Medical Policies - Therapy


Inhaled Nitric Oxide

Number:THE801.038

Effective Date:10-15-2017

Coverage:

*CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT*

Inhaled nitric oxide may be considered medically necessary as a component of treatment of hypoxic respiratory failure (see Note) in neonates born at 34 weeks and 0 days of gestation or greater when both of the following criteria are met:

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

Neonate does not have a congenital diaphragmatic hernia (CDH).

The diagnostic use of inhaled nitric oxide may be considered medically necessary as a method of assessing pulmonary vasoreactivity in persons with pulmonary hypertension.

Other indications for inhaled nitric oxide are considered experimental, investigational, and/or unproven, including but not limited to:

Treatment of premature neonates born at less than 34 weeks and 0 days of gestation with hypoxic respiratory failure;

Treatment of adults and children with acute hypoxemic respiratory failure;

Postoperative use in adults and children with congenital heart disease;

In lung transplantation, during and/or after graft reperfusion.

NOTE: The following criterion for hypoxic respiratory failure has been reported: An oxygenation index (OI) of at least 25 on 2 measurements made at least 15 minutes apart. (The 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 or more is often used as a criterion to initiate ECMO therapy.)

Description:

Nitric oxide is an endogenous compound that relaxes vascular smooth muscle by binding intracellularly to heme moieties of soluble guanylate cyclase; this activates guanylate synthase, resulting in increased synthesis of cyclic guanosine 3',5'-monophosphate (cGMP) and subsequent smooth muscle vasodilation. It increases the partial pressure of arterial oxygen (PaO2) by dilating the better ventilated areas of the lung and redistributing blood flow from areas with low ventilation/perfusion (V/Q) ratios to areas with normal ratios.

Background

Inhaled nitric oxide (INO) has been proposed to reduce hypoxic respiratory failure in neonates and for several other applications.

Hypoxic respiratory failure may result from respiratory distress syndrome, persistent pulmonary hypertension, meconium aspiration, pneumonia, or sepsis. Its treatment typically includes oxygen support, mechanical ventilation, induction of alkalosis, neuromuscular blockade, or sedation. Extracorporeal membrane oxygenation is an invasive technique that may be considered in neonates when other therapies fail. INO is both a vasodilator and a mediator in many physiologic and pathologic processes. INO has also been proposed for use in preterm infants less than 34 weeks of gestation.

Another potential application of INO is to improve oxygenation in patients with acute hypoxemic respiratory failure, including acute respiratory distress syndrome and acute lung injury. These conditions are associated with inflammation of the alveolar-capillary membrane, which leads to hypoxemia and pulmonary hypertension.

In addition, there are several potential uses in surgery. One is the proposed use of INO to manage 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. Another potential surgical application is use of INO in lung transplantation to prevent or reduce reperfusion injury.

Regulatory Status

In 1999, INOmax™ (Ikaria, Clinton, NJ) was cleared for marketing 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 (>34 weeks) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension.” In 2015, Mallinckrodt (Dublin, Ireland) acquired Ikaria.

In 2014, Advanced Inhalation Therapies received orphan drug designation for its proprietary formulation of nitric oxide as an adjunctive treatment of cystic fibrosis by the FDA.

Rationale:

Hypoxic Respiratory Failure in Term or Near-Term Neonates

A number of randomized controlled trials (RCTs) and a Cochrane review of RCT data on inhaled nitric oxide (INO) in infants with hypoxia born at or near-term (>34 weeks of gestation) have been published. The Cochrane review, last updated in 2006, identified 14 trials. (2) Eleven trials compared INO to control (placebo or standard neonatal intensive care) in infants with moderately severe illness scores; 4 of these trials allowed back-up treatment with INO if infants continued to satisfy the same criteria after a prespecified period of time. Another 2 trials included infants with moderately severe disease and compared immediate INO with INO only when infants’ conditions deteriorated to a more severe illness. One of the trials included only infants with diaphragmatic hernia. The remaining trial compared INO with high-frequency ventilation.

In all 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 provided in Table 1.

