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(Chest. 1999;115:1407-1417.)
© 1999 American College of Chest Physicians

Nitric Oxide in Adult Lung Disease*

C. Michael Hart, MD, FCCP

* From Indiana University and Roudebush Veterans Administration Medical Center, Indianapolis, IN. Supported by grants from the Veterans Administration Research Service, the National Institutes of Health, and the American Diabetes Association.

Correspondence to: Mike Hart, MD, Indiana University, 1001 W 10th St, WD-OPW-425, Indianapolis, IN 46202-2879; e-mail: cmhart{at}iupui.edu


   Abstract
TOP
 Abstract
Introduction
 Background
 Pulmonary Actions of Nitric...
 Inhaled Nitric Oxide Delivery
 Conclusion
 References
 
Advances in the understanding of nitric oxide as a biological mediator and a therapeutic tool continue to accumulate at a rapid rate. This review provides an update on recent developments pertinent to the role of nitric oxide in adult lung disease. After a brief review of basic nitric oxide biochemistry and physiology, the evidence supporting the role of nitric oxide in the regulation of vascular and airway tone in the normal lung is considered. Clinical studies addressing the pathophysiological role of nitric oxide in pulmonary hypertension, airway disease, and lung injury are reviewed, and the application of inhaled nitric oxide therapy is discussed.

Key Words: ARDS • lung disease • nitric oxide • nitric oxide synthase • peroxynitrite • pulmonary hypertension


   Introduction
TOP
 Abstract
 Introduction
Background
 Pulmonary Actions of Nitric...
 Inhaled Nitric Oxide Delivery
 Conclusion
 References
 
Little more than a decade ago, nitric oxide was regarded as a noxious gaseous component of air pollution. Since that time, intense basic and clinical investigation has revealed that nitric oxide is produced by a variety of human tissues and is involved in the regulation of diverse physiological processes. Excellent reviews on the physiology, biochemistry, and basic understanding of nitric oxide biology have been published recently.1 2 3 However, the rapid and dramatic increase in research and new information in this field strains the ability of the practicing physician to keep abreast of recent developments and their clinical relevance. The goal of this report is to provide the reader with a concise review of recent studies pertinent to nitric oxide and its potential role in the pathophysiology and treatment of adult lung disease. The reader is referred elsewhere for reviews on the application of inhaled nitric oxide in the perinatal period.4 5


   Background
TOP
 Abstract
 Introduction
 Background
Pulmonary Actions of Nitric...
 Inhaled Nitric Oxide Delivery
 Conclusion
 References
 
What Is Nitric Oxide and How Does It Exert Its Biological Effects?
An appreciation of the role of nitric oxide in adult lung disease requires a basic understanding of nitric oxide biochemistry and physiology. Nitric oxide is a gaseous molecule that contains an unpaired electron. It is extremely lipophilic and readily diffuses across membranes down its concentration gradient. As a result of its chemical structure, the unpaired electron confers considerable reactivity to the molecule, which accounts for many of its biological effects (Fig 1 ). For instance, nitric oxide reacts with iron in heme-containing proteins or with iron-sulfur centers to modulate the activities of critical intracellular enzymes. Perhaps the most salient example of this reaction involves the diffusion of nitric oxide from vascular endothelial cells to underlying vascular smooth muscle cells, where nitric oxide reacts with iron in the heme group of soluble guanylate cyclase, altering its conformation and thereby activating the enzyme. Activated guanylate cyclase produces cyclic guanosine 3',5'-monophosphate (cGMP), which promotes smooth muscle cell relaxation (Fig 2 ). These biochemical events mediate the potent vasodilatory effects of nitric oxide and provide a signaling mechanism by which intravascular stimuli modulate vascular tone and blood flow. In a similar fashion, nitric oxide activates soluble guanylate cyclase in platelets, attenuating platelet aggregation and adhesion. In contrast, the reaction of nitric oxide with protein-bound iron in the mitochondrial respiratory chain and nuclear DNA synthesizing enzymes of microorganisms inhibits their activities and contributes to microbial killing and host defense.1 Finally, nitric oxide reacts with the heme prosthetic group of hemoglobin to form methemoglobin, a reaction that inactivates nitric oxide and thereby limits its ability to mediate cellular changes in the circulation at sites remote from its production.



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  		Figure 1. Common chemical reactions of nitric oxide. Nitric oxide (·NO) reacts with a variety of targets to mediate its effects (clockwise from top right). Nitric oxide reacts with transition metals (M) to alter their valence (x). An example of this reaction is the conversion of ferrous iron (Fe2+) in the heme moiety of hemoglobin (Hb2+) to ferric iron (Fe3+) forming methemoglobin (Hb3+). ·NO reacts at rapid rates with superoxide anion to form ONOO-. In solution, ·NO reacts with O2 to form the inactive metabolite nitrite (NO2-), whereas in the gas phase, ·NO reacts with oxygen to produce the oxidizing gas NO2. ·NO also reacts with thiol groups (RSH) to produce nitrosothiols (RS-NO). The reactive pathway followed by ·NO is determined by the biochemical characteristics of the various components of the system.

 


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  		Figure 2. Endothelium-dependent vasorelaxation. Intravascular stimuli (eg, receptor-mediated agonists or shear stress) cause transient elevations in vascular endothelial cell calcium (Ca2+) concentration. These Ca2+ transients activate the endothelial NOS isoform (type III NOS), which produces nitric oxide (·NO). Nitric oxide diffuses out of the endothelial cells into adjacent vascular smooth muscle cell layers, where it stimulates soluble guanylate cyclase to increase production of cGMP. cGMP promotes smooth muscle relaxation.

 
Nitric oxide also undergoes several additional biologically important reactions. In solution, nitric oxide reacts with oxygen to form the inactive metabolites nitrate and nitrite. In the gaseous state, nitric oxide reacts with oxygen to form nitrogen dioxide (NO2), a toxic gas formed at a rate proportional to the concentrations of nitric oxide and oxygen. Nitric oxide also reacts rapidly with the oxygen-centered radical superoxide to form peroxynitrite (ONOO-), a potent oxidizing species that may contribute to tissue injury in acute lung injury syndromes6 7 and to the microbiocidal activity of nitric oxide. It must be emphasized, however, that the interactions among nitric oxide, its metabolites, and other free-radical mediators are complex and defy simple categorization. For example, although nitric oxide combines with superoxide to form ONOO-, a metal-independent lipid peroxidation initiator, nitric oxide also combines with lipid peroxide intermediates to inhibit lipid peroxidation.8 Current evidence indicates that the pro- or antiperoxidative effects of nitric oxide are determined not only by the concentration of nitric oxide but also by the relative concentrations and rates of production of other free-radical mediators.9 Nitric oxide and nitrite also interact with neutrophil myeloperoxidase to stimulate oxidative reactions during inflammation.10 These findings emphasize that nitric oxide can exert detrimental as well as beneficial effects. However, critical deficits in our understanding of the behavior of nitric oxide in complex biological systems limit our ability to predict accurately which effects will predominate in any given pathophysiological state. Finally, nitric oxide also reacts with thiol moieties of both protein and nonprotein sulfhydryls to form nitrosothiols, which may exhibit biological effects similar to those of nitric oxide and have considerably longer half-lives.11 S-Nitrosylation may also modulate target protein function; thus, nitric oxide does not depend on a single receptor or target to exert its physiological effects. Rather, the diversity of nitric oxide's reactivities contributes to the complexity of effects exerted by this ubiquitous signaling molecule.

How Is Nitric Oxide Produced and How Is Its Production Controlled?
Nitric oxide synthase (NOS) produces nitric oxide from the amino acid arginine and generates citrulline as a product (Fig 3 ). Three NOS isoforms have been identified that differ in sequence, cofactor requirements, tissue distribution, and activity (Table 1 ).12 The first, the type I NOS isoform, has also been referred to as neuronal or brain NOS because of its expression predominantly in neuronal tissues.13 The regulation of type I NOS activity occurs largely through control of intracellular calcium levels. Stimuli that transiently increase intracellular calcium concentrations cause increases in type I NOS activity and nitric oxide production. In contrast, the second, inducible NOS or type II isoform does not require increases in intracellular calcium for its activity. Its expression and activity are increased by inflammatory molecules (eg, cytokines or endotoxin) that increase the transcription and translation of the type II NOS gene, leading to sustained nitric oxide production.14 The inducible type II NOS isoform is also distinguished from the constitutive (type I and type III) isoforms by the higher levels of nitric oxide it produces (nanomolar vs picomolar). The third isoform, type III NOS, was originally isolated from endothelial tissues and as a result has been termed eNOS. Like type I NOS, type III NOS is constitutively expressed, and its activity is largely stimulated by increases in intracellular calcium concentration, although post-translational modifications of the enzyme, pH, cofactor availability and association with other intracellular proteins also regulate enzyme activity.12 15 This simplified categorization of NOS isoforms continues to be refined and grossly oversimplifies the complexity of NOS regulation in vivo. For example, although type I NOS and type III NOS were originally conceptualized as constitutively expressed proteins, it is now recognized that immunologic stimuli can influence their tissue expression.



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  		Figure 3. The generation of nitric oxide from arginine. In the presence of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) and other cofactors, NOS converts O2 and the amino acid L-arginine to nitric oxide and L-citrulline.

