efficacy of prescribed medications. Hydrocodone is largely dependent on CYP2D6 metabolism for analgesia, ondansetron is inactivated by CYP2D6, and oxycodone analgesia is largely independent of CYP2D6. The objective was to determine if CYP2D6 medication coingestion decreases the effectiveness of hydrocodone., Methods: This was a prospective observational study conducted in an academic U.S. emergency department (ED). Subjects were included if they had self-reported pain or nausea and were excluded if they were unable to speak English, were less than 18 years of age, had liver or renal failure, or carried diagnoses of chronic pain or cyclic vomiting. Detailed drug ingestion histories for the preceding 48 hours prior to the ED visit were obtained. The patient's pain and nausea were quantified using a 100-mm visual analog scale (VAS) at baseline prior to drug administration and following doses of hydrocodone, oxycodone, or ondansetron. We used a mixed model with random subject effect to determine the interaction between CYP2D6 drug ingestion and study drug effectiveness. Odds ratios (ORs) were calculated to compare clinically significant VAS changes between CYP2D6 users and nonusers., Results: A total of 250 (49.8%) of the 502 subjects enrolled had taken at least one CYP2D6 substrate, inhibitor, or inducing pharmaceutical, supplement, or illicit drug in the 48 hours prior to ED presentation. CYP2D6 drug users were one-third as likely to respond to hydrocodone (OR = 0.33, 95% confidence interval [CI] = 0.1 to 0.8) and more than three times as likely as nonusers to respond to ondansetron (OR = 3.4, 95% CI = 1.3 to 9.1). There was no significant difference in oxycodone effectiveness between CYP2D6 users and nonusers (OR = 0.53, 95% CI = 0.3 to 1.1)., Conclusions: CYP2D6 drug-drug interactions appear to change effectiveness of commonly prescribed drugs in the ED. Drug-drug interaction should be considered prior to prescribing CYP2D6 drugs., (© 2014 by the Society for Academic Emergency Medicine.)

While the use of performance enhancing substances by professional, collegiate, and Olympic athletes is well described, the rate of use in the general population is not well studied. We explored the use of energy drinks, dietary supplements, and prescription medications for the enhancement of athletic performance among college students using an ongoing survey system. We conducted a multi-round online questionnaire collecting data from self-identified students at two-year colleges, four-year colleges, online courses, or technical schools at least part-time during the specified sampling period. The sample is obtained through the use of a survey panel company in which respondents voluntarily register. Survey data were collected from December, 2010 through August, 2011. Subjects who reported participating in athletics were asked if they used any of the following substances to enhance athletic performance (1) energy drinks (2) dietary supplements (3) prescription medications within the last year. Data were analyzed from October, 2011 through January, 2012. There were 462 college students who responded to the survey reporting they participate in sports at various levels. Of these, 397 (85.9 %) responded that within the last year they used energy drinks, dietary supplements, or prescription medications to enhance athletic performance. Energy drinks had the highest prevalence (80.1 %), followed by dietary supplements (64.1 %) and prescription medications (53.3 %). Use was most prevalent amongst intercollegiate athletes (89.4 %) followed by club (88.5 %) and intermural (82.1 %) participants. The vast majority of survey respondents reported using energy drinks, dietary supplements, and prescription medications within the last year for athletic performance enhancement.

Introduction: There are few reports summarizing the effectiveness of oral and intravenous (IV) acetylcysteine. We determined the proportion of acetaminophen poisoned patients who develop hepatotoxicity (serum transaminase > 1000 IU/L) when treated with oral and IV acetylcysteine., Methods: Studies were double abstracted by trained researchers. We determined the proportions of patients who developed hepatotoxicity for each route using a random effects model. Studies were further stratified by early and late treatment., Results: We screened 4,416 abstracts; 16 articles, including 5,164 patients, were included in the meta-analysis. The overall rate of hepatotoxicity for the oral and IV routes were 12.6% and 13.2%, respectively. Treatment delays are associated with a higher rate of hepatotoxicity., Conclusion: Studies report similar rates of hepatotoxicity for oral and IV acetylcysteine, but direct comparisons are lacking. While it is difficult to disentangle the effects of dose and duration from route, our findings suggest that the rates of hepatotoxicity are similar for oral and IV administration.

Objective: To report a case of accidental amphotericin B overdose that was treated with plasmapheresis., Case Summary: A 60-year-old woman with a history of kidney transplant 4 years prior to presentation for a congenital abnormality was admitted for a suspected systemic fungal infection. The patient inadvertently received intravenous amphotericin B deoxycholate 250 mg (4.3 mg/kg) over 2 hours instead of prescribed liposomal amphotericin B. The medication error was discovered 16 hours after administration. She had normal vital signs at that time and reported abdominal pain and general malaise. Results of a metabolic panel were significant for a creatinine level of 2.1 mg/dL and CO₂ of 17 mg/dL. Her serum amphotericin B concentration 33 hours after the initial dose was 4.9 μg/mL. She subsequently received 5 courses of plasmapheresis and 3 courses of hemodialysis and ultimately did not develop any further renal injury, as well as hemolysis, cardiovascular collapse, dysrhythmias, or severe electrolyte abnormalities., Discussion: The dosing differences between nonliposomal and liposomal preparations of amphotericin B can be as high as 50-fold. Reported adverse events from overdose in both animal models and human case reports include renal insufficiency, hemolysis, thrombocytopenia, electrolyte abnormality, and cardiac dysrhythmias. There have been previous reports of similar errors that have led to death. Furthermore, amphotericin B has been shown to be poorly dialyzable. Our patient's serum amphotericin B concentration decreased after she received plasmapheresis, and she did not develop severe complications., Conclusions: We describe a patient who survived a 4-fold overdose of amphotericin B because of a medication error. The use of plasmapheresis may have enhanced the elimination of amphotericin B and may have contributed to the positive outcome. However, the role of plasmapheresis in amphotericin overdose is not fully understood.

Study Objective: Δ-9-Tetrahydrocannabinol homologs have been increasingly abused since their introduction in 2004. Such products were used as a "legal high" for those wishing to experience cannabinoid effects while evading basic drugs-of-abuse testing. We describe a series of exposures to products marketed as synthetic cannabinoids to better characterize the clinical effects in these patients., Methods: All Δ-9-tetrahydrocannabinol homolog exposures reported to the National Poison Data System between January 1, 2010, and October 1, 2010, were extracted with National Poison Data System generic codes and product codes for Δ-9-tetrahydrocannabinol homologs. Only cases involving a single-agent exposure to Δ-9-tetrahydrocannabinol homologs as the major category were analyzed. Descriptive statistics were generated for demographic data, management site, products involved, symptoms, duration of effects, treatments, and severity of clinical effects., Results: During the 9-month study period, there were 1,898 exposures to Δ-9-tetrahydrocannabinol homologs; 1,353 of these cases were single-agent exposures. The mean age was 22.5 years (SD 8.86 years). Most cases were reported in men (n=1,005; 74.3%). The majority of exposures were acute (88.2%; n=1,193). The most common clinical effect was tachycardia (37.7%; n=510). Seizures were reported in 52 patients (3.8%). The majority of clinical effects lasted for fewer than 8 hours (n=711; 78.4%) and resulted in 1,011 non-life-threatening clinical effects (92.9%). The most common therapeutic intervention was intravenous fluids (n=343; 25.3%). There was 1 death (0.1%)., Conclusion: The majority of cases were in young men intentionally abusing spice. Most exposures resulted in non-life-threatening effects not requiring treatment, although a minority of exposures resulted in more severe effects, including seizures., (Copyright © 2012. Published by Mosby, Inc.)

Study Objective: We evaluate the ability of 4 sampling methods to generate representative samples of the emergency department (ED) population., Methods: We analyzed the electronic records of 21,662 consecutive patient visits at an urban, academic ED. From this population, we simulated different models of study recruitment in the ED by using 2 sample sizes (n=200 and n=400) and 4 sampling methods: true random, random 4-hour time blocks by exact sample size, random 4-hour time blocks by a predetermined number of blocks, and convenience or "business hours." For each method and sample size, we obtained 1,000 samples from the population. Using χ(2) tests, we measured the number of statistically significant differences between the sample and the population for 8 variables (age, sex, race/ethnicity, language, triage acuity, arrival mode, disposition, and payer source). Then, for each variable, method, and sample size, we compared the proportion of the 1,000 samples that differed from the overall ED population to the expected proportion (5%)., Results: Only the true random samples represented the population with respect to sex, race/ethnicity, triage acuity, mode of arrival, language, and payer source in at least 95% of the samples. Patient samples obtained using random 4-hour time blocks and business hours sampling systematically differed from the overall ED patient population for several important demographic and clinical variables. However, the magnitude of these differences was not large., Conclusion: Common sampling strategies selected for ED-based studies may affect parameter estimates for several representative population variables. However, the potential for bias for these variables appears small., (Copyright © 2012. Published by Mosby, Inc.)

Black widow spider envenomation is commonly reported to poison centers. Black widow spider envenomation produces a clinical syndrome, known as latrodectism, characterized by headache, nausea, vomiting, several muscle cramping and pain, joint stiffness, hypertension, and regional diaphoresis. Black widow spider antivenom (Merck & Co, Inc, West Point, PA USA) is an effective and relatively safe treatment option. There is 1 clear case of anaphylaxis secondary to black widow spider antivenom reported in the medical literature. Here, we report a case of anaphylaxis to antivenom. A 12-year-old boy presented to the emergency department (ED) with diffuse, severe pain 2 1/2 hours after being bitten by a black widow spider on the right lower extremity. In the ED, the patient failed analgesic therapy with fentanyl and was given black widow spider antivenom. Within 45 minutes, he exhibited signs and symptoms consistent with anaphylaxis, including wheezing, chest tightness, pruritus, and urticarial rash. The patient was given standard therapy for anaphylaxis, and all of his signs and symptoms (including the pain secondary to the black widow envenomation) resolved over 6 hours of observation. Leading experts agree that the use of antivenom is indicated in cases of severe envenomation not responsive to standard therapy. Despite concern that the antivenom is an equine-derived whole IgG and can precipitate early hypersensitivity reactions, there is only 1 other reported case of anaphylaxis to the antivenom in the medical literature.

As molecular techniques have improved, investigators have attempted to improve pharmaceutical efficacy and safety by making trait associations with genomic, epigenomic, transcriptomic, proteomic, and metabolomic polymorphisms. The 'omics era has seen screening assays for pharmaceutical efficacy and safety translated into clinical practice. This manuscript will discuss each 'omic field and the screening assays available to the clinician. While success has been demonstrated in each 'omic field, many challenges remain. Assays need wider availability, predictive values remain low, and costs remain high. In order for clinicians to realize improved efficacy and safety due 'omic screens, development of improved techniques, combining of 'omic assays, and increased clinical utilization is necessary. This is an exciting time for investigators and clinicians that desire improved pharmaceutical therapy.

Many clinicians hoped that the completion of the Human Genome Project would result in "individualized drug therapy," i.e., determining the right medication at the right dose 100% of the time based upon the individual's genetics. The pharmacogenomic prediction of drug efficacy and safety has not become a reality due to continuing realization of the complexity dictating the human-drug interaction. New methods of metabolomics, proteomics, and transcriptomics that account for this complexity hold promise for translational researchers hoping to increase drug efficacy and decrease drug toxicity.

Background: Black widow spider (Latrodectus spp.) envenomation remains the most clinically significant spider envenomation in the US. The syndrome is characterized by painful muscle rigidity and autonomic disturbances. Treatment has ranged from symptomatic care to administration of specific antivenom. Declining antivenom availability and, possibly, the fear of hypersensitivity allergic reactions, has limited antivenom use in the US., Objective: To describe Latrodectus spp. exposures and the subsequent treatment reported to US poison centers; the secondary objective was to identify factors associated with shorter duration of symptoms (<24 hours)., Methods: All Latrodectus spp. exposures reported to the National Poison Data System (NPDS) between January 1, 2000, and December 31, 2008, were reviewed. Cases with at least minor clinical effects due to Latrodectus spp. exposure were extracted. Descriptive statistics were generated. The probability that symptom duration was less than 24 hours was modeled, using logistic regression., Results: From 2000 through 2008, a total of 23,409 Latrodectus spp. exposures were reported in 47 states; 9872 cases had at least minor clinical effects and were included in the subsequent analysis. Exposures peaked in September and fell to a nadir in January and February. Fifty-eight percent of the cases involved males, and the mean (SD) age was 31.5 (17.4) years. Sixty-five percent of the patients had minor clinical effects, 33.5% had moderate effects, 1.4% had major effects, and there were no deaths. Antivenom use was associated with symptom duration of less than 24 hours in moderate and major outcome groups. There was no evidence of shorter symptom duration in patients who received benzodiazepines or calcium. Adverse drug reactions were more common in patients receiving benzodiazepines and antivenom., Conclusions: In the US, most symptomatic Latrodectus spp. exposures reported to the NPDS are minor. Few patients receive antivenom, although antivenom is associated with shorter symptom duration among moderate and major outcomes.

