Clinical UM Guideline

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

Note: For a high-level overview of this document, please see “Summary for Members and Families” below.

Medically Necessary:

I.  Therapeutic uses of inhaled nitric oxide (iNO)

Therapeutic use of iNO is considered medically necessary when either criterion A or B is met:

1. Inhaled nitric oxide is considered medically necessary as a component of the treatment of hypoxic respiratory failure (see definition) in neonates (see definition) when all the following criteria are met:
   1. The neonate was born at 34 or more weeks of gestation; and
   2. Conventional therapies have failed; and
   3. Neonate does not have a congenital diaphragmatic hernia; and
   4. Treatment duration does not exceed 14 days, or until the underlying hypoxic respiratory failure has resolved, whichever occurs first;
      or
2. Inhaled nitric oxide is considered medically necessary in the perioperative management of congenital heart disease when all the following criteria (1, 2, and 3) are met:
   1. The treated individual is an infant age 1 year (365 days) or less, regardless of estimated gestational age at birth; and
   2. There is preserved left ventricular function; and
   3. Administered in either of the following clinical scenarios (a or b):
      1. As a prophylactic therapy when all the criteria (i, ii, and iii) are met; and
         1. Initiated at either of the following times:
            1. During surgical repair; or
            2. Immediately following surgical repair;
               and
         2. Individual is at high risk of developing pulmonary hypertensive crises (for example, those with documented high preoperative pulmonary blood flow or elevated pulmonary artery pressures); and
         3. Continued until either of the following occurs (whichever occurs first):
            1. the individual meets criteria for extubation; or
            2. for a maximum of 14 days;
               or
      2. As a postoperative bridge to therapy when both the criteria (i and ii) are met:
         1. Severe pulmonary hypertension defined as a systolic pulmonary artery pressure equal to or exceeding 50% of the systolic systemic arterial pressure on invasive hemodynamic monitoring; and
         2. Clinical instability attributable to pulmonary hypertension following congenital heart disease surgery is documented by echocardiography, invasive hemodynamic monitoring, or both.

II.  Diagnostic use of inhaled nitric oxide (iNO)

Inhaled nitric oxide is considered medically necessary to perform acute vasoreactivity testing during cardiac catheterization for the assessment of pulmonary vascular reactivity in pulmonary hypertension, as follows*:

A.  Pediatric pulmonary hypertension

Acute vasoreactivity testing with inhaled nitric oxide is considered medically necessary when all of the following criteria are met:

1. Confirmed or suspected pulmonary hypertension requiring cardiac catheterization; and
2. Cardiac catheterization is being performed; and
3. Testing is performed to guide therapy, prognosis, or operability assessment.

B.  Adult pulmonary hypertension

Acute vasoreactivity testing with inhaled nitric oxide is considered medically necessary for adult individuals undergoing cardiac catheterization when all of the following criteria are met:

1. Idiopathic, heritable, or drug-induced pulmonary arterial hypertension; and
2. Mean pulmonary artery pressure greater than 20 mm Hg; and
3. Pulmonary artery wedge pressure less than or equal to 15 mm Hg; and
4. Pulmonary vascular resistance greater than 2 Wood Units.

*Note: Diagnostic assessment of iNO’s therapeutic effects are typically observed within 10 to 15 minutes of administration.

Not Medically Necessary:

Inhaled nitric oxide is considered not medically necessary when the criteria above are not met and for all other indications, including, but not limited to:

1. Treatment of hypoxic respiratory failure in premature neonates born at less than 34 weeks gestational age; regardless of the individual's current corrected age or chronological age at time of treatment.
2. Treatment of neonates with pulmonary hypertension when criteria above are not met;
3. Treatment of acute respiratory distress syndrome in adults.

This document describes clinical studies and expert recommendations and explains when use of inhaled nitric oxide is clinically appropriate. The following summary does not replace the medical necessity criteria or other information in this document. The summary may not contain all of the relevant criteria or information. This summary is not medical advice. Please check with your healthcare provider for any advice about your health.

Key Information

Inhaled nitric oxide, also called iNO, is a gas treatment where a person breathes in a small amount of a medical gas through a mask or breathing tube. iNO helps relax blood vessels in the lungs to improve oxygen levels without lowering blood pressure in the rest of the body. This treatment may help some newborns with severe breathing failure linked to high blood pressure in the lungs. It may also be used around the time of heart surgery in some infants born with heart disease, and as a short test during heart catheterization to see how the lung blood vessels respond in children or adults with high pressure in the arteries feeding their lungs (pulmonary hypertension).

What the Studies Show

Studies in babies who are not severely premature and cannot get enough oxygen into the blood (hypoxic respiratory failure) show that inhaled nitric oxide can improve oxygen levels and reduce the need for a heart-lung machine (ECMO). Review articles and randomized trials support its use in these babies when standard treatment has not worked. In contrast, studies in premature newborns have had mixed results. Large reviews and guidance statements recommend against routine or rescue (emergency) use of iNO in most premature babies, because it does not improve survival or reduce the risk of developing a chronic lung problem called bronchopulmonary dysplasia (BPD).

The evidence is also mixed outside this newborn group. Studies and practice guidance do not support routine use for a condition called congenital diaphragmatic hernia (CDH), and some reports found worse outcomes. For testing high blood pressure in the lungs, inhaled nitric oxide is a short-acting medicine used during a heart catheterization to see if the blood vessels in the lungs can relax. When used immediately before surgery for heart problems present at birth for babies at high risk, some studies found fewer dangerous spikes in lung artery pressure. Other reviews found the evidence was limited and not consistent. In adults with acute respiratory distress syndrome (ARDS), studies found only short-term improvement in oxygen levels without better survival, and some studies raised safety concerns.

When is Inhaled Nitric Oxide Clinically Appropriate?

Inhaled nitric oxide may be appropriate in these situations:

• Newborns with severe low oxygen levels when:
  • The baby was born at 34 weeks of gestation or later; and
  • Standard treatments have not worked; and
  • The baby does not have a diaphragmatic hernia; and
  • Treatment is used for 14 days or less, or until the condition improves, whichever comes first.
• Infants 1 year old or younger with congenital heart disease (CHD) around surgery when:
  • Heart pumping function is preserved; and
  • Used during or right after surgery in those at high risk of lung blood pressure crises; or
  • Used after surgery when there is severe lung high blood pressure and the baby’s condition is unstable.
• Children with high blood pressure in the lungs (pulmonary hypertension) when:
  • It is used as a test during a cardiac catheterization procedure; and
  • Pulmonary hypertension is known or suspected; and
  • The test is needed to guide care.
• Adults with certain types of pulmonary hypertension when:
  • It is used as a test during a cardiac catheterization procedure; and
  • The condition has no known cause, is inherited, or is drug-related; and
  • Lung artery pressure and resistance meet specific levels.

When is this not Clinically Appropriate?

Inhaled nitric oxide is not recommended for babies born very early (before 34 weeks of gestation). Studies in these babies have had mixed results, and large reviews show that this treatment does not clearly improve survival or other important health outcomes. Some studies also suggest it may increase the risk of certain complications. More research is needed to understand if this treatment may help specific groups of premature babies.

This treatment is also not recommended for newborns with high blood pressure in the lungs when the criteria above are not met, or for adults with severe lung failure (ARDS).

For babies with a condition called CDH, studies and guidelines do not support routine use because benefits have not been shown and some studies suggest worse outcomes.

In adults with severe lung failure, inhaled nitric oxide may improve oxygen levels for a short time but does not improve survival and may cause harm, such as kidney problems.

Inhaled nitric oxide is not recommended for uses other than those listed above. Use of treatments that do not have proven benefits exposes a person to health risks without expected benefit.

(Return to Description)

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

When services may be Medically Necessary when criteria are met:

When services are Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met, for all other diagnoses not listed; or for situations designated in the Clinical Indications section as not medically necessary.

Summary

Inhaled nitric oxide (iNO) is a selective pulmonary vasodilator with benefit established in a narrow set of indications. Evidence from randomized trials and meta-analyses supports its use in term and near-term neonates with hypoxic respiratory failure, in targeted perioperative management of congenital heart disease (CHD) in infants, and as a diagnostic agent for acute vasoreactivity testing (AVT) in pulmonary hypertension. Evidence does not support routine use in premature neonates under 34 weeks of gestation, in congenital diaphragmatic hernia (CDH), or in adult acute respiratory distress syndrome (ARDS), where trials show no meaningful outcome benefit and, in some subgroups, potential harm. Across supported indications, iNO is framed as a short-term adjunctive therapy rather than a first-line or prolonged intervention.

Discussion

Therapeutic Uses

Hypoxic Respiratory Failure in Term and Near-Term Neonates

The use of inhaled nitric oxide (iNO) is medically necessary in neonates born at ≥ 34 weeks of gestation with hypoxic respiratory failure when conventional therapies have failed and congenital diaphragmatic hernia (CDH) is absent. This criterion reflects a consistent body of evidence demonstrating that iNO improves oxygenation and reduces the need for extracorporeal membrane oxygenation (ECMO) in term and near-term neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension (PH). Randomized trials and meta-analyses have not established a consistent independent mortality benefit. Benefits are most pronounced in individuals with persistent pulmonary hypertension of the newborn (PPHN), where selective pulmonary vasodilation improves ventilation-perfusion matching.

Restriction to term and near-term neonates is supported by randomized trials and meta-analyses showing clear benefit in this group, in contrast to preterm populations where outcomes are inconsistent or unfavorable. Routine iNO use in neonates with CDH is not supported because trials and registry studies have not demonstrated reduced ECMO use or mortality and observational data suggest possible harm, likely related to underlying pulmonary hypoplasia and altered hemodynamics. Selective rescue use in CDH with severe pulmonary hypertension, as recognized in the American Heart Association and American Thoracic Society (AHA/ATS) guidelines, reflects individualized specialist management and is not generalized for routine coverage.

The requirement that conventional therapies (such as optimized ventilation, oxygenation, and management of underlying conditions) be attempted first reflects the role of iNO as an adjunctive rather than first-line intervention. Limiting treatment duration to a maximum of 14 days or until clinical resolution is consistent with clinical trial protocols and product labeling, as iNO is intended as a short-term supportive therapy without evidence of additional benefit from prolonged use.

Perioperative Management of Congenital Heart Disease

iNO is medically necessary in infants age 1 year (365 days) or less with preserved left ventricular function in carefully defined perioperative settings, reflecting its role in managing pulmonary vascular instability associated with congenital heart disease (CHD) surgery.

Prophylactic use is supported for high-risk individuals when delivered through the ventilatory circuit during immediate perioperative management. Evidence from randomized trials demonstrates that iNO reduces the incidence of pulmonary hypertensive crises (PHCs) and shortens time to extubation in individuals with elevated pulmonary blood flow or pressures. These effects are attributable to selective pulmonary vasodilation that reduces pulmonary vascular resistance (PVR) and stabilizes postoperative hemodynamics. This is distinct from nitric oxide delivered into the cardiopulmonary bypass (CPB) oxygenator, for which the 2022 NITRIC randomized trial (Schlapbach, 2022) did not demonstrate benefit in young children undergoing congenital heart surgery. Limiting use to high-risk individuals reflects the absence of benefit in unselected populations and avoids unnecessary exposure.

Postoperative bridge therapy is supported for individuals with severe pulmonary hypertension and clinical instability following surgery. In this setting, iNO provides rapid reduction in pulmonary artery pressures and improves oxygenation, serving as a temporizing measure while underlying hemodynamic disturbances are addressed or longer-acting therapies are initiated. The requirement for objective hemodynamic evidence (for example, pulmonary artery pressure ≥ 50% of systemic pressure) and documented instability ensures appropriate use in clinically significant disease.

