Successful Treatment of Confirmed Severe Bupropion Cardiotoxicity With Veno-Arterial Extracorporeal Membrane Oxygenation Initiation Prior to Cardiac Arrest.

Bupropion is a substituted cathinone (ß-keto amphetamine) norepinephrine/dopamine reuptake inhibitor andnoncompetitive nicotinic acetylcholine receptor antagonist that is frequently used to treat major depressive disorder. Bupropion overdose can cause neurotoxicity and cardiotoxicity, the latter of which is thought to be secondary to gap junction inhibition and ion channel blockade. We report a patient with a confirmed bupropion ingestion causing severe cardiotoxicity, for whom prophylactic veno-arterial extracorporeal membrane oxygenation (ECMO) was successfully implemented. The patient was placed on the ECMO circuit several hours before he experienced multiple episodes of hemodynamically unstable ventricular tachycardia, which were treated with multiple rounds of electrical defibrillation and terminated after administration of lidocaine. Despite a neurological examination notable for fixed and dilated pupils after ECMO cannulation, the patient completely recovered without neurological deficits. Multiple bupropion and hydroxybupropion concentrations were obtained and appear to correlate with electrocardiogram interval widening and toxicity.

Minding the osmol gap: a sentinel event and subsequent laboratory investigation.

INTRODUCTION: Many hospitals are unable to determine toxic alcohol concentrations in a clinically meaningful time frame. Thus, clinicians use surrogate markers when evaluating potentially poisoned patients. INDEX CASE: A patient presented after an intentional antifreeze (ethylene glycol) ingestion with an osmol gap of -10.6 that remained stable one hour later. Further investigation revealed that the serum osmolality was calculated and not measured. The true osmol gap was 16.4, which correlated to a measured ethylene glycol concentration of 808 mg/L (80.8 mg/dL, 13.0 mmol/L). SURVEY: A telephone survey of hospital laboratories in our catchment area was performed to investigate the potential for similar events. RESULTS: Thirty-eight (47 percent) hospitals responded. No laboratories were able to test for toxic alcohols. One hospital (2.6 percent) reported routinely calculating osmolality based on chemistries, while two hospitals (5.3 percent) reported scenarios in which this might occur. Thirty-five (92.1 percent) hospitals could directly measure osmolality. Two hospitals (5.3 percent) were reliant on outside laboratories for osmolality measurement. LIMITATIONS: The 47 percent response rate and one geographic area are significant limitations. DISCUSSION: Over 10 percent of hospitals that responded could have significant difficulty assessing patients with toxic alcohol ingestion. CONCLUSIONS: Until the standard of rapidly obtaining toxic alcohol concentrations is broadly implemented, we recommend that policies and procedures be put in place to minimize errors associated with the determination of the osmol gap.

A "madd"-ening confounding: fruit seeds mimicking enteral drug concealment by computed tomography.

OBJECTIVE: To highlight the similarity between madd fruit seeds and enteral drug concealment ("body packing") on computed tomography when evaluated by Hounsfield Units. CASE REPORT: A 13-year-old girl from Senegal presented to the Emergency Department with severe abdominal pain. Examination showed right lower quadrant tenderness with rebound. Computed tomography scan of the abdomen and pelvis revealed smooth, well circumscribed, multiple intraluminal foreign bodies measuring up to 2 cm in size with Hounsfield Units measuring up to 200. The emergency department radiologist reported that these were suspicious for "body packer packets" of either opioids or cocaine, based on their appearance and Hounsfield Unit characteristics. Dietary history later revealed consuption of madd fruit (Saba senegalensis) seeds, which can cause bezoar formation and intestinal obstruction. CONCLUSION: Madd fruit seeds may appear similar to drug packets on computed tomography with similar Hounsfield Unit characteristics. History and clinical context are paramount to avoid misdiagnosis.

Confirmed Fatal Colchicine Poisoning in an Adolescent with Blood and Bile Concentrations-Implications for GI Decontamination?

