Nitric Oxide, Inhalational (INO)

Number: 0518

Policy

1. Aetna considers inhaled nitric oxide (INO) therapy medically necessary as a component of the treatment of hypoxic respiratory failure in neonates 34 weeks gestation or greater when both of the following criteria are met:

   1. Neonates do not have congenital diaphragmatic hernia; and
   2. When conventional therapies such as administration of high concentrations of oxygen, hyperventilation, high-frequency ventilation, the induction of alkalosis, neuromuscular blockade, and sedation have failed or are expected to fail.

   Note: Use of INO therapy for more than 4 days is subject to medical necessity review.

2. Aetna considers INO therapy medically necessary for post-operative management of pulmonary hypertensive crisis in infants and children with congenital heart disease.

3. Aetna considers the diagnostic use of INO medically necessary as a method of assessing pulmonary vaso-reactivity in persons with pulmonary hypertension.

4. Aetna considers INO therapy experimental and investigational for all other indications because of insufficient evidence in the peer-reviewed literature, including any of the following:

   • Acute bronchiolitis; or
   • Acute hypoxemic respiratory failure in children (other than those who meet the medical necessity criteria above) and in adults; or
   • Acute pulmonary embolism, or
   • Acute respiratory distress syndrome or acute lung injury; or
   • Bronchopulmonary dysplasia, prevention in preterm infants without hypoxic respiratory failure; or
   • Lung / liver transplantation, prevention of ischemia-reperfusion injury/acute rejection following lung or liver transplantation; or
   • Malaria, adjunctive treatment; or
   • Sickle cell disease, treatment of vaso-occlusive crises or acute chest syndrome (sickle cell vasculopathy); or
   • Treatment of mycobacterium and pseudomonas aeruginosa infections in persons with cystic fibrosis; or
   • Treatment of persons with congenital diaphragmatic hernia; or
   • Treatment of pulmonary hypertension associated with pulmonary fibrosis; or
   • Treatment of right heart failure after hemorrhagic shock and trauma pneumonectomy.

Note: INO therapy is considered medically necessary for no longer than 14 days if the oxygen desaturation has been resolved. Medical director review required for use beyond 14 days.

Background

Nitric oxide is a colorless, slightly water-soluble gas that is produced through cellular metabolism. In the body, nitric oxide is involved in oxygen transport to the tissues, the transmission of nerve impulses and other physiological activities. Inhaled nitric oxide (iNO) is a pulmonary vasodilator, proposed for the treatment of hypoxic respiratory failure associated with persistent pulmonary hypertension. It is most often utilized in conjunction with ventilatory support in term or near-term (greater than 34 weeks gestation) neonates to improve oxygenation and decrease the need for extracorporeal membrane oxygenation (ECMO). When inhaled, pulmonary vasodilation occurs and an increase in the partial pressure of arterial oxygen results. Dilation of pulmonary vessels in well ventilated lung areas redistributes blood flow away from lung areas where ventilation/perfusion ratios are poor. An example of a commercially available brand of nitric oxide includes, but may not be limited to, INOmax.

Respiratory Failure is a clinical syndrome that is defined either by the inability to rid the body of carbon dioxide or establish an adequate blood oxygen level. Acute respiratory failure is the most common problem seen in the term, near-term (born at 34 or more weeks of gestation), and pre-term (less than 34 weeks of gestation) infants admitted to neonatal intensive care units.  Acute respiratory failure in term and near-term neonates is usually a consequence of meconium aspiration syndrome, sepsis, pulmonary hypoplasia, and primary pulmonary hypertension of the newborn.  According to current guidelines, management of infants with respiratory failure includes administration of high concentrations of oxygen, hyperventilation, high-frequency ventilation, the induction of alkalosis, neuromuscular blockade, ante-natal steroids for the prevention of respiratory distress syndrome, use of post-natal steroids for the prevention of chronic lung disease, as well as inhaled nitric oxide (INO) therapy.  A systematic review of the evidence (Finer and Barrington, 2003) concluded: "On the evidence presently available, it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia."

In pre-term infants, the most common cause of acute respiratory failure is respiratory distress syndrome as a result of surfactant deficiency.  According to the available literature, treatment of preterm infants usually entails exogenous surfactant administration.

Clinical studies have shown that inhaled nitric oxide is a selective pulmonary vasodilator without significant effects on the systemic circulation.  There is sufficient scientific evidence that INO therapy improves oxygenation and ventilation, reduces the need for extracorporeal membrane oxygenation (ECMO), and lowers the incidences of chronic lung disease and death among infants with respiratory failure.  Moreover, the literature indicates that INO does not appear to increase the incidence of adverse neurodevelopmental, behavioral, or medical sequelae in these high-risk neonates.  Infants with congenital diaphragmatic hernia have been shown not to benefit from INO therapy.  Furthermore, INO therapy has not shown to be associated with significant benefits in pre-term infants.  A systemic review of the evidence (Barrington and Finer, 2003) concluded: "The currently published evidence from randomized trials does not support the use of inhaled nitric oxide in preterm infants with hypoxic respiratory failure."

In a randomized, double-blind, placebo-controlled study (n = 207), Schreiber et al (2003) examined the effect of INO during the first week of life on the incidence of chronic lung disease and death in premature infants (less than 34 weeks' gestation) who were undergoing mechanical ventilation for the respiratory distress syndrome.  The authors concluded that the use of INO in premature infants with the respiratory distress syndrome decreases the incidence of chronic lung disease and death.  However, in an editorial, Martin (2003) stated “At present, the data reported by Schreiber et al are intriguing but should be considered preliminary. We must wait for essential additional data from ongoing randomized trials of nitric oxide in premature infants before this therapy is introduced outside of clinical trials…”.

Bronchopulmonary dysplasia is a chronic lung condition marked by inflammation occurring in premature infants due to mechanical injury, oxygen toxicity or infection while mechanically ventilated as treatment for respiratory distress syndrome. In a multi-center, randomized, blinded, controlled study, Van Meurs and associates (2005) examined if INO reduced the rate of death or broncho-pulmonary dysplasia (BPD) in such infants.  A total of 420 neonates, born at less than 34 weeks of gestation, with a birth weight of 401 to 1,500 g, and with respiratory failure more than 4 hours after treatment with surfactant were randomly assigned to receive inhaled NO (5 to 10 ppm) or placebo (simulated flow).  The rate of death or BPD was 80 % in the NO group, as compared with 82 % in the placebo group and the rate of BPD was 60 % versus 68 %.  There were no significant differences in the rates of severe intra-cranial hemorrhage or peri-ventricular leukomalacia.  Post hoc analyses suggest that rates of death and BPD are reduced for infants with a birth weight greater than 1,000 g, whereas infants weighing 1,000 g or less who are treated with INO have higher mortality and increased rates of severe intra-cranial hemorrhage.  These investigators concluded that INO does not decrease the rates of death or BPD in critically ill premature infants weighing less than 1,500 g and more studies are needed to determine whether INO benefits infants with a birth weight of 1,000 g or more.

Mestan and colleagues (2005) conducted a prospective, longitudinal follow-up study of premature infants (mean gestational age of 27.2 weeks) who were administered INO or placebo to examine neurodevelopmental outcomes at 2 years of corrected age.  Neurological examination, neurodevelopmental assessment and anthropometric measurements were made by examiners who were blind to the children's original treatment assignment.  A total of 138 children (82 % of survivors) were evaluated.  In the group given INO, 17 of 70 children (24 %) had abnormal neurodevelopmental outcomes, defined as either disability (cerebral palsy, bilateral blindness, or bilateral hearing loss) or delay (no disability, but one score of less than 70 on the Bayley Scales of Infant Development II), as compared with 31 of 68 children (46 %) in the placebo group.  This effect persisted after adjustment for birth weight and sex, as well as for the presence or absence of chronic lung disease and severe intra-ventricular hemorrhage or peri-ventricular leukomalacia.  The improvement in neurodevelopmental outcome in the group given INO was primarily due to a 47 % decrease in the risk of cognitive impairment.  These investigators concluded that premature infants treated with INO have improved neurodevelopmental outcomes at 2 years of age.

In an editorial accompanying the contrasting articles by Van Meurs et al and Mestan et al, Martin and Walsh (2005) stated that “two large, multicenter, randomized trials of prolonged inhaled nitric oxide exposure beginning shortly after birth are completing enrollment …. Pending the results, it is prudent to avoid the use of inhaled nitric oxide in preterm infants in the first week of life.  The benefits and risks of inhaled nitric oxide need further scrutiny before its use becomes widespread”.  These two large studies have since been published; however the findings are contradictory (Ballard et al, 2006; Kinsella et al, 2006).

The study by Ballard et al (2006) was a randomized, stratified, double-blind, placebo-controlled trial of INO at 21 centers involving infants with a birth weight of 1,250 g or less who needed ventilatory support between 7 and 21 days of age.  Treated infants received decreasing concentrations of NO, beginning at 20 ppm, for a minimum of 24 days.  The primary outcome was survival without BPD at 36 weeks of post-menstrual age.  Among 294 infants receiving NO and 288 receiving placebo, birth weight (766 g and 759 g, respectively), gestational age (26 weeks in both groups), and other characteristics were similar.  The rate of survival without BPD at 36 weeks of post-menstrual age was 43.9 % in the group receiving NO and 36.8 % in the placebo group (p = 0.042).  The infants who received INO were discharged sooner (p = 0.04) and received supplemental oxygen therapy for a shorter time (p = 0.006).  There were no short-term safety concerns.  The authors concluded that INO therapy improves the pulmonary outcome for premature infants who are at risk for BPD when it is started between 7 and 21 days of age and has no apparent short-term adverse effects.

Kinsella and colleagues (2006) performed a multi-center, randomized study involving 793 newborns who were 34 weeks of gestational age or less and had respiratory failure requiring mechanical ventilation.  Newborns were randomly assigned to receive either INO (5 ppm) or placebo gas for 21 days or until extubation, with stratification according to birth weight (500 to 749 g, 750 to 999 g, or 1,000 to 1,250 g).  The primary outcome was a composite of death or BPD at 36 weeks of post-menstrual age.  Secondary outcomes included severe intra-cranial hemorrhage, peri-ventricular leukomalacia, and ventriculomegaly.  Overall, there was no significant difference in the incidence of death or BPD between patients receiving INO and those receiving placebo (71.6 % versus 75.3 %, p = 0.24).  However, for infants with a birth weight between 1,000 and 1,250 g, as compared with placebo, INO therapy reduced the incidence of BPD (29.8 % versus 59.6 %); for the cohort overall, such treatment reduced the combined end point of intra-cranial hemorrhage, peri-ventricular leukomalacia, or ventriculomegaly (17.5 % versus 23.9 %, p = 0.03) and of peri-ventricular leukomalacia alone (5.2 % versus 9.0 %, p = 0.048).  Inhaled nitric oxide therapy did not increase the incidence of pulmonary hemorrhage or other adverse events.  The authors concluded that among premature newborns with respiratory failure, low-dose INO did not reduce the overall incidence of BPD, except among infants with a birth weight of at least 1,000 g, but it did reduce the overall risk of brain injury.