The requirement for preserved left ventricular function reflects physiologic considerations, as pulmonary vasodilation in the setting of left ventricular dysfunction may worsen pulmonary edema and hemodynamic compromise.

Hemodynamic Assessment: Acute Vasoreactivity Testing (AVT)

iNO is medically necessary for AVT during cardiac catheterization in selected pediatric participants with suspected or confirmed pulmonary hypertension, and in adults with idiopathic, heritable, or drug-induced pulmonary arterial hypertension who meet hemodynamic criteria for precapillary disease, when the result will directly inform management.

A. Pediatric Pulmonary Hypertension

In pediatric populations, guideline recommendations support routine vasoreactivity testing during cardiac catheterization when pulmonary hypertension is suspected or confirmed. iNO is used due to its rapid onset, short duration, and selective pulmonary effects, allowing controlled assessment of pulmonary vascular responsiveness.

AVT provides critical information for:

• Identifying candidates for calcium channel blocker therapy,
• Assessing disease severity and prognosis,
• Determining operability for congenital heart disease repair or transplantation.

The requirement that testing be performed during catheterization and used to guide clinical decision-making reflects its role as an integral component of invasive hemodynamic evaluation rather than a standalone diagnostic test.

B. Adult Pulmonary Hypertension

In adults, the use of AVT with iNO is appropriately restricted to a narrowly defined subgroup with idiopathic, heritable, or drug-induced pulmonary arterial hypertension who meet hemodynamic criteria for precapillary disease. This restriction aligns with European Society of Cardiology and European Respiratory Society (ESC/ERS) guideline recommendations and reflects evidence that meaningful vasoreactivity, and corresponding therapeutic implications, occurs primarily in this population.

Hemodynamic thresholds (mean pulmonary artery pressure [mPAP] > 20 mm Hg, pulmonary artery wedge pressure ≤ 15 mm Hg, and PVR > 2 Wood units) ensure accurate identification of precapillary pulmonary arterial hypertension. In this setting, AVT identifies individuals who demonstrate a favorable vasodilatory response and may benefit from calcium channel blocker therapy, a group known to have improved long-term outcomes.

Limiting AVT to this subgroup avoids inappropriate testing in other forms of pulmonary hypertension, where vasoreactivity is uncommon and may not confer prognostic or therapeutic benefit.

Not Medically Necessary Uses

Use of iNO outside the above criteria is not considered medically necessary due to lack of demonstrated clinical benefit or potential for harm.

Premature neonates (< 34 weeks of gestation): Extensive randomized trials and meta-analyses show no consistent improvement in survival or major outcomes, with some evidence of increased risk in certain subgroups. The 2015 AHA/ATS guidelines (Abman, 2015) do recognize a narrow subgroup in whom iNO may be beneficial (Class IIa; Level of Evidence B): preterm infants with severe hypoxemia primarily due to PPHN physiology rather than parenchymal lung disease, particularly in the setting of prolonged rupture of membranes and oligohydramnios. Coverage determinations in this subgroup are made on a case-by-case basis.

Neonates not meeting defined criteria: Absence of appropriate clinical context (e.g., failure of conventional therapy or confirmed PPHN) limits the likelihood of benefit.

Routine use in CDH: Randomized trials and registry data have not demonstrated reduced ECMO use or mortality; observational data suggest possible harm. Selective rescue use in CDH with severe pulmonary hypertension under specialist management is not covered under this guideline.

Routine or unselected postoperative use after congenital heart surgery: Benefit has not been demonstrated outside the specific high-risk prophylactic and rescue criteria above (Wong, 2019).

Nitric oxide delivered into the cardiopulmonary bypass oxygenator: The 2022 NITRIC randomized trial (Schlapbach, 2022) in 1371 children < 2 years of age found no effect on ventilator-free days or secondary outcomes.

Prophylactic iNO in adult left ventricular assist device (LVAD) implantation: Randomized trial evidence (Potapov, 2011) did not demonstrate a significant reduction in right ventricular dysfunction (RVD) or other clinical outcomes.

Acute respiratory distress syndrome (ARDS) in adults: Evidence demonstrates only transient improvement in oxygenation without survival benefit and potential safety concerns, including renal impairment.

COVID-19 acute hypoxemic respiratory failure (AHRF) outside of clinical trials: Available data do not establish clinical benefit.

Other investigational uses: Including but not limited to acute bronchiolitis, sepsis, sickle cell vaso-occlusive crisis, lung transplant ischemia-reperfusion prevention, and interstitial lung disease. Evidence is limited to small studies with inconsistent results.

Introduction to iNO

iNO is a selective pulmonary vasodilator without significant effects on the systemic circulation. iNO therapy can improve oxygenation and ventilation, reduce the need for ECMO, and lower the incidence of chronic lung disease and death among term and near-term infants with respiratory failure. In 1999, the U.S. Food and Drug Administration (FDA) approved INOmax^® (nitric oxide for inhalation) (iNO Therapeutics LLC, Bridgewater, NJ) for use, in conjunction with ventilatory support and other appropriate agents, in the treatment of term and near-term (greater than 34 weeks of gestation) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension. iNO improves oxygenation and reduces the need for ECMO. INOmax is contraindicated in neonates known to be dependent on right-to-left shunting of blood.

Respiratory failure is commonly seen in the term, near-term (born at 34 or more weeks of gestation), and preterm (less than 34 weeks of gestation) infants admitted to neonatal intensive care units with many possible causes, including meconium aspiration syndrome, sepsis, pulmonary hypoplasia, primary pulmonary hypertension of the newborn, and surfactant deficiency. Management of infants with respiratory failure is largely supportive and includes administration of oxygen, mechanical ventilation, neuromuscular blockade, steroids, exogenous surfactant, and iNO therapy. ARDS in preterm infants, a type of respiratory failure, is commonly the result of surfactant deficiency and less often due to pulmonary hypertension with shunting. Thus, treatment of ARDS varies for term, near-term, and preterm neonates.

Conventional therapies

Management of pulmonary hypertension typically includes treatment of underlying diseases such as respiratory distress syndrome (RDS) and neonatal infections, promoting optimal lung recruitment, and ensuring adequate ventilation and oxygenation to minimize hypoxemic pulmonary vasoconstriction. Optimizing cardiac output is essential to support systemic and pulmonary blood flow. Pulmonary vasodilation with iNO is helpful for term and near-term infants with pulmonary hypertension (PH) that persists after achieving optimal lung recruitment. Both hyperinflation and atelectasis are associated with increased PVR. The goal of ventilation should be to keep the lungs optimally inflated, maintain arterial carbon dioxide tension (PaCO₂) in the 35 to 50 mm Hg range, avoid severe hypoxemia by maintaining arterial oxygen tension (PaO₂) greater than 50 mm Hg, oxygen saturation targets between 90% and 97%, and blood pH between 7.3 and 7.4 (Mani, 2024).

Inhaled nitric oxide is intended for short-term use as a supportive therapy in AHRF. Clinical studies and guideline recommendations evaluate iNO as a temporizing intervention to improve oxygenation and stabilize cardiopulmonary status while underlying disease processes are addressed, rather than as a prolonged therapy. Consistent with product labeling, treatment is limited to a maximum duration of 14 days or discontinued earlier once the underlying hypoxic respiratory failure has resolved or the individual meets criteria for weaning from ventilatory support. There is no evidence demonstrating additional clinical benefit with prolonged use beyond this period, and extended therapy has not been shown to improve clinically meaningful outcomes.

Term and Near-Term Neonates

iNO therapy has been shown to improve oxygenation and ventilation, reduce the need for ECMO, and lower the incidence of chronic lung disease and death among term and near-term infants with respiratory failure (Clark, 2000; Neonatal Inhaled Nitric Oxide Study Group, 1997b).

Barrington and colleagues (2017) evaluated the use of iNO for respiratory failure in infants born at or near term gestation. The authors included 17 studies that compared iNO therapy to standard therapy without iNO, 10 of which were determined to be of moderate to high quality. iNO appeared to result in improved outcomes for term and near-term hypoxemic infants. Oxygenation was improved in approximately 50% of infants receiving iNO. Infants with CDH had slightly worse outcomes with iNO. The authors concluded, “iNO is effective at an initial concentration of 20 ppm for term and near-term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia.”

While iNO remains the principal inhaled pulmonary vasodilator used in PPHN after optimization of conventional therapies, a significant proportion of neonates show incomplete or absent response. Kim (2026) conducted a retrospective cohort study of 114 neonates with PPHN treated with iNO (mean gestational age, 38.1 ± 3.4 weeks) and classified early response patterns based on changes in the oxygenation index (OI) within the first 24 hours. Among the cohort, 20.2% were fast responders, 51.8% were slow responders, and 28.1% were non-responders. Among the 32 non-responders, 16 received adjunctive intravenous treprostinil. Despite greater baseline illness severity (higher OI, lower gestational age, and more frequent inotropic support), treprostinil-exposed non-responders achieved earlier tapering of iNO to 10 ppm compared with unexposed non-responders (log-rank test, p=0.005), and treprostinil exposure was independently associated with earlier clinical stabilization in a multivariable Cox model (hazard ratio (HR), 4.99; 95% confidence interval (CI), 1.47-16.98; p=0.010). No significant differences in ECMO use or mortality were observed between groups, and no major adverse effects related to treprostinil were reported. The authors concluded that classifying early iNO response patterns could help identify neonates who may benefit from adjunctive therapies such as treprostinil, though the study was limited by its retrospective single-center design and small sample size.

Congenital Diaphragmatic Hernia (CDH)

CDH is caused by a defect in the diaphragm that leads to protrusion of abdominal contents into the thorax and interferes with normal lung development (Chandrasekharan, 2017; Gien, 2016). In severe cases, CDH is associated with lung hypoplasia and immaturity, PPHN and cardiac dysfunction. Secondary to pulmonary hypertension, there is shunting of blood from right to left. An early randomized controlled trial (RCT) of infants 34 weeks of gestation or more with CDH did not find any significant improvement in survival or oxygenation with iNO treatment (Neonatal Inhaled Nitric Oxide Study Group, 1997a). iNO is not FDA-approved for the treatment of PPHN caused by CDH and is also contraindicated in neonates known to be dependent on right-to-left shunting of blood (INOmax product information, 2023). However, the use of iNO for the treatment of CDH appears to be continuing.

Malowitz and colleagues (2014) examined mortality and medical interventions (including iNO) for neonates born with CDH. Infants 34 weeks of gestation or more with CDH from 29 neonatal intensive care units (NICUs) born between 1999 and 2012 were identified. Only NICUs with an average of two or more CDH cases per year were included. Mortality and the proportion of infants exposed to medical interventions, during 4 periods of time (1999-2001, 2002-2004, 2005-2007, and 2008-2012) were examined. A total of 760 infants with CDH were identified. Use of iNO increased from 20% of infants to 50%, sildenafil use increased from 0 to 14%, and milrinone use increased from 0 to 22% (p<0.001) from the 1999 to 2001 period to the 2008 to 2012 period. Overall mortality (28%) did not significantly change over time as compared to the earliest time period. The authors reported that “despite the evidence for harm and lack of evidence for efficacy, iNO use has significantly increased.” Additionally, they indicated that the safety and efficacy of interventions (including iNO) in infants with CDH require randomized clinical trials or prospective cohort studies of comparative effectiveness with careful data collection.

