Using Intradialytic Systolic Blood Pressure Slopes to Guide Ultrafiltration in Hemodialysis Patients: A Validation Study and Clinical Trial
Phase: NA
Conditions: ESRD, Extracellular Fluid Alteration, Hypertension
Sponsor: University of Texas Southwestern Medical Center

Official title: Using Intradialytic Systolic Blood Pressure Slopes to Guide 
Ultrafiltration in Hemodialysis Patients: A Validation Study and Clinical 
Trial 
 
NCT number: NCT03303391 
IRB Approved date: June 8, 2017 

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Using Intradialytic Systolic Blood 
Pressure Slopes to Guide 
Ultrafiltration in Hemodialysis 
Patients:  
A Validation Study and Clinical Trial 
________________________________________________ 
 
Date:                                             08March2017  
 
 
Version Number: 
 
 
 1.0 
 
 
Funding Agency:  
                    National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 
 
 
Names and Addresses: 
 
 
 
 
Lead Investigator:   
 
Peter Van Buren, MD 
The University of Texas Southwestern Medical Center 
Internal Medicine 
Division of Nephrology 
7th Floor, Suite 711 
5939 Harry Hines Blvd. 
Dallas, Texas 75390-8523 
Phone: 214-645-8293 
Fax: 214-645-8903 
Email: peter,VanBuren@utsw.edu   
     
 
 
 
 
 
 

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PROTOCOL 
1. AIMS 1-3 COMMON APPROACH ELEMENTS  
This project’s overall objective is to develop a broadly applicable method to assess extracellular volume (ECV) 
and guide precise ultrafiltration to minimize mortality risk factors in maintenance hemodialysis (HD) patients.  
Our central hypothesis is that prospectively prescribing ultrafiltration based on intradialytic blood pressure 
slopes (IBPS) from recent treatments will be superior to standard care at reducing ambulatory blood pressure 
and ECV without increasing risk for intradialytic hypotension. 
To test this, we will conduct an un-blinded randomized clinical trial with an embedded cross sectional study in 
the baseline period of the trial:  
In Aim 1, we will implement a cross sectional study using baseline measurements from our clinical trial.  
We aim to establish the mean IBPS from the prior 2 weeks as a validated clinical metric for assessing ECV 
compared to bioimpedance spectroscopy analysis (BIA) that can be used in nearly all HD patients.   
 In Aim 2, we will conduct a randomized clinical trial comparing ultrafiltration prescriptions based on 
IBPS to standard care prescriptions driven by clinical determination of the individual treating nephrologist.  We 
will establish that the IBPS guided approach more effectively modifies two primary mortality risk factors in HD 
patients: ambulatory blood pressure and ECV excess.  We will also assess the mechanistic effect of our 
intervention by simultaneously measuring total peripheral resistance and cardiac index at baseline and end.   
 In Aim 3, we will analyze data from the trial in Aim 2 to determine if IBPS guided therapy is as safe as 
standard care by comparing the incidence of intradialytic hypotension and the intradialytic systolic blood 
pressure nadir.  
 
      1. A   RESEARCH DESIGN:  The overall design is a randomized clinical trial (Figure 1).  An initial analysis 
of baseline measurements for this trial will comprise the data for Aim 1.  Additional subjects who are eligible, 
but not interested in participating in the whole duration of the clinical trial, may participate in Aim 1 only by 
getting one set of measurements.  Aims 2 and 3 will involve the comparison of outcomes between two 
assigned groups from beginning to end of the trial. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Patient Population:  We will utilize consecutive sampling to identify patients that are eligible for our study.  
There are approximately 500 prevalent patients in the 3 UT-Southwestern affiliated hemodialysis units at any 
point in time.  We have contacted each individual UTSW nephrologist and obtained permission to review 
medical records to identify patients that meet the inclusion and exclusion criteria.  Inclusion criteria are age >18 
years and the presence of hypertension.  We will define hypertension as a mean systolic blood pressure 
greater than 140 mmHg pre-dialysis or greater than 130 mmHg post-dialysis over a 2-week screening period. 
The pre dialysis blood pressures, post dialysis blood pressures, the lowest blood pressures, and all intradialytic 
blood pressure measurements are typically obtained every 30 minutes during treatment are electronically 
stored in the patients DaVita medical records.  Exclusion criteria are in Table 1.  
 