In an editorial that accompanied the two afore-mentioned papers, Stark (2006) stated that the use of INO therapy in preterm infants awaits more data, especially longer-term follow-up of children in the studies by Ballard et al (2006) as well as Kinsella et al (2006).  In the meantime, the use of INO in this setting should be limited to clinical trials.

Bhandari and Bhandari (2007) stated that BPD is a chronic lung disease associated with premature birth and characterized by early lung injury.  Over the past 4 decades, there have been significant changes in its definition, pathology and radiological findings as well as management of BPD.  Management of the acute phase and later stages of this lung disease continue to evolve.  Use of non-invasive ventilatory techniques, recombinant human superoxide dimutase and Clara Cell 10 and INO are some novel approaches that are being studied.  In a Cochrane review, Barrington and Finer (2007) examined if INO would reduce mortality, BPD, intra-cranial hemorrhage, or neurodevelopmental disability in preterm infants with respiratory disease.  The authors concluded that INO as rescue therapy for very ill preterm infants undergoing ventilation does not seem to be effective and may increase severe intra-cranial hemorrhage.  Later use of inhaled INO to prevent BPD does not seem to be effective.  Early routine use of INO for mildly sick, preterm infants seems to decrease the risk of serious brain injury and may improve rates of survival without BPD.  They stated that further studies are needed to confirm these findings, to define groups most likely to benefit, and to describe long-term outcomes.

Huddy et al (2008) stated that trials of INO in preterm infants with severe respiratory failure have to date shown no evidence of benefit, and there have been no trials reporting follow-up to 4 years of age.  The INNOVO trial recruited 108 infants (55 INO arm and 53 controls) from 15 neonatal units.  By 1 year of age 59 % had died, and 84 % of the survivors had signs of impairment or disability.  These researchers reported the long-term clinical effectiveness and costs of adding NO to the ventilator gases of preterm infants with severe respiratory failure.  Children were assessed at age 4 to 5 years by interview, examination, cognitive and behavioral assessments.  The outcome data were divided into 7 domains and were described as normal, impaired or disabled (mild, moderate or severe) by the degree of functional loss.  Overall, 38 of the 43 survivors had follow-up assessments.  In the INO group 62 % (34/55) had died or were severely disabled, compared to 70 % (37/53) in the no INO group (relative risk [RR] 0.89, 95 % confidence interval [CI]: 0.67 to 1.16).  There was no evidence of difference in the levels of impairment or disability between the 2 groups in any of the domains studied, or of cost differences, among the survivors.  The authors concluded that for this group of babies with severe respiratory failure there was no evidence of difference in the longer-term outcome between those babies allocated to INO and those who were allocated to no INO.

Mercier and associates (2010) tested the hypothesis that INO at a low concentration, started early and maintained for an extended period in babies with mild respiratory failure, might reduce the incidence of BPD.  A total of 800 preterm infants with a gestational age at birth of between 24 weeks and 28 weeks plus 6 days (inclusive), weighing at least 500 g, requiring surfactant or continuous positive airway pressure for respiratory distress syndrome within 24 hrs of birth were randomly assigned in a 1-to-1 ratio to INO (5 parts per million) or placebo gas (nitrogen gas) for a minimum of 7 days and a maximum of 21 days in a double-blind study done at 36 centers in 9 countries in the European Union.  Care providers and investigators were masked to the computer-generated treatment assignment.  The primary outcome was survival without development of BPD at post-menstrual age 36 weeks.  Analysis was by intention-to- treat.  A total of 399 infants were assigned to INO, and 401 to placebo; 395 and 400, respectively, were analysed.  Treatment with INO and placebo did not result in significant differences in survival of infants without development of BPD (258 [65 %] of 395 versus 262 [66 %] of 400, respectively; RR 1.05, 95 % CI: 0.78 to 1.43); in survival at 36 weeks' post-menstrual age (343 [86 %) of 399 versus 359 [90 %] of 401, respectively; 0.74, 0.48 to 1.15); and in development of BPD (81 [24 %] of 339 versus 96 [27 %] of 358, respectively; 0.83, 0.58 to 1.17).  The authors concluded that early use of low-dose INO in very premature babies did not improve survival without BPD or brain injury, suggesting that such a preventive treatment strategy is unsuccessful.

In an Agency for Healthcare Research and Quality’s assessment on “Inhaled nitric oxide in preterm infants”, Allen et al (2010) systematically reviewed the evidence on the use of INO in preterm infants born at or before 34 weeks gestation age who receive respiratory support.  They searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Studies (CENTRAL) and PsycInfo in June 2010.  They also searched the proceedings of the 2009 and 2010 Pediatric Academic Societies Meeting and ClinicalTrials.gov.  They identified additional studies from reference lists of eligible articles and relevant reviews, as well as from technical experts.  Questions were developed in collaboration with technical experts, including the chair of the upcoming National Institutes of Health Office of Medical Applications of Research Consensus Development Conference.  These researchers limited their review to randomized controlled trials (RCTs) for the question of survival or occurrence of BPD and for the question on short-term risks.  All study designs were considered for long-term pulmonary or neurodevelopmental outcomes, and for questions about whether outcomes varied by subpopulation or by intervention characteristics.  Two investigators independently screened search results, and abstracted data from eligible articles.  These investigators identified a total of 14 RCTs, reported in 23 articles, and 8 observational studies.  Mortality rates in the neonatal internsive care unit (NICU) did not differ for infants treated with INO versus those not treated with INO (RR 0.97 (95 % CI: 0.82 to 1.15)).  Broncho-pulmonary dysplasia at 36 weeks for INO and control groups also did not differ (RR 0.93 (0.86, 1.003) for survivors).  A small difference was found between INO and control infants in the composite outcome of death or BPD (RR 0.93 (0.87, 0.99)).  There was inconsistent evidence about the risk of brain injury from individual RCTs, but meta-analyses showed no difference between INO and control groups.  These researchers found no evidence of differences in other short-term risks.  There was no evidence to suggest a difference in the incidence of cerebral palsy (RR 1.36 (0.88, 2.10)), neurodevelopmental impairment (RR 0.91 (0.77, 1.12)), or cognitive impairment (RR 0.72 (0.35, 1.45)).  Evidence was limited on whether the effect of INO varies by subpopulation or by characteristics of the therapy (timing, dose and duration, mode of delivery, or concurrent therapies).  The authors concluded that there was a 7 % reduction in the risk of the composite outcome of death or BPD at 36 weeks PMA for infants treated with INO compared to controls, but no reduction in death or BPD alone.  They stated that further studies are needed to explore particular subgroups of infants and to assess long-term outcomes including function in childhood.  They stated that there is currently no evidence to support the use of INO in preterm infants with respiratory failure outside the context of rigorously conducted RCTs.

To provide health care professionals, families, and the general public with a responsible assessment of currently available data regarding the benefits and risks of INO in premature infants, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Heart, Lung, and Blood Institute, and the Office of Medical Applications of Research of the National Institutes of Health (Cole et al, 2011) convened a consensus-development conference.  Findings from a substantial body of experimental work in developing animals and other model systems suggest that NO may enhance lung growth and reduce lung inflammation independently of its effects on blood vessel resistance.  Although this work demonstrates biological plausibility and the results of RCTs in term and near-term infants were positive, combined evidence from the 14 RCTs of INO treatment in premature infants of gestation of 34 weeks or less shows equivocal effects on pulmonary outcomes, survival, and neurodevelopmental outcomes.

A National Institutes of Health Consensus Development Conference on inhaled nitric oxyten in premature infants (Cole, et al., 2010) had the following recommendations:

1. Taken as a whole, the available evidence does not support use of inhaled nitric oxide in early routine, early rescue, or later rescue regimens in the care of premature infants <34 weeks gestation who require respiratory support.
2. There are rare clinical situations, including pulmonary hypertension or hypoplasia, that have been inadequately studied in which inhaled nitric oxide may have benefit in infants <34 weeks gestation. In such situations, clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties.
3. Basic research and animal studies have contributed to important understandings of inhaled nitric oxide benefits on lung development and function in infants at high risk of bronchopulmonary dysplasia. These promising results have only partly been realized in clinical trials of inhaled nitric oxide treatment in premature infants. Future research should seek to understand this gap.
4. Predefined subgroup and post hoc analyses of previous trials showing potential benefit of inhaled nitric oxide have generated hypotheses for future research for clinical trials. Prior strategies shown to be ineffective are discouraged unless new evidence emerges. The positive results of one multicenter trial, which was characterized by later timing, higher dose, and longer duration of treatment, require confirmation. Future trials should attempt to quantify the individual effects of each of these treatment-related variables (timing, dose, and duration), ideally by randomizing them separately.
5. Based on assessment of currently available data, hospitals, clinicians, and the pharmaceutical industry should avoid marketing inhaled nitric oxide for premature infants <34 weeks gestation.

An American Academy of Pediatrics clinical report on the use of inhaled nitric oxide in preterm infants (Kumar, et al., 2014) reached the following conclusions:

1. The results of randomized controlled trials, traditional meta-analyses, and an individualized patient data meta-analysis study indicate that neither rescue nor routine use of iNO improves survival in preterm infants with respiratory failure (Evidence quality, A; Grade of recommendation, strong).
2. The preponderance of evidence does not support treating preterm infants who have respiratory failure with iNO for the purpose of preventing/ameliorating BPD, severe intraventricular hemorrhage, or other neonatal morbidities (Evidence quality, A; Grade of recommendation, strong).
3. The incidence of cerebral palsy, neurodevelopmental impairment, or cognitive impairment in preterm infants treated with iNO is similar to that of control infants (Evidence quality, A).
4. The results of 1 multicenter, randomized controlled trial suggest that treatment with a high dose of iNO (20 ppm) beginning in the second postnatal week may provide a small reduction in the rate of BPD. However, these results need to be confirmed by other trials.
5. An individual-patient data metaanalysis that included 96% of preterm infants enrolled in all published iNO trials found no statistically significant differences in iNO effect according to any of the patient-level characteristics, including gestational age, race, oxygenation index, postnatal age at enrollment, evidence of pulmonary hypertension, and mode of ventilation.
6. There are limited data and inconsistent results regarding the effects of iNO treatment on pulmonary outcomes of preterm infants in early childhood.

