Intensive Care Interventions Among Children With Toxicologic Exposures to Cardiovascular Medications.

OBJECTIVES: Interventions requiring a PICU are rare in toxicologic exposures, but cardiovascular medications are high-risk exposures due to their hemodynamic effects. This study aimed to describe prevalence of and risk factors for PICU interventions among children exposed to cardiovascular medications. DESIGN: Secondary analysis of Toxicology Investigators Consortium Core Registry from January 2010 to March 2022. SETTING: International multicenter research network of 40 sites. PATIENTS: Patients 18 years old or younger with acute or acute-on-chronic toxicologic exposure to cardiovascular medications. Patients were excluded if exposed to noncardiovascular medications or if symptoms were documented as unlikely related to exposure. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 1,091 patients in the final analysis, 195 (17.9%) received PICU intervention. One hundred fifty-seven (14.4%) received intensive hemodynamic interventions and 602 (55.2%) received intervention in general. Children less than 2 years old were less likely to receive PICU intervention (odds ratio [OR], 0.42; 95% CI, 0.20-0.86). Exposures to alpha-2 agonists (OR, 2.0; 95% CI, 1.11-3.72) and antiarrhythmics (OR, 4.26; 95% CI, 1.41-12.90) were associated with PICU intervention. In the sensitivity analysis removing atropine from the composite outcome PICU intervention, only exposures to calcium channel antagonists (OR, 2.12; 95% CI, 1.09-4.11) and antiarrhythmics (OR, 4.82; 95% CI, 1.57-14.81) were independently associated with PICU intervention. No independent association was identified between PICU intervention and gender, polypharmacy, intentionality or acuity of exposure, or the other medication classes studied. CONCLUSIONS: PICU interventions were uncommon but were associated with exposure to antiarrhythmic medications, calcium channel antagonists, and alpha-2 agonists. As demonstrated via sensitivity analysis, exact associations may depend on institutional definitions of PICU intervention. Children less than 2 years old are less likely to require PICU interventions. In equivocal cases, age and exposure to certain cardiovascular medication classes may be useful to guide appropriate disposition.

Toxicities of herbal abortifacients.

BACKGROUND: In the post-Roe era, barriers to facility-based abortions may lead to an increased incidence of self-managed abortions. While misoprostol-based medication abortions have significant literature supporting its safety profile, there is a knowledge deficit within the medical community regarding the toxicities of commonly used herbal abortifacients. METHODS: This is a narrative review, based on a MEDLINE and HOLLIS database search, of self-managed abortion methods with herbal abortifacients and their associated toxicities. RESULTS: Common herbal abortifacients with significant morbidity and mortality implications include pennyroyal, blue cohosh, rue, and quinine. Other commonly reported abortifacients considered to be less toxic also are discussed in brief. Special considerations for hepatic, cardiac, renal, and hematologic toxicities are important in patients with significant exposures to these herbal substances. CONCLUSION: There is an anticipated increase in the utility of herbal xenobiotics for self-managed abortions with post-Roe restrictions to standard mifepristone-misoprostol protocols. Frontline providers should be aware of the associated toxicities and have special considerations when treating a poisoned patient in this population.

Performance-enhancing drugs and the Olympics.

The rules of fair play in sport generally prohibit the use of performance-enhancing drugs (PEDs). The World Anti-Doping Agency (WADA) oversees global antidoping regulations and testing for elite athletes participating in Olympic sports. Efforts to enforce antidoping policies are complicated by the diverse and evolving compounds and strategies employed by athletes to gain a competitive edge. Now between the uniquely proximate 2021 Tokyo and 2022 Beijing Olympic Games, we discuss WADA's efforts to prevent PED use during the modern Olympic Games. Then, we review the major PED classes with a focus on pathophysiology, complexities of antidoping testing, and relevant toxicities. Providers from diverse practice environments are likely to care for patients using PEDs for a variety of reasons and levels of sport; these providers should be aware of common PED classes and their risks.

Clinical Effects of Pediatric Clonidine Exposure: A Retrospective Cohort Study at a Single Tertiary Care Center.

