Medical Policy



Subject: Inhaled Nitric Oxide
Document #: MED.00076 Current Effective Date:    10/01/2017
Status: Revised Last Review Date:    05/04/2017

Description/Scope

This document addresses the use of inhaled nitric oxide (INO or iNO). INO has been investigated as a technique to improve oxygenation in critically ill individuals with hypoxic respiratory failure, both to reduce mortality and, in neonates, to reduce the need for extracorporeal membrane oxygenation (ECMO). Hypoxic respiratory failure may result from respiratory distress syndrome (RDS), persistent primary pulmonary hypertension, pulmonary hypoplasia, congenital diaphragmatic hernia (CDH), meconium aspiration, pneumonia, or sepsis.

Position Statement

Medically Necessary:

I.  Inhaled nitric oxide is considered medically necessary as a component of the treatment of hypoxic respiratory failure* in term and near-term (born at 34 or more weeks of gestation) neonates when both of the following criteria are met:

  1. Conventional therapies have failed or are expected to fail, for example, administration of high concentrations of oxygen, hyperventilation, high frequency ventilation, the induction of alkalosis, neuromuscular blockade and sedation; and
  2. Neonate does not have a congenital diaphragmatic hernia.

*Hypoxic respiratory failure is defined as an oxygenation index (OI) of at least 25 recorded on 2 measurements made at least 15 minutes apart. The OI is calculated as the mean airway pressure in centimeters (cms) of water multiplied by the fraction of inspired oxygen divided by the partial pressure of arterial oxygen times 100. An OI of 25 is associated with a 50% risk of requiring ECMO or dying. An OI of 40 is often used as a criterion to initiate ECMO therapy.

II.  Inhaled nitric oxide is considered medically necessary as a method of assessing pulmonary vasoreactivity in individuals with pulmonary hypertension.

Investigational and Not Medically Necessary:

Other indications for treatment using inhaled nitric oxide are considered investigational and not medically necessary, including, but not limited to its use in treating adult respiratory distress syndrome, premature neonates (less than 34 weeks of gestation) and post-operative management of congenital heart disease.

Rationale

Term and Near Term Neonates

In 1999, the U.S. Food and Drug Administration (FDA) approved INOmax® (nitric oxide for inhalation) (INO Therapeutics, Hazelwood, MO) for use, in conjunction with ventilatory support and other appropriate agents, for the treatment of term and near-term (greater than 34 weeks) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension, where it improves oxygenation and reduces the need for extracorporeal membrane oxygenation. INOmax  is contraindicated in neonates known to be dependent on right-to-left shunting of blood.

Published clinical studies report that INO therapy improves oxygenation and ventilation, reduces the need for ECMO and lowers the incidence of chronic lung disease and death among term/near-term infants with respiratory failure (Clark, 2000; Neonatal Inhaled Nitric Oxide Study Group, 1997b). One study suggested that a maximum of 4 days of INO 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. Konduri (2004) randomized 299 infants in respiratory failure to receive early (OI 15-25) versus control (OI ≥ 25) treatment with INO and found no significant reduction in the incidence of ECMO mortality in the early treatment group.

An updated 2017 Cochrane Review by Barrington and colleagues evaluated the use of INO for respiratory failure in infants born at or near term gestation. The authors included 17 studies in their review. However, most results were obtained from 10 studies of moderate to high quality evidence, which compared INO therapy to standard therapy without INO. INO appeared to result in improved outcomes for term and near-term hypoxemic infants. Oxygenation was improved in approximately 50% of infants receiving INO. Infants with CDH had slightly worse outcomes with INO. The authors concluded "INO is effective at an initial concentration of 20 ppm for term and near-term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia."

The American Academy of Pediatrics (AAP) (2000; reaffirmed 2010) policy statement regarding the use of INO in neonates with respiratory failure supports its use for the indications, dosing, administration and monitoring outlined on the product information label and approved by the FDA. The AAP's recommendations are as follows:

Congenital Diaphragmatic Hernia (CDH)

CDH is a very complex and uncommon condition characterized by a defect in the diaphragm leading to protrusion of abdominal contents into the thorax interfering with normal development of the lungs (Chandrasekharan, 2017; Gien, 2016). In the most severe cases of CDH, lung hypoplasia and immaturity associated with persistent pulmonary hypertension of the newborn (PPHN) and cardiac dysfunction occur. Secondary to pulmonary hypertension, there is shunting of blood from right to left. An early randomized controlled trial (RCT) of infants 34 weeks gestation or more with CDH did not find any significant improvement in survival or oxygenation (Nitric Oxide Study Group, 1997a). INO is not FDA approved for the treatment of PPHN caused by CDH and is also contraindicated in neonates known to be dependent on right-to-left shunting of blood (INOmax PI, 2015). However, the use of INO for the treatment of CDH appears to be continuing.

Malowitz and colleagues (2014) examined mortality and medical interventions (including INO) for neonates born with CDH. Infants 34 weeks gestation or more with CDH from 29 neonatal intensive care units (NICUs) born between 1999 and 2012 were identified. Only NICUs with an average of two or more CDH cases per year were included. Mortality and the proportion of infants exposed to medical interventions, during four periods of time: 1999–2001, 2002–2004, 2005–2007, and 2008–2012 were examined. A total of 760 infants with CDH were identified. Use of iNO increased from 20% of infants to 50%, sildenafil use increased from 0 to 14%, and milrinone use increased from 0 to 22% (p<0.001) from 1999-2001 to 2008-2012. Overall mortality (28%) did not significantly change over time as compared to the earliest time period. The authors reported "that despite the evidence for harm and lack of evidence for efficacy, INO use has significantly increased." Additionally they indicated that the safety and efficacy of interventions (including INO) in infants with CDH requires randomized clinical trials or prospective cohort studies of comparative effectiveness with careful data collection.

Putnam and colleagues (2016) performed a review of the Congenital Diaphragmatic Hernia Study Group (CDHSG) registry from January 1, 2007 to December 31, 2014. A total of 3367 newborns with CDH from 70 centers were entered into the registry. Sixty-eight centers (97.1%) used INO during the study. A positive association between INO use and mortality per center was reported. Treatment with INO was associated with a 15% higher absolute mortality rate after taking into account multiple "patient and operative characteristics." The authors concluded: "current data are lacking to support the widespread use of INO in this patient population because more recent data have found that its use may be associated with worse outcomes."

The American Association for Respiratory Care (AARC) (2010) published an evidence-based clinical practice guideline for INO in neonates with acute hypoxic respiratory failure. The AARC recommendations included that: "INO should not be used routinely in newborns with congenital diaphragmatic hernia."

