Author: Larry Bernstein, MD
Creagh-BrownBC, Griffiths MJD, Evans TW. “Bench-to-bedside review: Inhaled nitric oxide therapy in adults”. Crit Care. 2009; 13(3): 221. Published online 2009 May 29. doi: 10.1186/cc7734. PMCID: PMC2717403.
Part I. Basic and downstream effects of inhaled NO
Inhaled nitric oxide (NO), a mediator of vascular tone produces pulmonary vasodilatation with low pulmonary vascular resistance. The route of administration delivers NO selectively improving oxygenation. Developments in our understanding of the cellular and molecular actions of NO may help to explain the results of randomised controlled trials of inhaled NO.
Nitric oxide (NO), a determinant of local blood flow is formed by the action of NO synthase (NOS) on L-arginine in the presence of molecular oxygen. Inhaled NO results in preferential pulmonary vasodilatation it lowers pulmonary vascular resistance (PVR), correcting hypoxic pulmonary vasoconstriction (HPV). However, in the therapeutic use of gaseous NO to patients with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), and related conditions, evidence of a benefit is disappointing.
Administration of inhaled nitric oxide to adults
The licensed indication of inhaled NO is restricted to persistent pulmonary hypertension in neonates. Pharma-ceutical NO is costly, and raises concerns over potential adverse effects of NO. Therefore, an advisory board under the auspices of the European Society of Intensive Care Medicine and the European Association of Cardiothoracic Anaesthesiologists published recommendations in 2005 . The sponsor had no authorship or editorial control over the content of the meetings or any subsequent publication.
The NO is administered as a NO/nitrogen mixture to the tubing of ventilated patients, and the NO and NO2 concen-trations are monitored, with methemoglobin levels measured regularly. Even though rapid withdrawal induces rebound pulmonary hypertension, it is avoided by gradual withdrawal . There is variation in vasodilatory response to administered NO between patients  and in the same patient, and there is a leftward shift in the dose-response curve with use. Toxicity and loss of the therapeutic effect is a risk of excessive NO administration . A survey of 54 intensive care units in the UK as well as results of a European survey revealed that the most common usage was in treating ARDS, followed by pulmonary hypertension , . The only use of therapeutic inhaled NO usage in US adult patients reported from a single medical site (2000 to 2003) reveals that the most common application was in the treatment of RVF in patients after cardiac surgery and then, in surgical and medical patients for refractory hypoxemia.
Inhaled nitric oxide in acute lung injury and acute respiratory distress syndrome
ALI and ARDS are characterised by hypoxemia despite high inspired oxygen (PaO2/FiO2 [arterial partial pressure of oxygen/fraction of inspired oxygen] ratios of less than 300 mm Hg [40 kPa] and less than 200 mm Hg [27 kPa], respectively) in the context of evidence of pulmonary edema, and the absence of left atrial hypertension suggestive of a cardiogenic mechanism . Pathologically, there is alveolar inflammation and injury leading to increased pulmonary capillary permeability and a serous alveolar fluid with inflammatory infiltrate. This is manifest clinically as hypoxemia, inadequate alveolar perfusion, venous-arterial shunting, atelectasis, and reduced compliance.
Since 1993, when the first investigation on the effects of NO on adult patients with ARDS was published , there have been several randomised controlled trials (RCTs) examining the effect in ALI/ARDS (Table 1). The first systematic review and meta-analysis  found no beneficial effect on mortality or ventilator-free days. A more recent meta-analysis that considered 12 RCTs with a total of 1,237 patients  concluded:  no mortality benefit,  improved oxygenation at 24 hours (13% improvement in PaO2/FiO2 ratio) at the cost of increased risk of renal dysfunction (relative risk 1.50, 95% confidence interval 1.11 to 2.02). Based on a trend to increased mortality in patients receiving NO, the authors suggested that it not be used in ALI/ARDS. Why the NO fails to improve patient outcomes requires clarifying the effects of inhaled NO that occur outside the pulmonary vasculature.
Studies of inhaled nitric oxide in adult patients with acute lung injury/acute respiratory distress syndrome
The biological action of inhaled nitric oxide
NO was first identified as an endothelium-derived growth factor (EDGF) and an important determinant of local blood flow . NO reacts very rapidly with free radicals, certain amino acids, and transition metal ions. The action of NOS on the semi-essential amino acid L-arginine in the presence of molecular oxygen and its identity with EDGF was the basis for the Nobel discovery of Furthgott and others . Three isoforms of NO are: neuronal NOS, inducible NOS (iNOS or NOS2), and endothelial NOS (eNOS or NOS3). Calcium-independent iNOS generates higher concentrations of NO  than the other isoforms and its role has been implicated in the pathogenesis septic shock.
Exogenous NO is administered by controlled inhalation or through intravenous administration of NO donors. It was thought to have no remote or non-pulmonary effects. The effect NO has on circulating targets is shown. (Figure 1).
