snake bite research article

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• Published: 20 May 2023

Identifying high snakebite risk area under climate change for community education and antivenom distribution

• Masoud Yousefi 1 , 2 ,
• Saeed Hosseinian Yousefkhani 1 ,
• Marc Grünig 3 ,
• Anooshe Kafash 4 ,
• Mahdi Rajabizadeh 5 , 6 &
• Eskandar Rastegar Pouyani 7  

Scientific Reports volume  13 , Article number:  8191 ( 2023 ) Cite this article

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• Climate change
• Ecological epidemiology
• Ecological modelling
• Public health

Snakebite is one of the largest risks from wildlife, however little is known about venomous snake distribution, spatial variation in snakebite risk, potential changes in snakebite risk pattern due to climate change, and vulnerable human population. As a consequence, management and prevention of snakebite is hampered by this lack of information. Here we used habitat suitability modeling for 10 medically important venomous snakes to identify high snakebite risk area under climate change in Iran. We identified areas with high snakebite risk in Iran and showed that snakebite risk will increase in some parts of the country. Our results also revealed that mountainous areas (Zagros, Alborz, Kopet–Dagh mountains) will experience highest changes in species composition. We underline that in order to improve snakebite management, areas which were identified with high snakebite risk in Iran need to be prioritized for the distribution of antivenom medication and awareness rising programs among vulnerable human population.

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Introduction

Snakebite envenoming is a medical emergency and an important health problem worldwide 1 , 2 , 3 . Up to 5 million snakebites occur each year leading to about 100,000 deaths annualy 2 , 4 , 5 , 6 . Despite recent attention to the challenge of snakebite 3 , 5 , 7 , 8 , 9 , 10 little is known about the distribution of venomous snakes, and therefore the spatial variation in snakebite risk and accessibility of vulnerable human population to healthcare system 3 . Further, the potential shift of high risk areas for snakebite due to climate change remains unknown. As a consequence, management of snakebite is hampered by this lack of information around the globe 3 , 11 . To ensure successful snakebite management it is necessary to identify high snakebite risk areas.

Identifying areas with high risk of snakebite can help us to locate target areas for awareness raising programs and to effectively provide antivenoms to the most vulnerable groups 2 , 12 , 13 . While our knowledge on current snakebite risk patterns remains limited 2 , 14 , venomous snakes are responding to climate change by shifting their habitats to cope with global warming 2 , 15 , 16 , 17 . Thus, the complexity of snakebite management further increases and therefore calls for more efforts to identify high snakebite risk areas under climate change 2 , 10 .

Habitat Suitability Models (HSMs) are practical tools to predict the impacts of climate and land use changes on species distribution 18 , 19 , 20 , identify their future distribution 21 , document changes in species composition 22 , 23 by correlating species occurrence records to climatic variables 18 . Moreover, HSMs can be used to predict changes in distribution and interaction of species and their host or prey and predator in changing climate 24 , 25 , 26 . In recent years, HSMs are used in predicting snakebite risk areas under current and future climate change, identifying vulnerable human population 2 , 13 , 27 , 28 , 29 , 30 , and have even been shown to correlate with snakebite incidences 28 . In these studies, venomous snakes’ habitat suitability was considered as an indicator of snakebite risk 2 , 13 , 27 .

Iran is home to 15 terrestrial venomous snakes including one of the most famous snake in the world named Spider tailed viper, Pseudocerastes urarachnoides 31 . While all 15 species are medically important, four species ( Echis carinatus Macrovipera lebetina , Naja oxiana , and P. persicus ) are more widespread in Iran and are therefore responsible for the most snakebite incidents in the country 32 . Although previous studies investigated the challenge of snakebite in Iran by reporting snakebite incidents 32 , 33 still little is known about medically important venomous snakes’ distribution and potential changes in their distribution under climate change 17 , 34 , 35 , 36 . Previous studies have shown that climate change will change distribution pattern of biodiversity including snakes in Iran 37 . While suitable habitats of some species will expand under climate change some others will lose considerable proportion of their suitable range. For instance, Yousefi et al. 17 showed that mountains vipers of genus Montivipera will lose their suitable habitat and will shift to higher altitude to track their suitable climate. As model projections showed that species like E. carinatus and P. persicus will experience an expansion of suitable habitat area due to warming climate, this may lead to an increasing number of envenoming events 38 .

In order to mitigate the risk of snakebite and to identify vulnarable human populations, developing snakebite risk maps becomes crucial 2 . Thus, to effectively manage snakebite problem in Iran the aims of this study are (i) modeling the habitat suitability of medically important venomous snakes; (ii) determining hotspots of snakebite risk; (iii) quantifying changes in medically important venomous snakes’ composition due to climate change; (iv) identifying vulnerable populations to snakebite envenoming by considering exposure to snakebite and accessibility to health centers. The results of this study will guide responsible health organizations for the distribution of antivenom medication and awareness raising programs in the country.

Modeling the impacts of climate change (years 2041–2070 SSP126 (Fig. S1 ), SSP585 (Fig. S2 ) and 2071–2100 SSP126 (Fig. S3 ), SSP585 (Fig.  1 )) on habitat suitability of the 10 medically important venomous snakes showed that suitable habitats of five species ( E. carinatus , Gloydius halys , Montivipera latifii , P. persicus and Walterinnesia aegyptia ) will increase while five species will lose ( M. lebetina , M . raddei , N. oxiana , P. urarachnoides and Vipera eriwanensis ) some of their suitable habitat under climate (Fig.  1 ). Results of the evaluation metrics of the models were presented in Fig.  2 . The evaluation metrics values were highest for M. latifii while the values were lowest for the E. carinatus .

Snakebite risk maps of the 10 species ( Echis carinatus ( a ), Gloydius halys ( b ), Macrovipera lebetina ( c ), Montivipera latifii ( d ), Montivipera raddei ( e ), Naja oxiana ( f ), Pseudocerastes persicus ( g ), Pseudocerastes urarachnoides ( h ), Vipera eriwanensis ( i ), Walterinnesia aegyptia ( j )) under current and future (year 2071–2100 SSP585) climatic. Maps were generated using QGIS 3.4.1 ( https://www.qgis.org ).

Results of the evaluation metrics (AUC and TSS) of the 10 medically important snakes’ models.

Variable importance

Estimating variable importance for the 10 medically important venomous snakes showed that growing degree days heat sum above 10 °C followed by annual precipitation were the most important predictor of habitat suitability of the 10 snakes when averaged across all species (Fig.  3 ). Growing degree days heat sum above 10 °C was the most important determinants of suitable habitats of M. raddei , N. oxiana , P. persicus and V. eriwanensis , annual precipitation was identified the most influential predictor of habitat suitability for E. carinatus , M. lebetina and W. aegyptia and precipitation of driest quarter turn out to be the most important predictor of habitat suitability of G. halys , M. latifii and P. urarachnoides .

Boxplot of the variables (annual precipitation (Bio12), precipitation of the driest quarter (Bio17), temperature seasonality (Bio4), growing degree days heat sum above 10 °C (GDD) and slope) importance averaged across the 12 species. Boxplot was created in R environment ( https://cran.r-project.org ).

Hotspot of snakebite in Iran

By multiplying snakebite risk models of the 10 medically important venomous snakes (Fig.  4 ) we found that hotspots of snakebite in Iran are located in north west of Iran, Alborz mountains, and west of Zagros mountains. Zagros mountains have low richness of medically important venomous snakes under current climatic conditions but under climate change snakebite risk will increase in the mountains in particular under SSP585 scenario for years 2071–2100.

Hotspots of snakebite risk by multiplying habitat suitability models of the 10 medically important venomous snakes in Iran under current ( a ) and future climatic conditions (2041–2070 SSP126 ( b ), 2041–2070 SSP585 ( c ), 2071–2100 SSP126 ( d ), 2041–2070 SSP585 ( e )). Maps were generated using QGIS 3.4.1 ( https://www.qgis.org ).

Species composition change

We compared similarity of medically important venomous snakes’ composition by comparing current and future distribution of the 10 medically important venomous snakes (Fig.  5 ). We found that under SSP585 for years 2041–2070 and 2071–2100 mountainous areas (Zagros, Alborz, Kopet–Dagh mountains) will experience highest changes in species composition.

Similarity maps showing change in species composition by comparing current and future distribution (2041–2070 SSP126 ( a ), 2041–2070 SSP585 ( b ), 2071–2100 SSP126 ( c ), 2041–2070 SSP585 ( d )) of the 10 medically important venomous snakes. Maps were generated using QGIS 3.4.1 ( https://www.qgis.org ).

Vulnerability to snakebite

Vulnerability to snakebite was modeled by considering exposure to snakebite plus accessibility to healthcare centers. Results showed that central parts of Iran and north east of the country have largest areas which are vulnerable to snakebite. Under climate change geographic pattern of snakebite risk will change especially in Zagros Mountains and areas vulnerable to snakebite will increase (Fig.  6 ).

Vulnerability to snakebite maps (exposure to snakebite (the 10 medically important venomous snakes) plus accessibility to healthcare centers), current ( a ), 2041–2070 SSP126 ( b ), 2041–2070 SSP585 ( c ), 2071–2100 SSP126 ( d ), 2071–2100 SSP585 ( e ). Maps were generated using QGIS 3.4.1 ( https://www.qgis.org ).

Snakebite is a neglected tropical disease and important health problem 39 , leading to thousands of fatal incidents and many more disabilities annually. Hereby, the rural population is at a higher risk of snakebite due to limited access to healthcare facilities, resulting in delayed administration of antivenom, which is a critical factor in the treatment of snakebite 14 , 40 . To ensure successful snakebite management and reduce snakebite incidents, identifying high snakebite risk areas under current and future climate is highly relevant. Here we mapped areas with high risk snakebite in Iran under current and future climate based on 10 medically important venomous snakes.

We found that the North west of Iran, Alborz mountains, and west of Zagros mountains have the highest richness of medically important venomous snakes and thus are regions with high snakebite risk. Our study confirms the results of previous studies on the importance of climate on distribution of venomous snakes of Iran 13 , 15 , 34 , 38 . Further, we showed that growing degree days heat sum above 10 °C followed by annual precipitation were the most important predictors of habitat suitability of the 10 snakes in Iran. Growing degree days heat sum above 10 °C is the most important variable because it influences the growth and development of plants and insects during the growing season which directly and indirectly influence prey availability for the snakes 41 .

Developing snakebite management strategies based solely on the current distribution of medically significant venomous snake species may be risky, as recent studies have demonstrated that climate change is capable of altering the potential distribution of these species 10 , 29 . Furthermore, model predictions suggest that climate change may lead to changes in the composition and species richness of medically significant venomous snake species, which could subsequently modify the pattern of snakebite risk 10 , 29 . Predicted changes in medically important venomous snakes’ hotspot and composition in mountains regions of Iran may result in previously less affected populations to venomous snakes becoming more exposed. The future snakebite risk models developed in this study can be useful to raise awareness among the people who might be at risk of envenoming under climate change and by considering potential changes in snakebite risk pattern for antivenom distribution in the future. Together, this may support reducing the numbers of deaths and cases of disability due to snakebite envenoming 2 , 10 , 42 .

Access to antivenom can help to reduce mortality and morbidity of snakebite envenoming 42 . Mapping medically important venomous snakes’ current and future distribution is critical for knowing where antivenin for each species is needed 2 . Beside determining areas with less accessibility to medical facilities is necessary to identify the most vulnerable populations 2 , 42 . Our models, showing the most vulnerable areas to snakebite in Iran can guide antivenom distribution by the Ministry of Health and Medical Education across the country.

WHO introduced community empowerment and engagement as an important strategy to prevent and control snakebite envenoming 39 . Areas identified at risk of snakebite have high priority to guide snakebite mitigation and training measures for health teams and local people in Iran 2 . Farmers, shepherd and nomads who encounter snakes in their everyday life while working on farms or grazing their livestock are the most vulnerable groups. Thus, awareness raising programs should focus on these population groups. In most snakebite accidents the snakes were not identified and therefore no specific treatment can be applied. Educating local communities in areas with high snakebite risk to be able to identify venomous snakes should therefore be prioritized 40 . Moreover, despite the importance of the snakebite in Iran still health workers are not familiar with all medically important venomous snakes of Iran. Thus, beside local people, it is necessary to regularly educate health workers in the country. Some occupations are associated with higher risk of encountering venomous snakes such as protected areas rangers, foresters and tour guides. Thus, organizations responsible for these occupations like Department of Environment and Department of Natural Resources and Watershed Management can run awareness raising and training workshops in high snakebite risk areas to educate them how to avoid snakebite and to seek health care instead seeking care from traditional healers 39 .

Venomous snakes have secretive behavior and life history thus studying snakebite risk is a challenging task especially in developing countries like Iran 43 , 44 . Using citizen science is a promising avenue to overcome lack of knowledge on distribution of venomous snake 43 . We encourage using citizen science in Iran as increasing number of young people are getting interested in herping in the country. Their observations on venomous snakes’ distribution in areas with limited data can be used to develop high resolution distribution maps and more accurate models. To be able to use herpers observations in snakes and snakebite studies their observations should be documented with a photograph and deposited in relevant databases like iNaturalist or HerpMapper 43 .

Conclusions

Identifying high snakebite risk areas under climate change, distribution of effective antivenoms, and education are four key factors in snakebite management. In this study, we predicted the impacts of climate change on 10 medically important venomous snakes, their richness, community composition and identified vulnerable snakebite area. This research study has important implications for snakebite management in Iran. As shown in other studies 13 , 27 , 28 , 29 , 30 , 45 , 46 and confirmed in this research HSMs developed based on distribution of medically important venomous snakes can guide public policies for the distribution of antivenom medication and identification of regions with higher snakebite risk to guide mitigation and training measures for vulnerable populations as well as health teams. It should be noted that population density, educational level, income, etc. could are also important variables that affect people’s living standards and their exposure to snake habitat proximity. But since these predictors are not available at high spatial resolution, we were unable to consider them. Apart from Iran, snakebite is an important challenge in other Middle Eastern countries 32 , 47 . Our approach in modeling snakebite risk and mapping vulnerability to snakebite under current and future climate can be applied in other countries to reduce snakebite incidents in the region.

Species data

In this study, distribution records of medically important venomous snakes of Iran 31 gathered from different sources as follows: fieldworks, online databases (GBIF, VertNet), published books and papers ranging from 2000 to 2022. After gathering distribution records from different sources, we removed duplicates and thinned distribution records to match with climatic layers’ resolution (1 km 2 ). Considering some species like M. kuhrangica , Bungarus sindnus , Cerastes gasperettii , and Eristicophis macmahoni have restricted range 31 and limited distribution records it was not possible to develop robust habitat suitability models for them thus they were removed from further analysis 31 . We considered M. lebetina and M. razii together as one taxonomic unit 31 . We found enough distribution records to build habitat suitability model for 10 medically important venomous snake species ( E. carinatus (148 points), G. halys (34 points), M. lebetina (150 points), M. latifii (20 points), M. raddei (23 points), N. oxiana (51 points), P. persicus (151 points), P. urarachnoides (22 points), V. eriwanensis (54 points), W. aegyptia (32 points)) in Iran 31 (Figs. 7 and 8 ).

Distribution records of the 10 medically important venomous snakes ( Echis carinatus (148 points), Gloydius halys (34 points), Macrovipera lebetina (150 points), Montivipera latifii (20 points), Montivipera raddei (23 points), Naja oxiana (51 points), Pseudocerastes persicus (151 points), Pseudocerastes urarachnoides (22 points), Vipera eriwanensis (54 points), Walterinnesia aegyptia (32 points)) on a topographic overview of Iran. Map was generated using QGIS 3.4.1 ( https://www.qgis.org ).

Photographs of medically important venomous snakes of Iran ( Gloydius halys ( a ), Pseudocerastes persicus ( b ), Montivipera latifii ( c ), Vipera eriwanensis ( d ), Pseudocerastes urarachnoides ( e ), Montivipera raddei ( f ) and Echis carinatus ( g )). All photos were taken in the species natural habitats. Photos by Masoud Yousefi.

Predictor variables

For climate data, we used CHELSA high resolution climatologies version 2.1 48 .This platform provides downscaled climate data for current and future climate conditions. We downloaded the bioclimatic variables at a 30 arcsec (~ 1 km) resolution for current climate and future climate (years 2041–2070 and 2071–2100) scenarios from five different CMIP6 Global Circulation Models (GCMs) (GFDL-ESM4, IPSL-CM6A-LR, MPI-ESM1-2-HR, MR-ESM2-0, UKESM1-0-LL). CMIP6 GCMs are state-of-the-art and using several GCMs is reducing the uncertainty coming from the single GCMs. The selected scenarios are corresponding to the available data. Further, we used two (SSP126, SSP585) different shared socioeconomic pathways (SSPs) for each GCM to represent the uncertainty of future CO2 emissions and therefore the expected change in climate. As predictor variables for habitat suitability modelling, we selected four bioclimatic variables including growing degree days heat sum above 10 °C (GDD), temperature seasonality (Bio4), annual precipitation (Bio12) and precipitation of the driest quarter (Bio17). Bioclimatic variables are gridded layers containing information about the climate in a particular region. They are derived variables from the monthly min, max, mean temperature, and mean precipitation values and were developed for species distribution modeling and related ecological applications. Those variables have shown to be reliable predictors for SDMs in a multitude of studies. Growing degree days are the heat sum of all days above the 10 °C temperature accumulated over 1 year, temperature seasonality is defined as standard deviation of the monthly mean temperatures, annual precipitation is the accumulated precipitation amount over 1 year and precipitation of the driest quarter is defined as the accumulated precipitation within the driest quarter. The selection was a combination of choosing species specific biologically relevant predictors and removing autocorrelated variables 13 , 34 , 38 . Additionally, we added slope as a fifth predictor variable. Slope was calculated from the Shuttle Radar Topography Mission (SRTM) digital elevation model 49 at a 30 arcsec (~ 1 km) resolution with the terrain function of the raster package (version 3.4–13 50 ). We included slope because it is an important predictor for habitat suitability of snakes. While climatic variables change over time, slope remains constant. However, future habitat suitability will still depend highly on slope. For instance, species occurring in flat areas will not adapt to terrain with steep slopes, even though the climate might become more suitable in the steep slopes. Including this variable thus is important to not overestimate the magnitude of change. For the SDM predictor variables, we chose biologically relevant variables and removed some correlated variables during this process as described in the methods section. We started with all bioclimatic variables and reduced the number of predictors in an empirical process of adding and removing variables to the SDMs in order to improve their performance. As all bioclimatic variables are derived from temperature and precipitation, some of those variables are highly correlated (e.g. maximum temperature and temperature of the warmest month). Excluding auto-correlated variables can help to avoid violating the assumption of independence of data points. Therefore, it is important to reduce the number of variables and select those which are less correlated and therefore improve the accuracy and reliability of the SDM.

