Splanchnic Nerve Block for Therapy of Chronic Heart Failure (Splanchnic III)
Phase: PHASE2
Conditions: Chronic Heart Failure
Sponsor: Duke University

Splanchnic Nerve Block for Therapy of Chronic Heart Failure (Splanchnic III) 
Clinicaltrials.gov number: NCT04575428 
Duke IRB number: Pro00103788 
Date: May 1th 2023 

Research Abstract
Please type your Research Abstract here:
The Research Abstract should summarize the main points of your study in one paragraph. The following 
guidelines may help you:
1. Purpose and objective (1-2 sentences)
2. Study activities and population group (2-4 sentences)
3. Data analysis and risk/safety issues (1-2 sentences)
Splanchnic vasoconstriction may contribute to decompensation of chronic heart failure (HF) via volume 
redistribution from the splanchnic vascular bed to the central compartment. This is a sympathetically 
mediated reflex and can be interrupted through a splanchnic nerve block (SNB). We hypothesize that 
interruption of the efferent/afferent innervation of the splanchnic vasculature will decrease cardiac 
congestion and improve renal function in patients presenting with HF.
We have already obtained preliminary safety and efficacy data in acute and chronic heart failure patients 
with temporary (<24 h) SNB. Now we would like to apply a prolonged SNB in chronic heart failure patients 
using a long acting agent.  
Research Summary
State your primary study objectives
1. We will determine if splanchnic nerve blockade decreases cardiac preload as measured by invasive
hemodynamics.
2. We will determine if splanchnic nerve blockade will improve invasive hemodynamics during exercise.
3. We will determine if splanchnic nerve blockade improves symptoms of shortness of breath.
State your secondary study objectives
N/A
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Standard Research Summary Template
This is the regular (generic) research summary template which is required  for all regular applications (unless 
your protocol fits under the other research summary templates in this category).  Use of these instructions is 
helpful for ensuring that the research summary contains all necessary elements.
Standard Research Summary
Purpose of the Study
Objectives & hypotheses to be tested

1.  
2.  
3.  
We will determine if splanchnic nerve blockade decreases cardiac preload as measured by 
invasive hemodynamics.
We will determine if splanchnic nerve blockade will improve invasive hemodynamics during 
exercise.
We will determine if splanchnic nerve blockade improves symptoms of shortness of breath.
Background & Significance
Should support the scientific aims of the research
Heart failure (HF) is a leading cause of morbidity and mortality, affecting more than 6 million adults in the 
US alone.  Cardiovascular congestion with resultant limitation in physical activity is the hallmark of chronic 
1
and decompensated HF. While it is well-accepted that the extent of fluid volume congestion is closely 
associated with clinical outcomes 
, the concept of fluid and salt overload as the primary drivers of 
2-4
symptomatic decompensation (with resting or exercise-induced dyspnea) has been challenged.
 Notably, 
5,6
about 50% of patients gain only minor weight (<2pounds or <2kg based on the study) in the days prior to 
a hospitalization.
 Additionally, intracardiac filling pressures in patients with HF commonly start to 
7,8
increase before any significant weight changes occur preceding an admission for clinical decompensation.9,1
 In our own analysis of the ASCEND-HF trial, 26% of patients had no weight loss (+/-1kg change) and 
0
8% actually experienced weight gain (³1kg) during a HF hospitalization, suggesting that net volume loss is 
not necessary for symptomatic relief.
 
11 Taken together, an increase in central filling pressures 
occurs in many cases in the absence of weight gain or total body volume increase 4,12, which 
lead us and others to suggest a contribution of 
 to the mechanism of 
volume redistribution
cardiac decompensation
 
In chronic HF, cardiopulmonary congestion is the main determinant of exercise intolerance, which 
manifests itself as exertional dyspnea and/or fatigue.
 Many HF patients have normal hemodynamics 
13,14
at rest 
, but there is growing evidence of profoundly abnormal hemodynamic response to exercise 
15
characterized by rapid and marked elevation in filling pressures.
 Exercise-induced intra-cardiac 
13,16
decompensation, whether driven by fluid overload or volume redistribution, in most cases is only an 
intermittent phenomenon as pressures return to baseline values during recovery.  
       The abdominal compartment has been implicated as a key contributor to the complex 
pathophysiology of HF given that it is the main storage compartment of intravascular blood volume. The 
highly vascular organs such as the liver, spleen and bowel are able to “store” or “recruit” large blood 
volumes within minutes in and out of the splanchnic vascular compartment.
 Animal and human data 
17-20
indicates that these blood shifts can significantly alter cardiac and central vascular hemodynamics.
 
