The ESC guideline on AHF…discussing nitrates!

7 Jan

Welcome back on the EMDutch website….the website talking about emergency medicine below sealevel. And because we, the people living below sealevel (It sound more scary than it is), use nitroglycerin (NTG) for acute decompensated heart failure, that is what we will be mainly talking about. I know there are other vasodilators out there, like nitroprusside and nesiritide, but for us NTG is the vasodilator/nitrate of choice!

Nitroglycerin is a nitrate that causes venodilation at low doses and arterial dilation at higher doses. (1) There is little doubt about its effectiveness in AHF and it lacks significant side effects (2), but its use is limited by marked underdosing in clinical practice. (3) And this is so true in my own hospital! Nurses and fellow doctors are used to giving 150ug/h in stable chest pain patients, which they can titrate up to 500 ug/h. In acute heart failure (with a normal-high blood pressure) this is just not enough.

You have to be aggressive, don’t be scared and treat your patient! They want to be treated…fast! An infusion rate I found in the literature (4) is: start at 10-20 ug/min and titrate upward in stepwise fashion using 10-60 ug/min, looking at improvement of symptoms, development of side effects, change of blood pressure, or a maximum dose of 200-500ug/min!!! Elkayam, et al (5) found…and I quote: “The potential benefit of nitroglycerin seems to be limited by a decreased vasodilatory response in patients with heart failure, which requires an active titration of the drug and the use of high doses (>120 ug/min). In addition, the initial beneficial hemodynamic effect achieved with the appropriate dose of nitroglycerin is associated with neurohumoral activation and limited by an early development of nitrate tolerance that leads to a marked attenuation of the initial effect.”

As been said above, there is little doubt about its effectiveness in AHF. Why is that? Most studies of the role of NTG in AHF are limited to small-cohort hemodynamic evaluations without cardiovascular outcome data. (1) These studies showed benefit from nitrate therapy in terms of decreased pulmonary capillary wedge pressure, increased cardiac output and increased cardiac index. (6) But is this where I am really interested in? No! I am interested in 2 things, does it cause symptom relieve and does it decrease mortality/morbidity?

First the symptom relieve:
Cottor, et al (7) found and improvement in pulse rate, respiratory rate and O2-saturation in the high dose nitrate + low dose furosemide group, when compared to the high-dose furosemide + low dose nitrate group, indicating that these patients (probably) feel better and less dyspnoeic. On the other hand, the VMAC trial of nesiritide (8), which used relative low doses of NTG!! (mean 41 +/- 61 ug/min) resulted in a decrease of 3.8 mmHg of PCWP, but no significant improvement of dyspnea was found when compared with placebo.

On mortality and morbidity a good powered study is still lacking. The study by Cottor did show a lower rate in death (and mechanical ventilation and MI) in the high-dose nitrates + lowe-dose furosemide group.

So where do we stand on NTG (nitrates) in AHF?A lot of its use has been based on small-cohort hemodynamic evaluations and the ESC guideline states that only 2 (I could only find the article by Cottor, et al, but, as you can see in the comments Iwan found the other one. In this article: different treatment protocols were studies for pre-hopsital pulmonary oedema. It showed no evident synergistic effect of any of the drugs NTG, morpine & furosemide. The was some indication that furosemide might have caused clinically important problems with fluid and electrolyte management in some of the patients and morphine didn’t show any improvement and did show adverse effents in the 1st hours. It suggests that nitroglycerin is beneficial in the management of presumed pre-hospital pulmonary edema, while morphine and furosemide may not add anything to its efficacy, and may be potentially deleterious in some of these patients.) randomized trials have established the efficacy of i.v. nitrates in combination with furosemide and have demonstrated that dose titration to the highest haemodynamically tolerable dose of nitrates is superior to furosemide alone. There are no outcome trials with NTG vs placebo, and given the low cost and availability of NTG, it is unlikely that a study like this will be preformed.

In conclusion, I couldn’t find the evidence I was hoping for. In my mind NTG is a incredibly good medication for AHF without hypotension. Like all you folks out there I have seen it work and would expect to find tons of evidence supporting it. I did find the article by Cottor, indicating that high-dose nitrates with low-dose furosemide is better than the other way around and this what I was expecting to find!
In my mind, based on 5 years of clinical practice (yes, yes, only 5 years, I am still pretty young) and what I have read about it, NTG (along with NIV) is the cornerstone of treatment and maybe, just maybe, furosemide shouldn’t even be in there, but that will be discussed next time!

So remember, in normo-/hypertensive patients with AHF, be aggressive with the NTG and titrate upward fast!

Until next time and let me know if you have any comments!

Egon Zwets

List of references


6 Responses to “The ESC guideline on AHF…discussing nitrates!”

  1. Iwan Dierckx January 8, 2013 at 00:18 #

    I think this is the other study you’re looking for:

    Great blog as always. Looking forward to the next one

  2. Egon Zwets January 8, 2013 at 22:08 #

    Thanx Iwan, it looks interesting…I will take a look at it and maybe add it in the post!

  3. Laura January 10, 2013 at 23:20 #

    Thank you Egon. Nice work again!

    EMPractice ADHF 2006 states ‘To date, no prospective studies on its effects on mortality have been published’. That endpoint is still vague. I strongly believe that our first goal in the ED is symptom relieve, without causing adverse events, and without worsening morbidity / mortality (so not using Morphine).

    A number of studies described the beneficial effect of nitrates in reducing afterload (and preload) and I agree that high doses, as much as the blood pressure allows, is THE best treatment in acute heart failure with hypertension and pulmonary edema.
    However: in the Netherlands a lot of patients with AHF are presented to the ED by ambulance. Almost every general practitioner or ambulance-nurse already administered Furosemide iv. in pts wit AHF. That is: also in patients with no signs on examination of fluid overload. That means that my (our?) clinical judgement about the role of nitrates may be clouded by the Furosemide. I do sometimes, but seldom, get the chance to treat my patients with nitrates alone. If I do, I’m still really enthousiastic about its effect. As long as Furosemide is still a emergency treatment in the cardiology guidelines, it will be hard to change the prehospital treatment in favor of our faith in nitrates!
    My impression is also that NIV is less frequent needed in the ED (that is in the firat 1-2h of treatment) when agressive therapy with nitrates is instituted. What’s your experience?

    • Egon Zwets January 25, 2013 at 19:32 #

      I use NIV very often for acute pulmonary edema and I love it! Maybe a non-rebeathing mask would do the same, but I start in these pt with CPAP! And I love it! About the furosemide…..I agree, ambulance personal always give diuretics and morphine so it is difficult to say what nitrates + NIV alone would do!

  4. Egon Zwets January 25, 2013 at 19:31 #

    I use NIV very often for acute pulmonary edema and I love it! Maybe a non-rebeathing mask would do the same, but I start in these pt with CPAP! And I love it! About the furosemide…..I agree, ambulance personal always give diuretics and morphine so it is difficult to say what nitrates + NIV alone would do!

  5. more at adultsexcams89 October 9, 2013 at 13:28 #

    Very nice article. I definitely love this site. Thanks!

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