Randomized Trial of Dialysate Sodium in Chronic Hospitalized Hemodialysis Patients
Phase: NA
Conditions: Intra-dialytic Hypotension
Sponsor: Brigham and Women's Hospital

 
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IRB DETAILED PROTOCOL 
Title: Cardiovascular effects of intra-dialytic hypotension - Randomized trial of 
dialysate sodium in chronic hospitalized hemodialysis patients 
PI: Finnian Mc Causland, MBBCh, MMSc 
Date: 08/01/2017 
Version: 7 
Sponsor: NIH-NIDDK 
 
PARTNERS HUMAN RESEARCH COMMITTEE 
DETAILED PROTOCOL 
 
I. BACKGROUND AND SIGNIFICANCE  
 
Hemodialysis (HD) is a life-sustaining treatment for patients with end stage renal 
disease, but carries with it a high associated morbidity and mortality. Approximately 
50% of patients on HD die within three years after starting treatment.  This mortality 
rate is comparable to, or exceeds that of, many types of cancer.1 Around 41% of 
deaths in prevalent patients and 38% of deaths in incident patients are attributable to 
cardiovascular causes, of which over 50% are ascribed to arrhythmia or sudden 
cardiac death.2  
 
Hemodialysis and intra-dialytic hypotension     
Intra-dialytic hypotensive (IDH) events can be defined as an abrupt decline in blood 
pressure that causes symptoms and/or requires an intervention.3, 4 They are common, 
affecting up to one third of maintenance HD sessions.5-7  Detrimental associations of 
greater magnitude of systolic blood pressure (SBP) decline during HD include: 
development of myocardial stunning,8 regional wall motion abnormalities,9, 10 
elevations in troponin,11 cerebral hypo-perfusion,12 vascular access thrombosis13 and 
greater mortality.14, 15 Even without documented symptoms, a decline of >30mmHg in 
SBP from pre- to post-HD has been independently associated with greater 
cardiovascular and all-cause mortality.16 Thus, the magnitude of intra-dialytic SBP 
decline is an important and modifiable risk factor for adverse outcomes.   
 
Intra-dialytic SBP decline, cardiac arrhythmia & cerebral ischemia 
The rate of sudden cardiac death in HD patients was approximately 50 per 1000 
patient years in 2010, accounting for 26.5% of deaths in prevalent patients.2 It is 
possible that many of these are related to cardiac arrhythmias.  The prevalence of 
arrhythmia in chronic HD patients is estimated to range between 21-34%, using 24-48 
hour Holter monitoring.17, 18       
 
HD patients have high rates of stroke and transient ischemic attacks (205 per 
1000 patient years in 2010), with stroke accounting for 2.3% of the mortality among 
incident patients.2  Brain infarcts have been reported in close temporal proximity to 
the dialysis procedure,19 with decreased intra-dialytic cerebral blood flow correlating 
with intra-dialytic decline in SBP.12  Silent cerebral infarction is estimated to affect up 
to 50% of chronic HD patients, and is independently associated with greater risk of 
subsequent adverse cardiovascular events.20  
 
Intra-dialytic SBP decline and hospitalized HD patients     
HD patients had an average of 1.9 hospitalizations per year (12 inpatient days) during 
2010, 30% of which were cardiovascular-related, with a re-hospitalization rate of 

 
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37%.2 Our preliminary data suggests a high event rate for intra-dialytic hemodynamic 
instability in chronic HD patients admitted to hospital, with over 28% having a 
decline of ≥30 mmHg.  Rapid solute removal by HD generates temporary osmotic 
gradients between the intra-vascular and intra-cellular compartments, promoting 
trans-cellular fluid movement and resultant hypotension.21, 22 Manipulation of osmotic 
gradients, e.g. using higher dialysate sodium, may ameliorate excess SBP decline 
during HD.  However, associations with thirst, inter-dialytic weight gain and 
hypertension have tempered the use of higher dialysate sodium in outpatients.23-25 
There have been few well-designed interventional studies in the hospital setting, 
where chronic HD patients are more likely to benefit from interventions to promote 
hemodynamic stability.   
 
The optimal dialysate sodium is unknown     
Some clinicians have proposed to lower the dialysate sodium (less or equal to the 
serum sodium) so as to minimize diffusive sodium gain during HD.26 We and others 
reported that higher dialysate sodium in certain circumstances may associate with 
lower rates of hospitalization and mortality.27, 28 This may relate to less marked 
decline in SBP.  The variability of dialysate sodium use across the United States and 
internationally speaks to the lack of evidence from well conducted studies.27, 28 
 
The current methods of treating IDH available for use in the Brigham (other than 
manipulating the dialysate sodium concentration), depending on treating physician 
preference, include the following: 
- 
Cooled dialysate - by lowering the temperature to ~35-36 degrees Celsius, it 
has been shown that the frequency of IDH is lowered.  However, many 
patients do not tolerate these lower temperatures. 
- 
 Isolated ultrafiltration or reduced ultrafiltration rate - these procedures require 
lengthening of the procedure or additional treatments, which greatly reduces 
patient compliance.  Furthermore, they do not prevent IDH in those with 
impaired baroreceptor activation. 
 
This proposal aims to assess the effects of higher (142 mmol/L) versus lower (138 
mmol/L) dialysate sodium (DNa) use in adult chronic hemodialysis patients admitted 
to hospital on intra-dialytic blood pressure and biomarkers of cardiac ischemia.    
 
We will randomly assign subjects to higher versus lower DNa during their hospital 
stay, up to a maximum of six HD sessions.   
 
 
II. SPECIFIC AIMS 
 
For adult patients with end-stage kidney disease requiring hemodialysis who are 
admitted to hospital, we will test the following aims: 
 
Aim 1 
Test if higher (142 mmol/L) versus lower (138 mmol/L) dialysate sodium reduces the 
magnitude of intra-dialytic SBP decline during hospitalized HD sessions. 
 
Hypothesis: Higher dialysate sodium use will results in less decline in intra-dialytic 
SBP during hospitalized hemodialysis sessions.  

 
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Aim 2 
Test if higher (142 mmol/L) versus lower (138 mmol/L) dialysate sodium results in 
less cardiac injury as measured by change in high sensitivity Troponin I (hsTnI) one 
day post-dialysis. 
 
Hypothesis: Higher dialysate sodium use will result in less elevation of hsTnI 
measured one day post dialysis. 
 
 
III. SUBJECT SELECTION 
 
Inclusion criteria     
Chronic HD (>90 days); age ≥18y; informed consent; first admission during study 
period; Inpatients; Informed consent or surrogate consent with assent of adult subject.  
 
 
Exclusion criteria 
Use of pressors; pre-dialysis serum sodium <=128mmol/L or > 145 mmol/L; pre-
dialysis SBP >180 mmHg; intensive care stay earlier in admission; expected length of 
stay <24 hours (e.g. admission for HD access procedure); acute coronary syndrome 
within seven days; acute stroke (as defined by an attending neurologist based on 
symptoms and cerebral imaging; all potential strokes are reviewed by the neurology 
service in BWH); institutionalized individuals; pregnancy; Outpatients. 
 
Pregnant individuals will be excluded because of the unknown effects of higher 
dialysate sodium on teratogenicity.  All women of childbearing age will be screened 
before their first dialysis session for pregnancy using serum beta hCG measurements 
within 72 hours of study initiation.  Subjects with a positive pregnancy test cannot 
take part in the study.   
 
RECRUITMENT METHODS 
Eligible patients will be identified by reviewing the inpatient patient lists and by 
discussion with the attending physicians covering the said services and from the 
subject’s attending of record.   
 
In all cases we will approach the attending physician of prospective subjects to 
describe the study and obtain verbal consent to approach patients for recruitment; the 
attending physician or medical staff caring for the patient will be the first to make 
contact with patients to describe the study briefly and ask permission for us to enter 
the room and explain the study in more detail. 
   
It is possible that some eligible patients may be specific patients of the investigating 
study doctors.  In these cases, in order to avoid these patients feeling an obligation to 
participate, we will ask a colleague to make the first contact with them, to determine 
if they are interested in participating in the study.   
 
We will emphasize to all potential subjects that their participation is entirely 
voluntary and will in no way affect their care. 
 

 
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It is possible that some eligible patients may be specific patients of the investigating 
study doctors.  In these cases, in order to avoid these patients feeling an obligation to 
participate, we will ask a physician colleague or research assistant to make the first 
contact with them, to determine if they are interested in participating in the study.  
   
