Capacity of community health centers to treat snakebite envenoming in indigenous territories of the Brazilian Amazon.

INTRODUCTION: The deaths from and morbidities associated with snakebites - amputations, loss of function in the limb, visible scarring or tissue damage - have a vast economic, social, and psychological impact on indigenous communities in the Brazilian Amazon, especially children, and represent a real and pressing health crisis in this population. Snakebite clinical and research experts have therefore proposed expanding antivenom access from only hospitals to include the community health centers (CHC) located near and within indigenous communities. However, there are no studies examining the capacity of CHCs to store, administer, and manage antivenom treatment. In response to this gap, the research team calling for antivenom decentralization developed and validated an expert-based checklist outlining the minimum requirements for a CHC to provide antivenom. METHODS: The objective of this study was thus to survey a sample of CHCs in indigenous territories and evaluate their capacity to provide antivenom treatment according to this accredited checklist. The checklist was administered to nurses and doctors from 16 CHCs, two per indigenous district in Amazonas/Roraima states. RESULTS: Our results can be conceptualized into three central findings: 1) most CHCs have the capacity to provide antivenom treatment, 2) challenges to capacity are human resources and specialized items, and 3) antivenom decentralization is feasible and appropriate in indigenous communities. CONCLUSION: Decentralization would provide culturally and contextually appropriate care accessibility to a historically marginalized and underserved population of the Brazilian Amazon. Future studies should examine optimal resource allocation in indigenous territories and develop an implementation strategy in partnership with indigenous leaders. Beyond the indigenous population, the checklist utilized could be applied to community health centers treating the general population and/or adapted to other low-resource settings.

Development and validation of a minimum requirements checklist for snakebite envenoming treatment in the Brazilian Amazonia.

BACKGROUND: Currently, antivenoms are the only specific treatment available for snakebite envenoming. In Brazil, over 30% of patients cannot access antivenom within its critical care window. Researchers have therefore proposed decentralizing to community health centers to decrease time-to-care and improve morbidity and mortality. Currently, there is no evidence-based method to evaluate the capacity of health units for antivenom treatment, nor what the absolute minimum supplies and staff are necessary for safe and effective antivenom administration and clinical management. METHODS: This study utilized a modified-Delphi approach to develop and validate a checklist to evaluate the minimum requirements for health units to adequately treat snakebite envenoming in the Amazon region of Brazil. The modified-Delphi approach consisted of four rounds: 1) iterative development of preliminary checklist by expert steering committee; 2) controlled feedback on preliminary checklist via expert judge survey; 3) two-phase nominal group technique with new expert judges to resolve pending items; and 4) checklist finalization and closing criteria by expert steering committee. The measure of agreement selected for this study was percent agreement defined a priori as ≥75%. RESULTS: A valid, reliable, and feasible checklist was developed. The development process highlighted three key findings: (1) the definition of community health centers and its list of essential items by expert judges is consistent with the Brazilian Ministry of Health, WHO snakebite strategic plan, and a general snakebite capacity guideline in India (internal validity), (2) the list of essential items for antivenom administration and clinical management is feasible and aligns with the literature regarding clinical care (reliability), and (3) engagement of local experts is critical to developing and implementing an antivenom decentralization strategy (feasibility). CONCLUSION: This study joins an international set of evidence advocating for decentralization, adding value in its definition of essential care items; identification of training needs across the care continuum; and demonstration of the validity, reliability, and feasibility provided by engaging local experts. Specific to Brazil, further added value comes in the potential use of the checklist for health unit accreditation as well as its applications to logistics and resource distribution. Future research priorities should apply this checklist to health units in the Amazon region of Brazil to determine which community health centers are or could be capable of receiving antivenom and translate this expert-driven checklist and approach to snakebite care in other settings or other diseases in low-resource settings.

Scaling up antivenom for snakebite envenoming in the Brazilian Amazon: a cost-effectiveness analysis.

