Faculty Bibliography

Background: Extracorporeal membrane oxygenation (ECMO) is a rescue therapy for patients with acute respiratory distress syndrome (ARDS) and refractory cardiogenic shock. Patients with diphenhydramine overdose can develop severe cardiotoxicity, including wide-complex tachycardia leading to cardiac arrest. There are no reported cases of confirmed diphenhydramine poisoning successfully treated with ECMO Hypothesis: ECMO is effective in severe diphenhydramine poisoning with ARDS and refractory cardiogenic shock. Methods: Single-patient chart review. Case: An 18-year-old female with a history of depression was brought to the emergency department (ED) after being found unresponsive in her car with an empty package of diphenhydramine and empty bottle of ibuprofen Initial emergency medical services (EMS) vital signs were BP 60 mmHg/palp, HR 114 bpm, and RR 12 bpm. Bag-valve mask ventilation was initiated en route to the hospital. In the ED, the patient was unresponsive and then began actively seizing. Cardiac monitoring revealed a wide-complex tachycardia, and then the patient went into a pulseless electrical activity (PEA) cardiac arrest Return of spontaneous circulation occurred after 6 min of CPR during which she was intubated and received intravenous sodium bicarbonate, epi-nephrine, dextrose, calcium, and normal saline. Despite vasopressors and maximum ventilator support, the patient developed ARDS and refractory cardiogenic shock. She was placed on veno-arterial (VA) ECMO. The patient received VA ECMO for 3 days, then veno-venous (VV) ECMO for 11 days, and mechanical ventilation foratotalof21 days. Her course was complicated by rhabdomyolysis, acute kidney injury requiring dialysis, acute liver failure, and compartment syndrome of her left lower extremity necessitating fasciotomy. She was discharged to inpatient rehabilitation neurologically intact 30 days after presentation. A serum diphenhydramine concentration obtained in the ED on arrival was 6000 ng/mL (50-100 ng/mL). Acetaminophen, salicylate, and urine toxicology testing were all negative. Discussion: We believe this is the first case of confirmed diphenhydra-mine poisoning successfully treated with ECMO. This case report supports the use of ECMO in poisonings with cardiovascular collapse secondary to a cardiac toxin. Conclusion: ECMO can be used as a life-saving treatment modality in severe diphenhydramine overdose refractory to conventional therapy

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: Amygdalin, marketed misleadingly by the misnomer "Vitamin B17", is a cyanogenic glycoside found in certain seeds (apricot, bitter almond, etc.). When swallowed, it is hydrolyzed in the small intestine into cyanide, and absorbed systemically. Despite a ban from the U.S. FDA and a Cochrane Review concluding no benefit to treat cancer, amygdalin is still available for purchase over the internet in 500mg capsules, each containing up to 30mg of cyanide. Thus, an estimated adult LD50 is as few as four capsules. We present a massive intentional overdose of amygdalin, with delayed recurrent hyperlactatemia, and successful combination antidotal therapy. Case report: A 33-year-old woman presented to the ED approximately 5 h after intentionally ingesting 40 capsules of 500mg amygdalin (20 g). On arrival, her vital signs were: HR 127/min, BP 112/65mmHg, RR 25/min, SpO2 98%. She was in agitated delirium, diaphoretic and mydriatic with an ECG notable for QTc 538ms. Lorazepam 2mg and magnesium sulfate 2 g were administered for agitation and prolonged QTc, respectively. Within 30 min of sedation, she became comatose, more tachypneic/diaphoretic, and hypotensive; therefore, 5 g hydroxocobalamin was empirically administered. Her pre-treatment venous blood gas showed: pH 7.27, pCO2 17.1mmHg, HCO3 7.7mmol/l, and lactate 14.1mmol/l. After initial treatment, she was noted to have oral foaming and hypoxia, so was intubated with sodium bicarbonate pre-treatment and another 5 g of hydroxocobalamin was given along with 25 g of sodium thiosulfate. Her BP normalized, QTc shortened, and lactate fell to 0.9mmol/l. Approximately 12 h later, her BP decreased to 60 s/40 s, her lactate increased to 8.1mmol/l and her QTc prolonged to 547 ms. Norepinephrine and vasopressin were started, activated charcoal was given and magnesium sulfate, sodium bicarbonate, hydroxocobalamin and sodium thiosulfate were redosed as previously with an improvement in vital signs, decrease in QTc and clearance of lactate. Her course was complicated by pneumonia, requiring continued sedation and ventilation, but she was extubated with no neurologic deficits on hospital day 9. Initial serum cyanide concentration was found to be 400mcg/l. Case discussion: Given that each 500mg capsule of amygdalin contains up to 30mg of cyanide, this patient ingested as much as 1.2 g of cyanide. The first-line antidote, hydroxocobalamin, has a binding ratio of 50:1 by molecular weight. So, for every 5 g of hydroxocobalamin, only approximately 100mg (4-5 capsules) of hydrogen cyanide will be sequestered. As might be expected, toxicity recurred due to ongoing absorption and/or decreased motility to the distal gut, where the majority of cyanide absorption may occur. Finally, we demonstrate the need to redose hydroxocobalamin and sodium thiosulfate in the case of recurrent cyanide toxicity from massive amygdalin overdose. Conclusions: Amygdalin remains a significant threat to human life with no role as a clinical therapeutic. Internet marketers should be held accountable by government authorities. We present a case of severe, recurrent cyanide toxicity secondary to massive amygdalin overdose, requiring multiple staggered doses of hydroxocobalamin and sodium thiosulfate

