Dialysate temperature reduction for intradialytic hypotension for people with chronic kidney disease requiring haemodialysis

Yasushi Tsujimoto; Hiraku Tsujimoto; Yukihiko Nakata; Yuki Kataoka; Miho Kimachi; Sayaka Shimizu; Tatsuyoshi Ikenoue; Shingo Fukuma; Yosuke Yamamoto; Shunichi Fukuhara

doi:10.1002/14651858.CD012598.pub2

. 2019 Jul 5;2019(7):CD012598. doi: 10.1002/14651858.CD012598.pub2

Dialysate temperature reduction for intradialytic hypotension for people with chronic kidney disease requiring haemodialysis

Yasushi Tsujimoto ^1,^✉, Hiraku Tsujimoto ², Yukihiko Nakata ³, Yuki Kataoka ⁴, Miho Kimachi ¹, Sayaka Shimizu ¹, Tatsuyoshi Ikenoue ¹, Shingo Fukuma ¹, Yosuke Yamamoto ¹, Shunichi Fukuhara ¹

Editor: Cochrane Kidney and Transplant Group

PMCID: PMC6609546 PMID: 31273758

Abstract

Background

Intradialytic hypotension (IDH) is a common complication of haemodialysis (HD), and a risk factor of cardiovascular morbidity and death. Several clinical studies suggested that reduction of dialysate temperature, such as fixed reduction of dialysate temperature or isothermal dialysate using a biofeedback system, might improve the IDH rate.

Objectives

This review aimed to evaluate the benefits and harms of dialysate temperature reduction for IDH among patients with chronic kidney disease requiring HD, compared with standard dialysate temperature.

Search methods

We searched Cochrane Kidney and Transplant's Specialised Register up to 14 May 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov.

Selection criteria

All randomised controlled trials (RCTs), cross‐over RCTs, cluster RCTs and quasi‐RCTs were included in the review.

Data collection and analysis

Two authors independently extracted information including participants, interventions, outcomes, methods of the study, and risks of bias. We used a random‐effects model to perform quantitative synthesis of the evidence. We assessed the risks of bias for each study using the Cochrane ’Risk of bias’ tool. We assessed the certainty of evidence using Grades of Recommendation, Assessment, Development and Evaluation (GRADE).

Main results

We included 25 studies (712 participants). Three studies were parallel RCTs and the others were cross‐over RCTs. Nineteen studies compared fixed reduction of dialysate temperature (below 36°C) and standard dialysate temperature (37°C to 37.5°C). Most studies were of unclear or high risk of bias. Compared with standard dialysate, it is uncertain whether fixed reduction of dialysate temperature improves IDH rate (8 studies, 153 participants: rate ratio 0.52, 95% CI 0.34 to 0.80; very low certainty evidence); however, it might increase the discomfort rate compared with standard dialysate (4 studies, 161 participants: rate ratio 8.31, 95% CI 1.86 to 37.12; very low certainty evidence). There were no reported dropouts due to adverse events. No study reported death, acute coronary syndrome or stroke.

Three studies compared isothermal dialysate and thermoneutral dialysate. Isothermal dialysate might improve the IDH rate compared with thermoneutral dialysate (2 studies, 133 participants: rate ratio 0.68, 95% CI 0.60 to 0.76; I² = 0%; very low certainty evidence). There were no reports of discomfort rate (1 study) or dropouts due to adverse events (2 studies). No study reported death, acute coronary syndrome or stroke.

Authors' conclusions

Reduction of dialysate temperature may prevent IDH, but the conclusion is uncertain. Larger studies that measure important outcomes for HD patients are required to assess the effect of reduction of dialysate temperature. Six ongoing studies may provide much‐needed high quality evidence in the future.

Plain language summary

Dialysate temperature reduction for intradialytic hypotension for people with chronic kidney disease requiring haemodialysis

What is the issue?

An increasing number of patients with chronic kidney disease need haemodialysis (HD). When the kidneys are not able to remove enough waste from the blood, HD is used to clean the blood and to remove the excess water via a dialysis machine. Intradialytic hypotension (IDH) is a common complication of HD that is characterized by a sudden drop in blood pressure (BP) with hypotensive symptoms such as dizziness, weakness, nausea, and fatigue, and is a risk factor of cardiovascular morbidity and mortality. In general, a decrease in body temperature is associated with contraction of vessels, and an increase in BP. However, the widely used dialysate temperature is 37°C, and the body temperature is likely to increase during standard dialysis. Removal of heat with cool dialysate might be beneficial to haemodynamic stability. Additionally, fixed empirical reduction of dialysate temperature is simple and easy to adopt in daily practice, however it can increase patient discomfort such as cold sensations, shivering, and related symptoms.

What did we do?

We collected all data from studies of patients with CKD requiring HD that reported data on IDH, discomfort rate and other important outcomes. We included 25 studies comprising 712 participants in the review, and performed meta‐analysis to estimate the effect of cooling dialysate.

What did we find?

The quality of included studies was generally very low due to the risk of bias, small sample size, and a lack of information.

We found very low quality evidence that fixed reduction of dialysate temperature decreased the incidence of IDH compared with standard dialysate and increased the discomfort rate. When patient discomfort is minimal, reduction of the dialysate temperature may be an option to reduce IDH. However, no study reported the long‐term outcomes such as death or heart disorders.

Conclusions

There is limited data suggesting that the reduction of dialysate temperature may prevent IDH, but the conclusion is very uncertain. Larger studies that measure important outcomes such as IDH or mortality for HD patients are required to assess the effect of reducing dialysate temperature.

Summary of findings

Background

Description of the condition

Chronic kidney disease (CKD) is a global concern. According to the 2010 Global Burden of Disease study, CKD was ranked 27th in the list of causes of total number of global deaths in 1990 (age‐standardized annual death rate of 15.7 per 100,000), but rose to 18th in 2010 (annual death rate 16.3 per 100,000) (Lozano 2012). The number of end‐stage kidney disease (ESKD) patients receiving renal replacement therapy (RRT) was more than 2 million in 2011, and increased approximately 8% annually (Couser 2011; White 2008). Haemodialysis (HD) is the main modality of RRT, with almost 90% of dialysis patients under maintenance HD (Jain 2012). Patients with maintenance HD gain weight because of their inability to excrete urine. The excess water is removed by ultrafiltration during HD.

