Conditions: Heart Failure Heart Failure Acute Acute Cardiac Failure Acute Cardiac Pulmonary Edema
Keywords: Heart Failure Acute Heart Failure Pulmonary Edema Lung Ultrasound Extra vascular lung water B-lines Diuretics Nitrates
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 52
Healthy volunteers: no

Brief summary:
Nearly 80% of acute heart failure (AHF) patients admitted to the hospital are initially treated in the emergency department (ED). Once admitted, within 30 days post-discharge, 27% of patients are re-hospitalized or die. Attempts to improve outcomes with novel therapies have all failed. The evidence for existing AHF therapies are poor: No currently used AHF treatment is known to improve outcomes. ED treatment is largely the same today as 40 years ago. Congestion, such as difficulty breathing, weight gain, and leg swelling, is the primary reason why patients present to the hospital for AHF. Treating congestion is the cornerstone of AHF management. Yet half of all AHF patients leave the hospital inadequately decongested.

Although it is the investigators' belief patients are often inadequately decongested in the ED, it is common teaching within emergency medicine to focus on vasodilators and avoid or minimize diuretics, especially in those patients with elevated blood pressure. This practice is largely driven by retrospective analyses or small studies suggesting vasodilators are efficacious and IV loop diuretics may be associated with harm. The evidence base to guide early ED management is poor, and the AHA/ACC guidelines provide little to no guidance for ED treatment. This reflects the lack of high quality data, a critical unmet need that the investigators will address in this study.

Using clearance of LUS B-lines as the study endpoint, the investigators will study whether a diuretic intense vs. nitrate intense strategy achieves better decongestion. Although nearly two decades old, a small study of 100 patients suggested a nitrate intense strategy led to better outcomes in AHF patients with pulmonary edema when compared with a diuretic intense strategy. The investigators aim to perform a small pilot study, in hypertensive patients (SBP \> 140mmHg) to test such a strategy to inform a larger, more definitive multicenter randomized trial.

Detailed description:
The primary goal of the N-FURIOUS pilot trial is to determine whether a nitrate intense strategy safely reduces congestion, defined by LUS B-lines, better than a diuretic intense strategy.

This pilot trial is designed to provide the necessary and sufficient information for a larger, definitive trial.

PUBLIC HEALTH IMPACT:

Over one million hospitalizations for AHF occur every year in the US. Within 30 days after hospitalization, over 25% of AHF patients will be dead or re-hospitalized. By one year after hospitalization, up to 67% of patients will be re-hospitalized and 36% will be dead. Worldwide, the costs of AHF exceed 100 billion annually. For patients aged 65 years and older, AHF is the most common and most expensive reason for hospitalization. Despite major reductions in morbidity and mortality for chronic HF, considerably less progress has been seen in AHF.

The emergency department (ED) initiates diagnosis and management for the vast majority of AHF patients. Nearly 80% of all admissions originate from the ED. Delays in diagnosis, misdiagnosis, and delayed or improper treatment are costly, associated with greater morbidity and mortality. Despite this crucial starting role, ED AHF pharmacological management today is largely the same as 40 years ago. In fact, guidelines state: "the treatment of AHF remains largely opinion-based with little good evidence to guide therapy." Consensus statements from the American Heart Association as well as a working group from the NHLBI on ED AHF management further corroborate this lack of evidence: "the evidence base on which this foundation of acute care is built is astonishly thin." There remains a critical unmet need for evidence based ED AHF management.

Limitations of Current AHF Therapy:

There are currently no Class I, Level of Evidence A therapeutic guideline recommendations for AHF, highlighting the unmet need. In fact, therapeutic recommendations from the ACCF/AHA begin with hospital based management, highlighting the absence of ED based evidence. The last ED based guidelines were published in 2007 and have yet to be updated. The investigators argue this lack of evidence leads to tremendous variation in ED care. Combined, this contributes to worse outcomes.

Targeting Congestion in AHF:

Freedom from congestion is associated with improved outcomes; yet many patients leave the hospital inadequately decongested. In fact, many patients leave the hospital without a pre-discharge assessment of congestion. The investigators would argue, many ED AHF patients are poorly assessed prior to hospitalization. The absence of robust, reliable methods to assess congestion is a primary reason why it is not assessed. A recent consensus statement published in 2010 highlights this fact: "…no method to assess congestion prior to discharge has been validated." While physical exam is currently the cornerstone of congestion assessment, it lacks sensitivity and inter-rater reliability. The ED is the beginning of AHF management for \>75% of admitted patients; delays in diagnosis, misdiagnosis, and resultant delays in management are associated with greater morbidity and mortality.

Initial Therapy:

IV loop diuretics are the mainstay of AHF management. Yet emergency physicians are often reluctant to use IV loop diuretics, largely influenced by small studies and retrospective studies suggesting an association with harm. Nitrates are either recommended above diuretics or even to replace diuretics in popular blogs, podcasts, or online forums. Arguably, neither IV loop diuretics nor nitrates have definitive outcome data regarding efficacy or harm. This is evident in guidelines, where IV loop diuretics receive a class I, B indication, and nitrates a IIb, A recommendation. The evidence that does exist supports their use. Whether one should be used before another, both, how to combine them, and in whom, is not well defined.

Lung Ultrasound as an Endpoint:

For years, the lungs have been considered 'off-limits' to ultrasound: with aerated lungs, the ultrasound beam is reflected and scattered due to acoustic mismatch. However, in the setting of pulmonary congestion, extra vascular lung water (EVLW) can be directly visualized and quantitated. Lung ultrasound measurement of B-lines are an objective, semi-quantitative measure of extra vascular lung water (EVLW). B-lines are well-defined, vertical echogenic lines, originating from water-thickened interlobular septa. They are a marker of congestion.

Arms:
arm 1: Patients randomized to the Nitrate intense strategy will be treated according to protocol with nitrates in combination with IV loop diuretics. This protocol only involves therapies used in everyday AHF clinical practice. arm 2: Patients randomized to the Diuretic intense strategy will be treated according to protocol with IV loop diuretics in combination with nitrates. This protocol only involves therapies used in everyday AHF clinical practice.

Interventions: intervention 1: Nitrates intervention 2: Loop Diuretics
Intervention descriptions: intervention 1: For patients randomized to the Nitrate intense arm, the treatment protocol will be initiated and continued until there is a decrease in B-lines to ≤ 15 or 6 hours of care has been delivered, whichever comes first.

Treatment protocol:

1. IV furosemide (unless already given) (All patients receive at minimum 20 mg IV furosemide or equivalent)
2. SL nitroglycerin (400 ucg) will be given every 5 minutes, a total of three times. (May be repeated) (Held if SBP decreases to \< 120 mmHg)
3. Reassessment every 2 hours. If LUS B-lines \>15, repeat step 2. If \< 15, stop algorithm. intervention 2: For patients randomized to the Diuretic intense arm, the treatment protocol will be initiated and continued until there is a decrease in B-lines to ≤ 15 or 6 hours of care has been delivered, whichever comes first.

Treatment protocol:

1. Patients receive 1 inch topical nitropaste
2. IV Loop diuretic dose = patients total oral dose (max dose of 200 mg IV)
3. Reassessment every 2 hours. If LUS B-lines \>15, repeat step 2. If \< 15, stop algorithm.

Protocol document:
Prot_SAP_000.pdf: 
“Nitroglycerin vs. Furosemide using Lung Ultrasound Pilot Trial” 
(N-FURIOUS) 
Principal Investigator: Peter S. Pang MD 
IND/IDE Sponsor: N/A 
Funded by: American Heart Association 
Draft or Version Number:  v.3.7 
July 30, 2019 
 
 
ClinicalTrials.gov Identifier: NCT03259165 
 
 
 
Summary of Changes Amendment A012 
 
1. Changes to eligibility criteria 
2.  Updated treatment algorithm  
3. Clarification of timing of dyspnea assessments 
 
 
 
 
 
 
 


 
ii 
 
Table of Contents 
LIST OF ABBREVIATIONS ...................................................................................................................................... 4 
STATEMENT OF COMPLIANCE ............................................................................................................................ 4 
PROTOCOL SUMMARY ........................................................................................................................................... 5 
SCHEMATIC OF STUDY DESIGN ......................................................................................................................... 6 
1 
KEY ROLES ................................................................................................................................................... 7 
2  
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE........................ 7 
2.1 
Background Information ..................................................................................................................... 7 
2.2 
Rationale .............................................................................................................................................. 7 
2.3 
Potential Risks and Benefits .............................................................................................................. 9 
2.3.1 
Known Potential Risks .................................................................................................... 9 
2.3.2 
Known Potential Benefits ........................................................................................... 109 
3 
OBJECTIVES AND PURPOSE ............................................................................................................... 109 
4 
STUDY DESIGN AND ENDPOINTS ........................................................................................................ 10 
4.1 
Description of the Study Design ..................................................................................................... 10 
4.2.1 
Primary Endpoint ....................................................................................................... 1110 
4.2.2 
Exploratory Endpoints ................................................................................................... 11 
5 
STUDY ENROLLMENT AND WITHDRAWAL ........................................................................................ 11 
5.1 
Participant Inclusion Criteria ............................................................................................................ 11 
5.2 
Participant Exclusion Criteria ...................................................................................................... 1211 
5.3 
Strategies for Recruitment and Retention ..................................................................................... 12 
5.4 
Participant Withdrawal or termination ........................................................................................ 1312 
5.4.1 
Reasons for Withdrawal or Termination ................................................................. 1312 
5.4.2 
Handling of Participant Withdrawals or termination ............................................. 1312 
6 
STUDY AGENT ........................................................................................................................................... 13 
6.1 
Study Agent(s) and Control Description ........................................................................................ 13 
6.1.1 
Dosing & Dose escalation ........................................................................................ 1413 
6.1.2 
Duration of Therapy ...................................................................................................... 15 
7 
STUDY PROCEDURES AND SCHEDULE ............................................................................................. 15 
7.1 
Study Procedures/Evaluations ........................................................................................................ 15 
7.1.1 
Study specific procedures ............................................................................................ 15 
7.1.2 
Standard of care study procedures............................................................................. 15 
7.2 
Laboratory Procedures/Evaluations ............................................................................................... 15 
7.2.1 
Clinical Laboratory Evaluations ................................................................................... 15 
7.3 
Study Schedule ............................................................................................................................. 1615 
7.3.1 
Screening.................................................................................................................... 1615 
7.3.2 
Enrollment/Baseline ...................................................................................................... 16 
7.3.3 
Follow-up & Final study visit ........................................................................................ 16 
7.3.4 
Schedule of Events Table ............................................................................................ 16 
7.5 
Concomitant Medications ................................................................................................................ 18 
7.6 
Prohibited Medications, Treatments, and Procedures ................................................................ 18 
8 
ASSESSMENT OF SAFETY ..................................................................................................................... 18 
8.1 
Specification of Safety Parameters ................................................................................................ 18 
8.1.1 
Definition of Adverse Events (AE) .............................................................................. 18 
8.1.2 
Definition of Serious Adverse Events (SAE) ............................................................. 19 
8.2 
Classification of an Adverse Event ................................................................................................. 19 
8.2.1 
Severity of Event ........................................................................................................... 19 


