Nitroglycerin vs. Furosemide Using Lung Ultrasound Pilot Trial (N-FURIOUS)

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.

Heart Failure, Acute Heart Failure, Pulmonary Edema, Lung Ultrasound, Extra vascular lung water, B-lines, Diuretics, Nitrates

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.

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.

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: IV furosemide (unless already given) (All patients receive at minimum 20 mg IV furosemide or equivalent) 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) Reassessment every 2 hours. If LUS B-lines >15, repeat step 2. If < 15, stop algorithm.

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

The total number of B-lines at the conclusion of ED AHF management or maximum of 6 hours after enrollment, whichever comes first.

A patient reported measurement of dyspnea using both 5 and 7-point Likert scales in a standardized position

B-lines <= 15 at the conclusion of ED AHF management or maximum of 6 hours after enrollment, whichever comes first

Physical exam includes peripheral edema, jugular venous distention, pulmonary and cardiac auscultation

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