Background: In 2016, the American Association of Poison Control Centers/National Poison Data System (AAPCC/NPDS) recorded over one million exposure calls for children under 6-years-old with 12.8% requiring management in a healthcare facility. While widely used as a method of poisoning surveillance and epidemiologic information, the AAPCC/NPDS requires active reporting and is subject to significant underreporting of cases. Objective: The aim of this study was to assess the reporting of pediatric poisoning cases treated at healthcare facilities (HCF) to our regional poison control center (PCC) based on poison exposure category. Methods: This analysis builds on a previously unpublished retrospective review assessing factors associated with PCC reporting. We obtained poisoning visit information from two databases: PCC Toxicall and the Statewide Planning and Research Cooperative System (SPARCS) over a 4-year period (2010-2014). SPARCS is an all payer database that collects patient demographics, diagnoses, treatments, and charges for all inpatient hospital services and emergency department visits. Children under 6-years-old treated at a HCF located within the PCC primary catchment area with ICD9 diagnosis codes 960-979, 981-987, or 989 were identified in SPARCS. These cases were then uniquely matched to PCC Toxicall on patient age, sex, healthcare facility, name, and admission date. The resulting matched dataset was used to describe PCC reporting for visits within each poison category. ICD9 diagnosis codes were grouped into poison categories consistent with AAPCC/NPDS major categories. We calculated the proportions of each poison category reported to the PCC and determined which poison categories had highest and lowest percentages of reporting. We used descriptive statistics to characterize the data. Results: We identified 11,620 children in SPARCS under the age of six years treated in a local HCF with a poisoning diagnosis code; 59.8% (N=6951) of these patients were matched to a reported PCC Toxicall case. The poison categories with the largest percentage of cases reported to PCC included: anticonvulsants (N=73, 84.9% reported; RR 1.45, p<001), cardiovascular drugs (N=420, 80.7% reported; RR 1.40, p<001), antihistamines (N=336, 79.8% reported; RR 1.37, p<001)), antidepressants (N=115, 79.1% reported; RR 1.35, p<001), and sedatives/hypnotics (N=405, 77.8% reported; RR 1.34, p<001). Of the unreported cases (N=4669), the poison categories with the smallest percentage of cases reported to PCC included: venom (N=755, 0.3% reported; RR 0.004, p<001), heavy metals/lead (N=117, 1.7% reported; RR 0.03, p<001), CO/gases (N=972, 15.4% reported; RR 0.25, p<001), plants/mushrooms (N=84, 16.7% reported; RR 0.28, p<001), and antimicrobials (N=183, 56.3% reported; RR 0.97, p=.62). Conclusions: Environmental exposures, including heavy metals/ lead and carbon monoxide, were associated with a high percentage of underreporting to our regional PCC. These findings suggest an area for focused outreach and education regarding the availability of the PCC in the consultation and treatment of all types of pediatric poisoning exposures, specifically including non-medicinal/environmental exposures

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