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Aetna Aetna
Clinical Policy Bulletin:
Nitric Oxide, Inhalational (INO)
Number: 0518


Policy

  1. Aetna considers inhaled nitric oxide (INO) therapy medically necessary as a component of the treatment of hypoxic respiratory failure in neonates when both of the following criteria are met:

    1. Neonates do not have congenital diaphragmatic hernia; and
    2. When conventional therapies such as administration of high concentrations of oxygen, hyperventilation, high-frequency ventilation, the induction of alkalosis, neuromuscular blockade, and sedation have failed or are expected to fail.

    Note: Use of INO therapy for more than 4 days is subject to medical necessity review.

  2. Aetna considers the diagnostic use of INO medically necessary as a method of assessing pulmonary vaso-reactivity in persons with pulmonary hypertension.

  3. Aetna considers INO therapy experimental and investigational for all other indications because of insufficient evidence in the peer-reviewed literature, including any of the following:

    • Acute bronchiolitis; or
    • Acute hypoxemic respiratory failure in children (other than those who meet the medical necessity criteria above) and in adults; or
    • Acute respiratory distress syndrome or acute lung injury; or
    • As adjunctive therapy of malaria; or
    • Post-operative management of pulmonary hypertension in infants and children with congenital heart disease; or
    • Prevention of ischemia-reperfusion injury/acute rejection following lung transplantation; or
    • Treatment of persons with congenital diaphragmatic hernia; or
    • Treatment of vaso-occlusive crises or acute chest syndrome in persons with sickle cell disease (sickle cell vasculopathy).

See also CPB 0546 - Extracorporeal Membrane Oxygenation (ECMO); and  CPB 0691 - Breath Tests of Airway Inflammation: Exhaled Nitric Oxide and Exhaled Breath Condensate pH.



Background

This policy is based on the American Academy of Pediatrics' (2000) policy statement "Use of Inhaled Nitric Oxide".

Acute respiratory failure is the most common problem seen in the term, near-term (born at 34 or more weeks of gestation), and pre-term (less than 34 weeks of gestation) infants admitted to neonatal intensive care units.  Acute respiratory failure in term and near-term neonates is usually a consequence of meconium aspiration syndrome, sepsis, pulmonary hypoplasia, and primary pulmonary hypertension of the newborn.  According to current guidelines, management of infants with respiratory failure includes administration of high concentrations of oxygen, hyperventilation, high-frequency ventilation, the induction of alkalosis, neuromuscular blockade, ante-natal steroids for the prevention of respiratory distress syndrome, use of post-natal steroids for the prevention of chronic lung disease, as well as inhaled nitric oxide (INO) therapy.  A systematic review of the evidence (Finer and Barrington, 2003) concluded: "On the evidence presently available, it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia."

In pre-term infants, the most common cause of acute respiratory failure is respiratory distress syndrome as a result of surfactant deficiency.  According to the available literature, treatment of preterm infants usually entails exogenous surfactant administration.

Clinical studies have shown that inhaled nitric oxide is a selective pulmonary vasodilator without significant effects on the systemic circulation.  There is sufficient scientific evidence that INO therapy improves oxygenation and ventilation, reduces the need for extracorporeal membrane oxygenation (ECMO), and lowers the incidences of chronic lung disease and death among infants with respiratory failure.  Moreover, the literature indicates that INO does not appear to increase the incidence of adverse neurodevelopmental, behavioral, or medical sequelae in these high-risk neonates.  Infants with congenital diaphragmatic hernia have been shown not to benefit from INO therapy.  Furthermore, INO therapy has not shown to be associated with significant benefits in pre-term infants.  A systemic review of the evidence (Barrington and Finer, 2003) concluded: "The currently published evidence from randomized trials does not support the use of inhaled nitric oxide in preterm infants with hypoxic respiratory failure."

In a randomized, double-blind, placebo-controlled study (n = 207), Schreiber et al (2003) examined the effect of INO during the first week of life on the incidence of chronic lung disease and death in premature infants (less than 34 weeks' gestation) who were undergoing mechanical ventilation for the respiratory distress syndrome.  The authors concluded that the use of INO in premature infants with the respiratory distress syndrome decreases the incidence of chronic lung disease and death.  However, in an editorial, Martin (2003) stated “At present, the data reported by Schreiber et al are intriguing but should be considered preliminary. We must wait for essential additional data from ongoing randomized trials of nitric oxide in premature infants before this therapy is introduced outside of clinical trials…”.

In a multi-center, randomized, blinded, controlled study, Van Meurs and associates (2005) examined if INO reduced the rate of death or bronchopulmonary dysplasia (BPD) in such infants.  A total of 420 neonates, born at less than 34 weeks of gestation, with a birth weight of 401 to 1,500 g, and with respiratory failure more than 4 hours after treatment with surfactant were randomly assigned to receive inhaled NO (5 to 10 ppm) or placebo (simulated flow).  The rate of death or BPD was 80 % in the NO group, as compared with 82 % in the placebo group and the rate of BPD was 60 % versus 68 %.  There were no significant differences in the rates of severe intra-cranial hemorrhage or peri-ventricular leukomalacia.  Post hoc analyses suggest that rates of death and BPD are reduced for infants with a birth weight greater than 1,000 g, whereas infants weighing 1,000 g or less who are treated with INO have higher mortality and increased rates of severe intra-cranial hemorrhage.  These investigators concluded that INO does not decrease the rates of death or BPD in critically ill premature infants weighing less than 1,500 g and more studies are needed to determine whether INO benefits infants with a birth weight of 1,000 g or more.