Modeling snakebite risk under current and future climate

For modelling the suitable habitat of the snake species under current and future climate, we used an equally weighted ensemble approach of five different habitat suitability modeling algorithms (HSM algorithms). We used GLMs ( base R-package; R environment 51 ), GAMs ( gam R-package version 1.20.1 52 ), GBMs ( gbm R-packge version 2.1.8 53 ), RandomForests ( randomForest R-package version 2.1.8 54 ) and Maxent ( dismo R-package version 1.3-5 55 ). For each species, we generated 5000 pseudo-absences by randomly sampling coordinates from the ecoregions where the species occurred and down- weighted the absences in the model algorithms to balance the presence-absence prevalence to 0.5 56 . To assess model performance, we used a split-sample approach (70% training data and 30% evaluation data) with 20 repetitions. The total number of points was 685 in which 480 points (70%) were used for as training data. Performance was measured using the area under the receiver operating characteristic curve (AUC) 57 , 58 and True Skill Statistics (TSS) 59 . TSS values range from − 1 to + 1, where + 1 indicates perfect performance and value of zero meaning random predictions. AUC values range from 0 to 1, a value of 0.5 indicates that the performance of the model is not better than random, while values closer to 1.0 indicate better model performance 57 , 58 , 59 . We additionally checked the projections of the models visually (expert-based evaluation). Binary classifications were done using the sensitivity–specificity sum maximization approach (R package presenceAbsence 1.1.9 60 ). Model variable importance was assessed using the variables_importance function of the biomod2 package (version 3.5.1 61 ) for GLMs, GAMs and GBMs, the importance function of the randomForest package (version 2.1.8 54 ) for RandomForest models and the ecospat. maxentvarimport function of the ecospat package (version 3.2 62 ) for Maxent models. We evaluated the importance of each variable across the different algorithms to show the variation in variable importance.

Mapping snakebite hotspot, community composition changes and vulnerability to snakebite

To map the snakebite hotspot, we calculated the species richness of the 10 medically important venomous snakes by stacking binary habitat suitability maps of all species and calculating the sum for each grid cell in R 51 . For the community composition analysis, species richness maps were converted to matrices and then compared with the ecospat.CommunityEval function of the ecospat package (version 3.2 62 ). Finally, to map vulnerability to snakebite across the country we considered two factors a) distance to cities which can provide primary health care services (accessibility to health care) and b) exposure to medically important venomous snakes (binary habitat suitability maps). We calculated a distance-to-city layer as the distance of each grid cell to the nearest city using the distance function of the raster package (version 3.4-13 50 ). For each species we masked the binary habitat suitability map with the distance-to-city layer to get a vulnerability to snakebite map for each medically important venomous snake. For the final risk maps, we multiplied the species richness maps with the distance-to-city layer. From this we extracted the values from the vulnerability to snakebite maps for each cell to get the vulnerability index.

Data availability

The datasets generated and analysed during the current study are available from the sources described in the manuscript and also the corresponding author on reasonable request.

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Acknowledgements

We would like to thank the Iranian National Science Foundation (Project Number: 99021952) for supporting this research.

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Anooshe Kafash

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M.Y. conceived and designed this study. M.Y., M.R., A.K., S.H.Y. and E.R.P. collected distribution data, M.G. performed statistical analyses. M.Y. and A.K prepared the maps. M.Y. wrote the manuscript with inputs from M.G. (method section). All authors read, revised, and approved the final manuscript.

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Yousefi, M., Yousefkhani, S.H., Grünig, M. et al. Identifying high snakebite risk area under climate change for community education and antivenom distribution. Sci Rep 13 , 8191 (2023). https://doi.org/10.1038/s41598-023-35314-1

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Predictive spatial correlation analysis of snakebites of krishna district, india.

• Motru Vijaya Raju
• A. Sudhir Babu
• P. Krishna Subba Rao

Microsystem Technologies (2024)

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Managing snakebite

• Related content
• Peer review
• Ravikar Ralph , professor 1 ,
• Mohammad Abul Faiz , professor of medicine (retired) 2 ,
• Sanjib Kumar Sharma , professor and head 3 ,
• Isabela Ribeiro , scientific lead 4 ,
• François Chappuis , professor 5
• 1 Department of Internal Medicine, Christian Medical College, Vellore, Tamil Nadu, 632004, India
• 2 Dev Care Foundation, Dhaka-1209, Bangladesh
• 3 Department of Internal Medicine, B.P. Koirala Institute of Health Sciences, Dharan, 76500, Nepal
• 4 Dynamic Portfolio, Drugs for Neglected Diseases initiative (DND i) , 15 Chemin Louis-Dunant, 1202, Geneva, Switzerland
• 5 Division of Tropical and Humanitarian Medicine, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 6, Geneva, CH 1211, Switzerland
• Correspondence to: R Ralph ravikar_ralph{at}yahoo.com

What you need to know

Bites from venomous snakes can result in bleeding, paralysis, long term disability, and death

Immobilise the bitten limb when transporting the patient to a medical facility; the universal use of pressure immobilisation is controversial, and tourniquets are not recommended

The 20-minute whole blood clotting test is a simple bedside test to screen for and monitor coagulopathy in resource-limited settings

Assess vital parameters and initiate resuscitation measures if the patient is clinically unstable with signs of bleeding, shock, paralysis, or respiratory distress

Intravenous antivenom is recommended in patients with systemic symptoms; the dose and type depend on likely snake species, local guidelines, and availability

Snakebite affects between 1.8 to 2.7 million people worldwide each year, and it is estimated to cause between 80 000 and 138 000 deaths. 1 2 A mixture of toxins (venom) is injected into the body following bite by a venomous snake. 3 Envenoming can be a highly dynamic clinical event. Symptoms can progressively worsen to a life-threatening emergency. Snakebites can have long term physical sequelae such as amputation, paralysis and disability, and psychological health consequences. 4 5 6 7

Snakebite envenoming is more common in South and South-East Asia (2 million annually), sub-Saharan Africa (420 000) and Latin America (150 000). 1 2 These regions also report a high burden of deaths from snakebite (100 000, 32 000, and 5000 deaths respectively) possibly due to poor access to medical aid. 1 2 Delayed diagnosis and treatment can worsen prognosis. 8 9 10 11 The World Health Organization recognised snakebite as a neglected tropical disease in 2017 and called for concerted global action to reduce deaths and disability. 12

In this clinical update, we present an approach to evaluation and management of snakebites for primary care providers in resource-limited settings in endemic regions. The principles of management are broadly similar, but it is beyond the scope of this article to cover clinical syndromes and management for the varied snake species globally.

Sources and selection criteria

We searched the Cochrane Library, Google, and PubMed, using the MeSH terms: “(snakebite, diagnosis and treatment guidelines) and (snake, scientific names of individual snake species, snakebite, envenoming, venom, and antivenom)”. Research papers and case reports from Latin America, South and South-East Asia, and sub-Saharan Africa were retrieved. There were no language restrictions. Additional articles were obtained by citation tracking of review and original articles. Although the search focused on key papers published in the past five years, older publications of importance have been included. The review also drew from the widely established African and South-East Asian regional guidelines on the treatment and prevention of snakebite envenoming.

Who is at risk of snakebite?

Rural communities in tropical countries are worst affected. 13 14 15 16 Agricultural workers, hunter-gatherers, herders, fishermen, and rural families living in precarious housing conditions with outdoor toilets have a higher risk of snakebite. Their living environments intersect with snake habitats. 12 Men between 10 and 40 years are more commonly affected. 4 15 17 18 19 20 Non-mechanised farming techniques, barefoot farming, and sleeping on the floor further increase the risk. 16 21 Bites are more common during wetter months, when agricultural activities and breeding season for snakes potentially converge. 15 17 20 22 23

How does envenoming occur?

Most medically important snakes in these regions belong to two taxonomic families 24 25 26 27 :

Viperidae— African adders and bush vipers, Asian pit vipers, mamushis, habus, and New World rattlesnakes, moccasins, bushmasters, and lanceheads

Elapidae— African and Asian cobras, African mambas, African rinkhals, Asian kraits, Australian and Papuan venomous snakes, Asian and New World coral snakes and sea snakes

Venomous snakes inject venom during a bite using specialised grooved or hollow teeth called fangs. The fangs are connected to venom glands on each side of the upper jaw via a duct. 28 Viperids usually have long foldable front-fangs, while those in elapids are short and fixed ( fig 1 ). 28 Depending on fang length, venom is introduced either subcutaneously or intramuscularly. 3

Difference in fangs between elapids and viperids. A) Elapids have short, fixed, front fangs. B&C) Vipers have much longer and retractable front fangs. (Photos courtesy of Ahmad Khaldun Ismail)

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Some snakes with fangs towards the back of the mouth (“non-front-fanged colubroids” such as African boomslang and vine snakes, South American racers, and Asian yamakagashis) and the burrowing asps (or stiletto snakes) whose unique jaw kinesis coupled with exceptional neck flexure allow for a single protruding fang to be jabbed sideways or backwards, can also cause envenoming. 3 28 29 Spitting cobras and rinkhals can eject venom over several metres, often delivering venom droplets into the eyes of the animal or human perceived to be a threat. 30 31 32

What are the clinical effects of snakebite?

Not all people with a snakebite have clinical symptoms. Often bites are by non-venomous snakes. Sometimes venomous snakes do not inject venom during a bite. 33

Clinical manifestations vary between species of snakes (see box 1 ). 3 Some toxins in venom exert local effects such as swelling, blistering, bruising, and necrosis at the bite site. 24 25 Other toxins can be distributed systemically through lymphatics and blood vessels and act at distant sites. See supplementary text for an overview of important sites and pathophysiology of venom-toxin action. Common systemic effects include bleeding, paralysis, generalised rhabdomyolysis, and acute kidney injury. Venom injection deep into a limb can cause tissue swelling in the tightly constrained space and compromise neurovascular function. 54 55 This manifests as “acute compartment syndrome.” 24 25 31

Clinical effects of snakebite

Local effects.

Bite site— Swelling, blistering, bruising, necrosis (usual after bites by cobras and vipers, with some exceptions in each family, and burrowing asps) 24 25

Acute compartment syndrome after deep bite into a limb —Intense pain, abnormal sensations, or a cold, pulseless, immobile limb 24 25

Venom ophthalmia from entry of venom droplets or spray into the eyes —Intense pain, redness, blepharitis, blepharospasm, and corneal erosions 31

Systemic effects

Vascular— Envenoming by most viperid and Australopapuan elapid species and some non-front-fanged colubroids can trigger clotting failure, platelet abnormalities, and vessel wall damage. 34 35 36 Effects range from clotting test abnormalities to mild bite site or mucosal bleeds to severe spontaneous systemic or intracranial haemorrhage 24 25

Shock —From bleeding or plasma extravasation systemically or into the swollen, bitten limb, myocardial dysfunction, pituitary bleeds, vasodilation, sepsis, and anaphylaxis 29 36 37 38 39 40 41 42

Neuromuscular— Most elapid and some viperid venoms can cause paralysis by action at the nerve (presynaptic) or muscle fibre (postsynaptic) of the neuromuscular junction. 24 25 Weakness of eye muscles initially present as ptosis, diplopia, and blurred vision. This is followed by sequential weakness of bulbar (dysphagia, dysphonia, and drooling), neck, respiratory, and limb muscles 43

Generalised muscle destruction is caused by envenoming by sea snakes and some elapid and viperid species. 24 25 This manifests as muscle pain and tenderness, especially of the neck, trunk, and proximal limbs with dark urine 29

Acute kidney injury likely results from secondary effects such as hypotension, fibrin-platelet microthrombi in capillaries and arterioles, and immune or haem related tubular damage, or directly from effect of venom 44 45 46 47 48 49 50 51 52 53

How do patients present?

Patients usually give a history of being bitten by a snake, except those who experience painless nocturnal bites by kraits while asleep. 22 56 57 Patients are often fearful and anxious. Occasionally, painful bites may be mistaken for a puncture wound from a thorn or sharp stone and be ignored initially. 58 Some patients, especially children, bitten by highly venomous snakes, may present with cardiovascular collapse, unconsciousness, bleeding, paralysis, or respiratory failure and may not provide a clear history of snakebite. 44 59 It is important to consider envenoming in these situations in regions where snakebites are common. 24 25

Nausea, vomiting, abdominal pain, and headache are non-specific symptoms but must be monitored as these may herald serious complications such as uraemia, acute pituitary or intracranial bleeds, and anaphylaxis. 24

What first aid can be provided?

Reassure the person about prompt first aid and medical assistance to allay fears. Arrange for rapid transport to the nearest medical facility, preferably with access to antivenom and critical care support. 60

Immobilise the person, and especially the bitten limb to slow venom spread. 24 Remove rings and other tight objects around the limb. 61 A systematic review identified pressure immobilisation with an elastic bandage or pad (at a comfortable pressure) at the bite site as an effective first aid measure to slow venom spread, but the quality of evidence was very low. 62 63 Its use is variable, and it is discouraged in most practice and guidelines because of the uncertainty of benefit and possibility of worsening local tissue damage. 15 29 62 64 65 66 67 However, pressure immobilisation is generally recommended for neurotoxic elapid bites in some regions. 68 Its clinical efficacy and risk of worsening soft tissue injury in local envenoming have not been adequately assessed. 24 29 66 69 A small study (15 patients) in Myanmar found that pressure pads were effective in reducing venom spread in Russell’s viper bite, and local effects after pad application were no more severe than those before treatment. 70

Tourniquets can cause severe local damage and gangrene and must not be used. 24 25 It is common for communities to resort to traditional therapies such as wound incisions, cauterisation, and application of herbs, minerals, or animal excrement. These can delay access to effective treatment and may cause more harm. 15 71 72 Irrigate eyes with copious amounts of water if there is exposure to venom. 31

What to cover on initial assessment?

Rural and remote primary care centres are often the first point of medical aid for people with a snakebite. Laboratory and intensive care services at such facilities are often limited. A competent clinical assessment is vital to guide management and referral decisions. 14 73 74 75 76

Snakebite envenoming can quickly worsen into a life-threatening emergency. Assess vital parameters to identify if the patient is critical or at risk for shock, respiratory failure, and cardiac arrest. 24 25 Published severity scores for snakebite are unreliable. 3 The Glasgow coma scale score and pupillary reactions can be misleading in patients with advanced paralysis who are unable to open their eyes or respond to painful stimuli and should be avoided in these circumstances. 24

Reassure clinically stable patients. Ask about their symptoms to determine the presence, nature, and extent of envenoming. Details about the site, circumstances, and timing of the bite can reflect distinctive features of epidemiology, habitats, and periods of activity of medically important snakes locally and help infer likely biting-species. 3 24 25

Inquire about medications, substance use, and comorbidities as these can influence diagnosis and outcomes. Recent ethanol or recreational drug use may modify presenting symptoms. Antiplatelets or anticoagulants may worsen bleeding and interfere with key blood tests. Shock in patients with pre-existing coronary artery disease can precipitate a myocardial infarction. 3

Examination

Bite site— Look for fang marks, retained fangs, bleeding, swelling, bruising, discoloration, and blisters. 24 Fang marks do not confirm snakebite since bites by lizards, fish, rodents, large spiders, and some insects and thorns also leave paired punctures. 3 Their absence does not preclude envenoming, as many snake species produce faint or undetectable bites. 22 24 25 56 77 78 Raised vertical, red, tender streaks on the bitten limb suggest lymphangitis. 3 24 25 Regional lymph nodes may be enlarged and tender with bruised overlying skin. 3 24 25 Note any tourniquets, ligatures, wound incisions or cauterisation, and local traditional remedies as these may lead to specific complications requiring management. 24 25 For instance, tourniquets and ligatures, if left on for long, can cause severe local damage including ischaemia, necrosis, and gangrene. Similarly, incisions and local applications can lead to local bacterial infections, sepsis, and tetanus. 18 79 80

Systemic examination —Look for signs of coagulopathy such as sub-conjunctival, retinal, nasal, and gingivobuccal bleeds, ecchymoses and internal haemorrhage (such as intracranial, pericardial, pleural, and retroperitoneal). 24 25 Assess extraocular movements, bulbar function, and muscle power. 24 25 Look for ptosis, muscle tenderness, and jaw stiffness. 24 25 Jaw stiffness is a prominent but often overlooked feature in sea snake envenoming that, unlike trismus, can be reduced by sustained pressure on the lower jaw. 81

Identifying snake species —Occasionally patients or accompanying persons may bring the killed snake for identification or have a picture of it. A herpetologist can be consulted to help identify the species. 29 Identification of snakes based on description by victims or recognition from pictures is often unreliable. 29 82 83 Identifying biting-species helps avoid unnecessary antivenom in patients bitten by non-venomous snakes or by species whose venoms are not neutralised by available products. It can help select appropriate antivenom in countries with products specific against single species and anticipate clinical progression. However, delaying emergency treatment until the species is identified is unnecessary.

Knowledge of local snake species, comparison of clinical effects in the patient against established species-specific syndromes, and consideration of the circumstances and timing of the incident can help infer likely biting species. 29 82 This approach is widely used to guide treatment with polyspecific antivenom in endemic areas of Africa and Asia. 82 84 Snake identification tests based on venom antigen are valuable research tools but are currently unavailable for routine clinical use except in Australia. 85

What tests can be performed?

Perform a baseline 20-minute whole blood clotting test (20WBCT) to screen for coagulopathy in patients without overt bleeding. The 20WBCT is a simple, rapid, and inexpensive bedside test to screen for and monitor coagulopathy in areas with limited access to emergency laboratory facilities. 29 86 87 Collect a sample of venous blood from the patient and place a few millilitres into a clean dry test tube. Leave it undisturbed for 20 minutes at ambient temperature. Unclotted blood that runs out or a friable clot that readily breaks down on tipping the tube once at 20 minutes indicates a possible clotting disorder ( fig 2 ). 24 25

Examples of the 20-minute whole blood clotting test. A) With normal blood, a clot is seen at 20 minutes after sample collection. B) Incoagulable blood at 20 minutes, from a patient with Russell’s viper envenoming

Most clinical validation studies on the 20WBCT report a sensitivity of 82-89% and specificity of 82-98%. One study indicated that the test might potentially miss one of every five coagulopathic patients. 88 89 A recent systematic review and meta-analysis of the 20WBCT to evaluate its accuracy in detecting coagulopathy (defined as INR >1.4 or fibrinogen <100 mg/dL) revealed an 84% sensitivity and 91% specificity using the international normalised ratio (INR) as reference standard and 72% sensitivity and 94% specificity using plasma fibrinogen as reference standard. 90 The test was less sensitive in detecting milder coagulopathy (median INR for patients with a false negative 20WBCT was 1.9 (IQR 1.6 to 12, skewness of 1.06 and kurtosis of −0.83) and resolution of coagulopathy following antivenom administration (sensitivity 5% to 67%).

