Home Educatione-Learning Inhaled Nitric Oxide Therapeutic Uses and Potential Hazards
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Inhaled Nitric Oxide Therapeutic Uses and Potential Hazards

PCCSU Volume 25, Lesson 22

PCCSU

The American College of Chest Physicians offers this lesson as a review of a previously offered self-study program. The program provides information on pulmonary, critical care, and sleep medicine issues. CME is no longer available for the PCCSU program.

Objectives

  • Update your knowledge and understanding of pulmonary medicine topics.
  • Update your knowledge and understanding of critical care medicine topics.
  • Update your knowledge and understanding of sleep medicine topics.
  • Learn clinically useful practice procedures.

CME Availability

Effective July 1, 2013, PCCSU Volume 25 is available for review purposes only.

Effective December 31, 2012, PCCSU Volume 24 is available for review purposes only.

Effective December 31, 2011, PCCU Volume 23 is available for review purposes only. CME credit for this volume is no longer being offered

Effective December 31, 2010, PCCU Volume 22 is available for review purposes only. CME credit for this volume is no longer being offered.

Accreditation Statement

The American College of Chest Physicians is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

CME Statement

Credit no longer available as of July 1, 2013.

Disclosure Statement

The American College of Chest Physicians (CHEST) remains strongly committed to providing the best available evidence-based clinical information to participants of this educational activity and requires an open disclosure of any potential conflict of interest identified by our faculty members. It is not the intent of CHEST to eliminate all situations of potential conflict of interest, but rather to enable those who are working with CHEST to recognize situations that may be subject to question by others. All disclosed conflicts of interest are reviewed by the educational activity course director/chair, the Education Committee, or the Conflict of Interest Review Committee to ensure that such situations are properly evaluated and, if necessary, resolved. The CHEST educational standards pertaining to conflict of interest are intended to maintain the professional autonomy of the clinical experts inherent in promoting a balanced presentation of science. Through our review process, all CHEST CME activities are ensured of independent, objective, scientifically balanced presentations of information. Disclosure of any or no relationships will be made available for all educational activities.

CME Availability

Volume 25 Through June 30, 2013
Volume 24 Through December 31, 2012
Volume 23 Through December 31, 2011
Volume 22 Through December 31, 2010

Hardware/software requirements: Web browsing device with working Web browser.

PCCSU Volume 25 Editorial Board

Editor-in-Chief
Steven A. Sahn, MD, FCCP

Director, Division of Pulmonary and Critical Care Medicine, Allergy, and Clinical Immunology
Medical University of South Carolina
Charleston, SC

Dr. Sahn has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Deputy Editor
Richard A. Matthay, MD, FCCP

Professor of Medicine
Section of Pulmonary and Critical Care Medicine
Yale University School of Medicine
New Haven, CT

Dr. Matthay has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Alejandro C. Arroliga, MD, FCCP
Professor of Medicine
Texas A&M Health Science Center
College of Medicine
Temple, TX

Dr. Arroliga has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Paul D. Blanc, MD, FCCP
Professor of Medicine
University of California, San Francisco
San Francisco, CA

Dr. Blanc has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health, Flight Attendants Medical Research Institute – university grant monies
University of California San Francisco, US Environmental Protection Agency, California Environmental Protection Agency Air Resources Board – consultant fee
Habonim-Dror Foundation Board of Trustees – fiduciary position

Guillermo A. do Pico, MD, FCCP
Professor of Medicine
University of Wisconsin Medical School
Madison, WI

Dr. do Pico has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Ware G. Kuschner, MD, FCCP
Associate Professor of Medicine
Stanford University School of Medicine
Palo Alto, CA

Dr. Kuschner has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Teofilo Lee-Chiong, MD, FCCP
Associate Professor of Medicine
National Jewish Medical Center
Denver, CO

Dr. Lee-Chiong has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health – grant monies (from sources other than industry)
Covidien, Respironics, Inc. – grant monies (from industry-related sources)
Elsevier – consultant fee

Margaret Pisani, MD, MPH, FCCP
Assistant Professor of Medicine
Yale University School of Medicine
New Haven, CT