 
iii 
 
8.2.2 
Relationship to either strategy of care ........................................................................ 19 
8.2.3 
Expectedness ................................................................................................................ 20 
8.3 
Time Period and Frequency for Event Assessment and Follow-Up .......................................... 20 
8.4 
Reporting Procedures ...................................................................................................................... 20 
8.4.1 
Adverse Event Reporting ............................................................................................. 20 
8.4.2 
Serious Adverse Event Reporting ............................................................................... 20 
8.5 
Study Halting Rules .......................................................................................................................... 21 
8.6 
Safety Oversight ................................................................................................................................ 21 
9 
CLINICAL MONITORING ........................................................................................................................... 21 
10 
STATISTICAL CONSIDERATIONS .......................................................................................................... 21 
10.1 
Statistical and Analytical Plans ....................................................................................................... 21 
10.2 
Statistical Hypotheses ...................................................................................................................... 21 
10.3 
Analysis Datasets ............................................................................................................................. 21 
10.4 
Description of Statistical Methods .............................................................................................. 2221 
10.4.1 
General Approach ..................................................................................................... 2221 
10.4.2  
Baseline Descriptive Statistics ................................................................................ 2221 
10.4.3 
Analysis of the Primary Efficacy Endpoint(s) ............................................................ 22 
10.4.4 
Analysis of the EXPLORATORY Endpoint(s) ........................................................... 23 
10.4.5 
Safety Analyses ............................................................................................................. 23 
10.4.6 
Adherence and Retention Analyses ....................................................................... 2423 
10.4.7 
Planned Interim Analyses ............................................................................................ 24 
10.5 
Sample Size ....................................................................................................................................... 24 
10.6 
Measures to Minimize Bias .............................................................................................................. 24 
10.6.1 
Enrollment/ Randomization/ Masking Procedures ................................................... 24 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS .................................. 24 
12 
QUALITY ASSURANCE AND QUALITY CONTROL ......................................................................... 2524 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS .............................................................................. 2625 
13.1 
Ethical Standard ............................................................................................................................ 2625 
13.2 
Institutional Review Board ........................................................................................................... 2625 
13.3 
Informed Consent Process .............................................................................................................. 26 
13.3.1 
Consent/assent and Other Informational Documents Provided to Participants ... 26 
13.3.2 
Consent Procedures and Documentation .................................................................. 26 
13.4 
Participant and data Confidentiality ................................................................................................ 26 
14 
DATA HANDLING AND RECORD KEEPING ..................................................................................... 2726 
14.1 
Data Collection and Management Responsibilities ................................................................. 2726 
14.2 
Study Records Retention ................................................................................................................. 27 
14.3 
Protocol Deviations ........................................................................................................................... 27 
15 
STUDY ADMINISTRATION ................................................................................................................... 2827 
15.1 
Study Leadership .......................................................................................................................... 2827 
16 
CONFLICT OF INTEREST POLICY ......................................................................................................... 28 
17  
Additional Training Materials ...................................................................................................................... 28 
17.1 
lung ultrasound training overview ................................................................................................... 28 
17.2 
ultrasound secure transfer protocol ............................................................................................ 3938 
17.3 
Core lab procedure and lung ultrasound protocol .................................................................... 4039 
18  
LITERATURE REFERENCES ..................................................................................................................... 1 
 


 
4 
 
LIST OF ABBREVIATIONS 
 
AHF 
Acute Heart Failure 
USA 
United States of America 
HF 
Heart Failure 
ED 
Emergency department 
EP 
Emergency Physician 
LUS 
Lung ultrasound 
DAOOH 
Days alive and out of hospital 
NIV 
Non-invasive ventilation (positive pressure ventilation) 
NTG 
Nitroglycerin 
IV 
Intravenous 
SL 
Sub-lingual 
AKI 
Acute Kidney Injury 
WRF 
Worsening renal function 
WHF 
Worsening heart failure 
AE 
Adverse event 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
Hgb 
Hemoglobin 
Hct 
Hematocrit 
IEC 
Institutional Ethics Committee 
IRB 
Institutional Review Board 
GCP 
Good clinical practice 
QC  
Quality Control 
CTSL 
Clinical and Translational Sciences Lab at IU 
IU 
Indiana University 
IWRS 
Internet Web-based Randomization System 
 
STATEMENT OF COMPLIANCE 
This study will be conducted in full accordance with the Good Clinical Practice: Consolidated Guideline approved by the 
International Conference on Harmonization (ICH) and any applicable national and local laws and regulations (e.g., 
Title 21 Code of Federal Regulations [21CFR] Parts 50, 54, 56, 312, and 314).  Any episode of noncompliance will be 
documented. 
The Investigators are responsible for performing the study in accordance with this protocol and the ICH and Good 
Clinical Practice (GCP) guidelines and for collecting, recording, and reporting the data accurately and properly.  
Agreement of each Investigator to conduct and administer this study in accordance with the protocol will be 
documented in separate study agreements with the sponsor and other forms as required by national authorities. 
Each Investigator is responsible for ensuring the privacy, health, and welfare of the patients during and after the study 
and must ensure that trained personnel are immediately available in case of a medical emergency.  


 
5 
 
The Principal Investigator at each center has the overall responsibility for the conduct and administration of the study at 
that center and for contacts with study management, with the Independent Ethics Committee/Institutional Review 
Board (IEC/IRB), and with local authorities. 
 
INVESTIGATOR AGREEMENT 
 
I have read this protocol and agree: 
• 
To conduct the study as outlined herein, in accordance with current Good Clinical Practices (GCPs), the guiding 
principles of the Declaration of Helsinki and complying with the obligations and requirements of Clinical 
Investigators and all other requirements listed in 21 CFR Part 312, local regulations, and according to the study 
procedures provided by Indiana University 
• 
Not to implement any changes to the protocol without prior agreement from Indiana University and prior 
review and written approval from the IRB/EC, except as would be necessary to eliminate an immediate hazard 
to study patient(s), or for administrative aspects of the study. 
• 
To ensure that all persons assisting me with the study are adequately informed about their study-related duties 
as described in the protocol. 
• 
To completely inform all patients in this study concerning the pertinent details and purpose of the study prior to 
their agreement to participate in the study in accordance with GCP and regulatory authority requirements. 
• 
That I will be responsible for maintaining each patient’s consent form in the study file and provide each patient 
with a signed copy of the consent form. 
 
Investigator Name and Title: 
 
 
 
Institution Address: 
 
 
 
 
 
 
 
Signature: _____________________________________________  
Date: ____________ 
 
PROTOCOL SUMMARY 
Title: 
“Nitroglycerin vs. Furosemide using Lung Ultrasound Pilot Trial” (N-FURIOUS) 
 
Précis: 
Of the one million admissions for AHF in the US, approximately 80% are initially managed 
in the ED.  Outcomes from AHF are poor: nearly 25% are dead or re-hospitalized within 30 
days of discharge. The evidence base to treat AHF is limited.  In fact, there are no 
pharmacologic therapies with Class I, Level A guideline recommendations.  The acute 


 
6 
 
treatment of patients today is largely the same as 40 years ago.  This proposal aims to 
build the evidence base for ED AHF care.   
 
Using a two-site, randomized controlled design, this pilot study will test whether a nitrate 
intense strategy more effectively reduces congestion, defined by LUS B-lines, better than 
a diuretic intense strategy. 
 
Objectives: 
 
1: To determine whether a nitrate intense strategy safely reduces congestion, defined by 
LUS B-lines, better than a diuretic intense strategy. 
2. To demonstrate feasibility of recruitment and compliance with study protocol to inform 
future study design and enrollment projections, an external site will also test our study 
protocol. 
Endpoint 
A comparison of total B-lines at the conclusion of ED AHF management or maximum of 6 
hours after enrollment, whichever comes first. 
Population: 
Emergency department (ED) AHF patients.  All patients who meet inclusion and no 
exclusion criteria will be enrolled during their ED visit within 3 hours of presentation.  
Phase: 
2 
Number of Sites 
enrolling participants: 
Two sites (3 total hospitals).  Projected sample size, n=70. 
Description of Study 
Agent:  
Nitrate intense vs. Diuretic intense AHF treatment strategy   
Study Duration: 
2 years.  There will be three months of start up, and one month of study conclusion work.  
Enrollment will occur over 20 months, which equals 3.5 patients month.  As there will be 
staggered start up to determine replication, approximately 1-2 patients/month.   
Participant Duration: 
30 days post discharge 
 
SCHEMATIC OF STUDY DESIGN 
 
*whichever comes first 
**Presentation is definied as first time recorded when placed in a room to be treated.  This allows patients to still be enrolled 
despite a long waiting room time 


 
7 
 
1 
KEY ROLES 
Our team of investigators is uniquely qualified to successfully complete this study. We leverage complementary 
experience and expertise, in particular, early (ED) enrollment, lung ultrasound, congestion management, and clinical 
trials.  Most importantly, we have worked close together for nearly 10 years.1-24 
 (PI) is an Associate Professor in Emergency Medicine 
Indiana University School of Medicine (IU 
SOM).  
Frances Russell MD is the Director of the Division of Ultrasound and Directs the US Fellowship in the Department of 
Emergency Medicine at IU SOM. She will lead the study operations related to LUS image acquisition at IU SOM.  
Xiaochun Li PhD, from the Department of Biostatistics at Indiana University will lead the data core.  
Sean Collins MD (Vanderbilt University), Vice-Chair of Research, will be the site PI at Vanderbilt.  
Robinson Ferre MD is an Assistant Professor of Emergency Medicine at Vanderbilt University and Director of the 
Division of Emergency Ultrasound and Associate Program Director of the emergency ultrasound fellowship.  He will lead 
the study operations related to LUS image acquisition at Vanderbilt.  
Luna Gargani MD is an Assistant Professor of Cardiology at the University of Pisa. She will direct the core imaging lab.   
In her role, she will only see blinded images; never any patient identifiable information. 
2  
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE  
 
2.1 
BACKGROUND INFORMATION  
Over one million hospitalizations for AHF occur every year in the US. Within 30 days after hospitalization, over 25% of 
AHF patients will be dead or re-hospitalized.25 By one year after hospitalization, up to 67% of patients will be re-
hospitalized and 36% will be dead.26  Worldwide, the costs of AHF exceed 100 billion annually.27 For patients aged 65 
years and older, AHF is the most common and most expensive reason for hospitalization.28 Despite major reductions in 
morbidity and mortality for chronic HF, considerably less progress has been seen in AHF.29-31  
The emergency department (ED) initiates diagnosis and management for the vast majority of AHF patients. Nearly 80% 
of all admissions originate from the ED. Delays in diagnosis, misdiagnosis, and delayed or improper treatment are costly, 
associated with greater morbidity and mortality.32,33 Despite this crucial starting role, ED AHF pharmacological 
management today is largely the same as 40 years ago.34 In fact, guidelines state: “the treatment of AHF remains 
largely opinion-based with little good evidence to guide therapy.”35  Consensus statements from the American Heart 
Association as well as a working group from the NHLBI on ED AHF management further corroborate this lack of 
evidence: “the evidence base on which this foundation of acute care is built is astonishly thin.”9,12 There remains a critical 
unmet need for evidence based ED AHF management. 
 
