Inhaled Nitric Oxide: A Selective Pulmonary Vasodilator: Current Uses and Therapeutic
`Potential
`Fumito Ichinose, Jesse D. Roberts, Jr and Warren M. Zapol
`
`Circulation
`
`2004;109:3106-3111
`Circulation. 
`doi: 10.1161/01.CIR.0000134595.80170.62
`is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
`Copyright © 2004 American Heart Association, Inc. All rights reserved.
`Print ISSN: 0009-7322. Online ISSN: 1524-4539
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`Review: Cardiovascular Drugs
`
`Inhaled Nitric Oxide
`A Selective Pulmonary Vasodilator
`Current Uses and Therapeutic Potential
`
`Fumito Ichinose, MD; Jesse D. Roberts, Jr, MD; Warren M. Zapol, MD
`
`Since the recognition of nitric oxide (NO) as a key
`
`the
`endothelial-derived vasodilator molecule in 1987,
`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 pharma-
`cology 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 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 con-
`trolled 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 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 Action
`After inhalation, NO diffuses rapidly across the alveolar-
`capillary membrane into the subjacent smooth muscle of pul-
`monary 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 PDE isozymes, PDE5 is considered to be
`the most active cGMP-hydrolyzing PDE in smooth muscle (for
`review, see the work by Rybalkin et al8). PDE5 has a high
`affinity for cGMP and is selectively inhibited by compounds
`such as zaprinast, sildenafil, and verdenafil.
`In addition to its pulmonary vasodilating effects, inhaled
`NO has several other effects in the lung. For instance, inhaled
`NO has been shown to cause bronchodilation9,10 and to
`possess antiinflammatory11 and antiproliferative12 effects.
`
`Enhancement of Ventilation-Perfusion Matching
`by NO Inhalation
`The intrapulmonary distribution of ventilation and blood flow
`[ventilation-perfusion (V˙ /Q˙ ) distribution] is a major determi-
`nant of the efficiency of transpulmonary oxygenation and
`determines the partial pressure of oxygen in systemic arterial
`blood (PaO2). In the normal lung, a low oxygen tension constricts
`the vascular bed in hypoxic regions and redistributes blood flow
`
`From the Departments of Anesthesia and Critical Care (F.I., J.D.R., W.M.Z.) and Pediatrics (J.D.R.), Massachusetts General Hospital, and Harvard
`Medical School, Boston, Mass.
`Dr Roberts is a member of the Scientific Advisory Board of INOTherapeutics, a company that sells inhaled nitric oxide gas. Dr Roberts is not
`compensated for this activity by the company. The Massachusetts General Hospital owns patents covering the use of nitric oxide inhalation, which it has
`licensed to INO Therapeutics, a division of AGA Linde, and Dr Zapol receives a portion of the royalties.
`Correspondence to Fumito Ichinose, MD, Department of Anesthesia and Critical Care, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114.
`E-mail ichinose@etherdome.mgh.harvard.edu
`(Circulation. 2004;109:3106-3111.)
`© 2004 American Heart Association, Inc.
`Circulation is available at http://www.circulationaha.org
`
`DOI: 10.1161/01.CIR.0000134595.80170.62
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`Ichinose et al
`
`Inhaled Nitric Oxide
`
`3107
`
`Figure 1. NO signaling pathway in the
`lung. PKG indicates cGMP-dependent pro-
`tein kinases; NOS, NO synthase; L-arg,
`L-arginine; sGC, soluble guanylate cycla-
`ses; and RSNO, S-nitrosothiol.
`
`dilators ameliorates pulmonary hypertension in some infants, in
`many it does not. Extracorporeal membrane oxygenation
`(ECMO) therapy is lifesaving for some infants with pulmonary
`hypertension; however, it is costly, invasive, and associated with
`important morbidities.
