Coverage Policies

Effective Date:

a)    This policy will apply to all services performed on or after the above revision date which will become the new effective date.

b)    For all services referred to in this policy that were performed before the revision date, contact customer service for the rules that would apply.

1)    QualChoice considers inhaled nitric oxide (INO) therapy medically necessary to treat hypoxic respiratory failure in term and near term (born at 34 or more weeks of gestation) neonates without congenital diaphragmatic hernia.

2)    QualChoice considers INO medically necessary as a method of assessing pulmonary vasoreactivity in members with pulmonary hypertension.

3)    Any other use of INO, including but not limited to acute respiratory distress syndrome (ARDS), use in preterm (born before 34 weeks) neonates, or use in neonates with diaphragmatic hernia, is considered experimental, investigational, or unproven.

1)    Inhaled nitric oxide is considered medically necessary for the treatment of hypoxic respiratory failure in term or near-term (born at 34 weeks or greater gestational age) neonates without congenital diaphragmatic hernia.  Use for more than 14 days is subject to medical necessity review.

2)    INO is also considered medically necessary as a method of assessing pulmonary vasoreactivity in patients with pulmonary hypertension undergoing diagnostic catheterization.

3)    INO is not considered medically necessary for any other use, including the following:

a)  Acute bronchiolitis (J21.0 – J21.9)

b)  Adult Respiratory Distress Syndrome (J80) or acute lung injury (S27.301A –

     S27.301D, S27.302A – S27.302D, S27.309A – S27.309D)

c)  Post-operative management of pulmonary hypertension in infants and

     children with congenital heart disease (Q24.2 – Q24.9)

d)  Prevention of Broncho-pulmonary dysplasia in neonates

e) Treatment of term or near term neonates with diaphragmatic hernia (Q79.0 – Q79.1)

f)  Treatment of premature (born at less than 34 weeks) neonates (P07.20-P07.36) with

     or without pulmonary hypertension

g)  Treatment of vaso-occlusive crises or acute chest syndrome in persons with sickle

     cell disease (D57.00 – D57.01, D57.211 – D57.219, D57.411 – D57.419, D57.811 –

     D57.819)

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

Treatment of pre-term infants has remained controversial.  While iNO improves oxygenation in pre-term infants with severe respiratory failure, demonstrating improvements in survival and in long term outcomes has proven elusive.  Schreiber (2003), in a randomized trial of 207 premature infants, demonstrated lower incidence of chronic lung disease and death.  Other randomized trials (Van Meurs 2005, Kinsella 2006) have failed to replicate his results.  Meta-analysis by the Johns Hopkins University Evidence-based Practice Center of 11 randomized controlled trials revealed that treatment with iNO did not increase survival. 

In the EUNO trial, Mercier (2010) randomized 800 preterm infants (24-29 weeks) requiring surfactant or continuous positive airway pressure for respiratory distress syndrome within 24 hours of birth to low dose nitric oxide or placebo (nitrogen).  Treatment did not result in significant differences in survival without development of BPD, in survival to 36 weeks postmenstrual age, or in development of BPD.

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

Shah concluded that INO improves survival in very premature infants with PROM, but his study involved only 26 infants and compared them to historical controls. 

1)    NIH Consensus Development Statement on Inhaled Nitric Oxide Therapy for Premature Infants. NIH Consensus and State-of-the-Science Statements 2010; 27(5)

2)    American Academy of Pediatrics.  Committee on Fetus and Newborn.  Use of inhaled nitric oxide.  Pediatrics 2000; 106(2 Pt 1):344-345.

3)    Allen MC, et al.  Inhaled nitric oxide in infants.  AHRQ Evidence Report/Technology Assessment Number 195, 2010

4)    Mercier JC et al.  Inhaled nitric oxide for prevention of Broncho pulmonary dysplasia in premature babies (EUNO): a randomized controlled trial.  Lancet 2010; 376:346-54.

5)    Shah DM and Kluckow M.  Early functional echocardiogram and inhaled nitric oxide:  Usefulness in managing neonates born following extreme preterm premature rupture of membranes. J Pediatric Child Health 2011 Jun; 47(6);340-5

6)    Kinsella et al. Inhaled nitric oxide in premature neonates with severe hypoxaemic respiratory failure: a randomized controlled trial.  Lancet 1999; 354:1061-5

7)    Afshari A, Brok J, Møller AM, Wetterslev J. Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) and acute lung injury in children and adults. Cochrane Database Syst Rev. 2010;(7):CD002787

8)    Van Meurs et al.  Inhaled nitric oxide for premature infants with severe respiratory failure. NEJM 2005; 353(1):13-22

9)    Schreiber MD et al.  Inhaled nitric oxide in premature infants with the respiratory distress syndrome.  NEJM 2003; 349:2099-107