Remdesivir Discontinuation Decisions Based on Thresholds of Aminotransferase in an Observational Registry.

BACKGROUND: Remdesivir is an antiviral approved by the US Food and Drug Administration (FDA) for treatment of coronavirus disease 2019 (COVID-19), and aminotransferase elevation is commonly reported. Thresholds to be considered for discontinuation due to alanine aminotransferase (ALT) elevation differ between the FDA and European Medicines Agency (EMA). The primary objective was to describe aminotransferase thresholds being used in real-world practice for discontinuation of remdesivir in patients with COVID-19, and compare them with labeled recommendations. METHODS: This study used a descriptive design based on an ongoing national registry of adverse events, the FDA ACMT COVID-19 ToxIC (FACT) pharmacovigilance project, with 17 participating health systems in the USA. Cases were identified retrospectively for an 18-month period (23 November 2020-18 May 2022). Classification of discontinuation as premature and due to aminotransferases was based on chart documentation by the treating team. RESULTS: Of 1026 cases in the FACT registry, 116 cases were included with supplemental data forms completed for aminotransferase elevation with remdesivir, defined a priori for inclusion as ALT doubling or increasing by ≥ 50 U/L. ALT was elevated prior to remdesivir in 47% and increased above baseline during dosing by a median of 92 U/L [interquartile range (IQR) 51-164, max 8350]. Remdesivir was discontinued early in 37 (31.9%) patients due to elevated aminotransferases. The ALT threshold for premature discontinuation was median 200 U/L (IQR 145-396, range 92-5743). Among patients with premature discontinuation of remdesivir for aminotransferase elevation, only 21.6% met FDA criteria to consider discontinuation, and 40.5% met prior EMA criteria to consider discontinuation. CONCLUSION: In this descriptive study of real-world practice in the USA, clinicians are overall making more conservative treatment decisions than are recommended for consideration in approved drug labeling of discontinuation, with wide variation in the aminotransferase thresholds being used.

Adverse Events in Pregnant Patients Treated with Coronavirus Disease 2019 Therapeutics.

BACKGROUND: Pregnant patients are at high risk of maternal and fetal complications from Coronavirus Disease 2019 (COVID-19) infections. The COVID-19 pandemic prompted a surge in the development and repurposing of therapies for the SARS-CoV-2 virus. Evidence is sparse on the efficacy and safety of these therapies in pregnant patients. Our objective was to describe adverse events (AEs) to COVID-19 therapeutics in pregnant patients. METHODS: This was a case series of AEs reported to the FDA ACMT COVID-19 ToxIC (FACT) Pharmacovigilance Project between November 23, 2020, and June 28, 2022. FACT is an ongoing toxicosurveillance project at 17 sites to proactively identify and report AEs associated with COVID-19 therapeutics. Abstracted information includes demographics, case narratives, exposure details, clinical information, pregnancy details, treatments, and outcomes. RESULTS: Forty-six COVID-19-positive pregnant patients who developed AEs following COVID-19 therapeutics were reported to the FACT Pharmacovigilance Project over 19 months. The most reported medications were remdesivir in 22 patients (47.8%) and casirivimab/imdevimab in 8 patients (17.4%). Four patients (8.7%) had life-threatening clinical manifestation, and 16 patients (34.8%) required intervention to prevent permanent damage. The most common maternal and fetal events were elevated serum alanine aminotransferase (26.1%) and non-reassuring fetal heart patterns (20.0%), respectively. CONCLUSIONS: This case series reports AEs of elevated serum alanine aminotransferase, maternal bradycardia, maternal hypothermia, non-reassuring fetal heart patterns, and emergent or unplanned cesarean sections following administration of several COVID-19 therapeutics. This study was not designed to definitely identify causation, and further study is needed to evaluate the causal role of these therapeutics in AEs affecting pregnant COVID-19 patients.

Deep learning neural network derivation and testing to distinguish acute poisonings.

