Snake antivenom for snake venom induced consumption coagulopathy
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effects of antivenom for the recovery from venom induced consumption coagulopathy in people with snake envenoming.
Background
Description of the condition
Snake envenoming is a major medical problem in the tropical world. The estimated burden of snake bite is approximately 421,000 cases of envenoming with 20,000 fatalities annually, although there may be as many as 1,841,000 envenomings and 94,000 deaths (Kasturiratne 2008).
Venom induced consumption coagulopathy is one of the major clinical manifestations of snake envenoming and may be complicated by fatal haemorrhage (Isbister 2010a). Venom induced consumption coagulopathy has previously been referred to by a number of different terms, including disseminated intravascular coagulation, defibrination syndrome and procoagulant coagulopathy (Isbister 2010b). Venom induced consumption coagulopathy results from the action of snake procoagulant toxins on human coagulation factors causing consumption of these clotting factors leading to multiple factor deficiencies (Isbister 2009a). There are many examples of procoagulant snake toxins that cause venom induced consumption coagulopathy, including prothrombin activators in Echis carinatus, Pseudonaja textilis, Notechis scutatus venoms (Rosing 1992; Joseph 2001; Rosing 2001), factor X activators in Dabois russelii, Bothrops atrox, Cerastes cerastes, Bungarus, Ophiophagus venom (Tans 2001), factor V activators in Bothrops atrox, Naja naja oxiana, Vipera venom (Rosing 2001), thrombin‐like enzymes in Agkistrodon contortrix contortrix venom (Swenson 2005), and plasminogen activators in Trimeresurus stejnegeri venom (Sanchez 2006). Venom induced consumption coagulopathy can result in bleeding if there is trauma or spontaneous haemorrhage in cases where the venom also contains a haemorrhagin (e.g. E. carinatus). Major haemorrhage in vital organs, such as intracranial haemorrhage, is the most serious issue and is often fatal.
A number of laboratory clotting times and clotting factor studies are used to diagnose and monitor venom induced consumption coagulopathy, including the prothrombin time/international normalised ratio, the activated partial thromboplastin time, and the 20‐minute whole blood clotting test. These play a major role in diagnosis, assessment and treatment of venom induced consumption coagulopathy (Isbister 2010a).
Description of the intervention
Antivenom is the primary treatment for snake envenoming (Lalloo 2003; Isbister 2010c). Antivenoms contain polyclonal antibodies raised against one or more snake venoms. They may contain whole immunoglobulins, but more commonly, pepsin or papain digested fragments of immunoglobulins such as F(ab')2 or Fab. They are made by injecting venom into either horses, sheep or goats, and then collecting blood and separating out the specific antibodies to the snake venom. Intravenous administration of antivenom to patients with snake envenoming binds to circulating snake toxins which aims to neutralise or eliminate the toxins and therefore prevent or reverse the clinical effects of envenoming. Monovalent antivenoms are raised against a single snake species, while polyvalent antivenoms are raised against more than one species.
Immediate hypersensitivity reactions to the foreign proteins (immunoglobulins) in snake antivenoms are the major adverse effect of antivenom treatment, including life threatening anaphylaxis (Nuchprayoon 1999; Lalloo 2003; Gawarammana 2004; de Silva 2011; Isbister 2012). Manufacturing protocols and methods of snake antivenoms are different in various regions in the world and the standardisation of snake antivenom production remains problematic.
How the intervention might work
Antibodies in the antivenom bind to the toxic components in snake venom. Early administration of antivenom will bind the circulating procoagulant snake toxins and potentially prevent, delay or lessen the severity of venom induced consumption coagulopathy. In the majority of patients who have already developed venom induced consumption coagulopathy, antivenom is used to neutralise circulating toxins and allow recovery of venom induced consumption coagulopathy. However, the effectiveness and mechanism of action of antivenom in already developed venom induced consumption coagulopathy remains unclear (Isbister 2009b). Recovery of the coagulopathy depends on re‐synthesising clotting factors which is not directly affected by antivenom administration (Isbister 2010a).