`In ventilated newborn animals with acute pulmonary hy-
`pertension, inhaled NO rapidly increases lung blood flow
`without causing systemic hypotension.19,20 Similar observa-
`tions of selective pulmonary vasodilation induced by inhaled
`NO have been made in ventilated newborn animals with
`pulmonary hypertension caused by sepsis, lung hypoplasia, or
`inflammation.21–24 In severely hypoxemic babies with pulmo-
`nary hypertension,
`inhaled NO rapidly increases arterial
`oxygen tension without causing systemic hypotension.25,26
`Randomized controlled studies demonstrated that NO inha-
`lation safely improves arterial oxygen levels and decreases
`
`Figure 2. Differing pathophysiological effects of inhaled pulmo-
`nary vasodilators and intravenous vasodilators. SNP indicates
`sodium nitroprusside; TNG, nitroglycerine; PGI2, prostaglandin
`I2; Qs/Qt, right-to-left shunt fraction; and SVR, systemic vascular
`resistance.
`
`toward lung regions with better ventilation and a higher intra-
`alveolar partial pressure of oxygen. Inhaled NO enhances this
`mechanism by increasing blood flow to well-ventilated lung
`areas that, in some diseases, have an elevated vasomotor tone.
`This vasodilatory effect of inhaled NO is in marked contrast to
`intravenously administered vasodilators. Such intravenous
`agents produce diffuse dilation of the pulmonary vasculature,
`including areas of nonventilated lung, thereby increasing in-
`trapulmonary shunting and reducing the PaO2 (Figure 2). The
`beneficial effects of inhaled NO to reduce intrapulmonary
`shunting and oxygenation have been demonstrated in patients
`with acute respiratory distress syndrome.13,14
`
`Metabolic Fate of Inhaled NO
`After inhalation, NO diffuses into the bloodstream and rapidly
`reacts with oxyhemoglobin to form methemoglobin (metHb)
`and nitrate and with deoxyhemoglobin to form iron-nitrosyl-Hb.
`Of note, recent reports describe a possible role for intravascular
`NO-derived molecules in conserving and stabilizing NO bioac-
`tivity that may contribute to the regulation of regional blood flow
`and oxygen delivery.15,16 Almost 70% of inhaled NO is excreted
`within 48 hours as nitrate in the urine.17 Blood levels of nitrate
`have been reported to increase ⬇4-fold during breathing of 80
`ppm NO.15
`
`Clinical Applications of Inhaled NO
`Pulmonary Hypertension of the Newborn
`Pulmonary hypertension in the newborn may be idiopathic or
`associated with premature closure of the ductus arteriosus,
`pneumonia, meconium aspiration, prematurity, or lung hypopla-
`sia.18 In many infants with pulmonary hypertension, right-to-left
`shunting of venous blood across the patent ductus arteriosus and
`foramen ovale produces severe systemic hypoxemia. In other
`patients, closure of these vascular conduits causes right-side
`heart failure and systemic hypotension. Although treatment with
`high levels of inspired oxygen, alkalosis, and intravenous vaso-
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`3108
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`Circulation
`
`June 29, 2004
`
`the need for ECMO therapy.27,28 On the basis of these data,
`the US Food and Drug Administration approved the use of
`inhaled NO for the treatment of newborns with hypoxic
`respiratory failure associated with clinical or echocardio-
`graphic evidence of pulmonary hypertension.