Table 1. Main Findings From a 2016 Cochrane Meta-Analysis

Number of Studies

INO, n/N (%)

Control, n/N (%)

Risk Ratio

(95% CI)

Combined outcome: death, or extracorporeal membrane oxygenation

Backup use of INO not allowed(n=6)

149/418(36%)

194/335(58%)

0.65 (0.55 to 0.76)

Backup use of INO 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 1.79)

Death

Backup use of INO not allowed(n=6)

35/417(8%)

33/337(10%)

0.92 (0.58 to 1.48)

Backup use of INO allowed(n=3)

9/79(11%)

12/83(13%)

0.86 (0.37 to 1.98)

All studies(N=9)

44/496(9%)

45/420(11%)

0.91 (0.60 to 1.37)

Extracorporeal membrane oxygenation

Backup use of INO not allowed(n=6)

128/418(31%)

181/337(54%)

0.61 (0.51 to 0.72)

Backup use of INO allowed(n=3)

11/24(45%)

11/31(35%)

1.14 (0.63 to 2.02)

All studies(N=9)

139/442(31%)

192/368(52%)

0.63 (0.54 to 0.75)

CI: confidence interval; INO: inhaled nitric oxide

The investigators found that INO in hypoxic infants reduced the incidence of the combined end point of death or need for extracorporeal membrane oxygenation (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 INO 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 the need for ECMO only. When findings of 8 studies were pooled, the RR was 0.63 (95% CI, 0.54 to 0.75).

Section Summary: Hypoxic Respiratory Failure in Term or Near-Term Neonates

Evidence from RCTs and a meta-analysis of RCTs support the use of INO in term or near-term infants to improve the net health outcome. Pooled analyses of RCT data have found that INO leads to a significant reduction in the need for ECMO, and in the combined outcome of ECMO or death.

Hypoxic Respiratory Failure in 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 about the risk of intraventricular hemorrhage associated with INO in premature infants.

Numerous RCTs and several systematic reviews on INO for treating hypoxic respiratory failure in preterm neonates 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; they included 14 unique RCTs. Studies had sample sizes ranging from 29 to 800 patients, 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 (e.g., 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 of 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 of 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 of postmenstrual age among survivors found a RR of 0.93 (95% CI, 0.86 to 1.00).

A 2010 Cochrane review, like the AHRQ-sponsored systematic review, also 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. Nine trials selected patients for treatment based on oxygenation criteria, 3 studies routinely used INO in infants with pulmonary disease, and 2 studies assessed late treatment based on risk of BPD. Study findings were not pooled. The Cochrane reviewers 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 multicenter industry-sponsored study, known as the European Union Nitric Oxide trial, evaluated low-dose INO therapy. The study included 800 preterm infants (gestational age at birth between 24 weeks 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 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 of postmenstrual age, overall survival (OS) at 36 weeks of postmenstrual age, and BPD at 36 weeks of postmenstrual age. Survival without BPD at 36 weeks of postmenstrual age was attained by 258 (65%) of patients in the INO group and 262 (66%) of patients in the placebo group, a nonstatistically significant difference (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 of postmenstrual age was 81 (24%) in the INO 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 (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; i.e., 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 (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 to 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 (e.g., hospitalization rates, use of respiratory medications, growth).

Newer studies, such as an RCT with 124 premature newborns published by Kinsella et al. (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: Hypoxic Respiratory Failure in Premature Neonates

A large number of RCTs have evaluated INO for premature neonates, and most trials have reported no significant difference on primary end points such as mortality and BPD. Meta-analyses of these RCTs have not found better outcomes with INO than placebo or other control interventions in premature neonates.

Acute Hypoxemic Respiratory Failure in Adults and Children

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). 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 (i.e., not a preventive measure), and had less than 50% crossover between groups. Findings were not stratified by adult and pediatric populations. A pooled analysis of data from the 9 trials (total N=1142 patients) 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 partial pressure of oxygen, arterial [PaO2]/fraction of expired oxygen [FIO2] ≤100 mm Hg) or in patients with mild-to-moderate ARDS (baseline PaO2/FIO2>100 mg Hg).