Mestan and colleagues (2005) conducted a prospective, longitudinal follow-up study of premature infants (mean gestational age of 27.2 weeks) who were administered INO or placebo to examine neurodevelopmental outcomes at 2 years of corrected age.  Neurological examination, neurodevelopmental assessment and anthropometric measurements were made by examiners who were blind to the children's original treatment assignment.  A total of 138 children (82 % of survivors) were evaluated.  In the group given INO, 17 of 70 children (24 %) had abnormal neurodevelopmental outcomes, defined as either disability (cerebral palsy, bilateral blindness, or bilateral hearing loss) or delay (no disability, but one score of less than 70 on the Bayley Scales of Infant Development II), as compared with 31 of 68 children (46 %) in the placebo group.  This effect persisted after adjustment for birth weight and sex, as well as for the presence or absence of chronic lung disease and severe intra-ventricular hemorrhage or peri-ventricular leukomalacia.  The improvement in neurodevelopmental outcome in the group given INO was primarily due to a 47 % decrease in the risk of cognitive impairment.  These investigators concluded that premature infants treated with INO have improved neurodevelopmental outcomes at 2 years of age.

In an editorial accompanying the contrasting articles by Van Meurs et al and Mestan et al, Martin and Walsh (2005) stated that “two large, multicenter, randomized trials of prolonged inhaled nitric oxide exposure beginning shortly after birth are completing enrollment …. Pending the results, it is prudent to avoid the use of inhaled nitric oxide in preterm infants in the first week of life.  The benefits and risks of inhaled nitric oxide need further scrutiny before its use becomes widespread”.  These two large studies have since been published; however the findings are contradictory (Ballard et al, 2006; Kinsella et al, 2006).

The study by Ballard et al (2006) was a randomized, stratified, double-blind, placebo-controlled trial of INO at 21 centers involving infants with a birth weight of 1,250 g or less who needed ventilatory support between 7 and 21 days of age.  Treated infants received decreasing concentrations of NO, beginning at 20 ppm, for a minimum of 24 days.  The primary outcome was survival without BPD at 36 weeks of post-menstrual age.  Among 294 infants receiving NO and 288 receiving placebo, birth weight (766 g and 759 g, respectively), gestational age (26 weeks in both groups), and other characteristics were similar.  The rate of survival without BPD at 36 weeks of post-menstrual age was 43.9 % in the group receiving NO and 36.8 % in the placebo group (p = 0.042).  The infants who received INO were discharged sooner (p = 0.04) and received supplemental oxygen therapy for a shorter time (p = 0.006).  There were no short-term safety concerns.  The authors concluded that INO therapy improves the pulmonary outcome for premature infants who are at risk for BPD when it is started between 7 and 21 days of age and has no apparent short-term adverse effects.

Kinsella and colleagues (2006) performed a multi-center, randomized study involving 793 newborns who were 34 weeks of gestational age or less and had respiratory failure requiring mechanical ventilation.  Newborns were randomly assigned to receive either INO (5 ppm) or placebo gas for 21 days or until extubation, with stratification according to birth weight (500 to 749 g, 750 to 999 g, or 1,000 to 1,250 g).  The primary outcome was a composite of death or BPD at 36 weeks of post-menstrual age.  Secondary outcomes included severe intra-cranial hemorrhage, peri-ventricular leukomalacia, and ventriculomegaly.  Overall, there was no significant difference in the incidence of death or BPD between patients receiving INO and those receiving placebo (71.6 % versus 75.3 %, p = 0.24).  However, for infants with a birth weight between 1,000 and 1,250 g, as compared with placebo, INO therapy reduced the incidence of BPD (29.8 % versus 59.6 %); for the cohort overall, such treatment reduced the combined end point of intra-cranial hemorrhage, peri-ventricular leukomalacia, or ventriculomegaly (17.5 % versus 23.9 %, p = 0.03) and of peri-ventricular leukomalacia alone (5.2 % versus 9.0 %, p = 0.048).  Inhaled nitric oxide therapy did not increase the incidence of pulmonary hemorrhage or other adverse events.  The authors concluded that among premature newborns with respiratory failure, low-dose INO did not reduce the overall incidence of BPD, except among infants with a birth weight of at least 1,000 g, but it did reduce the overall risk of brain injury.

In an editorial that accompanied the two afore-mentioned papers, Stark (2006) stated that the use of INO therapy in preterm infants awaits more data, especially longer-term follow-up of children in the studies by Ballard et al (2006) as well as Kinsella et al (2006).  In the meantime, the use of INO in this setting should be limited to clinical trials.

