Blood Volume Analysis - Guided Heart Failure Management
Phase: NA
Conditions: Heart Failure, Congestive Heart Failure
Sponsor: Duke University

 
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Blood Volume Analysis - Guided Heart Failure Management 
 
NCT04111185 
 
Document Date: February 24, 2020 
 
 

 
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1. Protocol Title  
Blood Volume Analysis- Guided Heart Failure Management 
 
2. Background 
Heart failure (HF) is a leading cause of morbidity and mortality in the US. Simply put, the 
numbers are alarming. HF affects more than 6 million adults in the United States (US) alone.1 It 
is the most common cause of hospitalization among Medicare beneficiaries and outcomes 
remain unacceptably poor. The key hallmark of acute heart failure (HF) is vascular congestion. 
Despite its central role in the pathophysiology of HF, our understanding of congestion remains 
limited. The current HF pathophysiologic model suggests that congestion is the result of volume 
retention, and therefore therapies (such as diuretics and ultrafiltration) have generally targeted a 
suspected volume overload. Despite this, the therapeutic benefits of fluid removal strategies on 
short and long term outcomes have been modest or absent. More recently the concept of fluid 
gain as cause of cardiac decompensation has been challenged. Our recent work proposed a 
new concept of cardiac congestion and decompensation, which may play a critical role in the 
pathophysiology of congestion in a significant portion of patients. This disruptive concept 
suggests that cardiovascular congestion is the result of blood redistribution from the abdominal 
(splanchnic) compartment to the heart and lungs. To allow a personalized treatment of patients 
with HF it is imperative to understand whether a patient has fluid overload and if so to what 
extent. To date the assessments of congestion is often limited to surrogates of intravascular 
pressure and volume, which often provide an incomplete and, in some instances, a false 
impression of a patient’s congestion status. Volume overload, based on clinical examination 
parameters (presence of jugular venous distension, peripheral edema and orthopnea, an S3 
and positive hepato-jugular reflex)1, 2 increases in body weight,3, 4 natriuretic peptides5, 
estimates of plasma volume6 and even invasive hemodynamic measurements7, 8 lack sufficient 
sensitivity and specificity to accurately assess a patient’s intravascular volume status. Yet, the 
use of blood volume analysis (BVA) via I131-labeled human serum albumin indicator-dilution 
technique, the gold-standard test to determine the intra-vascular volume, could overcome many 
of the limitations of conventionally used surrogate markers.  
While it is well recognized that the extent of 
fluid volume congestion is closely associated 
with clinical outcomes,9-12 the extent to which 
decongestion is achieved with diuretic therapy 
is highly variable and often less than clinically 
suspected.11, 13, 14 Our preliminary data 
supports that current surrogate markers of 
congestion lack accuracy to estimate the true 
blood volume.6 Given the limitations in clinical 
assessment of congestion and volume 
overload, an accurate assessment of blood 
volume using a standardized indicator-dilution 
technique with I-131-labeled albumin could 
provide distinct clinical benefit. This technique 
is considered to be the gold-standard for the 
quantitative assessment of plasma and total 
blood volume analysis given its precision, 
reproducibility, and clinical validity.17 
Retrospective studies using this technique have 
Figure 1: Heterogeneity in blood volume 
parameters. From Miller W, et al. JACC HF 2014 

 
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demonstrated marked heterogeneity in volume status in patients with acute and chronic HF11, 13, 
15 and uncovered unrecognized subclinical hypervolemia in asymptomatic and symptomatic HF 
patients (Figure 1).15, 16 Most recent retrospective evidence now suggests that BVA- guided HF 
management could improve clinical outcomes such as HF rehospitalization and mortality in 
patients admitted with acute HF.16 Consistent with our paradigm shifting hypothesis and 
preliminary data, inappropriate redistribution of intra-vascular volume might be an additional 
important driver of cardiac decompensation and can explain an increase in central filling 
pressures in the absence of weight gain or total body volume increase 11, 17, 18. Supportive 
evidence is provided by body volume analysis using the I131-labeled human serum albumin 
indicator-dilution technique. Using this technology studies found that chronic HF patients with 
persistent symptoms are in 35% of cases hypovolemic or euvolemic11 and the same was even 
true for patients admitted for decompensated HF (34%).19, 20  
 
In an attempt to gather preliminary experience with the Daxor BVA technology, we enrolled 
and performed BVA measurements in 14 patients with acute and chronic HF within a 3 months 
window as part of a Duke approved IRB protocol (Pro00100536, Adrian Hernandez).  
 
