Elsevier

Critical Care Clinics

Volume 18, Issue 1, January 2002, Pages 45-68
Critical Care Clinics

Inhaled nitric oxide in ARDS

https://doi.org/10.1016/S0749-0704(03)00064-2Get rights and content

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ENDOGENOUS NITRIC OXIDE

The critical role of an intact and functional endothelium in modulating vascular tone was realized more than 20 years ago. In 1980, Furgott and Zawadzki 29 reported that acetylcholine-induced vasodilation of arterial vascular smooth muscle required an endothelial-derived relaxing factor (EDRF) that was released by the endothelial cells and diffused into adjacent smooth muscle cells where it activated soluble guanylate cyclase and increased intracellular cGMP levels. In 1987, two groups of

INHALED NITRIC OXIDE

Nitrogen oxides are naturally occurring gases in the environment, although under normal conditions their concentrations are extremely small. Nitric oxides are produced when nitrogen and oxygen are combined with heat. Nitric oxide and nitrogen dioxide (NO2) are found in polluted air, decaying organic material and cigarette smoke.66 The Occupational Safety and Health Administration (OSHA) has set a tolera ble exposure limit for nitric oxides of 25 ppm for up to 8 hours per day.

When inhaled, NO

EFFECTS OF INHALED NITRIC OXIDE ON PULMONARY VASCULAR TONE

Numerous studies have demonstrated that endogenous NO is important in modulating pulmonary vascular tone in healthy people15, 85 and that impaired synthesis of endogenous NO may be involved in the pathophysiology of primary and secondary pulmonary arterial hypertension.35 Inhibition of endogenous NO synthesis has been shown to augment acute hypoxic pulmonary vasoconstriction and the pulmonary vasoconstrictor effects of many agents such as endothelin-1, angiotensin II, and thromboxane.2, 3 In

EFFECT OF INHALED NITRIC OXIDE ON GAS EXCHANGE

Although the initial rationale for the use of iNO in lung disease was to improve pulmonary hemodynamics, the most striking effect of this therapy may be its ability to improve oxygenation markedly. This effect is in contrast to other pulmonary vasodilators that usually worsen gas exchange by indiscriminately decreasing pulmonary vascular tone in the poorly ventilated lung. Because it is a gas, iNO is delivered only to ventilated areas of the lung and preferentially to areas of the lung that are

EFFECT OF INHALED NITRIC OXIDE ON PULMONARY CAPILLARY PERMEABILITY AND INFLAMMATION

Inhaled NO can affect pulmonary vascular permeability through several mechanisms. First, by decreasing pulmonary venous tone, iNO may reduce hydrostatic forces in pulmonary capillaries.9, 14 Second, iNO may reduce pulmonary vascular permeability directly by inhibiting oxidant injury.21, 38, 75 Inhaled NO can act as a free radical scavenger and attenuate oxidative damage to pulmonary vascular endothelium. Finally, there is evidence that iNO can inhibit inflammatory responses in the lung. In one

NONRANDOMIZED CONTROLLED STUDIES OF INHALED NITRIC OXIDE IN ACUTE RESPIRATORY DISTRESS SYNDROME

Numerous trials of iNO in ARDS have been reported since the initial study by Rossaint and co-workers80 in 1993. Almost all these studies were single-cohort studies in which patients served as their own controls. These studies had several objectives: (1) to determine if iNO has beneficial effects on cardiopulmonary hemodynamics and gas exchange; (2) to demonstrate that iNO can be administered without ad verse effects to patients or staff; and (3) to determine the optimal dose of iNO. In earlier

RANDOMIZED, CONTROLLED TRIALS OF INHALED NITRIC OXIDE IN ACUTE RESPIRATORY DISTRESS SYNDROME

The results of nonrandomized trials strongly suggested that iNO produced significant improvements in PAP and oxygenation in most patients with ARDS. Furthermore, the studies suggested that the acute beneficial effects of iNO could be sustained during long-term treatment. These findings quickly raised hopes that the use of iNO in ARDS would improve outcome. The first three randomized, controlled trials of iNO in ARDS were published in 1998. Two of the reports were small studies from single

FAILURE OF INHALED NITRIC OXIDE TO IMPROVE OUTCOME IN ACUTE RESPIRATORY DISTRESS SYNDROME

It is unclear why randomized, controlled trials have failed to show that iNO improves outcome in ARDS. Previous studies have shown that most patients with ARDS do not die of hypoxic respiratory failure.62 Why then should a therapy that improves oxygenation affect mortality in ARDS? Previous studies have suggested that pulmonary arterial hy pertension contributes to mortality in ARDS.94 Reducing pulmonary arterial pressure with iNO was one reason to hope that survival in ARDS could be improved.

IMPROVING RESPONSE TO INHALED NITRIC OXIDE

Although most patients with acute lung injury will have some improvement in gas exchange, the degree of response is variable and may not be meaningful in a substantial number of patients. Many studies have attempted to identify clinical features that could help predict re sponse to iNO. A favorable response to iNO has been correlated with baseline pulmonary vascular tone,12, 78, 93 the degree of alveolar recruitment,76, 78 a high degree of initial venous admixture,81 increased cardiac output,8

COMBINATION THERAPIES WITH INHALED NITRIC OXIDE

Because of the unique mechanism by which it works, iNO may enhance the ability of other forms of ventilatory support to improve oxygenation. A number of studies have examined the effect of combining iNO and prone positioning in adult patients with ARDS.16, 34, 57, 72, 79 In most studies57, 72, 79 more patients responded to prone positioning than to iNO, and the improvement in oxygenation was slightly better with prone positioning than with iNO. The number of patients in each study was small,

THE FUTURE OF INHALED NITRIC OXIDE IN ADULT PATIENTS WITH ACUTE LUNG INJURY

Despite the lack of proven benefit in clinical outcomes, many investigators continue to evaluate iNO for short-term symptomatic treatment of hypoxemic respiratory failure and pulmonary vasoconstriction in adult patients. Randomized clinical studies of patients with carefully defined disease states characterized by severe pulmonary hypertension or hypoxemia still are needed to identify patients who may benefit from iNO. The combination of iNO with other agents that increase pulmonary vascular

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