The American Pediatric Surgical Association (APSA) Outcomes and Evidence Based Practice (OEBP) committee (Puligandla, 2015) issued recommendations for CDH care. Evidence for the use of INO in neonates with CDH was obtained from three RCTs (Clark, 2000; Kinsella, 1997, NINOS Study Group, 1997a) and a Cochrane review (Finer, 2006). The quality of evidence was limited due to the age of available studies (over 10 years old) and by modest sample sizes. The committee concluded that based on level 2 evidence "iNO cannot be recommended to routinely treat pulmonary hypertension in CDH patients (grade C recommendation)." A grade C recommendation was defined as Level 4 studies (case series) or extrapolation from Level 2 (cohort studies low quality RCTs, outcomes research) or 3 (case control studies). The authors further noted that certain practice patterns continue, such as the use of INO despite evidence showing no benefit.

Premature Neonates

Studies involving the use of INO for premature neonates (less than 34 weeks of gestation) are currently inconclusive and use of this treatment remains controversial for premature infants with severe respiratory failure. In a double-blind, randomized, placebo controlled, single-center trial, Schreiber and colleagues (2003) examined the effect of INO during the first week of life on the incidence of chronic lung disease and death in premature infants (n=207) requiring mechanical ventilation and surfactant-replacement therapy (mean gestational age, 27.2 ± 2.7 weeks). Compared to the control group, the treatment group experienced a lower incidence of death or chronic lung disease (48.6% vs. 63.7%). In a post hoc analysis, the authors concluded those infants with mild to moderate respiratory distress were most likely to benefit. While these results were promising, an accompanying editorial pointed out that the significant difference between the two groups was in part related to the unexpectedly high rate of unfavorable outcomes (death or chronic lung disease) in the control group (Martin, 2003). The author also noted an uncertainty about the overall safety of INO in premature infants, in addition to uncertainty about optimal dosage, timing, and duration of therapy.

Mestan and colleagues (2005) conducted a prospective, longitudinal follow-up study of premature infants who had received INO or placebo to investigate neurodevelopmental outcomes at 2 years of age. The study included 138 children (82% of survivors who had participated in the Schreiber 2003 study). Neurologic examination, neurodevelopmental assessment and anthropometric measurements were made by examiners who were unaware of the children's original treatment assignment. 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 (relative risk [RR], 0.53; 95% confidence interval [CI], 0.33 to 0.87; p=0.01).

Van Meurs and colleagues (2005) conducted a randomized controlled trial (n=420) on neonates less than 34 weeks gestation, with a birth weight of 401 to 1500 grams, and with severe respiratory failure to determine if INO treatment would reduce the incidence of bronchopulmonary dysplasia (BPD) or death. The rate of death or BPD was 80% in the INO group, as compared with 82% in the placebo group (RR, 0.97; 95% CI, 0.86 to 1.06; p=0.52), and the rate of BPD was 60% versus 68% (RR, 0.90; 95% CI, 0.75 to 1.08; p=0.26). There were no significant differences in the rates of severe intracranial hemorrhage or periventricular leukomalacia. Post hoc analyses suggest rates of death and BPD are reduced for infants with a birth weight greater than 1000 grams, whereas infants weighing 1000 grams or less who are treated with INO have higher mortality and increased rates of severe intracranial hemorrhage. The authors concluded use of INO in critically ill premature infants weighing less than 1500 grams does not decrease the rates of death or BPD and suggested further trials are required to determine whether INO benefits infants with a birth weight of 1000 grams or more.

According to a review by Kinsella (2006a), trials of INO in premature newborns have resulted in conflicting outcomes. The authors reported that results of ongoing trials will help clarify the potential risks and benefits of INO therapy in this population. A multicenter, randomized trial (Kinsella, 2006b) investigated the safety and efficacy of early inhaled, low dose INO therapy in a multicenter, randomized trial. This study involved 793 newborns who were 34 weeks or less gestational age and had respiratory failure requiring mechanical ventilation. Random assignments were made of either INO (5 parts per million [ppm]) or placebo gas for 21 days or until extubation with stratification according to birth weight. The authors concluded that among premature newborns with respiratory failure, low-dose INO did not reduce the overall incidence of bronchopulmonary dysplasia, except among those with a birth weight of at least 1000 grams, but it did reduce the overall risk of brain injury. Long-term follow-up studies of these infants are ongoing to determine later outcomes of early INO therapy.

Ballard and colleagues (2006), in a randomized, stratified, double-blind, placebo controlled trial of INO, studied infants with a gestational age of 26 weeks and a birth weight of 1250 grams or less who required ventilation between 7 and 21 days of age. A total of 294 infants received INO and 288 received a placebo. The survival rate without BPD at 36 weeks postmenstrual age was 43.9% in the group receiving INO and 36.8% in the group receiving a placebo. The authors concluded that prolonged INO therapy initiated between 7 and 21 days of age in preterm infants receiving mechanical ventilation improved survival without BPD and without short-term adverse effects. However, the authors further noted that definitive recommendations regarding the use of INO among infants at high risk for BPD await further long-term neurodevelopmental follow-up in completed trials.

Hintz and colleagues (2007) studied neurodevelopmental outcomes at 18-22 months in 420 premature infants less than 34 weeks of gestation, weighing less than 1500 grams with severe respiratory failure. These infants were previously enrolled in the National Institute of Child Health and Human Development Preemie iNO trial which was a multicenter, randomized, placebo controlled study of INO. Study findings did not reveal reduced death or improved neurodevelopmental outcomes in the infants exposed to INO. The authors concluded until more information is obtained, routine use of INO among premature infants should be restricted to research settings.

A randomized study by Van Meurs and colleagues (2007) examined INO use in 29 infants greater than 1500 grams but less than 34 weeks gestation with severe respiratory failure. The small sample size limited definite conclusions, but suggested that INO does not affect the rate of bronchopulmonary dysplasia and death.

Di Fiore and colleagues (2007) assessed the effect of INO on resistance and compliance in ventilated preterm infants with evolving BPD. A total of 71 ventilated preterm infants were enrolled in a randomized, double-blinded, placebo controlled multicenter study; 37 infants received placebo gas and 34 infants received INO. Results indicated there was no effect of INO on expiratory resistance or compliance at 1 hour, 1 week or 2 weeks of study gas administration. Study limitations included a small sample size and a number of infants lost to follow-up due to extubation and other factors.

Huddy and colleagues (2008) reported results of a multicenter RCT (INNOVO trial) which studied neonatal ventilation with INO versus ventilatory support without INO for severe respiratory failure in preterm infants. A total of108 infants (55 INO arm and 53 controls) from 15 neonatal units were recruited and followed up to age 4 or 5 years. By 1 year of age, 59% had died and 84% of the survivors had signs of impairment or disability. Children were assessed at age 4 to 5 years by examination, interview, cognitive, and behavioral assessments. The outcomes were divided into seven domains and were described as normal, impaired or disabled (mild, moderate or severe) by the degree of functional loss. Thirty-eight of the 43 survivors had follow-up assessments. In the INO group 62% (34/55) had died or were severely disabled as compared to 70% (37/53) in the no INO group (RR, 0.89; 95% CI, 0.67 to 1.16). Only 8 children of the original 108 recruited to the trial were classified as normal across all of the domains at 4 to 5 years of age.