We do not plan on any specific outreach or recruitment of women or minorities; 
BWH cares for a large number of under-served minorities and women, so we 
anticipate diverse enrollment. 
 
The PHRC policy on Obtaining and Documenting Informed Consent of Subjects who 
do not Speak English will be followed where appropriate 
(http://healthcare.partners.org/phsirb/nonengco.htm).   
 
 
IV. SUBJECT ENROLLMENT 
a. Methods of enrollment, including procedures for patient registration and/or 
randomization 
b. Procedures for obtaining informed consent (including timing of consent process) 
c. Treatment assignment, and randomization (if applicable) 
 
Where possible, subjects will be approached for informed consent at least 24 hours 
before potential study initiation.  However, due to the acuity of renal replacement in 
many circumstances, there may be occasions where subjects have less than 12 hours 
to give informed consent.   
 
Study MDs (licensed physician investigators) will obtain consent from participants.  
Study MDs, such as the Principal Investigator and Co-Investigator, will be available 
to discuss the study in detail with potential subjects who have specific questions.   
 
Some patients may be unable to provide informed consent due to altered mental 
status.  For patients who are unable to consent (with a Folstein mini-mental score of 
23 or less) we will contact the next of kin in person to discuss the study in detail.  For 
subjects enrolled by surrogate consent, we will re-assess their ability to provide 
consent at each subsequent dialysis visit.  Surrogate consent will be sought in the 
following hierarchy: (1) a court-appointed guardian with authority to consent to 
participation in the research or authority to make health care decisions for a class of 
diagnostic and therapeutic decisions that are inclusive of the proposed research; (2) a 
health care proxy or person with durable powers of attorney, whose authority includes 
making health care decisions inclusive of the proposed research; or (3) a spouse, an 
adult child, or other close family member. Study staff will direct surrogates to 
exercise substituted judgment on behalf of the potential study subject (i.e. "how 
would the subject have felt about participating") rather than their own wishes with 
respect to research.  The relationship of the surrogate to the subject will be recorded 
in the research record.  Assent of subjects will be a requirement for participation in 
the research unless the subject is incapable of giving assent due to his/her medical 
condition. In some cases, the patient will be unable to provide a legible signature, 
time and date on the consent form. For those instances, a witness will also sign, date 
and time the consent form.  
 

 
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Randomization will be performed by means of a permuted block design, with blocks 
consisting of four subjects with a 1:1 allocation ratio to higher versus lower DNa.   A 
random coded list will be generated before study initiation and kept in a locked 
drawer in the Dialysis Director’s locked office.  The random list be generated 
utilizing the program software available on www.randomization.com.  Study staff 
involved in recruitment, data procurement and analysis will not have access to this 
list. Study staff, after enrolling the next subject, will contact the Dialysis Director to 
obtain the next random treatment assignment, which he will provide to the dialysis 
charge nurse, thereby maintaining blinding of the study staff.  By necessity, the 
treating dialysis nurse and dialysis charge nurse will be aware of the treatment 
assignment, but will be advised not to disclose this to the patient or other staff.   
 
Otherwise, subjects will be dialyzed according to the treating physician’s routine care, 
who will also be blinded to the treatment assignment.  However, unblinding of the 
treating physician will be allowed by specific request in relation to a need to know the 
treatment assignment for clinical care.   
 
We plan to recruit 200 patients in total, for 140 to complete the study.   
   
 
V. STUDY PROCEDURES 
a. Study visits and parameters to be measured (e.g., laboratory tests, x-rays, and 
other testing) 
b. Drugs to be used (dose, method, schedule of administration, dose modifications, 
toxicities), include Toxicity Grading Scale (if applicable) 
c. Devices to be used 
d. Procedures/surgical interventions, etc. 
e. Data to be collected and when the data is to be collected 
 
Study visits and parameters to be measured 
 
We will obtain data, hemodynamic parameters and blood samples in the following 
manner: 
 
Hemodynamic parameters 
All subjects will be weighed before and after their dialysis session.  Blood pressure 
and heart rate will be measured before, after and every 15 minutes during the dialysis 
procedure by a calibrated standard ambulatory blood pressure cuff.  These 
measurements are performed and recorded by the dialysis nursing staff as per 
standard nursing protocols.    
 
Symptom questionnaire 
Dialysis related symptoms will be recorded at the end of each study session via the 
use of a symptom questionnaire and the dialysis thirst inventory.   
 
