Clinical Policy Title: Inhaled nitric oxide

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1 Clinical Policy Title: Inhaled nitric oxide Clinical Policy Number: Effective Date: June Initial Review Date: February 19, 2014 Most Recent Review Date: March 6, 2018 Next Review Date: March 2019 Policy contains: Inhaled nitric oxide. Respiratory distress. Pediatric pulmonary hypertension. Related policies: None. ABOUT THIS POLICY: Select Health of South Carolina has developed clinical policies to assist with making coverage determinations. Select Health of South Carolina s clinical policies are based on guidelines from established industry sources, such as the Centers for Medicare & Medicaid Services (CMS), state regulatory agencies, the American Medical Association (AMA), medical specialty professional societies, and peerreviewed professional literature. These clinical policies along with other sources, such as plan benefits and state and federal laws and regulatory requirements, including any state- or plan-specific definition of medically necessary, and the specific facts of the particular situation are considered by Select Health of South Carolina when making coverage determinations. In the event of conflict between this clinical policy and plan benefits and/or state or federal laws and/or regulatory requirements, the plan benefits and/or state and federal laws and/or regulatory requirements shall control. Select Health of South Carolina s clinical policies are for informational purposes only and not intended as medical advice or to direct treatment. Physicians and other health care providers are solely responsible for the treatment decisions for their patients. Select Health of South Carolina s clinical policies are reflective of evidence-based medicine at the time of review. As medical science evolves, Select Health of South Carolina will update its clinical policies as necessary. Select Health of South Carolina s clinical policies are not guarantees of payment. Coverage policy Select Health of South Carolina considers the use of inhaled nitric oxide for the management of at- or near-term infants at risk for pulmonary hypertension to be clinically proven and, therefore, medically necessary when all of the following criteria are met (Barrington, 2017a and 2017b; Hansmann, 2016; Kaestner, 2016; DiBlasi, 2010; FDA, 1999): Inhaled nitric oxide is a component treatment of respiratory failure associated with pulmonary hypertension. Infants are at 35 weeks of gestation. There is no presence of congenital diaphragmatic hernia. Inhaled nitric oxide is performed in centers with Level 3 or Level 4 neonatal intensive care units and referral access to extracorporeal membrane oxygenation. Select Health of South Carolina considers the use of inhaled nitric oxide for respiratory distress in infants at <35 weeks of gestation to be investigational and, therefore, not medically necessary (Askie, 2017; Hasan, 2017; Kumar, 2014; Askie, 2011; Cole, 2011). 1

2 Limitations: All other uses of inhaled nitric oxide are not medically necessary (Gebistorf, 2016; Hayes, 2014). Alternative covered services: Standard medical care as found in the peer-reviewed medical journals for the treatment of asthma, respiratory distress, chronic lung disease, and pulmonary disease in infants and newborns. Background Nitric oxide is a free radical gas serving formed from the actions of nitric oxide synthease catalyzing the abduction of guanidine nitrogen from arginine, raising intracellular levels of cyclic-guanosine 3, 5 - monophosphate and yielding nitric oxide and water (National Center for Biotechnology Information, 2018). The nitric oxide synthease isoenzymes are expressed in the epithelium of the airways in both normal and asthmatic subjects. Physiologically, nitric oxide causes vasodilatation and relaxation of airway smooth muscles. It inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. In the face of inflammatory processes, more nitric oxide is produced and, in turn, is reduced in the face of glucocorticosteroids. Inhaled nitric oxide: Inhaled nitric oxide has been proposed as a treatment option for pulmonary hypertension and hypoxemic respiratory failure. The U.S. Food and Drug Administration (FDA) approved inhaled nitric oxide (marketed as INOmax gas, Mallinckrodt Hospital Products IP Limited, Hampton, New Jersey) as a vasodilator to improve oxygenation and reduce the need for extracorporeal membrane oxygenation in term and near-term (>34 weeks of gestation) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension, in conjunction with ventilatory support and other appropriate agents (FDA, 1999). FDA warns of rebound pulmonary hypertension syndrome following abrupt discontinuation from inhaled nitric oxide, methemoglobinemia, airway injury, and heart failure as a result of nitric oxide (FDA, 2004). Off-label use is widespread (Keszler, 2012). Searches Select Health of South Carolina searched PubMed and the databases of: UK National Health Services Centre for Reviews and Dissemination. Agency for Healthcare Research and Quality s (AHRQ s) National Guideline Clearinghouse and other evidence-based practice centers. The Centers for Medicare & Medicaid Services (CMS). 2