In settings with laboratory support, additional tests might include a complete blood count, coagulation studies, and biochemical assays including creatinine phosphokinase (CPK), serum creatinine, blood urea, and electrolytes. 3 A low haematocrit usually occurs with blood loss. Higher than normal values may indicate haemoconcentration from systemic plasma extravasation. Peripheral neutrophilic leucocytosis represents a general inflammatory response and confirms systemic envenoming. Severe thrombocytopenia contributes to bleeding diatheses. It may indicate microangiopathic haemolysis when accompanied by schistocytes in the blood film and acute kidney injury. Prothrombin and activated partial thromboplastin times, D dimer, fibrinogen, and fibrin degradation products are more sensitive indicators of venom induced clotting disturbances. Blood urea, serum creatinine, and electrolyte concentrations help screen and monitor acute kidney injury. CPK levels above 10 000 units/L indicate severe rhabdomyolysis. Unexplained hypoglycaemia (venous blood glucose <55 mg/dL) can be an important clue to acute hypopituitarism following snake envenoming. 91

How is snakebite managed?

Resuscitation and supportive care.

Admit all snakebite patients for observation for a minimum of 24 hours. The onset of symptoms may be delayed but can worsen rapidly. Inform patients and/or their relatives about potential complications, treatment, and critical-care measures using simple language, after emergency medical stabilisation. If required, explain the need for referral clearly.

Promptly manage airway obstruction, respiratory paralysis, and shock by restoring airway, oxygen, intubation, and assisted ventilation as needed, and intravenous fluids. Figure 3 summarises the management of snakebite. Choose sites of venous access such as the hands, wrists, and in some cases the feet where haemostasis by external pressure is most likely to succeed. 24 Avoid central venous or arterial punctures before establishing a negative 20WBCT. 24 Ensure that an intravenous line and resuscitation facilities are in place before releasing tourniquets, since this may trigger pronounced clinical deterioration. 92 Avoid aspirin or other NSAIDs to control pain as they can exacerbate bleeding diathesis. 3

Flowchart for the management of snakebite

Monitor vital parameters and urine output at regular intervals in all patients. The 20WBCT can be repeated as it is sometimes negative initially, and coagulopathy may be detected later. 24 25

Guidelines from the WHO recommend antivenom treatment for patients with shock, spontaneous systemic bleeding, uncoagulable blood, neurotoxicity, black urine, acute kidney injury, rapidly progressive local swelling, and bites by species known to cause local necrosis and digital bites. 24 25

Antivenoms are whole or fragmented immunoglobulins fractionated from the plasma of domesticated animals hyper-immunised with venom from one or more snake species over variable periods. 93 They are highly specific and will neutralise only the venoms used in their production and those of a few closely related species. 93 Polyspecific antivenoms are raised against a mixture of venoms from more than one species. Antivenoms raised against venom from a single species are monospecific. 93

Early administration of antivenom prevents or limits haemodynamic alterations, progression of coagulopathy to clinically overt bleeding, postsynaptic neurotoxicity, myotoxicity, acute kidney injury, and local tissue damage. 24 25 94 Physiological levels of clotting factors are at least partially restored within a median of six hours with sufficient doses of specific antivenoms. 45 95 96 97 98 99 100 101

Robust clinical data on the safe and effective initial dose of antivenom are lacking for most products. 102 Clinicians often rely on manufacturers’ recommendations provided as package inserts or labels, but these can be unreliable. 103 104 We suggest following national protocols or standard regional guidelines for dose. 24 25 Administration is always intravenous, as bolus or diluted in saline solution over 10-60 minutes, at the same dose for adults and children. 24 Repeat administration of antivenom if bleeding persists, if weakness or cardiovascular signs worsen within two hours, or if a 20WBCT is positive at six hours after antivenom administration. 3

The effectiveness of antivenoms in treating established neurotoxicity, soft tissue damage, and acute kidney injury is not established. 24 25 94 105 106 Additional treatments are indicated for these.

Other treatments

Neostigmine with atropine is a potentially useful adjunct in patients bitten by snakes such as some cobras with postsynaptic neurotoxins in their venom. Its use must never delay or preclude antivenom treatment or intubation. 24

Administer a tetanus toxoid booster in all patients except in those with coagulopathy, in which case injection is postponed until haemostasis is achieved. 3 Aspirate large tense bullae to facilitate nursing the bitten limb, pre-empt spontaneous rupture, and prevent secondary infection. Broad spectrum antibiotics are indicated only if the wound has been incised or there are signs of necrosis, wound infection, or abscess formation. 3 Surgical debridement or amputation of gangrenous digits or limbs and skin grafting may be needed. 24 25 Fasciotomies are rarely justified since compartment pressures usually remain within normal limits. 3 107

Risk of adverse reactions with antivenom

Monitor patients for adverse reactions in the first two hours of antivenom administration ( box 2 ). 29 Anaphylaxis or pyrogenic reactions occur early (within minutes or hours). Mechanistic studies suggest that most events are not IgE mediated and thus cannot be accurately predicted by skin tests for immediate hypersensitivity. 109 However, their incidence and severity can be reduced by a prophylactic subcutaneous injection of low dose adrenaline. 108 110 Pyrogenic reactions result from product contamination during manufacture. 111

Clinical features and frequency of adverse reactions to antivenom

Anaphylaxis symptoms.

Nausea, vomiting, abdominal pain, and diarrhoea

Life threatening shock, bronchospasm, and angioedema 108

Pyrogenic reactions

These present with fever, rigors, and vasodilation with or without hypotension

Late or serum-sickness type reactions 24

Nausea, vomiting, diarrhoea

Itching or recurrent wheals

Joint and muscle aches or joint swelling

Lymph node enlargement

Proteinuria and kidney disease

Depending on the dose, speed of administration, and product quality, the risk of any early reaction varies from 3% to more than 80% in studies from Latin America and South Asia. About 5-10% of such events are associated with life threatening consequences. 29 98 108 110 112 The incidence of fatal reactions is unclear because of confusion with symptoms of envenoming, but some have been reported. 112

Treat anaphylaxis at the earliest sign. 24 25 Suspend antivenom administration and inject adrenaline intramuscularly, ideally into the upper lateral thigh. 24 25 Additional treatment includes intravenous antihistamines and glucocorticoids and inhaled bronchodilators for bronchospasm. 24 25 Anaphylaxis can recur, and glucocorticoids do not prevent recurrence. 112 On resolution of the episode, cautiously resume antivenom in patients with a definite indication for continued treatment. 24 25 Treat pyrogenic reactions with physical cooling, antipyretics, and intravenous fluids. 24 25

Late reactions may manifest a week after administration. 108 111 113 Their incidence varies widely from 5% to 56% in observational studies and trials using differing diagnostic criteria. 108 WHO guidelines recommend a five-day course of oral antihistamines for those with serum-sickness type late reactions, and a five-day course of prednisolone in those who fail antihistamine therapy after the first two days. 24 25

Whom to refer?

Patients with persistent bleeding despite repeated antivenom treatment or having respiratory and renal failure may require urgent supportive measures such as blood transfusion, mechanical ventilation, and renal replacement therapy respectively. 24 25 If these are not available, arrange for transfer to a specialised centre. Patients with substantial bleeding, worsening paralysis, dropping urine output, refractory shock, anaphylaxis non-responsive to adrenaline, or compartment syndrome may also require specialist management and intensive care. 24

Having contact details of emergency transport and the referral centre readily available can avoid delays. Inform the receiving hospital about the patient’s condition over the phone and send a referral letter with details of assessment and treatment. 114

What to cover on discharge and follow-up?

Patients who are clinically stable or asymptomatic with persistently negative 20WBCT after 24 hours may be discharged. Educate patients and their families on snakebite prevention and first aid, preferably using printed leaflets with clear visually represented information and minimal reliance on text. 3 12

Inform patients who have received antivenom to report late adverse reactions. Arrange a follow-up after two weeks to review late reactions and sequelae.

What are the long-term sequelae of snakebite?

There is insufficient data on long term sequelae after a snakebite. 6 Amputations following snakebite-related soft tissue injuries range from 5908 to 14 614 annually in sub-Saharan Africa, based on a meta-analysis of data published between 1970 and 2010. 4 Even in patients not requiring amputations, tissue loss may result in chronic ulcers, malignant transformation, and scarring. 29 Musculoskeletal sequelae such as contractures, wasting, and joint stiffness affected up to 3% of snakebite survivors in a study of 816 patients in Sri Lanka. 115 Cerebrovascular accidents result in persisting limb weakness and visual or cognitive impairment. 29 Eye exposure to venom can result in blindness. 31 Some patients with acute kidney injury may progress to chronic renal failure. 116 117 118 119 120 Limited data from case reports and observational studies from South Asia indicate that chronic hypopituitarism, a sequel of acute pituitary haemorrhage, can present as fatigue, arrested puberty, amenorrhoea, and hypothyroidism as late as 10 years after the bite. 37 91 121 122 123 Snakebite survivors also have higher rates of post-traumatic stress disorder and depression compared with matched controls. 5 7 Ensuring access to physiotherapy, psychological services, and specialists, as needed, can be essential in managing long term sequelae of snake bite.

Areas for future research

High-quality randomised controlled clinical trials evaluating the feasibility and effectiveness of pressure immobilisation in bites by different snake species

Large, well designed clinical trials to establish safety, effectiveness, and optimal dose of antivenoms. The risks of anaphylaxis and sensitisation to animal proteins in antivenoms place ethical limitations on conventional phase I/II designs. 124 Some literature suggests that model based adaptive designs, as used to test anticancer drugs, could be safer alternatives for antivenom testing 95 102 124

Studies on envenoming syndromes to establish species-syndrome correlation and aid early identification of snake species

Clinical trials to evaluate the effectiveness and safety of adjunctive treatment options including small molecular therapeutics such as secretory phospholipase A2 inhibitors (varespladib/varespladib-methyl), matrix metalloproteinase inhibitors (batimastat and marimastat), and peptide and oligomer based technologies such as toxin-specific monoclonal antibodies and aptamers 125 126

Observational studies with long post-discharge follow-up to determine the prevalence, severity, clinical progression, and risk factors of long term sequelae from snakebite

Additional resources

Information on the spatial ecology of medically important venomous snakes, antivenom products, and the location of antivenom manufacturers by country or region can be obtained from the World Health Organization’s Snakebite Information and Data Platform https://www.who.int/teams/control-of-neglected-tropical-diseases/snakebite-envenoming/snakebite-information-and-data-platform .

Information on envenoming profiles of different snakes and their management can be obtained from the following sites:

African snakebites— WHO. Guidelines for the prevention and clinical management of snakebite in Africa . 2010. https://apps.who.int/iris/handle/10665/204458

South-East Asian snakebites— WHO. Guidelines for the management of snakebites. 2nd ed. 2016. https://apps.who.int/iris/handle/10665/249547

Global snakes database— University of Adelaide. Clinical toxicology resources: Snakes. www.toxinology.com

Education into practice

Think about the last time you treated a patient with snakebite. Reflect on the challenges you encountered while diagnosing and treating envenoming. What changes, if any, might you make to your approach next time?

How do you review a snakebite patient as an outpatient discharge? Think about common persisting physical and psychological problems that you might have noticed during review. To what extent was the patient able to share difficulties in returning to routine life? How might you involve the patient in making decisions about long term?

How patients were involved in the creation of this article

No patients were involved in the creation of this article.

Acknowledgments

We thank Abdulrazaq Habib, Bayero University, Kano, Nigeria; Colin J Forsyth, Drugs for Neglected Diseases initiative-North America; Ahmad Khaldun Ismail, Profesor Madya, Department of Emergency Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia; José María Gutiérrez, Instituto Clodomiro Picado, Facultad de Microbiología, Universidad de Costa Rica, Costa Rica; and Scott A Weinstein, Women’s and Children’s Hospital, North Adelaide, Australia for their instructive comments on this manuscript.

Supplementary illustrations on the pathophysiology of venom-toxin action were created with BioRender.com

Contributors: RR formulated and wrote the initial draft. All authors searched the literature, framed manuscript content, contributed to critical revisions and approved of the final version. RR is the guarantor of this article.

The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. The authors are fully responsible for the contents and editorial decisions for this manuscript.

Competing interests: We have read and understood BMJ policy on declaration of interests and have no relevant interests to declare.

Provenance and peer review: Commissioned; externally peer reviewed.

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ .

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Snake Bite Management: A Scoping Review of the Literature

Affiliations.

• 1 The University of Toledo College of Medicine, Toledo, Ohio.
• 2 Department of Plastic and Reconstructive Surgery, The Ohio State University College of Medicine, Columbus, Ohio.
• PMID: 33936914
• PMCID: PMC8084039
• DOI: 10.1097/GOX.0000000000003506

Background: Around the world, snake bite envenomation remains an underreported human health hazard. Envenomation can cause local and systemic complications, especially when there is a lack of antivenom availability. Although there are established guidelines regarding snake bite management acute care, there is a paucity of data regarding surgical intervention and the plastic surgeon's role treating this unique patient population.

Methods: A review was conducted identifying relevant published articles involving snake bite management and treatment in PubMed and EMBASE.

Results: One hundred ten articles were identified and 77 met inclusion criteria. Snake bite envenomation can result in complications that are dependent upon a variety of variables. The literature has shown the best field treatment to be timely transportation to the nearest medical facility, along with antivenom administration. The cytotoxic, hemotoxic, and neurotoxic effects of venom can cause a variety of local soft tissue and systemic complications. Surgical interventions such as fasciotomies, wound debridements, skin grafts, and tissue flaps may be necessary in these patients to optimize functional and aesthetic outcomes. Disparities in access to care in resource limited settings are discussed.

Conclusions: Global health disparities and insufficient antivenom distribution create an inequality of care in snake bite patients. Plastic surgeons have an important role in managing acute and chronic complications of snake bite envenomations that can lead to improved patient outcomes.

Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.

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• Volume 6, Issue 10
• Snakebites and COVID-19: two crises, one research and development opportunity
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• http://orcid.org/0000-0002-9795-0787 Diogo Martins 1 , 2 ,
• http://orcid.org/0000-0001-9974-7195 Julien Potet 3 ,
• Isabela Ribeiro 4
• 1 Snakebites Priority Area , Wellcome Trust , London , UK
• 2 Faculty of Public Health and Policy , London School of Hygiene & Tropical Medicine , London , UK
• 3 Neglected Tropical Diseases Advisor , Médecins Sans Frontières Access Campaign , Geneva , Switzerland
• 4 Research and Development - Dynamic Portfolio Unit , Drugs for Neglected Diseases initiative , Geneva , Switzerland
• Correspondence to Dr Diogo Martins; D.Martins{at}wellcome.org

https://doi.org/10.1136/bmjgh-2021-006913

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• health policy

Summary box

Despite inherent differences, Snakebite Envenoming and COVID-19 have much in common in terms of research and development (R&D) challenges and opportunities.

Both crises require a diversified portfolio of R&D solutions, ranging from diagnostics to treatments, that can effectively work and be accessible in different resource settings.

Collaborative clinical research and streamlined regulatory pathways are critical to accelerate these candidates in the R&D pipeline.

Transformative progress is possible with a concerted approach that aligns strong political will, coordinated financing and the needs of the most marginalised communities.

As the world battles COVID-19, other longstanding global health challenges continue to cause illness, suffering and death. Among them is the neglected crisis of snakebite envenoming (SBE): in the year after the COVID-19 pandemic was declared, an estimated 2.7 million SBE led to over 100 000 deaths and 400 000 long-term disabilities in the poorest and most rural communities of Asia, Africa and Latin America. 1 Yet the tools used to combat SBE remain woefully inadequate and underexplored, with the most commonly-used antivenom treatments still based on 19th-century technologies.

An oft-heard concern during the COVID-19 crisis is that shifts in research and development (R&D) spending may reduce support for neglected tropical diseases (NTDs) like SBE. Indeed, in April 2020 the WHO issued interim guidance to postpone NTD programmes and activities because of the pandemic. 2 The direct and indirect impacts of COVID-19 will likely endure for years.

Yet at the same time, long-term opportunities for SBE have also emerged. Notwithstanding major differences in nature, magnitude and global visibility of these two public health crises, experience gained with COVID-19 can be successfully applied to NTDs, and SBE specifically. In this article, we briefly recap the challenging status of current SBE tools and identify key lessons and recommendations from COVID-19 that could help refocus funding and accelerate progression of novel SBE candidates in the R&D pipeline. Our aim is to highlight the enormous promise of finally bringing 21st-century technologies and approaches to the age-old problem of SBE.

The SBE status quo

SBE poses major unmet medical needs for both diagnosis and treatment, including a reliance on antivenoms as the cornerstone of treatment. While antivenoms save lives and prevent sequelae, they also present myriad challenges (see box 1 ). These range from not knowing for many patients what snake species was involved (key information for selecting which serum to use) to the limited manufacturing capacity in high-burden regions—exacerbated by the complicated, expensive method needed to produce antivenoms. Additional, postmanufacturing challenges include a lack of clinical testing or proper quality control for many circulating products as well as difficulties ensuring availability and access, not least the need for an effective cold chain management system to distribute and store most available products.

Challenges with using antivenoms in snakebite envenoming treatment

Still uses early 1900’s complex production process that cannot be fully standardised (isolation from hyperimmune plasma of immunised animals, usually horses). Technical innovations such as IgG and (Fab')2 purification have been introduced but not uniformly adopted across manufacturers. 11

Usually specific for one or few snake species, but products are often used in settings where they do not target all medically important species.

Unknown efficacy and safety profiles for many products, few of which have been evaluated in robust clinical trials. 7

Insufficient quality control based on WHO guidelines, leading to many ineffective products in circulation. 1

Supply shortages that lead to severely limited access, especially in sub-Saharan Africa. 1

High prices, leading to potentially catastrophic cost when victims need to pay out of pocket. 12

Key COVID-19 lessons for closing the SBE R&D gap

Need for a robust portfolio of candidate products.

COVID-19 and SBE management and control each require a wide variety of tools, and therefore an R&D pipeline with candidates based on a variety of strategies—since inevitably some products will fail. As of December 2020, the global pipeline for COVID-19 candidates contained over 1000 potential new vaccines, therapeutics and diagnostics. 3 Although we lack a complete picture of the SBE product pipeline, recent data indicate that half of R&D funding between 2007 and 2018 focused on basic research, with the remaining minimal, fluctuating resources divided across biologics, drugs and, to a very limited extent, drugs and diagnostics. 4

The result is that, despite their limitations, antivenoms remain the only tool available in low-resource settings, while promising next-generation therapeutic and diagnostic approaches based on newer strategies languish in the pipeline (see table 1 ).