INTRODUCTION: Colchicine is commonly used to treat diseases like acute gouty arthritis. However, colchicine has a very narrow therapeutic index, and ingestions of > 0.5mg/kg can be deadly. We report a fatal acute colchicine overdose in an adolescent. Blood and postmortem bile colchicine concentrations were obtained to better understand the degree of enterohepatic circulation of colchicine. CASE REPORT: A 13-year-old boy presented to the emergency department after acute colchicine poisoning. A single dose of activated charcoal was administered early but no other doses were attempted. Despite aggressive interventions such as exchange transfusion and veno-arterial extracorporeal membrane oxygenation (VA-ECMO), the patient died 8 days later. Postmortem histology was notable for centrilobular necrosis of the liver and a cardiac septal microinfarct. The patient's blood colchicine concentration on hospital days 1 (~30 hours post-ingestion), 5, and 7 was 12ng/mL, 11ng/mL, and 9.5ng/mL, respectively. A postmortem bile concentration obtained during autopsy was 27ng/mL. DISCUSSION: Humans produce approximately 600mL of bile daily. Assuming that activated charcoal would be able to adsorb 100% of biliary colchicine, using the bile concentration obtained above, only 0.0162mg of colchicine per day would be able to be adsorbed and eliminated by activated charcoal in this patient. CONCLUSION: Despite supportive care, activated charcoal, VA-ECMO, and exchange transfusion, modern medicine may not be enough to prevent death in severely poisoned colchicine patients. Although targeting enterohepatic circulation with activated charcoal to enhance elimination of colchicine sounds attractive, the patient's low postmortem bile concentration of colchicine suggests a limited role of activated charcoal in enhancing elimination of a consequential amount of colchicine.

Jamaican Susumber Berry Poisoning Mimicking Acute Stroke.

BACKGROUND: Stroke mimics are non-vascular conditions that present with acute focal neurological deficits, simulating an acute ischemic stroke. Susumber berry (SB) toxicity is a rare cause of stroke mimic with limited case reports available in the literature. OBJECTIVES: We report four new cases of SB toxicity presenting as stroke mimic, and we performed a systematic review. METHODS: MEDLINE/EMBASE/WoS were searched for "susumber berries," "susumber," or "solanum torvum." RESULTS: 531 abstracts were screened after removal of duplicates; 5 articles and 2 conference abstracts were selected describing 13 patients. A total of 17 patients who ingested SB and became ill were identified, including our 4 patients. All but one presented with acute neurologic manifestation; 16 (94%) presented with dysarthria, 16 (94%) with unstable gait, 8 (47%) with nystagmus/gaze deviation, 10 (59%) with blurry vision, and 5 (29%) with autonomic symptoms. Six (35%) required ICU admission, and 3 (18%) were intubated. Fourteen (82%) had a rapid complete recovery, and 3 were hospitalized up to 1 month. CONCLUSIONS: SB toxicity can cause neurological symptoms that mimic an acute stroke typically with a posterior circulation symptom complex. Altered SB toxins (from post-harvest stressors or temperature changes) might stimulate muscarinic/nicotinic cholinergic receptors or inhibit acetylcholinesterase, causing gastrointestinal, neurological, and autonomic symptoms. In cases of multiple patients presenting simultaneously to the ED with stroke-like symptoms or when stroke-like symptoms fail to localize, a toxicological etiology (such as SB toxicity) should be considered.

Clozapine Toxicity in Two Young Siblings Due to a Pharmacy Dispensing Error: a Pediatric Case Report.

INTRODUCTION: Clozapine is an atypical antipsychotic used to treat refractory schizophrenia; in both therapeutic use and overdose, it can cause significant toxicity. We report two young siblings who developed altered mental status after ingesting clozapine due to a pharmacy dispensing error. CASE REPORT: A 5-year-old girl and her 19-month-old sister presented to the emergency department (ED) with altered mental status after they took their first dose of what was believed to be cimetidine, prescribed to treat molluscum contagiosum. Both children were discharged after a brief period of observation in the ED. Two days later, when the older child continued to be symptomatic, their mother used a web-based pill identifier and discovered that the pills dispensed by the pharmacy were 200 mg clozapine tablets, not the cimetidine that had been prescribed. Ingestion was confirmed with an elevated serum clozapine concentration in the older child of 17 mcg/L at 85 hours post-ingestion (adult therapeutic range: 350-600 mcg/L). Both children had complete resolution of their symptoms 4 days following the ingestion with supportive care alone. DISCUSSION: We report two cases of pediatric clozapine toxicity due to a pharmacy dispensing error. The error was due, in part, to similarly named medications being stored adjacent to each other on a shelf. Dispensing errors are not rare occurrences and their root causes are multi-factorial. This case demonstrates the importance of reducing such errors, particularly for medications with potential for severe toxicity.

