Oral varespladib for the treatment of snakebite envenoming in India and the USA (BRAVO): a phase II randomised clinical trial.

INTRODUCTION: Snakebite envenoming (SBE) results in over 500 000 deaths or disabling injuries annually. Varespladib methyl, an oral inhibitor of secretory phospholipase A2, is a nearly ubiquitous component of snake venoms. We conducted a phase II clinical trial to assess efficacy and safety of oral varespladib methyl in patients bitten by venomous snakes. METHODS: This double-blind, randomised, placebo-controlled trial enrolled patients in emergency departments in India and the USA. Patients with SBE were randomly assigned (1:1) to receive varespladib methyl or placebo two times per day for 1 week. All patients received standard of care, including antivenom. The primary outcome was change in the composite Snakebite Severity Score (SSS) measuring the severity of envenoming, from baseline to the average composite SSS at 6 and 9 hours. RESULTS: Among 95 patients randomised August 2021 through November 2022, the most common snakebites were from Russell's vipers (n=29), copperheads (n=18) and rattlesnakes (n=14). The SSS improved from baseline to the average at 6 and 9 hours by 1.1 (95% CI, 0.7 to 1.6) in the varespladib group versus 1.5 (95% CI, 1.0 to 2.0) in the placebo group (difference -0.4, 95% CI, -0.8 to 0.1, p=0.13). While key secondary outcomes were not statistically different by treatment group, benefit was seen in the prespecified subgroup initiating study drug within 5 hours of bite (n=37). For this early treatment group, clinically important differences were observed for illness severity over the first week, patient-reported function on days 3 and 7 and complete recovery. No death or treatment emergent serious adverse event occurred. CONCLUSION: For emergency department treatment of snakebites, the addition of varespladib to antivenom did not find evidence of difference for the primary outcome based on the SSS. A potentially promising signal of benefit was observed in patients initiating treatment within 5 hours of snakebite.

A Case Report of Crotalidae Immune F(ab')2-associated Coagulopathy Recurrence in a Preschool-age Child.

Introduction: Pit viper envenomation may cause coagulopathy. The coagulopathy has been treated with crotalidae polyvalent immune fragment antigen-binding (Fab) ovine antivenom for the last few decades in the United States and usually corrects the acute coagulopathy within hours. Days after receiving Fab, coagulopathy may recur in approximately half of the patients. Another divalent antivenom, crotalidae immune F(ab')2 (equine)-F(ab')2-was approved by the US Food and Drug Administration for the treatment of pit viper envenomation. F(ab')2 is composed of two linked antigen-binding fragments of immunoglobulin G. Several studies have demonstrated that F(ab')2 is less likely to be associated with recurrence. There is no reported case of F(ab')2-associated late coagulopathy in very young patients. We report the first case of recurrence associated with F(ab')2 use in a preschool-age child. Case Report: A preschool-age male developed leg swelling and hypofibrinogenemia after rattlesnake envenomation. F(ab')2 was administered to stabilize the leg edema and to correct the hypofibrinogenemia. The patient improved clinically and was discharged on hospital day five. Seven days after the rattlesnake envenomation, he returned to the emergency department as instructed. Laboratory data revealed recurrent hypofibrinogenemia. Conclusion: There are two antivenoms available in the US to treat crotalid envenomation, Fab and F(ab')2. F(ab')2 is less likely to be associated with recurrent coagulopathy in comparison to Fab. We report the first case of recurrence associated with F(ab')2 in a preschool-age child. It is important that the emergency physician be aware of potential F(ab')2-associated recurrent coagulopathy. Adult and pediatric patients may need to follow up to be evaluated for hypofibrinogenemia and/or thrombocytopenia after receiving F(ab')2.

Severe outcomes following pediatric cannabis intoxication: a prospective cohort study of an international toxicology surveillance registry.

INTRODUCTION: An increasing number of jurisdictions have legalized recreational cannabis for adult use. The subsequent availability and marketing of recreational cannabis has led to a parallel increase in rates and severity of pediatric cannabis intoxications. We explored predictors of severe outcomes in pediatric patients who presented to the emergency department with cannabis intoxication. METHODS: In this prospective cohort study, we collected data on all pediatric patients (<18 years) who presented with cannabis intoxication from August 2017 through June 2020 to participating sites in the Toxicology Investigators Consortium. In cases that involved polysubstance exposure, patients were included if cannabis was a significant contributing agent. The primary outcome was a composite severe outcome endpoint, defined as an intensive care unit admission or in-hospital death. Covariates included relevant sociodemographic and exposure characteristics. RESULTS: One hundred and thirty-eight pediatric patients (54% males, median age 14.0 years, interquartile range 3.7-16.0) presented to a participating emergency department with cannabis intoxication. Fifty-two patients (38%) were admitted to an intensive care unit, including one patient who died. In the multivariable logistic regression analysis, polysubstance ingestion (adjusted odds ratio = 16.3; 95% confidence interval: 4.6-58.3; P < 0.001)) and cannabis edibles ingestion (adjusted odds ratio = 5.5; 95% confidence interval: 1.9-15.9; P = 0.001) were strong independent predictors of severe outcome. In an age-stratified regression analysis, in children older than >10 years, only polysubstance abuse remained an independent predictor for the severe outcome (adjusted odds ratio 37.1; 95% confidence interval: 6.2-221.2; P < 0.001). As all children 10 years and younger ingested edibles, a dedicated multivariable analysis could not be performed (unadjusted odds ratio 3.3; 95% confidence interval: 1.6-6.7). CONCLUSIONS: Severe outcomes occurred for different reasons and were largely associated with the patient's age. Young children, all of whom were exposed to edibles, were at higher risk of severe outcomes. Teenagers with severe outcomes were frequently involved in polysubstance exposure, while psychosocial factors may have played a role.

