Faculty Bibliography

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/CONCLUSIONS: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.

BACKGROUND:Illicitly manufactured fentanyl and fentanyl analogues (IMFs) are being increasingly suspected in overdose deaths. However, few prior outbreaks 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 opioid use disorder who presented to two urban emergency departments (EDs) with opioid toxicity after insufflating a substance they believed to be cocaine. CASE REPORTS/METHODS:Over a period of under three hours, nine patients from five discrete locations were brought to two affiliated urban academic EDs. All patients denied prior illicit opioid use. All patients endorsed insufflating cocaine shortly prior to ED presentation. Soon after exposure, all developed lightheadedness and/or respiratory depression. Seven patients received naloxone en route to the hospital; 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 were discharged home after observation. Blood +/- urine samples were obtained from eight patients. 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. DISCUSSION/CONCLUSIONS:IMF-contamination of illicit drugs remains a public health concern that does not appear to be restricted to heroin. This confirmed outbreak demonstrates that providers should elevate their level of suspicion for concomitant unintentional IMF exposure even in cases of non-opioid drug intoxication. Responsive public health apparatuses must prepare for future IMF-contamination outbreaks.

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.

Introduction: Suicide attempts by poisoning are increasing and suicide occurrence may be associated with seasonality. We performed a retrospective analysis of poisoning exposure data from a single Poison Control Center (PCC) to determine if suicide attempts were associated with season, day of the week, and/or US holidays.Methods: We analyzed exposure cases identified as "intentional overdose - suspected suicide attempt" over 2009-2012. We used singular spectrum analysis (SSA) to detect cyclic patterns in the data and then performed Poisson regression and t-tests to determine if the number of cases were associated with season, day of the week, and US holidays.Results: There were 42,578 cases of "intentional overdose - suspected suicide" during the study period. Singular Spectrum Analysis (SSA) showed that the number of cases associated with poisoning suicide attempts peaked in the Spring and dipped in the Fall. Regression analysis showed higher numbers of suspected suicide attempts from intentional overdose in spring compared with winter by 1.07 times (p = 0.003), and on Sunday (p < 0.001), Monday (p < 0.001), and Thursday (p = 0.02) compared with Saturday by at least 1.09 times. No significant difference was seen for most holidays except for lower numbers of cases around Christmas (3 days before and after; 22.0 vs. 32.3 on control dates, p < 0.001).Conclusions: Suicide attempts by poisoning are associated with season of the year and some days of the week. Further research is required determine reasons for these associations and implementation of public health interventions.

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: 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