Study objectives: Bolus intravenous nitroglycerin is a potential innovation for the management of severe acute decompensated heart failure (ADHF) but has undergone limited clinical evaluation. Although previous studies have demonstrated improved outcomes, the effect of adding bolus intravenous nitroglycerin to standard American Heart Association (AHA) treatment of severe ADHF has not been defined. Our primary objective is to evaluate the feasibility of using this novel therapeutic approach in the management of severe ADHF. Secondary objectives include an assessment of the safety and efficacy of bolus intravenous nitroglycerin. Methods: This study was designed as an unblinded pilot intervention trial of the addition of bolus intravenous nitroglycerin to standard AHA treatment for ADHF. The eligible study population included all adult patients (age ≥18 years) presenting to the emergency department of Detroit Receiving Hospital (Detroit, MI: annual census ∼85,000) or Sinai-Grace Hospital (Detroit, MI: annual census ∼62,000) with a clinical diagnosis of ACPE. The prespecified goal was to enroll 30 patients. The main inclusion criterion was a systolic blood pressure of 160 mm Hg or greater or a mean arterial pressure of 120 mm Hg or greater. Patients with a suspected or proven right ventricular infarction, known or suspected pregnancy, or a history of intolerance to nitroglycerin and those requiring immediate intubation or cardiopulmonary resuscitation were excluded. The study was approved by the institutional review board of Wayne State University, and written informed consent was obtained from all patients (or proxy) before initiation of the protocol. On enrollment, baseline hemodynamic values and a serum brain natriuretic peptide level were obtained. Initial treatment of all patients consisted of 100% oxygen (by NRB), 3 doses of sublingual nitroglycerin (0.4 mg), and intravenous furosemide (60 to 100 mg). Administration of morphine sulfate (3 to 5 mg) was permitted but not encouraged. Patients without improvement were then started on the intervention protocol, which included initiation of a nitroglycerin infusion (0.3 to 0.5 μg/kg per minute) with concurrent administration of a dose of bolus intravenous nitroglycerin (2 mg). Titration of the infusion (≤400 μg/min) and repeated dosing of bolus intravenous nitroglycerin (2 mg) was allowed every 3 to 5 minutes, up to a total of 10 doses, at the discretion of the treating physician. Ventilatory assistance with endotracheal intubation or biphasic positive airway pressure and administration of additional pharmacologic therapy was permitted at any point at the discretion of the treating physician. The primary efficacy endpoint was rate of endotracheal intubation. Secondary efficacy endpoints included the need for ICU admission and total hospital length of stay. Primary safety endpoints included the incidence of cardiac or neurovascular complications and symptomatic hypotension. Descriptive statistics are provided. Results: Twenty-eight patients were enrolled. Mean age was 61.57 years (±15.01 years); 89.3% were black and 64.3% were men; 89.3% had a history of heart failure, 92.9% had hypertension, and 35.7% had coronary artery disease; 76.5% were noted with New York Heart Association heart failure classification III or IV, and the median brain natriuretic peptide level was 1,849 pg/mL. Baseline vital signs (mean±SD) were as follows: mean arterial pressure 155.11 mm Hg (±23.49 mm Hg); pulse rate 114.93 beats/min (±24.85 beats/min), and respiratory rate 31.07 breaths/min (±6.77 breaths/min). Mean protocol intervention time was 18.21 minutes (±14.97 minutes). Symptom improvement was reported in 24 patients (85.7%). Mean dosing of bolus intravenous nitroglycerin was 6.50 mg (±3.47 mg). Mean nitroglycerin infusion rate was 38.82 μg/min (±28.04 μg/min), and mean intravenous furosemide was 85.00 mg (±24.11 mg). Other administered medications included morphine (11 patients), angiotensin-converting enzyme inhibitors (10 patients), and β-blockers (3 patients). Patients were monitored for a mean period of 75.46 minutes (±69.84). During this time, significant reductions from baseline vital signs were noted (mean Δ [95% confidence interval (CI)]: pulse rate 20.96 beats/min [95% CI 14.49 to 27.44], and respiratory rate 8.59 breaths/min [95% CI 5.49 to 11.69]). Four patients (14.3%) required endotracheal intubation, and 2 (7.1%) needed biphasic positive airway pressure. Four patients (14.3%) had acute myocardial infarction. There were no neurovascular complications. One patient (3.6%) developed symptomatic hypotension. Ten patients (35.7%) were admitted to the ICU. The median length of stay was 4.06 days (range 14.31). Conclusion: Treatment of ADHF with bolus intravenous nitroglycerin is feasible. Addition of bolus intravenous nitroglycerin to standard AHA therapy results in dramatic hemodynamic and respiratory improvement without the development of excess adverse events. A decrease in the need for endotracheal intubation and ICU admission, as well as hospital length of stay, may also be associated, but comparison trials are needed.