Background: Snakebite envenoming (SBE) affects nearly three million people yearly, causing up to 180,000 deaths and 400,000 cases of permanent disability. Brazil's state of Amazonas is a global hotspot for SBE, with one of the highest annual incidence rates per 100,000 people, worldwide. Despite this burden, snake antivenom remains inaccessible to a large proportion of SBE victims in Amazonas. This study estimates the costs, and health and economic benefits of scaling up antivenom to community health centers (CHCs) and hospitals in the state. Methods: We built a decision tree model to simulate three different antivenom scale-up scenarios: (1) scale up to 95% of hospitals, (2) scale up to 95% of CHCs, and (3) scale up to 95% of hospitals and 95% of CHCs. We consider each scenario with and without a 10% increase in demand for antivenom among SBE victims. For each scenario, we model the treatment costs averted, deaths averted, and disability-adjusted life years (DALYs) averted from a societal, health system, and patient perspective relative to the status quo and over a time horizon of one year. For each scenario and perspective, we also calculate the incremental cost per DALY averted and per death averted. We use a willingness to pay threshold equal to the 2022 gross domestic product (GDP) per capita of Brazil. Findings: Scaling up antivenom to 95% of hospitals averts up to 2022 DALYs, costs up to USD $460 per DALY averted from a health system perspective, but results in net economic benefits up to USD $4.42 million from a societal perspective. Scaling up antivenom to 95% of CHCs averts up to 3179 DALYs, costs up to USD $308 per DALY averted from a health system perspective, but results in net economic benefits up to USD $7.35 million from a societal perspective. Scaling up antivenom to 95% of hospitals and CHCs averts up to 3922 DALYs, costs up to USD $328 per DALY averted from a health system perspective, but results in net economic benefits up to USD $8.98 million from a societal perspective. Interpretation: All three antivenom scale up scenarios - scale up to 95% of hospitals, scale up to 95% of CHCs, and scale up to 95% of hospitals and 95% of CHCs - avert a substantial proportion of the SBE burden in Amazonas and are cost-saving from a societal perspective and cost-effective from a health system perspective. Funding: W.M. and J.S. were funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq productivity scholarships). W.M. was funded by Fundação de Amparo à Pesquisa do Estado do Amazonas (PRÓ-ESTADO, call n. 011/2021-PCGP/FAPEAM, call n. 010/2021-CT&I ÁREAS PRIORITÁRIAS, call n. 003/2022-PRODOC/FAPEAM, POSGRAD/FAPEAM) and by the Ministry of Health, Brazil (Proposal No. 733781/19-035). Research reported in this publication was supported by the Fogarty International Center of the National Institutes of Health under Award Number R21TW011944. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Fixing the leaky physician-scientist pipeline: Integrated-dedicated research period programs in emergency medicine.

Emergency physicians (EPs) are well positioned to perform medical research. EPs are exposed to a wide range of disease types, medical specialties, and treatment modalities. Furthermore, emergency medicine (EM) serves as the safety net for the U.S. health care system. The diverse exposure provides a vast opportunity for EP to perform many worthwhile research projects. Yet, EM has historically had the lowest amount of funding and a lower number of National Institutes of Health-funded research projects. Many suggest the etiology is a "leaky" educational pipeline with loss of many potential physician-scientists over the training and development course. Current research training options for the EM physician-scientist includes MD-PhD, 4-year EM residency program and postresidency fellowships. While each has its advantages and disadvantages, we describe an additional educational alternative of EM physician-scientists, which we have named the integrated-dedicated research period within an EM residency. We describe the features of these programs and preliminary results from the graduates and current trainees.

"Two Cultures in Favor of a Dying Patient": Experiences of Health Care Professionals Providing Snakebite Care to Indigenous Peoples in the Brazilian Amazon.