Ellsworth et al (2014) found that, despite the NIH consensus statement, rates of use of iNO in preterm infants continued to rise.  The investigators queried the Pediatrix Medical Group Clinical Data Warehouse for the years 2009 to 2013 to describe first exposure iNO use among all admitted neonates stratified by gestational age.  Between 2009 and 2013, the rate of iNO utilization in 23- to 29-week neonates increased from 5.03 % to 6.19 %, a relative increase of 23 % (CI: 8 % to 40 %; p = 0.003).  Of all neonates who received iNO therapy in 2013, nearly 50 % were less than 34 weeks' gestation, with these infants accounting for more than 50 % of all first exposure iNO days each year of the study period.  The investigators concluded that the rates of off-label iNO use in preterm infants continue to rise despite evidence revealing no clear benefit in this population.  The investigators stated that this pattern of iNO prescription is not benign and comes with economic consequences.

Commenting on the findings of Ellsworth et al, Finer and Evans (2014) concluded that "The evidence does not justify the current rates of usage of iNO in preterm infants.  This treatment is hugely expensive and may be harmful in the smallest infants.  There is a need for a local and collective effort to rationalize this usage through development of clinical guidelines and more targeted clinical trials".

Donohue et al (2011) reviewed the evidence on the use of INO in infants born at 34 weeks or less gestation who receive respiratory support.  Medline, Embase, the Cochrane Central Register of Controlled Studies, PsycInfo, ClinicalTrials.gov, and proceedings of the 2009 and 2010 Pediatric Academic Societies meetings were searched in June 2010.  Additional studies from reference lists of eligible articles, relevant reviews, and technical experts were considered.  Two investigators independently screened search results and abstracted data from eligible articles.  They focused on mortality, BPD, the composite outcome of death or BPD, and neurodevelopmental impairment.  A total of 14 RCTs, 7 follow-up studies, and 1 observational study were eligible for inclusion.  Mortality rates in the NICU did not differ for infants treated with INO compared with controls (RR: 0.97, 95 % CI: 0.82 to 1.15); BPD at 36 weeks for INO and control groups also did not differ for survivors (RR: 0.93, 95 % CI: 0.86 to 1.003).  A small difference was found in favor of INO in the composite outcome of death or BPD (RR: 0.93, 95 % CI: 0.87 to 0.99).  There was no evidence to suggest a difference in the incidence of cerebral palsy (RR: 1.36, 95 % CI: 0.88 to 2.10), neurodevelopmental impairment (RR: 0.91, 95 % CI: 0.77 to 1.12), or cognitive impairment (RR: 0.72, 95 % CI: 0.35 to1.45).  The authors concluded that there was a 7 % reduction in the risk of the composite outcome of death or BPD at 36 weeks for infants treated with INO compared with controls but no reduction in death alone or BPD.  They stated that there is currently no evidence to support the use of INO in preterm infants with respiratory failure outside the context of rigorously conducted RCTs.

Inhaled nitric oxide therapy has also not been proven to improve outcomes in children and adults with acute respiratory failure.  A systemic review of the evidence (Sokol et al, 2003) of INO for acute hypoxemic respiratory failure in children and adults reached the following conclusions: “Nitric oxide did not demonstrate any statistically significant effect on mortality and transiently improved oxygenation in patients with hypoxemic respiratory failure.  Lack of data prevented assessment of other clinically relevant end points.  Currently there is also insufficient evidence to support the use of INO for the prevention of ischemia-reperfusion injury/acute rejection following lung transplantation, or the treatment of vaso-occlusive crises in patients with sickle cell disease.”

A systematic review of 5 randomized controlled clinical trials of INO versus placebo or no therapy for acute hypoxemic respiratory failure (including acute lung injury, adult respiratory distress syndrome, and other diagnoses) in adults and children concluded that INO produced modest improvements in oxygenation for up to 72 hours but had no effect on mortality (pooled RR using fixed effects model, 0.98; 95 % CI: 0.66 to 1.44) or on the duration of mechanical ventilation (Sokol et al, 2003).

In a systematic review and meta-analysis on the use of INO to treat ALI/ARDS, Adhikari et al (2007) concluded that INO is associated with limited improvement in oxygenation in patients with ALI or acute respiratory distress syndrome (ARDS) but confers no mortality benefit and may cause harm.  The authors do not recommend its routine use in these severely ill patients.

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

Extra corporeal membrane oxygenation (ECMO) is used for individuals whose heart and lungs cannot normally function on their own. The individual’s blood passes through a tube to the ECMO machine where it is oxygenated by an artificial lung and is returned to the body. A study by Clark et al (2000) suggested that a maximum of 4 days of INO should be tried before ECMO is considered.  Limiting the duration of INO may avoid delaying ECMO beyond the point at which its effectiveness may be reduced.

Pulmonary hypertension is abnormally elevated blood pressure within the pulmonary circuit. Inhaled nitric oxide may also be used as a diagnostic test to determine vasodilator responsiveness in patients with pulmonary hypertension (Gildea et al, 2003).  Because of its short half-life and lack of systemic effects, "it is expected that the use of inhaled nitric oxide will become standard practice in all centers in the future" (British Cardiac Society, 2001).  Long-term use of INO has also been described in patients with primary pulmonary hypertension, but its clinical application has been limited because of the compound's short half-life (Gildea et al, 2003).

In a Cochrane review, Bizzarro and Gross (2005) examined the effectiveness of INO in the post-operative management of infants and children with congenital heart disease.  The objectives were to compare the effects of post-operative INO versus placebo and/or conventional management on infants and children with congenital heart disease.  The primary outcome was mortality, and the secondary outcomes were length of hospital stay, assessment of neurodevelopmental disability, number of pulmonary hypertensive crises, changes in hemodynamics including mean pulmonary arterial pressure, mean arterial pressure, and heart rate, changes in oxygenation measured as the ratio partial pressure of oxygen:fraction of inspired oxygen (PaO2:FiO2), as well as measurement of maximum methemoglobin level as a marker of toxicity.  These investigators observed no differences with the use of INO as compared with control in the majority of outcomes reviewed.  No data were available for analysis with respect to several clinical outcomes including long-term mortality and neurodevelopmental outcome.  They found it difficult to draw valid conclusions because of concerns regarding methodological quality, bias, sample size, and heterogeneity.

Al Hajeri et al (2008) stated that acute chest syndrome has been defined as a new infiltrate that is visible on chest X-ray, and is associated with one or more symptoms (e.g., cough, fever, dyspnea, new-onset hypoxia, sputum production, or tachypnea).  Symptoms and complications of this syndrome, whether of infectious or non-infectious origin, vary widely in patients with sickle cell disease.  Lung infection tends to predominate in children, while infarction appears more common in adults.  However, these are often interrelated and may occur concurrently.  The differences in clinical course and severity are suggestive of multiple causes for acute chest syndrome.  Successful treatment depends principally on high-quality supportive care.  The syndrome and its treatment have been extensively studied, but the response to antibiotics, anticoagulants, and other conventional therapies remains disappointing.  The potential of INO as a treatment option has more recently provoked considerable interest.  In a Cochrane review, these researchers evaluated the effectiveness of INO for treating acute chest syndrome by comparing improvement in symptoms and clinical outcomes against standard care.  No studies identified were eligible for inclusion.  The authors concluded that there is a need for well-designed, adequately-powered randomized controlled studies to assess the risks and benefits of INO as an adjunct to established therapies.

Porta and Steinhorn (2008) stated that more than a decade of intensive research has resulted in the current role of INO as the only selective pulmonary vasodilator for the treatment of persistent pulmonary hypertension in the newborn (PPHN).  This therapy continues to be studied intensively to better define its mechanism of action and role in PPHN treatment.  Furthermore, there remains intense interest in possible new uses inn newborns, as well as strategies that may enhance its effectiveness.  The authors reviewed several areas of current research on amplification of NO signaling in the neonatal pulmonary vasculature, the current knowledge about the role of INO in other conditions such as congenital diaphragmatic hernia and congenital heart disease.

Sickle cell anemia is a chronic hereditary blood disease, occurring primarily among Africans or persons of African descent, in which abnormal hemoglobin causes red blood cells to become sickle shaped and nonfunctional. It is characterized by enlarged spleen, chronic anemia, lethargy, weakness, joint pain and blood clot formation. Kato and Gladwin (2008) noted that recent research has suggested a syndrome of hemolysis-associated vasculopathy in patients with sickle cell disease, which features severe hemolytic anemia and leads to scavenging of NO and its biochemical precursor l-arginine.  This diminished bioavailability of NO promotes a hemolysis-vascular dysfunction syndrome, which includes pulmonary hypertension, cutaneous leg ulceration, priapism, and ischemic stroke.  Additional correlates of this vasculopathy include activation of endothelial cell adhesion molecules, platelets, and the vascular protectant hemeoxygenase-1.  Some known risk factors for atherosclerosis are also associated with sickle cell vasculopathy, including low levels of apolipoprotein AI and high levels of asymmetric dimethylarginine, an endogenous inhibitor of NO synthase.  Identification of dysregulated vascular biology pathways in sickle vasculopathy has provided a focus for new clinical trials for therapeutic intervention, including INO, sodium nitrite, L-arginine, phosphodiesterase-5 inhibitors, niacin, inhaled carbon monoxide, and endothelin receptor antagonists.

Arul and Konduri (2009) noted that the use of INO in extremely low birth weight neonates for the prevention of adverse outcomes like chronic lung disease and neurological injury has been investigated, but the findings remain inconclusive.  Soll (2009) stated that INO has been used to treat both term and preterm infants with respiratory failure.  Term infants with persistent pulmonary hypertension, either as a primary cause or secondary to other disease processes, respond to INO with improvement in oxygenation indices and a decreased need for ECMO.  Infants with congenital diaphragmatic hernia are the exception to this finding, with little clinical benefit observed with INO treatment.  Although respiratory disease in preterm infants has a component of increased pulmonary vascular resistance, little benefit of INO administration has been observed in premature infants either early in their course or later as a treatment to prevent the evolution of chronic lung disease.