3. Purpose of the Study  
Our objective is to develop personalized treatment approaches to the treatment of acute HF. 
The central hypothesis is that BVA will allow improved congestion phenotyping of acute HF 
patients given the ability to directly and accurately measure blood volume. Knowledge of 
specific congestion phenotypes will be the basis for targeted treatment algorithms. The specific 
objectives are: 
Perform a pragmatic randomized pilot study (N=50) with blood volume analysis (BVA) – guided 
treatment strategy vs standard of care in patients admitted for acute decompensated HF  
A: Study effects of unblinded BVA results on provider treatment choices and clinical endpoints  
B: Develop a new BVA-guided treatment algorithm based on the observed experience with BVA 
at Duke   
 
4. Design & Procedures 
Perform a pragmatic randomized pilot study (N=50) with BVA- guided treatment strategy vs 
standard of care in patients admitted for acute decompensated HF.  
The main intent for this pilot study is to gather information on optimal study design, treatment 
recommendations and sample size for a future planned pivotal trial.  
Design: Pragmatic pilot study of patients admitted with acute HF. Upon enrollment patients will 
be randomized to either the unblinded arm (BVA- guided treatment), or blinded arm (Standard 
of care treatment), where BVA results will not be provided to patients or provider team. The 
study is planned to start in the Spring, 2020 and be open for enrollment for 1 year. (Figure 2) 

 
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Population: Patients presenting to Duke Hospital with a history of HF and worsening symptoms 
of HF will be enrolled in the study. Exclusion criteria are: Ongoing pregnancy, age <18 years, 
post heart transplantation or ongoing mechanical circulatory support, and end stage renal 
disease. 
 
Treatment protocol: A pre-determined assortment of demographic and medical information will 
be gathered for all patients upon admission, 24h, 48h, 72h and upon completion of repeat BVA 
and upon discharge. See flow chart below (Table 1). 
 
Table 1: Patient assessments during the study. SOC indicates standard of care and CS 
indicates clinical study related procedures. 
 
Required Assessment 
Baseline Day 1 
Day 2  
Day 3 
Day 
before 
discharge  
Discharge  
30 days 
post 
discharge  
Consent/Randomization 
X 
(CS) 
 
 
 
 
 
 
Medications 
X 
(SOC) 
X 
(SOC) 
X 
(SOC) 
X 
(SOC) 
X 
(SOC) 
X  
(SOC) 
X  
(CS) 
Vitals 
(BP, HR, RR, SpO2, 
weight) 
X 
(SOC) 
X 
(SOC) 
X 
(SOC) 
X 
(SOC) 
X 
(SOC) 
X  
(SOC) 
 
Orthostatic vitals 
X 
(CS) 
 
 
 
X 
(CS) 
X 
(CS) 
 
Urine output 
X 
(SOC) 
X 
(SOC) 
X 
(SOC) 
X 
(SOC) 
 
X 
(SOC) 
X 
(SOC) 
 
Labs: BMP, NT-
proBNP, urine sodium, 
CA-125 
X 
(SOC/CS) 
X 
(SOC/C
S) 
 
X  
(SOC/CS) 
X 
(CS)  
 
 
BVA 
X 
(CS) 
 
 
 
X 
(CS) 
 
 
Dyspnea Questionnaire 
X 
(CS) 
X 
(CS) 
X 
(CS) 
X 
(CS) 
X 
(CS) 
X 
(CS) 
X 
(CS) 
Impedance and lung 
fluid content 
measurement 
X 
(CS) 
 
 
 
X 
(CS) 
X 
(CS) 
 
Echocardiogram 
X 
(SOC/CS) 
 
 
 
X 
(SOC/CS) 
 
 
Pulse Wave Analysis 
X 
(CS) 
 
 
 
X 
(CS) 
 
 
Physician questionnaire 
X 
(CS) 
 
 
 
X 
(CS) 
 
 

 
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Phone Call 
 
 
 
 
 
 
X 
(CS) 
 
Following enrollment, subjects will undergo the following tests/measurements. Some 
procedures occur as part of standard of care testing (SOC) while some testing will be performed 
as part of the clinical study (CS). All of the following tests have been approved in the present 
combination in Pro00100536, PI: Adrian Hernandez. 
 
-  
IV line will be placed (SOC) 
- 
If the subject is female and childbearing potential and has not had a pregnancy test 
since the arrival to the hospital, a blood pregnancy test will be done (SOC). If positive 
the subject will be excluded from the study.  
-  
Blood work: Basic metabolic panel (BMP) (SOC), N-terminal pro-brain natriuretic 
peptide (NT-proBNP) (CS), urine sodium (CS), CA-125 (CS). This will require an extra 
lab draw. Expected blood loss is <20ml. 
-  
Blood volume analysis The described BVA technique is an FDA approved technology 
for the purpose of volume measurement. It is currently used in clinical practice on 
patients with syncope, heart failure and sepsis to determine the exact intravascular 
volume and their components such as plasma volume and red blood cell volume.  
 
