Ethical approval for trial has been obtained from Nottingham Ethics Committee for all participating centres prior to study initiation and patient enrolment. The study will be performed in accordance with the Research Governance Framework, International Conference on Harmonisation Good Clinical Practice Guideline and the 2000 Scotland Revision of the Declaration of Helsinki. All participants are to provide written informed consent before any trial related procedure can occur.
Patients must fulfil the following eligibility criteria to be considered for the study enrolment or participation:
1. Patients having in-centre HD at least 3 times per week.
2. Willing and able to provide consent.
3. Male and female, age
1. Exposure to haemodialysis for >180
2. Contraindications for using MRI (eg. pacemakers and metal implants, pregnancy or lactating)
3. Inability to tolerate MRI due to claustrophobia
4. New York Heart Association grade IV heart failure
5. Mental incapacity to consent
The schedule of events is summarized in Figure
. The trial is a multicentre, prospective, randomised, un-blinded, controlled trial. Patients will be recruited from 4 research sites and randomised 1:1 to the control group or intervention group. Randomisation will be in a single block by sealed envelopes generated by an independent statistician. The control group will use a dialysate temperature of 37°C for 12
months. The intervention group will have an individualised cooled dialysate temperature for 12
months. This will be set at 0.5°C less than the patient’s own temperature, determined from the mean of 6 prior treatment sessions with a tympanic thermometer, up to a maximum of 36°C, ensuring a minimum temperature separation of 1°C between groups. Adherence to the allocated dialysate temperature will be regularly checked and recorded by nursing staff at each research site enabling distinction between the prescribed and delivered dialysate temperatures. Analysis will be by intention-to-treat regardless of any crossover between delivered temperatures.
This is an un-blinded study. Therefore, after randomisation, the investigators, HD unit staff and patient will be aware of group allocation. This is necessary to ensure adherence to the study protocol. There will be blinding of treatment allocation for analysis of cardiac images for the primary outcome.
Patients in each trial arm will undergo standard management, as per local HD unit protocols with the exception of dialysate temperature.
Cardiac and cerebral magnetic resonance imaging
Contrast-free cardiac and cerebral MRI will be performed at baseline and 12
months when the patient has been established on HD with a stable dry weight unchanged for at least 4
weeks. Studies will occur on non-dialysis days at two centres using a 1.5
T MRI scanner (GE Signa HDxt 1.5
T, GE Healthcare, Milwaukee,US). Acquisition will include serial contiguous short-axis cines piloted from vertical or horizontal long axis of the left ventricle using ECG-gated steady-state in free precession sequences in accordance with validated methodologies [27
]. Analysis will be performed with the anonymised images off-line by planimetry using commercially available software for assessment of ventricular volumes and mass. Brain MRI will examine the integrity and microstructure of white matter using diffusion tensor imaging. The anonymised images will be analysed off-line for diffusivity and anisotropy corrected for brain volume.
Cognitive assessment will be performed on the same day as the MRI scans at baseline and 12
months. The Montreal Cognitive Assessment is a validated tool for the detection of mild cognitive impairment with higher sensitivity and specificity than the Folstein Mini-Mental State Examination for the detection of mild cognitive impairment [28
]. Trail Making Tests A and B will be used to examine attention and mental flexibility.
