Exhaled nitric oxide : Influence of mechanical ventilation and vasoactive agents

Abstract: Nitric oxide (NO) is produced at various locations within the respiratory tract and is present in exhaled breath. It is firmly established that the levels of NO in exhaled air are increased in inflammatory disorders such as asthma and breath testing is now being introduced as a new diagnostic tool in clinical practice. Serious inflammatory conditions, both pulmonary and systemic, are common in critically ill patients on mechanical ventilation in the intensive care unit and NO measurements might be of value also in this setting. However, data on exhaled NO in this context have been scarce, likely because of methodological difficulties. In this project we have developed methods for studying exhaled NO in anesthetized mechanically ventilated patients with endotracheal intubation. We first used these methods to further characterize the anatomical origin of exhaled NO and then to study the possible release of NO in exhaled air upon administration of vasoactive agents known to interfere with endogenous NO generation. For comparison, measurements of exhaled NO were also performed in conscious subjects using a highly standardized and established single-breath method. By studying exhaled NO in patients with endotracheal intubation under general anesthesia as well as conscious subjects with or without a permanent tracheostomy we could confirm that the upper airways contribute substantially to both exhaled and inhaled NO. With a negative pressure aspiration system we could fractionate exhaled NO into alveolar and airway sources in patients with intubated trachea. This method enables more sophisticated analysis of exhaled NO in the anesthetized patient, which in turn increases the likelihood of finding useful clinical applications for NO measurements in this setting. A pig model was used to study if endogenous NO release evoked by vasoactive agents could be detected in exhaled air. We found that a variety of endothelium-dependent (e.g. acetylcholine, bradykinin, and endothelin-1) and endothelium-independent (e.g. nitroglycerin) vasoactive substances induced reproducible and agent-specific increases in exhaled NO. This NO likely originates from the pulmonary vascular endothelium in the alveolar region. In the last part of the thesis we went on to study responses in exhaled NO upon administration of acetylcholine and nitroglycerin in humans. Patients undergoing open-heart surgery were studied before and after cardiopulmonary bypass, a condition associated with transient pulmonary endothelial dysfunction. Acetylcholine elicited a dose-dependent increase in exhaled NO which was unaffected after cardiopulmonary bypass, while basal exhaled NO levels and the response to nitroglycerin were decreased. In conclusion: We have developed methods to measure exhaled NO in mechanically ventilated patients, and investigated the contribution of NO from different parts of the respiratory tract. These methods can be used to evaluate exhaled NO as a disease marker in critically ill patients and also to study online the effects of pharmaceutical agents on endogenous NO release.