Dr. Pisani has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Stephen I. Rennard, MD, FCCP
Professor of Medicine
University of Nebraska Medical Center
Omaha, NE

Dr. Rennard has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

AstraZeneca, Biomark, Centocor, Novartis – grant monies (from industry-related sources)

Almirall, Aradigm, AstraZeneca, Boehringer Ingelheim, Defined Health, Dey Pharma, Eaton Associates, GlaxoSmithKline, Medacrop, Mpex, Novartis, Nycomed, Otsuka, Pfizer, Pulmatrix, Theravance, United Biosource, Uptake Medical, VantagePoint – consultant fee/advisory committee

AstraZeneca, Network for Continuing Medical Education, Novartis, Pfizer, SOMA – speaker bureau

Ex Officio
Gary R. Epler, MD, FCCP

Clinical Associate Professor of Medicine
Harvard Medical School
Brigham & Women's Hospital
Boston, MA

Dr. Epler has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Lilly Rodriguez
ACCP Staff Liaison

By Ivan Katz, RRT

Mr. Katz is Registered Respiratory Therapist at the University of California Medical Center - San Francisco, San Francisco, California.

Mr. Katz has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within this chapter.

Objectives

  1. Explore the history and genesis of the development of nitric oxide as an inhaled pharmacologic agent.
  2. Examine the structure, function, and mechanism of action that this signaling molecule expresses.
  3. Describe pathophysiologic conditions and patient populations for which inhaled nitric oxide (iNO) is currently considered.
  4. Understand the potential hazards and complications of iNO administration.
  5. Investigate recent applications and new directions in research for this distinctive and versatile molecule.

Key words: hypoxemia; nitric challenge; nitric oxide; pulmonary arterial hypertension

Abbreviations: ADP = adenosine diphosphate; ATP = adenosine triphosphate; ATPase = enzyme that catalyzes adenosine triphosphate; BPD = bronchopulmonary dysplasia; cGMP = cyclic guanosine monophosphate; ECMO = extra corporeal membrane oxygenation; Fio2 = fraction of inspired oxygen; GMP = guanosine monophosphate; GTP = guanosine-triphosphate; iNO = inhaled nitric oxide; LVAD = left ventricular assist device; NO = nitric oxide; NOS = nitric oxide synthase; P = pyrophosphate; PAH = pulmonary arterial hypertension; Pao2 = partial pressure of oxygen in arterial blood; PAP = pulmonary arterial pressure; PDE = phosphodiesterase; PPHN = persistent pulmonary hypertension of the newborn; Sao2 = saturation of oxygen in arterial blood; sGC = soluble guanylyl cyclase; V/Q = ventilation perfusion ratio

Knowledge Gap

Inhaled nitric oxide (iNO) therapy is a well-established treatment for newborns with hypoxemic respiratory failure. Despite this narrow US Food and Drug Administration-approved indication, the role of iNO has been expanded for other clinical indications in both infants and adults. Ongoing research shows great promise and potential for the augmentation of nitric oxide therapy alone and in concert with other adjunctive therapies for even greater expansion of its use. Potential adverse effects, however, need to be taken into account.

Historical Background

In 1847, following upon the work done by the French chemist Theophile-Jules Pelouez on nitrocellulose (gun cotton), a highly flammable compound used as a propellant for conventional projectile weapons of the time, Ascanio Sobrero discovered nitroglycerine, originally referred to as “pyroglycerine.” When Sobero put a small amount on his tongue, it produced a violent headache. Two years later, Constantin Hering exploited the headache-inducing properties of nitroglycerine as a homeopathic remedy. Alfred Nobel, of the eponymous Nobel Prize, combined nitroglycerine with diatomaceous earth and other absorbent materials, inventing dynamite, which he began manufacturing in 1851, thus acquiring much of his fortune. Nobel had angina but, ironically, refused to use nitroglycerine medicinally. Sir Thomas Lauder Brunton, a Scottish physician and a father of modern pharmacology, recommended its use for angina as early as 1867. Nitroglycerine officially entered into the British pharmacopoeia in an addendum, listed as a remedy for hypertension in 1890.

