Inhaled nitric oxide (iNO) for preventing prematurity-related bronchopulmonary dysplasia (BPD): 7-year follow-up of the European Union Nitric Oxide (EUNO) trial.

OBJECTIVES: Most studies of inhaled nitric oxide (iNO) for prevention of bronchopulmonary dysplasia (BPD) in premature infants have focused on short-term mortality and morbidity. Our aim was to determine the long-term effects of iNO. METHODS: A 7-year follow-up was undertaken of infants entered into a multicenter, double-blind, randomized, placebo-controlled trial of iNO for prevention of BPD in premature infants born between 24 and 28 weeks plus six days of gestation. At 7 years, survival and hospital admissions since the 2-year follow-up, home oxygen therapy in the past year, therapies used in the previous month and growth assessments were determined. Questionnaires were used to compare general health, well-being, and quality of life. RESULTS: A total of 305 children were assessed. No deaths were reported. Rates of hospitalization for respiratory problems (6.6 vs. 10.5%, iNO and placebo group, respectively) and use of respiratory medications (6.6 vs. 9.2%) were similar. Two patients who received iNO and one who received placebo had received home oxygen therapy. There were no significant differences in any questionnaire-documented health outcomes. CONCLUSIONS: iNO for prevention of BPD in very premature infants with respiratory distress did not result in long-term benefits or adverse long-term sequelae. In the light of current evidence, routine use of iNO cannot be recommended for prevention of BPD in preterm infants.

Inhaled nitric oxide for neonates with persistent pulmonary hypertension of the newborn in the CINRGI study: time to treatment response.

BACKGROUND: Substantial numbers of neonates with hypoxic respiratory failure (HRF) do not immediately respond to inhaled nitric oxide (iNO) and are often labeled as non-responders. This retrospective data analysis assessed time to treatment response in the iNO key registration trial. METHODS: Treatment response was defined as a ≥10% increase in partial pressure of arterial oxygen (PaO2) or a ≥10% decrease in oxygenation index (OI) after initiation of study gas without the need for extracorporeal membrane oxygenation (ECMO). The proportion of patients showing a response at 30 min, 1 h, 24 h, and >24 h after iNO or placebo initiation was calculated and stratified by baseline PaO2 and OI. RESULTS: Data from 248 patients (iNO: n = 126; placebo: n = 122) were included; 66 patients receiving iNO showed improvement in oxygenation without needing ECMO versus 38 receiving placebo. Of the 66 iNO responders, 73% responded within ≤30 min, 9% within ≤1 h, 12% within ≤24 h, and 6% after 24 h. Of the 38 patients with improvement in oxygenation without needing ECMO while receiving placebo, 53% showed improvement within ≤30 min, 16% within ≤1 h, 29% within ≤24 h, and 3% after 24 h. Baseline disease severity was not predictive of time to response. Of the 48 patients in the iNO treatment group who were classified as non-responders due to eventual need for ECMO and not included in the analysis of responders, 40 (83%) had an initial improvement in oxygenation during iNO therapy. CONCLUSIONS: Changes in PaO2 and OI after iNO initiation appear to be imprecise biomarkers of response to therapy in neonates with HRF. In some patients treated with iNO, it took up to 24 h to achieve improvement in oxygenation without need for ECMO, and a majority of those who eventually required ECMO did show an initial improvement in oxygenation during iNO treatment. Thus, reliable, objective, early criteria for iNO response still need to be established, and initial PaO2/OI responses should be interpreted with caution, particularly when considering discontinuing iNO therapy.

Efficacy of inhaled nitric oxide in neonates with hypoxic respiratory failure and pulmonary hypertension: the Japanese experience.

OBJECTIVE: To analyze data from a registry of Japanese neonates with hypoxic respiratory failure associated with pulmonary hypertension (PH) to compare the effectiveness of inhaled nitric oxide (iNO) in neonates born <34 weeks vs. ≥34 weeks gestational age (GA). MATERIALS AND METHODS: iNO was administered according to approved Japanese product labeling. Study data were collected before iNO administration and at predefined intervals until discontinuation. RESULTS: A total of 1,114 neonates were included (n=431, <34 weeks GA; n=675, ≥34 weeks GA; n=8, missing age data). Mean decrease from baseline oxygenation index (OI) was similar in both age groups. OI reduction was more pronounced in the <34 weeks subgroups with baseline OI ≥25. Survival rates were similar in the <34 weeks GA and ≥34 weeks GA groups stratified by baseline OI (OI<15, 89% vs. 93%; 15≤OI<25, 85% vs. 91%; 25≤OI≤40, 73% vs. 79%; OI>40, 64% vs. 66%). CONCLUSION: iNO improved oxygenation in preterm neonates as effectively as in late preterm and term neonates, without negative impact on survival. If clinically significant PH is present, as measured by pulse oximetry or echocardiography, a therapeutic trial of iNO might be indicated for preterm neonates.

