Blue Cross of Idaho Logo

Express Sign-on

Thank you for registering with Blue Cross of Idaho

If you are an Individual or Family Member, please register here.

If you are a Medicare Advantage or Medicare Supplement member, please register here.

New Options for Affordable Health Insurance
MP 8.01.37 Inhaled Nitric Oxide

Medical Policy    
Section
Therapy 
Original Policy Date
8/18/00
Last Review Status/Date
Reviewed with literature search/10:2014
Issue
10:2014
  Return to Medical Policy Index

Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically. 


Description

Hypoxic respiratory failure may result from respiratory distress syndrome (RDS), persistent pulmonary hypertension, meconium aspiration, pneumonia, or sepsis. Its treatment typically includes oxygen support, mechanical ventilation, and induction of alkalosis, neuromuscular blockade, or sedation. Extracorporeal membrane oxygenation (ECMO) is an invasive technique that may be considered in neonates when other therapies fail. Inhaled nitric oxide (NO) is both a vasodilator and a mediator in many physiologic and pathologic processes.

INOmax, a commercially available inhaled NO product, is U.S. Food and Drug Administration (FDA)-approved for use in term and near-term neonates with hypoxic respiratory failure along with respiratory support and other appropriate treatments. Inhaled NO has also been proposed for use in preterm infants less than 34 weeks’ gestation. Another potential application of inhaled NO is to improve oxygenation in patients with acute hypoxemic respiratory failure (AHRF), including acute respiratory distress syndrome (ARDS) and acute lung injury. These conditions are associated with inflammation of the alveolar-capillary membrane which leads to hypoxemia and pulmonary hypertension. In addition, inhaled nitric oxide is proposed for management of pulmonary hypertension after cardiac surgery in infants and children with congenital heart disease. In congenital heart disease patients, increased pulmonary blood flow can cause pulmonary hypertension. Cardiac surgery can restore the pulmonary vasculature to normal, but there is the potential for complications including postoperative pulmonary hypertension, which can prevent weaning from ventilation and is associated with substantial morbidity and mortality.

Regulatory Status

In 1999, INOmax™ (Ikaria®, Clinton, NJ) was approved by the U.S. Food and Drug Administration (FDA) through the 510(k) process for the following indication: “INOmax, in conjunction with ventilatory support and other appropriate agents, is indicated 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.”


Policy 

 

Inhaled nitric oxide may be considered medically necessary as a component of treatment of hypoxic respiratory failure in neonates born at more than 34 weeks of gestation.

Other indications for inhaled nitric oxide are investigational, including, but not limited to, its use in premature neonates born at less than or equal to 34 weeks of gestation and adults and children with acute hypoxemic respiratory failure.


Policy Guidelines

Inhaled nitric oxide appears to be of greatest benefit in individuals for whom primary or secondary pulmonary hypertension is a component of hypoxic respiratory failure.

The benefit of inhaled nitric oxide appears limited in term or near-term infants whose hypoxic respiratory failure is due to diaphragmatic hernia.

The following criterion for hypoxic respiratory failure has been reported:

  • An oxygenation index of at least 25 on 2 measurements made at least 15 minutes apart.

(The oxygenation index [OI] is calculated as the mean airway pressure times 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 extracorporeal membrane oxygenation [ECMO] or dying. An OI of 40 is often used as a criterion to initiate ECMO therapy.)

Clinical input from academic medical centers and specialty societies obtained in 2012 indicated that:

  • Prolonged use of INO [inhaled NO] beyond 1-2 weeks has not been shown to improve outcomes. Use of INO beyond 2 weeks of treatment is therefore not recommended.
  • If ECMO is initiated in near-term neonates, inhaled NO should be discontinued as there is no benefit to combined treatment.

 


Benefit Application
BlueCard/National Account Issues

 

Due to the relatively high cost of inhaled nitric oxide, institutions using this therapy may want to negotiate a separate carve-out reimbursement structure. In many cases, nitric oxide therapy is initiated on an emergency basis, and thus the institution may not seek precertification/prior approval. Thus many of these requests may be reviewed retrospectively.


Rationale 

This policy was created in 2000 with a literature search using MEDLINE and was updated regularly with MEDLINE searches. Most recently, the literature was reviewed through September 15, 2014. Following is a summary of the key literature published to date.