Other systematic reviews and meta-analyses had similar findings. A 2011 meta-analysis by Afshari et al. selected 14 trials, most of which included adults with ARDS or acute lung injury. (9) Three trials included pediatric populations (neonates were excluded). 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 did not reduce the number of ventilator- free days or shorten the duration of mechanical ventilation, and there was no 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 acute hypoxemic respiratory failure in children and adults. (10) The Cochrane reviewers conducted only 1 pooled analysis of 2 studies. The meta-analysis did not find a significant impact of INO on mortality without crossover of placebo failures to INO treatment (pooled RR=0.98; 95% CI, 0.66 to 1.44).

A 2015 RCT, published after these meta-analyses, focused on pediatric ARDS. (11) Eligibility criteria for this trial by Bronicki et al. included age between 44 weeks postconception and 16 years, an oxygenation index score of 12 or higher as determined by 2 measurements 30 minutes to 4 hours apart, chest radiograph with pulmonary infiltrates, and mechanically ventilated for 7 days or fewer. Immunocompromised children were excluded. A total of 55 patients were randomized to INO (n=26) or placebo (nitrogen gas; n=29). Study gas was continued until death, until the patient was ventilator-free, or on day 28, whichever came first. The attending staff were blinded to which gas a patient received. Analyses were per protocol; 2 patients randomized to the INO group withdrew from the study and 1 patient inadvertently received INO and was analyzed in that group. The primary outcome (a composite of number of days alive and ventilator-free days at 28 days after randomization) was a mean (SD) of 14.7 (8.11) days in the INO group and 9.11 (9.47) days in the placebo group; the between-groups difference was marginally statistically significant (p=0.05). The survival rate did not differ significantly between groups. Twenty-two (91.7%) of 24 in the INO group and 21 (72.4%) of 29 in the placebo group survived to 28 days (p=0.07). The rate of ECMO-free survival was 22 (91.7%) of 24 in the INO group and 15 (51.7%) of 29 in the placebo group; this analysis significantly favored the INO group (p<0.01). The trial was originally designed to enroll 169 patients per arm but was stopped early due to slow enrollment, raising the possibility that it was underpowered to detect clinically meaningful differences between groups.

Section Summary: Acute Hypoxemic Respiratory Failure in Adults and Children

Several systematic reviews of RCTs have not found that INO significant reduces mortality or shortens the duration of mechanical ventilation in adults and children with acute hypoxic respiratory failure. One 2015 RCT in children with ARDS found significantly better ECMO-free survival but not OS in children who received INO versus placebo gas. Given the large body of literature showing a lack of benefit in patients of various ages, the 2015 RCT does not provide sufficient new data to conclude that INO improves the net health outcome in pediatric patients with ARDS.

Assessment of Pulmonary Vasoreactivity

Randomized controlled trials (RCTs), case series, and nonrandomized comparative studies have been published regarding the diagnostic use of inhaled nitric oxide as a method of assessing pulmonary vasoreactivity in persons with pulmonary hypertension.

In 2002, Balzar et al., in a small randomized trial 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. (12) 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 parts per million (ppm) nitric oxide 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.

In 2011, Krasuski et al., evaluated the ability of vasodilator response to predict survival in a heterogeneous group of individuals with pulmonary hypertension. (13) 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 2010, Barst et al., 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. (14) 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.

Section Summary: Assessment of Pulmonary Vasoreactivity

Available evidence from RCTs, case series, and nonrandomized comparative studies found INO a safe and effective screening agent for pulmonary vasoreactivity. In addition, The Pediatric Pulmonary Hypertension Network, The American Heart Association and American Thoracic Society and 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) include guidelines and/or recommendations on the use of inhaled nitric oxide (INO) as part of vasoreactivity testing detailed in the Practice Guidelines and Position Statements section.

Adults and Children With Congenital Heart Disease Who Have Undergone Heart Surgery

Children

A 2014 Cochrane review by Bizzarro et al. identified 4 RCTs (total N=210 patients) comparing postoperative INO and placebo or usual care in the management of children with congenital heart disease. (15) All trials included participants who were identified as having pulmonary hypertension in the preoperative or postoperative period. Three trials were parallel group, and 1 was a crossover. Mortality was the primary outcome of the Cochrane meta-analysis. Two trials (n=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 INO group and 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 likewise 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 reviewers 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 the methodologic quality of studies, sample sizes, and heterogeneity between studies. These results did not support a benefit for INO treatment for this patient group. Wide confidence intervals around the pooled treatment effects reflect the relative paucity of data available for each outcome.

The RCT with the largest sample size was published by Miller et al. in Australia in 2000. (16) The trial 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 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 episodes (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 to eligibility for extubation was significantly shorter in the INO group (80 hours) than in the placebo group (112 hours; 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 no significant difference in median time to discharge from intensive care (138 hours for INO vs 162 hours for placebo; 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 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. (17) This double-blind trial was conducted at 8 centers in the United States and Germany. Patients were randomized to 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). Patients continued use of INO or placebo until they were extubated, reached the study criteria for RVD, or were treated for 48 hours, whichever came 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. For example, 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: Children and Adults With Congenital Heart Disease Who Have Undergone Heart Surgery

Evidence from a number of small RCTs and a 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.

Lung Transplantation

Tavare and Tsakok reviewed the literature on whether prophylactic INO in patients undergoing a lung transplant reduces morbidity and mortality. (18) They identified 6 relevant studies, 2 RCTs (Meade et al., [19] Perrin et al. [20]) and 4 uncontrolled cohort studies. They also identified a third RCT (Botha et al. [21]), which they excluded from the review because they did not view the outcomes in that study as clinically useful. The reviewers observed that there are few controlled studies and all published studies, including the RCTs, had small sample sizes. Moreover, they noted that no RCTs found that INO reduced mortality or morbidity (e.g., time to extubation, length of hospital stay) and thus concluded that “it is difficult to currently recommend the routine use of prophylactic inhaled NO in lung transplant surgery.” Published RCTs are summarized in Table 2.

Table 2. Summary of RCTs Evaluating INO After Lung Transplantation

Study

N

Interventions

Primary End Points

Synopsis of Findings

Meade et al. (2003)

84

INO 20 parts per million 10 minutes after reperfusion versus placebo gas mixture

Duration of mechanical ventilation from admission to ICU to first successful extubation

No statistically significant difference in time to successful extubation (mean, 25.7 h in INO group versus 27.3 h in control group; p=0.76). No statistically in secondary outcomes (e.g., severe reperfusion injury, time to hospital discharge, hospital mortality, 30-d mortality).

Perrin et al. (2006)

30

INO 20 parts per million at reperfusion for 12 h versus no intervention

Not specified

No statistically significant differences between groups on outcomes (e.g., ICU length of stay, duration of ventilation, fluid balance during 24 h after ICU admission)

Botha et al. (2007)

20

Prophylactic INO 20 parts per million versus standard gas mixture during 30 minutes of reperfusion

Not specified

No statistically significant differences between groups in development of grade II-III primary graft dysfunction or gas exchange

ICU: intensive care unit; INO: Inhaled nitric oxide; RCT: randomized controlled trial.

Section Summary: Lung Transplantation

Three small RCTs have evaluated INO after lung transplantation and none found statistically significant improvements in health outcomes. A systematic review of RCTs and observational studies concluded that there is insufficient evidence to support routine use of INO after lung transplant.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 3.

Table 3. Summary of Key Trials

NCT No.

Trial Name

Planned Enrollment

Completion Date

Ongoing

NCT01958944a

Phase II Prospective, Open Labeled, Multi-Center, Evaluation of the Safety and Tolerability of Nitric Oxide Given Intermittently Via Inhalation to Subjects With Cystic Fibrosis

9

Mar 2016

NCT00515281

Inhaled Nitric Oxide and Neuroprotection in Premature Infants

484

Apr 2016

NCT01939301

Randomized Trial of Inhaled Nitric Oxide to Treat Acute Pulmonary Embolism

78

Jun 2017

NCT: national clinical trial.

a Denotes industry-sponsored or cosponsored trial.

Summary of Evidence

For individuals who are neonates and are term or near-term at birth and have hypoxic respiratory failure who receive inhaled nitric oxide (INO), the evidence includes randomized controlled trials (RCTs) and a systematic review. Relevant outcomes are overall survival, hospitalizations, resource utilization, and treatment-related morbidity. Evidence from RCTs and a meta-analysis support the use of INO in term or near-term infants. Pooled analyses of RCT data have found that INO leads to a significant reduction in the need for extracorporeal membrane oxygenation (ECMO) and in the combined outcome of ECMO or death. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.

For individuals with pulmonary hypertension there is sufficient data published demonstrating the safety and efficacy of the diagnostic use of INO as a method of assessing pulmonary vasoreactivity.

For individuals who are neonates and are premature at birth and have hypoxic respiratory failure who receive INO, the evidence includes RCTs and systematic reviews. Relevant outcomes are overall survival, hospitalizations, resource utilization, and treatment-related morbidity. A large number of RCTs have evaluated INO for premature neonates, and most trials have reported no significant difference on primary end points such as mortality and bronchopulmonary dysplasia. Systematic reviews have not found better outcomes with INO than placebo or other control interventions in premature neonates. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have acute hypoxemic respiratory failure (non-neonates) who receive INO, the evidence includes RCTs and systematic reviews. Relevant outcomes are overall survival, hospitalizations, resource utilization, and treatment-related morbidity. Several systematic reviews of RCTs have not found that this significantly impacts mortality or duration of mechanical ventilation in adults or children with acute hypoxic respiratory failure. One 2015 RCT in children with acute respiratory distress syndrome found significantly better ECMO-free survival but not overall survival in children who received INO versus placebo gas. Given the large body of literature showing a lack of benefit in patients of various ages, the 2015 RCT does not provide sufficient new data to conclude that INO improves the net health outcome in this subgroup of patients. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have congenital heart disease who underwent heart surgery who receive INO, the evidence includes RCTs and a systematic review. Relevant outcomes are overall survival, hospitalizations, resource utilization, and treatment-related morbidity. Evidence from a number of small RCTs and a 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 found that treatment with INO did not improve of postoperative outcomes in adults with congestive heart failure. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have lung transplant who receive INO, the evidence includes RCTs and a systematic review. Relevant outcomes are overall survival, hospitalizations, resource utilization, and treatment- related morbidity. Several small RCTs have evaluated INO after lung transplantation and have not found statistically significant improvement in health outcomes. A systematic review of RCTs and observational studies concluded that there is insufficient evidence to support routine use of INO after lung transplant. The evidence is insufficient to determine the effects of the technology on health outcomes.

Clinical input from academic medical centers and specialty societies obtained by the Blue Cross Blue Shield Association in 2012 indicated that:

Prolonged use (>1-2 weeks) of INO 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, INO should be discontinued because there is no benefit to combined treatment.

Practice Guidelines and Position Statements

Pediatric Pulmonary Hypertension Network

In 2016, The Pediatric Pulmonary Hypertension Network (a network of clinicians, researchers, and centers) published recommendations for use of INO in premature infants with severe pulmonary hypertension. (22) Key recommendations are: “(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….”

National Institutes of Health

In 2011, a National Institutes of Health consensus development conference statement on INO for premature infants was published. (23) The statement was based on the Agency for Healthcare Research and Quality?sponsored systematic review of the literature, previously described. (2) 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 uncertainties.”

American Academy of Pediatrics

In 2000, the American Academy of Pediatrics (AAP) issued recommendations on the use of INO in pediatric patients. (24) The recommendations stated that “Inhaled nitric oxide therapy should be given using the indications, dosing, administration and monitoring guidelines outlined on the product label.” 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 recommendations did not address the use of INO in premature infants

American Heart Association and American Thoracic Society

In 2015, the American Heart Association and American Thoracic Society issued guidelines for the treatment of pediatric pulmonary hypertension. (25) 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):

Inhaled nitric oxide (iNO) is indicated to reduce the need for extracorporeal membrane oxygenation (ECMO) support in term and near-term infants with persistent PH of the newborn (PPHN) or hypoxemic respiratory failure who have an oxygenation index that exceeds 25 (Class I; Level of Evidence A).

