Table 2

Core outcome set (COS) for intervention research on different intervention types

COS for research on interventions that prevent adverse reaction to snake antivenom
Consensus ‘what’ outcomes part of COSConsensus recommendation on ‘how’ outcomes part of COS should be measured
Outcome definitionTime point
Anaphylaxis or early antivenom reaction (develops immediately or within hours of administering snake antivenom)Definition: Proportion of people with anaphylaxis as defined by World Allergy Organization Anaphylaxis Guidance 2020*
Data type: Dichotomous
Definition is available in Table 2/ Figure 1/ of Cardona V, Ansotegui IJ, Ebisawa M, et al. World allergy organization anaphylaxis guidance 2020. World Allergy Organ J. 2020 Oct 30;13(10):100 472.

  • 6 hours from randomisation, for randomised controlled trials (RCTs).

  • 6 hours from intervention, for other non-randomised intervention designs

Death (all-cause/cause-specific)Definition: All-cause mortality
Data type: Dichotomous

  • 4 weeks (28 days) from randomisation, for RCTs.

  • 4 weeks (28 days) from intervention, for other non-randomised intervention designs

Requirement of ICU (intensive care unit) admission and/or duration of ICU stayDefinition: Proportion of patients who were admitted to ICU
Data type: Dichotomous
Note: Studies should clearly report the specific criteria used for ICU admission and discharge in trial sites

  • 4 weeks (28 days) from randomisation, for RCTs.

  • 4 weeks (28 days) from intervention, for other non-randomised intervention designs

COS for research on interventions for management of the bitten part, for example, for the management of wounds, bacterial infections and or swelling of the limbs, compartment syndrome
Consensus was not obtained for any outcome
COS for research on interventions specific to management of neurotoxic manifestations, for example, ventilation-different modalities, neostigmine, edrophonium
Consensus ‘what’ outcomes part of COSConsensus recommendation on ‘how’ outcomes part of COS should be measured
Outcome definitionTime point
Death (all-cause/cause-specific)Definition: All-cause mortality
Data type: Dichotomous

  • 4 weeks (28 days) from randomisation, for RCTs.

  • 4 weeks (28 days) from intervention for other non-randomised intervention designs

Neuro-muscular paralysisDefinition: Time taken for complete reversal of paralysis in at least one of the two muscle groups (extraocular and bulbar) and respiratory paralysis
Data type: time to event
Note: Outcome assessors should be mandatorily trained and a standard operating procedure developed for the purpose.		Not applicable.
Respiratory distress (breathing problem):Definition: Proportion of patients with severe respiratory distress, which is defined† by, having any one of below

  1. Talks in words (ie, in not phrases or sentences)

  2. Accessory muscles being used

  3. Oxygen (O2) saturation (on air) <92%

  4. Respiratory Rate(RR)<12/min or >20/min

  5. Partial pressure of carbon dioxide (PaCO2)>45 mm Hg

  6. Single breath count (number of digits counted in one exhalation) <25


Data type: Dichotomous

  • 24 hours from randomisation, for RCTs

  • 24 hours from intervention, for other non-randomised intervention designs

Duration of mechanical ventilationDefinition: Time in hours the person is in mechanical ventilation(initiation of ventilatory support to the onset of weaning.)
Data type: time to event
Note: Studies should clearly report criteria for use of mechanical ventilation, both its onset and termination.		Not applicable.
Duration of ICU stayDefinition: Time from admission to discharge from ICU—in hours
Data type: time to event
Note: Studies should clearly report the specific criteria used for ICU admission and discharge in trial sites.		Not applicable.
COS for research on interventions (treatments) specific to management of the haematological (blood) manifestations, for example, blood products—different types, plasma exchange, heparin and recombinant factors
Consensus ‘what’ outcomes part of COSConsensus recommendation on ‘how’ outcomes part of COS should be measured
Outcome definitionTime point
Death (all-cause/cause-specific)Definition: All-cause mortality
Data type: Dichotomous

  • 4 weeks (28 days) from randomisation, for RCTs.

