We hypothesized that inhaled nitric oxide treatment of premature infants at risk for bronchopulmonary dysplasia would not adversely affect endogenous surfactant function or composition.
As part of ...the Nitric Oxide Chronic Lung Disease Trial of inhaled nitric oxide, we examined surfactant in a subpopulation of enrolled infants. Tracheal aspirate fluid was collected at specified intervals from 99 infants with birth weights <1250 g who received inhaled nitric oxide (20 ppm, weaned to 2 ppm) or placebo gas for 24 days. Large-aggregate surfactant was analyzed for surface activity with a pulsating bubble surfactometer and for surfactant protein contents with an immunoassay.
At baseline, before administration of study gas, surfactant function and composition were comparable in the 2 groups, and there was a positive correlation between minimum surface tension and severity of lung disease for all infants. Over the first 4 days of treatment, minimum surface tension increased in placebo-treated infants and decreased in inhaled nitric oxide-treated infants. There were no significant differences between groups in recovery of large-aggregate surfactant or contents of surfactant protein A, surfactant protein B, surfactant protein C, or total protein, normalized to phospholipid.
We conclude that inhaled nitric oxide treatment for premature infants at risk of bronchopulmonary dysplasia does not alter surfactant recovery or protein composition and may improve surfactant function transiently.
Objective To assess whether late surfactant treatment in extremely low gestational age (GA) newborn infants requiring ventilation at 7-14 days, who often have surfactant deficiency and dysfunction, ...safely improves survival without bronchopulmonary dysplasia (BPD). Study design Extremely low GA newborn infants (GA ≤28 0/7 weeks) who required mechanical ventilation at 7-14 days were enrolled in a randomized, masked controlled trial at 25 US centers. All infants received inhaled nitric oxide and either surfactant (calfactant/Infasurf) or sham instillation every 1-3 days to a maximum of 5 doses while intubated. The primary outcome was survival at 36 weeks postmenstrual age (PMA) without BPD, as evaluated by physiological oxygen/flow reduction. Results A total of 511 infants were enrolled between January 2010 and September 2013. There were no differences between the treated and control groups in mean birth weight (701 ± 164 g), GA (25.2 ± 1.2 weeks), percentage born at GA <26 weeks (70.6%), race, sex, severity of lung disease at enrollment, or comorbidities of prematurity. Survival without BPD did not differ between the treated and control groups at 36 weeks PMA (31.3% vs 31.7%; relative benefit, 0.98; 95% CI, 0.75-1.28; P = .89) or 40 weeks PMA (58.7% vs 54.1%; relative benefit, 1.08; 95% CI, 0.92-1.27; P = .33). There were no between-group differences in serious adverse events, comorbidities of prematurity, or severity of lung disease to 36 weeks. Conclusion Late treatment with up to 5 doses of surfactant in ventilated premature infants receiving inhaled nitric oxide was well tolerated, but did not improve survival without BPD at 36 or 40 weeks. Pulmonary and neurodevelopmental assessments are ongoing. Trial registration ClinicalTrials.gov : NCT01022580.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Severe bronchopulmonary dysplasia (BPD), which is associated with high mortality and morbidity, is thought to be the result of mechanical, inflammatory, and oxidant injury to the immature lung, and ...includes the development of pulmonary hypertension with vascular remodeling.
A phase II pilot study was conducted to determine the effect of inhaled nitric oxide (iNO) on oxygenation in severe BPD. This was an open-labeled, noncontrolled trial to evaluate safety and determine appropriate dosing for a future randomized controlled trial. Infants were eligible for enrollment if they were >/=4 weeks of age and ventilator dependent with a mean airway pressure of >/=10 cm H2O and an FIO2 of >/=0.45. Study infants received iNO (20 ppm) for 72 hours, and FIO2 was adjusted to maintain oxygen saturations of >92%. Infants who had a >/=15% reduction in FIO2 after 72 hours received prolonged treatment with low-dose iNO, weaning by 20% every 3 days as tolerated.
Sixteen preterm infants (23-29 weeks of gestation), age 1 to 7 months, were enrolled. Eleven of 16 infants had a significant increase in PaO2 after 1 hour of iNO (median change, 24 mm Hg; range, -15 to 59 mm Hg; P <.01), but there was no significant change in PaCO2. After 72 hours of iNO, 11 infants had >/=15% reduction in FIO2, and 7 of the 11 had >/=35% reduction (P <. 01). Among the 11 infants who responded to iNO after 72 hours, 10 had a sustained improvement in oxygenation throughout their course of treatment (duration, 8-90 days), and ventilator support could also be decreased. No adverse effects from iNO (increased methemoglobin, bleeding, or increased plasma 3-nitrotyrosine) were observed. Four of the 11 infants (36%) who responded to iNO ultimately weaned off mechanical ventilation and 4 died, whereas all the infants who failed to respond to iNO either died or continue to require mechanical ventilation.