Effect of inhaled nitric oxide on oxygen therapy, mechanical ventilation, and hypoxic respiratory failure.

To assess the role of inhaled nitric oxide (iNO) in reducing the need for oxygen therapy, decreasing time on mechanical ventilatory support, and attenuating probability of hypoxic respiratory failure severity progression, we reviewed published reports of phase III iNO studies in neonates with hypoxic respiratory failure and pulmonary hypertension, as well as a novel post-hoc analysis of data from the Clinical Inhaled Nitric Oxide Research Group Initiative (CINRGI) study population not been previously reported. The post-hoc analysis of the CINRGI study showed that iNO shortens the duration of oxygen therapy versus placebo (17 vs. 34 days; P<0.05); the CINRGI retrospective analysis by Konduri et al. showed earlier administration of iNO (oxygenation index [OI] 15-25) yielded a 48% relative reduction vs. placebo in number of patients who progressed to OI≥30 (16.7% vs. 32.2%; P=0.002). Golombek and Young's pooled analysis of phase III studies showed a rapid improvement in oxygenation after initiation of iNO therapy versus controls in each study, and a significant reduction in median ventilation duration (11 vs. 14 days; P=0.003). A study by Gonzalez et al. revealed that earlier iNO administration in infants with mild to moderate hypoxic respiratory failure (OI 10-30) resulted in a decreased duration of oxygen therapy versus placebo (11.5 vs. 18.0 days; P<0.03) and reduced the probability of developing severe hypoxic respiratory failure.

Target versus actual oxygenation index at initiation of inhaled nitric oxide in neonates with hypoxic respiratory failure: survey results from 128 patient cases.

BACKGROUND: Inhaled nitric oxide (iNO) is a well-established treatment for neonatal hypoxic respiratory failure (HRF). However, iNO therapy initiation criteria have not been standardized. This report describes a follow-up survey administered to neonatologists who had completed an Awareness, Trial, and Usage Survey. The objectives were to compare stated target oxygenation index (OI) versus actual OI at which iNO is initiated in respondents' patients and identify factors associated with iNO initiation at other levels. METHODS: Neonatologists provided iNO-treated HRF patient data. Target and actual OI at initiation were determined. Patient groups were stratified by actual OI deviation from target [<4; at (±3); above: 4-10, 11-20, >20; not measured]. Reasons for above-target OI were determined. RESULTS: Of 83 invited neonatologists, 26 (31%) participated, providing data for 128 patients; 85/128 patients (66%) had OI measured at initiation with neonatologist-stated mean target OI 18.8±5.8. Actual mean OI was 26.2±10.3. iNO was initiated ≤ target in 30/85 patients (35%); most [55/85 (65%)] had iNO initiated when OI was above target. Patients aged ≤1 day and those receiving a fraction of inspired oxygen (FiO2) of 1.0 for more than 1 h had highest OIs at initiation. CONCLUSIONS: Among surveyed neonatologists who treat infants with HRF with pulmonary hypertension (PH), there is a disparity between stated target versus actual OI for iNO initiation, particularly among infants <1 day old and those receiving FiO2 of 1.0 for more than 1 h. In term/near-term neonates with HRF with PH, neonatologists should consider implementing treatment protocols to ensure iNO initiation at stated target OI levels.

A Randomized, Multicenter, Blinded Pilot Study Assessing the Effects of Gaseous Nitric Oxide in an Ex Vivo System of Human Lungs.

