Intravenous Nitrates or Furosemide for Pulmonary Edema?

Source: Cotter G, et al. Lancet 1998;351:389-393.

Traditional treatment of acute congestive heart failure and pulmonary edema consists of a multi-pronged attack, including intravenous furosemide, morphine, oxygen, and often, nitrates. Cotter and colleagues asked whether high-dose nitrate therapy in the form of bolus isosorbide dinitrate (ISDN) administration would be more effective than continuous high-dose furosemide for treatment of pulmonary edema. The time course and hemodynamic actions of both agents are well known. While both are vasodilators, nitrates have greater venodilator action and considerable arterial and arteriolar effects at high doses, which reduce left ventricular afterload, and should improve stroke volume and ejection fraction.

The study was performed on patients in the emergency room who had classic signs and symptoms of acute congestive heart failure with confirmed pulmonary edema on chest x-ray and an oxygen saturation of more than 90%. All patients were treated with oxygen in the upright position and were given a single dose of morphine and 40 mg of furosemide. The study comprised two groups; one receiving a 3 mg bolus of ISDN every five minutes and the other receiving an 80 mg bolus of furosemide every 15 minutes as well as intravenous ISDN 1 mg/h, increasing by 1 mg/h every 10 minutes. The ISDN group received no further furosemide after the initial dose. A variety of parameters were measured, and treatment was continued in both groups until oxygen saturation increased to 96% or greater, or systolic blood pressure fell by 30% or to less than 90 mmHg. Patients were intubated as needed. Primary outcome was a combination end point of death, need for mechanical ventilation within 12 hours of admission, or the development of Q-wave myocardial infarction.

One hundred four patients were randomly assigned to either of the two groups. Group A, the high-dose nitrate cohort, received a mean dose of ISDN of 11.4 mgs; Group B received a mean ISDN dose of 1.4 mg. For both groups, the furosemide doses averaged 56 mg and 200 mg, respectively. Arterial pressure fell in both groups (19% in the nitrate arm and 15% in the furosemide arm; P = ns), and excessive pressure drop (> 30%) occurred in equal numbers in both groups (10-13%). Intubation and mechanical ventilation was less in the ISDN group (P = 0.004), as was myocardial infarction (P = 0.005). The composite end point was substantially reduced in the ISDN group: 13 of 52 patients (25%) vs. 24 of 52 patients (46%) (P = 0.04). Secondary outcomes, including heart and respiratory rate and oxygen saturation were better in the ISDN group. Cotter et al conclude that high-dose, intravenous ISDN by repeat bolus injection was more effective than furosemide in controlling pulmonary edema and the need for ventilation and may be more effective in reducing the incidence of myocardial infarction. They stress that the nitrate induced significant reductions in both preload and afterload that should result in increased cardiac performance, whereas furosemide, while effective, presumably decreased preload but not afterload. The average dose in the diuretic cohort was 200 mg of furosemide, which implies that higher doses are not beneficial in the treatment of severe pulmonary edema. They suggest that high-dose nitrates decreased ischemia more rapidly and to a greater degree, which may have contributed to the reduced incidence of myocardial infarction.

An accompanying editorial takes a positive stand for nitrate treatment but points out some of the study limitations, such as many patients with pulmonary edema are not fluid overloaded, so redistribution rather than reduction of circulating volume may be a more appropriate approach. It suggests that a single bolus injection of nitrate would be preferable to repeated ISDN injections, and that a large, randomized trial is required to demonstrate that such an approach is effective in patients who are already on chronic, long-acting nitrate or diuretic therapy.

Comment by Jonathan Abrams, MD

The results of this study should be of no surprise to most American physicians, who are accustomed to using intravenous nitroglycerin (NTG) for the treatment of acute congestive heart failure. While not used in this Israeli study or commented upon in the editorial, easy availability of intravenous NTG in emergency rooms and intensive care units in the United States represent ready access to effective treatment of pulmonary edema. Intravenous ISDN has been used in Europe and Scandinavia for many years but is not available in the United States. There are no obvious reasons why either ISDN or NTG should be more effective, so long as reasonable doses are administered in a controlled and careful fashion (i.e., stopping the infusion at the appearance of hypoperfusion or significant decreases in blood pressure). Nitrates are extremely potent venodilators at low dose, and, at higher concentrations, afterload reduction and resistance vessel dilatation ensues, typically with a rise in stroke volume in patients with depressed left ventricular function. In this report, almost 50% of patients had hypertension, 40% had diabetes, and 60-70% had known ischemic heart disease. Echocardiography revealed significant valvular disease that might have been responsible for pulmonary edema in approximately 15%, with 17-27% having some degree of mitral regurgitation. The mean ejection fraction in both groups was 42%, indicating that many of these patients had substantial left ventricular systolic dysfunction.

There have been a variety of previous reports indicating that intravenous NTG induces substantial clinical benefits in the setting of acute myocardial ischemia, including myocardial infarction or unstable angina. This study confirms these observations. It would appear that flogging patients with continued high-dose diuretic, particularly in the absence of significant fluid overload, is not as effective as reducing afterload and preload, and possibly increasing nutrient coronary blood supply with nitrate therapy. One could presumably achieve similar results with repetitive doses of sublingual or oral spray NTG. Intravenous NTG has the distinct advantage of being readily up or down titrated, as necessary, when significant hypotension or reflex tachycardia develops. In summary, this study appears to confirm the use of organic nitrate therapy for severe, acute congestive heart failure. The optimal agent for such individuals is not clear, but sodium nitroprusside is an attractive option. There are old data suggesting that nitroprusside might be deleterious in the presence of acute myocardial ischemia, but these observations have generally been in the absence of acute congestive heart failure. It is likely that nitroprusside, intravenous NTG, or ISDN have equivalent effectiveness. These agents should be used early and vigorously in acute pulmonary edema-but with great care, as a fall in central aortic pressure clearly is a potential adverse outcome.

Dr. Abrams is Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque.