Application of Multivariate Generalized Linear Mixed Model to Identify Effect of Dialysate Temperature on Physiologic Indicators among Hemodialysis Patients

Introduction: One of the complications of hemodialysis treatment is hypotension, which can increase morbidity and mortality and compromise dialysis efficacy. Dialysate temperature is an important factor that contributes to hemodynamic stability during hemodialysis. This study investigated the effect of dialysate temperature on the patients' blood pressure and pulse rate. Model-based approaches were used to produce more reliable results compared with traditional methods. Methods: A total of 30 patients were studied during 9 dialysis sessions. Dialysate temperatures were 37° C, 36° C and 35° C. A joint longitudinal model was used to analyze both responses of blood pressure and pulse rate, simultaneously. Results: The results showed that low-dialysate temperature was not significantly associated with higher systolic blood pressure (p>0.05) or a higher pulse rate (p>0.05) either during or after dialysis. Pulse rate and blood pressure were higher for women during dialysate (p<0.001). However, increasing age was associated with higher blood pressure and a lower pulse rate (p<0.001). Conclusion: Using several separate, repeated measure analysis of variances may produce misleading results, when there is more than one response variable measured over time, Multivariate statistical methods (including joint longitudinal models), should be used.

MyTEMP: Statistical Analysis Plan of a Registry-Based, Cluster-Randomized Clinical Trial

Background: Major Outcomes with Personalized Dialysate TEMPerature (MyTEMP) is a 4-year cluster-randomized clinical trial comparing the effect of using a personalized, temperature-reduced dialysate protocol versus a dialysate temperature of 36.5°C on cardiovascular-related death and hospitalization. Randomization was performed at the level of the dialysis center (“the cluster”). Objective: The objective is to outline the statistical analysis plan for the MyTEMP trial. Design: MyTEMP is a pragmatic, 2-arm, parallel-group, registry-based, open-label, cluster-randomized trial. Setting: A total of 84 dialysis centers in Ontario, Canada. Patients: Approximately 13 500 patients will have received in-center hemodialysis at the 84 participating dialysis centers during the trial period (April 3, 2017, to March 1, 2021, with a maximum follow-up to March 31, 2021). Methods: Patient identification, baseline characteristics, and study outcomes will be obtained primarily through Ontario administrative health care databases held at ICES. Covariate-constrained randomization was used to allocate the 84 dialysis centers (1:1) to the intervention group or the control group. Centers in the intervention group used a personalized, temperature-reduced dialysate protocol, and centers in the control group used a fixed dialysate temperature of 36.5°C. Outcomes: The primary outcome is a composite of cardiovascular-related death or major cardiovascular-related hospitalization (defined as a hospital admission with myocardial infarction, congestive heart failure, or ischemic stroke) recorded in administrative health care databases. The key secondary outcome is the mean drop in intradialytic systolic blood pressure, defined as the patients’ predialysis systolic blood pressure minus their nadir systolic blood pressure during the dialysis treatment. Anonymized data on patients’ predialysis and intradialytic systolic blood pressure were collected at monthly intervals from each dialysis center. Analysis plan: The primary analysis will follow an intent-to-treat approach. The primary outcome will be analyzed at the patient level as the hazard ratio of time-to-first event, estimated from a subdistribution hazards model. Within-center correlation will be accounted for using a robust sandwich estimator. In the primary analysis, patients’ observation time will end if they experience the primary outcome, emigrate from Ontario, or die of a noncardiovascular cause (which will be treated as a competing risk event). The between-group difference in the mean drop in intradialytic systolic blood pressure obtained during the dialysis sessions throughout the trial period will be analyzed at the center level using an unadjusted random-effects linear mixed model. Trial status: The MyTEMP trial period is April 3, 2017, to March 31, 2021. We expect to analyze and report results by 2023 once the updated data are available at ICES. Trial registration: MyTEMP is registered with the US National Institutes of Health at clincaltrials.gov (NCT02628366). Statistical analytic plan: Version 1.1 June 15, 2021.

Separate and combined effects of cold dialysis and intradialytic exercise on the thermoregulatory responses of hemodialysis patients: a randomized-cross-over study

Background The separate and combined effects of intradialytic exercise training (IET) and cold dialysis (CD) on patient thermoregulation remain unknown. This study assessed the thermoregulatory responses of hemodialysis patients under four different hemodialysis protocols: a) one typical dialysis (TD) protocol (dialysate temperature at 37 °C), b) one cold dialysis (CD) protocol (dialysate temperature at 35 °C), c) one typical dialysis protocol which included a single exercise bout (TD + E), d) one cold dialysis protocol which included a single exercise bout (CD + E). Methods Ten hemodialysis patients (57.2 ± 14.9 years) participated in this randomized, cross-over study. Core and skin temperatures were measured using an ingestible telemetric pill and by four wireless iButtons attached on the skin, respectively. Body heat storage (S) calculated using the thermometric method proposed by Burton. Results The TD and TD + E protocols were associated with increased S leading to moderate effect size increases in core body temperature (as high as 0.4 °C). The low temperature of the dialysate during the CD and the CD + E protocols prevented the rise in S and core temperature (p > 0.05), even during the period that IET took place. Conclusions TD and IET are accompanied by a moderate level of hyperthermia, which can be offset by CD. We recommended that CD or with IET can prevent the excessive rise of S. Trial registration Clinical Trial Registry number: NCT03905551 (clinicaltrials.gov), DOR: 05/04/2019,

Evaluation of the effect of Cooled HaEmodialysis on Cognitive function in patients suffering with end-stage KidnEy Disease (E-CHECKED): feasibility randomised control trial protocol

Background Cognitive impairment is common in haemodialysis (HD) patients and is associated independently with depression and mortality. This association is poorly understood, and no intervention is proven to slow cognitive decline. There is evidence that cooler dialysis fluid (dialysate) may slow white matter changes in the brain, but no study has investigated the effect of cooler dialysate on cognition. This study addresses whether cooler dialysate can prevent the decline in cognition and improve quality of life (QOL) in HD patients. Methods This is a multi-site prospective randomised, double-blinded feasibility trial. Setting: Four HD units in the UK. Participants and interventions: Ninety HD patients randomised (1:1) to standard care (dialysate temperature 36.5 °C) or intervention (dialysate temperature 35 °C) for 12 months. Primary outcome measure: Change in cognition using the Montreal Cognitive Assessment (MoCA). Secondary outcome measures: Recruitment and attrition rates, reasons for non-recruitment, frequency of intradialytic hypotension, depressive symptom scores, patient and carers burden, a detailed computerised cognitive test and QOL assessments. Analysis: mixed method approach, utilising measurement of cognition, questionnaires, physiological measurements and semi-structured interviews. Discussion The results of this feasibility trial will inform the design of a future adequately powered substantive trial investigating the effect of dialysate cooling on prevention and/or slowing in cognitive decline in patients undergoing haemodialysis using a computerised battery of neuro-cognitive tests. The main hypothesis that would be tested in this future trial is that patients treated with regular conventional haemodialysis will have a lesser decline in cognitive function and a better quality of life over 1 year by using cooler dialysis fluid at 35 °C, versus a standard dialysis fluid temperature of 36.5 °C. This also should reflect in improvements in their abilities for activities of daily living and therefore reduce carers’ burden. If successful, the treatment could be universally applied at no extra cost. Trial registration ClinicalTrials.gov NCT03645733. Registered retrospectively on 24 August 2018.

Evaluation of the Effect of Cooled Haemodialysis on cognitive Function in Patients suffering with End-stage Kidney Disease (E-CHECKED): Feasibility Randomised Control Trial Protocol

Background: Cognitive impairment is common in haemodialysis (HD) patients and is associated independently with depression and mortality. This association is poorly understood, and no intervention is proven to slow cognitive decline. There is evidence that cooler dialysis fluid (dialysate) may slow white matter changes in the brain, but no study has investigated the effect of cooler dialysate on cognition. This study addresses whether cooler dialysate can prevent the decline in cognition and improve quality of life (QOL) in HD patients.Methods: This is a multi-site prospective randomised, double-blinded feasibility trial. Setting: Four HD units in the United Kingdom.: Participants and interventions Ninety HD patients randomised (1:1) to standard care (dialysate temperature 36.5C) or intervention (dialysate temperature 35°C) for 12 months. Primary outcome measure: Change in cognition using the Montreal Cognitive Assessment (MoCA). Secondary outcome measures: Recruitment and attrition rates, reasons for non-recruitment, frequency of intradialytic hypotension, depressive symptom scores, patient and carers burden, a detailed computerised cognitive test and QOL assessments. Analysis: mixed method approach, utilising measurement of cognition, questionnaires, physiological measurements and semi-structured interviews.Discussion: The results of this feasibility trial will inform the design of a future adequately powered substantive trial investigating the effect of dialysate cooling on prevention and/ or slowing in cognitive decline in patients undergoing haemodialysis using a computerised battery of neuro-cognitive tests. The main hypothesis that would be tested in this future trial is that patients treated with regular conventional haemodialysis will have a lesser decline in cognitive function and a better quality of life over one year by using cooler dialysis fluid at 35°C, versus a standard dialysis fluid temperature of 36.5°C. This also should reflect in improvements in their abilities for activities of daily living and therefore, reduce carers' burden. If successful, the treatment could be universally applied at no extra cost.Trial registration: ClinicalTrials.gov Identifier: NCT03645733. Registered retrospectively on August 24, 2018.