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

The American Association for Respiratory Care (AARC) (2010) published an evidence-based clinical practice guideline for iNO in neonates with AHRF. The AARC recommendations included that “iNO should not be used routinely in newborns with congenital diaphragmatic hernia.”

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

In 2023, Noh published the results of a multicenter cohort study using data from the Congenital Diaphragmatic Hernia Study Group to assess the impact of early iNO use in the first 3 days of life prior to the use of extracorporeal life support (ECLS). Of the 1777 participants in the study, 863 (48.6%) received early iNO. The authors reported that participants receiving iNO had lower birth weight, larger defect sizes, more severe pulmonary hypertension, and abnormal ventricular size and function. After controlling for these factors, early iNO use was associated with increased mortality (odds ratio (OR), 2.06; p=0.03) and increased ECLS use (OR, 3.44; p<0.001). They concluded that iNO in the first 3 days of life prior to ECLS was not associated with a reduction in mortality or ECLS and the widespread use of iNO in this population requires reconsideration.

Premature Neonates

Studies involving the use of iNO for premature neonates (less than 34 weeks of gestation) are currently inconclusive and use of this treatment remains controversial for premature infants with severe respiratory failure.

Prior to 2017, the evidence base for inhaled nitric oxide (iNO) in premature neonates evolved from early optimism to overall negative or inconclusive conclusions. Initial small randomized trials suggested potential benefit. For example, Schreiber (2003) reported reduced death or chronic lung disease, with follow-up data (Mestan, 2005) suggesting improved neurodevelopmental outcomes. However, these findings were tempered by concerns about study validity, including unusually poor outcomes in the control group and uncertainty regarding safety, dosing, and treatment timing.

Subsequent larger and more rigorous trials produced inconsistent or negative results. Trials such as Van Meurs (2005) and Kinsella (2006b) found no overall reduction in death or bronchopulmonary dysplasia (BPD), although subgroup signals (for example, infants >1000 g) suggested possible differential effects. Other studies (Ballard, 2006) reported modest improvements in survival without BPD with later or prolonged therapy, but these findings were not consistently replicated and required long-term confirmation. Neurodevelopmental follow-up studies (Hintz, 2007) failed to demonstrate sustained benefit.

By the late 2000s, additional trials and physiologic studies continued to show mixed or absent effects on key outcomes such as pulmonary function, survival, and long-term disability (Di Fiore, 2007; Huddy, 2008; Van Meurs, 2007). Larger multicenter trials, including Mercier (2010), reinforced the lack of benefit, showing no improvement in survival without BPD even with early and prolonged therapy.

This accumulation of evidence led to more definitive conclusions in pooled analyses. The Askie (2011) meta-analysis of over 3000 infants found no significant reduction in death, chronic lung disease, or severe neurologic events, with no identifiable benefiting subgroup. Longer-term follow-up data (Durrmeyer, 2013) and later RCTs (Kinsella, 2014) continued to show no meaningful improvement in survival or major outcomes.

Overall, by the mid-2010s, the trajectory of evidence had shifted from early promise and subgroup hypotheses to consistent findings that iNO does not improve clinically meaningful outcomes in preterm infants when used routinely or as rescue therapy. This body of evidence established the foundation for guideline recommendations against routine use in this population.

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

Hasan and colleagues (2017) conducted an RCT to determine if iNO would decrease the incidence of BPD in premature infants. Included participants were < 30 weeks gestation, weighed < 1250 g, had a postnatal age of 5 to 14 days, and required mechanical ventilation or positive pressure respiratory support. The primary outcome was the rate of survival without BPD at 36 weeks’ postmenstrual age (PMA). The researchers randomized the participants to receive either iNO (n=229) or a placebo (n=222); however, several participants died or were withdrawn, leaving 208 participants in the iNO group and 204 in the placebo group. The iNO group received iNO at 20 ppm for 24 days. At the end of the study, the survival rate was 34.9% for the iNO group and 31.5% for the placebo group (OR, 1.17; 95% CI, 0.79 to 1.73). The rate of severe BPD, postnatal corticosteroid use, average length of positive pressure support, oxygen therapy, and hospitalization days did not differ between the groups. In addition, neurodevelopmental assessments at 18-24 months were similar between the groups. The authors concluded that iNO “appears to be safe but did not improve survival without BPD.”

In 2017, Baczynski and colleagues published results from a retrospective cohort study over a 6-year follow-up period to describe short- and long-term outcomes of 89 preterm neonates (born <35 weeks) with severe acute pulmonary hypertension in response to rescue iNO therapy (> 1 hour iNO exposure). Primary outcomes included survival without disability and mortality. Overall response rate (defined as fraction of inspired oxygen [FiO₂] reduced by ≥ 0.20) to iNO was 46%. Neonates who responded showed improved survival without disability (51% vs. 15%; p<0.01), lower mortality (34% vs. 71%; p<0.01) and lower disability among survivors (17% vs. 50%; p=0.06). The authors concluded that, “A positive response to rescue iNO in preterm infants with acute pulmonary hypertension is associated with survival benefit, which is not offset by long-term disability.” Prospective study is warranted to confirm these findings.

Carey and colleagues (2018) performed a retrospective cohort study to determine whether iNO improves in-hospital survival for extremely premature neonates with RDS. Using 2004 to 2014 data from the Clinical Data Warehouse, the researchers analyzed 37,909 neonates born at 22 to 29 weeks who had RDS and required mechanical ventilation. The primary outcome was mortality (defined as death before discharge). The researchers matched 2 cohorts of 971 participants each: a cohort who received iNO during the first 7 days of life and a matched cohort who had not received iNO initially. A total of 348 and 325 participants died before discharge in the iNO group and matched group, respectively. The researchers did not find a significant association between iNO use and mortality (HR, 1.08; 95% CI, 0.94 to 1.25; p=0.29). They concluded:

Off-label prescription of iNO does not improve survival in extremely premature neonates with RDS. Neonates whose RDS is associated with PPHN have high rates of mortality and morbidity, neither of which is reduced by treatment with iNO in the first week of life. Among those without a concomitant diagnosis of PPHN, iNO therapy was associated with increased mortality.

The 2010 Agency for Healthcare Research and Quality (AHRQ) evidence report and subsequent guidance concluded that neither rescue nor routine iNO use improves survival in preterm infants with respiratory failure and that the evidence does not support iNO for preventing or ameliorating BPD, severe intraventricular hemorrhage (IVH), or other neonatal morbidities.

In 2020, Chandrasekharan and colleagues conducted a retrospective analysis of prospectively collected data to evaluate survival and neurodevelopmental impairment at 18 to 26 months in 1732 extremely low birth weight infants (less than 1000 g) born prior to 26 weeks with early hypoxemic respiratory failure. In total, 338 infants received iNO. Mortality among those treated with iNO was 54.1% compared with 44.4% mortality in infants not exposed; this difference was not statistically significant after adjusting for confounding variables. The authors concluded that in infants born prior to 26 weeks' gestation with hypoxemic respiratory failure, use of iNO did not significantly impact mortality or neurodevelopmental impairment at 18 to 26 months.

A 2023 systematic review and meta-analysis by Zheng and colleagues evaluated the efficacy and safety of iNO in preventing BPD and aiding in clinical decision-making. Included were data from 11 RCTs with 3651 preterm infants (≤ 34 weeks of gestation). After analysis of the studies, the iNO groups were associated with a lower incidence of BPD than the control groups (risk ratio [RR], 0.91; 95% CI, 0.85-0.97; p=0.006). There were no statistically significant differences in the incidence of in-hospital mortality between the iNO and control groups (RR, 1.02; 95% CI, 0.89-1.16; p=0.79). Secondary outcome measures included the incidence of IVH (Grade 3/4) or periventricular leukomalacia (PVL), pulmonary hemorrhage and necrotizing enterocolitis (NEC). Analysis revealed no significant difference in the incidence of IVH (Grade 3/4) or PVL between the iNO group and the control group (RR, 0.92; 95% CI, 0.77-1.09; p=0.34) or in pulmonary hemorrhage rate (RR, 0.83; 95% CI, 0.55-1.25; p=0.37). Analysis revealed a significant difference in NEC rate between the 2 groups (RR, 1.33; 95% CI, 1.04-1.71; p=0.03); however, those who were treated with an initial dose of 10 ppm iNO showed no significant difference in incidence of NEC while those who received an initial dose of 5 ppm iNO had greater rates of NEC. The analysis showed an initial dose of iNO of 10 ppm given to preterm infants ≤ 34 weeks of gestation appeared to be more effective at reducing BPD than conventional treatment and iNO given at an initial dose of 5 ppm had a comparable incidence of in-hospital mortality and adverse events compared to conventional treatment plus placebo. The authors concluded, “More research is required to improve the in-hospital mortality and safety of iNO in this setting.”

Boly (2023) reported the results of a retrospective analysis of 107 infants born 22 to 26 weeks of gestation who received iNO for hypoxic respiratory failure, defined as FiO₂ of ≥ 0.5 or OI ≥ 10. All participants received iNO for 12 hours or more. Response to iNO treatment was determined 2 hours after initiation of therapy by consensus of three neonatologists, all of whom were blinded to the clinical outcomes. Positive response was defined as a FiO₂ decrease of ≥0.2 or an OI decrease of ≥20%. Conversely, a negative response was defined as an FiO₂ increase of ≥ 0.2 or an OI increase of ≥ 20%. If these criteria were not met, then the case was determined to be a non-responder. A total of 67 participants were deemed to be responders, 27 non-responders and 13 negative responders. In logistic regression modeling, postnatal age (OR, 1.1; p=0.01), but not gestational age (OR, 0.9; 95% CI, 0.7-1.3), was associated with a positive response. No intergroup differences were reported, including markers of clinical illness severity, including respiratory severity score, OI, FiO₂, pH, receipt of cardiotropic support, and inotrope score immediately prior to iNO initiation. For the positive response group, 67% of participants had acute pulmonary hypertension, 9% had sepsis or systemic inflammatory response syndrome (SIRS), and 24% had lung disease (p<0.001). For the no response group, only 15% had acute pulmonary hypertension, 26% had a hemodynamically significant patent ductus arteriosus (PDA), 7% had sepsis or SIRS, and 52% had severe lung disease. For the negative response group, 33% had a hemodynamically significant PDA, 42% had sepsis or SIRS, and 25% had severe lung disease. The proportion of infants with pulmonary hypertension was highest among responders (p<0.001), while PDA was higher in both non-responder and negative responders (p=0.02), and lung parenchymal disease was higher (p=0.003) among non-responders. The primary outcome, a combined outcome of death or grade 3 BPD, was lower in the positive response group versus the no response and negative response groups (67% vs. 85% and 100%, respectively, p=0.01). No intergroup differences were reported with regard to the duration of invasive ventilation after iNO and the incidence of NEC, IVH, PVL, and age at discharge. The authors concluded that extremely premature infants have a positive response rate to iNO comparable to term infants when used for PH in the transitional period. Additionally, they noted that infants with a negative response to iNO had worse outcomes, necessitating the determination of the underlying physiology of hypoxemic neonatal respiratory failure prior to iNO initiation.

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

More recent research continues to explore specific niches. Baczynski and colleagues (2025), in a prospective observational cohort study of very preterm neonates receiving iNO for acute pulmonary hypertension, found that responsiveness to iNO (greater reduction in FiO₂) was associated with lower mortality for neonates with early acute pulmonary hypertension (diagnosed in the first 7 days). This suggests that for a subset of very preterm infants with early acute PH who respond to iNO, there may be benefit, though the prognostic role in late acute PH (diagnosed after 7 days) was less clear.

