Therapeutic donor hypothermia following brain death to improve the quality of transplanted organs

Objectives

This is a protocol for a Cochrane Review (intervention). The objectives are as follows:

This review aims to examine the benefits and harms of therapeutic donor hypothermia in recipients or organs donated after brain death.

Background

Description of the condition

Solid organ transplantation is the optimal treatment for patients living with end‐stage organ failure. However, there remains a shortage of optimal organs for donation.

The process of brain death is known to cause significant injury to organs (Bera 2020; Chudoba 2017; Homme 2007; Meyfroidt 2019). Therefore, efforts to optimise the perioperative care of these donors should be maximised to achieve the best outcomes and graft function in transplant recipients. These improved outcomes may also facilitate increased use of organs from expanded criteria donors, therefore, growing the donor pool. Despite these potential benefits, few interventions have been researched in this population.

Description of the intervention

Standard clinical practice is to maintain normothermia (a core body temperature between 36°C and 38°C) following brainstem death up to the point of organ donation. As thermoregulation becomes impaired following brain death (due to loss of thalamic and hypothalamic function, peripheral vasodilation and reduced metabolic rate), spontaneous donor hypothermia is not uncommon, frequently requiring rewarming interventions to maintain normothermia (Homme 2007; Powner 1990; Smith 2004).

Therapeutic donor hypothermia is a process in which donors are deliberately allowed to reach a core body temperature of < 35.5°C before organ retrieval (Yacono 2017). This may be achieved by passive methods (allowing donors to spontaneously cool to their target temperature), active non‐invasive methods (such as using fans, ice packs, or specific external cooling systems to promote cooling), or active invasive methods (such as bladder irrigation, invasive cooling lines, or temperature controlled humidified gases during invasive ventilation) to achieve the desired core temperature. The degree of therapeutic hypothermia can be also classified into mild (34.0°C to 35.5°C), moderate (32.0°C to 33.9°C), moderately deep (30.0°C to 31.9°C) and deep (< 30°C) (So 2010). Importantly, this differs from accidental hypothermia, which is commonly due to environmental factors leading to a reduced core body temperature in patients before their arrival in hospital and has a different severity grading (Avellanas 2019).

Therapeutic hypothermia is classically divided into three stages: induction, maintenance and rewarming (Polderman 2009). Given the study population of interest in this review, it is unlikely that the rewarming phase will be used during their clinical care. The optimal depth, duration and method of achieving therapeutic hypothermia is debated and may vary according to its clinical indication. It is commonly employed as a neuroprotective strategy in patients following cardiac arrest and in children with hypoxic ischaemic encephalopathy (Song 2012). In addition, there is considerable ongoing research to establish its efficacy in the care of patients with refractory status epilepticus, hepatic encephalopathy, traumatic brain injury and acute ischaemic stroke (Corry 2012; Crompton 2017; Lee 2017; Song 2012).

How the intervention might work

Hypothermia has complex and profound physiologic implications on the body. Notably, it reduces metabolism with even moderate hypothermia of 32°C to 34°C resulting in a 50% to 60% reduction in basal metabolic rate (Polderman 2009; So 2010). It also leads to reduced oxygen‐derived free radical production and less oxidative stress on tissues. While these mechanisms have primarily been used for the purposes of neuroprotection, these same mechanisms may confer similar protection to other organs that may go on to be donated.

This is particularly important given the physiologic changes that occur following brain death, notably with changes in vasomotor tone leading to dramatic swings in blood pressure and sometimes precipitating cardiovascular collapse (Homme 2007). Before this derangement can be corrected by clinicians, the resulting hypoperfusion may have led to tissue damage which could impair the function of later donated organs, therefore, worsen outcomes for recipients. The effects of therapeutic hypothermia may confer some protection to these organs from these physiologic insults.