Eligible subjects agreeing to participate in all aims will be assigned to one of two study groups based on 
computer-generated randomization stratified by gender: IBPS-based management or Standard of Care 
(detailed in Aim 2).  The presence of contraindications to BIA (see Table 1, #10-12) would not exclude a 
subject from participating in Aims 2 and 3.  Such subjects would complete all study procedures except the BIA 
and NICOM.  The outcomes of Aims 2 and 3 (ambulatory blood pressure and intradialytic hypotension) would 
still be ascertained.  Eligible subjects not willing to undergo randomization into a 16 week trial (Aims 2-3) may 
participate in the BIA and measurements in Aim 1 only. 
 
In short subjects may participate in Aim 1 only, Aims 2 and 3 only, or all Aims based on individual exclusion 
criteria and preference.  We have successfully recruited more than 125 HD patients over the past several 
years for various prospective research studies and continue to maintain support from DaVita dialysis units (see 
Letters of Support). 
 
 
 
Table 1: Exclusion Criteria for Aims 1-3 
Exclusion Criteria 
Justification 
For Aims 1-3 
 
1. 
Hemodialysis Vintage <1 month 
Patients that are newly started on hemodialysis do not have a dry weight that is 
firmly established. 
2. 
Pregnancy 
The patient will need specialized fluid removal goals beyond the parameters of our 
study to optimize outcome of the pregnancy 
3. 
Nadir Systolic Blood Pressure <95 
mmHg during screening 
This defines patients at increased risk for mortality and highest risk for 
complications with additional fluid removal during dialysis.  This is frequently 
associated with ECV-independent blood pressure during dialysis including related 
to advanced heart failure or autonomic neuropathy 
4. 
Pre or Post Dialysis Systolic Blood 
Pressure >180 mmHg 
This threshold identifies high risk patients who may need more aggressive 
pharmacologic therapy which will be left to the discretion of the patient’s 
nephrologist. 
5. 
Decrease in Systolic Blood pressure 
>60 mmHg from pre to post dialysis  
Further increases in ultrafiltration would be increase further risk for hemodynamic 
instability 
6. 
Ultrafiltration Rate >13 mL/hr/kg 
In observational studies, this rate is associated with increased mortality; faster 
ultrafiltration may put patient at risk for increased morbidity or mortality 
7. 
Peridialytic Midodrine Use 
This can acutely influence intradialytic blood pressure in an ECV-independent way.  
Midodrine is used to treat intradialytic hypotension and is frequently used in 
patients with autonomic neuropathy 
8. 
Intradialytic Clonidine Use 
This can acutely influence intradialytic blood pressure in an ECV-independent way.  
This is used to treat severe hypertension during dialysis, and these patients 
frequently have ECV-independent etiology of hypertension, including possible 
medication non-adherence 
9. 
Documented Antihypertensive 
Medication Non-adherence 
This can acutely influence intradialytic blood pressure in an ECV-independent way.   
Aim 1 Only 
10. Amputated Extremity (excluding 
fingers, toes, hands, or feet) 
Bioimpedance measurements of extracellular water are less accurate if all 4 major 
limbs are not present. 
11. Presence of cardiac defibrillator, 
pacemaker 
The current from the bioimpedance electrodes may interfere with the function of 
these devices 
12. Presence of metal prostheses 
Bioimpedance measurements are less accurate if implanted metal is present 

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Study Procedures:  All procedures will be conducted by authorized personnel from the UT Southwestern 
research team consisting of the principal investigator and research nurses/coordinators. 
 
Baseline Information: 
Demographics and Data: Study personnel will conduct in-person interviews to ascertain medical comorbidities.  
Laboratory data (obtained every 1-4 weeks as part of HD unit protocol) will be obtained from the medical chart.   
 
Intradialytic Blood Pressure Measurements:  Subjects will have blood pressure measurements obtained during 
HD using the HD machine built-in sphygmomanometer.  Measurements will be obtained every 30 minutes and 
more frequently in the event of hemodynamic instability.  Measurements will be obtained in the non-access 
arm and electronically stored in patient records.  We will obtain all measurements from the 6 prior treatments 
and use linear regression to calculate the IBPS.    
 
Ambulatory Blood Pressure Measurement: Immediately after a mid-week HD treatment, a Spacelabs 90207 
cuff will be placed on the patient’s non-access arm.  The first cuff inflation will occur in the HD unit, and the 
subject will be instructed to wear the cuff for 44 hours until the next HD treatment.  The cuff will inflate every 30 
minutes from 6 a.m. to 10 p.m. and every hour during the night.   
 
Bioimpedance Spectroscopy Analysis  (BIA): Bioimpedance analysis involves state of the art non-invasive 
measurements of extracellular water volumes in maintenance HD patients as demonstrated by comparison to 
bromide dilution, the gold standard ECV measurement in humans[1, 2].  Opposition to electrical current in the 
body is measured as reviewed in detail in Kuhlman[3].  Our device (Impedimed SFB7) calculates 
compartmental water volumes using Cole-Cole model plots of measured reactance and resistance at varying 
frequencies and using the Hanai equation[4, 5] accounting for height, weight, and sex.  Our device is FDA 
approved to measure ECV in healthy individuals, and also measures intracellular water volumes which can 
then be used with ECV to provide measurements of total body water.   
 
Impedance Cardiography: We will use bioreactance (Cheetah Non-Invasive Cardiac Output Monitor: NICOM) 
to obtain measurements of cardiac output (and index) and systolic blood pressure, from which total peripheral 
resistance (and index) will be calculated.  This non-invasive procedure involves detection of intrabeat changes 
in voltage phase shifts following the application of electric current.  The phase shift reflects the change in 
thoracic fluid volume with each heartbeat.  Our device has been validated for measuring cardiac output in 
intensive care patients, patients with congestive heart failure and HD patients[6-8]. 
 
 2. SPECIFIC APPROACH BY AIM 
AIM 1: The premise for this aim is that there is a need to develop widely-available, easily-
implementable method for accurate assessment of ECV in HD patients.   The objective of this aim is to 
establish the association between ECV excess and IBPS from multiple treatments in hypertensive HD 
patients.   We will test the working hypothesis that when measuring blood pressure every 30 minutes over 
6 treatments, there will be a positive correlation between the mean systolic IBPS and the ECV/body weight 
measured with BIA in a cohort of 66 hypertensive HD patients.  We have calculated the IBPS from a single 
treatment from 49 hypertensive HD patients in a more heterogeneous cohort who also have pre and post-HD 
BIA measurements.  The median slope was -3.36 mmHg/hour (interquartile range -9 mmHg/hr, +3.5 
mmHg/hour).  There is a positive correlation between the IBPS and the ratio of ECV/body weight measured 
after HD (Pearson correlation coefficient 0.4, p=0.008).  The post-HD correlation was 0.5 in men (n=32, 
p=0.01), but was 0.3 in the smaller group of women (n=17, p=0.2).  It is necessary to demonstrate that the 
overall relationship between IBPS and ECV/body weight 1) persists when evaluating IBPS from multiple recent 
HD treatments and 2) is stronger in a more homogeneous cohort of HD patients without the extremely high or 
low intradialytic blood pressures that are more likely related to comorbid medical diseases than changes in 
ECV.  It is also necessary to better define the association of this relationship with gender in a larger number of 
subjects with more equal distribution of men and women.   
 
 

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RESEARCH DESIGN AIM 1:  We will use a cross sectional study design to determine the association between 
systolic IBPS and measurements of post-HD ECV/body weight using BIA in hypertensive HD patients.   
Limitations of BIA include that it cannot be used in patients with amputations or implanted metal prostheses 
due to inaccurate measurements.  It cannot be used in pregnant individuals or those with cardiac defibrillators 
or pacemakers due to safety concerns.  For this reason, additional exclusion criteria unique to this aim will be 
patients with 1) amputations of major extremity, 2) cardiac defibrillator or pacemaker, or 3) implanted metallic 
device (see Exclusion Criteria #10-12 above).   
 