BACKGROUND: Pediatric clonidine ingestions frequently result in emergency department visits and admission for cardiac monitoring. Detailed information on the clinical course and specifically time of vital sign abnormalities of these patients is lacking. OBJECTIVE: The objective of this study was to provide descriptive analysis of the rates and times to vital sign abnormalities, treatment, disposition, and outcomes in a single-center cohort of pediatric patients with report of clonidine poisoning. METHODS: We performed a retrospective cohort study of patients younger than 21 years who presented to a large, urban, tertiary care center with a report of single substance clonidine exposure between January 2004 and November 2017. Patients were dichotomized into younger (≤9 years or younger) and older (10-21 years) groups based on the expected physiologic and psychologic differences between older and younger children. RESULTS: Eighty-eight patients met our inclusion criteria. Younger patients (≤9 years or younger; n = 47) were more likely to be exposed to someone else's medication (53%) and older patients (10-21 years; n = 41) overwhelmingly (85%) were exposed to their own medication. Thirty-nine (45%) became bradycardic, 27 (32%) became bradypneic, and 38 (44%) became hypotensive. Eighty percent of patients had depressed mental status. Thirty-three (38%) patients received at least one dose of naloxone (median 0.07 mg/kg; interquartile range 0.03-0.11 mg/kg). Of those who received naloxone, 50% had a documented clinical response. CONCLUSIONS: In this study of patients at a pediatric tertiary referral center, pediatric patients with report of clonidine exposures were likely to exhibit altered mental status and frequently develop vital sign abnormalities. Naloxone exhibited some effectiveness; given its wide safety margin, high-dose naloxone should be used in critically poisoned non-opioid-dependent patients. Because adolescents are much more likely to ingest their own clonidine medication, counseling with parents and other caregivers regarding safe medication storage is paramount.

Clonidine Compounding Error: Bradycardia and Sedation in a Pediatric Patient.

BACKGROUND: Clonidine is a centrally-acting α-2 agonist used in the treatment of hypertension and attention-deficit/hyperactivity disorder, among other off-label uses. In overdose, it can cause sedation, bradycardia, and hypotension. Clonidine can be compounded as a liquid formula for patients who are unable to take pills, however, this can add to the risk of dosing errors. CASE REPORT: A 12-year-old boy diagnosed with autism, prescribed buspirone and clonidine, presented to the emergency department for altered mental status. His examination revealed generalized sedation, bradycardia (heart rate 30-40 beats/min), and hypotension (blood pressure 82/48 mm Hg). Resuscitation included i.v. crystalloids and multiple doses of atropine. Over the next 24 h, his vital signs and mental status normalized. He displayed no infectious symptoms or focal neurologic deficits. His parents noted that his medications had been refilled recently at the compounding pharmacy; because he was unable to take pills, his medications were in liquid formulation. Because his signs and symptoms were suspicious for a central α-2 agonist overdose, his clonidine preparation was sent to a reference laboratory for analysis. This analysis revealed the concentration was approximately eight times higher than indicated on its label. WHY SHOULD AND EMERGENCY PHYSICIAN BE AWARE OF THIS?: Compounding pharmacy errors can be a source of toxicity, even if there is no known history of an overdose. Recognizing the toxidrome of sedation, respiratory depression, bradycardia, hypotension, and miosis will lead to appropriate treatment of the patient and should prompt an investigation of the medication error to prevent further harm.

Myocardial Infarct After Marijuana Inhalation in a 16-year-old Adolescent Boy.

Many reports of marijuana-associated myocardial infarct (MI) are limited by incomplete evaluation of the toxicologic exposure, a lack of definitive anatomic findings, and the potential for comorbid coronary atherosclerosis inherent in an adult population. We report a 16-year-old adolescent boy who presented with chest pain after smoking marijuana and was found to have acute MI. Electrocardiogram showed diffuse ST-segment elevations. Exhaustive toxicologic testing confirmed the presence of Δ-9-tetrahydrocannabinol metabolite and ruled out other drugs of abuse. Echocardiography demonstrated moderate global left ventricular systolic dysfunction. Coronary angiography demonstrated no focal coronary lesions or obstruction. Right ventricular septal endomyocardial samples biopsied 36 hours after the onset of pain showed a subendocardial acute MI with a sparse neutrophilic infiltrate. One month after the event, magnetic resonance imaging showed a severely dilated left ventricle and moderately to severely depressed global systolic function. Late gadolinium enhancement consistent with myocardial fibrosis was seen in nearly all myocardial segments. Our unusually well-documented findings strengthen the potential association between marijuana and MI. Furthermore, we demonstrate a disease distribution supporting a process that affects the coronary circulation globally, likely at the distal, small-vessel level.

A Case Report of Reversible Takotsubo Cardiomyopathy after Amphetamine/Dextroamphetamine Ingestion in a 15-Year-Old Adolescent Girl.

Stimulant medications are used in the treatment of attention deficit hyperactivity disorder and serious cardiac complications can occur when these medications are abused. We present a 15-year-old adolescent girl who was found to have a Takotsubo cardiomyopathy after acute amphetamine/dextroamphetamine ingestion.