INTRODUCTION: Normothermic ex vivo lung perfusion (EVLP) is used to evaluate and condition donor lungs for transplantation. The objective of this study was to determine whether administration of exogenous nitric oxide during EVLP contributes to improvement of lung health. METHODS: A multicenter, blinded, two-arm, randomized pilot study evaluated the effect of gaseous nitric oxide (gNO) administered during EVLP on donor lungs rejected for transplantation. gNO introduced into the perfusate at 80 parts per million (ppm) was compared with perfusate alone (P). An open-label substudy assessed inhaled nitric oxide gas (iNO) delivered into the lungs at 20 ppm via a ventilator. Primary endpoints were an aggregate score of lung physiology indicators and total duration of stable EVLP time. Secondary endpoints included assessments of lung weight and left atrium partial pressure of oxygen (LAPO2). RESULTS: Twenty bilateral donor lungs (blinded study, n = 16; open-label substudy, n = 4) from three centers were enrolled. Median (min, max) total EVLP times for the gNO, P, and iNO groups were 12.4 (8.6, 12.6), 10.6 (6.0, 12.4), and 12.4 (8.7, 13.0) hours, respectively. In the blinded study, median aggregate scores were higher in the gNO group compared to the P group at most time points, suggesting better lung health with gNO (median score range [min, max], 0-3.5 [0, 7]) vs. P (0-2.0 [0, 5] at end of study). In the substudy, median aggregate scores did not improve for lungs in the iNO group. However, both the gNO and iNO groups showed improvements in lung weight and LAPO2 compared to the P group. CONCLUSIONS: The data suggest that inclusion of gNO during EVLP may potentially prolong duration of organ stability and improve donor lung health, which warrants further investigation.

Use of inhaled nitric oxide in preterm vs term/near-term neonates with pulmonary hypertension: results of the PaTTerN registry study.

OBJECTIVE: To evaluate inhaled nitric oxide (iNO) in preterm (PT) vs term/near-term (TNT) neonates with hypoxic respiratory failure (HRF) and pulmonary hypertension (PH) in an observational registry (PaTTerN). STUDY DESIGN: Non-inferiority study comparing PT neonates of GA ≥ 27 to <34 weeks vs TNT neonates of GA ≥ 34 to ≤40 weeks with HRF associated with PH, who received iNO for 24-96 h during the first 0-7 days after birth. Primary endpoint: Achieving ≥25% decrease in oxygenation index/surrogate oxygenation index during iNO treatment. RESULTS: Of 140 neonates (PT, n = 55; TNT, n = 85), the primary endpoint was achieved in 50 (90.9%) PT vs 75 (88.2%) TNT neonates (difference [95% CI]: 0.027 [-0.033, 0.087]); PT neonates achieved non-inferiority interval, and the study was stopped early based on prespecified criteria. CONCLUSIONS: Use of iNO for improving oxygenation in PT neonates with HRF associated with PH is at least as effective as in TNT neonates. CLINICAL TRIAL REGISTRATION: #NCT03132428, registered April 27, 2017.

Rationale for Use of an FDA-Cleared Delivery System for Administration of Inhaled Nitric Oxide in Patients Undergoing Magnetic Resonance Imaging.

Inhaled nitric oxide (iNO) is a pulmonary vasodilator approved for use to improve lung function in neonates >34 weeks' gestational age with hypoxic respiratory failure and pulmonary hypertension. Infants with severe respiratory disease frequently require magnetic resonance imaging (MRI) scans for evaluation of treatment and diagnosis of concurrent disease processes. Until 2015, incompatibility between the standard iNO delivery system components and the magnetic field within the MRI setting required iNO treatment to be interrupted for MRI, which could increase risk of deoxygenation and rebound pulmonary hypertension. In some cases, patients had to forego or delay MRI in order to maintain uninterrupted iNO delivery. The US Food and Drug Administration cleared the first iNO delivery system specifically modified for conditional use with MRI scanners (INOmax DSIR ® Plus MRI) in 2015, based on the determination that the MRI-cleared system met the performance standards equivalent to the standard system. The system design and manufacturer risk management activities, as well as the regulatory requirements for clearance and continued use, provide necessary safeguards to ensure that high-risk neonates receive uninterrupted iNO in a safe manner. Anecdotal reports suggest that adoption of the MRI-cleared system may help optimize care for critically ill neonates who require concurrent administration of iNO and MRI scanning. Further research will be necessary to quantify the nature and magnitude of clinical improvements associated with adoption of the MRI iNO delivery system.

Compatibility and Safety Implications Associated with Interfacing Medical Devices in Neonatal Respiratory Care: A Case Example Using the Inhaled Nitric Oxide Delivery System.

Over the past decade, international organizations have instituted strict regulations for the safe use of connected medical devices. The International Organization for Standardization and the Medical Device Single Audit Program instituted certifications to ensure that connected devices are compatible and operate within their proper clinical parameters. These efforts came about, in part, as a consequence of clinicians' decisions to use nonstandard, modified, or improvised devices for purposes outside the original manufacturers' approved parameters. Unapproved device modifications can be associated with increased risk of dosing errors, monitoring errors, tubing misconnections and serious or potentially fatal adverse events; furthermore, health care providers who implement unapproved device modifications may assume legal and financial liability should harm come to patients as a consequence of the modification. Using the inhaled nitric oxide delivery system as an example, the objective of this paper is to raise awareness of the potential dangers associated with unapproved modification and interfacing of therapeutic gas delivery systems and ventilators in the neonatal intensive care unit setting. The paper also highlights the rationale and necessity for rigorous validation processes that ensure that interfaced medical devices perform as intended in the clinical setting.