• View inline

Examples of promising products in the R&D pipeline for SBE

Impact of innovative pathways for research and regulatory approval

Innovating clinical research and streamlining regulatory approaches have been crucial to accelerating the progress of COVID-19 candidate products. Some of the most successful COVID-19 clinical trials, designed to produce definitive, actionable results, have been large, multisite, multicountry and/or consortium-based trials using a platform-based approach to facilitate integration and standardisation 5 —for example, the UK-based Recovery trial of treatment for hospitalised patients. 6 In many cases, regulatory pathways were also streamlined and fast-tracked without compromising the robustness of the respective assessments. Given the scarcity of rigorous clinical studies on efficacy or safety of antivenoms, 7 similar collaborative approaches will be essential to efficiently advance appropriate products through the R&D pipeline and ensure accelerated review and approval.

Importance of diversified financing and incentives for R&D

The year 2020 has shown dramatically that with enough resources, focus and political will, significant improvements are possible far faster than with ‘business-as-usual’ approaches. While there are no precise numbers for worldwide spending on COVID-19 R&D in 2020, overall R&D spending in biopharma increased 23% (to US$44 billion) from 2019, much of which was on the new disease. Over US$9 billion in funding announcements had been made across public, philanthropic and industry partners to support candidate products as of October 2020. 3 One year into the pandemic, several highly effective vaccines and many diagnostic products had already received market authorisation.

In contrast, between 2007 and 2018 global funding for SBE research totalled only US$57 million (a mean annual investment of less than 5 million). 4 According to the latest G-Finder report, funding for snakebite-related R&D totalled US$10.29 million in 2019, equivalent to only 0.3% of all R&D investment in neglected diseases 8 —although still, an increase of over 60% (US$3.7 m) from 2018. Much of this growth came from the UK, which provided three-quarters of all SBE global funding in 2019. Industry funding also doubled. Together, these increases drove a near-fourfold rise in funding for snakebite biologics (up US$ 5.4 million). Still, the total R&D investment remains quite small and is currently in extreme jeopardy since the UK, as the main investor, recently announced funding cuts effective in mid-2021 of up to 90% for many NTD programmes, 9 decreases which will severely impact ongoing SBE projects. More broadly, this chronic underfunding has slowed progress in R&D for new technologies and has limited development of solutions to ensure that safe, effective and accessible products reach the markets where they are most needed.

Imperative to address inequities and priorities from resource-limited settings

Despite the massive budgets and innovation driving COVID-19 product development, a huge imbalance remains in mid-2021 between high-income and low-income countries in availability of these tools, especially highly effective vaccines—and consequently in the severity of the pandemic. Most funding so far has strongly prioritised the needs of wealthy countries, and decisions have been made largely by people in and from these settings. Furthermore, though many innovations have been driven by public funding and/or public-interest research institutions, there are presently only very limited requirements known for transparency on R&D and manufacturing costs, or contractual requirements for equitable access. Since populations in poorer countries bear the overwhelming burden of SBE, it is crucial that R&D priorities are driven by their needs and decision-makers, and that investments include robust guarantees for access, potentially including transfer of manufacturing technologies and build-up of production capacity in high-burden regions.

Conclusions

The past year has demonstrated extraordinary global capacity for R&D mobilisation. Meanwhile, for both COVID-19 and SBE, there have been few solutions and relatively little funding for the health priorities of low-resource settings.

Still, successes with COVID-19 reveal tremendous opportunities to catalyse investments and close the R&D gap for snakebite. Reviving R&D for SBE must involve:

A global R&D strategy which considers an end-to-end approach, from basic research to strategies for remote, marginalised communities to access successful products.

Development of clinical trial platforms or networks to facilitate standardisation of methodologies, integration of results, and rapid assessment of new tools for SBE management.

Streamlining regulatory pathways to facilitate R&D, encourage innovation and speed the approval of new products given the extreme, longstanding neglect of SBE.

A coordinated investment strategy which capitalises on available public funding and leverages greater commitment from the private sector, including biotech firms. It should clearly link R&D objectives with financial incentives that promote both innovation and equitable access to SBE interventions.

High-burden regions must be at the centre of R&D agendas, an obligation underpinning these recommendations.

A post-pandemic world may appear distant for most NTD-affected countries, given the enormous gaps in their access to new products that are gradually controlling the pandemic in high-income regions. But as NTD programmes resume the research community must harness newlygained knowledge, partnerships and collaborative approaches to accelerate progress towards the ambitious 2030 NTD targets 1 10 and the reduction of health inequities. Each of these components will become increasingly important for success in achieving the WHO goal of reducing death and disability from SBE by 50% within a decade. That time approaches. We must stand ready to challenge the status quo and deliver transformational change.

Data availability statement

This paper does not report any original data. It is based solely on data reported publicly in the citations listed.

Ethics statements

Patient consent for publication.

Not applicable.

Acknowledgments

We thank Julie Archer (DNDi), Rob Hooft (independent consultant) and Nick Cammack (Wellcome Trust) for the helpful contributions to this commentary, and Zoe Fanning (MSF) for the editorial assistance.

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Handling editor Soumyadeep Bhaumik

Twitter @dcorreiamartins

Contributors All authors conceptualised the main argument of the paper, with input from Patricia Kahn (MSF-USA, New York). DM wrote the initial outline, IR the initial draft. All authors provided technical feedback and edits, approved the final manuscript, and were responsible for the decision to submit for publication. PK provided ongoing editorial support.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests None declared.

Provenance and peer review Not commissioned; externally peer reviewed.

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• Open access
• Published: 21 March 2023

Clinical predictors of early surgical intervention in patients with venomous snakebites

• Hsiao-Yu Lu   ORCID: orcid.org/0000-0002-7733-678X 1 ,
• Yan-Chiao Mao   ORCID: orcid.org/0000-0002-8561-0582 2 , 3 , 4 , 5 ,
• Po-Yu Liu   ORCID: orcid.org/0000-0001-8006-4917 6 , 7 ,
• Kuo-Lung Lai   ORCID: orcid.org/0000-0003-0867-9612 8 ,
• Cheng-Yeu Wu   ORCID: orcid.org/0000-0002-8341-7965 9 ,
• Yueh-Chi Tsai   ORCID: orcid.org/0000-0002-4512-3456 9 , 10 ,
• Jung-Hsing Yen   ORCID: orcid.org/0000-0002-5781-2320 9 ,
• I.-Chen Chen   ORCID: orcid.org/0000-0002-3237-5005 9 &
• Chih-Sheng Lai   ORCID: orcid.org/0000-0001-6940-866X 9 , 10  

European Journal of Medical Research volume  28 , Article number:  131 ( 2023 ) Cite this article

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Venomous snakebites induce tissue destruction and secondary infection; however, the optimal timing of surgical intervention for these complications remains unknown. This study assessed the clinical predictors of early surgical intervention in patients with snakebites.

This retrospective study included 63 patients (45 men and 18 women) with venomous snakebites. In addition to the snake species, the demographics, affected body parts, clinical characteristics, and ultrasound findings of the patients in the surgical (32 patients) and nonsurgical (31 patients) groups were analyzed and compared.

A higher incidence of acute compartment syndrome, local ecchymosis, skin necrosis, bullae, blisters, and fever was found in the surgical group than in the nonsurgical group, and ultrasound findings of the absence of Doppler flow were more frequently noted in the surgical group than in the nonsurgical group. After adjustment using a multivariate logistic regression model, only advanced age, Naja atra bite, local ecchymosis, and bulla or blister formation remained significant factors for surgical intervention. Furthermore, comparison of the outcomes of patients who received early (≤ 24 h) and late (> 24 h) surgical intervention revealed that the duration of continuous negative pressure wound therapy (6 vs. 15 days; P  = 0.006), duration of hospital stay (13 vs. 26 days; P  = 0.002), and duration of outpatient follow-up (15 vs. 36 days; P  < 0.001) were significantly lower in patients who received early surgical intervention. The final reconstructive surgery was simple among the patients who received surgical intervention within 24 h of being bitten ( P  = 0 . 028).

In patients with snakebites, advanced age, high-risk clinical manifestations (e.g., local ecchymosis and bulla or blister formation), and Naja atra envenomation are predictors of surgical intervention within 24 h.

Many snake varieties thrive in Taiwan’s subtropical climate. Six major venomous snakes— Naja atra (Chinese cobra), Bungarus multicinctus (Taiwanese krait), Protobothrops mucrosquamatus (brown-spotted pit viper), Trimeresurus stejnegeri (green bamboo viper), Deinagkistrodon acutus (sharp-nosed pit viper), and Daboia siamensis (Siamese Russell’s viper)—are found throughout Taiwan [ 1 ]. Snakebites are a major public health concern, with the nationwide annual incidence of snake bites being 40.49 per million people in Taiwan [ 1 ]. According to the World Health Organization’s 2016 guidelines for the management of snakebites, antivenom administration is the most essential treatment strategy for venomous snakebites [ 2 , 3 , 4 , 5 , 6 ].

Although the systemic treatment of patients with venomous snakebites is essential, local treatment cannot be neglected. Local necrotic tissue debridement or finger or toe amputation can cause disability. Herzel et al. [ 7 ] reported a 25% amputation rate among patients with severe snakebites. Despite proper treatment, venomous snakebites can cause death or the loss of a body part, thereby affecting patients’ quality of life.

Indications for surgical intervention in snakebite are fairly clear, although the timing of intervention remains subject to debate. Mao et al. [ 8 ] have advocated surgical intervention for patients with wound necrosis, abscess formation, gangrene in digits, and necrotizing fasciitis. Su et al. [ 9 ] reported that Taiwanese patients with Naja atra envenomation who present with skin ecchymosis or require a high antivenom dose should be evaluated to determine the requirement of immediate surgery. Naja atra , Protobothrops mucrosquamatus , and Trimeresurus stejnegeri bites mainly induce local tissue injuries [ 10 , 11 , 12 ]. A neurotoxic effect is temporary or absent in Naja atra bites [ 10 ]. Although some studies have recommended the surgical removal of snake venom as the immediate treatment approach [ 9 , 13 , 14 , 15 , 16 , 17 ], other studies have indicated that this approach may cause soft tissue damage, leading to a failed skin graft or flap, amputation, or osteomyelitis and ultimately resulting in poor prognosis [ 6 , 18 , 19 ]. Thus, the recommended protocol for venomous snakebites is the administration of antivenom, followed by delayed debridement [ 3 , 6 , 18 ]. Moreover, Cumpston [ 19 ] did not recommend surgical intervention for patients with Crotalinae envenomation. The requirement and optimal timing of surgery for venomous snakebite cases remain controversial. If the requirement of surgery in such cases can be predicted, interventions such as fasciotomy, dermotomy, fasciectomy, and debridement can be performed promptly, thereby reducing the risks of tissue damage and comorbidity.

In this study, we assessed the snake species, clinical symptoms, ultrasound findings, and timing and incidence of surgical intervention to determine the clinical predictors of surgical intervention in venomous snakebite cases.

In this retrospective study, the electronic medical records of patients with venomous snakebites who received only medical (antivenom or antibiotic) treatment or a combination of medical and surgical treatment between January 2016 and March 2022 at Taichung Veterans General Hospital were reviewed. Patients who were ≥ 20 years old and were hospitalized due to snakebites were included in this study. Patients who underwent surgery unrelated to the bite site area were excluded. The snake species were identified after examining patients with snakebites who were brought to the emergency department (ED) or by asking the patient to identify the snake in a picture shown to them in the ED. Patients with snakebites for which the culprit snake could not be identified were included in either the other or negative identification group.

The patients were divided into two groups: surgical and nonsurgical groups. In addition to the snake species, the patients’ demographics, bitten body parts, clinical characteristics, and findings of ultrasound imaging of the bite site performed within 24 h were compared. The six P’s were used to diagnose acute compartment syndrome related to snakebites: pain, paresthesia, pallor, paralysis, poikilothermia, and pulselessness [ 3 , 20 , 21 ]. If the patients presented with any one of these symptoms, they were considered to have impending compartment syndrome. If the patients presented with more than two of these symptoms, they were highly suspected of having acute compartment syndrome. Fasciotomy or dermotomy was indicated if acute compartment syndrome was suspected at the bite site. Ultrasound imaging of the bite site was performed within 24 h by one of the authors (K-L Lai) by using a 12-MHz linear array probe. The imaging was performed to identify the location of tissue edema and the presence or absence of Doppler flow. The surgical group was further divided into two subgroups: one subgroup that underwent surgery within 24 h of being bitten and the other underwent subgroup that underwent surgery after 24 h. The wounds of the patients in both the subgroups were postoperatively treated with negative pressure wound therapy (NPWT), and their dressing foams were changed twice per week. After surgical intervention, bite wounds were treated with NPWT immediately after the signs of toxicity and infection spread subsided. The snake species; patients’ demographics, bitten body parts, and clinical characteristics; total antivenom dose; timing of surgical intervention; number of debridements; duration of dressing changes following NPWT; requirement of final reconstructive surgery; duration of hospital stay; and follow-up periods until complete wound healing were compared between the subgroups.

The clinical data and outcomes are summarized as frequencies and percentages. The chi-squared test, Fisher’s exact test, or the Mann–Whitney U test was performed to determine the associations between baseline parameters and surgical intervention outcomes. A P value of < 0.05 was considered significant. Univariate and multivariate logistic regression analyses were conducted to analyze the factors significantly associated with surgical intervention, and odds ratios and relevant 95% confidence intervals were calculated. All data were analyzed using SPSS version 22.0 (2013 release; IBM Corp., Armonk, NY, USA). This study was approved by the Institutional Review Board of Taichung Veterans General Hospital (Approval Number CE21125A).

From January 2016 to March 2022, a total of 64 patients presented with venomous snakebites. One of these patients was excluded because he underwent surgery that was unrelated to the snakebite area. Of the 63 included patients, 31 patients had relatively mild symptoms of toxicity, did not require surgery, and were administered antivenom and hospitalized for empiric antibiotic therapy, symptom relief, wound care, and vital sign monitoring. They were discharged as soon as their wound became smooth and their vital signs were stable. No patient in the nonsurgical group required rehospitalization or surgical intervention. In total, 32 patients with severe local symptoms required surgical intervention to alleviate tissue swelling, control infection, and clean necrotic debris (Fig.  1 ).

Of the included patients, 32 received surgical intervention and 31did not. TCVGH: Taichung Veterans General Hospital

This study included 45 men and 18 women, with both surgical and nonsurgical groups predominantly consisting of men (62.5% and 80.6%, respectively; P  = 0.111). Overall, 59.4% of the patients in the surgical group had been bitten by Naja atra . By contrast, Trimeresurus stejnegeri bites were predominant (32.3%) in the nonsurgical group ( P  < 0.001). Acute compartment syndrome (Fig.  2 ) was more highly suspected in the surgical group than in the nonsurgical group (34.4% vs. 3.2%; P  = 0.002). Local ecchymosis (Fig.  3 ; 87.5% vs. 51.6%; P  = 0.002); skin necrosis (Fig.  4 ; 28.1% vs.3.2%; P  = 0.013); bullae or blisters (56.3% vs.9.7%; P  < 0.001); fever with a temperature of ≥ 38 °C,as measured using a tympanic thermometer (31.2% vs.3.2%; P  = 0.003); and positive ultrasound findings of absence of Doppler flow (Fig.  5 ; 68.8% vs.0%; P  < 0.001) were more commonly noted in the surgical group than in the nonsurgical group (Table 1 ). No patient required admission to the intensive care unit (ICU), ventilator support, or inotropic support; developed systemic bleeding; or died during the study period.

Acute compartment syndrome of the left hand 8 h after being bitten by Naja atra

Local ecchymosis on the right thumb 10 h after being bitten by Naja atra

Skin necrosis on the left dorsal hand 48 h after being bitten by Naja atra

Subcutaneous interstitial edema (white arrow) and absence of Doppler flow were noted on ultrasound

To identify the factors associated with surgical intervention, snakebite cases were included in regression analyses. The results of univariate logistic regression analysis revealed that advanced age, Naja atra bite, suspicion of acute compartment syndrome, local ecchymosis, skin necrosis, bulla or blister formation, and fever were significantly associated with surgical intervention (Table 2 ). Furthermore, the results of multivariate logistic regression analysis performed using a forward stepwise selection model revealed that only advanced age, Naja atra bite, local ecchymosis, and bulla or blister formation were significantly associated with surgical intervention.

Upper limb bites (66.7% vs. 29.4%; P  = 0.035) and suspicion of acute compartment syndrome (80% vs. 11.8%; P  < 0.001) were significantly more common among the patients who underwent initial surgery within 24 h of being bitten than among those who underwent initial surgery after 24 h. The venomous snake species and other clinical manifestations (including local ecchymosis, bulla or blister formation, fever, and positive bacterial wound culture) did not differ significantly between the surgical subgroups (Table 3 ). The median number of days till the initial surgery in the patients who underwent surgery within and after 24 h of being bitten was 0.5 days (interquartile range [IQR], 0.5–1.0 days) and 7 days (IQR, 1.5–15.0 days), respectively. The median number of times an operation for debridement was performed (2 vs.4 times; P  = 0.012), median number of days between the application of NPWT dressing foams(6 vs. 15 days; P  = 0.006), median duration of hospital stay (13 vs. 26 days; P  = 0.002), and median period of outpatient follow-up until complete wound healing (15 vs. 36 days; P  < 0.001) were significantly lower among the patients who underwent initial surgery within 24 h of being bitten than among those who underwent initial surgery after 24 h (Table 4 ). The final reconstructive wound closure surgery was simpler for the within 24 h group than for the later than 24 h group, except for one patient who required a free flap due to severe skin necrosis with tendon exposure ( P  = 0.028).

Several factors affect the requirement of surgical intervention in patients with venomous snakebites. Suspicion of acute compartment syndrome; symptoms of local ecchymosis, skin necrosis, bullae or blisters, and fever; Naja atra envenomation; and ultrasound findings of absence of Doppler flow are predictors of the need for surgery in patients with snakebites.

The optimal timing and role of surgical intervention for the treatment of venomous snakebites remain controversial. Many studies have not recommended surgical intervention [ 3 , 8 , 19 , 22 , 23 ]; however, most of these studies were conducted in North America and focused on pit viper snakes. In a study conducted in India, Chattopadhyay et al. [ 24 ] reported that 24% of patients required surgical intervention. In South Korea, debridement was required in 46 of 111 patients (41.4%) with snakebites [ 18 ]. In another study conducted in South Korea [ 25 ], fasciotomy was required in 10.8% of patients who had an intracompartmental pressure of > 40 mmHg and symptoms of compartment syndrome. In other studies conducted in Taiwan, many patients with Naja atra envenomation required surgical intervention [ 8 , 26 , 27 ]. Treatments for venomous snakebites widely vary depending on the specific region and snake species. This study compared the outcomes of patients who underwent surgery within and after 24 h of being bitten. Our findings can help surgeons determine the timing for necessary interventions and the surgical procedures for patients with venomous snakebites.

The venom of Naja atra , a common snake species in Taiwan, consists of a cardiotoxin, neurotoxin, and hemotoxinin addition to phospholipase A2. The cardiotoxin is the most harmful to humans because it synergistically acts with phospholipase A2 to induce local tissue necrosis after snakebites [ 26 , 28 , 29 , 30 ]. Surgical debridement of venomous snakebite cases reduces intracompartmental pressure, and the interstitial fluid and infectious pathogens can be drained and eradicated, respectively, through controlled tissue destruction. Su et al. [ 9 ] suggested that patients presenting with ecchymosis on the bite wound or requiring high antivenom doses are highly likely to require surgical intervention. Additionally, admission to the ICU, ventilator support, ionotropic support, and coagulative parameter abnormalities may be indicators of bite severity and therefore of the need for early surgical intervention. Recently, Lai et al. [ 10 ] reported that lower limb bites, limb swelling, bulla or blister formation, gastrointestinal effects, and fever are clinical predictors of surgery after Naja atra envenomation. This finding is consistent with that of our study. The timing of surgery may be affected by the availability of a medical facility and venom specialist, identification of snake species, patient’s response to antivenom, and observation period depending on the snake species.

In this study, the patients who underwent initial surgery after 24 h had a higher proportion of lower extremity bites and a lower incidence of suspected acute compartment syndrome; therefore, their clinical observation period was longer, and surgical intervention was not performed until more than 24 h after the bite. These patients required significantly more NPWT dressing foam changes, longer hospital stays, and more outpatient follow-up visits than those who underwent their initial surgery within 24 h.

Patients who require surgical intervention to reduce tissue swelling and necrosis and to control infection may benefit from early surgery. In such patients, early surgery can prevent the development of necrotizing fasciitis, preclude extensive tissue destruction beyond the bite site, and reduce the size of the surgical wound. We found that the patients who underwent surgery within 24 h had fewer overall bite-related surgeries and NPWT dressing foam changes, leading to shorter hospital stays and fewer outpatient follow-up visits. Moreover, earlier surgical intervention may be associated with a simple final reconstructive surgery. A larger study population is necessary to verify this finding. Surgical intervention is crucial for the treatment of venomous snakebites; hence, the identification of clinical predictors to support the surgeons’ decision of performing early surgical intervention is crucial for the management of venomous snakebites.

In several studies, sonography predominantly revealed swelling in the subcutaneous tissues after snakebites [ 31 , 32 , 33 , 34 ]. Sonography is a simple and noninvasive procedure to assess venom-related tissue injury. In our surgical group, 68.8% of the patients had a positive ultrasound finding. We also used vascular techniques to detect perfusion patterns in the affected local tissue. Ultrasound findings of absence of Doppler flow indicate insufficient vascular perfusion, which can cause local tissue necrosis. Early surgical intervention may mitigate the progression of edema, inflammation, and necrosis. A combination of physical examination and sonography may be beneficial to assess the severity and prognosis of snakebite envenomation. However, the ideal timing of the scan in relation to the time of bite is not standardized. A higher number of patients and more serial ultrasound examinations will be required to evaluate the progression of envenomation and determine the efficacy of sonography in assessing snakebites.

Negative pressure wound therapy (NPWT) is often used in chronic and acute wound care [ 35 ]. It can effectively drain local exudates and reduce local inflammatory reactions [ 36 ]. A combination of surgical intervention and NPWT for snake bites has been proven to be effective for controlling the release of inflammatory cytokines (interleukin-6, interleukin-10, and tumor necrosis factor-α) and alleviating systemic inflammatory reactions [ 37 ]. Significant limb swelling regression has also been noted [ 37 ]. In our surgical group that underwent initial surgery within 24 h, the use of NPWT reduced the need for subsequent complicated reconstructive surgery. Therefore, our treatment strategy is safe and effective.

True compartment syndrome after snakebites is rare [ 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. The diagnosis of compartment syndrome with the indication of fasciotomy is based on the clinical findings of pallor, pulselessness, pain, color change in the fingers, and increased swelling in the affected area [ 3 , 20 , 21 ]. The presence of disproportional pain caused by passive flexion or extension of adjoining distal joints in the tightly swollen extremity is a key indicator (or perhaps the only indicator) that proceeding with fasciotomy is necessary rather than waiting for pulselessness or signs of paralysis. Measurement of intracompartmental pressure is not recommended when the diagnosis is clinically evident [ 20 ]. Most medical institutions in Taiwan do not have any intracompartmental pressure measurement equipment. When clinical findings suggest acute compartment syndrome and the patient fails to respond to adequate and prompt antivenom administration, fasciotomy or dermotomy may be appropriate. Follow-up combined with NPWT can reduce the comorbidity of patients with snakebites.

This study has several limitations that should be addressed. First, the small sample size limited the power of our study to detect significant differences. Second, the inclusion of a patient population from a single institution may have limited the generalizability of our findings. However, most surgeons involved in this study were trained at the same institute, thereby reducing variability in snakebite management at our institution. Third, because this retrospective study has certain selection biases, the results should be cautiously interpreted. Fourth, a comparison of the outcomes between early and late intervention groups for both upper and lower limbs may be beneficial and will be addressed in our future research. Finally, we focused on clinical symptoms to determine the timing of surgical intervention and did not compare the laboratory data between patients with and without surgical intervention. Moreover, the species of venomous snakes may vary throughout the island. Hence, we suggest modifying the treatment depending on the snake species and accessibility to antivenom.

In patients with snakebites, advanced age, high-risk clinical manifestations (e.g., local ecchymosis and bulla or blister formation), Naja atra envenomation, and ultrasound findings of absence of Doppler flow are predictors of surgical intervention. Patients receiving surgical intervention within 24 h may require fewer overall bite-related surgeries and NPWT applications, leading to shorter hospital stays and fewer outpatient follow-up visits. Our findings can be helpful for patient management following snakebites. Additional studies with larger samples are warranted to support our findings.

Availability of data and materials

The data that support the findings of this study are available from the corresponding author, Chih-Sheng Lai, upon reasonable request.

Abbreviations

Length of hospital stay

Negative pressure wound therapy

Split-thickness skin graft

Taichung Veterans General Hospital

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Hsiao-Yu Lu

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HYL wrote the manuscript, and approved its final version. YCM, PYL, KLL, CYW, YCT, JHY, ICC contributed to the idea, supervised the project, and approved its final version. CSL conceived the idea, formatted the data, wrote the manuscript, and approved its final version. All authors read and approved the final manuscript.

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Lu, HY., Mao, YC., Liu, PY. et al. Clinical predictors of early surgical intervention in patients with venomous snakebites. Eur J Med Res 28 , 131 (2023). https://doi.org/10.1186/s40001-023-01101-x

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Assessing knowledge and awareness regarding snakebite and management of snakebite envenoming in healthcare workers and the general population: A systematic review and meta-analysis

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Affiliation Australian Venom Research Unit, Department of Biochemistry and Pharmacology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia

Affiliation Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Australia

• Afsana Afroz, 
• Bodrun Naher Siddiquea, 
• Aishwarya Narendra Shetty, 
• Timothy N. W. Jackson, 
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Published: February 9, 2023

• https://doi.org/10.1371/journal.pntd.0011048
• Reader Comments

Snakebite envenoming is a serious and life-threatening medical condition that predominantly affects people living in rural communities across Africa, Asia, and Latin America. As our climate changes, there is a growing concern that negative human–snake interactions will increase. Our ability to prevent and manage snakebite requires effective antivenoms as well as knowledge regarding the prevention and management of snakebite among healthcare workers and affected communities across the globe. This systematic review aims to assess existing levels of knowledge regarding snakebite prevention and management in both healthcare workers and affected communities.

This review was conducted on studies reporting quantitative measurements to evaluate knowledge and practice regarding snakebite prevention and management published in major databases between 1 January 2000 and 31 December 2021. Random effects modelling was used to obtain the pooled proportion. Heterogeneity (I 2 ) was tested, and sensitivity analyses performed.

Out of 3,697 records, 16 studies from 12 countries assessing 7,640 participants were included. Four of the studies were ranked as good quality studies, 9 as fair, and 3 as poor. This study results demonstrated that 56% of the study population answered the knowledge question correctly (95% CI 48% to 63%, p < 0.001). High heterogeneity was observed (I 2 = 97.29%), with marginal publication bias (Egger’s regression test, p = 0.0814). Participants had relatively higher knowledge concerning use of antivenom as preferred treatment, followed by snakebite prevention, knowledge of signs and symptoms of snakebite, knowledge of first-aid, and knowledge of treatment. Participants had lower knowledge relating to types of snakes and the identification of snakes.

Adequate knowledge about snakebites and its management among the general population and healthcare workers was 56%. Healthcare workers and communities across Asia showed higher relative knowledge compared to those in Africa and the Middle East. These data suggest that further education is needed in both the general population and among healthcare workers to ensure that appropriate preventative and patient management techniques are being utilised in snakebite endemic regions. Greater local awareness of the risks and appropriate management of snakebite is required to reduce the burden of snakebite mortality and morbidity.

Citation: Afroz A, Siddiquea BN, Shetty AN, Jackson TNW, Watt AD (2023) Assessing knowledge and awareness regarding snakebite and management of snakebite envenoming in healthcare workers and the general population: A systematic review and meta-analysis. PLoS Negl Trop Dis 17(2): e0011048. https://doi.org/10.1371/journal.pntd.0011048

Editor: Wuelton M. Monteiro, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado, BRAZIL

Copyright: © 2023 Afroz et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All data relevant to the study are included in the article or uploaded as supplementary information .

Funding: AA, TNWJ, and ADW are funded by the National Health and Medical Research Council ( nhmrc.gov.au : Grant ID 13/093/002 AVRU). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Snakebite is an ecological phenomenon. Snakes bite either to defend themselves from a potential predator or to secure a meal. Human snakebite, therefore, is either defensive, or a case of mistaken identity [ 1 ]. Snakebite envenoming is a neglected tropical disease (NTD) that may result in a life-threatening pathology. The burden of snakebite envenoming varies dramatically between regions and disproportionately impacts rural communities in tropical regions of the Global South, particularly Africa, Asia, and Latin America [ 2 – 4 ]. This uneven distribution of the impacts of envenoming are hypothesised to result from occupational practises (e.g., non-mechanised, low-cost farming), poorly constructed houses, and low access to protective clothing (i.e., covered footwear and long pants) that characterise human life in lower socioeconomic rural settings [ 5 – 7 ]. Such practices increase the likelihood of human–snake interaction resulting in snakebite, and the impact on these communities is further compounded by the limited access to healthcare and the untenably high cost of treatment [ 8 ], which acts to further exacerbate the poverty cycle.

Recent estimates suggest that between 1.8 to 2.7 million people are envenomed by snakes each year resulting in annual deaths of between 81,000 and 138,000 [ 6 , 9 , 10 ]. Of those that do survive the initial bite, an estimated 400,000 individuals are left with permanent disfigurement or disability [ 8 ]. However, accurate information on the true scale of snakebite in impacted regions has proven difficult to obtain [ 11 ]. The lack of mandatory reporting on snakebite envenoming coupled with a historical reluctance of some governments to report accurate data have made it difficult to properly resource and respond to snakebite as a regional health issue. In Nepal, where 90% of the population lives in rural areas, only 480 snake bites and 22 deaths were reported by the Ministry, whereas a community-based study of Eastern Nepal alone reported 4,078 bites and 396 deaths [ 12 ]. Similar discrepancies between official and community-reported data have also been observed in India, where a community-based study reported between 40,900 to 50,900 snakebites in 2005, a figure almost 30 times higher than official government numbers [ 8 ].

Traditional antivenoms, comprising horse or other animal-derived immunoglobulins, have been the leading treatment for snakebite envenoming for more than a century [ 6 ]. These medicines are produced using techniques that have subsequently changed little, besides the refining of methods of inoculation and purification. While the World Health Organization (WHO) provides guidelines for improved standard operating procedures of antivenom manufacture [ 13 ], it is also important to assess current levels of awareness in both community groups and healthcare professionals regarding how best to prevent and manage snakebite. Survival following snakebite envenoming is significantly improved by the rapid application of first aid, such as pressure immobilisation bandages, and the administration of life saving antivenoms to neutralise the venom toxins. This dual phase management of snakebite requires both a public aware of local venomous snake species and appropriate snakebite first aid measures and local hospitals with knowledgeable clinicians and readily available and appropriate medicines.

Despite the importance of basic knowledge and awareness concerning snakebite envenoming, multiple studies have found that many healthcare workers in snakebite endemic regions have poor general knowledge of the snakebite crisis [ 14 ]. A study by Michael and colleagues reported that doctors in Nigeria had poor knowledge of venomous snakes, snakebite first aid, treatment, and prevention [ 2 ]. Similar gaps in baseline knowledge and treatment confidence regarding snakebite patient management were found in doctors across Hong Kong [ 15 ], Laos [ 16 ], Nepal, and West Bengal [ 17 , 18 ], with the authors of some studies noting that core textbooks regarding snakebite patient management were outdated and provided inaccurate information [ 18 , 19 ].

Among the general population, including at-risk sectors of the population that work outdoors such as farmers, plantation workers, and herdsmen, knowledge of snakebite and appropriate responses are often limited [ 20 , 21 ]. Use of traditional methods such as making incisions, sucking the venom, and application of tight tourniquets [ 22 , 23 ], relying on witchcraft and traditional healers [ 24 ], and use of tourniquets [ 25 , 26 ] remain the most commonly used first-aid among general population especially in the rural communities in developing countries. On the other hand, adequate knowledge of snakes, their habits, and the timely and appropriate first-aid can reduce the likelihood and consequences of snakebite among people at high risk of coming into contact with snakes [ 27 ].

Socioeconomic and cultural factors influence treatment-seeking behaviours and may lead to individuals bitten by snakes opting for traditional practices rather than hospital care. A lack of money or transportation, or distrust of “Western medicine,” may influence a decision to attend hospital. Compounding this lack of confidence, staff at many health centres are insufficiently trained to treat snakebites, and even if the drug is on hand, it may be too expensive for many victims [ 28 ]. Additionally, many antivenoms need to be kept refrigerated to stay stable and effective [ 6 ]. In low-resource settings with frequent power cuts, even in cities, keeping them cold can be nearly impossible. Families may seek help instead from a traditional healer, who may apply leaves or ash from burned animal bones, or tie a tourniquet around the bitten limb, which can dangerously restrict blood flow [ 29 ]. Some botanical treatments do ease pain and reduce swelling, but they cannot save a victim’s life [ 29 ]. The entry into some markets of inappropriate, untested, or even fake antivenom products has further undermined confidence in antivenom therapy generally.

It seems reasonable to conjecture that the burden of snakebite morbidity and mortality may be reduced by a combination of appropriate use of medicines and equipment, adequate training of healthcare workers, and increased awareness of appropriate health-seeking behaviour among the at-risk population. It is thus crucial to gain an understanding of the level of knowledge of the general population and healthcare workers in managing a patient. There is a paucity of data concerning the domain-level knowledge of snakes and snakebite awareness and management in impacted communities and their healthcare workers. This systematic review will draw upon recent studies (selected according to criteria discussed in the Methods section) to assess the level of knowledge regarding prevention and management (outcome) of snakebite among healthcare workers and members of at-risk communities (population).

This systematic review and meta-analysis aimed to assess knowledge and awareness that healthcare workers and the general population have regarding snakebites, and its snakebite prevention and management. The review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines [ 30 ] and was registered on PROSPERO (Reg No: CRD42022377613). The review process is illustrated in Fig 1 and the PRISMA checklist has been included as supporting information ( S1 PRISMA Checklist ). Ethics approval was not required as this study was based on the published literature.

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https://doi.org/10.1371/journal.pntd.0011048.g001

Selection criteria

Studies reporting any form of quantitative assessment, measurement, and/or evaluation of knowledge and practice regarding snakebite envenomation and preventive measures, including first-aid, were included. To assess contemporary practises, the selection was limited to articles published in the English language and published in the year 2000 or later. Several studies were identified that reported snake conservation and attitude towards snakes in the absence of specific treatment knowledge and practise, these studies were excluded from the analysis. Qualitative studies, editorials, case reports, and study duplicates were also excluded. To highlight the full state of the field study quality was not a contributing factor to inclusion. Full inclusion and exclusion criteria have been provided in Table 1 .

https://doi.org/10.1371/journal.pntd.0011048.t001

Search strategy and study selection

Medline, Embase, CINAHL, and Cochrane databases were searched between 1 January 2000 and 31 December 2021 by 2 authors (BNS and AS) independently, using key terms prepared by a senior librarian at the University of Melbourne. The primary keywords for the search strategy included “knowledge,” “practice,” and “snake-bite.” Searched articles were stored and managed using citation software EndNote X20. A detailed description of the search strategy has been provided as supporting information ( S1 Table ).

Following these searches, BNS and AS independently screened the titles and abstracts of the articles obtained from the search and excluded those articles that did not meet the eligibility criteria. The bibliography of all articles meeting the selection criteria was also screened for additional studies. The final set of 16 articles were selected following a full read and discussion between BNS, AS, and AA. Any disagreement was resolved by the study lead, AA.

Study outcomes

The primary outcome of this study was to assess knowledge and awareness of snakebite and snakebite management in healthcare workers and the general population that is summarised in the Table 2 . Although most of the studies uses similar questionnaire to assess the knowledge, in a few of the studies there were differences in questionnaire contents. Thus, the research team grouped the studies into 6 different domains by grouping the common and frequent questions reported by the included studies. This included signs and symptoms of snakebite, snakebite first-aid, treatment, antivenom, and preventive measures associated with the health-seeking behaviour of the general population and the management procedures of the healthcare providers. The secondary outcomes included the determination of estimated knowledge scores by continent, target population, and study quality (i.e., good, fair, poor). Six key knowledge domains were identified to enable more direct comparisons of the primary outcome: knowledge of antivenom as preferred; knowledge of overall treatment; knowledge of signs and symptoms of snakebite; knowledge of first-aid; knowledge of types of snake or identification of snakes; and knowledge of snakebite prevention.

https://doi.org/10.1371/journal.pntd.0011048.t002

Data extraction and quality assessment

Data from the included articles was independently charted by BNS and AS using Microsoft Excel. Their results were compared and cross-checked by AA and minor discrepancies were resolved through discussion and consensus. The key variables extracted were as follows: publication identifiers (authors, year of publication, journal), study characteristics/methodology (country where the study was conducted, study setting, study design, study population, sample size), participants’ demographics (gender, age, education), and main study findings (prevalence of correct knowledge/mean knowledge score and associated factors). Missing data were sought from study authors, where required.

Study quality was assessed independently by BNS and AS using the quality assessment tool for observational cohort and cross-sectional studies produced by the National Heart, Lung and Blood Institute (NHLBI) [ 31 ]. The tool assesses internal validity and risk of bias based on 14 criteria. Each criterion was rated as “yes,” “no,” “cannot determine,” “not applicable,” or “not reported.” The overall quality of the study was then rated as “good,” “fair,” and “poor,” details can be found as supporting information ( S2 Table ). Minor discrepancies were resolved by lead author, AA.

Data analysis

Quantitative data included the proportion of people with good knowledge toward the outcome across the 6 key domains: knowledge on signs and symptoms of snakebite, knowledge about first-aid, knowledge on overall treatment, knowledge on types of snakes or identification of snakes, knowledge about antivenom as a preferred treatment, and knowledge about prevention. Data were extracted from each study and analysed by the author (AA) and cross-checked by the senior author (AW); any discrepancies were resolved through discussion.

The overall knowledge score in percentages extracted from each study included in this systematic review were reported as pooled percentages using random-effect model. Common and frequent questions reported by the included studies were grouped into 6 knowledge domains including: treatment, signs and symptoms of snakebite, first-aid, snake identification/type, and prevention. The average scores of each domain were then reported as percentages.

The pooled proportion of knowledge and awareness of snakebites and snakebite management was determined using a random-effect model at a 95% confidence interval (CI) [ 32 ]. Resulting data were presented in forest plots. Random-effect modelling was used as this method demonstrates better properties in the presence of heterogeneity (if any) by accounting for both within-study and between-study variances [ 32 ]. Heterogeneity among studies was tested using the χ 2 -test on Cochran’s Q statistic, which was calculated by means of H and I 2 indices. The I 2 index represents the percentage of total heterogeneity across studies based on true between-study differences rather than on chance. I 2 with a cutoff of ≥75% [ 33 ] and a nonsignificant ( p -value >0.05) result was taken as evidence of no heterogeneity. To identify the possible sources of substantial/considerable heterogeneity, sensitivity analysis was conducted by continent, target population, and study quality (good, fair, poor). Egger’s regression test was used to examine publication bias and the symmetry of the funnel plots was evaluated as previously published [ 34 ]. CI was used to evaluate whether differences in prevalence/proportion were statistically significant. As prevalence/proportion cannot fall below 0% or above 100%, the CI is trimmed at 0% and 100% [ 32 ]. All statistical analyses were conducted using Stata V.16 (StataCorp., College Station, Texas, United States of America).

A total of 3,697 articles, published between 1 January 2000 and 31 December 2021, were retrieved from across the 4 databases and through our additional manual searches. After removing duplicate records and screening by titles and abstracts, 28 articles were included for full-text reading. Of these, 13 articles did not meet the established inclusion criteria and were excluded from further analysis. The countries studied and the regional envenoming estimates are presented in Fig 2 (2A and 2B). One article was added from manual screening of the bibliography of the included articles.

(2A) World map with annual envenoming estimates across the globe vs. (2B) countries with studies included in the current review. Knowledge scores, study populations, and sample size have been provided. For countries with multiple studies, mean knowledge scores have been provided and noted. Study populations include HC = Health Care Workers (clinicians, nurses, medical students, etc.) and POP = General population (the direct link to the base layer of the map: https://commons.wikimedia.org/wiki/File:BlankMap-World.svg ).

https://doi.org/10.1371/journal.pntd.0011048.g002

Sixteen studies [ 2 , 4 , 14 , 16 , 18 , 19 , 28 , 35 – 43 ] from 12 countries or territories, reporting knowledge of snakebite and snakebite management from 7,640 participants, were included in the quantitative analyses. All studies included in the analysis were online or hospital-based cross-sectional studies.

Study characteristics

Study features and participant characteristics have been summarised in Table 3 . Participants were 53.9% male with reported ages ranging from 12 to 90 years. Participants’ education ranged from pre-literate to university-level education. The majority of study participants were from the general population (66.0%; n = 5,043), 27.4% were healthcare providers including doctors, nurses, traditional healers ( n = 2,095), and 6.6% were medical students ( n = 502). The majority of participants were from Asia (77.8%; n = 5,942), 17.0% were from Africa ( n = 1,298), and 5.2% were from the Middle East ( n = 400). Of the 16 studies, 4 were ranked as good, 9 as fair, and 3 as poor, in accordance with the NHLBI quality assessment tool.

https://doi.org/10.1371/journal.pntd.0011048.t003

Pooled knowledge and awareness of snakebite management across studies

The primary outcome of this study was to assess the knowledge and awareness of snakebite and its prevention and management in healthcare workers and the general population. This included knowledge of signs and symptoms of snakebite, snakebite first-aid, treatment, antivenom, and preventive measures that led to health-seeking behaviour in the general population and the management procedures of healthcare providers. The pooled proportion of people with adequate knowledge of the outcome across the 16 studies is presented in Fig 3 . These findings demonstrated that 56% of the present study population answered the knowledge question correctly (95% CI 48% to 63%, p < 0.001). High heterogeneity was observed (I 2 = 97.29%), with marginal publication bias (Egger’s regression test, p = 0.0814).

https://doi.org/10.1371/journal.pntd.0011048.g003

Domain-specific knowledge

To identify possible causes of the substantial heterogeneity observed across the studies, 6 domains of knowledge were identified to enable more direct comparisons: knowledge of overall treatment, knowledge of antivenom as the preferred treatment, knowledge of signs and symptoms of snakebite, knowledge of first-aid, knowledge of types of snakes or identification of snakes, and knowledge of snakebite prevention, study-wise details can be found in Table 4 .

https://doi.org/10.1371/journal.pntd.0011048.t004

Fig 4 represents the pooled prevalence of 60% of good knowledge (95% CI 53% to 67%, p < 0.001) in the total of 6 key domains. Heterogeneity was high (I 2 = 96.76%) and publication bias was observed for the total score of the 6 identified domains (Egger’s regression test, p = 0.149) in the studies. A summary of the pooled knowledge scores obtained by the sample for each of the knowledge domains relevant to snakebite management has been provided in Table 5 .

https://doi.org/10.1371/journal.pntd.0011048.g004

https://doi.org/10.1371/journal.pntd.0011048.t005

Participants had relatively higher knowledge concerning use of antivenom as preferred treatment (78%, CI 65% to 92%), <0.001, I 2 = 98.55), followed by snakebite prevention (73%, CI 52% to 93%, p < 0.001, I 2 = 99.71), knowledge of signs and symptoms of snakebite (66%, CI 52% to 81%, p < 0.001, I 2 = 99.06), knowledge of first-aid (57%, CI 46% to 67%, p < 0.001, I 2 = 98.18), and knowledge of treatment (56%, CI 47% to 66%, p < 0.001, I 2 = 94.87). Participants had lower knowledge relating to types of snakes and the identification of snakes (54%, CI 46% to 63%, p < 0.001, I 2 = 93.27). High heterogeneity and publication bias was observed in all these subgroup analyses. The specific domain wise proportion of good knowledge is detailed in Fig 5 .

https://doi.org/10.1371/journal.pntd.0011048.g005

Sensitivity analysis

Sensitivity analysis was conducted to identify possible sources of substantial/considerable heterogeneity. This analysis was conducted by continent, target population, and study quality (i.e., good, fair, poor), respectively. The results are presented in Table 6 .

https://doi.org/10.1371/journal.pntd.0011048.t006

The proportion of good knowledge varied between continents. Participants from Asia (60%, CI 50% to 70%, I 2 = 97.30, p < 0.001) had better knowledge compared to Africa (49%, CI 33% to 65%, I 2 = 97.24, p < 0.001), and the Middle East (47%, CI 42% to 52%, I 2 = 0.03%, p = 0.42). However, the difference was not significant as the respective CIs overlapped. The proportion of knowledge was similar and slightly higher among the general population (56%, CI 37% to 75%, I 2 = 98.69, p < 0.001) and the healthcare providers (56%, CI 47% to 66%, I 2 = 95.21, p < 0.001) compared to the medical students (52%, CI 39% to 64%, I 2 = 87.90, p < 0.001). These differences were not significant. The pooled prevalence of good knowledge was higher for the studies ranked as poor (59%, CI 38% to 79%, I 2 = 97.05, p < 0.001), followed by good (58%, CI 50% to 65%, I 2 = 82.39, p < 0.001), and fair (54%, CI 42% to 66%, I 2 = 98.11, p < 0.001).

Sensitivity analysis of the overall knowledge on the key 5 questions revealed a similar trend for the continents and quality assessment. In the target population group, healthcare workers had better knowledge (62%, CI 52% to 72%, I 2 = 95.88, p < 0.001) compared the general population (57%, CI 43% to 72%, I 2 = 97.70, p < 0.001) and the medical students (58%, CI 53% to 63%, I 2 = 19.70, p < 0.001).

A sensitivity analysis was done on specific domains considering the target population, results can be found in Table 5 . The proportion of good knowledge was similar for both the general population and the healthcare workers, 55% (CI 48% to 62%, I 2 = 78.42) and 54% (33% to 75%, I 2 = 97.47), respectively, in the domain of knowledge on types of snakes and identification of snakes. Healthcare workers had higher knowledge about signs and symptoms of snakebite (73%, CI 64% to 83%, I 2 = 92.29), first-aid (65%, CI 47% to 83%, I 2 = 98.06), and knowledge about prevention (79%, CI 42% to 100%, I 2 = 99.30). Healthcare workers had higher adequate knowledge on use of antivenom as the preferred treatment (81%, CI 61% to 1.00%, I 2 = 97.91) compared to the general population (77%, CI 55% to 98%, I 2 = 98.91). Knowledge concerning overall treatment strategy was assessed among the healthcare workers only and the proportion of adequate knowledge was 56% (CI 47% to 66%, I 2 = 94.87).

Snakebite envenoming is a neglected tropical disease (NTD) that places a significant burden on many countries across South and Southeast Asia, sub-Saharan Africa, Latin America, and Australasia [ 11 , 44 ]. Combatting snakebite requires not only access to lifesaving antivenoms, but also communities and health systems that have the knowledge required to prevent and manage venomous snakebites. As snakebite envenoming is an ecological disease, we may speak of the production and distribution of effective antivenoms combining with knowledge of snakes and snakebite to constitute an “ecology of practice”—a composite “tool”—for mitigating the burden of this NTD [ 45 ]. This systematic review investigated community and healthcare worker knowledge and awareness on snakebite prevention and management with a view to gaining an understanding of the status of this ecology of practice in affected communities. Knowledge included signs and symptoms of snakebite, first-aid, treatment, antivenom, and preventive measures that lead to the health-seeking behaviour of the general population and the management procedure of the healthcare providers.

Data were compiled from 16 studies across 12 countries or territories, reporting 7,640 participants’ knowledge of snakebite, its treatment and management. The proportion of adequate knowledge was highest among participants from Asia (60%) compared to Africa (49%) and the Middle East (47%). All the studies included in this systematic review were from low and lower-middle-income countries in the tropical and equatorial regions of the world. No study from high-income countries met the inclusion criteria for this systematic review, though it is noted that some parts of North America [ 46 , 47 ] and Australasia [ 11 , 48 ] are prone to snakebite envenoming and fatality.

The study demonstrated a pooled adequate knowledge score of 56% among the study population. However, to account for the differences in how the included studies assessed knowledge of snakebite management and mitigation, we also undertook a pooled assessment of adequate knowledge. This enabled more direct comparison and encompassed 6 selective knowledge domains: antivenom as the preferred treatment, overall treatment, symptoms of snakebite, first-aid, snake identification/types, and prevention. When the pooled adequate knowledge for the total of domains was calculated, it was found to be higher (60%) compared to the overall pooled knowledge score of 56%.

Participants had relatively high knowledge of snakebite prevention (73%), though lower knowledge of specific snake species and how to identify them (54%). Knowledge of how to effectively prevent snakebite is fundamental to reducing the morbidity and mortality of envenoming in snakebite endemic regions. Preventative measures are most effective when they consider the local context in which snakebites occur. This includes the circumstances of how most venomous bites occur, where venomous species are likely to be encountered and what times of the day, night, or year they’re most active. For example, in south Asia, venomous kraits ( Bungarus spp.) bite almost exclusively at night when people are sleeping on the ground in their homes [ 49 ]. In these areas, sleeping under mosquito nets considerably reduce the risk of nocturnal bites [ 50 ]. Sleeping on raised beds has also shown some promise in preventing snakebites [ 51 ]. In other snakebite endemic regions, the use of long pants and closed footwear is thought to be an effective strategy for preventing snakebites [ 51 , 52 ]. Again, such context-specific knowledge highlights the importance of adopting an ecological or contextual “stance”: community education focused on reducing the risk of bites via the cultivation of an ecology of practice likely offers an effective means of mitigating or reducing the impact of snakebite in these areas [ 53 ]. Such measures are also key to ensuring that local snake populations are not negatively impacted by their proximity to human communities. Snakes remain an important part of the local ecology and act to control rodent populations that are often detrimental to local agriculture and human health.

In the studies reviewed, knowledge regarding snakebite prevention was relatively high among both the general population (79%) and healthcare workers (68%). These findings were in line with previous studies conducted among doctors and communities in snakebite prevalent countries [ 2 , 40 ]. However, it is worth highlighting that there are no controlled studies investigating either the adequacy of the questions posed to participants in the studies—i.e., whether or not success in answering them translates into real-world knowledge of snakebite prevention—or indeed whether such knowledge in fact results in a reduction of snakebite incidents. Much research remains to be conducted in this area.

Effective first aid and treatment methods are essential to reduce the mortality and morbidity of snakebite patients. According to the WHO, appropriate first aid involves moving the person away from the area where the bite occurred, remove constricting clothing and jewellery, immobilizing the person and splinting the bitten limb to reduce movement. In some cases—e.g., within Australasia—pressure immobilisation bandages may be recommended. The person should be reassured and closely monitored as they are transported to a nearby health facility. Here, we found that participants had a reasonable knowledge of first aid overall (57%). The proportion of good knowledge about first aid was higher among healthcare workers (65%) compared to the general population (46%). Considerable gaps in knowledge still exist regarding the appropriate the first aid treatment given to snakebite victims, including the evidence base for any particular treatment. Research on the effectiveness of first aid measures is required alongside community education to ensure that at-risk individuals are aware of the appropriate first aid response for snakes’ endemic in their areas.

Approximately 33% of the participants were found to rely on “traditional” or “alternative” treatments for snakebite. These treatments often have negligible scientific support [ 22 , 54 , 55 ] and in some cases (e.g., bite site scarification, tourniquets) may be actively harmful [ 56 ]. In some instances, it may be possible to incorporate traditional healers and healing practices into the management of snakebite, particularly if they do not impede or delay the administration of antivenoms and other appropriate treatments [ 57 ]. For example, traditional healers could be provided with training regarding how to appropriately detect signs of envenoming and encouraged to use their position within communities to refer patients to local health facilities for appropriate patient management.

It is impossible to definitively state ahead of time whether a bite from any given snake or snake species will cause significant sequelae. Thus, a bite from any venomous or unidentified species of snake must be considered a life-threatening emergency. Given the diversity of potentially dangerous snake (including >700 species worldwide with high-pressure venom systems and a number of “non-front-fanged” species), it is of paramount importance for healthcare workers and those at risk to be able to recognise the signs and symptoms of envenoming from different venomous species in snakebite-endemic regions. Previous studies have indicated that inadequate knowledge of snake identification and snakebite symptoms can lead to increased mortality due to envenoming [ 58 , 59 ]. The results of this study indicate that overall, 54% of the participants answered questions regarding types of snakes or identification of snakes correctly. Knowledge of snake identification was found to be similar among both the general population and healthcare workers. Research has also previously indicated that healthcare workers lack knowledge and training in snake identification by signs and symptoms, and this lack of awareness results in ineffective snakebite management and increased medical errors [ 60 , 61 ]. Developing methods for accurate identification of species-specific envenoming and its proper management (i.e., administration of appropriate antivenom) by qualified healthcare workers proves significant in reduced mortality and morbidity associated with snakebites [ 62 , 63 ]. Our study results showed that there was a high level of pooled knowledge among healthcare workers (71%) in identifying the signs and symptoms after venomous snakebites. These findings are promising though the small sample size here must be noted.

Where snakebites cannot be prevented, ready access to safe and effective antivenoms and appropriate patient management from skilled medical practitioners can be lifesaving. Following a snakebite, pathological sequelae may rapidly progress towards life-threatening consequences, and appropriate medical treatment should be sought without delay. Where broad spectrum antivenom products are unavailable, effective management of snakebite patients requires specialised knowledge to administer appropriate antivenoms. Interestingly, we found that the general population had better knowledge regarding appropriate snakebite treatments (71%) than their counterparts in healthcare (59%). However, it should be noted that the public were only assessed on the appropriate use of antivenom in general. Studies have consistently reported a low level of knowledge among healthcare professionals on appropriate snakebite management. With similar gaps in knowledge evident in health sectors of developed countries, such as the United Kingdom and Hong Kong, and in low-middle income countries, such as Nigeria, Bangladesh, Lao People’s Democratic Republic, and Cameroon [ 2 , 15 , 16 , 35 , 64 , 65 ].

To the best of our knowledge, this is the first systematic review and meta-analysis aiming to assess knowledge about snakebite and its prevention and management among the general population and healthcare workers. This systematic review has several strengths and limitations. Firstly, all included studies were cross-sectional surveys and quantitative in nature, which means that they were unable to represent any causal associations and the exclusion of qualitative studies may limit the scope and potential of this study. Secondly, it should also be noted that the heterogeneity in the evaluated outcomes was high. While a range of sensitivity analyses were performed to identify the sources of heterogeneity, it is noted that a more standardised approach to the collection of snakebite knowledge data would enable more robust findings to be found and stronger conclusions to be drawn. A wide heterogeneity was also observed in the pooled knowledge prevalence. This was partly explained by the differences in the questionnaire contents, measurement and scoring systems. The studies ranked as good in the NHLBI quality assessment tool were found to be more homogeneous. Thirdly, this review excluded articles published in languages other than English. Given the high rates of snakebite across Southeast Asia, sub-Saharan Africa, Latin America, and the Middle East, it is possible that studies which could have provided valuable insight here were instead excluded. Additionally, due to the lack of sufficient subgroup information, this review was unable to assess the knowledge in age, gender, or education groups.

The pooled proportion of good knowledge about snakebites and its management among the general population and healthcare workers was 56%. According to the survey methods utilised, participants had relatively higher knowledge regarding snakebite prevention (73%), though lower knowledge regarding snake identification (54%). These data suggest that there is a significant need for greater awareness and education of the appropriate preventative and treatment measures for snakebite for both communities and healthcare workers alike in snakebite endemic regions. Such education should include knowledge regarding local venomous snake species, their movement and behaviours; signs and symptoms of envenomation; primary first-aid for appropriate patient management and the importance of rapid health-seeking behaviours and appropriate snakebite treatment administration to reduce the burden of snakebite mortality and morbidity. The degree to which this knowledge translates into an opposite ecology of practice that contributes to the reduction of snakebite remains to be assessed. Additional studies on heterogeneous populations from other parts of the world are also needed.

Learning Points

• Snakebite envenoming is a neglected tropical disease (NTD) that places a significant burden on communities and health systems across the globe.
• Adequate knowledge about snakebite and snakebite management among the general population and healthcare workers was 56%.
• There is a significant need for greater awareness and education in both the general population and among healthcare workers to ensure that appropriate preventative and patient management techniques are being utilised in snakebite endemic regions.
• Future studies should look to standardise measures assessing snakebite knowledge and patient management to enable direct comparisons and ensure successful interventions are transferable to other snakebite endemic regions.
• The degree to which this knowledge translates into an opposite ecology of practice that contributes to the reduction of snakebite remains to be assessed.
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Supporting information

S1 prisma checklist. checklist addressing the introduction, methods, results, and discussion sections of the systematic review report..

https://doi.org/10.1371/journal.pntd.0011048.s001

S1 Table. Search strategy: Ovid Medline (R).

https://doi.org/10.1371/journal.pntd.0011048.s002

S2 Table. Quality assessment results for the included studies following the National Heart, Lung and Blood Institute (NHLBI) quality assessment for observational cohort and cross-sectional studies.

https://doi.org/10.1371/journal.pntd.0011048.s003

Acknowledgments

We acknowledge the intellectual support received from the Librarian of the University of Melbourne.

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• 53. Calvete Chornet JJ, Lomonte B, Saviola AJ, Bonilla Murillo F, Sasa Marín M, Williams DJ, et al. Mutual enlightenment: A toolbox of concepts and methods for integrating evolutionary and clinical toxinology via snake venomics and the contextual stance. Toxicon: X. 2021;Volumes 9–10, 100070. https://doi.org/10.1016/j.toxcx.2021.100070

First report of a prolonged bite by a Western Whip Snake, Hierophis viridiflavus carbonarius (Bonaparte 1833) (Serpentes, Colubridae), resulting in pronounced local oedema

• Fabio Savini Via Sant’Agà, 47521 Cesena, Italy

Although extensive research has been conducted on snake venoms, the effects of bites inflicted by non-front-fanged colubroid snakes remain incompletely understood, particularly for species of uncertain medical relevance. The Western Whip Snake ( Hierophis viridiflavus ) is a colubrid snake typically classified as non-venomous and harmless to humans. Nevertheless, old works reporting the presence of Duvernoy's glands in this species raise questions regarding its presumed lack of venom. This report presents the first case of a prolonged bite from a wild Western Whip Snake ( Hierophis viridiflavus carbonarius ) that occurred in Italy, and provides a detailed account of the resulting effects. The primary symptom experienced by the bitten subject was painless, marked local oedema, which subsided within 24h after the bite. The clinical manifestations observed in the current study suggest that Hierophis viridiflavus could have the potential to inflict bites that lead to mild local effects consistent with envenoming.

Copyright (c) 2024 Ignazio Avella, Fabio Savini, Matteo Di Nicola

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How a Snake Uses Its Sense of Smell

These reptiles and their social networks are understudied, according to researchers applying scents to different snakes to assess their behavior.

By Asher Elbein

Say the words “animal self-recognition,” and many scientists will think of chimpanzees, crows and elephants.

For the first time, researchers — employing an innovative twist on the mirror test — have found evidence that garter snakes can distinguish themselves from others, using not sight but scent.

“Reptiles are massively understudied,” said Noam Miller, a comparative psychologist at Wilfrid Laurier University in Ontario, Canada, and an author of the paper, published on Wednesday in the journal Proceedings of the Royal Society B . “There’s a bias out there that they’re these boring, not very cognitive animals, and that’s completely wrong. That’s one of the reasons why we got very interested in studying them and showing the complex cognitive things they can do.”

One traditional sign of animal cognition has generally been the mirror test, Dr. Miller said, or whether an animal can learn to recognize itself in a reflective surface, a trait thought to be a proxy for more sophisticated intelligence. Pioneered by primate researchers in the 1970s, the test typically involves marking an animal with paint somewhere that is visible only in the mirror and waiting to see if it investigates the change.

Similar tests have since been done with a range of species: elephants ( passed ), pandas ( failed ), roosters ( passed ) and even fish like the cleaner wrasse ( passed ).

But the mirror test is geared toward animals that are primarily visual. Many species — such as snakes — rely primarily on their sense of smell, Dr. Miller said. In 2017, researchers devised an olfactory version of the test for dogs. (They passed.)

Two different species of snakes were tested in the new study. In one corner: North American eastern garter snakes, predators of insects and fish with a surprisingly complex social life . In the other, African ball pythons, a largely solitary, sedentary snake that ambushes rodents.

Snakes, like humans, have oils in their skin that leave a scent trail. The team rubbed makeup removal pads along the undersides of both snakes to collect scent samples, some of which they doctored with olive oil. They placed the pads at either ends of long, narrow boxes and offered the snakes several choices: between their own odor and straight olive oil; their own odor modified with olive oil; and the modified or unmodified odors of other snakes of the same species.

The team measured the snakes’ interest by gauging how long they flicked their tongues to taste the air — longer indicated sustained interest, he said. The ball pythons showed no apparent distinction. But the garter snakes zeroed in on their own tampered smell and ignored variations of the other snakes’ smells.

“Essentially, it seems like if others smell weird, they don’t care,” Dr. Miller said. “If they smell weird, that’s something they need to investigate.”

Recent research has found that eastern garter snakes are remarkably social, gathering in large groups to hibernate in the winter and forming networks — complete with “friends ” — during their active season.

As a more gregarious species, they may be more attuned toward a need to distinguishing themselves from others. One possible explanation of how self-recognition works is the ability to recognize the difference between self and “not-self,” Dr. Miller said. “That then ties it to social behaviors.”

It’s hard to say, however, whether ball pythons’ failure to pass the test is down to a lack of ability or a lack of interest, he added. Continuing research in his lab suggests that ball pythons, while more solitary, are socially complex.

But with over 5,000 species of living snakes inhabiting a range of different environments, he said, the family as a whole offers a wide array of opportunities to figure out what ecologies and behaviors might drive animals to actively distinguish themselves. Future tests might focus on tree-dwelling species, or on vipers like rattlesnakes, which recent research suggested prefer to den with kin and get less stressed around other snakes . Granted, the rattlesnake is also “harder to work with in a lab full of undergrads,” Dr. Miller said.

“In a lot of ways, I think their experimental paradigm is more powerful than the mirror tests,” said Rulon Clark, a biologist at San Diego State University who has researched snake social behavior and was not involved in the study. “A highly reflective mirrored surface doesn’t have a lot of ecological analogues. But encountering and understanding the importance of chemical cues left by yourself and your conspecifics is probably a deeply important aspect of the natural history of these animals.”

“Our research links how snakes experience themselves with how they experience the world around them,” said Morgan Skinner, a biologist at Wilfrid Laurier University and an author of the study. “It also demonstrates that when you can do this effectively in an experiment, you can find cognitive capabilities that some might find surprising.”

Little is known about the social structures of snakes and other reptiles, Dr. Miller said. “And if we want to understand the fundamental building blocks of social structure, we need to study a wider range of species rather than just rats and pigeons all the time.”

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Two periodical cicada broods are appearing in a 16-state area in the Midwest and Southeast for the first time in centuries. Can you get rid of them? Do they bite? We answer your questions .

Aside from chimps and humans, researchers have found clear evidence of menopause in only five species — all of them whales. A new study looks at the possible causes for it .

Scientists never imagined that the blind cave salamanders called olms willingly left their caves. Then, they discovered several at aboveground springs in northern Italy .

According to a common narrative that male mammals tend to be larger than female ones. A new study paints a more complex picture .

Daddy longlegs, the group of splendidly leggy arachnids also known as harvestmen, have been thought to have just two eyes. New research has uncovered four more vestigial ones .

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Snake Bite in South Asia: A Review

Emilie alirol.

1 Division of International and Humanitarian Medicine, Geneva University Hospitals, Geneva, Switzerland

Sanjib Kumar Sharma

2 B. P. Koirala Institute of Health Sciences, Dharan, Nepal

Himmatrao Saluba Bawaskar

3 Bawaskar Hospital and Research Centre, Raigad, India

Ulrich Kuch

4 Biodiversity and Climate Research Centre, Frankfurt am Main, Germany

François Chappuis

Snake bite is one of the most neglected public health issues in poor rural communities living in the tropics. Because of serious misreporting, the true worldwide burden of snake bite is not known. South Asia is the world's most heavily affected region, due to its high population density, widespread agricultural activities, numerous venomous snake species and lack of functional snake bite control programs. Despite increasing knowledge of snake venoms' composition and mode of action, good understanding of clinical features of envenoming and sufficient production of antivenom by Indian manufacturers, snake bite management remains unsatisfactory in this region. Field diagnostic tests for snake species identification do not exist and treatment mainly relies on the administration of antivenoms that do not cover all of the important venomous snakes of the region. Care-givers need better training and supervision, and national guidelines should be fed by evidence-based data generated by well-designed research studies. Poorly informed rural populations often apply inappropriate first-aid measures and vital time is lost before the victim is transported to a treatment centre, where cost of treatment can constitute an additional hurdle. The deficiency of snake bite management in South Asia is multi-causal and requires joint collaborative efforts from researchers, antivenom manufacturers, policy makers, public health authorities and international funders.

Introduction

Since ancient times, snakes have been worshipped, feared, or loathed in South Asia. Cobras appear in many tales and myths and are regarded as sacred by both Hindus and Buddhists. Unfortunately, snakes remain a painful reality in the daily life of millions of villagers in this region. Indeed, although antivenom is produced in sufficient quantities by several public and private manufacturers, most snake bite victims don't have access to quality care, and in many countries, both morbidity and mortality due to snake bites are high. The neglected status of snake bite envenoming has recently been challenged [1] but as outlined below, apart from the production of antivenom, snake bite envenoming in South Asia shares all the characteristics of a neglected tropical disease. This review aims at summarizing and discussing the epidemiology, clinical features, diagnosis, and treatment of snake bite envenoming in South Asia (Bangladesh, Bhutan, India, Nepal, Pakistan, and Sri Lanka).

Methodology

Articles were identified by searching Medline through PubMed using various combinations of terms including “snake,” “snake bite,” “envenoming,” and “venom.” Research papers and case reports from Bangladesh, Bhutan, India, Nepal, Pakistan, and Sri Lanka were retrieved, as were significant papers from other Asian countries. Additional articles were obtained by citation tracking of review and original articles. The review also drew on conference proceedings and original research conducted by the authors.

Epidemiology

An accurate measure of the global burden of snakebite envenoming remains elusive despite several attempts to estimate it and, apart from a few countries, reliable figures on incidence, morbidity, and mortality are scarce [2] – [4] . South Asia is by far the most affected region [2] , [4] . India has the highest number of deaths due to snake bites in the world with 35,000–50,000 people dying per year according to World Health Organization (WHO) direst estimates [2] , [4] . In Pakistan, 40,000 bites are reported annually, which result in up to 8,200 fatalities [4] , [5] . In Nepal, more than 20,000 cases of envenoming occur each year, with 1,000 recorded deaths [6] . In Sri Lanka, around 33,000 envenomed snake bite victims are reported annually from government hospitals [4] , [7] . A postal survey conducted in 21 of the 65 administrative districts of Bangladesh estimated an annual incidence of 4.3 per 100,000 population and a case fatality of 20% [8] . However, existing epidemiological data remain fragmented and the true impact of snake bites is very likely to be underestimated. Surveys in rural Sri Lanka showed that hospital data record less then half of the deaths due to snakebite [9] – [11] . In Nepal, a review of district hospital records showed that national figures underestimated the incidence of snake bite by one order of magnitude [12] . The highest figures reported in Asia so far come from a community-based survey conducted in southeast Nepal in 2002, which revealed annual incidence and mortality rates of 1,162/100,000 and 162/100,000, respectively [13] . Figures of a similar magnitude were recently also obtained in a nation-wide community-based survey in Bangladesh (M. R. Rahman, personal communication).

Snake bite is an important occupational injury affecting farmers, plantation workers, herders, and fishermen. Open-style habitation and the practice of sleeping on the floor also expose people to bites from nocturnal snakes. As summarized in Table 1 , several epidemiological studies have outlined characteristics of snake bite victims in the region. Bites are more frequent in young men, and generally occur on lower limbs. The incidence of snake bites is higher during the rainy season and during periods of intense agricultural activity [14] , [15] . Snake bite incidence and mortality also increase sharply during extreme weather events such as floods. During the 2007 monsoon flood disaster in Bangladesh, snake bite was the second most common cause of death, after drowning, eclipsing mortality from diarrheal and respiratory diseases and illustrating how important snake bite can be in this region compared to other health problems [16] .

Venomous Snakes in South Asia

The number of different snake species found south of the Himalayas is estimated to be around 300, including about 67 front-fanged venomous species of the families Elapidae and Viperidae [17] – [21] .

Viperid snakes are represented by 26 species belonging to the true vipers (subfamily Viperinae) and pit vipers (Crotalinae). Among the true vipers, Russell's viper ( Daboia russelii ) is associated with the highest morbidity and mortality. In Anuradhapura District, Sri Lanka, up to 73% of all admitted snake bites are attributed to this species [22] whose distribution extends north to the Indus valley of Pakistan and Kashmir, to the foothills of the Himalayas in Nepal and Bhutan and to Bangladesh in the east. Saw-scaled vipers ( Echis carinatus and E. sochureki ) are other very important viperine species that inhabit open and dry environments. E. sochureki causes numerous bites in northern India and has long been regarded as one of Pakistan's deadliest snakes [17] , [23] ; E. carinatus is regionally highly abundant and causes many bites in parts of western and southern India [18] and in arid coastal areas of northern Sri Lanka [24] . Three other species of true vipers that occur in the west of South Asia are the Levantine viper ( Macrovipera lebetina ) and two species of desert vipers ( Eristicophis macmahoni and Pseudocerastes persicus ). Although their bites have been considered to be comparatively rare, they are capable of causing severe envenoming [25] , [26] .

Pit vipers belonging to various genera [27] , [28] have traditionally been regarded as being of lesser concern in South Asia. However, these snakes occur in most habitat types from mangroves to the high mountains, and some species are common in gardens and agricultural landscapes. Envenoming by green pit vipers is very common in wide regions of Bangladesh and Nepal [12] , [29] , and bites by the mountain pit viper ( Ovophis monticola ) occur in Nepal where it is the most frequently encountered venomous snake at altitudes of 900–2,700 m [21] , [30] . Although causing few fatalities, bites by these species produce marked local effects that can result in chronic conditions and permanent sequelae [31] , [32] . In southern India, recent studies have reported massive morbidity among plantation workers due to bites by a much smaller species, the Malabar pit viper ( Trimeresurus malabaricus ) [33] . Hump-nosed pit vipers ( Hypnale hypnale and H. nepa ) are also emerging as medically important species in the region, and can cause renal failure and haemostatic dysfunctions [34] , [35] . Several fatalities due to H. hypnale envenoming, for which there is no specific antivenom, were reported in India and Sri Lanka [34] , [36] , [37] .

The family Elapidae is represented by at least 17 terrestrial species (including cobras, king cobras, kraits, and coral snakes) and numerous species of sea snakes in South Asia. Bites by cobras ( Naja species), which are best known for raising their head and anterior body and spreading their neck as a hood in defence, typically occur outdoors in the late afternoon [17] , [18] . The spectacled cobra ( Naja naja ), one of India's commonest snakes, causes numerous cases of envenoming every year [38] . In the northern and eastern parts of the Indian subcontinent, the monocellate cobra ( N. kaouthia ) also belongs to the medically important snakes. A third cobra species, N. oxiana , occurs in the northwest [18] , [20] , [21] . Kraits ( Bungarus species) are slender, nocturnal snakes that often enter human dwellings at night in search of prey. Consequently, many victims of krait bites are bitten while asleep. Case fatality rates of krait envenoming reach up to 77%–100% without treatment [17] , [39] . Traditionally, most krait bites in South Asia have been attributed to the common krait ( Bungarus caeruleus ), however, in South Asia alone there are eight species of Bungarus , several of which are morphologically similar to B. caeruleus . Several studies have demonstrated that a number of these are medically important in the region [40] – [43] . Coral snakes are smaller elapid snake species that are brightly coloured. They are rarely encountered by humans and thus are thought to cause few bites, but fatalities have been reported [44] . Sea snakes are large, paddle-tailed and primarily marine snakes that feed on fish and fish eggs. They are often caught in the nets of fishermen who are at risk of bites while handling them. Most fatalities following sea snake bites are attributed to Enhydrina schistosa [45] but the species identity of sea snakes involved in bites in South Asia has only very rarely been established [46] , [47] .

An often overlooked problem is that of nonvenomous or mildly venomous species. They represent the vast majority of living snakes, and may be mistaken for venomous snakes and/or involved in snake bite in South Asia. Rat snakes ( Ptyas species, Coelognathus species) are large, rapidly moving snakes that are often confused with cobras. Most notoriously, several genera of small nonvenomous snakes share the same colour pattern as kraits [19] , [48] . Wolf snakes ( Lycodon species) are of particular concern in this regard because some of them (e.g., Lycodon aulicus ) are very common inside and around houses and bite aggressively if disturbed [40] .

This species diversity has a significant public health impact: in addition to increasing the risk of bites in all kinds of environments, it complicates clinical management with respect to both diagnosis and treatment, as well as antivenom design and manufacture and control strategies.

Clinical Features of Snake Bite Envenoming

A widespread belief is that snake bites inevitably result in envenoming. However, bites by nonvenomous snakes are common and bites by venomous species are not always accompanied by the injection of venom (dry bites). A large survey conducted in ten hospitals of southern Nepal revealed that envenoming occurred in only 10% of the victims [12] . In Kerala, India, only 219 out of 635 patients (34%) with proven snake bite developed signs of systemic envenoming [49] . Likewise, in Bangladesh the proportion of nonenvenomed bites reported in hospital-based studies varied between 60% and 80% [29] , [50] . Moreover, as symptoms associated with panic or stress sometimes mimic early envenoming symptoms, clinicians may have difficulties in determining whether envenoming occurred or not.

When envenoming does occur, it can be rapidly life-threatening. Snake venom is a complex mixture of toxins and enzymes, each of which may be responsible for one or more distinct toxic actions. In bites by South Asian viperid snakes, envenoming results in local pain and tissue damage, characterised by swelling, blistering, bleeding, and necrosis at the bite site, sometimes extending to the whole limb [17] . Viperid venoms can also induce coagulopathy and platelet dysfunction, leading to spontaneous systemic haemorrhages and persistent bleeding from fang marks, wounds, or gums ( Figure 1 ). Intracranial bleeding, including anterior pituitary haemorrhage, and multi-organ failure are common causes of death [51] . A prospective study conducted in Anuradhapura District, Sri Lanka, showed that 92% of patients with Russell's viper envenoming presented with local swelling and 77% had haemostatic disturbances [7] . In addition, Russell's viper can cause acute renal failure and neurotoxicity, as has been shown in several studies conducted in south India and Sri Lanka [7] , [22] , [49] , [52] .