2.2 
RATIONALE  
Limitations of Current AHF Therapy 
There are currently no Class I, Level of Evidence A therapeutic guideline recommendations for AHF, highlighting the 
unmet need.4,5  In fact, therapeutic recommendations from the ACCF/AHA begin with hospital based management, 
highlighting the absence of ED based evidence.37  The last ED based guidelines were published in 2007 and have yet to 
be updated.42  We argue this lack of evidence leads to tremendous variation in ED care. Combined, this contributes to 
worse outcomes. 
 


 
8 
 
Targeting Congestion in AHF 
Freedom from congestion is associated with improved outcomes;43-48 yet many patients leave the hospital inadequately 
decongested.43,49-52 In fact, many patients leave the hospital without a pre-discharge assessment of congestion.38,39 We 
would argue many ED AHF patients are poorly assessed prior to hospitalization. The absence of robust, reliable methods 
to assess congestion is a primary reason why it is not assessed.39,53 A recent consensus statement published in 2010 
highlights this fact: “…no method to assess congestion prior to discharge has 
been validated.”39 While physical exam is currently the cornerstone of 
congestion assessment, it lacks sensitivity and inter-rater reliability.53,54 The ED 
is the beginning of AHF management for >75% of admitted patients;55,56  delays 
in diagnosis, misdiagnosis, and resultant delays in management are associated 
with greater morbidity and mortality.32,33  
Initial Therapy 
IV loop diuretics are the mainstay of AHF management.  Yet emergency 
physicians are often reluctant to use IV loop diuretics, largely influenced by 
small studies and retrospective studies suggesting an association with harm. 
Nitrates are either recommended above diuretics or even to replace diuretics in popular blogs, podcasts, or online 
forums.  Arguably, neither IV loop diuretics nor nitrates have definitive outcome data regarding efficacy or harm. This is 
evident in guidelines, where IV loop diuretics receive a class I, B indication, and nitrates a IIb, A recommendation.  The 
evidence that does exist supports their use.  Whether one should be used before another, both, how to combine them, 
and in whom, is not well defined. 
Lung Ultrasound as an Endpoint 
For years, the lungs have been considered ‘off-limits’ to ultrasound: with aerated lungs, the ultrasound beam is reflected 
and scattered due to acoustic mismatch.57,58 However, in the setting of pulmonary congestion, extra vascular lung water 
(EVLW) can be directly visualized and quantitated.58-60 Lung ultrasound measurement of B-lines are an objective, semi-
quantitative measure of extra vascular lung water (EVLW).60 B-lines are well-defined, vertical echogenic lines, originating 
from water-thickened interlobular septa.60 (Figure 1) They are a marker of congestion.  
LUS improves diagnostic accuracy and is highly reproducible.61-67  Intra and inter-observer variability of B-line capture 
and summary have been reported as low as 5.1% and 7.4%, respectively.68 In a recent meta-analysis, LUS was the best 
test to affirm the diagnosis of AHF, more than natriuretic peptide (NP) (likelihood ratio positive for the diagnosis of AHF 
by LUS was 7.4 (95% CI 4.2-12.8) and LR negative 0.16, (95% CI 0.05-0.51)).61 This may reflect the additional value of LUS 
when patients have chronically elevated NP levels.  Recent guideline and consensus statements also support the use of 
LUS for diagnosis.69-73   


 
9 
 
Importantly, B-lines are a dynamic marker. In dialysis patients, B-lines decrease markedly pre/post dialysis.74 In AHF 
patients, B lines generally decrease throughout hospitalization.75,76  However, persistence of B-lines pre-discharge 
identifies patients at higher risk for worse outcomes.76,77 B-lines even outperformed BNP as a 
prognostic marker.75 Finally, serial measurement of B-lines are both easy to learn and 
perform.62,63,78-80 LUS is also low cost, and does not involve radiation. Computerized 
diagnostic aids have already been pilot tested with excellent results, demonstrating the ease 
of B-
line scoring.81 Hand held machines perform as well as a standard ECHO platform or US machines.63,82 The ease of LUS 
will facilitate its generalizability and dissemination. Non-physicians 
may be future users of bedside LUS assessment, further supporting 
its generalizability.  
.  
2.3 
POTENTIAL RISKS AND BENEFITS  
 
2.3.1 KNOWN POTENTIAL RISKS  
Overview. Current ED AHF treatment involves the use of non-
invasive ventilation (NIV), IV loop diuretics, and IV, SL, or topical 
vasodilators.  Each of these are highlighted in guidelines.  However, 
the level of evidence supporting these treatments is relatively 
weak, with the strongest evidence supporting the use of IV loop 
diuretics.  The evidence is even weaker for ED AHF treatment; for example, the AHA/ACC guidelines begin with 
hospitalization, highlighting the lack of evidence for ED AHF care. Although the evidence is weak, these medications are 
the current standard of care for AHF. There are NO novel therapies or unapproved treatments. 
Common Risks. The greatest risks are not necessarily different than those already associated with these therapies.  
However, the risk may or may not be increased due to use of these treatments in a guided protocol strategy or when 
one therapy (nitrates or diuretics) are used initially over the other.  To mitigate these risks, this study is being conducted 
in an ED setting, where ICU level care is routinely provided.  If needed, rescue therapy with either drug (or additional 
therapies) may be provided. 
For IV loop diuretics, commonly encountered risks include potential acute kidney injury (AKI) and over diuresis leading to 
hypovolemia which can lead to circulatory collapse and possibly vascular thrombosis and embolism, particularly in 
elderly patients. Electrolyte depletion may also occur especially in patients receiving higher doses and a restricted salt 
intake. Hypokalemia may develop, especially with brisk diuresis, inadequate oral electrolyte intake, when cirrhosis is 
present, or during concomitant use of corticosteroids, ACTH, licorice in large amounts, or prolonged use of laxatives. 
Digitalis therapy may exaggerate metabolic effects of hypokalemia, especially myocardial effects. Per routine standard 
of care at each of the sites, electrolytes are routinely checked during the initial 24-48 hours of treatment.  These will be 
recorded. However, should no further electrolytes be measured after admission, there will be no pre-discharge lab 
draw.  While AKI may occur, more recent data suggests that failure to decongest is associated with greater risk for 
adverse outcomes than transient AKI.  To add a margin of safety, only patients with an eGFR ≥45 will be enrolled.  
Finally, we will assess eGFR prior to discharge (if measured as part of standard of care) to better understand whether 
our proposed strategy-of-care is associated with worsening renal function.   
For nitrates, the greatest risk is hypotension.  Marked sensitivity to the hypotensive effects of nitrates (manifested by 
nausea, vomiting, weakness, diaphoresis, pallor and collapse) may occur at therapeutic doses. Syncope due to nitrate 
vasodilation has been reported. Vertigo, weakness, palpitation and other manifestations of postural hypotension may 
T0
T1
Td
0
50
100
150
200
250
B-lines (n°)
Figure 2 


 
10 
 
develop occasionally, particularly in erect, immobile patients. All patients will have IV access for fluids, if needed.  Of 
note, the ESC guidelines allow for the potential use of IV nitrates in patients with a SBP > 110mmHg and only 
recommend avoiding them if the SBP is < 110 mmHg.  Another common side effect is headache which may be severe 
and persistent may occur immediately after use. This will be treated with Tylenol or other non-narcotic analgesic 
medication. Nitroglycerin may produce a burning or tingling sensation when administered sublingually. Flushing, drug 
rash, and exfoliative dermatitis have also been reported in patients receiving nitrate therapy. 
Potential Risks from Ultrasound: There are almost no risks to the use of ultrasound.  Ultrasound is what is currently used 
to visualize the fetus in pregnant patients.  The same type of ultrasound will be used for this study. There is NO radiation 
involved. The biggest complaint from use of ultrasound is the gel placed on the probe or body to improve visualization of 
the US waves is often cold. 
2.3.2 KNOWN POTENTIAL BENEFITS  
Patients enrolled in this study may receive a benefit such as feeling better faster. If the study shows that a nitrate or 
furosemide first strategy leads to faster resolution of congestion, future studies may explore early treatment in more 
detail.  If either strategy is not safe with the current study design, future patients may be spared the cost of ineffective 
ED AHF management, and spared the potential for any possible side effects.  
3 
OBJECTIVES AND PURPOSE 
Objectives: 
1: To determine whether a nitrate intense strategy safely reduces congestion, defined by LUS B-lines, better than a 
diuretic intense strategy. 
2. To demonstrate feasibility of recruitment and compliance with study protocol to inform future study design and 
enrollment projections, an external site will also test our study protocol. 
 
Purpose: 
This pilot trial is designed to provide the necessary and sufficient information for a larger, definitive trial.   
Hypothesis 1a: Nitrate intense treated patients will have less congestion, defined by LUS B-lines, than diuretic intense 
patients at 6 hours after start of treatment.   
Hypothesis 1b: Nitrate intense treated patients will have greater dyspnea relief then diuretic intense patients at 6 hours 
after start of treatment. 
 
4 
STUDY DESIGN AND ENDPOINTS 
 
4.1 
DESCRIPTION OF THE STUDY DESIGN 
A two-site, prospective, randomized, pilot trial comparing a nitrate intense vs. diuretic intense strategy.  All potential ED 
patients will receive an initial LUS scan. Performing LUS is within the standard of care and will be done at no cost to 
patients. It is not frequently used however, either for diagnosis, prognosis, or to guide clinical therapy. However, 
treating clinicians will be blinded to these results. If clinicians choose to perform their own LUS, those patients will not 
be excluded.  Patients who provide written informed consent and meet all inclusion and no exclusion criteria will be 
randomized 1:1 to either study arm. For randomized patients, study protocol will continue until there is a decrease in B-


 
11 
 
lines to ≤ 15 or 6 hours of care has been delivered. Subjects who are hospitalized prior to the completion of the 6 hour 
protocol may continue on the protocol until the six hour treatment window is concluded.  All images will be stored and 
overread by an independent, expert ultrasonographer blinded to treatment arm.  
Safety of patients are paramount.  If a potential life threatening etiology is identified, the clinical team will be made 
aware immediately, irrespective of randomization arm.  These occurrences will be recorded in the eCRF.  While this will 
be a rare event, we will a priori establish that an additional patient will be accrued into the study and an additional 
modified intent to treat population for analysis will be performed, excluding these patients where a life-threatening 
etiology was identified (i.e. pericardial tamponade). 
For patients who do NOT meet eligibility criteria, the results of their LUS will be provided to the clinical team as 
requested. 
 