In the years leading up to the first World War, the nitroglycerine industry flourished, exposing industrial workers to the nitrate that they inhaled and absorbed through their fingertips. Workers grumbled about “Monday disease,” severe pounding headaches that would manifest after return to work following a brief absence. Nitroglycerine paste was also prescribed at one time to treat impotence. For that indication, it was rubbed on the penis, triggering smooth muscle cell relaxation and thus filling the local vasculature with blood, causing penile tumescence. Such use of the paste also caused severe headaches in both sexual partners.

Scientists knew that nitroglycerine and related chemical moieties manifest an intriguing set of pharmacologic effects, but from its discovery through the first half of the 20th century, little progress was made explaining its function and activity at the cellular level. It was not until the early 1950s that a specific endogenous pulmonary vasodilator was hypothesized and a theory was proposed accounting for the activity of nitrates in this regard. In 1977, Ferid Murad discovered that the substance mediating the effects of nitroglycerine was, in fact, nitric oxide (NO). Ten years later, researchers Louis Ignarro and Salvador Moncada independently identified the endothelial-derived relaxing factor as NO. In 1998, biochemist Robert Furchgott, who had discovered endothelial-derived relaxing factor; pharmacologist Louis Ignarro; and physician Ferid Murad all received the Nobel Prize for their discoveries concerning NO as the key second messenger, “signal molecule” for the cardiovascular system.1

Since then, NO has been heralded as a wonder substance, and it was even decreed “molecule of the year” in 1992. Although its primary role is as a vasodilator, NO also has been variously credited with the prevention of atherosclerosis by inhibiting aggregation of platelets, reducing free radicals, slowing vascular aging, and suppressing pathologic vascular muscle growth by causing hypertrophy of the vessels. All of these actions could play a role in the prevention of heart disease.

Structure and Function

L22StrandFun

NO is a diatomic colorless gaseous molecule. It is a free radical found naturally in the atmosphere and produced endogenously through a reaction catalyzed by variants of the enzyme nitric oxide synthase (NOS) acting on the “semiessential” amino acid l-arginine.2 Semiessential refers to the limited native biosynthesis of arginine, yielding quantities insufficient to support all of its metabolic functions and thus requiring exogenous supplementation. Although there are multiple NOS enzymatic variants, including bNOS (constitutive neuronal-type nitric oxide synthase), cNOS (constitutive NO synthase), and iNOS (inducible NO synthase), this lesson focuses on eNOS, the dominant production pathway and the one that is active in healthy vascular endothelial cells.3

Highly reactive, NO is also present naturally in the ambient environment. In the atmosphere, it occurs in concentrations of 10 to 100 parts per billion. It is also an important byproduct of combustion. For example, NO levels of 400 to 1,000 parts per million (ppm) have been measured in exhaled tobacco smoke. Commercially, NO is produced by the oxidation of ammonia at 750°C to 900°C (normally at 850°C) with platinum as the catalyst: 4 NH3 + 5 O2 → 4 NO + 6 H2O.

NO is a neurotransmitter essential to the inflammatory response and host immunity. It is also the signaling molecule involved in the second messenger system responsible for the regulation of smooth muscle tone. A signaling molecule is a substance producing a cellular response that, in turn, activates a cascade of intracellular events through an agent called a second messenger. Although typically a signaling molecule never enters the interior of the target cell but becomes affixed to a specific binding site on its surface, NO acts differently from that model. It is a free radical that easily penetrates the cell membrane (Fig 1), activating soluble guanylyl cyclase (sGC), also known as guanylate or guanyl cyclase. It does so by binding directly to its heme moiety to form a ferrous-nitrosyl-heme complex, leading to the creation of cyclic guanosine monophosphate (cGMP) (Fig 2). In this form, it binds to its principal mediator cGMP-dependent protein kinase (Fig 3), an important enzyme that activates the catalytic transfer of a phosphate from adenosine triphosphate (ATP) to target proteins through phosphorylation. This, in turn, acts as the stimulus producing the biological actions of interest. Of the greatest relevance here are cyclic nucleotide-gated channels on the surface of the cell membrane and on the surface of the sarcoplasmic reticulum (Fig 4), key in the active transport of ions across the phospholipid bilayer (Fig 5).


