The current acute management of patients with acute decompensated heart failure (ADHF) in florid pulmonary edema barely resembles the management I observed during medical school over a decade ago. Patients routinely roll into the emergency department (ED) with the loud whistle of prehospital non-invasive ventilation (NIV) machines. The early prehospital and ED use of NIV has made intubation of patients with pulmonary edema from ADHF uncommon. Morphine, once doled out in ADHF for vasodilatory properties and sympathetic nervous system, has been abandoned in ADHF due to observations of harm.^1,2 Bedside ultrasounds are wheeled into rooms to confirm diagnoses and initiate treatment in a matter of minutes and prior to portable chest radiographs. Physicians may order nitroglycerin to be dosed in milligrams and nurses may hang nitroglycerin drips with initial rates >200 μg/min without balking at the dose.

Recently, the American College of Emergency Physicians clinical policy committee released updated guidelines on the management of acute heart failure syndromes that reflect some of these changes.³ Three of the four recommendations in the clinical policy are probably standard in most EDs.

• Point-of care lung ultrasound is sufficiently accurate and can be used in conjunction with the history and physical exam to diagnose acute heart failure (Level B).
• Physicians may consider early administration of diuretics in patients with acute heart failure syndromes, provided the clinician is certain about the diagnosis and the patient has signs of volume overload (Level C).
• Physicians should not rely on current heart failure risk stratification tools to identify patient that can be directly discharged home from the ED. However, several tools may be used to identify high risk patients that should not be discharged home such as the Ottawa Heart Failure Risk Scale (OHFRS; Level B), the Emergency Heart Failure Mortality Risk Grade for 7-day mortality (EHMRG7) or the STRATIFY decision tool (Level C). These tools are neither sufficiently sensitive nor specific to be used as the sole criteria for decision-making.

The remaining recommendation, however, may be less routine, depending on local practice patterns and training. The new ACEP clinical policy includes a recommendation that we consider the use of high-dose nitroglycerin in hypertensive patients with ADHF, albeit as a consensus recommendation. This is consistent with a recommendation from the European Society of Cardiology that nitroglycerin can be given as 1–2 mg boluses in severely hypertensive patients with acute pulmonary edema.⁴ The use of nitroglycerin in AHDF is not new—it is the most commonly used vasodilator. However, there is little consensus regarding starting dose for nitroglycerin. Infusions are often initiated at 5-10 μg/min and then titrated up for effect.⁵ However, the additional benefit of afterload reduction, which is beneficial in ADHF, only comes at higher doses. As a result, there has been interest in using high-dose nitroglycerin early in the treatment of ADHF presenting with significantly elevated blood pressures.

What is “high-dose” nitroglycerin?

The definition of “high-dose” nitroglycerin varies. Some may consider an infusion of 200-400 μg/min “high-dose,” while others consider boluses of 1-3 mg “high-dose” nitroglycerin. In the open-label, non-randomized study that forms the basis of the ACEP clinical policy recommendation, patients received a 2 mg bolus of nitroglycerin and a nitroglycerin drip was started at a low rate (0.3-0.5 μg/kg/min) with titration up to 400 μg/min. Additional 2 mg boluses of nitroglycerin could be given every 3-5 minutes.⁶ A 2021 study gave patients a bolus of 0.6 to 1 mg of nitroglycerin, depending on systolic blood pressure, and initiated an infusion at 100 μg/min that could be titrated based on blood pressure.⁷

Who may be appropriate patient for high-dose nitroglycerin?

The studies of high-dose nitroglycerin typically include patients with clinical signs of ADHF with pulmonary edema, hypoxemia and/or dyspnea, and hypertension. The inclusion criteria vary with regard to minimum blood pressure threshold, but ≥160 mmHg is commonly used.^6,8

What is the potential benefit?

Studies of high-dose nitroglycerin consistently suggest a trend towards reduced need for endotracheal intubation, non-invasive ventilation, and admissions to critical care units.^6,8,9 This may be particularly important given strained hospital resources and critical care beds. Additionally, a short-term high-dose infusion or bolus doses of nitroglycerin can achieve rapid improvement in hemodynamics and symptoms, obviating the need for an infusion upon admission to the hospital. Unfortunately, most of these studies are small and not randomized; thus, the certainty of evidence regarding the magnitude of benefit is low.