Mercier and colleagues (2010) studied 800 preterm infants with a gestational age between 24 and 28 weeks plus 6 days with a weight of at least 500 grams, requiring surfactant or continuous positive airway pressure for RDS within 24 hours of birth. The infants were randomly assigned in a one-to-one ratio to either a placebo (nitrogen gas) or INO for a minimum of 7 days and a maximum of 21 days in a double-blind European multicenter study. The authors concluded:

INO at 5 ppm, started within the first 24 hours after birth and continued for a median of three weeks, does not improve survival without BPD in very preterm neonates with mild to moderate RDS. Our negative results should alter practice by helping to eliminate the use of INO in preterm infants developing bronchopulmonary dysplasia.

Askie and colleagues (2011) performed a meta-analysis of data from RCTs evaluating the efficacy of INO in preterm infants (less than 37 weeks' gestation). Included were data from 12 trials with a total of 3298 infants. The primary endpoints of the analysis were death or severe neurological events during the trial, and chronic lung disease (defined as receipt of supplemental oxygen at 36 weeks' postmenstrual age). Overall, death or chronic lung disease occurred in 59% of infants treated with INO and 61% of control infants. The difference between groups was not statistically significant; RR, 0.96; 95% CI, 0.92-1.01; p=0.11. Severe neurologic events occurred in 25% of infants in the INO group and 23% in the control group; RR, 1.12; 95% CI, 0.98-1.28; p=0.09. Subanalyses, (by birth weight, gestational age, race, etc.) did not find any characteristics significantly associated with a benefit from INO. The authors concluded that routine use of INO in preterm infants is not recommended.

In 2013, Durrmeyer and colleagues published 2-year outcomes of the European Union Nitric Oxide trial, a randomized controlled trial of inhaled nitric oxide in premature infants. Of the 800 original premature neonates, a total of 737 were available for evaluation at this time point. The evaluable children excluded those who were lost to follow-up or did not receive treatment. A total of 244 of 363 (67%) evaluable children at 2 years in the INO group survived without severe or moderate disability compared to 270 of 374 (72%) evaluable children in the placebo group. The difference in disability rates was not statistically significant, p=0.09. There were also no statistically significant differences between groups in other outcomes such as growth, hospitalization rates, or use of respiratory medications.

Kinsella and colleagues (2014) performed a multicenter RCT designed to assess the safety and efficacy of early, noninvasive iNO therapy in premature newborns that did not require mechanical ventilation. Enrollment criteria included gestational age of 34 weeks or less, birth weight between 500 and 1250 grams, postnatal age less than 72 hours and on supplemental oxygen per CPAP or nasal cannula. Prior to randomization, 124 newborns were stratified into three different groups by birth weight (500-749, 750-999, 1000-1250 grams) to iNO (10 ppm) or placebo gas (controls) until 30 weeks postmenstrual age. The primary outcome was a composite of death or BPD at 36 weeks postmenstrual age. Secondary outcomes included the need for and duration of mechanical ventilation, severity of BPD, and safety outcomes. No difference in the incidence of death or BPD was reported in the iNO and placebo groups (42% vs 40%, p=0.86, RR=1.06, 0.7-1.6). There were no differences between the treatment groups in the severity of BPD, the duration of mechanical ventilation, need for mechanical ventilation or safety outcomes including severe intracranial hemorrhage. The authors concluded:

Prolonged treatment with noninvasive iNO was safe but did not decrease the composite endpoint of death/BPD in newborns with birth weights of 500-1250 g treated within 72 hours after birth. Long-term follow-up studies of these infants are ongoing to determine later pulmonary and neurocognitive outcomes of early iNO therapy.

An updated 2017 Cochrane Review by Barrington and colleagues evaluated the use of INO for the treatment of respiratory failure in preterm infants. The authors located 17 randomized controlled trials of INO therapy in preterm infants. A total of 8 trials that provided early rescue treatment showed no significant effect of INO on mortality or bronchopulmonary dysplasia (BPD). Four studies examined the routine use of INO in preterm infants with pulmonary disease and no significant reduction in death or BPD occurred. Three trials evaluated later treatment with INO based on risk of BPD and no significant benefit was reported. The authors concluded that INO did not appear to be effective as rescue therapy or for early routine use and recommended further study for later use of INO to prevent BPD in preterm infants.

The current AAP (reaffirmed 2010) policy statement on the use of INO in neonates with respiratory distress states:

The limited data to date on hypoxic preterm neonates suggest that low-dose INO improves oxygenation but does not improve survival. Additional large randomized trials of INO in premature neonates are required because they may experience more toxic effects than term and near-term infants.

The Agency for Healthcare Research and Quality (AHRQ) (2010) in an evidence report on INO in preterm infants concludes: "There is currently no evidence to support the use of INO in preterm infants with respiratory failure outside the context of rigorously conducted randomized clinical trials."

In 2011, a National Institutes of Health (NIH) Consensus Development Conference Statement on INO for premature infants was published. The statement was based on the 2010 AHRQ-sponsored systematic review of the literature noted above. NIH conclusions included: "Taken as a whole, the available evidence does not support use of INO in early-routine, early-rescue, or later-rescue regimens in the care of premature infants of <34 weeks' gestation who require respiratory support."

An AAP clinical report (Kumar, 2014), reviewed existing data for the use of INO in preterm infants and provided guidance regarding its use in this population. The following summary was provided:

  1. The results of randomized controlled trials, traditional meta-analyses, and an individualized patient data meta-analysis study indicate that neither rescue nor routine use of iNO improves survival in preterm infants with respiratory failure (Evidence quality, A; Grade of recommendation, strong).
  2. The preponderance of evidence does not support treating preterm infants who have respiratory failure with iNO for the purpose of preventing/ ameliorating BPD, severe intraventricular hemorrhage, or other neonatal morbidities (Evidence quality, A; Grade of recommendation, strong).
  3. The incidence of cerebral palsy, neurodevelopmental impairment, or cognitive impairment in preterm infants treated with iNO is similar to that of control infants (Evidence quality, A).
  4. The results of 1 multicenter, randomized controlled trial suggest that treatment with a high dose of iNO (20 ppm) beginning in the second postnatal week may provide a small reduction in the rate of BPD. However, these results need to be confirmed by other trials.
  5. An individual-patient data metaanalysis that included 96% of preterm infants enrolled in all published iNO trials found no statistically significant differences in iNO effect according to any of the patient-level characteristics, including gestational age, race, oxygenation index, postnatal age at enrollment, evidence of pulmonary hypertension, and mode of ventilation.
  6. There are limited data and inconsistent results regarding the effects of iNO treatment on pulmonary outcomes of preterm infants in early childhood.