4.2.1 PRIMARY ENDPOINT 
 
The total number of B-lines at the conclusion of ED AHF management 
 
Main Secondary Endpoints: 
Dyspnea will also be assessed using a 5-point and 7-point Likert scale. 
B-lines <= 15 at the conclusion of ED AHF management 
 
4.2.2 EXPLORATORY ENDPOINTS 
The following table lists the exploratory endpoints 
Table 3: Exploratory Endpoints 
 
Total DAOOH through 30 days post-discharge 
Association of B-lines at discharge and 30 day outcomes 
Time to reach B-lines <15 
Association of baseline, discharge, and change of b-lines with 
30  day outcomes 
Change in physical exam findings  
All Cause readmissions, All cause ED re-visits 
5 
STUDY ENROLLMENT AND WITHDRAWAL 
 
5.1 
PARTICIPANT INCLUSION CRITERIA 
1) Age ≥ 21 years 
2) Presents with shortness of breath at rest or with minimal exertion 
3) Clinical diagnosis of AHF and presence of > 15 total bilateral B-lines distributed in at least 4 zones on initial LUS 
4) Hx of chronic HF and any one of the following: 
i. 
Chest radiograph consistent with AHF  
ii. 
Jugular venous distension 
iii. 
Pulmonary rales on auscultation 


 
12 
 
iv. 
Lower extremity edema 
v.  
BNP > 500pg/mL 
 
 
5.2 
PARTICIPANT EXCLUSION CRITERIA 
1) Chronic renal dysfunction, including ESRD or eGFR < 20ml//min/1.73m2.     
2) Shock of any kind. Any requirement for vasopressors or inotropes. 
3) SBP < 120  
4) Need for immediate intubation  
5) Acute Coronary Syndrome OR new ST-segment elevation/depression on EKG.  (troponin release outside of ACS is 
allowed)  
6) Fever >101.5ºF  
7) End stage HF: transplant list, ventricular assist device 
8) Anemia requiring transfusion 
9) Known interstitial lung disease 
10) Suspected acute lung injury or acute respiratory distress syndrome (ARDS) 
11) Pregnant or recently pregnant within the last 6 months 
12) Severe valvular disease 
13) Anuria 
14) Allergy or hypersensitivity to nitroglycerin, furosemide or sulfa 
15) Concern for cardiac tamponade or restrictive cardiomyopathy 
16) Elevated intracranial pressure 
17) Recent use of PDE5 inhibitors 
 
It is important to note that AHF is a clinical diagnosis. In other words, there is no test or image that 100% conclusively 
demonstrates a patient does or does not have AHF.  In most studies, 2 cardiologists who independently review the chart 
and agree its heart failure set the ‘gold standard.’  Thus, there will inevitably be instances where the ER will diagnose 
AHF and be wrong and vice-versa.  From a clinical standpoint however, patients are cared for based on their 
presumptive diagnosis.  Thus, instances where the ER diagnoses AHF and then the inpatient teams confirm an 
alternative diagnosis would NOT violate the spirit or actual intent of the study protocol.   
5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Each site will have a lead PI and US Director, along with a dedicated study team.  This study team, comprised of research 
assistants and coordinators, will perform both electronic screening (via tracking boards) and maintain a continuous 
physical presence in the ED to identify patients.. All patients with a final diagnosis of AHF at the time of hospital 
discharge will be considered to have AHF. 


 
13 
 
As we aim to design a pragmatic, ED-based study  our inclusion/exclusion criteria are relatively broad compared to other 
therapeutic clinical trials.   
Patients may be enrolled at anytime during their ED stay, but preferably within 3 hours of first placement in a room in 
the emergency department.  Time spent in the waiting room will not count towards these 3 hours. 
Screen Failures: 
Patients who sign an informed consent but who are not randomized will be considered Screen Failures. Only data for 
randomized patients will be entered into the CRF.  Serious adverse events should be reported for these patients from 
the time the ICF is signed through the time that the patient is declared a screen failure.  One expected reason for screen 
failure will be the absence of > 15 B-lines at baseline. 
 
 
5.4 
PARTICIPANT WITHDRAWAL OR TERMINATION 
 
5.4.1 REASONS FOR WITHDRAWAL OR TERMINATION 
In accordance with the guiding principles of the Declaration of Helsinki, any patient is free to withdraw from 
participating in this study at any time and for whatever reason, specified or unspecified, and without prejudice. 
Investigators should attempt to determine the cause of withdrawal and, if desired by the patient, to make it possible for 
the patient to continue to participate in the study.  The extent of a patient's withdrawal from the study (i.e. withdrawal 
from further study treatment, withdrawal from any further contact, etc.) should be documented.  Every effort should be 
taken to follow all randomized patients, to the extent that the patient will allow, for the full follow-up period. 
Investigators may discontinue study treatment for any other reasons concerning the health or well-being of the patient. 
The reason for and date of study discontinuation and the reason for and date of withdrawal from the study must be 
recorded on the CRF.  If study is discontinued because of an adverse event or a clinically significant abnormal laboratory 
test result, evaluations will continue until the event has resolved or stabilized or until a determination of a cause 
unrelated to the study procedure is made.  The specific event or laboratory finding(s) must be documented.  All 
evaluations should be performed, according to the protocol.   
5.4.2 HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION 
The Full Analysis Set (FAS) will include all randomized patients. In accordance with the intent-to-treat principle, patients 
will be analyzed by the group to which they were randomized. Misrandomized patients (patients randomized in error 
who did not receive any study intervention) will be excluded. Analyses in the FAS will constitute the main efficacy results 
for the primary and secondary study efficacy endpoints. 
The Per Protocol Set (PPS) will be a subset of the FAS and will exclude patients with major protocol violations.   The 
major protocol violations that will result in exclusion from the PPS will be identified prior to unblinding the treatment 
assignments for final analysis. Patients will be analyzed in the treatment group to which they were randomized. Results 
of analyses in this analysis population will support the primary efficacy analyses in the FAS. 
6 
STUDY AGENT 
 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION 
This study will test a nitrate intense vs. diuretic intense early AHF strategy.  No investigational therapies will be used.  No 
drugs or therapies that are not approved by the FDA will be allowed. 
 


 
14 
 
6.1.1 DOSING & DOSE ESCALATION 
The algorithm below 
outlines the treatment protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IV furosemide (unless already given) 
(All patients receive at minimum 20mg IV 
furosemide or equivalent) 
Nitrate Intense Strategy 
 
Diuretic Intense Strategy 
(All patients receive 1 inch topical 
nitropaste) 
Sub-Lingual NTG (400ucg) will be given q 5 
minutes x 3. (May be repeated) 
 (Held if SBP decreases to < 120mmHg) 
*IV and/or topical nitrates may also be given 
IV Loop Diuretic Dose 
(1x the total oral dose) 
- 
Max dose of 200mg IV 
furosemide 
Re-assess in 2 hours 
If LUS B-lines > 15, continue with 
algorithm. If < 15, stop algorithm 
Sub-Lingual NTG (400ucg) will be given q 5 
minutes x 3. (May be repeated) 
 (Held if SBP decreases to < 120mmHg) 
*IV and/or topical nitrates may also be given 
IV Loop Diuretic Dose 
Check UOP – if less than 1 cc/kg/hr, may: 
1. 1 to 2x single oral dose if on chronic 
therapy 
2. Repeat original IV dose 
3. Double original IV dose 
If > 1 cc/kg/hr, no more IV furosemide 
Re-assess in 2 hours 
If LUS B-lines > 15, continue with algorithm. 
If < 15, stop algorithm 
Algorithm ends at 6 hours after randomization^ 
Otherwise, patients are re-assessed every 2 hours until end of algorithm time or B-lines < 15. 


 
15 
 
^the protocol was designed to be an ED based protocol.  Thus, for patients who leave the ER prior to 6 hours, deviations from the 
algorithm will NOT be protocol violations. 
** ALL enrolled patients will be re-assessed at least twice during their ED stay, unless the patient is discharged from the ER or other 
clinical priority.  First re-assessment will occur within 2-4 hours of first TREATMENT.  Assessments outside this window are NOT 
allowed for study purposes unless at the discretion of the investigator.  The second re-assessment will occur EITHER 2-4 hours after 
the first OR prior to discharge from the ER or at 6 hours after start of treatment.  IF the pre-discharge assessment is missed in the ER, 
if possible, this should occurs ASAP after arrival to the hospital floor, unless completed within one hour of the last assessment. 
NOTE: the maximum dose allowed at any one time of IV Lasix is 200mg IV.  
NOTE: For additional IV loop diuretic doses, the options under Restart Algorithm are three options.  Clinical/Research team may 
choose one of the three loop diuretic dose options. 
NOTE: The protocol is not optional by the clinical team.  Of course, patient safety comes first, similar to all other interventional trials.  
However, similar to other interventional studies, once randomized, the study protocol should continue forward. 
NOTE: Urine output: An estimated urine output is acceptable. 
6.1.2 DURATION OF THERAPY 
Both arms will continue until 6 hours after randomization. 6 hours was chosen to avoid confounding by patients with 
overly long ED LOS. At minimum, patients should receive at least one round of treatment.  The protocol continues even 
if patients reach the floor. However, if in the opinon of the investigator, the protocol should not be continued once on 
the hospital floor, this is allowed and should be marked on the case report.   
7 
STUDY PROCEDURES AND SCHEDULE 
 
7.1 
STUDY PROCEDURES/EVALUATIONS 
7.1.1 STUDY SPECIFIC PROCEDURES  
The table below in section 7.3.4 highlights study specific procedures.  Only patients who sign written informed consent 
will undergo study specific procedures. 
7.1.2 STANDARD OF CARE STUDY PROCEDURES  
Except for the ED phase of management, there will be no other change to standard of care procedures for either 
treatment arm. Patients will continue to be followed during hospitalization, with at least one LUS performed within 48 
hours of randomization.  (Later than this window, but no more than 96 hours, is at the discretion of the site PI) 
7.2 
LABORATORY PROCEDURES/EVALUATIONS 
 
7.2.1 CLINICAL LABORATORY EVALUATIONS  
Lab testing will be analyzed by the clinical lab at each respective institution for baseline chemistry and 
hemoglobin/hematocrit values. This reflects our pragmatic approach.  If routine labs are performed clinically within 6 
hours of the follow up time-point, these results will be used for study purposes (Table 2).  If routine lab work is not 
drawn, the closest clinical lab draw will be recorded in the eCRF unless already recorded (i.e. the baseline value).  NO 
labs will be drawn for study purposes.  


