Pulsed administration of inhaled nitric oxide: Development, clinical applications, and future perspectives

Nitric oxide (NO) gas continues to be a widely studied and versatile treatment given its broad spectrum of physiological effects such as pulmonary vasodilation, improvement of oxygenation, anti-inflammatory, and antimicrobial effects. The idea of administering a pulsed dose of inhaled NO (PiNO) at the beginning of inhalation was developed in the last 20 years as an alternative to continuous inhalation of NO (CiNO) through the respiratory cycle. Across multiple studies, PiNO has repeatedly demonstrated similarly efficacious pulmonary vasodilation and oxygenation improvement as CiNO administration while consistently reducing total NO exposure and nitrogen dioxide (NO₂) formation. PiNO has proven to be an effective adjunctive treatment for patients with primary pulmonary hypertension among spontaneously breathing patients. In patients with chronic obstructive pulmonary disease (COPD), PiNO reduced pulmonary vascular resistance (PVR) in the short term, though further research remains necessary to demonstrate long-term benefits. Similarly, PiNO use in patients with interstitial lung disease has been associated with subjective improvements in exercise tolerance and quality of life. The effect of PiNO on PVR was also confirmed in mechanically ventilated subjects. In this setting, PiNO reduced anesthesia-associated hypoxemia and improved shunt fraction and oxygenation. Overall, the scientific body of evidence surrounding PiNO supports it as a safe, effective, and efficient alternative to CiNO delivery that can be utilized in a wide range of clinical settings. Future research may continue to expand the application of PiNO to different clinical settings.