Bhandari and Bhandari (2007) stated that BPD is a chronic lung disease associated with premature birth and characterized by early lung injury.  Over the past 4 decades, there have been significant changes in its definition, pathology and radiological findings as well as management of BPD.  Management of the acute phase and later stages of this lung disease continue to evolve.  Use of non-invasive ventilatory techniques, recombinant human superoxide dimutase and Clara Cell 10 and INO are some novel approaches that are being studied.  In a Cochrane review, Barrington and Finer (2007) examined if INO would reduce mortality, BPD, intra-cranial hemorrhage, or neurodevelopmental disability in preterm infants with respiratory disease.  The authors concluded that INO as rescue therapy for very ill preterm infants undergoing ventilation does not seem to be effective and may increase severe intra-cranial hemorrhage.  Later use of inhaled INO to prevent BPD does not seem to be effective.  Early routine use of INO for mildly sick, preterm infants seems to decrease the risk of serious brain injury and may improve rates of survival without BPD.  They stated that further studies are needed to confirm these findings, to define groups most likely to benefit, and to describe long-term outcomes.

Huddy et al (2008) stated that trials of INO in preterm infants with severe respiratory failure have to date shown no evidence of benefit, and there have been no trials reporting follow-up to 4 years of age.  The INNOVO trial recruited 108 infants (55 INO arm and 53 controls) from 15 neonatal units.  By 1 year of age 59 % had died, and 84 % of the survivors had signs of impairment or disability.  These researchers reported the long-term clinical effectiveness and costs of adding NO to the ventilator gases of preterm infants with severe respiratory failure.  Children were assessed at age 4 to 5 years by interview, examination, cognitive and behavioral assessments.  The outcome data were divided into 7 domains and were described as normal, impaired or disabled (mild, moderate or severe) by the degree of functional loss.  Overall, 38 of the 43 survivors had follow-up assessments.  In the INO group 62 % (34/55) had died or were severely disabled, compared to 70 % (37/53) in the no INO group (relative risk [RR] 0.89, 95 % confidence interval [CI]: 0.67 to 1.16).  There was no evidence of difference in the levels of impairment or disability between the 2 groups in any of the domains studied, or of cost differences, among the survivors.  The authors concluded that for this group of babies with severe respiratory failure there was no evidence of difference in the longer-term outcome between those babies allocated to INO and those who were allocated to no INO.

Mercier and associates (2010) tested the hypothesis that INO at a low concentration, started early and maintained for an extended period in babies with mild respiratory failure, might reduce the incidence of BPD.  A total of 800 preterm infants with a gestational age at birth of between 24 weeks and 28 weeks plus 6 days (inclusive), weighing at least 500 g, requiring surfactant or continuous positive airway pressure for respiratory distress syndrome within 24 hrs of birth were randomly assigned in a 1-to-1 ratio to INO (5 parts per million) or placebo gas (nitrogen gas) for a minimum of 7 days and a maximum of 21 days in a double-blind study done at 36 centers in 9 countries in the European Union.  Care providers and investigators were masked to the computer-generated treatment assignment.  The primary outcome was survival without development of BPD at post-menstrual age 36 weeks.  Analysis was by intention-to- treat.  A total of 399 infants were assigned to INO, and 401 to placebo; 395 and 400, respectively, were analysed.  Treatment with INO and placebo did not result in significant differences in survival of infants without development of BPD (258 [65 %] of 395 versus 262 [66 %] of 400, respectively; RR 1.05, 95 % CI: 0.78 to 1.43); in survival at 36 weeks' post-menstrual age (343 [86 %) of 399 versus 359 [90 %] of 401, respectively; 0.74, 0.48 to 1.15); and in development of BPD (81 [24 %] of 339 versus 96 [27 %] of 358, respectively; 0.83, 0.58 to 1.17).  The authors concluded that early use of low-dose INO in very premature babies did not improve survival without BPD or brain injury, suggesting that such a preventive treatment strategy is unsuccessful.

To provide health care professionals, families, and the general public with a responsible assessment of currently available data regarding the benefits and risks of INO in premature infants, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Heart, Lung, and Blood Institute, and the Office of Medical Applications of Research of the National Institutes of Health (Cole et al, 2011) convened a consensus-development conference.  Findings from a substantial body of experimental work in developing animals and other model systems suggest that NO may enhance lung growth and reduce lung inflammation independently of its effects on blood vessel resistance.  Although this work demonstrates biological plausibility and the results of randomized controlled trials (RCTs) in term and near-term infants were positive, combined evidence from the 14 RCTs of INO treatment in premature infants of gestation of 34 weeks or less shows equivocal effects on pulmonary outcomes, survival, and neurodevelopmental outcomes.

Donohue et al (2011) reviewed the evidence on the use of INO in infants born at 34 weeks or less gestation who receive respiratory support.  Medline, Embase, the Cochrane Central Register of Controlled Studies, PsycInfo, ClinicalTrials.gov, and proceedings of the 2009 and 2010 Pediatric Academic Societies meetings were searched in June 2010.  Additional studies from reference lists of eligible articles, relevant reviews, and technical experts were considered.  Two investigators independently screened search results and abstracted data from eligible articles.  They focused on mortality, BPD, the composite outcome of death or BPD, and neurodevelopmental impairment.  A total of 14 RCTs, 7 follow-up studies, and 1 observational study were eligible for inclusion.  Mortality rates in the neonatal intensive care unit (NICU) did not differ for infants treated with INO compared with controls (RR: 0.97, 95 % CI: 0.82 to 1.15); BPD at 36 weeks for INO and control groups also did not differ for survivors (RR: 0.93, 95 % CI: 0.86 to 1.003).  A small difference was found in favor of INO in the composite outcome of death or BPD (RR: 0.93, 95 % CI: 0.87 to 0.99).  There was no evidence to suggest a difference in the incidence of cerebral palsy (RR: 1.36, 95 % CI: 0.88 to 2.10), neurodevelopmental impairment (RR: 0.91, 95 % CI: 0.77 to 1.12), or cognitive impairment (RR: 0.72, 95 % CI: 0.35 to1.45).  The authors concluded that there was a 7 % reduction in the risk of the composite outcome of death or BPD at 36 weeks for infants treated with INO compared with controls but no reduction in death alone or BPD.  They stated that there is currently no evidence to support the use of INO in preterm infants with respiratory failure outside the context of rigorously conducted RCTs.

