Faculty Bibliography

Background: The opioid epidemic remains a significant public health problem in the United States. Illicitly manufactured fentanyl and fentanyl analogues (IMFs) are being increasingly identified in overdose deaths. Fentanyl is approximately 100 times more potent than morphine, and IMFs have become an economical way to adulterate or replace heroin among illicit drug distributors and patients with opioid use disorder (OUD). While adulteration by IMFs is increasingly recognized among patients with OUD, what has received less attention is the contamination of non-opioid illicit substances, such as cocaine, with IMFs. There are few prior outbreaks that have been reported thus far of patients with laboratory-confirmed IMF toxicity after reporting intent to use only nonopioid substances. Herein we report a case series of nine patients without OUD who presented to two urban emergency departments (EDs) with opioid toxicity after insufflating a substance they believed to be cocaine. Case Reports: Over a period of under three hours, nine patients from five discrete locations were brought to two affiliated urban academic EDs. All patients were in their third decade of life and denied prior illicit opioid use. Two patients reported prior opioid exposure in the form of prescribed analgesics only, both more than one year prior. One patient reported a remote history of deep venous thrombosis; all others denied any significant past medical history. All patients endorsed insufflating cocaine shortly prior to ED presentation. Over the seconds to minutes following insufflation, all patients developed lightheadedness, and seven patients lost consciousness. In all cases of loss of consciousness, Emergency Medical Services responded and found the patients to have varying degrees of respiratory depression. These seven patients received naloxone en route to the hospital (Table 1) and all had improvement in respiratory function by arrival to the ED. None of the patients required any additional naloxone administration in the ED. All nine patients reported nausea and/or emesis which resolved with symptomatic treatment. All nine patients were discharged to home after an observation period. Blood samples were obtained from eight patients, and urine samples from six of these. One patient declined laboratory testing. All patients who provided specimens tested positive for cocaine metabolites and had quantifiable IMF concentrations, as well as several detectable fentanyl derivatives, analogues, and synthetic opioid manufacturing intermediates. (Table 2) Discussion: The geographic and temporal proximity of our patients' presentations, combined with the overlap in fentanyl precursors and analogues found on laboratory testing strongly suggests a common source, though sample product was not available for confirmation. Interpretation of this data is subject to a number of limitations, including variations in time between exposure and lab collection limiting interpatient comparability.
Conclusion(s): IMF-contamination of illicit drugs remains a public health concern that does not appear to be restricted to heroin. Increasing prevalence implies that providers should elevate their level of suspicion for concomitant IMF exposure even in cases of non-opioid drug intoxication. Responsive public health apparatuses need to prepare for future IMF-contamination outbreaks. (Table Presented)

