Recently Sara Crager released a video on EM-RAP recommending inhaled milrinone or nitroglycerin as an emergency therapy for massive pulmonary embolism (in case you don’t have access to EM-RAP, an audio clip from the video is below). This is the first that I’ve heard of using inhaled nitroglycerin. It seems like a pretty neat idea, but is it ready for prime time? Let’s take a look at the evidence. But first, why bother with inhaled nitroglycerin at all?
the concept: STAT pulmonary vasodilation for the crashing massive PE patient
The driver of death in massive PE is right ventricular failure, which is in turn caused by pulmonary hypertension. So pulmonary vasodilation makes a lot of physiologic sense. Indeed, it turns out that the body’s response to PE is often to release pulmonary vasoconstrictors that make matters even worse.
The concept of using inhaled pulmonary vasodilators isn’t anything new. This has been tested in RCTs and shown to have some potential efficacy. Traditionally, one of two vasodilators are used – either inhaled nitric oxide or inhaled epoprostenol.
There are numerous logistic problems with these drugs. First, many hospitals lack one or both of them. Second, they take a long time to obtain and set up. Epoprostenol requires reconstitution by the pharmacy, whereas nitric oxide requires setting up a tank. For a crashing PE patient, neither option is fast.
Hence, the concept of using inhaled nitroglycerin. Unlike epoprostenol or nitric oxide, nitroglycerin is cheap, immediately available, and easily administered via a standard nebulizer. Inhaled nitroglycerin offers the ability to provide pulmonary vasodilation within minutes, which simply isn’t possible with traditional medications.
Inhaled nitroglycerin would be intended only as a short-term, stop-gap measure to bridge the patient to another therapy (e.g. inhaled nitric oxide, inhaled epoprostenol, or IV thrombolysis).
relationship of nitroglycerin and nitric oxide
Nitric oxide (NO) is traditionally utilized to cause pulmonary vasodilation. Logistically, this requires several components: a big nitric oxide tank, various connections, and a regulator.
Nitroglycerin is metabolized within the body, yielding nitric oxide. So, the ultimate active ingredient is the same (nitric oxide). Thus, nitroglycerin may be conceptualized as an inactive precursor of nitric oxide.
Once we understand that the physiologically active ingredient in nitric oxide and nitroglycerin is identical, then it makes even more sense to use inhaled nitroglycerin in pulmonary hypertension.
Yurtseven N et al 2003: Effect of nitroglycerin inhalation in patients with pulmonary hypertension undergoing mitral valve replacement surgery
This is a cohort study describing the hemodynamic effect of inhaled nitroglycerin in 20 patients with pulmonary hypertension who were intubated status post mitral valve replacement surgery.1 Patients were treated for five hours with 2.5 ug/kg/min of nitroglycerin (which was nebulized and introduced into the ventilator circuit). Hemodynamic measurements were obtained with pulmonary artery catheters before, during, and after administration of nitroglycerin.
Inhaled nitroglycerin was an effective pulmonary vasodilator, without causing systemic vasodilation or hypotension. The pulmonary vascular resistance was cut almost in half, with an attendant reduction in mean pulmonary artery pressure of ~18 mm. Oxygenation efficiency improved, as would be expected due to improved ventilation/perfusion matching (inhaled pulmonary vasodilators enhance blood flow to better-aerated areas of the lung, which improves oxygenation).
Goyal P et al. 2006: Efficacy of nitroglycerin inhalation in reducing pulmonary arterial hypertension in children with congenital heart disease.
This is a study involving 19 children with ventricular septal defects causing severe pulmonary hypertension, who were undergoing elective Swan-Ganz catheterization.2 Hemodynamics were recorded under three conditions:
- (1) Baseline hemodynamics.
- (2) Inhalation of 100% FiO2 (which causes pulmonary vasodilation). Oxygen was then discontinued, and hemodynamics were allowed to return to baseline.
- (3) Nebulization of 25 ug/kg/min nitroglycerin for ten minutes. The nitroglycerin was nebulized using air, so during this period patients were not exposed to any additional oxygen.
Results are shown below. There was no change in systemic hemodynamics. Inhaled oxygen was a very good pulmonary vasodilator, reducing the pulmonary vascular resistance by about 50%. Inhaled nitroglycerin was even better, causing ~75% reduction in the pulmonary vascular resistance. Oxygen saturation improved during the nitroglycerin nebulization, revealing an improvement in ventilation-perfusion matching.
Yurtseven N et al 2006: A comparison of the acute hemodynamic effects of inhaled nitroglycerin and iloprost in patients undergoing mitral valve surgery.
This is a single-center randomized controlled trial involving 100 patients with pulmonary hypertension who remained intubated status post mitral valve replacement surgery.3 Upon admission to the surgical ICU, patients were randomized to receive 20 ug/kg nitroglycerin or 2.5 ug/kg iloprost (a pulmonary vasodilator).
Both nitroglycerin and iloprost were safe and effective pulmonary vasodilators. Iloprost was slightly more effective.
Mandal B et al. 2010: Acute hemodynamic effects of inhaled nitroglycerin, intravenous nitroglycerin, and their combination with intravenous dobutamine in patients with secondary pulmonary hypertension.
The overall design of this trial is similar to that of Yurtseven et al above.4 40 patients with pulmonary hypertension were studied following cardiothoracic surgery (either mitral valve replacement or combined mitral and aortic valve replacement). Patients were sequentially treated for ten minutes with each of the following therapies:
- Inhaled nitroglycerin 2.5 ug/kg/min
- Intravenous nitroglycerin 2.5 ug/kg/min
- Inhaled nitroglycerin plus IV dobutamine at 10 ug/kg/min
- Intravenous nitroglycerin plus IV dobutamine at 10 ug/kg/min
Inhaled nitroglycerin reduced the pulmonary vascular resistance by 40%, without causing any significant impact on systemic vascular resistance or mean arterial pressure. Intravenous nitroglycerin had the same effect on pulmonary vascular resistance, but the intravenous administration also led to a drop in mean arterial pressure due to a reduction in systemic vascular resistance. Changes in hemodynamics occurred within 3-5 minutes, with an effect lasting about 20-30 minutes.
Singh R et al 2010: Inhaled nitroglycerin versus inhaled milrinone in children with congenital heart disease suffering from pulmonary artery hypertension
This was a single-center randomized controlled trial involving 35 children with pulmonary hypertension due to congenital heart disease causing a left-to-right shunt (mostly ventricular septal defects).5 Patients were randomized to receive either nitroglycerin or milrinone as a component of an elective Swan-Ganz catheterization. Three sets of data were collected:
- Baseline hemodynamics
- Hemodynamics following inhalation of 100% FiO2 (which causes pulmonary vasodilation). Oxygen was then discontinued and hemodynamics were allowed to return to baseline.
- Inhalation of either 50 ug/kg nitroglycerin or 50 ug/kg milrinone using a nebulizer (drugs were reconstituted in a volume of 3 ml and administered with a jet nebulizer at 8 liters/minute flow over 10 minutes).
The data are difficult to interpret. First, we notice that inhaled 100% oxygen has a striking effect at pulmonary vasodilation. Oxygen is known to cause pulmonary vasodilation, so this makes sense.
Both the milrinone and nitroglycerin treatments also caused dramatic drops in pulmonary vascular resistance. This is a bit difficult to interpret, because it’s possible that some component of this vasodilation was due to the oxygen provided as a component of the nebulization process. However, there are two reasons to believe that inhaled oxygen from the nebulizers wasn’t a major influence here:
- The authors used a 50% oxygen/air mixture to drive the nebulizer, in efforts to minimize the amount of oxygen being delivered.
- Mean pulmonary artery pressures were lower with milrinone and with nitroglycerin therapy, compared to 100% FiO2 treatment. This strongly suggests that the milrinone and the nitroglycerin are having physiologic effects (so we’re not seeing merely the effect of oxygen alone).
Another confusing bit here is that calculated systemic vascular resistance decreased with all therapies (100% oxygen, milrinone, and nitroglycerin). Generally, we wouldn’t expect these treatments to affect systemic vascular resistance. The measured effect on systemic vascular resistance may be an artifact due to the effect of increased left-to-right shunting on the mixed oxygen saturation (sampled using a pulmonary artery catheter):
- Pulmonary vasodilation decreases the right-sided pressures, which causes an increased left-to-right flow of blood through the shunt. This increased shunt fraction (Qp/Qs) was actually shown in the data above.
- Increased shunted blood will tend to increase oxygenation of blood in the pulmonary artery.
- Increased oxygenation in the pulmonary artery will artificially increase the calculated cardiac output (based on the Fick equation). The Fick equation doesn’t work perfectly here, because the mixed venous oxygen in the pulmonary arteries isn’t truly the mixed venous blood returning to the heart via the superior and inferior vena cavae.
- Finally, artificially increasing the cardiac output calculated by the Fick equation will cause the calculated systemic vascular resistance to be artificially low.
So, ultimately this study does have some limitations. However, overall, it seems to show the following:
- Administering nitroglycerin via a nebulizer in a non-intubated patient seems to be safe and effective.
- Nitroglycerin and milrinone seem to be equally effective pulmonary vasodilators.
- Rather high doses of nitroglycerin and milrinone were well tolerated (50 ug/kg over 10 minutes, equal to a rate of 5 ug/kg/min).
Fikry DM et al. 2016: Comparison of hemodynamic effects of inhaled milrinone and inhaled nitroglycerin in patients with pulmonary hypertension undergoing mitral valve surgery.
This is a prospective RCT involving 50 patients with pulmonary hypertension undergoing mitral valve surgery.6 Patients were randomized to receive either 5 mg of milrinone or 5 mg of nitroglycerin nebulized over 15 minutes immediately following discontinuation of cardiopulmonary bypass. This study evaluates the therapeutic use of inhaled pulmonary vasodilators in the acute perioperative period, which is different from the above studies (which evaluated patients who were fairly stable at baseline).
Both nitroglycerin and milrinone were successful in reducing pulmonary vascular resistance. The effect of nitroglycerin was shorter lasting, with less reduction in pulmonary vascular resistance 90 minutes after administration.
recap of what the evidence shows: physiologic effects of giving a crashing pulmonary hypertension patient a nitroglycerin neb
Administration of a nitroglycerin neb has roughly three physiologic effects:
- The neb comes along with oxygen administration. Even if the patient’s oxygenation was OK beforehand, oxygen is a pulmonary vasodilator – so the oxygen itself may improve pulmonary hemodynamics.
- Inhaled nitroglycerin will cause pulmonary vasodilation.
- Inhaled nitroglycerin may improve ventilation-perfusion matching, and thereby improve the oxygen saturation. This won’t matter for everyone, but it may benefit patients with hypoxemia.
These are all good things. It’s hard to sift out exactly which might be more important, but it seems that the nitroglycerin neb could bring a lot of goodness to the table.
nuts & bolts: practical aspects of dosing nitroglycerin nebs at the bedside
The optimal dose of inhaled nitroglycerin is unclear. The above studies suggest a reasonable dose might be on the order of 2.5-5 ug/kg/min. This correlates with about ~5 mg of nitroglycerin over 15 minutes (as recommended by Sara Crager in the EM-RAP video).
Using the concentration of nitroglycerin available in my unit (400 mcg/ml), this would be equivalent to nebulizing 12 ml of nitroglycerin over 15 minutes. So 12 ml of nitroglycerin could simply be nebulized, without any dilution or manipulation. The duration of action is only ~20-30 minutes, so nebulized treatments would probably need to be given repeatedly or continuously as a bridge to more definitive treatment (e.g. thrombolysis or a traditional inhaled vasodilator).
- Traditional inhaled pulmonary vasodilators (nitric oxide and epoprostenol) take a long time to set up and aren’t universally available. Therefore, they often aren’t feasible for immediate application in the crashing PE patient.
- Nitroglycerin is metabolized into nitric oxide. Therefore, nebulized nitroglycerin can be used to selectively deliver nitric oxide to the pulmonary vasculature.
- The above studies support that nebulized nitroglycerin is a safe and effective pulmonary vasodilator, both for non-intubated patients and intubated patients.
- Currently, nebulized nitroglycerin seems to be a reasonable intervention for the crashing PE patient. Unfortunately, given how rare and emergent this situation is, it’s unlikely that a large, multi-center RCT could ever be performed to prove this.
- EM:RAP: Hemodynamic management of massive PE by Sara Crager
- Inhaled nitroglycerine for PE (iNOPE trial, PulmCrit))
- Submassive & massive PE (IBCC)
- Eight pearls for the crashing PE patient (PulmCrit)
- Hemodynamic management of massive PE (Oren Friedman on EMCrit podcast)
- 1.Yurtseven N, Karaca P, Kaplan M, et al. Effect of nitroglycerin inhalation on patients with pulmonary hypertension undergoing mitral valve replacement surgery. Anesthesiology. 2003;99(4):855-858. doi:10.1097/00000542-200310000-00017
- 2.Goyal P, Kiran U, Chauhan S, Juneja R, Choudhary M. Efficacy of nitroglycerin inhalation in reducing pulmonary arterial hypertension in children with congenital heart disease. Br J Anaesth. 2006;97(2):208-214. doi:10.1093/bja/ael112
- 3.Yurtseven N, Karaca P, Uysal G, et al. A comparison of the acute hemodynamic effects of inhaled nitroglycerin and iloprost in patients with pulmonary hypertension undergoing mitral valve surgery. Ann Thorac Cardiovasc Surg. 2006;12(5):319-323. https://www.ncbi.nlm.nih.gov/pubmed/17095973.
- 4.Mandal B, Kapoor P, Chowdhury U, Kiran U, Choudhury M. Acute hemodynamic effects of inhaled nitroglycerine, intravenous nitroglycerine, and their combination with intravenous dobutamine in patients with secondary pulmonary hypertension. Ann Card Anaesth. 2010;13(2):138-144. doi:10.4103/0971-9784.62946
- 5.Singh R, Choudhury M, Saxena A, Kapoor P, Juneja R, Kiran U. Inhaled nitroglycerin versus inhaled milrinone in children with congenital heart disease suffering from pulmonary artery hypertension. J Cardiothorac Vasc Anesth. 2010;24(5):797-801. doi:10.1053/j.jvca.2009.10.024
- 6.Wang H, Gong M, Zhou B, Dai A. Comparison of inhaled and intravenous milrinone in patients with pulmonary hypertension undergoing mitral valve surgery. Adv Ther. 2009;26(4):462-468. doi:10.1007/s12325-009-0019-4