 
16 
 
7.3 
STUDY SCHEDULE 
7.3.1 SCREENING 
A signed and dated informed consent form will be obtained before any study-specific screening procedures are 
performed.  Results of evaluations obtained as part of routine medical care, which are performed prior to obtaining 
informed consent, may be used in place of the protocol-specified evaluations.  Patients will acknowledge and agree to 
the use of this information for the study by giving informed consent.  
At the Baseline Visit, patients will be assigned by the Internet Web-based Randomization System (IWRS) a unique 
permanent identification number (referred to as the patient identification number) such that all randomized patients 
from each center are given consecutive identification numbers by the IWRS in successive order of inclusion.  We will 
utilize the REDCap randomization module.  
Prospective study patients will have presented to the hospital for urgent therapy for AHF.  Potential patients will be 
identified either en route to or upon arriving at the ED/hospital. Routine assessments associated with usual patient care 
may be used for the purposes of screening and may be completed in any order. Study specific procedures must be 
completed only after Informed Consent is obtained.  
Patients may be enrolled at anytime during their ED stay, but preferably within 3 hours of first placement in a room in 
the emergency department.  Time spent in the waiting room will not count towards these 3 hours. 
The following procedures will be performed prior to or during Screening: 
• 
Obtain written informed consent (must be performed as the first study-specific procedure) 
• 
Review of prior medical history 
• 
Review of prior and concomitant medications 
• 
Physical examination (including height and weight when reasonably possible) 
• 
Vital signs measurements (includes systolic and diastolic blood pressures, heart rate, body temperature, oxygen 
saturation reading and respiratory rate) 
• 
12-Lead Electrocardiogram  
• 
Chest X-Ray (this is not a requirement however, for inclusion) 
• 
Blood collection for local laboratory tests, including BNP or NT-proBNP, and pregnancy test if applicable. 
• 
Inquiry about Adverse events 
7.3.2 ENROLLMENT/BASELINE 
Patients who continue to fulfill all of the eligibility criteria will be randomized.  In regards to the SBP; a single recording 
below 120mmHg does NOT disqualify the patient as long as the SBP returns > 120mmHg.  Randomization will occur via 
central IWRS system.  
7.3.3 FOLLOW-UP & FINAL STUDY VISIT 
Patients will be followed for a maximum of 30 days post-discharge.  There will be NO further in-person visits once 
discharged.  Patients will be called however at 30 days post-discharge ((+) 30 business days or at the discretion of the 
local site PI to assess vital status and re-hospitalizations or ED visits. 
7.3.4 SCHEDULE OF EVENTS TABLE 
 


 
17 
 
 Schedule of Events 
Screening 
Day 1 
T00 
Day 1 
T02-04 
Day 1 
T06 
Day 2-6 
T24-D6 
30 day follow up 
Informed consent (I/E) 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Medication history 
X 
 
 
 
 
 
Clinical Assessment# 
 
X 
X 
X 
X 
 
Body Weight, height, Vital 
Signs 
ED SOC 
VS only 
VS only 
VS only 
BW/VS only 
 
5-point and 7-point Likert 
scale 
 
X 
 
X 
X 
 
Labs: Electrolytes, 
hematology, NP, eGFR, 
Troponin 
ED SOC 
 
 
 
 
 
12-lead ECG 
ED SOC 
 
 
 
 
 
CXR 
ED SOC 
 
 
 
 
 
LUS B-lines 8 zone 
X 
(LUS T00) 
 
X 
X 
X^^ 
 
Nitrate vs. Diuretic intense 
management 
 
X 
X 
X 
 
 
Lab draw: eGFR, Hgb/Hct^ 
 
X 
 
 
 
 
eCRF/data 
collection/verification 
 
X 
 
 
 
X 
Assessment of AE/SAE's 
 
 
 
 
 
X 
Phone follow-up Vital Status 
 
 
 
 
 
X 


 
18 
 
SOC = standard of care, ED = Emergency Department, I/E = inclusion, exclusion, CV = cardiovascular, LUS = lung 
ultrasound, BW = body weight, NP = natriuretic peptide ^if collected as part of standard of care, will use that result. The 
last collected result will be used if not drawn on or close to discharge ^^ LUS to be performed up to 48 hours after 
hospitalization. If an obs unit patient, prior to discharge. 
Further detail regarding timing of assessments: [NOTE: given clinical circumstances (i.e. left the ER for a test, discussion 
with consultant, etc) – the SITE PI has final discretion to continue to image a patient before or after the allotted window. 
This time MUST be recorded in the eCRF] 
o T00:  initial LUS scan (in ED for screening and eligibility) 
o T02: 2-4 hours after initial treatment (in ED) (+/- 30 minutes) 
o T06: 2-4 hours after T02 or pre-ED discharge, whichever comes first (+/- 60 minutes) 
o T48: up to 48 hours after initial scan (Day 3) (+/- 12 hours) 
** For vital signs during hospitalization. The nearest vital signs to the LUS exam will be captured. 
7.5 
CONCOMITANT MEDICATIONS 
All medications administered within 14 days prior to and during screening will be recorded in the case report form.   
Medications that are not specifically prohibited are permitted at the Investigator’s discretion. 
7.6 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES  
No medications, treatments, or procedures are prohibited unless specifically mentioned in the eligibility criteria.  Patient 
safety and well-being are paramount: Any treatment deemed necessary may be utilized at the investigators discretion 
should there be any concern for the patients health. 
8 
ASSESSMENT OF SAFETY 
8.1 
SPECIFICATION OF SAFETY PARAMETERS 
Mortality, re-hospitalization, and ED visits through 30 days will be assessed for safety as well as efficacy 
Hypotension, defined as a  SBP < 100mmHg or decrease > 60mmHg from baseline, will be assessed as a safety endpoint.  
SBP Decrease Safety Margin: Patients whose SBP decreases to < 100mmHg at any time (measurement must be repeated 
twice, 15 minutes apart, unless symptomatic) or who develop evidence of clinical hypotension (i.e. weakness, dizziness, 
faint, chest discomfort) despite a SBP > 100mmHg will be immediately assessed and treated as needed, and all further 
strategy of care interventions will be halted.  Patient safety and care is paramount and takes precedence over all other 
considerations.  The clinical team may halt the study at any time.  If there are any questions, the PI or designee will make 
the final decision.   
8.1.1 DEFINITION OF ADVERSE EVENTS (AE) 
The Investigator and study staff are responsible for detecting and recording AEs and SAEs during scheduled safety 
evaluations and whenever such information is brought to their attention. This section of the protocol provides 
definitions and detailed procedures to be followed. During the follow up visit, the Investigator will question the patient 
about adverse events using an open question, taking care not to influence the patient’s answers, e.g. “Have you had any 
unusual symptoms or medical problems since the last visit?  If yes, please describe.” 
Subject payment 
 
X 
 
 
 
X 


 
19 
 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an 
investigational (medicinal) product or other protocol-imposed intervention, regardless of attribution.  
This includes the following:  
• AEs not previously observed in the subject that emerge during the protocol-specified AE reporting period.  
• Complications that occur as a result of protocol-mandated interventions  
• Preexisting medical conditions (other than the condition being studied) judged by the investigator to have worsened in 
severity or frequency or changed in character during the protocol-specified AE reporting period.  
• Abnormal laboratory values that fall into an abnormal range based upon the hospital’s laboratory standards, the 
abnormality was not preexisting prior to enrollment, and the abnormality leads to a new treatment within the AE time 
frame  
The AE and SAE reporting period extends to day 5 of hospitalization or discharge, whichever comes first, unless 
otherwise specified. 
8.1.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
An AE will be classified as an SAE if:  
• It results in death (i.e., the AE actually causes or leads to death).  
• It is life threatening (i.e., the AE, in the view of the investigator, places the subject at immediate risk of death. It does 
not include an AE that, had it occurred in a more severe form, might have caused death).  
• It requires or prolongs inpatient hospitalization.  
• It results in persistent or significant disability/incapacity (i.e., the AE results in substantial disruption of the subject’s 
ability to conduct normal life functions).  
• It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the 
subject or may require medical/surgical intervention to prevent one of the outcomes listed above).  
 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT 
 
8.2.1 SEVERITY OF EVENT 
The severity of each adverse event must be recorded as 1 of the choices on the following scale: 
Mild 
 
No limitation of usual activities 
Moderate 
Some limitation of usual activities 
Severe  
Inability to carry out usual activities 
An AE that is assessed as severe should not be confused with a SAE. 
8.2.2 RELATIONSHIP TO EITHER STRATEGY OF CARE 
Each reported AE will be described by its duration (i.e., start and end dates), regulatory seriousness criteria if applicable, 
and suspected relationship to study drug in accordance with definitions set forth at each IRB. In general, these 
relationships are categorized as likely, possible, unlikely and not related. Experience teaches that gray zone instances 


 
20 
 
will arise, and the site coordinators and PIs will be trained to adjudicate possible SAEs in a systematic fashion. To ensure 
consistency of SAE causality assessments, investigators will apply the following general guideline:  
Yes - There is a plausible temporal relationship between the onset of the AE and administration of the study drug and 
the AE cannot be readily explained by the subject’s clinical state, inter-current illness, or concomitant therapies; and/or 
the AE follows a known pattern of response to study drug or the AE abates or resolves upon discontinuation of study 
drug;  
No - Evidence exists that the AE has an etiology other than the study drug (e.g., preexisting medical condition, 
underlying disease, inter-current illness, or concomitant medication); and/or the AE has no plausible temporal 
relationship to the study drug.  
Adjudication of each AE will proceed as follows: First, the coordinator will consult the site PI to review the chart. Next, 
the PI will contact members of the clinical care team to clarify uncertainty related to inadequate documentation. Third, 
if the PI is unable to decide for certain if an AE or SAE occurred, he or she will have the option of sending a personal 
health identifier-stripped, written narrative of the event to the other site PIs who will vote up or down as to whether the 
event constituted an AE or SAE.  
8.2.3 EXPECTEDNESS  
The following signs, symptoms, observations and events are frequently observed in association with acute heart failure: 
dyspnea, orthopnea, paroxysmal nocturnal dyspnea, chest pain, fever, hypoxemia, rapid pulse, rapid respiratory rate, 
dizziness, syncope, altered mental status, confusion, anxiety, generalized weakness, anorexia, nausea, abdominal pain, 
back pain, early satiety, vomiting, pneumonia, acute renal failure, skin infection, cancer, surgery not related to 
treatment of pulmonary embolism, electrocardiography abnormalities (atrial arrhythmias, ventricular dysrhythmias, 
right bundle branch block, and ST and T wave changes), elevated troponin level, elevated BNP or NT ProBNP level, high 
white blood cell count,  pulmonary infiltrate, pleural effusion, cardiomegaly, electrolyte imbalances, need for oxygen 
therapy, need for vasopressor support, need for blood product transfusion, need for mechanical ventilation (invasive or 
non-invasive), need for physical or occupational therapy, need for analgesia, need for skilled nursing facility upon 
discharge, need for early follow up with physician, escalation of heart failure therapy, need for cardiac catheterization or 
PA line placement, need for sleep study.  
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
All AEs and SAEs will be followed through resolution, stabilization, or until the subject is lost-to-follow-up.  
The onset and end dates, duration, action taken regarding study drug, treatment administered, and outcome for each 
adverse event must be recorded on the CRF for randomized patients.  The relationship of each adverse event to study 
drug treatment and study procedures, and the severity and seriousness of each adverse event, as judged by the 
Investigator, must be recorded as described below. 
8.4 
REPORTING PROCEDURES 
8.4.1 ADVERSE EVENT REPORTING  
The study period during which AEs must be reported begins after informed consent is obtained and initiation of study 
treatment and for 5 days after ending study treatment.  Patients will be followed for 30 days for ED visits, re-
hospitalization, and mortality. Subject’s hospital discharge summaries will be examined at hospital discharge and all non-
exempt AEs will be investigated by examining necessary medical records.  
8.4.2 SERIOUS ADVERSE EVENT REPORTING  
All SAE’s will be reviewed within 48 hours and all AE’s within 7 days of discovery by the Study team   


 
21 
 
15 Calendar Day Written Report  
The Investigator will also be required to notify the IRBs and all participating investigators, in a written Safety Report, of 
any serious, unexpected AE that is considered reasonably or possibly related to the strategy-of-care arm  
72 hour reporting 
For the discovery of an unexpected serious adverse event thought to be related to study, the IRB will be informed within 
72 hours. 
8.5 
STUDY HALTING RULES  
As a small pilot study, there are no formal stopping rules.  
8.6 
SAFETY OVERSIGHT 
The PIs will be monitoring the study continuously throughout the study.  
A monitoring check will be performed at 50% enrollment (35 patients) and the following will be reviewed:   
1. 
Mortality 
2. 
Re-hospitalizations 
3. 
ICU utilization 
4. 
NIV and intubation 
5. 
Kidney function closest to discharge 
 