In 2016, Kinsella and colleagues for the Pediatric Pulmonary Hypertension Network proposed the following recommendations for the role of iNO in premature newborns:

  1. iNO therapy should not be used in premature infants for the prevention of BPD [bronchopulmonary dysplasia], as multicenter studies data have failed to consistently demonstrate efficacy for this purpose.
  2. iNO therapy can be beneficial for preterm infants with severe hypoxemia that is primarily due to PPHN [persistent pulmonary hypertension of the newborn] physiology rather than parenchymal lung disease, particularly if associated with prolonged rupture of membranes and oligohydramnios.
  3. iNO is preferred over other pulmonary vasodilators in preterm infants based on a strong safety signal from short- and long-term follow-up of large numbers of patients from multicenter randomized clinical trials for BPD prevention, and
  4. Placebo controlled trials are not feasible in the target population; therefore, alternate study designs such as the development of multicenter registries, informatics strategies, and other approaches should be used to address issues regarding the efficacy and safety of therapeutic options for preterm infants with life threatening PPHN physiology.

However, the authors encouraged additional research and concluded:

iNO therapy has successfully improved clinical management and has lowered the need for ECMO therapy in term and near-term infants, but more studies are needed to more precisely define its role in premature neonates. Although we recommend that iNO not be routinely used for the prevention of BPD, we believe that iNO therapy may have an important role for subgroups of preterm infants with severe PH, especially in the setting of PPHN physiology associated with oligohydramnios, lung hypoplasia, and sepsis. Owing to promising case series findings, extensive safety data in preterm infants from past metaRegister of Controlled Trials and the lack of safety or efficacy data concerning other targeted PH therapies (PH-specific drugs), we believe that it is reasonable to use iNO in this subgroup of critically ill preterm infants. We encourage ongoing research for the impact of iNO and other therapies in the setting of severe PH in preterm infants

Randomized trials of INO therapy in premature infants have yielded conflicting results in terms of its effect on the incidence of BPD, neurological events and neurobehavioral outcomes. This may be related to differences in severity of illness in the study subjects, dose of INO, and timing and duration of therapy, making it difficult to draw definitive conclusions regarding the use of INO in this population. The benefits and risks of INO need further study before its use can be recommended in the premature infant. Longer-term follow-up of study participants may help to clarify whether long-term health benefits result from INO therapy.

Assessment of Pulmonary Vasoreactivity

INO has also been studied as a diagnostic method of assessing pulmonary vasoreactivity in persons with pulmonary hypertension. A brief diagnostic trial (Atz, 1999) compared the ability of INO, oxygen (O2) and nitric oxide in oxygen (NO+O2) to identify reactive pulmonary vasculature in those with pulmonary hypertension during acute vasodilator testing at cardiac catheterization. In persons with pulmonary hypertension, decisions regarding suitability for corrective surgery, transplantation and assessment of long-term prognosis are based on results obtained during acute pulmonary vasodilator testing. Two groups consisting of 71 subjects were included for analysis in this study. In the first group, 46 subjects had hemodynamic measurements in room air (RA), 100% O2, return to RA and NO (80 parts per million [ppm] in RA). In the second group, 25 additional subjects were studied in RA, 100% O2 and 80 ppm NO in oxygen (NO+O2). In group one, O2 decreased pulmonary vascular resistance (PVR) from 17.2 ± 2.1 U.m2 to 11.1 ± 1.5 U.m2 (p<0.05). Nitric oxide caused a comparable decrease from 17.8 ± 2.2 U.m2 to 11.7 ± 1.7 U.m2 (p<0.05). In group 2, PVR decreased from 20.1 ± 2.6 U.m2 to 14.3 ± 1.9 U.m2 in O2 (p<0.05) and further to 10.5 ± 1.7 U.m2 in NO+O2 (p<0.05). A response of 20% or more reduction in PVR was seen in 22/25 individuals with NO+O2 compared with 16/25 in O2 alone (p=0.01). The authors concluded that INO and O2 produced a similar degree of selective pulmonary vasodilation, and combination testing with NO + O2 provided additional pulmonary vasodilation.

A small randomized trial (Balzer, 2002) investigated whether preoperative hemodynamic evaluation with O2 and INO could identify individuals with pulmonary hypertension who may be appropriate candidates for heart transplantation or corrective cardiac surgery, more accurately than an evaluation with O2 alone. The ratio of pulmonary and systemic vascular resistance (Rp:Rs) was determined at baseline while breathing 21% to 30% O2, and in 100% O2 and 100% O2 with 10 to 80 ppm NO to evaluate pulmonary vascular reactivity. A total of 78 individuals were determined to be operable. Of those, 74 had undergone surgery at the time data was collected. Twelve persons died or developed right heart failure secondary to pulmonary hypertension following surgery. Survivors were followed for a median duration of 26 months. Rp:Rs 0.33 and a 20% decrease in Rp:Rs from baseline had been chosen as two criteria for operability to retrospectively determine the efficacy of preoperative testing in selecting surgical candidates. In comparison to an evaluation with oxygen alone, sensitivity (64% versus 97%) and accuracy (68% versus 90%) were increased by an evaluation with O2 and NO when Rp:Rs 0.33 was used as the criterion for surgery. Specificity was only 8% when a 20% decrease in Rp:Rs from baseline was used as the criterion for operability. The authors indicated that a preoperative hemodynamic evaluation with a combination of supplemental O2 and INO may identify a greater number of candidates for corrective surgery or transplantation than a preoperative evaluation with O2 alone.

Barst and colleagues (2010), in an industry sponsored study, investigated whether a combination of INO and O2 was more effective than 100% O2 or INO alone for acute vasodilator testing in children. An open, prospective, randomized, controlled trial was conducted at 16 centers. A total of 136 children were enrolled and 121 completed the study. Children 4 weeks to 18 years of age with pulmonary hypertension (PH) and increased pulmonary vascular resistance (PVR) underwent right heart catheterization for acute vasodilator testing. All subjects were tested with each of three agents (80 ppm INO, 100% O2 and a combination of 80 ppm INO/100% O2) in three 10-minute treatment periods. Primary outcome measures were percentages of acute responders to each agent. Changes in PVR index and mean pulmonary arterial pressure vs. baseline were greater with INO/O2 vs. either O2 or INO alone (p<0.001). Survival at 1 year follow-up included (1) 90.9% of acute responders to the combination, compared with 77.8% of nonresponders to the combination, and (2) 85.7% of acute responders to O2 alone, compared with 80.6% of nonresponders to O2. There was no significant difference in acute responder rate with INO alone versus INO/O2; however, it was reported that the combination improved pulmonary hemodynamics acutely better than INO alone. One year survival data show similar rates between the INO/O2 and the O2 alone groups.