Compartment Syndrome after Crotalid Envenomation in the United States: A Review of the North American Snakebite Registry from 2013 to 2021 on Behalf of the ToxIC Snakebite Study Group.

INTRODUCTION: Compartment syndrome (CS) is a rare but serious complication after crotalid envenomation in the United States. Few data are available regarding the epidemiology and management of these cases. Significant controversy and misunderstanding over best practices, including measurement of compartment pressures and use of fasciotomy, exist for this syndrome. This study aims to describe presentation and management of suspected CS cases after native snakebite reported to the North American Snakebite Registry (NASBR). METHODS: This is an analysis of snakebite cases reported to the Toxicology Investigators Consortium NASBR between January 1, 2013 and December 31, 2021. Cases of native snakebite with documented concern for CS were included. RESULTS: Over an 8-y period, 22 cases of suspected CS were identified, representing 1% of all cases reported to the NASBR. Fasciotomies were performed in 41% (n=9) of these cases, most commonly to the upper extremity (67%, n=6). In cases of suspected CS, intracompartmental pressures (ICPs) were rarely measured (23%, n=5) and fasciotomies were performed without measurement of ICPs frequently (56%, n=5). In 1 case, ICPs were measured and found to be low (8 mm Hg) and fasciotomy was avoided. CONCLUSIONS: Measurement of compartment pressures in cases of suspected CS was uncommon in cases reported to the NASBR. Fasciotomy was commonly performed without measurement of compartment pressures.

Late hemotoxicity following North American rattlesnake envenomation treated with crotalidae immune F(ab')2 (equine) antivenom and crotalidae immune polyvalent Fab (ovine) antivenom reported to the North American Snakebite Sub-registry.

INTRODUCTION: Late hemotoxicity is common following rattlesnake envenomation treated with crotalidae immune polyvalent Fab (ovine) (FabAV). Initial clinical trials showed crotalidae immune F(ab')2 (equine) (Fab2AV) to be superior to FabAV in preventing late hemotoxicity, but this effect has not been demonstrated in broader populations. This study investigated late hemotoxicity in patients receiving Fab2AV or FabAV after rattlesnake envenomation. METHODS: This is a retrospective analysis of prospectively collected data from patients with snakebite reported to the ToxIC North American Snakebite Registry (NASBR) between January 1, 2019, and December 31, 2020. Inclusion criteria were rattlesnake envenomation and administration of antivenom. Patients were excluded if they received more than one type of antivenom. The primary outcome was occurrence of late hemotoxicity (platelets ≤120 k/mm3 or fibrinogen ≤170 mg/dL) in patients receiving Fab2AV and FabAV. Data collected included demographics, envenomation characteristics, laboratory values, and treatment administered. Statistics including t-test and Fisher's exact test were used. RESULTS: A total of 201 rattlesnake envenomated patients receiving antivenom were reported to the NASBR in the study period; 144 were included. 49 received Fab2AV alone, 45 received FabAV alone and 50 received both antivenoms. Baseline patient and envenomation characteristics were similar between the groups. Late hemotoxicity occurred in 2/49 patients in the Fab2AV group (4% (95% CI 0.7-12.6)) and in 19/45 patients in the FabAV group (42% (95% CI 28.4-59.0); absolute risk reduction 39.1% (95% CI 21.2-46.2) (p = 0.001). On follow up, 0 patients (0%) receiving Fab2AV were retreated with antivenom; 4 patients (9%) receiving FabAV were retreated (p = 0.049). CONCLUSIONS: In the North American Snakebite Registry, late hemotoxicity was less common in rattlesnake envenomated patients treated with Fab2AV compared to FabAV.

Varied Presentations of Pediatric Patients With Positive Cannabinoid Tests.

