Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema
CommentThis study compared high dose isosorbide dinitrate, given as 3 mg boluses every 5 minutes plus standard dose furosemide, to high dose furosemide plus a low dose infusion of isosorbide, for the treatment of acute pulmonary edema. The authors found a significant reduction in the need for intubation and in the rate of myocardial infarction in the high dose nitrates group.
From a methodological standpoint, the study appears to have been unblinded (or at most single-blinded). This important point is not stated explicitly anywhere in the article but can be inferred from the protocol and should have been addressed in the discussion. Significant bias can be introduced by lack of blinding. For example the decision to intubate a patient could easily be influenced by knowledge of treatment assignment.
This problem aside, studies that look at different combinations of accepted therapies are often harder to find funding for than those looking at new and often expensive treatments. Comparative studies of conventional approaches are much needed, however, and have the potential to produce significant clinical benefit at comparatively low cost. From this standpoint, I believe this is a valuable trial.
The direct applicability of this trial to clinical practice in the United States is limited, since bolus administration of intravenous isosorbide dinitrate is not used here. Further studies looking at other modalities of nitrate delivery and at varying doses will be needed and hopefully will be undertaken.
April 8, 1998
ReferencesReferences related to this article from the NLM's PubMed database.
Reader CommentsDate: Mon, 25 May 1998
From: "J.M. Pontious MD" <firstname.lastname@example.org>
With this review, I sense that there are significant selection biases up front in determining which patients to include in the study. Anytime that I hear selection criteria such as "considered to have CHF that was too severe and would probably require intubation"...gives me some anxiety from the onset.
The other issue (in addition to the fact that I can't give my patient bolus intravenous isosorbide dinitrate) is how do I make the "leap of faith" in treating my patients? I note that the PubMed references discuss Sublingual NTG, is it equivalent? IV NTG only, or would acute use of NTG paste work as well?
What dose of furosamide are they looking at for the low and high dose wings of the studies?
J.Michael Pontious M.D.
The problem of transferring the results to any other form of nitroglycerin is a major one, which greatly limits the applicability of this study.
Date: Wed, 23 Dec 1998
From: "Dr.D.Prabhakar" <email@example.com>
I have noticed that the use of nitroglycerin at the maximum tolerated dose titrated to clinical endpoints along with a maximal dose of furosemide is the best combination. I do not find any harm in giving both in large doses. What about the role of morphine ? My experience is it produces dramatic results.
I would agree that most of us who treat acute pulmonary edema tend to use high doses of nitrates, furosemide and often morphine, with acceptable results. For a condition that is so common, however, there is little data on the relative merits of these various therapies, which is what makes this study interesting. -- mj
Date: September 8, 1999
Especially in situations with high blood pressure and beginning pulmonary oedema / asthma cardiaque I have always been using GTN first line; in a wet lung simultaneously GTN plus Furosemide 60mg i.v. bolus.
As GTN should work faster, this has priority with me. I have both in my home visiting bag.
Date: November 11, 1999
There is a large haemodynamic data base on the effects of nitrates in acute myocardial infarction. As the authors state, the low-dose therapy acts mainly as a venodilator, but in the clinical dose-range, there are usually systemic arteriolar actions. Frusemide also acts as a venodilator to reduce cardiac pre-load. The benefits on cardiac pumping function depend on the degree of initial cardiac stretch and PCW. Lowering the 'wedge' into the physiological range (say 15 - 20 mmHg) from higher levels (20 - 30 mmHg) will usually increase cardiac output, whereas excessive pre-load reduction may, because of the Starling mechanism, lead to a further fall in the cardiac output. Without titration (based on Swan - Ganz measurements), the degree of preload reduction achieved is unpredictable. The hazard in using both loop diuretics and nitrates together are excessive pre-load falls with a lower cardiac output than would be achieved from each therapy used in isolation. In an ideal world, with a knowledge of the PCW, one could dose-titrate : clearly this is unrealistic in the real world of clinical medicine.
There are studies on the GTN patch in AMI, and on most types of nitrates. All types can be shown to be haemodymically effective. The optimal combination to use is a matter of empiricism and clinical experience; however in principle large doses of nitrates and loop diuretics used together may not always be a good plan!