Unlabelled: Patients frequent take acetaminophen to treat dental pain. One previous study found a high rate of overuse of nonprescription analgesics in an emergency dental clinic., Objectives: The purpose of this study is to determine if patients with dental pain are more likely to be treated for accidental acetaminophen poisoning than patients with other types of pain., Methods: We conducted a case-control study at 2 urban hospitals. Cases were identified by chart review of patients who required treatment for accidental acetaminophen poisoning. Controls were self-reported acetaminophen users taking therapeutic doses identified during a survey of emergency department patients. For our primary analysis, the reason for taking acetaminophen was categorized as dental pain or not dental pain. Our primary outcome was the odds ratio of accidental overdose to therapeutic users after adjustment for age, sex, alcoholism, and use of combination products using logistic regression., Results: We identified 73 cases of accidental acetaminophen poisoning and 201 therapeutic users. Fourteen accidental overdose patients and 4 therapeutic users reported using acetaminophen for dental pain. The adjusted odds ratio for accidental overdose due to dental pain compared with other reasons for use was 12.8 (95% confidence interval, 4.2-47.6)., Conclusions: We found that patients with dental pain are at increased risk to accidentally overdose on acetaminophen compared with patients taking acetaminophen for other reasons. Emergency physicians should carefully question patients with dental pain about overuse of analgesics., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Acetaminophen-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., Methods: Samples 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., Results: Trial 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., Conclusions: Lower 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.

Background: Repeated supratherapeutic ingestion (RSTI) of acetaminophen (APAP) is recognized as an important cause of APAP-related morbidity and mortality. This study describes the characteristics and clinical course of patients with RSTI, and identifies the risk factors for developing hepatotoxicity and death., Methods: This secondary analysis of a multicenter retrospective chart review studied patients treated with IV and/or oral N-acetylcysteine for acetaminophen poisoning. For this analysis, we included all subjects coded as RSTIs, defined as ingestions of greater than 4 g of APAP per 24 h over a period longer than 8 h. Data collected include demographics, coingestants, comorbidities, presenting laboratory data, and outcomes. The analysis includes descriptive statistics and associations of demographic and clinical factors with patient outcome., Results: Of the 503 patients enrolled, 119 (23.7%) were RSTI. The mean age was 39.6 years (SD ± 15); 63.9% of the patients were females, 60.5% Caucasians, 27.7% alcoholics, 5% malnourished, 10.9% had viral hepatitis, and 3.4% had other liver diseases. Coingestants included ethanol, opioids, and antihistamines (17.6, 48.7, and 19.3%, respectively). Among this group, 44 patients developed hepatotoxicity, two received liver transplants, and four died (37.0, 1.7, and 3.4%, respectively). The risk for hepatotoxicity increased with a history of alcoholism, viral hepatitis, and other liver diseases. A history of alcoholism and an elevated presenting serum creatinine were associated with increased risk for death/transplant. The lowest presenting ALT levels in a subject who developed hepatotoxicity and who died were 252 and 426 IU/l, respectively., Conclusion: RSTI-induced hepatotoxicity and poor outcomes can be predicted at the patient's presentation. All patients with RSTI who developed hepatotoxicity presented with an abnormal ALT. A history of alcoholism and an elevated creatinine at presentation are markers of increased risk for hepatotoxicity and death.