In Asia, coagulation defects and spontaneous bleeding are characteristic of bites by viperid snakes and are caused by procoagulant and haemorrhagic toxins in the snake venom. Image credit: D. A. Warrell .

Among the Elapidae, bites by N. naja and N. kaouthia can cause significant local swelling and sometimes extensive tissue necrosis of the bitten limb [31] , [38] , [53] , whereas bites by kraits or sea snakes do not usually cause signs of local envenoming and can be virtually painless. Cobra venom contains mainly postsynaptic neurotoxins, which bind and block acetylcholine receptors of the neuromuscular junction, while krait venom in addition contains presynaptic toxins that damage nerve endings [54] . Progressive descending paralysis is the hallmark of systemic envenoming by elapid snakes in South Asia ( Figure 2 ). Extraocular muscles are particularly sensitive to neuromuscular blockade, leading to a droop of upper eyelids (bilateral ptosis), a frequently observed early sign of paralysis [55] . Patients are often unable to protrude their tongue beyond the incisors and may present with difficulty speaking or swallowing. Limb weakness, loss of deep tendon reflexes, and fixed dilated pupils may follow. Once paralysis reaches the diaphragm and the intercostal muscles, victims usually die of respiratory failure if they are not adequately ventilated. Hospital-based studies in Sri Lanka showed that 48%–64% of B. caeruleus victims developed respiratory paralysis and required mechanical ventilation [15] , [56] . Although many clinical signs of neurotoxic envenoming by cobras and kraits are similar, with both genera able to cause respiratory failure within 30 minutes of the bite [57] , [58] , krait bite envenoming is often associated with a delayed onset and prolonged total period of paralysis. This is due to the function and effects of the most lethal components of krait venoms, beta-bungarotoxins, which destroy nerve terminals [59] . While coagulopathy and bleeding are common features of envenoming by certain elapid snakes in Australia and New Guinea [60] , clinical bleeding and clotting problems have not been reported after bites by South Asian elapids. Likewise, systemic myotoxicity following elapid snake bites was previously known only from sea snakes and some of their terrestrial relatives in Australia and New Guinea [60] . However, venom-induced generalized rhabdomyolysis and renal failure has recently also been observed in envenoming by the greater black krait ( B. niger ) in Bangladesh, further complicating clinical management (Faiz et al., unpublished data).

Envenoming by cobras, kraits and—in some areas—by Russell's viper frequently leads to progressive descending paralysis. Looking for the broken neck sign, which is caused by paralysis of the neck flexor muscles, should be part of the routine clinical assessment of patients. In this case, neuroparalysis persisted for five days despite antivenom treatment, but without progression toward respiratory failure. Image credit: H. S. Bawaskar .

The identification of snake species is crucial for optimal clinical management, because it allows clinicians to choose the appropriate treatment, anticipate complications, and therefore to improve prognosis. Moreover, as specific antivenoms are not available for South Asian pit vipers and most krait species, identifying these species would help to avoid wasting this expensive treatment and exposing patients to antivenom-induced adverse reactions. As mentioned above, bites by nonvenomous species are common and may throw clinicians into confusion.

Unfortunately, in many cases the biting snake is not seen, and if it is, its description by the victim is often misleading [40] . Even when the dead snake is brought to the health centre, misidentification is common. For example, hump-nosed pit vipers ( H. hypnale ) are frequently misidentified as saw-scale vipers ( E. carinatus ) in Kerala, India [34] . Consequently, many H. hypnale bite victims end up receiving ineffective antivenom. Throughout South Asia, krait bites are routinely attributed to B. caeruleus based on clinical syndromes and the great superficial similarity of B. caeruleus , B. sindanus , and B. walli . However, envenoming by krait species other than B. caeruleus that does not respond to available antivenoms may be common, as observed in Bangladesh (Faiz et al., unpublished data; Kuch et al., unpublished data).

Most physicians in South Asia have to rely on the circumstances of the bite and the clinical features of envenoming to infer the biting species. Coagulopathy, when present, is diagnostic of viper and pit viper bites in South Asia and can be observed using the 20-minute whole blood clotting test [61] . In Sri Lanka, B. caeruleus envenoming has a characteristic epidemiologic and clinical pattern [15] . Syndromic approaches have been proposed to assist physicians in identifying the biting species [61] and attempts have been made to develop clinical scores based on envenoming features [62] . However, careful studies of envenoming profiles are lacking for most species in this region. Thus, more clinical research using reliably identified snakes is needed to further explore differences in envenoming syndromes between additional species, and to evaluate their applied utility.

Immunoassays for detecting venom antigens in body fluids have been described for a number of species [63] – [65] , and attempts have been made to develop ELISA tests for South Asia [66] – [68] . Unfortunately, a narrow focus on an insufficient number of species and cross-reactivity between venoms has so far hindered the development of a reliable diagnostic test [64] , [69] . To limit the problem of cross-reactivity, the use of purified species-specific toxins for immunization or affinity-purified venom-specific polyclonal antibodies may be worth considering [70] . However, even then the paucity of reliable data on the diversity and distribution of venomous snakes in South Asia, the unavailability of venom for almost all of the species, and the very limited insight into venom variability even within the commonest species—all caused or promoted by restrictive wildlife legislation—remain major obstacles for the design and production of immunodiagnostics. Under these aspects, the use of forensic molecular techniques as an explorative and complementary tool for snake species diagnosis is promising. Forensic routine has shown that it is feasible to identify an aggressor (e.g., human or dog) based on trace DNA from bite marks [71] , and this is also possible in the case of snakes [72] . PCR amplification and sequencing of snake DNA obtained from bite-site swabs has recently been used to identify biting snakes in an animal model and in clinical cases from Bangladesh and Nepal (Kuch et al., unpublished data). The utility of this method as a clinical diagnostic tool, however, awaits further study.

Management of Snake Bite Victims and Recommended Treatment

Health workers in rural districts are usually poorly trained to manage snake bite envenoming, which is a complex emergency. A recent survey conducted in India and Pakistan showed that many doctors were unable to recognize systemic signs of envenoming [73] . Another study in northwest India revealed that most snake bite victims presenting at primary health centres received inadequate doses of antivenom and that out of 42 patients who required assisted ventilation, only one was intubated [74] . Improving the knowledge of care-givers at all levels of the health system is a challenge of paramount importance and great urgency in South Asia. Papua New Guinea, where snake bite management training programmes have been implemented in both rural and urban hospitals, could serve as an inspiring model in this regard.

Most experts agree that snake bite victims should be transported as quickly as possible to a medical centre where they can be clinically evaluated by qualified medical staff, and where antivenoms are available. In fact, time of transport was shown to be a crucial determinant of snake bite mortality in eastern Nepal [13] , and studies in southern India confirmed that delayed antivenom administration was associated with an increased risk of complications [49] , [75] . The bite victim should be reassured, the bitten limb immobilized with a makeshift splint or sling, and the patient transported. Walking is contraindicated, because muscular contractions promote venom absorption.

These simple recommendations are unfortunately rarely followed and vital time is often lost. The majority of victims first report to traditional healers [10] , [40] , [55] , [76] . Popular traditional treatments include chanting, incisions, attempts to suck venom from the bite site, and the application of herbal medicine or snake stones. Two studies in Nepal and Bangladesh showed that 90% and 98% of snake bite victims, respectively, used tourniquets ( Figure 3 ) [40] , [77] . In Bangladesh, incisions at and around the bite site were made in 28% of envenomed victims and in 13%–14% of those without signs of envenoming [40] . In northwest India, incision and drainage were practiced by 20% of patients [74] . These traditional measures are strongly contraindicated as they are ineffective and in most cases deleterious. For example, tourniquets cannot be safely left on for long without risking severe local damage including ischemia, necrosis, and gangrene [78] , [79] .

First-aid methods applied throughout South Asia are largely inadequate. Tourniquets in particular can have deleterious effects. This patient consulted after being bitten by a nonvenomous rat snake ( Ptyas mucosa ) that she had killed and brought for identification. After reassurance, local treatment, and observation, she was uneventfully discharged from the health post. Image credit: E. Alirol .

In 1979, Sutherland et al. recommended the pressure-immobilization method as an effective alternative first aid method [80] . According to the authors, the bitten limb should be bound firmly with a crepe bandage, starting distally around the toes or fingers and moving proximally. Although this technique has been extensively promoted in Australia, its efficacy remains controversial [81] . For example, a recent study in Australia showed that crepe bandages rarely generated optimal pressures compared with elasticized bandages [82] . In a study in India, pressure-immobilization was found to be difficult to apply correctly despite intense previous training of care providers [83] . In the Australian study, training did improve participants' ability to apply elasticized bandages [82] , and in a study in Papua New Guinea, participants living in an area where snake bites are common were very successful in gaining and retaining the ability of correctly applying pressure-immobilization (D. Williams, personal communication). This method is, however, contraindicated for viper and cobra bites as it may increase local tissue damage [81] , [84] and may contribute to delaying transport of the victim to a treatment centre.

Immunotherapy is the only specific treatment for snake bite envenoming. Antivenoms are produced by fractionation of plasma obtained from immunized animals, usually horses [85] . They can be either monovalent or polyvalent, depending on the number of species (single or multiple, respectively) whose venoms are used for immunization. Although monovalent antivenom has often been considered more efficacious, the production of polyvalent antivenom is preferred in many countries as snake species identification is generally not possible for the attending physician. Antivenoms have been available in South Asia for the past 60 years, and all existing products are manufactured by Indian companies. Traditionally, the production has focused on four species believed to be responsible for most deaths: N. naja , B. caeruleus , D. russelii , and E. carinatus . However, a number of other species that contribute to morbidity and mortality in the region have not been considered, and envenoming by these species usually does not respond adequately to existing antivenoms [34] , [36] .

The success of antivenom therapy depends on the ability of immunoglobulins to bind, extract, and eliminate toxins present in the body. While their efficacy in restoring haemostasis and cardiovascular functions is well established, the ability of antivenoms to prevent tissue damage and to reverse neurotoxicity is more controversial [56] , [86] , [87] . For instance, administration of antivenom to krait bite victims with established respiratory paralysis does not reverse paralysis [55] , [86] , [87] . This lack of clinical effectiveness often contributes to the administration of excessive amounts of antivenom [88] , [89] . Moreover, treatment outcome can vary greatly with the geographical area as the venom composition and antigenic properties of toxins can be highly variable across the range of a given snake species [90] , [91] . Indian antivenoms are produced using venoms from snakes captured in a tiny geographic area of the State of Tamil Nadu, and may therefore be less effective in other regions [92] . For example, the efficacy of Indian polyvalent antivenoms for the treatment of envenoming by Russell's viper in Sri Lanka is controversial [22] , [93] .

As a matter of fact, most of the antivenoms that are routinely used in South Asia have never been subjected to independent preclinical testing and formal evaluation in clinical trials. Their efficacy and safety profiles have not been properly established, and there is currently no evidence-based protocol for their administration and dosage. Up to 80% of patients treated with Indian antivenoms present one or more adverse effect(s) such as anaphylactoid or pyrogenic reactions, or late serum sickness [37] , [93] , [94] . While to our knowledge no fatal cases have been reported in South Asia, severe drug reactions occur and are likely to be under-reported. Adverse reactions can be efficiently managed by cheap, widely available drugs (e.g. antihistaminics, corticoids, adrenalin), but their prophylactic use yielded contradictory results [94] – [96] . The risk of severe adverse events exists but must be balanced against the life-saving potential of this treatment.

Antivenoms may be supplied free of cost by some ministries of health but their supply remains insufficient and irregular in several countries [12] , leading to the purchase of drugs by the patients' relatives. One vial of antivenom of Indian production costs around US$8–10, which is equivalent to several days of salary for poor farmers. Thus, many cannot afford to purchase the average 10–15 vials needed to reverse envenoming [97] .

Ancillary treatment

The management of envenomed snake bites is not limited to the administration of antivenoms. In the case of neurotoxic envenoming, artificial ventilation and careful airway management are crucial to avoid asphyxiation in patients with respiratory paralysis. Cases of complete recovery from severe neuromuscular paralysis without antivenom have been reported after prolonged artificial ventilation [98] .

Anticholinesterase drugs such as edrophonium can partly overcome blockade by postsynaptic neurotoxins and have shown good efficacy in cobra bite envenoming [61] , [99] . A few cases of successful anticholinesterase use have also been reported in krait bite envenoming in India [100] , but there is currently no treatment to stop the destruction of nerve endings by presynaptic krait toxins once this degeneration process has started.

Bacterial infections can develop at the bite site, especially if the wound has been incised or tampered with nonsterile instruments, and may require antibiotic treatment. However, there are currently no data supporting their systematic use [101] . A booster dose of tetanus toxoid should be administered but only in the absence of coagulopathy [17] . Necrosis on the bitten limb may require surgery and skin grafts, particularly in the case of cobra bites. If necrotic tissues are not removed, secondary bacterial infections can occur [53] . Tensed swelling, pale and cold skin with severe pain may suggest increased intracompartmental pressure in the affected limb. However, fasciotomy is rarely justified. In particular, it can be disastrous when performed before coagulation has been restored. A clear proof of significant compartment syndrome by measurement of substantially elevated intracompartmental pressures is a prerequisite [61] .

Control and Prevention

In practice, strategies to control snake populations and to prevent snake bites are nonexistent in South Asian countries. Many bites could be avoided by educating the population at risk. Sleeping on a cot (rather than on the floor) and under bed nets decreases the risk of nocturnal bites in Nepal [55] , [102] . Rubbish, termite mounds, and firewood, which attract snakes, can be removed from the vicinity of human dwellings. Attempts can be made to prevent the proliferation of rodents in the domestic and peridomestic area. Thatched roofs, and mud and straw walls are favoured hiding places for snakes and should be checked frequently. Many bites occur when people walking barefoot or wearing only sandals accidentally step on a snake. Using a torch/flashlight while walking on footpaths at night, and wearing boots [103] and long trousers during agricultural activities, could significantly reduce the incidence of bites.

A complementary strategy is to decrease the risk of dying from envenoming snake bites. Many areas where snake bite envenoming occurs are relatively inaccessible by road, especially during the rainy season, and transport to a health centre sometimes takes more than 24 hours [14] , [74] , [104] . In Nepal, a programme for rapid transport of snake bite victims by motorcycle volunteers to a specialized treatment centre significantly reduced the risk of fatal outcome (Sharma et al., manuscript in preparation).

While sub-Saharan Africa faces a dramatic crisis in antivenom production and supply [105] , [106] , shortage of antivenom is not the most pressing issue in South Asia. Indeed, it is estimated that India produces around one million vials of antivenom each year [107] . Despite these large volumes of production, several challenges persist that prevent appropriate management of snake bite victims in South Asia. Poor access to often inadequately equipped and staffed medical centres in rural areas, high cost of treatment, and inadequate use of antivenoms are major concerns [108] , [109] . Increased attention and means should be dedicated to snake bite envenoming by researchers, funding agencies, pharmaceutical industries, public health authorities, and supranational organisations, as all have contributed to keeping this important public health problem a truly neglected disease.

Box 1. Key Learning Points

• South Asia has the highest incidence and mortality rates of snake bite in the world.
• Bites by venomous snakes in this region can cause local tissue damage, neuroparalysis, systemic haemorrhages, generalized myotoxicity, acute renal failure, or complex combinations of these.
• Recommended first aid measures include reassurance of the snake bite victim, immobilization of the bitten limb, and rapid transport to a competent treatment centre.
• Antivenom is the only specific treatment for snake bite envenoming, but existing products cover only a very limited number of medically significant species.

Box 2. Five Key Papers in the Field

• Kasturiratne A, Wickremasinghe AR, de Silva N, Gunawardena NK, Pathmeswaran A, et al. (2008) The global burden of snakebite: A literature analysis and modelling based on regional estimates of envenoming and deaths. PLoS Med 5: e218. doi:10.1371/journal.pmed.0050218
• Warrell DA (1999) WHO Guidelines for the clinical management of snake bites in the South East Asia Region. SE Asian J Trop Med Publ Health 30: 1–83.
• World Health Organization (2007) Rabies and envenomings: A neglected public health issue. Geneva: WHO. Available at http://www.who.int/bloodproducts/animal_sera/rabies_envenomings/en/index.html
• Ariaratnam CA, Thuraisingam V, Kularatne SA, Sheriff MH, Theakston RD, et al. (2008) Frequent and potentially fatal envenoming by hump-nosed pit vipers ( Hypnale hypnale and H. nepa ) in Sri Lanka: Lack of effective antivenom. Trans R Soc Trop Med Hyg 102: 1120–1126.
• Gutiérrez JM, Theakston RDG, Warrell DA (2006) Confronting the neglected problem of snake bite envenoming: The need for a global partnership. PLoS Med 3: e150. doi:10.1371/journal.pmed.0030150

Box 3: Main Challenges

(1) Improving access

Access to care is hindered both by the remoteness of snake bite–prone areas and by the cost of snake bite management. A community survey in Nepal showed that snake bite envenoming represents a substantial financial burden for rural households [13] . Despite the mushrooming of well-equipped private clinics in some rural areas of India, poor villagers rarely have access to mechanical ventilation or dialysis.

(2) Improving clinical management

Simple and standardized protocols on snake bite management are needed. Despite the publication of regional guiding principles [61] , national protocols are not always consistent with each other (e.g., low initial dose of antivenom advised in Nepal versus high initial dose in India and Bangladesh), are often not available in peripheral health structures and are poorly explained to end users. Moreover, manufacturers' recommendations are often misleading [107] . In Nepal, the application of different protocols may play a role in the wide range (3%–58%) of case-fatality rates reported from various hospitals [12] .

(3) Improving diagnostic and treatment tools

The lack of field-applicable diagnostic tools to identify snake species contributes to poor case definitions [110] , mismanagement of patients, and uncertainties about snake bite epidemiology. Snake bite victims in South Asia are still reliant on old generations of antivenoms, and several venomous species are not covered by existing products [92] . The pharmacokinetic and pharmacodynamic properties, efficacy, and safety of most Indian antivenoms have never been studied or compared. WHO has recently endorsed the strengthening of antivenom production, and efforts are being made to help Indian manufacturers to improve the quality of existing products [108] . However, the impact of this approach on the cost of antivenom production needs to be carefully anticipated and closely monitored [1] .

(4) Improving knowledge

Improving the knowledge of both care-givers and rural communities is crucial. Health workers in rural districts are usually poorly trained to deal with this complex emergency. For example, many doctors in India and Pakistan appear to be unaware of the criteria for antivenom administration [73] . Education of rural communities on snake bite, avoidance of useless or dangerous first-aid measures, and the importance of rapid transport of victims to treatment centres should be widely implemented [13] .

The authors have declared that no competing interests exist.

The work of UK is supported by the LOEWE Programme of the State Government of Hessen, Germany and by the Wellcome Trust (Research grant GR079027MA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.