Faculty Bibliography

Objective: Clozapine is a second-generation antipsychotic medication used to treat refractory schizophrenia. There are limited reports of confirmed clozapine ingestions in young children. We report a case of two siblings who ingested clozapine due to a pharmacy dispensing error; both recovered with supportive care. Case report: A 5-year-old girl and her 19-month-old sister, both previously healthy, presented to the emergency department (ED) around 10 pm with lethargy and confusion soon after they both took their first evening dose of what was believed to be 200mg cimetidine, newly prescribed to treat molluscum contagiosum. In the ED, they were both tachycardic, but otherwise had ageappropriate vital signs. On physical examination, both children were noted to be lethargic and drooling with roving eye movements. The older sibling was also confused and agitated at times with abnormal arm movements. Both children were observed for four hours and discharged home. The 19-month-old remained somnolent, but returned to baseline the following afternoon. The 5-year-old was persistently lethargic and confused the following day, with some improvement 36 hours post-ingestion. Their mother was in close contact with their pediatrician during this time. Given the persistence of symptoms inconsistent with cimetidine, the mother examined the tablets in the prescribed bottle and through a pill identifier, identified the tablets as 200 mg clozapine. Both children were seen in the pediatrician's office on day two and day three post-ingestion with normal electrocardiograms and normal complete blood counts on day three. About 85 hours post-ingestion the older sibling's serum clozapine concentration was reported as 17 mug/L and norclozapine concentration as 55 mug/L (25-400 mug/L). The older sibling returned to her baseline 4 days post-ingestion. When the dispensing error was reported to the pharmacy, it was discovered that the bottles of cimetidine and clozapine had been placed next to one another on the shelf in the pharmacy. Further investigation into the error was undertaken and as a preliminary safety measure, clozapine was moved to a more secure location in the pharmacy. Three months post-exposure, both children were healthy with no sequelae noted on follow-up.
Conclusion(s): We describe two children who ingested clozapine and developed drooling and altered mental status. It took several days for the children to return to their baseline mental status, but complete recovery occurred with supportive care. Efforts should be taken to reduce pharmacy dispensing errors that can lead to serious toxicity in children

Objective: Clozapine-induced myocarditis has a high mortality rate secondary to cardiogenic shock. The Impella is a percutaneously inserted, microaxial flow, short-term ventricular support device. We describe a case of a patient with clozapine-induced fulminant myocarditis successfully bridged to recovery with placement of an Impella. Case report: A 26-year-old man with a history of schizoaffective disorder, epilepsy, and polysubstance use developed fever associated with malaise, nausea, and myalgias while admitted to inpatient psychiatry. His medications included: clozapine, valproic acid, lacosamide, lithium, trazodone, benztropine, and risperidone. Clozapine was started 18 days prior to onset of symptoms. Fever to 39.4 degreeC persisted for 2 days. On evaluation, his vital signs were: blood pressure 102/62 mmHg, heart rate 120/minute, respiratory rate 20/minute, oxygen saturations 90% (room air) and temperature 38.3 degreeC. On examination, he had tachycardia with no murmur, bibasilar rales, and jugulovenous distension. Laboratory testing was notable for a troponin of 45.6 ng/mL, brain natriuretic peptide (BNP) 696.8 pg/mL, lactate 5.6mmol/L, white blood cell count 11.0 x 10³ with 2.2% eosinophils, erythrocyte sedimentation rate (ESR) 6 mm/h, and C-reactive protein 194.3 mg/L. His electrocardiogram showed sinus tachycardia with a right bundle branch block (RBBB), ST depressions in V1 and V2, ST elevations in III, aVF, and aVR. Echocardiogram revealed left ventricle ejection fraction (LVEF) 35% with infero-lateral wall motion abnormalities. Clozapine was discontinued. The patient was transferred to the Cardiac Care Unit, where he became more tachypneic and was intubated. Cardiac catheterization found evidence of right heart failure with no coronary artery disease. An Impella CP device was placed via the right femoral artery for circulatory support. He was treated with vasopressors, inotropes, high-dose steroids and antibiotics. He developed worsening cardiogenic shock with an LVEF 10%. A left ventricular assist device (LVAD) and extracorporeal membrane oxygenation (ECMO) therapy were discussed, but he was not a candidate. Despite minimal pulsatile flow, the patient was supported by the Impella with flow up to 3.3 L/min. After 5 days, cardiac output improved, and the Impella was removed seven days after placement. He was extubated after 9 days. Prior to discharge, echocardiogram was repeated, and LVEF improved to 50%. Laboratory analysis for all rheumatologic and infectious studies were negative, and the onset of disease within 3 weeks of starting clozapine made clozapine- induced myocarditis the most likely diagnosis.
Conclusion(s): Circulatory support devices, such as the Impella should be considered a therapeutic option for management of cardiogenic shock in patients with clozapine-induced myocarditis

