Figures
Abstract
Background
Snakebite is a priority neglected tropical disease and causes a range of complications that vary depending on the snake species. Randomised clinical trials have used varied outcome measures that do not allow results to be compared or combined. In accordance with the Core Outcomes Measurements in Effectiveness Trials (COMET) initiative, this systematic review aims to support the development of a globally relevant core outcome set for snakebite.
Methods
All randomised controlled trials, secondary analyses of randomised controlled trials and study protocols investigating the efficacy of therapeutics for human snakebite envenoming were eligible for inclusion. Study screening and data extraction were conducted in duplicate by two independent reviewers. All primary and secondary outcome measures were extracted and compiled, as were adverse event outcome measures. Similar outcome measures were grouped into domains. The study was prospectively registered with PROSPERO: CRD42020196160.
Results
This systematic review included 43 randomised controlled trials, two secondary analyses and 13 study protocols. A total of 382 outcome measures were extracted and, after duplicates were merged, there were 153 unique outcomes. The most frequently used outcome domain (‘venom antigenaemia’) was included in less than one third of the studies. The unique outcomes were classified into 60 outcome domains. Patient-centred outcomes were used in only three of the studies.
Discussion
Significant heterogeneity in outcome measures exists in snakebite clinical trials. Consensus is needed to select outcome measures that are valid, reliable, patient-centred and feasible. The results of this systematic review strongly support the development of a core outcome set for use in snakebite clinical trials.
Author summary
Standardised outcome measures for snakebite randomised controlled trials are needed to enable results to be compared and combined between studies. This systematic review was conducted to understand the variations in outcome measure use in snakebite randomised controlled trials, and to create a comprehensive list of outcome measures from which to develop a core outcome set (COS). A total of 153 unique outcome measures were extracted from the 58 studies identified in this systematic review. Of these 153 unique outcome measures, 91 were used in only in a single study. Although a form of bedside whole blood clotting test was used in 30 of the 58 studies, 18 unique methods of measurement were identified. Only three studies, all conducted in the USA, included patient-centred outcomes. This systematic review demonstrates the strong need for a snakebite core outcome set, which will support the adoption of valid, reproducible, and patient-centred outcome measures, and enable downstream meta-analyses.
Citation: Abouyannis M, Aggarwal D, Lalloo DG, Casewell NR, Hamaluba M, Esmail H (2021) Clinical outcomes and outcome measurement tools reported in randomised controlled trials of treatment for snakebite envenoming: A systematic review. PLoS Negl Trop Dis 15(8): e0009589. https://doi.org/10.1371/journal.pntd.0009589
Editor: Abdulrazaq G. Habib, College of Health Sciences, Bayero University Kano, NIGERIA
Received: February 10, 2021; Accepted: June 24, 2021; Published: August 2, 2021
Copyright: © 2021 Abouyannis 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 relevant data are within the manuscript and its Supporting Information files.
Funding: The author MA was supported by a Wellcome Trust clinical PhD fellowship (grant number: 203919/Z/16/Z; The Wellcome Trust, https://wellcome.org/). The funder 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
Global estimates indicate that there are 1·8 million envenomings and 94,000 deaths each year due to snakebite, with the highest burden in sub-Saharan Africa and Asia [1].
There is significant within-species and between-species variability in the toxins found in snake venoms [2], which account for the broad range of clinical manifestations caused by envenoming [3]. Syndromes of systemic envenoming include neurotoxicity, haemorrhage, and coagulopathy. Local effects can range from swelling to tissue necrosis, and are an important cause of disability and limb amputation [4]. Other effects of envenoming include myotoxicity, hypotension, and renal injury.
There has been limited funding for snakebite research, with a global average of under 5 million USD invested per annum [5], and a resulting paucity of clinical trials [6]. Antivenom is the only specific therapy for treating the aetiological toxins injected during snakebite, yet their use is rarely supported by clinical efficacy data or a rigorous regulatory framework [7]. However, in 2017 the World Health Organization reinstated snakebite envenoming as a category A neglected tropical disease [8], and thus funding to support snakebite management is anticipated to increase. Appropriate outcome measures are vital for ensuring that findings are relevant to patients and can appropriately inform policy makers. They need to be valid and reliable, particularly when surrogate endpoints are relied upon.
The Core Outcome Measures in Effectiveness Trials (COMET) Initiative has advocated for and supported the development of core outcome sets (COS) in clinical research [9]. These are developed by collaborative groups of researchers, clinicians, and patients; to identify an agreed minimum set of outcome measures for a disease area. By using a core outcome set, it is easier to compare, contrast and combine results of clinical trials, which has rarely been possible in the field of snakebite [10,11]. The first step toward developing a COS is to undertake a systematic review of the existing literature to inform. This systematic review aims to describe the heterogeneity in outcome measures used across clinical trials and will provide a comprehensive resource of outcome measures that can be considered when developing a COS.
Methods
Search strategy and selection criteria
Databases were searched for randomised controlled trials and trial protocols wherein therapeutics that inhibit venom, or its downstream pathological effects, were studied. MEDLINE, Cochrane CENTRAL, Web of Science and Embase were searched from database inception until the 23rd of June 2020, with no language restriction, using the search terms ([“Snake bite” OR “snake envenomation” OR “snake venoms” OR “antivenoms” OR “antivenins] and [“randomised controlled trial” OR “randomised” OR “randomized” OR “randomly” OR “placebo” OR “double-blind” OR “single-blind” OR “clinical trial”]. Reference lists of included studies were searched. The following trial registries were searched: Australian trial register; International Standard Randomised Controlled Trial register; Clinical Trials Registry India; Chinese clinical trials registry; Clinical trial gov; Sri Lanka Clinical Trials Registry; Japan Primary Registries Network; WHO ICTRP. Full details of the search strategy were uploaded to PROSPERO (CRD42020196160).
Covidence systematic review software was used to compile, deduplicate and screen studies. Two reviewers (MA and DA) independently screened titles and abstracts, and subsequently the full-text articles. Full texts were translated to English language when necessary. Disagreements were resolved by consensus discussion with a third reviewer (HE). All reviewers (MA, DA and HE) are clinical academics with experience of interpreting clinical trials. Studies of adjunctive therapies that proposed to treat either antivenom hypersensitivity reactions or bite-site infection were excluded. Published secondary analyses of randomised controlled trials were included if they provided additional outcome measures.
Data extraction
Prespecified data (as reported in S1 Text) were independently extracted and standardised by two authors (MA and DA). All primary, secondary, and adverse event outcome measures were extracted verbatim from full-text articles and study protocols. Outcome measures were grouped into the following predefined categories: haemorrhage; coagulopathy; neurotoxicity; local tissue damage; renal injury; cardiotoxicity; myotoxicity; mortality; venom antigenaemia; additional antivenom requirement; functional status; scoring system; composite outcome; or other.
