Since the recognition of nitric oxide (NO) as a key endothelial-derived vasodilator molecule in 1987, the field of NO research has expanded to encompass many areas of biomedical research. It is now well established that NO is an important signaling molecule throughout the body. The therapeutic potential of inhaled NO as a selective pulmonary vasodilator was suggested in a lamb model of pulmonary hypertension and in patients with pulmonary hypertension in 1991.1,2 Because NO is scavenged by hemoglobin (Hb) on diffusing into the blood and is thereby rapidly inactivated, the vasodilatory effect of inhaled NO is limited largely to the lung. This is in contrast to intravenously infused vasodilators that can cause systemic vasodilation and severe systemic arterial hypotension.

Recent data indicate that inhaled NO can be applied in various diseases. For example, studies suggest that inhaled NO is a safe and effective agent to determine the vasodilatory capacity of the pulmonary vascular bed. This article summarizes the pharmacology and physiology of inhaled NO and reviews the current uses of inhaled NO for the treatment, evaluation, and prevention of cardiovascular and respiratory diseases.

### Chemistry of NO Gas

NO is a colorless, odorless gas that is only slightly soluble in water.3 NO and its oxidative byproducts (eg, NO2 and N2O4) are produced by the partial oxidation of atmospheric nitrogen in internal combustion engines, in the burning cinder cones of cigarettes, and in lightning storms. Medical-grade NO gas is produced under carefully controlled conditions, diluted with pure nitrogen, and stored in the absence of oxygen. The recent article by Williams4 provides a review of the chemistry of NO.

### Therapeutic Versus Endogenous NO Concentrations in the Airway

Although early studies of inhaled NO in the treatment of pulmonary hypertension used concentrations of 5 to 80 ppm, it has since been realized that concentrations >20 ppm provide little additional …

Inhaled nitric oxide: a selective pulmonary vasodilator: current uses and therapeutic potential

The therapeutic promise of nitric oxide (NO), a potent vasodilator, remains uncertain for adults, and licensed indications are restricted to pediatric practice. This review considers the biologic actions of inhaled nitric oxide, the clinical indications for its administration in adults, and an assessment of its potential therapeutic development.

Inhaled Nitric Oxide Therapy in Adults

A randomized, controlled clinical trial was performed with patients with acute respiratory distress syndrome (ARDS) to compare the effect of conventional therapy or inhaled nitric oxide (iNO) on oxygenation. Patients were randomized to either conventional therapy or conventional therapy plus iNO for 72 h. We tested the following hypotheses: (1) that iNO would improve oxygenation during the 72 h after randomization, as compared with conventional therapy; and (2) that iNO would increase the likelihood that patients would improve to the extent that the FI(O2) could be decreased by > or = 0.15 within 72 h after randomization. There were two major findings. First, That iNO as compared with conventional therapy increased Pa(O2)/FI(O2) at 1 h, 12 h, and possibly 24 h. Beyond 24 h, the two groups had an equivalent improvement in Pa(O2)/FI(O2). Second, that patients treated with iNO therapy were no more likely to improve so that they could be managed with a persistent decrease in FI(O2) > or = 0.15 during the 72 h following randomization (11 of 20 patients with iNO versus 9 of 20 patients with conventional therapy, p = 0.55). In patients with severe ARDS, our results indicate that iNO does not lead to a sustained improvement in oxygenation as compared with conventional therapy.

Inhaled nitric oxide versus conventional therapy: Effect on oxygenation in ARDS

A REMARKABLY exciting field of research has developed since nitric oxide (NO) was identified in 1987 as a key endothelium-derived relaxing factor (EDRF). The awarding of the 1998 Nobel prize in physiology or medicine to three seminal researchers in the field of NO biology provided the most recent evidence for the emerging prominence of this area of study. The understanding of the roles of NO in the cardiovascular, immune, and nervous systems; the isolation and localization of NO synthases (NOS); the manipulation of the genes for NOS, including their cloning and selective transfer or knock-out; and the therapeutic use of inhaled NO gas have revolutionized many fields of physiologic research and are influencing clinical therapy. Many insights into the mechanisms of action of NO have been gained. Since the reported applications of inhaled NO in the laboratory and in adult patients with primary pulmonary hypertension in 1991, hundreds of studies have been conducted to determine the clinical applicability of inhaled NO. In subgroups of severely ill and hypoxic children and adults, inhaled NO improves arterial oxygenation and selectively decreases pulmonary arterial hypertension (PAH). NO inhalation therapy, in combination with conventional or high-frequency oscillatory ventilation, can reduce the need for extracorporeal membrane oxygenation (ECMO), an expensive and invasive procedure in newborn patients with hypoxic respiratory failure. However, it remains uncertain whether NO inhalation improves survival rates in adults or children with severe lung injury. New applications for NO inhalation have been discovered. Recent studies indicate that inhaled NO may decrease intestinal ischemia–reperfusion injury and may be useful to treat thrombotic disorders. By increasing the oxygen affinity of sickle cell hemoglobin, inhaled NO may prevent or treat sickle cell crisis. This article reviews the relevant physiologic effects, therapeutic uses, side-effects, and toxicity of NO inhalation. The first portion of this article concentrates on the chemistry, biochemistry, toxicology, and biology of NO; the second portion summarizes the results of NO inhalation studies to date in experimental settings and the results of clinical studies in newborns, children, and adults.

Inhaled nitric oxide: basic biology and clinical applications.

Regulation of endothelial barrier function by reactive oxygen and nitrogen species.

Background : In acute lung injury, when pulmonary microvascular permeability is enhanced, transvascular fluid filtration mainly depends on pulmonary capillary pressure. Inhaled nitric oxide has been shown to decrease pulmonary capillary pressure. Therefore, the effect of inhaled nitric oxide at a concentration of 40 ppm on pulmonary transvascular albumin flux was studied in nine patients with acute lung injury. Methods : Transvascular albumin flux was measured by a double radioisotope method using 99m Tc-labeled albumin and 51 Cr-labeled autologous red blood cells. Radioactivity of both isotopes was externally measured over the right lung by a gamma scanner and simultaneously in arterial blood. The normalized ratio of 99m Tc/ 51 Cr lung to 99m Tc/ 51 Cr blood (normalized index) was calculated. The normalized slope index which is the slope of the regression line of the normalized index versus time represents the accumulation rate of albumin in the interstitial space of the lungs. Normalized slope index and pulmonary capillary pressure were determined before, during, and after inhalation of 40 ppm nitric oxide. Pulmonary capillary pressure was estimated using the visual analysis of the pressure decay curve after pulmonary artery occlusion. Results : Normalized slope index decreased from 0.0077 ± 0.0054 min -1 (SD) off nitric oxide to -0.0055 ± 0.0049 min -1 (P < 0.01) during nitric oxide and increased to 0.0041 ± 0.0135 min -1 after nitric oxide. Pulmonary capillary pressure declined from 24 ± 4 mmHg off nitric oxide to 21 ± 4 mmHg during nitric oxide (P < 0.01), whereas pulmonary artery wedge pressure and cardiac output did not change. Conclusions : It is concluded that 40 ppm inhaled nitric oxide decreases pulmonary transvascular albumin flux in patients with acute lung injury. This effect may be the result of the decrease in pulmonary capillary pressure.

P. Bräutigam

Papers

Inhaled nitric oxide reduces pulmonary transvascular albumin flux in patients with acute lung injury.

Doppelisotopen-Albuminfluxmessung: Diagnose und Therapiemonitoring des Acute Lung Injury