Inhaled nitric oxide therapy has also not been proven to improve outcomes in children and adults with acute respiratory failure.  A systemic review of the evidence (Sokol et al, 2003) of INO for acute hypoxemic respiratory failure in children and adults reached the following conclusions: “Nitric oxide did not demonstrate any statistically significant effect on mortality and transiently improved oxygenation in patients with hypoxemic respiratory failure.  Lack of data prevented assessment of other clinically relevant end points.  Currently there is also insufficient evidence to support the use of INO for the prevention of ischemia-reperfusion injury/acute rejection following lung transplantation, or the treatment of vaso-occlusive crises in patients with sickle cell disease.”

In a randomized controlled study (n = 385), Taylor et al (2004) concluded that low-dose INO (5 ppm) in patients with acute lung injury not due to sepsis and without evidence of non-pulmonary organ system dysfunction resulted in short-term oxygenation improvements but had no substantial impact on the duration of ventilatory support or mortality.  These investigators stated that the data do not support the routine use of INO in the treatment of acute lung injury or acute respiratory distress syndrome.  An accompanying editorial stated that “[t]he results of this trial consolidate earlier findings and support the notion that nitric oxide is not useful in the treatment of the majority of patients with ALI [acute lung injury] or ARDS [acute respiratory distress syndrome] (Adhikari and Granton, 2004).

A systematic review of 5 randomized controlled clinical trials of INO versus placebo or no therapy for acute hypoxemic respiratory failure (including acute lung injury, adult respiratory distress syndrome, and other diagnoses) in adults and children concluded that INO produced modest improvements in oxygenation for up to 72 hours but had no effect on mortality (pooled RR using fixed effects model, 0.98; 95 % CI: 0.66 to 1.44) or on the duration of mechanical ventilation (Sokol et al, 2003).

In a systematic review and meta-analysis on the use of INO to treat ALI/ARDS, Adhikari et al (2007) concluded that INO is associated with limited improvement in oxygenation in patients with ALI or ARDS but confers no mortality benefit and may cause harm.  The authors do not recommend its routine use in these severely ill patients.

In a Cochrane review, Afshari and colleagues (2010) evaluated the benefits and harms of INO in critically ill patients with acute hypoxemic respiratory failure (AHRF).  These researchers identified RCTs from electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 1); MEDLINE; EMBASE; Science Citation Index Expanded; International Web of Science; CINAHL; LILACS; and the Chinese Biomedical Literature Database (up to 31st January 2010).  They contacted trial authors, authors of previous reviews, and manufacturers in the field; and included all RCTs, irrespective of blinding or language, that compared INO with no intervention or placebo in children or adults with AHRF.  Two authors independently abstracted data and resolved any disagreements by discussion.  They presented pooled estimates of the intervention effects on dichotomous outcomes as RR with 95 % CI.  The primary outcome measure was all cause mortality.  These investigators performed subgroup and sensitivity analyses to assess the effect of INO in adults and children and on various clinical and physiological outcomes.  They assessed the risk of bias through assessment of trial methodological components and the risk of random error through trial sequential analysis.  A total of 14 RCTs with 1,303 participants; 10 of these trials had a high risk of bias were selected for analysis.  Inhaled NO showed no statistically significant effect on overall mortality (40.2 % versus 38.6 %) (RR 1.06, 95 % CI: 0.93 to 1.22; I(2) = 0) and in several subgroup and sensitivity analyses, indicating robust results.  Limited data demonstrated a statistically insignificant effect of INO on duration of ventilation, ventilator-free days, and length of stay in the ICU and hosptial.  These researchers found a statistically significant but transient improvement in oxygenation in the first 24 hours, expressed as the ratio of partial pressure of oxygen to fraction of inspired oxygen and the oxygenation index (MD 15.91, 95 % CI: 8.25 to 23.56; I(2) = 25 %).  However, INO appears to increase the risk of renal impairment among adults (RR 1.59, 95 % CI: 1.17 to 2.16; I(2) = 0) but not the risk of bleeding or methemoglobin or nitrogen dioxide formation.  The authors concluded that INO can not be recommended for patients with AHRF.  Inhaled NO results in a transient improvement in oxygenation but does not reduce mortality and may be harmful.

A study by Clark et al (2000) suggested that a maximum of 4 days of INO should be tried before ECMO is considered.  Limiting the duration of INO may avoid delaying ECMO beyond the point at which its effectiveness may be reduced.

Inhaled nitric oxide may also be used as a diagnostic test to determine vasodilator responsiveness in patients with pulmonary hypertension (Gildea et al, 2003).  Because of its short half-life and lack of systemic effects, "it is expected that the use of inhaled nitric oxide will become standard practice in all centers in the future" (British Cardiac Society, 2001).  Long-term use of INO has also been described in patients with primary pulmonary hypertension, but its clinical application has been limited because of the compound's short half-life (Gildea et al, 2003).