Establishing Consensus-based Objectives for the Creation of an Opioid Overdose Curriculum for Emergency Medical Services Clinicians.

OBJECTIVES: Emergency medical services (EMS) clinicians are on the front lines of the opioid epidemic and are often the first health care personnel system to contact patients experiencing opioid toxicity. Although national educational guidelines include opioid toxicity, no specific standardized prehospital educational objectives or competencies exist. The goal of this project was to identify objectives for an EMS opioid toxicity curriculum that could be used for EMS training. METHODS: A list of preliminary educational objectives from U.S. EMS training programs was compiled and reviewed by a group of experts. The Delphi method was used to attain consensus on a final list of objectives for an EMS opioid curriculum. RESULTS: A total of 107 opioid-related preliminary objectives were identified and then narrowed down to 81 preliminary objectives after accounting for redundancy. After four successive rounds of evaluating/accepting/rejecting objectives, 18 final objectives were identified and unanimously approved by the expert panel. CONCLUSION: We identified 18 objectives to serve as a framework for an opioid toxicity curriculum for EMS clinicians. These objectives can serve as a basis for creating a standardized didactic training program for EMS training programs nationwide. Further evaluation will be needed to explore the best means for educational program delivery.

Distinguishing between toxic alcohol ingestion vs alcoholic ketoacidosis: how can we tell the difference?

CONTEXT: Anion gap metabolic acidosis (AGMA) is common in patients presenting for emergency care. While some disease processes and ingestions are easily excluded, diagnosing toxic alcohol (TA) ingestion can be challenging. This is especially true if drug concentrations are not readily available, which forces clinicians to rely on surrogate markers. Like TA ingestion, alcoholic ketoacidosis (AKA) produces an elevated osmol gap and an AGMA. The aim of this study was to identify risk factors suggestive of AKA when TA ingestion was the primary alternative differential diagnosis. We hypothesized that the odds of an AKA diagnosis would increase as ethanol concentration increased. METHODS: This was a retrospective analysis of data from 2000 through 2019 from a single US Poison Control Center. Records were reviewed to identify cases coded as "methanol" or "ethylene glycol"; or coded as "alcohol" or "ethanol with acidosis." The case definition for AKA required: (1) documented alcohol use disorder; (2) urine or serum ketones or elevated blood beta-hydroxybutyrate concentration; (3) anion gap ≥ 14 mmol/L. The inclusion criterion for TAs was a detectable methanol or ethylene glycol concentration. RESULTS: Of 699 patients screened, 86 were diagnosed with AKA and 36 were diagnosed with TA ingestion. As ethanol concentration increased, the odds of an AKA diagnosis significantly increased (OR = 1.016, 95% CI 1.002-1.031, p = .03). CONCLUSIONS: In this retrospective analysis, the odds of diagnosing AKA instead of TA ingestion increased as ethanol concentration increased. The limited ability of common clinical factors to differentiate these diagnoses highlights the need to obtain quantitative TA concentrations in real time. Until prospective validation, interpretation of ketone concentrations and toxic alcohol concentrations (when available) will continue to guide decision making.

Current fatality rate of suspected cyclopeptide mushroom poisoning in the United States.