An Analysis of Time to Improvement in Oxygenation in Japanese Preterm and Late Preterm or Term Neonates With Hypoxic Respiratory Failure and Pulmonary Hypertension.

PURPOSE: We analyzed data from an ongoing registry to determine time to improvement in oxygenation in preterm and late preterm or term neonates with hypoxic respiratory failure and pulmonary hypertension receiving inhaled nitric oxide (iNO) in Japan. METHODS: Registry neonates received iNO ≤7 days after birth (February 26, 2010, to October 9, 2012). Efficacy and safety profile data were collected up to 96 h after iNO initiation and, if necessary, every 24 h thereafter and before iNO discontinuation. Patients were stratified by gestational age (GA), oxygenation index (OI), and shunt direction at baseline. FINDINGS: Data were evaluated for 1106 neonates (431 with a GA <34 weeks and 675 with a GA of ≥34 weeks). Sixty percent of patients had improved OI; rates were similar for those with GAs of <34 versus ≥34 weeks (61% vs 59%). Overall, mean time to improvement was 11.4 h and tended to be shorter in the groups with a GA <34 weeks versus ≥34 weeks (9.2 vs 12.9 h). Thirty percent of responding neonates required >1 h to achieve improvement in oxygenation. Neonates with higher baseline OI had the greatest decrease in OI during the first hour of treatment. The mortality rate was higher among iNO-treated patients with a baseline OI ≥25 versus those with OI ≥15 to <25 (25% vs 12%; P = 0.0073). IMPLICATIONS: iNO treatment provided acute, sustained improvement in oxygenation in neonates with GAs <34 and ≥34 weeks; 70% of patients had improvement within 1 h, but the remaining 30% took >1 h to respond. Initiation of iNO at lower OIs was associated with reduced mortality compared with higher OI.

The Burden of Hypoxic Respiratory Failure in Preterm and Term/Near-term Infants in the United States 2011-2015.

OBJECTIVES: This study quantified the burden of hypoxic respiratory failure (HRF)/persistent pulmonary hypertension of newborn (PPHN) in preterm and term/near-term infants (T/NTs) by examining health care resource utilization (HRU) and charges in the United States. METHODS: Preterms and T/NTs (≤34 and >34 weeks of gestation, respectively) having HRF/PPHN, with/without meconium aspiration in inpatient setting from January 1, 2011-October 31, 2015 were identified from the Vizient database (first hospitalization=index hospitalization). Comorbidities, treatments, HRU, and charges during index hospitalization were evaluated among preterms and T/NTs with HRF/PPHN. Logistic regression was performed to evaluate mortality-related factors. RESULTS: This retrospective study included 504 preterms and 414 T/NTs with HRF/PPHN. Preterms were more likely to have respiratory distress syndrome, neonatal jaundice, and anemia of prematurity than T/NTs. Preterms had significantly longer inpatient stays (54.1 vs 29.0 days), time in a neonatal intensive care unit (34.1 vs 17.5 days), time on ventilation (4.7 vs 2.2 days), and higher total hospitalization charges ($613 350 vs $422 558) (all P<0.001). Similar rates were observed for use of antibiotics (96.2% vs 95.4%), sildenafil (9.5% vs 8.2%), or inhaled nitric oxide (93.8% vs 94.2%). Preterms had a significantly higher likelihood of mortality than T/NTs (odds ratio: 3.6, 95% confidence interval: 2.3-5.0). CONCLUSIONS: The findings of more severe comorbidities, higher HRU, hospitalization charges, and mortality in preterms than in T/NTs underscore the significant clinical and economic burden of HRF/PPHN among infants. The results show significant unmet medical need; further research is warranted to determine new treatments and real-world evidence for improved patient outcomes.

Effect of Inhaled Nitric Oxide on Survival Without Bronchopulmonary Dysplasia in Preterm Infants: A Randomized Clinical Trial.