INTRODUCTION: Acute poisoning is a significant global health burden, and the causative agent is often unclear. The primary aim of this pilot study was to develop a deep learning algorithm that predicts the most probable agent a poisoned patient was exposed to from a pre-specified list of drugs. RESEARCH DESIGN & METHODS: Data were queried from the National Poison Data System (NPDS) from 2014 through 2018 for eight single-agent poisonings (acetaminophen, diphenhydramine, aspirin, calcium channel blockers, sulfonylureas, benzodiazepines, bupropion, and lithium). Two Deep Neural Networks (PyTorch and Keras) designed for multi-class classification tasks were applied. RESULTS: There were 201,031 single-agent poisonings included in the analysis. For distinguishing among selected poisonings, PyTorch model had specificity of 97%, accuracy of 83%, precision of 83%, recall of 83%, and a F1-score of 82%. Keras had specificity of 98%, accuracy of 83%, precision of 84%, recall of 83%, and a F1-score of 83%. The best performance was achieved in the diagnosis of single-agent poisoning in diagnosing poisoning by lithium, sulfonylureas, diphenhydramine, calcium channel blockers, then acetaminophen, in PyTorch (F1-score = 99%, 94%, 85%, 83%, and 82%, respectively) and Keras (F1-score = 99%, 94%, 86%, 82%, and 82%, respectively). CONCLUSION: Deep neural networks can potentially help in distinguishing the causative agent of acute poisoning. This study used a small list of drugs, with polysubstance ingestions excluded.Reproducible source code and results can be obtained at https://github.com/ashiskb/npds-workspace.git.

Classification of acute poisoning exposures with machine learning models derived from the National Poison Data System.

The primary aim of this pilot study was to develop a machine learning algorithm to predict and distinguish eight poisoning agents based on clinical symptoms. Data were used from the National Poison Data System from 2014 to 2018, for patients 0-89 years old with single-agent exposure to eight drugs or drug classes (acetaminophen, aspirin, benzodiazepines, bupropion, calcium channel blockers, diphenhydramine, lithium and sulfonylureas). Four classifier prediction models were applied to the data: logistic regression, LightGBM, XGBoost, and CatBoost. There were 201 031 cases used to develop and test the algorithms. Among the four models, accuracy ranged 77%-80%, with precision and F1 scores of 76%-80% and recall of 77%-78%. Overall specificity was 92% for all models. Accuracy was highest for identifying sulfonylureas, acetaminophen, benzodiazepines and diphenhydramine poisoning. F1 scores were highest for correctly classifying sulfonylureas, acetaminophen and benzodiazepine poisonings. Recall was highest for sulfonylureas, acetaminophen, and benzodiazepines, and lowest for bupropion. Specificity was >99% for models of sulfonylureas, calcium channel blockers, lithium and aspirin. For single-agent poisoning cases among the eight possible exposures, machine learning models based on clinical signs and symptoms moderately predicted the causal agent. CatBoost and LightGBM classifier models had the highest performance of those tested.

Respiratory failure in confirmed synthetic cannabinoid overdose.

CONTEXT: Synthetic cannabinoids (SCs) are a structurally heterogenous synthetic class of drugs of abuse. The objective was to describe the incidence of acute respiratory failure in Emergency Department (ED) patients with confirmed SC exposure, and to investigate the association between SC overdose with respiratory failure compared to non-SC overdose. METHODS: This was an observational cohort of ED patients ≥18 years with suspected cannabinoid overdose between 2015 and 2020 at two tertiary-care hospitals. Patient serum was analyzed via liquid chromatography/quadrupole time-of-flight mass spectrometry using a library with >800 drugs including novel psychoactive substances. The primary outcome was acute respiratory failure. DISCUSSION: Of 83 patients with suspected cannabinoid overdose, there were 29 confirmed SC overdoses: 5 F-MDMB-PICA (n = 18) and its metabolite 5OH-MDMB-PICA (n = 16), ADB-FUBINACA (n = 4), AB-CHIMINACA (n = 4), AB-FUBINACA (n = 1), AB-PINACA (n = 1), MDMB-4en-PINACA (n = 1), and 4 F-MDMB-BINACA (n = 1). Overall, incidence of acute respiratory failure was 31.3% (95%CI 21.6-42.4). Compared to non-SC overdose, confirmed SC overdose was significantly associated with respiratory failure (25.0% SC vs. 4.2% non-SC, p = 0.05). CONCLUSION: This study demonstrates that SCs are associated with respiratory failure. Since respiratory depression is a potentially lethal adverse effect of SC overdose, future research is warranted.