Because salicylism is a clinical diagnosis, the serum concentration should be interpreted in conjunction with the clinical presentation. A 26-year-old man presented to the Emergency Department with abdominal painand had extremely elevated serum triglycerides (>7000 mg/dL). Ethanol, acetaminophen, and salicylate concentrations were checked because of concern of self-injurious behavior, which returned at 13.1 mg/dL, undetectable, and >100 mg/dL, respectively. His basic metabolic panel revealed a bicarbonate of 23 mEq/L and an anion gap of 11. An arterial blood gas showed a pH 7.39 and a PCO2 of 36.6 mmHg. On physical examination, he was awake and alert, and had a respiratory rate of 12–14/min. The possible effect of hyperlipidemia to falsely elevate the salicylate concentration was recognized. He was treated for severe hypertriglyceridemia and as his triglyceride level dropped, his repeat salicylate concentration was <1 mg/dL. Since dfferent sized lipoproteins contribute variably to serum sample turbiditythey have the potential to interfere with the absorption of light thereby producing erroneous laboratory results . Clinicians need to be aware of the implications of severe hyperlipidemia and interference to prevent clinical errors based on false positive laboratory results

Background: Although silibinin reportedly improves mortality in patients with cyclopeptide-containing mushroom poisoning, such as Amanita Phalloides, randomized controlled data in humans are lacking. In fact, an ongoing uncontrolled trial of silibinin will likely compare cyclopeptide-associated mortality to historical controls. The purpose of this study was to examine the mortality rate of patients with suspected cyclopeptide-containing mushroom ingestions reported to a single poison control center (PCC) using the same clinical criteria as the current silibinin trial. Methods: This was a retrospective review of patients with presumed amanita phalloides ingestion using the same definitions as the current silibinin trial (NCT00915681): History of eating foraged mushrooms, gastrointestinal symptoms within 48 h of mushroom ingestion, and liver function tests (asparate transaminase (AST) or alanine transferase (ALT)) above the upper limit of normal within 48 h after mushroom ingestion. Toxicall data were searched for all human exposures reported from health care facilities between January 1, 2000 and December 31, 2017 in which ingestion of mushrooms were reported and the inclusion criteria previously mentioned were met. Case fatality rate and final diagnosis were recorded. Results: There were 1498 cases of human mushroom exposures reported to our PCC, of which 662 were from a health care facility and 36 met inclusion criteria. Demographics of the study population included: age range between 7 and 76 years and 26 (72%) were male. The AST and ALT ranged between 30-10,000 and 33-9000, IU/l, respectively. Three patients died resulting in a mortality rate of 8.3%. None of the three fatalities had laboratory confirmation of amanita phalloides. One patient in the study had an unconfirmed case of amanita phalloides who received silibinin and survived. There was one mycologist confirmed case of amanita phalloides who survived with supportive care alone. Additionally, there were two mycologist confirmed cases of chlorophyllum molybdites, as well as a woman ultimately diagnosed with choledocholithiasis. Although neither case involved amanita phalloides, both met inclusion criteria and survived. Conclusion: This retrospective review demonstrates a very low mortality rate in patients who meet the current criteria for enrollment in the silibinin trial. It also highlights the significant limitation of clinical inclusion criteria to confirm cyclopeptide mushroom ingestion. The presence of gastrointestinal symptoms within 48 h includes patients who had symptoms within the first 6 h of ingestion, making amanita phalloides ingestion less likely. Additionally, any abnormality in AST or ALT may lead to false positive inclusion secondary to rhabdomyolysis, a history of hepatic disease or concurrent alcohol use. Yet even with these major limitations, the mortality rate of presumed amanita phalloides ingestion is likely overestimated because many survivors had to be excluded for lack of AST or ALT reporting. In conclusion, using the current clinical criteria of the silibin trial, the mortality rate from presumed cyclopeptide containing mushroom ingestion is lower than previously documented. Using these flawed definitions, in order to demonstrate a 50% reduction in mortality from a conservative 10% mortality, the current silibinin trial would have to include over 200 patients to reach statistical significance with an alpha of 0.05 and a beta of 0.2

