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Background: Hump-nosed vipers (HNV; Hypnale spp) are one of the medically important venomous snakes in Sri Lanka and South-Western regions of India. The haemostatic dysfunction due to HNV bites is poorly characterized by standard diagnostic tests performed to identify coagulopathy. We aimed to determine the usefulness of rotational thromboelastometry (ROTEM) parameters compared to 20-minute whole blood clotting test (WBCT20) and prothrombin time (PT) in understanding the coagulopathy of HNV bites. Methods: Twenty-three HNV snakebite patients in a prospective study of 127 consecutive snakebites were recruited. After recording details of the clinical presentation, PT/international normalized ratio (INR), WBCT20 and ROTEM delta were performed at presentation. Results: In this preliminary study, none of the patients had clinically apparent bleeding. Coagulopathy was detected by either WBCT20, INR or ROTEM in 13 HNV patients. Eleven had a coagulopathy detectable by ROTEM (either abnormal EXTEM-CT, INTEM-CT or FIBTEM-MCF) but with negative WBCT20. Of them, only two had prolonged INR values. Two patients had positive WBCT20 but with normal ROTEM and INR values. The remaining 10 patients did not show any coagulopathy either by INR, ROTEM or WBCT20. Conclusion: In this preliminary study with small number of sample size, ROTEM parameters appeared to be more sensitive to subtle changes in coagulation compared to WBCT20. The clinical utility of detecting these changes and their usefulness in managing snakebite should be explored further in a larger study. [ABSTRACT FROM AUTHOR]

Background There are significant disparities in the burden of disease due to poisoning between children in low- and high-income countries (HICs). However, there is limited data on the impact of increasing pharmaceutical access in low income countries (LICs) and low-middle income countries (LMICs) on the epidemiology of and risk factors associated with poisoning in children in these settings. Furthermore, while strategies in HICs have effectively reduced the burden of disease due to poisonings in children, there is limited information regarding the efficacy of these interventions in LICs/LMICs. Methods We conducted a systematic review in eight databases for literature published between January 2000 to April 2022 to evaluate the epidemiology and risk factors associated with poisonings due to pharmaceuticals and effective strategies to prevent and manage them in children in LICs/LMICs. From 16061 retrieved articles, 41 were included in the final analysis. Findings Pharmaceuticals were a common cause of poisoning in children in LICs/LMICs, occurring in between 12.4% and 72.36% of cases. Major risk factors were unsafe medication storage and inadequate caregiver knowledge. Delayed access to care and younger age were associated with increased mortality. Prevention strategies that included education demonstrated improvements in knowledge; however, their impact on incidence and mortality was unclear. Management strategies detailed individual patient care interventions, most commonly gastric lavage and activated charcoal. Meanwhile, delayed presentation, limited provider knowledge, and inadequate laboratory resources to support therapeutic monitoring hindered optimal management. Conclusions The combination of educational interventions for prevention, along with regulatory processes to maximise medication storage and formulation safety, could be effective in reducing the burden of poisoning in LICs/LMICs. The development of national or regional protocols for the management of common medication poisonings, augmented by the development of poison control centers and expansion of laboratory access in facilities may help reduce the morbidity and mortality associated with pharmaceutical poisonings in children in LICs/LMICs. Further evidence regarding contextual factors, risk and benefit profiles, the pattern of poisoning, and the impact of preventive and treatment interventions specific to LICs/LMICs is needed to better refine recommendations in these settings. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

There is limited information on the risk of chronic kidney disease (CKD) following snakebite and its relationship with chronic interstitial nephritis in agricultural communities (CINAC). We aimed to investigate CKD in patients with a confirmed snakebite in rural Sri Lanka. Patients prospectively recruited to the Anuradhapura snakebite cohort with authenticated bites were followed up. Two groups of patients were followed up: 199 patients in group I with a snakebite (August 2013–October 2014), reviewed after 4 years, and 168 patients in group II with a snakebite (May 2017–August 2018), reviewed after one year, with serum creatinine (estimated glomerular filtration rate [eGFR]) and urinary albumin to creatinine ratio (ACR). There were 12/199 (6%) in group I and 9/168 (5%) in group II with AKI following snakebite; 3/12 in group I and 2/9 in group II had haemodialysis. On review after 1 and 4 years, no patient had CKD and all had an eGFR ≥60 mL/min/1.73m2. Of 234 patients with a creatinine measured on discharge, 17/140 in group I and 11/94 in group II had a low eGFR (<60mL/min/1.73m2). In group I, 14/17 had a normal eGFR after four years, including 11/12 who had AKI following snakebite, and the 3/17 with a low eGFR on review had CKD or co-morbidities for CKD. In group II, 10/11 had a normal eGFR after one year, including all nine patients with AKI following snakebite, and the one patient with a low eGFR on review had CKD. Fifty patients (25%) in group I and 43 (26%) in group II had a high urinary ACR on review, all but two in each group had microalbuminuria. Multivariate logistic regression showed in group I that only comorbidities for CKD were associated with high urinary ACR, and in group II comorbidities for CKD, snakebite associated AKI and snake type were associated with high urinary ACR. All nine patients from both groups with a low eGFR (CKD stages 3–5) had CKD prior to the snakebite or treatment for hypertension or diabetes. There was no significant association between snakebite-associated AKI and CKD in patients followed up from a snakebite cohort post-bite. Microalbuminuria was common in these patients but likely associated with hypertension, diabetes mellitus and CINAC in this rural farming population. [ABSTRACT FROM AUTHOR]