BACKGROUND: Cannabis (marijuana) is one of the most abused drugs worldwide. The increasing availability of cannabis has been associated with increased emergency department (ED) visits. There is a wide range of presentations documented in the recent literature, and the full scope of symptoms in young children is not fully known. OBJECTIVE: The primary objectives were to gather information regarding the characteristics in the presentation of the children with positive cannabinoid urine drug screen (UDS) results in the ED and to determine if there are certain common presentations with cannabinoid ingestion or inhalation. DESIGN/METHODS: This study was a descriptive retrospective chart review from March 2013 to June 2020 of pediatric patients <18 years old with positive UDS for cannabinoids. Data collected included age, gender, chief complaint, history, review of systems, vital signs, physical exam findings, laboratory studies, imaging findings, and disposition. Four hundred and twenty-two charts were included in the study. Analysis was done using Stata 13 (College Station, TX). RESULTS: The data showed that there was a significant increase in the number of pediatric patients with a positive UDS after cannabis legalization. Using cases from November 2013 to November 2019 showed 71% of cases presented after legalization on November 8, 2016 (Z=7.72, p<.01). The majority of cases were patients between the ages of 15 and 17 (78%). 43% (n=182) of patients presented with chief complaints of suicidal ideation. The other most common chief complaints were vomiting (8%, n=33), nausea (5%, n=22), trauma (5%, n=21), and altered mental status (AMS) (5%, n=20). The most common vital sign abnormalities included tachycardia (27%, n=115) and hypertension (18%, n=74). Forty-two percent of patients had tests ordered during their visit with 7% undergoing head computerized tomography. On the UDS, 28% of patients were positive for at least one other drug with amphetamine being the most common (13%, n=55). CONCLUSION: Our data showed a significant increase in the number of cases since the legalization of cannabis in 2016, supporting the need for ED physicians to become more familiar with cannabis intoxication and its complications. The presentations of these patients can vary greatly. Common presentations include suicidal ideation, nausea/vomiting, AMS, and trauma with vital sign abnormalities including tachycardia and hypertension. Physicians should continue to consider cannabis use when evaluating these pediatric complaints. It may decrease the number of tests ordered in this patient population.

Unwitting adult marijuana poisoning: a case series.

STUDY PURPOSE: With increasing state legalization, marijuana use has become commonplace throughout much of the United States. Existing literature on unintentional exposure focuses primarily on children.We report on a cluster of adults with unwitting marijuana exposure. METHODS: A cluster of cases were referred to the Medical Toxicology Service after ingesting marijuana-contaminated food at a family event. We conducted a retrospective analysis of twelve subject charts and a qualitative analysis with six of these subjects who willingly consented to be interviewed about their experiences. The study was approved by the Institutional Review Board. RESULTS: Three of the subjects (25%) required prolonged observation due to persistent symptoms. Eleven (92%) were urine immunoassay positive for tetrahydrocannabinol (THC). Two subjects (17%) tested positive for ethanol in their blood. Common symptoms experienced by the subjects included confusion (50%), difficulty speaking (67%), nausea (25%), tremors (17%), and feelings of unreality (33%). All interviewed subjects reported sleepiness and three (50%) reported a negative impact on work. Subjects also reported multiple emotions, including anger, confusion, disbelief, and helplessness. None of the cases resulted in admission for critical care or death. CONCLUSIONS: Our series illuminates effects of unwitting and/or unintentional marijuana exposure in adults. Unintentional marijuana poisonings have increased, but legal and regulatory barriers have limited the study of marijuana outside highly controlled conditions. While the marijuana exposure in this study did not result in admission for critical care or death, it did result in psychological distress and adversely affected work in some cases.

When It Comes to Snakebites, Kids Are Little Adults: a Comparison of Adults and Children with Rattlesnake Bites.

BACKGROUND: Rattlesnake envenomations are a significant cause of morbidity in the USA. While pediatric rattlesnake envenomations are relatively common, data comparing adult and pediatric patients with rattlesnake envenomations remain limited. METHODS: This multi-center retrospective study used the North American Snakebite Registry (NASBR), a sub-registry of the Toxicology Investigator's Consortium (ToxIC). All cases of rattlesnake envenomations between January 1, 2013, and December 31, 2017, which were entered into the NASBR, were reviewed. Clinical and laboratory parameters, as well as treatment and outcome measurements, were compared between adult and pediatric patients. RESULTS: A total of 420 unique cases were identified, including 94 pediatric patients. Adult patients were more likely to be male (76% vs. 62%; OR 1.98) and sustain upper extremity envenomations (57% vs. 25%; OR 4.4). After adjusting for bite location, adults were more likely to exhibit edema compared with pediatric patients. After controlling for envenomation location, there was no difference in rates of necrosis between adult and pediatric patients. Adults exhibited early hematologic toxicity less frequently than pediatric patients, but there was no difference in the rates of late hematologic toxicity. There were no differences in the rates of hypotension or intubation. CONCLUSION: While adult and pediatric patients have some differences in envenomation characteristics and laboratory parameters, adults and pediatric patients had similar rates of systemic toxicity, severity, length of stay, and late hematologic toxicity.

