ArticlesRandomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema
Introduction
Pulmonary oedema is a consequence of acute heart failure. This type of heart failure results from a sudden decrease in stroke volume, causing an increase in systemic vascular resistance, which in turn further reduces stroke volume, finally leading to pulmonary oedema.1 A combination of furosemide and nitrates is the standard treatment for pulmonary congestion. However, the effects of these two drugs have not been compared in a controlled clinical trial.2
Furosemide, when administered intravenously, causes venodilatation after 15 min, thus decreasing the preload of both right and left ventricles.3 Furosemide also induces diuresis, which starts 30 min after administration and peaks at 1–2 h.3, 4, 5, 6 However, furosemide also activates both the sympathetic and the renin angiotensin systems,7 increasing peripheral resistance. This effect might increase afterload and have a negative effect on cardiac output6 and stroke volume.
Nitrates are vasodilators. At low doses they induce only venodilatation, but as the dose is gradually increased they cause the arteries, including the coronary arteries, to dilate,8 thereby decreasing both preload and afterload.
In theory, patients with pulmonary oedema may benefit from higher doses of nitrates. Patients with heart failure have nitrate resistance, and many require high doses of nitrates for everyday treatment.9 Furthermore, since at high doses nitrates induce both general and coronary arteriodilatation, they reduce both preload and afterload and potentially increase cardiac output.6 In our study of the effects of high-dose nitrates administered as repeated intravenous boluses in the treatment of unstable angina, 33% of patients had significant pulmonary congestion that rapidly resolved on treatment with high-dose nitrates.10, 11 In a preliminary study, Bosc and colleagues12 administered isosorbide dinitrate as an intravenous 3 mg bolus to patients with cardiogenic pulmonary oedema, with good clinical response. We therefore used this regimen in our study.
The effect of intravenous isosorbide dinitrate peaks 5 min after administration.13 Administration of intravenous furosemide causes dilatation after 15 min and diuresis that starts within 30 min and peaks at 1–2 h.3 We therefore compared the effect of isosorbide dinitrate administered intravenously as a 3 mg bolus every 5 min (combined with low-dose furosemide) with that of furosemide, administered intravenously as an 80 mg bolus every 15 min (combined with low-dose nitrates), in the treatment of severe pulmonary oedema. The use of both drugs in both treatment groups, albeit in different ratios, was dictated by restrictions imposed by the hospital and national ethics committees who approved the study design.
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Patients
Patients were recruited from the Emergency Medical Services of the cities of Rishon-le-Tzion, Ramla, and Lod (total population about 250 000). All were screened by a physician and a paramedic for signs and symptoms of congestive heart failure, and all underwent electrocardiography (ECG) and chest radiography. Inclusion criteria were the presence of clinical pulmonary oedema that was confirmed by chest radiographic findings in the emergency room, and oxygen saturation of less than 90%, measured
Results
Between July 1, 1996, and June 30, 1997, 446 patients with symptoms and signs that suggested acute heart failure were screened by the Emergency Medical Services team (figure 1). We excluded 64 who had severe pulmonary oedema with respiratory failure that required immediate tracheal intubation and mechanical ventilation; 153 who had mild pulmonary congestion with oxygen saturation above 90% on admission; and 119 who met one or more of the exclusion criteria. Of the 110 patients who were randomly
Discussion
We undertook this study of patients who, before hospital admission, were treated in a mobile intensive-care unit for pulmonary oedema, to compare the safety and clinical efficacy of nitates and furosemide in the treatment of severe pulmonary oedema in a prospective randomised investigation.
The treatment protocol was designed not only to achieve rapid resolution of pulmonary oedema, but also to avoid significant hypotension. Treatment was administered in a stepwise way under stringent
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