17-19 Th
e main regulatory system for the splanchnic vascular capacitance (“storage-space”) are post-
ganglionic sympathetic fibers originating from the celiac plexus which control arterial and 
 These post-ganglionic sympathetic fibers in the celiac plexus receive input from 
venous vascular tone.
pre-ganglionic sympathetic fibers travelling via splanchnic nerves.
 
21,22 Activation of splanchnic nerves 
results in vasoconstriction and reduces splanchnic capacitance, therefore recruiting blood 
 
volume into the central circulation.19,21 In HF, a reduced splanchnic vascular capacitance23,24 co
uld be the mechanism underlying symptoms of exercise intolerance and could predispose to 
A compromised 
rapid decompensation with external fluid intake or retention (Figure 1).5,16,25 
vascular reservoir is likely unable to buffer shifts of fluid and actively contributes to the acute or chronic 
expulsion of fluid from the splanchnic vascular compartment to the central thoracic compartment. The 
redistribution of blood volume into the central circulation may lead to a sudden rise in pulmonary and left-
sided cardiac pressures in HF.
 This makes the splanchnic vascular compartment an attractive target 
5,6,26
in HF.
Prior Evidence: Mounting evidence questions the notion that congestion is merely the result of external 
volume overload or volume retention. Supportive evidence is provided by blood volume analysis using the I
-labeled human serum albumin indicator-dilution technique. Using this technology, studies found that 
131
chronic HF patients with persistent symptoms are in 35% of cases hypovolemic or euvolemic  and the 
4
same was even true for patients admitted for decompensated HF (34%).
 
27,28 The heterogeneity of clinical 
to explain increased filling pressures at rest 
presentation suggests the presence of an alternate mechanism 
or with exercise despite a lack of fluid retention.

Effective measures to decrease vascular congestion acutely or chronically remain an 
unmet clinical need. We recently identified the splanchnic nerves as potential contributors to 
the pathophysiology of HF and we proposed that a heightened splanchnic sympathetic tone 
contributes to cardiac decompensation and a short-term interruption of the splanchnic nerve 
signaling would reverse the process and thus alleviate HF sign and symptoms in select patients 
with acute and chronic HF.
 We first showed that splanchnic nerve stimulation results in acute 
5,6,24
hemodynamic changes, with a decrease in splanchnic vascular compliance and increase in cardiac preload.1
 HF is characterized by a heightened global sympathetic tone, yet untargeted pharmacological 
7,19
reduction in sympathetic tone can be insufficient to result in effective splanchnic vasodilation and be 
detrimental due to unintended cardiovascular effects.
 Consequently, a targeted reduction of the 
29
splanchnic sympathetic tone in chronic HF could provide a therapy for patients with cardiopulmonary 
congestion at a resting state or state of activity.
Our preliminary proof-of-concept work in patients with acute decompensated and chronic HF 
showed promise for the concept of splanchnic nerve modulation in HF (
).
 In a series of two 
Figure 2
38
small first-in-human studies for acute decompensated HF (N=13)
 (Late-Breaker at ESC-HF 2018, 
25,38
Vienna, Austria, 
) and chronic HF (N=17) (Young Investigator Competition, ESC-HF 2019, 
NCT02669407
Athens, Greece,
), we found that a splanchnic nerve block (SNB) with lidocaine (90 min 
 NCT03453151
duration of action) and ropivacaine (24 hours duration of action) acutely reduced resting and exercise-
 intra-cardiac filling pressures, associated with improved patient symptoms and functional 
induced
capacity.
Our two proof-of-concept studies and the well-established safety profile of permanent splanchnic 
nerve blockade in patients with intractable abdominal pain (e.g., due to pancreatitis or cancer) provide the 
foundation for our study.
 A body of literature (>3,000 published cases) on non-HF patients suggests 
30-33
that the side effects of permanent splanchnic nerve blockade (surgical or interventional via alcohol 
injection) are restricted to 48-h post procedure. Most common side effects include orthostatic hypotension 
(80%) followed by gastrointestinal symptoms (60%). Interestingly, transient orthostatic hypotension due 
an increase in splanchnic vascular storage capacity, is clinically prevented by aggressive pre-procedural 
hydration.
 Historically (1930-1950’s) surgical denervation of splanchnic nerves has also been applied in 
33
form of the so-called splanchnicectomy for treatment of uncontrolled hypertension. While it was shown to 
be effective to reduce sympathetic tone and reduce blood pressure, the discovery of antihypertensive 
medications made this surgical procedure obsolete.
 Long-term pharmacological blockade of the celiac 
34
plexus/splanchnic nerves with Botulinum toxin (BTX) has been previously reported to be safe and effective 
in a case of refractory hypertension.
 Finally, our group has extensive experience with neuromodulation 
35
which includes the application of BTX to epicardial fat pads for prevention of post-operative atrial fibrillation
 and stellate ganglion blockade for ventricular arrhythmias.
 