Intradialytic hypotension (IDH) is a common complication of HD. There is no consensus on the definition of IDH, but IDH is commonly defined as a drop in blood pressure during dialysis procedure and/or hypotensive symptoms such as dizziness, weakness, nausea, cramps, blurred vision, and fatigue (Assimon 2017; K/DOQI 2005; Santoro 2002). The pathophysiology of IDH is diverse. It could be the result of an inadequate cardiovascular response to the reduction in blood volume that occurs when the ultrafiltration volume is large (Leypoldt 2002). One process may involve an imbalance between a reduced effective circulating volume and the compensatory plasma refilling mechanism, wherein fluid from the interstitial and intracellular space is translocated into the intravascular compartment (Nesrallah 2013). Additionally, IDH can also be induced by several vasoactive substances such as adenosine or nitric oxide, which may be synthesized or released during dialysis (Sulowicz 2006). Recent studies have shown that haemodynamic instability is associated with impaired baroreflex sensitivity; a decrease in asymmetric dimethylarginine (ADMA), a naturally occurring nitric oxide synthase inhibitor, and inadequate vasopressin response (Chesterton 2010; Csiky 2008; Dubin 2011; Thompson 2009). Another study using echocardiography suggests that a blood pressure (BP) drop within a HD session is associated with HD‐induced myocardial stunning (Burton 2009). Repeated decreases in organ perfusion due to IDH can introduce chronic organ injury over time (Nesrallah 2013). Moreover, several studies have shown an association between IDH and cardiovascular morbidity and mortality (Burton 2009; Sands 2014; Shoji 2004; Stefansson 2014; Tisler 2003). IDH is also associated with vascular access thrombosis, dysrhythmias, and mesenteric venous infarction (K/DOQI 2005). Risk factors associated with IDH include old age, female gender, Hispanic ethnicity, long dialysis vintage, high intradialytic weight gain, high dialysis dose, anaemia, diabetes, low predialysis BP, high osmolarity, and high body mass index (Mc Causland 2013; Mc Causland 2015; Sands 2014; Stefansson 2014; K/DOQI 2005).

Description of the intervention

Dialysate is heated by heating elements in the HD machine as the blood temperature decreases through an extracorporeal circuit. The widely used dialysate temperature is 37°C (Daugirdas 2007; K/DOQI 2005; Toth‐Manikowski 2016). The body temperature is likely to increase during standard dialysis with the dialysate temperature of 37°C (Rosales 2000). The dialysis procedure itself affects body temperature regulation. There have been several clinical studies that investigated the effect of reduction of dialysate temperature for haemodynamic stability (Jost 1993; Maggiore 2002; van der Sande 2009; Zitt 2008). A simple intervention for lowering blood temperature is fixed empirical reduction of dialysate temperature. Alternative interventions are implemented by monitoring blood temperature (core temperature) in the arterial and venous bloodline (Selby 2006). This biofeedback system can adjust the dialysate temperature in response to the calculated body temperature and enable the implementation of isothermic dialysis, in which arterial temperature remains unchanged from the patient’s baseline level (van der Sande 2009). In contrast, lower dialysate temperature may cause high frequency of discomfort, a cold sensation, or shivering (K/DOQI 2005).

How the intervention might work

Peripheral and cutaneous vasoconstriction is considered an important component for the ultrafiltration‐induced decrease in blood volume (Schneditz 2003). HD patients tend to be hypovolaemic as ultrafiltration progresses during HD (Bos 2000; Leypoldt 2002). Hypovolaemia causes underfilling in the cardiac chambers, then cardiovascular response increases the arteriolar or venous tone. However, patients with impaired cardiovascular response cannot offset the volume reduction, and suffer a drop in BP (Santoro 2002). In general, a decrease in body temperature is associated with a decrease in blood flow to the compliant cutaneous circulation, an increase in total peripheral resistance, and an increase in BP (Schneditz 2003). One study reported that left ventricular contractility increased during cool dialysis (Levy 1992), while another observed that SBP was higher in the cool dialysate group but core temperature remained stable during dialysis (van der Sande 1999). Removal of heat with cool dialysate might activate autoregulatory mechanisms to preserve core temperature, which results in beneficial haemodynamic stability. In addition, a recent study showed the protective effect of cooling dialysate on dialysis‐induced ischaemic brain injury (Eldehni 2015).

Why it is important to do this review

IDH remains an issue for chronic HD patients. The frequency of IDH was reported as 20% to 30% among patients undertaking HD (Davenport 2008a; Davenport 2008b). In addition, the incidence of IDH is likely to rise because an increasing number of older patients are expected to develop ESKD (K/DOQI 2005). Since IDH could introduce clinically relevant complications such as mortality and cardiovascular morbidity, evaluation of easy, cost‐effective, and safe interventions should be evaluated to address this problem. Reduction of dialysate temperature could be an easy intervention for preventing IDH. The intervention could also be applied to patients in various settings because standard dialysis consoles have a dialysate temperature regulator; therefore, it can be applied universally and reduce the need for nursing involvement (Eldehni 2015; Toth‐Manikowski 2016). Further, no additional cost is needed to conduct fixed reduction of dialysate temperature. While there are various methods of reducing dialysate temperature, optimal temperature or methods of temperature reduction to prevent IDH remain uncertain (Maggiore 2002; Santoro 2002; Selby 2006; Toth‐Manikowski 2016). A recent systematic review has reported the effect of cooling dialysis on IDH; however, the study has several limitations, including non‐reporting of the risk of bias judgment, assessment of the carry‐over effect for the cross‐over studies (if there was IDH in the session before cross‐over, the patients and medical staffs would try to prevent it in the session after cross‐over), exclusion of comparisons between different types of cooling methods, and exclusion of children and modalities other than HD (Mustafa 2016). To that end, we conducted a systematic review of the effects and harms of reduction of dialysate temperature.