Conversely, a masked RCT by Mirza and colleagues (2025) evaluated iNO treatment for early pulmonary hypertension (diagnosed by echocardiogram within 72 ± 24 hours of life, in which preexisting hypoxic respiratory failure was not an exclusion criterion for randomization) in infants born ≤ 29 weeks' gestation. The trial was terminated early for futility by the Data Safety Monitoring Committee, as iNO treatment did not reduce the risk of the primary outcome of death or BPD at 36 weeks PMA. This finding reinforces the lack of benefit for iNO in extremely preterm infants with early echocardiographic evidence of pulmonary hypertension who do not have significant hypoxic respiratory failure.

Diagnostic and Therapeutic Applications in Pulmonary Hypertension and Cardiac Care

Inhaled nitric oxide has been studied for its role in assessing pulmonary vasoreactivity and managing complications in pulmonary hypertension (PH) and CHD. This section examines iNO’s applications in diagnostic testing, postoperative management, clinical guidelines, and areas requiring further research, based on available evidence.

Assessment of Pulmonary Vasoreactivity

AVT with inhaled nitric oxide (iNO) is an established component of invasive hemodynamic assessment in individuals with pulmonary hypertension and is performed during cardiac catheterization. AVT evaluates the responsiveness of the pulmonary vasculature to short-acting vasodilators and provides clinically actionable information to guide management, including identification of candidates for calcium channel blocker therapy, assessment of disease severity and prognosis, and determination of operability for interventions such as CHD repair or transplantation. Due to its rapid onset, short duration of action, and selective pulmonary vasodilatory effects, iNO is well suited for controlled, reversible testing in this setting.

Guideline recommendations support the use of AVT in both pediatric and adult populations, with important differences in individual selection. The AHA/ATS recommend that cardiac catheterization in children with suspected or confirmed pulmonary hypertension include vasoreactivity testing to guide management decisions (Abman, 2015). In contrast, the ESC/ERS restrict AVT in adults to a narrowly defined subgroup with idiopathic, heritable, or drug-associated pulmonary arterial hypertension who meet hemodynamic criteria for precapillary disease (mPAP > 20 mm Hg, pulmonary artery wedge pressure ≤ 15 mm Hg, and PVR > 2 Wood units) (Humbert, 2022). In this population, AVT is used to identify individuals who demonstrate acute pulmonary vasodilation, defined as a reduction in mPAP of at least 10 mm Hg to an absolute value of 40 mm Hg or less with preserved or increased cardiac output, as these individuals may benefit from calcium channel blocker therapy.

Clinical studies demonstrate that iNO produces rapid and selective pulmonary vasodilation and is effective in identifying vasoreactive individuals during catheterization. Comparative studies indicate that iNO provides reductions in PVR similar to or greater than oxygen alone, while combined administration of iNO and oxygen may identify a higher proportion of responders (Atz, 1999; Balzer, 2002; Barst, 2010). In addition, vasoreactivity assessed with iNO has been associated with improved survival and may support risk stratification in individuals with pulmonary hypertension (Krasuski, 2011).

The clinical utility of AVT varies by pulmonary hypertension etiology. In pulmonary arterial hypertension (World Health Organization [WHO] Group 1), AVT identifies a small subset of individuals with favorable hemodynamic responses and improved outcomes. However, in other forms of pulmonary hypertension, such as WHO Group 3 disease associated with lung disorders or hypoxia, vasoreactivity responses are less common and may not confer the same prognostic benefit. Limited evidence suggests that reductions in PVR during testing in these populations may reflect more advanced disease rather than therapeutic responsiveness, supporting guideline recommendations to restrict AVT to appropriate subgroups (Strick, 2025).

Based on nationally recognized guidelines, diagnostic assessment of iNO’s therapeutic effects is typically observed within 10 to 15 minutes of administration (DiBlasi, 2010; Mitra, 2023).

Pediatric Guidelines for iNO Use

The therapeutic efficacy of iNO varies based on the underlying pathophysiology, and this pattern extends to pediatric participants. The 2015 American Heart Association and American Thoracic Society guidelines for pediatric pulmonary hypertension provide specific recommendations for iNO use, particularly in acute settings and included various Class I recommendations (Abman, 2015).

The following recommendations related to iNO were graded as Class I:

• 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). It is additionally noted that AVT may be studied with iNO (20-80 ppm), 100% oxygen, inhaled or intravenous PGI₂ analogs, or intravenous adenosine or sildenafil.
• In addition to conventional postoperative care, iNO and/or inhaled PGI₂ should be used as the initial therapy for pulmonary hypertensive crises (PHCs) and right-sided heart failure (Class I; Level B).

Additional recommendations included in the guidelines related to iNO were:

• iNO can be beneficial for preterm infants with severe hypoxemia that is due primarily to PPHN physiology rather than parenchymal lung disease, particularly if associated with prolonged rupture of membranes and oligohydramnios (Class IIa; Level of Evidence B).
• iNO therapy can be used to improve oxygenation in infants with congenital diaphragmatic hernia (CDH) and severe PH but should be used cautiously in participants with suspected left ventricular dysfunction (Class IIa; Level of Evidence B).
• Treatment with iNO can be effective for infants with established bronchopulmonary dysplasia (BPD) and symptomatic PH (Class IIa; Level of Evidence C).

Class of recommendation estimates the magnitude of the treatment effect, considering risks versus benefits, and the evidence and agreement that a given treatment or procedure is useful or effective. Class I indicates clear benefit, Class II indicates less certainty or varying opinions, and Class III indicates potential harm. The Level of Evidence estimates the certainty or precision of the treatment effect:

• Level A: Data derived from multiple randomized controlled trials (RCTs) or meta-analyses.
• Level B: Data derived from a single RCT or nonrandomized studies.
• Level C: Primary source of recommendation is consensus opinion, case studies, or standard of care, often used when inadequate data are available.

The 2022 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 (Humbert, 2022) recommended “Inhaled nitric oxide, inhaled iloprost, or i.v. epoprostenol are recommended for performing vasoreactivity testing” (Class I, Level C). The guideline identifies iNO at 10 to 20 parts per million (ppm) for 5 to 10 minutes as the standard of care for vasoreactivity testing.

Postoperative Management of Congenital Heart Disease

Emerging evidence suggests the use of iNO for specific indications in the postoperative period for neonates and infants undergoing cardiac procedures, particularly for the prevention or treatment of PHCs and severe pulmonary hypertension.

Prophylactic and Rescue Therapy

Studies have evaluated iNO for preventing and treating PHCs and severe PH in neonates and infants post-CHD surgery. The primary evidence for prophylactic use comes from a foundational randomized, double-blind, placebo-controlled trial by Miller and colleagues (2000). This study investigated routine low-dose iNO (10 ppm) administered from the operating room until just before extubation in 124 infants at high risk (due to high pulmonary blood flow or pressure) undergoing corrective congenital heart surgery. The study found that iNO significantly reduced the median number of PHCs [(4 vs. 7; adjusted RR of about 0.65)] and shortened the time to meeting extubation criteria by approximately 32 hours (80 hours vs. 112 hours) without detectable adverse effects, concluding that routine prophylactic low-dose iNO after congenital heart surgery in high-risk infants lessens the risk of PHCs and shortens the postoperative course (Miller, 2000).

For established postoperative PH, Journois and colleagues (1994), in a prospective case series of 17 infants with critical pulmonary artery hypertension after CHD operations where conventional therapy had failed, showed that 20 ppm of iNO led to a significant decrease in mPAP and an increase in arterial oxygen saturation. Fifteen of the 17 children were discharged from the intensive care unit (ICU), suggesting therapeutic potential. Similarly, Russell and colleagues (1998) conducted a prospective, randomized, double-blind, placebo-controlled study in 40 pediatric participants with preoperative pulmonary hypertension (PH). The key analysis focused on the subgroup of 13 individuals who emerged from CPB with PH (defined as mPAP > 50% of mean systemic arterial pressure [MSAP]). In these specific individuals, iNO (80 ppm, a dose also sometimes considered for rescue therapy) significantly reduced mPAP by 19% over 20 minutes compared to a 9% rise with placebo, with no systemic hemodynamic compromise; iNO had no effect in individuals who left bypass without PH. This study by Russell and colleagues (1998) therefore supports the utility of iNO as an effective therapeutic, or rescue, option for immediate post-bypass PH rather than routine prophylaxis.

iNO Delivery via Cardiopulmonary Bypass (CPB)

Alternative delivery methods, such as administration into the CPB circuit, have been investigated. The administration of iNO during CPB has also shown promise for improving outcomes. James and colleagues (2016), in an RCT of 198 children, found that administering 20 ppm of nitric oxide into the CPB oxygenator significantly reduced the incidence of low cardiac output syndrome, particularly in younger infants and those undergoing more complex surgeries, and also lowered the need for ECMO. Kolcz and colleagues (2022), in a prospective randomized study of 97 participants undergoing Fontan surgery, reported that iNO administered into the oxygenator during CPB led to shorter respiratory support time, shorter intensive care unit (ICU) stays, lower post-CPB pulmonary artery pressure, and improved metabolic markers, suggesting cardioprotective and anti-inflammatory effects.

Real-World Data on Perioperative iNO Use and Safety

Large-scale observational studies have provided real-world data on perioperative iNO use. A large, prospective, post-marketing study in Japan by Matsugi and colleagues (2024) involving 2817 participants undergoing cardiac surgery included a substantial pediatric cohort (n=1375, defined by the authors as participants aged <15 years). The study provided detailed age categorizations within this group, notably identifying 295 'Neonates (≤ 28 days after birth)' and an additional 670 participants in their 'Neonate to < 1 year' group. These 2 youngest groups collectively represent a significant cohort of 965 participants under 1 year of age, offering extensive real-world data on this demographic. The study found that perioperative iNO was generally well tolerated and associated with significant improvements in hemodynamics (such as central venous pressure in pediatrics) and oxygenation (e.g., PaO₂/FiO₂ ratio) in this young population. Further supporting real-world observations, Gaudard and colleagues (2018), in a prospective multicenter observational study of 236 participants in France and Belgium using a new integrated iNO delivery system, specifically included 38 neonates treated for PPHN and 81 children (median age 0.2 years) treated for PH after cardiac surgery, alongside 117 adults. They reported generally low rates of iNO-related adverse events, with rebound hypertension observed in 2.6% of neonates and 1.2% of children. While methemoglobinemia >2.5% was noted in 12% of monitored neonates (3 of 25), it was not seen in the monitored children. This study highlighted the safety profile of iNO administered with modern delivery systems in these distinct pediatric and neonatal populations according to then-current practices. This body of evidence supports the selective use of iNO in the postoperative setting for neonates and infants undergoing CHD surgery, specifically for prophylactic administration in high-risk individuals to prevent PHCs and as bridge therapy for severe pulmonary hypertension when clinical instability due to confirmed pulmonary hypertension occurs, provided there is preserved left ventricular function in both settings.