Importance: Bronchopulmonary dysplasia (BPD) occurs in approximately 40% of infants born at younger than 30 weeks' gestation and is associated with adverse pulmonary and neurodevelopmental outcomes. Objective: To test whether administration of inhaled nitric oxide to preterm infants requiring positive pressure respiratory support on postnatal days 5 to 14 improves the rate of survival without BPD. Design, Setting, and Participants: This intent-to-treat study was a randomized clinical trial performed at 33 US and Canadian neonatal intensive care units. Participants included 451 neonates younger than 30 weeks' gestation with birth weight less than 1250 g receiving mechanical ventilation or positive pressure respiratory support on postnatal days 5 to 14. Enrollment spanned from December 23, 2009, to April 23, 2012, and neurodevelopmental outcome studies were completed by April 4, 2014. Interventions: Placebo (nitrogen) or inhaled nitric oxide initiated at 20 ppm was decreased to 10 ppm between 72 and 96 hours after starting treatment and then to 5 ppm on day 10 or 11. Infants remained on the 5-ppm dose until completion of therapy (24 days). Main Outcomes and Measures: The primary outcome was the rate of survival without BPD at 36 weeks' postmenstrual age (PMA). Secondary outcomes included BPD severity, postnatal corticosteroid use, respiratory support, survival, and neurodevelopmental outcomes at 18 to 24 months' PMA. Results: In total, 222 infants (52.3% male [n = 116]) received placebo, and 229 infants (50.2% male [n = 115]) received inhaled nitric oxide. Their mean (SD) gestation was 25.6 (1.5) vs 25.6 (1.4) weeks, and their mean (SD) birth weight was 750 (164) vs 724 (160) g. Survival without BPD at 36 weeks' PMA was similar between the placebo and inhaled nitric oxide groups (31.5% [n = 70] vs 34.9% [n = 80]) (odds ratio, 1.17; 95% CI, 0.79-1.73). Rates for severe BPD (26.6% [55 of 207] vs 20.5% [43 of 210]) and postnatal corticosteroid use for BPD (41.0% [91 of 222] vs 41.5% [95 of 229]) and the mean (SD) days of positive pressure respiratory support (55 [40] vs 54 [42]), oxygen therapy (88 [41] vs 91 [59]), and hospitalization (105 [37] vs 108 [54]) were equivalent between the 2 groups. No differences in the incidence of common morbidities were observed. Respiratory outcomes on discharge to home, at 1 year, and at age 18 to 24 months' PMA and neurodevelopmental assessments at 18 to 24 months' PMA did not differ between groups. Conclusions and Relevance: Inhaled nitric oxide, initiated at 20 ppm on postnatal days 5 to 14 to high-risk preterm infants and continued for 24 days, appears to be safe but did not improve survival without BPD at 36 weeks' PMA or respiratory and neurodevelopmental outcomes at 18 to 24 months' PMA. Trial Registration: clinicaltrials.gov Identifier: NCT00931632.

Inhaled nitric oxide in term/late preterm neonates with hypoxic respiratory failure: estimating the financial impact of earlier use.

OBJECTIVE: We reported recently that early use of inhaled nitric oxide therapy (iNO) for term and late preterm infants with hypoxic respiratory failure (HRF) at an oxygenation index (OI) of ≥15 and <20 is associated with earlier discharge from the hospital, relative to babies treated at OI ≥25. The objective of the present analysis is to determine whether earlier use of iNO in this cohort leads to lower cost of medical care. METHODS: We used a decision-analytic model, which was developed to compare hospital resource use and costs associated with early versus standard use of iNO in HRF. The model population included infants with moderate HRF caused by primary pulmonary hypertension with an OI ≥15 and <20. A hypothetical case population of 1000 patients was assumed and probabilistic sensitivity analyses were completed where all the clinical inputs into the model were varied. Two deterministic sensitivity analyses were also completed, one surrounding the hospital cost inputs and another surrounding the cost of iNO. RESULTS: Early iNO was associated with fewer hospital days, fewer days of ventilation and fewer hours on extracorporeal membrane oxygenation (ECMO). In probabilistic sensitivity analyses, total costs per patient were $88,518 ± $7574 and $92,581 ± $9664 for early iNO and standard iNO, respectively. The probability of early iNO being cost-effective was approximately 72%, based on a willingness to pay $100,000 or less to prevent ECMO therapy and/or death. In both deterministic sensitivity analyses, early iNO was cost-saving. CONCLUSION: Our analysis shows that early use of iNO at an OI of ≥15 and <20 may be associated with shorter hospitalizations and a decreased cost of care for term/late preterm infants with HRF associated with pulmonary hypertension. Our results are based on clinical data from a single trial; future research using data from real-world practice is warranted.