36
37,38 Together, published evidence and 
our data indicates the potential importance of splanchnic nerve modulation as a treatment for 
HF, providing a strong scientific premise for further investigation in this field. 
 
Design & Procedures
Describe the study, providing detail regarding the study intervention (drug, device, physical 
procedures, manipulation of the subject or the subject’s environment, etc.). Discuss justifications for 
placebo control, discontinuation or delay of standard therapies, and washout periods if applicable. 
Identify procedures, tests and interventions performed exclusively for research purposes or more 
frequently than standard of care. Include alternative therapies, concurrent therapies discontinued per 
protocol, risk benefit ratio, and use of tissue/specimens. Discuss monitoring during washout periods if 
applicable. Include brief description of follow-up, if any.
 
Study design. The present study will be a prospective open-label pilot study to help establish feasibility, 
safety and enable dose finding for BTX. The schedule of events is presented in 
. Following a 
Figure 3
baseline invasive (right heart catheterization) cardiopulmonary exercise testing (CPX) patients will undergo 
unilateral celiac plexus block (
), followed by repeat hemodynamic testing in the following 
Figures 2 and 4
90 minutes. Repeat CPX (with and without hemodynamic testing) will occur at 2, 4, 8 weeks. A 12 month 
phone call to investigate vital status, HF hospitalizations will conclude the study. Functional testing at 
baseline and follow up will be supplemented by a series of minimally invasive and non-invasive measures 
of static and dynamic blood volume distribution (radionuclear plethysmography, bioelectrance, hepatic vein 
ultrasound), congestion parameters (biomarkers, BVA), autonomic nervous tone (catecholamines, 

baroreflex, and heart rate variability) and symptom questionnaires (Likert and Visual Analog scale). Given 
high volume of patients and right heart catheterizations (>1,000 per year) and our experience with 
enrolling patients in the preliminary studies, we anticipate to complete recruitment within 2 years. 
Figure 3.  Study Flow
Table 1: Schedule of events (CS, clinical study; SOC, standard of care/clinical)
  
Required 
Assessment
Pre-
Procedu
re (Day 
1)
Baselin
e (Intr
a-
Proced
ure)
Block Post-
Block 
Procedu
re
48 
Hour
s
Week
1
Week 2 Week 4 Week 8 Mont
h 6
Mont
h 12
Vitals
(BP, HR, RR, 
SpO2, weight)
X (CS)
X(CS)
X(CS)
X(CS)
X(CS)
Orthostatic 
vitals
X(CS)
X(CS)
X(CS)
X (CS)
X (CS)
Non-Invasive 
Testing*
X(CS)
X(CS)
X(CS)
X (CS)
X (CS)
Pregnancy test
X (SOC)
Labs: BMP 
(SOC), pro-BNP 
(CS), CA-125 
(CS), urine 
sodium (CS),
X (CS
/SOC)
X (CS
/SOC)
X (CS
/SOC)
X (CS
/SOC)
X (CS
/SOC)
Labs
Renin,
Angiotensin 
II,     Vasopressi
n,
Plasma 
Catecholamines
X (CS)
X (CS)
X (CS)
X (CS)
X (CS)
X(CS) X(CS)
X(CS) X(CS)

Dyspnea and 
EQ-5D-3L 
Questionnaires
X (CS)
X(CS)
X(CS) 
X (CS)
X(CS) 
Six minute walk 
test
X (CS)
X(CS)
X(CS) 
X (CS)
X(CS) 
Blood volume - 
Daxor
X (CS)
X (CS)
Heart rate 
variability
X (CS)
X (CS)
X (CS)
X (CS)
X (CS)
X (CS)
Right Heart 
Cath (RHC)
X (CS, 
SOC)
X (CS)
Scintigraphy
X (CS)
X (CS)
Invasive CPX
(peak VO2) 
X (CS)
X (CS)
CPX (peak VO2)
X (CS)
X (CS)
Echocardiogram
X (CS)
X (CS)
X (CS)
X (CS)
X (CS)
Renal 
ultrasound (to 
be done by 
Marat)
X (CS)
X (CS)
X (CS)
X(CS) 
X (CS)
Splanchnic 
nerve block
X
(CS) 
Phone Call
X 
(CS)
X 
(CS)
X 
(CS)
X 
(CS)
*Non-Invasive Testing
Device Name
Approval
Indication
CardioSet
Investigational measures lung volume using impedance technology
ReDS unit
FDA
measures lung fluid content using radiofrequency 
waves
Sphygmocor
FDA
measures arterial stiffness through a brachial cuff
Bedside Ultrasound
FDA
performed of the heart, abdomen, kidney and 
diaphragm to assess left ventricular function, inferior 
vena cava dimensions and collapsibility, hepatic vein 
blood flow and portal vein flow and peripheral renal 
flow of the kidney
Musculoskeletal 
Ultrasound
FDA
Utilizes muscle metabolic imaging derived from point 
of care musculoskeletal ultrasound for muscle mass, 
intramuscular glycogen content and intramuscular 
adipose tissue content
InBody
FDA
Bioelectrical Impedance Spectroscopy: Segmental 
bioelectrical impedance spectroscopy (BIS) is another 
non-invasive way of assessing muscle quality 
assessment.
VO2Master Pro
FDA
compact, mobile and wireless (bluetooth) breath-by-
breath metabolic cart to assess the cardio-metabolic 
and cardio-respiratory capacity /effort during training 
(Rehab)
PhysioFlow 
Hemodynamics
FDA
non-invasive hemodynamic monitor. It provides 
continuous, accurate, reproducible and sensitive 
measurements of cardiac output, stroke volume, 
systemic vascular resistance and left cardiac work 
index.
Portalite and Moxy
Investigational
assessment of muscle- and brain mitochondrial 
function  during cardiopulomonary exercise testing. 
The device is developed to measure concentration 
changes of oxyhemoglobin and deoxyhemoglobin with 
near infrared light.
WHOOP strap 3.0
Investigational measures heart rate variability and  heart rate
Questionnaire
Dyspnea
7-point Likert scale and Visual Analog Scale
EQ-5D-3L
Quality of Life

Device Name
FDA Approval 
(Yes/No)
Indication
CardioSet
No
measures lung volume using impedance technology
ReDS unit
Yes
measures lung fluid content using radiofrequency 
waves
Sphygmocor
Yes
measures arterial stiffness through a brachial cuff
Bedside Ultrasound
Yes
performed of the heart, abdomen, kidney and 
diaphragm to assess left ventricular function, inferior 
vena cava dimensions and collapsibility, hepatic vein 
blood flow and portal vein flow and peripheral renal 
flow of the kidney
Musculoskeletal Ultrasound
Yes
Utilizes muscle metabolic imaging derived from point 
of care musculoskeletal ultrasound for muscle mass, 
intramuscular glycogen content and intramuscular 
adipose tissue content
InBody
Yes
Bioelectrical Impedance Spectroscopy: Segmental 
bioelectrical impedance spectroscopy (BIS) is another 
non-invasive way of assessing muscle quality 
assessment.
VO2Master Pro
No
compact, mobile and wireless (bluetooth) breath-by-
breath metabolic cart to assess the cardio-metabolic 
and cardio-respiratory capacity /effort during training 
(Rehab)
PhysioFlow Hemodynamics
Yes
non-invasive hemodynamic monitor. It provides 
continuous, accurate, reproducible and sensitive 
measurements of cardiac output, stroke volume, 
systemic vascular resistance and left cardiac work 
index.
Portalite and Moxy
No
assessment of muscle- and brain mitochondrial 
function  during cardiopulomonary exercise testing. 
The device is developed to measure concentration 
changes of oxyhemoglobin and deoxyhemoglobin with 
near infrared light.
WHOOP strap 3.0
No
measures heart rate variability and  heart rate
Testing procedures
Blood volume analysis and scintigraphy: Blood volume analysis will be performed using I131-
radiolabelled albumin. The injection of the drug and associated blood draws will be completed in the 
nuclear lab. Patients will have a baseline blood sample drawn (4ml). Then, patients will be injected the 
radiolabeled albumin. After 12, 16 and 20 minutes we draw additional blood samples. The blood samples 
will be processed at the Duke nuclear laboratory using the Daxor analyzer or sent to Daxor Inc. for 
processing. If sent to Daxor for processing we will only share deidentified blood samples. Samples will be 
labelled with case number. We will provide patients age, gender and weight, which are needed for data 
calculation.
Following injection of the agent, the patient will also receive a 
 (Multiple Gated Acquisition 
MUGA Scan
sca
) is a noninvasive tool for assessing the function of the heart. The 
 produces a moving image 
n
MUGA scan
of the beating heart but also allows to image the abdomen, and from this image several important features 
can be determined about the health of the cardiac ventricles and blood distribution. 
Following injection of the technetium99, patients will be placed under a scintigraphy camera which will pick 
up the counts of radiation over the chest and abdomen. We will record resting counts over both 
compartments (chest /abdomen). Then patient will perform up to 5 min low resistance leg exercise while 
supine on a stepper placed at bed end. Counts will be recorded over both compartments during exercise. 
Blood draws reported above will occur during resting recording. The exercise will occur after the 20 min 
blood draw is complete. Total duration of the study is anticipated to be 30 min. 
The I-131 (Volumex) will either be administered by the nuclear medicine technician or Marat Fudim, MD. 
Both have received training from the manufacturer. 
 