L22Fig1

Figure 1. Endothelial phospholipid bilayer. Nitric oxide absorption is characterized by rapid diffusion through the endothelial cell membrane of the type 1 pneumocyte and into the cytosol of the smooth muscle sarcoplasm. ATPase = enzyme that catalyzes adenosine triphosphate.


L22Fig2

Figure 2. Bonding of nitric oxide to sGC and production of cGMP. Molecular nitric oxide binds to the heme moiety of sGC to form a ferrous-nitrosyl-heme complex, which catalyzes the dephosphorylation of GTP to form cGMP and P. ATPase = enzyme that catalyzes adenosine triphosphate; sGC = soluble guanylyl cyclase; cGMP = cyclic guanosine monophosphate; GTP = guanosine-triphosphate; P = pyrophosphate.


L22Fig3

Figure 3. cGMP activates cGMP-dependent protein kinase. As intracellular cGMP proliferates, it binds to deactivated cGMP-dependent protein kinase, resulting in the activation of the enzyme. See Figures 1 and 2 for expansion of abbreviations.


L22Fig4

Figure 4. Activated kinase affixes to voltage-gated cation channels. cGMP-dependent protein kinase migrates to and binds at C-terminus sites of cyclic nucleotide gated channels. See Figures 1 and 2 for expansion of abbreviations.


L22Fig5

Figure 5. Hyperpolarization of smooth muscle fibers. ATP drives active ion channels, forcing some Ca2+ ions from the intracellular medium, inhibiting influx of Ca2+ at L-type Ca2+ ion channels and sequestering Ca2+ within the sarcoplasmic reticulum. ADP = adenosine diphosphate. See Figures 1 and 2 for expansion of abbreviations.


Smooth muscle motility, specifically relaxation, is accomplished by reducing intracellular calcium ion concentrations by four mechanisms: NO lowers the influx of calcium into the cell, increases the ejection of calcium ions from the cell, sequesters ionic calcium in the sarcoplasmic reticulum, and decreases calcium mobilization. These effects are accomplished by activated protein kinase binding to active ionic channels, including the plasma membrane Ca2+-pumping ATPase and the Na+/Ca2+ active gate, thus forcibly driving ionic calcium against its concentration gradient. Concurrently, Ca2+ ions are extracted through the Na+/Ca2+ exchanger gate. This has the effect of hyperpolarizing the cell and thereby inhibiting depolarization and smooth muscle contraction. Were there to be an influx of calcium ions instead, Ca2+ would bind to calmodulin, which, in turn, activates myosin light chain kinase, an enzyme causing the phosphorylation of myosin, resulting in cross-bridge activation and leading to muscle contraction.

Practical Therapeutic Applications of NO

NO, classified as an antianginal agent and vasodilator, operates by promoting selective smooth muscle relaxation. This leads to a reduction in pulmonary arterial pressures, as well as a reduction in the ratio of pulmonary to systemic arterial pressures. The increase in blood flow promotes an improvement in the ventilation perfusion ratio (V/Q) matching. This improvement in gas exchange is due to vascular relaxation resulting primarily from the administration of NO and secondarily from improved absorption of oxygen, also a powerful pulmonary vasodilator, reducing intrapulmonary shunting.

The clearest role for NO-based intervention is in neonatal oxygenation. In neonates, as pulmonary pressures decline and systemic pressures maintain their postnatal high levels, fetal circulation is replaced by an adult pattern. A failure to make this transition characterizes most abnormalities that lead to persistent pulmonary hypertension (PPHN) in neonates, with the exception of those caused by structural defects such as congenital heart defects. In adult hypoxemic states due to more heterogeneous pathologic conditions, the potential role of NO therapy is less clear, as will be discussed later in this lesson.