Differentiating Delirium From Sedative/Hypnotic-Related Iatrogenic Withdrawal Syndrome: Lack of Specificity in Pediatric Critical Care Assessment Tools.

OBJECTIVES: To identify available assessment tools for sedative/hypnotic iatrogenic withdrawal syndrome and delirium in PICU patients, the evidence supporting their use, and describe areas of overlap between the components of these tools and the symptoms of anticholinergic burden in children. DATA SOURCES: Studies were identified using PubMed and EMBASE from the earliest available date until July 3, 2016, using a combination of MeSH terms "delirium," "substance withdrawal syndrome," and key words "opioids," "benzodiazepines," "critical illness," "ICU," and "intensive care." Review article references were also searched. STUDY SELECTION: Human studies reporting assessment of delirium or iatrogenic withdrawal syndrome in children 0-18 years undergoing critical care. Non-English language, exclusively adult, and neonatal intensive care studies were excluded. DATA EXTRACTION: References cataloged by study type, population, and screening process. DATA SYNTHESIS: Iatrogenic withdrawal syndrome and delirium are both prevalent in the PICU population. Commonly used scales for delirium and iatrogenic withdrawal syndrome assess signs and symptoms in the motor, behavior, and state domains, and exhibit considerable overlap. In addition, signs and symptoms of an anticholinergic toxidrome (a risk associated with some common PICU medications) overlap with components of these scales, specifically in motor, cardiovascular, and psychiatric domains. CONCLUSIONS: Although important studies have demonstrated apparent high prevalence of iatrogenic withdrawal syndrome and delirium in the PICU population, the overlap in these scoring systems presents potential difficulty in distinguishing syndromes, both clinically and for research purposes.

A review of the carcinogenic potential of glyphosate by four independent expert panels and comparison to the IARC assessment.

The International Agency for Research on Cancer (IARC) published a monograph in 2015 concluding that glyphosate is "probably carcinogenic to humans" (Group 2A) based on limited evidence in humans and sufficient evidence in experimental animals. It was also concluded that there was strong evidence of genotoxicity and oxidative stress. Four Expert Panels have been convened for the purpose of conducting a detailed critique of the evidence in light of IARC's assessment and to review all relevant information pertaining to glyphosate exposure, animal carcinogenicity, genotoxicity, and epidemiologic studies. Two of the Panels (animal bioassay and genetic toxicology) also provided a critique of the IARC position with respect to conclusions made in these areas. The incidences of neoplasms in the animal bioassays were found not to be associated with glyphosate exposure on the basis that they lacked statistical strength, were inconsistent across studies, lacked dose-response relationships, were not associated with preneoplasia, and/or were not plausible from a mechanistic perspective. The overall weight of evidence from the genetic toxicology data supports a conclusion that glyphosate (including GBFs and AMPA) does not pose a genotoxic hazard and therefore, should not be considered support for the classification of glyphosate as a genotoxic carcinogen. The assessment of the epidemiological data found that the data do not support a causal relationship between glyphosate exposure and non-Hodgkin's lymphoma while the data were judged to be too sparse to assess a potential relationship between glyphosate exposure and multiple myeloma. As a result, following the review of the totality of the evidence, the Panels concluded that the data do not support IARC's conclusion that glyphosate is a "probable human carcinogen" and, consistent with previous regulatory assessments, further concluded that glyphosate is unlikely to pose a carcinogenic risk to humans.

Evolving trends of pharmaceutical poisonings associated with QRS complex prolongation.

