Temperature and Bicarbonate: Hemodynamic Effects During Dialysis

Study Overview
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Brief Summary
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To elucidate the role of dialysate temperature and bicarbonate on hemodynamic parameters, plasma pH and electrolytes that potentially mediate this effect, the investigators wish to conduct a single-blinded, randomized, controlled, crossover study, specifically examining the effects of A fixed low temperature dialysate of 35°C compared to a fixed dialysate temperature of 37°C. A low dialysate bicarbonate concentration of 30 mmol/L compared to a high dialysate bicarbonate concentration of 38 mmol/L.

Detailed Description
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Background Intradialytic hypotension (IDH) is a common complication of hemodialysis (HD) and is considered one of the most frequent complications with a prevalence between 10-12% depending on the definition of IDH (1). IDH has been associated with inefficient dialysis (2), vascular access thrombosis (3) and mortality (4,5). Orthostatic hypotension (OH) is another common complication in HD with a prevalence around 42% in patients initiating HD treatment (6). OH is significantly associated with worse outcome in HD patients in terms of an increased two-year mortality (4) and increased risk of all-cause death (6). Understanding the mechanisms underlying IDH and OH has the potential to optimize HD treatment, in order to minimize the occurrence of IDH and OH, potentially improving not only patient mortality and morbidity but also the everyday comfort of chronic HD patients when receiving dialysis treatment. This study will investigate the hemodynamic effect of alterations in dialysate bicarbonate and dialysate temperature. Dialysate temperature Several clinical studies have examined the effect of low temperature dialysate (LTD) on IDH, but only few have examined the hemodynamic response in detail with intradialytic measurements of cardiac output (CO), central blood volume (CBV) and total peripheral resistance (TPR) (7-14). Generally, the studies confirm a blood pressure (BP) stabilizing effect of LTD, but diverse results are found on changes in CO, CBV and TPR. Some studies found greater increase in TPR during dialysis with LTD compared to a higher dialysate temperature (8,9,11,14). Other studies found that intradialytic CBV (7,12) and CO (12) improved considerably with LTD. One previous study (14) examined OH in relation to use of LTD, but not with detailed intradialytic hemodynamic measurements. The study showed that both supine and upright mean arterial blood pressure (MAP) were significantly lower after dialysis with a dialysate temperature of 37°C compared to a dialysate temperature of 35°C. Furthermore, the increase in TPR was greater during dialysis with LTD. Dialysate bicarbonate Few studies have investigated the effect of dialysate bicarbonate (DB) concentration on intradialytic hemodynamics and results have been conflicting. Lower DB (from 32 to 26 mmol/L or a reduction of 6 mmol/L, respectively) was in two cross-over studies (15,16) shown to increase systolic BP (SBP) by approximately 5 mmHg, whereas a third study reported no significant effect on BP (17). One of these studies also found an increase in TPR with lower DB (16). IDH has been associated with lower DB in one of the previously mentioned cross-over studies (15), but this association was not found by Gabutti et al in 2005 (17) or in larger observational studies (17-19). Manipulation of DB inevitably affects plasma pH of the patient during dialysis. Thus, if pH decreases with DB-induced acidosis, hydrogen ions displace cations such as calcium from protein binding sites. DB-induced alkalosis on the other hand increases pH, which promotes increased protein binding, which decreases free cation levels. At the same time, intracellular sequestration of potassium at high pH levels has also been speculated to lower plasma potassium levels (20). Consequently, by changing DB a range of electrolytes including calcium are potentially affected which could impact neuromuscular function and thereby intradialytic hemodynamic parameters and the frequency of IDH and OH (17,21-26). Hypotheses Hemodialysis or hemodiafiltration (HdF) sessions with a decreased dialysate temperature (35°C vs. 37°C) or decreased DB concentration (30 mmol/L vs. 38 mmol/L) will have the following effects: An increase in SBP, MAP and orthostatic blood pressure (OBP). An increase in one or more of the following: Cardiac output (CO), total peripheral resistance (TPR), central blood volume (CBV), stroke volume (SV) and/or heart rate (HR). A decrease in the frequency of IDH and OH. Study participants Participants will be recruited from the maintenance HD and HdF population associated with the Department of Renal Medicine at Aarhus University Hospital in Denmark. These include the Dialysis Clinic at Aarhus University Hospital as the main hub and satellite dialysis clinics in Randers and Horsens. Power and sample size Measurements from 30 randomly selected HD patients in our clinic yielded SD = 23 mmHg for the difference between