Similarly, hypothermia has been shown in other clinical settings to protect against ischaemia reperfusion injury (Bashtawi 2021; Crompton 2017; Talma 2016; Tashili‐Fahadan 2018). Ischaemia reperfusion injury is inevitable in transplantation, and the duration of both cold and warm ischaemic times are key factors determining graft outcome (Monbaliu 2005; Summers 2012; Tanner 2012). As such, it is hoped that therapeutic donor hypothermia may reduce the effects of ischaemia reperfusion injury and improve recipients' outcomes.

Why it is important to do this review

Given the large number of patients awaiting organ transplantation and the paucity of available optimal organs, every effort should be made to increase the number of suitable organs available for transplantation. Despite this, research into specific interventions to improve the quality of organs prior to donation in donors following brain death is scarce (Chudoba 2017). 

Therapeutic hypothermia is an intervention with a growing evidence base to support its use in clinical practice, particularly for its effects on preventing tissue damage from oxidative stress and ischaemia reperfusion injury. However, it is not without risk and the adverse effects of hypothermia range from increased risk of infection to fatal arrhythmia and cardiac arrest (Homme 2007). It also places demands on critical care nursing staff, which are only appropriate if the intervention demonstrates benefit (Papageorgiou 2017). When applied to organ donation, therapeutic hypothermia in donors following brain death may increase the quality of transplanted organs by conferring protection from hypoperfusion and ischaemia reperfusion injury, ultimately leading to improved graft function and better patient‐centred outcomes for recipients.

Even within its current recognised indications, there is ongoing debate about the optimal implementation strategy, target temperature, method of cooling and duration of therapy with a constantly evolving evidence base to help refine best practices (Dankiewicz 2019; Polderman 2009; Schafer 2021). 

Therefore, this review is essential to assess the extent and quality of current evidence to inform whether or not therapeutic hypothermia is safe and efficacious in improving the quality of transplanted organs in donors following brain death. 

Objectives

This review aims to examine the benefits and harms of therapeutic donor hypothermia in recipients or organs donated after brain death.

Methods

Criteria for considering studies for this review

Types of studies

All randomised controlled trials (RCTs) and quasi‐RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) looking at therapeutic donor hypothermia following brainstem death to improve the quality of transplanted organs. 

Types of participants

Inclusion criteria

For donors

All organ donors who have received a formal diagnosis of brain death, regardless of age, ethnicity or sex.

As the criteria for diagnosing death by neurological criteria can vary between countries (Johnson 2017), for the purposes of this review, brain death will be considered to be any that satisfy the recommendations for the determination of brain death outlined by the World Brain Death Project (Greer 2020). That is a clinical examination that demonstrates coma, brainstem areflexia and apnoea in patients with an established neurological diagnosis that can lead to irreversible loss of brain function and where confounders of clinical examination and mimics of brain death have been excluded.

Practically, this will include both: 1) Whole brain death, defined as the irreversible cessation of all functions of the entire brain, including the brainstem, or 2) Brainstem death, defined as the irreversible loss of the capacity for consciousness and the irreversible loss of the ability to breathe, and are the criteria that are used throughout the United States, United Kingdom and most European countries.

For recipients

In receipt of one of the following organs regardless of age, ethnicity, or sex: heart, lung, liver, kidney, pancreas.

Exclusion criteria

For donors

Donation following circulatory death, as donor hypothermia would be an unacceptable pre‐mortem intervention in this cohort.

For recipients

No specific exclusion criteria

Types of interventions

This review will include passive, active non‐invasive, and active invasive methods of achieving therapeutic hypothermia.

Passive

• Allowing donors to spontaneously reach their target temperature 

Active non‐invasive

• The use of fans, ice packs

• Adjusting room temperature 

• Removing clothing and/or blankets etc. 

• Water circulating blankets 

• Air circulating blankets

• Water‐circulating gel‐coated pads

Active invasive

• Intravascular heat exchange system

• Bladder irrigation 

• Peritoneal irrigation 

• Pleural irrigation

Or any combination of the above methods. This review will also consider the following.