In the Brazilian Amazon, deaths and disabilities from snakebite envenomations (SBEs) are a major and neglected problem for the indigenous population. However, minimal research has been conducted on how indigenous peoples access and utilize the health system for snakebite treatment. A qualitative study was conducted to understand the experiences of health care professionals (HCPs) who provide biomedical care to indigenous peoples with SBEs in the Brazilian Amazon. Focus group discussions (FGDs) were carried out in the context of a three-day training session for HCPs who work for the Indigenous Health Care Subsystem. A total of 56 HCPs participated, 27 in Boa Vista and 29 in Manaus. Thematic analysis resulted in three key findings: Indigenous peoples are amenable to receiving antivenom but not to leaving their villages for hospitals; HCPs require antivenom and additional resources to improve patient care; and HCPs strongly recommend a joint, bicultural approach to SBE treatment. Decentralizing antivenom to local health units addresses the central barriers identified in this study (e.g., resistance to hospitals, transportation). The vast diversity of ethnicities in the Brazilian Amazon will be a challenge, and additional studies should be conducted regarding preparing HCPs to work in intercultural contexts.

Snakebite envenoming in Brazilian children: clinical aspects, management and outcomes.

Snakebite envenoming is currently considered a neglected tropical disease, which affects over 5 million people worldwide, and causes almost 150 000 deaths every year, as well as severe injuries, amputations and other sequelae. Snakebite envenoming in children, although proportionally less frequent, is generally more severe, and represents an important challenge for pediatric medicine, since they often result in worse outcomes. In Brazil, given its ecological, geographic and socioeconomic characteristics, snakebites are considered an important health problem, presenting approximately 30 000 victims per year, approximately 15% of them in children. Even with low snakebite incidence, children tend to have higher snakebite severity and complications due to the small body mass and same venom volume inoculated in comparison to adults, even though, due to the lack of epidemiological information about pediatric snakebites and induced injuries, it is difficult to measure the treatment effectiveness, outcomes and quality of emergency medical services for snakebites in children. In this review, we report how Brazilian children are affected by snakebites, describing the characteristics of this affected population, clinical aspects, management, outcomes and main challenges.

Perspectives on snakebite envenoming care needs across different sociocultural contexts and health systems: A comparative qualitative analysis among US and Brazilian health providers.

With the advancements in therapeutics and available treatment options, almost all deaths and permanent disabilities from snakebite envenoming (SBE) are preventable. The challenge lies in implementing these evidence-based treatments and practices across different settings and populations. This study aims to compare data on provider perceptions of SBE care across health systems and cultural contexts to inform potential implementation science approaches. We hypothesize different health systems and cultural contexts will influence specific perceived needs to provide adequate snakebite care within central tenets of care delivery (e.g., cost, access, human resources). We previously conducted exploratory descriptive studies in the US and Brazil in order to understand the experience, knowledge, and perceptions of health professionals treating SBE. In the US, in-depth interviews were performed with emergency physicians from January 2020 to March 2020. In BR, focus group discussions were conducted with health professionals from community health centers at the end of June 2021. The focus group discussions (BR) were originally analyzed through an inductive thematic analysis approach. We conducted a secondary qualitative analysis in which this codebook was then applied to the interviews (US) in a deductive content analysis. The analysis concluded in August 2022. Brazil participants were physicians (n=5) or nurses (n=20) from three municipalities in the State of Amazonas with an average of three years of professional experience. US participants were emergency physicians (n=16) with an average of 15 years of professional experience. Four main themes emerged: 1) barriers to adequate care on the patient and/or community side and 2) on the health system side, 3) perceived considerations for how to address SBE, and 4) identified needs for improving care. There were 25 subthemes within the four themes. These subthemes were largely the same across the Brazil and US data, but the rationale and content within each shared subtheme varied significantly. For example, the subtheme "role of health professionals in improving care" extended across Brazil and the US. Brazil emphasized the need for task-shifting and -sharing amongst health care disciplines, whereas the US suggested specialized approaches geared toward increasing access to toxicologists and other referral resources. Despite similar core barriers to adequate snakebite envenoming care and factors to consider when trying to improve care delivery, health professionals in different health systems and sociocultural contexts identified different needs. Accounting for, and understanding, these differences is crucial to the success of initiatives intended to strengthen snakebite envenoming care. Implementation science efforts, with explicit health professional input, should be applied to develop new and/or adapt existing evidence-based treatments and practices for SBE.