within-treatment changes in SBP (non-standardized conditions). Assuming a lower SD due to standardized BP-measurements and strict in- and exclusion criteria an SD = 12 mmHg was used as a reasonable estimate. Sample size calculation with Stata/IC 16.1 (StataCorp, 4905 Lakeway Dr, College Station, TX 77845, USA) using analysis for a one-sample mean test (t-test), assuming a minimal detectable difference in means (mean difference between the two within-treatment changes in SBP) = 10 mmHg; SD = 12 mmHg; two-sided significance level (alpha) = 0.05; power=0.80 resulted in 14 participants. However, to account for dropout of two participants, a sample size of 16 was chosen. Dialysis machines, filters, and dialysate composition Dialysis console Fresenius 5008F (Fresenius Medical Care, Bad Homburg, Germany) and HD or HdF filters regularly used for treatment of the patient will be used in all dialysis sessions. The standard dialysate prescribed for each individual patient will be used in all dialysis sessions thereby maintaining similar composition regarding electrolytes such as sodium, potassium, calcium, magnesium and chloride. Bicarbonate concentration will only be adjusted in the sessions investigating low (30 mmol/L) and high (38 mmol/L) DB concentration, respectively. Dialysate will be prepared on-line by the dialysis machine. Blood flow rate and dialysate flow rate will be kept as usual and will remain equal in all sessions regardless of intervention. Ultrafiltration rate will be kept constant and equal in the two dialysis sessions. The same applies for the volume of substitution fluid in HdF. Orthostatic hypotension (OH) OH is defined as a reduction in SBP of at least 20 mmHg or in DBP of at least 10 mmHg within 3 minutes of standing (27). Intradialytic hypotension (IDH) IDH is defined as a decrease in SBP ≥20 mmHg or a decrease in MAP ≥10 mmHg associated with clinical events/symptoms (e.g. muscle cramps, abdominal discomfort, nausea or vomiting, dizziness or fainting, restlessness or anxiety, yawning or signing) and/or need for intradialytic interventions (Trendelenburg positioning, fluid administration, reduction in ultrafiltration rate, reduction of blood flow rate) or dialysis treatment cessation (28). Intradialytic measurements Cardiac output (CO) will be obtained by a previously validated ultrasound dilution technique using Hemodialysis Monitor HD03, Flow-QC tubing sets, and clip-on flow/dilution sensors from Transonic Systems Inc., Ithaca, NY, USA (29-32). The ultrasound sensors will be positioned on the arterial and venous Flow-QC tubing set using standard ultrasound gel to secure good contact. Access recirculation in the AV-fistula can invalidate CO-measurements. A built-in recirculation protocol will be used to check for access recirculation using injection of 10 mL isotonic saline into the venous blood line prior to the first CO-measurement. If recirculation is detected the dialysis needles will most likely be reinserted. CO will be measured in duplicate by injecting a bolus of 30 mL 37°C isotonic saline into the venous blood line within 5 seconds. If results deviate more than 15% a third measurement will be done. The mean of the two closest recordings will serve as the result. With the Transonic device intradialytic hemodynamic parameters are obtained at 10, 70, 130, 190, and 230 minutes. Patients will be lying in a supine position with the head elevated 20 degrees. Before each CO measurement HR and BP will be measured. MAP, TPR, and SV are derived by the following equations: MAP = diastolic BP + 1/3 x (systolic BP - diastolic BP) CO = SV x HR = MAP/TPR CBV is defined as the volume of blood in the heart, lungs and great vessels and is estimated with the Transonic device based on the CO measurement. Blood samples and handling of biological material Following the same time pattern as the Transonic measurements an arterial blood gas will be drawn from the arterial cannula. Eleven blood samples will be taken from the arterial blood line via the AV-cannula used for dialysis treatment. Four of the samples will be regular blood samples of 3-4 mL, whereas 7 of the samples will be arterial blood gases of 1 mL. Thus, per session 22 mL blood per participant is collected which adds up to a total of 88 mL for the entire study period. The purpose of this is to determine several essential parameters: Electrolytes such as calcium, magnesium, and potassium Acid-base status: pH, standard bicarbonate, standard base excess Hemoglobin, hematocrit Urea for the determination of Kt/V and URR. White cell count and C-reactive protein in the first blood sample in order to confirm the absence of infection All blood samples will be transferred to the laboratory according to standard routine and analyzed according to current clinical standards at Department of Clinical Biochemistry, Aarhus University Hospital or local Department of Clinical Biochemistry normally servicing our satellite dialysis clinics in Randers and Horsens. Blood gas tests are analyzed using ABL blood gas analyzer (Radiometer, Radiometer Medical ApS, Brønshøj Denmark). All blood samples will be destroyed after analysis. No samples will be stored in a biobank.

