Interventions for improving sleep quality in people with chronic kidney disease

Abstract

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

This review aims to look at the benefits and harms of interventions for improving sleep quality among adults and children with CKD.

Background

Description of the condition

Sleep duration and quality is commonly decreased in people with chronic kidney disease (CKD) and sleep disorders are often present even in the early stages of CKD. The prevalence rate of any sleep disorder in CKD ranges from 45% to 80% in adults with end‐stage kidney disease (ESKD) and affected approximately half of patients with earlier stages of CKD (Iliescu 2004). The true prevalence is uncertain due to heterogeneous definitions of sleep quality including problems initiating or maintaining sleep, early or difficulty waking, restlessness, tiredness on waking, and daytime sleepiness (Murtagh 2010). Risk factors of sleep disturbance in the general population such as older age, male gender, obesity, smoking, increased neck circumference and diabetes are also prevalent in the CKD population (Roumelioti 2011). Dialysis treatment modality may impact sleep dysfunction. People treated with automated peritoneal dialysis (PD) appear to have less severe sleep‐related breathing disorders (SBD) compared to continuous ambulatory PD patients (Roumelioti 2016). Kidney transplantation is associated with a low rate of sleep disorder (Mavanur 2010).

Among people with CKD, sleep disorders have been associated with impaired neuro cognition, including inattention, lower performance at school or productivity at work, and driving related accidents (Stabouli 2016, Ezzat 2015). CKD is associated with sleep apnoea (central and obstructive), in part due to altered ventilatory control and upper airway obstruction (Markou 2006; Sim 2009). Poor sleep quality is a source of patient stress and is linked to lower health‐related quality of life (Iliescu 2003), depression and greater use of antidepressants, narcotics and hypnotic medications, and worse life expectancy in people with a range of kidney function (Elder 2008; Kumar 2010; Unruh 2006). Overall, impaired sleep is experienced by patients as changes in their sleep‐wake cycle (insomnia, excessive sleepiness or both) and sleep‐disordered breathing (Young 2004). Contributing factors include restless legs syndrome (RLS) or periodic leg movement, night‐time dialysis care, depressed mood and anxiety, increased prescribing of neuroactive medications and analgesia, pain and itch, and altered sleep hygiene including napping during the day (Ogna 2016). Sleep disorder has been associated with increased cardiovascular risk and may contribute to the morbidity and mortality of people with advanced (stages 4 to 5) CKD or treated with dialysis (Roumelioti 2011). Some studies have shown that sleep disturbances are associated with increased cardiovascular risk and arterial hypertension (Gonçalves 2007), subclinical atherosclerosis (Drager 2009), coronary heart disease (Hung 1990), heart failure (Hedner 1990), arrhythmias (Hoffstein 1994), cerebrovascular disease (Munoz 2006), type 2 diabetes mellitus and dysglycaemia (Botros 2009; Shpirer 2011), metabolic syndrome and its components (Assoumou 2012; Kono 2007) and dyslipidaemia (Assoumou 2012;Drager 2010). The major causes for a disordered sleep in CKD and in ESKD derive from biological, psychological, and environmental factors (Ahmad 2013; Ezzat 2015). Putative determinants of sleep disorders in ESKD include serum concentrations of creatinine, urea, phosphorus, parathyroid hormone (PTH), anaemia, nocturnal hypoxaemia, blood pressure, disease intrusiveness, time on dialysis, and comorbidity. Psychological factors and treatment‐related factors (such as nocturnal dialysis) may cause alterations in sleep and insomnia in CKD patients (De Santo 2008).

Description of the intervention

Due to the variable causes of altered sleep quality in people with CKD, a range of interventions are used including behavioural therapy with or without medication. A suggested approach to management of sleep has been to identify and treat any specific cause including disordered breathing, RLS, pruritus, depression and anxiety, or pain (Murtagh 2010). General approaches to sleep management include a range of behavioural therapies such as sleep hygiene, stimulus control and avoidance of caffeine, alcohol, and daytime sleeping, short‐term hypnotics to re‐establish sleep patterns, exercise, and complementary therapies (Jespersen 2015). CKD may constrain the use of neuroactive medications, which can lead to dependence if used in the longer‐term.

How the intervention might work

Numerous interventions including behavioural therapy, exercise, pharmacological agents and complementary therapy in addition to specific treatments for conditions associated with sleep impairment have individual mechanisms of action. In general, the effectiveness and safety of treatments may differ in people with CKD due to the frequency of additional severe symptoms including fatigue, pain, and depression, inactivity and frailty, and the altered metabolism of commonly‐used medications that may cause over‐sedation or lead to interactions with other treatments.