 

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  		Table 1. Characteristics of NOS Isoforms

 
In the human lung, NOS isoforms are expressed in the vascular, airway, and parenchymal tissue compartments.16 NOS expression has been demonstrated in macrophages, mast cells, neutrophils, nonadrenergic noncholinergic (NANC) neurons, fibroblasts, vascular smooth muscle cells, platelets, arterial and venous endothelial cells, and epithelial cells.17 Within these cell types, NOS has been associated with virtually all intracellular compartments, including the nucleus, endoplasmic reticulum, mitochondria, Golgi apparatus, and plasma membrane.12 This diffuse distribution of NOS isoforms indicates that nitric oxide potentially modulates numerous physiological and pathophysiological processes in the lung.

Nitric Oxide in the Healthy Lung
Several lines of evidence indicate that the constitutive expression of NOS and the intravascular production of nitric oxide participate in the regulation of pulmonary vascular reactivity in the normal lung. NOS inhibitors caused pulmonary vasoconstriction when administered to normal volunteers, demonstrating that the tonic or constitutive production of nitric oxide by the pulmonary vasculature regulates pulmonary vascular tone and resistance under normal conditions.18 NOS inhibitors also enhanced hypoxia-induced increases in pulmonary vascular resistance,19 whereas inhaled nitric oxide prevented hypoxia-induced pulmonary vasoconstriction in normal volunteers,20 suggesting that nitric oxide can also regulate the response to vasoconstrictive stimuli in the lung. These findings, along with numerous studies cited later, emphasize that the pulmonary effects due to nitric oxide produced endogenously by vascular or airway cells can be replicated or enhanced, in many cases, by the inhalation of exogenous nitric oxide. Thus, for the remainder of this review, evidence pertinent to effects of endogenous and exogenous nitric oxide is integrated as specific categories of lung disease are considered.

In addition to its effects on vascular tone, the continuous production of nitric oxide in the pulmonary vasculature may also play an important role in vascular homeostasis through its ability to inhibit such proinflammatory events as platelet activation and aggregation21 and leukocyte adhesion.22 Nitric oxide produced by inflammatory cells participates in host defense against specific microorganisms,17 and nitric oxide produced by inhibitory NANC neurons modulates bronchomotor tone. Thus, current evidence indicates that nitric oxide plays an important role in the regulation of vascular, airway, and inflammatory events. The unregulated and excessive production of nitric oxide by type II NOS during states of poorly controlled inflammation contributes to vasodilation, hypotension, and dysregulated vascular responses.23 In contrast, deficient production of nitric oxide in the pulmonary vasculature is associated with pulmonary hypertension. Taken together, these findings indicate that the carefully controlled production of nitric oxide is critical for normal lung functioning and suggest that alterations in nitric oxide production may participate in the pathophysiology of diverse lung disorders.


   Pulmonary Actions of Nitric Oxide in Disease
TOP
 Abstract
 Introduction
 Background
 Pulmonary Actions of Nitric...
Inhaled Nitric Oxide Delivery
 Conclusion
 References
 
Pulmonary Hypertension
Decreased expression of NOS in the pulmonary vascular endothelium of patients with both primary and secondary forms of pulmonary hypertension suggests that sustained attenuation of pulmonary vascular nitric oxide production is associated with clinically significant alterations in pulmonary vascular tone.24 Autopsy or biopsy specimens demonstrated that the endothelial expression of NOS was absent or reduced in patients with primary or secondary forms of pulmonary hypertension compared with control subjects, whereas the expression of NOS in the airway epithelium from these patient groups was comparable. The degree of endothelial NOS expression was indirectly proportional to morphologic alterations of pulmonary hypertension in the artery wall and pulmonary vascular resistance. These studies provide provocative evidence that impaired pulmonary vascular endothelial nitric oxide production plays a role in the pathogenesis of pulmonary hypertension. It remains to be demonstrated whether decrements in NOS expression are the proximate cause of pulmonary hypertension or are merely secondary manifestations contributing to disease progression. The role of deficient nitric oxide production in secondary pulmonary hypertension is further supported by an examination of the pulmonary vascular responses of patients with severe COPD, most of whom had cystic fibrosis and were awaiting lung transplantation.25 In the pulmonary vessels from COPD patients, vascular relaxation in response to agents that produce endothelium-dependent vasorelaxation by stimulating vascular endothelial cell nitric oxide production (acetylcholine and adenosine diphosphate) was impaired approximately 50% compared with control vessels from lobectomy specimens of cancer patients. In contrast, vasorelaxation responses to endothelium-independent vasodilators (eg, nitroprusside) were not impaired in the COPD vessels compared with the control. These findings suggest a potential relationship between pulmonary vascular endothelial dysfunction and the progression of airway disease in COPD. Other studies, however, have found endothelial dysfunction to be an inconsistent finding in patients with COPD.26 Additional studies will be required to determine whether altered pulmonary vascular endothelial nitric oxide production plays a pathogenetic role in the vascular remodeling of patients with obstructive airway disease. Low concentrations of inhaled nitric oxide prevented hypoxia-induced pulmonary hypertension in rats.27 Although numerous mediators undoubtedly contribute to vascular remodeling in pulmonary hypertension, current evidence suggests that nitric oxide plays an important role in pulmonary vascular homeostasis, modulating the outcome of constrictive, mitogenic, or inflammatory stimuli.

The inhalation of exogenous nitric oxide can also decrease pulmonary hypertension and right ventricular dysfunction secondary to hypoxia,20 and it can ameliorate the severity of a variety of other cardiopulmonary disorders, including idiopathic pulmonary fibrosis28 and ARDS (reviewed later). Interestingly, for reasons that remain unclear, the dose of inhaled nitric oxide required to reduce pulmonary hypertension has often been reported to substantially exceed the dose required to generate improvements in oxygenation.29 One possible explanation for this discrepancy is that only at higher concentrations does inhaled nitric oxide diffuse through the lung to low ventilation-perfusion (/) or shunt areas to cause vasodilation in a sufficient fraction of the vascular bed to reduce pulmonary hypertension.

Airway Disease
Exhaled gas from normal subjects contains 0.1 to 100 parts per billion (ppb) nitric oxide. The upper airway rather than circulatory or systemic sources generates most of the nitric oxide in exhaled gas.30 31 Exhaled nitric oxide concentration is determined not only by alterations in endogenous nitric oxide production but also by the nitric oxide concentration inhaled in ambient air.32 Nonetheless, under normal conditions, the majority of exhaled nitric oxide is produced by type II NOS expressed by the airway epithelium33 and the paranasal sinuses.34 Reductions in exhaled nitric oxide concentrations in normal subjects caused by breathing hypoxic gas mixtures suggest that airway nitric oxide concentrations could be acutely altered by reductions in inhaled oxygen tension, providing a potential mechanism for hypoxia-induced vasoconstriction in the lung.30 The potent effects of nitric oxide on vascular smooth muscle and its presence in the major conducting airways raise the possibility that it could contribute to regulation of airway smooth muscle tone.

The precise role that nitric oxide plays in the regulation of airway function remains poorly defined. Inhaled NOS inhibitors inhibited endogenous airway nitric oxide production and significantly decreased the exhaled nitric oxide concentrations of normal subjects but failed to alter airway conductance at baseline or following inhalation of methacholine.35 Similarly, the administration of 60 ppm nitric oxide had little effect on the specific airway conductance of normal or COPD patients but slightly increased airway conductance in patients with asthma or in those with airway hyperreactivity following the inhalation of methacholine.36 When compared with inhaled ß-agonists, however, nitric oxide in concentrations of < 100 ppm was a weak bronchodilator with little effect on airway tone.36 37 In another study, inhaled nitric oxide worsened gas exchange in COPD patients, probably because of its inhibition of hypoxic pulmonary vasoconstriction and worsening of / matching in the lung.38 These observations led to the postulate that inhaled nitric oxide exerts the greatest benefit to gas exchange in the lung in which the pathophysiology stems primarily from intrapulmonary shunt (eg, ARDS) rather than / mismatching, which occurs in COPD. In summary, current evidence indicates that nitric oxide in the airway, whether endogenously produced or exogenously administered, is a relatively weak bronchodilator whose role in the regulation of bronchial tone remains to be firmly established.

In addition to these controversial effects on bronchomotor tone, nitric oxide in the airway may serve several additional purposes. First, the localized release of nitric oxide by inflammatory cells participates in host defense against diverse microorganisms in the airway.17 Second, nitric oxide released from NANC neurons in the conducting airways also provides a neurally mediated bronchodilator pathway that opposes the bronchoconstricting effects of cholinergic pathways.39 From a more practical standpoint, exhaled nitric oxide levels are proportional to the degree of airway hyperresponsiveness in patients with mild asthma40 and provide a potential marker for airway inflammation in patients with asthma or bronchiectasis.41 42 43 Thus, although current evidence does not support the application of inhaled nitric oxide as a bronchodilator, additional studies of airway nitric oxide production may provide insights into the functions of endogenously produced nitric oxide in the airways and novel methods for monitoring airway inflammation or airway response to therapy.

Acute Lung Injury and ARDS
Perhaps the most extensively studied application of nitric oxide in adult lung disease involves its therapeutic inhalation during the course of acute lung injury. Current concepts in the pathogenesis of acute lung injury indicate that inhaled or circulating factors cause inhomogeneous injury to the lung. The resulting vasoconstriction and microvascular occlusion lead to / mismatching, intrapulmonary shunting, arterial hypoxemia, and pulmonary hypertension, recognized in its more severe manifestations as ARDS. The clinical application of systemic vasodilators in this syndrome, although effective at lowering pulmonary vascular resistance, is complicated by systemic hypotension and worsening of intrapulmonary shunting and arterial hypoxemia. In contrast, inhaled nitric oxide selectively "vasodilates" or promotes perfusion of ventilated alveoli that contain nitric oxide while simultaneously diverting blood flow away from alveoli that are less well ventilated (Fig 4 ). The vasodilatory properties of inhaled nitric oxide are limited to the pulmonary vascular bed because nitric oxide is inactivated through its reaction with hemoglobin in red blood cells. This reaction limits the half-life of nitric oxide in the circulation and prevents systemic hemodynamic effects.20 Nitric oxide is also inactivated by reacting with oxygen dissolved in plasma to form nitrite.



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  		Figure 4. Proposed mechanism for improvements in oxygenation in ARDS patients treated with inhaled nitric oxide. Top, A: inhomogenous lung injury in ARDS creates two theoretical populations of alveolar-capillary units (x and y). Blood flow to those regions with decreased ventilation produces areas of low / ratios. Admixture of blood perfusing low / regions (x) with blood from areas with more normal / ratios (y) creates hypoxemia ({downarrow}PaO2). Bottom, B: inhaled nitric oxide (black dots) distributes preferentially to those areas with greater ventilation, stimulating localized vasodilation and enhanced blood flow to well-ventilated lung units while simultaneously "stealing" perfusion from more poorly ventilated areas. The net effect is improved / matching and reduced hypoxemia ({uparrow}PaO2).

 
Studies in experimental animal models of acute lung injury induced by a variety of stimuli, eg, oleic acid, endotoxin, hyperoxia, paraquat, and pancreatitis to name a few, have demonstrated that inhaled nitric oxide at concentrations of < 100 ppm reduces pulmonary vascular resistance with little effect on systemic hemodynamics while simultaneously improving hypoxemia. At these concentrations of inhaled nitric oxide, adverse consequences and tachyphylaxis were not observed. Survival data from these models are not consistent. For example, one study employing a hyperoxia (95% oxygen)-induced model of lung injury in the rat noted that inhalation of 5 to 10 ppm nitric oxide caused a statistically significant improvement in survival at 6 days.44 In a separate study, 100% oxygen caused significant lung leak and lipid peroxidation in a rat model. Although NOS inhibitors exacerbated and 10 ppm inhaled nitric oxide attenuated oxygen-induced derangements in this study, nitric oxide failed to improve survival.45

In human trials, > 30 studies have now reported the application of inhaled nitric oxide to patients with ARDS.46 Many of these studies, however, consist of small numbers of patients, lack appropriate control subjects, and use varying doses and methods of delivery of inhaled nitric oxide in combination with other therapeutic modalities. Furthermore, the subjects in these studies comprise a heterogenous population of ARDS patients. Taken together, these factors have prevented the definitive assessment of the use of inhaled nitric oxide therapy in ARDS patients. In general, however, these studies suggest that in the absence of sepsis 60 to 80% of ARDS patients will respond to inhaled nitric oxide at doses of < 20 ppm, exhibiting at least 20% increases in the ratio of PaO2 to the fraction of inspired oxygen and 10 to 20% reductions in intrapulmonary right-to-left shunt or pulmonary artery pressure. Response rates in patients with septic ARDS have been lower for reasons that remain unclear but could be related to the concomitant systemic administration of vasopressors that antagonize the vasodilatory effects of nitric oxide.47 48 The duration of the response to inhaled nitric oxide in ARDS patients is controversial. In a subset of ARDS patients from one study, prolonged inhalation (> 7 days) of nitric oxide provided persistent improvements in oxygenation and pulmonary hemodynamics without evidence of tachyphylaxis,49 although a recent randomized controlled trial demonstrated that improvements in oxygenation in ARDS patients induced by inhaled nitric oxide were transient, lasting for < 24 h.50

