Elsevier

The Lancet

Volume 351, Issue 9100, 7 February 1998, Pages 389-393
The Lancet

Articles
Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema

https://doi.org/10.1016/S0140-6736(97)08417-1Get rights and content

Summary

Background

Nitrates and furosemide, commonly administered in the treatment of pulmonary oedema, have not been compared in a prospective clinical trial. We compared the efficacy and safety of these drugs in a randomised trial of patients with severe pulmonary oedema and oxygen saturation below 90%.

Methods

Patients presenting to mobile emergency units with signs of congestive heart failure were treated with oxygen 10 L/min, intravenous furosemide 40 mg, and morphine 3 mg bolus. 110 patients were randomly assigned either to group A, who received isosorbide dinitrate (3 mg bolus administered intravenously every 5 min; n=56) or to group B, who received furosemide (80 mg bolus administered intravenously every 15 min, as well as isosorbide dinitrate 1 mg/h, increased every 10 min by 1 mg/h; n=54). Six patients were withdrawn on the basis of chest radiography results. Treatment was continued until oxygen saturation was above 96% or mean arterial blood pressure had decreased by 30% or to below 90 mm Hg. The main endpoints were death, need for mechanical ventilation, and myocardial infarction. The analyses were by intention to treat.

Findings

Mechanical ventilation was required in seven (13%) of 52 group-A patients and 21 (40%) of 52 group-B patients (p=0·0041). Myocardial infarction occurred in nine (17%) and 19 (37%) patients, respectively (p=0·047). One patient in group A and three in group B died (p=0·61). One or more of these endpoints occurred in 13 (25%) and 24 (46%) patients, respectively (p=0·041).

Interpretation

High-dose isosorbide dinitrate, given as repeated intravenous boluses after low-dose intravenous furosemide, is safe and effective in controlling severe pulmonary oedema. This treatment regimen is more effective than high-dose furosemide with low-dose isosorbide nitrate in terms of need for mechanical ventilation and frequency of myocardial infarction.

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.

Section snippets

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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