What is the potential harm?

Two primary potential harms arise in the administration of nitroglycerin—hypotension and headache. Fortunately, hypotension is uncommon and transient, occurring in approximately two to three percent of patients in studies of high-dose nitroglycerin.^6,7,10–12 …Additionally, one of the benefits of nitroglycerin is the quick “on and off,” the half-life is about 3 minutes. As a result, the hypotension observed in these studies resolved within minutes.

How does one bolus nitroglycerin?

The delivery of nitroglycerin boluses can also vary, such that even if there is a reluctance to administer a bolus of nitroglycerin, the same dose can be effectively achieved. For example, a bolus can be administered as a slow intravenous push. Alternatively, one may encounter less resistance achieving a bolus of nitroglycerin by utilizing an infusion rate of 300-500 μg/min for a few minutes. “High-dose” or bolus dose nitroglycerin may seem like an outrageous dose compared to low-dose infusions; however, the dose may not be as high-dose as we think. We routinely administer 0.4 mg of sublingual nitroglycerin to patients with chest pain. Although the bioavailability may vary based on sublingual technique, this is approximately the same as 160 μg of intravenous nitroglycerin. Some prehospital services will administer 0.4–0.8 mg of sublingual nitroglycerin, sometimes repeated over 10–15 minutes to achieve an effective “bolus” of nearly 0.5 mg.^7,11

Enthusiasm for high-dose nitroglycerin in severe ADHF is no longer fringe. The professional society endorsements for high-dose nitroglycerin push high-dose nitroglycerin in ADHF with pulmonary edema from cutting-edge to mainstream and may facilitate the use of this approach for select patients.

Dr. Westafer (@Lwestafer) is an attending physician and research fellow at Baystate Medical Center, clinical instructor at the University of Massachusetts Medical School in Worcester, and co-host of FOAMcast.

References

1. Peacock WF, Hollander JE, Diercks DB, et al. Morphine and outcomes in acute decompensated heart failure: an ADHERE analysis. Emerg Med J. 2008;25(4):205–9.
2. Miró Ò, Gil V, Martín-Sánchez FJ, et al. Morphine use in the ED and outcomes of patients with acute heart failure: A propensity score-matching analysis based on the EAHFE registry. Chest. 2017;152(4):821–32.
3. American College of Emergency Physicians Clinical Policies Subcommittee (Writing Committee) on Acute Heart Failure Syndromes. Clinical policy: Critical issues in the evaluation and management of adult patients presenting to the emergency department with acute heart failure syndromes: Approved by ACEP board of directors, June 23, 2022. Ann Emerg Med. 2022;80(4):e31–59.
4. McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599–726.
5. UpToDate [Internet]. [cited 2023 Jan 11]; Available from: https://www.uptodate.com/contents/treatment-of-acute-decompensated-heart-failure-specific-therapies.
6. Levy P, Compton S, Welch R, et al. Treatment of severe decompensated heart failure with high-dose intravenous nitroglycerin: a feasibility and outcome analysis. Ann Emerg Med. 2007;50(2):144–52.
7. Mathew R, Kumar A, Sahu A, Wali S, Aggarwal P. High-dose nitroglycerin bolus for sympathetic crashing acute pulmonary edema: A prospective observational pilot study. J Emerg Med. 2021;61(3):271–7.
8. Wilson SS, Kwiatkowski GM, Millis SR, Purakal JD, Mahajan AP, Levy PD. Use of nitroglycerin by bolus prevents intensive care unit admission in patients with acute hypertensive heart failure. Am J Emerg Med. 2017;35(1):126–31.
9. Cotter G, Metzkor E, Kaluski E, et al. Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema. Lancet. 1998;351(9100):389–93.
10. Patrick C. Prehospital safety of intravenous bolus dose nitroglycerin in acute pulmonary edema patients. J Am Coll Cardiol. 2022;79(9):543.
11. Perlmutter MC, Cohen MW, Stratton NS, Conterato M. Prehospital treatment of acute pulmonary edema with intravenous bolus and infusion nitroglycerin. Prehosp Disaster Med. 2020;35(6):663–8.
12. Wang K, Samai K. Role of high-dose intravenous nitrates in hypertensive acute heart failure. Am J Emerg Med. 2020;38(1):132–7.