A systematic review and meta-analysis of clinical signs, symptoms, and imaging findings in patients with suspected renal colic.

Study Objective: The objective of this study was to conduct a systematic review and meta-analysis of the diagnostic accuracy of the clinical signs, symptoms, laboratory investigations, and imaging modalities commonly used in patients with clinically suspected renal colic. Methods: We conducted this systematic review and meta-analysis according to an a priori, registered protocol (PROSPERO CRD42017055153). A literature search was performed using MEDLINE and EMBASE from inception to July 2, 2020. We assessed the risk of bias using Quality Assessment of Diagnostic Accuracy Studies-2, calculated likelihood ratios (LRs), and applied a random-effects model for meta-analysis. Results: Among 7641 references screened, 76 were included in the systematic review and 53 were included in the meta-analyis. The overall pooled prevalence for ureteral stones was 63% (95% confidence interval [CI], 58%-67%). No individual demographic feature, symptom, or sign when present had an LR+ ≥2.0 for identifying ureterolithiasis. A (Sex, Timing and Origin of pain, race, presence or absence of Nausea, and Erythrocytes) STONE score ≥10 increased (sensitivity 0.49, specificity 0.91, LR 5.3 [95% CI, 4.1-6.7]) and a STONE score <6 reduced the likelihood of ureteral stones (sensitivity 0.94, specificity 0.43, LR 0.15 [95% CI, 0.10-0.22]). Standard-dose (sensitivity 0.96, specificity 0.94, LR+ 16 [95% CI, 11-23], LR- 0.05 [95% CI, 0.03-0.07]) and low-dose computed tomography (CT) scanning (sensitivity 0.93, specificity 0.94, LR+ 17 [95% CI, 8.8-31], LR- 0.08 [95% CI, 0.03-0.19]) were the most useful imaging techniques for identifying patients with or without ureteral stones. Conclusions: Individual signs, symptoms, or the presence of microscopic hematuria do not substantially impact the likelihood of ureteral stones in patients with clinically suspected renal colic. The STONE score at high and low thresholds and a modified STONE score at a high threshold may sufficiently guide physicians' decisions to obtain imaging. Low-dose, non-contrast CT imaging provides superior diagnostic accuracy compared with all other imaging index tests that are comparable with standard CT imaging. Limitations of the evidence include methodological shortcomings and considerable heterogeneity of the included studies.

Pregnancy outcomes after snakebite envenomations: A retrospective cohort in the Brazilian Amazonia.

Snakebite envenomations (SBEs) in pregnant women can result in adverse maternal or neonatal effects, such as abortion, placental abruption, preterm labor, fetal malformations, and maternal, fetal or neonatal deaths. Despite the high incidence of SBEs in the Brazilian Amazon, there is no literature on the impact of SBEs on pregnancy outcomes. The objective of this study was to describe clinical epidemiology and outcomes associated with SBEs in women of childbearing age and pregnant women in the state of Amazonas, Western Brazilian Amazon, from 2007 to 2021. Information on the population was obtained from the Reporting Information System (SINAN), Mortality Information System (SIM) and Live Birth Information System (SINASC) for the period from 2007 to 2021. A total of 36,786 SBEs were reported, of which 3,297 (9%) involved women of childbearing age, and 274 (8.3%) involved pregnant women. Severity (7.9% in pregnant versus 8.7% in non-pregnant women) (P = 0.87) and case-fatality (0.4% in pregnant versus 0.3% in non-pregnant women) rates were similar between groups (P = 0.76). Pregnant women who suffered snakebites were at higher risk for fetal death (OR: 2.17, 95%CI: 1.74-2.67) and neonatal death (OR = 2.79, 95%CI: 2.26-3.40). This study had major limitations related to the completeness of the information on the pregnancy outcomes. Although SBE incidence in pregnant women is low in the Brazilian Amazon, SBEs increased the risk of fetal and neonatal deaths.

