ID: 22738685
Title: Rapid and complete bioavailability of antidotes for organophosphorus nerve agent and cyanide poisoning in minipigs after intraosseous administration.
Abstract: Management of chemical weapon casualties includes the timely administration of antidotes without contamination of rescuers. Personal protective equipment makes intravenous access difficult but does not prevent intraosseous drug administration. We therefore measured the systemic bioavailability of antidotes for organophosphorus nerve agent and cyanide poisoning when administered by the intraosseous, intravenous, and intramuscular routes in a small study of Göttingen minipigs. Animals were randomly allocated to sequentially receive atropine (0.12 mg/kg by rapid injection), pralidoxime (25 mg/kg by injection during 2 minutes), and hydroxocobalamin (75 mg/kg during 10 minutes) by the intravenous or intraosseous route, or atropine and pralidoxime by the intramuscular route. Plasma concentrations were measured for 6 hours to characterize the antidote concentration-time profiles for each route. Maximum plasma concentrations of atropine and pralidoxime occurred within 2 minutes when administered by the intraosseous route compared with 8 minutes by the intramuscular route. Maximum plasma hydroxocobalamin concentration occurred at the end of the infusion when administered by the intraosseous route. The mean area under the concentration-time curve by the intraosseous route was similar to the intravenous route for all 3 drugs and similar to the intramuscular route for atropine and pralidoxime. This study showed rapid and substantial antidote bioavailability after intraosseous administration that appeared similar to that of the intravenous route. The intraosseous route of antidote administration should be considered when intravenous access is difficult.

ID: 23689094
Title: Patterns of cyanide antidote use since regulatory approval of hydroxocobalamin in the United States.
Abstract: Sodium nitrite and sodium thiosulfate are common cyanide antidotes. Hydroxocobalamin was approved for use in the United States in 2006. Our objective was to determine the frequency of antidote use as reported to the US poison centers from 2005 to 2009 and describe which antidotes were used in critically ill cyanide toxic patients. We performed a retrospective review over 5 years (2005-2009) from 61 US poison centers. We identified all cyanide-exposed cases that received a cyanide antidote. Variables collected included demographics, gastric decontamination, antidote used, predefined serious clinical effects (hypotension, cardiac arrest, respiratory arrest, and coma), and predefined serious therapies (cardiopulmonary resuscitation, vasopressors, atropine, anticonvulsant, antidysrhythmic, and intubation/ventilation). One trained abstractor abstracted each chart to a standardized electronic form. Another investigator audited 20% of the charts. Kappa values were calculated. One hundred sixty-five exposures were identified. Mean age was 42 years (range, 3-93 years). Seventy-one percent were male. Exposures were 27% ingestion and 53% inhalation. Thirty-two percent of the ingestions were suicide attempts. Twenty percent (32 of 157) of all cases died. Over all years reported, hydroxocobalamin was administered to 29% (45 of 157) of patients, sodium nitrite to 25%, and sodium thiosulfate to 46%. Hydroxocobalamin use increased from 24% to 54% from 2007 to 2009, respectively (P = 0.024). Sodium thiosulfate use decreased from 73% to 31% (P = 0.002) and sodium nitrite use decreased from 26% to 14% (P = 0.39). The proportion of cases with serious clinical effects that received hydroxocobalamin increased each year, and the proportion that received other antidotes decreased. Hydroxocobalamin was also administered more often in cases that required serious therapies and increased each year. Hydroxocobalamin use for cyanide toxicity increased each year as reported to the US poison centers. Reported use of sodium thiosulfate and sodium nitrite decreased over the same years. In addition, hydroxocobalamin was used more often each year in critically ill cyanide toxic patients than were sodium nitrite or sodium thiosulfate.