Objectives

This review aimed to evaluate the benefits and harms of dialysate temperature reduction for IDH among patients with CKD requiring HD, compared with standard dialysate temperature. In addition, we compared the benefits and harms of different types of dialysate temperature reduction for IDH.

Methods

Criteria for considering studies for this review

Types of studies

We included 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 were eligible if the number of clusters or the average size of each cluster, the outcome data regardless of cluster design for the total number of individuals, and an estimate of intracluster (or intraclass) correlation coefficient (ICC) were available.

We included data from cross‐over RCTs.

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

Types of participants

Inclusion criteria

All patients undergoing maintenance HD, haemofiltration (HF) and haemodiafiltration (HDF) with minimum dialysis vintage of three months.

Exclusion criteria

Patients on peritoneal dialysis
Patients undergoing continuous RRT
Patients undergoing sustained low‐efficiency dialysis (SLED)
Patients undergoing home HD.

Types of interventions

The experimental conditions were any methods of reduction of dialysate temperature. We considered the following comparisons.

Fixed reduction of dialysate temperature (below 36°C) versus standard dialysate temperature (37°C to 37.5°C)
Reduction of core temperature (below 36°C) using a biofeedback device versus standard dialysate temperature (37°C to 37.5°C)
Isothermic dialysis defined as maintenance of core temperature using a biofeedback device versus standard dialysate temperature (37°C to 37.5°C)
Reduction of arterial temperature using a biofeedback device versus fixed reduction of dialysate temperature (below 36°C)
Isothermic dialysis defined as maintenance of artery temperature using a biofeedback device versus fixed reduction of dialysate temperature (below 36°C)
Reduction of arterial temperature using biofeedback device versus isothermic dialysis defined as maintenance of arterial temperature using a biofeedback device
Any other methods of reduction of dialysate temperature versus standard dialysate temperature (37°C to 37.5°C).

Types of outcome measures

Primary outcomes

IDH rate (the proportion of dialysis sessions with episodes of IDH during follow‐up) was defined as follows.
- Intradialytic decrease in systolic blood pressure (SBP) by 20 mmHg or more, or a decrease in mean arterial pressure (MAP) by 10 mmHg associated with symptoms that include abdominal discomfort, yawning, sighing, nausea, vomiting, muscle cramps, restlessness, dizziness, and anxiety (K/DOQI 2005).
- Decrease in SBP by 20 mmHg or more, or in MAP by 10 mmHg or more, associated with a clinical event and the need for nursing intervention (Kooman 2007).
- Drop in SBP to < 90 mmHg or an absolute value > 30 mmHg, associated with symptoms of hypotension and lack of response to the supine position, but necessitating resuscitation with intravenous normotonic or hypertonic fluid administration (Tisler 2003).
- Decrease in SBP of at least 10 mmHg or a SBP of < 100 mmHg, with symptoms such as cramps, nausea, vomiting, and dizziness (Fortin 2010).
- Drop in SBP < 90 mmHg or of at least 20 mmHg with accompanying clinical symptoms (Maheshwari 2015).
- Hypotensive episode requiring either saline infusion, lowering of the ultrafiltration rate (UF) or reduction in blood flow during the HD session (Mc Causland 2013).
- Intradialytic decrease in SBP by > 30 mmHg to a level of < 90 mmHg (Sands 2014).
- 40 mmHg drop in SBP (Shoji 2004).
- We also accepted criteria that was similar to the above.
Death (all causes)
Discomfort rate defined as a cold sensation, shivering, and related symptoms.

Secondary outcomes

Acute coronary syndrome: diagnosis based on electrocardiographic changes, elevation of enzymes or confirmed during post‐mortem examination.
All strokes: sudden focal neurologic deficit caused by cerebrovascular thrombosis, and categorized as ischaemic, haemorrhagic, or unspecified.
Quality of life (QoL) measured by a validated scale system such as Kidney Disease Quality of Life (KDQoL), or Choices for Healthy Outcomes in Caring for ESRD (CHOICE) Health Experience Questionnaire (CHEQ) (Hays 1994; Wu 2001).
Dropout rate due to adverse events.
Rate of vasoconstrictor use (defined as any use of vasoconstrictor per dialysis session).
Lowest SBP during dialysis. If the authors reported any BP measure other than the lowest SBP during dialysis, we extracted it according to the following hierarchy: i) the lowest mean BP (MBP) during dialysis; ii) SBP at the end of dialysis; iii) MBP at the end of dialysis; iv) mean SBP during dialysis, and v) mean MBP during dialysis.
Lowest body temperature (BT) during dialysis.
Urea clearance‐based dialysis adequacy (Kt/V_urea).
Vascular thrombosis defined as an access that has clotted, without blood flow in patients with arteriovenous fistula or graft.
New onset dysrhythmias.
Mesenteric venous thrombosis.
Post‐HD fatigue measured by a validated scale system such as the Fatigue Severity Scale (Krupp 1989).

Search methods for identification of studies

Electronic searches

We searched the Cochrane Kidney and Transplant Specialised Register up to 14 May 2019 through contact with the Information Specialist using search terms relevant to this review. The Specialised Register contains studies identified from the following sources.

Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL).
Weekly searches of MEDLINE OVID SP.
Handsearching of kidney‐related journals and the proceedings of major kidney conferences.
Searching of the current year of EMBASE OVID SP.
Weekly current awareness alerts for selected kidney and transplant journals.
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, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available on the Cochrane Kidney and Transplant website.

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

Searching other resources

Reference lists of review articles, relevant studies and clinical practice guidelines.
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 was used to obtain titles and abstracts of studies that may be relevant to the review. The titles and abstracts were screened independently by two authors, who discarded studies that were not applicable; however, studies and reviews that might include relevant data or information on studies were retained initially. Two authors independently assessed retrieved abstracts and, if necessary, the full text of these studies to determine which studies satisfied the inclusion criteria.

Data extraction and management

Two authors carried out data extraction independently using a structured, pilot‐tested Excel data extraction form. Any disagreements were 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: 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.