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

Background: The "Pollyanna Phenomenon," an optimism for useful interventions appearing as efficacious as useless ones, was first described in 1992[1]. An editorial written in 1997 highlighted this phenomenon regarding passive data collection from Poison Control Centers (PCCs) and its limitations related to minimally symptomatic or asymptomatic patients[2]. PCCs continue to collect data passively with an immense data pool. Despite these "big data," limitations to PCC research persist. The term toxicovigilance was borne from this editorial and suggestions were made to improve PCC data fidelity and to overcome the "Pollyanna Phenomenon." We investigated PCC research over the past 40+ years to determine the impact of this editorial on toxicovigilance[2].
Method(s): We searched PubMed and EMBASE for PCC research from 1978 to 2020 using these search terms: "Poison Center", "Poison Control Center", "Poison Centre", "Poison Control Centre." Research articles before 1997 established a baseline for research quality[2]. Research articles from 1997 to April 2020, served as the intervention group assessing for changes in the quality of research and were examined for evidence of toxicovigilance. Articles were included in this study based on the following criteria: written in English; classified as original research; performed in a PCC setting, and the study objective was focused on an identifiable xenobiotic or xenobiotics. Each article was assessed for toxicovigilance based on the following criteria: confirmation of said xenobiotic(s) either qualitatively or quantitatively, study methodology (retrospective or prospective), and clinical recommendations made "beyond the scope of study methodology." If a study did not confirm xenobiotics' presence analytically, the study was considered to make recommendations beyond the scope of the study methodology.
Result(s): Our search initially identified 1614 articles. A random sample of 400 articles was chosen for review. From 1978-1997, 88 articles were initially identified. Twenty-five studies met inclusion criteria. Fifteen were retrospective and ten were prospective. Two studies confirmed exposure confirmation analytically in each group. Ten retrospective studies made clinical recommendations based on their conclusions, none of which confirmed the analytical presence of xenobiotic(s). Ten prospective studies made clinical recommendations with only two analytically confirming the presence of the xenobiotic. From 1998-2020, 138 research studies met inclusion criteria of which 117 were retrospective and 19 were prospective. Of these two groups, 19 and 7 had analytically confirmed xenobiotic presence in the retrospective and prospective studies, respectively. Sixty-eight retrospective studies and ten prospective studies made clinical recommendations without analytically confirming xenobiotic exposures. Comparing the baseline and intervention groups, we observed an increase in the frequency of retrospective studies with a similar proportion making clinical recommendations while lacking confirmation of exposures. There was an increase in rates of xenobiotic confirmation by 2% in the intervention period.
Conclusion(s): Toxicovigilance appears to be lacking in many PCC studies. Despite vast advancements in analytical techniques and the ability to gather and record data, the "Pollyanna Phenomenon" remains vibrant in PCC research. Efforts towards improving the frequency of analytical testing and confirmation of xenobiotic exposure are essential to improve PCC data collection and research and must be considered prerequisites for journal publication. (Table Presented)

Objective: Hyperthermia is a life-threatening complication of agitated delirium, and a potential consequence of sympathomimetic, anticholinergic, or oxidative phosphorylation uncoupling xenobiotics. Failure to promptly cool a hyperthermic patient leads to morbid sequelae, including rhabdomyolysis, acute kidney injury, ischemic hepatitis (shock liver), disseminated intravascular coagulation, and possibly death. The primary objective of this study is to assess one Poison Control Center's (PCC) experience with hyperthermic patients, specifically as it relates to the use of ice or water bath treatment. Secondary objectives include characterizing mortality rate, ambient temperatures at the time of presentation, and initial laboratory abnormalities.
Method(s): This is a retrospective analysis of data from a single PCC from 2014 to 2019. A structured query language search (SQL) of Toxicall

BACKGROUND:We report a patient with a massive hydroxychloroquine overdose manifested by profound hypokalemia and ventricular dysrhythmias and describe hydroxychloroquine toxicokinetics. CASE REPORT/METHODS:A 20-year-old woman (60 kg) presented 1 h after ingesting 36 g of hydroxychloroquine. Vital signs were: BP, 66 mmHg/palpation; heart rate, 115/min; respirations 18/min; oxygen saturation, 100% on room air. She was immediately given intravenous fluids and intubated. Infusions of diazepam and epinephrine were started. Activated charcoal was administered. Her initial serum potassium of 5.3 mEq/L decreased to 2.1 mEq/L 1 h later. The presenting electrocardiogram (ECG) showed sinus tachycardia at 119 beats/min with a QRS duration of 146 ms, and a QT interval of 400 ms (Bazett's QTc 563 ms). She had four episodes of ventricular tachydysrhythmias requiring cardioversion, electrolyte repletion, and lidocaine infusion. Her blood hydroxychloroquine concentration peaked at 28,000 ng/mL (therapeutic range 500-2000 ng/mL). Serial concentrations demonstrated apparent first-order elimination with a half-life of 11.6 h. She was extubated on hospital day three and had a full recovery. CONCLUSION/CONCLUSIONS:We present a massive hydroxychloroquine overdose treated with early intubation, activated charcoal, epinephrine, high dose diazepam, aggressive electrolyte repletion, and lidocaine. The apparent 11.6 hour half-life of hydroxychloroquine was shorter than previously described.