`
`Preventing Chronic Lung Disease in the Newborn
`Although advanced ventilator and medical therapies such as
`high-frequency ventilation and exogenous surfactant decrease
`the airway injury associated with the respiratory care of
`premature infants,
`the incidence of chronic lung disease
`remains high and causes important morbidity. Experimental
`data indicate that NO decreases vascular cell proliferation and
`that chronic NO inhalation may decrease the pulmonary
`vascular disease observed in the newborn lung.12,29 Recently,
`a randomized, placebo-controlled clinical study in a single
`center demonstrated that 7 days of NO inhalation prevents
`chronic lung disease in premature infants.30
`
`Safety and Cost-Effectiveness of Inhaled NO in
`the Newborn
`Large clinical trials have demonstrated that NO inhalation is
`safe in the hypoxemic term newborn. Inhaled NO has not
`been associated with clinically evident bleeding in babies
`with pulmonary disease. In premature babies, studies suggest
`that inhaled NO does not increase the incidence of intraven-
`tricular hemorrhages.30 –33
`Several studies indicate that NO inhalation is a cost-effective
`therapy for treating newborns with hypoxic respiratory failure in
`part because it decreases the need for ECMO.34,35
`
`Diagnostic Use of Inhaled NO
`Pulmonary Vasoreactivity Testing in the Cardiac
`Catheterization Laboratory
`Demonstration of a positive response to vasodilating agents in
`patients with pulmonary hypertension correlates with a favorable
`long-term clinical outcome.36 Although a number of vasodila-
`tors, including intravenous prostacyclin and calcium channel
`blockers, have been used for diagnostic testing during cardiac
`catheterization, systemic administration of these agents can
`produce severe hypotension, increased intrapulmonary right-to-
`left shunting, and death.37,38 In contrast, recent studies indicate
`that inhaled NO safely and effectively assesses the capacity for
`pulmonary vasodilation in pediatric39 and adult patients40,41 with
`pulmonary hypertension without causing systemic hypotension
`and predicts responsiveness to medical vasodilator therapy.42
`For example, a ⬎20% decrease in pulmonary artery pressure or
`pulmonary vascular resistance (PVR) to inhaled NO accurately
`predicts a subsequent response to oral vasodilators such as
`nifedipine.38,43 According to a survey in 2000, 94% of pediatric
`cardiologists consider inhaled NO to be useful in testing pulmo-
`nary vasoreactivity in the cardiac catheterization laboratory.44
`
`Treatment of Perioperative Pulmonary
`Hypertension With Inhaled NO
`Congenital Heart Disease
`Postoperative pulmonary hypertensive crises are an important
`cause of morbidity and mortality after surgery for congenital
`heart disease45 and may be precipitated by diminished NO
`production resulting from endothelial dysfunction.46 Inhaled NO
`
`has been reported to ameliorate the postoperative pulmonary
`hypertension of congenital heart disease47 and to decrease the
`need for postoperative ECMO.48 In a randomized double-blind
`study, Miller and colleagues49 examined the effects of the
`prophylactic use of inhaled NO in high-risk infants undergoing
`congenital heart surgery. They reported that compared with
`placebo, infants who after surgery inhaled 10 ppm NO contin-
`uously until just before extubation had fewer pulmonary hyper-
`tensive crises and shorter times to eligibility for extubation.
`
`Cardiac Transplantation
`Pulmonary hypertension in the cardiac transplant recipient is a
`major cause of right-side heart failure and early death. Goals in
`the management of acute right ventricular (RV) failure include
`preservation of coronary perfusion through maintenance of
`systemic blood pressure and reducing RV afterload by decreas-
`ing the PVR.50 Inhaled NO has been shown in a small group of
`patients to selectively reduce PVR and to enhance RV stroke
`work after cardiac transplantation.51
`
`Insertion of Left Ventricular Assist Device
`RV dysfunction occurs in 20% to 50% of patients after insertion
`of a left ventricular assist device (LVAD).52 The ability of the
`RV to pump sufficient quantities of blood to the LVAD is
`critically related to the intrinsic contractility of the RV and the
`RV afterload, which is influenced by the PVR. The PVR is
`usually elevated in patients with long-standing congestive heart
`failure and can be further increased in the early postoperative
`period by the effects of cardiopulmonary bypass. A trial of
`inhaled NO is recommended before implantation of an RV assist
`device is considered because this invasive procedure may be
`avoided if there is a salutary response to inhaled NO.53 In a
`randomized, double-blinded trial, Argenziano and coworkers54
`demonstrated the hemodynamic benefits of inhaled NO (de-
`creased pulmonary artery pressure and increased LVAD flow) in
`LVAD recipients with pulmonary hypertension.