In a Cochrane review, Bizzarro and Gross (2005) examined the effectiveness of INO in the post-operative management of infants and children with congenital heart disease.  The objectives were to compare the effects of post-operative INO versus placebo and/or conventional management on infants and children with congenital heart disease.  The primary outcome was mortality, and the secondary outcomes were length of hospital stay, assessment of neurodevelopmental disability, number of pulmonary hypertensive crises, changes in hemodynamics including mean pulmonary arterial pressure, mean arterial pressure, and heart rate, changes in oxygenation measured as the ratio PaO2:FiO2, as well as measurement of maximum methemoglobin level as a marker of toxicity.  These investigators observed no differences with the use of INO as compared with control in the majority of outcomes reviewed.  No data were available for analysis with respect to several clinical outcomes including long-term mortality and neurodevelopmental outcome.  They found it difficult to draw valid conclusions because of concerns regarding methodological quality, bias, sample size, and heterogeneity.

Al Hajeri et al (2008) stated that acute chest syndrome has been defined as a new infiltrate that is visible on chest X-ray, and is associated with one or more symptoms (e.g., cough, fever, dyspnea, new-onset hypoxia, sputum production, or tachypnea).  Symptoms and complications of this syndrome, whether of infectious or non-infectious origin, vary widely in patients with sickle cell disease.  Lung infection tends to predominate in children, while infarction appears more common in adults.  However, these are often interrelated and may occur concurrently.  The differences in clinical course and severity are suggestive of multiple causes for acute chest syndrome.  Successful treatment depends principally on high-quality supportive care.  The syndrome and its treatment have been extensively studied, but the response to antibiotics, anticoagulants, and other conventional therapies remains disappointing.  The potential of INO as a treatment option has more recently provoked considerable interest.  In a Cochrane review, these researchers evaluated the effectiveness of INO for treating acute chest syndrome by comparing improvement in symptoms and clinical outcomes against standard care.  No studies identified were eligible for inclusion.  The authors concluded that there is a need for well-designed, adequately-powered randomized controlled studies to assess the risks and benefits of INO as an adjunct to established therapies.

Porta and Steinhorn (2008) stated that more than a decade of intensive research has resulted in the current role of INO as the only selective pulmonary vasodilator for the treatment of persistent pulmonary hypertension in the newborn (PPHN).  This therapy continues to be studied intensively to better define its mechanism of action and role in PPHN treatment.  Furthermore, there remains intense interest in possible new uses inn newborns, as well as strategies that may enhance its effectiveness.  The authors reviewed several areas of current research on amplification of NO signaling in the neonatal pulmonary vasculature, the current knowledge about the role of INO in other conditions such as congenital diaphragmatic hernia and congenital heart disease.

Kato and Gladwin (2008) noted that recent research has suggested a syndrome of hemolysis-associated vasculopathy in patients with sickle cell disease, which features severe hemolytic anemia and leads to scavenging of NO and its biochemical precursor l-arginine.  This diminished bioavailability of NO promotes a hemolysis-vascular dysfunction syndrome, which includes pulmonary hypertension, cutaneous leg ulceration, priapism, and ischemic stroke.  Additional correlates of this vasculopathy include activation of endothelial cell adhesion molecules, platelets, and the vascular protectant hemeoxygenase-1.  Some known risk factors for atherosclerosis are also associated with sickle cell vasculopathy, including low levels of apolipoprotein AI and high levels of asymmetric dimethylarginine, an endogenous inhibitor of NO synthase.  Identification of dysregulated vascular biology pathways in sickle vasculopathy has provided a focus for new clinical trials for therapeutic intervention, including INO, sodium nitrite, L-arginine, phosphodiesterase-5 inhibitors, niacin, inhaled carbon monoxide, and endothelin receptor antagonists.

In a prospective, multi-center, double-blind, randomized, placebo-controlled clinical trial, Gladwin et al (2011) examined if INO reduces the duration of painful crisis in patients with sickle cell disease (SCD) who present to the emergency department or hospital for care.  A total of 150 SCD patients with vaso-occlusive pain crisis (VOC) were randomly assigned to receive up to 72 hours of INO or inhaled nitrogen placebo.  The primary end point was the time to resolution of painful crisis, defined by (i) freedom from parenteral opioid use for 5 hours; (ii) pain relief as assessed by visual analog pain scale scores of 6 cm or lower (on 0 to 10 scale); (iii) ability to walk; and (iv) patient's and family's decision, with physician consensus, that the remaining pain could be managed at home.  There was no significant change in the primary end point between the INO and placebo groups, with a median time to resolution of crisis of 73.0 hours (95 % CI: 46.0 to 91.0) and 65.5 hours (95 % CI: 48.1 to 84.0), respectively (p = 0.87).  There were no significant differences in secondary outcome measures, including length of hospitalization, visual analog pain scale scores, cumulative opioid usage, and rate of acute chest syndrome.  Inhaled nitric oxide was well-tolerated, with no increase in serious adverse events.  Increases in venous methemoglobin concentration confirmed adherence and randomization but did not exceed 5 % in any study participant.  Significant increases in plasma nitrate occurred in the treatment group, but there were no observed increases in plasma or whole blood nitrite.  The authors concluded that among patients with SCD hospitalized with VOC, the use of INO compared with placebo did not improve time to crisis resolution.