Mapping of clinical management resources for snakebites and other animal envenomings in the Brazilian Amazon.

Snakebite envenomings (SBEs) and other envenomings triggered by venomous animals (VAEs) represent a significant disease burden in Brazil, with 29,152 SBEs reported in 2021 alone with nearly half of those occurring in the remote Brazilian Amazon. In 2021, Brazil recorded 240,294 envenomings from snakes, scorpions, spiders, and caterpillars. Therefore, there is an unequal distribution of SBEs with high morbidity and mortality in the Brazilian Amazon. The severity of SBEs increases when patients require more than 6 h to access antivenom treatment, a common issue for the rural and indigenous populations. Understanding currently available resources and practices in Amazon remote areas of Brazil can serve to inform future interventions and guide health care policies. This study aims to develop a resource map of existing healthcare resources for the Brazilian Amazon's clinical management of VAEs with emphasis in SBEs, which will aid future strategic interventions. Data collection included a literature review, secondary data collected by government departments and organizational records, GIS mapping activities, and expert input. Our framework was guided by the three levels of healthcare service ecosystem analysis (macro, meso, and micro). Our resource map lays out a comprehensive overview of antivenom access, the distribution landscape, differences in patient transportation, and barriers to access healthcare that face populations in the Brazilian Amazon.

Delayed Recognition of Severe Systemic Envenomation after Copperhead Bite: A Case Report.

INTRODUCTION: We report a case of severe systemic copperhead, Agkistrodon contortrix, envenomation that resulted in long-term sequelae. CASE REPORT: A 72-year-old man presented to the emergency department after suffering a copperhead snakebite. He developed severe systemic toxicity before local tissue injury developed. Clinicians did not initially recognize his envenomation syndrome and sought alternative explanations for his systemic symptoms before polyvalent immune fab (ovine) antivenom was administered. Although the patient improved, he was discharged with new stage three chronic kidney disease. CONCLUSION: Although rare, copperhead envenomation can cause severe systemic toxicity. Envenomation should be promptly treated with antivenom.

Validation of a Culturally Relevant Snakebite Envenomation Clinical Practice Guideline in Brazil.

Snakebite envenoming (SBE) is a neglected tropical disease with significant global morbidity and mortality. Even when antivenom is available in low-resource areas, health workers do not receive adequate training to manage SBEs. This study aims to develop and validate a clinical practice guideline (CPG) for SBE management across Brazil. A panel of expert judges with academic and/or technical expertise in SBE management performed content validation. The content validity index (CVI) score was 90% for CPG objectives, 89% for structure and presentation and 92% for relevance and classified the CPG as valid. A semantic validation was performed by analyzing focus group discussions with doctors and nurses from three municipalities of the Brazilian Amazon, after a 5-day meeting during which the CPG was presented. Two central themes emerged: knowledge acquired during the meeting and recommendations for improving the CPG. Based on these results, the CPG was revised into a final version. This study presents the successful development and validation process of a CPG for SBE management, which is targeted to a specific low-resource, high-burden setting. This development and validation process can be adapted to other settings and/or other neglected tropical diseases.

Patient-level interventions to reduce alcohol-related harms in low- and middle-income countries: A systematic review and meta-summary.