In neonates, the use of NO as a medical gas (iNO) has been approved by the US Food and Drug Administration (FDA) since 1999 and endorsed by the American Academy of Pediatrics for hypoxic respiratory failure in term and near-term newborns and in whom conventional ventilator therapy has failed, with the following recommendations5:

  • Select infants should be cared for at centers capable of delivering multiple modes of ventilatory support and rescue therapies.
  • An echocardiogram should be administered to rule out congenital heart disease.
  • iNO therapy should be delivered using the guidelines printed on the product label. Furthermore, developments of facility specific treatment protocols are encouraged.
  • iNO should be administered by qualified and trained physicians in facilities capable of multisystem support and preferably extra corporeal membrane oxygenation (ECMO).
  • If ECMO is unavailable, patient transfer to centers with that capability as well as contingency failure criteria should be considered.
  • iNO centers should provide long-term medical and neurodevelopmental follow-up and detailed data collection.

iNO ventilation is used for neonates with gestational age 34 weeks or greater with hypoxemia caused by respiratory failure, which is defined as an oxygen index of greater than 25 with maximal oxygenation support through traditional ventilation or high-frequency oscillating ventilation or with echocardiographic evidence of pulmonary hypertension.6

More than one-third of all neonatal mortality can be attributed to respiratory failure; this impacts 2% of all live births. Of neonates with respiratory failure, PPHN represents the underlying cause in 10%. Of these 10%, up to 25% of those manifesting moderate to severe PPHN do not survive. Moreover, up to 25% of those that do survive are at higher risk for neurodevelopmental disabilities.

An assortment of pathologic states are associated with PPHN. Meconium aspiration, respiratory distress syndrome, and pneumonias all cause lung parenchymal diseases and constitute a group of disorders precipitating pathologically constricted pulmonary vasculature. Illnesses such as hypoplastic vasculature secondary to congenital diaphragmatic hernia belong to another group. Yet another group includes disease resulting in remodeled pulmonary vasculature or idiopathic PPHN. Much remains to be learned about fetal and neonatal pulmonary vasculature. Studies in fetal lambs show that ligation of the ductus arteriosus leads to subsequent attenuation of pulmonary eNOS gene expression due to decreases in eNOS protein, NOS enzymatic activity, and eNOS messenger RNA abundance, resulting in pulmonary vascular remodeling.7

In any case, the use of iNO for all of these conditions represents an important addition to the therapeutic armamentarium available in neonatal intensive care. For PPHN, Roberts and colleagues8 found that inhaled NO doubled systemic oxygenation in 16 of 30 infants (53%), whereas conventional therapy without iNO increased oxygenation in only 2 of 28 infants (7%). Long-term therapy with inhaled NO sustained systemic oxygenation in 75% of the infants who had initial improvement. ECMO was required in 71% of the control group and 40% of the NO group. Nonetheless, the number of deaths was similar in the two groups. Of note, inhaled NO did not cause systemic hypotension.

Inhaled NO has been used for the treatment of bronchopulmonary dysplasia (BPD), a pathologic process due to insults that either inhibit or disrupt normal lung development. This can include BDP iatrogenically induced by excessive oxygen therapy or brought about by ventilator-induced lung injury. In one single center trial of 207 premature infants,9 evidence indicated that iNO might decrease the incidence of BPD and death in prematurely born infants.

Subsequent multicenter trials10 have confirmed that premature infants with a birth weight greater than 1000 g had a better survival rate following iNO. Nonetheless, it should be noted that Ikaria, currently the sole provider of US iNO delivery systems, does not endorse iNO for BPD; their product literature states that iNO is ineffective in the prevention of BDP based on the results of a number of large randomized trials.11