ID: 24091052
Title: Limitations and challenges in treatment of acute chemical warfare agent poisoning.
Abstract: Recent news from Syria on a possible use of chemical warfare agents made the headlines. Furthermore, the motivation of terrorists to cause maximal harm shifts these agents into the public focus. For incidents with mass casualties appropriate medical countermeasures must be available. At present, the most important threats arise from nerve agents and sulfur mustard. At first, self-protection and protection of medical units from contamination is of utmost importance. Volatile nerve agent exposure, e.g. sarin, results in fast development of cholinergic crisis. Immediate clinical diagnosis can be confirmed on-site by assessment of acetylcholinesterase activity. Treatment with autoinjectors that are filled with 2mg atropine and an oxime (at present obidoxime, pralidoxime, TMB-4 or HI-6) are not effective against all nerve agents. A more aggressive atropinisation has to be considered and more effective oximes (if possible with a broad spectrum or a combination of different oximes) as well as alternative strategies to cope with high acetylcholine levels at synaptic sites should be developed. A further gap exists for the treatment of patients with sustained cholinergic crisis that has to be expected after exposure to persistent nerve agents, e.g. VX. The requirement for long-lasting artificial ventilation can be reduced with an oxime therapy that is optimized by using the cholinesterase status for guidance or by measures (e.g. scavengers) that are able to reduce the poison load substantially in the patients. For sulfur mustard poisoning no specific antidote is available until now. Symptomatic measures as used for treatment of burns are recommended together with surgical or laser debridement. Thus, huge amounts of resources are expected to be consumed as wound healing is impaired. Possible depots of sulfur mustard in tissues may aggravate the situation. More basic knowledge is necessary to improve substantially therapeutic options. The use of stem cells may provide a new and promising option.

ID: 26562770
Title: Conceptual approaches for treatment of phosgene inhalation-induced lung injury.
Abstract: Toxic industrial chemicals are used throughout the world to produce everyday products such as household and commercial cleaners, disinfectants, pesticides, pharmaceuticals, plastics, paper, and fertilizers. These chemicals are produced, stored, and transported in large quantities, which poses a threat to the local civilian population in cases of accidental or intentional release. Several of these chemicals have no known medical countermeasures for their toxic effects. Phosgene is a highly toxic industrial chemical which was used as a chemical warfare agent in WWI. Exposure to phosgene causes latent, non-cardiogenic pulmonary edema which can result in respiratory failure and death. The mechanisms of phosgene-induced pulmonary injury are not fully identified, and currently there is no efficacious countermeasure. Here, we provide a proposed mechanism of phosgene-induced lung injury based on the literature and from studies conducted in our lab, as well as provide results from studies designed to evaluate survival efficacy of potential therapies following whole-body phosgene exposure in mice. Several therapies were able to significantly increase 24h survival following an LCt50-70 exposure to phosgene; however, no treatment was able to fully protect against phosgene-induced mortality. These studies provide evidence that mortality following phosgene toxicity can be mitigated by neuro- and calcium-regulators, antioxidants, phosphodiesterase and endothelin receptor antagonists, angiotensin converting enzymes, and transient receptor potential cation channel inhibitors. However, because the mechanism of phosgene toxicity is multifaceted, we conclude that a single therapeutic is unlikely to be sufficient to ameliorate the multitude of direct and secondary toxic effects caused by phosgene inhalation.

ID: 28577109
Title: Phosgene-induced acute lung injury (ALI): differences from chlorine-induced ALI and attempts to translate toxicology to clinical medicine.
Abstract: Phosgene (carbonyl dichloride) gas is an indispensable chemical inter-mediate used in numerous industrial processes. There is no clear consensus as to its time- and inhaled-dose-dependent etiopathologies and associated preventive or therapeutic treatment strategies. Cardiopulmonary function was examined in rats exposed by inhalation to the alveolar irritant phosgene or to the airway irritant chlorine during and following exposure. Terminal measurements focused on hematology, protein extravasation in bronchoalveolar lavage (BAL), and increased lung weight. Noninvasive diagnostic and prognostic endpoints in exhaled breath (carbon dioxide and nitric oxide) were used to detect the clinically occult stage of pulmonary edema. The first event observed in rats following high but sublethal acute exposure to phosgene was the stimulation of alveolar nociceptive vagal receptors. This afferent stimulation resulted in dramatic changes in cardiopulmonary functions, ventilation: perfusion imbalances, and progressive pulmonary edema and phospholipoproteinosis. Hematology revealed hemoconcentration to be an early marker of pulmonary edema and fibrin as a discriminating endpoint that was positive for the airway irritant chlorine and negative for the alveolar irritant phosgene. The application of each gas produced typical ALI/ARDS (acute lung injury/acute respiratory distress syndrome) characteristics. Phosgene-induced ALI showed evidence of persistent apnea periods, bradycardia, and shifts of vascular fluid from the peripheral to the pulmonary circulation. Carbon dioxide in expired gas was suggestive of increased ventilation dead space and appeared to be a harbinger of progressively developing lung edema. Treatment with the iNOS inhibitor aminoguanidine aerosol by inhalation reduced the severity of phosgene-induced ALI when applied at low dose-rates. Symptomatic treatment regimens were considered inferior to causal modes of treatment.

ID: 29104014
Title: Continuous positive airway pressure: An early intervention to prevent phosgene-induced acute lung injury.
Abstract: Exposure to toxic industrial chemicals such as phosgene may occur through accidental or deliberate release. Inhalation may result in an acute lung injury which manifests as hypoxaemia with insufficient oxygen being delivered to the tissues resulting in hypoxia, respiratory failure and death. No effective pharmacological therapy currently exists and treatment remains supportive, often requiring intensive care facilities. In a mass casualty scenario the logistical burden of managing exposed individuals would rapidly overwhelm healthcare systems. This highlights the need to develop post exposure therapeutic strategies to minimise injury severity and increase survival in individuals exposed to toxic chemicals. Our research objective was to investigate a commercial off the shelf (COTS) therapy; ambient air continuous positive airway pressure (CPAP) support, initiated 1h post exposure to explore the concept that early intervention with positive airway pressure would reduce or ameliorate lung injury following exposure to phosgene. This study has demonstrated that CPAP, initiated before overt signs of exposure become manifest, significantly improved survival as well as improving some clinically relevant physiological measures of phosgene-induced acute lung injury over 24h.

ID: 30668997
Title: Phosgene-induced lung edema: Comparison of clinical criteria for increased extravascular lung water content with postmortem lung gravimetry and lavage-protein in rats and dogs.
Abstract: Phosgene-induced acute lung injury (ALI) is characterized by a concentration x time (Cxt)-dependent increased pulmonary vascular permeability, phenotypically manifested as potentially life-threatening acute lung edema. In contemporary animal bioassays, the quantification of protein in bronchoalveolar lavage fluid (BAL) is taken as an unequivocal endpoint suggestive of disruption of alveolar barrier function. However, extravasated protein can only be a surrogate endpoint for assessing the extravascular fluid dynamics of the lung. This pathophysiological hallmark of ALI is diagnosed and quantified in vivo in humans by assessing the accumulation of excess extravascular lung water (EVLW). The Point of Departure (POD) of the Cxt relationship of this adverse outcome pathway should also constitute the basis for setting safe occupational and emergency response values. Unlike the EVLW approach, toxicology-based animal models utilize postmortem analyses of total protein in BAL and lung weights as the basis for human risk assessment. With either approach, it remains difficult to unequivocally evaluate pulmonary edema in terms of etiopathology and specificity, i.e., cardiogenic and hydrostatic versus increased permeability edema. The objective of this paper is to retrospectively analyze the clinical scoring of the severity grades of in vivo EVLWs from humans with the respective postmortem biomarkers BAL protein and collagen versus wet lung weights in rats and dogs exposed by inhalation to phosgene gas. Despite the different methodological approaches taken in humans and animals, the EVLW-based predicted thresholds for the onset of pulmonary edema and potentially life-threatening severe pulmonary edema were in remarkable agreement. Data from dogs appear to more aptly reflect the human etiopathology and should be given preference over data from rodents. Especially in rats, elevations in BAL protein may lead to a marked overestimation of the edematous potency of phosgene due to secreted protein into airways. In summary, increased lung weight in rats and dogs scaled favorably with the human-EVLW and was shown to be the biomarker of choice for the scaling lung edema. Caution is advised when using BAL protein in isolation as a surrogate endpoint of pulmonary edema.

ID: 32020997
Title: Antidotes in Poisoning.
Abstract: Antidotes are agents that negate the effect of a poison or toxin. Antidotes mediate its effect either by preventing the absorption of the toxin, by binding and neutralizing the poison, antagonizing its end-organ effect, or by inhibition of conversion of the toxin to more toxic metabolites. Antidote administration may not only result in the reduction of free or active toxin level, but also in the mitigation of end-organ effects of the toxin by mechanisms that include competitive inhibition, receptor blockade or direct antagonism of the toxin. Reduction in free toxin level can be achieved by specific and non-specific agents that bind to the toxin. The most commonly used non-specific binding agent is activated charcoal. Specific binders include chelating agents, bioscavenger therapy and immunotherapy. In some situations, enhanced elimination can be achieved by urinary alkalization or hemadsorption. Competitive inhibition of enzymes (e.g. ethanol for methanol poisoning), enhancement of enzyme function (e.g. oximes for organophosphorus poisoning) and competitive receptor blockade (e.g. naloxone, flumazenil) are other mechanisms by which antidotes act. Drugs such as N-acetyl cysteine and sodium thiocyanate reduce the formation of toxic metabolites in paracetamol and cyanide poisoning respectively. Drugs such as atropine and magnesium are used to counteract the end-organ effects in organophosphorus poisoning. Vitamins such as vitamin K, folic acid and pyridoxine are used to antagonise the effects of warfarin, methotrexate and INH respectively in the setting of toxicity or overdose. This review provides an overview of the role of antidotes in poisoning. Chacko B, Peter JV. Antidotes in Poisoning. Indian J Crit Care Med 2019;23(Suppl 4):S241-S249.

ID: 33206558
Title: Activation of the carotid body increases directly recorded cardiac sympathetic nerve activity and coronary blood flow in conscious sheep.
Abstract: Activation of the carotid body (CB) using intracarotid potassium cyanide (KCN) injection increases coronary blood flow (CoBF). This increase in CoBF is considered to be mediated by co-activation of both the sympathetic and parasympathetic nerves to the heart. However, whether cardiac sympathetic nerve activity (cardiac SNA) actually increases during CB activation has not been determined previously. We hypothesized that activation of the CB would increase directly recorded cardiac SNA, which would cause coronary vasodilatation. Experiments were conducted in conscious sheep implanted with electrodes to record cardiac SNA and diaphragmatic electromyography (dEMG), flow probes to record CoBF and cardiac output, and a catheter to record arterial pressure. Intracarotid KCN injection was used to activate the CB. To eliminate the contribution of metabolic demand on coronary flow, the heart was paced at a constant rate during CB chemoreflex stimulation. Intracarotid KCN injection resulted in a significant increase in directly recorded cardiac SNA frequency (from 24 ± 2 to 40 ± 4 bursts/min; P < 0.05) as well as a dose-dependent increase in mean arterial pressure (79 ± 15 to 88 ± 14 mmHg; P < 0.01) and CoBF (75 ± 37 vs. 86 ± 42 mL/min; P < 0.05). The increase in CoBF and coronary vascular conductance to intracarotid KCN injection was abolished after propranolol infusion, suggesting that the increased cardiac SNA mediates coronary vasodilatation. The pressor response to activation of the CB was abolished by pretreatment with intravenous atropine, but there was no change in the coronary flow response. Our results indicate that CB activation increases directly recorded cardiac SNA, which mediates vasodilatation of the coronary vasculature.

ID: 33414048
Title: Two Cases of Thyrotoxicosis due to Redotex Ingestion, a Mexican Weight Loss Drug.
Abstract: Redotex™ is a Mexican weight-loss supplement that is not U.S. Food and Drug Administration-approved. It consists of the following five ingredients: tri-iodothyronine 75 μg, atropine 0.36 mg, diazepam 8 mg, aloin 16 mg, and d-norpseudoephedrine 50 mg per tablet. There are few case reports with clinically severe ingestions. We report two cases of clinical thyrotoxicosis due to use of Redotex. A 29-year-old woman presented to the emergency department (ED) with anxiety and palpitations. She reported taking Redotex daily for 1 week. Her temperature was 37.1°C, blood pressure (BP) was 166/104 mm Hg, and heart rate (HR) was 140 beats/min. Laboratory analysis was significant for a bicarbonate level of 20 mmol/L (reference 22-29 mmol/L), free T4 0.75 ng/dL (reference 0.93-1.70 ng/dL), and thyroid-stimulating hormone (TSH) 0.05 uIU/mL (reference 0.27-4.20 uIU/mL). She was treated with 2 mg i.v. lorazepam and 20 mg oral propranolol. A 37-year-old woman presented with chest pain, palpitations, and nausea after taking Redotex 1 to 2 tablets daily for 6 weeks. Her HR was 134 beats/min and BP was 130/66 mm Hg. Thyroid function tests on initial presentation showed a TSH of 0.013 uU/mL, free T4 of 0.24 ng/dL, and free T3 of >30 pg/mL. She was treated with propranolol 1 mg i.v. twice per day and 2 doses of lorazepam 1 mg. Both patients had resolution of their symptoms. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: When taken chronically and at recommended doses, Redotex can present with clinically significant T3 thyrotoxicosis. This has not been seen in prior reports.

ID: 33484734
Title: Phosgene inhalation toxicity: Update on mechanisms and mechanism-based treatment strategies.
Abstract: Phosgene (carbonyl dichloride) gas is an indispensable high-production-volume chemical intermediate used worldwide in numerous industrial processes. Published evidence of human exposures due to accidents and warfare (World War I) has been reported; however, these reports often lack specificity because of the uncharacterized exposure intensities of phosgene and/or related irritants. These may include liquid or solid congeners of phosgene, including di- and triphosgene and/or the respiratory tract irritant chlorine which are often collectively reported under the umbrella of phosgene exposure without any appreciation of their differences in causing acute lung injury (ALI). Among these irritants, phosgene gas is somewhat unique because of its poor water solubility. This prevents any appreciable retention of the gas in the upper airways and related trigeminal sensations of irritation. By contrast, in the pulmonary compartment, amphiphilic surfactant might scavenge this lipophilic gas. The interaction of phosgene and the surfactant may affect basic physiological functions controlled by Starling's and Laplace's laws, which can be followed by cardiogenic pulmonary edema. The phenotypic manifestations are dependent on the concentration × exposure duration (C × t); the higher the C × t is, the less time that is required for edema to appear. It is hypothesized that this type of edema is caused by cardiovascular and colloid osmotic imbalances to initial neurogenic events but not because of the injury itself. Thus, hemodynamic etiologies appear to cause imbalances in extravasated fluids and solute accumulation in the pulmonary interstitium, which is not drained away by the lymphatic channels of the lung. The most salient associated findings are hemoconcentration and hypoproteinemia. The involved intertwined pathophysiological processes coordinating pulmonary ventilation and cardiopulmonary perfusion under such conditions are complex. Pulmonary arterial catheter measurements on phosgene-exposed dogs provided evidence of 'cor pulmonale', a form of acute right heart failure produced by a sudden increase in resistance to blood flow in the pulmonary circulation about 20 h postexposure. The objective of this review is to critically analyze evidence from experimental inhalation studies in rats and dogs, and evidence from accidental human exposures to better understand the primary and secondary events causing cardiopulmonary dysfunction and an ensuing life-threatening lung edema. Mechanism-based diagnostic and therapeutic approaches are also considered for this form of cardiogenic edema.

ID: 35149144
Title: Assessment of the serum glucose/potassium GLU/K ratio as a predictor of intermediate syndrome following acute anticholinesterase exposure.
Abstract: The widespread use of anticholinesterase-containing pesticides accounts for the considerable morbidity and mortality in Egypt and worldwide. Few studies have investigated the predictors of intermediate syndrome (IMS). Therefore, in this study, we assessed the adequacy of the serum glucose/potassium (GLU/K) ratio as an early reliable tool to predict IMS incidence following intoxication with acute anticholinesterase compounds. A prospective cross-sectional study was conducted among patients who presented to Tanta University Poison Control Center, Egypt, and were diagnosed with acute anticholinesterase intoxication between January and August, 2021. Patients were categorized based on the primary outcome into IMS (+) and IMS (-) groups. Overall, 243 patients were included, among whom 44 (18.1%) had IMS as the complication. Younger individuals with age ranging between 18 and < 25 years constituted the main exposed age category in both groups. Vomiting and abdominal colic were the most commonly noted complaints in the included patients (94.2% and 63.8% of patients, respectively). The delay, length of hospital stay, mean blood pressure, O2 saturation, Glasgow Coma Scale score, random blood glucose level, K concentration, GLU/K ratio, and dose of atropine administered were significant IMS predictors on an individual basis, and the GLU/K ratio was the most significant IMS predictor. At a cutoff value of > 41.07%, the GLU/K ratio could significantly predict IMS (areas under the curves = 0.971, p < 0.001) with 93% accuracy, 93.2% sensitivity, and 93% specificity. Although the clear pathophysiology of IMS remains to be elucidated, our results provide insight into the significant contribution of neurological affection, apart from the well-known direct toxic effect on muscles. Moreover, we demonstrated a significant association between the development of IMS and severity of organophosphorus compounds' exposure. Physicians should be vigilant to detect IMS early upon admission using the GLU/K ratio, which is a useful early IMS predictor.

ID: 35952445
Title: Analysis of bisaminotetrazole cobinamide, a next-generation antidote for cyanide, hydrogen sulfide and methanethiol poisoning, in swine plasma by liquid chromatography-tandem mass spectrometry.
Abstract: Cyanide, hydrogen sulfide, and methanethiol are common toxic inhalation agents that inhibit mitochondrial cytochrome c oxidase and result in cellular hypoxia, cytotoxic anoxia, apnea, respiratory failure, cardiovascular collapse, seizure and potentially death. While all are occupational gas exposure hazards that have the potential to cause mass casualties from industrial accidents or acts of terrorism, only cyanide has approved antidotes, and each of these has major limitations, including difficult administration in mass-casualty settings. While bisaminotetrazole cobinamide (Cbi(AT)2) has recently gained attention because of its efficacy in treating these metabolic poisons, there is no method available for the analysis of Cbi(AT)2 in any biological matrix. Hence, in this study, a simple and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the analysis of Cbi(AT)2 in swine plasma. The method is extremely simple, consisting of protein precipitation, separation and drying of the supernatant, reconstitution in an aqueous solvent, and LC-MS/MS analysis. The method produced an LOD of 0.3 μM with a wide dynamic range (2 - 500 μM). Inter- and intraassay accuracies (100 ± 12 % and 100 ± 19 %, respectively) were acceptable and the precision (<12 % and < 9 % relative standard deviation, respectively) was good. The developed method was used to analyze Cbi(AT)2 from treated swine and the preliminary pharmacokinetic parameters showed impressive antidotal behavior, most notably a long estimated elimination half-life (t1/2 = 37.5 h). This simple and rapid method can be used to facilitate the development of Cbi(AT)2 as a therapeutic against toxic cyanide, hydrogen sulfide and methanethiol exposure.

ID: 37429600
Title: Recent advances in cholinergic mechanisms as reactions to toxicity, stress, and neuroimmune insults.
Abstract: This review presents recent studies of the chemical and molecular regulators of acetylcholine (ACh) signaling and the complexity of the small molecule and RNA regulators of those mechanisms that control cholinergic functioning in health and disease. The underlying structural, neurochemical, and transcriptomic concepts, including basic and translational research and clinical studies, shed new light on how these processes inter-change under acute states, age, sex, and COVID-19 infection; all of which modulate ACh-mediated processes and inflammation in women and men and under diverse stresses. The aspect of organophosphorus (OP) compound toxicity is discussed based on the view that despite numerous studies, acetylcholinesterase (AChE) is still a vulnerable target in OP poisoning because of a lack of efficient treatment and the limitations of oxime-assisted reactivation of inhibited AChE. The over-arching purpose of this review is thus to discuss mechanisms of cholinergic signaling dysfunction caused by OP pesticides, OP nerve agents, and anti-cholinergic medications; and to highlight new therapeutic strategies to combat both the acute and chronic effects of these chemicals on the cholinergic and neuroimmune systems. Furthermore, OP toxicity was examined in view of cholinesterase inhibition and beyond in order to highlight improved small molecules and RNA therapeutic strategies and assess their predicted pitfalls to reverse the acute toxicity and long-term deleterious effects of OPs.

