False-Negative Confirmatory Testing in Patients With Cannabinoid-Positive Urine Drug Screens.

This cross-sectional study discusses false-negative results associated with a change in the reporting threshold of 11-nor-9-carboxy-Δ9-tetrahydrocannabinol.

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.

Characterization of pediatric beta-adrenergic antagonist ingestions reported to the National Poison Data System from 2000 to 2020.

BACKGROUND: When ingested by children, small quantities of beta-adrenergic antagonists (BAA) are described as dangerous and even potentially lethal ("one pill can kill"). We characterize demographics, clinical characteristics, and the rate of serious outcomes among pediatric patients with reported BAA ingestions. METHODS: This study was a retrospective review of U.S. patients <20 years old with reported single-agent BAA ingestions presenting to a health care facility between January 2000 and February 2020 for whom a poison control center was consulted. Data were abstracted from the National Poison Data System (NPDS). Medical outcomes were assessed by the NPDS scale of no effect, minor effect, moderate effect, major effect, and death. All relevant NPDS fatality narratives were reviewed. RESULTS: A total of 35,436 reported exposures were identified. A total of 29,155 (82.3%) were <6 years old, of which 29,089 (99.8%) were unintentional. Twenty-five patients (<0.1%) <6 years old had major effects. A total of 2316 (8.8%) of patients with no/mild effects were admitted to a critical care unit. Of all cases, 1460 (4.1%) had hypotension and 1403 (4.0%) had bradycardia. One hundred nineteen (0.3%) developed hypoglycemia. The only four fatalities resulted from intentional ingestions in patients >10 years old who sustained cardiac arrest in the prehospital setting. CONCLUSIONS: Reported BAA ingestions in this multiyear national pediatric cohort caused infrequent toxicity, and no fatalities resulted from an unintentional ingestion. The frequency of bradycardia, hypotension, and hypoglycemia were low. While severely poisoned patients require aggressive treatment, 8.8% of patients were admitted to a critical care unit despite having no or mild effects, which suggests an opportunity to reduce resource utilization.

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.

Disparate Utilization of Urine Drug Screen Nationwide in the Evaluation of Acute Chest Pain.

INTRODUCTION: Urine drug screens (UDS) have unproven clinical utility in emergency department (ED) chest pain presentations. A test with such limited clinical utility may exponentiate biases in care, but little is known about the epidemiology of UDS use for this indication. We hypothesized that UDS utilization varies nationally across race and gender. METHODS: This was a retrospective observational analysis of adult ED visits for chest pain in the 2011-2019 National Hospital Ambulatory Medical Care Survey. We calculated the utilization of UDS across race/ethnicity and gender and then characterized predictors of use via adjusted logistic regression models. RESULTS: We analyzed 13,567 adult chest pain visits, representative of 85.8 million visits nationally. Use of UDS occurred for 4.6% of visits (95% CI 3.9%-5.4%). White females underwent UDS at 3.3% of visits (95% CI 2.5%-4.2%), and Black females at 4.1% (95% CI 2.9%-5.2%). White males were tested at 5.8% of visits (95% CI 4.4%-7.2%), while Black males were tested at 9.3% of visits (95% CI 6.4%-12.2%). A multivariate logistic regression model including race, gender, and time period shows significantly increased odds of ordering UDS for Black patients (odds ratio [OR] 1.45 (95% CI 1.11-1.90, p = 0.007)) and male patients (OR 2.0 (95% CI 1.55-2.58, p < 0.001) as compared to White patients and female patients. CONCLUSION: We identified wide disparities in the utilization of UDS for the evaluation of chest pain. If UDS were used at the rate observed for White women, Black men would undergo nearly 50,000 fewer tests annually. Future research should weigh the potential of the UDS to magnify biases in care against the unproven clinical utility of the test.

Diphenhydramine-Induced Antimuscarinic Delirium Treated with Physostigmine and Transdermal Rivastigmine.

INTRODUCTION: Recurrent physostigmine shortages present a challenge to healthcare providers treating antimuscarinic delirium. Other centrally acting acetylcholinesterase inhibitors such as rivastigmine may represent a therapeutic alternative or adjunct during physostigmine shortage; however, previous reports of use have not documented serum antimuscarinic toxin concentrations, limiting evaluation of effectiveness. Combination therapy with physostigmine and rivastigmine has not been described. In this report, the authors present a case of diphenhydramine-induced antimuscarinic delirium with elevated diphenhydramine serum concentrations treated with physostigmine and transdermal rivastigmine without observed adverse effect. CASE REPORT: A 48-year-old female presented to an emergency department after ingesting 3.75 g (41.2 mg/kg) of diphenhydramine. She had antimuscarinic delirium with a presenting serum diphenhydramine concentration of 1500 ng/mL (therapeutic range, 25-112 ng/mL) and required two doses of physostigmine to avert intubation prior to intensive care unit (ICU) admission. At hospital hour 22, in the ICU, antimuscarinic delirium persisted but no further physostigmine was available due to hospital shortage. Therefore, a 9.5-mg transdermal rivastigmine patch was applied. By hospital hour 24, her delirium had resolved. A serum diphenhydramine concentration at hospital hour 25 was elevated at 760 ng/mL. Transdermal rivastigmine was discontinued at hospital hour 48 without recurrent delirium. Despite persistent normal mental status after rivastigmine discontinuation, the patient had a dry mouth, difficulty urinating, and mydriasis until hospital day 5. She never developed muscarinic toxicity. DISCUSSION: Transdermal rivastigmine may be a useful treatment alternative or adjunct during physostigmine shortage for antimuscarinic delirium and has a long duration of action without aspiration risk. Muscarinic toxicity was not observed.