Yogaman: An Inexpensive, Anatomically-detailed Chest Tube Placement Trainer.

INTRODUCTION: Opportunities for chest tube placement in emergency medicine training programs have decreased, making competence development and maintenance with live patients problematic. Available trainers are expensive and may require costly maintenance. METHODS: We constructed an anatomically-detailed model using a Halloween skeleton thorax, dress form torso, and yoga mat. Participants in a trial session completed a survey regarding either their comfort with chest tube placement before and after the session or the realism of Yogaman vs. cadaver lab, depending on whether they had placed <10 or 10 or more chest tubes in live patients. RESULTS: Inexperienced providers reported an improvement in comfort after working with Yogaman, (comfort before 47 millimeters [mm] [interquartile ratio {IQR}, 20-53 mm]; comfort after 75 mm [IQR, 39-80 mm], p=0.01). Experienced providers rated realism of Yogaman and cadaver lab similarly (Yogaman 79 mm [IQR, 74-83 mm]; cadaver lab 78 mm [IQR, 76-89 mm], p=0.67). All evaluators either agreed or strongly agreed that Yogaman was useful for teaching chest tube placement in a residency program. CONCLUSION: Our chest tube trainer allowed for landmark identification, tissue dissection, pleura puncture, lung palpation, and tube securing. It improved comfort of inexperienced providers and was rated similarly to cadaver lab in realism by experienced providers. It is easily reusable and, at $198, costs a fraction of the price of available commercial trainers.

Assessing the Effect of a Medical Toxicologist in the Care of Rattlesnake-envenomated Patients.

BACKGROUND: Rattlesnake envenomation is an important problem in the United States, and the management of these envenomations can be complex. Despite these complexities, however, the majority of such cases are managed without the involvement of a medical toxicologist. The primary objective of this study was to evaluate the impact of a medical toxicology service (MTS) on the length of stay (LOS) of such patients. METHODS: The authors conducted a retrospective study at six centers in California. Patients were included if they were admitted in the 2 years before the establishment of a MTS (pre-MTS) or in the 2 years after the creation of a MTS (post-MTS). RESULTS: A total of 300 subjects were included (169 pre-MTS, 131 post MTS). Baseline characteristics between the pre-MTS and post-MTS groups were very similar. The creation of a MTS was associated with a significant reduction in the mean (95% confidence interval) LOS (69.5 [59.1-79.9] hours vs. 48.1 [41.4-54.8] hours). This reduced LOS was not associated with any statistically significant change in readmission rates. CONCLUSION: Rattlesnake bite patients treated by a medical toxicologist have a significantly reduced LOS compared to those without direct involvement of a medical toxicologist.

Toxicity of energy drinks.

PURPOSE OF REVIEW: 'Energy drinks', 'energy shots' and other energy products have exploded in popularity in the past several years; however, their use is not without risk. Caffeine is the main active ingredient in energy drinks, and excessive consumption may acutely cause caffeine intoxication, resulting in tachycardia, vomiting, cardiac arrhythmias, seizures, and death. The effects of chronic high-dose caffeine intake in children and adolescents are unknown. Caffeine may raise blood pressure, disrupt adolescent sleep patterns, exacerbate psychiatric disease, cause physiologic dependence, and increase the risk of subsequent addiction. RECENT FINDINGS: Coingestion of caffeine and ethanol has been associated with increased risk-taking behaviors, harm to adolescent users, impaired driving, and increased use of other illicit substances. The toxicity of ingredients often present in energy drinks, such as taurine, niacin, and pyridoxine, is less well defined. Recent and significant literature describing adverse events associated with energy drink use are reviewed. SUMMARY: Although prior studies have examined the effects of caffeine in adolescents, energy drinks should be considered a novel exposure. The high doses of caffeine, often in combination with ingredients with unknown safety profiles, mandates urgent research on the safety of energy drink use in children and adolescents. Regulation of pediatric energy drink use may be a necessary step once the health effects are further characterized.

Toxicology in the ICU: Part 1: general overview and approach to treatment.

Poisonings, adverse drug effects, and envenomations continue to be commonly encountered. Patients often present critically ill and warrant ICU admission. Many other patients who are initially stable have the potential for rapid deterioration and require continuous cardiopulmonary and neurologic monitoring. Given the potential for rapid deterioration, and because patients need continuous monitoring, ICU admission is frequently required. This article is the first of a three-part series to be published in CHEST; it discusses general management, laboratory tests, enhanced elimination, and emerging therapies. The second article will address the management of specific overdoses; the last will cover plants, mushrooms, envenomations, and heavy metals.