In contrast, a large retrospective database study by Wong and colleagues (2019) from the Pediatric Health Information System (PHIS, 2004-2015) explored outcomes associated with postoperative iNO in pediatric cardiac surgery admissions. The study analyzed over 40,000 admissions without pre-existing pulmonary hypertension, where 1.8% received iNO, and nearly 1700 admissions with pulmonary hypertension, where 11.6% received iNO. In participants without pulmonary hypertension, regression analyses demonstrated that iNO administration was independently associated with increased length of stay (by 10.2 days) and increased inpatient mortality (OR 2.45). For participants with pulmonary hypertension, iNO was associated with a significant increase in length of stay (by 3.4 days) but no statistically significant decrease in mortality. The authors concluded that postoperative iNO was associated with increased length of stay without improved inpatient mortality, and in those without pre-existing pulmonary hypertension, it was linked to increased mortality. This study highlighted concerns about routine iNO use in unselected populations, while acknowledging limitations inherent to administrative database analyses.

Postoperative Inhaled Nitric Oxide in Congenital Heart Disease

Early systematic reviews reported uncertainties regarding the benefits of routine postoperative iNO. For example, a 2014 Cochrane review by Bizzarro and colleagues identified 4 RCTs comparing postoperative iNO versus placebo or conventional management in 210 infants and children with CHD and pulmonary hypertension. The primary outcomes were mortality prior to discharge and long-term mortality. Pooled analysis showed no statistically significant differences in mortality prior to discharge (OR, 1.67, p=0.50), changes in mean pulmonary arterial pressure (mPAP; p=0.36), mean arterial pressure (MAP; p=0.40), or heart rate (HR; p=1.00). Pulmonary hypertensive crises (PHCs; p=0.79) and changes in the PaO₂:FiO₂ ratio (p=0.46) were reported in only 1 trial (Day, 2000). Day and colleagues defined severe pulmonary hypertension as systolic pulmonary artery pressure equal to or exceeding 50% of systolic systemic arterial pressure immediately on separation from bypass. The largest trial (Miller, 2000, n=124), deemed of high methodological quality, investigated PHC and mortality but could not be fully included in the meta-analysis due to skewed data presentation and unsuccessful attempts to obtain usable data. No data were available on long-term mortality, length of intensive care unit/hospital stay, or neurodevelopmental disability. Two trials had low risk of bias, but the evidence was rated very low quality due to small sample sizes, low event rates, and heterogeneity in iNO dosing, duration, and individual characteristics, though heterogeneity was not significant for most outcomes (e.g., I²=0% for MAP, HR). A significant increase in methemoglobin levels was observed in the iNO group (p<0.00001), but levels remained below toxicity thresholds. The authors concluded that valid conclusions were difficult due to methodological concerns, small sample sizes, and heterogeneity, stating the evidence “neither establishes benefit nor definitively rules it out,” and called for adequately powered RCTs with standardized protocols.

Not all systematic reviews reached the same conclusions. In 2020, a systematic review by Villarreal and colleagues determined the effect of iNO on hemodynamics, gas exchange, and hospitalization characteristics in children immediately following CPB surgery. A total of eight studies met inclusion criteria (six crossover studies and two RCTs; only one study [James, 2016] was not included in the Cochrane review above). As noted above, most of the studies had low enrollment, methodologic flaws and heterogeneous outcomes. Contrary to the Cochrane review, Villarreal and colleagues concluded that administration of iNO in children immediately after CPB decreased mPAP (p<0.01) and decreased the arterial carbon dioxide concentration (p<0.01) without significantly altering other hemodynamic parameters. The study reported a statistically shorter duration of mechanical ventilation and intensive care unit length of stay. Further study is warranted given the inconsistent conclusions upon systematic review.

iNO in CPB: Findings from Randomized Trial

Large-scale trials have also yielded results that do not consistently support certain iNO applications. In 2022, a double-blind RCT was published by Schlapbach and colleagues that enrolled 1371 children (< 2 years of age) undergoing congenital heart surgery. The study’s main objective was to determine the effect of nitric oxide (at 20 ppm) administered directly into the CPB oxygenator (n=679) compared to standard care CPB without nitric oxide (n=685); the primary end point was the number of ventilator-free days from the initiation of bypass until day 28 of follow-up. Secondary end points included a composite of low cardiac output syndrome, extracorporeal life support, or death; length of stay in the intensive care unit; length of stay in the hospital; and postoperative troponin levels. At study end, the primary outcome, number of ventilator-free days, did not differ significantly between the nitric oxide and standard care group (p=0.92). The study authors concluded that, in “children younger than two years undergoing CPB surgery for CHD, the use of nitric oxide via CPB did not significantly affect the number of ventilator-free days. These findings do not support the use of nitric oxide delivered into the CPB oxygenator during heart surgery.”

Prophylactic Inhaled Nitric Oxide in Adult Left Ventricular Assist Device Implantation

Potapov and colleagues (2011) conducted a study to evaluate the prophylactic use of iNO in adults undergoing left ventricular assist device (LVAD) implantation for congestive heart failure. A double-blind trial was conducted between 2003 and 2008 at 8 centers in the United States and Germany. Individuals were randomized to receive iNO (40 ppm) (n=73) or placebo (n=77) beginning at least 5 minutes before the first weaning attempt from mechanical ventilation. The primary study outcome was RVD. Continued use of iNO or placebo occurred until the study participants were extubated, reached the study criteria for RVD, or were treated for 48 hours, whichever occurred first. Individuals were permitted to cross over to open-label iNO if they failed to wean from mechanical ventilation, still required pulmonary vasodilator support at 48 hours, or met criteria for RVD. Thirteen of 150 randomized participants (9%) did not receive the study treatment. In addition, crossover to open-label iNO occurred in 15 of 73 participants (21%) in the iNO group and 20 of 77 (26%) in the placebo group. In an intention-to-treat (ITT) analysis, the RVD criteria were met by 7 of 73 (9.6%) participants in the iNO group and 12 of 77 (15.6%) participants in the placebo group. This difference was not statistically significant (p=0.33). Other outcomes also did not differ significantly between groups. For example, the mean number of days on mechanical ventilation was 5.4 in the iNO group and 11.1 in the placebo group (p=0.77), and the mean number of days in the hospital was 41 in each group.

Inhaled Nitric Oxide Therapy in Specific Congenital Conditions: Total Anomalous Pulmonary Venous Connection

Gujja (2023) published the results of an RCT involving 80 participants with total anomalous pulmonary venous connection (TAPVC) undergoing corrective surgery and treated postoperatively with either milrinone alone after removal of the aortic cross-clamp (n=40) or milrinone after cross-clamp removal plus iNO in the ICU (n=40). At 24 hours and 48 hours post-procedure, a significant reduction in pulmonary artery pressure (p=0.004 and p<0.0001, respectively) and significant improvement in systemic arterial pressure (MAP) (p=0.0081 and p<0.00004, respectively) were reported in the iNO group. With the exception of reintubations (n=4 in the milrinone group vs. n=1 in the iNO group; p=0.0478), no significant differences between groups were reported with regard to adverse events. The authors noted several limitations to their study, including limitations in measuring PVR, cardiac output, and pulmonary artery pressures to monitor the effectiveness of iNO therapy.

Other Potential Uses

Sokol and colleagues (2003), in a review of the published literature for the use of iNO in children and adults with respiratory distress, evaluated 5 RCTs including 535 children and adults with AHRF, and concluded iNO did not demonstrate any statistically significant effect on mortality and transiently improved oxygenation. Lack of data prevented assessment of other clinically relevant end points.

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

In a systematic review and meta-analysis, Adhikari and colleagues (2014) investigated whether iNO reduces hospital mortality in individuals with severe ARDS (PaO₂/FiO₂ ≤ 100 mm Hg) as compared to those with mild-moderate ARDS (100 < PaO₂/FiO₂ ≤ 300 mm Hg). Parallel-group RCTs comparing nitric oxide with control (placebo or no gas) in mechanically ventilated adults or post-neonatal children with ARDS were independently selected. Nine trials (n=1142 participants) met inclusion criteria. Nitric oxide was not observed to reduce mortality in individuals with severe ARDS (RR, 1.01; 95% CI, 0.78 to 1.32; p=0.93; n=329, 6 trials) or mild-moderate ARDS (RR, 1.12; 95% CI, 0.89 to 1.42; p=0.33; n=740, 7 trials). The authors concluded there was no beneficial effect of nitric oxide on mortality among individuals with ARDS, regardless of the severity of hypoxemia at randomization. They further noted that given the lack of related ongoing or recently completed randomized trials, new data addressing the effectiveness of nitric oxide in those with ARDS and severe hypoxemia will not be available for the foreseeable future.

A prospective, randomized placebo-controlled trial (Bronicki, 2015) assessed the use of iNO for improved oxygenation and decreased duration of mechanical ventilation in children with ARDS. A total of 55 children from 9 centers were randomized to either placebo or iNO. Treatment continued until death, removal of ventilator support, or 28 days after the start of therapy. The primary study outcome was ventilator-free days 28 days after randomization. A trend toward an improved OI in the iNO group compared with the placebo group at 4 hours became significant at 12 hours. There was no difference in the OI between groups at 24 hours. Days alive and ventilator-free at 28 days was increased in the iNO group, 14.2 ± 8.1 and 9.1 ± 9.5 days (iNO and placebo groups, respectively, p=0.05). Overall survival at 28 days did not reach statistical significance, 92% (22 of 24) in the iNO group and 72% (21 of 29) in the placebo group (p=0.07). However, the rate of ECMO-free survival was significantly greater in those randomized to iNO, 92% (22 of 24) vs. 52% (15 of 29) for those receiving placebo (p<0.01). A significant study limitation was the limited number of participants enrolled. The authors concluded that a prospective RCT with more robust enrollment is indicated.

Additionally, there is insufficient evidence to support the use of iNO for the prevention of ischemia-reperfusion injury/acute rejection following lung transplantation, the treatment of acute lung injury, mechanically ventilated adults with COVID-19, or vaso-occlusive crises in those with sickle cell disease (Aboursheid, 2022; Dellinger, 1998; Lubinsky, 2022; Lundin, 1999; Reiter Meade, 2003; Taylor, 2004; Weiner, 2003).

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

Tal and colleagues (2018) conducted a double-blind RCT to assess the safety, tolerability, and efficacy of iNO for infants with moderately severe bronchiolitis. A total of 43 participants, aged 2 to 11 months, were randomized to either receive iNO (n=21) or a placebo (n=22). The mean clinical score, which included respiratory rate, use of accessory muscles, wheezes/crackles, and percentage of room-air oxygen saturation, was 7.86 (± 1.1) for the iNO group and 8.09 (± 1.2) for the placebo group. Adverse events were reported for 47.6% of the iNO group and 59.1% for the placebo group, and each group had 4 participants who experienced serious adverse events. There were no deaths or bleeding events. In terms of tolerability, 2 participants in the iNO group discontinued treatment compared with 2 participants in the placebo group. The authors concluded that the results are encouraging, but large-scale trials are needed to further assess the safety and benefits.

