Assessing Platelet Mitochondrial Dysfunction in a Murine Model of Acute Acetaminophen Toxicity.

INTRODUCTION: Acetaminophen (APAP) toxicity remains a significant cause of adult and pediatric liver failure in North America and Europe. Previous research has evaluated the impaired mitochondrial function associated with APAP toxicity. The primary aim of this study was to evaluate the effects of APAP toxicity on platelet mitochondrial function using platelet oxygen consumption in a murine model in vivo. Our secondary objectives were to determine the effect of 4-MP on platelet mitochondrial function and hepatic toxicity in the setting of APAP overdose, and to correlate platelet mitochondrial function with other markers of APAP toxicity. METHODS: Male C57Bl/6 mice were randomized to receive APAP (300 or 500 mg/kg) or vehicle followed 90 minutes later by either 4-MP (50 mg/kg) or vehicle via intraperitoneal injection. Mice were euthanized 0, 12, or 24 hours later and platelets isolated from cardiac blood and counted. Platelet oxygen consumption (POC) was determined using a closed-system respirometer. Liver injury was assessed by measuring alanine transferase (ALT) and histological evaluation. RESULTS: Injection of 500 mg/kg APAP led to increased POC versus pair-matched control (vehicle) (p < 0.001). Administration of 4-MP did not affect POC in control or 300 mg/kg APAP mice. In mice receiving 500 mg/kg APAP and 4-MP, POC decreased significantly compared to mice receiving 500 mg/kg APAP alone (p < 0.01). Serum and histological analysis confirmed APAP-induced hepatic damage in mice receiving 500 mg/kg APAP and these effects blunted by treatment with 4-MP. CONCLUSIONS: Platelet oxygen consumption as a measure of mitochondrial function may be useful as a biomarker of hepatic APAP toxicity in the setting of moderate to severe overdose. Treatment with 4-MP decreases hepatic necrosis and may mitigate the harmful effects of APAP on platelet mitochondrial function detected via POC.

Fostering the Next Generation of Researchers: a Sustainable Mentoring Program for Early Career Toxicologists in Scientific Abstract Review.

The presentation of abstracts at scientific meetings is an important step in the dissemination of scientific discovery. Most scientific meetings recruit volunteer experts to evaluate and score submitted abstracts to determine which ones qualify for presentation. Reviewing an abstract is an important service to one's specialty, but there is typically no formal training or required instruction during medical toxicology fellowship on scientific abstract scoring. In order to provide structured training in abstract review, the American College of Medical Toxicology (ACMT) Research Committee launched the Annual Scientific Meeting (ASM) Abstract Review Mentor program in 2021. The goals of this program were to train fellows how to score scientific abstracts and provide them with new mentor connections to toxicologists outside of their training program. After evaluating 3 years of data from participating fellows-in-training and faculty mentors, we conclude that ACMT's Abstract Review Mentor program was successful in training future reviewers and fostering external mentorship relationships. All participants reported their experience in this program will change how they submit future abstracts to scientific meetings, help their future service as an abstract reviewer, and motivate their involvement in other specialty-related research activities. Implementing an abstract review training program is sustainable and a vital strategy for enhancing the dissemination of scientific discovery and training the next generation of medical toxicology researchers.

Detection of ingested nitromethane and reliable creatinine assessment using multiple common analytical methods.

AIM: Nitromethane, found in fuels used for short distance racing, model cars, and model airplanes, produces a falsely elevated serum creatinine with standard creatinine analysis via the Jaffé method. Erroneous creatinine elevation often triggers extensive testing, leads to inaccurate diagnoses, and delayed or inappropriate medical interventions. Multiple reports in the literature identify "enzymatic assays" as an alternative method to detect the true value of creatinine, but this ambiguity does not help providers translate what type of enzymatic assay testing can be done in real time to determine if there is indeed false elevation. METHODS: We report seven cases of ingested nitromethane where creatinine was determined via Beckman Coulter® analyser using the Jaffé method, Vitros® analyser, or i-Stat® point-of-care testing. Nitromethane was detected and semi-quantified using a common clinical toxic alcohol analysis method, and quantified by headspace-gas chromatography-mass spectrometry. RESULTS: When creatinine was determined using i-Stat® point-of-care testing or a Vitros® analyser, levels were within the normal range. Comparatively, all initial creatinine levels obtained via the Jaffé method were elevated. Nitromethane concentrations ranged from 42 to 310 µg/mL. CONCLUSIONS: These cases demonstrate reliable assessment of creatinine through other enzymatic methods using a Vitros® analyser or i-STAT®. Additionally, nitromethane is detectable and quantifiable using routine alcohols gas chromatography analysis and by headspace-gas chromatography-mass spectrometry.

Pilot Trial of Intravenous Lipid Emulsion Treatment for Severe Nifedipine-Induced Shock.

Animal studies and human case reports show promise in using lipid rescue to treat refractory calcium channel antagonist toxicity. However, the majority of research and clinical experience has focused on non-dihydropyridine agents. Thus, we sought to investigate the value of lipid emulsion (ILE) therapy for dihydropyridine-induced shock. This IACUC-approved study utilized seven swine that were sedated with alpha-chloralose, mechanically ventilated, and instrumented for drug delivery and hemodynamic measures. After stabilization and basal measures, nifedipine (0.01875 mg/kg/min) was infused until imminent cardiac arrest (seizure, end tidal CO2 < 10 mmHg, bradydysrhythmia, or pulseless electrical activity). Animals then received a 7 mL/kg bolus of 20% lipid emulsion via central catheter. Lipid circulation was visually confirmed by the presence of fat in peripheral arterial blood. Hemodynamics were continuously monitored until 10 min after lipid bolus. Surviving animals were euthanized. Pre- and post-lipid treatment parameters were analyzed using the Wilxocon signed rank test (p <0.05 significant). Nifedipine toxicity was characterized by vasodilatory hypotension, impaired vascular contractility, and tachycardia with terminal bradycardia. The median time to imminent cardiac arrest from start of nifedipine infusion was 218 min. Lipid treatment did not improve hemodynamics or restore circulation in any animal. There was no benefit from lipid rescue in this model of nifedipine toxicity. Further study of ILE for dihydropyridine toxicity is warranted but initial animal model results are not promising.

"Bath salts" and "plant food" products: the experience of one regional US poison center.

Abuse of psychogenic substances sold as "bath salts" and "plant food" has escalated in recent years in the United States (USA). Previous reports suggest regional differences in the primary active ß-keto phenylalkylamines found in these products and the corresponding signs and symptoms reported after exposure. Currently, there are only limited studies describing the clinical effects associated with reported "bath salts" exposure in the USA. This study describes the clinical effects associated with "bath salt" and "plant food" exposures as reported to the poison center serving the state of North Carolina (Carolinas Poison Center). We performed a retrospective review of the Carolinas Poison Center database for all cases of reported human exposure to "bath salt" and "plant food" products from 2010 to 2011 with specific attention to clinical effects and routes of exposure. Additionally, we reviewed therapies used, trended the volume of exposure cases reported over the study period, and evaluated the distribution of calls within state counties using descriptive statistics. Carolinas Poison Center received 485 total calls and 409 reported exposure calls regarding "bath salt" or "plant food" products between January of 2010 and December of 2011. The peak of reported exposures occurred in May of 2011. Clinical effects commonly reported in the exposure cases generated from these calls included tachycardia (53.3 %, n = 218), agitated/irritable (50.4 %, n = 206), hallucination/delusions (26.7 %, n = 109), and hypertension (25.2 %, n = 103). In addition to intravenous fluids, common therapies included benzodiazepines (46.0 %, n = 188), sedation (13.4 %, n = 55), alkalinization (3.90 %, n = 16), antihistamine (4.16 %, n = 17), and intubation (3.67 %, n = 15). Haloperidol was the antipsychotic agent used most often to treat agitation (n = 40). Serious complications associated with reported exposure to "bath salt" and "plant food" products included rhabdomyolysis, renal failure, excited delirium syndrome, and death. While treatments have not been empirically determined, sedation with benzodiazepines, aggressive cooling for hyperthermic patients, and use of small doses of antipsychotics for choreoathetoid movements not controlled with benzodiazepines are not likely to be harmful.

Death following recreational use of designer drug "bath salts" containing 3,4-Methylenedioxypyrovalerone (MDPV).

INTRODUCTION: 3,4-Methylenedioxypyrovalerone (MDPV) is a designer stimulant drug that has gained popularity in the USA. Although adverse effects of MDPV have been described, to our knowledge, this is the first reported death. CASE REPORT: We report the case of a 40-year-old male who injected and snorted "bath salts" containing MDPV and subsequently became agitated, aggressive, and experienced a cardiac arrest. He was resuscitated after his initial arrest; however, he developed hyperthermia, rhabdomyolysis, coagulopathy, acidosis, anoxic brain injury, and subsequently died. DISCUSSION: This is the first case in the medical literature to report death due to isolated confirmed MDPV intoxication. The manner of death is also consistent with excited delirium syndrome.

Anaphylaxis with Latrodectus antivenin resulting in cardiac arrest.

Latrodectus mactans antivenin is a safe and effective therapy for severe black widow spider envenomations when given to most patients. We report a case of a 37-year-old male with a history of asthma that was given L. mactans antivenin for symptoms related to a black widow envenomation and developed a severe anaphylactic reaction resulting in cardiac arrest. When traditional therapies failed, the patient was given methylene blue for anaphylactic shock resulting in a 30-h period of hemodynamic stability. Despite initial resuscitation, the patient ultimately died 40 h after presentation. Under the right circumstances, L. mactans antivenin remains a safe and effective therapy for severe black widow envenomations. However, anaphylaxis is a risk for those receiving this therapy, even when the antivenin is diluted and given as an infusion. We report the first death related to diluted L. mactans antivenin given as an infusion.

Fatal pulmonary edema after acute occupational exposure to nitric acid.

BACKGROUND: Nitric acid (HNO(3)) is a solution of nitrogen dioxide (NO(2)) in water commonly used as an industrial chemical and cleaner. Oxides of nitrogen liberated as nitric acid interact with the environment to cause inhalation injuries. The coexistence of HNO(3) with varying oxides of nitrogen likely results in the large continuum of symptoms related to HNO(3) exposure and varying times of onset--acute, subacute, and delayed. Furthermore, dyspnea and evidence of acute lung injury may not occur for several hours after exposure and can lead to rapidly progressive acute respiratory distress syndrome (ARDS). OBJECTIVES: This case illustrates to physicians and occupational health personnel that HNO(3) inhalation may initially appear benign and that onset of severe effects may be delayed. CASE REPORT: A 66-year-old man developed delayed-onset pulmonary edema, ARDS, and fatal circulatory collapse 53 h after occupational exposure to HNO(3). CONCLUSION: This case serves to increase awareness among emergency physicians, as well as occupational health personnel, that patients exposed to HNO(3) may initially be asymptomatic. Patients should be evaluated and observed regardless of the severity or benign nature of symptoms, which occur immediately after exposure, as the most severe symptoms are often delayed in onset and rapidly progressive.