In an attempt to avoid the shortcomings of smaller trials, multicenter, prospective studies have been initiated.51 52 53 54 For instance, a randomized, double- blind, placebo-controlled, phase II study was recently performed with ARDS patients to evaluate the safety of inhaled nitric oxide in doses from 1.25 to 80 ppm. The major endpoints examined in this study included mortality, days alive while off mechanical ventilation, and days alive after oxygenation improved sufficiently to allow extubation.51 The major findings from this study of 177 immunocompetent patients with nonseptic ARDS demonstrated that inhaled nitric oxide caused few adverse effects over the 28-day study period and caused small but significant improvements in oxygenation. However, a significant improvement in mortality attributable to inhaled nitric oxide could be demonstrated only by post hoc analysis of the data from the subgroup of patients receiving 5 ppm inhaled nitric oxide. Analysis of all patients receiving nitric oxide demonstrated no improvement in mortality, confirming observations from a previous retrospective study,55 as well as preliminary results from the prospective Swedish trial.53 Recent editorials have presented dichotomous viewpoints emphasizing the failure of the American phase II trial to support the use of inhaled nitric oxide in ARDS,56 as well as the potential benefit that subgroups of ARDS patients might derive from this therapy.57 A phase III trial is currently underway in this country to further examine the efficacy of inhaled nitric oxide in ARDS and its ability to reduce mortality.

Numerous studies have also investigated the relative benefits of combining inhaled nitric oxide with other therapeutic modalities. For instance, improvements in oxygenation in ARDS patients caused by inhaled nitric oxide were further augmented by the simultaneous administration of agents that enhance hypoxic pulmonary vasoconstriction, including almitrine58 59 and phenylephrine.60 Because many of the hemodynamic effects of inhaled nitric oxide are mediated by the stimulation of smooth muscle guanylate cyclase and the formation of cGMP, several investigators have examined the ability of phosphodiesterase inhibitors, eg, dipyridamole61 and zaprinast,62 to enhance the effect of inhaled nitric oxide by preventing phosphodiesterase-mediated cGMP degradation. The simultaneous administration of positive end-expiratory pressure63 or the use of prone positioning64 may also enhance the beneficial effects of inhaled nitric oxide in ARDS patients. Inhaled nitric oxide also lowered increases in pulmonary vascular resistance caused by permissive hypercapnic ventilation in ARDS patients.65 Taken together, these studies emphasize that inhaled nitric oxide should be examined not only as a single agent but as a component of combined modality treatment strategies in ARDS.

In addition to the ability of inhaled nitric oxide to modulate pulmonary blood flow and gas exchange, a growing body of literature suggests that it might alter several events in the pathogenesis of acute lung injury and ARDS. For instance, inhaled nitric oxide inhibited neutrophil activation and the production of inflammatory mediators in the lungs of ARDS patients.66 67 Furthermore, the ability of inhaled nitric oxide to inhibit platelet adhesion could potentially modulate the development of microvascular thrombosis in acute lung injury.68 Numerous studies in a variety of systems have demonstrated that nitric oxide can exert either pro- or antioxidative effects depending, in part, on the type and quantity of oxygen radical species present.9 Finally, several studies have described the ability of nitric oxide to attenuate lung leak in ARDS,69 as well as in oxidant-induced models of ARDS,44 70 71 suggesting that nitric oxide may promote the barrier function of the alveolar-capillary membrane. The mechanisms of these effects of nitric oxide remain to be clarified, and, as recently emphasized, confirmation that these beneficial effects of nitric oxide will translate into improved patient outcomes will require carefully designed studies with rigorously selected patient populations.72

Other Potential Applications of Nitric Oxide in Adult Lung Disease
The vasodilatory effects of inhaled nitric oxide on the pulmonary vasculature have prompted investigations into a variety of additional applications of inhaled nitric oxide. One promising use appears to be in the assessment of pulmonary vascular reactivity in patients with pulmonary hypertension. Inhaled nitric oxide (10 to 40 ppm) was compared with prostacyclin in patients with primary pulmonary hypertension.73 Vasodilatory responses to the two drugs were comparable, with no additive effects observed when both drugs were administered. Inhaled nitric oxide proved advantageous in this study because it had no effect on systemic hemodynamics and caused no side effects. Inhaled nitric oxide also has demonstrated its usefulness in the assessment of reversibility of pulmonary hypertension in patients with chronic congestive heart failure.74 In the future, nitric oxide may also prove to be easier to administer, to be less costly, and to have quicker onset/offset than other systemically administered vasoactive agents. Isolated reports have suggested that inhaled nitric oxide has provided benefits in diverse clinical situations, including the management of end-stage primary pulmonary hypertension,75 pulmonary hypertension in patients following mitral valve replacement for mitral stenosis,76 end-stage idiopathic pulmonary fibrosis,28 and lung allograft dysfunction.77 78 79 80 Inhaled nitric oxide has also been shown to have significant effects on vascular reactivity in patients prone to developing high-altitude pulmonary edema81 and to increase the oxygen affinity of erythrocytes in patients with sickle cell disease.82