González and Ochoa (2010) reviewed the evidence on treatment of acute bronchiolitis.  These investigators stated that there is sufficient evidence on the lack of effectiveness of most interventions tested in bronchiolitis.  Apart from oxygen therapy, fluid therapy, aspiration of secretions and ventilation support, few treatment options will be beneficial.  There are doubts about the effectiveness of inhaled bronchodilators (salbutamol or adrenaline), with or without hypertonic saline solution, suggesting that these options should be selectively used as therapeutic trials in moderate-to-severe bronchiolitis.  Heliox and non-invasive ventilation techniques, methylxanthine could be used in cases with respiratory failure, in patients with apnea, and surfactant and inhaled ribavirin in intubated critically ill patients.  The available evidence does not recommend the use of oral salbutamol, subcutaneous adrenaline, anti-cholinergic drugs, inhaled or systemic corticosteroids, antibiotics, aerosolized or intravenous immunoglobulin, respiratory physiotherapy and other therapeutic approaches including nitric oxide, recombinant human deoxyribonuclease, recombinant interferon, and nebulized furosemide.

Adhikari and colleagues (2014) examined if NO reduces hospital mortality in patients with severe ARDS (PaO2/FIO2 less than or equal to 100 mm Hg) but not in patients with mild-moderate ARDS (100 less than PaO2/FIO2 less than or equal to 300 mm Hg) at the time of randomization.  Data were collected from Medline, Embase, and Cochrane CENTRAL electronic databases (inception to May 2013); proceedings from 5 conferences (to May 2013); and trial registries. No language restrictions were applied.  Two authors independently selected parallel-group RCTs comparing NO with control (placebo or no gas) in mechanically ventilated adults or post-neonatal children with ARDS.  Two authors independently extracted data from included trials.  Trial investigators provided subgroup data.  Meta-analyses used within-trial subgroups and random-effects models.  A total of 9 trials (n = 1,142 patients) met inclusion criteria.  Overall methodological quality was good.  Nitric oxide did not reduce mortality in patients with severe ARDS (risk ratio, 1.01 [95 % CI: 0.78 to 1.32]; p = 0.93; n = 329, 6 trials) or mild-moderate ARDS (risk ratio, 1.12 [95 % CI: 0.89 to 1.42]; p = 0.33; n = 740, 7 trials).  Risk ratios were similar between subgroups (interaction p = 0.53).  There was no between-trial heterogeneity in any analysis (I = 0 %).  Varying the PaO2/FIO2 threshold between 70 and 200 mm Hg, in increments of 10 mm Hg, did not identify any threshold at which the NO-treated patients had lower mortality relative to controls.  The authors concluded that NO does not reduce mortality in adults or children with ARDS, regardless of the degree of hypoxemia.  Given the lack of related ongoing or recently completed randomized trials, new data addressing the effectiveness of NO in patients with ARDS and severe hypoxemia will not be available for the foreseeable future.

Dzierba et al (2014) stated that ARDS and ALI are conditions associated with an estimated mortality of 40 to 50 %.  The use of inhaled vasodilators can help to improve oxygenation without hemodynamic effects.  These investigators reviewed relevant studies addressing the safety and effectiveness of iNO and aerosolized epoprostenol (aEPO) in the treatment of life-threatening hypoxemia associated with ARDS and ALI.  In addition, they provided a practicable guide to the clinical application of these therapies.  A total of 9 prospective RCTs were included for iNO reporting on changes in oxygenation or clinical outcomes; 7 reports of aEPO were examined for changes in oxygenation.  Based on currently available data, the use of either iNO or aEPO is safe to use in patients with ALI or ARDS to transiently improve oxygenation.  No differences have been observed in survival, ventilator-free days, or attenuation in disease severity.  The authors concluded that further studies with consistent end-points using standard delivery devices and standard modes of mechanical ventilation are needed to determine the overall benefit with iNO or aEPO.

Inhaled nitric oxide should be administered using FDA-approved devices (e.g., INOmax is one form of INO that has FDA approval for the treatment of hypoxic respiratory failure in neonates).

Kinsella et al (2014) evaluated the safety and effectiveness of early, non-invasive INO therapy in premature newborns who do not require mechanical ventilation.  These researchers performed a multi-center randomized trial including 124 premature newborns who required non-invasive supplemental oxygen within the first 72 hours after birth.  Newborns were stratified into 3 different groups by birth weight (500 to 749, 750 to 999, 1,000 to 1,250 g) prior to randomization to INO (10 ppm) or placebo gas (controls) until 30 weeks post-menstrual age.  The primary outcome was a composite of death or BPD at 36 weeks post-menstrual age.  Secondary outcomes included the need for and duration of mechanical ventilation, severity of BPD, and safety outcomes.  There was no difference in the incidence of death or BPD in the INO and placebo groups (42 % versus 40 %, p = 0.86, RR = 1.06, 0.7 to 1.6).  Broncho-pulmonary dysplasia severity was not different between the treatment groups.  There were no differences between the groups in the need for mechanical ventilation (22 % versus 23 %; p = 0.89), duration of mechanical ventilation (9.7 versus 8.4 days; p = 0.27), or safety outcomes including severe intra-cranial hemorrhage (3.4 % versus 6.2 %, p = 0.68).  The authors concluded that they found that INO delivered non-invasively to premature infants who have not progressed to early respiratory failure is a safe treatment, but does not decrease the incidence or severity of BPD, reduce the need for mechanical ventilation, or alter the clinical course.

An UpToDate review on “Prevention of bronchopulmonary dysplasia” (Adams and Stark, 2015) states that “Inhaled nitric oxide, as available evidence does not support its use …. We do not recommend the use of inhaled nitric oxide to prevent BPD in preterm infants”.

Bhat and colleagues (2105) stated that acute pulmonary embolism (PE) is usually a complication secondary to migration of a deep venous clot or thrombi to lungs, but other significant etiologies include air, amniotic fluid, fat, and bone marrow.  Regardless of the underlying etiology, little progress has been made in finding an effective pharmacologic intervention for this serious complication.  Among the wide spectrum of PE, massive PE is associated with considerable morbidity and mortality, primarily due to severely elevated pulmonary vascular resistance leading to right ventricular failure, hypoxemia, and cardiogenic shock.  Inhaled nitric oxide has been proposed as a potential therapeutic agent in cases of acute PE in which hemodynamic compromise secondary to increased pulmonary vascular resistance is present, based on INO's selective dilation of the pulmonary vasculature and anti-platelet activity.  A systematic search of studies using the PubMed database was undertaken in order to assess the available literature.  Although there are currently no published RCTs on the subject, except a recently publish phase I trial involving 8 patients, several case reports and case series described and documented the use of INO in acute PE.  The majority of published reports had documented improvements in oxygenation and hemodynamic variables, often within minutes of administration of INO.  These reports, when taken together, raise the possibility that INO may be a potential therapeutic agent in acute PE.  However, based on the current literature, it is not possible to conclude definitively whether INO is safe and effective.  The authors concluded that these case reports underscored the need for RCTs to establish the safety and effectiveness of INO in the treatment of massive acute PE.

The Pediatric Acute Lung Injury Consensus Conference Group’s consensus statement on pediatric respiratory distress syndrome (2015) had a recommendation against the routine use of INO for pediatric RDS.

Malaria

Hawkes et al (2011) stated that severe malaria remains a major cause of global morbidity and mortality.  Despite the use of potent anti-parasitic agents, the mortality rate in severe malaria remains high.  Adjunctive therapies that target the underlying pathophysiology of severe malaria may further reduce morbidity and mortality.  Endothelial activation plays a central role in the pathogenesis of severe malaria, of which angiopoietin-2 (Ang-2) has recently been shown to function as a key regulator.  Nitric oxide is a major inhibitor of Ang-2 release from endothelium and has been shown to decrease endothelial inflammation and reduce the adhesion of parasitized erythrocytes.  Low-flow INO gas is a U.S. FDA-approved treatment for hypoxic respiratory failure in neonates.  These researchers described the protocol of a randomized controlled trial that examined the use of INO as adjunctive therapy of severe malaria.  This prospective, parallel-arm, randomized, placebo-controlled, blinded clinical trial compares adjunctive continuous INO at 80 ppm to placebo (both arms receiving standard anti-malarial therapy), among Ugandan children aged 1 to 10 years of age with severe malaria.  The primary endpoint is the longitudinal change in Ang-2, an objective and quantitative biomarker of malaria severity, which will be analyzed using a mixed-effects linear model.  Secondary endpoints include mortality, recovery time, parasite clearance and neurocognitive sequelae.  Noteworthy aspects of this trial design include its efficient sample size supported by a computer simulation study to evaluate statistical power, meticulous attention to complex ethical issues in a cross-cultural setting, and innovative strategies for safety monitoring and blinding to treatment allocation in a resource-constrained setting in sub-Saharan Africa.

Bergmark et al (2012) noted that there are approximately 225 to 600 million new malaria infections worldwide annually, with severe and cerebral malaria representing major causes of death internationally.  The role of NO in the host response in cerebral malaria continues to be elucidated, with numerous known functions relating to the cytokine, endovascular and cellular responses to infection with Plasmodium falciparum.  Evidence from diverse modes of inquiry suggests NO to be critical in modulating the immune response and promoting survival in patients with cerebral malaria.  This line of investigation has culminated in the approval of 2 phase II randomized prospective clinical trials in Uganda studying the use of INO as adjuvant therapy in children with severe malaria.  The strategy underlying both trials is to use the systemic anti-inflammatory properties of INO to "buy time" for chemical anti-parasite therapy to lower the parasite load.

Hawkes et al (2015) hypothesized that adjunctive INO would improve outcomes in children with severe malaria. A randomized, blinded, placebo-controlled trial of INO at 80 ppm by non-rebreather mask versus room air placebo as adjunctive treatment to artesunate in children with severe malaria was conducted.  The primary outcome was the longitudinal course of angiopoietin-2 (Ang-2), an endothelial biomarker of malaria severity and clinical outcome.  A total of 180 children were enrolled; 88 were assigned to INO and 92 to placebo (all received IV artesunate).  Ang-2 levels measured over the first 72 hours of hospitalization were not significantly different between groups.  The mortality at 48 hours was similar between groups [6/87 (6.9 %) in the INO group vs 8/92 (8.7 %) in the placebo group; odds ratio [OR] 0.78, 95 % CI: 0.26 to 2.3; p = 0.65].  Clinical recovery times and parasite clearance kinetics were similar (p > 0.05).  Methemoglobinemia greater than 7 % occurred in 25 % of patients receiving INO and resolved without sequelae.  The incidence of neurologic deficits (less than 14 days), acute kidney injury, hypoglycemia, anemia, and hemoglobinuria was similar between groups (p > 0.05).  The authors concluded that INO at 80 ppm administered by non-rebreather mask was safe but did not affect circulating levels of Ang-2.  They stated that alternative methods of enhancing endothelial NO bioavailability may be necessary to achieve a biological effect and improve clinical outcome.