Background: Ibuprofen has a wide range of systemic toxicities in the setting of massive overdose. We describe a case of a 29-yearold woman with an overdose of ibuprofen who developed hypothermia, shock, alerted mental status, acute liver failure, and profound metabolic acidosis requiring hemodialysis. Case report: A 29-year-old woman presented to the emergency department (ED) with altered mental status 10 h after taking approximately 300 tabs of 200mg ibuprofen. The ED providers noted somnolence and disorientation on presentation. Her initial vital signs were: blood pressure, 109/63mmHg; pulse, 111 beats/ min; respiratory rate, 17 breaths/min; temperature, 98-F; and bedside glucose, 89mg/dl. During her ED course, she became hypothermic to 93.0-F (rectal) and decreasingly responsive. She was intubated for airway protection. Her initial laboratory studies showed: serum creatinine, 1.4mg/dl; blood urea nitrogen, 17mg/dl; and an anion gap metabolic acidosis (AGMA) with anion gap (AG) of 17 and venous pH of 7.23; lactate, 1.2 mmol/l. Urinalysis was negative for ketones. Acetaminophen, acetylsalicylic acid, and ethanol were all negative. Her initial liver function tests were all within normal limits. Initial urine toxicology drug screen was positive for barbiturates; a subsequent screen was negative. On hospital day (HD) 2, her AG increased to 26 and pH decreased to 7.11. She was started on a continuous intravenous infusion of sodium bicarbonate at 30 mEq/h. Her serum ibuprofen concentration on HD 3 was 330mcg/ml (therapeutic range 10-50mcg/ml). During admission, she developed acute oliguric kidney failure and required renal replacement therapy on HD 4. She also developed acute hepatotoxicity; her peak aspartate transaminase (AST) concentration was >717 U/l (laboratory maximum upper limit); alanine transaminase (ALT) 1873 U/l; bilirubin, 5.0mg/dl, and INR 1.9. A liver transplant center was contacted for evaluation, but her mental status began to improve by HD 4 and liver function ultimately improved. She became hypotensive only after her transaminases began to rise, briefly requiring norepinephrine. Over the course of her 14-day hospital stay, her hemodynamic status, liver function, and kidney function all improved. She was transferred to a psychiatric unit for management of major depression on HD 15. Case discussion: Most cases of acute ibuprofen overdose involve mild to moderate gastrointestinal distress and a self-limited acute kidney injury. This case illustrates the rare but serious potential consequences of massive NSAID overdose. Ibuprofen, as a propionic acid, can directly lead to profound elevated AGMA that usually precedes metabolic acidosis from acute kidney injury. Hypothermia, CNS depression, and hepatotoxicity, all seen in this case, have also been described previously, although rarely together, and the mechanisms are not well elucidated. Interestingly, a false positive urine assay for barbiturates has been described in the setting of ibuprofen use. Conclusion: Ibuprofen is widely used in clinical practice and readily available in large quantities without a prescription. Although uncommon, systemic toxicity in cases of massive ibuprofen overdose is possible and may be delayed. Providers encountering cases of ibuprofen overdose should be cognizant of the clinically important consequences described in this case