Nerve Block Procedure. The unilateral, left-sided, temporal bilateral celiac plexus block will be 
performed by the interventional pain specialty team in the catheterization laboratory, with continuous 
hemodynamic monitoring similarly to our previously published experience.
 The celiac plexus block will be 
24
performed under fluoroscopic guidance in the posterior chest wall (vertebral space L1) to guarantee 
maximal safety (
). We will use a mix of 3 ml of lidocaine 1.55 with 1:10000 epinephrine, 10 ml of 
Figure 2
0.5% ropivacaine and up to 1.5 U/kg of BTX Type A. Lidocaine with epinephrine is used for procedural 

safety to exclude intravascular injection. In the present study we will start at a lower dose of the BTX 
(dose finding). We will plan to increase dose or decrease per Kg unit does for Botox based on 4 week 
assessment. 
The dosing up titration scheme (Scenario 1) is as following:
1. The 1st and 2nd subject receiving the block splanchnic procedure - 75Units of Botox, (not more than 1.5
Units/kg) follow up at 2 weeks with CPX and 4 weeks with invasive CPX and 8 weeks with CPX
2.
 - if prior dose tolerated, no safety
The 3rd and 4th subject receiving the block splanchnic procedure
issues at 4 weeks than proceed with dose increase to: 100Units of Botox, (not more than 1.5Units/kg)
follow up at 2 weeks with CPX and 4 weeks with invasive CPX and 8 weeks with CPX
3.
 - Scenario 1: if prior dose tolerated, no
The 5th and 6th subject receiving the block splanchnic procedure
safety issue and satisfactory efficacy at 4 weeks than patient 5/6 will get injection of 100Units of Botox
again (not more than 1.5Units/kg) with follow up at 2 weeks with CPX and 4 weeks with invasive CPX and
8 weeks with CPX   Satisfactory efficacy is defined as >25% reduction with exercise wedge pressure
   Scenario 2: if prior dose tolerated, no safety issue and efficacy not satisfactory at 4 weeks than patient 5
/6 will get injection of 125Units of Botox (not more than 1.5Units/kg) with follow up at 2 weeks with CPX 
and 4 weeks with invasive CPX and 8 weeks with CPX. 
Dose down titration scheme is as following: If BP is too low (newly <90mmHg, independent of heart failure 
medication changes done clinically) or patient report orthostatic symptoms we will return for the next 
patient to the preceeding lower Botox dose. If symptoms of orthostasis of hypotension are experienced 
already at the lowest dose we will drop the injection dose to 50 Units (not more than 1.5U/kg) . The 
effects of ropivacaine are expected to occur as early as 15 minutes and last for 24h. The acute effects will 
serve as confirmation of procedural success and provide reassurance that BTX was injected in the right 
location. BTX is a neurotoxin that blocks cholinergic neurotransmission and offers temporary autonomic 
modulation via ganglionic block. The peak pharmacological properties of BTX are expected at 2 weeks post 
injection. The estimated duration of BTX effect is up to 4-6 months.39,40
Selection of Subjects
List inclusion/exclusion criteria and how subjects will be identified.
Subjects will be identified by screening the Duke University Medical Center or Duke Raleigh outpatient 
heart failure and catheterization clinic environments.  All study subjects will have an electively scheduled 
right heart cathetherization, 
with or without an invasive cardiopulmonary exercise. 
by the cardiologist, 
Subjects with Cardiomems device will already have the device in place prior to the electively scheduled 
right heart catheterization.  
Inclusion Criteria:
1. Age 18-90
2. Patients with or without Cardiomems device implanted
3. Followed at DUMC for known or suspected diagnosis of HF (NYHA stage 2-3, Class C-D), including patients
on inotropic medication
4. Systolic blood pressure (SBP) > 100mmHg
5. History of HF hospitalization or ER visit or IV diuretic use in the last 12 months.
6. Patients will be included regardless of left ventricular ejection fraction.
Exclusion Criteria:
1. Contraindicated medications:

Anticoagulation at the time the procedure or in case of recent warfarin use an INR >1.4. Anticoagulation 
includes: warfarin, or novel oral anticoagulants like dabigatran, rivaroxaban, apixaban, endoxaban or full 
dose intravenous heparin products or bivalirudin and fondaparinux). Antiplatelet agents besides aspirin 
such as ticagrelor, prasugrel, Plavix are also considered to be a contraindication if used at time point of 
procedure. 
Immunosuppressive medications for solid organ transplant
2. HF medication regimen: Initiation of HF medications (in the 48 hours preceding the study) such as beta
blockers, ACEI, ARB, aldosterone receptor blockers, calcium channel blockers of any type, central
sympatholytics like clonidine, moxonidine,
       
3. Recent acute MI or hemodynamic instability:
Acute MI (STEMI or Type I NSTEMI) within 7 days.
·
Evidence of progressive cardiogenic shock within 48 hours
·
4. Certain forms of HF:
Restrictive cardiomyopathy
·
Constrictive pericarditis
·
Pericardial effusion with evidence of tamponade
·
Severe valvular stenosis requiring intervention
·
5. Severe bleeding risk:
Known history of an increased bleeding risk
·
Thrombocytopenia (< 50,000)
·
6. Significant comorbidities:
End-stage renal disease CKD stage 5 due to primary renal pathology
·
Severe scoliosis of the thoracic spine
·
History of lung disease other than asthma and COPD (like interstitial fibrosis, cystic fibrosis,
·
pneumonitis, lung cancer etc.)
Respiratory instability (dependent on >4 L nasal cannula for a saturation >90% SpO2)
·

Exclude severe fixed pulmonary hypertension
·
History of organ transplant (heart , lung, liver, pancreases, small bowel).
·
7. Pregnancy: patients of childbearing age will be tested with pregnancy tests, unless they had a hysterectomy
or removal of their ovaries.
8. Procedure
Unable to tolerate procedure as determined by  or investigator
Will be excluded if invasive hemodynamics on study date determine that the  does not have elevated filling
pressures at rest or stress. Following pressures/situations will exclude the : wedge pressure < 15mmHg (<
12mmHg on inotrope) at rest and < 25mmHg with peak stress (< 22 with inotropes) and greater than the central
venous pressure or  determined by study personnel to be at risk for nerve block related complications.
Subject Recruitment and Compensation
Describe recruitment procedures, including who will introduce the study to potential subjects. Describe 
how you will ensure that subject selection is equitable and all relevant demographic groups have access 
to study participation (per 45 CFR 46.111(a) (3)). Include information about approximately how many 
DUHS subjects will be recruited. If subjects are to be compensated, provide specific prorated amounts 
to be provided for expenses such as travel and/or lost wages, and/or for inducement to participate.
Potential subjects will be identified via two potential pathways. Research team will screen the 
outpatient scheduled RHC cases and send a recruitment letter to the subject once their primary 
care provider has agred to the study. The subject will be contacted over the phone if the 
subject has not replied to the letter in at least 10 days per policy. The subject will be provided 
with any additional information he/she wants. In a second scenario the primary provider 
approaches the study team with a potential case. In both cases the subject will be notified 
about being approached on the day of the study about a second approach in person by a heal 
care provider known to the patien for potential consent.
 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 for a total of $300 for their participation in this clinical study. 
The subjects will receive $100 at the following visits: Procedure visit, 2 week follow-up, and 2 
month visit.
Consent Process
Complete the consent section in the iRIS Submission Form.
Subject’s Capacity to Give Legally Effective Consent
If subjects who do not have the capacity to give legally effective consent are included, describe how 
diminished capacity will be assessed. Will a periodic reassessment occur? If so, when? Will the subject 
be consented if the decisional capacity improves?

1.  
2.  
1.  
2.  
1.  
2.  
3.  
4.  
5.  
6.  
3.  
4.  
5.  
6.  
1.  
Subject has to be able to understand the English language and understand the 
study process including all potential risk and benefits to the subject. Any subject 
where 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 capacity, will be excluded from the study.
This is a FDA regulated study, therefore, this eConsent platform will comply with 21 CFR Part 11 
requirements, which include regulations on electronic records and electronic signatures.
Study Interventions
If not already presented in #4 above, describe study-related treatment or use of an investigational 
drug or biologic (with dosages), or device, or use of another form of intervention (i.e., either physical 
procedures or manipulation of the subject or the subject’s environment) for research purposes.
The study subjects will participant in the following study tests and procedures:
Invasive Test:
Regional nerve block under fluoroscopic guidance: A solution of ropivacaine 12 cc (approximately 2.5 
 