Bangirana and co-workers (2018) carried out a randomized, double-blind, placebo-controlled trial of iNO versus placebo as an adjunctive therapy for severe malaria in Uganda.  Children received study gas for a maximum 72 hours (iNO, 80 parts per million; room air placebo).  Neurocognitive testing was performed on children (less than 5 years of age) at 6 month follow-up.  The neurocognitive outcomes assessed were overall cognition (a composite of fine motor, visual reception, receptive language, and expressive language), attention, associative memory, and the global executive composite.  Main outcomes were attention, associative memory, and overall cognitive ability.  A total of 61 children receiving iNO and 59 children receiving placebo were evaluated; 42 children (35.0 %) were impaired in at least 1 neurocognitive domain.  By intention-to-treat analysis, there were no differences in unadjusted or unadjusted age-adjusted z-scores for overall cognition (β (95 % CI): 0.26 (-0.19 to 0.72), p = 0.260), attention (0.18 (-0.14 to 0.51), p = 0.267), or memory (0.14 (-0.02 to 0.30), p = 0.094) between groups by linear regression.  Children receiving iNO had a 64 % reduced RR of fine motor impairment than children receiving placebo (RR, 95 % CI: 0.36, 0.14 to 0.96) by log binomial regression following adjustment for anti-convulsant use.  The authors concluded that severe malaria is associated with high rates of neurocognitive impairment.  Treatment with iNO was associated with reduced risk of fine motor impairment.  Moreover, they stated that these results need to be prospectively validated in a larger study powered to assess cognitive outcomes in order to evaluate whether strategies to increase bioavailable NO are neuroprotective in children with severe malaria.

The authors stated that the drawbacks of this study included a relatively short follow-up period (6 months) with a single cognitive assessment.  A longer follow-up period would permit an evaluation of children as they start school and have greater cognitive demands.  This was important as cognitive deficits have been shown to persist over at least a year of follow-up.  The sample size for this study was calculated based on estimated longitudinal changes in angiopoietin-2 over hospitalization.  This study was likely under-powered to detect more subtle cognitive differences between trial arms, particularly as the population consisted of a heterogeneous group of children with different manifestations of severe malaria.  Lastly, as cognitive assessment tools are validated within specific age ranges, these researchers were limited to evaluating neurocognitive function to children of less than 5 years of age given the mean age of children presenting with severe malaria in this population.

Pulmonary Hypertensive Crisis in Infants and Children with Congenital Heart Disease

Gorenflo and Gu (2010) stated that congenital heart disease (CHD) is responsible for PH in children in about 50 % of cases. This pre-operative dynamic PH can be super-imposed and aggravated by acute post-operative PH or persist as chronic PH, especially in children who are not operated on early enough.  Inhaled iloprost is used for the post-operative management of PH in infants and children with CHD.  In a prospective open-label proof-of-concept study, the effectiveness of INO and inhaled iloprost were directly compared.  Primary endpoints were the occurrence of a major or minor pulmonary hypertensive crisis.  No significant difference between the effects of INO versus iloprost on peri-operative PH was observed.  Neither substance on its own prevented pulmonary hypertensive crises in high-risk infants, so a combination of both substances should be tested in future trials.  In China, there were more than 4 million untreated CHD patients.  More than 50 % of them were untreated adults.  Acute pulmonary vaso-reactivity tests were performed in CHD patients between 9 months and 43 years of age using inhaled iloprost, in order to find out whether a pre-operative response to inhaled iloprost is a good predictor for the post-operative performance of these patients.  The results showed that patient selection criteria for surgery should include both a 20 % reduction in pulmonary vascular resistance (PVR) index after iloprost inhalation and a resulting PVR index less than 11 Wood U/m(2).  Congenital heart disease children between 14 days and 11 years of age took part in a placebo-controlled pilot study that investigated the role of aerosolized iloprost in the treatment of PH after corrective surgery.  They received either low- or high-dose iloprost or placebo.  Inhaled iloprost significantly improved hemodynamics in a dose-dependent manner and prevented reactive PH and pulmonary hypertensive crises in most of these mechanically ventilated children after CHD repair.

Loukanov and colleagues (2011) stated that guidelines recommend the use of INO to treat perioperative pulmonary hypertensive crises (PHTCs), but treatment with INO is not an ideal vasodilator. Aerosolized iloprost may be a possible alternative to INO in this setting.  In a pilot study, these investigators compared the effect INO and aerosolized iloprost in preventing PHTCs.  Investigator-initiated, open-label, randomized clinical trial in 15 infants (age range of 77 to 257 days) with left-to-right shunt (11 out of 15 with additional trisomy 21), and PH (i.e., mean pulmonary artery pressure [PAP] greater than 25 mmHg) after weaning from cardio-pulmonary bypass.  Patients were randomized to treatment with INO at 10 ppm or aerosolized iloprost at 0.5 µg/kg (every 2 hours).  The observation period was 72 hours after weaning from cardio-pulmonary bypass.  The primary end-point was the occurrence of PHTCs; the secondary end-points were mean PAP, duration of mechanical ventilation, safety of administration, and in-hospital mortality.  A total of 7 patients received INO and 8 patients received iloprost.  During the observation period, 13 of the 15 patients had at least 1 major or minor PHTC.  There was no difference between the groups with regard to the frequency of PHTCs, mean PAP and duration of mechanical ventilation (p > 0.05).  The authors concluded that in this pilot study, aerosolized iloprost had a favorable safety profile; larger trials are needed to compare its effectiveness to INO for the treatment of PHTCs.

Brunner and associates (2014) stated that PHTC is an important cause of morbidity and mortality in patients with pulmonary arterial hypertension secondary to CHD (PAH-CHD) who require cardiac surgery. At present, prevention and management of peri-operative PHTC is aimed at optimizing cardio-pulmonary interactions by targeting prostacyclin, endothelin, and NO signaling pathways within the pulmonary circulation with various pharmacological agents.  This review was aimed at familiarizing the practitioner with the current pharmacological treatment for dealing with peri-operative PHTC in PAH-CHD patients.  Given the life-threatening complications associated with PHTC, proper peri-operative planning can help anticipate cardio-pulmonary complications and optimize surgical outcomes in this patient population.  The authors concluded that evidence suggested that the historical mainstay, INO, remains the 1st-line monotherapy, although it is far from ideal.  They noted that according to a European consensus, a therapeutic trial of INO entails administration of 20 ppm when post-operative PAH is present.  Therefore, routine use of INO (from 5 to 20 to a maximum of 80 ppm) is the first choice when patients are at high risk of PH crisis.  The optimal dose of INO is the lowest possible dose that provides control of PAP.

Furthermore, the American Heart Association (AHA) and American Thoracic Society (ATS)’s guideline on “Pediatric pulmonary hypertension” (2015) recommended the use of INO to reduce the need for ECMO in term and near-term infants with PPHN or hypoxemic respiratory failure who have an oxygenation index that exceeds 25.

Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is a type of pulmonary (lung) failure that may result from any disease that causes large amounts of fluid to collect in the lungs. ARDS is not itself a specific disease, but a syndrome. In a randomized controlled study (n = 385), Taylor et al (2004) concluded that low-dose INO (5 ppm) in patients with acute lung injury not due to sepsis and without evidence of non-pulmonary organ system dysfunction resulted in short-term oxygenation improvements but had no substantial impact on the duration of ventilatory support or mortality.  These investigators stated that the data do not support the routine use of INO in the treatment of acute lung injury or acute respiratory distress syndrome.  An accompanying editorial stated that “[t]he results of this trial consolidate earlier findings and support the notion that nitric oxide is not useful in the treatment of the majority of patients with ALI [acute lung injury] or ARDS [acute respiratory distress syndrome] (Adhikari and Granton, 2004).

Karam and colleagues (2017) stated that ARDS is associated with high mortality and morbidity.  While INO has been used to improve oxygenation, its role remains controversial.  In a systematic review, these researchers examined the effects of INO on mortality in adults and children with ARDS.  They included all RCTs, irrespective of date of publication, blinding status, outcomes reported or language.  The primary outcome measure was all-cause mortality.  These investigators performed several subgroup and sensitivity analyses to evaluate the effect of INO.  There was no statistically significant effect of INO on longest follow-up mortality (INO group 250/654 deaths (38.2 %) versus control group 221/589 deaths (37.5 %; RR (95 % CI) 1.04 (0.9 to 1.19)).  These researchers found a significant improvement in PaO2 /FI O2 ratio at 24 hours (mean difference (95 % CI) 15.91 (8.25 to 23.56)), but not at 48 or 72 hours, while 4 trials indicated improved oxygenation in the INO group at 96 hours (MD (95 % CI) 14.51 (3.64 to 25.38)).  There were no statistically significant differences in ventilator-free days, duration of mechanical ventilation, resolution of multi-organ failure, quality of life (QOL), length of stay (LOS) in ICU or hospital, cost-benefit analysis and methemoglobin and nitrogen dioxide levels.  There was an increased risk of renal impairment (RR (95 % CI) 1.59 (1.17 to 2.16)) with INO.  The authors concluded that there is insufficient evidence to support the use of INO in any category of critically ill patients with ARDS despite a transient improvement in oxygenation, since mortality is not reduced and it may induce renal impairment.

Dani and associates (2017) state that iNO cannot be recommended for the routine treatment of respiratory failure in premature neonates, but it has been suggested that the effectiveness of iNO therapy should be further studied in more select preterm infants, such as those with persistent PPHN.  These researchers evaluated the frequency of PPHN in very preterm infants with severe RDS, to assess the effectiveness of iNO in these patients, and to individuate possible predictive factors for the response to iNO in preterm infants with RDS.  They retrospectively studied infants of less than 30 weeks of gestational age or birth weight of less than 1,250 g, who were affected by severe RDS and treated with iNO during the 1st week of life.  Clinical characteristics of infants with or without echocardiographic diagnosis of PPHN were compared, as well as those of responder or non-responder to iNO therapy.  Effectiveness of iNO was evaluated by recording changes of MAP, FiO2 , SpO2 /FiO2 ratio, and oxygenation index (OI) before, and 3 ± 1, 6 ± 1, 12 ± 3, 24 ± 6, 48 ± 6, and 72 ± 12 hours after beginning therapy.  These investigators studied 42 (4.6 %) infants, of whom 28 (67 %) had PPHN and 14 (33 %) did not; iNO therapy was associated with improved oxygenation in both the groups but it was quicker in the PPHN than in the non-PPHN group.  Multi-variate analysis showed that FiO2 greater than 0.65, diagnosis of PPHN, and birth weight of greater than 750 g independently predicted effectiveness of iNO in very preterm infants with RDS.  The authors found that PPHN is a frequent complication of severe RDS in very preterm infants and iNO therapy could improve their oxygenation earlier than in infants without PPHN.  Moreover, they stated that iNO therapy is not recommended for the routinely treatment of RDS in premature neonates; but in cases of concurrent diagnosis of PPHN it should be considered carefully.