Background: Bites by the hump-nosed pit vipers (HNPV) of the genus Hypnale are the commonest type of venomous snakebites in Sri Lanka. Their bites frequently cause local effects while rarely causing systemic envenoming, that may include acute kidney injury and coagulopathy. There are 3 species of genus Hypnale including H. hypnale, H. zara and H. nepa from which latter two are endemic to Sri Lanka. Virtually all studies on HNPV bites in Sri Lanka are focused on adults except two studies in paediatric group. The aims of this study were to describe the epidemiology and clinical manifestations of HNPV bites in a group of children admitted to a tertiary care hospital in Sri Lanka. Methodology/Principal findings: This was a prospective observational study carried out in Teaching Hospital Ratnapura, Sri Lanka over 27 months commencing from May 2020 including all children aged up to 14 years with the history of HNPV bites. There were 40 (55.6%) HNPV bites, of them 28 (70%) were males. The age was 84 months (50.2–120 months). Majority (n = 21;52.5%) were bitten during day-time (06:00–17:59) in home gardens (n = 20; 50%) on lower limbs (n = 24;60%). Most children (n = 30;75%) were admitted to the medical facility < 4 hour after the snakebite [90 min (40–210 min)] and the hospital stay was 4 days (3–5 days). Local envenoming was observed in 38 patients (95%) and systemic effects developed in 4 patients (10%) as mild coagulopathy. Local effects include local pain (n = 30; 94%), swelling (n = 38;95%), blistering (n = 11;27.5%), necrosis at the site of bite (n = 11; 27.5%), regional lymph node enlargement (n = 8;20%) and local bleeding (n = 4;10%). For the local effects, surgical interventions were needed in 10 children (25%) and 3 (7.5%) of them developed acute compartment syndrome leading to fasciotomy. Leucocytosis (n = 28;78%) and eosinophilia (n = 9;27%) were the prominent laboratory findings. All got recovered except in patients with fasciotomy who got permanent scar. Conclusions/Significance: Hump-nosed pit viper bites mostly cause local effects and rarely systemic envenoming in children. Compartment syndrome is common in children following their bites. Author summary: Snakebite is a neglected tropical disease affecting mostly rural communities who are engaging in agricultural activities. Many studies focus on adult snakebites and very few are describing on snakebites in paediatric group. Therefore, the understanding of epidemiological and clinical profile of snakebites in children is lacking and poorly characterized. In Sri Lanka, hump-nosed pit viper (Hypnale spp.) causes the commonest venomous snakebites because it inhabits all over the country and is found frequently in human habitat. We undertook a clinical study in Teaching Hospital Ratnapura in order to describe clinical and epidemiological characteristics of HNPV bites in children. There were 40 (56%) children with HNPV bites from which 95% (n = 38) developed local envenoming such as local pain, swelling, blistering and necrosis at the site of bite. Systemic envenoming was observed in 4 (10%) who had mild coagulopathy and 3 (7.5%) had non-specific envenoming features including abdominal pain and headache. The prominent finding was the occurrence of compartment syndrome in some children (n = 3;7.5%) who needed to open limb compartment (fasciotomy). [ABSTRACT FROM AUTHOR]

The African viperid snake genera Atheris, Cerastes, and Proatheris are closely related, similar in size, but occupy extremely divergent ecological niches (arboreal in tropical rainforests, fossorial in deserts, and swamp-dwelling, respectively). Their venoms have not previously been subjected to comparative analyses for their action upon the coagulation of blood, most notably with significant data deficiencies from Atheris and Proatheris. In contrast, the closely related genus Echis is well-documented as capable of producing potent procoagulant effects. In light of this, we set out to compare the coagulotoxic actions of Atheris ceratophora, A. chlorechis, A. desaixi, A. nitschei, A. squamigera, C. cerastes, C. cerastes gasperettii, C. vipera, and Proatheris superciliaris and explore potential pharmacological interventions to reestablish normal blood coagulation. All venoms displayed extremely potent procoagulant effects, over twice as fast as the most potent Echis reported to date. Although Cerastes is used in the immunising mixture of two different regionally available antivenoms (Inoserp-MENA with C. cerastes, C. cerastes gasperettii, C. vipera and Saudi Arabian polyvalent with C. cerastes), none of the other species in this study are included in the immunising mixture of any antivenom. Notably, all the Cerastes species were only neutralised by the Inoserp-MENA antivenom. C. cerastes venom was not neutralised well by the Saudi Arabian antivenom, with the low levels of recognition for any of the Cerastes venoms suggesting a strong regional variation in the venom of this species, as the C. cerastes venom tested was of African (Tunisian) origin versus Saudi locality used in that antivenom's production. The other antivenoms (Micropharm EchiTAbG, ICP EchiTAb-Plus-ICP, Inosan Inoserp Pan-Africa, Premium Serums PANAF Sub-Sahara Africa, South African Vaccine Producers Echis, South African Vaccine Producers Polyvalent) all displayed trivial-to-no ability to neutralise the procoagulant toxicity of any of the Atheris, Cerastes, or Proatheris venoms. Comparative testing of the enzyme inhibitors DMPS, marimastat, and prinomastat, revealed a very potent neutralising capacity of marimastat, with prinomastat showing lower but still significant potency at the same molar concentration, while a 5× molar concentration of DMPS had no apparent effect on procoagulant venom effects normalized by the other inhibitors. These results and methods contribute to the body of knowledge of potential clinical effects and data necessary for evidence-based advancement of clinical management strategies. [ABSTRACT FROM AUTHOR]

Venom-induced thrombocytopenia (VIT) is one of the most important hemotoxic effects of a snakebite, which is often associated with venom-induced consumptive coagulopathy (VICC). Refractory thrombocytopenia without significant coagulation abnormalities has also been reported after envenomation by some viperid snakes; however, the mechanisms are not well understood and therapeutic strategies are lacking. Here, we found that patients injured by Daboia siamensis or Agkistrodon halys snakes, who were resistant to standard antivenom treatment, had developed coagulopathy-independent thrombocytopenia. Venoms from these viperid snakes, rather than from the elapid snake (Bungarus multicinctus), induced platelet surface expression of neuraminidase-1 (NEU-1), and significantly increased the desialylation of the glycoproteins on human platelets. The desialylated platelets caused by viperid snake venoms were further internalized by macrophages, which resulted in reduced platelet numbers in peripheral blood. Importantly, neuraminidase inhibitor significantly decreased viper venom-induced platelet desialylation, therefore inhibiting platelet phagocytosis by macrophages, and alleviating venom-induced thrombocytopenia. Collectively, these findings support an important role for desialylated platelet clearance in the progression of viper envenomation-induced, coagulopathy-independent thrombocytopenia. Our study demonstrates that the neuraminidase inhibitor may be a potential therapy or adjuvant therapy to treat snakebite-induced thrombocytopenia. [ABSTRACT FROM AUTHOR]

Disseminated intravascular coagulation (DIC) has been understood as a consumptive coagulopathy. However, impaired hemostasis is a component of DIC that occurs in a progressive manner. The critical concept of DIC is systemic activation of coagulation with vascular endothelial damage. DIC is the dynamic coagulation/fibrinolysis disorder that can proceed from compensated to decompensated phases, and is not simply impaired hemostasis, a misunderstanding that continues to evoke confusion among clinicians. DIC is a critical step of disease progression that is important to monitor over time. Impaired microcirculation and subsequent organ failure due to pathologic microthrombi formation are the pathophysiologies in sepsis-associated DIC. Impaired hemostasis due to coagulation factor depletion from hemodilution, shock, and hyperfibrinolysis occurs in trauma-associated DIC. Overt-DIC diagnostic criteria have been used clinically for more than 20 years but may not be adequate to detect the compensated phase of DIC, and due to different underlying causes, there is no "one-size-fits-all criteria." Individualized criteria for heterogeneous conditions continue to be proposed to facilitate the diagnosis. We believe that future research will provide therapeutics using new diagnostic criteria. Finally, DIC is also classified as either acute or chronic, and acute DIC results from progressive coagulation activation over a short time and requires urgent management. In this review, we examine the advances in research for DIC. [ABSTRACT FROM AUTHOR]