Blood collection 
Blood will be collected at the start and end of the first and second hemodialysis 
procedures (15-20mL each dialysis session; 40mL maximum total).   
Blood tests will be collected in an EDTA tube and a serum gel tube immediately after 
insertion of access needles or connection to dialysis catheters (after withdrawing 

 
6
10mLs initially as per standard care in the dialysis unit).  Blood samples will be 
centrifuged, and plasma will be aliquoted into 0.5cc tubes and placed in the -80 
freezer for storage until ready to analyze.  A single post-dialysis EDTA tube will be 
collected after the first and second dialysis sessions.   
 
All biological samples will be stored with unique study IDs that are not labeled with 
any unique indentifying information, such as name, MRN or birthdates.   
 
Data collection and management 
We will perform chart review and enter demographic information, clinical and 
laboratory data into a secure electronic database.  Data for collection, when available, 
will include: 
1. Demographics - age, race, and sex. 
2. Comorbid illness - diabetes, cerebral vascular disease, peripheral vascular disease, 
malignancy, coronary artery disease and heart failure. 
3. Laboratory data – in addition to the samples outlined above, complete blood count 
and electrolytes will be available as part of routine clinical care for subjects.  Online 
Kt/V, a measure of dialysis adequacy will be available for all subjects on 
hemodialysis.   
4. Medications/fluids - list of all active medications, type and volume of intravenous 
fluids administered during dialysis; dialysis prescription details. 
5. Treatment parameters – access, blood pressures, heart rates, weights, duration of 
session, blood flow, dialysate flow, and dialysate prescription.  
 
Data will also be collected regarding length of stay and readmissions.   
 
Primary end-point definition 
The primary end-point will be the magnitude of systolic blood pressure decline, 
defined as the pre-dialysis SBP minus the nadir intra-dialytic SBP.  
 
Interventions 
The higher dialysate sodium concentration will be 142 mmol/L; the lower dialysate 
sodium concentration will be 138 mmol/L.   These concentrations will be used for the 
duration of the study period, up to a maximum of six sessions.  Afterwards the 
dialysate sodium concentration will be determined by the treating in-house dialysis 
doctor.  All other treatment parameters will be determined by the treating physicians.   
 
 
VI. BIOSTATISTICAL ANALYSIS 
 
Analytic approach    
Intra-dialytic SBP decline:  The primary outcome will be the average magnitude of 
pre-hemodialysis SBP – nadir SBP during dialysis for the primary analyses, using a 
repeated measures analysis design. This will be assessed at each of the first six HD 
sessions during the hospital admission.  In secondary analyses we will examine 
alternative definitions of intra-dialytic hemodynamic instability, as outlined in Aim 1. 
SBP’s will be measured at 15 minute intervals throughout the HD procedure.   
Cardiac Biomarkers:  hsTnI will measured from samples prior to and 20 hours after 
the first HD study sessions using the Architect (Abbott) platform; the limit of 
detection of the assay is 1.2 ng/L; the 99th percentile among healthy subjects is 16 

 
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ng/L; and the 10% coefficient of variation (CV) concentration is 3.9 ng/L.29  
Tolerability and Safety Parameters (Pre-dialysis SBP, thirst scores and inter-dialytic 
weight gain)   During each study session patients will be asked to complete a 
symptom questionnaire, including the dialysis thirst inventory.30 BP’s will be 
measured with an appropriately sized cuff after having the patient resting quietly for 5 
minutes, the arm supported at heart level and before the dialysis access is needled. An 
average of two readings will be taken on each occasion.  BP’s between HD sessions 
will also be collected from each patients’ end-of-bed chart to assess effects of the 
intervention on inter-dialytic blood pressure control.  Inter-dialytic weight gain will 
be recorded pre- and post-dialysis in the inpatient HD unit.  For bed-bound patients, 
pre-dialysis weights will be ascertained from weights recorded on the hospital floor, 
or from calibrated bed weights.   
 
Power  
We will aim to recruit 70 subjects to each arm.  We will report two-way comparisons 
with an alpha=0.05.  We will inspect and plot all BP measurements over time and 
assess trends descriptively.  Assuming a mean SBP decline of 24 mmHg, with 
standard deviation of 12 mmHg,31  we will have 90% power to detect a difference of 
6.6 mmHg and 80% power to detect a difference of 5.7 mmHg between groups.  If 
recruitment is slower than anticipated, even with n=55 in each arm, we will have 80% 
power to detect a difference of 6.5 mmHg for the primary outcome.  If the SD was as 
high as 24 mmHg, we would still have 80% power to detect a difference of 11.7 
mmHg.   
 
