What is the role of nitrates in managing acute pulmonary hypertension?

From the Guidelines

Nitrates are beneficial in acute pulmonary hypertension by causing vasodilation and reducing pulmonary vascular resistance, as supported by the most recent guideline evidence from 2022 1.

Key Points

• Intravenous nitroglycerin (starting at 5-10 mcg/min, titrated up to 200 mcg/min as needed) or sodium nitroprusside (starting at 0.3 mcg/kg/min, maximum 10 mcg/kg/min) are the preferred agents for acute management.
• These medications work by increasing nitric oxide levels, which activates guanylate cyclase, increases cGMP, and ultimately causes smooth muscle relaxation in the pulmonary vasculature.
• This reduces right ventricular afterload and improves cardiac output.
• When administering nitrates, blood pressure should be monitored continuously as hypotension is a common side effect.
• Patients should be in a monitored setting with IV access established.
• Nitrates should be used cautiously in patients taking phosphodiesterase-5 inhibitors like sildenafil due to risk of severe hypotension.
• For longer-term management after the acute phase, oral nitrates like isosorbide mononitrate (20-40 mg twice daily) may be considered, though they are generally less effective for pulmonary hypertension than for systemic hypertension.

Considerations

• The use of nitrates in patients with heart failure with preserved ejection fraction (HFpEF) is not recommended for routine use, as shown in the NEAT-HFpEF trial 1.
• However, nitrates may be beneficial in patients with HFpEF and symptomatic coronary artery disease (CAD) for symptomatic relief.
• The 2024 international consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations suggests the use of specific management strategies, including pulmonary arterial hypertension–specific targeted therapy, like phosphodiesterase-5 inhibitors, endothelin receptor antagonists, inhaled pulmonary vasodilators, or drugs that enhance the nitric oxide–cyclic guanosine monophosphate biological pathway 1.
• The 2022 AHA/ACC/HFSA guideline for the management of heart failure recommends nitrate therapy to reduce pulmonary congestion and improve exercise tolerance in patients with heart failure with reduced ejection fraction (HFrEF) 1.

From the FDA Drug Label

CLINICAL PHARMACOLOGY The principal pharmacological action of Nitroglycerin Injection is relaxation of vascular smooth muscle and consequent dilatation of peripheral arteries and veins, especially the latter Dilatation of the veins promotes peripheral pooling of blood and decreases venous return to the heart, thereby reducing left ventricular end-diastolic pressure and pulmonary capillary wedge pressure (preload). Intravenous nitroglycerin reduced central venous pressure (CVP), right atrial pressure (RAP), pulmonary arterial pressure (PAP), pulmonary-capillary wedge pressure (PCWP), pulmonary vascular resistance (PVR), and systemic vascular resistance (SVR).

The role of nitrates, such as nitroglycerin, in managing acute pulmonary hypertension is to reduce pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR) by relaxing vascular smooth muscle and dilating peripheral arteries and veins. This effect helps to decrease the workload on the heart and improve cardiac output. However, it is essential to note that the effectiveness of nitrates can be limited by the development of tolerance, and their use should be carefully managed to avoid this issue 2. Key points include:

• Reduction of pulmonary arterial pressure (PAP)
• Reduction of pulmonary vascular resistance (PVR)
• Relaxation of vascular smooth muscle
• Dilatation of peripheral arteries and veins

From the Research

Role of Nitrates in Managing Acute Pulmonary Hypertension

• Nitrates, such as nitroglycerin, have been shown to be effective in managing acute pulmonary hypertension by reducing pulmonary artery pressures and pulmonary vascular resistance 3, 4, 5.
• The use of nitrates in patients with pulmonary hypertension has been found to produce marked hemodynamic improvement, with benefits including decreased pulmonary vascular resistance, decreased mean pulmonary artery pressure, and increased cardiac index 3, 4, 5.
• Nitroglycerin has been found to be particularly useful in patients with secondary pulmonary hypertension and cor pulmonale, as it can decrease systolic, diastolic, and mean pulmonary arterial pressures without causing significant changes in systemic blood pressure or cardiac index 4.
• Inhaled nitroglycerin has also been studied as a potential treatment for acute pulmonary hypertension in children with congenital heart disease, with some studies suggesting its benefit in uncorrected cases during catheterization procedures 6.
• However, the use of nitrates in managing acute pulmonary hypertension may be limited by the potential for hypotensive events, systemic hypoxemia, and nitrate resistance or attenuated response 3, 7.
• Further research is needed to fully understand the benefits and risks of nitrate therapy in patients with pulmonary hypertension, including the optimal dosing and potential side effects of repeated administration 3, 6.