We translated any studies reported in non‐English language journals before assessment. Where more than one publication of one study existed, we grouped reports together and used the publication with the most complete data in the analyses. Where relevant outcomes were only published in earlier versions, the authors used these data. The authors also highlighted any discrepancies between published versions.

Assessment of risk of bias in included studies

Two authors independently assessed the following items 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 were expressed as risk ratios (RR) with 95% confidence intervals (CI). For rate outcomes, results were expressed as rate ratios with 95% CI. In the case of zero events, we added 0.5 to each count according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Where continuous scales of measurement were used to assess the effects of treatment (BP, body temperature, and heart rate), we used the mean difference (MD).

If the studies included in a review included a mixture of change‐from‐baseline and final value scores, we used the MD method in RevMan according to Chapter 9.4.5.2 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Unit of analysis issues

Cluster randomised studies

For dichotomous data, we applied the design effect and calculated effective sample size and number of events using ICC and the average cluster size, as described in chapter 16.3.5 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

If the ICC was not reported, we used the ICC of similar studies as a substitute. For continuous data, only the sample size was reduced; means and standard deviation remained unchanged (Higgins 2011).

Randomised cross‐over studies

In the protocol, we planned to consider only data from the first period.

However, there was no study that reported first period data, and we could not obtain the data from any included studies by contacting the authors. We therefore used paired data that were potentially affected by carry‐over effects, and judged the risk of bias due to carry‐over effects in the other bias domain.

For multiple‐arm studies, we included all intervention groups that were relevant to the review.

Dealing with missing data

We requested any further information required from the original author by written correspondence (e.g. emailing or writing to corresponding authors) and included any relevant information obtained in this manner in the review. We carefully evaluated important numerical data such as screened, randomised patients as well as intention‐to‐treat, as‐treated and per‐protocol population, and investigated attrition rates, e.g. drop‐outs, losses to follow‐up and withdrawals. The authors also critically appraised issues of missing data and imputation methods (e.g. last‐observation‐carried‐forward) (Higgins 2011).

Assessment of heterogeneity

We first assessed the heterogeneity by visual inspection of the forest plot. Heterogeneity was then analysed using a Chi² test on N‐1 degrees of freedom, with an alpha of 0.10 used for statistical significance, and with the I² test (Higgins 2003). We interpreted the I² values as follows.

0% to 40%: might not be important
30% to 60%: moderate heterogeneity
50% to 90%: might 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 2011).

Assessment of reporting biases

We assessed heterogeneity by visual inspection of the forest plot.

If the number of eligible studies was 10 or more, we planned to use Egger’s test to assess the potential existence of reporting bias (Higgins 2011).

Data synthesis

Data were pooled using the random‐effects model.

Subgroup analysis and investigation of heterogeneity

Where possible, we used subgroup analyses for primary outcomes to explore possible sources of heterogeneity. We treated a study as a subgroup with a covariate if more than 80% of the included participants in a study had a covariate. We tested 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 performed 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

Sensitivity analysis

Where possible, we performed sensitivity analyses in order to explore the influence of the following factors on effect size.

Repeating the analysis excluding unpublished studies
Repeating the analysis restricted to studies 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 dominated the results
Repeating the analysis using a fixed‐effect model instead of random‐effects model
Repeating the analysis restricted to a study protocol that excludes co‐interventions for IDH, such as mannitol, hypertonic saline, or vasoconstrictors.

'Summary of findings' tables

We presented the main results of the review in 'Summary of findings' tables. These tables presented 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 (Schunemann 2011a). The 'Summary of findings' tables also included 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‐trial risk of bias (methodological quality), directness of evidence, heterogeneity, precision of effect estimates and risk of publication bias (Schunemann 2011b).

We presented the following outcomes in the 'Summary of findings' tables.

Death (all causes)
Acute coronary syndrome
Stroke
IDH rate
Rate of dropout due to adverse events
Discomfort rate.

Results

Description of studies

Results of the search

We identified 67 records. After screening titles and abstracts 52 records potentially met our inclusion criteria and after full‐text review 25 studies (38 records) were included and 7 studies (9 records) were excluded. Four ongoing studies were identified (IRCT201306268140N2; IRCT2016060228219N1; Maheshwari 2015; MY TEMP 2017). One study (Kuhlmann 1996) was potentially eligible but has not been incorporated into the review due to a lack of information. These studies and will be assessed in a future update of this review (Figure 1).

Included studies

See Characteristics of included studies.

Study design

Three studies were parallel RCTs (Niyyar 2006; Odudu 2012; Rad 2017) and 22 were cross‐over RCTs.

Sample size

Included studies were mainly small. Samples sizes ranged from 5 to 113 participants. Five studies included 50 or more participants (Ebrahimi 2017; Maggiore 2002; Odudu 2012; Rad 2017; Santoro 2002a).

Setting

Studies were mainly conducted in single centres. Twelve studies did not state the setting of participant recruitment (Beerenhout 2004; Gritters 2005; Manning 1995; Marants 2018; Niyyar 2006; Quereda 1988; Santoro 2002a; Selby 2006b; Shin 1994; Sterrett 1999; van der Sande 2009; Zitt 2008).

Participants

Different types of participants were included in different studies including stable, hypotension‐prone, or those not taking α‐ or β‐adrenergic blocking antihypertensive therapy. Eight studies did not report any eligibility criteria (Manning 1995; Marants 2018; Quereda 1988; Santoro 2002a; Sherman 1984; Sterrett 1999; van der Sande 2000; van der Sande 2001).