OBJECTIVE: This study was designed to determine the fatality rate of suspected cyclopeptide-containing mushroom ingestions reported to the National Poison Data System (NPDS). BACKGROUND: Although silibinin reportedly improves survival in suspected cyclopeptide-containing mushroom ingestions, the greater than 20% untreated fatality rate that is often cited is based on decades-old data. An ongoing open-label silibinin trial will likely use historical cases as comparators. A recent single poison control center (PCC) study showed a fatality rate of 8.3%. This study was designed to validate those findings in the NPDS. METHODS: This study was an 11-year (1/1/2008-12/31/2018) retrospective review of suspected cyclopeptide-containing mushroom ingestions reported to NPDS. Inclusion and exclusion criteria were the same as the ongoing silibinin trial: Age >2-years-old; history of eating foraged mushrooms; gastrointestinal symptoms within 48 h of mushroom ingestion; and aminotransferases above the upper limit of normal within 48 h after ingestion. Each original participating PCC confirmed eligibility, diagnosis, treatment, and outcome on included cases. RESULTS: During the study period, 8,953 mushroom exposures were reported to NPDS, of which 296 met inclusion criteria. The PCC survey response rate was 60% (28/47 PCCs), and the individual case response rate was 59% (174/296). Twenty-six cases were subsequently excluded leaving 148 included cases. The overall mortality rate was 8.8% (13/148). Mortality in silibinin/silymarin-treated vs untreated cases was 9.5% (4/42), vs 8.5% (9/106), respectively. A mycologist identified mushrooms in 16.9% of cases (25/148), of which 80% (20/25) were cyclopeptide-containing. Among these confirmed cases, the mortality rate was 10% (1/10) in both silibinin/silymarin-treated and untreated cases. CONCLUSIONS: The contemporary mortality rate of patients with presumed cyclopeptide-mushroom poisoning is only 8.8%. This likely represents improved supportive care for patients with acute liver injury and should be considered the current standard for historical controls in the United States.

A Pharmacokinetic Analysis of Hemodialysis for Metformin-Associated Lactic Acidosis.

OBJECTIVE: Although hemodialysis is recommended for patients with severe metformin-associated lactic acidosis (MALA), the amount of metformin removed by hemodialysis is poorly documented. We analyzed endogenous clearance and hemodialysis clearance in a patient with MALA. METHODS: A 62-year-old man with a history of type II diabetes mellitus presented after several days of vomiting and diarrhea and was found to have acute kidney injury (AKI) and severe acidemia. Initial serum metformin concentration was 315.34 µmol/L (40.73 µg/mL) (typical therapeutic concentrations 1-2 µg/mL). He underwent 6 h of hemodialysis. We collected hourly whole blood, serum, urine, and dialysate metformin concentrations. Blood, urine, and dialysate samples were analyzed, and clearances were determined using standard pharmacokinetic calculations. RESULTS: The total amount of metformin removed by 6 h of hemodialysis was 888 mg, approximately equivalent to one therapeutic dose. Approximately 142 mg of metformin was cleared in the urine during this time. His acid-base status and creatinine improved over the following days. No further hemodialysis was required. CONCLUSION: We report a case of MALA likely secondary to AKI and severe volume depletion. The patient improved with supportive care, sodium bicarbonate, and hemodialysis. Analysis of whole blood, serum, urine, and dialysate concentrations showed limited efficacy of hemodialysis in the removal of metformin from blood, contrary to previously published data. Despite evidence of acute kidney injury, a relatively large amount of metformin was eliminated in the urine while the patient was undergoing hemodialysis. These data suggest that clinical improvement is likely due to factors besides removal of metformin.

Toxicokinetics of hydroxychloroquine following a massive overdose.

BACKGROUND: We report a patient with a massive hydroxychloroquine overdose manifested by profound hypokalemia and ventricular dysrhythmias and describe hydroxychloroquine toxicokinetics. CASE REPORT: 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: 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.

Not your regular high: cardiac dysrhythmias caused by loperamide.