Study Procedures:  
1. Intradialytic Blood Pressure Slope: We will obtain recorded blood pressure measurements from the prior 6 
treatments. We will calculate the average systolic IBPS (mmHg/hour) using linear regression analysis.  The 
slope will be our primary independent variable.    
2. Extracellular Volume Excess:  We will use whole body multifrequency BIA (Impedimed SFB7) to measure 
ECV, intracellular volume, and total body volume before and 20 minutes after a mid-week HD treatment.  
We will use the ratio of post-HD ECV/body weight (L/kg) as our primary dependent variable.  This is a 
recognized metric for determination of ECV excess[9].   
 
Statistical Analysis Plan and Power Calculation for Sample Size (Aim 1) 
This aim’s primary outcome is the correlation between mean IBPS and post-HD ECV/body weight.  We will 
determine this with Pearson correlation analysis.  In our preliminary data analysis of 49 HD patients, we 
demonstrated a significant association between ECV/body weight and systolic IBPS from one HD treatment 
(r=0.4, p=0.008).  We aim to establish that an even stronger correlation exists in a more homogeneous 
population with less extremes of blood pressure and blood pressure changes (see Exclusion criteria 3-8 
above).  We also aim to establish associations within each gender.  Assuming 80% power at a 0.05 
significance level, we would need the following sample sizes to show the following correlations: 15 subjects for 
r=0.6, 23 subjects for r=0.5, 33 subjects for r=0.4 using Pearson correlation analysis.  To confirm our 
assumption of normal distribution, we would need at least 30 subjects.  We intend to recruit at least 66 subjects 
(33 of each gender) to ensure that we can demonstrate a strong correlation within each gender.  Our expected 
Aim 2 sample size is 74 subjects (most of which will have BIA measurements), so we expect to have more 
than adequate sample size for Aim 1.  Exploratory analyses will include correlation of ECV/body weight with 
diastolic blood pressure slope and overall change in blood pressure from pre to post dialysis as well as 
correlations involving ECV/total body volume with IBPS.   
 
EXPECTED OUTCOMES (Aim 1) 
We expect, for our primary outcome, that there will be a positive correlation between post-HD ECV/body 
weight and the mean IBPS of 0.6.  We expect that the standard deviation in our cohort’s IBPS will be smaller 
than that of our preliminary data cohort due to 1) a more homogenous population (see Exclusion criteria 3-8) 
excluding patients whose blood pressure changes are more likely to be related to ECV-independent 
comorbidities (autonomic neuropathy, medication non-adherence, advanced heart failure) and 2) calculation of 
the mean IBPS over 6 treatments, not a single treatment.  We expect the ECV/body weight to be higher in men 
than women, but the correlations between ECV/body weight and IBPS will be similar.  We expect that the 
association between IBPS and pre-HD ECV/body weight will not be as strong as with the slopes and post-HD 
ECV/body weight because pre-HD measurements are more reflective of acute, not chronic ECV excess.  
Based on our preliminary data, we do not expect as strong a correlation will exist with ECV/total body volume 
and IBPS.     
 
POTENTIAL PROBLEMS AND ALTERNATIVES (Aim 1) 
Our hypothesis is strongly supported by our preliminary data.  In the unlikely event that our experiment proves 
this invalid, we will have laboratory data and data on total body volume, dialysis prescription, antihypertensive 
medication use, and ultrafiltration rates to better understand which factors best associate with IBPS in various 
subgroups.  There are some patients whose intradialytic blood pressure would likely be influenced by ECV-
independent factors.   
 

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This includes 1) patients with very high amounts of acute and chronic ECV who have extremely high 
ultrafiltration rates (>13 mL/hr/kg) that may induce intravascular volume depletion in the absence of ECV 
depletion and 2) patients with large decreases in intradialytic blood pressure related to acute loss of total 
peripheral resistance (patients with diabetes for many years with autonomic neuropathy, patients with 
sympathetic nervous system dysfunction, patients taking antihypertensive medications during HD).  Our 
exclusion criteria minimize the risk of these factors impacting our study.  
 