Interventions

Nineteen studies compared fixed reduction of dialysate temperature (below 36°C) and standard dialysate temperature (37°C to 37.5°C) (Ayoub 2004; Beerenhout 2004; Ebrahimi 2017; Gritters 2005; Jost 1993; Levy 1992; Manning 1995; Marants 2018; Odudu 2012; Parker 2007; Quereda 1988; Rad 2017; Sajadi 2016; Selby 2006b; Sherman 1984; Shin 1994; van der Sande 2000; van der Sande 2001; Zitt 2008). The differences in the prescribed dialysate temperature in the intervention and the control arms varied from 1°C to 2.2°C. Three studies used a biofeedback device and compared isothermal dialysate and thermoneutral dialysate (Maggiore 2002; Santoro 2002a; van der Sande 2009). In all studies, thermal balance was controlled by means of a Blood Temperature Monitor (BTM; Fresenius Medical Care, Bad Homberg, Germany). Of these, one study also compared reduction of arterial temperature using a biofeedback device, and isothermic dialysate and thermoneutral dialysate (van der Sande 2009). Two studies compared standard dialysate temperature and dialysate temperature set to the individualized tympanic temperature, measured by tympanic thermometer (Jefferies 2011; Sterrett 1999). One study compared standard dialysate and dialysate temperature individualized to each subject, 1°C lower than their mean pre‐dialysis oral temperature (Niyyar 2006).

Outcomes

We requested further information, including the first phase data of cross‐over studies such as baseline characteristics or outcomes, from the corresponding authors. The data were no longer available for Niyyar 2006, and we received no response from any other authors (Ayoub 2004; Beerenhout 2004; Ebrahimi 2017; Gritters 2005; Jefferies 2011; Jost 1993; Levy 1992; Maggiore 2002; Parker 2007; Quereda 1988; Sajadi 2016; Santoro 2002a; Selby 2006b; Sherman 1984; Shin 1994; Sterrett 1999; van der Sande 2000; van der Sande 2001; van der Sande 2009; Zitt 2008). The following reported outcomes included data based on paired comparisons.

IDH: 10 studies (286 participants) (Ayoub 2004; Ebrahimi 2017; Gritters 2005; Jost 1993; Levy 1992; Maggiore 2002; Quereda 1988; Selby 2006b; Sherman 1984; van der Sande 2009). The definition of IDH varied across studies. Five studies used the definition of a fall of systolic BP below 90 to 100 mmHg or a decrease of systolic BP by more than 10 mmHg, accompanied with hypotensive symptoms (Ayoub 2004; Jost 1993; Maggiore 2002; Sherman 1984; van der Sande 2009). Two studies defined IDH as systolic blood pressure < 90 mmHg irrespective of symptoms (Levy 1992; Quereda 1988), and two studies used a composite of those definitions above (Ebrahimi 2017; Selby 2006b). Gritters 2005 did not describe the definition of IDH
Discomfort rate due to cool dialysate: 7 studies (189 participants) (Ayoub 2004; Ebrahimi 2017; Jefferies 2011; Sajadi 2016; Selby 2006b; van der Sande 2000; van der Sande 2009).
QoL: one study (10 participants) examined QoL (Selby 2006b)
Dropout rate due to adverse events: 12 studies (412 participants) (Beerenhout 2004; Ebrahimi 2017; Jefferies 2011; Jost 1993; Levy 1992; Maggiore 2002; Odudu 2012; Parker 2007; Quereda 1988; Rad 2017; Selby 2006b; van der Sande 2009)
Blood pressure: 18 studies (415 participants) (Ayoub 2004; Beerenhout 2004; Ebrahimi 2017; Gritters 2005; Jefferies 2011; Jost 1993; Levy 1992; Manning 1995; Maggiore 2002; Parker 2007; Quereda 1988; Selby 2006b; Sherman 1984; Shin 1994; Sterrett 1999; van der Sande 2000; van der Sande 2001; van der Sande 2009; Zitt 2008).
Body temperature: 8 studies (205 participants) (Ayoub 2004; Beerenhout 2004; Jefferies 2011; Jost 1993; Maggiore 2002; van der Sande 2000; van der Sande 2001; van der Sande 2009).
Kt/V_urea: 2 studies (Ayoub 2004; Maggiore 2002).
Death (all causes), acute coronary syndrome, or all strokes were no reported by any of the included studies.

Excluded studies

Seven studies were excluded (see Characteristics of excluded studies).

Two studies (Lima 2006; Lima 2012) were of participants with acute kidney injury and one study (NCT02593526) was of HD‐naive participants. One study had a co‐intervention other than dialysate temperature in the intervention group (Veljancic 2011): one study (Maggiore 1987) compared standard dialysate and warmer dialysate, one study (Dheenan 2001) compared cold dialysate and different sodium concentration, and one study (Hecking 2012a) used blood volume‐monitored regulation as an intervention.

Risk of bias in included studies

Most studies were of unclear or high risk of bias. See Figure 2 and Figure 3.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Random sequence generation

One study (Odudu 2012) used a computer‐generated random sequence. The other studies gave no indication or stated only “block randomisation” and were categorized as unclear.

Allocation concealment

One study (Maggiore 2002) used central randomisation, and one study (Odudu 2012) used sealed envelopes. The other studies gave no description and were categorized as unclear.

Blinding

Performance bias

We judged that blinding of the intervention was broken due to the nature of the intervention when studies compared fixed reduction of dialysate temperature (below 36°C) and standard dialysate temperature. Santoro 2002a compared energetically neutral dialysis (a net thermal energy transfer from the dialysate to the blood circuit equal to zero) and thermally neutral dialysis (the pre‐dialysis patient core temperature was constant). This study was categorized as unclear because it was not clear whether the participants were aware of the intervention and there was no description about blinding.

Detection bias

Outcome assessors were blinded in two studies (Ebrahimi 2017; Rad 2017). Three studies were open label and were judged as high risk (Maggiore 2002; Odudu 2012; Selby 2006b). Other studies gave no description and were categorized as unclear.

Incomplete outcome data

Three studies were classified as high risk for incomplete outcomes because of the exclusion of more than 10% of participants from the final analysis (Maggiore 2002; Odudu 2012; van der Sande 2009). Six studies were classified as low risk (Beerenhout 2004; Ebrahimi 2017; Jefferies 2011; Jost 1993; Levy 1992; Parker 2007) as all or almost all participants were followed up, however, it should be noted that the first phase data of these studies were absent. Other studies were categorized as unclear.