Use of fomepizole (4-methylpyrazole) for acetaminophen poisoning: A scoping review.

INTRODUCTION: Acetaminophen (paracetamol, APAP) poisoning is a prominent global cause of drug-induced liver injury. While N-acetylcysteine (NAC) is an effective antidote, it has therapeutic limitations in massive overdose or delayed presentation. The objective is to comprehensively review the literature on fomepizole as a potential adjunct antidote for acetaminophen toxicity. METHODS: A scoping review was performed using standardized search terms from inception through July 2021. RESULTS: Reports on fomepizole as a therapeutic adjunct for APAP toxicity span heterogeneous types of evidence. Eleven preclinical studies (in vitro and animal), fourteen case reports/series, and one human volunteer study were included. Fomepizole's action is mediated by inhibition of CYP2E1 to prevent oxidant stress generation, and inhibition of c-Jun N-terminal kinase (JNK) to decrease amplification of oxidant stress signaling to mitochondria. Studies have shown a reduction in oxidative metabolites likely by shunting metabolism away from CYP2E1 and a resultant decrease in liver injury in animals, independent of CYP2E1 interactions. Fomepizole has been linked to few adverse effects. CONCLUSION: Based on in vitro and animal studies, and bolstered by case reports, fomepizole likely offers benefit as an adjunct antidote for APAP toxicity, however this remains to be shown in a human trial. NAC remains the standard of care antidote, but given that fomepizole is approved and generally safe, it may be considered for APAP toxicity as off-label use by experienced clinicians, in rare circumstances associated with increased risk of hepatotoxicity despite standard NAC dosing. The marginal clinical benefit of fomepizole adjunct therapy beyond NAC monotherapy remains to be clearly defined, and routine use for APAP overdose is premature based on current evidence.

Toxic alcohol poisoning characteristics and treatments from 2000 to 2017 at a United States regional poison center.

BACKGROUND: Toxic alcohol exposures are an ongoing concern in the United States. In the US, few studies characterize the local epidemiology of toxic alcohols over time. OBJECTIVES: The objective was to examine the incidence of toxic alcohol ingestions and changes in management over time. METHODS: This retrospective cohort study evaluates toxic alcohol ingestion phone calls to a regional poison center in the United States covering four states. Data were queried for this poison center from the National Poison Data System (NPDS) using generic codes for each toxic alcohol. Inclusion criteria were ingestion of toxic alcohol, age ≥ 13 years, from January 1, 2000 to Dec 31, 2017. Exclusion criteria were unrelated effects coded in the medical outcome, duplicate data, or incomplete demographic data. RESULTS: Of 926 subjects (adults and teenagers), 71.5% were male, and the mean age was 34.5 years. Toxic alcohol ingestion was more common in individuals younger than 40 years, with a significant relationship between age and intentional abuse or misuse (p = 0.001). There was also a significant relationship between age and reason for ingestion, with younger patients more likely to be suicidal (p < 0.001). Ethyleneglycol was the most common toxic alcohol. There was no change in the incidence of toxic alcohol ingestions over the study period. The mortality rate was 1.7%, and 31.2%of patients were hospitalized in a critical care unit. Major effects and death were more common in younger patients (p < 0.001). There was a significant difference in medical outcomes based on the type of toxic alcohol(p = 0.03). Fomepizole was the most common treatment. A Poisson regression model found no change in fomepizole use during the study period (p = 0.1). Ethanol administration over the study period increased (p = 0.02), while hemodialysis decreased (p = 0.02). CONCLUSION: Data obtained from a single regional United States poison center showed low mortality related to toxic alcohol ingestions. The most prevalent toxic alcohol was Ethylene glycol. In all cases, toxic alcohol ingestion was higher in the 20-29-year-old age group. Reasons for ingestion, in most cases, were suicidal. Fomepizole was the most common treatment, ethanol administration as an antidote is rising, and hemodialysis utilization is decreasing. Data may not be nationally representative.