   Inhaled Nitric Oxide Delivery
TOP
 Abstract
 Introduction
 Background
 Pulmonary Actions of Nitric...
 Inhaled Nitric Oxide Delivery
Conclusion
 References
 
Guidelines from the National Institute for Occupational Safety and Health state that a time- weighted average of 25 ppm for nitric oxide constitutes a permissible exposure level.83 Because of nitric oxide production in the nasopharynx plus inhaled ambient nitric oxide levels, 70 to 130 ppb nitric oxide are inhaled into the lower airways of normal subjects.31 Despite the propensity for nitric oxide to form toxic secondary oxides of nitrogen (eg, NO2 or ONOO-) in the presence of high partial pressures of oxygen or superoxide, respectively, there is little evidence to suggest that the careful administration of inhaled nitric oxide in concentrations < 100 ppm has serious deleterious effects. One early report, however, documented the dramatic toxicity of higher oxides of nitrogen contaminating anesthetic gases.84 One easily measured form of toxicity in inhaled nitric oxide therapy is methemoglobin formation. The prolonged inhalation (> 14 days) of approximately 10 ppm nitric oxide to patients with severe ARDS was not associated with significant increases in methemoglobin.55 Furthermore, only 4 of 177 ARDS patients treated with <= 80 ppm inhaled nitric oxide had methemoglobin concentrations of > 5%.50 Some investigators have reported a rebound phenomenon with rapid hemodynamic and gas-exchange deterioration after discontinuing inhaled nitric oxide abruptly.85 86 Potential mechanisms explaining this inability to wean inhaled nitric oxide therapy include progression of the underlying disease process, acute increases in pulmonary vascular resistance leading to right ventricular overload and impaired left ventricular filling, down-regulation of endogenous nitric oxide production, and delayed recovery of other mechanisms regulating vascular tone.86

In 1994, a panel of experts sponsored by the National Heart, Lung and Blood Institute considered the safety and efficacy of inhaled nitric oxide therapy. Their report provides practical guidelines for the safe administration of inhaled nitric oxide therapy.87 Similar guidelines for the safe application of inhaled nitric oxide have been published recently in the United Kingdom.88 Because nitric oxide combines spontaneously with oxygen to form potentially toxic oxides of nitrogen (eg, NO2), delivery systems must ensure that the amount of time for nitric oxide to react with oxygen, and hence the amount of NO2 inhaled by the patient, be kept to a minimum. As a result, nitric oxide is commercially manufactured in stock tanks of inert gas (nitrogen).

The systems for delivering nitric oxide into the inspiratory limb of the ventilator circuit are quite variable and have been reviewed elsewhere.89 The clinician prescribing nitric oxide therapy must have a thorough understanding of nitric oxide biology and the ventilator circuitry used to deliver nitric oxide. In ventilator circuits that provide a constant flow of gas independent of patient demands, nitric oxide can be delivered at precisely controlled flow rates to the inspiratory limb of the ventilator circuit. On the other hand, in adult ventilators where flow rates fluctuate between inspiration and expiration and where minute ventilation and tidal volumes fluctuate according to patient parameters, the simple delivery of a constant flow of nitric oxide into the inspiratory limb would result in unacceptable variations in the concentration of nitric oxide inhaled.

To overcome these shortcomings, several techniques have been developed to synchronize the delivery of nitric oxide with inspiration, thereby decreasing the time that nitric oxide can react with oxygen to form detrimental higher oxides of nitrogen (eg, NO2) and more closely matching nitric oxide delivery to patient flow demands. Nitric oxide delivery during inspiration has been achieved with several techniques, including delivery through a nebulizer-type injection mechanism,65 blending with air or nitrogen before delivery into the air intake port of the ventilator,48 49 and injection through recently developed, digitally controlled nitric oxide intake valves.29 55 Significant variations in the individual patient's day-to-day response to inhaled nitric oxide require frequent reassessment of the optimal inhaled nitric oxide concentration to maximize its beneficial effects while simultaneously minimizing the detrimental effects of oxides of nitrogen. Therefore, concentrations of inhaled nitric oxide and oxides of nitrogen should be monitored continuously. Chemiluminescence and electrochemical techniques have been used to monitor gas from the distal end of the inspiratory limb of the ventilator circuit.90 91 Currently, chemiluminescence analyzers constitute the analytical standard for monitoring concentrations of nitric oxide and other oxides of nitrogen in the clinical setting. The performance characteristics of several commercially available chemiluminescence analyzers were compared recently.90 On the other hand, electrochemical detectors are cheaper, smaller, and sufficiently sensitive to monitor nitric oxide concentrations in the range between ppb and 20 ppm.91 These devices also accurately measured oxides of nitrogen. Clinicians should be aware that both pressure and humidity can influence the performance of electrochemical detectors.91 Methemoglobin levels should also be monitored frequently as an additional index of toxicity. Exhaled gas from patients breathing nitric oxide may be enriched with nitrogen oxides. As a result, systems to scavenge exhaled gases should be used to prevent their accumulation in the patient's room. Scavenging of oxides of nitrogen from the expiratory limb has been achieved by diverting the exhaled gas to wall suction, to the outdoors, or to canisters containing soda lime or other absorbent materials.88 Although many investigators report using these scavenging techniques, the necessity of this precaution remains controversial. Investigators in the United Kingdom have recently proposed that the scavenging of exhaled gases during nitric oxide administration is generally unnecessary in a well-ventilated unit with at least 10 to 12 air changes/h.88 As described above, the abrupt discontinuation of inhaled nitric oxide therapy should be avoided, and systems for delivering nitric oxide during transport should be available.86