3. AIM 2: The premise for this aim is there is a 
need for individualized fluid management 
interventions that minimize mortality risk 
factors in HD patients.  The objective of 
this aim is to demonstrate how IBPS-based 
ultrafiltration prescriptions affect 
ambulatory blood pressure and ECV in 
hypertensive HD patients.  We will test the 
working hypothesis that after 16-weeks, 
subjects randomized to our algorithm will have 
larger reductions in 1) ambulatory blood 
pressure during the interdialytic period, 2) 
post-HD ECV/body weight (measured with 
BIA), and 3) peripheral resistance compared 
to standard care.       
Based on our preliminary data showing a 
relationship between IBPS and ECV/body weight 
(Figure 2), we have developed an algorithm that 
assigns ultrafiltration goals based on the IBSP demonstrated over the prior two weeks.  With this algorithm 
detailed in Table 2 (below), subjects with the most negative slopes will have the least aggressive fluid removal 
while those with positive slopes will have the most aggressive prescriptions.   
 
RESEARCH DESIGN (Aim 2):  Our design for Aim 2 will be an un-blinded, randomized clinical trial comparing 
IBPS based fluid management to standard care.   
 
Patient Population:  We will use consecutive sampling to identify eligible participants from our UT 
Southwestern-affiliated HD units.  Inclusion and exclusion criteria are presented in the common approach 
section.  Subjects agreeing to participate will be assigned to one of two study groups based on computer-
generated randomization stratified by gender: IBPS-based management or Standard Care. 
 
Study Procedures:   
Baseline Information will be collected after subject enrollment (see Common Approach Elements above).   
 
Standard Care Group:  Subjects randomized to standard care will continue to be managed by their individual 
nephrologists.  In our units, 10 different nephrologists manage patients.  Each nephrologist evaluates individual 
patients in person once every 1-2 weeks to ascertain interval subjective events, physical examination, blood 
pressure, and laboratory data.  There are no mandatory changes at any visit.  The nephrologist has discretion 
to change blood pressure medications, target dry weight, and ultrafiltration goals based on his/her individual 
assessment of the patient’s needs.   
 
IBPS-Based Management:  Subjects in this arm will have ultrafiltration prescriptions ordered by study 
personnel based on the IBPS from the prior 2 weeks.  We will recalculate IBPS every month to as we expect 
IBPS to change with gradual ECV reduction throughout the course of the study.  At each monthly visit, study 
personnel will modify the prescription based on the prior 2 weeks of intradialytic blood pressure data. 
 
 
 

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The specific algorithm used to prescribe the ultrafiltration is shown in Table 2.  In addition to the ultrafiltration 
prescribed to achieve the patient’s prior dry weight, we will assign an pre-specified percentage of dry weight to 
be removed each treatment for 3 
consecutive treatments to 
establish a new dry weight.  After 
these 3 treatments, we will use 
this new dry weight as the target 
weight for ultrafiltration each visit 
until the next monthly evaluation.  In a given month, the minimal dry weight reduction would be 0% and the 
maximum would be 1.5% of the target weight.  New orders will be placed each month for 4 months.  
Our algorithm assigns a graded increase in additional ultrafiltration based on flat or positive IBPS compared to 
more negative slopes.  Our determination of 
the slope cutoffs is based on the quartiles 
of IBPS in our preliminary data of 49 
hypertensive HD patients (Figure 3).  Each 
increasing quartile reflects increasing post-
dialysis ECV excess, warranting a more 
aggressive ultrafiltration prescription.  The 
assigned intervention is derived from 
parameters in prior HD trials. In the 
intensive ultrafiltration arm of the Dry 
Weight Reduction in Hypertensive 
Hemodialysis Patients (DRIP) trial[10], the 
assigned fluid removal was the amount 
needed to offset interdialytic weight gain 
with an additional 1% of the patient’s body 
weight [10].  A separate trial using BIA to 
determine ultrafiltration goals used 
additional increments of 0.2 kg per 
treatment[11].  We believe our approach 
aiming for ultrafiltration goals within these parameters will be safe and efficacious.   
 
Dialysis Unit Procedures:  Intradialytic hypotension (systolic blood pressure >90 mmHg) or related symptoms 
will be managed per DaVita dialysis unit protocols including reduction of ultrafiltration and/or administration of 
saline (see Appendix attachment).  In subjects with recurrent symptomatic intradialytic hypotension, we will 
recommend an increase in dialysis time to minimize the ultrafiltration rate.  If intradialytic hypotension persists, 
dry weight will be increased back up.  If the assigned ultrafiltration prescription exceeds a ultrafiltration rate 13 
mL/hr/kg, we will adjust it to be no more than 13 mL/hr/kg.  Slopes will be repeated after 2 weeks at the new 
weight. 
  