Data synthesis
After merging duplicate outcome measures, a data driven approach was used to classify them into domains. Each domain represented a grouping of outcomes that were deemed to be measuring a similar parameter. Consensus on domain allocations and domain names was reached by the primary authors. The characteristics of the studies and the outcome measures were summarised using descriptive statistics. The methodological quality of the primary and secondary outcome measures was assessed by the independent reviewers (MA and DA) using an established tool (as reported in S2 Text) [12]. The reviewers assessed whether each outcome measure was clearly stated; clearly defined; and patient-centred.
R version 4.0.3 was used for all analyses. The protocol was prospectively registered with PROSPERO (42020196160).
Results
Study screening
The database searches identified 2,421 studies, of which 687 were duplicates (Fig 1). Review of titles and abstracts identified 79 potentially eligible studies. All full texts were obtained and two required translation to English language. Searching of clinical trial registries identified two further protocols. Following full text review, 43 randomised controlled trials, 13 trial protocols and two published secondary analyses were included. Amongst the 13 included protocols, 6 had been terminated and 7 were ongoing. Two published secondary analyses [13,14] utilised data from the clinical trial published by Gerardo et al [15] and reported the additional outcome measures ‘opiate use’ and ‘the physical function domain of the SF-36 questionnaire’. Table 1 details the characteristics of all the included studies.
Characteristics of included randomised controlled trials
The proportion of randomised controlled trials conducted in each region were: Asia, 51·2% (n = 22 of 43); South America, 25·6% (n = 11); North America, 9·3% (n = 4); Africa, 9·3% (n = 4) (all in Nigeria); and Australasia, 4·7% (2) (Fig 2). The proportion published per decade were: 1960–69, 2·3% (n = 1 of 43); 1970–79, 2·3% (n = 1); 1980–89, 14·0% (n = 6); 1990–99, 27·9% (n = 12); 2000–09, 25·6% (n = 11); 2010–19, 25·6% (n = 11); and 2020, 2·3% (n = 1). Across the 43 trials, 3,418 participants were randomised. The mean sample size was 79 (IQR 41–100) and in 74·4% (n = 32 of 43) of studies the sample size was ≤100. The majority (55·8%; n = 24 of 43) were single centre studies, and the four trials with the greatest number of recruitment sites (range 7–28 sites) were conducted exclusively in Australia or the USA. Double blinding was adopted in 44·1% (n = 19 of 43); single blinding in 4·7% (n = 2); and 51·1% (n = 22) were open label. No pre-specified time-period of follow-up was defined in 55·8% (n = 24) trials. Among those where a follow-up period was reported (n = 19), 89.5% (n = 17) were for a period of 28 days or less; 5·3% (n = 1) were for 3-months; and 5·3% (n = 1) were for 6-months. Amongst trials published since January 2000 (N = 23), 43·5% (n = 10) reported a sample size calculation; 65·2% (n = 15) reported the numbers of participants screened for eligibility; and 43·5% (n = 10) were registered with a protocol available.
The area of each circle is proportionate to the total number of trial participants randomised per country in studies published between 1946 and 2020. The area of the segments of each circle are proportionate to the sample size of individual RCTs (e.g., there has been one large trial and three small trials conducted in Nigeria). Each circle overlies the country that it refers to. Where circles would overlap they have been moved, and the edge of the circle touches the corresponding country. The key demonstrates the samples size that corresponds to the surface area of two example circles. World map sourced from the Natural Earth project (1:50m resolution version) https://www.naturalearthdata.com.
In 74·4% (n = 32 of 43) of randomised controlled trials, a method of identifying the biting snake, to species, genus or sub-family taxonomic rank, was used. The majority of trials combined two or more methods for identifying the snake. In 55·8% (n = 24) of clinical trials, the morphology of the dead snake was opportunistically assessed (when the specimen was brought into hospital), although other less specific methods of identification were often relied upon in these trials, such as an assessment of the clinical syndrome of envenoming. The clinical syndrome of envenoming (together with valid assumptions of locally prevalent snake species) was used to predict the biting species in 37·2% (n = 16) of clinical trials. Enzyme immunoassay, the participant’s description of the snake’s appearance, or a photograph of the biting snake (taken by the participant or a bystander) were assessed in 32·6% (n = 14), 18·6% (n = 8) and 4·7% (n = 2) of clinical trials, respectively. The UpSet plot (Fig 3) demonstrates the size of intersections between the different methods of snake identification used across the 43 included clinical trials. Amongst trials which identified the biting snake (n = 32), these were Viperidae in 87·5% (n = 28) of studies, and Elapidae in 12·5% (n = 4) of studies. The most commonly studied snake genera were Bothrops (34·4%; n = 11), Daboia (15·6%; n = 5) and Echis (12·1%; n = 4).
Upper bar chart, x axis: combinations of snake identification methods; y axis: number of randomised controlled trials using each combination of snake identification methods. Lower left bar chart, x axis: total numbers of randomised controlled trials using each individual method of snake identification; y axis: individual methods of snake identification.
Participants with coagulopathy or haemorrhagic envenoming were studied in 81·4% of trials (n = 35 of 43); local tissue damage in 69·8% (n = 30); renal injury in 25·6% (n = 11); neurotoxicity in 20·9% (n = 9); and myotoxicity in 2·3% (n = 1). Different antivenom products were compared in 44·2% (n = 19) of trials; different doses of the same antivenom product were compared in 23·3% (n = 10) of trials. Antivenom was compared to placebo in 9·3% (n = 4) of trials; in all of these, participants with severe envenoming were excluded [15,16] or the biting species was known to be associated with limited clinical manifestations [17,18]. Other therapies that were compared were: heparin, 9·3% (n = 4) [19–22]; fresh frozen plasma, 4·7% (n = 2) [23,24]; atropine and edrophonium, 2·3% (n = 1) [25]; edrophonium and amifampridine, 2·3% (n = 1) [26]; intravenous immunoglobulin, 2·3% (n = 1) [27]; and ‘Qingwen Baidu Decoction’ (a traditional Chinese medicine), 2·3% (n = 1) [28].