Background Studies have suggested a association between serum cholesterol values and severity of envenoming. The objective of the study was to correlate the serum cholesterol levels with severity of envenoming in victims of snakebite, across snake species in our patient population. Methods Retrospective secondary data analysis of health records of a cohort of snakebite victims treated at Little Flower Hospital, Angamaly, Kerala during June 2006–January 2008 was performed. The cholesterol values were assessed in 205 consecutive patients admitted with snakebite envenoming, within 24 h of admission and 10 h of overnight fasting. Lipid fractions were estimated from fasting serum through the standard CHOD-PAP method on a Hitachi analyzer. The cholesterol level was compared between victims with mild and serious envenoming to assess the proportion among each category with a low cholesterol (defined as ≤150 mg/dl as per institutional criteria). In addition, low cholesterol as a marker of severity was compared with other laboratory parameters suggesting severe envenoming such as low fibrinogen, low platelet count, neutrophilia, elevated creatinine, d-dimer, hepatic transaminases and albuminuria. Results Of the 146 victims with serious degree of snakebite envenoming 116 (79%) had low cholesterol values ≤150 mg%, while 30 (21%) had values >150 mg%. Of the patients with low cholesterol, 116 (78%) had serious envenoming, while 22% had mild envenoming. By contrast, 30 patients (21%) had values >150 mg%. The risk of moderate-severe envenoming with low cholesterol was 2.7 times (170%) that of victims with normal or high cholesterol on admission. Conclusions A low cholesterol on admission in victims of snake envenoming suggested a more severe degree of envenoming and likelihood of complications. [ABSTRACT FROM AUTHOR]

The availability of effective, reliably accessible, and affordable treatments for snakebite envenoming is a critical and long unmet medical need. Recently, small, synthetic toxin-specific inhibitors with oral bioavailability used in conjunction with antivenom have been identified as having the potential to greatly improve outcomes after snakebite. Varespladib, a small, synthetic molecule that broadly and potently inhibits secreted phospholipase A2 (sPLA2s) venom toxins has renewed interest in this class of inhibitors due to its potential utility in the treatment of snakebite envenoming. The development of varespladib and its oral dosage form, varespladib-methyl, has been accelerated by previous clinical development campaigns to treat non-envenoming conditions related to ulcerative colitis, rheumatoid arthritis, asthma, sepsis, and acute coronary syndrome. To date, twenty-nine clinical studies evaluating the safety, pharmacokinetics (PK), and efficacy of varespladib for non-snakebite envenoming conditions have been completed in more than 4600 human subjects, and the drugs were generally well-tolerated and considered safe for use in humans. Since 2016, more than 30 publications describing the structure, function, and efficacy of varespladib have directly addressed its potential for the treatment of snakebite. This review summarizes preclinical findings and outlines the scientific support, the potential limitations, and the next steps in the development of varespladib's use as a snakebite treatment, which is now in Phase 2 human clinical trials in the United States and India. [ABSTRACT FROM AUTHOR]

The article describes the case of a three-year-old girl who was bitten by a tiger snake at the forearm while playing on her grandparent's farm. Topics discussed include medical history of the girl, administration of antivenom on the child, and discussion on snake envenomation syndromes. Also included are multiple choice questions about the case report.

The acute effects of snakebite are often emphasized, with less information on long-term effects. We aimed to describe the long-term health effects perceived by patients followed up after confirmed snakebites. Two groups of snakebite patients (>18y) from the Anuradhapura snakebite cohort were reviewed: Group I had a snakebite during August 2013-October 2014 and was reviewed after 4 years, and group II had a snakebite during May 2017-August 2018, and was reviewed after one year. Patients were invited by telephone, by sending letters, or doing home visits, including 199 of 736 patients (27%) discharged alive from group I and 168 of 438 patients (38%) from group II, a total of 367 followed up. Health effects were categorised as musculoskeletal, impact on daily life, and medically unexplained. Health issues were attributed to snakebite in 107/199 patients (54%) from group I and 55/168 patients (33%) from group II, suggesting the proportion with health issues increases with time. Sixteen patients (all viperine bites) had permanent musculoskeletal problems, none with a significant functional disability affecting daily routine. 217/367 reported being more vigilant about snakes while working outdoors, but only 21/367 were using protective footwear at review. Of 275 farmers reviewed, only six (2%) had restricted farming activities due to fear of snakebite, and only one stopped farming. 104/199 (52%) of group I and 42/168 (25%) of group II attributed non-specific symptoms (fatigue, body aches, pain, visual impairment) and/or oral cavity-related symptoms (avulsed teeth, loose teeth, receding gums) to the snakebite, which cannot be explained medically. In multivariate logistic regression, farming, type of snake, antivenom administration, and time since snakebite were associated with medically unexplained symptoms. The latter suggests medically unexplained effects increased with time. Based on two groups of snakebite patients reviewed one and four years post-bite, we show that long-term musculoskeletal disabilities are uncommon and not severe in snakebite survivors in rural Sri Lanka. However, a large portion of patients complain of various non-specific general and oral symptoms, not explainable based on the known pathophysiology of snakebite. These perceived effects of snakebite were more common in patients with systemic envenoming, and were more frequent the longer the time post-bite. Author summary: Snakebite is a significant public health issue in the tropics, and the rural farming communities in developing countries are at the greatest risk of snakebite. The acute effects of snakebite are often emphasized in the literature. There is a severe dearth of prospective studies to obtain reliable data about the long-term impact. We aimed to describe the long-term health effects perceived by patients followed up after confirmed snakebites. We followed up 199 and 168 confirmed snakebite patients from a snakebite cohort in rural Sri Lanka four and one year after snakebite. One-third of the patients after one year and half of the patients after four years reported various long-term effects attributed to the snakebite, suggesting the proportion with health issues increases with time. However, only sixteen patients (all viperine bites) had permanent musculoskeletal problems, none with a significant functional disability affecting daily routine. Many patients complain of various non-specific and oral symptoms that they perceived as effects of the snakebite. Although these symptoms were more common in patients with systemic envenoming and viper bites, they cannot be explained as venom-induced effects, warranting a broader socio-cultural explanation. [ABSTRACT FROM AUTHOR]