Assessing cardiovascular performance during HD
Detailed characterisation of cardiovascular performance will be assessed during HD at baseline and 12
months. This occurs during the patient’s usual HD session in their own centre using the same portable data collecting instruments across all centres. 2-dimensional echocardiography will be performed using commercially available equipment (1.5-4Mhz probe, Vivid-I, GE Healthcare) by one of two trained technicians in the left lateral position. Sector width, frequency and depth will be adjusted to produce optimal border definition and a frame-rate of 50–80 per second. Standard apical 2 and 4-chamber image loops will be recorded pre-dialysis (rest) and 15 minutes before the end of dialysis (stress). Image loops will be anonymised and analysed off-line in random order for regional deformation using dedicated software (EchoPac, GE Vingmed). Continuous non-invasive cardiac output monitoring will be recorded using a thoracic bioreactance monitor (NICOM™, Cheetah Medical). This uses phase changes in alternating electrical current to derive cardiac output. This endows a greater precision and signal-to-noise ratio than impedance cardiography. The monitor is validated in both healthy and co-morbid adults [29
]. The Finometer™ (TNO Instruments) utilises a finger-cuff to detect beat-to-beat changes in digital arterial pressure and calibrates this against oscillometric brachial artery pressure. The Finometer™ is validated in critical care and HD settings [30
Arterial stiffness and body composition
Arterial stiffness measured by pulse wave velocity is independently associated with increased risk of cardiovascular disease in HD patients [31
]. Carotid-Femoral pulsewave velocity will be measured by a volume displacement technique [32
]. Pre-HD body composition and hydration status will be estimated by segmental multi-frequency bioimpedance [33
Primary study outcome
Change in resting LVEF by cardiac magnetic resonance (CMR) at 12
months compared to baseline between the intervention and control group.
Secondary study outcomes
· Left ventricular mass by CMR
· Regional myocardial deformation by speckle-tracking echocardiography and CMR tagging.
· A range of haemodynamic variables, including cardiac output, pulse rate, heart rate and frequency of intra-dialytic hypotension
· Change in body composition by bioimpedance
· Change in cerebral diffusion tensor MRI
· Change in cognitive assessment scores
· Change in soluble cardiac biomarkers
Rationale for primary outcome
We selected LVEF measured by CMR as the primary outcome because previous observational study showed mean reduction in LVEF by echocardiography of 13% over 12
months in patients who displayed RWMAs at baseline. RWMAs were abrogated in the short-term by a dialysate cooling strategy in a separate cohort [10
]. We also selected LVEF as an objective measure which is predictive of mortality and hospitalisations [34
]. A change in LVEF greater than 5% has been shown to be an important cut-off approaching the minimum clinically important difference [35
]. CMR is the gold-standard for measurement of left ventricular mass and volumes, allowing determination of the primary outcome to a much higher precision compared to alternative methods such as echocardiography. This markedly reduces the sample size required to detect between-group differences in an intervention trial, permitting lower costs and faster reporting of final results [37
]. Sample estimation is from a recent reference range study which used the same CMR acquisition and analytic techniques planned for this study [27
] and were performed by a medical statistician using commercially available software (Nquery Advisor v6).
Sample size estimation
The primary aim in this study is to detect a 5% difference in LVEF as measured by CMR between the control and intervention group after 12
months. Using a two sample t test and assuming a mean LVEF of 67% in the control arm and equal Standard Deviation in each group of 6% [27
], a study of 64 participants (32 per group) would permit the detection of a 5% difference in LVEF from baseline to 12
months between the intervention and control groups, with 90% power at 5%, 2-sided significance level. Allowing for study attrition and death of 10%, we aim to recruit 72 participants to achieve an evaluable sample of 64 participants.
All the continuous variables will be tested for normality using their histograms and normality tests. The primary endpoint will be compared between the two groups at specific time points using the Mann U Whitney or Independent T-test. Repeated measures analysis will be used for testing the difference on primary endpoint between tests across the whole period. Poisson regression analysis will be used for comparing the frequency of intra-dialytic RWMAs between the two groups. Haemodynamic variables and other secondary endpoints will be analysed using repeated measures and Bonferroni’s test for multiple comparisons. Paired tests, Wilcoxon Signed test or Paired T-test, will be used for comparing the primary and secondary endpoints between two time points within each group. An alpha error at 0.05 will be judged as significant. Analysis will be performed using SPSS for Windows, v16 or Stata v10. Statistical analysis will be based on an intention-to-treat principle with all data analysed according to the patient’s original study group allocation regardless of death, crossover or early withdrawal.
Monitoring for adverse events
The number and proportion of participants who report treatment-emergent adverse events will be summarized for each treatment group. Treatment emergent events include events that start on or after allocation to the study assigned dialysate temperature.
Commencing in September 2009, trial recruitment of 73 patients was completed by January 2012. Follow-up will be completed in January 2013 with results analysed and reported in mid-late 2013. Based on the final number recruited (73), the study has 90% power to detect a 5% difference in LVEF.