`
`Inhaled NO to Treat Ischemia-Reperfusion Injury
`Ischemia-reperfusion injury is one of the major causes of
`early graft failure after lung transplantation. Inhaled NO has
`been shown to attenuate ischemia-reperfusion injury in the
`lung and other organs in preclinical55 and in clinical stud-
`ies.56,57 However, a recent randomized, placebo-controlled
`study demonstrated that inhaling 20 ppm NO beginning 10
`minutes after reperfusion does not affect the physiological or
`clinical outcome of patients after lung transplantation.58
`
`Inhaled NO and Acute Respiratory
`Distress Syndrome
`In early clinical studies of patients with severe acute respira-
`tory distress syndrome,
`inhaled NO has been shown to
`produce selective pulmonary vasodilation,13 to decrease pul-
`monary capillary pressure59 and pulmonary transvascular
`albumin flux,60 and to improve oxygenation.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
`trials61,62 and in 3 multicenter randomized trials.63– 65 Because
`most patients dying from acute respiratory distress syndrome
`suffer from multiple organ failure, it is unlikely that the
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`beneficial effects of a lung-selective therapy such as inhaled
`NO will alter the overall survival rate.
`
`Chronic Obstructive Pulmonary Disease
`Severe chronic obstructive pulmonary disease (COPD) is
`frequently complicated by pulmonary hypertension and hy-
`poxemia. Systemic hypoxemia in COPD is caused primarily
`by V˙ /Q˙ mismatching and not by intrapulmonary right-to-left
`shunting (as in acute respiratory distress syndrome). A recent
`randomized controlled trial demonstrated that the combined
`use of supplemental oxygen and inhaled NO for a period of 3
`months via a portable inspiratory pulsing device caused a
`greater improvement of pulmonary hemodynamics than sup-
`plemental oxygen alone and did not worsen the oxygenation
`of COPD patients.66
`
`Toxicity and Side Effects of Inhaled NO
`Inhalation of low levels of NO appears to be safe. The major
`clinical toxicity is due to the formation of NO2 and methe-
`moglobinemia. A review of the toxicology of inhaled NO has
`recently been published.67
`
`Nitrogen Dioxide and Methemoglobinemia
`Formation of NO2 during NO breathing is dependent on the NO
`concentration, inspiratory oxygen concentration (FiO2), and res-
`idence time of these gases.68 Increased airway reactivity has
`been reported in humans after exposures to as low as 1.5 ppm
`NO2.69 At higher inhaled NO2 doses, pulmonary edema is the
`major toxicological effect70 and can result in death.71 In a
`simulation using a model lung and commercially available
`ventilators, production of NO2 during NO inhalation at 20 ppm
`appears to be minimal (⬍0.7 ppm) even with an FiO2 of 95%.72
`Inhaled NO can combine with Hb to form nitrosylhemo-
`globin, which is rapidly oxidized to metHb. The rates of
`uptake and release of NO from ferrous (Fe2⫹) Hb are 105- to
`106-fold greater than those of oxygen. Tissue hypoxia can be
`produced at excessive circulating metHb concentrations.67
`The enzyme metHb reductase rapidly converts metHb to Hb
`in the red blood cell.
`Blood metHb concentrations and inspired NO2 concentra-
`tions are frequently monitored during clinical administration
`of inhaled NO. Significant methemoglobinemia or NO2 for-
`mation is uncommon in patients breathing NO at doses ⱕ80
`ppm (see review by Steudel et al73).
`
`Rebound Pulmonary Hypertension
`Sudden discontinuation of inhaled NO can cause severe
`rebound pulmonary hypertension, an increase in intrapulmo-
`nary right-to-left shunting, and a decreased PaO2.13 It has been
`suggested that downregulation of endogenous NO synthesis
`and/or elevated endothelin-1 levels by inhaled NO is respon-
`sible in part for this rebound phenomenon.74,75 Although the
`precise underlying mechanisms remain to be elucidated, to
`avoid rebound pulmonary hypertension, a slow, stepwise
`reduction of the inhaled NO concentration is recommended.