INTRODUCTION: Tricyclic antidepressants often cause drug-induced QRS complex prolongation in overdose but are now less commonly prescribed. We sought to determine, among a contemporary cohort of patients, the pharmaceuticals independently associated with QRS complex prolongation in acute overdose. METHODS: We performed secondary analysis of data from the Toxicology Investigators Consortium (ToxIC) Core Registry. We included adult patients presenting from January 2016 through March 2023 with acute or acute-on-chronic pharmaceutical exposures. The primary outcome was QRS complex prolongation >0.12 s. Secondary outcomes included cardiac arrest, death, ventricular dysrhythmia, intensive care unit admission, initiation of vasopressors, and treatment with sodium bicarbonate. We used a multivariable logistic regression model with QRS complex prolongation as the outcome and individual pharmaceuticals of interest as independent variables. We assessed yearly trends of the contribution of relevant pharmaceuticals to QRS complex prolongation since 2016. RESULTS: Of 11,945 patients in the total cohort (median age 37 years, 6,652 [55.7%] female), 366 (3.1%) developed QRS complex prolongation. Of 9,417 patients included in the model, 290 (3.1%) developed QRS complex prolongation. Amitriptyline, nortriptyline, doxepin, imipramine, noxiptiline, bupropion, flecainide, carvedilol, propranolol, diphenhydramine, and lamotrigine poisonings were independent predictors of QRS complex prolongation. Flecainide poisoning conferred the greatest odds of QRS complex prolongation (OR 574.1; 95% CI: 88.3-12,747). The contribution of tricyclic antidepressants to QRS complex prolongation decreased from 38.8% to 17.6% of all patients with QRS complex prolongation from 2016 to 2022. In 2022, the proportion of QRS complex prolongation from diphenhydramine (20.6%) surpassed that of tricyclic antidepressants. DISCUSSION: This study provides insights into contemporary pharmaceutical poisoning associated with QRS complex prolongation. Tricyclic antidepressants remain clinically relevant exposures but are no longer the most common cause of drug-induced QRS complex prolongation. CONCLUSIONS: Bupropion, diphenhydramine, and antidysrhythmics are increasingly common causes of QRS complex prolongation, each associated with numerous severe outcomes in poisoning. Greater safety measures to protect patients from cardiovascular toxicity from these pharmaceuticals are warranted.

Pediatric antiarrhythmics and toxicity: A clinical review.

Antiarrhythmic medications are fundamental in the acute and chronic management of pediatric arrhythmias. Particularly in the pediatric patient population, associated antiarrhythmic toxicities represent important potential adverse effects. Emergency medicine clinicians must be skilled in the detection, workup, and management of antiarrhythmic toxicity. This is a clinical review of the indications, pharmacology, adverse effects, and toxicologic treatment of antiarrhythmics commonly used in the pediatric patient population.

Pharmaceutical Purchasing: a Review of the Landscape and Implications for Antidotal Therapies.

The management of the poisoned patient often requires the utilization of uncommonly used pharmaceutical interventions. These interventions can be associated with significant costs to both the patient and treating institution. Pharmaceutical supply shortages and issues with accessibility of antidotal therapies complicate the management of many toxic exposures. These challenges are an inherent property of the pharmaceutical purchasing infrastructure in the United States, which is a complicated network of public and private intra-institutional agreements. The cost and availability of any given therapy is dependent on the individual contracting agreements between the treating institution, payer, pharmacy benefit manager, manufacturer or wholesaler, and in some cases a specialty pharmacy. Small or remote hospitals may experience greater challenges related to insufficient patient volume to achieve predicable prescribing patterns of rare and expensive medications, necessitating consignment purchasing arrangements. Although pharmaceutical costs are the focus of recent legislative attention, these reforms are not expected to significantly alter the cost or availability of antidotal therapies.

Chronic Doxepin Toxicity Masquerading as Epilepsy in a 10-Year-Old Boy.

INTRODUCTION: Chronic tricyclic antidepressant toxicity is rarely described in children. Symptoms include confusion, ataxia, and seizures. Toxicity may result from dosing error, CYP2C19 and CYP2D6 genetic variability, and drug-drug interactions. Chronic doxepin toxicity has not been previously reported in children. Doxepin is prescribed for insomnia and depression, with a maximum off-label dose of 3 mg/kg in children. We present a case of chronic doxepin toxicity mimicking epilepsy in a child attributable to three potential factors: supratherapeutic dosing, pharmacogenomic variability, and drug-drug interactions. CASE REPORT: A 10-year-old boy with insomnia, diagnosed with epilepsy 6 months prior, presented to an emergency department with confusion, ataxia, and increasing seizure frequency. He was prescribed doxepin for insomnia and four antiepileptics for seizures. After admission, he had two seizures and remained confused. EKGs showed QRS prolongation, suggesting doxepin toxicity. Doxepin-nordoxepin combined serum concentration was 1419 ng/mL (therapeutic 100-300 ng/mL), confirming doxepin toxicity. Outpatient records showed onset of confusion and seizures as doxepin dose was gradually uptitrated to 300 mg nightly (4.41 mg/kg). Symptoms worsened following addition of clobazam (CYP2D6 inhibitor) and topiramate (CYP2C19 inhibitor). Following doxepin discontinuation, all symptoms resolved. CYP2D6 testing showed intermediate metabolizer phenotype (CYP2D6*1/*4; activity score = 1.0; copy number = 2.0). No seizures have occurred in more than one year since doxepin discontinuation. DISCUSSION: Caution must be exercised when prescribing doxepin. Pharmacogenomics, dose, drug-drug interactions, and age should be considered. Chronic toxicity should be contemplated in patients taking doxepin without acute overdose who present with persistent neurologic abnormalities including seizure.