BVA will be completed within 24h of admission and again within 24h before anticipated 
discharge. Each blood volume analysis will take about 60 minutes to complete. The 
agent will be delivered to the radiopharmacy and prepared by the radiopharmacy. The 
agent will be then transported and stored at the DMP/ Radiology. On the study day the 
agent will be taken from the DMP to the patient’s room for the injection. An intravenous 
line connected to a 50 ml saline solution will be inserted in an arm. This line will be used 
to inject a small amount of diagnostic radioactive material into the patient’s circulatory 
system. A second IV line will be placed to collect small samples of blood at timed 
intervals 15 min after injection of drug, then every 6 minutes for an additional 3 samples 
( 18, 24, and 30 minutes). Blood collection timeframes do not have to be exact but time 
of blood draw will be documented. Approximately 15 ml of blood will be drawn total. The 
collected blood samples will be processed in the DMP in the device provided by the 
company.  
 
On the report, values will be expressed as percentage (%) deviation from ideal volumes 
and the predicted normal BV was determined from patient’s height, weight and deviation 
from ideal body weight. The output on the BVA results will be shared with the clinical 
teams within an hour of processing as outlined in Figure 2. BVA results will be provided 
only to patients and providers in the unblinded/BVA- guided arm. In the BVA- guided arm 
the medical team will also be provided with data to inform the medical management of 
their patients based on observed BVA results (admission and prior to discharge).  
 
The current data supports that ideal patient-specific euvolemic target should be 8-10% 
above euvolemia. All recommendations will not be binding.  
 
Further, if there is a red-cell deficit of >20% the team in encouraged to consider 
therapies to augment the red blood cell pool. Treatment is up to the physician discretion. 
 
Similarly, the test might reveal red blood cell overload (polycythemia) which ideally is 
addressed by the medical team using whatever options are clinically available.   
 

 
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- 
Vital Signs: Recorded vital signs including weight, blood pressure, heart rate, 
respiratory rate, SpO2 
- 
Dyspnea questionnaire using a 7-point Likert scale and Visual Analog Scale (CS) 
- 
Orthostatic heart rate and blood pressure (5 minutes supine, 1+5 minutes sitting and 1+5 
minutes standing) on the day before procedure if the subject is an inpatient and again 
within 1 hour before procedure (CS). Also we will document whether subjects have 
symptoms bending over for 10 seconds (bendopnea).   
-  
Non-invasive Testing 
• 
Fluid Lung Content measurement of chest fluid content using the ReDSTM unit 
(Sensible Medical, Tenafly, NJ). The ReDS unit is a vest that emits radiofrequency 
waves to measures fluid content. The device is FDA approved. The measurement 
requires 10 minutes.  
• 
Impedance for lung water volume measure using the Cardioset which uses electrical 
impedance technique to determine intra-thoracic blood volume.  
• 
Arterial stiffness assessment (Pulse Wave Analysis): We will use the 
SphygmocorTM (AtCor Medical, Itasca, IL) to measure arterial stiffness. It is 
measured through a brachial cuff. This measurement requires 5 minutes.  
- 
Bedside ultrasound will be performed of the heart and abdomen. We will assess: left 
ventricular function, inferior vena cava dimensions and collapsibility. 
 
A phone call at 30 days will evaluate the vital status of the patient, potential changes in 
medications after discharge, and assess the patient’s symptoms via the standardized 
questionnaires.  
 
Physicians will be interviewed with a questionnaire at the time point of the BVA testing. The 
questionnaire will explore whether the unblinded BVA results changed the perception of the 
patients’ congestion status and if they will result in a change in management.  
 
Randomization process: Randomization will be performed by the study coordinator using 
computer software.  
 
Potential complications: 
- 
The radiation effective dose from a single administration of I-131 
albumin for blood volume measurement is 0.60 mSv which is equal 
to three chest x-ray exams.  It is equivalent to about 2 months of 
natural background exposure. 
 
5.  Selection of Subjects 
For this study we seek to enroll heart failure patients admitted for acute decompensated heart 
failure to the cardiology service at the Duke Hospital. All patients irrespective of gender, race, 
and ethnicity will be considered for the study.  
 
Exclusion criteria are:  
- 
Ongoing pregnancy  
- 
age <18 years  
- 
Recent acute MI or hemodynamic instability: Acute MI (STEMI or Type I NSTEMI) within 7 
days 
- 
post heart transplantation or ongoing mechanical circulatory support 
- 
Progressive cardiogenic shock 

 
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- 
Patients with Ventricular Assist Devices 
- 
End stage renal disease 
 
6.  Subject Recruitment & Compensation 
 
Potential subjects will be identified via two potential pathways.  
 
Inpatients will be identified within 24 h of the admission via screening of the admission logs 
and inpatient census. Consent process will occur in the subjects’ hospital rooms on Duke 
Hospital Divisions 7700/7100/7300/7200/3100/3300/7 East.  
 