9 
CLINICAL MONITORING 
Sites will be remotely monitored.  Should the need arise for further investigation, an independent monitor will be 
appointed to visit sites.  Each site has extensive clinical trial experience and the expectation for this need is low.  
Nevertheless, the PI will visit each site at least once per year for meeting with study staff and random surveillance. 
10 
STATISTICAL CONSIDERATIONS  
10.1 
STATISTICAL AND ANALYTICAL PLANS 
Previous work demonstrates the value of B-lines to improve both diagnosis and prognosis in AHF.   
10.2 
STATISTICAL HYPOTHESES 
• 
Hypothesis 1a: Nitrate intense treated patients will have less congestion, defined by LUS B-lines, than diuretic 
intense patients at 6 hours after start of treatment.   
• 
Hypothesis 1b: Nitrate intense treated patients will have greater dyspnea relief then diuretic intense patients at 6 
hours after start of treatment. 
• 
Hypothesis 2: Each site (n=3) will enroll ~2 patient per month for 12 months. 
10.3 
ANALYSIS DATASETS 
The Full Analysis Set (FAS) will include all randomized patients. In accordance with the intent-to-treat principle, patients 
will be analyzed by the group to which they were randomized. Misrandomized patients (patients randomized in error 


 
22 
 
who did not receive any study intervention) will be excluded. Analyses in the FAS will constitute the main efficacy results 
for the primary and secondary study efficacy endpoints. 
The Per Protocol Set (PPS) will be a subset of the FAS and will exclude patients with major protocol violations.   The 
major protocol violations that will result in exclusion from the PPS will be identified prior to unblinding the treatment 
assignments for final analysis. Patients will be analyzed in the treatment group to which they were randomized. Results 
of analyses in this analysis population will support the primary efficacy analyses in the FAS. 
10.4 
DESCRIPTION OF STATISTICAL METHODS 
10.4.1 GENERAL APPROACH 
As a small, exploratory, pilot study, we are uncertain the difference, if any, between the two arms in regards to B-lines 
after treatment. Unless stated otherwise, two-sided p values < 0.05 will be considered statistically significant, without 
regard to multiple comparisons. Statistical tables and listings and analyses will be produced using SAS release 9.1 or 
later (SAS Institute, Inc, Cary, NC, USA) or other validated statistical software. 
10.4.2  BASELINE DESCRIPTIVE STATISTICS 
We will tabulate baseline characteristics of the two trial arms for potential imbalance in variables. Continuous variables 
will be summarized by typical parameters such as mean, standard deviation and range and compared using two-sample 
T test (if the normality assumption holds) or Wilcoxon rank-sum test (if the normality assumption does not hold). 
Normality of distribution will be determined using the Kolmogorov-Smirnov goodness-of-fit test. Categorical data will be 
summarized by frequency and percentage and analyzed using the Chi-square or Fishers exact test, as appropriate. 
The use of prior and concomitant medications will be summarized.  The use and doses of IV and oral loop diuretics in 
furosemide equivalents will be summarized by treatment group.  Other concomitant medications will be coded using 
WHO Drug and summarized by treatment group according to Anatomic Therapeutic Classification and preferred term. 
 
10.4.3 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
The total number of B-lines at the conclusion of ED AHF management 
We will examine the distribution of B-lines measurements for the groups with and without events separately. Both 
absolute number and relative change will be evaluated.  Receiver Operating Characteristic (ROC) curves will be plotted 
together with area under the curve (AUC) calculated to understand the prediction performance of the B-line 
measurements. Sensitivity, specificity, positive and negative predictive values will be computed at a number of 
thresholds of B-line measurements to understand the trade-off between false positive and false negative. Confidence 
intervals of statistical measures will be constructed using the bootstrap method.91 Although 15 B-lines have been 
previously identified as a valid threshold, an alternative number may be more useful in the ED setting.   
Potential covariates will also be considered in a logistic regression setting to improve precision, which includes baseline 
co-morbidities, baseline medications (in particular guideline recommended therapies) in-hospital medications, baseline 
renal function, serum sodium, natriuretic peptide levels, troponin levels, renal function, baseline blood pressure, and 
discharge medications. Variables such as physical exam, other vital signs, and hemoconcentration may also be included. 
These covariates are known markers of risk and are standard of care assessments for the vast majority of AHF 
admissions. Covariates with univariately significant association with the outcome will be included together with the 
treatment indicator in a logistic regression model. Due to limited sample size, we will limit the number of covariates 
(including treatment indicator) such that there is 10 events per covariate.  
 


 
23 
 
ANALYSIS OF THE SECONDARY ENDPOINTS 
1. Dyspnea will also be assessed using a 5-point and 7-point Likert scale. 
 
Dyspnea will be assessed at the baseline and 6 hours later (or closest time point prior to ER discharge using two 
instruments. Dyspnea will also be assessed at any time between D2 and D/C. A 7-point Likert scale to determine change 
from baseline: 1) markedly worse, 2) moderately worse, 3) minimally worse, 4) no change, 5) minimally improved, 6) 
moderately improved, 7) markedly improved. However, patients may not recall accurately how they felt at baseline or 
be uncertain about when baseline was supposed to be. Also, patients with severe symptoms who don’t respond and 
patients whose symptoms were initially mild and have little room to improve may end up with similar change scores.  
Accordingly, symptoms were also assessed using an absolute scale. Change in dyspnoea can be calculated by subtracting 
scores. A 5-point Likert scale was used to document patients’ current status: 1) not short of breath at all, 2) mildly short 
of breath, 3) moderately short of breath, 4) severely short of breath, 5) very severely short of breath. 
Patients were placed at 45 degrees for all questioning. If patients were recently up and walking, at least 2 minutes of 
equilibration is required. 
Change scores between responses at baseline and 6 hours on the 5-point Likert scale items and the VAS were calculated 
by subtracting the baseline value from the 6-hour value.  These change scores were categorized as improvement, 
worsening and no change.  Fisher’s exact tests were used to compare the 3 groups by either definition on changes in the 
5-point Likert scale 
 
2. The comparison of binary endpoints (B-lines < 15) will be performed using Chi-square or Fishers exact test, as 
appropriate. 
As 15 B-lines have been previously shown to be associated with worse outcomes, a difference of 15 B lines will be 
considered significant for this study.   
 
10.4.4 ANALYSIS OF THE EXPLORATORY ENDPOINT(S) 
Exploratory Endpoints 
 
Total DAOOH through 30 days post-discharge 
Association of B-lines at discharge and 30 day outcomes 
Time to reach B-lines <15 
Association of baseline, discharge, and change of b-lines with 
30  day outcomes 
Change in physical exam findings  
All Cause readmissions, All cause ED re-visits 
 
DAOOH: Will be compared using T test or Wilcoxon rank-sum test, as appropriate. 
If the distribution of 30 day DAOOH is skewed, the T test may not perform satisfactorily. An alternative approach to 
evaluate the robustness of the analysis, is to treat DAOOH as an ordinal outcome and use the proportional odds (PO) 
regression model to compare the two arms. The PO model is a generalization of the Wilcoxon (Mann-Whitney) test to 
estimate the shift in the underlying distribution of DAOOH by the intervention. The PO regression allows for adjustment 
of baseline covariates to enhance power. 
For reproducibility analysis, generalized linear mixed-effects models will be fitted to estimate the inter- and intra-
observer variability, where both patients and observers are treated as random effects. 
10.4.5 SAFETY ANALYSES 


 
24 
 
Hypotensive events will be reported per treatment arm as well as other safety events ascertained during the study. 
Continuous variables will be summarized by typical parameters such as mean, standard deviation and range and 
compared using two-sample T test (if the normality assumption holds) or Wilcoxon rank-sum test (if the normality 
assumption does not hold). Normality of distribution will be determined using the Kolmogorov-Smirnov goodness-of-fit 
test. Categorical data will be summarized by frequency and percentage and analyzed using the Chi-square or Fishers 
exact test, as appropriate. 
As all cause mortality and re-hospitalizations will already be reported as part of the efficacy exploratory analyses, these 
will also be highlighted as safety analyses. 
10.4.6 ADHERENCE AND RETENTION ANALYSES 
Missing data: We will compare relevant patient characteristics between those who stay in the study and those who drop 
out to examine whether there are characteristics that discriminate between the two groups. It is possible that the 
dropout mechanism does not depend on unobserved outcomes (Missing At Random, or MAR),95 where no bias will be 
introduced by ignoring the missing-data mechanism. We can simply use all observed outcomes for the analysis. Under 
circumstances where power loss is of concern, we will use a multiple imputation96 procedure to make use of all relevant 
observed variables to enhance power. The SAS procedure MI and MIANALYZE will be used for implementation of this 
procedure. 
In case the dropouts are Missing Not At Random (MNAR), which means the likelihood of drop-out depends on an un-
observed outcome, potential bias can be introduced if the miss-data mechanism is ignored. We will make various 
assumptions regarding the missing-data process. With these assumptions, we will fit proper models, either in the form 
of selection model 97, pattern mixture model 95, or latent variable model 98 to account for the missing-data process. A 
sensitivity analysis will be conducted to compare the results based on different assumptions and models and assess the 
robustness of the inference. 
10.4.7 PLANNED INTERIM ANALYSES  
There is no planned formal interim analysis 
10.5 
SAMPLE SIZE OVERALL 
This pilot study is powered to show a difference of at least 7 B-lines between treatment arms. With a total of 70 subjects 
(i.e. 35 in each arm), we will have 82% power to detect an effect size of 0.7 on the number of B-lines, where the type I 
error rate is controlled at 0.05 (two sided).. 
Local Sample Size:  As a multicenter study, the expected enrollment at IU is half the patients or 35. However, up to 50 
patients may be enrolled depending on accrual rates at the other site. 
10.6 
MEASURES TO MINIMIZE BIAS 
10.6.1 ENROLLMENT/ RANDOMIZATION/ MASKING PROCEDURES 
Each site will be provided a block randomization table with variable block sizes of  2, 4, and 6. The data coordinating 
center will continuously monitor the recruitment until the targeted sample size is reached. We will utilize the REDCap 
Randomization module for web-based randomization. 
Due the nature of the intervention and the clinical setting, this is an unblinded trial. 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
If necessary and if appointed, the medical experts, study monitors, auditors, and health authority inspectors (or their 
agents) will be given direct access to source data and documentation (e.g., medical charts/records, laboratory test 


 
25 
 
results, printouts, videotapes) for source data verification, provided that patient confidentiality is maintained in 
accordance with local requirements. 
Each Investigator must maintain, at all times, the primary records (i.e., source documents) of each patient’s data.  
Examples of source documents are hospital records, office visit records; examining physician’s finding or notes, 
consultant’s written opinion or notes, laboratory reports, drug inventory, study drug label records, and CRFs that are 
used as the source. 
Each Investigator will maintain a confidential patient identification list that allows the unambiguous identification of 
each patient.  All study-related documents must be kept for a minimum of 5 years.  
12 
QUALITY ASSURANCE AND QUALITY CONTROL 
Protocol Amendments: No changes from the final approved (signed) protocol will be initiated without the prior written 
approval or favorable opinion of a written amendment by the IEC/IRB, except when necessary to eliminate immediate 
safety concerns to the patients or when the change involves only logistics or administration.  Each Investigator will sign 
the protocol amendment.  
The IRB/EC may provide expedited review and approval/favorable opinion for minor change(s) in ongoing studies.  
Protocol Deviations, Violations, and Exceptions:  A protocol deviation is non-adherence to protocol-specific study 
procedures or schedules that does not involve inclusion/exclusion criteria, primary objective variable criteria, and/or 
GCP guidelines.  Deviations are considered minor and do not impact the study. 
A protocol violation is any significant divergence from the protocol, i.e., non-adherence on the part of the patient, the 
Investigator, or the sponsor to protocol-specific inclusion/exclusion criteria, primary objective variable criteria, and/or 
GCP guidelines.  Protocol violations will be identified and recorded, by study center personnel. 
No exceptions to protocol-specific entry criteria will be granted to allow patients to enter a study.   
Information to Study Personnel: Each Investigator is responsible for giving information about the study to all staff 
members involved in the study or in any element of patient management, both before starting the practical 
performance of the study and during the course of the study (e.g., when new staff become involved).  Each Investigator 
must assure that all study staff members are qualified by education, experience, and training to perform their specific 
responsibilities.  These study staff members must be listed on the study center authorization form, (if required) which 
includes a clear description of each staff member’s responsibilities.  This list must be updated throughout the study, as 
necessary. 
The PI is responsible for explaining the protocol to all study staff, including each Investigator, and for ensuring their 
compliance with the protocol.  Additional information will be made available during the study when new staff become 
involved in the study and as otherwise agreed upon with either the Investigator or the study monitor. 
The handling of data, including data quality assurance, will comply with regulatory guidelines (e.g., ICH and GCP) and the 
sponsor’s or its designee’s SOPs and working instructions.  Data management and control processes specific to this study 
will be described in a data management plan.  When data management is outsourced, the contract organization will be 
responsible for the development and implementation of the data management plan.  
Data Quality Assurance: All data on the CRF will be entered into a validated database compliant with 21 CFR Part 11 
requirements.  In the case when data management is outsourced, the contract organization will be responsible for 
database quality assurance including, but not limited to, review of data entered into the CRFs by study center personnel 
for completeness and accuracy and instruction of the study personnel to make any required corrections. 
Data management at Indiana University will implement edit checks on the eCRF to enforce data integrity and 
compliance to the protocol and regulatory requirements.  Study center personnel will be responsible for entering study 
data on the eCRFs.  Data management will track eCRFs and review them for completeness, the presence of mandatory 


 
26 
 
values, consistency, and dated electronic signatures.  Queries identified during data discrepancy review will be sent to 
the study center personnel to be reviewed and resolved in a timely manner. 
Adverse Events will be coded using the MedDRA dictionary.  Concomitant medications will be coded using the WHO 
Drug dictionary.  Adverse Events and Concomitant Medications will be reviewed for coding consistency and 
completeness.  
At the end of the study, the database will be locked and the data will be released for reporting and statistical analysis. 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS  
13.1 
ETHICAL STANDARD  
The Investigator(s) will conduct the study in accordance with this protocol, the guiding principles of the Declaration of 
Helsinki, ICH GCP guidelines and applicable regulatory requirements.   
13.2 
INSTITUTIONAL REVIEW BOARD  
Before this study starts, the protocol will be submitted to each IEC/IRB for review.  As required, the study will not start at 
a given center before the IEC/IRB for the center provides written approval or a favorable opinion. The IRB will meet all 
FDA requirements governing IRBs (Code of Federal Regulations, Title 21, Part 56).  The IEC will meet local regulations. 
13.3 
INFORMED CONSENT PROCESS  
13.3.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO PARTICIPANTS 
Each patient must be provided with a statement that the investigation involves research and that the IRB/EC has 
approved solicitation of patients to participate; a fair explanation of the procedures to be followed and their purposes, 
including identification of any procedures which are experimental; a description in lay language of any possible side 
effects; a description of any attendant discomforts and risks reasonably to be expected; a description of any benefits 
reasonably to be expected; a disclosure of any appropriate alternative procedures that might be advantageous for the 
patient; an offer to answer any inquiries concerning the procedures, and instruction that the person is free to withdraw 
consent and discontinue participation in the project or activity at any time without prejudice to the patient.  The 
informed consent shall include a disclosure that the Investigator is being supported by the NIH to perform the stated 
research. 
13.3.2 CONSENT PROCEDURES AND DOCUMENTATION 
A properly executed, written consent in compliance with current U.S. federal code 21CFR part 50, or competent 
regulatory authority, shall be obtained from each patient prior to entering the study or prior to performing any unusual 
or non-routine procedure involving risk to the patient.   
A patient must give written consent to participate in the study.  This consent must be dated and retained by the 
Principal Investigator as part of the study records.  A copy shall be given to the patient.  The informed consent process 
must be documented in the patient’s source documents. 
Written and/or oral information about the study in a language understandable by the patient will be given to all 
patients. 
13.4 
PARTICIPANT AND DATA CONFIDENTIALITY  
Each Investigator must assure that the privacy and confidentiality of each study  patient’s personal identity and personal 
medical information is maintained at all times.  In order to maintain subject privacy and confidentiality, all CRFs, 
laboratory specimens, evaluation forms, reports, and other records, documents and image material that leave the site 


 
27 
 
will be identified only by an identification code.  This identification code shall on no occasion include study subject’s 
names, initials or date of birth.  
Personal medical information may release or review the personal health data of study patients shall take place solely 
within circumstance, and to third parties, specifically identified by the written informed consent document signed by the 
study patients, except as permitted by applicable laws and regulations for purposes of monitoring and data verification 
by the relevant regulatory authorities, the American Heart Association (AHA) and AHA’s properly authorized 
representatives, the quality assurance unit, or regulatory authorities.  Personal medical information will always be 
treated as confidential. 
14 
DATA HANDLING AND RECORD KEEPING  
14.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Each Investigator must keep a separate patient identification list showing code numbers, names, and dates of birth to 
allow unambiguous identification of each patient included in the study.  A note will be made in the medical records that 
the patient is participating in a clinical study. 
All required data will be recorded on the CRF by study center personnel according to the data entry guidelines provided 
by the PI or designee.  All CRFs must be kept in good order and updated so they always reflect the latest observations on 
the patients participating in the study. 
When paper CRFs are used, they will be completed legibly in black ink, with reasons given for missing data.  Any 
corrections to the data will be made in a manner that does not obscure the original entry and will be dated and initialed 
by the Investigator or assigned designee.  Each Investigator will sign the statement on the last page of the CRF. 
When eCRFs are used, electronic signatures of the Investigator (or designee) will be provided.   
Access to the eCRF for data entry and signature is controlled by user identification and password, which are provided by 
the PI or designee.  Study center personnel will be trained, by the PI or designee, in the use of eCRFs and application of 
electronic signatures before the start of the study. 
Because it is extremely important to have proper data collection in a timely manner, the Investigator shall complete the 
CRFs and on an ongoing basis.  If a study monitor is needed and study monitor requests additional data or clarification of 
data for the CRF, the request must be answered satisfactorily in a timely manner before the next monitoring visit. 
14.2 
STUDY RECORDS RETENTION  
All records related to the study (i.e., source data, source documents, CRFs, copies of protocols and protocol 
amendments, correspondence, patient identification lists, signed informed consent forms, and other essential 
documents) must be retained for a minimum of 5 years. 
Should an Investigator wish to assign the study records to another party or move them to another location, advance 
written notice will be given to the PI and AHA. 
14.3 
PROTOCOL DEVIATIONS  
A protocol deviation is non-adherence to protocol-specific study procedures or schedules that does not involve 
inclusion/exclusion criteria, primary objective variable criteria, and/or GCP guidelines.  Deviations are considered minor 
and do not impact the study. 
A protocol violation is any significant divergence from the protocol, i.e., non-adherence on the part of the patient, the 
Investigator, or the sponsor to protocol-specific inclusion/exclusion criteria, primary objective variable criteria, and/or 
GCP guidelines.  Protocol violations will be identified and recorded, by study center personnel. 


 
28 
 
No exceptions to protocol-specific entry criteria will be granted to allow patients to enter a study.   
CLINICAL TRIALS.GOV 
This study will be registered at the appropriate and required time by the PI, in conjunction with the DCC, to the 
government-operated clinical trial registry data bank, which contains registration, results, and other information about 
registered clinical trials at ClinicalTrials.gov. Federal law under FDAAA requires clinical trial information for certain 
clinical trials to be submitted to the data bank and this study will comply with all reporting requirements for clinical 
trials. 
 
15 
STUDY ADMINISTRATION 
15.1 
STUDY LEADERSHIP 
This study will be conducted at 2 sites in the United States, with 3 total hospitals.  Site 1) Indianapolis, IN at both the 
Eskenazi and Methodist hospitals (abbreviated as IU, Peter S. Pang, PI), Site 2) Nashville, TN at the University of 
Vanderbilt hospital (abbreviated as Vanderbilt, Sean P. Collins, PI). Each site PI will be a member of the steering 
committee.   
 
16 
CONFLICT OF INTEREST POLICY 
All investigators must adhere to national, regional, and local conflict of interest policies.  Prior to publication, all 
disclosures potentially relevant to this trial will be explicitly stated. 
 
17  
ADDITIONAL TRAINING MATERIALS  
17.1 
LUNG ULTRASOUND TRAINING OVERVIEW 
 
Lung Ultrasound Training Overview 
 
Each clinical site already has expertise in LUS (lung ultrasound).  However, to minimize variation, a standardized teaching 
format will be utilized, emphasizing the 8 zone scoring system.  Videos perform better to explain LUS and B-lines than a 
word document or PDF. Videos will be utilized for training purposes, however, a document representation is listed 
below. 
Why use lung ultrasound?  For all of the following reasons: 
a. It is fast 
b. No radiation 
c. Non invasive 
d. Repeatable 
 


 
29 
 
Ultrasound has been used at the bedside for years. Machines continue to get smaller and smaller and easier to move 
around. 
What is the difference between focused ultrasound and formal echocardiography or radiology studies?  Focused 
ultrasound does not replace formal echocardiography or formal radiology studies. It is meant to answer a binary clinical 
question.  For the purpose of our study, it is meant to guide AHF management.  [The figure below with red arrows shows 
examples of B-lines] 
 
 
 
Lung (or pulmonary ultrasound) is one of the easiest 
ultrasound assessments to learn and perform. Even in 
patients with a high BMI, the lung can be evaluated. 
Additionally, lung ultrasound has high inter-rater agreement. 
 
In this figure to the left, we are seeing B lines – vertical 
echogenic artifacts originating from the pleural line, 
extending to the bottom of the ultrasound screen and 
moving with lung sliding. In AHF patients, B-line assessment 
aids in diagnosis, prognosis and may guide acute 
management.  
 
 
 
Below is the curvilinear probe used for the images.  
 
