Critically Appraised Topic

Is high dose isosorbide dinitrate plus low dose furosemide more effective than the traditional use of high dose furosemide and low dose nitrates in the treatment of severe pulmonary edema?

Date: March 9, 1998

Appraised by: Deb Bynum, MD

Clinical Bottom Lines:

1) Patients treated with a standard low dose of furosemide (40mg) and high dose isosorbide dinitrate (3mg IV bolus every 5 minutes) required less mechanical ventilation and had a lower rate of myocardial infarctions than patients treated with low dose nitrates (starting dose of 1mg/hr of isosorbide dinitrate) and high dose furosemide (80 mg IV bolus furosemide every 15 minutes). There was a slightly, but not statistically significant, lower mortality rate in the group treated with high dose nitrates.

2): Patients treated with high dose nitrates also were noted to have improvements in secondary outcomes such as decreased respiratory rate, oxygen saturation, and pulse rate relative to the group treated with high dose furosemide and low dose nitrates.

3) There were no significant arrhythmias and few patients with excessive reductions in arterial blood pressure -- therefore both treatment regimens appeared to be safe and well tolerated.

The Evidence:

Randomised trial comparing high dose isosorbide plus low dose furosemide (group A) to high dose furosemide plus low dose nitrates (group B) in patients presenting to the ED with severe pulmonary edema confirmed on CXR and oxygen saturation levels of < 90%. All patients initially received 3 mg IV MSO4 and 40mg IV lasix prior to the randomised treatment protocol.

Comments:

1) Well done study with "hard" primary outcomes; analysis by intention to treat. However, the study was not blinded and the results may have been affected by bias ( for example, some patients in group A received more furosemide than the protocol outlined because of a perceived need for more diuresis).

2) The small difference in mortality was not statistically significant, but the power of the study was limited to find a difference in an outcome with a low incidence.

3) The decrease in need for mechanical ventilation in patients treated with high dose nitrate therapy compared to the more standard approach of high dose furosemide and low dose nitrates was significant with an ARR of 27% (NNT = 3.7); The ARR for MI in patients treated with high dose nitrates vs low dose nitrates plus high dose furosemide was 20% (NNT =5); The ARR for any primary event was 21% (therefore a NNT with high dose nitrates/low dose furosemide instead of high dose furosemide/low dose nitrates to prevent one bad event is 4.7).

4) Patients who required immediate intubation upon presentation to the ED or who had an oxygen saturation of greater than 90% were excluded. Also excluded were patients with a BP of less than 110/70 or who were on a significant amount of oral nitrates at home.

5) Overall, an interesting different approach to the management of severe pulmonary edema that warrants further investigation; It is speculated that at higher doses, nitrates reduce afterload with arteriodilatation in addition to their venodilating properties seen at lower doses.

Reference: Cotter, et al. Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemdie plus low-dose isosorbide dinitrate in severe pulmonary edema. The Lancet 1998: 351: 389-93.