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

Comment

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 

References

Reader Comments

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.
Associate Professor
Department of Family and Preventive Medicine
Program Director
OU/Enid Family Medicine
Enid, Oklahoma
http://www.fammed.ouhsc.edu/enid/enid.htm
 
 

The exclusion of patients who were considered to require urgent intubation certainly is a subjective one. However, since these patients were excluded before randomization, it should not have introduced bias in one direction or another. 

The problem of transferring the results to any other form of nitroglycerin is a major one, which greatly limits the applicability of this study.

The mean furosemide dose administered in the low dose group was 56 mg, in the high dose group it was 200 mg.  -- mj

Sir,

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.

Dr.D.Prabhakar
Cardiologist
Coronary Care Unit
ChennaiMedical College
Chennai - INDIA - 600 003
 

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
From: R.Kumm [r.kumm@ukf.net]

Great !

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.

Kind regards

R.Kumm

Date: November 11, 1999
From: Dr. Bernard Silke [b.silke@qub.ac.uk]

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!

----------------------
Dr. Bernard Silke, M.D., D.Sc., F.R.C.P.,
F.R.C.P.(I), F.R.C.P.(Edin), F.E.S.C.,
Reader in Pharmacology & Therapeutics,
The Queen's University of Belfast.
Consultant Physician, Belfast City Hospital.

Avoiding excessive preload reduction is definitely important.  In the absence of a Swan-Ganz catheter, closely monitoring BP is necessary.  Also, it should be noted that this was a trial of furosemide and nitrates in pulmonary edema, not in acute MI (although about a third of the patients in this trial did have an infarct).  Patients with acute ischemic syndromes may have stiffer ventricles and may be particularly sensitive to preload.  -- mj

 

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