 


 
30 
 
 
 
 
Below is a pictorial representation of the 8-zone scoring system. 
 
 
The eight zone protocol breaks each hemi-thorax into 4 zones, divided by the parasternal (PS) Line, Ant axillary line 
(AAL), posterior axillary line (PAL) and anatomic nipple line (ANL). In the clinical setting of suspected AHF, pulmonary 
edema is determined sonographically as greater than three B-lines in a rib space in at least two lung zones bilaterally.  


 
31 
 
For scoring purposes, a B line cut off of 10 has been described previously in the literature. This allows for a more precise 
quantification of pulmonary edema. B lines will be counted as the number seen per acoustic window.    
Machine settings 
• 
Enter patient data 
• 
Select curvilinear probe 
• 
Select thorax exam 
• 
Set depth to 18 cm 
• 
Set clip length to 6 seconds 
• 
Turn off tissue harmonics and multi-beam former 
• 
Adjust gain so that the rib shadow is black and pleural line is distinct 
 
 
Image acquisition 
• 
Patient supine 
• 
45 degrees of bed elevation (as possible, if not possible please note on CRF) 
 
 
 


 
32 
 
• 
Starting off on the Right in Zone 1: you want the indicator towards the patient’s head. Identify ribs by shadowing 
and identify a rib space (see image below) 
• 
Label R1 
• 
Then turn 90 degrees with indicator towards patient’s right so you are still in a rib space but the probe is 
HORIZONTAL 
• 
Scan within the zone until you see the area of most B lines 
• 
Record 6 second clip (this should include both inspiration and expiration) 
• 
Repeat the above for Right zones 2-4 and Left zones 1-4 
• 
Obtain VERTICAL R4 and L4 zones 
• 
10 TOTAL videos 
• 
After you leave the bedside, record the number of B lines on a standardized data collection form or in REDCap 
 
 
 
 
COUNTING B LINES 
 
 
 
• 
B lines are vertical echogenic artifacts that originate from the pleural line and extend to the bottom of the 
ultrasound screen 
• 
Below image is an example of how to count individual B lines 


 
33 
 
 
 
 
 
 
 
 
 
 
 
 
• 
In the situation where the whole footprint is ‘white out’ (see below image) count as 20 B lines 
• 
The maximum number of B lines per sector is 20 
• 
Count the maximum number of B lines you see 
• 
If half of the footprint is a ‘white out’ count as 10 B lines 
• 
Estimate percentage of white out 
• 
Count up and down from there 
 
 
 
 


 
34 
 
PLEURAL EFFUSION 
• 
Document pleural effusion as yes or no 
• 
Note the size (small, medium or large) 
• 
If pleural effusion and no lung is seen in the zone = 0 B lines 
• 
If pleural effusion and lung is seen = count number of B lines seen in lung 
 
 
 
For lung ultrasound we rely on the imaging of artifacts to interpret our scans.  The main artifact in the lung we see is 
called reverberation artifact.  The physics behind this artifact is briefly explained below.  
The ultrasound probe is constantly sending ultrasound waves towards whatever tissue is being imaged. When these 
sound waves get caught between 2 parallel surfaces that are highly reflective, they can bounce around between these 
highly reflective surfaces and take longer to return to the ultrasound machine.  
When this happens, you can have an echo that returns to the transducer after a single reflection and this echo will be 
displayed on the machine in the proper location. Sequential echoes may take longer to return to the transducer, and 
due to this increase in time the machine thinks that it is from a surface further away so it will appear deeper on the 
ultrasound image. So what you end up seeing are bright arcs that occur at equidistant intervals. 
Below are examples of normal lung, Bat sign, and A lines.   
Pleural line and recurrent A lines or reverberation artifact. We see this in normal lung and patients with COPD. 
 


 
35 
 
 


 
36 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
37 
 
 
The figure below shows B lines. These are vertical echogenic artifacts that originate from the pleural line, extend to the 
bottom of the ultrasound screen. 
Normal patients have < 3 B lines per rib space 
 
 
 
 
 


 
38 
 
 
 
B lines may be seen outside of AHF.  Clinical context is crucial!  The table below shows other reasons why B lines may be 
present. 
FOCAL 
DIFFUSE 
Infarct 
Pulmonary Edema 
Contusion 
ARDS 
Cancer 
Pulmonary Fibrosis 
Pneumonia/Pneumonitis 
 


 
39 
 
Beware if you do NOT see A lines!  Below are coalesced B lines.  So many B-lines blend together, it could look like normal 
lung but you note no A lines.  (This appears better in video).  This is, in fact, diffuse B lines.
 
 
17.2 
ULTRASOUND SECURE TRANSFER PROTOCOL 
Under the strict supervision of Indiana University data stewards, we will utilize IU BOX HEALTH, an online cloud storage 
and collaborative environment. IU BOX HEALTH accounts can only be set up via application to the IU data stewards for 
storage of critical health data.  Access to these secure storage sites are then shared with vetted users.  Two dedicated 
BOX HEALTH accounts will be set up for BLUSHED AHF. 
All sites currently use Q Path, a vendor based Ultrasound storage system. All sites plus the Core Lab use Q Path in their 
day to day storage and review of US images.  Images are securely transferred via wireless transmission from US 
machines to Q Path with PHI.   All images are stored securely under HIPAA grade security systems.  From Q Path, images 
are then exported to individual computers.  During this transfer, PHI is NOT transferred.   The only identifying cues left 
are date/time stamp, which may also be removed.  Additional, non-identifiable labels will be added for study purposes.  
These will then be uploaded into BOX HEALTH.   


 
40 
 
Two BOX HEALTH folders will be created, one for the investigators and the other for the Core Lab.  Prior to uploading to 
the Core Lab, the images will be de-identified to site by the database manager.  Furthermore, the images will be 
scrambled to avoid interpretation by acquisition order. This further minimizes bias by forbidding site knowledge and 
order of acquisition.  The de-identified images (both by site and PHI) will then be uploaded to the Core Lab BOX HEALTH 
storage folder for review by the Core Lab.     
All interpretations by the Core Lab will be entered into REDCap. 
 
17.3 
CORE LAB PROCEDURE AND LUNG ULTRASOUND PROTOCOL 
• 
An 8 zone LUS scan will be done at the following times: 
o T00:  initial LUS scan (in ED for screening and eligibility) 
o T02: 2-4 hours after initial treatment (in ED) (+/- 30 minutes) 
o T06: 2-4 hours after T02 or pre-ED discharge, whichever comes first (+/- 60 minutes) 
o T48: up to 48 hours after initial scan (Day 3) (+/- 12 hours) 
 
 
 
Data Collection Form 
• 
B lines 
Fi
2


 
41 
 
• 
Pleural effusion size and location 
• 
Who is performing the scan 
• 
Document time to perform scan 
o Begin with time stamp of first image and end with time stamp of last image +6s 
 
Training 
• 
Fill out pre-survey 
• 
Watch training video on LUS and scanning protocol (15-20 minutes) 
• 
Review 23 clips together with US director (20 minutes) 
• 
Hands-on scanning (30 minutes) 
• 
Perform 25 clips that have been reviewed by US director and signed off on prior to enrolling a patient (>75% of 
clips have B lines) 
• 
20% clips are reviewed by LUS Core Lab (Vicki) 
• 
Correlation coefficient 
 


 
42 
 


 
43 
 


 
 
 
 
18  
LITERATURE REFERENCES  
 
1. 
Alexander P, Alkhawam L, Curry J, et al. Lack of evidence for intravenous vasodilators in ED patients with acute heart failure: 
a systematic review. Am J Emerg Med. 2014. 
2. 
Collins SP, Levy PD, Lindsell CJ, et al. The rationale for an acute heart failure syndromes clinical trials network. J Card Fail. 
2009;15(6):467-474. 
3. 
Collins SP, Lindsell CJ, Pang PS, et al. Bayesian adaptive trial design in acute heart failure syndromes: Moving beyond the 
mega trial. Am Heart J. 2012;164(2):138-145. 
4. 
Collins SP, Lindsell CJ, Storrow AB, et al. Early changes in clinical characteristics after emergency department therapy for 
acute heart failure syndromes: identifying patients who do not respond to standard therapy. Heart Fail Rev. 
2012;17(3):387-394. 
5. 
Collins SP, Storrow AB, Levy PD, et al. Early management of patients with acute heart failure: state of the art and future 
directions--a consensus document from the SAEM/HFSA acute heart failure working group. Acad Emerg Med. 
2015;22(1):94-112. 
6. 
Felker GM, Butler J, Collins SP, et al. Heart Failure Therapeutics on the Basis of a Biased Ligand of the Angiotensin-2 Type 1 
Receptor: Rationale and Design of the BLAST-AHF Study (Biased Ligand of the Angiotensin Receptor Study in Acute Heart 
Failure). JACC Heart failure. 2015. 
7. 
Heart Failure Executive C, Peacock WF, Fonarow GC, et al. Society of Chest Pain Centers Recommendations for the 
evaluation and management of the observation stay acute heart failure patient: a report from the Society of Chest Pain 
Centers Acute Heart Failure Committee. Critical pathways in cardiology. 2008;7(2):83-86. 
8. 
Pang PS, Collins SP, Miro O, et al. The role of the emergency department in the management of acute heart failure: An 
international perspective on education and research. Eur Heart J Acute Cardiovasc Care. 2015. 
9. 
Peacock WF, Braunwald E, Abraham W, et al. National Heart, Lung, and Blood Institute working group on emergency 
department management of acute heart failure: research challenges and opportunities. J Am Coll Cardiol. 2010;56(5):343-
351. 
10. 
Peacock WF, Fonarow GC, Ander DS, et al. Society of Chest Pain Centers recommendations for the evaluation and 
management of the observation stay acute heart failure patient-parts 1-6. Acute cardiac care. 2009;11(1):3-42. 
11. 
Storrow AB, Lindsell CJ, Collins SP, et al. Standardized reporting criteria for studies evaluating suspected acute heart failure 
syndromes in the emergency department. Journal of the American College of Cardiology. 2012;60(9):822-832. 
12. 
Weintraub NL, Collins SP, Pang PS, et al. Acute heart failure syndromes: emergency department presentation, treatment, 
and disposition: current approaches and future aims: a scientific statement from the American Heart Association. 
Circulation. 2010;122(19):1975-1996. 
13. 
Collins SP, Pang PS, Butler J, Fonarow G, Metra M, Gheorghiade M. Revisiting cardiac injury during acute heart failure: 
further characterization and a possible target for therapy. Am J Cardiol. 2015;115(1):141-146. 
14. 
Pang PS, Collins SP, Sauser K, et al. Assessment of dyspnea early in acute heart failure: patient characteristics and response 
differences between likert and visual analog scales. Acad Emerg Med. 2014;21(6):659-666. 


 
 
 
 
15. 
Pang PS, Collins SP, Maisel A, Jesse R. Reply to: Decision algorithms are needed in acute heart failure in the emergency 
department. J Card Fail. 2013;19(2):147-148. 
16. 
Collins SP, Pang PS, Fonarow GC, Yancy CW, Bonow RO, Gheorghiade M. Is hospital admission for heart failure really 
necessary?: the role of the emergency department and observation unit in preventing hospitalization and rehospitalization. 
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