Types of studies

We will include all published, unpublished and ongoing randomised controlled trials (RCTs) to compare the reduction of dialysate temperature and normal temperature for IDH in HD patients.

Cluster RCTs will be eligible if the number of clusters or the average size of each cluster, the outcome data ignoring cluster design for the total number of individuals, and an estimate of intracluster (or intraclass) correlation coefficient (ICC) are available.

We will include data from cross‐over RCTs but will only consider data from the first period.

We will include quasi‐randomised trials (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) but exclude observational studies. No language restriction will be applied.

Types of participants

Types of interventions

The experimental conditions are any methods of reduction of dialysate temperature. We will consider the following comparisons.

1. Fixed reduction of dialysate temperature (below 36°C) versus standard dialysate temperature (37°C to 37.5°C)

2. Reduction of core temperature (below 36°C) using biofeedback device versus standard dialysate temperature (37°C to 37.5°C)

3. Isothermic dialysis defined as maintenance of core temperature using biofeedback device versus standard dialysate temperature (37°C to 37.5°C)

4. Reduction of arterial temperature using biofeedback device versus fixed reduction of dialysate temperature (below 36°C)

5. Isothermic dialysis defined as maintenance of artery temperature using biofeedback device versus fixed reduction of dialysate temperature (below 36°C)

6. Reduction of arterial temperature using biofeedback device versus isothermic dialysis defined as maintenance of arterial temperature using biofeedback device

7. Any other methods of reduction of dialysate temperature versus standard dialysate temperature (37°C to 37.5°C).

Types of outcome measures

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 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 trials to investigators known to be involved in previous studies.

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 a structured, pilot‐tested Excel data extraction form. Any disagreement will be resolved by discussion with a further author acting as an arbiter. The data extraction form included the following items.

• General information: title, authors, year of publication, trial registration number, language, and country

• Study characteristics including design, and setting

• Participants: total number, number of each age, sex, and comorbidity

• Interventions and comparisons: types of reduction of dialysate, duration, and co‐intervention

• Outcome: definition of outcomes, number of participants allocated, number of missing participants, number of events (dichotomous outcomes), standard deviation and mean (continuous outcomes)

• Risk of bias and publication status.

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 using the risk of bias assessment tool (Higgins 2011) (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

Dichotomous outcomes results will be expressed as risk ratio (RR) with 95% confidence intervals (CI). For rate outcomes, results will be expressed as rate ratio with 95% CI.

Where continuous scales of measurement are used to assess the effects of treatment (BP, body temperature, and heart rate), the mean difference (MD) or the standardised mean difference (SMD) will be used, if different scales have been used.

If the studies included in a review may include a mixture of change‐from‐baseline and final value scores, we will use the (unstandardised) mean difference method in RevMan according to Chapter 9.4.5.2 of the Cochrane handbook (Higgins 2011).

Unit of analysis issues

Dealing with missing data

Any further information required from the original author will be requested by written correspondence (e.g. emailing or writing to corresponding authors) 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. Heterogeneity will then be analysed using a Chi² test on N‐1 degrees of freedom, with an alpha of 0.10 used for statistical significance since we expect that there are not many relevant studies, and with the I² test (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

We will first assess the heterogeneity by visual inspection of the forest plot.

If the number of eligible studies is 10 or more, Egger’s test will be used to assess for the potential existence of reporting bias (Higgins 2011).

Data synthesis

Data will be pooled using the random‐effects model.

Subgroup analysis and investigation of heterogeneity

Subgroup analysis for primary outcomes will be used to explore possible sources of heterogeneity. We will treat a trial as a subgroup with a covariate if more than 80% of the included participants in a trial have a covariate. We will test the following subgroups.

• Age: children (< 18 years), adults (18 to 75 years), and elderly (≥ 75 years)

• Comorbid conditions: history of diabetes mellitus, acute coronary syndrome, IDH, and current use of antihypertensive drugs

• Dialysis vintage: < 10 years and ≥ 10 years

• Dialysis modality: HD, HF, HDF

• We will perform the following subgroup analysis for IDH outcome:

  • IDH definition: IDH defined by symptoms or intervention for hypotensive episode (e.g. saline flush, or lowering of the UF), and IDH defined by SBP irrespective of symptoms or intervention.

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

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 restricting study with low risk of selection bias (i.e. adequate random sequence generation and random allocation)

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

• Repeating the analysis using fixed effect model instead of random effects model

• Repeating the analysis with restriction of the study to a trial protocol which excludes co‐interventions for IDH, such as mannitol, hypertonic saline, or vasoconstrictors.