`
`Increased LV Filling Pressure
`Inhaled NO has been demonstrated to be a selective pulmo-
`nary vasodilator in heart failure patients, although breathing
`NO was often accompanied by an elevation in LV filling
`
`Ichinose et al
`
`Inhaled Nitric Oxide
`
`3109
`
`pressure in patients with severe LV dysfunction.37,76 Investi-
`gators learned that the elevation in LV filling pressure that
`occurs with NO breathing is due to the augmentation of
`filling into a relatively noncompliant LV and is not caused by
`a negative inotropic effect.77,78 Nonetheless, it is important to
`be aware of the possibility that inhaled NO can produce
`pulmonary vasodilation and may overwhelm a failing LV,
`thereby producing pulmonary edema.79
`
`Delivery and Monitoring of NO
`NO can be safely inhaled when delivered by face mask, by nasal
`cannula, or via an endotracheal tube. An ideal inhaled NO
`delivery device requires delivery synchronized with respiration
`and minimal production of NO2 and should be simple to use with
`full monitoring capacity (high and low alarms and precise
`monitoring of NO, NO2, and O2).80 This can be achieved with
`several commercially available systems. Although NO and NO2
`are more accurately measured by chemiluminescence devices,
`electrochemical detectors have proved adequate for measuring
`inhaled NO and NO2 levels and are integrated components of
`several clinical delivery systems.
`
`Future Directions
`Randomized clinical trials will unquestionably lead to a more
`precise definition of the role of inhaled NO in treating various
`clinical situations in which the physiological benefits of
`inhaled NO have been suggested by preclinical studies and
`uncontrolled clinical trials. Multicenter, randomized clinical
`trials are needed in several areas, including the diagnostic use
`of inhaled NO and treatment of postoperative pulmonary
`hypertension after adult cardiac surgery.51
`Although most patients breathe NO for a relatively short
`period of time (hours to days), long-term use of inhaled NO
`has been reported in a limited number of ambulatory patients
`with pulmonary hypertension,81,82 pulmonary fibrosis,83 and
`COPD.66 In this regard, pharmacologically extending the
`brief half-life of NO in the lung is an attractive strategy.
`Inhibitors of PDE5 such as zaprinast and sildenafil potentiate
`and/or prolong the pulmonary vasodilating effects of inhaled
`NO.84 – 86 Of note, sildenafil has been shown to be a selective
`pulmonary vasodilator in patients with pulmonary hyperten-
`sion.86 – 88 Exploration of the effects of PDE inhibitors alone
`and in combination with inhaled NO warrants further studies.
`In the last several years, data supporting the extrapulmo-
`nary effects of inhaled NO have accumulated. For example,
`inhaled NO appears to modestly inhibit platelet activation in
`some species89,90 and to attenuate neutrophil-mediated ische-
`mia-reperfusion injury.55 Decreased bioavailability of NO
`may contribute to the pathogenesis of sickle cell disease, and
`inhaled NO has been suggested to modulate the course of this
`disease.91 In this regard,
`the treatment of vaso-occlusive
`crises with inhaled NO in patients with sickle cell disease
`may become a promising therapy. Preliminary results from a
`randomized, double-blind, placebo-controlled trial demon-
`strated beneficial effects of inhaled NO in attenuating the
`intensity and duration of pain in acute vaso-occlusive crises
`in pediatric patients with sickle cell disease.92
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`3110
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`
`Conclusions
`Inhaled NO is the first vasodilator to produce truly selective
`pulmonary vasodilation. A large number of laboratory and
`clinical research studies have been performed to delineate the
`biochemistry, physiology, side effects, and clinical efficacy of
`inhaled NO in various diseases of children and adults. Nearly
`simultaneously, the clinical use of inhaled NO has become
`widespread. During the past 14 years, inhaled NO has been used
`to treat pulmonary hypertension and hypoxemia in tens of
`thousands of pediatric and adult patients worldwide. For many,
`it is lifesaving. The experimental use of inhaled NO continues to
`be a unique and fascinating approach to studying and treating
`diseases as diverse as acute rejection of the transplanted lung and
`sickle cell crisis. In evaluations of this complex field, it is critical
`that our view not become colored by a single study of a
`particular disease state. As with most medical advances, it is the
`accumulation of a wide-ranging body of clinical research that
`will eventually determine the place of NO inhalation therapy in
`our therapeutic armamentarium for a number of diseases.
`
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