Changes in alcohol-related hospital visits during COVID-19 in New York City.

BACKGROUND AND AIMS: Increased alcohol consumption has been proposed as a potential consequence of the coronavirus disease 2019 (COVID-19) pandemic. There has been little scrutiny of alcohol use behaviors resulting in hospital visits, which is essential to guide pandemic public policy. We aimed to determine whether COVID-19 peak restrictions were associated with increased hospital visits for alcohol use or withdrawal. Secondary objectives were to describe differences based on age, sex and race, and to examine alcohol-related complication incidence. DESIGN: Multi-center, retrospective, pre-post study. SETTING: New York City health system with five participating hospitals. PARTICIPANTS: Adult emergency department encounters for alcohol use, alcoholic gastritis or pancreatitis or hepatitis, alcohol withdrawal syndrome, withdrawal seizure or delirium tremens. MEASUREMENTS: Age, sex, race, site and encounter diagnosis. Encounters were compared between 2019 and 2020 for 1 March to 31 May. FINDINGS: There were 2790 alcohol-related visits during the 2019 study period and 1793 in 2020, with a decrease in total hospital visits. Of 4583 alcohol-related visits, median age was 47 years, with 22.3% females. In 2020 there was an increase in percentage of visits for alcohol withdrawal [adjusted odds ratio (aOR) = 1.34, 95% confidence interval (CI) = 1.07-1.67] and withdrawal with complications (aOR = 1.40, 95% CI = 1.14-1.72), and a decline in percentage of hospital visits for alcohol use (aOR = 0.70, 95% CI = 0.59-0.85) and use with complications (aOR = 0.71, 95% CI = 0.58-0.88). It is unknown whether use visit changes mirror declines in other chief complaints. The age groups 18-29 and 60-69 years were associated with increased visits for use and decreased visits for withdrawal, as were non-white race groups. Sex was not associated with alcohol-related visit changes despite male predominance. CONCLUSIONS: In New York City during the initial COVID-19 peak (1 March to 31 May 2020), hospital visits for alcohol withdrawal increased while those for alcohol use decreased.

Prevalence and description of kratom (Mitragyna speciosa) use in the United States: a cross-sectional study.