Increasingly, iNO is being used among adults, despite the fact that its FDA-approved indication is exclusively for near-term infant and newborns. Although off-label, iNO is frequently used for adults with pulmonary arterial hypertension and another superimposed acute process.12 INO also is used in the treatment for adult right-sided heart failure. For example, it has been used to increase right-sided ejection and left-sided preload by reducing pulmonary arterial pressure (PAP) and pulmonary vascular resistance, in particular in the context of left ventricular assist device (LVAD) use. Right ventricular afterload and contractility is essential for the LVAD to support systemic perfusion. In a randomized, double-blind trial, Argenziano and coworkers13 demonstrated that inhaled NO decreased PAP and increased LVAD flow in recipients of LVAD with pulmonary arterial hypertension (PAH). In another indication, the treatment of cardiogenic shock secondary to myocardial infarct has been shown to respond favorably to treatment from inhaled NO, demonstrating that mortality increases if coronary artery revascularization is delayed and cardiogenic shock results, despite normal left ventricular function. In a paper by Inglessis and colleagues,14 it was reported that delivery of NO at 80 ppm decreased PAP and improved cardiac index by 24%, likely by unloading the right ventricle. NO has also been used to off-load work of the right side of the heart after particularly stressful surgical interventions, such as mitral valve surgery.15

Beyond cardiovascular disease, iNO has also been applied in primary pulmonary disorders. Most prominently, iNO has been used as a presurgical bridge to lung transplantation for patients who are extremely compromised and posttransplantation in cases where reperfusion injury is suspected or highly likely. In the latter context, iNO is theoretically attractive because postoperatively, reperfusion injury can be a cause of lung transplant failure, and it has been speculated that adhesion and sequestration of leukocytes by activated pulmonary endothelium may contribute to ischemia secondary to reperfusion injuries. This is coupled with the well-documented antiinflammatory properties of NO and the observation that NO has been shown to reduce pulmonary ischemic injuries.16 Finally, iNO has been used as a salvage therapy in cases of severe refractory hypoxemia unresponsive to conventional ventilatory modalities, such as in pneumonia due to influenza A(H1N1) viral infection.17 Thus, inhaled NO has been used in the treatment of acute lung injury and acute respiratory distress syndrome, albeit with dubious results. Although a temporary improvement in Pao2/Fio2 ratio has been noted, days of support by mechanical ventilation and mortality remained unchanged. Nevertheless, iNO continues to be used as a salvage therapy in this context.18

There are several experimental models of iNO, including decreased thrombosis after coronary thrombolysis in dogs due to the platelet inhibition properties of NO19; increased mesenteric blood flow postischemia due to reperfusion injury in cats20; and a decrease in infarct size in experimental cardiac reperfusion injury.21 Experimentally, iNO is also linked to oxidization of extraerythrocytic hemoglobin and decreased hemolysis-induced vasoconstriction and renal dysfunction.22

Beyond iNO therapy per se, the “nitric oxide challenge” is a clinical prediction method for responsiveness to other pulmonary vasodilators. While challenge with IV vasodilators such as prostacyclines and calcium channel blockers has been employed in the assessment of PAH treatment responsiveness, these can have serious side effects. The utilization of a NO challenge has been demonstrated to be a safe and effective means to gather the same information. The test is conducted in a cardiac catheterization laboratory where hemodynamic values are monitored closely. Nitric oxide is delivered through a specialized facemask at a concentration starting typically at 20 ppm. A decrease in PAP and pulmonary vascular resistance are assessed. In a recent study defining positive response to calcium channel blockers, the consensus definition of a favorable response was revised to require a fall in mean PAP (mPAP) of 10 mm Hg or more (down to an mPAP of 40 mm Hg or less) with an unchanged or increased cardiac output.23 A positive response to a nitric challenge test indicates a likely favorable response to iNO therapy and also predicts that the patient will respond favorably to oral vasodilators such as nifedipine.24 It is also predictive of improved mid-term survival for patients with PAH secondary to congenital heart disease.25

Nitric Oxide Administration

Therapeutically, NO can be delivered artificially through a dedicated nitric oxide delivery device via flow-based oxygen delivery systems, such as a nasal cannula, or it can be intrained during mechanical ventilation via a specialized delivery system in tandem with a conventional ventilator. It is dispensed and measured in parts per million, and an appropriate physician’s order should be written in such units. Treatment typically starts with a NO concentration of 20 ppm. As NO is bled into a conventional ventilatory delivery system with an appropriately set medical gas mixture, the patient is observed for a positive response, defined as 20% increase in Pao2 or Sao2, which should occur within 15 or 20 min. NO concentrations are titrated down slowly as the pulmonary pressures and oxygenation issues resolve. Typically, NO will be weaned when the Fio2 on a ventilator is 40% and the positive end-expiratory pressure is 5 cm H2O. If used for cardiac support, the weaning parameters may not involve measures of mechanical ventilatory support. The course of treatment usually lasts between 3 days and as long as a few weeks.