In both groups, the treating nephrologist will have the liberty of adjusting blood pressure medications as 
deemed clinically necessary.   
 
Outcomes During The Study:   
Ambulatory Blood Pressure: The mean ambulatory systolic blood pressure will be the primary dependent 
variable.  We selected this variable because it is the blood pressure metric that best predicts mortality in HD 
patients[12].  Unlike BIA or NICOM, no subjects that would be excluded from obtaining ambulatory blood 
pressure measurements in this study.  All subjects will have baseline measurements of ambulatory blood 
pressure at week 0 following a mid-week treatment.  It will be repeated at week 16 following a mid-week 
treatment.   
 
BIA and NICOM: At baseline (week 0), all eligible subjects will undergo BIA and NICOM for measurements of 
ECV/body weight (see Aim 1) and total peripheral resistance index before and after a mid-week treatments.  
The procedures will all be repeated at week 8 and week 16 following a mid-week treatment. 
TABLE 2: Ultrafiltration Prescription Algorithm for Intervention Group 
Slope  
Intervention 
<-9 mmHg/hr 
Continue UF prescription.  Extend dialysis treatment length 
-9<x<-4 mmHg/hr 
Target Weight Reduction of 0.3% each treatment x1 week 
-4<x<+2 mmHg/hr 
Target Weight Reduction of 0.4% each treatment x 1 week 
>+2 mmHg/hr 
Target Weight Reduction of 0.5% each treatment x 1 week 

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Statistical Analysis Plan and Power Calculation for Sample Size (Aim 2) 
The primary outcome of this aim will be the ambulatory systolic blood pressure from baseline to 16 weeks.  
Secondary endpoints include ECV/body weight and total peripheral resistance, from baseline to 16 weeks.  We 
will use the two-sample t test to perform the unconditional comparison of the difference in endpoints over time 
between treatment and control groups. For conditional comparison, we will use the linear mixed effect model to 
estimate the fixed effect of the treatment group indicator, while adjusting for the fixed effects from baseline 
variables and time and the random effect within the same patient. We determined our sample size based on 
known effects of intense ultrafiltration on ambulatory blood pressure reduction.  In the DRIP trial[10], systolic 
blood pressure decreased by 13.9 mmHg in the intense ultrafiltration group and 6.9 mmHg in the standard 
group (95% CI -12.2 – 1 mmHg) after 8 weeks.  We expect a more modest decrease in systolic blood pressure 
due to our less aggressive approach per treatment. Assuming a standard deviation for the ambulatory systolic 
blood pressure change of 6 mmHg (this was approximately 2.7 mmHg in DRIP and our study will have a 
smaller sample size), we will be able to show with 90% power and an alpha of 0.05, that a between group 
difference ≥2.7 mmHg will occur.  If the normality assumption indeed holds in our observed data, this would 
require 14 subjects per arm, but we will recruit 30 subjects per arm to facilitate simple normality check such as 
the Q-Q plot.  Assuming a 25% dropout rate, we will aim to recruit 74 subjects (37 in each group). 
 
With our sample size (n=74), we will have 85% power to detect a 0.025 difference in the change 
between groups after 16 weeks in ECV/body weight.  This clinically significant difference is consistent with the 
difference in post-HD ECV/body weight we found in patients with intradialytic hypertension and HD controls 
[13].  Based on our prior experiences recruiting HD patients for clinical research, we expect that we will be able 
to enroll 1-2 patients each month (18 patients each year including excluding dropouts).    
 