3 Searches were conducted on January 17, Search terms were: "nitric oxide" (MeSH), inhaled nitric oxide, and respiratory distress. We included: Systematic reviews, which pool results from multiple studies to achieve larger sample sizes and greater precision of effect estimation than in smaller primary studies. Systematic reviews use predetermined transparent methods to minimize bias, effectively treating the review as a scientific endeavor, and are thus rated highest in evidence-grading hierarchies. Guidelines based on systematic reviews. Economic analyses, such as cost-effectiveness, and benefit or utility studies (but not simple cost studies), reporting both costs and outcomes sometimes referred to as efficiency studies which also rank near the top of evidence hierarchies. Findings: An AHRQ-funded evidence report on inhaled nitric oxide in preterm infants found a 7 percent reduction in the composite outcome of death or bronchopulmonary dysplasia at 36 weeks compared to control; however, there was insufficient evidence to support the use of inhaled nitric oxide outside of rigorous randomized controlled trials (RCTs) (Allen, 2010). A consensus panel from the American Association for Respiratory Care (AARC) made recommendations for: (1) a trial of inhaled nitric oxide in newborns 34 weeks of gestation with oxygen tension <100 mm Hg on 100 percent oxygen; (2) using inhaled nitric oxide starting early to reduce duration of mechanical ventilation; and (3) not using inhaled nitric oxide in infants with congenital diaphragmatic hernia, cardiac anomalies with right-to-left shunts, or heart failure (DiBlasi, 2010). The AARC relied on evidence compiled by the Cochrane Neonatal Group, which failed to find evidence to support inhaled nitric oxide as rescue therapy, but did find that early use of inhaled nitric oxide in preterm infants with respiratory conditions did not affect brain injury or mortality (Barrington, 2010). A National Institutes of Health (NIH) panel did not find evidence supporting the use of inhaled nitric oxide for rescue and care of infants with <34 weeks of gestation (Cole, 2011). Another meta-analysis of 14 published trials found significant differences in the design of published trials that precluded a determination of the salutary impact of inhaled nitric oxide (Askie, 2011). The American Academy of Pediatrics literature review found insufficient evidence to support treating preterm infants who have respiratory failure with inhaled nitric oxide and no evidence of a salutary impact on neurodevelopmental processes for infants who received inhaled nitric oxide compared to controls (Kumar, 2014). As a summary of the findings of the studies, the following points may be made: There is evidence to support the use of inhaled nitric oxide in term or late preterm infants with respiratory distress and pulmonary hypertension for its acute favorable impacts as a 3

4 smooth muscle relaxant on pulmonary vascular system and bronchiolar tree. Inhaled nitric oxide should not be used for more than four days because of toxicity, nor is it effective in treatment of hypoxemia related to congenital diaphragmatic hernia. Inhaled nitric oxide for treatment of preterm infants with respiratory distress, bronchopulmonary dysplasia, or pulmonary hypertension has not been standardized, and its impact is not known. The effectiveness of inhaled nitric oxide in adults with acute respiratory distress syndrome has not been demonstrated. The above recommendations for the use of inhaled nitric oxide are based on controlled clinical trials, except as mentioned in the first bullet. Policy update: We found three Cochrane reviews (Barrington, 2017a; Barrington 2017b [updated 2010]; Gebistorf, 2016) and two consensus statements (Hansmann, 2016; Kaestner, 2016) for this policy update. The new evidence found that inhaled nitric oxide is effective at an initial concentration of 20 ppm for term and near-term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia, but it is not an effective treatment for preterm infants (Barrington, 2017a and 2017b). For adults with acute respiratory distress syndrome, inhaled nitric oxide results in a transient improvement in oxygenation but not a reduction in mortality, and may increase renal impairment (Gebistorf, 2016). The European Paediatric Pulmonary Vascular Disease Network (EPPVDN) strongly supports inhaled nitric oxide for treating acute pulmonary vascular crisis and/or acute exacerbation of pediatric pulmonary hypertension, but only weakly supports inhaled nitric oxide for treating post-operative pediatric pulmonary hypertension in the intensive care unit (Hansmann, 2016; Kaestner, 2016). These results do not change previous findings. Therefore, no policy changes are warranted. In 2018, we identified one meta-analysis (Askie, 2017) and one multisite RCT (Hasan, 2017) that addressed the effects of inhaled nitric oxide on survival without bronchopulmonary dysplasia in high-risk preterm infants. Both studies lacked a standardized approach to treatment and enrollment criteria, and produced conflicting results. These findings are consistent with earlier conclusions, and no policy changes are warranted. Summary of clinical evidence: Citation Askie (2017) Content, Methods, Recommendations Race effects of inhaled nitric oxide in preterm infants Meta-analysis of individual participant data from three randomized, placebo-controlled trials that enrolled infants born at <34 weeks of gestation receiving respiratory support, had at least 15% (or 10 infants in each trial arm) of African American race, and used a starting inhaled nitric oxide of >5 parts per million with the intention to treat for seven 4