The NO molecule is highly reactive and extremely short-lived. The bulk of circulating NO is deactivated by readily binding to hemoglobin to form nitrosylmethemoglobin. Phosphodiesterases (PDEs), predominantly PDE5, regulate the magnitude and duration of vascular smooth muscle relaxation by catalyzing the breakdown of cGMP. The endogenous half-life of NO is 0.1 to 5 s, but when administered via mechanical ventilation (in a dose range of 5 to 80 ppm), the half-life increases to 15 to 30 s. Inhalation of NO selectively reaches the pulmonary vasculature; its rapid metabolism typically precludes any undesirable systemic effects, such as systemic hypotension.

Contraindications and Potential Hazards

While the contraindications to iNO are few, heart disease with left ventricular obstruction is noteworthy. These include severe aortic stenosis, interrupted aortic arch, severe left ventricular dysfunction, hypoplastic left-sided heart syndrome, or any condition in which left-sided heart pressures are elevated causing secondary pulmonary venous hypertension. These need to be addressed and corrected because the use of iNO in this context may lead to pulmonary edema.26

Other potential hazards or complications from iNO therapy are also noteworthy. Nitric oxide is responsible for increasing levels of cyclic GMP. This mediator is associated with a retardation of cellular proliferation essential to normal lung development. Nitric oxide also has been shown to carry the potential for mutagenic alterations in DNA through corruption and/or destruction of base pairs.27 In addition, NO is reactive with oxygen and can form nitrogen dioxide, an important oxidant pollutant capable of causing acute lung injury. In the presence of water, NO can form nitric acid, another potent irritant, while NO can also react with superoxide anion to form peroxynitrite, a cytotoxic free radical that disrupts surfactant activity and interferes with mitochondrial respiration.28 Moreover, at high levels (> 80 ppm) and for prolonged periods, iNO converts oxygen-carrying hemoglobin into methemoglobin, potentially leading to impaired tissue delivery of oxygen. In a study of nitric oxide inhalation for the acute treatment of sickle cell pain crisis, participants receiving iNO (80 ppm for 4 h followed by 40 ppm for 4 h) had significantly higher levels of methemoglobin in the venous blood. However, no methemoglobin value of the participants exceeded 5%, considered a minimal cutoff point for potential toxicity.29 There is also the potential for NO to act as an immunosuppressant and thus, theoretically, increase the risk of infection, which is likely to be nosocomial given the therapeutic context of iNO use. NO also has been shown to inhibit platelet agglutination and adhesion. Finally, even in lower exposure in the range of therapeutic dosages, NO has been shown to have the potential for a direct toxic effect on lung tissue. At very high exposure levels, NO is associated with hypoxemia, shortness of breath, pulmonary edema, and even fatal lung injury. All of these concerns and many more are thought to be containable provided dosages, and reactive intermediates are carefully monitored.

Abrupt reduction of NO concentrations or interruption of iNO therapy have been shown to cause a rapid reversal of any therapeutic gains, resulting in increased V/Q mismatching and increased pulmonary hypertension, leading to hemodynamic collapse.30 This is caused by the rapid influx of ionic calcium and a decrease in NOS. Following its ionic gradient, sequestered and extracellular ionic calcium floods back into the smooth muscle cells, triggering myosin cross-bridge activation and a dramatic increase in smooth muscle tone. This reduces blood flow and increases V/Q mismatching, increasing dead space ventilation.

Long-term follow-up data are only now beginning to become available. Increased incidences of moderate cerebral palsy and sensorineural hearing loss have been reported following neonatal iNO usage. No data yet exist for long-term effects such as bronchoreactivity, hematologic changes, or impact on immune function.