Quality of outcome measures
Amongst the trials and protocols (n = 56), 50·0% (n = 28) had a clearly stated primary outcome. Amongst studies published since January 2000 (n = 36), 69·4% (n = 25) had a clearly stated primary outcome. 80·0% (n = 20) of primary outcomes were clearly defined; 64% (n = 16) were clinical endpoints and 36% (n = 9) were laboratory markers; and 4·0% (n = 1) were patient centred. Across the secondary outcome measures from studies published since January 2000 (n = 226), 64·6% (n = 146) were clearly defined; 56.6% (n = 128) were clinical endpoints, 38.9% (n = 88) were laboratory markers, and 4.4% (n = 10) were exploratory; and 4·9% (n = 11) were patient centred.
Outcome measures
Across the 58 included studies, 382 outcome measures were extracted verbatim and, after duplicates were merged, 153 unique outcomes were identified. 59·5% of unique outcome measures were unique to a single study; 18·3% were used in two studies; 5·9%, in three studies; 4·6%, in four studies; and 11·8% were used in five or more studies. There was no single outcome that was used across all the studies, and the most frequently used outcome domain (‘venom antigenaemia’) was included in 32·8% of studies (n = 19 of 58). Venom antigenaemia was measured using various assays; the majority of which are not commercially available. 39·8% of the 382 extracted outcome measures did not report a specific timing of measurement. Amongst those with a time-point, 35·7% were measured for less than 24 hours; 42·6%, for less than a week; 16·5%, for less than a month; and 5·2% for up to 6-months. A summary of the durations of follow-up of outcome measures, grouped by category of envenoming, are presented in Fig 4. Full extracted outcome measure data is available in (S1 Data).
Fig 4 depicts the time-period of follow-up of outcome measures within each category. For each outcome measure, the latest time point of follow-up was identified. Time points were grouped as: up to 24 hours; up to 7 days; up to 28 days; up to 3 months; and over 3 months. Within each category, the proportion of outcome measures with follow-up until each time-point is defined. For example, mortality outcome measures were always followed up for over 7 days but were never followed up for more than 28 days. No outcome measures were followed up until between 28 days and 3 months, and therefore this time point is not displayed in Fig 4.
The 28 primary outcome measures were categorised as follows: composite outcome, 8; coagulopathy, 6; neurotoxicity, 4; local tissue damage, 2; additional antivenom requirement, 1; functional status, 1; myotoxicity, 1; renal injury, 1; scoring system, 1; venom antigenaemia, 1; and other, 2. Table 1 summarises these primary outcomes, and includes the verbatim data extraction. The outcomes categorised as ‘other’ included one of antivenom hypersensitivity reaction [29] and one which was poorly defined [30]. The majority of primary outcome measures (82·1%) were unique to a single study. Amongst studies with shared primary outcome measures, three by Isbister et al adopted return of INR to less than two [23,24,31] and two studies measured duration of invasive ventilation [32,33].
For the remainder of the analysis herein, the 153 unique primary and secondary outcome measures will be considered together. Outcome measures were classified into 60 domains, and these are detailed in their corresponding categories in Table 2.
Outcome measures in the category ‘coagulopathy’ were included in 72·4% of studies (n = 42 of 58). An outcome measure in the ‘bedside clotting test’ domain was used in 51·7% (n = 30) of studies and, within this domain, 18 unique methods of measurement were identified. These included various iterations of the ‘20-minute whole blood clotting test’, ‘Lee White clotting time’ and ‘bleeding time’, which were used in 15, 12 and 2 studies, respectively. The next most widely used coagulation domains were ‘fibrinogen quantification’ (29·3%; n = 17), and ‘clotting studies’ (24·1%; n = 14).
Outcome measures in the category ‘haemorrhage’ were adopted in 31·0% of studies (n = 18 of 58) and were grouped into the following domains: ‘cessation of local or systemic bleeding’; ‘anaemia’; ‘ISTH defined major bleeding’ and ‘blood transfusion requirement’. The most widely used was ‘cessation of local or systemic bleeding’ which was adopted in 15·5% of studies (n = 9) and was measured in four unique ways.
Neurotoxicity outcome measures were reported in 24·1% of studies. Amongst the 14 studies that used a neurotoxicity outcome measure, the most widely used were ‘ptosis’ (42·9% of studies); ‘requirement for invasive ventilation’ (42·9% of studies); and ‘duration of invasive ventilation’ (28·6% of studies). ‘Electromyography’ was used in 14·3% and ‘spirometry’ was used in 7·1% of studies with a neurotoxicity outcome measure.
Renal injury outcome measures were adopted in 24·1% of studies (n = 14 of 58) and were predominantly based on measurements of creatinine or urine output, with various cut-offs for defining abnormal. 5·2% (n = 3) of studies adopted the RIFLE or KDIGO criteria for defining acute kidney injury [34,35] including one study where it formed a component of a composite outcome [36]. The proportion of participants requiring renal replacement therapy were measured in 10·3% of studies (n = 6); all conducted in India [19,22,34,37–39].
Outcome measures that assessed local tissue damage were adopted in 32·8% of studies (n = 19 of 58). ‘Development of skin blistering or necrosis’ and ‘swelling measured by circumference of bitten limb’ were the most widely used, being included in 15.5% of studies (n = 9). The ‘need for amputation, skin grafting or debridement’ outcome domain was only adopted in one study.
The ‘multipoint scale of physical function’ domain was the most widely adopted measure of ‘functional status’ and included eight functional scales (as reported in S3 Text). All of these were patient-centred outcomes and were used in three studies; all conducted in the USA [13,15,40]. A scoring system, the ‘snakebite severity score’ [41], was used in a single study [42]. Composite outcomes were included in 13 studies, and each of these were unique and represented the primary outcome measures (Table 1).
Adverse event outcome measures
Amongst the trials and protocols (n = 56), there was a failure to record adverse event outcomes in 32·1% (n = 18) of studies. A total of 69 adverse event outcome measures were extracted verbatim, and were grouped as follows: ‘anaphylaxis’, 18; ‘early hypersensitivity reactions’, 6; ‘non-specific early reactions, 19; ‘pyrogenic reactions’, 3; full adverse event reporting (reporting of all serious adverse events), 8; ‘transfusion-related acute lung injury’, 2; and ‘serum sickness’, 13. Anaphylaxis was defined based on published criteria in five trials or protocols [23,24,31,43,44]. Serum sickness was defined based on reproducible clinical criteria in one published randomised controlled trial, and one trial protocol [42,43].
Discussion
Outcome measures used in clinical trials of snakebite envenoming vary considerably. Although varied outcome measures are needed to capture the diverse effects of envenoming by different species, variations within an outcome domain are undesirable. To achieve the WHO target of reducing snakebite deaths and disability by 50%, clinical trial outcome measures must include either direct measures of clinically relevant events or validated surrogate markers that are known to be associated with risk of disability or death.
This systematic review also demonstrates the troubling landscape of clinical trials in snakebite. Many recent trials did not use a sample size calculation, were single centre and were underpowered. Few clinical trials have been conducted in sub-Saharan Africa or the Middle East. Policy makers and clinicians are faced with a disturbing lack of data on which to evaluate antivenoms. Similar to our findings amongst randomised controlled trials of antivenoms, pre-clinical efficacy testing has used heterogenous methods that in a number of cases prevent comparisons between studies [45]. There is an urgent need for standardisation in the way that antivenoms are assessed, both pre-clinically and clinically.
Of further concern, many of the included clinical trials used unreliable methods for identifying the biting snake species. As the efficacy of antivenom is often snake species specific, knowing the biting species is important. Although the majority of trials utilised an assessment of the morphology of the dead specimen brought to the hospital, this was invariably opportunistic. For those participants who did not attend with the dead specimen, less specific methods were largely relied upon. Amongst eight of the 43 included clinical trials, participants were asked to recall and describe the appearance of the snake, and in a further 11 clinical trials no efforts were made to identify the biting species. The clinical syndrome of envenoming was used to predict the biting species in 16 clinical trials and, although this method can be reliable in settings where a single species is the predominant cause of coagulopathy, such as parts of West Africa, this is not reliable in various other settings. Unfortunately, reliable identification of the biting species remains challenging, particularly in LMIC settings, and further development of enzyme immunoassay and molecular based methods for snake identification are urgently needed.
There have been just nine randomised controlled trials that have included participants with neurotoxicity, with a combined sample size of 492 [25–27,32,38,39,46–48]. All except one study [26] took place in Asia. Many studies adopted measures of eyelid strength or requirement for mechanical ventilation. Outcomes used in other neuromuscular disorders may be useful. For example, the ‘myasthenic muscle score’ is a validated 100-point scale used to assess therapeutic efficacy in myasthenia gravis [49,50]. A scoring system has the advantage of capturing weakness of various muscle groups and providing a semi-quantitative measure that may more sensitively detect response to therapeutics. Spirometry, including measurement of forced vital capacity, offers a potentially sensitive and quantifiable measure of respiratory muscle strength and was used in one included study [25], although its validity in other neuromuscular disorders has been disappointing [51]. For phase III clinical trials, pragmatic endpoints with high clinical relevance will be important, such as the proportion of participants requiring intubation and ventilation.
Bleeding events were often poorly defined with insufficient detail to allow consistent replication in future studies [19,52–54]. Bleeding due to snake envenoming tends to involve small volume blood loss from the bite site, gums, or venepuncture sites. Although the International Society on Thrombosis and Haemostasis (ISTH) definition [55] of haemorrhage [23,24,31,36], or laboratory-based measures of anaemia [56–59], provide objective tools, bleeding events of this severity are rare in snakebite envenoming [60]. Furthermore, measures of haematocrit or packed cell volume [56–59] may under-estimate anaemia due to the concentration effect of venom-induced capillary leak syndrome [61].
A range of laboratory assays were used to assess for coagulopathy, and it is uncertain which is the most useful. The bedside clotting tests do not require any specialist equipment and can be conducted in remote rural settings where the majority of snakebites occur. The Lee White clotting time was used exclusively in studies from South America and Asia [19,37,38,62–67], whereas the 20-minute whole blood clotting test (20WBCT) has been used more widely [20,34,47,52–54,56,59,68–71]. Although the 20WBCT has been subject to more frequent validation than the Lee White clotting time, this has rarely been amongst participants that have received antivenom [24,72,73] and, therefore, bedside tests of whole blood clotting are inadequately validated for measuring response to treatment. A disadvantage of the 20WBCT is that it is binary rather than continuous. Sensitive continuous outcome measures are desirable for smaller studies such as phase II clinical trials.
Renal injury can result from envenoming by a range of snake species [74]. Outcome measures in snakebite clinical trials have focussed on acute renal injury; based on various thresholds of serum creatinine and oliguria. Internationally recognised criteria for the diagnosis of acute kidney injury are available [75–77], and these were adopted in three of the included studies [34,35], including within one composite outcome [36]. Although the need for renal replacement therapy (RRT) is an important measure, there is wide variation and no consensus on the optimal timing for initiating and stopping this in acute kidney injury [78]. Follow-up studies of adults and children with snake venom induced renal injury have demonstrated a 30% risk of progression to chronic kidney disease [79,80]. Chronic kidney disease is defined as an abnormality in the structure or functioning of the kidneys present for a minimum of 3 months [81]. No outcome measures fulfilled this definition and the need for longer follow-up of renal function in clinical trials should be considered.
Snakebite associated local tissue damage represents a varied spectrum of disease, ranging from swelling to necrosis, with complications including infection, contractures, and amputation. Although this range of disease was captured across the extracted outcomes, this was inconsistent between studies. Consensus on a list of outcomes, including details of how they should be measured, is needed. For example, limb swelling has been measured by circumference [18,27,35,47,63], distance of proximal extension [40,58,59], or limb volume [40,82].
Complications of local tissue damage can cause loss of physical function with a varying impact depending on an individual’s circumstances. Many people with snakebite are vulnerable and disability may significantly impact on their ability to work, subsistence farm or care for children. Patient-centred outcomes are key for capturing this, but such outcomes were only adopted in trials based in the USA [13,15,40]. The patient specific functional scale (PSFS) is simple (although does require numeracy) and allows patients to identify functions that are important to them. This tool has been validated for snakebite envenoming [13], although not in an LMIC setting.
Adverse event reporting varied significantly between the randomised controlled trials, and 32·1% of the included studies failed to report adverse events. As antivenom is an animal derived product, there is a significant risk of life-threatening anaphylaxis, yet only five of the 56 included studies used standardised published criteria for defining anaphylaxis. Given that the risk of anaphylaxis can vary substantially between antivenom products [7,83], it is essential that the rate of occurrence of these events can be reliably and consistently measured in clinical trials. Serum sickness was only reported as an outcome measure in 13 of the 58 included studies, and only two studies used clearly defined clinical criteria [42,43]. A standardised definition of anaphylaxis and serum sickness should be included in a core outcome set.
Limitations
When considering outcome measures for use in a core outcome set, it is important to ascertain whether they are valid, reliable, and feasible. Such an assessment was outside the scope of this study and will form the next stage of COS development. This systematic review did not restrict on the age or quality of the trials; however, this was important to ensure all outcome measures were captured. When describing the characteristics and quality of trials, data for studies published more recently were presented. At this stage there has not been any patient involvement and future work on COS development will strive to involve people who have directly experienced snakebite.
Conclusions
This study has identified significant heterogeneity of outcome measures in snakebite clinical trials. There is a strong need for a core outcome set, which will support the adoption of valid, reproducible, and patient-centred outcome measures, and enable downstream meta-analyses. Validated outcome measures are particularly important when assessing antivenom efficacy, as this expensive therapy is associated with a relatively high risk of adverse events. To provide global relevance that can span the diversity of snake species, outcomes that represent each of the syndromes of envenoming are needed. Through better outcome measures, together with increased global recognition of the importance of snakebite envenoming, high quality clinical trials in populations with the greatest burden of disease can be achieved.
Supporting information
S2 Text. Tool to assess methodological quality of outcome measures.
https://doi.org/10.1371/journal.pntd.0009589.s002
(DOCX)
S3 Text. Summary of all extracted multipoint scales of physical function.
https://doi.org/10.1371/journal.pntd.0009589.s003
(DOCX)
References
- 1. Kasturiratne A, Wickremasinghe AR, de Silva N, Gunawardena NK, Pathmeswaran A, Premaratna R, et al. The Global Burden of Snakebite: A Literature Analysis and Modelling Based on Regional Estimates of Envenoming and Deaths. PLoS Medicine. 2008;5: e218. pmid:18986210
- 2. Casewell NR, Jackson TNW, Laustsen AH, Sunagar K. Causes and Consequences of Snake Venom Variation. Trends in Pharmacological Sciences. 2020;41: 570–581. pmid:32564899
- 3. Gutiérrez JM, Calvete JJ, Habib AG, Harrison RA, Williams DJ, Warrell DA. Snakebite envenoming. Nature Reviews Disease Primers. 2017;3: 17063. pmid:28905944
- 4. Halilu S, Iliyasu G, Hamza M, Chippaux J-P, Kuznik A, Habib AG. Snakebite burden in Sub-Saharan Africa: estimates from 41 countries. Toxicon. 2019;159: 1–4. pmid:30594637
- 5.
Global funding for snakebite envenoming research. [cited 6 Apr 2020]. Available: https://wellcome.ac.uk/sites/default/files/global-funding-for-snakebite-envenoming-research-2007-2018.pdf
- 6. Alirol E, Lechevalier P, Zamatto F, Chappuis F, Alcoba G, Potet J. Antivenoms for Snakebite Envenoming: What Is in the Research Pipeline? PLOS Neglected Tropical Diseases. 2015;9: e0003896. pmid:26355744
- 7. Potet J, Smith J, McIver L. Reviewing evidence of the clinical effectiveness of commercially available antivenoms in sub-Saharan Africa identifies the need for a multi-centre, multi-antivenom clinical trial. PLoS Negl Trop Dis. 2019;13: e0007551–e0007551. pmid:31233536
- 8. Lancet editorial. Snake-bite envenoming: a priority neglected tropical disease. The Lancet. 2017;390: 2.
- 9. Kirkham JJ, Davis K, Altman DG, Blazeby JM, Clarke M, Tunis S, et al. Core Outcome Set-STAndards for Development: The COS-STAD recommendations. PLOS Medicine. 2017;14: e1002447. pmid:29145404
- 10. Habib AG, Warrell DA. Antivenom therapy of carpet viper (Echis ocellatus) envenoming: Effectiveness and strategies for delivery in West Africa. Toxicon. 2013;69: 82–89. pmid:23339853
- 11. Maduwage K, Buckley NA, de Silva HJ, Lalloo DG, Isbister GK. Snake antivenom for snake venom induced consumption coagulopathy. Cochrane Database Syst Rev. 2015; CD011428. pmid:26058967
- 12. Harman NL, Bruce IA, Callery P, Tierney S, Sharif MO, O’Brien K, et al. MOMENT–Management of Otitis Media with Effusion in Cleft Palate: protocol for a systematic review of the literature and identification of a core outcome set using a Delphi survey. Trials. 2013;14: 70. pmid:23497540
- 13. Gerardo CJ, Vissoci JRN, de Oliveira LP, Anderson VE, Quackenbush E, Lewis B, et al. The validity, reliability and minimal clinically important difference of the patient specific functional scale in snake envenomation. PLoS One. 2019;14. pmid:30835744
- 14. Freiermuth C., Gerardo C.J., Lavonas E.J., Rapp-Olsson M., Kleinschmidt K.C., Sharma K., et al. Antivenom administration was associated with shorter duration of opioid use in copperhead envenomation patients. Academic Emergency Medicine. 2018;25: S89. pmid:29742308
- 15. Gerardo CJ, Quackenbush E, Lewis B, Rose SR, Greene S, Toschlog EA, et al. The Efficacy of Crotalidae Polyvalent Immune Fab (Ovine) Antivenom Versus Placebo Plus Optional Rescue Therapy on Recovery From Copperhead Snake Envenomation: A Randomized, Double-Blind, Placebo-Controlled, Clinical Trial. Annals of Emergency Medicine. 2017;70: 233–244.e3. pmid:28601268
- 16. Reid H.A., Thean P.C., Martin W.J. Specific antivenene and prednisone in viper-bite poisoning: Controlled trial. British medical Journal. 1963;2: 1378–1380. pmid:14063030
- 17. Sellahewa KH, Gunawardena G, Kumararatne MP. Efficacy of Antivenom in the Treatment of Severe Local Envenomation by the Hump-Nosed Viper (Hypnale hypnale). The American Journal of Tropical Medicine and Hygiene. 1995;53: 260–262. pmid:7573709
- 18. Rojnuckarin P, Chanthawibun W, Noiphrom J, Pakmanee N, Intragumtornchai T. A randomized, double-blind, placebo-controlled trial of antivenom for local effects of green pit viper bites. Transactions of the Royal Society of Tropical Medicine and Hygiene. 2006;100: 879–884. pmid:16466758
- 19. Paul V, Pudoor A, Earali J, John B, Anil Kumar CS, Anthony T. Trial of low molecular weight heparin in the treatment of viper bites. J Assoc Physicians India. 2007;55: 338–342. pmid:17844693
- 20. Na Swe T, Lwin M, Ei Han K, Tun T, Tun P. Heparin therapy in Russell’s viper bite victims with disseminated intravascular coagulation: a controlled trial. Southeast Asian J Trop Med Public Health. 1992;23: 282–287. pmid:1345132
- 21. Lwin M, Nu Swe T, Than T, Than T, Tun P. Heparin therapy in Russell’s viper bite victims with impending DIC (a controlled trial). Southeast Asian J Trop Med Public Health. 1989;20: 271–277. pmid:2532790
- 22. Paul V, Prahlad KA, Earali J, Francis S, Lewis F. Trial of heparin in viper bites. J Assoc Physicians India. 2003;51: 163–166. pmid:12725259
- 23.
Isbister GK. Randomised controlled trial of fresh frozen plasma to speed the recovering of venom induced consumption coagulopathy in patients with Russell’s Viper envenoming in Sri Lanka. 2008 Dec. Report No.: ACTRN12608000611325. Available: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=83196
- 24. Isbister GK, Buckley NA, Page CB, Scorgie FE, Lincz LF, Seldon M, et al. A randomized controlled trial of fresh frozen plasma for treating venom-induced consumption coagulopathy in cases of Australian snakebite (ASP-18). Journal of Thrombosis and Haemostasis. 2013;11: 1310–1318. pmid:23565941
- 25. Watt G., Theakston R.D.G., Hayes C.G. Positive response to edrophonium in patients with neurotoxic envenoming by cobras Naja naja philippinensis. A placebo-controlled study. New England Journal of Medicine. 1986;315: 1444–1448. pmid:3537783
- 26. Trevett AJ, Lalloo DG, Nwokolo NC, Naraqi S, Kevau IH, Theakston RDG, et al. Failure of 3,4-diaminopyridine and edrophonium to produce significant clinical benefit in neurotoxicity following the bite of Papuan taipan (Oxyuranus scutellatus canni). Transactions of the Royal Society of Tropical Medicine and Hygiene. 1995;89: 444–446. pmid:7570895
- 27. Sellahewa KH, Kumararatne MP, Dassanayake PB, Wijesundera A. Intravenous immunoglobulin in the treatment of snake bite envenoming: a pilot study. Ceylon Med J. 1994;39: 173–175. pmid:7728916
- 28. Miao Y, Chen M, Huang Z. Clinical observation on treatment of snake bite induced disseminated intravascular coagulation by qinwen baidu decoction. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2003;23: 590–592. pmid:14503057
- 29.
Gawarammana IB. A Randomized controlled trial on the safety of ICP-AVRI-UOP Sri Lankan polyspecific antivenom compared to Indian AVS in patients with snakebite. 2016 Jun. Report No.: SLCTR/2016/012. Available: https://slctr.lk/trials/slctr-2016-012
- 30. Mousavi SR. Phase 3, multi-center, randomized, two-arm, parallel, double blinded, active controlled for non-inferiority evaluation of efficacy and safety of snake anti-venom produced by Padra Serum Alborz in comparison with snake anti-venom produced by Razi Vaccine and Serum Research Institute in snakebite victims. 2020 Feb. Available: https://www.irct.ir/trial/41983
- 31. Isbister GK, Jayamanne S, Mohamed F, Dawson AH, Maduwage K, Gawarammana I, et al. A randomized controlled trial of fresh frozen plasma for coagulopathy in Russell’s viper (Daboia russelii) envenoming. J Thromb Haemost. 2017;15: 645–654. pmid:28106331
- 32. Sarin K, Dutta TK, Vinod KV. Clinical profile & complications of neurotoxic snake bite & comparison of two regimens of polyvalent anti-snake venom in its treatment. Indian J Med Res. 2017;145: 58–62. pmid:28574015
- 33.
Kularatne S. Low dose versus high dose of Indian polyvalent snake antivenom in reversing neurotoxic paralysis in common krait (Bungarus cearulus) bites: an open labeled randomised controlled clinical trial in Sri Lanka. 2010 Jul. Report No.: SLCTR/2010/006. Available: https://slctr.lk/trials/slctr-2010-006
- 34. Sagar P, Bammigatti C, Kadhiravan T, Harichandrakumar KT, Swaminathan RP, Reddy MM. Comparison of two Anti Snake Venom protocols in hemotoxic snake bite: A randomized trial. Journal of Forensic and Legal Medicine. 2020;73: 1–7. pmid:32658754
- 35.
Krishnan B. Clinical effects of N-acetylcysteine on acute kidney injury and other serious morbidities in childrenwith snake envenomation: A randomized double blind placebo controlled study. 2016 Oct. Report No.: CTRI/2016/10/007360. Available: http://ctri.nic.in/Clinicaltrials/pdf_generate.php?trialid=15943&EncHid=&modid=&compid=%27,%2715943det%27
- 36.
Isbister GK. Randomised controlled trial investigating the effects of early snake antivenom administration. 2015 Mar. Report No.: ACTRN12615000264583. Available: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=367828
- 37. Thomas P, Jacob J. Randomised trial of antivenom in snake envenomation with prolonged clotting time. British Medical Journal. 1985;291: 177–178. pmid:3926113
- 38. Paul V, Pratibha S, Prahlad K, Earali J, Francis S, Lewis F. High-dose anti-snake venom versus low-dose anti-snake venom in the treatment of poisonous snake bites—a critical study. J Assoc Physicians India. 2004;52: 14–17. pmid:15633711
- 39. Tariang D, Philip P, Alexander G, Macaden S, Jeyaseelan L, Peter J, et al. Randomized controlled trial on the effective dose of anti-snake venom in cases of snake bite with systemic envenomation. J Assoc Physicians India. 1999;47: 369–371. pmid:10778516
- 40.
Kerns W. The Efficacy of Crotaline Fab Antivenom for Copperhead Snake Envenomations. clinicaltrials.gov; 2006 Mar. Report No.: NCT00303303. Available: https://clinicaltrials.gov/ct2/show/NCT00303303
- 41. Dart RC, Hurlbut KM, Garcia R, Boren J. Validation of a Severity Score for the Assessment of Crotalid Snakebite. Annals of Emergency Medicine. 1996;27: 321–326. pmid:8599491
- 42. Dart RC, Seifert SA, Boyer LV, Clark RF, Hall E, McKinney P, et al. A randomized multicenter trial of crotalinae polyvalent immune Fab (ovine) antivenom for the treatment for crotaline snakebite in the United States. Arch Intern Med. 2001;161: 2030–2036. pmid:11525706
- 43.
Isbister GK. A multicentre double-blind randomised placebo-controlled trial of early antivenom versus placebo in the treatment of red bellied black snake envenoming. 2011 Jun. Report No.: ACTRN12611000588998. Available: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=343001
- 44.
Lamb T. An Adaptive Clinical Trial to Determine the Optimal Initial Dose of Lyophilized, Species Specific Monovalent Antivenom for the Management of Systemic Envenoming by Daboia Siamensis (Eastern Russell’s Viper) in Myanmar. clinicaltrials.gov; 2020 Sep. Report No.: NCT04210141. Available: https://clinicaltrials.gov/ct2/show/NCT04210141
- 45. Ainsworth S, Menzies SK, Casewell NR, Harrison RA. An analysis of preclinical efficacy testing of antivenoms for sub-Saharan Africa: Inadequate independent scrutiny and poor-quality reporting are barriers to improving snakebite treatment and management. PLOS Neglected Tropical Diseases. 2020;14: e0008579. pmid:32817682
- 46. Watt G, Meade BD, Theakston RD, Padre LP, Tuazon ML, Calubaquib C, et al. Comparison of Tensilon and antivenom for the treatment of cobra-bite paralysis. Trans R Soc Trop Med Hyg. 1989;83: 570–573. pmid:2694492
- 47. Ariaratnam C.A., Sjostrom L., Raziek Z., Abeyasinghe S., Kularatne M., Arachchi R.W.K.K., et al. An open, randomized comparative trial of two antivenoms for the treatment of envenoming by Sri Lankan Russell’s viper (Daboia russelii russelii). Transactions of the Royal Society of Tropical Medicine and Hygiene. 2001;95: 74–80. pmid:11280073
- 48. Alirol E, Sharma SK, Ghimire A, Poncet A, Combescure C, Thapa C, et al. Dose of antivenom for the treatment of snakebite with neurotoxic envenoming: Evidence from a randomised controlled trial in Nepal. PLoS Negl Trop Dis. 2017;11: e0005612. pmid:28510574
- 49. Barnett C, Herbelin L, Dimachkie MM, Barohn RJ. Measuring Clinical Treatment Response in Myasthenia Gravis. Neurol Clin. 2018;36: 339–353. pmid:29655453
- 50. Sharshar T, Chevret S, Mazighi M, Chillet P, Huberfeld G, Berreotta C, et al. Validity and reliability of two muscle strength scores commonly used as endpoints in assessing treatment of myasthenia gravis. J Neurol. 2000;247: 286–290. pmid:10836621
- 51. Rieder P, Louis M, Jolliet P, Chevrolet J-C. The repeated measurement of vital capacity is a poor predictor of the need for mechanical ventilation in myasthenia gravis. Intensive Care Med. 1995;21: 663–668. pmid:8522671
- 52. Pardal PP de O, Souza SM, Monteiro MR de C da C, Fan HW, Cardoso JLC, França FOS, et al. Clinical trial of two antivenoms for the treatment of Bothrops and Lachesis bites in the north eastern Amazon region of Brazil. Trans R Soc Trop Med Hyg. 2004;98: 28–42. pmid:14702836
- 53. Otero-Patiño R, Segura A, Herrera M, Angulo Y, León G, Gutiérrez JM, et al. Comparative study of the efficacy and safety of two polyvalent, caprylic acid fractionated [IgG and F(ab’)2] antivenoms, in Bothrops asper bites in Colombia. Toxicon. 2012;59: 344–355. pmid:22146491
- 54. Cardoso JL, Fan HW, França FO, Jorge MT, Leite RP, Nishioka SA, et al. Randomized comparative trial of three antivenoms in the treatment of envenoming by lance-headed vipers (Bothrops jararaca) in São Paulo, Brazil. Q J Med. 1993;86: 315–325. pmid:8327649
- 55. Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3: 692–694. pmid:15842354
- 56. Abubakar IS, Abubakar SB, Habib AG, Nasidi A, Durfa N, Yusuf PO, et al. Randomised controlled double-blind non-inferiority trial of two antivenoms for saw-scaled or carpet viper (Echis ocellatus) envenoming in Nigeria. PLoS Negl Trop Dis. 2010;4: e767. pmid:20668549
- 57. Warrell DA, Warrell MJ, Edgar W, Prentice CR, Mathison J, Mathison J. Comparison of Pasteur and Behringwerke antivenoms in envenoming by the carpet viper (Echis carinatus). Br Med J. 1980;280: 607–609. pmid:7370603
- 58. Warrell D, Davidson N, Omerod L, Pope H, Watkins B, Greenwood B, et al. Bites by the saw-scaled or carpet viper (Echis carinatus): trial of two specific antivenoms. Br Med J. 1974;4: 437–440. pmid:4154124
- 59. Warrell D.A., Looareesuwan S., Theakston R.D.G. Randomized comparative trial of three monospecific antivenoms for bites by the Malayan pit viper (Calloselasma rhodostoma) in Southern Thailand: Clinical and laboratory correlations. American Journal of Tropical Medicine and Hygiene. 1986;35: 1235–1247. pmid:3538922
- 60. Lavonas EJ, Khatri V, Daugherty C, Bucher-Bartelson B, King T, Dart RC. Medically significant late bleeding after treated crotaline envenomation: a systematic review. Ann Emerg Med. 2014;63: 71–78.e1. pmid:23567063
- 61. Kendre PP, Jose MP, Varghese AM, Menon JC, Joseph JK. Capillary leak syndrome in Daboia russelii bite—a complication associated with poor outcome. Transactions of The Royal Society of Tropical Medicine and Hygiene. 2018;112: 88–93. pmid:29584906
- 62. Mendonça-da-Silva I, Tavares AM, Sachett J, Sardinha JF, Zaparolli L, Gomes Santos MF, et al. Safety and efficacy of a freeze-dried trivalent antivenom for snakebites in the Brazilian Amazon: An open randomized controlled phase IIb clinical trial. Calvete JJ, editor. PLOS Neglected Tropical Diseases. 2017;11: e0006068. pmid:29176824
- 63. Jorge MT, Cardoso JLC, Castro SCB, Ribeiro L, Franca F.OS, Sbrogio de Almeida ME, et al. A randomized “blinded” comparison of two doses of antivenom in the treatment of Bothrops envenoming in Sao Paulo, Brazil. Transactions of the Royal Society of Tropical Medicine and Hygiene. 1995;89: 111–114. pmid:7747293
- 64. Otero-Patino R, Cardoso JLC, Higashi HG, Nunez V, Diaz A, Toro MF, et al. A randomized, blinded, comparative trial of one pepsin-digested and two whole IgG antivenoms for Bothrops snake bites in Uraba, Colombia. American Journal of Tropical Medicine and Hygiene. 1998;58: 183–189. pmid:9580075
- 65. Otero R, Gutiérrez JM, Rojas G, Núñez V, Díaz A, Miranda E, et al. A randomized blinded clinical trial of two antivenoms, prepared by caprylic acid or ammonium sulphate fractionation of IgG, in Bothrops and Porthidium snake bites in Colombia: correlation between safety and biochemical characteristics of antivenoms. Toxicon. 1999;37: 895–908. pmid:10340829
- 66. Srimannarayana J, Dutta TK, Sahai A, Badrinath S. Rational use of anti-snake venom (ASV): trial of various regimens in hemotoxic snake envenomation. J Assoc Physicians India. 2004;52: 788–793. pmid:15909856
- 67. Otero R, Gutiérrez JM, Núñez V, Robles A, Estrada R, Segura E, et al. A randomized double-blind clinical trial of two antivenoms in patients bitten by Bothrops atrox in Colombia. The Regional Group on Antivenom Therapy Research (REGATHER). Trans R Soc Trop Med Hyg. 1996;90: 696–700. pmid:9015522
- 68. Meyer WP, Habib AG, Onayade AA, Yakubu A, Smith DC, Nasidi A, et al. First clinical experiences with a new ovine Fab Echis ocellatus snake bite antivenom in Nigeria: randomized comparative trial with Institute Pasteur Serum (Ipser) Africa antivenom. Am J Trop Med Hyg. 1997;56: 291–300. pmid:9129531
- 69. Smalligan R, Cole J, Brito N, Laing GD, Mertz BL, Manock S, et al. Crotaline snake bite in the Ecuadorian Amazon: randomised double blind comparative trial of three South American polyspecific antivenoms. BMJ. 2004;329: 1129. pmid:15539665
- 70. Otero R, León G, Gutiérrez JM, Rojas G, Toro MF, Barona J, et al. Efficacy and safety of two whole IgG polyvalent antivenoms, refined by caprylic acid fractionation with or without beta-propiolactone, in the treatment of Bothrops asper bites in Colombia. Trans R Soc Trop Med Hyg. 2006;100: 1173–1182. pmid:16698053
- 71. Qureshi H, Alam SE, Mustufa MA, Nomani NK, Asnani JL, Sharif M. Comparative cost and efficacy trial of Pakistani versus Indian anti snake venom. J Pak Med Assoc. 2013;63: 1129–1132. pmid:24601191
- 72. Thongtonyong N, Chinthammitr Y. Sensitivity and specificity of 20-minute whole blood clotting test, prothrombin time, activated partial thromboplastin time tests in diagnosis of defibrination following Malayan pit viper envenoming. Toxicon. 2020;185: 188–192. pmid:32712023
- 73. Ratnayake I, Shihana F, Dissanayake DM, Buckley NA, Maduwage K, Isbister GK. Performance of the 20-minute whole blood clotting test in detecting venom induced consumption coagulopathy from Russell’s viper (Daboia russelii) bites. Thromb Haemost. 2017;117: 500–507. pmid:28150853
- 74. Waiddyanatha S, Silva A, Siribaddana S, Isbister GK. Long-term Effects of Snake Envenoming. Toxins (Basel). 2019;11. pmid:30935096
- 75. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney inter, Suppl. 2012;2: 1–138.
- 76. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P, Acute Dialysis Quality Initiative workgroup. Acute renal failure—definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8: R204–212. pmid:15312219
- 77. Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007;11: R31. pmid:17331245
- 78. Palevsky PM, Metnitz PGH, Piccinni P, Vinsonneau C. Selection of endpoints for clinical trials of acute renal failure in critically ill patients. Current Opinion in Critical Care. 2002;8: 515–518. pmid:12454535
- 79. Sinha R, Nandi M, Tullus K, Marks SD, Taraphder A. Ten-year follow-up of children after acute renal failure from a developing country. Nephrol Dial Transplant. 2009;24: 829–833. pmid:18852189
- 80. Herath HMNJ, Wazil AWM, Abeysekara DTDJ, Jeewani NDC, Weerakoon KG a. D, Ratnatunga NVI, et al. Chronic kidney disease in snake envenomed patients with acute kidney injury in Sri Lanka: a descriptive study. Postgrad Med J. 2012;88: 138–142. pmid:22282736
- 81. Kidney Disease: Improving Global Outcomes (KDIGO). KDIGO Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. 2013 [cited 2 Oct 2020]. Available: https://kdigo.org/wp-content/uploads/2017/02/KDIGO_2012_CKD_GL.pdf
- 82. Ghorbani A. Determination of injective dexamethasone efficacy associate with anti venum in decrease of limb edema in snake bite patients. 2013 May. Available: https://en.irct.ir/trial/12056
- 83. Moran NF, Newman WJ, Theakston RDG, Warrell DA, Wilkinson D. High incidence of early anaphylactoid reaction to SAIMR polyvalent snake antivenom. Transactions of The Royal Society of Tropical Medicine and Hygiene. 1998;92: 69–70. pmid:9692158
- 84. Theakston RD, Fan HW, Warrell DA, Da Silva WD, Ward SA, Higashi HG. Use of enzyme immunoassays to compare the effect and assess the dosage regimens of three Brazilian Bothrops antivenoms. The Butantan Institute Antivenom Study Group (BIASG). The American journal of tropical medicine and hygiene. 1992;47: 593–604. pmid:1449200
- 85. Bush SP, Ruha A-M, Seifert SA, Morgan DL, Lewis BJ, Arnold TC, et al. Comparison of F(ab’)2 versus Fab antivenom for pit viper envenomation: a prospective, blinded, multicenter, randomized clinical trial. Clin Toxicol (Phila). 2015;53: 37–45. pmid:25361165
- 86. Boyer LV, Chase PB, Degan JA, Figge G, Buelna-Romero A, Luchetti C, et al. Subacute coagulopathy in a randomized, comparative trial of Fab and F(ab’)2 antivenoms. Toxicon. 2013;74: 101–108. pmid:23948058
- 87.
Jensen S. A randomized controlled trial (RCT) of a new monovalent antivenom (ICP Papuan taipan antivenom) for the treatment of Papuan taipan (Oxyuranus scutellatus) envenoming in Papua New Guinea to measure safety, minimum dose and effectiveness in the prevention of neurotoxic paralysis, arrest of coagulopathy and other effects of envenoming. 2012 Oct. Report No.: ACTRN12612001062819. Available: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=361999
- 88.
Grais R. Randomized, Double-blind, Non-inferiority Trial of Two Antivenoms for the Treatment of Snakebite With Envenoming. clinicaltrials.gov; 2016 Mar. Report No.: NCT02694952. Available: https://clinicaltrials.gov/ct2/show/NCT02694952
- 89.
Garcia W. Multicentric, Randomized,Controlled and Comparative Study to Evaluate the Efficacy of Two Treatment Schemes With Antivipmyn ® for the Treatment of Snake Bite Envenomation. clinicaltrials.gov; 2008 Mar. Report No.: NCT00639951. Available: https://clinicaltrials.gov/ct2/show/NCT00639951