Patients considered for this study will be identified within 24 h of admission. Prior to 
approaching the patient we will discuss the patient and his/her eligibility with the primary 
cardiology team. Study team will be introduced by the primary team. Ample time will be 
given to the patient to review the consent and have all questions answered. After the patient 
has consented to the study we will begin study related activities. The primary enrollment 
target is up to =50.  
 
Subjects will be informed that their participation is strictly voluntary. They will be assured 
that the decision to decline participation will have no impact on their care or the perceptions 
of their providers.  
 
The subject will be compensated $100 for participation in this clinical study. 
 
7.  Consent Process  
 
Candidate subjects will be informed of the risks and benefits of participation in the study. 
They will be informed of the study process and demands. They will be given a copy of the 
informed consent document to review and afforded adequate time to do so.  
 
Informed consent will be obtained prior to the study. Consent will be obtained by the study 
Principal Investigator (PI), Duke Heart Center study coordinators who are trained on the 
study and who have been trained on the informed consent process, and other key personnel 
as designated by the PI. Consent will be obtained in the subjects’ rooms. A subject is 
considered enrolled in this clinical study at the time at which the subject and investigator or 
authorized designee have personally signed and dated the Informed Consent Form. 
 
8.  Subject’s Capacity to Give Legally Effective Consent 
 
Subjects must to be able to understand the English language and understand the study 
process, including all potential risk and benefits. Any subject for whom the study personnel 
or treatment team has cause for concern regarding the subject’s ability to understand the 
study process or follow the consent process, will be excluded from the study. 
 
9.  Study Interventions 
-  Lab draws 
-  Vital signs 
- 
Orthostatic vital signs 
- 
Non-invasive imaging with ultrasound 
-     Non-invasive hemodynamic monitoring (heart rate variability, Sphygmocor ReDS, 

 
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Cardioset) 
-     Blood volume analysis  
 
 
10. Risk/Benefit Assessment 
 
 
This study is associated with only small risks and has the potential to provide significant 
insight into the physiology of the patient’s congestion. Risks are limited to the intravenous 
line placement, and radiation exposure.  
 
Anticipated benefits to the subject include detailed information on congestion status and 
extent of fluid overload, otherwise not captured with standard clinical care diagnostic 
methods. This newly obtained data will be provided back to the patient and provider which 
then can result in a change in clinical care. However the study or protocol does not have an 
influence on the clinical care the patient will receive as a result of the newly obtained 
information. 
 
11. Costs to the Subject 
 
Study-specific activities and assessments will be conducted at no additional cost to the 
subject. Subjects will still be responsible for standard of care procedures related to 
hospitalization for heart failure. 
 
12. Data Analysis & Statistical Considerations 
 
Descriptive statistics of continuous outcomes will include sample size, mean, median, 
standard deviation, minimum and maximum. For categorical outcomes, the number and 
percentage of subjects in each category will be presented. Statistical comparisons will be 
made using t-tests for continuous outcomes and chi square or Fisher’s exact test 
(depending on overall event rates) for categorical outcomes.  
 
13. Data & Safety Monitoring 
 
Significant adverse events associated with the study procedures are not expected. 30 day 
follow-up is planned. Should complications be encountered, they will be reported to the IRB 
within 10 working days or per IRB policy. The Principal Investigator will also provide an 
annual report of any side effects or problems to the IRB during the study renewal process.   
 
No protected health information associated with the study procedures will be sent outside of 
Duke. PHI (subject ID, height, weight, and gender) will be used internally for measuring the 
blood volume. Additionally, we will capture the birth year of the patient to perform the pulse 
wave analysis.  
 
 14. Privacy, Data Storage & Confidentiality –  
 
Data will be obtained by approved study personnel. An enrollment log will also be 
maintained in an Excel Spreadsheet on the Heart Center’s secured S:drive. The subject ID 
will also be stored on the folder to track subject enrollment and collection of data. Data will 
be recorded in Excel. Only deidentified data will be available for statistical analysis. All 
subject identifiers will be removed for database storage, statistical analysis and data 
reporting. This data will be stored on a study specific folder on the Duke server behind the 

 
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Duke firewall.  The subject ID code will be destroyed after data analysis is completed. 
Protected health information will not be used for any other purposes than those described in 
this protocol without obtaining further IRB approval.  This information will be used for 
research purposes only and subjects will never be contacted regarding information obtained 
through chart review. A designated statistician from the DCRI will provide support with 
statistical analysis. 
 
The adequacy of the Research Data Security Plan (RDSP) will be evaluated and approved 
by the Cardiology CRU prior to study conduct. 
 
Any publications or presentations that result from this research will not identify any subjects 
individually, and will present data in aggregate form only. 
  
Gathered data will be stored for at least 6 years.   
 
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