Arul and Konduri (2009) noted that the use of INO in extremely low birth weight neonates for the prevention of adverse outcomes like chronic lung disease and neurological injury has been investigated, but the findings remain inconclusive.  Soll (2009) stated that INO has been used to treat both term and preterm infants with respiratory failure.  Term infants with persistent pulmonary hypertension, either as a primary cause or secondary to other disease processes, respond to INO with improvement in oxygenation indices and a decreased need for ECMO.  Infants with congenital diaphragmatic hernia are the exception to this finding, with little clinical benefit observed with INO treatment.  Although respiratory disease in preterm infants has a component of increased pulmonary vascular resistance, little benefit of INO administration has been observed in premature infants either early in their course or later as a treatment to prevent the evolution of chronic lung disease.

González and Ochoa (2010) reviewed the evidence on treatment of acute bronchiolitis.  These investigators stated that there is sufficient evidence on the lack of effectiveness of most interventions tested in bronchiolitis.  Apart from oxygen therapy, fluid therapy, aspiration of secretions and ventilation support, few treatment options will be beneficial.  There are doubts about the effectiveness of inhaled bronchodilators (salbutamol or adrenaline), with or without hypertonic saline solution, suggesting that these options should be selectively used as therapeutic trials in moderate-to-severe bronchiolitis.  Heliox and non-invasive ventilation techniques, methylxanthine could be used in cases with respiratory failure, in patients with apnea, and surfactant and inhaled ribavirin in intubated critically ill patients.  The available evidence does not recommend the use of oral salbutamol, subcutaneous adrenaline, anti-cholinergic drugs, inhaled or systemic corticosteroids, antibiotics, aerosolized or intravenous immunoglobulin, respiratory physiotherapy and other therapeutic approaches including nitric oxide, recombinant human deoxyribonuclease, recombinant interferon, and nebulized furosemide.

In an Agency for Healthcare Research and Quality’s assessment on “Inhaled nitric oxide in preterm infants”, Allen et al (2010) systematically reviewed the evidence on the use of INO in preterm infants born at or before 34 weeks gestation age who receive respiratory support.  They searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Studies (CENTRAL) and PsycInfo in June 2010.  They also searched the proceedings of the 2009 and 2010 Pediatric Academic Societies Meeting and ClinicalTrials.gov.  They identified additional studies from reference lists of eligible articles and relevant reviews, as well as from technical experts.  Questions were developed in collaboration with technical experts, including the chair of the upcoming National Institutes of Health Office of Medical Applications of Research Consensus Development Conference.  These researchers limited their review to RCTs for the question of survival or occurrence of BPD and for the question on short-term risks.  All study designs were considered for long-term pulmonary or neurodevelopmental outcomes, and for questions about whether outcomes varied by subpopulation or by intervention characteristics.  Two investigators independently screened search results, and abstracted data from eligible articles.  These investigators identified a total of 14 RCTs, reported in 23 articles, and 8 observational studies.  Mortality rates in the NICU did not differ for infants treated with INO versus those not treated with INO (RR 0.97 (95 % CI: 0.82 to 1.15)).  Broncho-pulmonary dysplasia at 36 weeks for INO and control groups also did not differ (RR 0.93 (0.86, 1.003) for survivors).  A small difference was found between INO and control infants in the composite outcome of death or BPD (RR 0.93 (0.87, 0.99)).  There was inconsistent evidence about the risk of brain injury from individual RCTs, but meta-analyses showed no difference between INO and control groups.  These researchers found no evidence of differences in other short-term risks.  There was no evidence to suggest a difference in the incidence of cerebral palsy (RR 1.36 (0.88, 2.10)), neurodevelopmental impairment (RR 0.91 (0.77, 1.12)), or cognitive impairment (RR 0.72 (0.35, 1.45)).  Evidence was limited on whether the effect of INO varies by subpopulation or by characteristics of the therapy (timing, dose and duration, mode of delivery, or concurrent therapies).  The authors concluded that there was a 7 % reduction in the risk of the composite outcome of death or BPD at 36 weeks PMA for infants treated with INO compared to controls, but no reduction in death or BPD alone.  They stated that further studies are needed to explore particular subgroups of infants and to assess long-term outcomes including function in childhood.  They stated that there is currently no evidence to support the use of INO in preterm infants with respiratory failure outside the context of rigorously conducted RCTs.

Hawkes et al (2011) stated that severe malaria remains a major cause of global morbidity and mortality.  Despite the use of potent anti-parasitic agents, the mortality rate in severe malaria remains high.  Adjunctive therapies that target the underlying pathophysiology of severe malaria may further reduce morbidity and mortality.  Endothelial activation plays a central role in the pathogenesis of severe malaria, of which angiopoietin-2 (Ang-2) has recently been shown to function as a key regulator.  Nitric oxide is a major inhibitor of Ang-2 release from endothelium and has been shown to decrease endothelial inflammation and reduce the adhesion of parasitized erythrocytes.  Low-flow INO gas is a U.S. FDA-approved treatment for hypoxic respiratory failure in neonates.  These researchers described the protocol of a randomized controlled trial that examined the use of INO as adjunctive therapy of severe malaria.  This prospective, parallel-arm, randomized, placebo-controlled, blinded clinical trial compares adjunctive continuous INO at 80 ppm to placebo (both arms receiving standard anti-malarial therapy), among Ugandan children aged 1 to 10 years of age with severe malaria.  The primary endpoint is the longitudinal change in Ang-2, an objective and quantitative biomarker of malaria severity, which will be analyzed using a mixed-effects linear model.  Secondary endpoints include mortality, recovery time, parasite clearance and neurocognitive sequelae.  Noteworthy aspects of this trial design include its efficient sample size supported by a computer simulation study to evaluate statistical power, meticulous attention to complex ethical issues in a cross-cultural setting, and innovative strategies for safety monitoring and blinding to treatment allocation in a resource-constrained setting in sub-Saharan Africa.