5 Citation Barrington (2017a) Cochrane review Inhaled nitric oxide for respiratory failure in infants born at or near term Barrington (2017b; updated 2010) Cochrane review Inhaled nitric oxide for respiratory failure in preterm infants Hasan (2017) Effect of inhaled nitric oxide on survival without bronchopulmonary dysplasia in preterm infants Clinicaltrials.gov identifier: NCT Gebistorf (2016) Content, Methods, Recommendations days minimum. African American infants had a significant reduction in the composite outcome of death or bronchopulmonary dysplasia with inhaled nitric oxide: 49% treated vs 63% controls (relative risk, 0.77; 95% CI, 0.65 to 0.91; P =.003; interaction P =.016). There were no differences between racial groups for death. There was a significant difference between races (interaction P =.023) in the effects of inhaled nitric oxide on developing bronchopulmonary dysplasia in survivors, with the greatest effect in African American infants (P =.005). There was no difference between racial groups in the use of postnatal steroids, pulmonary air leak, pulmonary hemorrhage, or other measures of respiratory support. Systematic review and meta-analysis of 17 RCTs that compared inhaled nitric oxide versus control (placebo or standard care without inhaled nitric oxide) in infants with moderate or severe illness. Overall quality: moderate to high. Inhaled nitric oxide reduced the incidence of the combined endpoint of death or use of extracorporeal membrane oxygenation, and improved oxygenation in the short term, but no effect on mortality, incidence of disability, incidence of deafness, or infant development scores. Earlier administration reduced disease progression, but did not further decrease mortality or the need for extracorporeal membrane oxygenation. No clear correlation between echocardiographic evidence of persistent pulmonary hypertension of the newborn and response to inhaled nitric oxide. Outcomes of infants with diaphragmatic hernia were not improved (moderate-quality evidence). Systematic review and meta-analysis of 17 RCTs (3,957 total patients). Inhaled nitric oxide used as rescue therapy, early routine use in infants with pulmonary disease, or as later treatment based on risk of bronchopulmonary dysplasia has no significant effect on the risk of death, bronchopulmonary dysplasia, intraventricular hemorrhage, other serious brain injury, or adverse long-term neurodevelopmental outcomes. A RCT performed at 33 U.S. and Canadian neonatal intensive care units. Participants included 451 neonates <30 weeks' gestation with birth weight <1,250 g receiving mechanical ventilation or positive pressure respiratory support on postnatal days 5 to 14, randomized to either placebo (nitrogen) or inhaled nitric oxide. Inhaled nitric oxide, initiated at 20 ppm on postnatal days 5 to 14 to high-risk preterm infants and continued for 24 days, appears safe but did not improve survival without bronchopulmonary dysplasia at 36 weeks' post-menstrual age or respiratory and neurodevelopmental outcomes at 18 to 24 months' post-menstrual age. Cochrane review Systematic review and meta-analysis of 14 RCTs. 5