Term or near-term neonates

In 2006, a Cochrane review of randomized controlled trials (RCTs) on inhaled nitric oxide (INO) in infants with hypoxia born at or near-term (greater than 34 weeks’ gestation) was published. (1) The review identified 14 trials. Eleven trials compared INO to control (placebo or standard neonatal intensive care) in infants with moderate severity of illness scores; 4 of these trials allowed back-up treatment with nitric oxide (NO) if infants continued to satisfy the same criteria after a prespecified period of time. Another 2 trials included infants with moderate severity of disease; they compared immediate NO to NO only when infants’ conditions deteriorated to a more severe level of illness. One of the trials only included infants with diaphragmatic hernia. The remaining trial compared NO to high-frequency ventilation. In all of the studies, hypoxemic respiratory failure was required for study entry, and most also required echocardiographic evidence of persistent pulmonary hypertension. The main findings of the meta-analysis are as follows:

Table 1. Combined outcome, death, or Extracorporeal Membrane Oxygenation
 

No. of Studies

Inhaled NO, n/N (%)

Control, n/N (%)

Risk Ratio (95% CI)

Backup use of NO not allowed (n=6)

149/418 (36%)

194/335 (58%)

0.65 (0.55 to 0.76)

Backup use of NO allowed (n=3)

20/87 (23%)

14/75 (19%)

1.15 (0.67 to 1.97)

All studies (N=9)

169/505 (33%)

208/410 (51%)

0.68 (0.59 to 0.79)

CI: confidence interval; NO: nitric oxide

Table 2. Death

No. of Studies

Inhaled NO, n/N (%)

Control, n/N (%)

Risk Ratio (95% CI)

Backup use of NO not allowed (n=6)

35/417 (8%)

33/337(10%)

0.92(0.58to 1.48)

Backup use of NO allowed (n=3)

9/79 (11%)

12/83(13%)

0.86(0.37to 1.98)

All studies (N=9)

44/496 (9%)

45/420(11%)

0.91(0.60 to 1.37)


CI: confidence interval; NO: nitric oxide

Table 3. Extracorporeal Membrane Oxygenation

No. of Studies

Inhaled NO, n/N (%)

Control, n/N (%)

Risk Ratio (95% CI)

Backup use of NO not allowed (n=6)

128/418 (31%)

181/337(54%)

0.61(0.51to 0.72)

Backup use of NO allowed (n=3)

11/24(45%)

11/31(35%)

1.14 (0.63to 2.02)

All studies (N=9)

139/442(31%)

192/368(52%)

0.63(0.54to 0.75)


CI: confidence interval; NO: nitric oxide

 

The investigators found that INO in hypoxic infants reduced the incidence of the combined end point of death or need for ECMO compared with controls. In a pooled analysis of 9 studies, the risk ratio (RR) was 0.68 (95% confidence interval [CI], 0.59 to 0.79). The combined outcome of death or need for ECMO was also significantly reduced in a pooled analysis of the 6 studies in which backup nitric oxide was not allowed (RR=0.65; 95% CI, 0.55 to 0.76), but this was not the case in an analysis of the 3 studies in which NO was allowed (RR=1.15; 95% CI, 0.67 to 1.97). INO did not have a statistically significant effect on mortality as a sole outcome measure. In a pooled analysis of 9 studies, the RR was 0.91 (95% CI, 0.60 to 1.37). There was, however, a significant effect of INO on need for ECMO only. When findings of 8 studies were pooled, the RR was 0.63 (95% CI, 0.54 to 0.75).

Another meta-analysis was published in 2010 by Golombek and Young.(2) This study, however, was not based on a systematic review of the literature, and it included 3 industry-sponsored trials. The 3 trials (sample sizes of 235, 155, and 248, respectively) all compared INO at a starting dose of 20 ppm with a control treatment (100% oxygen, INO at 0 ppm, or nitrogen gas). The primary outcome was change in partial pressure of arterial oxygen (PaO2). A pooled analysis found that patients in the treatment group had a significantly higher mean PaO2 level after 30 minutes than patients in the control group (118.9 vs 68.3 mm Hg, p<0.001). In addition, after 30 minutes, there was a significantly higher increase from baseline in PaO2 in the INO group (54.9 mm Hg) than the control group (14.1 mm Hg) (p<0.001). Duration
of mechanical ventilation in patients who survived without ECMO, a secondary outcome of the analysis, was significantly lower in the INO group (11 days) than the control group (14 days) (p=0.003). The article did not report survival or need for ECMO.