Why it is important to do this review
Even though snake antivenom is the mainstay of the treatment for snake envenoming, there is controversy regarding the effectiveness of antivenom for venom induced consumption coagulopathy (Isbister 2010a). It is unlikely that antivenom can be administered early enough to prevent venom induced consumption coagulopathy because the procoagulant toxins in snake venoms act rapidly (Isbister 2010a). The more important question is whether the administration of antivenom will speed the recovery of venom induced consumption coagulopathy by inactivating the active toxins to allow re‐synthesis of clotting factors (Isbister 2010a). Recent observational clinical studies on Australian elapid envenomation, indicated that neither early (versus late) antivenom nor higher doses of antivenom (> one vial) were associated with more rapid recovery in venom induced consumption coagulopathy (Allen 2009; Isbister 2009b). In contrast, in Echis envenomation in Africa, the use of antivenom does appear to speed the recovery of the coagulopathy (Mion 2013). We aim to examine the clinical trial evidence regarding effectiveness of snake antivenom for venom induced consumption coagulopathy from all snake species.
Objectives
To assess the effects of antivenom for the recovery from venom induced consumption coagulopathy in people with snake envenoming.
Methods
Criteria for considering studies for this review
Types of studies
All randomised controlled trials (RCTs) in humans.
Types of participants
People of any age with snake envenoming who have already developed snake venom induced consumption coagulopathy. Diagnosis of venom induced consumption coagulopathy must be based on positive results from the 20‐minute whole blood clotting test and/or elevated international normalised ratio of < 2.
Types of interventions
Intravenous administration of snake antivenom regardless of the type of antivenom or the dose. People who were not treated with antivenom will be the comparison group.
Types of outcome measures
Primary outcomes
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Mortality
Secondary outcomes
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Major haemorrhages
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Time to improve clotting studies (e.g. time to international normalised ratio < 2; time to improve 20‐minute whole blood clotting test)
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Immediate systemic hypersensitivity reactions
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Serum sickness
Calculation of information size requirements
Snakebite mortality is very variable and has contributors other than venom induced consumption coagulopathy such as neurotoxicity, myotoxicty and acute renal injury. However, for simplicity we have taken the mortality rate from Kasturiratne 2008, which estimates an overall case‐fatality of around 5%. Using G*Power (http://www.gpower.hhu.de/en.html), the estimated sample size required in order to show this rate could be halved would require 2504 people in total.
Search methods for identification of studies
In order to reduce publication and retrieval bias we will not restrict our search by language, date or publication status.
Electronic searches
The Cochrane Injuries Group's Trials Search Co‐ordinator will search the following:
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Cochrane Injuries Group Specialised Register (latest version);
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The Cochrane Central Register of Controlled Trials (The Cochrane Library) (latest issue);
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Ovid MEDLINE(R), Ovid MEDLINE(R) In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R) 1946 to present;
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EMBASE Classic + EMBASE (OvidSP) 1947 to present;
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ISI Web of Science: Science Citation Index Expanded (1970 to present);
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ISI Web of Science: Conference Proceedings Citation Index‐Science (1990 to present);
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Current Awareness in Clinical Toxicology (latest update);
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Toxicology Literature Online (TOXLINE) (http://toxnet.nlm.nih.gov/cgi‐bin/sis/htmlgen?TOXLINE) (latest version);
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ClinicalTrials.gov (https://clinicaltrials.gov/);
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World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) Search Portal (http://apps.who.int/trialsearch/);
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OpenGrey (http://www.opengrey.eu/).
We will adapt the MEDLINE search strategy illustrated in Appendix 1 as necessary for each of the other databases. We will also incorporate search filters which are the modified version of the 'Cochrane Highly Sensitive Search Strategies for identifying randomized trials in MEDLINE' and to the EMBASE search strategy we will use 'Search filters for identifying randomized trials in EMBASE' as indicated in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Searching other resources
We will search the reference lists of all relevant studies and contact experts in the field in order to identify ongoing and completed studies. We will also run a search on Google and Google Scholar restricting the search results from 1947 to present, and will review at least 500 results to find relevant studies (Appendix 1).
Data collection and analysis
We will perform a systematic review following the instructions given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Selection of studies
Two authors (KM and GI) will independently scan the titles and abstracts of all articles identified by the search strategy. If either or both authors identifies the article as possibly being a report that meets the inclusion criteria, we will obtain the full text of the published article. Both authors will review the full text of each article to determine if the article meets the inclusion criteria. We will resolve disagreement between two authors at this stage by consensus. We will provide details of included and excluded studies in the appropriate tables with the review.
The two authors will independently review each article that meets inclusion criteria, and extract data from the article onto a standard data extraction form. We will then compare these data forms. In the event of disagreement between the authors, we will seek the opinion of a third author (NB). For ambiguous studies and where there are insufficient data, we will attempt to contact the authors of the articles for further clarification and more information. We will grade the studies for quality, using the instructions given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Data extraction and management
Two authors (KM and GI) will extract data on the following items onto a standard form.