BACKGROUND: Disease and disability from alcohol use disproportionately impact people in low- and middle-income countries (LMICs). While varied interventions have been shown to reduce alcohol use in high-income countries, their efficacy in LMICs has not been assessed. This systematic review describes current published literature on patient-level alcohol interventions in LMICs and specifically describes clinical trials evaluating interventions to reduce alcohol use in LMICs. METHODS AND FINDINGS: In accordance with PRISMA, we performed a systematic review using an electronic search strategy from January 1, 1995 to December 1, 2020. Title, abstract, as well as full-text screening and extraction were performed in duplicate. A meta-summary was performed on randomized controlled trials (RCTs) that evaluated alcohol-related outcomes. We searched the following electronic databases: PubMed, EMBASE, Scopus, Web of Science, Cochrane, WHO Global Health Library, and PsycINFO. Articles that evaluated patient-level interventions targeting alcohol use and alcohol-related harm in LMICs were eligible for inclusion. No studies were excluded based on language. After screening 5,036 articles, 117 articles fit our inclusion criteria, 75 of which were RCTs. Of these RCTs, 93% were performed in 13 middle-income countries, while 7% were from 2 low-income countries. These RCTs evaluated brief interventions (24, defined as any intervention ranging from advice to counseling, lasting less than 1 hour per session up to 4 sessions), psychotherapy or counseling (15, defined as an interaction with a counselor longer than a brief intervention or that included a psychotherapeutic component), health promotion and education (20, defined as an intervention encouraged individuals' agency of taking care of their health), or biologic treatments (19, defined as interventions where the biological function of alcohol use disorder (AUD) as the main nexus of intervention) with 3 mixing categories of intervention types. Due to high heterogeneity of intervention types, outcome measures, and follow-up times, we did not conduct meta-analysis to compare and contrast studies, but created a meta-summary of all 75 RCT studies. The most commonly evaluated intervention with the most consistent positive effect was a brief intervention; similarly, motivational interviewing (MI) techniques were most commonly utilized among the diverse array of interventions evaluated. CONCLUSIONS: Our review demonstrated numerous patient-level interventions that have the potential to be effective in LMICs, but further research to standardize interventions, populations, and outcome measures is necessary to accurately assess their effectiveness. Brief interventions and MI techniques were the most commonly evaluated and had the most consistent positive effect on alcohol-related outcomes. TRIAL REGISTRATION: Protocol Registry: PROSPERO CRD42017055549.

BITES study: A qualitative analysis among emergency medicine physicians on snake envenomation management practices.

INTRODUCTION: Antivenom is currently considered standard treatment across the full spectrum of severity for snake envenomation in the United States. Although safe and effective antivenoms exist, their use in clinical practice is not universal. OBJECTIVE: This study explored physicians' perceptions of antivenom use and experience with snake envenomation treatment in order to identify factors that influence treatment decisions and willingness to administer. METHODS: We conducted a qualitative study including in-depth interviews via online video conferencing with physicians practicing in emergency departments across the United States. Participants were selected based on purposive sampling methods. Data analysis followed inductive strategies, conducted by two researchers. The codebook and findings were discussed within the research team. FINDINGS: Sixteen in-depth interviews with physicians from nine states across the US were conducted. The participants' specialties include emergency medicine (EM), pediatric EM, and toxicology. The experience of treating snakebites ranged from only didactic education to having treated over 100 cases. Emergent themes for this manuscript from the interview data included perceptions of antivenom, willingness to administer antivenom and influencing factors to antivenom usage. Overall, cost-related concerns were a major barrier to antivenom administration, especially in cases where the indications and effectiveness did not clearly outweigh the potential financial burden on the patient in non-life- or limb-threatening cases. The potential to decrease recovery time and long-term functional impairments was not commonly reported by participants as an indication for antivenom. In addition, level of exposure and perceived competence, based on prior education and clinical experience, further impacted the decision to treat. Resources such as Poison Center Call lines were well received and commonly used to guide the treatment plan. The need for better clinical guidelines and updated treatment algorithms with clinical and measurable indicators was stated to help the decision-making process, especially among those with low exposure to snake envenomation patients. CONCLUSIONS: A major barrier to physician use of antivenom is a concern about cost, cost transparency and cost-benefit for the patients. Those concerns, in addition to the varying degrees of awareness of potential long-term benefits, further influence inconsistent clinical treatment practices.