There are few controlled clinical trials in medical toxicology to guide treatment decisions. Given the relative paucity of definitive data, we determined the types of evidence used to support treatment recommendations given in three major toxicology textbooks. One author reviewed the acetaminophen, tricyclic antidepressant, calcium channel blocker plus any relevant antidote chapters in three textbooks: Goldfranks Toxicologic Emergencies, Critical Care Toxicology, and Medical Toxicology. We identified statements that gave a treatment recommendation and classified the citation using the following system: No citation, general review article, in vitro study, animal study, case reports (n<3), case series (n>2), retrospective study, prospective observational study, and controlled clinical trial. Proportions for each type of citation with 95% confidence intervals were determined. We identified 469 treatment recommendations. We could not classify 57/742 citations. A large number of statements were not referenced (14%, 95% CI 12-17%). The most common citation types were case reports (28%, 95% CI 25-31%) and animal studies (18%, 16-21%). The proportions for the remaining types of citations were: review article (9%, 7-11%), clinical trials (9%, 7-11%), retrospective studies (8%, 6-10%), prospective observational studies (5%, 3-6%), and case series (4%, 3-6%). There is a need for more systematic studies of poisoned patients. As case reports are commonly used to support treatment recommendations, they should be held to rigorous scientific standards and include information to assess the validity of the conclusions. Case reports and animal studies are commonly used as evidence to support treatment recommendations in medical toxicology textbooks.

Study Objective: To describe the changes in serum alanine aminotransferase (ALT) levels in nondrinkers receiving acetaminophen for 10 days., Design: Prospective, open-label study., Setting: Outpatient clinical research center., Patients: Twenty-four healthy volunteers who reported an average alcohol consumption of less than one drink/day for the 30 days preceding study enrollment., Intervention: Patients were administered acetaminophen 4 g/day for 10 days (study days 1-10)., Measurements and Main Results: Serum ALT level, total bilirubin level, and international normalized ratio (INR) were measured on study days 0, 4, 7, 9, 11, and 14. Median ALT level increased from 24 U/L on day 0 to 39 U/L on day 7, and remained elevated through day 11 (39 U/L); these increases were statistically significant (p=0.0002). Median ALT level began to trend down by day 14 (35 U/L). Fourteen subjects (58%) had ALT levels above the upper limit of normal; the largest elevation was 3.8 times the upper limit of normal (day 7). No increases in INR or total bilirubin level were noted during the study, and no subject developed symptoms of liver injury (e.g., abdominal pain, jaundice)., Conclusion: Daily use of acetaminophen at the maximum dose of 4 g/day for 10 days caused asymptomatic ALT level elevations in subjects who do not consume alcohol. The clinical implication of these elevations remains unclear. Future studies should evaluate ALT changes and their clinical effects when acetaminophen is given for long periods of time.

Background: Serum transaminase activity is a common measure of liver injury used in clinical trials. The use of a point of care device to monitor serum transaminases would allow immediate evaluation of this safety endpoint and may be less expensive than standard laboratory testing., Purpose: The objective of this study was to compare a point of care transaminase test to a standard laboratory measurement., Methods: Subjects were healthy adults participating in a clinical trial measuring the effects of therapeutic doses of acetaminophen on serum transaminase activity. For this study, serum transaminase activity was determined every 3days for 14days. At each measurement, a sample was sent to the clinical laboratory for measurement and also analyzed using a point of care device (Cholestech LDX, Hayward CA). The results were compared using a Bland-Altman plot to identify bias and we also measured the agreement between the techniques for categorizing samples as "low", "normal" or "elevated"., Results: One hundred thirty three samples from 35 subjects were compared. The 95% confidence interval for the limits of agreement between the LDX and the clinical laboratory was -8.46 to 27.09IU/L. Agreement for classification as low, normal or elevated was moderate between the two methods (Kappa=0.37)., Conclusion: The point of care device provided moderate agreement with the laboratory transaminase measurement. However, use of the device would have resulted in misclassification of approximately 1/3 of samples. We do not recommend this point of care device for the measurement of serum transaminases in clinical trials.