BACKGROUND AND AIMS: Mitragyna speciosa ('kratom') contains mu opioid partial agonists. It is widely available, and occasionally used as a home remedy for opioid use disorder. The Drug Enforcement Agency considers kratom a drug of concern; however, prevalence of use and role in drug misuse are unknown. This study aimed to characterize kratom use in the United States. DESIGN: Cross-sectional Survey of Non-Medical Use of Prescription Drugs (NMURx) Program, 2018 third quarter and 2019 first quarter. SETTING: A validated non-probability online survey in the United States. PARTICIPANTS: A total of 59 714 respondents aged 18 years or older, weighted to represent the adult US population (n = 252 063 800). MEASUREMENTS: In addition to prevalence of past-year kratom and other drug use, behavior proportions were estimated. The Drug Abuse Screening Test (DAST-10) estimated consequences of drug abuse. FINDINGS: The estimated prevalence of past-year kratom use in the adult US population was 0.8% [95% confidence interval (CI) = 0.7-0.9], representing 2 031 803 adults. Life-time prevalence was 1.3% (95% CI = 1.2-1.4), representing 3 353 624 adults. Kratom users were younger (mean 35 years, P < 0.001), with higher proportions of males (61.0 versus 48.6%, P < 0.001), students (14.1 versus 7.5%, P < 0.001) and health-care professionals (9.7 versus 4.5%, P < 0.001) and fewer bachelor's/advanced degree graduates (33.4 versus 42.6%, P < 0.001) compared with non-users. Results were inconclusive on whether there was a difference in kratom use by race, household income or employment status. Among those with past-year kratom use, 36.7% (95% CI = 32.1-41.3) non-medically used prescription opioids, 21.7% (95% CI = 18.0-25.5) used illicit opioids, 54.4% (95% CI = 49.5-59.3) used another illicit drug and 67.1% (95% CI = 62.5-71.8) used cannabis. The DAST-10 profile was more often substantial/severe in kratom users (21 versus 1%, P < 0.001) compared with non-users. CONCLUSIONS: Estimated United States past-year prevalence of kratom use is 0.8%, and kratom users tend to have more serious substance abuse profiles than non-users or users of cannabis, alcohol or cigarettes. To our knowledge, this is the first description of kratom use at the national level.

Opioid Use Disorder and COVID-19: Biological Plausibility for Worsened Outcomes.

BACKGROUND: Alarms have been raised that COVID-19 may disproportionately affect certain populations with substance use disorders, particularly Opioid Use Disorder (OUD), however warnings have largely focused on social risks such as reduced availability of services. Objectives: This commentary highlights three plausible biological mechanisms for potentially worsened outcomes in patients with OUD who contract COVID-19. Results: Opioid-related respiratory depression may amplify risks of hypoxemia from COVID-19 viral pneumonia. Complex opioid immune modulation may impact host response to COVID-19, though the effect direction and clinical significance are unclear. Drug-drug interactions may affect individuals with OUD who are co-administered medications for OUD and medications for COVID-19, particularly due to cardiac adverse effects. Conclusions/Importance: There are plausible biological mechanisms for potentially worsened outcomes in patients with OUD who contract COVID-19; these mechanisms require further study, and should be considered in individuals with OUD.

Kratom (Mitragyna Speciosa) Liver Injury: A Comprehensive Review.

Kratom (Mitragyna speciosa) leaves contain the mu opioid partial agonists mitragynine and 7-hydroxymitragynine. The US Drug Enforcement Agency considers it a 'drug of concern', and the US FDA is reviewing kratom, but there is a paucity of information regarding health effects. Liver injury is often cited as a potential health consequence, however the same few case reports are repeatedly referenced, without a broader context. Furthermore, reports have largely lacked standardized causality assessment methods. The objective is to evaluate causality in kratom liver injury, through a comprehensive scoping review of human cases, and by reviewing epidemiologic, animal, and mechanistic reports that relate to kratom liver injury. Hepatotoxicity causality was systematically examined using the Roussel Uclaf Causality Assessment Method (RUCAM) for case reports. Biopsy findings, potential pathophysiologic mechanisms, and management options are discussed. This review identified 26 case reports and abstracts, in addition to 7 cases reported from the Drug-Induced Liver Injury Network, 25 in FDA databases, and 27 in internet user forums. Latency periods to symptom onset had a median of 20.6 days and mean of 21 days (range 2-49). Common presenting signs and symptoms were abdominal discomfort, jaundice, pruritis, and dark urine. Histologic findings were predominantly cholestatic, although, biochemically, the condition was heterogenous or mixed; the median R ratio was 3.4 and the mean was 4.6 (range 0.24-10.4). Kratom likely causes liver injury based on the totality of low-quality human evidence, and, in the context of epidemiologic, animal, and mechanistic studies. It remains unclear which subgroups of users are at heightened risk.

Complex regional pain syndrome following a centipede bite: a case report.