Warfarin Overdose in an Adolescent Not Dependent on Anticoagulation: Reversal Strategy and Kinetics.

INTRODUCTION: Warfarin induces coagulopathy. Guidelines protocolize reversal of supratherapeutic international normalized ratio (INR) in patients dependent on anticoagulation, but practices vary for reversing warfarin-induced coagulopathy after overdose in non-warfarin-dependent patients. CASE REPORT: This is the report of a 15-year-old female who ingested her father's warfarin (100-200 mg) in a self-harm attempt. At hour 24 post-ingestion, her INR was 2.00 and she was admitted for monitoring. Reversal of coagulopathy was initially deferred pending the INR trend. The INR was 5.10 at hour 60 and 2.5 mg oral vitamin K1 (VK1) was given. At hour 85, the INR peaked at 6.67 and she received a second oral dose of 2.5 mg VK1. On day 8, she was medically cleared with an INR of 1.31. On day 11, she developed lower abdominal pain and diarrhea. Imaging revealed a duodenal hematoma, and symptoms improved spontaneously. She was again medically cleared 13 days post-ingestion. Her serum warfarin concentration peaked at 19 mcg/mL at hour 46. Serial warfarin concentrations were obtained, demonstrating first-order elimination kinetics and a 30-hour half-life. CONCLUSION: A restrictive approach to coagulopathy reversal in non-warfarin-dependent patients with intentional warfarin overdose may result in worsening coagulopathy, bleeding, and lengthy hospital stay. Given the risk for significant, prolonged coagulopathy, these patients should be treated early with VK1, with subsequent serial INR monitoring and probable additional VK1 dosing. Delayed peak warfarin concentrations support consideration of gastrointestinal decontamination in late presenters.

Thiocyanate toxicity: a teaching case.

Introduction: Thiocyanate can cause gastrointestinal, neurologic, and cardiovascular toxicity. Additionally, it interferes with multiple laboratory assays. We present a case of acute thiocyanate toxicity. Case: A 17-year-old female presented with an intentional thiocyanate ingestion. Her course was notable for delirium, wide complex tachycardia, and presumed seizure activity with concurrent lactatemia, acidemia, and narrowing of her arterio-venous oxygen gradient. She received lipid emulsion therapy (LET). While hemodialysis was considered, she recovered without additional treatment. After resolution of her critical illness, a serum cyanide concentration was 0.21 mcg/mL. She had laboratory testing notable for hyperchloremia, hypocalcemia, hypokalemia, and an elevated salicylate concentration attributed to interference by thiocyanate. The thiocyanate was eliminated via first-order kinetics with a half-life of 61.6 hours. Discussion: Thiocyanate poisoning may cause cardiac and neurologic toxicity. Laboratory evidence of impaired cellular respiration in this case suggests possible in vivo conversion to cyanide, however this is not proven. Cyanide antidotal treatment was not administered for this patient, however LET was given based on thiocyanate's lipophilicity. Hemodialysis is known to effectively remove thiocyanate from the blood, however the patient improved without it. The patient's laboratory derangements were due to thiocyanate interference with ion selective electrode and colorimetric analyzer technology. Conclusions: Thiocyanate can cause cardiac and neurologic toxicity, and interferes with several laboratory assays. Theoretically, LET and cyanide antidotal treatment may be useful, but this requires further investigation. Thiocyanate toxicity should be managed supportively, and hemodialysis may be used in severe cases.

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.

Impact of a Mandatory Prescription Drug Monitoring Program Check on Emergency Department Opioid Prescribing Rates.

BACKGROUND: Prescription drug monitoring programs (PDMPs) exist in 49 states to guide opioid prescribing. In 40 states, clinicians must check the PDMP prior to prescribing an opioid. Data on mandated PDMP checks show mixed results on opioid prescribing. OBJECTIVES: This study sought to examine the impact of the Massachusetts mandatory PDMP check on opioid prescribing for discharges from an urban tertiary emergency department (ED). METHODS: This was a retrospective cohort study of discharges from one ED from 7/1/2010-10/15/2018. The primary outcome was the monthly percentage of patients discharged from the ED with an opioid prescription. The intervention was Massachusetts mandating a PDMP check for all opioid prescriptions. Prescribing was compared pre- and post-mandate. Interrupted time series (ITS) analysis accounted for known declining trends in opioid prescribing. RESULTS: Of 273,512 ED discharges, 35,050 (12.8%) received opioid prescriptions. Mean monthly opioid prescribing decreased post-intervention from 15.1% (SD ± 3.5%) to 5.1% (SD ± 0.9%; p < 0.001). ITS showed equal pre and post-intervention slopes (-0.002, p = 0.819). A small immediate decrease occurred in prescribing around the mandated check: a 3-month level effect decrease of 0.018 (p = 0.039), 6-month level effect 0.019 (p = 0.023), and a 12-month level effect of 0.020 (p = 0.019). The 24-month level effect was not decreased. CONCLUSION: Prior to the mandated PDMP check, ED opioid prescribing was declining. The mandate did not change the rate of decline but was associated with a non-sustained drop in opioid prescribing immediately following enactment.

A Geographically Distinct Case of Fatal Methanol Toxicity from Ingestion of a Contaminated Hand Sanitizer Product During the COVID-19 Pandemic.

The COVID-19 pandemic has triggered outbreaks of unanticipated toxicities, including methanol toxicity. Multiple methanol outbreaks have been described, including contaminated hand sanitizer in the southwest USA. In this case, we describe a fatal case of methanol toxicity from hand sanitizer ingestion, geographically separated from the outbreak in the southwest USA and prior to the announcement of nationwide warnings by the Food and Drug Administration (FDA). The product was identified as one later recalled by the FDA for methanol contamination. Additionally, the consumption in this case was related to a desire to conceal alcohol consumption from family members. This case of methanol toxicity should increase awareness of the ease of which contaminated products can be widely distributed and of the use of alternative ethanol-containing products to obscure relapse in alcohol use disorder.

Pharmaceutical Compounding: a History, Regulatory Overview, and Systematic Review of Compounding Errors.

INTRODUCTION: Medications are compounded when a formulation of a medication is needed but not commercially available. Regulatory oversight of compounding is piecemeal and compounding errors have resulted in patient harm. We review compounding in the United States (US), including a history of compounding, a critique of current regulatory oversight, and a systematic review of compounding errors recorded in the literature. METHODS: We gathered reports of compounding errors occurring in the US from 1990 to 2020 from PubMed, Embase, several relevant conference abstracts, and the US Food and Drug Administration "Drug Alerts and Statements" repository. We categorized reports into errors of "contamination," suprapotency," and "subpotency." Errors were also subdivided by whether they resulted in morbidity and mortality. We reported demographic, medication, and outcome data where available. RESULTS: We screened 2155 reports and identified 63 errors. Twenty-one of 63 were errors of concentration, harming 36 patients. Twenty-seven of 63 were contamination errors, harming 1119 patients. Fifteen errors did not result in any identified harm. DISCUSSION: Compounding errors are attributed to contamination or concentration. Concentration errors predominantly result from compounding a prescription for a single patient, and disproportionately affect children. Contamination errors largely occur during bulk distribution of compounded medications for parenteral use, and affect more patients. The burden falls on the government, pharmacy industry, and medical providers to reduce the risk of patient harm caused by compounding errors. CONCLUSION: In the US, drug compounding is important in ensuring access to vital medications, but has the potential to cause patient harm without adequate safeguards.

Opioid-associated amnestic syndrome: Description of the syndrome and validation of a proposed definition.

OBJECTIVE: An opioid-associated amnestic syndrome (OAS) characterized by acute onset memory loss and bilateral hippocampal signal abnormalities on brain imaging in the setting of a history of opioid use, most notably fentanyl, has been reported. To date, however, there is no case definition to assist neurologists and other clinicians in identifying this syndrome. A multi-disciplinary collaboration of physicians, including neurologists, propose diagnostic criteria for OAS using cases that have been published in the medical literature or presented at conferences. METHODS: Cases were classified as confirmed, probable, or possible based on brain imaging findings and history or analytical testing supporting opioid use. Published articles and presentations were identified by discussion with public health authorities and a systematic search of PubMed. Included were articles, abstracts or posters through November 2019 that presented case reports or case series of a new-onset amnestic syndrome associated with bilateral hippocampal injury on imaging and/or prior opioid or other substance use. The percentages of cases that would meet confirmed, probable, or possible criteria were calculated. RESULTS: Twenty-three publications from all sources met criteria for inclusion, accounting for 40 unique cases. Based on the case definition of OAS, 50% (20/40) were confirmed, 25% (10/40) were probable and 25% (10/40) were possible. CONCLUSION: The development of a validated, formal case definition for OAS can assist neurologists and other clinicians in evaluating patients with amnesia and a history of opioid use.

Difficult Intraoperative Heparinization Following Andexanet Alfa Administration.

Direct oral anticoagulants are now commonplace, and reversal agents are recently becoming available. Andexanet alfa (AnXa), approved by the United States Food and Drug Administration in 2018, is a novel decoy molecule that reverses factor Xa inhibitors in patients with major hemorrhage. We present a case of a 70-year-old man taking rivaroxaban with hemodynamic instability from a ruptured abdominal aortic aneurysm. He received AnXa prior to endovascular surgery, and intraoperatively he could not be heparinized for graft placement. Consideration should be given to the risks and benefits of AnXa administration in patients who require anticoagulation after hemorrhage has been controlled.