Bergmark et al (2012) noted that there are approximately 225 to 600 million new malaria infections worldwide annually, with severe and cerebral malaria representing major causes of death internationally.  The role of NO in the host response in cerebral malaria continues to be elucidated, with numerous known functions relating to the cytokine, endovascular and cellular responses to infection with Plasmodium falciparum.  Evidence from diverse modes of inquiry suggests NO to be critical in modulating the immune response and promoting survival in patients with cerebral malaria.  This line of investigation has culminated in the approval of 2 phase II randomized prospective clinical trials in Uganda studying the use of INO as adjuvant therapy in children with severe malaria.  The strategy underlying both trials is to use the systemic anti-inflammatory properties of INO to "buy time" for chemical anti-parasite therapy to lower the parasite load.

Adhikari and colleagues (2014) examined if NO reduces hospital mortality in patients with severe ARDS (PaO2/FIO2 less than or equal to 100 mm Hg) but not in patients with mild-moderate ARDS (100 less than PaO2/FIO2 less than or equal to 300 mm Hg) at the time of randomization.  Data were collected from Medline, Embase, and Cochrane CENTRAL electronic databases (inception to May 2013); proceedings from 5 conferences (to May 2013); and trial registries (http://www.clinicaltrials.gov as well as http://www.controlled-trials.com).  No language restrictions were applied.  Two authors independently selected parallel-group RCTs comparing NO with control (placebo or no gas) in mechanically ventilated adults or post-neonatal children with ARDS.  Two authors independently extracted data from included trials.  Trial investigators provided subgroup data.  Meta-analyses used within-trial subgroups and random-effects models.  A total of 9 trials (n = 1,142 patients) met inclusion criteria.  Overall methodological quality was good.  Nitric oxide did not reduce mortality in patients with severe ARDS (risk ratio, 1.01 [95 % CI: 0.78 to 1.32]; p = 0.93; n = 329, 6 trials) or mild-moderate ARDS (risk ratio, 1.12 [95 % CI: 0.89 to 1.42]; p = 0.33; n = 740, 7 trials).  Risk ratios were similar between subgroups (interaction p = 0.53).  There was no between-trial heterogeneity in any analysis (I = 0 %).  Varying the PaO2/FIO2 threshold between 70 and 200 mm Hg, in increments of 10 mm Hg, did not identify any threshold at which the NO-treated patients had lower mortality relative to controls.  The authors concluded that NO does not reduce mortality in adults or children with ARDS, regardless of the degree of hypoxemia.  Given the lack of related ongoing or recently completed randomized trials, new data addressing the effectiveness of NO in patients with ARDS and severe hypoxemia will not be available for the foreseeable future.

Dzierba et al (2014) stated that ARDS and ALI are conditions associated with an estimated mortality of 40 to 50 %.  The use of inhaled vasodilators can help to improve oxygenation without hemodynamic effects.  These investigators reviewed relevant studies addressing the safety and effectiveness of iNO and aerosolized epoprostenol (aEPO) in the treatment of life-threatening hypoxemia associated with ARDS and ALI.  In addition, they provided a practicable guide to the clinical application of these therapies.  A total of 9 prospective RCTs were included for iNO reporting on changes in oxygenation or clinical outcomes; 7 reports of aEPO were examined for changes in oxygenation.  Based on currently available data, the use of either iNO or aEPO is safe to use in patients with ALI or ARDS to transiently improve oxygenation.  No differences have been observed in survival, ventilator-free days, or attenuation in disease severity.  The authors concluded that further studies with consistent end-points using standard delivery devices and standard modes of mechanical ventilation are needed to determine the overall benefit with iNO or aEPO.

Inhaled nitric oxide should be administered using FDA-approved devices (e.g., INOmax is one form of INO that has FDA approval for the treatment of hypoxic respiratory failure in neonates).