EXPECTED OUTCOMES (Aim 2) 
We expect the IBPS-based ultrafiltration group to have ≥3 mmHg greater reduction in mean ambulatory 
systolic blood pressure from baseline to 16 weeks than the standard care group.  We expect that such 
differences could be as high as 7 mmHg based on the DRIP trial.  Because our algorithm assigns fluid removal 
objectively and most hypertensive HD patients have ECV excess that is difficult to identify clinically, we expect 
that subjects assigned to our algorithm will be assigned more fluid removal over the course of the study than 
those in the standard care group.  We expect the outcomes to include improvement in chronic ECV excess as 
shown by greater reduction in post-HD ECV and ECV/body weight.  We expect to also see reduction in post-
HD total peripheral resistance.  We do expect ambulatory blood pressure to decrease in the standard care 
group due to patient motivated lifestyle changes while in a clinical trial.  However, we expect that the decrease 
in blood pressure will be of greater magnitude in our IBPS-based ultrafiltration group as specified above.  We 
expect our algorithm will optimize fluid removal and that the change in post-HD ECV/body weight will be 
≥0.025 in the IBPS-based ultrafiltration group compared to standard care.  
 
POTENTIAL PROBLEMS AND ALTERNATIVES (Aim 2) 
In the unlikely event our Aim 1 hypothesis is proven invalid and fails to show as robust association between 
IBPS and ECV as hypothesized, the evidence remains strong that intensifying ultrafiltration lowers blood 
pressure.  Aim 2 will provide an opportunity to determine if an algorithmic alternative to the arbitrary 
prescription approach in standard care is more effective at achieving that goal, and it will provide a mechanistic 
assessment of how gradual changes in ECV impact vascular resistance and cardiac output in HD patients.   
 
Potential problems in Aim 2 include the possibility that patients with severely uncontrolled BP will need 
major changes in antihypertensive medications during the study.  In this case, blood pressure slopes may be 
modified despite no change to the patient’s ECV.  We will minimize this risk by excluding patients with poor 
control of blood pressure (pre or post HD systolic BP> 180 mmHg) and history of medication non-adherence.  
In the unlikely event that our intervention fails to improve blood pressure or ECV in the overall population, we 
will be able to explore which subgroups did appear to achieve benefit so that we can further refine our 
algorithm.  
 

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In some clinical studies, measurements obtained with BIA have been used to guide fluid removal.  The 
inability to include subjects with amputations, cardiac defibrillators or pacemakers in the 16 week clinical trial 
would reduce our ability to achieve the necessary sample size and would limit our ability to generalize our 
findings to many other hypertensive HD patients.  Subsequently, the measurements obtained with BIA in this 
aim will only be used as secondary outcomes among those subjects that have no exclusion criteria for its use. 
Another potential marker for ECV excess that has been considered is the slope of intradialytic hematocrit using 
relative blood volume monitoring as an estimate of intravascular volume.  Our primary concern with this is that 
the device used for this application is currently on FDA recall.  Furthermore, there is prior evidence from a 
randomized trial showed that mortality and hospitalization increased in patients who had blood volume 
monitoring[14].   
 
4. AIM 3: The premise for this aim is there is a need for fluid management approaches that minimize 
intradialytic hypotension.  The objective of this aim is to demonstrate how IBPS-based 
ultrafiltration prescriptions affect intradialytic hypotension.   We will test the working hypothesis 
that in a randomized trial (Aim 2) using IBPS to guide ultrafiltration, the frequency of intradialytic 
hypotension, the intradialytic systolic blood pressure nadir, and the occurrence of intradialytic symptoms 
will be similar in subjects randomized to our algorithm and standard care.   
Recurrent intradialytic hypotension, defined as systolic blood pressure <90 mmHg) is a mortality risk 
factor, such that blindly and aggressively removing large amounts of fluid to manage ECV excess may cause 
more harm than good in some patients with ECV 
excess.  For HD patients that cannot adhere to the strict 
dietary sodium and fluid restriction recommendations, 
there is currently no standardized approach to remove 
sufficient fluid during dialysis to prevent ECV excess 
without inducing large decreases in blood pressure. In 
our preliminary data, the nadir systolic blood pressure is 
significantly lower in patients in lower quartiles of IBPS 
(more negative slopes) compared to the upper quartiles 
(positive slope) as shown in Figure 4.  Our graded 
ultrafiltration algorithm assigns less ultrafiltration to 
those patients with steep negative slopes and therefore 
avoids overly aggressive fluid removal in patients that 
are least likely to tolerate it.   
 