On the Horizon

Preliminary studies indicate that the efficacy of iNO can be augmented by a variety of agents and strategies. Experimentally, inhibiting cGMP-specific PDE (PDE5) with zaprinast showed a positive response suggestive of a synergistic interaction.31 In another study,32 addition of either iNO or recombinant superoxide dismutase (rhSOD) decreased PDE5 expression and activity in an experimental animal model of PPHN and increased cGMP levels to those comparable with control animals. These data suggest that ventilation in experimental PPHN with 100% O2 impairs cGMP-mediated vasodilation in part due to increased PDE5 expression and activity. The addition of either iNO or rhSOD normalized PDE5 and cGMP levels. Thus, therapies designed to decrease PDE5 and increase cGMP, such as iNO and rhSOD, may prove useful in the treatment of PPHN in newborn infants. Also, Evgenov and colleagues33 demonstrated that in lambs with acute pulmonary hypertension, BAY 41-2272, a potent pulmonary vasodilator, augmented and prolonged the pulmonary vasodilator response to inhaled NO. It should be remembered that concomitant oxygen therapy, also a powerful pulmonary vasodilator, provides a synergistic vasodilatory response when combined with iNO.

These experimental animal studies have already had an impact on iNO administration and augmentation strategies in the treatment of humans. For example, sildenafil has been shown to prolong the pulmonary vasodilator effects of iNO in patients with pulmonary hypertension.34 It also decreases the rebound effect associated with rapid weaning or discontinuation of iNO for patients with pulmonary hypertension.35 This was also found to be the case with patients suffering from congestive heart failure.36 Other cotreatment strategies combining iNO with various agents are likely to emerge, potentially expanding clinical indications for iNO therapy.

Conclusions

Inhaled NO therapy has entered the mainstream as a highly effective pulmonary vasodilator for newborn infants with pulmonary hypertension or hypoxemic respiratory failure. As a result of its success within this limited scope, the use of iNO has now expanded to other clinical indications in both infants and adults. Current experimental research is very promising for the augmentation of NO therapy alone and in concert with other adjunctive therapies. Nonetheless, the potential risks of therapeutic dosing or overexposure need to be kept in view.


References

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  2. Moncada S, Higgs A. The l-arginine-nitric oxide pathway. N Engl J Med. 1993;329(27):2002-2012.
  3. Alderton WK, Cooper CE, Knowles RG. Nitric oxide synthases: structure, function and inhibition. Biochem J. 2001;357(Pt 3):593-615.
  4. Lucas KA, Pitari GM, Kazerounian S, et al. Guanylyl cyclases and signaling by cyclic GMP. Pharmacol Rev. 2000;52(3):375-414.
  5. American Academy of Pediatrics Committee on Fetus and Newborn. Use of inhaled nitric oxide. Pediatrics. 2000;106(2 Pt 1):344-345.
  6. Throckmorton DC. Primary medical review of inhaled nitric oxide (I-NO). NDA 20-845 Food and Drug Administration Division of Cardio-Renal Drug Products (HFD-110). Octover 29, 1999. http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/20845_INOmax_medr_P1.pdf. Accessed December 1, 2011.
  7. Shaul PW, Yuhanna IS, German Z, Chen Z, Steinhorn RH, Morin FC III. Pulmonary endothelial NO synthase gene expression is decreased in fetal lambs with pulmonary hypertension. Am J Physiol. 1997; 272(5 Pt 1):L1005-L1012.
  8. Roberts JD Jr, Fineman JR, Morin FC III, et al. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn: the Inhaled Nitric Oxide Study Group. N Engl J Med. 1997;336(9):605-610.
  9. Schreiber MD, Gin-Mestan K, Marks JD, Huo D, Lee G, Srisuparp P. Inhaled nitric oxide in premature infants with the respiratory distress syndrome. N Engl J Med. 2003;349(22):2099-2107.
  10. Van Meurs KP, Wright LL, Ehrenkranz RA, et al; Preemie Inhaled Nitric Oxide Study. Inhaled nitric oxide for premature infants with severe respiratory failure. N Engl J Med. 2005;353(1):13-22.
  11. US Food and Drug Administration. INOmax (nitric oxide) for inhalation: highlights of prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020845s011lbl.pdf. Accessed December 1, 2011.
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