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General information about the article (title of the article, source, publication year, years the study was conducted, language of publication, etc.).
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Clinical trial characteristics: design, diagnostic ascertainment, standard care provided, randomisation, allocation concealment, interventions, drop‐out and lost to follow up rates, definitions of outcomes, and methods of outcome assessment.
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Patients: inclusion and exclusion criteria, sample size, base line characteristics (e.g. age of the patients, past history of bleeding, anticoagulant therapy or coagulation disorders, clinical severity on enrolment etc.).
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Interventions: type of antivenom (polyvalent or monovalent), manufacturer, dose of antivenom (number of vials or mg), duration of administration, timing of administration of antivenom after the bite.
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Outcomes: mortality, major haemorrhage (according to the definition by the International Society on Thrombosis and Haemostasis), time to improved clotting function defined as either the time to international normalised ratio < 2 or time until a negative result of the 20‐minute whole blood clotting test, length of hospital stay, systemic hypersensitivity reactions.
Assessment of risk of bias in included studies
Two authors (KM and GI) will independently assess the included studies for risk of bias in the following areas. We will assess risk of bias using the suggested domains and guidance provided in the Cochrane Collaboration's tool for assessing risk of bias (Higgins 2011). We will assess random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attribution bias), selective reporting (reporting bias), and other sources of bias (in particular, funding source). If there is insufficient information we will initially judge domains as "unclear risk" and will attempt to clarify the risk of bias by contacting the study authors. We plan to include all studies irrespective of the risk of bias; however, we plan to perform a sensitivity analysis. If the sensitivity analysis shows substantial differences, we will present alternative estimates that exclude studies with high or unclear risk of bias.
Sequence generation of the randomisation process
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Low risk: using random number tables, computer random number generation, coin tossing, stratified or block randomisation, shuffling cards or envelopes, throwing dice, drawing lots or other valid methods
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High risk: "quasi" randomisation, date of birth, day of visit, identification number or record results, alternate allocation
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Unclear risk: not described or not enough information to make a clear judgement
Allocation concealment
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Low risk: allocation concealment is described and would not allow either the investigator or participants to know or influence treatment group assignment at the time of study entry
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Acceptable methods include central randomisation (phone, web, pharmacy) or sequentially numbered, opaque sealed envelopes
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High risk: the method of allocation is not concealed (e.g. random sequence known to staff in advance, envelopes or packaging with out all safeguards or a non‐randomised and predictable sequence)
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Unclear risk: trial either did not describe the method of allocation concealment or reported an approach that clearly was not adequate
Blinding of participants and personnel
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Low risk: blinding, and unlikely that the blinding could have been broken, or no blinding, or incomplete blinding but outcome unlikely to be influenced
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High risk: no blinding, incomplete or broken blinding and outcome likely to be influenced
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Unclear risk: not described or not enough information to make a clear judgment
Blinding of outcome assessment
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Low risk: Blinding of outcome assessors was clearly maintained, or no blinding but measurements unlikely to be influenced
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High risk: no blinding, or broken blinding, and measurements likely to be influenced
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Unclear risk: not described or not enough information to make a clear judgment
Intention‐to‐treat analysis
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Low risk: Specifically reported that intention‐to‐treat analysis was undertaken by the authors, or report that makes it unmistakable that intention‐to‐treat was undertaken for the primary analysis
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High risk: No report of an intention‐to‐treat analysis being conducted
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based on an intention‐to‐treat analysis
Incomplete outcome data
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Low risk: No missing data, reasons for missing data not related to outcomes, missing data balanced across groups and proportion missing or plausible effect size not enough to have a clinically relevant effects
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High risk: reasons related to outcome and imbalance in number or reasons, proportions missing or plausible effect size enough to have clinically relevant effect, "as treated" analysis with substantial departure from allocation, inappropriate use of imputation
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Unclear risk: not described or not enough information to make a clear judgment
Selectiveness of outcome reporting
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Low risk: method is available and all pre‐specified outcomes of interest are reported in the pre‐specified way, protocol not available but it is clear that all pre‐specified and expected outcomes of interest are reported
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High risk: outcomes not reported as pre‐specified or expected e.g. missing, added, subset, unexpected measurement or methods. Outcomes reported incomplete and cannot enter a meta‐analysis
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Unclear risk: not described or not enough information to make a clear judgment
Reporting bias
Methods for dealing with reporting bias in reviews of diagnostic accuracy studies are relatively underdeveloped. Consequently, we will interpret our results cautiously and with an awareness of the likelihood of reporting bias. We will consider using funnel plots.