6 Citation Inhaled nitric oxide for acute respiratory distress syndrome Hansmann (2016) for the EPPVDN Expert consensus statement on the diagnosis and treatment of pediatric pulmonary hypertension Kaestner (2016) for the EPPVDN Pediatric pulmonary hypertension in the intensive care unit Hayes (2014) Inhaled nitric oxide for acute respiratory distress syndrome in adults Kumar (2014) for the American Academy of Pediatrics Guidance: inhaled nitric oxide in preterm infants Askie (2011) Content, Methods, Recommendations Overall quality: moderate-to-high with low-to-moderate risk of bias. No statistically significant effects of inhaled nitric oxide on ventilator-free days (five RCTs, 804 participants) or any mortality measure in any age group. Statistically significant improvement at 24 hours in partial pressure of oxygen in arterial blood (PaO2)/fraction of inspired oxygen (FiO2) (11 trials, 614 participants) and in oxygenation index (five RCTs, 368 participants). Statistically significant increase in renal failure in the inhaled nitric oxide groups. Inhaled nitric oxide is mainly used in the intensive care unit setting and is useful in patients with acute pulmonary vascular crisis and/or acute exacerbation of pulmonary hypertension in the setting of an underlying parenchymal lung disease and/or pediatric pulmonary hypertension (strong recommendation; moderate-quality evidence). Inhaled nitric oxide may be considered for treatment of postoperative pulmonary hypertension in mechanically ventilated patients to improve oxygenation and reduce the risk of pulmonary hypertensive crisis (weak recommendation; moderate-quality evidence). Systematic review of three RCTs (549 total patients). Overall quality: high with low risk of bias. Inhaled nitric oxide does not improve clinical outcomes for adult patients who have acute respiratory distress syndrome. There is a lack of a mortality benefit, a marginal benefit on arterial oxygenation, and the potential risk of renal impairment. The results of RCTs, traditional meta-analyses, and an individualized patient data metaanalysis indicate neither rescue nor routine use of inhaled nitric oxide improve survival in preterm infants with respiratory failure (evidence quality, A; grade of recommendation, strong). The preponderance of evidence does not support treating preterm infants who have respiratory failure with inhaled nitric oxide to prevent or ameliorate bronchopulmonary dysplasia, severe intraventricular hemorrhage, or other neonatal morbidities (evidence quality, A; grade of recommendation, strong). The incidence of cerebral palsy, neurodevelopmental impairment, or cognitive impairment in preterm infants treated with inhaled nitric oxide is similar to that of control infants (evidence quality, A). There are limited data and inconsistent results of the effects of inhaled nitric oxide on pulmonary outcomes of preterm infants in early childhood. Inhaled nitric oxide in preterm infants (< 37 weeks of gestation) Individual-patient data meta-analysis of 12 RCTs (3,298 infants). No statistically significant effect of inhaled nitric oxide on death, chronic lung disease, or severe neurologic events on imaging. 6

7 Citation Cole (2011) NIH Consensus Development Conference Statement: inhaled nitric oxide for premature infants ( 34 weeks of gestation) DiBlasi (2010) for the AARC Guideline: inhaled nitric oxide for neonates with acute hypoxic respiratory failure Content, Methods, Recommendations No statistically significant differences in inhaled nitric oxide effect according to any of the patient-level characteristics tested (gestational age, race, oxygenation index, postnatal age at enrollment, evidence of pulmonary hypertension, and mode of ventilation). A starting inhaled nitric oxide dose of >5 ppm versus 5 ppm improved outcome (interaction P =.02); effect of higher starting doses on outcomes is inconclusive. Conclusion: Routine use of inhaled nitric oxide for treatment of respiratory failure is not recommended. Evidence suggests biological plausibility. Combined evidence from 14 RCTs shows equivocal effects on pulmonary, survival, and neurodevelopmental outcomes. Recommends a short trial (30 to 60 minutes) of inhaled nitric oxide in newborns (>34 weeks of gestation, <14 days of age) with PaO2 <100 mm Hg on FIO2 1.0 and/or an oxygenation index >25 (Grade 1A). - Inhaled nitric oxide should be judged by an improvement in PaO2 or oxygenation index; if there is no response, inhaled nitric oxide should be discontinued (Grade 1A). Recommends inhaled nitric oxide therapy early in the disease course, which potentially reduces the length of mechanical ventilation, oxygen requirement, and stay within the intensive care unit (Grade 1A). No routine use of inhaled nitric oxide in newborns with: - Congenital diaphragmatic hernia (Grade 1A). - Cardiac anomalies dependent on right-to-left shunts, congestive heart failure, and lethal congenital anomalies (Grade 2C). - Congenital heart disease for postoperative management of hypoxia (grade 2C). The recommended starting dose for inhaled nitric oxide is 20 ppm (Grade 1A). References Professional society guidelines/other: Cole FS, Alleyne C, Barks JD, et al. NIH Consensus Development Conference statement: Inhaled nitricoxide therapy for premature infants. Pediatrics Feb; 127(2): DOI: /peds Hansmann G, Apitz C. Treatment of children with pulmonary hypertension. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK. Heart. 2016; 102 Suppl 2: ii67 ii85. DOI: /heartjnl