OBJECTIVE: Loperamide, a non-prescription anti-diarrheal agent, is a peripheral mu-opioid receptor agonist that is excluded from the blood-brain barrier by p-glycoprotein at therapeutic doses. Overdoses of loperamide penetrate the central nervous system (CNS), leading to abuse. We report cardiac conduction abnormalities and dysrhythmias after ingestion of a recreational supra-therapeutic dose of loperamide confirmed with an elevated blood loperamide concentration. CASE DETAILS: A 48-year-old woman with a history of alcohol and benzodiazepine abuse presented to the emergency department (ED) with somnolence, weakness and slurred speech. She was taking 20 to 40 tablets of 2 mg loperamide 1-2 times/day for weeks along with clonazepam and whiskey. Vital signs were: blood pressure (BP), 124/90 mmHg; heart rate (HR), 88/min; respiratory rate(RR), 20/min; T, 36.9 °C; O2 saturation 100% on room air (RA). Glucose was 6.4 mmol/L. Electrocardiogram (ECG) had a ventricular rate of 58/min, QRS 164 ms, QT 582 ms with no discernable p-waves. Lactate was 3.5 mmol/L and potassium was 6.2 mEq/L. Labs were notable for an anion gap of 20 mEq/L, ethanol of 3.9 mmol/L, creatinine of 2.3 mg/dL and loperamide concentration of 210 ng/mL (average therapeutic plasma concentration 1.2 ng/mL). She became hypotensive, but responded to fluids. Following treatment for hyperkalemia with calcium, insulin, dextrose, and hypertonic sodium bicarbonate a repeat ECG had a ventricular rate of 66/min, QRS 156 ms, and QT 576 ms. Magnesium was given and pacer pads were placed. During the infusion of magnesium, her BP fell to 92/58 mmHg with a HR of 54/min, RR 14/min, O2 saturation of 97% on RA so the infusion was stopped. The ECG after the magnesium infusion had a ventricular rate of 51/min, QRS of 134 ms, and QT 614 ms. In the ICU she had multiple runs of non-sustained ventricular tachycardia that did not require therapy. Over the next 48 h she improved and was transferred to a floor bed. On day four of hospitalization the patient left against medical advice. At that time, her ECG showed sinus tachycardia with a heart rate 114/min, QRS 82 ms, QT 334 ms. DISCUSSION: Loperamide produces both QRS and QT prolongation at supra-therapeutic dosing. A blood loperamide concentration of 210 ng/mL is among the highest concentrations reported. Supra-therapeutic dosing of loperamide is promoted on multiple drug-use websites and online forums as a treatment for opioid withdrawal, as well as for euphoric effects. With the current epidemic of prescription opioid abuse, toxicity related to loperamide, an opioid agonist that is readily available without a prescription is occurring more frequently. It is important for clinicians to be aware of the potentially life-threatening toxicity related to loperamide abuse in order to provide proper diagnosis, management and patient education.

Outcomes among buprenorphine-naloxone primary care patients after Hurricane Sandy.

BACKGROUND: The extent of damage in New York City following Hurricane Sandy in October 2012 was unprecedented. Bellevue Hospital Center (BHC), a tertiary public hospital, was evacuated and temporarily closed as a result of hurricane-related damages. BHC's large primary care office-based buprenorphine clinic was relocated to an affiliate public hospital for three weeks. The extent of environmental damage and ensuing service disruption effects on rates of illicit drug, tobacco, and alcohol misuse, buprenorphine medication supply disruptions, or direct resource losses among office-based buprenorphine patients is to date unknown. METHODS: A quantitative and qualitative semi-structured survey was administered to patients in BHC's primary care buprenorphine program starting one month after the hurricane. Survey domains included: housing and employment disruptions; social and economic support; treatment outcomes (buprenorphine adherence and ability to get care), and tobacco, alcohol, and drug use. Open-ended questions probed general patient experiences related to the storm, coping strategies, and associated disruptions. RESULTS: There were 132 patients enrolled in the clinic at the time of the storm; of those, 91 patients were recruited to the survey, and 89 completed (98% of those invited). Illicit opioid misuse was rare, with 7 respondents reporting increased heroin or illicit prescription opioid use following Sandy. Roughly half of respondents reported disruption of their buprenorphine-naloxone medication supply post-event, and self-lowering of daily doses to prolong supply was common. Additional buprenorphine was obtained through unscheduled telephone or written refills from relocated Bellevue providers, informally from friends and family, and, more rarely, from drug dealers. CONCLUSIONS: The findings highlight the relative adaptability of public sector office-based buprenorphine treatment during and after a significant natural disaster. Only minimal increases in self-reported substance use were reported despite many disruptions to regular buprenorphine supplies and previous daily doses. Informal supplies of substitute buprenorphine from family and friends was common. Remote telephone refill support and a temporary back-up location that provided written prescription refills and medication dispensing for uninsured patients enabled some patients to maintain an adequate medication supply. Such adaptive strategies to ensure medication maintenance continuity pre/post natural disasters likely minimize poor treatment outcomes.