Goldbart (2023) reported the results of another double-blind RCT involving 89 infants with bronchiolitis receiving 150 ppm NO plus supporting treatment (n=28), 85 ppm NO plus supporting treatment (n=32), or oxygen or air plus supporting treatment (n=29). Treatment was applied for 40 minutes, 4 times a day for up to 5 days. The primary end point was a composite measure, referred to as “fit for discharge”, which included time to 1) sustained oxygen saturation ≥ 92% on room air and 2) reaching a clinical modified Tal (mTal) score < 5. The mTal score is itself a composite measure composed of four measurements: respiratory rate, lung sound, room-air SpO₂, and use of accessory muscles. A significant difference between groups in favor of the 150 ppm group was found vs. both the 85 ppm and control groups (HR, 2.11; p=0.041 and HR, 2.32; p=0.0486, respectively). No significant differences were reported between the 85 ppm and control groups (p=0.76). Time to sustained room-air SpO₂ > 92% was significantly better in the 150 ppm group compared to the control group (HR, 2.62; p=0.039), but not compared to the 85 ppm group (p=0.56). Time to hospital discharge was significantly better in the 150 ppm group compared to both the 85-ppm and the control groups (HR, 2.01; p=0.046 and HR, 2.28; p=0.043, respectively). No significant differences between groups were reported in regard to adverse events. The author noted several limitations to this study, including no acceptable definitive outcomes defined in the literature regarding acute viral bronchiolitis, viral load not expected to change significantly within 3 days of treatment, and lung function tests being difficult to perform in this age group. They also noted that the sample size is of concern, as no power calculations were conducted. They concluded:

The goal of this study was to obtain information about the trend of the therapeutic dose-response to 85 and 150 ppm NO compared with standard treatment empirically, and it was not powered to demonstrate statistical significance but rather to evaluate the dose-response relationship in the efficacy end points.

Di Fenza (2023) studied 200 adults with acute ventilation-dependent hypoxemic respiratory failure related to COVID-19 infection in an RCT comparing iNO to standard care (n=100 per group). Participants in the iNO arm received 80 ppm for the first 42 hours following enrollment. The median duration of iNO therapy of > 20 ppm was 10.8 days. The final analysis included 99 iNO group participants and 94 control group participants. The primary outcome was change in arterial oxygenation (PaO₂/FiO₂) at 48 hours. The mean change in PaO₂/FiO₂ at 48 hours in the iNO group was 28.3 mm Hg and -1.4 mm Hg in the usual care arm (no p value was provided). iNO group participants had a 71.9% and 71.4% probability of having a lower risk of death at 28 days and 90 days, respectively, compared to control group participants (RR for 28-day mortality, 0.85 and 90-day mortality, 0.87). No serious adverse events related to iNO therapy were reported. The authors concluded that iNO therapy improved PaO₂/FiO₂ in critically ill individuals with ventilation-dependent COVID-19 infections, but did not alter mortality or duration of ventilation. The authors noted that the study was not powered to test whether iNO therapy reduces mortality, but indicated the need for further study. Further, treating providers were not blinded and no placebo was used in the control group, leaving open a potential source of bias in the results.

Freidkin (2024) reported on an RCT evaluating the acute effect of iNO on the exercise capacity of individuals with advanced interstitial lung disease. A total of 44 participants were treated with either iNO or placebo prior to a 6-Minute Walk Test (6-MWT). The authors reported no significant differences between groups with regard to 6-MWT distance (p=0.29). The authors concluded that the use of iNO was safe but did not provide any benefits with regard to 6-MWT outcomes.

Beyond respiratory failure and perioperative settings, the potential role of iNO in the acute management of right heart failure due to pulmonary hypertension has also been explored. Ogo (2026) conducted the PHiNO study, a Phase 2, investigator-initiated, randomized, open-label, parallel-group trial of 30 adults with acute severe right heart failure (World Health Organization [WHO] functional class III or higher with fluid retention and low cardiac output) due to pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. Participants were randomized 1:1 to receive iNO (initiated at 20 ppm and titrated up to 40 ppm) or no iNO (control) for a 7-day treatment period. For the primary end point, iNO significantly reduced PVR within 30 minutes of initiation compared with the control group (mean change, −2.41 ± 2.47 vs. +0.80 ± 1.03 Wood units; between-group difference, −3.21 Wood units; 95% CI, −4.633 to −1.785). As secondary end points, serum B-type natriuretic peptide (BNP) levels and inferior vena cava diameter decreased significantly in the iNO group over the 7-day study period, suggesting a reduction in right ventricular overload and congestion. No serious adverse events were observed, and methemoglobin levels remained within safe limits throughout the study. The authors concluded that iNO is a promising rapid-acting, selective pulmonary vasodilator for the acute treatment of right heart failure due to pulmonary hypertension and may serve as a safe bridge to longer-acting approved pulmonary hypertension therapies. Limitations included the small sample size, open-label design, single-center setting, and the short follow-up period, which restricted assessment of sustained efficacy and long-term outcomes.

Acute respiratory distress syndrome (ARDS) beyond the neonatal period: A life-threatening condition in which widespread inflammation damages the barrier between the blood vessels and the air sacs (alveoli) in the lungs. This damage allows fluid and inflammatory cells to leak into the air sacs, making the lungs stiff and severely impairing the ability of oxygen to reach the bloodstream. ARDS can affect both adults and children and is most commonly triggered by pneumonia, sepsis, aspiration of stomach contents, major trauma, or pancreatitis. Diagnosis is based on the acute onset of low blood oxygen levels, bilateral lung opacities on chest imaging, and the exclusion of heart failure as the primary cause.

Acute respiratory distress syndrome (ARDS) in the neonatal period: A life-threatening inflammatory lung condition in newborns that occurs when infection, aspiration, or other triggers cause inflammatory damage to the developing lung tissue, leading to surfactant dysfunction, fluid leakage into the air sacs (alveoli), and impaired oxygen exchange. It can affect newborns of any gestational age. Neonatal ARDS is distinct from neonatal respiratory distress syndrome (RDS), which is caused by a primary deficiency of surfactant due to lung immaturity in preterm infants. Diagnosis is based on the 2017 Montreux definition, which requires acute onset, diffuse lung opacities on chest imaging, a known trigger, and exclusion of neonatal RDS due to surfactant deficiency alone.

Acute respiratory failure beyond the neonatal period: Acute respiratory failure in children and adults is defined as a condition characterized by an abrupt loss in lung function resulting in inadequate gas exchange, with an acute fall in PaO₂ below 60 mm Hg (hypoxia) or PaCO₂ >45-50 mm Hg (hypercapnia), or both.

• Type 1 (hypoxemic) respiratory failure presents with PaO₂ <60 mm Hg (or SaO₂ <88-90%) with normal or low PaCO₂, resulting from ventilation-perfusion mismatch, intrapulmonary shunting, diffusion impairment, hypoventilation, or low inspired oxygen tension.
• Type 2 (hypercapnic) respiratory failure is defined by PaCO₂ ≥45 mm Hg and pH <7.35, resulting from alveolar hypoventilation, increased dead space fraction, or increased CO₂ production.

Acute respiratory failure in the neonatal period: Neonatal acute respiratory failure is characterized by the body's inability to maintain adequate tissue oxygenation or effective carbon dioxide elimination, or both, arising from an imbalance between respiratory workload and ventilatory function. It is generally identified by 2 or more of the following criteria: PaCO₂ >60 mm Hg, PaO₂ <50 mm Hg, oxygen saturation <80% with FiO₂ of 1.0, and pH <7.25. This condition results from pulmonary, cardiovascular, or metabolic abnormalities and is marked by extensive lung inflammation and damage to the alveolar epithelium and vascular endothelium. Common pulmonary causes in term and near-term neonates include meconium aspiration syndrome, congenital pneumonia, respiratory distress syndrome, persistent pulmonary hypertension of the newborn (PPHN), pulmonary hypoplasia, and congenital diaphragmatic hernia (CDH). Severity is often assessed using the Oxygenation Index (OI), calculated as (MAP × FiO₂ × 100)/PaO₂, with cutoffs of OI ≤15 for mild, 16-25 for moderate, 26-40 for severe, and >40 for very severe respiratory failure.

Chronological age (also called postnatal age): The elapsed time since birth. This is distinct from other age measurements used in neonatal care. Chronological age is insufficient on its own for clinical decision-making in neonates, particularly for preterm infants, because it does not account for developmental maturity. For this reason, corrected age is used alongside chronological age in neonatology care.

Congenital diaphragmatic hernia (CDH): Occurs when the diaphragm, the muscle that separates the chest from the abdomen, fails to close during prenatal development. This opening allows contents of the abdomen (stomach, intestines and/or liver) to migrate into the chest, impacting the growth and development of the lungs.

Congenital heart disease: A problem with the structure of the heart that is present at birth. Congenital heart defects are the most common type of birth defect. The defects can involve the walls of the heart, the valves of the heart, and the arteries and veins near the heart. Some of the most common defects include ventricular/atrial septal defects, tetralogy of Fallot, patent ductus arteriosus (PDA), and valve stenosis.

Corrected age, otherwise known as gestationally corrected age (GCA), is based on the age the child would be if the pregnancy had actually gone to term. Generally, after a corrected postnatal age of 24 months, no further correction will be made.

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

Gestational age: A term used during pregnancy to describe how far along the pregnancy is. It is measured in weeks, from the first day of the mother’s last menstrual cycle to the current date. The average healthy pregnancy ranges from 38 to 42 weeks.

Hypoxic respiratory failure: An oxygenation index (OI) of at least 25 recorded on 2 measurements made at least 15 minutes apart. The OI is calculated as (mean airway pressure in centimeters [cm] of water × fraction of inspired oxygen [FiO₂] × 100) / partial pressure of arterial oxygen. An OI of 25 is associated with a 50% risk of requiring ECMO or dying. An OI of 40 is often used as a criterion to initiate ECMO therapy.

Infant: A child from birth up to 1 year (12 months) of age.

Neonatal period: The first 28 days of life (birth through day 27) for term infants. For preterm infants, it extends to 44 weeks of postconceptional age (gestational age plus chronological age). This period represents a time of exceptionally high mortality risk, with approximately 38% of all under-5 deaths occurring during these first 28 days, and three-quarters of neonatal deaths happening in the first week of life.

Persistent pulmonary hypertension of the newborn (PPHN): A clinical syndrome characterized by failure of the pulmonary circulation to achieve or sustain the normal drop in pulmonary vascular resistance (PVR) at birth, resulting in increased PVR, right-to-left shunting, and severe hypoxemia in the absence of structural congenital heart disease (CHD). Clinical diagnosis is considered when hypoxemia is refractory to oxygen therapy or lung recruitment strategies (PaO₂ <55 mm Hg despite FiO₂ of 1.0) associated with a preductal to postductal oxygen gradient >20 mm Hg. Echocardiographic diagnosis is made by demonstrating extrapulmonary right-to-left shunting at the ductal or atrial level, near or supra-systemic pulmonary arterial pressures, and Doppler evidence of tricuspid regurgitation in the absence of severe pulmonary parenchymal disease. PPHN is confirmed by the presence of a right-to-left shunt through the ductus arteriosus or foramen ovale, or both, without accompanying heart disease, irrespective of pulmonary artery pressure. During cardiac catheterization, pulmonary hypertension is defined as pulmonary arterial pressure >25-30 mm Hg.

Pulmonary hypertension (PH): For individuals older than a corrected age of 3 months, PH is defined as a hemodynamic state in which mean pulmonary arterial pressure (mPAP) at rest exceeds 20 mm Hg. It is designated as precapillary PH when PVR is >2 Wood units and pulmonary arterial wedge pressure is ≤15 mm Hg. Symptoms typically manifest when systolic pulmonary artery pressure rises above roughly one-quarter of systemic systolic pressure. On echocardiography, a peak tricuspid regurgitation velocity > 2.8 m/s together with characteristic right heart or pulmonary artery structural changes strongly suggests the diagnosis and should prompt confirmation. Confirmation for adults and older children is best done by direct measurement during right heart catheterization. Because PVR is physiologically high until after the perinatal transition, right heart catheterization is used sparingly in neonates. PPHN can be diagnosed when there is echocardiographic evidence of systemic or suprasystemic pulmonary pressures (for example, tricuspid regurgitation > 2.8-3 m s⁻¹, right-to-left shunting, septal flattening) rather than a fixed numerical mPAP threshold.