New paradigm of inhaled nitric oxide (NO) action. Figure 1 illustrates the interactions between inhaled NO and the contents of the pulmonary capillaries. Although NO was considered to be inactivated by hemoglobin (Hb), proteins including Hb and albumin contain reduced sulphur (thiol) groups that react reversibly with NO causing it to lose its vasodilating properties. A stable derivate, in the presence of oxyhemoglobin, is formed by a reaction resulting in nitrosylation of a cysteine residue of the β subunit of Hb. The binding of NO to the heme iron predominates in the deoxygenated state . If circulating erythrocytes store and release NO peripherally in areas of low oxygen tension, this augments peripheral blood flow and oxygen delivery via decreased systemic vascular resistance . Thus, NO can act as an autocrine or paracrine mediator but when stabilised may exert endocrine influences . In addition to de novo synthesis, supposedly inert anions nitrate (NO3-) and nitrite (NO2-) can be recycled to form NO, and nitrite might mediate extra-pulmonary effects of inhaled NO . In the hypoxic state, NOS cannot produce NO and deoxy-hemoglobin catalyses NO release from nitrite, potentially providing a hypoxia-specific vasodilatory effect. Given that effects of inhaled NO are mediated in part by S-nitrolysation of circulating proteins, therapies aiming at directly increasing S-nitrosothiols have been developed.
Introduce another effect. When inhaled with high concentrations of oxygen, gaseous NO slowly forms the toxic product NO2, but other potential reactions include nitration (addition of NO2+), nitrosation (addition of NO+), or nitrosylation (addition of NO), and reaction with reactive oxygen species such as superoxide to form reactive nitrogen species (RNS) such as peroxynitrite (ONOO-). These reactions of NO, potentially cytotoxic NO2 , and covalent nitration of tyrosine in proteins by RNS lead to measures of oxidative stress.
In a small observational study, inhaled ethyl nitrite safely reduced PVR without systemic side effects in persistent pulmonary hypertension of the newborn . In animal models, pulmonary vasodilatation was maximal in hypoxia and had prolonged duration of action after cessation of administration .
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Creagh-BrownBC, Griffiths MJD, Evans TW. “Bench-to-bedside review: Inhaled nitric oxide therapy in adults”. Crit Care. 2009; 13(3): 221. Published online 2009 May 29. doi: 10.1186/cc7734. PMCID: PMC2717403.
This article is modified from a review series on Gaseous mediators, edited by Peter Radermacher.
Other articles in the series can be found online athttp://ccforum.com/series/gaseous_mediators
Part II. Application of inhaled NO and circulatory effects
NO activates soluble guanylyl cyclase by binding to its heme group to form cyclic guanosine 3’5′-monophosphate (cGMP) activating a protein kinase. Consequently, myosin sensitivity to calcium-induced contraction is reduced lowering the intracellular calcium concentration as a result of activating calcium-sensitive potassium channels and inhibiting release of calcium. The smooth muscle cell (SMC) relaxation with decrease in pulmonary vascular resistance (PVR) and decreased RV after load could improve cardiac output. However, left ventricular impairment associated with decrease in PVR allows increased RV output to a greater extent than the left ventricle can accommodate and the increase in left atrial pressure reinforces pulmonary edema.
Inhaled NO augments the normal physiological mechanism of hypoxic pulmonary ventilation (HPV) and improves systemic oxygenation (Figure 2). The effects of inhaled NO on systemic oxygenation are limited. Experiments show that intravenously administered vasodilators counteract HPV . However, the non-pulmonary effects of inhaled NO include increased renal and hepatic blood flow and oxygenation .
Hypoxic pulmonary vasoconstriction (HPV). (a) Normal ventilation-perfusion (VQ) matching. (b) HPV results in VQ matching despite variations in ventilation and gas exchange between lung units. (c) Inhaled nitric oxide (NO) augmenting VQ matching by vasodilating.
Non-cardiovascular effects relevant to lung injury
Neutrophils are important cellular mediators of ALI. Limiting neutrophil production of oxidative species and proteolysis reduces lung injury. In neonates, prolonged administration of NO diminished neutrophil-mediated oxidative stress . Neutrophil deformability and CD18 expression were reduced in animal models  accomp-anied by decreases in adhesion and migration . These changes limit damage to the alveolar-capillary membrane and the accumulation of protein-rich fluid within the alveoli. Platelet activation and aggregation, intra-alveolar thrombi, contribute to ALI. Inhaled NO attenuates the procoagulant activity in animal models of ALI  and a similar effect is seen in patients with ALI , but also in healthy volunteers [23,24]. In patients with ALI, decreased surfactant activity in the alveoli and noncompliance, as we recall is hyaline membrane disease accompanied by impaired pulmonary function . The deleterious effects of the NO damages the alveolar wall with loss of surfactant by reactions with RNS . Finally, prolonged exposure to NO in experimental models impairs cellular respiration .