Objectives: Blinded outcome assessment decreases bias in human clinical trials. The necessity of blinded outcome assessment on animal studies is unknown. The authors determined the effect of knowledge of treatment group on assessment of time to seizure in an animal model of cocaine poisoning., Methods: Four subjects observed 20 animal experiments where all animals were administered a high dose of cocaine and placebo. For each experiment, two of the observers were told the animal had been treated with placebo and two were told the animal had been treated with a medication expected to delay the onset of seizures. Each observer recorded the time from cocaine administration to onset of seizure. The median time to seizure was compared between observers told the animal received placebo and those told the animal received active treatment., Results: Seizures were reported by all subjects in 12 animals and by no subjects in five animals, and there was disagreement in three animals. The reported median time to seizure was similar for observers told that the animals were treated with placebo and those told they were treated with study medication., Conclusions: It is feasible to determine whether unblinded assessments are biased in an animal study. Knowledge of treatment group did not bias the assessment of time to seizure in this animal model., (2010 by the Society for Academic Emergency Medicine)

Context: Hypothermia improves neurological outcome for comatose survivors of out-of-hospital cardiac arrest. Use of computer controlled high surface area devices for cooling may lead to faster cooling rates and potentially improve patient outcome., Objective: To compare the effectiveness of surface cooling with the standard blankets and ice packs to the Arctic Sun, a mechanical device used for temperature management., Design, Setting, and Patients: Multi-center randomized trial of hemodynamically stable comatose survivors of out-of-hospital cardiac arrest., Intervention: Standard post-resuscitative care inducing hypothermia using cooling blankets and ice (n=30) or the Arctic Sun (n=34)., Main Outcome Measures: The primary end point was the proportion of subjects who reached a target temperature within 4h of beginning cooling. The secondary end points were time interval to achieve target temperature (34 degrees C) and survival to 3 months., Results: The proportion of subjects cooled below the 34 degrees C target at 4h was 71% for the Arctic Sun group and 50% for the standard cooling group (p=0.12). The median time to target was 54 min faster for cooled patients in the Arctic Sun group than the standard cooling group (p<0.01). Survival rates with good neurological outcome were similar; 46% of Arctic Sun patients and 38% of standard patients had a cerebral performance category of 1 or 2 at 30 days (p=0.6)., Conclusions: While the proportion of subjects reaching target temperature within 4h was not significantly different, the Arctic Sun cooled patients to a temperature of 34 degrees C more rapidly than standard cooling blankets., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Background: Acute cocaine poisoning causes neuroexcitation and can be fatal. The toxic effects of cocaine can be attenuated by antagonists of serotonin, muscarinic cholinergic, and dopamine receptors. Olanzapine, an atypical antipsychotic medication, is an antagonist of these receptors. The objective of this study is to evaluate the efficacy of olanzapine pretreatment for attenuation of acute cocaine toxicity using a mouse model., Methods: Eighty male CF-1 mice were randomly assigned to olanzapine (1 mg/kg) or placebo pretreatment. Fifteen minutes later, all animals received 103 mg/kg intraperitoneal cocaine., Results: Overall mortality was 11% for olanzapine-treated animals and 45% for placebo. Olanzapine also appeared to alter the characteristics of seizures due to cocaine., Conclusions: In this model of acute cocaine toxicity, olanzapine pretreatment attenuated acute cocaine toxicity. Olanzapine should be evaluated further as a potential treatment for acute cocaine poisoning.

Background: Many patients present to dental clinics for treatment of painful conditions. Prior to seeking treatment, many of these patients will self-medicate with non-prescription analgesics (NPA), and some will unintentionally overdose on these products. The objective of this study is to describe the use of NPA among dental patients., Methods: All adult patients presenting to an urban dental clinic during a two-week period in January and February of 2001 were approached to participate in this research project. Trained research assistants using a standardized questionnaire interviewed patients. Patient demographics and the NPA usage over the 3 days preceding the office visit were recorded. We defined a supra-therapeutic dose as any dose greater than the total recommended daily dose stated on package labeling., Results: We approached 194 patients and 127 participated. The mean age of participants was 35.5 years, 52% were male. Analgesic use preceding the visit was reported by 99 of 127 patients, and most (81/99) used a NPA exclusively. Fifty-four percent of NPA users were taking more than one NPA. NPA users reported using ibuprofen (37%), acetaminophen (27%), acetaminophen/aspirin combination product (8%), naproxen (8%), and aspirin (4%). Sixteen patients reported supra-therapeutic use of one or more NPA (some ingested multiple products): ibuprofen (14), acetaminophen (3), and naproxen (5)., Conclusion: NPA use was common in patients presenting to a dental clinic. A significant minority of patients reported excessive dosing of NPA. Ibuprofen was the most frequently misused product, followed by naproxen and acetaminophen. Though mostly aware of the potential toxicity of NPA, many patients used supra-therapeutic dosages.