Krasuski and colleagues (2011) evaluated the ability of vasodilator response to predict survival in a heterogeneous group of individuals with pulmonary hypertension. A total of 214 treatment-naive subjects with pulmonary hypertension were enrolled in the study between November 1998 and December 2008. Vasoreactivity was assessed during inhalation of iNO. There were 51 deaths (25.9%) over a mean follow-up period of 2.3 years. Kaplan-Meier analysis demonstrated that vasodilator responders had significantly improved survival (p<0.01). The authors concluded that "vasodilator responsiveness to iNO is an important method of risk stratifying PH patients, with results that apply regardless of clinical etiology."

In 2015, the American Heart Association and American Thoracic Society issued guidelines for the treatment of pediatric pulmonary hypertension. Included were the following recommendations related to INO that were graded as a Class I; Level of Evidence A (meaning that the procedure/treatment was deemed useful/effective with sufficient evidence from multiple randomized trials or meta-analyses).

Additional lower level recommendations included in the guidelines related to INO were:

Class of recommendation and level of evidence is described in the guideline as follows:

Class of Recommendation is an estimate of the magnitude of the treatment effect, with consideration given to risks versus benefits and the evidence and agreement that a given treatment or procedure is or is not useful or effective (Class I or II). Class III designation is applied for interventions that may cause harm to the patient. The Level of Evidence is an estimate of the certainty or precision of the treatment effect. The writing committee reviews and ranks evidence supporting each recommendation, with the weight of evidence ranked as Level of Evidence A, B, or C according to specific definitions. For conditions in which inadequate data are available, recommendations are based on expert consensus and clinical experience and are ranked as Level of Evidence C. The committee reviewed and ranked evidence supporting current recommendations with the weight of evidence ranked as Level A if the data were derived from multiple RCTs or meta-analyses. The committee ranked available evidence as Level B when data were derived from a single RCT or nonrandomized studies. Evidence was ranked as Level C when the primary source of the recommendation was consensus opinion, case studies, or standard of care.

The 2015 Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension (Galiè and colleagues) reported that INO at 10-20 parts per million (ppm) is the standard of care for vasoreactivity testing.

Other Potential Uses

Sokol (2003), in a review of the published literature for the use of INO in children and adults with respiratory distress, evaluated five randomized controlled trials including 535 children and adults with acute hypoxemic respiratory failure, and concluded INO did not demonstrate any statistically significant effect on mortality and transiently improved oxygenation. Lack of data prevented assessment of other clinically relevant endpoints.

A 2010 Cochrane review by Afshari and colleagues identified 14 randomized controlled trials which compared INO with no intervention or placebo in a total of 1303 participants consisting of both children and adults with acute hypoxemic respiratory failure (AHRF). AHRF was described as acute RDS and acute lung injury characterized by an inflammatory process of the alveolar-capillary membrane that may occur as a result of a primary lung disease or secondary to systemic disease processes. A significant but transient improvement in oxygenation was found in the first 24 hours; however, INO appeared to increase the risk of renal impairment among adults. The authors concluded that "INO cannot be recommended for patients with AHRF. INO results in a transient improvement in oxygenation but does not reduce mortality and may be harmful."

In a systematic review and meta-analysis, Adhikari and colleagues (2014) investigated whether INO reduces hospital mortality in individuals with severe acute respiratory distress syndrome (ARDS) (PaO2/FIO2 ≤ 100 mm Hg) as compared to those with mild-moderate ARDS (100 < PaO2/FIO2 ≤ 300 mm Hg). Parallel-group RCTs comparing nitric oxide with control (placebo or no gas) in mechanically ventilated adults or post-neonatal children with ARDS were independently selected. Nine trials (n=1142 subjects) met inclusion criteria. Nitric oxide was not observed to reduce mortality in individuals with severe ARDS (risk ratio, 1.01 [95% CI, 0.78-1.32]; p=0.93; n=329, six trials) or mild-moderate ARDS (risk ratio, 1.12 [95% CI, 0.89-1.42]; p=0.33; n=740, seven trials). The authors concluded there was no beneficial effect of nitric oxide on mortality among individuals with ARDS, regardless of the severity of hypoxemia at randomization. They further noted that given the lack of related ongoing or recently completed randomized trials, new data addressing the effectiveness of nitric oxide in those with ARDS and severe hypoxemia will not be available for the foreseeable future.

A small, prospective, randomized placebo controlled trial (Bronicki, 2015) assessed the use of INO for improved oxygenation and decreased duration of mechanical ventilation in children with ARDS. A total of 55 children from nine centers were randomized to either placebo or INO. Treatment continued until death, removal of ventilator support, or 28 days after the start of therapy. The primary study outcome was ventilator-free days at 28 days post randomization. A trend toward an improved oxygenation index (OI) in the INO group compared with the placebo group at 4 hours became significant at 12 hours. There was no difference in the OI between groups at 24 hours. Days alive and ventilator-free at 28 days was increased in the INO group, 14.2 ± 8.1 and 9.1 ± 9.5 days (INO and placebo groups, respectively, p=0.05). Overall survival at 28 days did not reach statistical significance, 92% (22 of 24) in the INO group and 72% (21 of 29) in the placebo group (p=0.07). However, the rate of extracorporeal membrane oxygenation-free survival was significantly greater in those randomized to INO 92% (22 of 24) vs 52% (15 of 29) for those receiving placebo (p<0.01). A significant study limitation was the small number of subjects enrolled. The authors concluded that a larger prospective, randomized controlled trial is indicated.

Additionally, there is insufficient evidence to support the use of INO for the prevention of ischemia-reperfusion injury/acute rejection following lung transplantation, or the treatment of acute lung injury, or vaso-occlusive crises in those with sickle cell disease (Dellinger, 1998; Lundin, 1999; Reiter Meade, 2003; Taylor, 2004; Weiner, 2003).

A 2014 Cochrane review by Bizzaro and colleagues identified four randomized controlled trials comparing the effects of postoperative INO versus placebo or conventional management of 210 infants and children with congenital heart disease. The primary outcome of the review was mortality. No differences were observed between groups with respect to mortality (p=0.50), number of pulmonary hypertensive crises (p=0.79), change in mean pulmonary arterial pressure (p=0.16), mean arterial pressure (p=0.40), heart rate (p=1.00), changes in oxygenation, and measurement of maximum methaemoglobin level as a marker of toxicity. The authors noted the lack of data on long-term mortality, length of stay in an intensive care unit or hospital, and neurodevelopmental disability. They also had concerns about methodological quality of studies, sample size, and heterogeneity between studies. These results do not support a benefit for postoperative INO treatment for infants and children with congenital heart disease.