Carey and colleagues (2018) noted that iNO is increasingly prescribed to extremely premature neonates with RDS.  Most of this off-label use occurs during the 1st week of life.  These investigators studied this practice, hypothesizing that it would not be associated with improved survival.  They queried the Pediatrix Medical Group Clinical Data Warehouse to identify all neonates born at 22 to 29 weeks' gestation from 2004 to 2014.  In this study sample, these researchers included singletons who required mechanical ventilation for treatment of RDS and excluded those with anomalies.  The primary outcome was death before discharge.  Through a sequential risk set approach, each patient who received iNO during the first 7 days of life ("case patient") was matched by using propensity scores to a patient who had not received iNO at a chronological age before the case patient's iNO initiation age (defined as the index age for the matched pair).  The association between iNO status and in-hospital mortality was evaluated in a Cox proportional hazards regression model by using age as the time scale with patients entering the risk set at their respective index age.  Among 37,909 neonates in this study sample, these researchers identified 993 (2.6 %) who received iNO.  The 2 matched cohorts each contained 971 patients.  These investigators did not observe a significant association between iNO exposure and mortality (hazard ratio [HR], 1.08; 95 % CI: 0.94 to 1.25; p = 0.29).  The authors concluded that off-label prescription of iNO is not associated with reduced in-hospital mortality among extremely premature neonates with RDS.

Congenital Diaphragmatic Hernia

On behalf of the Pediatric Cardiac Intensive Care Society, Chen and colleagues (2016) reviewed the pharmacologic therapeutic options for PAH in the cardiac ICU (CICU) and summarized the most-recent literature supporting these therapies.  These investigators carried out a literature search for prospective studies, retrospective analyses, and case reports evaluating the safety and efficacy of PAH therapies.  Specific targeted therapies developed for the treatment of adult patients with PAH have been applied for the benefit of children with PAH.  With the exception of INO, there are no FDA-approved medications for children with PAH.  Unfortunately, data on treatment strategies in children with PAH were limited by the small number of randomized controlled clinical trials evaluating the safety and efficacy of specific treatments.  The therapeutic options for PAH in children focused on endothelial-based pathways.  Calcium channel blockers (CCBs) are recommended for use in a very small, select group of children who are responsive to vasoreactivity testing at cardiac catheterization.  Phosphodiesterase type 5 (PDE-5) inhibitor therapy is the most-commonly recommended oral therapeutic option in children with PAH.  Prostacyclins provide adjunctive therapy for the treatment of PAH as infusions (IV and subcutaneous) and inhalation agents.  INO is the 1st-line vasodilator therapy in persistent pulmonary hypertension of the newborn and is commonly used in the treatment of PAH in the ICU.  Endothelin receptor antagonists have been shown to improve exercise tolerance and survival in adult patients with PAH.  Soluble guanylate cyclase stimulators are the 1st drug class to be FDA-approved for the treatment of chronic thromboembolic pulmonary hypertension.  The authors concluded that literature and data supporting the safe and effective use of PAH therapies in children in the CICU were limited.  Extrapolation of adult data has afforded safe medical treatment of pulmonary hypertension in children.

Putnam and colleagues (2016) described the spectrum of INO use among patients with congenital diaphragmatic hernia (CDH); and its association with pulmonary hypertension (pHTN) and mortality.  These researchers performed a review of prospectively collected patient data in the Congenital Diaphragmatic Hernia Study Group registry between January 1, 2007, and December 31, 2014, from 70 participating centers in 13 countries.  A total of 3,367 newborn infants diagnosed with CDH and entered into the registry were reviewed.  On the basis of echocardiogram (ECG) data, pHTN was defined as right ventricular systolic pressure greater than or equal to 2/3 of the systemic systolic pressure.  Propensity score and regression analyses were performed.  Main outcome measures: included variability in INO use and its association with pHTN and mortality.  These outcomes were formulated prior to data evaluation.  A total of 68  (97.1 %) centers used INO.  Of 3,367 patients with CDH (1,366 [40.6 %] females; median estimated gestational age, 38 weeks; range of 23 to 42 weeks), a total of 2,047 (60.8 %) received INO; the mean percentage of those receiving INO per center was 62.3 % (range of 0 % to 100 %).  Median INO dose and duration were 20 (range of 0.1 to 80) ppm and 8 (range of 0 to 100) days.  Of the 2,174 infants with pHTN, 1,613 infants (74.2 %) received INO.  Of the 943 infants without pHTN, 343 infants (36.4 %) were treated with INO.  Based on propensity score analysis incorporating 10 clinically relevant variables, the use of INO was significantly associated with increased mortality (average treatment effect on the treated: 0.15; 95 % CI: 0.10 to 0.20).  The authors concluded that the use of INO was common but highly variable among centers, and 36 % of patients without pHTN received INO therapy.  Based on data from 70 centers, the use of INO in patients with CDH may be associated with increased mortality.  They stated that future efforts should be directed toward data-driven standardization of INO use to ensure cost-effective practices.

On behalf of the Canadian Congenital Diaphragmatic Hernia Collaborative, Puligandla and colleagues (2018) stated that INO is indicated for confirmed supra-systemic PAH without left ventricular dysfunction, provided lung recruitment is adequate. In the absence of clinical or echocardiographic response, INO should be stopped. These investigators supported the use of INO for the treatment of severe pulmonary hypertension (with preserved left ventricular function and adequate lung recruitment), but recommend its discontinuation if no clinical improvement is observed within 24 hours of beginning treatment.

In an UpToDate chapter on congenital diaphragmatic hernia in the neonate, Hedrick and Adzick (2019) stated: "Although several studies have shown that iNO does not appear to have long-term benefits, iNO administration is widespread in patients with CDH. In our center, prior to placing the patient on ECMO, we utilize iNO in select patients with respiratory failure due to pulmonary hypertension despite having receiving maximal ventilatory support." 

Preterm Infants

Persistent Pulmonary Hypertension in Newborn Babies

Smith and Perez (2016) stated that NO is a potent, selective pulmonary vasodilator that has been proven to decrease PVR and has been part of the treatment arsenal for PPHN.  In 2009, the approach to the use of INO at Winnie Palmer Hospital for Women and Babies (WPH) changed to emphasize avoiding invasive ventilation while maintaining optimal ventilation to perfusion ratio, avoiding hyperventilation and alkalosis agents, and avoiding hyperoxemia and hyperoxia exposure.  In a retrospective chart review, these investigators described the outcomes of babies whose primary treatment for PPHN was non-invasive (NIV) INO.  Inclusion criteria were greater than 34 weeks' gestation, ECG evidence of PPHN within the first week of life, and NIV INO as the primary treatment.  A total of 24 babies met criteria: 21 solely treated non-invasively, 3 required invasive support.  Supplemental oxygen need was greater than or equal to 50 % for 21 babies pre-INO treatment and dropped to less than 30 % for all babies post-INO.  Average exposure to supplemental oxygen was 6.3 days.  Mean duration of INO administration was 2.5 days.  Average LOS was 14 days; and all babies survived.  The authors concluded that the findings of this review showed a low incidence of escalation to invasive ventilation; non-invasive INO was found to be an effective and well-tolerated frontline approach for treating PPHN in near-term and term infants with an intact respiratory drive.  Moreover, they stated that further studies could provide the necessary evidence on clinical outcomes as well as cost-effectiveness to guide best practice.

Administration of Nitric Oxide During Extracorporeal Membrane Oxygenation

Tadphale and associates (2016) evaluated the outcomes associated with the use of INO during extra-corporeal membrane oxygenation (ECMO).  These investigators performed post-hoc analysis of data from an existing administrative national database, Pediatric Health Information system (2004 to 2014).  Multivariable logistic regression models were fitted to study the effect of INO during ECMO on study outcomes.  A total of 42 children's hospitals across the United States were included in this analysis.  Patients in the age group from 1 day through 18 years admitted to an ICU who received ECMO during their hospital stay were included.  A total of 6,419 patients met inclusion criteria.  Of these, INO was used among 3,629 patients during ECMO run.  Approximately 50 % of the study patients received INO at ECMO initiation.  The proportion of patients receiving INO during ECMO decreased with increasing duration of ECMO.  After adjusting for patient characteristics and center variables, use of INO was not associated with any survival benefit.  However, higher proportion of patients receiving INO were associated with prolonged hospital LOS and prolonged duration of ECMO.  In adjusted models, the hospital charges were higher in the INO group.  The median hospital costs among patients receiving INO were higher by $39,732 (95 % CI: $31,074 to $48,390) as compared to the patients who did not receive INO, after adjusting for patient (including hospital LOS) and center level variables.  As the duration of INO therapy increased, proportion of patients with prolonged duration of ECMO and prolonged hospital LOS increased.  The authors concluded that this large observational analysis of use of INO during ECMO called into question the benefits of INO among patients receiving ECMO for pulmonary or cardiac failure.  They stated that given the inability to determine type of ECMO and control for severity of illness, these findings should be interpreted as exploratory.

Liver Transplantation

Fukazawa and Lang (2016) stated that ischemia-reperfusion injury (IRI) continues to be a major contributor to graft dysfunction, thus supporting the need for therapeutic strategies focused on minimizing organ damage especially with growing numbers of extended criteria grafts being utilized, which are more vulnerable to cold and warm ischemia.  Nitric oxide has been demonstrated to play major roles in vascular homeostasis, neurotransmission, and host defense inflammatory reactions.  Under conditions of ischemia, NO has consistently been demonstrated to enhance microcirculatory vasorelaxation and mitigate pro-inflammatory responses, making it an excellent strategy for patients undergoing organ transplantation.  Clinical studies designed to test this hypothesis have yielded very promising results that included reduced hepato-cellular injury and enhanced graft recovery without any identifiable complications.  By what means NO facilitates extra-pulmonary actions is up for debate and speculation.  The general premise is that there are NO-containing intermediates in the circulation, that ultimately mediate either direct or indirect effects.  A plethora of data exists explaining how NO-containing intermediate molecules form in the plasma as S-nitrosothiols (e.g., S-nitrosoalbumin), whereas other compelling data suggested nitrite to be a protective mediator.  The authors discussed the use of INO as a way to protect the donor liver graft against IRI in patients undergoing liver transplantation.