Selective reporting

Five studies referred to their protocols (Ebrahimi 2017; Odudu 2012; Rad 2017; Sajadi 2016; Selby 2006b), but one was not accessible because the registry website was archived (Selby 2006b). Four studies with available protocols did not report pre‐defined outcomes, and did not pre‐define the cut‐off or reported outcomes with multiple cut‐offs (Ebrahimi 2017; Odudu 2012; Rad 2017; Sajadi 2016).

Other potential sources of bias

We judged cross‐over RCTs to be at high risk of bias due to the carry‐over effect. Moreover, we could not assess the baseline imbalance because these studies did not report the baseline characteristics classified by the interventions that the participants were allocated to in the first phase of the studies.

Effects of interventions

See: Table 1; Table 2

Summary of findings for the main comparison. Fixed reduction of dialysate temperature compared to standard dialysate temperature for patients requiring haemodialysis.

Fixed reduction of dialysate temperature compared to standard dialysate temperature for patients requiring haemodialysis
Patient or population: patients requiring haemodialysis  Setting: dialysis centre  Intervention: fixed reduction of dialysate temperature  Comparison: standard dialysate temperature
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
	Risk with standard dialysate temperature	Risk with fixed reduction of dialysate temperature
Intradialytic hypotension rate  follow up: median 3 weeks	251 episodes per 1,000 person‐dialysis session	131 episodes per 1,000 person‐dialysis session  (85 to 201)	RR 0.52  (0.34 to 0.80)	153 (8)	⊕⊝⊝⊝  VERY LOW ^{1 2}
Discomfort rate  Follow up: median 4 weeks	25 episodes per 1,000 person‐dialysis session	208 episodes per 1,000 person‐dialysis session  (47 to 928)	Rate ratio 8.31  (1.86 to 37.12)	81 (4)	⊕⊝⊝⊝  VERY LOW ^{1 2}
Dropout due to adverse events  Follow up: median 3 weeks	Nine studies (268 participants) reported there were no dropouts due to adverse events		‐	268 (9)	Not graded
Death (all causes)	No studies reported the outcome		‐	‐	‐
Acute coronary syndrome	No studies reported the outcome		‐	‐	‐
Stroke	No studies reported the outcome		‐	‐	‐
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    RR: risk ratio; CI: Confidence interval
GRADE Working Group grades of evidence  High certainty: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Isothermal dialysate compared to thermoneutral dialysate in patients requiring haemodialysis
Patient or population: patients requiring haemodialysis  Setting: dialysis centre  Intervention: isothermal dialysate  Comparison: thermoneutral dialysate
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
	Risk with thermoneutral dialysate	Risk with Isothermal dialysate
Intradialytic hypotension rate  follow up: range 3 to 8 weeks	410 episodes per 1,000 person‐dialysis session	279 episodes per 1,000 person‐dialysis session  (246 to 312)	Rate ratio 0.68  (0.60 to 0.76)	133 (2)	⊕⊝⊝⊝  Very low ^{1 2}
Discomfort rate  Follow up: mean 3 weeks	One study reported that none of the patients allocated to isothermal or thermoneutral dialysate experienced shivering		‐	17 (1)	Not graded
Dropout due to adverse event  follow up: range 3 to 8 weeks	There were no reported dropouts due to adverse events in the 2 studies		‐	133 (2)	Not graded
Death (all causes)	No study reported the outcome		‐	‐	‐
Acute coronary syndrome	No study reported the outcome		‐	‐	‐
Stroke	No study reported the outcome		‐	‐	‐
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: Confidence interval
GRADE Working Group grades of evidence  High certainty: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Database	Search terms
CENTRAL	dialysis:ti,ab,kw hemodialysis or haemodialysis):ti,ab,kw hemodiafiltration or haemodiafiltration):ti,ab,kw (hemofiltration or haemofiltration):ti,ab,kw {or #1‐#4} (dialysis next solution):ti,ab,kw ((hemodialysis next solution) or (haemodialysis next solution)):ti,ab,kw (dialysis next fluid):ti,ab,kw ((hemodialysis next fluid) or (haemodialysis next fluid)):ti,ab,kw dialyate:ti,ab,kw {or #6‐#10} temperature:ti,ab,kw heat:ti,ab,kw cold:ti,ab,kw cool:ti,ab,kw warm:ti,ab,kw tepid:ti,ab,kw lukewarm:ti,ab,kw {or #12‐#18} {and #5, #11, #19}
MEDLINE	Renal Replacement Therapy/ Renal Dialysis/ Hemodiafiltration/ Hemodialysis, home/ exp Hemofiltration/ dialysis.tw. (hemodialysis or haemodialysis).tw. (hemofiltration or haemofiltration).tw. (hemodiafiltration or haemodiafiltration).tw. or/1‐9 exp Dialysis Solutions/ dialysis solution$.tw. dialysis fluid$.tw. (hemodialysis solution$ or haemodialysis solution$).tw. (hemodialysis fluid$ or haemodialysis fluid$).tw. dialy#ate$.tw. or/11‐16 exp Temperature/ temperature.tw. reduc$.tw. heat$.tw. cool$.tw. cold$.tw. warm$.tw. tepid.tw. lukewarm.tw. or/18‐26 and/10,17,27
EMBASE	exp renal replacement therapy/ extended daily dialysis/ hemodialysis/ home dialysis/ hemofiltration/ hemodiafiltration/ dialysis.tw. (hemodialysis or haemodialysis).tw. (hemofiltration or haemofiltration).tw. (hemodiafiltration or haemodiafiltration).tw. renal replacement therapy‐dependent renal disease/ or/1‐11 Hemodialysis Fluid/ Dialysis Fluid/ Dialysate/ dialysis solution$.tw. dialysis fluid$.tw. (hemodialysis solution$ or haemodialysis solution$).tw. (hemodialysis fluid$ or haemodialysis fluid$).tw. dialy#ate$.tw. or/13‐20 Temperature/ Heat/ Cold/ High Temperature/ Low Temperature/ temperature.tw. heat$.tw. cool$.tw. cold$.tw. warm$.tw. tepid.tw. lukewarm.tw. or/22‐33 and/12,21,34