Potapov and colleagues (2011) conducted a study to evaluate the prophylactic use of INO in adults undergoing left ventricular assist device (LVAD) implantation for congestive heart failure. A double-blind trial was conducted between 2003 and 2008 at eight centers in the United States and Germany. Individuals were randomized to receive INO (40 ppm) (n=73) or placebo (n=77) beginning at least 5 minutes before the first weaning attempt from mechanical ventilation. The primary study outcome was right ventricular dysfunction (RVD). Continued use of INO or placebo occurred until the study subjects were extubated, reached the study criteria for RVD or were treated for 48 hours, whichever occurred first. Individuals were permitted to crossover to open-label INO if they failed to wean from mechanical ventilation, still required pulmonary vasodilator support at 48 hours or met criteria for RVD. Thirteen of 150 randomized subjects (9%) did not receive the study treatment. In addition, crossover to open-label INO occurred in 15 of 73 subjects (21%) in the INO group and 20 of 77 (26%) in the placebo group. In an intention-to-treat (ITT) analysis, the RVD criteria were met by 7 of 73 (9.6%) subjects in the INO group and 12 of 77 (15.6%) subjects in the placebo group. This difference was not statistically significant (p=0.33). Other outcomes also did not differ significantly between groups. For example, the mean number of days on mechanical ventilation was 5.4 in the INO group and 11.1 in the placebo group (p=0.77), and the mean number of days in the hospital was 41 in each group.

A small prospective randomized single center trial (Trzeciak and colleagues, 2014) evaluated 50 adults with severe sepsis and systolic blood pressure less than 90 mm Hg despite intravascular volume expansion and/or serum lactate greater than or equal to 4.0 mmol/L. After macrocirculatory resuscitation goals were met, subjects were randomized to 6 hours of iNO (40 ppm) or sham inhaled nitric oxide administration. The primary outcome measure was microcirculatory flow index change. Secondary outcome measures were lactate clearance and change in Sequential Organ Failure Assessment score. Of the 50 adults enrolled, 28 (56%) required vasopressor agents and 15 (30%) died. Despite increased levels of plasma nitrite with iNO treatment, no improvement was observed in microcirculatory flow, lactate clearance, or organ dysfunction. No association was found between changes in microcirculatory flow and lactate clearance or organ dysfunction.

Summary

In summary, there is insufficient evidence in the published literature demonstrating the safety and efficacy of INO for any use, other than as a component of the treatment of hypoxic respiratory failure in term and near-term (born at 34 or more weeks of gestation) neonates under specific circumstances and as a method of assessing pulmonary vasoreactivity in individuals with pulmonary hypertension.

Background/Overview

INO has been investigated for a variety of uses. However, the only FDA approved indication is in conjunction with ventilatory support and other appropriate agents, for the treatment of term and near-term (greater than 34 weeks) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension, where it improves oxygenation and reduces the need for extracorporeal membrane oxygenation.

Acute respiratory failure is the most common problem seen in the term, near-term (born at 34 or more weeks of gestation), and preterm (less than 34 weeks of gestation) infants admitted to neonatal intensive care units. Management of infants with respiratory failure may include one or more of the following: administration of high concentrations of oxygen, hyperventilation, high-frequency ventilation, the induction of alkalosis, neuromuscular blockade, ante-natal steroids for the prevention of RDS, use of postnatal steroids for the prevention of chronic lung disease, as well as INO therapy (INO is a selective pulmonary vasodilator without significant effects on the systemic circulation). Treatment of preterm infants usually involves exogenous surfactant administration. Some near-term and term infants with certain respiratory disorders may receive surfactant also.

Acute respiratory failure in both term and near-term neonates is usually a consequence of meconium aspiration syndrome, sepsis, pulmonary hypoplasia, and primary pulmonary hypertension of the newborn. INO therapy improves oxygenation and ventilation, reduces the need for ECMO, and lowers the incidences of chronic lung disease and death among term and near-term infants with respiratory failure. In term and near-term neonates, the role of INO functions primarily as a vasodilator to treat pulmonary hypertension, often due to meconium aspiration or bacterial pneumonia.

In preterm neonates, the most common cause of acute respiratory failure is RDS as a result of surfactant deficiency. In preterm neonates with respiratory failure, pulmonary hypertension with shunting is less of a clinical problem. Therefore, these 2 groups of neonates (term/near-term and preterm) represent different clinical issues and the results of INO in term/near-term neonates cannot be extrapolated to preterm neonates. In addition, there is concern regarding the possible risk of intraventricular hemorrhage associated with INO in premature infants.

Definitions

Extracorporeal membrane oxygenation (ECMO): An invasive technique used in neonates to treat hypoxic respiratory failure. ECMO therapy involves the use of a heart/lung machine to bypass the infant's circulation through the heart and lungs, in an effort to improve circulatory oxygenation levels until the infant is able to breathe more efficiently on their own. It is generally considered a surgical procedure and performed in the intensive care setting.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.  

When services may be Medically Necessary when criteria are met: 

ICD-10 Procedure  
3E0F7SD Introduction of nitric oxide gas into respiratory tract, via natural or artificial opening
   
ICD-10 Diagnosis  
I27.0 Primary pulmonary hypertension
I27.20-I27.29 Other secondary pulmonary hypertension
I27.83 Eisenmenger's syndrome
I27.9 Pulmonary heart disease, unspecified
P07.30 Preterm newborn, unspecified weeks of gestation
P07.37-P07.39 Preterm newborn, gestation age 34/35/36 completed weeks
P22.0-P22.9 Respiratory distress of newborn
P24.01 Meconium aspiration with respiratory symptoms
P24.11 Neonatal aspiration of (clear) amniotic fluid and mucus with respiratory symptoms
P24.81 Other neonatal aspiration with respiratory symptoms
P24.9 Neonatal aspiration, unspecified
P28.0 Primary atelectasis of newborn
P28.5 Respiratory failure of newborn
P28.9 Respiratory condition of newborn, unspecified
P29.30 Pulmonary hypertension of newborn

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met, for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

References

Peer Reviewed Publications:

  1. Adhikari NK, Dellinger RP, Lundin S, et al. Inhaled nitric oxide does not reduce mortality in patients with acute respiratory distress syndrome regardless of severity: systematic review and meta-analysis. Crit Care Med. 2014; 42(2):404-412.
  2. Askie LM, Ballard RA, Cutter GR, et al.; Meta-analysis of Preterm Patients on Inhaled Nitric Oxide Collaboration. Inhaled nitric oxide in preterm infants: an individual-patient data meta-analysis of randomized trials. Pediatrics. 2011; 128(4):729-739.
  3. Atz AM, Adatia I, Lock JE, Wessel DL. Combined effects of nitric oxide and oxygen during acute pulmonary vasodilator testing. J Am Coll Cardiol. 1999; 33(3):813-819.
  4. 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.
  5. Balzer DT, Kort HW, Day RW, et al. Inhaled nitric oxide as a preoperative test (INOP Test I): the INOP Test Study Group. Circulation. 2002; 106(12 Suppl 1):76-81.
  6. Barst RJ, Agnoletti G, Fraisse A, et al.; NO Diagnostic Study Group. Vasodilator testing with nitric oxide and/or oxygen in pediatric pulmonary hypertension. Pediatr Cardiol. 2010; 31(5):598-606.
  7. Bronicki RA, Fortenberry J, Schreiber M, et al. Multicenter randomized controlled trial of inhaled nitric oxide for pediatric acute respiratory distress syndrome. J Pediatr. 2015; 166(2):365-369.
  8. Chandrasekharan PK, Rawat M, Madappa R, et al. Congenital diaphragmatic hernia - a review. Matern Health Neonatol Perinatol. 2017; 3:6.
  9. Clark RH, Kueser TJ, Walker MW, et al. Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. Clinical Inhaled Nitric Oxide Research Group. N Eng J Med. 2000; 342(7):469-474.
  10. Dellinger RP, Zimmerman JL, Taylor RW, et al. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Crit Care Med. 1998; 26(1):15-23.
  11. Di Fiore JM, Hibbs AM, Zadell AE, et al. The effect of inhaled nitric oxide on pulmonary function in preterm infants. J Perinatol. 2007; 27(12):766-771.
  12. Durrmeyer X, Hummler H, Sanchez-Luna M, et al; European Union Nitric Oxide Study Group. Two-year outcomes of a randomized controlled trial of inhaled nitric oxide in premature infants. Pediatrics. 2013; 132(3):e695-e703.
  13. Field D, Elbourne D, Truesdale A, et al. Neonatal ventilation with inhaled nitric oxide versus ventilatory support without inhaled nitric oxide for preterm infants with severe respiratory failure: the INNOVO multicentre randomised controlled trial (ISRCTN 17821339). Pediatrics. 2005; 115(4):926-936.
  14. Gien J, Kinsella JP. Management of pulmonary hypertension in infants with congenital diaphragmatic hernia. J Perinatol. 2016; 36 Suppl 2:S28-31.
  15. Hamon I, Fresson J, Nicolas M-B, et al. Early inhaled nitric oxide improves oxidative balance in very preterm infants. Pediatr Res. 2005; 57(5 Pt 1):637-643.
  16. Hintz SR, Van Meurs KP, Perritt R, et al. Neurodevelopmental outcomes of premature infants with severe respiratory failure enrolled in a randomized controlled trial of inhaled nitric oxide. J Pediatr. 2007; 151(1):16-22, 22.e1-e3.
  17. Huddy CL, Bennett CC, Hardy P, et al; INNOVO Trial Collaborating Group. The INNOVO multicentre randomized controlled trial: neonatal ventilation with inhaled nitric oxide versus ventilatory support without nitric oxide for severe respiratory failure in preterm infants: follow up at 4-5 years. Arch Dis Child Fetal Neonatal Ed. 2008; 93(6):F430-F435.
  18. Kinsella JP. Inhaled nitric oxide therapy in premature newborns. Curr Opin Pediatr. 2006a; 18(2):107-111.
  19. Kinsella JP, Cutter GR, Steinhorn RH, et al. Noninvasive inhaled nitric oxide does not prevent bronchopulmonary dysplasia in premature newborns. J Pediatr. 2014; 165(6):1104-1108.
  20. Kinsella JP, Cutter GR, Walsh WF, et al. Early inhaled nitric oxide therapy in premature newborns with respiratory failure. N Engl J Med. 2006b; 355(4):354-364.
  21. Kinsella JP, Steinhorn RH, Krishnan US, et al. Recommendations for the use of inhaled nitric oxide therapy in premature newborns with severe pulmonary hypertension. J Pediatr. 2016; 170:312-314.
  22. Kinsella JP, Truog WE, Walsh WF, et al. Randomized, multicenter trial of inhaled nitric oxide and high-frequency oscillatory ventilation in severe, persistent pulmonary hypertension of the newborn. J Pediatr. 1997; 131(1 Pt 1):55-62.
  23. Konduri GG. New approaches for persistent pulmonary hypertension of newborns. Clin Perinatol. 2004; 31(3):591-611.
  24. Konduri GG, Solimano A, Sokol GM, et al. A randomized trial of early versus standard inhaled nitric oxide therapy in term and near-term newborn infants with hypoxic respiratory failure. Pediatrics. 2004; 113(3Pt1): 559-564.
  25. Krasuski RA, Devendra GP, Hart SA, et al. Response to inhaled nitric oxide predicts survival in patients with pulmonary hypertension. J Card Fail. 2011; 17(4):265-271.
  26. Lundin S, Mang H, Smithies M, et al. Inhalation of nitric oxide in acute lung injury: results of a European multicentre study. The European Study Group of Inhaled Nitric Oxide. Intensive Care Med. 1999; 25(9):911-919.
  27. Malowitz JR, Hornik CP, Laughon MM, et al. Management practice and mortality for infants with congenital diaphragmatic hernia. Am J Perinatol. 2015; 32(9):887-894.
  28. Martin RJ. Nitric oxide for preemies – not so fast. N Engl J Med 2003; 349(22):2157-2159.
  29. Mercier JC, Hummler H, Durrmeyer X, et al.; EUNO Study Group. Inhaled nitric oxide for prevention of bronchopulmonary dysplasia in premature babies (EUNO): a randomised controlled trial. Lancet. 2010; 376(9738):346-354.  
  30. Mestan KK, Marks JD, Kurt Hecox K, et al. Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide N Engl J Med. 2005; 353(1):23-32.
  31. Neonatal Inhaled Nitric Oxide Study Group (NINOS). Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. Pediatrics. 1997a; 99(6):838-845.
  32. Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. N Engl J Med. 1997b; 336(9):597-604.
  33. Potapov E, Meyer D, Swaminathan M, et al. Inhaled nitric oxide after left ventricular assist device implantation: a prospective, randomized, double-blind, multicenter, placebo-controlled trial. J Heart Lung Transplant. 2011; 30(8):870-878.
  34. Putnam LR, Tsao K, Morini F, et al; Congenital Diaphragmatic Hernia Study Group. Evaluation of variability in inhaled nitric oxide use and pulmonary hypertension in patients with congenital diaphragmatic hernia. JAMA Pediatr. 2016; 170(12):1188-1194.
  35. Reiter Meade MO, Granton JT, Matte-Martyn A, et al. A randomized trial of inhaled nitric oxide to prevent ischemia-reperfusion injury after lung transplantation. Am J Respir Crit Care Med. 2003; 167(11):1483-1489.
  36. Schreiber MD, Gin-Mestan K, Marks JD, et al. Inhaled nitric oxide in premature infants with the respiratory distress syndrome. N Engl J Med. 2003; 349(22):2099-2107.
  37. Subhedar N, Dewhurst C. Is nitric oxide effective in preterm infants? Arch Dis Child Fetal Neonatal Ed. 2007; 92(5):F337-341.
  38. Taylor RW, Zimmerman JL, Dellinger RP, et al.; Inhaled Nitric Oxide in ARDS Study Group. Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial. JAMA. 2004; 291(13):1603-1609.
  39. Trzeciak S, Glaspey LJ, Dellinger RP, et al. Randomized controlled trial of inhaled nitric oxide for the treatment of microcirculatory dysfunction in patients with sepsis*. Crit Care Med. 2014; 42(12):2482-2492.
  40. Van Meurs KP, Hintz SR, Ehrenkranz RA, et al. Inhaled nitric oxide in infants >1500 g and <34 weeks gestation with severe respiratory failure. J Perinatol. 2007; 27(6):347-352.
  41. 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.
  42. Weiner DL, Hibberd PL, Betit P, et al. Preliminary assessment of inhaled nitric oxide for acute vasoocclusive crisis in pediatric patients with sickle cell disease. JAMA. 2003; 289(9):1136-1142.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Abman SH, Hansmann G, Archer SL, et al.; American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; Council on Clinical Cardiology; Council on Cardiovascular Disease in the Young; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Surgery and Anesthesia; and the American Thoracic Society. Pediatric Pulmonary Hypertension: Guidelines From the American Heart Association and American Thoracic Society. Circulation. 2015; 132(21):2037-2099.
  2. Afshari A, Brok J, Møller AM, Wetterslev J. Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) and acute lung injury in children and adults. Cochrane Database Syst Rev. 2010;(7):CD002787.
  3. Allen MC, Donohue P, Gilmore M, et al. Inhaled Nitric Oxide in Preterm Infants. Evidence Report/Technology Assessment No. 195. (Prepared by Johns Hopkins University Evidence-based Practice Center under Contract No. 290-2007-10061-1). AHRQ Publication No. 11-E001. Rockville, MD: Agency for Healthcare Research and Quality. October 2010. Available at: http://www.ahrq.gov/downloads/pub/evidence/pdf/inoinfants/inoinfants.pdf. Accessed on March 30, 2017.
  4. American Academy of Pediatrics. Committee on Fetus and Newborn Use of inhaled nitric oxide. Pediatrics 2000. Reaffirmed 2010; 106(2 Pt 1):344-345.
  5. Barrington KJ, Finer NN, Pennaforte T. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database Syst Rev. 2017; (3):CD000509.
  6. Barrington KJ, Finer N, Pennaforte T, Altit G. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev. 2017; (1):CD000399.
  7. Bizzarro M, Gross I, Barbosa FT. Inhaled nitric oxide for the postoperative management of pulmonary hypertension in infants and children with congenital heart disease. Cochrane Database Syst Rev. 2014; (7):CD005055.
  8. Cole FS, Alleyne C, Barks JD, et al. NIH Consensus Development Conference statement: inhaled nitric-oxide therapy for premature infants. Pediatrics. 2011; 127(2):363-369.
  9. DiBlasi RM, Myers TR, Hess DR. Evidence-based clinical practice guideline: inhaled nitric oxide for neonates with acute hypoxic respiratory failure: American Association for Respiratory Care (AARC). Respir Care. 2010; 55(12):1717-1745.
  10. Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev. 2006; (4):CD000399.
  11. Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016; 37(1):67-119.
  12. INOmax® [Product Information], Hazelwood, MO. INO Therapeutics; October 2015. Available at: http://inomax.com/wp-content/uploads/2015/01/INOmax-PI-web-2013-03.pdf. Accessed on March 30, 2017.
  13. Kumar P.; Committee on Fetus and Newborn; American Academy of Pediatrics. Use of inhaled nitric oxide in preterm infants. Pediatrics. 2014; 133(1):164-170.
  14. Nitric Oxide. In: DrugPoints® System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated February 23, 2017. Available at: http://www.micromedexsolutions.com. Accessed on March 30, 2017.
  15. Nitric Oxide Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS® ) Online, Hudson, Ohio. Lexi-Comp., Inc. Last revised January 1, 2007. Accessed on March 30, 2017.
  16. Puligandla PS, Grabowski J, Austin M, et al. Management of congenital diaphragmatic hernia: A systematic review from the APSA outcomes and evidence based practice committee. J Pediatr Surg. 2015; 50(11):1958-1970.
  17. Sokol J, Inhaled nitric oxide for acute hypoxemic respiratory failure in children and adults. Cochrane Database Systematic Reviews. 2003(1):CD0027877.
Index