Context: Complex Regional Pain Syndrome (CRPS) is a chronic neuropathic pain condition associated with autonomic features. To date, the development of CRPS following centipede bite has not been reported. We report a case of CRPS likely secondary to a centipede bite.Case details: A 31-year-old female was bitten by a centipede on the right 2nd toe. She was initially treated with analgesics, and two weeks later developed severe pain, allodynia, pruritus, and edema of the right foot, with hyperpigmentation over the affected toe. The X-ray, ultrasound, electromyography, nerve conduction velocity studies of the foot, blood chemistries, and erythrocyte sedimentation rate showed no abnormalities. The patient was diagnosed with CRPS type 1 by fulfilling the Budapest criteria. She was treated with gabapentin, amitriptyline, desloratadine, and fluoxetine, along with physical rehabilitation. Clinical symptoms gradually improved, and resolved at approximately 9 months with persistent hyperpigmentation.Discussion: Centipede bite may be an eliciting event for CRPS. It is unknown whether direct bite trauma or envenomation was the primary etiology in this case. Awareness of this condition is important for early diagnosis and appropriate management.

Blood lead level risk factors and reference value derivation in a cross-sectional study of potentially lead-exposed workers in Iran.

OBJECTIVES: This exploratory investigation aimed to measure blood lead levels and associated risk factors in exposed workers in Iran, and to derive appropriate reference values for blood lead in this population as a means of epidemiological comparison. DESIGN: Cross-sectional. SETTING: Manufacturing plants with potential lead exposure in Southern Khorasan Province, Iran. PARTICIPANTS: The study included 630 workers, selected through stratified random sampling. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary measures in this exploratory investigation were venous blood lead concentration (BLC) and associated risk factors of age, gender, work experience, cigarette smoking and history of opium use. The secondary measures were symptoms associated with lead toxicity. Data analyses were conducted using Student's t-test, Mann-Whitney U test, one-way analysis of variance, Kruskal-Wallis test, Spearman correlation coefficient and regression analysis. RESULTS: Mean and median BLCs were 6.5±8.1 µg/dL and 3.9 µg/dL (IQR: 2.9-5.8), respectively. Of the subjects, 85 (13.5%) had BLC ≥10 µg/dL. The derived reference BLC value in this study was 30 µg/dL for men and 14 µg/dL for women. Increasing work experience and age were associated with BLC >10 µg/dL. Radiator manufacturers were up to 12.9 times (95% CI 4.6 to 35, p<0.005) more likely than painters to have BLC >10 µg/dL. Most subjects reported multiple symptoms. CONCLUSIONS: The mean BLC was above the maximum recommended concentration. There was a significant relationship between higher BLC and age or working in a printing factory or radiator manufacturing. These findings can direct efforts towards reducing occupational lead exposure.

Lacosamide Overdose: A Case of QRS Prolongation and Seizure.

BACKGROUND: Lacosamide is a third-generation antiepileptic drug. Its likely mechanism of action is via neuronal sodium channel blockade, via a unique manner compared with other antiepileptic drugs that block sodium channels. A paucity of information exists regarding lacosamide overdosage. Lacosamide overdosage is thought to cause QRS prolongation and seizures, due to its effect of sodium channel blockade. The potential efficacy of sodium bicarbonate to reverse the effects of lacosamide has not been well studied. Furthermore, prior reports of lacosamide toxicity have occurred in the setting of concomitant polypharmacy. Thus, the isolated toxic effects of the drug have not been well elucidated. CASE REPORT: We report a case of a suspected, single-ingestion overdose on lacosamide. The patient developed signs of cardiotoxicity and seizure. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: After lacosamide overdosage, the emergency physician must be capable of acute management of subsequent lacosamide toxicity. Understanding the mechanisms of action causing toxicity due to this drug can help the clinician to anticipate the interventions that may be needed or useful to treat this potentially toxic ingestion.