Official Title
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Hemodynamic Effects of Low vs. High Dialysate Temperature or Bicarbonate Concentration in Chronic Hemodialysis Patients

Conditions
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End Stage Renal Disease on Dialysis

Intervention / Treatment
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* Other: Low dialysate temperature
* Other: High dialysate temperature
* Other: Low dialysate bicarbonate concentration
* Other: High dialysate bicarbonate concentration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Regular dialysis (HD or HDF) therapy for >3 months Age >18 years Stable and functional arteriovenous (AV)-fistula Able to achieve a dialysis blood flow > 250 mL Able to stand up for a minimum of 10 min Able to undergo a 4 hour dialysis session without eating, drinking or sleeping Proven cabable of cumulative ultrafiltration of 2% of end-dialytic weight (EDW) Able to give informed consent to participation in the study Hematocrit >30% BMI >18 and <35 Exclusion Criteria: Central venous catheter for HD or HDF Recirculation in AV-fistula Acute myocardial infarction within 3 months Atrial fibrillation Active malignant or infectious diseases Cerebrovascular incident within 3 months Pregnancy Alcohol or drug abuse History of interruptions during HD or untimely termination of HD treatment

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: The study will be a single-blinded, randomized, controlled, crossover study with each participant being his or her own control. Participants will be blinded to the intervention and the order of the interventions will be random. Participants will be randomized using bloc randomization. We will create two blocs with 8 participants in each. The four dialysis sessions will be conducted on the same weekday each week, which results in a 1-week wash-out period with standard dialysis treatment between interventions.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Low temperature<br>Dialysate temperature | Other: Low dialysate temperature<br>* 35°C<br>|
| Active Comparator: High temperature<br>Dialysate temperature | Other: High dialysate temperature<br>* 37°C<br>|
| Active Comparator: Low bicarbonate<br>Dialysate bicarbonate concentration | Other: Low dialysate bicarbonate concentration<br>* 30 mmol/L<br>|
| Active Comparator: High bicarbonate<br>Dialysate bicarbonate concentration | Other: High dialysate bicarbonate concentration<br>* 38 mmol/L<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood pressure (BP) | SBP (mmHg), Mean BP (mmHg) and Ortostatic BP (mmHg) | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intradialytic cardiac output | CO (L/min) | 4 weeks | 
| Intradialytic total peripheral resistance | TPR (mmHg/(L/min)) | 4 weeks | 
| Intradialytic stroke volume | SV (mL) | 4 weeks | 
| Intradialytic heart rate | HR (beats/min) | 4 weeks | 
| Intradialytic central blood volume | CBV (L) | 4 weeks | 
| Intradialytic mean arterial blood pressure | MAP (mmHg) | 4 weeks | 
| Plasma calcium | Calcium (mmol/L) | 4 weeks | 
| Plasma potassium | Potassium (mmol/L) | 4 weeks | 
| Plasma magnesium | Magnesium (mmol/L) | 4 weeks | 
| Intradialytic hypotension (IDH) | IDH frequency (number of events) | 4 weeks | 
| Ortostatic hypotension (OH) | OH frequency (number of events) | 4 weeks |