These researchers stated that IRI has been well-characterized the liver especially as it relates to liver resections and liver transplantation.  The contribution of NO deficiency is a newer finding and may have a central role in the pathogenesis of this injury.  Replenishing the liver with NO via either by inhalation, inhaled or intravenous nitrate or via other donor drugs represents a pragmatic means of mitigating injury.  Clinical studies incorporating INO provided evidence in mitigating injury from IRI; INO has demonstrated repeated efficacy without any demonstrable metabolic or hematological toxicities.  Costs of routine NO administration during liver transplantation is negligible when the entire spectrum of care is considered.  Therefore, NO has a potential to be a good therapeutic option for organ resuscitation in liver transplantation, especially for the extended criteria (marginal quality) donors given that there is a surge in use of extended criteria donors to expand donor pool, but further investigation is still needed for routine clinical use.

Right Heart Failure after Hemorrhagic Shock and Trauma Pneumonectomy

Lubitz and colleagues (2017) noted that hemorrhagic shock and pneumonectomy causes an acute increase in PVR.  The increase in PVR and right ventricular (RV) afterload leads to acute RV failure, thus reducing left ventricular (LV) preload and output; INO lowers PVR by relaxing pulmonary arterial smooth muscle without remarkable systemic vascular effects.  These researchers hypothesized that with hemorrhagic shock and pneumonectomy, INO can be used to decrease PVR and mitigate right heart failure.  A hemorrhagic shock and pneumonectomy model was developed using sheep, which received lung protective ventilatory support and were instrumented to serially obtain measurements of hemodynamics, gas exchange, and blood chemistry.  Heart function was assessed with ECG.  After randomization to study gas of INO 20 ppm (n = 9) or nitrogen as placebo (n = 9), baseline measurements were obtained.  Hemorrhagic shock was initiated by exsanguination to a target of 50 % of the baseline mean arterial pressure (MAP). The resuscitation phase was initiated, consisting of simultaneous left pulmonary hilum ligation, via median sternotomy, infusion of autologous blood and initiation of study gas.  Animals were monitored for 4 hours.  All animals had an initial increase in PVR; and PVR remained elevated with placebo; with INO, PVR decreased to baseline.  Echocardiography showed improved RV function in the INO group while it remained impaired in the placebo group.  After an initial increase in shunt and lactate and decrease in mixed venous oxygen saturation (SvO2), all returned toward baseline in the INO group but remained abnormal in the placebo group.  The authors concluded that these findings indicated that by decreasing PVR, INO decreased RV afterload, preserved RV and LV function, and tissue oxygenation in this hemorrhagic shock and pneumonectomy model; suggesting that INO may be a useful clinical adjunct to mitigate right heart failure and improve survival when trauma pneumonectomy is needed.

Acute Pulmonary Embolism

Kline and associates (2017) hypothesized that administration of iNO plus oxygen to subjects with submassive PE will improve right ventricular (RV) systolic function and reduce RV strain and necrosis, while improving patient dyspnea, more than treatment with oxygen alone.  These investigators described the rationale and protocol for a registered (NCT01939301), nearly completed phase II, 3-center, randomized, double-blind, controlled trial.  Eligible patients have pulmonary imaging-proven acute PE.  Subjects must be normotensive, and have RV dysfunction on echocardiography or elevated troponin or brain natriuretic peptide (BNP) and no fibrinolytics.  Subjects receive NO plus oxygen or placebo for 24 hours (± 3 hours) with blood sampling before and after treatment, and mandatory echocardiography and high-sensitivity troponin post-treatment to assess the composite primary end-point.  The sample size of n = 78 was predicated on 30 % more iNO-treated patients having a normal high-sensitivity troponin (less than 14 pg/ml) and a normal RV on echocardiography at 24 hours with α = 0.05 and β = 0.20.  Safety was ensured by continuous spectrophotometric monitoring of percentage of methemoglobinemia and a pre-defined protocol to respond to emergent changes in condition.  Blinding was ensured by identical tanks, software, and physical shielding of the device display and query of the clinical care team to assess blinding efficacy.  The authors concluded that they had enrolled 78 patients over a 31-month period.  No patient has been withdrawn as a result of a safety concern, and no patient has had a serious adverse event (AE) related to NO.

Bronchiolitis

In a pilot, randomized, double-blinded, controlled, phase IIa clinical trial, Tai and colleagues (2018) determined the safety, tolerability (primary outcome) and efficacy (secondary outcome) of high-dose iNO for the treatment of infants with moderately severe bronchiolitis.  Intermittent inhalations of NO 160 ppm for 30 mins or oxygen/air (control) were given 5 times/day to hospitalized infants (2 to 11 months) with acute bronchiolitis.  Oxygen saturation, methemoglobin, and nitric dioxide (NO2 ) levels and vital signs were monitored.  A total of 43 infants were enrolled.  Baseline characteristics were comparable in both study groups.  Mean clinical score, comprised of 4 components: respiratory rate, use of accessory muscles, wheezes and crackles, and % room-air oxygen saturation, was 7.86 (±1.1) and 8.09 (±1.2) in the NO and control groups, respectively, consistent with moderate severity.  The overall frequency of AEs was similar between the groups.  Repeated NO inhalations did not result in increased inhaled NO2 levels or cumulative effect on methemoglobin levels.  Secondary outcomes of efficacy were measured by LOS in hours: LOS did not differ between groups.  However, in a post-hoc analysis of a subgroup of infants hospitalized for greater than 24 hours (n = 24), the median LOS was shorter in the NO (41.9 hours) than in the control group (62.5 hours) (p = 0.014).  The authors concluded that this study was unable to detect a difference in side effects using intermittent high-dose iNO or supportive treatment alone, in infants with moderate bronchiolitis; preliminary efficacy outcomes were encouraging.

Mycobacterium Infection in Cystic Fibrosis

Yaacoby-Bianu and associates (2018) stated that mycobacterium abscessus is one of the most antibiotic-resistant pathogens in cystic fibrosis (CF) patients; and NO has broad-spectrum antimicrobial activity.  Clinical studies indicated that it is safe and tolerable when given as 160 ppm intermittent inhalations.  These researchers performed a prospective study on the use of compassionate adjunctive iNO therapy in 2 CF patients with persistent mycobacterium abscessus infection.  No AEs were reported.  Both subjects showed significant reduction in quantitative polymerase chain reaction (qPCR) results for mycobacterium abscessus load in sputum during treatment; estimated colony forming unit decreased from 7,000 to 550 and from 3,000 to 0 for patient 1 and patient 2, respectively.  The authors concluded that intermittent inhalation with 160 ppm NO was well-tolerated, safe and resulted in significant reduction of mycobacterium abscessus load.  They stated that this approach may constitute an adjuvant therapeutic approach for CF patients with mycobacterium abscessus lung disease; however, further studies are needed to define dosing, duration and long-term clinical outcome.

Pseudomonas Aeruginosa  Infection in Cystic Fibrosis

Howlin and colleagues (2017) noted that despite aggressive antibiotic therapy, bronchopulmonary colonization by pseudomonas aeruginosa (P. aeruginosa) causes persistent morbidity and mortality in patients with CF.  Chronic P. aeruginosa infection in the CF lung is associated with structured, antibiotic-tolerant bacterial aggregates known as biofilms.  These researchers had demonstrated the effects of non-bactericidal, low-dose NO as a novel adjunctive therapy for P. aeruginosa biofilm infection in CF in an ex-vivo model and a proof-of-concept (POC), double-blind clinical trial.  Submicromolar NO concentrations alone caused disruption of biofilms within ex-vivo CF sputum and a statistically significant decrease in ex-vivo biofilm tolerance to tobramycin and tobramycin combined with ceftazidime.  In the 12-patient, randomized clinical trial, 10 ppm NO inhalation caused significant reduction in P. aeruginosa biofilm aggregates compared with placebo across 7 days of treatment.  The authors concluded that their study had demonstrated the potential for the use of low-dose NO to enhance antibiotic treatment of biofilm infections.  Moreover, they stated that although the practical challenges in delivering iNO to CF patients were considerable, future novel NO donor antibiotics might prove to be a more feasible approach to targeting biofilms

The authors stated that the main drawback of this study was the small sample size (n = 12) and between-patient variation in clinical and microbiological parameters.  This rendered formal statistical analyses difficult, but they were able to incorporate repeated measurements over time to improve power.  Variability in the qPCR results between the NO and placebo groups was probably due to sample heterogeneity in chronically infected patients.  Despite these limitations, FISH image analysis data demonstrated a treatment effect and provided a POC for the low-dose NO approach.  Similarly, the analysis of the changes in systemic NO status following low-dose iNO was likely compounded by inter-individual differences in NO processing.

Hypoxemic Respiratory Failure

In an observational study, Berger and colleagues (2020) characterized contemporary use of INO in pediatric acute respiratory failure and examined relationships between clinical variables and outcomes.  These researchers evaluated the relationship of INO response to patient characteristics including right ventricular dysfunction and clinician responsiveness to improved oxygenation.  They hypothesized that prompt clinician responsiveness to minimize hyperoxia would be associated with improved outcomes.  This trial was carried out at 8 sites of the Collaborative Pediatric Critical Care Research Network; subjects were 151 patients who received INO for a primary respiratory indication.  Clinical data were abstracted from the medical record beginning at INO initiation and continuing until the earliest of 28 days, ICU discharge, or death.  Ventilator-free days, oxygenation index, and Functional Status Scale were calculated.  Echocardiographic reports were abstracted assessing for PH, right ventricular dysfunction, and other cardiovascular parameters.  Clinician responsiveness to improved oxygenation was determined.  A total of 130 patients (86 %) who received INO had improved oxygenation by 24 hours.  PICU mortality was 29.8 %, while a new morbidity was identified in 19.8 % of survivors.  Among patients who had echocardiograms, 27.9 % had evidence of PH, 23.1 % had right ventricular systolic dysfunction, and 22.1 % had an atrial communication.  Moderate or severe right ventricular dysfunction was associated with higher mortality.  Clinicians responded to an improvement in oxygenation by decreasing FIO2 to less than 0.6 within 24 hours in 71 % of patients.  Timely clinician responsiveness to improved oxygenation with INO was associated with more ventilator-free days but not less cardiac arrests, mortality, or additional morbidity.  The authors concluded that clinician responsiveness to improved oxygenation was associated with less ventilator days.  Algorithms to standardize ventilator management may improve signal-to-noise ratios in future trials enabling better assessment of the effect of INO on patient outcomes.  Furthermore, confining studies to more selective patient populations such as those with right ventricular dysfunction may be needed.