Evaluation of the Effect of Cooled Haemodialysis on cognitive Function in Patients suffering with End-stage Kidney Disease (E-CHECKED): Feasibility Randomised Control Trial Protocol

Background: Cognitive impairment is common in haemodialysis (HD) patients and is associated independently with depression and mortality. This association is poorly understood, and no intervention is proven to slow cognitive decline. There is evidence that cooler dialysis fluid (dialysate) may slow white matter changes in the brain, but no study has investigated the effect of cooler dialysate on cognition. This study addresses whether cooler dialysate can prevent the decline in cognition and improve quality of life (QOL) in HD patients.Methods: This is a multi-site prospective randomised, double-blinded feasibility trial. Setting: Four HD units in the United Kingdom.: Participants and interventions Ninety HD patients randomised (1:1) to standard care (dialysate temperature 36.5C) or intervention (dialysate temperature 35°C) for 12 months. Primary outcome measure: Change in cognition using the Montreal Cognitive Assessment (MoCA). Secondary outcome measures: Recruitment and attrition rates, reasons for non-recruitment, frequency of intradialytic hypotension, depressive symptom scores, patient and carers burden, a detailed computerised cognitive test and QOL assessments. Analysis: mixed method approach, utilising measurement of cognition, questionnaires, physiological measurements and semi-structured interviews.Discussion: The results of this feasibility trial will inform the design of a future adequately powered substantive trial investigating the effect of dialysate cooling on prevention and/ or slowing in cognitive decline in patients undergoing haemodialysis using a computerised battery of neuro-cognitive tests. The main hypothesis that would be tested in this future trial is that patients treated with regular conventional haemodialysis will have a lesser decline in cognitive function and a better quality of life over one year by using cooler dialysis fluid at 35°C, versus a standard dialysis fluid temperature of 36.5°C. This also should reflect in improvements in their abilities for activities of daily living and therefore, reduce carers' burden. If successful, the treatment could be universally applied at no extra cost.Trial registration: ClinicalTrials.gov Identifier: NCT03645733. Registered retrospectively on August 24, 2018. URL: https://clinicaltrials.gov/ct2/show/NCT03645733

Separate and combined effects of cold dialysis and intradialytic exercise on the thermoregulatory responses of hemodialysis patients

Background: The separate and combined effects of intradialytic exercise training (IET) and cold dialysis (CD) on patient thermoregulation remain unknown. This study assessed the thermoregulatory responses of hemodialysis patients under four different hemodialysis protocols: a) one typical dialysis (TD) protocol (dialysate temperature at 37°C), b) one cold dialysis (CD) protocol (dialysate temperature at 35°C), c) one typical dialysis protocol which included a single exercise bout (TD+E), d) one cold dialysis protocol which included a single exercise bout (CD+E). Methods: Ten haemodialysis patients (57.2±14.9 years) participated in the study. Core and skin temperatures were measured using an ingestible telemetric pill and by four wireless iButtons attached on the skin, respectively. Body heat storage (S) calculated using the thermometric method proposed by Burton. Results: The TD and TD+E protocols were associated with increased S leading to moderate effect size increases in core body temperature (as high as 0.4°C). The low temperature of the dialysate during the CD and the CD+E protocols prevented the rise in S and core temperature (p>0.05), even during the period that IET took place. Conclusions: TD and IET are accompanied by a moderate level of hyperthermia, which can be offset by CD. We recommended that CD or with IET can prevent the excessive rise of S. Trial registration: Clinical Trial Registry number: NCT03905551 (clinicaltrials.gov), DOR: 05/04/2019, https://clinicaltrials.gov/ct2/show/NCT03905551?term=NCT03905551&draw=2&rank=1

P1243ABSOLUTE BLOOD VOLUME VARIATIONS INFLUENCED BY DIALYSATE TEMPERATURE DURING HAEMODIALYSIS

Background and Aims Intradialytic hypotension is a common complication in haemodialysis. Vascular refilling occurs to preserve haemodynamic stability. Recent studies report a feasible and noninvasive method to determine absolute blood volume, which would allow us to estimate vascular refilling during haemodialysis. During years, it has been proposed that lowering the dialysate temperature could improve intradialytic hypotension outcomes in patients undergoing chronic haemodialysis. The objective of this study is to analyze if lowering dialysate temperature modifies variations in absolute blood volume during haemodialysis. Method The study was performed in 51 patients under haemodialysis treatment. During two different sessions, relative blood volume was assessed using dialysate temperatures of 35.5ºC (cool dialysate) and 36.5ºC (neutral dialysate). Absolute blood volume and vascular refilling were calculated using Kron et al methodology (Hemodial Int. 2016;20(3):484–91). Intradialytic hypotension was defined as a systolic blood pressure below 85 mmHg or a drop of pressure above 20 mmHg accompanied by symptoms. Statistical analysis was performed using paired t-Test or Wilcoxon rank sum. Results 31 episodes of intradialytic hypotension were observed, 14 under cool dialysate and 26 during neutral dialysate. We did not found statistically differences in absolute blood volume or in refilling volume between cool and warm dialysate temperature. In the group of patients with intradialytic hypotension (Table 1) we observed lower drop in absolute blood volume in the 35.5ºC dialysate group (0.59 L) versus 36.5ºC group (0.72 L). Although no statistically significant differences were found in vascular refilling volumes, when cool dialysate was used refilling tended to be higher. Conclusion It seems that in selected groups of patients the use of cool dialysate could improve absolute blood volume stability during HD treatments, although further studies are needed.