8 Kaestner M, Schranz D, Warnecke G, et al. Pulmonary hypertension in the intensive care unit. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK. Heart. 2016; 102 Suppl 2: ii57 ii66. DOI: /heartjnl Kumar P; Committee on Fetus and Newborn. Use of inhaled nitric oxide in preterm infants. Pediatrics Jan; 133(1): DOI: /peds Peer-reviewed references: Allen MC, Donohue P, Gilmore M, et al. Inhaled Nitric Oxide in Preterm Infants. Evidence Report/Technology Assessment No (Prepared by Johns Hopkins University Evidence-based Practice Center under Contract No ). AHRQ Publication No. 11-E001. Rockville, MD: Agency for Healthcare Research and Quality. October AHRQ website: Accessed January 16, Askie LM, Ballard RA, Cutter GR, et al. Meta-analysis of Preterm Patients on Inhaled Nitric Oxide Collaboration. Inhaled nitric oxide in preterm infants: An individual-patient data meta-analysis of randomized trials. Pediatrics Oct; 128(4): DOI: /peds Askie LM, Davies LC, Schreiber MD, et al. Race Effects of Inhaled Nitric Oxide in Preterm Infants: An Individual Participant Data Meta-Analysis. J Pediatr DOI: /j.jpeds Barrington KJ, Finer N, Pennaforte T, Altit G. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev. 2017; 1: Cd DOI: / CD pub3.(a) Barrington KJ, Finer N, Pennaforte T. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database Syst Rev. 2017; 1: Cd DOI: / CD pub5.(b) DiBlasi RM, Myers TR, Hess DR. Evidence-based clinical practice guideline: inhaled nitric oxide for neonates with acute hypoxic respiratory failure. Respir Care Dec; 55(12): Respiratory Care Journal website. Accessed January 16, Gebistorf F, Karam O, Wetterslev J, Afshari A. Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) in children and adults. Cochrane Database Syst Rev. 2016; (6): Cd DOI: / CD pub3. Hayes Inc., Hayes Medical Technology Report. Inhaled Nitric Oxide for Acute Respiratory Distress Syndrome (ARDS) in Adults. Lansdale, Pa. Hayes Inc.; 2016 (Updated 2016). 8

9 Hasan SU, Potenziano J, Konduri GG, et al. Effect of Inhaled Nitric Oxide on Survival Without Bronchopulmonary Dysplasia in Preterm Infants: A Randomized Clinical Trial. JAMA Pediatr. 2017; 171(11): /jamapediatrics Hayes, Inc. Hayes Medical Technology Directory Report. Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) in adults. Lansdale, Pa.: Hayes, Inc. October 26, INOmax (Nitric oxide). Approval letter. December 23, FDA website. Accessed January 16, INOmax (Nitric oxide). Supplemental approval letter. June 15, FDA website. Accessed January 16, Nitric oxide. MeSH database. National Center for Biotechnology Information website. Accessed January 16, Keszler M. Guidelines for Rational and Cost-Effective Use of ino Therapy in Term and Preterm Infants. J Clin Neonatol Apr; 1(2): DOI: / CMS National Coverage Determinations (NCDs): No NCDs identified as of the writing of this policy. Local Coverage Determinations (LCDs): No LCDs identified as of the writing of this policy. Commonly submitted codes Below are the most commonly submitted codes for the service(s)/item(s) subject to this policy. This is not an exhaustive list of codes. Providers are expected to consult the appropriate coding manuals and bill in accordance with those manuals. CPT Code Description Comments Pharmacologic agent administration (eg, inhaled nitric oxide, intravenous infusion of nitroprusside, dobutamine, milrinone, or other agent) including assessing hemodynamic measurements before, during, after and repeat pharmacologic agent administration, when performed (List separately in addition to code for primary procedure) 9

10 CPT Code Description Comments Ventilation assist and management, initiation of pressure or volume preset ventilators for assisted or controlled breathing; hospital inpatient/observation, initial day Ventilation assist and management, initiation of pressure or volume preset ventilators for assisted or controlled breathing; hospital inpatient/observation, each subsequent day ICD-10 Code Description Comments P07.38 Preterm newborn, gestational age 35 completed weeks P07.39 Preterm newborn, gestational age 36 completed weeks P29.3 (Persistent)primary pulmonary hypertension of newborn HCPCS Level II Code N/A Description Comments 10