Cardiac catheterization should include acute vasoreactivity testing (AVT) unless there is a specific contraindication (Class I; Level of Evidence A). Additionally, noted is that AVT may be studied with iNO (20–80 ppm), 100% oxygen, inhaled or intravenous PGI2 analogs, or intravenous adenosine or sildenafil.

European Society of Cardiology and the European Respiratory Society

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. (26)

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CODING:

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

93463

HCPCS Codes

None

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

1. Nitric Oxide. Micromedex ® Solutions, Truven Health Analytics 2016. (December 2009). Available at < http://www.micromedexsolutions.com> (accessed – 2016 September 21).

2. 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

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. Barrington 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. Dec 2014; 165(6):1104-1108 e1101. 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 21372277

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. Bronicki RA, Fortenberry J, Schreiber M, et al. Multicenter randomized controlled trial of inhaled nitric oxide for pediatric acute respiratory distress syndrome. J Pediatr. Feb 2015; 166(2):365-369 e361. PMID 25454942

12. 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. PMID 12354713

13. 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. PMID 21440863

14. 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. PMID 20405117

15. 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

16. 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

17. 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

18. Tavare AN, Tsakok T. Does prophylactic inhaled nitric oxide reduce morbidity and mortality after lung transplantation? Interact Cardiovasc Thorac Surg. Nov 2011; 13(5):516-520. PMID 21791520

19. 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. Jun 1 2003; 167(11):1483-1489. PMID 12770854

20. Perrin G, Roch A, Michelet P, et al. Inhaled nitric oxide does not prevent pulmonary edema after lung transplantation measured by lung water content: a randomized clinical study. Chest. Apr 2006; 129(4):1024-1030. PMID 16608953

21. Botha P, Jeyakanthan M, Rao JN, et al. Inhaled nitric oxide for modulation of ischemia-reperfusion injury in lung transplantation. J Heart Lung Transplant. Nov 2007; 26(11):1199-1205. PMID 18022088

22. 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. Mar 2016; 170:312-314. PMID 26703869

23. Cole FS, Alleyne C, Barks JD, et al. National Institutes of Health (NIH) Consensus Development Conference statement: inhaled nitric-oxide therapy for premature infants. Pediatrics. Feb 2011; 127(2):363-369. PMID 21220405

24. 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

25. 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. PMID 26534956

26. 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. PMID 26320113

27. Nitric Oxide. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2016 May) Therapy 8.01.37

Policy History:

Date Reason
10/15/2017 Reviewed. No changes.
2/15/2017 New medical document. Inhaled nitric oxide may be considered medically necessary as a component of treatment of hypoxic respiratory failure (see Note) in neonates born at 34 weeks and 0 days of gestation or greater 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 (CDH). The diagnostic use of inhaled nitric oxide may be considered medically necessary as a method of assessing pulmonary vasoreactivity in persons with pulmonary hypertension. Other indications for inhaled nitric oxide are considered experimental, investigational, and/or unproven, including but not limited to: treatment of premature neonates born at less than 34 weeks and 0 days of gestation with hypoxic respiratory failure; treatment of adults and children with acute hypoxemic respiratory failure; postoperative use in adults and children with congenital heart disease; and in lung transplantation, during and/or after graft reperfusion. NOTE: The following criterion for hypoxic respiratory failure has been reported: An oxygenation index (OI) of at least 25 on 2 measurements made at least 15 minutes apart. (The 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 or more is often used as a criterion to initiate ECMO therapy.)

Archived Document(s):

Title:Effective Date:End Date:
Inhaled Nitric Oxide11-01-202101-14-2023
Inhaled Nitric Oxide10-15-202010-31-2021
Inhaled Nitric Oxide11-15-201910-14-2020
Inhaled Nitric Oxide01-15-201911-14-2019
Inhaled Nitric Oxide10-15-201701-14-2019
Inhaled Nitric Oxide02-15-201710-14-2017
Back to Top