teaspoons) and Botox 75-125 units (approximately 0.25 teaspoons), into the space around a nerve, called 
the splanchnic nerve, which controls the blood vessels in your intestines. These drugs will be delivered 
using a long needle placed between the patient's ribs in the mid-region of the back.  The placement of the 
needle will be performed by an anesthesiologist experienced with the needle placement, with the 
assistance of x-ray guidance. The subject's measurement will be monitored for 60 minutes post-block. 
Cardiopulmonary exercise:  The subject will exercise by pedaling on a bike in a supine position for about 
.  
2-5 minutes, before stopping to rest The catheter will remain in the subject's heart to measure pressures 
while exercising to provide  information about the subject's exercise ability.   
Non-Invasive Tests:
Vital Signs (Orthostatic vital signs)
Imaging with ultrasound, impedance, radiofrequency
Fluid content in the body and lungs:  The subject will wear a vest that emits radiofrequency waves 
to measure fluid content (ReDs Vest).  The InBody uses Bioelectrical Impedance Spectroscopy to 
determine fluid content in the subject's body.
Lung impedance: electrodes will be attached to the subject's upper back and chest to determine 
the intra-thoracic blood volume (CardioSet)
Arterial stiffness using a brachial cuff. A cuff will be applied to your arm, similar to a blood 
pressure cuff, and a hand held probe will be placed on your groin and arm.     The cuff will inflate 
and will measure pulse wave changes in your blood vessels (Sphygmocor)
Cardiac Hemodynamics: the PhysioFlow device measures the subject's cardiac output, stroke 
volume, systemic vascular resistance and left cardiac work index.
Oxygen Utilization: VO2 Master Pro  (Oxygen consumption) will be used to measure 
oxygen consumption during rest and exercise.  PortaLite and MOXY will measure 
oxygen concentration during exercise. 
 Heart Rate Variability: The WHOOP strap 3.0 will measure heart rate and heart rate 
variability and will be worn for approximately one hour.  
6 minute walk test to measure your exercise capacity and endurance.
Questionnaires about the subject's feeling about their shortness of breath and breathing at rest
Cardiopulmonary (CPX) Testing:  Exercise testing with the subject using an upright bike.  The subject 
will exercise at their maximum effort.  The subject will be monitored for exercise intolerance, shortness 
of breath, or pain in the chest. The subject will wear a face mask to measure oxygen intake and carbon 
dioxide output.
MUGA Scan: non-invasive imaging method to evaluate the function of your heart.  This scan will help 
determine more information about the health of the subject's  cardiac ventricles and blood distribution.
Laboratory Tests:
 
Blood Volume Analysis: Administration of a small amount of plasma protein, albumin, containing a 
small amount of radioactive iodine (injected through the PIV). The radioactive iodine labeled albumin 

2.  
3.  
1.  
2.  
3.  
protein (blood volume solution) will be administered through the PIV line. Blood samples will be 
  
withdrawn before administration of the blood volume solution and 12, 16 and 20 minutes after 
administration. The blood samples will be processed at the Duke Nuclear Lab
 
oratory using the Daxor 
Analyzer for further processing
Biomarkers: Blood samples will be taken before the procedure and after the procedure for analysis of NT 
pro-BNP (indication of worsening heart failure) and  CA-125 (indication of inflammation).   
Autonomic Nervous System regulators:  Blood samples will be taken in the catheterization lab before and 
after the splanchnic block.  The samples will be processed and sent out to labs that specialize in analyzing 
these samples for hormones angiotensin II, vasopressin, catecholamines, and metanephrines.
Risk/Benefit Assessment
Include a thorough description of how risks and discomforts will be minimized (per 45 CFR 46.111(a) (1 
and 2)). Consider physical, psychological, legal, economic and social risks as applicable. If vulnerable 
populations are to be included (such as children, pregnant women, prisoners or cognitively impaired 
adults), what special precautions will be used to minimize risks to these subjects? Also identify what 
available alternatives the person has if he/she chooses not to participate in the study. Describe the 
possible benefits to the subject. What is the importance of the knowledge expected to result from the 
research?
Procedural risks of splanchnic nerve blocks have been extensively studied. Risks 
associated with this anesthetic nerve block are uncommon. Patients undergoing 
this procedure have a small risk (<1%) risk of developing local anesthetic 
systemic toxicity as a complication of regional anesthesia. Symptoms include 
non-specific central nervous system effects (altered mental status, agitation, 
seizures) and cardiac arrest. We have now completed 28 cases in the first pilot 
trial using lidocaine/ropivacaine and found no acute or chronic complications.
 
Mild complications like local pain at injection site, orthostatic hypotension and 
gastrointestinal dysmotility are time limited and improve with resolution of the 
anesthetic block. Severe complications like pneumothorax possibly requiring a 
chest tube, aortic vessel puncture with retroperitoneal bleed or hematothorax 
and spinal cord injury with possible paralysis. These are very rare since 
placement of the needle occurs under fluoroscopic guidance.
 
