J. Med. Toxicol. DOI 10.1007/s13181-014-0458-4 ANNUAL MEETING ABSTRACTS 2015 ACMT Annual Scientific Meeting, March 27–29, 2015 Clearwater Beach, FL 1. Efficacy of Trypsin in Treating Coral Snake Envenomation in the 2. Lipid Emulsion Rapidly Activates Insulin Signaling Both Alone Porcine Model and to Combat Toxicity During Bupivacaine-Induced Sensitization of IRS1 Parker-Cote JL, O’Rourke D, Brewer KL, Lertpiriyapong K, Girard J, Bush SP, Miller SN, Punja M, Meggs WJ Fettiplace MR, Kowal K, Young A, Ripper R, Lis K, Weinberg G Brody School of Medicine at Eastern Carolina University, Greenville, University of Illinois at Chicago, Chicago, IL, USA NC, USA Background: Recent publications have identified that local anesthetics Background: Though current definitive treatment for Micrurus fulvius uncouple insulinergic signaling by inhibitiing pi3k/Akt and lipid emul- fulvius envenomation is antivenin, this horse serum treatment carries sion activates Akt/GSK-3β following ischemia–reperfusion. Further- risks, and the antivenin for M. fulvius (Eastern coral snake) envenomation more, while it is clear that lipid emulsion exerts a cardiotonic effect, it is no longer in production. Therefore, investigation in alternative treat- is unclear through what pathway this effect functions. ments for M. fulvius envenomation is warranted. Hypothesis: We hypothesized that bupivacaine uncouples insulinergic Research Question: The objective of this study is to assess the efficacy signaling which sensitizes the heart to insulinergic signaling during of trypsin, a protease, in an in vivo porcine model by the local injection of recovery (via feedback to IRS1) and lipid emulsion activates insulinergic trypsin after M. fulvius venom injection. signaling, potentiating the recovery effect. Methods: Thirteen female pigs received a 1-mL subcutaneous injection Methods: Forty-two male Sprague–Dawley rats received 10 mg/kg of Eastern coral snake venom (10 mg/mL) in the right distal hind limb bupivacaine over 20 s, followed by either nothing or 10 mL/kg ILE (30 % (27-gauge needle; depth, 3 mm) and were then randomized into control Intralipid®). Following sacrifice at 0 (control), 1.5, 5, or 10 min after start-of- (n=7) or experimental (n=6) groups. One-minute post-injection animals infusion, heart, liver, and kidney were frozen and/or preserved. An additional were either injected with 1 mL of saline (control) or 1 mL of trypsin set of three animals was exposed to 10 mL/kg ILE and sacrificed at the 5- solution (experimental; 100 mg/mL) at the site of venom injection on the min time point; a final set of three animals was pre-treated with pi3k inhihitor right distal hind limb of all pigs. Investigators responsible for assessment Wortmannin, then subjected to 10 mg/kg bupivacaine, and sacrificed at of toxicity and study endpoints were blinded to group assignment. Mon- 10 min. Protein was extracted, and phosphorylation level was quantified itoring occurred continuously the first 4 h, at which point surviving for Akt, p70, s6, IRS, and Gsk-3β. Additional lysates were extracted for animals were extubated, and then every 8 h for the next 3 days for signs glycogen quantification. Tissue was also prepared for electron microscopy. of toxicity: respiratory rate<15 breaths per minute (bradypnea), apnea, Results: High-concentration bupivacaine blocked insulinergic signaling (in falling pulse oximetry, and agonal respirations. Fisher’s exact test was heart and kidney) via rapid de-phosphorylation of Akt/GSK-3β/p70/s6. Once used to determine differences in the toxicity and survival rates in control drug concentration dropped below channel blocking thresholds, a rebound versus treated animals. hyper-activation was observed. Blocking insulin signaling with Wortmannin Results: Control pigs were more likely to develop signs of toxicity (p= exacerbated toxicity indicating the need for sensitization during recovery. Lipid 0.009) and less likely to survive to 12 (p=0.002) or 24 h (p=0.009) than treatment rapidly phosphorylated upstream insulingergic targets (Akt) with a treated pigs. Four of the six treated pigs survived to the end of the study, delayed re-phosphorylation of downstream targets in insulin sensitive tissue (3 days post-injection) versus 0 of the control pigs. The two trypsin (heart) but not in insulin-insensitive tissue (kidney). Furthermore, in the treatment animals that did not survive showed signs of toxicity at 844.5 absence of toxicity, lipid emulsion drove Akt phosphorylation. The sensitivity ±178.9 min versus controls 263.42±36.5 min. to insulin signaling was confirmed by increased glycogen accumulation in Conclusion: Local injection of trypsin, a proteolytic enzyme, at the site of lipid treatment using both biochemical assay and electron microscopy. envenomation decreased the toxicity of eastern coral snake venom and Discussion: Bupivacaine toxicity blocks insulinergic signaling, and the increased survival significantly. Further investigation is required to deter- sensitization to insulin-signaling via IRS1 de-phosphorylation is required mine the efficacy trypsin injection at later treatment injection times. for recovery. Lipid emulsion potentiates the recovery by its ability to drive insulinergic signaling in the absence of toxicity. Conclusion: In addition to its ability to sequester toxins, the benefit of lipid emulsion in combatting cardiac toxicity may be modulated its pro- insulinergic effect. 