Additional Approaches for Manipulating Nitric Oxide Production and Availability
Although inhaled nitric oxide represents an effective method for delivering nitric oxide to the lung, other approaches for targeting delivery of nitric oxide to nonpulmonary sites have been explored and represent alternative strategies that could potentially target nitric oxide to the lung. For instance, the modification of nitric oxide donor compounds by the addition of alkyl moieties has been exploited to prevent the spontaneous release of nitric oxide and to increase delivery to the liver, where hepatic enzymes stimulate the release of nitric oxide. This organ-specific nitric oxide delivery strategy effectively reduced experimentally induced liver damage in an animal model.92 Gene therapy that increases the expression of NOS at localized sites is also under exploration as a strategy to enhance the local rate of nitric oxide production in specific vascular beds.93 94 As discussed previously, investigators have also examined the simultaneous administration of nitric oxide and phosphodiesterase inhibitors to enhance increases in cGMP and to amplify cyclic nucleotide-dependent effects of nitric oxide.61 62 On the other hand, NOS inhibitors have been used to examine the role of endogenous nitric oxide in various physiological and pathophysiological processes. For instance, NOS inhibitors have been examined as an experimental form of therapy for disorders (eg, sepsis) that are thought to involve the overproduction of nitric oxide or its metabolites.23 Future clinical studies will probably define additional strategies for manipulating the nitric oxide pathway in vivo, because basic investigation continues to refine our understanding of nitric oxide biology.


   Conclusion
TOP
 Abstract
 Introduction
 Background
 Pulmonary Actions of Nitric...
 Inhaled Nitric Oxide Delivery
 Conclusion
References
 
These studies indicate that nitric oxide plays a critical role in pulmonary vascular function and dysfunction. Current evidence indicates that nitric oxide may have beneficial effects under certain circumstances but detrimental effects under others. Nitric oxide also participates in airway function, in the regulation of inflammation, and in a variety of other factors in the pathogenesis of lung disease. Inhaled nitric oxide can be administered to patients with few short-term adverse effects. It provides selective pulmonary vasodilation in a variety of lung diseases associated with pulmonary hypertension while having little effect on systemic hemodynamics. Currently, however, it represents a promising but still experimental form of therapy for adult lung disease. Numerous issues remain to be addressed before inhaled nitric oxide can be routinely applied. First and foremost, large trials are needed to demonstrate whether inhaled nitric oxide alters outcome. Additional progress is needed in the development of safe, reliable, and affordable methods for delivering nitric oxide to patients with lung disease. Specific patient groups that respond to inhaled nitric oxide will need to be defined, and the optimal concentration and duration of therapy must be established. Improved methods for identifying responsive patients will be needed, and the optimal time for initiating inhaled nitric oxide therapy will need to be established. Additional studies investigating nitric oxide in combination with other traditional or experimental forms of therapy will help clarify whether nitric oxide therapy has any role to play in combined modality approaches of treating lung disease. Success in addressing these issues will depend on continued advances in our understanding of how nitric oxide regulates or participates in the pathogenesis of lung disease at a cellular and molecular level and the successful translation of that specific knowledge into clinical trials.


   Footnotes
 
Abbreviations: cGMP = cyclic 3',5'-guanosine monophosphate; NANC = nonadrenergic noncholinergic; NO2 = nitrogen dioxide; NOS = nitric oxide synthase; ONOO- = peroxynitrite; ppb = parts per billion; / = ventilation/perfusion

Received for publication June 26, 1998. Accepted for publication September 1, 1998.


   References
TOP
 Abstract
 Introduction
 Background
 Pulmonary Actions of Nitric...
 Inhaled Nitric Oxide Delivery
 Conclusion
 References
 

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