Pulmonary hypertensive crisis (PHC) is defined as a sudden and potentially lethal increase in pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) that causes acute right-sided heart failure accompanied by systemic hypotension, myocardial ischemia, and at times bronchoconstriction. The hemodynamic diagnostic criteria for a major PHC include:

• Sudden increase in the ratio of PAP to systemic artery pressure >0.75
• Increase in central venous pressure >20%
• Decrease in systemic blood pressure >20%
• Decrease in systemic oxygen saturation <90%
• Signs of low cardiac output

The diagnosis of postoperative PHC is based on a sudden increase in PAP, followed sequentially by increased right atrial and right ventricular end-diastolic pressures, decreased systemic and mixed venous oxygen saturations, decreased systemic pressure, and decreased cardiac output. Bronchoconstriction or increased airway resistance may accompany these hemodynamic changes.

Pulmonary vascular resistance (PVR): A hemodynamic parameter that represents the resistive afterload on the right ventricle from the pulmonary circulation, calculated as the ratio of the transpulmonary pressure gradient to pulmonary blood flow.

• PVR is calculated using the formula: PVR = (mPAP − PAWP) / CO, where mPAP is mean pulmonary artery pressure, PAWP is pulmonary arterial wedge pressure, and CO is cardiac output. The result is expressed in Wood units (WU), where 1 WU = 80 dynes·s·cm⁻⁵. For individuals with intracardiac shunts, pulmonary blood flow (Qp) rather than systemic blood flow (Qs) must be used in the calculation to avoid overestimation in left-to-right shunts or underestimation in right-to-left shunts.
• In adults, the normal range for PVR is 0.3-2.0 WU. However, the upper limit of normal varies by age: 0.76 ± 0.3 WU for age <24 years, 0.86 ± 0.4 WU for 24-50 years, 1.1 ± 0.2 WU for 51-69 years, and 1.1 ± 0.5 WU for ≥70 years. A PVR >2.0 WU is considered abnormal and, when combined with elevated mean pulmonary artery pressure (mPAP), defines precapillary pulmonary hypertension. PVR <1.5 WU (120 dynes·s·cm⁻⁵) is considered normal by echocardiographic assessment.
• In children, PVR is traditionally indexed to body surface area as pulmonary vascular resistance index (PVRI), with a normal range of ≤3 WU·m². The criterion of PVRI ≥3 WU·m² is used in the definition of pulmonary arterial hypertension in children. Indexing is emphasized in children because blood flows change proportionally with body size while the transpulmonary pressure gradient does not. PVR is determined during right heart catheterization, which is the gold standard for hemodynamic assessment. It can also be estimated noninvasively by echocardiography using the Abbas equation: PVR (WU) = peak tricuspid regurgitation velocity/right ventricular outflow tract velocity time integral.

Ventilation-perfusion (V/Q) mismatch: An imbalance between alveolar ventilation and pulmonary capillary perfusion within lung units, resulting in inefficient gas exchange across the alveoli and capillaries.

Peer-Reviewed Publications:

1. Adhikari NK, Dellinger RP, Lundin S, et al. Inhaled nitric oxide does not reduce mortality in patients with acute respiratory distress syndrome regardless of severity: systematic review and meta-analysis. Crit Care Med. 2014; 42(2):404-412.
2. Ahmed MS, Giesinger RE, Ibrahim M, et al. Clinical and echocardiography predictors of response to inhaled nitric oxide in hypoxic preterm neonates. J Paediatr Child Health. 2019; 55(7):753-761.
3. Askie LM, Ballard RA, Cutter GR, et al. Meta-analysis of preterm patients on inhaled nitric oxide collaboration. Inhaled nitric oxide in preterm infants: an individual-patient data meta-analysis of randomized trials. Pediatrics. 2011; 128(4):729-739.
4. Atz AM, Adatia I, Lock JE, Wessel DL. Combined effects of nitric oxide and oxygen during acute pulmonary vasodilator testing. J Am Coll Cardiol. 1999; 33(3):813-819.
5. Baczynski M, Ginty S, Weisz DE, et al. Short-term and long-term outcomes of preterm neonates with acute severe pulmonary hypertension following rescue treatment with inhaled nitric oxide. Arch Dis Child Fetal Neonatal Ed. 2017; 102(6):F508-F514.
6. Baczynski M, Weisz D, Thomas L, et al. Response to inhaled nitric oxide and mortality among very preterm neonates with pulmonary hypertension. JAMA Netw Open. 2025; 8(2):e2458843.
7. Ballard RA, Truog WE, Cnaan A, et al.; NO CLD Study Group. Inhaled nitric oxide in preterm infants undergoing mechanical ventilation. N Engl J Med. 2006; 355(4):343-353.
8. 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.
9. 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.
10. Boly TJ, Dagle JM, Klein JM, et al. Response categorization and outcomes in extremely premature infants born at 22-26 weeks gestation that received inhaled nitric oxide for hypoxic respiratory failure. J Perinatol. 2023; 43(3):324-331.
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. 2015; 166(2):365-369.
12. Campbell BT, Herbst KW, Briden KE, et al. Inhaled nitric oxide use in neonates with congenital diaphragmatic hernia. Pediatrics. 2014; 134(2):e420-e426.
13. Carey WA, Weaver AL, Mara KC, Clark RH. Inhaled nitric oxide in extremely premature neonates with respiratory distress syndrome. Pediatrics. 2018; 141(3):e20173108.
14. Chandrasekharan P, Lakshminrusimha S, Chowdhury D, et al. Early hypoxic respiratory failure in extreme prematurity: mortality and neurodevelopmental outcomes. Pediatrics. 2020; 146(4):e20193318.
15. Chandrasekharan PK, Rawat M, Madappa R, et al. Congenital diaphragmatic hernia - a review. Matern Health Neonatol Perinatol. 2017; 3:6.
16. Clark RH, Kueser TJ, Walker MW, et al. Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. Clinical Inhaled Nitric Oxide Research Group. N Engl J Med. 2000; 342(7):469-474.
17. Day RW, Hawkins JA, McGough EC, et al. Randomized controlled study of inhaled nitric oxide after operation for congenital heart disease. Ann Thorac Surg. 2000; 69(6):1907-1913.
18. Dellinger RP, Zimmerman JL, Taylor RW, et al. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Crit Care Med. 1998; 26(1):15-23.
19. Di Fenza R, Shetty NS, Gianni S, et al.; Nitric Oxide Investigators. High-dose inhaled nitric oxide in acute hypoxemic respiratory failure due to COVID-19: a multicenter phase II trial. Am J Respir Crit Care Med. 2023; 208(12):1293-1304.
20. Di Fiore JM, Hibbs AM, Zadell AE, et al. The effect of inhaled nitric oxide on pulmonary function in preterm infants. J Perinatol. 2007; 27(12):766-771.
21. Durrmeyer X, Hummler H, Sanchez-Luna M, et al.; European Union Nitric Oxide Study Group. Two-year outcomes of a randomized controlled trial of inhaled nitric oxide in premature infants. Pediatrics. 2013; 132(3):e695-e703.
22. Field D, Elbourne D, Truesdale A, et al. Neonatal ventilation with inhaled nitric oxide versus ventilatory support without inhaled nitric oxide for preterm infants with severe respiratory failure: the INNOVO multicentre randomised controlled trial (ISRCTN 17821339). Pediatrics. 2005; 115(4):926-936.
23. Freidkin L, Kramer MR, Rosengarten D, et al. The acute effect of inhaled nitric oxide on the exercise capacity of patients with advanced interstitial lung disease: a randomized controlled trial. BMC Pulm Med. 2024; 24(1):226.
24. Gaudard P, Barbanti C, Rozec B, et al. New modalities for the administration of inhaled nitric oxide in intensive care units after cardiac surgery or for neonatal indications: a prospective observational study. Anesth Analg. 2018; 126(4):1234-1240.
25. Gien J, Kinsella JP. Management of pulmonary hypertension in infants with congenital diaphragmatic hernia. J Perinatol. 2016; 36 Suppl 2:S28-S31.
26. Goldbart A, Lavie M, Lubetzky R, et al. Inhaled nitric oxide for the treatment of acute bronchiolitis: a multicenter randomized controlled clinical trial to evaluate dose response. Ann Am Thorac Soc. 2023; 20(2):236-244.
27. Gujja S, Prajapati M, Chuada TR, et al. Outcome of obstructed total anomalous pulmonary venous connection (TAPVC) repair patients with milrinone versus milrinone and inhaled nitric oxide (INO): a prospective randomized observational study. Ann Card Anaesth. 2023; 26(2):177-182.
28. Hamon I, Fresson J, Nicolas MB, et al. Early inhaled nitric oxide improves oxidative balance in very preterm infants. Pediatr Res. 2005; 57(5 Pt 1):637-643.
29. 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):1081-1089.
30. Hintz SR, Van Meurs KP, Perritt R, et al. Neurodevelopmental outcomes of premature infants with severe respiratory failure enrolled in a randomized controlled trial of inhaled nitric oxide. J Pediatr. 2007; 151(1):16-22, 22.e1-e3.
31. Huddy CL, Bennett CC, Hardy P, et al.; INNOVO Trial Collaborating Group. The INNOVO multicentre randomized controlled trial: neonatal ventilation with inhaled nitric oxide versus ventilatory support without nitric oxide for severe respiratory failure in preterm infants: follow up at 4-5 years. Arch Dis Child Fetal Neonatal Ed. 2008; 93(6):F430-F435.
32. James C, Millar J, Horton S, et al. Nitric oxide administration during paediatric cardiopulmonary bypass: a randomised controlled trial. Intensive Care Med. 2016; 42(11):1744-1752.
33. Journois D, Pouard P, Mauriat P, et al. Inhaled nitric oxide as a therapy for pulmonary hypertension after operations for congenital heart disease. J Thorac Cardiovasc Surg. 1994; 107(4):1129-1135.
34. Kim TH, Youn SE, Chung S-H. Clinical impact of treprostinil in neonates with persistent pulmonary hypertension refractory to inhaled nitric oxide: a retrospective cohort study. Medicine. 2026; 105(1):e46984.
35. Kinsella JP. Inhaled nitric oxide therapy in premature newborns. Curr Opin Pediatr. 2006a; 18(2):107-111.
36. Kinsella JP, Cutter GR, Steinhorn RH, et al. Noninvasive inhaled nitric oxide does not prevent bronchopulmonary dysplasia in premature newborns. J Pediatr. 2014; 165(6):1104-1108.
37. Kinsella JP, Cutter GR, Walsh WF, et al. Early inhaled nitric oxide therapy in premature newborns with respiratory failure. N Engl J Med. 2006b; 355(4):354-364.
38. Kinsella JP, Truog WE, Walsh WF, et al. Randomized, multicenter trial of inhaled nitric oxide and high-frequency oscillatory ventilation in severe, persistent pulmonary hypertension of the newborn. J Pediatr. 1997; 131(1 Pt 1):55-62.
39. Kolcz J, Karnas E, Madeja Z, Zuba-Surma EK. The cardioprotective and anti-inflammatory effect of inhaled nitric oxide during Fontan surgery in patients with single ventricle congenital heart defects: a prospective randomized study. J Intensive Care. 2022; 10(1):48.
40. Konduri GG. New approaches for persistent pulmonary hypertension of newborns. Clin Perinatol. 2004; 31(3):591-611.
41. Konduri GG, Solimano A, Sokol GM, et al. A randomized trial of early versus standard inhaled nitric oxide therapy in term and near-term newborn infants with hypoxic respiratory failure. Pediatrics. 2004; 113(3 Pt 1):559-564.
42. 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.
43. Lawrence KM, Monos S, Adams S, et al. Inhaled nitric oxide is associated with improved oxygenation in a subpopulation of infants with congenital diaphragmatic hernia and pulmonary hypertension. J Pediatr. 2020; 219:167-172.
44. Lubinsky AS, Brosnahan SB, Lehr A, et al. Inhaled pulmonary vasodilators are not associated with improved gas exchange in mechanically ventilated patients with COVID-19: a retrospective cohort study. J Crit Care. 2022; 69:153990.
45. Lundin S, Mang H, Smithies M, et al. Inhalation of nitric oxide in acute lung injury: results of a European multicentre study. The European Study Group of Inhaled Nitric Oxide. Intensive Care Med. 1999; 25(9):911-919.
46. Maddux AB, Mourani PM, Banks R, et al. Inhaled nitric oxide use and outcomes in critically ill children with a history of prematurity. Respir Care. 2021; 66(10):1549-1559.
47. Malowitz JR, Hornik CP, Laughon MM, et al. Management practice and mortality for infants with congenital diaphragmatic hernia. Am J Perinatol. 2015; 32(9):887-894.
48. Mani S, Mirza H, Ziegler J, Chandrasekharan P. Early pulmonary hypertension in preterm infants. Clin Perinatol. 2024; 51(1):171-193.
49. Martin RJ. Nitric oxide for preemies - not so fast. N Engl J Med. 2003; 349(22):2157-2159.
50. Matsugi E, Takashima S, Doteguchi S, et al. Real-world safety and effectiveness of inhaled nitric oxide therapy for pulmonary hypertension during the perioperative period of cardiac surgery: a post-marketing study of 2817 patients in Japan. Gen Thorac Cardiovasc Surg. 2024; 72(5):311-323.
51. Mercier JC, Hummler H, Durrmeyer X, et al.; EUNO Study Group. Inhaled nitric oxide for prevention of bronchopulmonary dysplasia in premature babies (EUNO): a randomised controlled trial. Lancet. 2010; 376(9738):346-354.
52. Mestan KK, Marks JD, Kurt Hecox K, et al. Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide. N Engl J Med. 2005; 353(1):23-32.
53. Miller OI, Tang SF, Keech A, et al. Inhaled nitric oxide and prevention of pulmonary hypertension after congenital heart surgery: a randomized double-blind study. Lancet. 2000; 356(9240):1464-1469.
54. Mirza H, Garcia J, Zussman M, et al. Inhaled nitric oxide treatment of early pulmonary hypertension to reduce the risk of death or bronchopulmonary dysplasia in infants born extremely preterm: a masked randomized controlled trial. J Pediatr. 2025; 278:114427.
55. Neonatal Inhaled Nitric Oxide Study Group (NINOS). Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. Pediatrics. 1997a; 99(6):838-845.
56. Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. N Engl J Med. 1997b; 336(9):597-604.
57. Noh CY, Chock VY, Bhombal S, et al.; Congenital Diaphragmatic Hernia Study Group. Early nitric oxide is not associated with improved outcomes in congenital diaphragmatic hernia. Pediatr Res. 2023; 93(7):1899-1906.
58. Ogo T, Ueda J, Tsuji A, et al. A phase 2, randomized, clinical trial of inhaled nitric oxide for acute severe right heart failure with pulmonary hypertension (PHiNO study). Circ J. 2026 Mar 21; [Epub ahead of print].
59. Potapov E, Meyer D, Swaminathan M, et al. Inhaled nitric oxide after left ventricular assist device implantation: a prospective, randomized, double-blind, multicenter, placebo-controlled trial. J Heart Lung Transplant. 2011; 30(8):870-878.
60. Puligandla PS, Grabowski J, Austin M, et al. Management of congenital diaphragmatic hernia: a systematic review from the APSA outcomes and evidence based practice committee. J Pediatr Surg. 2015; 50(11):1958-1970.
61. Putnam LR, Tsao K, Morini F, et al.; Congenital Diaphragmatic Hernia Study Group. Evaluation of variability in inhaled nitric oxide use and pulmonary hypertension in patients with congenital diaphragmatic hernia. JAMA Pediatr. 2016; 170(12):1188-1194.
62. Reiter Meade MO, Granton JT, Matte-Martyn A, et al. A randomized trial of inhaled nitric oxide to prevent ischemia-reperfusion injury after lung transplantation. Am J Respir Crit Care Med. 2003; 167(11):1483-1489.
63. Russell IAM, Zwass MS, Fineman JR, et al. The effects of inhaled nitric oxide on postoperative pulmonary hypertension in infants and children undergoing surgical repair of congenital heart disease. Anesth Analg. 1998; 87(1):46-51.
64. Schlapbach LJ, Gibbons KS, Horton SB, et al. Effect of nitric oxide via cardiopulmonary bypass on ventilator-free days in young children undergoing congenital heart disease surgery: the NITRIC randomized clinical trial. JAMA. 2022; 328(1):38-47.
65. Schreiber MD, Gin-Mestan K, Marks JD, et al. Inhaled nitric oxide in premature infants with the respiratory distress syndrome. N Engl J Med. 2003; 349(22):2099-2107.
66. Strick DJ, Tanba C, Kaplan MA, et al. A prospective analysis of vasoreactivity and mortality in WHO group 3 pulmonary hypertension. Pulm Circ. 2025; 15(2):e70078.
67. Subhedar N, Dewhurst C. Is nitric oxide effective in preterm infants? Arch Dis Child Fetal Neonatal Ed. 2007; 92(5):F337-F341.
68. Tal A, Greenberg D, Av-Gay Y, et al. Nitric oxide inhalations in bronchiolitis: a pilot, randomized, double-blinded, controlled trial. Pediatr Pulmonol. 2018; 53(1):95-102.
69. Taylor RW, Zimmerman JL, Dellinger RP, et al.; Inhaled Nitric Oxide in ARDS Study Group. Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial. JAMA. 2004; 291(13):1603-1609.
70. Trzeciak S, Glaspey LJ, Dellinger RP, et al. Randomized controlled trial of inhaled nitric oxide for the treatment of microcirculatory dysfunction in patients with sepsis. Crit Care Med. 2014; 42(12):2482-2492.
71. Van Meurs KP, Hintz SR, Ehrenkranz RA, et al. Inhaled nitric oxide in infants >1500 g and <34 weeks of gestation with severe respiratory failure. J Perinatol. 2007; 27(6):347-352.
72. Van Meurs KP, Wright LL, Ehrenkranz RA, et al.; Preemie Inhaled Nitric Oxide Study. Inhaled nitric oxide for premature infants with severe respiratory failure. N Engl J Med. 2005; 353(1):13-22.
73. Villarreal EG, Aiello S, Evey LW, et al. Effects of inhaled nitric oxide on haemodynamics and gas exchange in children after having undergone cardiac surgery utilising cardiopulmonary bypass. Cardiol Young. 2020; 30(8):1151-1156.
74. Weiner DL, Hibberd PL, Betit P, et al. Preliminary assessment of inhaled nitric oxide for acute vasoocclusive crisis in pediatric patients with sickle cell disease. JAMA. 2003; 289(9):1136-1142.
75. Wong J, Loomba RS, Evey L, et al. Postoperative inhaled nitric oxide does not decrease length of stay in pediatric cardiac surgery admissions. Pediatr Cardiol. 2019; 40(8):1559-1568.
76. Zheng Y, Wu Q, Han S. Inhaled nitric oxide in premature infants for preventing bronchopulmonary dysplasia: a meta-analysis. BMC Pediatr. 2023; 23(1):139.

Government Agency, Medical Society, and Other Authoritative Publications:

1. Abman SH, Hansmann G, Archer SL, et al.; American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; Council on Clinical Cardiology; Council on Cardiovascular Disease in the Young; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Surgery and Anesthesia; and the American Thoracic Society. Pediatric pulmonary hypertension: guidelines from the American Heart Association and American Thoracic Society. Circulation. 2015; 132(21):2037-2099.
2. Aboursheid T, Albaroudi O, Alahdab F. Inhaled nitric oxide for treating pain crises in people with sickle cell disease. Cochrane Database Syst Rev. 2022;7(7):CD011808.
3. Afshari A, Brok J, Moller 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.
4. Allen MC, Donohue P, Gilmore M, et al. Inhaled nitric oxide in preterm infants. Evidence Report/Technology Assessment No. 195. (Prepared by Johns Hopkins University Evidence-based Practice Center under Contract No. 290-2007-10061-1). AHRQ Publication No. 11-E001. Rockville, MD: Agency for Healthcare Research and Quality. October 2010. Available at: https://www.ahrq.gov/downloads/pub/evidence/pdf/inoinfants/inoinfants.pdf. Accessed on May 15, 2026.
5. Barrington KJ, Finer NN, Pennaforte T. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database Syst Rev. 2017;(3):CD000509.
6. Barrington KJ, Finer N, Pennaforte T, Altit G. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev. 2017;(1):CD000399.
7. Bizzarro M, Gross I, Barbosa FT. Inhaled nitric oxide for the postoperative management of pulmonary hypertension in infants and children with congenital heart disease. Cochrane Database Syst Rev. 2014;(7):CD005055.
8. Cole FS, Alleyne C, Barks JD, et al. NIH Consensus Development Conference statement: inhaled nitric-oxide therapy for premature infants. Pediatrics. 2011; 127(2):363-369.
9. DiBlasi RM, Myers TR, Hess DR. Evidence-based clinical practice guideline: inhaled nitric oxide for neonates with acute hypoxic respiratory failure: American Association for Respiratory Care (AARC). Respir Care. 2010; 55(12):1717-1745.
10. Eunice Kennedy Shriver National Institute of Child Health and Human Development. Infant mortality. National Institutes of Health. Updated October 29, 2021. Available at: https://www.nichd.nih.gov/health/topics/factsheets/infant-mortality. Accessed on May 15, 2026.
11. Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev. 2006;(4):CD000399.
12. 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):CD002787.
13. Humbert M, Kovacs G, Hoeper MM, et al.; ESC/ERS Scientific Document Group. 2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022; 43(38):3618-3731.
14. INOmax^® [Product Information], Bridgewater, NJ. INO Therapeutics LLC; 2023. Available at: https://www.inomax.com/downloads/Inomax-PI.pdf. Accessed on May 15, 2026.
15. Kinsella JP, Steinhorn RH, Krishnan US, et al. Recommendations for the use of inhaled nitric oxide therapy in premature newborns with severe pulmonary hypertension. J Pediatr. 2016; 170:312-314.
16. Kumar P; Committee on Fetus and Newborn; American Academy of Pediatrics. Use of inhaled nitric oxide in preterm infants. Pediatrics. 2014; 133(1):164-170.
17. Mitra S, Altit G. Inhaled nitric oxide use in newborns. Paediatr Child Health. 2023; 28(2):119-127.
18. 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.

1. American Lung Association. Pulmonary hypertension. Available at: https://www.lung.org/lung-health-diseases/lung-disease-lookup/pulmonary-hypertension. Accessed on May 15, 2026.
2. Pulmonary Hypertension Association. About pulmonary hypertension. Available at: https://phassociation.org/pulmonary-hypertension/what-is-ph/. Accessed on May 15, 2026.

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

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