Snake envenomation is a medical emergency capable of causing local and systemic complications. However, information on venomous snakebite in dogs in South Korea is scarce. In this study, fifty-nine dogs treated at a private veterinary clinic from 2004 to 2021 were retrospectively studied. The aim was to characterize the demographics, elapsed time between snakebite and veterinary clinic presentation, laboratory findings, clinical signs, treatments, adverse reactions to antivenom, and prognosis of venomous snakebite. Snakebite was mostly observed between 12 p.m. and 5 p.m. from April to October. On the days of envenomation, the weather conditions were mostly cloudy, followed by rain/precipitation, and least frequently fair weather. Grassland was the most common incident location, and leashed dog walking was the most frequent activity when snakebite occurred. The main local symptoms were edema, hemorrhagic discharge, cutaneous erythema, ulceration, and necrosis. Major systemic clinical signs were tachypnea, tachycardia, altered mentation, ptyalism, and hypotension. Based on the time interval between snakebite and presentation at the veterinary clinic, two groups were defined: <4 h (Group 1, 49.2%) and ≥4 h (Group 2, 50.8%). Systemic inflammation was more frequently observed in Group 2. The level of C-reactive protein at presentation (p = 0.036) and the highest-level during hospitalization (p = 0.023) were significantly elevated in Group 2 (≥4 h). The dogs in Group 2 displayed more frequent muscle damage (increased creatine kinase) than the dogs in Group 1, and a higher level of creatine kinase was associated with delayed (≥4 h) presentation after snakebite (p = 0.003). All of the dogs were treated symptomatically, and 34 dogs (58%) received antivenom. Treatment with antivenom showed no adverse reactions in this study. All of the treated dogs recovered. One dog was euthanized without any treatment due to respiratory distress, hypotension, and cost constraints. In conclusion, this study provides baseline information on venomous snakebite in dogs in South Korea. The prognosis was excellent, especially when the dogs were treated within 4 h. [ABSTRACT FROM AUTHOR]

There is evidence of cross-neutralisation between common toxin groups in snake venoms and therefore the potential for antivenoms to be effective against species they are not raised against. Here we present a 49 year old female bitten by an unknown pit-viper in Nepal. She developed a venom induced consumption coagulopathy with an unrecordable international normalised ratio and undetectable fibrinogen. On return to Australia 5 days post-bite she was treated successfully with one antivenom raised against Malayan pit viper and green pit viper venoms (Haemato-polvalent antivenom from Thailand) and then subsequently with another antivenom raised against American pit-viper venoms (Antivipmyn). Presumed pit viper venom was detected in patient sera with an enzyme immunoassay against Hypnale hypnale venom. There was increased absorbance before antivenom compared to non-envenomed control samples, which then decreased after the administration of each antivenom. The recurrence of venom detected by enzyme immunoassay between antivenom doses was accompanied by a recurrence of the coagulopathy. Cross reactivity between the unknown venom and both antivenoms was supported by the fact that no venom was detected in the pre-antivenom samples after they were incubated in vitro with both antivenoms. This case and investigation of the venom and antivenoms suggest cross-neutralisation between pit vipers, including pit vipers from different continents. [ABSTRACT FROM AUTHOR]

Objective: The objective was to identify the highest quality global emergency medicine (GEM) research published in 2022. The top articles are compiled in a comprehensive list of all the year's GEM articles and narrative summaries are performed on those included., Methods: A systematic PubMed search was conducted to identify all GEM articles published in 2022 and included a manual supplemental screen of 11 organizational websites for gray literature (GRAY). A team of trained reviewers and editors screened all identified titles and abstracts, based on three case definition categories: disaster and humanitarian response (DHR), emergency care in resource-limited settings (ECRLS), and emergency medicine development (EMD). Articles meeting these definitions were independently scored by two reviewers using rubrics for original research (OR), review (RE) articles, and GRAY. Articles that scored in the top 5% from each category as well as the overall top 5% of articles were included for narrative summary., Results: The 2022 search identified 58,510 articles in the main review, of which 524 articles screened in for scoring, respectively, 30% and 18% increases from last year. After duplicates were removed, 36 articles were included for narrative summary. The GRAY search identified 7755 articles, of which 33 were scored and one was included for narrative summary. ECRLS remained the largest category (27; 73%), followed by DHR (7; 19%) and EMD (3; 8%). OR articles remained more common than RE articles (64% vs. 36%)., Conclusions: The waning of the COVID-19 pandemic has not affected the continued growth in GEM literature. Articles related to prehospital care, mental health and resilience among patients and health care workers, streamlining pediatric infectious disease care, and disaster preparedness were featured in this year's review. The continued lack of EMD studies despite the global growth of GEM highlights a need for more scholarly dissemination of best practices., (© 2023 Society for Academic Emergency Medicine.)

Background: Russell’s viper (Daboia russelii) of Family Viperidae is a highly venomous snake in Sri Lanka and is responsible for the most snakebite deaths. It commonly causes coagulopathy and neuroparalysis. Thrombotic microangiopathy (TMA) including the triad of acute kidney injury (AKI), thrombocytopenia and microangiopathic hemolysis is a rare complication of its bites. There are two clinical entities of TMA including hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) of which, only few records of TMA and HUS following Russell’s viper bites are available in literature.Case presentation: Two patients presented with TMA following Russell’s viper bites. A 36-year-old male who got coagulopathy, respiratory failure, AKI, signs of HUS, and he completely recovered with antivenom and 8 cycles of hemodialysis and discharged on day 19 of snakebite. The other patient was a 66-year-old female who had delayed coagulopathy and persistent drowsiness, the signs of TTP. She required antivenom with 9 cycles of hemodialysis and 6 cycles of therapeutic plasma exchange and got recovered after 30 days in hospital that included intensive care treatments.Discussion: Russell’s viper venom causes activation of Factor V and X which results venom induced consumption coagulopathy and bleeding. The venom also blocks neuromuscular junction and causes neuroparalysis, which are commonly manifested as ptosis and external ophthalmoplegia. It also has direct nephrotoxic effects and there are fibrin depositions in renal microvasculature thereby, causing renal ischemia. In the spectrum of HUS-TTP of TMA, HUS is suggested when there is a severe renal involvement, and TTP is diagnosed when neurological impairment is prominent.Conclusion: Atypical presentations like TMA and HUS may rarely occur following Russell’s viper bites. Further evidence of similar observations is needed to confirm the clinical entity of TTP following Daboia russelii bites.

Background: Snake bite envenoming is a neglected tropical disease with variable clinical presentation, neurotoxic manifestations (respiratory paralysis), rhabdomyolysis, cardiotoxicity, autonomic hyperactivity, and/or coagulation abnormalities. There is limited data on the clinical course of the envenomation in an incidentally diagnosed COVID-19 patient. Case presentation: A 17-year-old male with history of snake bite and neuroparalysis developed shortness of breath. He was treated with lyophilized polyvalent anti-snake venom (ASV) on admission in the emergency department and mechanical ventilation. Subsequently, he tested positive for COVID-19 infection. No immunomodulatory therapy was administered, and patient was extubated on the 5th day of ICU admission without any neurological deficit. Conclusions: Coinfections of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus with snake bite poisoning lead to diagnostic dilemmas and controversies in management practices. Abnormalities of coagulation need to be cautiously addressed, and cause of development of pneumonia needs to be identified. The rapid recovery of the patient in our case theoretically can be explained on the organ-protective potential of snake-derived peptides; a large case series is however needed to prove the same. [ABSTRACT FROM AUTHOR]