 
CPT Codes / HCPCS Codes / ICD-9 Codes
Other CPT codes related to the CPB:
94002 - 94004
99503
ICD-9 codes covered if selection criteria are met:
416.0, 416.8 Primary pulmonary hypertension or other chronic pulmonary heart diseases [except post-operative management in infants and children with congenital heart disease]
747.83 Persistent fetal circulation
748.5 Agenesis, hypoplasia, and dysplasia of lung
748.60 - 748.69 Other anomalies of lung
748.8 Other specified anomalies of respiratory system
768.5 - 768.9 Birth asphyxia
769 Respiratory distress syndrome
770.12 Meconium aspiration with respiratory symptoms
770.84 Respiratory failure of newborn
771.81 Septicemia [sepsis] of newborn
ICD-9 codes not covered for indications listed in the CPB:
084.0 - 084.9 Malaria
282.42 Sickle-cell thalassemia with crisis
282.60 - 282.69 Sickle-cell disease
466.11 - 466.19 Acute bronchiolitis
517.3 Acute chest syndrome
518.5 Pulmonary insufficiency following trauma and surgery
518.82 Other pulmonary insufficiency, not elsewhere classified
745.0 - 747.49 Congenital heart disease [if reported for post-operative management of pulmonary hypertension in infants and children]
756.6 Anomalies of diaphragm [congenital diaphragmatic hernia]
765.21 - 765.27 Less than 24 completed weeks of gestation to 33-34 completed weeks of gestation
860.0 Pneumothorax without mention of open wound into thorax
860.1 Pneumothorax with open wound into thorax
860.2 Hemothorax without mention of open wound into thorax
860.3 Hemothorax with open wound into thorax
860.4 Pneumohemothorax without mention of open wound into thorax
860.5 Pneumohemothorax with open wound into thorax
861.20 - 861.22 Injury to lung, without mention of open wound into thorax
861.30 - 861.32 Injury to lung, with open wound into thorax
996.84 Complications of transplanted lung
Other ICD-9 codes related to the CPB:
765.27 - 765.29 35-37 or more completed weeks of gestation
997.91 Complications affecting other specified body systems, not elsewhere classified, hypertension
V45.89 Other postprocedural status


The above policy is based on the following references:
  1. No authors listed. American Academy of Pediatrics. Committee on Fetus and Newborn. Use of inhaled nitric oxide. Pediatrics. 2000;106(2 Pt 1):344-345.
  2. Gnanaratnem J, Finer NN. Neonatal acute respiratory failure. Curr Opin Pediatr. 2000;12(3):227-232.
  3. Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev. 2006;(4):CD000399.   
  4. Barrington KJ, Finer NN. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database Syst Rev. 2006;(1):CD000509.
  5. Hoehn T, Krause MF, Buhrer C. Inhaled nitric oxide in premature infants -- A meta-analysis. J Perinat Med. 2000;28(1):7-13.
  6. Finer NN, Barrington KJ. Nitric oxide therapy for the newborn infant. Semin Perinatol. 2000;24(1):59-65.
  7. Walsh-Sukys MC, Tyson JE, Wright LL, et al. Persistent pulmonary hypertension of the newborn in the era before nitric oxide: Practice variation and outcomes. Pediatrics. 2000;105(1 Pt 1):14-20.
  8. No authors listed. Inhaled nitric oxide in term and near-term infants: Neurodevelopmental follow-up of the Neonatal Inhaled Nitric Oxide Study Group (NINOS). J Pediatr. 2000;136(5):611-617.
  9. Clark RH, Kueser TJ, Walker MW, et al. Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. N Engl J Med. 2000;342(7):469-474.
  10. No authors listed. Early compared with delayed inhaled nitric oxide in moderately hypoxaemic neonates with respiratory failure: A randomized controlled trial.The Franco-Belgium Collaborative NO Trial Group. Lancet. 1999;354:1066-1071.
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  31. Martin RJ, Walsh MC. Inhaled nitric oxide for preterm infants – Who benefits? N Engl J Med. 2005;353(1):82-84.
  32. Rea RS, Ansani NT, Seybert AL. Role of inhaled nitric oxide in adult heart or lung transplant recipients. Ann Pharmacother. 2005;39(5):913-917.
  33. Griffiths MJ, Evans TW. Inhaled nitric oxide therapy in adults. N Engl J Med. 2005;353(25):2683-2695.
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  35. Hoehn T, Krause MF, Buhrer C. Meta-analysis of inhaled nitric oxide in premature infants: An update. Klin Padiatr. 2006;218(2):57-61.
  36. Santacruz JF, Diaz Guzman Zavala E, Arroliga AC. Update in ARDS management: Recent randomized controlled trials that changed our practice. Cleve Clin J Med. 2006;73(3):217-219, 223-225, 229 passim.
  37. Perrin G, Roch A, Michelet P, et al. Inhaled nitric oxide does not prevent pulmonary edema after lung transplantation measured by lung water content: A randomized clinical study. Chest. 2006;129(4):1024-1030.
  38. Ballard RA, Truog WE, Cnaan A, et al; NO CLD Study Group. Inhaled nitric oxide in preterm infants undergoing mechanical ventilation. N Engl J Med. 2006;355(4):343-353.
  39. Kinsella JP, Cutter GR, Walsh WF, et al. Early inhaled nitric oxide therapy in premature newborns with respiratory failure. N Engl J Med. 2006;355(4):354-364.
  40. Stark AR. Inhaled NO for preterm infants--getting to yes? N Engl J Med. 2006;355(4):404-406.
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  42. Duchscherer G, Guo B. The use of nitric oxide in acute respiratory distress syndrome. IHE Report. Edmonton, AB: Institute for Health Economics (IHE); April 2007.
  43. Adhikari NK, Burns KE, Friedrich JO, et al. Effect of nitric oxide on oxygenation and mortality in acute lung injury: Systematic review and meta-analysis. BMJ. 2007;334(7597):779.
  44. Van Marter LJ. Progress in discovery and evaluation of treatments to prevent bronchopulmonary dysplasia. Biol Neonate. 2006;89(4):303-312.
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Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial, general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to change.
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