• The depth of hypothermia (mild, moderate, moderately deep or deep) 

• How the target temperature was measured (e.g. oesophageal, rectal or tympanic thermometers and whether the temperature was monitored continuously or intermittently)

• The duration of hypothermia prior to organ retrieval 

• The time in which the target temperature was achieved 

• Whether the target temperature was achieved or not

• The setting in which these interventions were being delivered prior to organ retrieval (while we expect donors receiving therapeutic hypothermia to be almost exclusively cared for in critical care units, it is possible that they may also receive these interventions in emergency departments, operating theatres or other clinical settings).

Types of outcome measures

The outcomes selected have been based on expert opinion, previous literature in the field and the SONG core outcome sets for transplantation as specified by the Standardised Outcomes in Nephrology Initiative (SONG 2017).

Primary outcomes

• Death‐censored graft survival (for all organ types)

• Adverse events, including but not limited to:

  • Allograft thrombosis

  • Cancer

  • Infection

  • In‐hospital death 

  • Severe arrhythmia and cardiac arrest 

  • Liver disorders: measured using alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma‐glutamyl transferase (GGT), alkaline phosphatase (ALP) and bilirubin

  • Thrombocytopenia 

  • Requirement for organ support for organs other than that transplanted

• Transplant utilisation (i.e. the number of organs transplanted from each donor)

Secondary outcomes

For all organ recipients

• Delayed graft function (DGF)

• Primary nonfunction

• Acute rejection

• Patient survival

• Quality of life (QoL) and life participation 

• Cardiovascular disease 

Organ‐specific outcome measures

• Kidney: estimated glomerular filtration rate (eGFR) at one year and maximal follow‐up

• Liver: early allograft dysfunction (seven days) and ischaemic type biliary complications at one year and maximal follow‐up

• Pancreas: this will be assessed primarily using the Igls consensus criteria: glycated haemoglobin (HbA1c), occurrence of severe hypoglycaemia, > 50% reduction in insulin requirements and increase in C‐peptide levels (Rickels 2018). We will also include within one year or maximal follow‐up

• Lung: graft function measured using the pulmonary graft dysfunction (PGD) score at one year or maximal follow‐up

• Heart: left ventricular ejection fraction, cardiac allograft vasculopathy, and New York Heart Association (NYHA) score at one year or maximal follow‐up.

Search methods for identification of studies

Electronic searches

We will search the Cochrane Kidney and Transplant Register of Studies through contact with the Information Specialist using search terms relevant to this review. The Register contains studies identified from the following sources:

1. Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)

2. Weekly searches of MEDLINE OVID SP

3. Searches of kidney and transplant journals and the proceedings and abstracts from major kidney and transplant conferences

4. Searching the current year of EMBASE OVID SP

5. Weekly current awareness alerts for selected kidney and transplant journals

6. Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Studies contained in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE based on the scope of Cochrane Kidney and Transplant. Details of search strategies and a list of handsearched journals, conference proceedings and current awareness alerts are available on the Cochrane Kidney and Transplant website under CKT Register of Studies.

See Appendix 1 for search terms used in strategies for this review.

Searching other resources

1. Reference lists of review articles, relevant studies and clinical practice guidelines.

2. Contacting relevant individuals/organisations seeking information about unpublished or incomplete studies.

3. Grey literature sources (e.g. abstracts, dissertations and theses), in addition to those already included in the Cochrane Kidney and Transplant Register of Studies, will not be searched.

Data collection and analysis

Selection of studies

The search strategy described will be used to obtain titles and abstracts of studies that may be relevant to the review. The titles and abstracts will be screened independently by two authors (TH, ST), who will discard studies that are not applicable; however, studies and reviews that might include relevant data or information on studies will be retained initially. Two authors will independently assess retrieved abstracts (TH, ST) and, if necessary, the full text of these studies to determine which studies satisfy the inclusion criteria. Disagreements will be resolved in consultation with a third author (CW).