INOmax
INO
iNO
Nitric Oxide (Inhaled) as a Treatment of Respiratory Failure

The use of specific product names is illustrative only.  It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History

Status

Date

Action

  10/01/2017 Updated Coding section with 10/01/2017 ICD-10-CM diagnosis code changes.
Revised 05/04/2017 Medical Policy & Technology Assessment Committee (MPTAC) review. Formatting updated in Position Statement section. Abbreviations (INO and CDH) removed from Position Statement section. Rationale and References sections updated.
Revised 05/05/2016 MPTAC review. Medically necessary statement updated to include assessment of pulmonary vasoreactivity in individuals with pulmonary hypertension. Investigational and not medically necessary statement updated with the removal of "as a method of assessing pulmonary vaso-reactivity in persons with pulmonary hypertension." Abbreviations spelled out in position statement. Rationale and References sections updated. Updated Coding section and removed ICD-9 codes.
Reviewed 05/07/2015 MPTAC review. Description, Rationale and Reference sections updated.
Reviewed 05/15/2014 MPTAC review. Description, Rationale, Reference, and Index sections updated.
Revised 05/09/2013 MPTAC review. Investigational and not medically necessary statement updated with additional conditions. Rationale, Background and Reference sections updated.
Reviewed 11/08/2012 MPTAC review. Rationale, Background and Reference updated.
Reviewed 11/17/2011 MPTAC review. Rationale and References updated.
Reviewed 11/18/2010 MPTAC review. Rationale and References updated.
Reviewed 11/19/2009 MPTAC review. Rationale, background and references updated.
Reviewed 11/20/2008 MPTAC review. Rationale and references updated.
Reviewed 11/29/2007 MPTAC review. Rationale and references updated. The phrase "investigational/not medically necessary" was clarified to read "investigational and not medically necessary."
  04/01/2007 Updated Coding section with 04/01/2007 HCPCS changes; removed code S1025 deleted 03/31/2007.
Reviewed 12/07/2006 MPTAC review. Updated references. No change to position statement. 
Revised 12/01/2005 MPTAC review. 
Reviewed 09/22/2005 MPTAC review. Revisions based on Pre-merger Anthem and Pre-merger WellPoint. Harmonization.
Pre-Merger Organizations

Last Review Date

 Document Number

Title

Anthem, Inc.

 

  No prior document
WellPoint Health Networks, Inc.

12/02/2004

2.05.12 Inhaled Nitric Oxide as a Treatment of Respiratory Failure