Why it is important to do this review

People with CKD have identified the importance of research focused on developing better treatments to reduce symptoms of CKD (Manns 2014; Tong 2008). In this review, we will summarise the current evidence for treatments to improve sleep quality in CKD given the range of causes of impaired sleep, the heterogeneity in potential treatments, the impact of sleep changes on quality of life and prognosis, and the relative priority placed on research to manage symptoms by patients and caregivers.

Objectives

This review aims to look at the benefits and harms of interventions for improving sleep quality among adults and children with CKD.

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 interventions for improving sleep quality in adults and children with CKD.

Types of participants

Inclusion criteria

Adults and children with CKD (as defined by Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for evaluation and management of CKD (KDIGO 2013) including all stages of CKD. We will include people treated with dialysis, those who have ESKD treated with supportive care, recipients of a kidney transplant, and those with earlier stages (I to 4) of CKD.

Exclusion criteria

None.

Types of interventions

We plan to evaluate all interventions for sleep management including the following.

• Behavioural interventions that include sleep hygiene education, stimulus control, relaxation, sleep restriction, cognitive therapy, and cognitive‐behavioural therapy

• Stimulus control

• Pharmacological treatments (benzodiazepines, non‐benzodiazepine hypnotics, antidepressants, melatonin agonists, orexin receptor antagonists)

• Interventions for disordered breathing (patient education, weight loss, exercise, physiotherapy, sleep positioning, positive airway pressure, oral appliances, upper airway surgery, dialysis management)

• Exercise and other complementary interventions including music therapy, relaxation therapy, meditation, and hypnotherapy

• Optimisation of renal replacement therapy (dialysis).

We will consider any mode, frequency, and duration of therapy, interventions administered in any clinical setting, and irrespective of the people involved in intervention delivery.

Types of outcome measures

Primary outcomes

1. Sleep quality as measured by a sleep‐specific quality of life measure: we will use the Pittsburgh Sleep Quality Index (PSQI) questionnaire, the Kidney Disease Quality of Life (KDQoL‐SF) or polysomnography (PSG) as appropriate measures to assess the sleep‐related quality of life

2. Sleep onset latency

3. Total sleep time

4. Sleep interruption: number of awakenings and waking after sleep onset

5. Sleep efficiency: percent of time spent in bed asleep

6. Adverse events (as reported by investigators)

Secondary outcomes

1. Depression

2. Anxiety

3. Health‐related quality of life

4. Fatigue

5. Daytime sleepiness

6. Death

7. Hospital admission

8. Major cardiovascular event

We will include studies that measure outcomes using standardised questionnaires with established reliability and validity (e.g. Beck Depression Inventory (BDI), State‐Trait Anxiety Inventory (STAI), Short‐Form 36 (SF‐36)). We will extract endpoints as post‐intervention mean or change scores, together with standard deviations (SD), or the number of participants experiencing one or more events.

We will consider the study period and follow‐up as described in the included studies. When assessing outcomes in relation to time points we will group the data as: immediate post‐intervention, short‐term (post‐intervention to one month), medium‐term (between one and three months follow‐up), and long‐term (more than three months follow‐up) effects. We will report all primary outcomes in a table of Summary of findings for the main comparison.

Due to the heterogeneity of sleep disorders, interventions and clinical outcomes, we will categorise sleep disorders according to aetiology. Where possible we will group results by outcomes (so that all information for each category of sleep disorder and associated interventions will be grouped by the impact of the intervention on outcomes).

To maximize clinical utility, we will separate studies according to clinical setting (CKD/dialysis/transplant and for adults and children). We anticipate few studies and will structure our results to ensure that the choices of categories and interventions in the analyses are clearly shown. Where necessary, we may need to show the overview of our results structure using a diagram to explain to the reader how the information is presented.

Search methods for identification of studies

We will not apply any restrictions on date, language, or publication status when searching or selecting eligible studies. We will be using standard Cochrane methods including a highly sensitive strategy designed by the Information Specialist to identify eligible studies for this review.

Electronic searches

We will search the Cochrane Kidney and Transplant Specialised Register through contact with the Information Specialist using search terms relevant to this review. The Cochrane Kidney and Transplant Specialised 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. Handsearching of kidney‐related journals and the proceedings of major kidney conferences

4. Searching of 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 Specialised Register are identified through search strategies for CENTRAL, MEDLINE, and EMBASE based on the scope of Cochrane Kidney and Transplant. Details of these strategies, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available in the Specialised Register section of information about Cochrane Kidney and Transplant.

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. Letters seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies.

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, 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 and, if necessary the full text, of these studies to determine which studies satisfy the inclusion criteria.