Other minor risks can include (in order of report in literature and experience at 
Duke):
Pain at puncture site and intercostal neuralgia
Gastrointestinal dysmotility including diarrhea, constipation and abdominal cramping as well as 
nausea
Bleeding at puncture site
 
We will perform the splanchnic block for chronic heart failure, which is a new 
indication. The splanchnic nerve block has now been studied by us for acute
/chronic heart failure but not been studied in the setting of chronic disease. We 
do not expect unexpected side effects other than stated above but unexpected 
side effects cannot be excluded. For safety purposes subjects enrolled in this 
study will remain monitored for several hours after the SNB and re-examined at 
2 weeks.
 
Anticipated benefits to the subject include improvement in central vascular 
congestion with a reduction in cardiac preload and pulmonary arterial pressures 
as well as left sided filling pressures. A reduction in cardiac pressures is also 
likely to improve symptoms of congestion, including shortness of breath.
 

Further it is expected that a decongestion of the central veins and interruption 
of the cardiorenal reflex loop will result in an improvement in renal function as 
measured by urine output. This will further contribute to the decongestion of 
the subject’s vasculature.
 
While both of those effects are only temporary (up to 6 months, the benefit 
provided by the brief episode of decongestion can provide lasting symptomatic 
improvement.
 
Given prior pilot studies and theoretical framework we expect a symptomatic 
improvement of patients during the nerve block. Given that we have not seen 
any side effects in acute heart failure patients after the nerve block wore off we 
do not expect comparable effects in chronic heart failure patiens when their 
block wears off given similar pathophysiology.
Costs to the Subject
Describe and justify any costs that the subject will incur as a result of participation; ordinarily, subjects 
should not be expected to pay for research without receiving direct benefit.
All testing and services performed only for the purposes of the clinical study will 
be provided at no cost to the research subject. However, the subject or the 
subject’s health insurance or Medicare is responsible for all costs that are part 
of usual medical care that would have happened if the subject were not in the 
clinical study. If the subjects health insurance or Medicare requires any co-
payment, co-insurance, or deductible, the subject will be responsible for making 
that payment. Anything not paid by either the study sponsor or the subject’s 
health insurance company will be billed directly to the subject for payment.
Data Analysis & Statistical Considerations
Describe endpoints and power calculations. Provide a detailed description of how study data will be 
analyzed, including statistical methods used, and how ineligible subjects will be handled and which 
subjects will be included for analysis. Include planned sample size justification. Provide estimated time 
to target accrual and accrual rate. Describe interim analysis including plans to stop accrual during 
monitoring. Phase I studies, include dose escalation schema and criteria for dose escalation with 
definition of MTD and DLT.
Cynthia Green in the Duke Heart Center will be preforming the statistics for the 
Splanchnic III study. We will perform descriptive statistics. Statistical 
comparisons will be made using t-tests for continuous outcomes and chi square 
or fisher’s exact test. Unless otherwise specified, a two-sided 0.05 level of 
significance will be used to declare change in pre-and post-procedure variables 
different.
 There is no direct measure of technical success following attempted block of 
the splanchnic nerves. Procedural success to block the splanchnic nerves will be 
assumed in 70% of the cases based on the experience in splanchnic nerve 
blocks in patients with intractable cancer.
Data & Safety Monitoring

Summarize safety concerns, and describe the methods to monitor research subjects and their data to 
ensure their safety, including who will monitor the data, and the frequency of such monitoring. If a 
data monitoring committee will be used, describe its operation, including stopping rules and frequency 
of review, and if it is independent of the sponsor (per 45 CFR 46.111(a) (6)).
Due to the experimental nature of this intervention, data will be recorded after 
each subject completes the intervention for signs of unintended negative 
effects. These include hypotension, worsening renal function, or clinical 
deterioration. Additionally, subject’s electronic medical data will be screened for 
any traumatic complications from the nerve block at 2 weeks, and 6 months 
post-procedure.
Unanticipated severe adverse events will be reported to the IRB per IRB policy.
In accordance with federal regulations the PI will monitor for review, and promptly report to 
the IRB, appropriate institutional officials, sponsor, coordinating center and the appropriate 
regulatory agency head, all unanticipated problems involving risks to subjects or others that 
occur in the course of a subject’s participation in  research study, in accordance with  (45 CFR 
46.103(b)(5)(i) and 21 CFR 56.108(b)(1)), all AE reports will be reported per the DUHS IRB 
policies.
Privacy, Data Storage & Confidentiality
Complete the Privacy and Confidentiality section of the iRIS submission form.
Describe Role of External Personnel:
N/A