Why you should read this article: • To enhance your knowledge of the prevalence and pathophysiology of snake bites • To enable you to recognise the signs and symptoms of snake bites and how to determine their severity • To understand the steps that need to be taken when assessing and managing patients with a suspected or confirmed snake bite Snake bites are a relatively rare presentation to emergency departments in the Western world. In the UK, there were 510 cases of snake bites between 2004 and 2010. However, it is important that nurses are aware of how to assess and manage these presentations and understand the importance of ascertaining information on factors such as the type of snake involved and how long the snake was biting the patient for. This article uses a case study to discuss the assessment and management of snake bites, and provides information on the steps nurses should take to manage patients presenting with a snake bite. [ABSTRACT FROM AUTHOR]

Daboia siamensis (Russell's viper) is a highly venomous and medically important snake in China, as well as much of Asia. There is minimal information on the pharmacological activity of the venom of the Chinese species, and currently no commercially available specific antivenom in China. This has led to the use of non-specific antivenoms to treat D. siamensis envenomation. In this study, the in vitro neurotoxicity and myotoxicity of D. siamensis venom was examined and the efficacy of four antivenoms was investigated, including the recently developed Chinese D. siamensis monovalent antivenom (C-DsMAV) and three commercially available antivenoms (Thai D. siamensis (Thai-DsMAV) monovalent antivenom, Deinagkistrodon acutus monovalent antivenom (DaAV), and Gloydius brevicaudus monovalent antivenom (GbAV). D. siamensis venom (10–30 µg/mL) caused the concentration-dependent inhibition of indirect twitches in the chick biventer cervicis nerve muscle preparation, without abolishing contractile responses to exogenous agonists ACh or CCh, indicating pre-synaptic neurotoxicity. Myotoxicity was also evident at these concentrations with inhibition of direct twitches, an increase in baseline tension, and the partial inhibition of ACh, CCh, and KCl responses. The prior addition of C-DsMAV or Thai-DsMAV prevented the neurotoxic and myotoxic activity of D. siamensis venom (10 µg/mL). The addition of non-specific antivenoms (GbAV and DaAV) partially prevented the neurotoxic activity of venom (10 µg/mL) but failed to neutralize the myotoxic effects. We have shown that D. siamensis venom exhibits in vitro weak presynaptic neurotoxicity and myotoxicity, which can be prevented by the pre-addition of the Chinese and Thai Russell's viper antivenoms. Non-specific antivenoms were poorly efficacious. There should be further development of a monospecific antivenom against D. siamensis envenomation in China. [ABSTRACT FROM AUTHOR]

In India, polyvalent antivenom is the mainstay treatment for snakebite envenoming. Due to batch-to-batch variation in antivenom production, manufacturers have to estimate its efficacy at each stage of IgG purification using the median effective dose which involves 100–120 mice for each batch. There is an urgent need to replace the excessive use of animals in snake antivenom production using in vitro alternatives. We tested the efficacy of a single batch of polyvalent antivenom from VINS bioproducts limited on Echis carinatus venom collected from three different locations—Tamil Nadu (ECVTN), Goa (ECVGO) and Rajasthan (ECVRAJ)—using different in vitro assays. Firstly, size-exclusion chromatography (SEC-HPLC) was used to quantify antivenom–venom complexes to assess the binding efficiency of the antivenom. Secondly, clotting, proteolytic and PLA2 activity assays were performed to quantify the ability of the antivenom to neutralize venom effects. The use of both binding and functional assays allowed us to measure the efficacy of the antivenom, as they represent multiple impacts of snake envenomation. The response from the assays was recorded for different antivenom–venom ratios and the dose–response curves were plotted. Based on the parameters that explained the curves, the efficacy scores (ES) of antivenom were computed. The binding assay revealed that ECVTN had more antivenom–venom complexes formed compared to the other venoms. The capacity of antivenom to neutralize proteolytic and PLA2 effects was lowest against ECVRAJ. The mean efficacy score of antivenom against ECVTN was the greatest, which was expected, as ECVTN is mainly used by antivenom manufacturers. These findings pave a way for the development of in vitro alternatives in antivenom efficacy assessment. [ABSTRACT FROM AUTHOR]

There are an estimated 5.4 million snakebite cases every year. People with snakebite envenoming suffer from severe complications, or even death. Although some review articles cover several topics of snakebite envenoming, a review of the cases regarding cerebral complications, especially rare syndromes, is lacking. Here, we overview 35 cases of snakebite by front-fanged snakes, including Bothrops, Daboia, Cerastes, Deinagkistrodon, Trimeresurus, and Crotalus in the Viperidae family; Bungarus and Naja in the Elapidae family, and Homoroselaps (rare cases) in the Lamprophiidae family. We also review three rare cases of snakebite by rear-fanged snakes, including Oxybelis and Leptodeira in the Colubridae family. In the cases of viper bites, most patients (17/24) were diagnosed with ischemic stroke and intracranial hemorrhage, leading to six deaths. We then discuss the potential underlying molecular mechanisms that cause these complications. In cases of elapid bites, neural, cardiac, and ophthalmic disorders are the main complications. Due to the small amount of venom injection and the inability to deep bite, all the rear-fanged snakebites did not develop any severe complications. To date, antivenom (AV) is the most effective therapy for snakebite envenoming. In the six cases of viper and elapid bites that did not receive AV, three cases (two by viper and one by elapid) resulted in death. This indicates that AV treatment is the key to survival after a venomous snakebite. Lastly, we also discuss several studies of therapeutic agents against snakebite-envenoming-induced complications, which could be potential adjuvants along with AV treatment. This article organizes the diagnosis of hemotoxic and neurotoxic envenoming, which may help ER doctors determine the treatment for unidentified snakebite. [ABSTRACT FROM AUTHOR]

Background: Hump-nosed pit viper is a medically important deadly venomous snake in Sri Lanka and is the commonest cause of venomous snakebites in the country. It frequently causes local effects and systemic manifestations such as acute kidney injury and coagulopathy that occur in less than 10% of all bites. This also includes some atypical presentations such as thrombotic microangiopathy and myocardial infarction. Currently, no antivenom is available for hump-nosed pit viper bites in Sri Lanka, and patients are managed with supportive treatment. This case illustrates an acute ischemic stroke following a hump-nosed viper bite, which is the second case in the literature.Case Presentation: A 71-year-old a Sinhalese male patient presented with left-sided hemiparesis with mouth deviation on day 2 of hump-nosed viper (Hypnale spp.) bite on the right foot. Non-contrast computed tomography of brain showed right ischemic stroke in internal capsule. He was given antiplatelets and statins and continued supportive treatment including limb physiotherapy and speech therapy. He recovered completely and was discharged on day 4 with clinic follow-up.Conclusions: Physicians should be aware that ischemic cerebral infarcts may occur following hump-nosed pit viper bites. [ABSTRACT FROM AUTHOR]

