Inhaled Nitric Oxide Versus Conventional Therapy

Michael, John R.; Barton, Richard G.; Saffle, Jeffrey R.; Mone, Mary C.; Markewitz, Boaz A.; Hillier, Karen; Elstad, Mark R.; Campbell, Edward J.; Troyer, Brett E.; Whatley, Ralph E.; Liou, Theodore G.; Samuelson, Wayne M.; Carveth, Holly; Hinson, Doug M.; Morris, Stephen; Davis, Byron L.; Day, Ronald W.

doi:10.1164/ajrccm.157.5.96-10089

Cited by 254 publications

(130 citation statements)

References 46 publications

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“…In randomized clinical trials, inhaled nitric oxide was associated with a transient improvement in oxygenation in adults with ARDS without any survival benefit. [16][17][18][19][20] In a systematic review and meta-analysis of patients with acute lung injury or ARDS from 12 trials, inhaled nitric oxide was associated with modest improvements in oxygenation (13% increase in P aO 2 /F IO 2 until days 3-4 of administration), no effect on mean pulmonary artery pressure, and no effect on survival or duration of mechanical ventilation. 21 Period 1 is defined as prior to the start of the epoprostenol infusion, and period 2 is defined as during the epoprostenol infusion.…”

Section: Discussionmentioning

confidence: 99%

Predictors of Outcome in 216 Subjects With ARDS Treated With Inhaled Epoprostenol

Pacheco

Arnold²,

Skrupky³

et al. 2013

Respir Care

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Section: Discussionmentioning

confidence: 99%

Predictors of Outcome in 216 Subjects With ARDS Treated With Inhaled Epoprostenol

Pacheco

Arnold²,

Skrupky³

et al. 2013

Respir Care

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“…Because of the vasodilatory effects of NO, inhalation of this agent has been used as a therapeutic approach to decrease the pulmonary vascular resistance in well-ventilated, ie, NO-accessible lung areas, and thereby improve oxygenation in patients with acute respiratory distress syndrome (ARDS) (Michael et al, 1998;Payen, 1998;Troncy et al, 1998). Unfortunately, NO inhalation, although initially improving gas exchange, did not lead to sustained improvement of oxygenation compared with conventional therapy in the hitherto performed controlled studies (Michael et al, 1998;Payen, 1998).…”

mentioning

confidence: 99%

“…Unfortunately, NO inhalation, although initially improving gas exchange, did not lead to sustained improvement of oxygenation compared with conventional therapy in the hitherto performed controlled studies (Michael et al, 1998;Payen, 1998). Nonvasodilation-related effects of inhaled NO, currently not well understood, have been suggested to explain this finding.…”

mentioning

confidence: 99%

Cell-Specific Nitric Oxide Synthase-Isoenzyme Expression and Regulation in Response to Endotoxin in Intact Rat Lungs

Ermert

Ruppert

Günther

et al. 2002

Laboratory Investigation

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SUMMARY:Nitric oxide (NO) produced by NO synthase (NOS) serves as a ubiquitous mediator molecule involved in many physiologic lung functions, including regulation of vascular and bronchial tone, immunocompetence, and neuronal signaling. On the other hand, excessive and inappropriate NO synthesis in inflammation and sepsis has been implicated in vascular abnormalities and cell injury. At least three different NOS isoforms (neuronal/brain [bNOS], inducible [iNOS], and endothelial [eNOS]) have been described, which are all expressed in normal lung tissue. We investigated the cell-specific expression of bNOS, iNOS, and eNOS in perfused control rat lungs and lungs undergoing stimulation with endotoxin in the presence and absence of plasma constituents. Lung immunohistochemistry and quantitative evaluation of staining intensity showed endotoxininduced increase in iNOS expression in particular in bronchial epithelial cells, cells of the bronchus-associated lymphoid tissue (BALT), alveolar macrophages, and vascular smooth muscle cells in a time-and dose-dependent fashion. In endothelial cells, which did not express iNOS at baseline, newly induced iNOS was found in response to endotoxin. In contrast, expression of eNOS was markedly suppressed under endotoxin challenge, particularly in bronchial epithelium, BALT, and alveolar macrophages but also in vascular smooth muscle cells and endothelial cells. eNOS expression in bronchial smooth muscle cells was not altered. In contrast to iNOS and eNOS, cellular expression of bNOS in epithelial cells, nerve fibers, BALT, and endothelial cells did not change in response to endotoxin. All changes in NOS regulation were found to be independent of plasma constituents. We conclude that endotoxin exerts a profound impact on the cell-specific NOS regulation in a large number of lung cell types. Prominent features include de novo synthesis or up-regulation of iNOS, in contrast to down-regulation of eNOS, which may well contribute to vascular abnormalities, inflammatory sequelae, and loss of physiologic functions in septic lung failure. (Lab Invest 2002, 82:425-441).

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“…13 However, subsequent clinical trials reported disappointing outcome results. Inhaled NO therapy did not affect the duration of ventilatory support or mortality in 2 single-center pilot trials 61,62 and in 3 multicenter randomized trials. [63][64][65] Because most patients dying from acute respiratory distress syndrome suffer from multiple organ failure, it is unlikely that the beneficial effects of a lung-selective therapy such as inhaled NO will alter the overall survival rate.…”

Section: Inhaled No and Acute Respiratory Distress Syndromementioning

confidence: 99%

Inhaled Nitric Oxide

2004

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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. Pharmacology and Physiology of Inhaled NO Chemistry of NO GasNO is a colorless, odorless gas that is only slightly soluble in water. 3 NO and its oxidative byproducts (eg, NO 2 and N 2 O 4 ) 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 Williams 4 provides a review of the chemistry of NO. Therapeutic Versus Endogenous NO Concentrations in the AirwayAlthough 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 Ͼ20 ppm provide little additional hemodynamic benefit in most patients. In some adults with acute respiratory failure, the effective concentrations of inhaled NO required to improve oxygenation can be as low as 10 ppb. 5,6 Of note, NO has been detected in exhaled human breath. The majority of exhaled NO in normal humans appears to be derived from nasal bacterial flora (25 to 64 ppb), with lower concentrations measured in the mouth, trachea, and distal airway (1 to 6 ppb). 5,7 Mechanism of ActionAfter inhalation, NO diffuses rapidly across the alveolarcapillary membrane into the subjacent smooth muscle of pulmonary vessels to activate soluble guanylate cyclase (Figure 1). This enzyme mediates many of the biological effects of NO and is responsible for the conversion of GTP to cGMP. Increased intracellular concentrations of cGMP relax smooth muscle via several mechanisms. The physiological actions of cGMP are limited to its area of synthesis by its hydrolysis to GMP by cyclic nucleotide phosphodiesterases (PDE) or by its export from the cell. Of the 11 reported...

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Inhaled Nitric Oxide Versus Conventional Therapy

Cited by 254 publications

References 46 publications

Predictors of Outcome in 216 Subjects With ARDS Treated With Inhaled Epoprostenol

Predictors of Outcome in 216 Subjects With ARDS Treated With Inhaled Epoprostenol

Cell-Specific Nitric Oxide Synthase-Isoenzyme Expression and Regulation in Response to Endotoxin in Intact Rat Lungs

Inhaled Nitric Oxide

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