High-Dose Isosorbide Dinitrate Plus Low-Dose Furosemide Versus High-Dose Furosemide Plus Low-Dose Isosorbide Dinitrate in Severe Pulmonary Edema - Isosorbide Dinitrate Plus Low-Dose Furosemide Versus High-Dose Furosemide Plus Low-Dose Isosorbide Dinitrate in Severe Pulmonary Edema


The goal of this randomized trial was to compare high-dose furosemide to high-dose isosorbide among patients with severe pulmonary edema.


Patients with severe pulmonary edema may require less ventilatory support with the use of high-dose nitrates in addition to furosemide.

Study Design

Study Design:

Patients Screened: 446
Patients Enrolled: 110
Mean Follow Up: 24 hours
Mean Patient Age: Mean age 74 years
Female: 48
Mean Ejection Fraction: 42.3 ± 11.0% in Group A, and 42.7 ± 13.0% in Group B

Patient Populations:

  • Presence of pulmonary edema (confirmed on chest X-ray)
  • Oxygen saturation <90% prior to supplemental oxygen administration


  • Prior treatment with greater than 40 mg of oral nitrate daily
  • Isosorbide mononitrate use more than twice daily
  • Isosorbide trinitrate use more than three times per day
  • Use of greater than 80 mg of furosemide per day
  • Blood pressure less than 110/70 mm Hg
  • History of allergic reaction to study drugs

Primary Endpoints:

  • In-hospital death
  • Need for mechanical ventilation within 12 hours (determined by oxygen saturation <80% for more than 20 minutes; progressive deterioration of oxygen saturation to below 80%; progressive dyspnea, apnea, or severe arrhythmias)
  • Myocardial infarction within 24 hours (determined by Q waves on ECG, increase in creatine phosphokinase above upper limit of normal, or MB fraction >6%)
  • Severe bradyarrhythmias or tachyarrhythmias
  • Excessive reduction in mean blood pressure (30% below baseline or below 90 mm Hg)

Secondary Endpoints:

Changes in heart rate, respiratory rate, and oxygen saturation within one hour of treatment

Drug/Procedures Used:

  • Group A: 3 mg bolus of isosorbide dinitrate every five minutes
  • Group B: 80 mg bolus of furosemide every 15 minutes and isosorbide dinitrate 1 mg/h (increased by 1 mg/h every 10 minutes)
Treatment was continued until oxygenation was ≥96% or mean arterial blood pressure was <90 mm Hg or decreased by 30%. All medications were given intravenously.

Concomitant Medications:

Both groups received oxygen at 10 l/min, 40 mg furosemide, and 3 mg morphine at presentation.

Principal Findings:

  • The criteria for mechanical ventilation were less often met in patients randomized to Group A (13% vs. 40%, p=0.004).
  • Myocardial infarction occurred less often in Group A (17% vs. 37%, p=0.047).
  • There was no significant difference in the mortality between the two groups (p=0.61).


Among patients with severe pulmonary edema with blood pressure ≥110/70, treatment with sequential boluses of isosorbide dinitrate was less often associated with myocardial infarction and less often met criteria for mechanical ventilation compared to sequential boluses of furosemide.


Cotter G, Metzkor E, Kaluski E, et al. Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema. Lancet 1998;351:389-93.

Clinical Topics: Heart Failure and Cardiomyopathies, Statins, Acute Heart Failure

Keywords: Isosorbide Dinitrate, Pulmonary Edema, Myocardial Infarction, X-Rays, Arterial Pressure, Nitrates, Respiration, Artificial, Diuretics, Heart Failure, Oxygen, Furosemide, Vasodilator Agents

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