  • 4 weeks (28 days) from intervention for other non-randomised intervention designs

Duration of ICU stayDefinition: Time from admission to discharge from ICU—in hours
Data type: time to event
Note: Studies should clearly report the specific criteria used for ICU admission and discharge in trial sites		Time point: not applicable
BleedingDefinition: Proportion of people developing major haemorrhage, as defined by the International Society on Thrombosis and Haemostasis as
(1) fatal bleeding,
(2) symptomatic bleeding in a critical organ,
(3) bleeding resulting in a drop in haemoglobin >20 g/L or
(4) requiring 2 or more units of whole blood or red cell blood transfusion.
Data type: Dichotomous

  • 24 hours, 48 hours and 7 days from randomisation, for RCTs. All time points should be reported.

  • 24 hours, 48 hours and 7 days from intervention for other non-randomised intervention designs. All time points should be reported.

Blood clotting and blood coagulabilityDefinition: Proportion of patients with abnormal blood coagulability, assessed by the whole blood clotting test (20 WBCT)‡
Data Type: Dichotomous
Note: Only a single-use clean, dry, glass test tube should be used for the test. There is no clinical evidence indicating validity of the test when plastic containers are used. Outcome assessors should be blinded, trained and a standard operating procedure developed for the purpose.

  • 6 hours, 12 hour, 24 hours and 7 days§ from randomisation, for RCT. All time points should be reported.

  • 6 hours, 12 hours, 24 hours and 7 days§ from intervention for other non-randomised intervention designs. All time points should be reported.

Acute kidney failure/injury or requirement of dialysisDefinition: Proportion of patients who develop AKI, as defined by the KDIGO diagnostic criteria should be met (any one of the three):

  1. An increase in serum creatinine by ≥0.3 mg/dL (≥26.5 µmol/L) within 48 hours

  2. An increase in serum creatinine to ≥1.5 times baseline within the previous 7 days

  3. Urine volume ≤0.5 mL/kg/hour for 6 hours


Data type: Dichotomous

  • 4 weeks (28 days) from randomisation, for RCTs.

  • 4 weeks (28 days) from intervention for other non-randomised intervention designs

COS for research on interventions (treatments) that act against the snake venom
Consensus ‘what’ outcomes part of COSConsensus recommendation on ‘how’ outcomes part of COS should be measured
Outcome definitionTime point
Death (all-cause/cause-specific)Definition: All-cause mortality
Data type: Dichotomous

  • 4 weeks (28 days) from randomisation, for RCTs.

  • 4 weeks (28 days) from intervention for other non-randomised intervention designs

Anaphylaxis or early antivenom reaction (develops immediately or within hours of administering snake antivenom)Definition: Proportion of people with anaphylaxis as defined by World Allergy Organization Anaphylaxis Guidance 2020*
Data type: Dichotomous
Note: Available in table 2/figure 1 of Cardona V, Ansotegui IJ, Ebisawa M, et al. World allergy organization anaphylaxis guidance 2020. World Allergy Organ J. 2020 Oct 30;13(10):100 472.

  • 6 hours from randomisation, for RCTs.

  • 6 hours from intervention, for other non-randomised intervention designs

Respiratory distress (breathing problem)Definition: Proportion of patients with severe respiratory distress, defined† by having any one of below

  1. Talks in words (ie, in not phrases or sentences)

  2. Accessory muscles being used

  3. Oxygen(O2) saturation (on air) <92%

  4. Respiratory Rate (RR) <12/min or >20/min

  5. partial pressure of carbon dioxide (PaCO2) >45 mm Hg

  6. Single breath count (number of digits counted in one exhalation) <25


Data type: Dichotomous

  • 24 hours from randomisation, for RCTs

  • 24 hours from intervention, for other non-randomised intervention designs

Requirement of mechanical ventilationDefinition: Proportion of patients requiring mechanical ventilation
Data type: Dichotomous
Note: Studies should clearly specify the criteria for deeming a patient requiring mechanical ventilation. This criterion can be used in facilities with no mechanical ventilation too.

  • 48 hours from randomisation, for RCTs.

  • 48 hours from intervention for other non-randomised intervention designs

BleedingDefinition: Proportion of people developing major haemorrhage, as defined by the International Society on Thrombosis and Haemostasis as (1)
fatal bleeding, (2) symptomatic bleeding in a critical organ, (3) bleeding resulting in a drop in haemoglobin >20 g/L or (4) requiring 2 or more units of whole blood or red cell transfusion.
Data type: Dichotomous

  • 24 hours, 48 hours and 7 days from randomisation, for RCTs. All time points should be reported.

  • 24 hours, 48 hours and 7 days from intervention for other non-randomised intervention designs. All time points should be reported.

Blood clotting and blood coagulabilityDefinition: Proportion of patients with abnormal blood coagulability, assessed by the 20 WBCT‡
Data type: Dichotomous
Note: Only a single-use clean, dry, glass test tube should be used for the test. There is no clinical evidence indicating validity of the test when plastic containers are used. Outcome assessors should be blinded, trained and a standard operating procedure developed for the purpose.

  • 6 hours, 12 hours and 24 hours, from randomisation, for RCTs. All time points should be reported.

  • 6 hours, 12 hours and 24 hours, from intervention for other non-randomised intervention designs. All time points should be reported.

Acute kidney failure(AKI)/injury or requirement of dialysisDefinition: Proportion of patients who develop AKI, as defined by the KDIGO diagnostic criteria should be met (any one of the three)

  1. An increase in serum creatinine by ≥0.3 mg/dL (≥26.5 µmol/L) within 48 hours

  2. An increase in serum creatinine to ≥1.5 times baseline within the previous 7 days

  3. Urine volume ≤0.5 mL/kg/hour for 6 hours


Data type: Dichotomous

  • 4 weeks (28 days) from randomisation, for RCTs.

  • 4 weeks (28 days) from intervention for other non-randomised intervention designs

  • *The World Allergy Organization definition is widely recognised globally and endorsed by 52 national professional organisations, including in South Asia by the Indian College of Allergy and Applied Immunology, and Pakistan Allergy Asthma and Immunology Society.

  • †This is a consensus-derived definition based on the review of guidelines for acute respiratory distress (GINA) and snakebite by the Ministry of Health and Family Welfare, India, and in alignment with broader principles of respiratory physiology. Respiratory distress (breathing problem) though related to neuroparalysis was seen as an important outcome for decision-making. However, for snakebite, and in South Asia, no robust validated tool is available. The consensus derived criterion included clinical measures, such that the evidence generated is in alignment with existing clinical practice in South Asia, and that trials on snakebite ought to be carried out in primary health centres, where advanced equipment might not be available. The criterion is designed, such that it can be used for all patients, irrespective of intubation status.

  • ‡The 20 WBCT was chosen because it is simple to measure, and evidence developed from trials, using it as an outcome would directly translate to practice in the South Asian context. A recent systematic review(*Lamb T, Abouyannis M, de Oliveira SS, et al. The 20 min whole blood clotting test (20 WBCT) for snakebite coagulopathy-A systematic review and meta-analysis of diagnostic test accuracy. PLoS Negl Trop Dis. 2021 Aug 10;15(8): e0009657) found that WBCT 20 is a highly specific and fairly sensitive bedside test for detecting coagulopathy in snakebite. It should also be noted that a COS is a minimal standard, and trialist might choose other measures (eg, international normalised ratio or INR), should resources be available, but such measures do not translate directly for practice in primary health centres and many under-resourced secondary and tertiary hospitals (which do not have 24 X 7 laboratory support), which is where people affected by snakebite present to. Inclusion of WBCT 20, in the COS enables conduct of trials in wider types of health facilities.

  • §Time point of 7 days is recommended only for specific species, which cause long-term or recurrent coagulopathy. An indicative list is provided below:

    • Trimeresurus erythrurus (spot tailed/red tailed green pit viper).

    • Rhabdophis subminiatus (red-necked keelback).

    • Trimeresurus salazar (Salazar’s pitviper).

    • Naja kaouthia (Monocle cobra).

    • Naja naja (Spectacled cobra).

    • Daboia russelii (Russell’s viper).