Nitroglycerin vs. Furosemide Using Lung Ultrasound Pilot Trial
Nitroglycerin vs. Furosemide Using Lung Ultrasound Pilot Trial
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.
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.
Inclusion Criteria:

 -  Age ≥ 21 years

 -  Presents with shortness of breath at rest or with minimal exertion

 -  Clinical diagnosis of AHF and presence of > 15 total bilateral B-lines distributed in
 at least 4 zones on initial LUS

 -  Hx of chronic HF and ANY ONE OF THE FOLLOWING:

 -  [Chest radiograph consistent with AHF

 -  Jugular venous distension

 -  Pulmonary rales on auscultation

 -  Lower extremity edema

 -  BNP > 500pg/mL]

 Exclusion Criteria:

 -  Chronic renal dysfunction, including ESRD or eGFR < 20 ml//min/1.73m2.

 -  Shock of any kind. Any requirement for vasopressors or inotropes.

 -  SBP < 120

 -  Need for immediate intubation

 -  Acute Coronary Syndrome OR new ST-segment elevation/depression on EKG. (troponin
 release outside of ACS is allowed)

 -  Fever >101.5ºF

 -  End stage HF: transplant list, ventricular assist device

 -  Anemia requiring transfusion

 -  Known interstitial lung disease

 -  Suspected acute lung injury or acute respiratory distress syndrome (ARDS)

 -  Pregnant or recently pregnant within the last 6 months

 -  Severe valvular disease

 -  Anuria

 -  Allergy or hypersensitivity to nitroglycerin, furosemide or sulfa

 -  Concern for cardiac tamponade or restrictive cardiomyopathy

 -  Elevated intracranial pressure

 -  Recent use of PDE5 inhibitors