Data extraction and management

Data extraction will be carried out independently by two authors (TH, ST) using standard data extraction forms. Disagreements will be resolved in consultation with a third author (CW). Studies reported in non‐English language journals will be translated before assessment. Where more than one publication of one study exists, reports will be grouped together, and the publication with the most complete data will be used in the analyses. Where relevant outcomes are only published in earlier versions, these data will be used. Any discrepancy between published versions will be highlighted.

Assessment of risk of bias in included studies

The following items will be independently assessed by two authors (TH, ST) using the risk of bias assessment tool (Higgins 2022) (see Appendix 2).

• Was there adequate sequence generation (selection bias)?

• Was allocation adequately concealed (selection bias)?

• Was knowledge of the allocated interventions adequately prevented during the study?

  • Participants and personnel (performance bias)

  • Outcome assessors (detection bias)

• Were incomplete outcome data adequately addressed (attrition bias)?

• Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?

• Was the study apparently free of other problems that could put it at risk of bias?

Measures of treatment effect

For dichotomous outcomes (e.g. DGF and primary graft nonfunction), results will be expressed as risk ratio (RR) with 95% confidence intervals (CI). Where continuous measurement scales are used to assess treatment effects (e.g. eGFR and length of stay), the mean difference (MD) will be used. 

We aim to analyse graft survival and patient survival as time‐to‐event data and perform meta‐analyses of log hazard ratios (HR) using the general inverse‐variance method, as described in Chapter 10 of the Cochrane Handbook (Higgins 2022). Where HR are reported (with CIs and/or P values), these will be used directly. Where a study performs time‐to‐event analyses but does not report an HR, one will be imputed using techniques described in Tierney 2007. The results of these analyses will be expressed as HR with 95% CI.

If available data in included studies are insufficient to allow time‐to‐event analysis, we may need to analyse survival as a dichotomous variable at set time points (one, three, and five years). In this instance, we will use one‐year graft survival as a primary outcome.

Where standard deviations (SD) are not given, they will be obtained directly from available statistics (e.g. standard errors) using the Cochrane RevMan Calculator. Where only median and interquartile ranges are given, we will use methods described in Wan 2014 to estimate mean and SD. If none of these is possible, SDs will be imputed from other studies (Furukawa 2006).

Unit of analysis issues

We do not anticipate any unit of analysis issues as we do not expect any cluster‐randomised or cross‐over studies to be included in this review. If such studies are present, we will deal with these as described in sections 23.1 and 23.2 of the Cochrane Handbook (Higgins 2022).

Dealing with missing data

Any further information required from the original author will be requested by written correspondence (e.g. emailing the corresponding author/s). Any relevant information obtained in this manner will be included in the review. Evaluation of important numerical data such as screened, randomised patients as well as intention‐to‐treat, as‐treated and per‐protocol population will be carefully performed. Attrition rates, for example, drop‐outs, losses to follow‐up and withdrawals, will be investigated. Issues of missing data and imputation methods (e.g. last‐observation‐carried‐forward) will be critically appraised (Higgins 2022).

Assessment of heterogeneity

We will first assess the heterogeneity by visual inspection of the forest plot. We will quantify statistical heterogeneity using the I² statistic, which describes the percentage of total variation across studies that is due to heterogeneity rather than sampling error (Higgins 2003). A guide to the interpretation of I² values will be as follows.

• 0% to 40%: might not be important

• 30% to 60%: may represent moderate heterogeneity

• 50% to 90%: may represent substantial heterogeneity

• 75% to 100%: considerable heterogeneity.

The importance of the observed value of I² depends on the magnitude and direction of treatment effects and the strength of evidence for heterogeneity (e.g. P value from the Chi² test or a CI for I²) (Higgins 2022).

Assessment of reporting biases

If possible, funnel plots will be used to assess for the potential existence of small study bias (Higgins 2022).

Data synthesis

Data will be pooled using the random‐effects model, but the fixed‐effect model will also be used to ensure robustness of the model chosen and susceptibility to outliers.

Subgroup analysis and investigation of heterogeneity

To assess the impact of heterogeneity, we plan to perform the following subgroup analyses if sufficient data are present: 

• The effect of mild versus moderate, versus moderately deep, versus deep hypothermia as the physiological effects of lower temperatures may have different treatment effects.

• Passive versus active non‐invasive versus active invasive methods of achieving hypothermia as risks and benefits may differ in these groups.

• Rapidly achieved target temperature (e.g. within four hours of initiation of therapy) compared to cases where a longer time to achieve target temperature was observed, as the rate of cooling may influence the rate of adverse events (So 2010). 

• Standard criteria versus extended criteria donors, as this is likely to influence the quality of organs and the likelihood of adverse outcomes.

• Studies that specify a specific minimum duration of cooling (e.g. 12 hours) prior to organ retrieval compared to studies that do not assess whether there is a temporal relation between time spent in therapeutic hypothermia, benefits and adverse events. 

• An analysis of only organs that were not subject to prolonged cold and warm ischaemic times, as this is known to affect graft outcomes. 

• Organs that were well immunologically matched compared to those that were not well immunologically matched in case any benefits or adverse effects are not observed in either group. 

Adverse effects will be tabulated and assessed with descriptive techniques, and, where possible, the risk difference with 95% CI will be calculated for each compared to no treatment or placebo/sham procedure. 

Sensitivity analysis

We will perform sensitivity analyses to explore the influence of the following factors on effect size:

• Repeating the analysis, excluding unpublished studies

• Repeating the analysis taking account of the risk of bias, as specified

• Repeating the analysis, excluding any very long or large studies to establish how much they dominate the results

• Repeating the analysis excluding studies using the following filters: diagnostic criteria, language of publication, source of funding (industry versus other), and country.

Summary of findings and assessment of the certainty of the evidence

We will present the main results of the review in 'Summary of findings' tables. These tables present key information concerning the certainty of the evidence, the magnitude of the effects of the interventions examined, and the sum of the available data for the main outcomes (Schunemann 2022a). The 'Summary of findings' tables also include an overall grading of the evidence related to each of the main outcomes using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach (GRADE 2008; GRADE 2011). The GRADE approach defines the certainty of a body of evidence as the extent to which one can be confident that an estimate of effect or association is close to the true quantity of specific interest. This will be assessed by two authors (TH, ST). The certainty of a body of evidence involves consideration of the within‐study risk of bias (methodological quality), directness of evidence, heterogeneity, precision of effect estimates and risk of publication bias (Schunemann 2022b). 

Given sufficient available evidence, we plan to create a summary of findings table for each organ type. We plan to present the following outcomes in the 'Summary of findings' tables:

• Graft survival 

• Patient survival 

• DGF

• Primary graft non‐function

• Graft function (by the organ‐specific measurements of organ function listed in Types of outcome measures)

• Acute rejection 

• Adverse events related to hypothermia

What's new

Date	Event	Description
31 January 2023	Amended	Author order corrected (due to technical error)

History

Protocol first published: Issue 1, 2023

Appendices

Appendix 1. Electronic search strategies

Database	Search terms
CENTRAL	(organ transplant*):ti,ab,kw (heart transplant*):ti,ab,kw (pancreas transplant*):ti,ab,kw (lung transplant*):ti,ab,kw (liver transplant*):ti,ab,kw ("heart lung transplant*"):ti,ab,kw (kidney transplant*):ti,ab,kw {or #1‐#7} MeSH descriptor: [Hypothermia, Induced] this term only (therapeutic hypothermia):ti,ab,kw (donor and hypothermia):ti,ab,kw targeted temperature management:ti,ab,kw (induced and hypothermia):ti,ab,kw {or #9‐#13} {and #8, #14}
MEDLINE	Organ Transplantation/ exp Heart Transplantation/ Kidney Transplantation/ exp Lung Transplantation/ Pancreas Transplantation/ Liver Transplantation/ organ transplant$.tw. heart transplant$.tw. pancreas transplant$.tw. lung transplant$.tw. liver transplant$.tw. heart‐lung Transplant$.tw. or/1‐12 Hypothermia, Induced/ (donor adj3 hypothermia).tw. therapeutic hypothermia.tw targeted temperature management.tw. (induced adj2 hypothermia).tw. or/14‐18 and/13,19
EMBASE	organ transplantation/ heart transplantation/ liver transplantation/ pancreas transplantation/ kidney transplantation/ lung transplantation/ heart lung transplantation/ or/1‐7 induced hypothermia/ therapeutic hypothermia.tw. (donor adj3 hypothermia).tw. targeted temperature management.tw. (induced adj2 hypothermia).tw. or/9‐13 and/8,13

 

Appendix 2. Risk of bias assessment tool

Potential source of bias	Assessment criteria
Random sequence generation Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence	Low risk of bias: Random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimisation (minimisation may be implemented without a random element, and this is considered to be equivalent to being random).
	High risk of bias: Sequence generated by odd or even date of birth; date (or day) of admission; sequence generated by hospital or clinic record number; allocation by judgement of the clinician; by preference of the participant; based on the results of a laboratory test or a series of tests; by availability of the intervention.
	Unclear: Insufficient information about the sequence generation process to permit judgement.
Allocation concealment Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment	Low risk of bias: Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study (e.g. central allocation, including telephone, web‐based, and pharmacy‐controlled, randomisation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes).
	High risk of bias: Using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non‐opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.
	Unclear: Randomisation stated but no information on method used is available.
Blinding of participants and personnel Performance bias due to knowledge of the allocated interventions by participants and personnel during the study	Low risk of bias: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.
	High risk of bias: No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.
	Unclear: Insufficient information to permit judgement
Blinding of outcome assessment Detection bias due to knowledge of the allocated interventions by outcome assessors.	Low risk of bias: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.
	High risk of bias: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.
	Unclear: Insufficient information to permit judgement
Incomplete outcome data Attrition bias due to amount, nature or handling of incomplete outcome data.	Low risk of bias: No missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; missing data have been imputed using appropriate methods.
	High risk of bias: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; ‘as‐treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.
	Unclear: Insufficient information to permit judgement
Selective reporting Reporting bias due to selective outcome reporting	Low risk of bias: The study protocol is available and all of the study’s pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way; the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified (convincing text of this nature may be uncommon).
	High risk of bias: Not all of the study’s pre‐specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. sub‐scales) that were not pre‐specified; one or more reported primary outcomes were not pre‐specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study.
	Unclear: Insufficient information to permit judgement
Other bias Bias due to problems not covered elsewhere in the table	Low risk of bias: The study appears to be free of other sources of bias.
	High risk of bias: Had a potential source of bias related to the specific study design used; stopped early due to some data‐dependent process (including a formal‐stopping rule); had extreme baseline imbalance; has been claimed to have been fraudulent; had some other problem.
	Unclear: Insufficient information to assess whether an important risk of bias exists; insufficient rationale or evidence that an identified problem will introduce bias.

Contributions of authors

1. Draft the protocol: TH, ST, ET, CW

2. Study selection: TH, ST

3. Extract data from studies: TH, ST

4. Enter data into RevMan: TH, ST

5. Carry out the analysis: TH, ST

6. Interpret the analysis: TH, ST, ET, CW

7. Draft the final review: TH, ST, ET, CW

8. Disagreement resolution: ET, CW

9. Update the review: TH, ST, ET, CW

Sources of support

Internal sources

• No sources of support provided

External sources

• No sources of support provided

Declarations of interest

• Thomas J Hoather: no relevant interests were disclosed

• Samuel J Tingle: no relevant interests were disclosed

• Emily R Thompson: no relevant interests were disclosed

• Colin Wilson: no relevant interests were disclosed

Edited (no change to conclusions)