Section Summary

Evidence from RCTs and meta-analyses of RCTs support the use of INO in term or near-term infants to improve the net health outcome. These data have established that the use of INO leads to a reduction in the need for ECMO but is not sufficient to conclude that there is a reduction in mortality.

Premature Neonates

In near-term neonates, the role of INO primarily functions as a vasodilator to treat pulmonary hypertension, often due to meconium aspiration or bacterial pneumonia. However, in preterm neonates with respiratory failure, pulmonary hypertension with shunting is not a clinical problem. Therefore, these 2 groups of neonates represent distinct clinical issues, and the results of INO in 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.

Numerous RCTs and several systematic reviews have been published. In 2011, an Agency for Healthcare Research and Quality (AHRQ)‒sponsored systematic review of randomized trials on INO for premature infants (<35 weeks of gestation) was published.(3) Thirty-one articles were initially selected; these included 14 unique RCTs. Studies had sample sizes ranging from 29 to 800, and data from 3461 infants were available for the review. The primary outcomes of the AHRQ analysis were survival and
bronchopulmonary dysplasia (BPD). Regardless of how mortality was reported or defined (eg, death within 7 days or 28 days, or death in the neonatal intensive care unit), there was no statistically significant difference between the INO group and control group in any of the 14 RCTs, or in pooled analyses of RCTs. For example, in a pooled analysis of 11 trials that reported death by 36 weeks’ postmenstrual age or in the neonatal intensive care unit, the RR was 0.97 (95% CI, 0.82 to 1.15). Twelve trials reported data on BPD at 36 weeks’ postmenstrual age, and despite variations in reporting of BPD, there was no significant benefit of INO treatment in any trial. A pooled analysis of data from 8 trials reporting BPD at 36 weeks’ postmenstrual age among survivors resulted in a RR of 0.93 (95% CI, 0.86 to 1.00).

A Cochrane review was published in 2010 and, like the AHRQ-sponsored systematic review, identified 14 RCTs on the efficacy of INO as a treatment of respiratory failure in preterm infants.(4) The authors categorized studies into 3 categories depending on entry criteria. There were 9 trials that selected patients for treatment based on oxygenation criteria, 3 studies that routinely used INO in infants with pulmonary disease, and 2 studies of late treatment based on risk of BPD. Study findings were not pooled. The authors of the Cochrane review concluded that INO was not effective at reducing mortality or BPD in any of the 3 categories.

The largest trial to date was published in 2010 by Mercier et al.(5) This was a multicenter industrysponsored study known as the European Union Nitric Oxide trial, and it evaluated low-dose INO therapy. The study included 800 preterm infants (gestational age at birth between 24 and 28 weeks 6 days) who weighed at least 500 grams and required surfactant or continuous positive airway pressure for respiratory distress syndrome within 24 hours of birth. Patients were randomized to receive treatment with INO 5 ppm (n=399) or placebo-equivalent nitrogen gas (n=401). Therapy was given for 7 to 21 days (mean duration, 16 days). Of 800 patients, 792 (99%) received their assigned treatment, and all 800 were included in the intention-to-treat analysis.

Primary outcomes were survival without BPD at 36 weeks’ postmenstrual age, overall survival (OS) at 36 weeks’ postmenstrual age, and BPD at 36 weeks’ postmenstrual age. Survival without BPD at 36 weeks’ postmenstrual age, was attained by 258 (65%) of patients in the INO group and 262 (66%) of patients in the placebo group, a difference that was not statistically significant (RR=1.05; 95% CI, 0.78 to 1.43, p=0.73). OS at 36 weeks’ postmenstrual age was attained by 343 (86%) in the INO group and 359 (90%) in the control group (RR=0.74; 95% CI, 0.48 to 1.15; p=0.21). The percent of patients with BPD at 36 weeks’ postmenstrual age was 81 (24%) in the NO group and 96 (27%) in the control group (RR=0.83; 95% CI, 0.58 to 1.17; p=0.29). The secondary end point of survival without brain injury at gestational age 36 weeks also did not differ significantly between groups (RR=0.78; 95% CI, 0.53 to 1.17; p=0.23). This end point was attained by 181 (69%) patients in the INO group and 188 (76%) patients in the placebo group.

Rates of serious adverse events (AEs; ie, intraventricular hemorrhage, periventricular leukomalacia, patient ductus arteriosus, pneumothorax, pulmonary hemorrhage, necrotizing enterocolitis, sepsis) were 158 (40%) of 395 patients in the INO group and 164 (41%) of 397 patients in the control group, p=0.72. The most common AE was intracranial hemorrhage, which affected 114 (29%) in the INO group and 91 (23%) in the control group (exact p value not reported).

In 2013, Durrmeyer et al published 2-year outcomes of the European Union Nitric Oxide trial.(6) Of the original 800 patients, 737 (92%) were evaluable at this time point. The evaluable children excluded those who did not receive treatment or who were lost to follow-up. A total of 244 (67%) of 363 evaluable children at 2 years in the INO group survived without severe or moderate disability compared with 270 (72%) of 374 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 hospitalization rates, use of respiratory medications, or growth.

Newer studies, such as an RCT with 124 premature newborns published by Kinsella et al in 2014, continue to find a lack of benefit of INO for reducing the rate of mortality or BPD, or reducing the need for mechanical ventilation.(7)

Section Summary

A large number of RCTs evaluate INO for premature neonates, with most trials reporting no difference on primary end points. Meta-analyses of these RCTs have not found better outcomes with INO in premature neonates. This evidence does not support the routine use of INO in preterm infants.

Adults and Children With Acute Hypoxemic Respiratory Failure

A number of RCTs and several meta-analyses of RCTs have been published on the efficacy of INO for treating acute respiratory distress syndrome (ARDS) and acute lung injury (together known as acute hypoxemic respiratory failure [AHRF]). Most recently, a 2014 meta-analysis by Adhikari et al identified 9 RCTs conducted with adults or children (other than neonates) in which at least 80% of patients, or a separately reported subgroup, had ARDS.(8) Moreover, the trials included in the review compared INO with placebo or no gas, used INO as a treatment of ARDS (ie, not a preventive measure), and had less than 50% crossover between groups. A pooled analysis of data from the 9 trials (total N=1142) found no statistically significant benefit of INO on mortality (RR=1.10; 95% CI, 0.94 to 1.29; p=0.24). In a preplanned subgroup analysis, INO did not reduce mortality in patients with severe ARDS (baseline PaO2/ fraction of expired oxygen [FIO2] ≤100 mm Hg) or in patients with mild to moderate ARDS (baseline PaO2/FIO2 >100mg Hg).

Other systematic reviews and meta-analyses had similar findings. A 2011 meta-analysis by Afshari et al included 14 trials, most of which included adults with a mixture of ARDS and acute lung injury.(9) Three trials included pediatric populations (neonates were excluded), and 1 trial included mostly adults. The primary outcome was all-cause mortality. A pooled analysis of mortality data from all 14 trials at longest follow-up reported deaths in 265 (40.2%) of 660 patients in the INO group and 228 (38.6%) of 590 patients in the control group. The difference between groups was not statistically significant (RR=1.06; 95% CI, 0.93 to 1.22). Results did not differ in subgroups of adults and children. In other pooled analyses, INO was not found to have a beneficial effect on the number of ventilator-free days or the duration of mechanical ventilation. Regarding AEs, a meta-analysis did not find a significant difference in bleeding rates between groups. However, a pooled analysis of 4 trials with data on renal impairment found a significant increase in events in the group receiving INO. AEs occurred in 91 (18.1%) of 503 patients in the INO group and 51 (11.5%) of 442 patients in the control group (RR=1.59; 95% CI, 1.17 to 2.16). Exact numbers of events were not reported for most secondary or subgroup analyses.

A 2003 Cochrane systematic review identified 5 RCTs comparing INO and placebo for AHRF.(10) The Cochrane authors conducted only 1 pooled analysis, which combined findings from 2 studies. The metaanalysis did not find a significant impact of INO on mortality in studies without crossover of failures to treatment with INO (pooled RR=0.98; 95% CI, 0.66 to 1.44). The largest individual trial was published by Taylor et al in 2004 and did not report improvements for patients treated with INO.(11) Investigators randomly assigned 385 patients with acute lung injury to receive either low-dose INO or placebo. Patient selection criteria included no more than 72 hours from the onset of lung injury and absence of sepsis or nonpulmonary organ system dysfunction. The authors reported that INO was not associated with an  improvement in number of days alive or days off ventilation. A followup, a priori analysis of long-term pulmonary function, was published in 2012.(12) Of 385 randomized
patients in the original study, 92 (24%) participated in the 6-month follow-up, 55 in the INO group and 41 in the placebo group. Of 14 pulmonary function measures reported, 5 differed significantly between groups at the p less than 0.05 level. For example, the mean forced expiratory volume (percent predicted) was 80.2% in the INO group and 69.6% in the placebo group (p=0.042). One of the 5 measures, total lung capacity (percent predicted) differed significantly between groups at the p less than 0.01 level (93.3% in the INO group, 76.1% in the placebo group). The analysis was limited by the small number of randomized patients who participated.

Section Summary

Evidence from numerous RCTs and multiple systematic reviews of these RCTs did not find significant effects of INO on mortality or duration of mechanical ventilation in adults and children with AHRF. This evidence suggests that INO is not an effective treatment for this patient population.

Postoperative Use in Adults and Children With Congenital Heart Disease

Children

A 2014 Cochrane review by Bizzarro et al identified 4 RCTs comparing postoperative INO versus placebo or usual care in the management of children with congenital heart disease.(13) All of the trials included participants who were identified as having pulmonary hypertension in the preoperative or postoperative period. Studies included a total of 210 participants. Three trials were parallel group trials, and 3 was a crossover trial. Mortality was the primary outcome of the Cochrane meta-analysis. Two trials with a total of 162 patients reported mortality before discharge. A pooled analysis of findings from these 2 trials did not find a significant difference in mortality between the group receiving INO compared with the control group (OR=1.67; 95% CI, 0.38 to 7.30). Among secondary outcomes, a pooled analysis of 2 studies did
not find a significant between-group difference in mean pulmonary arterial hypertension (pooled treatment effect, -2.94 mm Hg; 95% CI, -9.28 to 3.40), and a pooled analysis of 3 studies did not find a significant difference between groups in mean arterial pressure (pooled treatment effect, -3.55 mm Hg; 95% CI, -11.86 to 4.76). Insufficient data were available for pooled analyses of other outcomes. The authors noted the lack of data on long-term mortality, length of stay in an intensive care unit or hospital, and neurodevelopmental disability, and also had concerns about methodologic quality of studies, sample size, and heterogeneity between studies. These results do not support a benefit for NO treatment for this patient group. Wide Cis around the pooled treatment effects reflect the relatively small amount of data available on each outcome.

The trial with the largest sample size was published by Miller et al in Australia in 2000.(14) The study included 124 infants (median age, 3 months) who were candidates for corrective heart surgery. Eligibility requirements included presence of congenital heart lesions, high pulmonary flow pressure, or both, and objective evidence of pulmonary hypertension in the immediate preoperative period. Participants were randomized to receive INO gas 10 ppm (n=63) or placebo nitrogen gas (n=61) after surgery until just before extubation. Randomization was stratified by presence (45/124 [36%]) or absence (79/124 [64%]) of Down syndrome. The primary outcome was reduction of pulmonary hypertensive crisis (PHTC) episodes, defined as a pulmonary/systemic artery pressure ratio more than 0.75. Episodes were classified as major if there was a fall in systemic artery pressure of at least 20% and/or a fall in transcutaneous oxygen saturation to less than 90%. Episodes were classified as minor if the systemic artery pressure and transcutaneous oxygen saturation remained stable. The study found that infants who received INO after surgery had significantly fewer PHTC (median, 4) than those who received placebo (median, 7) (unadjusted RR=0.66; 95% CI, 0.59 to 0.74; p<0.001). Among secondary outcomes, the median time until eligibility for extubation was significantly shorter in the INO than placebo group, 80 versus 112 hours, respectively (p=0.019). There were 5 deaths in the INO group and 3 deaths in the placebo group; this difference was not statistically significant (p=0.49). Similarly, there was not a significant difference in median time to discharge from intensive care, 138 hours in the NO group and 162 hours in the placebo group (p>0.05). Although this trial reported a reduction in pulmonary hypertensive crisis episodes, changes in this physiologic outcome did not result in improvements in survival or other clinical outcomes. The study was likely to have been underpowered to detect differences in these more clinically relevant secondary outcomes.

Adults

A 2011 trial by Potapov et al evaluated the prophylactic use of INO in adult patients undergoing left ventricular assist device (LVAD) implantation for congestive heart failure.(15) This double-blind trial was conducted at 8 centers in the United States and Germany. Patients were randomized to receive INO (40 ppm) (n=74) 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). Patients continued use of INO or placebo until they were extubated, reached the study criteria for RVD, or were treated for 48 hours, whichever occurred first. Patients 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 (9%) of 150 randomized patients did not receive the study treatment. In addition, crossover to open-label INO occurred in 15 (21%) of 73 patients in the INO group and 20 (26%) of 77 in the placebo group. In an intention-to-treat analysis, RVD criteria were met by 7 (9.6%) of 73 patients in the INO group and 12 (15.6%) of 77 patients in the placebo group; this difference was not statistically significant (p=0.33). Other outcomes also did not differ significantly between groups, eg, mean number of days on mechanical ventilation (5.4 in the INO group vs 11.1 in the placebo group; p=0.77) and mean number of days in the hospital (41 in each group).