Other sources of bias
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Low risk: Studies appears to be free of other sources of bias such as imprecision (e.g. small sample size), diversity (e.g. inadequate dose, unusual population)
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High risk: baseline imbalance, blocked randomisation in unblinded trials, non‐randomised studies, recruitment bias in cluster‐randomised trials
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Unclear risk: not described or not enough information to make a clear judgment
Measures of treatment effect
Dichotomous data
We will present dichotomous data outcomes as risk ratios (RRs) with 95% confidence intervals (CIs) for individual trials.
Continuous data
We will present continuous data outcomes with mean differences (MDs) and 95% CIs. We will calculate mean difference if possible as these results are easier for clinicians and readers to interpret; we will use standardised mean differences (SMDs) when different scales are used in the trials.
Ordinal data
We will report the types of adverse events and complications.
Unit of analysis issues
Individual participants are the unit of analysis. To answer our primary question (does antivenom improve venom induced consumption coagulopathy compared to no antivenom treatment) we will in the first instance simply combine all active intervention groups of the study into a single group and compare their outcomes to the control groups(s) not receiving antivenom. We may also explore comparison of doses or types of antivenom (post‐hoc).
Dealing with missing data
We will contact the authors of the original studies if essential data are missing from their trial reports. If we receive no reply after eight weeks, we will extract the available data from the published reports. We will assess the missing data and attrition rates for each of the included studies and report the number of participants who are included in the final analysis as a proportion of all participants in the study.
Assessment of heterogeneity
We will evaluate statistical heterogeneity using the Chi2 test to assess for heterogeneity between trials, and the I2 statistics for quantifying heterogeneity across studies (roughly interpreted as follows: 0 to 30%: probably not important; 31 to 60%: may represent moderate heterogeneity; 61 to 75%: may represent substantial heterogeneity; 76 to 100%: very considerable heterogeneity) as outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We expect considerable heterogeneity due to considerable variation across trials in setting, snake, intervention and outcomes. We intend to use a random effects model to account for this heterogeneity in any summary estimates of effect. We may also (post‐hoc) look for plausible explanations of heterogeneity. We will discuss the implications of heterogeneity and how they relate to external validity in the discussion.
Assessment of reporting biases
Systematic difference between reported and unreported findings are referred to as reporting bias. We will include selective outcome reporting assessment as part of the 'Risk of bias table' and also under 'Intention‐to‐treat analysis' (Assessment of risk of bias in included studies).
We will assess publication biases by using funnel plots when there are at least 10 studies included in the meta‐analysis.
Data synthesis
We will analyse the data using the Cochrane Collaboration statistical software, Review Manager 2014. We will express results for dichotomous outcomes as RRs with 95% CIs and continuous outcomes as MDs. We will present data in a 'Summary of findings' table according to Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines as well as the method described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). The table will include mortality, major haemorrhages, time to improved clotting (e.g. time to international normalised ratio < 2 or time to normalised result of the 20‐min whole blood clotting test), immediate systemic hypersensitivity reactions and serum sickness as outcomes.
We will present dichotomous outcomes such as mortality, number of haemorrhages, number of immediate type hypersensitivity reactions, number of cases of serum sickness as RRs with 95% CIs for individual trials. For dichotomous data meta‐analysis we will use a Mantel‐Haenszel random‐effects model. For continuous outcomes (time to improve clotting studies) that have been recorded as MDs, SMDs or standard deviations (SDs) with 95% CIs, we will use an inverse variance random‐effects model. If we find two or more studies assessing the same outcomes we will perform meta‐analysis. If meta‐analysis is not possible we will write a narrative summary of the study findings and follow alternative methods as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Subgroup analysis and investigation of heterogeneity
Where possible (if sufficient data and information are available) we will perform subgroup analysis based on the following factors, which are thought to affect outcomes after venom induced consumption coagulopathy:
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type of snake envenoming (elapids and viperids);
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type of snake antivenoms;
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dose of antivenom.
Sensitivity analysis
We will restrict sensitivity analyses to include studies with both adequate allocation concealment and blinded outcome assessment.