We studied the neutralisation of Sri Lankan Russell's viper (Daboia russelii) and Australian mulga snake (Pseudechis australis) venom-induced myotoxicity by Indian (Vins and Bharat) and Australian (Seqirus) polyvalent antivenoms, using the in vitro chick biventer skeletal muscle preparation. Prior addition of Bharat or Vins antivenoms abolished D. russelii venom (30 µg/mL)-mediated inhibition of direct twitches, while Australian polyvalent antivenom was not protective. Bharat antivenom prevented, while Vins and Australian polyvalent antivenoms partially prevented, the inhibition of responses to exogenous KCl. Myotoxicity of Mulga venom (10 µg/mL) was fully neutralised by the prior addition of Australian polyvalent antivenom, partially neutralised by Vins antivenom but not by Bharat antivenom. Although the myotoxicity of both venoms was partially prevented by homologous antivenoms when added 5 min after the venom, with an increasing time delay between venom and antivenom, the reversal of myotoxicity gradually decreased. However, antivenoms partially prevented myotoxicity even 60 min after venom. The effect of antivenoms on already initiated myotoxicity was comparable to physical removal of the toxins by washing the bath at similar time points, indicating that the action of the antivenoms on myotoxicity is likely to be due to trapping the toxins or steric hindrance within the circulation, not allowing the toxins to reach target sites in muscles. [ABSTRACT FROM AUTHOR]

Snakebite envenoming affects more than 250,000 people annually in sub-Saharan Africa. Envenoming by Dispholidus typus (boomslang) results in venom-induced consumption coagulopathy (VICC), whereby highly abundant prothrombin-activating snake venom metalloproteinases (SVMPs) consume clotting factors and deplete fibrinogen. The only available treatment for D. typus envenoming is the monovalent SAIMR Boomslang antivenom. Treatment options are urgently required because this antivenom is often difficult to source and, at US$6000/vial, typically unaffordable for most snakebite patients. We therefore investigated the in vitro and in vivo preclinical efficacy of four SVMP inhibitors to neutralise the effects of D. typus venom; the matrix metalloproteinase inhibitors marimastat and prinomastat, and the metal chelators dimercaprol and DMPS. The venom of D. typus exhibited an SVMP-driven procoagulant phenotype in vitro. Marimastat and prinomastat demonstrated equipotent inhibition of the SVMP-mediated procoagulant activity of the venom in vitro, whereas dimercaprol and DMPS showed considerably lower potency. However, when tested in preclinical murine models of envenoming using mixed sex CD1 mice, DMPS and marimastat demonstrated partial protection against venom lethality, demonstrated by prolonged survival times of experimental animals, whereas dimercaprol and prinomastat failed to confer any protection at the doses tested. The preclinical results presented here demonstrate that DMPS and marimastat show potential as novel small molecule-based therapeutics for D. typus snakebite envenoming. These two drugs have been previously shown to be effective against Echis ocellatus VICC in preclinical models, and thus we conclude that marimastat and DMPS should be further explored as potentially valuable early intervention therapeutics to broadly treat VICC following snakebite envenoming in sub-Saharan Africa.

Worsening COVID-19 severity in patients with opioid use disorder (OUD) is plausible based on biological mechanisms (respiratory effects, immune mechanisms, drug-drug interactions) and social/environmental factors. The hypothesis was that among Emergency Department (ED) and hospitalized patients with COVID-19, OUD is associated with a higher incidence of COVID-19 mortality. Patients reported using ivermectin for prophylaxis (60%), for treatment of documented COVID-19 (21%), and for treatment of symptoms of undocumented COVID-19 (14%). It is possible that pregnant patients using fentanyl, cocaine, or methamphetamine either do not attend our obstetric clinics or that these patients were already referred to our internal SUD clinic for pregnant patients. [Extracted from the article]

Background: Sea snakes are venomous snakes found in the warm parts of the Indo-Pacific, including around Australia. Most sea snake envenoming causes myotoxicity, but previous Australian case reports describe neurotoxicity. We aimed to describe the epidemiology and clinical presentation of Australian sea snake envenoming and the effectiveness of antivenom. Methods: Patients were recruited to the Australian Snakebite Project (ASP), an Australia-wide prospective observational study recruiting all patients with suspected or confirmed snakebite >2 years. Information about demographics, bite circumstances, species involved, clinical and laboratory features of envenoming, and treatment is collected and entered into a purpose-built database. Results: Between January 2002 and August 2020, 13 patients with suspected sea snake bite were recruited to ASP, 11 were male; median age was 30 years. Bites occurred in Queensland and Western Australia. All patients were in or around, coastal waters at the time of bite. The species involved was identified in two cases (both Hydrophis zweifeli). Local effects occurred in 9 patients: pain (5), swelling (5), bleeding (2), bruising (1). Envenoming occurred in eight patients and was characterised by non-specific systemic features (6) and myotoxicity (2). Myotoxicity was severe (peak CK 28200 and 48100 U/L) and rapid in onset (time to peak CK 13.5 and 15.1 h) in these two patients. Non-specific systemic features included nausea (6), headache (6), abdominal pain (3), and diaphoresis (2). Leukocytosis, neutrophilia, and lymphopenia occurred in both patients with myotoxicity and was evident on the first blood test. No patients developed neurotoxicity or coagulopathy. Early Seqirus antivenom therapy was associated with a lower peak creatine kinase. Conclusion: While relatively rare, sea snake envenoming is associated with significant morbidity and risk of mortality. Early antivenom appears to have a role in preventing severe myotoxicity and should be a goal of therapy. [ABSTRACT FROM AUTHOR]

Snake venoms have evolved primarily to immobilize and kill prey, and consequently, they contain some of the most potent natural toxins. Part of that armory is a range of hemotoxic components that affect every area of hemostasis, which we have harnessed to great effect in the study and diagnosis of hemostatic disorders. The most widely used are those that affect coagulation, such as thrombin-like enzymes unaffected by heparin and direct thrombin inhibitors, which can help confirm or dispute their presence in plasma. The liquid gold of coagulation activators is Russell's viper venom, since it contains activators of factor X and factor V. It is used in a range of clotting-based assays, such as assessment of factor X and factor V deficiencies, protein C and protein S deficiencies, activated protein C resistance, and probably the most important test for lupus anticoagulants, the dilute Russell's viper venom time. Activators of prothrombin, such as oscutarin C from Coastal Taipan venom and ecarin from saw-scaled viper venom, are employed in prothrombin activity assays and lupus anticoagulant detection, and ecarin has a valuable role in quantitative assays of direct thrombin inhibitors. Snake venoms affecting primary hemostasis include botrocetin from the jararaca, which can be used to assay von Willebrand factor activity, and convulxin from the cascavel, which can be used to detect deficiency of the platelet collagen receptor, glycoprotein VI. This article takes the reader to every area of the diagnostic hemostasis laboratory to appreciate the myriad applications of snake venoms available in diagnostic practice. [ABSTRACT FROM AUTHOR]