Control of venom-induced tissue injury in copperhead snakebite patients: a post hoc sub-group analysis of a clinical trial comparing F(ab')2 to Fab antivenom.

INTRODUCTION: Fab antivenom (FabAV) halts progression of tissue injury and improves recovery in copperhead snakebite. It is unknown if F(ab')2AV does as well. The objective of this study was to compare control of tissue injury in copperhead snakebite patients treated with F(ab')2AV versus FabAV. METHODS: We performed a post hoc analysis of copperhead envenomated patients in a clinical trial comparing F(ab')2AV to FabAV. The outcomes for this analysis are the number of repeat doses required to obtain initial control, the number of patients requiring unscheduled doses during maintenance, and the time from antivenom administration to initial control. RESULTS: Twenty-one (13 F(ab')2AV, 8 FabAV) were copperhead patients. Median age was 46 years with a male predominance. Baseline severity was similar. One (8%) F(ab')2AV and 2(25%) FabAV patients required repeat initial dosing, difference = 17%, (95%CI -18, 57%). One (8%) F(ab')2AV and 1(13%) FabAV patients required additional doses after maintenance, difference = 5%, (95%CI -27, 45%). Median time to initial control was 2.7 range (2.0, 9.3) hours and 3.5 range (2.0, 7.4) for F(ab')2AV and FabAV respectively, difference -0.8 h (95% CI -2.6, 0.9). CONCLUSIONS: This exploratory analysis suggests that the available measures of the control of venom-induced tissue injury are similar between antivenom subgroups.

The BRAVO Clinical Study Protocol: Oral Varespladib for Inhibition of Secretory Phospholipase A2 in the Treatment of Snakebite Envenoming.

INTRODUCTION: Snakebite is an urgent, unmet global medical need causing significant morbidity and mortality worldwide. Varespladib is a potent inhibitor of venom secretory phospholipase A2 (sPLA2) that can be administered orally via its prodrug, varespladib-methyl. Extensive preclinical data support clinical evaluation of varespladib as a treatment for snakebite envenoming (SBE). The protocol reported here was designed to evaluate varespladib-methyl for SBE from any snake species in multiple geographies. METHODS AND ANALYSIS: BRAVO (Broad-spectrum Rapid Antidote: Varespladib Oral for snakebite) is a multicenter, randomized, double-blind, placebo-controlled, phase 2 study to evaluate the safety, tolerability, and efficacy of oral varespladib-methyl plus standard of care (SoC) vs. SoC plus placebo in patients presenting with acute SBE by any venomous snake species. Male and female patients 5 years of age and older who meet eligibility criteria will be randomly assigned 1:1 to varespladib-methyl or placebo. The primary outcome is the Snakebite Severity Score (SSS) that has been modified for international use. This composite outcome is based on the sum of the pulmonary, cardiovascular, nervous, hematologic, and renal systems components of the updated SSS. ETHICS AND DISSEMINATION: This protocol was submitted to regulatory authorities in India and the US. A Clinical Trial No Objection Certificate from the India Central Drugs Standard Control Organisation, Drug Controller General-India, and a Notice to Proceed from the US Food and Drug Administration have been obtained. The study protocol was approved by properly constituted, valid institutional review boards or ethics committees at each study site. This study is being conducted in compliance with the April 1996 ICH Guidance for Industry GCP E6, the Integrated Addendum to ICH E6 (R2) of November 2016, and the applicable regulations of the country in which the study is conducted. The trial is registered on Clinical trials.gov, NCT#04996264 and Clinical Trials Registry-India, 2021/07/045079 000062.