Introduction: Overdoses of bupropion XL can result in severe morbidity and mortality. Prolonged toxicity may be related to slow drug release through a complex drug delivery system (DDS). Treatment of bupropion toxicity is largely supportive and includes activated charcoal (AC) and/or whole-bowel irrigation (WBI) with PEG-ELS. However, data are lacking on bupropion adsorption to AC, and the effects of PEG-ELS on drug release from the DDS and on AC adsorption. Aims: The primary aim of this study is to measure the in vitro effects of AC and PEG-ELS in a simulated human gastrointestinal model at therapeutic dosing and mimicking an overdose scenario. Methods: There were two main series; simulated gastric and simulated intestinal contents. Each series had five arms done in triplicate at a final volume of 500 ml at 37 degreeC, and repeated at two bupropion XL doses; 300mg and 3000 mg. Study arms were: (1) bupropion only; (2) bupropion plus 50 g AC added at 1 h (AC Only); (3) bupropion plus 250 ml PEG-ELS added at 1 h (PEG Only); (4) bupropion plus 50 g AC added at 1 h and 250 ml PEGELS added at 1.5 h; (5) bupropion plus 250 ml PEG-ELS added at 1 h and 50 g AC added at 1.5 h. Samples were collected at 0 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h to determine the bupropion concentration using HPLC. Areas under the isotherm curve at 8 h (AUC 8 h) were calculated and overall differences in mean AUC 8 h were tested using analysis of variance; post-hoc pairwise comparisons were performed using Tukey student t-tests. All analysis was stratified by initial bupropion concentration. Results: At the 300mg dose (Figure 1), compared to control, the study arms (AC, PEG or both) were all associated with differences in the AUC 8 h (p<.01) and not altered by fluid pH (p=.513). Also at this dose, all experimental arms had a lower AUC 8 h compared to control, though the effect size for the PEG Only arm was smaller (p=.02). At the 3000mg dose (Figure 2), the mean AUC 8 h was lowest in the AC Only group and highest in the PEG Only group. Compared to control, the AC Only group had the lowest AUC 8 h in both types of fluids (p<.01). The experimental arm with PEG added to AC lowered AUC 8 h in intestinal fluid (p<.01) but not in gastric fluid (p=.052). Both experimental arms that started with PEG were not significantly different compared to control (p>.05). Overall, AUC's were higher in gastric fluid compared to intestinal fluid (p<.01). Conclusions: In this in vitro model, AC adsorbs bupropion, though that adsorption appears to be affected by the specific media (gastric versus intestinal fluid). These results also suggest that PEG-ELS interferes with AC adsorption of bupropion. The clinical significance of this is unknown. This study was partially funded by a research grant from the American Academy of Clinical Toxicology

Objective: Clozapine is an atypical antipsychotic that is used primarily for refractory schizophrenia. Clozapine exhibits not only dopaminergic effects, but also has antimuscarinic properties and a strong affinity for the 5-hydroxytryptamine (5-HT2) receptors in the brain. Here, we present an unusual case of serotonin toxicity associated with clozapine withdrawal. Case report: A 22-year-old man with a history of bipolar disorder presented to the Emergency Department with altered mental status. Vital signs upon arrival were blood pressure 137/57 mmHg, heart rate 129/min, respiratory rate 20/min, and temperature, 37.7 degreeC. Physical examination demonstrated a depressed mental status as well as rigid tone with hyperreflexia and clonus in the lower extremities. The patient was admitted to the intensive care unit (ICU) for management of presumed serotonin toxicity. His head computerised tomography (CT) scan and cerebral spinal fluid studies were negative for evidence of structural or infectious etiologies. On further questioning, it was discovered that the patient had recently stopped taking his clozapine. No other medications, including over-the-counter or supplements, or drugs of abuse were reported. In the ICU, he continued to exhibit muscular rigidity, despite the administration of lorazepam and benztropine. He was restarted on clozapine while in the ICU and his symptoms began to improve. He was medically cleared on day 14 of admission. Conclusion: Here, we present an unusual case of presumed serotonin toxicity triggered by clozapine withdrawal. In the literature, there are few reports of this phenomenon [1]. It is hypothesized that clozapine use downregulates 5-HT2 receptors and discontinuation of clozapine leads to up-regulation of the 5-HT2 receptors. This can predispose to serotonin toxicity, especially when a selective serotonin re-uptake inhibitor (SSRI) or another serotonergic agent is involved. Case reports suggest that symptoms occur as soon as 24 hours after stopping. While this mechanism has been reported in other drugs with serotonin receptor activity like clomipramine [2], reports of serotonin toxicity in clozapine withdrawal without a serotonergic agent on board is rarely reported