Abdominal pain is known to be an early clinical predictor of severe systemic Russell's viper (RV) envenomation and is often associated with the later development of coagulopathy and neurotoxicity. The mechanism of abdominal pain is unknown, but we postulated it might be due to intestinal microvascular endothelial gut damage. Gut-toxicity can be detected using the novel biomarker Intestinal Fatty Acid Binding Protein (IFABP). We also wanted to explore the mechanisms and consequences of this toxicity by measuring procalcitonin as a specific marker of sepsis triggered by bacterial endotoxin, and serum cystatin-C (CysC) as a measure of acute kidney injury. We hypothesised that severe gut-injury might lead to gut-barrier failure, translocation of gastrointestinal microorganisms, associated sepsis and systemic inflammatory response syndrome (SIRS), with a possible exacerbation of snake-bite severity, including acute kidney injury that was previously attributed to direct venom effects. Serial plasma samples previously collected from 16 RV envenomations with abdominal pain, 15 RV envenomations without abdominal pain and 25 healthy controls were assayed for IFABP. A subgroup of these RV envenomations were assayed for procalcitonin (n = 24) and serum CysC (n = 11). The median peak IFABP for RV envenomations was much higher than healthy controls [3703.0 pg/mL (IQR 2250.1–13702.0 pg/mL) vs. 270.1 pg/mL (IQR 153.5–558.0 pg/mL) (p < 0.001)]. There was no difference in those with and without abdominal pain [3801.4 pg/mL (IQR 2080.5–22446.3 pg/mL) vs. 3696.6 pg/mL (IQR 2280.3–4664.7 pg/mL) (p = 1.0)]. Peak procalcitonin levels were elevated in envenomed patients 30.1 ng/ml (IQR: 13.1–59.7 ng/ml) with a level >2ng/mL indicative of severe sepsis] and also correlated with peak IFABP (r = 0.55, p = 0.006, n = 24). Peak serum CysC was also elevated and also correlated with IFABP (r = 0.71, p = 0.037, n = 9). IFABP is significantly elevated indicating enterocyte damage occurs in RV envenomation. IFABP correlated with markers of sepsis (procalcitonin) and acute kidney injury (serum CysC) suggesting that enterocyte damage resulting in translocation of microbial associated molecular patterns (MAMPs) contributes to RV envenomation associated SIRS and sepsis. [ABSTRACT FROM AUTHOR]

Antivenom has been used successfully to treat systemic and progressive, local manifestations of envenomations inflicted by Echis coloratus, the second most common cause of snake envenomation in Israel. There is a paucity of published data regarding the use of monovalent (equine) immunoglobulin G antivenom in children. This study describes outcomes from the regimen used in two large, tertiary care pediatric centers. A retrospective chart review of children admitted with definite or probable signs of Echis coloratus envenomation to Sourasky (Tel Aviv) and Soroka (Be'er Sheva) Medical Centers from January 1st 2008–to June 1st 2019. Extracted data included age, location of bite, time to hospital arrival, laboratory test results, complications, time to antivenom administration if indicated, adverse effects of the antivenom, and outcomes. Indications for antivenom were: diagnosis of Echis coloratus as the etiology of envenomation, local and systemic signs e.g. skin puncture wounds, swelling of the involved limb, local hematoma, and abnormal coagulation blood test results. During the study period, 11 children were treated with intravenous Echis coloratus antivenom. Median age was 9 years and 10 of 11 patients were male. Two patients underwent fasciotomy; in one, compartment syndrome was diagnosed by pressure measurement, and in the second, clinically. One patient developed mild urticaria 30 min after initiation of the antivenom; the treatment was stopped and then restarted at a slower rate after he was treated with hydrocortisone and diphenhydramine. No further adverse reactions were observed. In children, Echis coloratus antivenom appeared to be effective and safe for the treatment of systemic and progressive local manifestations of envenomation by Echis coloratus. [ABSTRACT FROM AUTHOR]

Background: Snakebite is a neglected problem with a high mortality in India. There are no simple clinical prognostic tools which can predict mortality in viper envenomings. We aimed to develop and validate a mortality-risk prediction score for patients of viper envenoming from Southern India. Methods: We used clinical predictors from a prospective cohort of 248 patients with syndromic diagnosis of viper envenoming and had a positive 20-minute whole blood clotting test (WBCT 20) from a tertiary-care hospital in Puducherry, India. We applied multivariable logistic regression with backward elimination approach. External validation of this score was done among 140 patients from the same centre and its performance was assessed with concordance statistic and calibration plots. Findings: The final model termed VENOMS from the term "Viper ENvenOming Mortality Score included 7 admission clinical parameters (recorded in the first 48 hours after bite): presence of overt bleeding manifestations, presence of capillary leak syndrome, haemoglobin <10 g/dL, bite to antivenom administration time > 6.5 h, systolic blood pressure < 100 mm Hg, urine output <20 mL/h in 24 h and female gender. The lowest possible VENOMS score of 0 predicted an in-hospital mortality risk of 0.06% while highest score of 12 predicted a mortality of 99.1%. The model had a concordance statistic of 0·86 (95% CI 0·79–0·94) in the validation cohort. Calibration plots indicated good agreement of predicted and observed outcomes. Conclusions: The VENOMS score is a good predictor of the mortality in viper envenoming in southern India where Russell's viper envenoming burden is high. The score may have potential applications in triaging patients and guiding management after further validation. Author summary: More than 58,000 people die of snakebites each year in India. Russell's viper, saw scaled viper and pit vipers are widely distributed and medically important venomous snakes in India responsible for significant deaths and disabilities. Clinicians need easy-to-use bedside tools to make decisions on which patients are at a higher risk of dying after viper bites. In this study, conducted in Southern India, where Russell's viper is the commonest viper causing bites, we have evolved and validated a simple risk prediction score. This uses seven clinical and laboratory features to estimate a patient's risk of dying in the hospital due to the bite. The study showed that the score has good predictive ability when tested in a similar population of patients. We expect that the score is the first step in developing a tool that is likely to help health workers and doctors assess a patient's risk in primary-care peripheral or rural settings to help decide on early referral of high-risk patients who are likely to worsen. [ABSTRACT FROM AUTHOR]

In agreement with this, recent studies have demonstrated that the outcome of rodent lethality assays are heavily influenced by the -neurotoxin activity of snake venoms, when -neurotoxins are present in the venoms ([13]; [14]). Keywords: lethality; snake venom; antivenom; LD50; ED50; rodent; mouse EN lethality snake venom antivenom LD50 ED50 rodent mouse 1 4 4 02/08/22 20220203 NES 220203 Introduction Snakebite is a major public health problem in the tropics, being closely associated with agricultural economy, poverty and underdevelopment. Procoagulant Snake Venoms Have Differential Effects in Animal Plasmas: Implications for Antivenom Testing in Animal Models. However, sustaining sufficient -neurotoxin concentrations at the neuromuscular junction to maintain inhibition of the nAChR depends on the relative abundance of the -neurotoxins in the particular snake venom as well as the amount of venom injected during the snakebite. [Extracted from the article]