ID: 38344049
Title: Calcium Channel Blocker Overdose.
Abstract: Emergency medicine residents and medical students on emergency medicine rotation. Calcium channel blocker (CCB) overdoses can be severe with potentially serious adverse outcomes. CCBs work by blocking the calcium channels on smooth and cardiac muscle tissue. At low dose ranges, dihydropyridine CCBs (such as nifedipine, amlodipine, and nicardipine) block the L-type calcium receptors in the peripheral vasculature, whereas non-dihydropyridine CCBs (such as: verapamil and diltiazem) affect the L-type calcium receptors in the myocardium.1 Because of this distinction, dihydropyridine CCB toxicity manifests as arterial vasodilation and non-dihydropyridine CCB toxicity is associated with cardiac manifestations such as bradycardia and negative inotropy.2 It is important to note that in high concentrations (such as in overdoses), CCBs lose specificity for their specific receptors and can show all the manifestations of toxicity such as bradycardia, peripheral vasodilation, and hypotension. Patients can develop both vasoplegic shock from peripheral vasodilation and cardiogenic shock. This is a high acuity low occurrence case with infrequently used but specific treatments, and thus this case provides educational value. At the end of this oral board session, examinees will: (1) demonstrate ability to evaluate a patient with undifferentiated shock with bradycardia and discuss the differential diagnosis, (2) recognize the signs and symptoms of calcium channel blocker overdose, (3) demonstrate ability to manage treatment of a patient with calcium channel overdose. This oral board case followed the standard American Board of Emergency Medicine-style case in a tertiary care hospital with access to all specialists and resources needed. This case was tested using 12 resident volunteers ranging from PGY 1-2 in an ACGME (Accreditation Council for Graduate Medical Education) accredited emergency medicine residency program. Immediate feedback was solicited both from the learners and from the evaluators following the debriefing session. Residents were asked to evaluate the educational value of the case using a 1-5 Likert scale (5 being excellent). Evaluators were asked to score the residents using the ACGME core competencies with a scale of 1-8, 1-4 being unacceptable and 5-8 being acceptable. Seven PGY1 residents and five PGY2 residents, thus twelve residents in total, completed the case. The average score was 5.10/8. Three residents missed zero critical actions. The most common critical action missed was consulting cardiology or cardiothoracic surgery for circulatory support options. Many residents failed to recognize that the patient did not have a perfusing blood pressure at the beginning of the case and did not start CPR. Although most residents recognized the patient's hemodynamic collapse was from a calcium channel blocker overdose, most did not know the treatment for this beyond atropine and intravenous fluids.The learners rated the educational value of the case as 4.9/5. Seven residents reported that the case definitely increased their medical knowledge; five residents reported that it somewhat increased their medical knowledge. All residents rated the case as helpful in preparing to manage this medical condition. The educational content from this case was effective. This is a high acuity low occurrence case that has unique treatments that are not commonly used. This makes this case excellent for practice and discussion. We learned during implementation that this case has a high degree of difficulty compared to other cases, and junior learners will need more prompting. It is also important for the proctor to keep the case moving because there is a lot to cover in the allotted amount of time. Calcium channel blocker overdose, toxicology.

ID: 38374946
Title: Systolic hypertension as side effect of topical low dose atropine drops.
Abstract: To present a case of increased systemic hypertension and pupil dilation related to low dose atropine eyedrops. A thirteen-year-old male with progressive myopia received atropine 0.05% ophthalmic drops to slow down myopia progression. He exhibited systemic systolic hypertension, photophobia, and bilateral nonreactive mydriasis. The atropine drops were discontinued, and his blood pressure and pupillary function normalized. This case demonstrates sensitivity to low dose atropine with increased systemic blood pressure and pupillary dilation.

ID: 38465519
Title: Clinical pharmacokinetics of atropine oral gel formulation in healthy volunteers.
Abstract: Sialorrhea or drooling is a common problem in children and adults with neurodevelopmental disorders. It can negatively impact the quality of life due to its physical and psychological manifestations. Providers commonly prescribe atropine eye drops for topical administration to the oral mucosa, as an off-label treatment to manage sialorrhea. However, the off-label use of atropine eye drops can be associated with medication and dosing errors and systemic side effects. To address these limitations of treatment, we developed a mucoadhesive topical oral gel formulation of atropine as an alternative route to off-label administration of atropine eye drops. In this clinical pharmacokinetic (PK) study, we evaluated the safety and PK of atropine gel (0.01% w/w) formulation after single-dose administration to the oral mucosa in 10 healthy volunteers. The PK data showed that after topical administration to the oral mucosa, atropine followed a two-compartment PK profile. The maximum plasma concentration and area under the curve extrapolated to infinite time were 0.14 ng/mL and 0.74 h·ng·mL-1 , respectively. The absorption rate constant calculated by the compartmental analysis was 0.4 h-1 . Safety parameters, such as heart rate, blood pressure, and oxygen saturation, did not significantly change before and after administration of the gel formulation, and no adverse events were observed in all participants who received atropine gel. These data indicate that atropine gel formulation has a satisfactory PK profile, is well-tolerated at the dose studied, and can be further considered for clinical development as a drug product to treat sialorrhea.