The mean difference in hsTnI according to higher vs. lower DNa will be 
assessed with standard t-tests or non-parametric tests, according to the observed 
distribution.  Assuming 70% of patients will have at least two inpatient HD sessions, 
a total of 49 patients per arm will have complete data for determining the difference in 
hsTnI measurements before and after the HD study session.  We will have 80% 
power, at alpha=0.05, to detect mean differences of 0.82 log pg/mL in hsTnI for 
higher vs. lower DNa, assuming mean change of 3.27 ±1.43 log pg/mL (preliminary 
data).  For the analyses of pre-dialysis SBP, we will have 80% power to detect a 
difference in means of 12.4 mmHg for higher vs. lower DNa, assuming mean 152 ±26 
mmHg.32  For the analyses of thirst scores, we will have 80% power to detect a 
difference in means of 3.5 units, assuming mean score of 20.3 ±7.3 units.30 For the 
analyses of inter-dialytic weight gain, we will have 80% power to detect a difference 
in means of 0.7 kg, assuming mean 2.7 ±1.5 kg.33 
 
 
VII. RISKS AND DISCOMFORTS (Stratify by common and uncommon) 
a. Complications of surgical and non-surgical procedures, etc. 
b. Drug side effects and toxicities 
c. Device complications/malfunctions 
d. Psychosocial (non-medical) risks 
 
Complications of surgical and non-surgical procedures 
Where possible, collection of blood will occur at the same time that samples are being 
collected as part of routine clinical care.  The risks of collection from an arteriovenous 
fistula, arteriovenous graft or peripheral vein relate to bruising at the site of draw and 
transient dizziness. The risks of blood draw from a central line include a small risk of 
introducing infection.  Blood drawing can contribute to the development of anemia, 

 
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which can cause symptoms related to inadequate oxygen delivery in patients with 
severe anemia (Hematocrit <21%) and myocardial ischemia (Hct <30%). Repeated 
blood draws can also increase the need for blood transfusions, particularly in those 
with inadequate bone marrow responses.   We will therefore withhold blood draws 
from patients under the following circumstances: 
a) Active myocardial ischemia and hematocrit < 30% 
b) Severe anemia (hematocrit <21%) 
c) Active bleeding 
When the patient’s physician feels that blood drawing would be unsafe or poorly 
tolerated. 
 
 
Potential intervention side effects 
Risks from higher dialysate sodium use include greater thirst, inter-dialytic weight 
gain and hypertension.   
Risks from lower DNa use include more frequent low blood pressure events.   
 
Psychosocial and non-medical risks 
The risk of loss of privacy is small.  We will use study IDs rather than medical record 
numbers to label and track specimens and results. Medical Record Numbers will be 
linked to study IDs in a file that is located on a password-protected secure computer 
and in a study notebook kept in the principal investigator’s locked office.  Subjects 
will have the option to opt out of the study at any time.   
 
 
VIII. POTENTIAL BENEFITS 
Subjects may benefit from taking part in this study by the possibility of their blood 
pressure during dialysis remaining closer to the normal range and may have less 
adverse symptoms during dialysis. 
 
We hope the findings of this study will shed light on the role of changes in osmolality 
in relation to the development of intra-dialytic hypotension and symptoms.  By 
building upon these findings we hope to further our research in order to facilitate 
improved outcomes in these patients in the longer term.   
 
 
IX. MONITORING AND QUALITY ASSURANCE 
 
As our trial is a small physiological study, involving relatively small numbers of 
subjects, short term interventions and endpoints which are not serious or irreversible, 
the principal investigator will have primary responsibility for monitoring the trial 
from a scientific integrity and participant safety standpoint.  Safety data will be 
reviewed when 20%, 40%, 60%, 80% and 100% of the target enrolment has been 
achieved. 
We will report any adverse events to the IRB per PHRC reporting guidelines.  
Unanticipated problems involving risks to subjects or others including adverse events 
will be reported to the PHRC in accordance with PHRC unanticipated problems 
reporting guidelines.   
 
 

 
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