Section Summary

Evidence from a number of small RCTs, and 1 systematic review of these trials did not find a significant benefit for INO on mortality and other health outcomes in the postoperative management of children with congenital heart disease. There is less evidence on INO for adults with congenital heart disease. One RCT did not find a significant effect of treatment with INO on reduction of postoperative outcomes in adults with congestive heart failure who had LVAD surgery.

Ongoing and Unpublished Clinical Trials

Study of Inhaled Nitric Oxide and Respiratory Outcomes in Late Preterm Infants (NCT01748045)(16): This double-blind RCT is comparing INO with placebo in preterm infants (born at gestational age of 30-36 weeks) who require breathing support. The primary end point is the proportion of patients alive without the need for intubation or mechanical support in the first year of life. The estimated enrollment is 60 patients; the study is listed as recruiting patients.

Inhaled nitric oxide for the treatment of bronchopulmonary dysplasia in preterm infants (NCT00931632)(17): This multicenter, double-blind, randomized trial is comparing INO with placebo in preterm infants who require intubation during days 5 to 14 after birth. The primary outcome will be survival without bronchopulmonary dysplasia at 36 weeks’ postmenstrual age. Estimated enrollment is 450 patients. This study is listed as ongoing but not recruiting; its status was last verified in August 2013.

Inhaled Nitric Oxide and Neuroprotection in Premature Infants (NOVA2) (NCT00515281)(18): This is a double-blind RCT evaluating whether INO improves neurologic outcomes in premature infants (birth weight ≤1500 g, <31 weeks of gestation). The treatment group will receive INO, combined with oxygen or room air, until 33 weeks corrected age, and the control group will receive INO for the first 7 days, then oxygen or room air, as clinically appropriate, until 33 weeks corrected age. The estimated enrollment is 484 patients and the expected date of study completion is April 2016.

Clinical Input Received From Physician Specialty Societies and Academic Medical Centers

In response to requests, clinical input was received while the policy was under review in 2010 and 2012. While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

2012 Input

Input was received through 2 physician specialty societies and 9 academic medical centers. There was consensus agreement that INO may be considered medically necessary as a component of treatment of hypoxic respiratory failure in neonates born at more than 34 weeks of gestation. There was general agreement with the criterion in the Policy Guidelines section for hypoxic respiratory failure, ie, an oxygenation index of at least 25 on 2 measurements made at least 15 minutes apart. In addition, input was mixed on whether other indications for INO should be considered investigational. Several reviewers stated that they thought INO is clinically useful for the postoperative treatment of selected patients with congenital heart disease.

In addition, clinician reviewers generally agreed that INO should be discontinued when ECMO is initiated. There was near-consensus agreement that prolonged use of INO (eg, beyond 1-2 weeks in near-term neonates) does not improve outcomes, ie, beyond a transient improvement in oxygenation. However, there was a wide range of responses to the question on how long INO should be continued once it is initiated, with most reviewers who responded citing an upper limit of not more than 2 weeks.

2010 Input

Input was received through 4 physician specialty societies and 5 academic medical centers. The clinical input was consistent in its agreement with the policy statements on treatment of hypoxic respiratory failure in neonates born at 34 or more weeks of gestation and adults with ARDS and was mixed for the statement on premature neonates born at less than 34 weeks’ gestation. There was no consensus or near-consensus among reviewers on potential additional medically necessary indications for INO therapy.

Summary of Evidence

There is evidence from a Cochrane systematic review of 14 randomized controlled trials (RCTs) that inhaled nitric oxide (INO) improves the net health outcome in hypoxic term or near-term infants. Other systematic reviews of RCTs did not find evidence of a net benefit from INO among preterm infants when used in the first 3 days of life for severe respiratory failure or after the first 3 days of life to prevent bronchopulmonary dysplasia. In children and adults with acute hypoxemic respiratory failure, systematic
reviews of RCTs did not find that INO treatment had a significant effect on mortality or duration of mechanical ventilation. Thus, INO may be considered medically necessary to treat term and near-term infants and investigational for other indications.

Practice Guidelines and Position Statements

In 2011, a National Institutes of Health Consensus Development Conference Statement on INO for premature infants was published.(19) The statement was based on the Agency for Healthcare Research and Quality‒sponsored systematic review of the literature, previously described.(3) Conclusions include:

“Taken as a whole, the available evidence does not support use of INO (inhaled NO) in early-routine, early-rescue, or later-rescue regimens in the care of premature infants of <34 weeks’ gestation who require respiratory support.”

“There are rare clinical situations, including pulmonary hypertension or hypoplasia, that have been inadequately studied in which INO may have benefit in infants of <34 weeks’ gestation. In such situations, clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining ncertainties.”

In 2000, the American Academy of Pediatrics (AAP) issued recommendations regarding the use of INO in pediatric patients.(20) The recommendations were reaffirmed on April 1, 2010, and stated that “Inhaled nitric oxide therapy should be given using the indications, dosing, administration and monitoring guidelines outlined on the product label.” This recommendation is consistent with the policy statement. In addition, AAP recommended the following:

  • INO should be initiated in centers with extracorporeal membrane oxygenation capability.
  • Centers that provide INO therapy should provide comprehensive long-term medical and neurodevelopmental follow-up.
  • Centers that provide INO therapy should establish prospective data collection for treatment time course, toxic effects, treatment failure, and use of alternative therapies and outcomes.
  • Administration of INO for indications other than those approved by the U.S. Food and Drug Administration (FDA) or in other neonatal populations, including compassionate use, remains experimental.

The AAP policy statement does not address the use of INO in premature infants.

U.S. Preventive Services Task Force Recommendations
Use of inhaled nitric oxide is not a preventive service.

Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.

References: 

  1. Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev. 2006(4):CD000399. PMID 17054129
  2. Golombek SG, Young JN. Efficacy of inhaled nitric oxide for hypoxic respiratory failure in term and late preterm infants by baseline severity of illness: a pooled analysis of three clinical trials. Clin Ther. May 2010;32(5):939-948. PMID 20685502
  3. Donohue PK, Gilmore MM, Cristofalo E, et al. Inhaled nitric oxide in preterm infants: a systematic review. Pediatrics. Feb 2011;127(2):e414-422. PMID 21220391
  4. arrington KJ, Finer N. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database Syst Rev. 2010(12):CD000509. PMID 21154346
  5. Mercier JC, Hummler H, Durrmeyer X, et al. Inhaled nitric oxide for prevention of bronchopulmonary dysplasia in premature babies (EUNO): a randomised controlled trial. Lancet. Jul 31 2010;376(9738):346-354. PMID 20655106
  6. Durrmeyer X, Hummler H, Sanchez-Luna M, et al. Two-year outcomes of a randomized controlled trial of inhaled nitric oxide in premature infants. Pediatrics. Aug 12 2013;132(3):e695-703. PMID 23940237
  7. Kinsella JP, Cutter GR, Steinhorn RH, et al. Noninvasive Inhaled Nitric Oxide Does Not Prevent Bronchopulmonary Dysplasia in Premature Newborns. J Pediatr. Jul 22 2014. PMID 25063725
  8. 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. Feb 2014;42(2):404-412. PMID 24132038
  9. Afshari A, Brok J, Moller AM, et al. Inhaled nitric oxide for acute respiratory distress syndrome and acute lung injury in adults and children: a systematic review with meta-analysis and trial sequential analysis. Anesth Analg. Jun 2011;112(6):1411-1421. PMID 1372277
  10. Sokol J, Jacobs SE, Bohn D. Inhaled nitric oxide for acute hypoxemic respiratory failure in children and adults. Cochrane Database Syst Rev. 2003(1):CD002787. PMID 12535438
  11. Taylor RW, Zimmerman JL, Dellinger RP, et al. Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial. JAMA. Apr 7 2004;291(13):1603-1609. PMID 15069048
  12. Dellinger RP, Trzeciak SW, Criner GJ, et al. Association between inhaled nitric oxide treatment and long-term pulmonary function in survivors of acute respiratory distress syndrome. Crit Care. Mar 2 2012;16(2):R36. PMID 22386043
  13. 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. PMID 24991723
  14. Miller OI, Tang SF, Keech A, et al. Inhaled nitric oxide and prevention of pulmonary hypertension after congenital heart surgery: a randomised double-blind study. Lancet. Oct 28 2000;356(9240):1464-1469. PMID 11081528
  15. 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. Aug 2011;30(8):870-878. PMID 21530317
  16. Sponsored by Tufts Medical Center (collaborator Ikaria). Study of Inhaled Nitric Oxide and Respiratory Outcomes in Late Preterm Infants (NCT01748045). www.clinicaltrials.gov. Accessed September, 2014.
  17. Sponsored by INO Therapeutics. Inhaled nitric oxide (INO) for the prevention of bronchopulmonary dysplasia (BPD) in preterm infants (NCT00931632). www.clinicaltrials.gov. Accessed June, 2012.
  18. Sponsored by University of Chicago. Inhaled Nitric Oxide and Neuroprotection in Premature Infants (NOVA2) (NCT00515281). www.clinicaltrials.gov. Accessed July, 2014.
  19. Cole FS, Alleyne C, Barks JD, et al. NIH Consensus Development Conference statement: inhaled nitric-oxide therapy for premature infants. Pediatrics. Feb 2011;127(2):363-369. PMID 21220405 
  20. American Academy of Pediatrics. Committee on Fetus and Newborn. Use of inhaled nitric oxide. Pediatrics. Aug 2000;106(2 Pt 1):344-345. PMID 10920164
      

Codes

Number

Description

CPT    No specific CPT code 
ICD-9 Procedure  00.12 Administration of inhaled nitric oxide 
ICD-9 Diagnosis  769  Respiratory distress syndrome 
   770.84 Respiratory distress syndrome of newborn
ICD-10-CM (effective 10/1/15) P22.0 Respiratory distress syndrome of newborn
  P28.5 Respiratory failure of newborn
ICD-10-PCS (effective 10/1/15)   ICD-10-PCS would only be used if the procedure is done inpatient.
   3E0F7SD Introduction, respiratory tract, via natural or artificial opening, gas, nitric oxide
Type of Service  Anesthesiology 
Place of Service  Intensive Care 

Index

Inhaled Nitric Oxide, Treatment of Respiratory Failure
Nitric Oxide, Inhaled, Treatment of Respiratory Failure
Respiratory Failure, Nitric Oxide  


Policy History
Date Action Reason
08/18/00 Add to Therapy section New policy
12/15/00 Replace policy Revised to include information regarding BlueCard or
 
National Account
10/08/02 Replace policy Policy updated with new references; policy statement unchanged
02/25/04 Replace policy Policy updated with literature review; references added, additional discussion of inhaled nitric oxide in premature infants. No change in policy statement
03/15/05 Replace policy Policy updated with literature review; no change in policy statement. Reference number 9 added
03/7/06 Replace policy Policy updated with literature review; no change in policy statement. Further discussion of inhaled NO in premature infants included. References renumbered, reference numbers 7–9 added
09/11/08 Replace policy  Policy updated with literature review; no change in policy statements. Reference numbers 19-23 added
07/08/10 Replace policy Policy updated with literature review through May 2010; clinical input reviewed; no change in policy statements. Rationale substantially re-written; Reference numbers 1, 2, and 9-11 added; other references renumbered/removed.
7/14/11 Replace policy Policy updated with literature review through May 2011. Title changed to “Inhaled Nitric Oxide.” Medically necessary statement changed to “more than 34 weeks of gestation” to be consistent with age range of FDA-approved indication. Investigational policy statement changed to “less than or equal to 34 weeks of gestation” and several additional indications were specifically mentioned: adults and children with acute hypoxemic respiratory failure and postoperative management of pulmonary hypertension in children with congenital heart disease. Reference numbers 2, 4-5, 10-11, 13, 14, 16, 17 and 19 added; other references renumbered/removed
9/13/12 Replace policy Policy updated with literature review through July 2012. In investigational policy statement, postoperative management of pulmonary hypertension in children with congenital heart disease removed from investigational policy statement. Clinical input added. Information added to Policy Guidelines on recommended duration of use of inhaled NO. In addition, statement added to Policy Guidelines that If ECMO is initiated in near-term neonates inhaled NO should be discontinued as there is no benefit to combined treatment. Reference numbers 4, 10 and 13 added; other references renumbered/removed.
10/10/13 Replace policy Policy updated with literature review through August 15, 2013. No change to policy statements. References 4, 7, and 16 added; other references renumbered/removed.
10/09/14 Replace policy Policy updated with literature review through September 15, 2014. No change to policy statements. References 7-8, 13, and 16 added.