RESEARCH DESIGN (Aim 3):   
We will use a randomized clinical trial comparing IBPS 
based fluid management to standard care comprised of the subjects participating in Aim 2 (see above). 
   
Study Procedures:  IBPS Based Fluid Management: See Aim 2.   
Intradialytic Hypotension Measurement:  A systolic blood pressure nadir <90 mmHg will be the definition of 
intradialytic hypotension.  We are using this definition because it is the metric of intradialytic hypotension that 
has the strongest independent association with mortality[15].  Consistent with dialysis unit protocol, blood 
pressure will be measured with an automated sphygmomanometer attached to the dialysis machine every 30 
minutes during the dialysis treatment and more frequently in the context of hemodynamic instability.  We will 
obtain blood pressure records from each treatment, including the lowest blood pressure measured.  An 
occurrence of intradialytic hypotension will not be counted more than once per treatment.  Secondary 
outcomes will be the systolic blood pressure nadir.   
 
Intradialytic Interventions:  We will obtain HD records for each treatment to document the frequency of 
recorded intradialytic symptoms (cramping, dizziness, nausea/vomiting), as well as the frequency and type of 
intervention used to manage these symptoms (reduction/cessation of ultrafiltration; administration of 
intravenous fluid; transport to hospital).   
 

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Statistical Analysis Plan (Aim 3):  This aim’s primary outcome is the difference in intradialytic hypotension 
between subjects randomized to IBPS-based ultrafiltration or standard care.  We will use a generalized mixed 
linear model with an event indicator for intradialytic hypotension as the response, controlling for within subject 
correlation.  Based on our preliminary data, patients with lower than median IBPS had nadir blood pressure of 
108.4 (15.7) mmHg compared to 126.8 (13.1) mmHg (p=0.003) in patients above the median. There were five 
subjects with nadir SBP less than 100 mmHg during HD, and two of these subjects had nadir SBP <90 
compared to zero and zero in the steeper slope group.  Our sample size is determined based on our 
calculations for the primary outcome in Aim 2.  We will compare systolic blood pressure nadir throughout the 
study using mixed model repeated measures analysis similar to other continuous outcomes in Aim 2.     
 
EXPECTED OUTCOMES (Aim 3) 
We expect that the risk of intradialytic hypotension will be similar in subjects randomized to IBPS-based 
ultrafiltration and standard care. Because of our exclusion criteria, we do not expect intradialytic hypotension to 
be common in our clinical trial subjects.  We expect our graded algorithm to appropriately balance the intensity 
of ultrafiltration with the baseline intradialytic hypotension risk.  This balanced approach will be reintroduced 
every month in the intervention group with reassessment of the IBPS.  Therefore, we do not expect the 
incidence of intradialytic hypotension to increase much more than baseline in this same group.  We also expect 
the nadir systolic blood pressure and number of treatments with cramps and dizziness to be similar in the two 
groups.  If these outcomes are similar, we will interpret this as an indication that our algorithm does not 
introduce any new risk to patients compared to standard care and is a safe alternative that requires evaluation 
in a long term clinical trial.   
 
POTENTIAL PROBLEMS AND ALTERNATIVES (Aim 3) 
In the event that Aim 2’s hypothesis is proven invalid, it is still necessary to known if our algorithmic approach 
to standard care ultrafiltration causes less intradialytic hypotension.   
 
Because intradialytic hypotension and ultrafiltration rate are strongly associated, another approach to minimize 
the risk for intradialytic hypotension is to slow the ultrafiltration rate.  While lowering the target ultrafiltration 
volume would achieve this, it would simultaneously increase the risk for ECV excess.  Lengthening the dialysis 
treatment time is another strategy that enables similar (or more) absolute fluid removal at a slower rate.  The 
major limitation of this approach is the logistic application to the population of nearly 500,000 ESRD patients on 
HD in the United States.  Survey data has demonstrated a general unwillingness of HD patients to come in for 
extra treatments or have increased dialysis time on a regular basis[16].  It is critical to develop a novel 
approach that remains applicable to the present environment of dialysis care.  Furthermore, our approach 
would remain relevant even in the context of an institutionalized increase in dialysis times. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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P. Van Buren, Protocol Version: 1.0, Date: 08March 2017  
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