Clinical Perspectives with Long‐Term Pulsed Inhaled Nitric Oxide for the Treatment of Pulmonary Arterial Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a chronic, progressive disease of the pulmonary vasculature with a high morbidity and mortality. Its pathobiology involves at least three interacting pathways – prostacyclin (PGI2), endothelin, and nitric oxide (NO). Current treatments target these three pathways utilizing PGI2 and its analogs, endothelin receptor antagonists, and phosphodiesterase type-5 (PDE-5) inhibitors. Inhaled nitric oxide (iNO) is approved for the treatment of hypoxic respiratory failure associated with pulmonary hypertension in term/near-term neonates. As a selective pulmonary vasodilator, iNO can acutely decrease pulmonary artery pressure and pulmonary vascular resistance without affecting cardiac index or systemic vascular resistance. In addition to delivery via the endotracheal tube, iNO can also be administered as continuous inhalation via a facemask or a pulsed nasal delivery. Consistent with a deficiency in endogenously produced NO, long-term pulsed iNO dosing appears to favorably affect hemodynamics in PAH patients, observations that appear to correlate with benefit in uncontrolled settings. Clinical studies and case reports involving patients receiving long-term continuous pulsed iNO have shown minimal risk in terms of adverse events, changes in methemoglobin levels, and detectable exhaled or ambient NO or NO2. Advances in gas delivery technology and strategies to optimize iNO dosing may enable broad-scale application to long-term treatment of chronic diseases such as PAH.

Care of the Patient With Pulmonary Arterial Hypertension

“…Nitric oxide readily crosses the alveolar-capillary membrane and quickly binds with hemoglobin, making it inactive, thus making it a selective pulmonary vasodilator. 25 Five potential issues with NO exist. First, NO has an extremely short half-life, a few seconds, requiring continuous administration of NO.…”

“…Second, patients on NO may cause increased levels of methemoglobin, but this is rarely an issue for patients receiving less than 100 ppm. 25 Third, NO may combine with oxygen to form nitrogen dioxide, a potentially toxic gas. 24 Care must be used to limit the time NO is exposed to oxygen, and nitrogen dioxide levels should be monitored, which is standard with the INOMax delivery system.…”

“…Nitric oxide can be safely delivered by pulsed nasal cannula or face mask to patients with chronic PAH. 25 Finally, shortterm NO, in combination with oxygen, can be used to determine the patient's vasoreactivity at the time of diagnosis, which may predict a patient's long-term prognosis. 20,31 Sildenafil works indirectly on the NO pathway.…”

Medical Therapies for the Treatment of Pulmonary Arterial Hypertension: How Do We Choose?

“…Currently inhaled nitric oxide (iNO) has no role in the longterm management of PAH, having been assessed in pulsed nasal delivery and facemask form in small single-centre settings only [21,22].…”

Pediatric Cardiac Intensive Care Society 2014 Consensus Statement

“…The study suggested that 5–40 ppm of inhaled NO therapy may be appropriate and safe, while sustained treatment with 80 ppm NO increases the risk of adverse events. (77, 78)…”