ID: 38768837
Title: Baseline physiological data from anesthetized pigs in a VX intoxication model.
Abstract: Over the past fifty years, swine models have been used for organophosphorus intoxication studies. Among these studies and others on the swine model in general, some physiological data, especially cholinesterase activity highly impacted by organophosphorus compounds like nerve agent VX, still need to be completed. To support and compare our model to others, we have published the experimental protocol, the physiological values of 31 juvenile anesthetized pigs, and the 6 h-follow-up of six supplementary anesthetized control animals and 7 VX-intoxicated pigs. We reported hemodynamics and respiratory parameters, blood levels in several biochemical parameters, blood gas, and complete blood count and compared them to the literature. We also focused on tissue and blood cholinesterase activities and detailed them for acetylcholinesterase and butyrylcholinesterase. After establishing a broad physiological data set consistent with the literature, we reported several cardio-respiratory parameters that seem more affected by an organophosphate intoxication, like heart rate, arterial blood pressure, cardiac output, and respiratory rate. Within the blood, oxygen saturation (SpO2), lactatemia, base excess, and glycemia can also be measured and associated with the other parameters to evaluate the life-threatening status. This swine model is currently used to develop and evaluate medical countermeasures against organophosphate nerve agent intoxications.

ID: 38778957
Title: Successful Treatment of a Patient with brain tissue edema associated with Olanzapine overdose.
Abstract: Olanzapine is one of the atypical antipsychotic agents which is being increasingly used, and it is synthetic derivative of thienobenzodiazepine with antipsychotic, and antinausea, and antiemetic activities. Olanzapine overdose is mainly associated with the development of anticholinergic toxicity and is characterized by central nervous system (CNS) suppression, tachycardia, and delirium. As little is yet known about the effects of this agent in toxic doses, it is important to report the features of overdose. Herein, we reported a 28-year-old male with a history of mental illness and substance abuse, who was admitted in a comatose state with generalized tonic-clonic seizures. Head computed tomography (CT) and cerebrospinal fluid (CSF) analysis revealed significant cerebral edema and raised intracranial pressure, indicative of olanzapine-induced neurotoxicity. Management involved immediate cessation of olanzapine, administration of intravenous mannitol for cerebral edema, and supportive care. The patient's condition gradually improved with these interventions. Elevated olanzapine plasma concentration confirmed the diagnosis of overdose. Cranial pressure-lowering treatment has a certain effect on improving the condition of patients.

ID: 41481233
Title: BML-111 mitigates phosgene-induced acute lung injury in rats by activating ACE2.
Abstract: Phosgene is a highly toxic asphyxiating gas and also an important chemical raw material. Phosgene has been regarded as an environmental pollutant, and the accidental leakage of phosgene in the process of industrial production has posed a serious threat to related occupational groups. Phosgene exposure may lead to acute lung injury (ALI), marked by inflammation, heightened vascular permeability, and potentially life-threatening pulmonary edema. BML-111 is a lipid A4 receptor agonist which is compound with anti-inflammatory and antioxidant properties. The involvement of BML-111 in mitigating phosgene-induced ALI and the underlying mechanisms remain unclear. In this study, we established a phosgene induced ALI rat model, examined the effects of phosgene exposure on lung tissue and bronchoalveolar lavage fluid (BALF) of rats, and evaluated the lung tissue pathology, lung wet weight, lung coefficient and respiratory function of phosgene exposed rats after intervention with BML-111. The levels of pro-inflammatory cytokines and oxidative stress markers were measured in BALF and lung tissue. This study showed that BML-111 notably enhanced respiratory function, mitigated ALI severity, and reduced pulmonary edema in phosgene-exposed rats. Mechanistically, these protective effects were attributed to a reduction in pro-inflammatory cytokines and oxidative stress, alongside an enhancement of overall antioxidant capacity. Furthermore, it was found that the activation of ACE2 is a key mechanism through which BML-111 exerts its protection. The findings suggest that BML-111 can alleviate phosgene-induced ALI in rats by activating ACE2, thereby inhibiting inflammatory responses and oxidative stress. BML-111 shows promise as a preventive candidate for treating phosgene-induced ALI.