The failure of inhaled NO to improve outcome in ALI/ARDS is therefore potentially due to several factors. First, patients with ALI/ARDS die of multi-organ failure, as the actions of NO are not expected to improve the outcome of multi-organ failure, which is a cytokine driven process leading to circulatory collapse. Indeed, the expected beneficial effect of inhaled NO is abrogated by detrimental downstream systemic effects discussed. Second, ALI/ARDS is a heterogeneous condition with diverse causes. Finally, using inhaled NO without frequent dose titration risks unwanted systemic effects without the expected benefits.
Other clinical uses of inhaled nitric oxide
Pulmonary hypertension and acute right ventricular failure
RVF may develop when there is abnormally elevated PVR and/or impaired RV perfusion. Table 2 lists common causes of acute RVF. The RV responds poorly to inotropic agents but is exquisitely sensitive to after load reduction.
Reducing PVR will have beneficial effects on cardiac output and therefore oxygen delivery. In the context of high RV afterload with low systemic pressures or when there is a limitation of flow within the right coronary artery , RV failure triggers a backward failure of venous return, as diagrammatically represented in Figure 3.
Pathophysiology of right ventricular failure. CO, cardiac output; LV, left ventricle; PAP, pulmonary artery pressure; PVR, pulmonary vascular resistance; RV, right ventricle.
Inhaled NO is used when RV failure complicates cardiac surgery, as cardiopulmonary bypass per se causes diminished endogenous NO production . There is marked variation in response to inhaled NO between patients  and in the same patient over time. After prolonged use, there is a leftward shift in the dose-response curve. The risk of excessive NO administration is associated with toxicity and loss of the therapeutic effect without regular titration against a therapeutic goal . Further, cardiac transplantation may be complicated by pulmonary hypertension and RVF that are improved with NO . Early ischemia-reperfusion injury after lung transplantation manifests clinically as pulmonary edema and is a cause of significant morbidity and mortality [33,34]. Although NO has been administered in this circumstance , it hasn’t prevented ischemia-reperfusion injury in clinical lung transplantation . Inhaled NO has been used successfully in patients with cardiogenic shock and RVF associated with acute myocardial infarction [37,38,46], and in patients with acute RVF following acute pulmonary venous thrombo-emboli [39, 47]. An explanation is needed in view of the downstream effects of systemic vasoconstriction and MOF previously identified. No systematic evaluation of inhaled NO and its effect on clinical outcome has been conducted in these conditions.
Acute chest crises of sickle cell disease
Acute chest crises are the second most common cause of hospital admission in patients with sickle cell disease (SCD) and are responsible for 25% of all related deaths . Acute chest crises are manifest by fever, respiratory symptoms or chest pain, and new pulmonary infiltrate on chest x-ray. The major contributory factors are related to vaso-occlusion. Hemolysis of sickled erythrocytes releasing Hb into the circulation generates reactive oxygen species and reacts with NO . In SCD, the free Hb depletes NO. In addition arginase 1 is released, depleting the arginine needed for NO production, . While secondary PVH is common in adults with SCD the physiological rationale for the use of inhaled NO needs to be considered, except for the complication just referred to. Thus far, iNO has failed to demonstrate either persistent improvements in physiology or beneficial effects on any accepted measure of outcome in clinical trials (other than its licensed indication in neonates). Therefore, inhaled NO is usually reserved for refractory hypoxemia.
Potential problems in designing and conducting RCTs in the efficacy of inhaled NO are numerous. Blinded trials will be difficult to conduct as the effects of inhaled NO are immediately apparent. Recruitment is limited as there is little time for consent/assent or randomization. Finally, industry funding might cast doubt on the independence of the trial results.
Inhaled NO is an unproved tool in the intensivist’s armamentarium of rescue therapies for refractory hypoxemia even though it has an established role in managing complications of cardiac surgery and in heart/lung transplantation. The current place for inhaled NO in the management of ALI/ARDS, acute sickle chest crisis, acute RV failure, and acute pulmonary embolism is a rescue therapy.
ALI: acute lung injury; ARDS: acute respiratory distress syndrome; Hb: haemoglobin; HPV: hypoxic pulmonary vasoconstriction; iNO: inhaled nitric oxide; iNOS: inducible nitric oxide synthase; NO: nitric oxide; NO2: nitrogen dioxide; NOS: nitric oxide synthase; PaO2/FiO2: arterial partial pressure of oxygen/fraction of inspired oxygen; PVR: pulmonary vascular resistance; RCT: randomised controlled trial; RNS: reactive nitrogen species; RV: right ventricle; RVF: right ventricular failure; SCD: sickle cell disease; SMC: smooth muscle cell.
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