Abstract: Snake venoms contain toxins that activate the coagulation network and cause venom-induced consumption coagulopathy. A previously developed mathematical model of the coagulation network was refined and used to describe and predict the time course of changes in the coagulation factors following envenomation by Brown snake (Pseudonaja spp.), Tiger snake (Notechis scutatus), Rough-scaled snake (Tropidechis carinatus) and Hoplocephalus spp. (Stephens banded, Pale headed and Broad headed). Simulations of the time course of the change in coagulation factors were compared to data obtained from a large prospective study of Australian snake bites – the Australian Snakebite Project. The model predictions were also compared against data for partial and complete VICC obtained from the same study. The model simulations were used to understand the differences in consumption and recovery of clotting factors in partial versus complete VICC as well as among bites from different snake types. The model suggested that the venoms were absorbed almost instantaneously and provided a reasonable prediction of the observed concentration of clotting factors over time in patients bitten by Australian elapid snakes. The model predictions suggested a higher consumption of factors (fibrinogen, II and IX in particular) in patients with complete VICC compared to those with partial VICC. The model also predicted that snakes with “Xa-like” venoms may produce a less severe VICC than snakes with “Xa:Va-like” venoms. [Copyright &y& Elsevier]

Venom-induced consumption coagulopathy and thrombocytopenia are common and potentially severe manifestations of viperid snakebite envenoming since they contribute to local and systemic hemorrhage. Therefore, the assessment of the efficacy of antivenoms to neutralize coagulopathic and thrombocytopenic toxins should be part of the preclinical evaluation of these drugs. To evaluate the efficacy of the polyvalent (Crotalinae) antivenom produced in Costa Rica, in this study we have used a mouse model of coagulopathy and thrombocytopenia induced by the venom of Bothrops asper, based on the bolus intravenous (i.v.) injection of venom. When venom and antivenom were incubated before injection, or when antivenom was administered i.v. immediately after venom injection, venom-induced hemostatic alterations were largely abrogated. We also studied the recovery rate of clotting parameters in conditions where antivenom was administered when mice were coagulopathic. Some parameters recovered more rapidly in antivenom-treated mice than in control envenomed animals, but others showed a spontaneous recovery without antivenom. This is due to a rapid clearance of plasma venom levels in these experimental conditions. This implies that models based on the bolus i.v. injection of venom have limitations for assessing the effect of antivenom in the recovery of clotting alterations once coagulopathy has developed. It is suggested that alternative models should be developed based on a slower systemic absorption of venom. Overall, our findings provide a protocol for the preclinical evaluation of antivenoms and demonstrate that the polyvalent antivenom is effective in neutralizing the toxins of B. asper venom responsible for coagulopathy and thrombocytopenia., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Marilla Lamela Méndez works for Capris S.A., which distributes equipment and reagents for rotational thromboelastometry analysis.Erika Camacho, Alexandra Rucavado, Teresa Escalante, Mariángela Vargas, Álvaro Segura and José María Gutiérrez work at Instituto Clodomiro Picado, Universidad de Costa Rica, where the antivenom used in this study is manufactured., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Abstract: There is limited information on envenoming by snakes of the genus Hoplocephalus from Eastern Australia. We investigated the clinical and laboratory features of patients with definite Hoplocephalus spp. bites including antivenom treatment, recruited to the Australian Snakebite Project. There were 15 definite Hoplocephalus spp. bites based on expert identification including eight by Hoplocephalus stephensi (Stephen’s banded snakes), four by Hoplocephalus bungaroides (broad-headed snake) and three by H. bitorquatus (pale-headed snake). Envenoming occurred in 13 patients and was similar for the three species with venom induced consumption coagulopathy (VICC) in all envenomings. Seven patients had an INR >12 and partial VICC, with only incomplete fibrinogen consumption, occurred in three patients. Systemic symptoms occurred in eight patients. Myotoxicity and neurotoxicity did not occur. H. stephensi venom was detected in all three H. stephensi envenomings (1.1, 44 and 81 ng/mL) for whom pre-antivenom blood samples were available, and not detected in one without envenoming. In two cases with post-antivenom blood samples, venom was not detected after tiger snake antivenom (TSAV) was given. In vitro binding studies demonstrated that TSAV concentrations of 50mU/mL are sufficient to bind the majority of free H. stephensi venom components at concentrations above those detected in envenomed patients (100 ng/mL). Eleven patients received antivenom, median dose 2 vials (Range: 1 to 5 vials), which was TSAV in all but one case, where polyvalent antivenom was used. Immediate hypersensitivity reactions occurred in six cases including one case of anaphylaxis. Envenoming by Hoplocephalus spp. causes VICC and systemic symptoms, making it clinically similar to brown snake (Pseudonaja spp.) envenoming. Based on in vitro studies reported here, patients may be treated with one vial of TSAV, although one vial of brown snake antivenom may also be sufficient. [Copyright &y& Elsevier]

Abstract: Venom-induced consumption coagulopathy occurs in snake envenoming worldwide but the interaction between procoagulant snake venoms and human coagulation remains poorly understood. We aimed to evaluate an assay using endogenous thrombin potential (ETP) to investigate the procoagulant properties of a range of Australian whole venoms in human plasma and compared this to traditional clotting and prothrombinase activity studies. We developed a novel modification of ETP using procoagulant snake venoms to trigger thrombin production. This was used to characterise the relative potency, calcium and clotting factor requirements of five important Australian snake venoms and efficacy of commercial antivenom, and compared this to prothrombinase activity and clotting assays. All five venoms initiated thrombin generation in the absence and presence of calcium. Pseudonaja textilis (Brown snake; p <0.0001), Hoplocephalus stephensii (Stephen’s-banded snake; p <0.0001) and Notechis scutatus (tiger snake; p =0.0073) all had statistically significant increases in ETP with calcium. Venom potency varied between assays, with ETP ranging from least potent with Oxyuranus scutellatus (Taipan) venom to intermediate with N. scutatus and H. stephensii venoms to most potent with P. textilis and Tropidechis carinatus (Rough-scale snake) venoms. ETPs for N. scutatus, T. carinatus and H. stephensii venoms were severely reduced with factor V deficient plasma. Antivenom neutralized the thrombin generating capacity but not prothrombin substrate cleaving ability of the venoms. Contrary to previous studies using clotting tests and factor Xa substrates, these venoms differ in calcium requirement. ETP is a useful assay to investigate mechanisms of other procoagulant venoms and is a robust method of assessing antivenom efficacy. [Copyright &y& Elsevier]