Data extraction and management

Data extraction will be carried out independently by two authors using standard data extraction forms. 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. From each study, we will extract the following information.

1. General information: author, year of publication, title, publication source, country, language

2. Study design: design (e.g. parallel or cross‐over), method of randomisation and concealment, nature of the control group, blinding of study assessments, washout period in cross‐over design, inclusion criteria exclusion criteria

3. Participants: total sample size, number in experimental group, number in control group, age, gender, stage of CKD, ethnicity, diagnosis, comorbidity, sleep quality and reason for impaired sleep, duration of sleep impairment, previous or additional treatments

4. Intervention: type of treatment employed, provider, setting, length and frequency of treatment, duration of intervention, implementation

5. Outcomes: methods of assessment, primary and secondary outcome measures, pre‐test means and post‐test means or change scores and SD for all groups for all outcomes specified, numbers of participants experiencing one or more event, number of participants at risk, follow‐up duration

We will report the results of our findings separately focusing on sleep disorder categories and based on different stages of CKD.

Assessment of risk of bias in included studies

The following items will be independently assessed by two authors using the risk of bias assessment tool (Higgins 2011) (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 a risk of bias?

Measures of treatment effect

For dichotomous outcomes (adverse events, death, major adverse cardiovascular event, fatigue, depression, anxiety) results will be expressed as risk ratio (RR) with 95% confidence intervals (CI). Where continuous scales of measurement are used to assess the effects of treatment (sleep assessments, health‐related quality of life, daytime sleepiness, depression, anxiety, fatigue), the mean difference (MD) will be used, or the standardised mean difference (SMD) if different scales have been used.

Unit of analysis issues

Cluster‐randomised studies

We anticipate that studies using clustered randomisation will have controlled for clustering effects. In case of doubt, we will contact the first authors to ask for individual participant data to calculate an estimate of the intra cluster correlation coefficient (ICC). If this is not possible, we will obtain external estimates of the ICC from a similar study or from a study of a similar population as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). When the ICC is established, we will use it to re‐analyse the study data. If ICCs from other sources are used, we will report this and conduct sensitivity analyses to investigate the effect of variation in the ICC.

Cross‐over studies

Cross‐over studies will be analysed using combined data from all study periods, or using first period data if combined data is not available.

Studies with more than two treatment arms

If more than one of the interventions is a sleep intervention, and there is sufficient information in the study to assess the similarity of the interventions, we will combine similar interventions to allow for a single pair‐wise comparison.

Dealing with missing data

Any further information required from the original author will be requested by written correspondence (e.g. emailing corresponding author) and 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 (for example, last‐observation‐carried‐forward) will be critically appraised (Higgins 2011).

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 confidence interval for I²) (Higgins 2011).

Assessment of reporting biases

If possible, funnel plots will be used to assess for the potential existence of small study bias (Higgins 2011).

Data synthesis

We will report the results of our findings separately focusing on sleep disorder categories and based on different stages of CKD.

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. Adverse effects will be tabulated and assessed with descriptive techniques, as they are likely to be different for the various interventions used. Where possible, the risk difference with 95% CI will be calculated for each adverse effect, either compared to no treatment or to another agent.

Subgroup analysis and investigation of heterogeneity

Subgroup analysis will be used to explore possible sources of heterogeneity (e.g. participants, interventions and study quality such as age, stage of CKD, country, duration of treatment or follow‐up and study quality).

The range of sleep disorders is complex and the pathobiologies of each are sufficiently different that a framework for sleep disorder categories will be used as a framework for analysis.

We will therefore use the following sleep disorder categories to construct the review and analyse data:

1. Insomnias: insomnia and short sleeper

2. Hypersomnias: narcolepsy; idiopathic hypersomnia; insufficient sleep syndrome; long sleeper; excessive daytime sleepiness (EDS)

3. SDB: mild‐moderate‐severe obstructive sleep apnoea (OSA); central sleep apnoea; child sleep apnoea; snoring

4. Circadian rhythm sleep‐wake disorders: irregular sleep‐wake rhythm; delayed sleep‐wake phase; advanced sleep‐wake phase

5. Parasomnias: confusional arousals; sleep walking; sleep terrors; nightmares; sleep eating disorder; sleep talking; night awakening

6. Sleep movement disorders: RLS; periodic limb movements (PLMs); sleep leg cramps; bruxism; rapid eye movement behaviour Disorders (RED); limb pains; pruritus; itch.

We will report the treatment comparisons by sleep disorder and as a total including all studies when there is no evidence of substantial heterogeneity between groups. We will report the results of our findings separately for people with earlier stages of CKD, those with ESKD treated with dialysis, those with ESKD treated with supportive care and recipients of a kidney transplant.

Sensitivity analysis

We will perform sensitivity analyses in order to explore the influence of the following factors on effect size.

• Repeating the analysis excluding unpublished studies

• Repeating the analysis taking account of 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' tables

We will present the main results of the review in 'Summary of findings' tables. These tables present key information concerning the quality of the evidence, the magnitude of the effects of the interventions examined, and the sum of the available data for the main outcomes (Schünemann 2011a). 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). The GRADE approach defines the quality 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. The quality of a body of evidence involves consideration of within‐study risk of bias (methodological quality), directness of evidence, heterogeneity, precision of effect estimates and risk of publication bias (Schünemann 2011b). We plan to present the following outcomes in the 'Summary of findings' tables:

• Sleep quality

• Sleep onset latency

• Sleep efficiency

• Health‐related quality of life

• Fatigue

• Depression

• Major cardiovascular event

Appendices

Appendix 1. Electronic search strategies

Database	Search terms
CENTRAL	MeSH descriptor: [Sleep] explode all trees MeSH descriptor: [Sleep Disorders] explode all trees MeSH descriptor: [Sleep Apnea Syndromes] explode all trees sleep*:ti,ab,kw (Word variations have been searched) {or #1‐#4} MeSH descriptor: [Kidney Diseases] explode all trees MeSH descriptor: [Renal Replacement Therapy] explode all trees MeSH descriptor: [Renal Insufficiency] explode all trees MeSH descriptor: [Renal Insufficiency, Chronic] explode all trees dialysis:ti,ab,kw (Word variations have been searched) hemodialysis or haemodialysis:ti,ab,kw (Word variations have been searched) hemofiltration or haemofiltration:ti,ab,kw (Word variations have been searched) hemodiafiltration or haemodiafiltration:ti,ab,kw (Word variations have been searched) kidney disease* or renal disease* or kidney failure or renal failure:ti,ab,kw (Word variations have been searched) ESRF or ESKF or ESRD or ESKD:ti,ab,kw (Word variations have been searched) CKF or CKD or CRF or CRD:ti,ab,kw (Word variations have been searched) CAPD or CCPD or APD:ti,ab,kw (Word variations have been searched) predialysis or pre‐dialysis:ti,ab,kw (Word variations have been searched) {or 6‐18} {and 5, 19}
MEDLINE	exp Sleep/ exp Sleep Disorders/ sleep$.tw. exp Sleep Apnea Syndromes/ or/1‐4 Kidney Diseases/ exp Renal Replacement Therapy/ Renal Insufficiency/ exp Renal Insufficiency, Chronic/ dialysis.tw. (hemodialysis or haemodialysis).tw. (hemofiltration or haemofiltration).tw. (hemodiafiltration or haemodiafiltration).tw. (kidney disease* or renal disease* or kidney failure or renal failure).tw. (ESRF or ESKF or ESRD or ESKD).tw. (CKF or CKD or CRF or CRD).tw. (CAPD or CCPD or APD).tw. (predialysis or pre‐dialysis).tw. or/6‐18 and/5,19
EMBASE	exp sleep disorder/ exp sleep/ sleep$.tw. or/1‐3 exp renal replacement therapy/ kidney disease/ chronic kidney disease/ kidney failure/ chronic kidney failure/ mild renal impairment/ stage 1 kidney disease/ moderate renal impairment/ severe renal impairment/ end stage renal disease/ renal replacement therapy‐dependent renal disease/ kidney transplantation/ (hemodialysis or haemodialysis).tw. (hemofiltration or haemofiltration).tw. (hemodiafiltration or haemodiafiltration).tw. dialysis.tw. (CAPD or CCPD or APD).tw. (kidney disease* or renal disease* or kidney failure or renal failure).tw. (CKF or CKD or CRF or CRD).tw. (ESRF or ESKF or ESRD or ESKD).tw. (predialysis or pre‐dialysis).tw. ((kidney or renal) adj (transplant* or graft* or allograft*)).tw. or/5‐26 and/4,27

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. Coordinate the review: Suetonia Palmer

2. Draft the protocol: Suetonia Palmer

3. Study selection: Patrizia Natale, Suetonia Palmer

4. Extract data from studies: Patrizia Natale, Marinella Ruospo

5. Enter data into RevMan: Patrizia Natale, Marinella Ruospo

6. Carry out the analysis: Patrizia Natale, Suetonia Palmer

7. Interpret the analysis: All authors

8. Draft the final review: Suetonia Palmer

9. Keep the review up to date: Suetonia Palmer

Declarations of interest

None known.

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