Treatment of Pain Crises in People With Sickle Cell Disease

Aboursheid and colleagues (2019) stated that in individuals with SCD, sickled red blood cells cause the occlusion of small blood vessels that presents as episodes of severe pain known as pain crises or vaso-occlusive crises.  The pain can occur in the bones, chest, or other parts of the body, and may last several hours to days.  Pain relief during crises includes both pharmacologic and non-pharmacologic treatments.  The efficacy of INO in pain crises has been a controversial issue and hypotheses have been made suggesting a beneficial response due to its vasodilator properties.  Yet no conclusive evidence has been presented.  Ina Cochrane review, these investigators examined the available RCTs, which addressed this topic.  To capture the available body of evidence evaluating the safety and efficacy of the use of INO in treating pain crises in people with SCD; and to evaluate the treatment's relevance, robustness, and validity, in order to better-guide medical practice in the fields of hematology and palliative care (since recent literature appeared to favor the involvement of palliative care for those people).  These investigators searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Hemoglobinopathies Trials Register.  Unpublished work was identified by searching the abstract books of the European Hematology Association conference; the American Society of Hematology conference; the British Society for Hematology Annual Scientific Meeting; the Caribbean Health Research Council Meetings; and the National Sickle Cell Disease Program Annual Meeting.  Date of most recent search: September 19, 2019.  These researchers also searched ongoing study registries, date of most recent search: September 26, 2019.  Randomized and quasi-randomized trials comparing INO with placebo, or standardized way of treatment of pain crises in people with sickle cell disease.

Two authors independently assessed trial quality and extracted data (including AE data).  A 3rd author helped clarify any disagreement.  When the data were not reported in the text, these researchers attempted to extract the data from any table or figure available.  They contacted trial authors for additional information.  They assessed the quality of the evidence using the GRADE criteria.  These investigators identified 6 trials, 3 of which (188 subjects) were eligible for inclusion in the review.  There were equal numbers of males and females; and most subjects were adults, although 1 small trial was conducted in a children's hospital and recruited children over the age of 10 years.  All 3 parallel trials compared INO (80 ppm) to placebo (room air) for 4 hours; 1 trial continued administering NO (40 ppm) for a further 4 hours.  This extended trial had an overall low risk of bias; however, in the remaining 2 trials these researchers had concerns about the risk of bias from the small sample size and additionally a high risk of bias due to financial conflicts of interest in one of these smaller trials.  They were only able to analyze some limited data from the 8-hour trial and report the remaining results narratively.  The time to pain resolution was only reported in 1 trial (150 subjects), showing there may be little or no difference between the 2 groups: with INO median 73.0 hours (95 % CI: 46.0 to 91.0) and with placebo median 65.5 hours (95 % CI: 48.1 to 84.0) (low-quality evidence).  No trial reported on the duration of the initial pain crisis.  Only 1 large trial reported on the frequency of pain crises in the follow-up period and found there may be little or no difference between the INO and placebo groups for a return to the ED, RR 0.73 (95 % CI: 0.31 to 1.71) or for re-hospitalization, RR 0.53 (95 % CI: 0.25 to 1.11) (150 subjects; low-quality evidence).  There may be little or no difference between treatment and placebo in terms of reduction in pain score at any time=point up to 8 hours (150 subjects).  The 2 smaller trials reported a beneficial effect of INO in reducing the VAS pain score after four hours of the intervention, but these trials were small and limited compared to the first trial.  Analgesic use was reported not to differ greatly between the INO group and placebo group in any of the 3 trials, but no analyzable data were provided.  The median duration of hospitalization was reported by 2 trials, in the largest trial the placebo group had the shorter duration and in the second smaller (pediatric) trial hospitalization was shorter in the treatment group.  Only the largest trial (150 subjects) reported serious AEs, with no increase in the INO group during or after the intervention compared to the control group (acute chest syndrome occurred in 5 out of 75 subjects from each group, pyrexia in 1 out of 75 subjects from each group, dysphagia and a drop in hemoglobin were each reported in 1 out of 75 subjects in the INO group, but not in the placebo group) (low-quality evidence).  The authors concluded that the currently available trials do not provide sufficient evidence to determine the effects (benefits or harms) of using INO to treat pain (vaso-occlusive) crises in individuals with SCD.  These researchers stated that large-scale, long-term trials are needed to provide more robust data in this area.  Patient-important outcomes (e.g., measures of pain and time to pain resolution and amounts of analgesics used), as well as use of healthcare services should be measured and reported in a standardized form.

Pulmonary Hypertension Associated With Pulmonary Fibrosis

Nathan and colleagues (2020) noted that the interstitial lung diseases include a variety of disorders, many of which are characterized by fibrotic changes (fILD).  Of the fILDs, Idiopathic pulmonary fibrosis is the most common.  Pulmonary hypertension frequently complicates fILD and is associated with impaired functional capability, lower physical activity, and significantly reduced life expectancy.  There is no proven treatment for patients with fILD-PH.  These investigators reported findings from the first cohort of a phase-IIb/III clinical trial with pulsed INO in patients with fILD-PH.  Subjects in cohort 1 were randomized to INO 30 μg/kg ideal body weight/hour (INO30) or placebo for 8 weeks of blinded treatment; subjects then transitioned to open-label extension (OLE) on INO30 followed by dose escalation to INO45 then INO75.  Activity monitoring was used to evaluate changes in daily activity; safety and efficacy were evaluated.  A total of 23 patients were randomized to INO30 and 18 to placebo.  During blinded treatment, INO30 subjects showed an average improvement in moderate/vigorous physical activity (MVPA) and remained stable in overall activity.  Placebo subjects showed an average drop of 26 % in MVPA and a 12 % drop in overall activity.  The INO group had an improvement in oxygen saturation.  During OLE, subjects maintained their activity levels including placebo subjects who transitioned from a decline to a maintenance in all activity parameters; INO at all doses (30, 45, and 75) was safe and well-tolerated.  The authors concluded that treatment with INO30 demonstrated clinically and statistically significant benefit in MVPA and clinically significant benefit in overall activity.  In the OLE, higher doses of INO were also safe and well-tolerated while showing maintenance in activity parameters.  These findings need to be further investigated.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+": :
CPT codes covered if selection criteria are met:
Inhaled nitric oxide (INO) therapy - no specific code:
Other CPT codes related to the CPB:
94002 - 94004	Ventilation assist and management, initiation of pressure or volume preset ventilators for assisted or controlled breathing
93463	Pharmacologic agent administration (eg, inhaled nitric oxide, intravenous infusion of nitroprusside, dobutamine, milrinone, or other agent) including assessing hemodynamic measurements before, during, after and repeat pharmacologic agent administration, when performed (List separately in addition to code for primary procedure)
99503	Home visit for respiratory therapy care (e.g., bronchodilator, oxygen therapy, respiratory assessment, apnea evaluation)
ICD-10 codes covered if selection criteria are met:
I27.0	Primary pulmonary hypertension
I27.20 - I27.29	Other secondary pulmonary hypertension
P07.20 - P07.39	Disorders of newborn related to short gestation
P22.0	Respiratory distress syndrome of newborn
P28.5	Respiratory failure of newborn
P29.30 - P29.38	Persistent fetal circulation
P36.0 - P36.9	Bacterial sepsis of newborn
P84	Other problems with newborn [birth asphyxia]
P91.60 - P91.63	Hypoxic ischemic encephalopathy [HIE]
Q33.1	Accessory lobe of lung
Q33.2	Sequestration of lung
Q33.3	Agenesis of lung
Q33.4	Congenital bronchiectasis
Q33.5	Ectopic tissue in lung
Q33.6	Congenital hypoplasia and dysplasia of lung
Q33.8	Other congenital malformations of lung
Q33.9	Congenital malformation of lung, unspecified
ICD-10 codes not covered for indications listed in the CPB:
A31.0 - A31.9	Infection due to other mycobacteria
B50.0 - B54	Malaria
B96.5	Pseudomonas (aeruginosa) (mallei) (pseudomallei) as the cause of diseases classified elsewhere
D57.00 - D57.219 D57.411 - D57.819	Sickle-cell disorders
E84.0 - E84.9	Cystic fibrosis
I26.09, I26.99	Other pulmonary embolism with or without acute cor pulmonale
I50.1 - I50.9	Heart failure [after hemorrhagic shock and trauma pneumonectomy]
J21.0 - J21.9	Acute bronchiolitis
J80	Acute respiratory distress syndrome
J84.10	Pulmonary fibrosis, unspecified
J84.112	Idiopathic pulmonary fibrosis
J84.17	Other interstitial pulmonary diseases with fibrosis in diseases classified elsewhere
J95.1 - J95.3	Acute and chronic pulmonary insufficiency following surgery
J95.821 - J95.822	Postprocedural respiratory failure
J96.00 - J96.02	Acute respiratory failure
J96.20 - J96.22	Acute and chronic respiratory failure
J98.4	Other disorders of lung
J99	Respiratory disorders in diseases classified elsewhere
Q20.0 - Q26.9	Congenital heart disease [if reported for post-operative management of pulmonary hypertension in infants and children]
Q79.0	Congenital diaphragmatic hernia
R57.1	Hypovolemic shock [hemorrhagic shock]
R57.9	Shock, unspecified [hemorrhagic shock]
S21.301+ - S21.309+	Unspecified open wound of unspecified front wall of thorax with penetration into thoracic cavity, initial encounter
S27.0xx+	Traumatic pneumothorax A
S27.1xx+	Traumatic hemothorax A
S27.2xx+	Traumatic hemopneumothorax A
S27.301+ - S27.399+	Unspecified open wound of unspecified front wall of thorax with penetration into thoracic cavity, initial encounter
T86.40 - T86.49	Complications of liver transplant [ischemia-reperfusion injury/acute rejection following liver transplantation]
T86.810 - T86.819	Complications of lung transplant
Z90.2	Acquired absence of lung [part of] [trauma pneumonectomy]

The above policy is based on the following references: