Faculty Bibliography

Objective: Ranolazine is an antianginal drug, used for chronic angina refractory to first line agents. In oral therapeutic doses, the time to peak plasma concentration is 2-5 hours, with a halflife of 7 hours. High oral doses can produce dizziness, nausea, and vomiting. Ranolazine affects cardiac conduction in multiple ways. It inhibits the late phase of the inward sodium current in myocardial cells. This current exchanges Ca2+ via a Na+/Ca2+ antiporter, which causes calcium-induced calcium release from the sarcoplasmic reticulum. Thus, ranolazine indirectly acts as a calcium channel blocker. Ranolazine also inhibits the delayed rectifier potassium current (hERG) causing QT prolongation. In cellular models, ranolazine blocks neuronal sodium channels. This may underlie the occurrence of seizures reported in overdose. Few reports of ranolazine overdoses exist, limiting definitive management recommendations. We present a case report of a fatal ranolazine overdose. Case report: A 67-year-old man with a past medical history of hypertension, coronary artery disease, chronic angina, and schizophrenia presented to the emergency department with a complaint of emesis. He reported ingesting approximately 30 g of extended-release ranolazine several hours prior in a suicide attempt. Physical examination demonstrated an alert male in no acute distress. Vitals signs were: blood pressure 160/87 mmHg; heart rate 72 beats/min; respiratory rate 18 breaths/minute; and pulse oximetry 99% (room air). An electrocardiogram (ECG) showed normal sinus rhythm (73 beats/minute), QTC 434ms and QRS 96 ms. Laboratory analysis showed normal electrolytes, renal and hepatic function. Acetaminophen, ethanol, and salicylate concentrations were undetectable. Seven hours after presentation, he developed acute altered mental status with confusion. The ECG showed a first-degree atrioventricular block at 66 beats/minute; PR, 220 ms; QRS 108 ms; and QTC, 450 ms. Nine hours after presentation, three convulsive episodes occurred, each lasting several minutes, before spontaneously resolving. Shortly thereafter, he developed pulseless electrical activity for 20 minutes, followed by ventricular tachycardia, and ultimately asystole. He received defibrillation, continuous cardiopulmonary resuscitation, and advanced cardiac life support, but resuscitation was unsuccessful. An ante-mortem serum ranolazine concentration was 12 mg/L (therapeutic 0.4-6.1mg/L). Ranolazine is primarily metabolized by CYP3A and CYP2D6. The contributions of his home medications atorvastatin, clonazepam, and clopidogrel (CYP3A substrates) to his clinical picture are unknown.
Conclusion(s): Based on limited literature reports and this case, ranolazine overdose can cause severe morbidity and delayed mortality, despite initial apparent clinical stability. Patients with ranolazine overdose should be closely monitored for rapid cardiac and neurologic decompensation along with potential consideration for extracorporeal life support (ECLS)

Objective: We present a patient who developed prolonged coma following treatment of ethanol withdrawal with large doses of diazepam and demonstrated prolonged elimination toxicokinetics. Case report: A 68-year-old man who drank 5-6 alcoholic beverages/day was admitted for an elective transcatheter aortic valve replacement. Two days post-procedure, he developed agitation and was presumptively treated for ethanol withdrawal with diazepam (470 mg IV over 24 hours). He remained comatose for four days prompting a toxicology consult. On day 7 of persistent coma from presumed benzodiazepine excess, flumazenil (0.5 mg) was administered; he opened his eyes for the first time, began speaking, and answering simple questions, but 30 minutes later was comatose again. Flumazenil infusion 0.25mg/h was trialed with unclear effect. His hospitalization was complicated by gastrointestinal bleeding and mild ischemic stroke deemed noncontributory to his clinical status. The flumazenil infusion was discontinued 1 week later. His evaluation was extensive (brain magnetic resonance imaging and computerised tomography, lumbar puncture, and blood cultures) and unremarkable. On hospital week 4, he became only gradually more awake, and was eventually discharged to a rehabilitation facility on hospital week 6, awake, conversive but still confused. Six weeks later, he was discharged home fully recovered. He remains amnestic to his hospitalization. Serum diazepam and nordiazepam concentrations were determined via liquid-chromatography mass-spectrometry. Concentrations obtained four days after the last dose were: diazepam 963 mug/L (therapeutic: 200-1000 mug/L) and nordiazepam 240 mug/L (therapeutic: 100-1500 mug/L). Elimination kinetics were calculated with apparent half-lives of 294 hours and 797 hours for diazepam and nordiazepam, respectively. Genotyping of CYP3A4 and CYP2C19, the two primary metabolizers of diazepam, demonstrated no abnormalities.
Conclusion(s): Diazepam demonstrated extremely atypical elimination kinetics despite normal renal and hepatic function. Acute tolerance which is expected after prolonged benzodiazepine exposure was not clearly demonstrated. The relationship between his serum concentration and clinical status is unclear at this time

PURPOSE/OBJECTIVE:The aim of this study was to determine rates of and possible reasons for guideline-discordant ordering of CT pulmonary angiography for the evaluation of suspected pulmonary embolism (PE) in the emergency department. METHODS:A retrospective review was performed of 212 consecutive encounters (January 6, 2016, to February 25, 2016) with 208 unique patients in the emergency department that resulted in CT pulmonary angiography orders. For each encounter, the revised Geneva score and two versions of the Wells criteria were calculated. Each encounter was then classified using a two-tiered risk stratification method (PE unlikely versus PE likely). Finally, the rate of and possible explanations for guideline-discordant ordering were assessed via in-depth chart review. RESULTS:The frequency of guideline-discordant studies ranged from 53 (25%) to 79 (37%), depending on the scoring system used; 46 (22%) of which were guideline discordant under all three scoring systems. Of these, 18 (39%) had at least one patient-specific factor associated with increased risk for PE but not included in the risk stratification scores (eg, travel, thrombophilia). CONCLUSIONS:Many of the guideline-discordant orders were placed for patients who presented with evidence-based risk factors for PE that are not included in the risk stratification scores. Therefore, guideline-discordant ordering may indicate that in the presence of these factors, the assessment of risk made by current scoring systems may not align with clinical suspicion.

Objective: Beta-adrenergic antagonists (BAAs) and calcium channel blockers (CCBs) negatively affect chronotropy and inotropy and are administered for many indications. The frequency of adverse reactions when BAAs and CCBs are administered concomitantly is infrequently described [1]. We reviewed the incidence of hemodynamic instability in patients in whom both a BAA and CCB were administered within a pharmacologically relevant time period.
Method(s): This was a quality improvement initiative in emergency department (ED) patients, performed at an urban, tertiary care hospital network from 1 October 2016 to 30 September 2018. Adult patients (>=18 years) who received both an intravenous BAA and CCB (in either order) within 6 hours were included. Primary outcomes were the incidence of bradycardia (heart rate <60 bpm) or hypotension (systolic blood pressure <90mmHg) after administration of the second medication. Secondary outcomes were associated diastolic blood pressure changes and administratively assigned primary and secondary diagnoses.
Result(s): Overall 56 ED patients met inclusion criteria. The median time between medication administration was 110 minutes for the cohort. The median decrease in pulse was 42 bpm. The median decrease in systolic blood pressure was 26mmHg, and the median diastolic blood pressure decrease was 11mmHg. According to the prespecified endpoints, 8.9% developed bradycardia, 8.9% developed systolic hypotension, and 17.9% developed either complication. These complications occurred at median times after second medication administration of 36 minutes for bradycardia and 10 minutes for hypotension. The most common diagnosis in patients who received concomitant BAA and CCB administration was atrial fibrillation (n= 39). All patients who developed bradycardia had atrial fibrillation (n= 4) or atrial flutter (n= 1). All patients who developed hypotension had atrial fibrillation (n= 5).
Conclusion(s): Despite a lack of published data, the administration of both BAAs and CCBs within 6 hours can cause significant hypotension and bradycardia in emergency department patients. Avoidance of concurrent administration of these medication classes or assurance of antidotal availability or pretreatment (i.e. with calcium salts) should be strongly encouraged