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.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Intradialytic hypotension	8		Rate Ratio (Random, 95% CI)	0.52 [0.34, 0.80]
2 Discomfort rate: cold sensation, shivering, and related symptoms	4		Rate Ratio (Random, 95% CI)	8.31 [1.86, 37.12]
3 Mean BP at the end of dialysis	8	188	Mean Difference (IV, Random, 95% CI)	6.46 [2.84, 10.08]
4 Change in body temperature during dialysis	5	102	Mean Difference (IV, Random, 95% CI)	‐0.44 [‐0.56, ‐0.32]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Intradialytic hypotension	2		Rate Ratio (Random, 95% CI)	0.68 [0.60, 0.76]
2 Change in SBP during dialysis	2	266	Mean Difference (IV, Random, 95% CI)	6.59 [2.44, 10.74]
3 Change in body temperature during dialysis	2	266	Mean Difference (IV, Random, 95% CI)	‐0.40 [‐0.60, ‐0.21]

Methods	Study design: cross‐over RCT Follow‐up period: 3 months Duration of study: April 2002 to June 2002
Participants	Country: New Zealand Setting: single centre Inclusion criteria: not reported Number: 10; hypotension‐prone group (5); stable BP group (5) Mean age ± SD: 59.8 ± 5.5 years Sex: not reported Exclusion criteria: recent surgical intervention; severe anaemia; problems related to vascular access; coronary artery disease; AKI; recent illnesses
Interventions	Treatment arm Cool dialysate temperature (35℃) for 3 dialysis sessions Control arm Standard dialysate temperature (36.5℃) for 3 dialysis sessions
Outcomes	IDH rate Discomfort rate defined as cold sensation, shivering, and related symptoms Mean SBP during dialysis Body temperature during dialysis Urea clearance‐based dialysis adequacy (Kt/V_urea)
Notes	Funding source: none We requested further information but there was no response
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study was described as randomised; method of randomisation was not reported
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Patients were informed about the temperature of each dialysis session, as they can feel  the cool dialysis
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Insufficient information to permit judgement: no description about the first phase data including missing values; dropouts not reported
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement: the protocol was not available
Other bias	High risk	Carry‐over effects potentially existed; no description for the assessment of the baseline imbalance of first period of the cross‐over study

Methods	Study design: parallel RCT Follow‐up period: 12 months Duration of study: not reported
Participants	Country: USA Setting: not reported Inclusion criteria: stable HD patients Number: treatment group (11); control group (13) Age: not reported Sex (M/F): not reported Exclusion criteria: not reported
Interventions	Treatment group Dialysate temperature individualized to each subject, 1°C lower than their mean pre‐dialysis oral temperature Control group Dialysate temperature 37°C
Outcomes	Dropout rate due to adverse events Pre‐dialysis SBP
Notes	Abstract‐only publication Funding source: NINR‐NR004340 We requested further information but the data were no longer available
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study was described as randomised; method of randomisation was not reported
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Blinding was not feasible because of the nature of the intervention
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Insufficient information to permit judgement: No description about the missing data
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement: The protocol was not available
Other bias	Unclear risk	Insufficient information to permit judgement: No description for the assessment of the baseline imbalance

Study	Reason for exclusion
Dheenan 2001	Wrong interventions: cool dialysate versus dialysate with higher sodium concentration
Hecking 2012a	Wrong interventions: cool dialysate in combination with blood volume‐monitored regulation
Lima 2006	Wrong population: patients with AKI
Lima 2012	Wrong population: patients with AKI
Maggiore 1987	Wrong interventions: warmer dialysate (39°C to 41°C) versus standard dialysate
NCT02593526	Wrong population: patients were HD naive (Patient may still enrol as long as no more than 12 weeks of in‐centre HD have been performed prior to randomisation)
Veljancic 2011	Wrong interventions: wool dialysate in combination with blood volume monitoring

Methods	Study design: unclear Follow‐up period: not reported Duration of study: not reported
Participants	Country: Germany Setting: not reported Inclusion criteria: not reported Enrolled: 28 Age: not reported Sex: not reported Exclusion criteria: not reported
Interventions	Treatment arm Intended maintenance of BT Control arm Standard extracorporeal HD defined by a constant dialysate temperature of 37°C
Outcomes	MAP
Notes	We could not judge whether the study design was randomised to the limited information

Trial name or title	Effect of lowering dialysate temperature on the quality of haemodialysis in patients undergoing haemodialysis in 5t Azar hospital
Methods	Single‐centre cross‐over RCT
Participants	Inclusion criteria The samples included the patients undergoing HD at 5th Azar Hospital having: hypotension in more than 30% of dialysis sessions (more than three sessions), during one month before the study; 3 times dialysis/week with sodium bicarbonate solution; patients did not receive analgesic, anti‐hypertensive and anti‐spasm during four hours before dialysis; no history of chronic infections, heart failure, chronic lung disease, drugs or alcohol abuse or required treatment for mental disorders, severe anaemia, coronary artery disease; aged > 18 years old and more than 3 month's dialysis treatment
Interventions	In cross‐over study, patients are assessed during 24 dialysis sessions; the first group received HD for 12 sessions using cool dialysate (35.5°C) and the second group is on HD with standard dialysate temperature (37°C). Then the method of treatment is replaced in two groups for the next 12 sessions. Each patient gets dialysis once with routine temperature and once with cool dialysate. Patients are assessed during 24 dialysis sessions; the first group receives HD for 12 sessions using cool dialysate (35.5°C) and the second group is on HD with standard dialysate temperature (37°C). Then the method of treatment is replaced in two groups for the next 12 sessions. During the study, all the dialysis conditions are maintained the same, except temperature of dialysate (37°C or 35.5°C). All patients are on HD using GAMBRO AK96 HD machine
Outcomes	Dialysis adequacy Blood pressure Temperature
Starting date	22 June 2013
Contact information	Mollaei Einollah Kilometer 2 Goran‐Sari, Golestan University of Medical Sciences, Gorgan Gorgan Golestan, Islamic Republic of Iran 00981714426900 Mollaei@goums.ac.ir
Notes

