Therapeutic Role of Nitric Oxide in Respiratory Disease

Thomas E. Siddons, BSc, Mohammed Asif, MA, BMBCh, FRCS, and Tim W. Higenbottam, MD, MA, BSc, FRCP, University of Sheffield, Sheffield, United Kingdom

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Abstract

The anatomic target of inhaled nitric oxide (NO) is the vascular smooth muscle cells that surround the small resistance arteries in the lungs. As NO diffuses through the alveolar membrane, it reaches these smooth muscle cells, causing an increase in the levels of cyclic guanosine monophosphate that in turn sets off a chain of events resulting in the reduction of smooth muscle tone. Inhaled NO therapy is used in adult respiratory distress syndrome and persistent pulmonary hypertension of the neonate because it reduces pulmonary artery pressure and vasodilates the blood vessels in ventilated regions. This reduces the shunt fraction and simultaneously increases PaO2.. In chronic obstructive pulmonary disease, alveoli may be partially ventilated; inhaling NO creates shunting. Pulsed NO delivered at selected intervals during or at the beginning of inspiration may guide the NO to where it can offer maximum benefit -- the well-ventilated areas of the lungs. This approach reduces the volume and dose of NO needed to sustain a patient and reduces the size of the cylinder, allowing the patient to be more mobile. NO that comes into contact with oxygen forms NO2, which can cause acute lung injury, particularly pneumonitis or pulmonary edema. Rebound hypertension can sometimes occur when weaning a patient off continuously delivered NO. This phenomenon has not been experienced with pulsed NO over the long term.

In recent years, inhaled nitric oxide (NO) has been subject to widespread investigation. It was first discovered in 1987 as the factor responsible for the biological properties of endothelium-derived relaxing factor.[1] Since then, our understanding of this unique molecule has grown exponentially. Inhaled NO therapy is commonly used in intensive care units to treat patients with adult respiratory distress syndrome (ARDS), and it appears that inhaled NO is effective in treating conditions that result in pulmonary hypertension, such as, persistent pulmonary hypertension of the neonate (PPHN), and in diseases characterized by disturbances in gas exchange, such as chronic obstructive pulmonary disease (COPD).

There are few consistent guidelines for the administration and monitoring of inhaled NO. As a result, efforts have been made to determine how to deliver a consistent dose through an effective delivery system with accurate monitoring of ventilated patients. Large-scale clinical trials that evaluate the safety and efficacy of inhaled NO therapy as well as the feasibility of using inhaled NO in an ambulatory setting are needed to establish these guidelines.

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