3. Long-Term Outcomes Following Deliberate Self-Poisoning in Teens: A Population-Based Study Finkelstein Y1, Macdonald E2, Hollands S2,HutsonJR1, Sivilotti MLA3, Mamdani MM1,2, Koren G2,JuurlinkDN1,2, For the Canadian Drug Supported by the 2012–2013 Emergency Medicine Foundation/Medical Safety and Effectiveness Research Network (CDSERN) Toxicology Foundation Research Grant 1University of Toronto, ON, Canada; 2Institute for Clinical Evaluative Sciences, Toronto, ON, Canada; 3Queen’s University, Kingston, ON, Canada Previously published as: Parker-Cote JL, et al. Efficacy of trypsin in treating coral snake envenomation in the porcine model. Ann Emerg Background: Suicide is the third most common cause of death among Med: 2014: 64 (4) 4:138–139. Reprinted with permission of the journal. American teens, and deliberate self-poisoning is the leading method of J. Med. Toxicol. attempted suicide. Unlike violent methods, survival following self- sity of Pennsylvania, Philadelphia, PA, USA; 4New York University poisoning is common, providing an opportunity for secondary preven- School of Medicine, New York, NY, USA tion. The long-term risk of completed suicide in teens following discharge from the emergency department after a first self-poisoning episode is Background: Carisoprodol is a muscle relaxant with significant abuse unknown. potential that has been implicated in tens of thousands of emergency Objectives: Primarily to determine rates of suicide relative to controls and department (ED) visits annually, alone or in combination with other secondarily, to explore predictors of subsequent suicide. central nervous system (CNS) depressants. Methods: Using multiple linked provincial healthcare databases, we conduct- Research Question: To characterize trends in carisoprodol utilization in ed a population-based study of all teens aged 10 to 19 years presenting to an US outpatient offices, clinics, and EDs in the setting of rising rates of Ontario hospital after a first self-poisoning episode from 2001 to 2011 and prescription drug abuse and associated overdoses. compared their outcomes with age- and sex-matched controls (1:50). Methods: A retrospective review of data from the CDC’s National Hos- Results: We identified 23,167 teens discharged after a first self-poisoning pital Ambulatory Medical Care Survey (NHAMCS) and National Ambu- episode. Their median age was 16 (IQR 15 to 18) years, and 16,056 (69 %) latory Medical Care Survey (NAMCS) 2001–2010 was performed. All were female. Acetaminophen was the most common agent ingested, followed adult (age, ≥18 years) ED and ambulatory care visits during which by antidepressants and NSAIDs. Altogether, 3,838 (17 %) patients were carisoprodol was either administered or prescribed were included. Visits subsequently hospitalized with repeat self-poisoning. The self-poisoning during which there was concomitant use of opioid analgesics (OAs) or patients were compared with 1,158,350 matched controls for all analyses. benzodiazepines were also evaluated. The proportion of visits during which Over a median follow-up of 7.7 (interquartile range (IQR), 4.6 to 10.1) years the included medications were administered or prescribed was tabulated, and cumulative 164,877 person-years, 127 individuals in the self-poisoning and trends were analyzed using survey-weighted logistic regression. cohort committed suicide (0.55 %), compared with 362 suicides in the control Results: Between 2001 and 2010, there were an estimated 7.6 billion adult group (0.03 %). The risk of suicide in the self-poisoning cohort was markedly ambulatory care visits, of which an estimated 28.2 million (0.4 %) visits increased relative to controls (adjusted hazard ratio (HR), 18.1 [95 % CI, 14.8 included a carisoprodol prescription. Out of an estimated 900 million ED to 22.2]). The median time from first self-poisoning to suicide was 3.0 (IQR, visits between 2001 and 2010, 2.1 million (0.2 %) visits received 1.2 to 5.4)years. Predictors of suicide in self-poisoning teens included male carisoprodol in the ED or at discharge. The proportion of carisoprodol sex (HR, 2.21; 95 % CI, 1.55 to 3.15), age older than 15 years on index self- utilization did not change significantly in the ambulatory care setting and poisoning (HR, 1.73; 95 % CI, 1.02 to 2.95), diagnosis of depression (HR, decreased in the ED when 2001–2002 was compared with 2009–2010; 1.59; 95 % CI, 1.06 to 2.38) and a visit to a psychiatrist in the previous year however, there was an increase in the absolute number of visits over time. (HR,2.15;95%CI,1.42to3.26). An OA was concomitantly used frequently with carisoprodol in both Conclusions: A first hospital presentation for deliberate self-poisoning settings, but there was no proportional increase over time (Table).