We conclude that the use of low-dose iNO may improve oxygenation in some infants with severe BPD, allowing decreased FIO2 and ventilator support without evidence of adverse effects. Randomized clinical trials of low-dose iNO for BPD are warranted.
We compared serial measurements of inflammatory mediators and markers in infants treated with inhaled nitric oxide or placebo to assess the effects of inhaled nitric oxide therapy on lung ...inflammation during bronchopulmonary dysplasia. We investigated relationships between respiratory severity scores and airway concentrations of inflammatory markers/mediators.
As part of the Nitric Oxide (to Prevent) Chronic Lung Disease trial, a subset of 99 infants (52 placebo-treated infants and 47 inhaled nitric oxide-treated infants; well matched at baseline) had tracheal aspirate fluid collected at baseline, at 2 to 4 days, and then weekly while still intubated during study gas treatment (minimum of 24 days). Fluid was assessed for interleukin-1beta, interleukin-8, transforming growth factor-beta, N-acetylglucosaminidase, 8-epi-prostaglandin F2alpha, and hyaluronan. Results were normalized to total protein and secretory component of immunoglobulin A.
At baseline, there was substantial variability of each measured substance and no correlation between tracheal aspirate fluid levels of any substance and respiratory severity scores. Inhaled nitric oxide administration did not result in any time-matched significant change for any of the analytes, compared with the placebo-treated group. There was no correlation between any of the measured markers/mediators and respiratory severity scores throughout the 24 days of study gas administration. In the posthoc analysis of data for inhaled nitric oxide-treated infants, there was a difference at baseline in 8-epi-prostaglandin F2alpha levels for infants who did (n = 21) and did not (n = 26) develop bronchopulmonary dysplasia at postmenstrual age of 36 weeks.
Inhaled nitric oxide, as administered in this study, seemed to be safe. Its use was not associated with any increase in airway inflammatory substances.
To evaluate components of pulmonary surfactant and identify mutations in the surfactant protein B gene (SP-B) of a term infant with severe respiratory distress and chronic lung disease. PATIENT AND ...TESTING: Respiratory distress developed in an infant delivered at term, and he required extracorporeal bypass support for 2 weeks. Until his unexpected death at 9.5 months, he was ventilator and oxygen dependent and required continual dexamethasone therapy. Tracheobronchial lavage samples were analyzed for content of surfactant proteins (SPs), and DNA from blood samples were sequenced and analyzed by polymerase chain reaction restriction analysis for the presence of SP-B gene mutations. Surfactant lipid composition and function, the contents of SPs and their messenger RNAs (mRNAs), and the immunostaining pattern for SPs were determined in postmortem lung tissue.
The lavage sample contained SP-A but not SP-B, and DNA restriction analysis indicated that the patient and his mother were heterozygous for the previously described 121ins2 mutation of SP-B. Postmortem lung tissue contained normal levels of SP-A and its mRNA, a low but detectable level of SP-B, and near normal content of SP-B mRNA. SP-C was abundant on staining, and some 6-kd precursor was present in tissue. A surfactant fraction was deficient in phosphatidylglycerol and was not surface active. On DNA sequencing, a point mutation was found in exon 7 of the patient's SP-B gene allele without the 121ins2 mutation, resulting in a cysteine for arginine substitution, and the father was a carrier for the same mutation.
We describe a patient who is a compound heterozygote with a new mutation and only a partial deficiency of SP-B. Some forms of inherited SP-B deficiency may have low expression of immunoreactive and possibly functional SP-B with milder lung disease and longer survival. These infants may benefit from glucocorticoid therapy and may not develop antibodies to SP-B after either lung transplant or gene therapy.
In this multicenter, randomized trial of preterm newborns with a birth weight of 1250 g or less who required ventilatory support, the initiation of inhaled nitric oxide between days 7 and 21 of life ...significantly reduced the risk of death or chronic lung disease and the duration of both hospitalization and supplemental oxygen therapy. Using a regimen of inhaled nitric oxide therapy different from that in the companion report by Kinsella et al., this group also found inhaled nitric oxide to be beneficial in preterm infants with respiratory failure.
In preterm newborns with a birth weight of 1250 g or less who required ventilatory support, the initiation of inhaled nitric oxide between days 7 and 21 of life significantly reduced the risk of death or chronic lung disease and the duration of both hospitalization and supplemental oxygen therapy.
Survival among preterm infants has improved markedly in recent decades, in large part because of the ability to enhance fetal-lung maturation with antenatal corticosteroids and manage the respiratory distress syndrome. Chronic lung disease, or bronchopulmonary dysplasia,
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is now the most important long-term pulmonary complication in these infants and is associated with prolonged hospitalization and long-term pulmonary and neurodevelopmental problems.
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Severe bronchopulmonary dysplasia is associated with inflammation,
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pulmonary hypertension,
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and increased airway resistance,
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as well as abnormalities of lung growth, including disturbed angiogenesis and alveolarization.
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Inhaled nitric oxide is an effective treatment for pulmonary hypertension . . .
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