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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Inhaled NO in Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction due to chronic bronchitis or emphysema. COPD is a progressive disease and may or may not be accompanied by airway hyperreactivity. This disorder affects approximately 14 million people in the United States: 12.5 million have bronchitis and 1.65 millionhave emphysema.[16]Since 1982, these figures have risen by a staggering 41.5%; an increase that reflects this countries previous smoking habits. Smoking remains the number one risk factor for developing the disease. The damage caused by smoking that results in COPD is irreversible.Treatment includes the cessation of smoking, preservation of long- and short-term lung function, and minimizing exacerbations. The goal of treatment is to reduce further damage and maintain a reasonable quality of life.

The aim of inhaled NO therapy in COPD is to preserve lung function by maintaining adequate gas exchange. However, if NO is inhaled continuously at concentrations between 10 and 40 ppm, it has a tendency to worsen gas exchange.[17] The theory as to how continuous inhalation of NO worsens gas exchange in COPD is best explained by comparison with how NO improves gas exchange in ARDS.

In ARDS, many alveoli are filled with fluid and unventilated. NO can not reach these unventilated areas and instead vasodilates the vessels in the well-ventilated regions of the lung, causing a reduction in the shunt fraction. However, shunting does not substantially contribute to the patterns of ventilation/perfusion mismatch commonly associated with COPD (Figure 1). In COPD, many areas of the lung are partially ventilated as opposed to being fully ventilated or not ventilated at all . Therefore, if NO were to cause vasodilatation in these regions, it would only reduce the proportion of blood flowing through more optimally ventilated regions, resulting in a concomitant decrease in PaO2.

Ventilation/perfusion distribution determined by using the multiple inert gas elimination technique. This pattern of large areas of lung that are well perfused but poorly ventilated is common in patients with severe bronchitis.

There are several ways to approach this problem. One is to deliver supplementary oxygen along with NO, although results of the studies that have investigated this method vary--some investigators have reported increases in PaO2 and others have found the opposite.[17,18] Another approach to the problem is to selectively deliver NO to well-ventilated regions of the lungs. Pulsing NO at selected intervals during or at the beginning of inspiration may offer some control over its effects. Pulsed delivery of combined NO and oxygen may maximize the potential benefit of this form of therapy in patients with COPD.

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