Trial name or title	Effects of cool dialysate on sleep quality in patients undergoing haemodialysis
Methods	Single‐centre cross‐over RCT
Participants	Inclusion criteria Consent for participation in the study; aged > 18 years and maximum 75 years; suffering from vision, hearing loss; not suffering from clear mental disorders and severe emotional mood disorders, which prevent effective communication; patients with chronic renal failure (patients who last had dialysis 6 months previously); patients receiving dialysis treatment 3 times/week and each session for 4 hours; not suffering from endocrine disorders (such as hypothyroidism, hyperparathyroidism); patients who have received scores higher than 5 Pittsburgh Sleep Quality Index; patients with haemoglobin levels > 8 mg/dL; lack of debilitating diseases and disorders such as severe chronic heart, respiratory, hepatic, history of seizures and severe neuropathy based on medical records and patient history; lack of psychiatric disorders (schizophrenia, anxiety, depression) or dementia, or stay in psychiatric wards because of the items listed; no history of kidney transplant Exclusion criteria Patients who develop acute complications during HD (disequilibrium syndrome, embolism, dysrhythmia, cardiac, respiratory arrest, coma); patients who discontinued their dialysis for any reason; patients who are referred for kidney transplants (patients who receive kidney transplantations during the study); the patient's death, patients who cannot tolerate cold dialysis; the patient's unwillingness to continue to participate in the study
Interventions	Control temperature of HD fluid (dialysate) is regulated at 37°C. Type of filter, coefficient of ultra‐filtration, blood flow rate and type of apparatus are constant during the study Intervention Temperature of HD fluid is regulated on (35.5°C) and type of filter, coefficient of ultra‐filtration, blood flow rate are not changed
Outcomes	No outcome of interest was defined
Starting date	22 Sep 2016
Contact information
Notes

Trial name or title	Effect of cool vs. warm dialysate on toxin removal: rationale and study design
Methods	A single‐centre, randomised cross‐over study
Participants	Inclusion criteria Adult patients male or female (aged 21 to 70 years) Minimum dialysis vintage of 3 months Stable on HD Blood access capable of delivering the blood flow rate > 250 mL/min Exclusion criteria History of recurring or persistent hypotension in the past 1 month Pregnant woman Severely hypertensive patients (SBP > 180 mmHg and/or DBP > 115 mmHg) Severely hypotensive patients (SBP < 100 mmHg and/or DBP < 60 mmHg) Paradoxically hypertensive patients whose BP increases by > 20% of baseline during dialysis (in the past 1 month) History of recent myocardial infarction or unstable angina (within the past 6 months) Significant valvular disease, i.e. severe aortic stenosis and moderate‐severe mitral regurgitation Patients with end‐stage organ disease e.g. COPD, recent or debilitating CVA Patients with left ventricular dysfunction, chronic heart failure and older age group more than 70 years Patient with recent stroke (within the past 6 months) History of known arrhythmia Participation in another clinical intervention trial Unable to consent
Interventions	Intervention Cool dialysis with dialysate temperature at 35.5°C Control Warm dialysis with dialysate temperature at 37°C
Outcomes	IDH rate Lowest SBP during dialysis Urea clearance‐based dialysis adequacy (Kt/V_urea)
Starting date	July 2013
Contact information	Vaibhav Maheshwari LF Dialysis Center, National University Hospital, Singapore, SGN, Singapore, 298135
Notes

Trial name or title	Major Outcomes With Personalized Dialysate TEMPerature (MyTEMP)
Methods	Cluster RCT
Participants	Patients undergoing HD in the dialysis centres that meet the following criteria Inclusion criteria The medical director of the dialysis centre must provide informed consent and be willing to transition their patients to receive temperature‐reduced personalized HD (if randomised to the intervention) or stay with the standard 36.5°C HD temperature during the course of the studies (if randomised to the control group); and The centre must care for a minimum of 15 patients being treated with conventional in‐centre HD 3 times/week. Exclusion criteria The centre cares for less than 15 patients being treated with conventional in‐centre HD 3 times/week
Interventions	Intervention Dialysis centres randomised to the intervention arm provided temperature‐reduced personalized HD. A nurse set the temperature of the dialysate to 0.5°C below each patient's body temperature measured just before starting the dialysis treatment. We are aware that some dialysis machines (e.g. Fresenius 5008) are only able to modify dialysate temperature by 0.5°C increments. For centres with those machines, the temperature should be lowered by a minimum of 0.5°C and a maximum of 0.9°C. Control Dialysis centres in the control group provided usual care, which is standard dialysis using a fixed dialysate temperature of 36.5°C
Outcomes	Primary outcome Composite outcome of all‐cause mortality or major cardiovascular event rate Secondary outcomes Cardiovascular‐related mortality; Hospitalisation for non‐fatal myocardial infarction; Hospitalisation for non‐fatal ischaemic stroke; Hospitalisation for non‐fatal congestive heart failure; Composite outcome of all‐cause mortality or major cardiovascular event; and HD sessions complicated by IDH
Starting date	3 April, 2017
Contact information	Amit X Garg, London Health Sciences Centre, London, Ontario, Canada, N6A5W9
Notes	Trial registration: NCT02628366

PERMALINK

Dialysate temperature reduction for intradialytic hypotension for people with chronic kidney disease requiring haemodialysis

Yasushi Tsujimoto

Hiraku Tsujimoto

Yukihiko Nakata

Yuki Kataoka

Miho Kimachi

Sayaka Shimizu

Tatsuyoshi Ikenoue

Shingo Fukuma

Yosuke Yamamoto

Shunichi Fukuhara

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Inclusion criteria

Exclusion criteria

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Cluster randomised studies

Randomised cross‐over studies

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

'Summary of findings' tables

Results

Description of studies

Results of the search

1.

Included studies

Study design

Sample size

Setting

Participants

Interventions

Outcomes

Excluded studies

Risk of bias in included studies

2.

3.

Allocation

Random sequence generation

Allocation concealment

Blinding

Performance bias

Detection bias

Incomplete outcome data

Selective reporting

Other potential sources of bias

Urea clearance‐based dialysis adequacy (Kt/V_urea)

Urea clearance‐based dialysis adequacy (Kt/V_urea)