Genetic variation in CRHR1 is associated with short-term respiratory response to corticosteroids in preterm infants at risk for bronchopulmonary dysplasia.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is an orphan disease and advances in prevention and treatment are lacking. The clinical efficacy of systemic corticosteroid therapy to reduce the severity of lung disease and BPD is highly variable. Our objective was to assess whether candidate SNPs in corticosteroid metabolism and response genes are associated with short-term phenotypic response to systemic corticosteroids in infants at high risk for BPD. METHODS: Pharmacogenetic analysis of data from a large randomized controlled trial (TOLSURF) in infants treated with dexamethasone or hydrocortisone using multivariate linear regression. The primary outcome was a change in respiratory severity score (RSS, mean airway pressure x FiO2) at day 7 of corticosteroid treatment. RESULTS: rs7225082 in the intron of CRHR1 is significantly associated with the magnitude of decrease in RSS 7 days after starting treatment with systemic corticosteroid (meta-analysis P = 2.8 × 10-4). Each T allele at rs7225082 is associated with a smaller absolute change in RSS at day 7, i.e., less response to systemic corticosteroids. CONCLUSIONS: Genetic variability is associated with corticosteroid responsiveness with regard to respiratory status in preterm infants. Identification of genetic markers of corticosteroid responsiveness may allow for therapeutic individualization, with the goal of optimizing the risk-to-benefit ratio for an individual child.

Correction: Genetic variation in CRHR1 is associated with short-term respiratory response to corticosteroids in preterm infants at risk for bronchopulmonary dysplasia.

In the original version of this article, the Supplementary Information file contained incorrect reference numbers. 'Supplemental Table S1' has now been replaced with the corrected version, in which the correct reference numbers are cited. The authors would like to apologise for this error.

Acute Post-Tracheostomy Clinical Decompensations in Infants-Are There Predictive Markers?

OBJECTIVE: To report on the population of infants receiving a tracheostomy, identify acute post-tracheostomy clinical decompensations, and seek predictive markers associated with acute complications following the placement of a tracheostomy. STUDY DESIGN: Retrospective deidentified clinical data was provided by the Infant Pulmonary Data Repository at Children's Mercy Hospital, Kansas City. Data from infants undergoing tracheostomy from January 1, 2008 through September 30, 2016 were divided into one of two study groups based on clinical correlations: (1) no acute decompensations within 72 hours post-tracheostomy or (2) acute clinical decompensation defined as sustained escalation of respiratory care within the 72 hours following tracheostomy. RESULTS: Thirty-four percent of infants undergoing tracheostomy during this period developed acute post-tracheostomy clinical decompensations. Elevated pre-tracheostomy positive end expiratory pressure, mean airway pressure, and echocardiogram findings suggestive of pulmonary hypertension (PH) or ventricular dysfunction were associated with acute post-tracheostomy clinical decompensations. Additionally acute post-tracheostomy clinical decompensation was associated with higher rate of death prior to discharge. CONCLUSION: Infants requiring higher respiratory support and infants with PH or ventricular dysfunction are at risk of acute post-tracheostomy clinical decompensation, thus identifying these patients may lead to better pre-tracheostomy counseling and potentially targeted treatments to decrease this risk.

A Novel Method of Measuring Fractional Exhaled Nitric Oxide in Tracheostomized Ventilator-Dependent Children.

BACKGROUND: The lower airway concentration of fractional exhaled nitric oxide (FENO) is unknown in children with chronic lung disease of infancy who have tracheostomy for long-term mechanical ventilation. We aimed to evaluate an online method of measuring FENO in a cohort of ventilator-dependent children with a tracheostomy and to explore the relationship between the peak FENO concentration (FENO peak) and the degree of respiratory support using the respiratory severity score. METHODS: We conducted a prospective cross-sectional study in 31 subjects who were receiving long-term respiratory support through a tracheostomy. We measured the FENO peak and FENO plateau concentration from the tip of the tracheostomy tube using a nitric oxide analyzer in subjects during a quiet state while being mechanically ventilated. We obtained 2 consecutive 2-min duration measurements from each subject. The FENO peak, exhaled NO output (equal to the FENO peak × minute ventilation), and pulmonary NO excretion (exhaled NO output/weight) were calculated and correlated with the respiratory severity score. RESULTS: The median FENO peak was 2.69 ppb, and the median FENO plateau was 1.57 ppb. The coefficients of repeatability between the 2 consecutive measurements for FENO peak and FENO plateau were 0.74 and 0.59, respectively. The intraclass coefficient between subjects within the cohort was 0.988 (95% CI 0.975-0.994, P < .001) for FENO peak and 0.991 (95% CI 0.982-0.996, P < .001) for FENO plateau. We found that the FENO peak was directly correlated with minute ventilation, but we did not find a direct relationship between the FENO peak concentration, exhaled NO output, or pulmonary NO excretion and respiratory severity score. CONCLUSIONS: FENO peak and plateau concentration can be measured online easily with a high degree of reliability and repeatability in infants and young children with a tracheostomy. FENO peak concentration from the lower airway is low and influenced by minute ventilation in children receiving mechanical ventilation.

Exhaled nitric oxide and tracheal endothelin-1 in preterm infants with and without RDS.

We measured exhaled nitric oxide and tracheal aspirate endothelin-1 to determine relationships between these substances and alterations in pulmonary gas exchange during respiratory distress syndrome (RDS) in comparison to those obtained from control preterm infants without RDS. Eight infants with RDS had measurements made at 24 hr and again at 48-72 hr. Eight control infants were studied once at 24-48 hr of life. Exhaled gas was analyzed on-line, and minute excretion of NO (V(NO)) was calculated. ET-1 was determined by immunoassay. Median V(NO) at 24 hr in RDS was 0.405 nl/min/kg (range, 0.30 -0.79), which subsequently declined by 48-72 hr to 0.166 nl/min/kg (P < 0.01). The V(NO) in RDS infants was significantly higher than time-matched V(NO) in controls, with a median of 0.099 nl/min/kg (range, 0.03-0.27; P < 0.001). ET-1 was not correlated with initial V(NO) in the RDS or control patients. In conclusion, in RDS, V(NO) decreases as gas exchange improves. ET-1 is detectable in tracheal aspirate samples in both groups of infants.

Hyperoxia and tidal volume: Independent and combined effects on neonatal pulmonary inflammation.

BACKGROUND: Hyperoxia and tidal volume mechanical ventilation are independent factors in the genesis of lung injury, but it remains unclear the extent to which each is responsible or contributes to this process in newborns. OBJECTIVES: To study the independent and combined effects of hyperoxia and tidal volume mechanical ventilation on the induction of lung inflammation in a newborn piglet model of ventilator-induced lung injury. METHODS: Following exposure to either ambient air or F(I)O2 = 1.0 for a period of 3 days, newborn piglets were randomized to receive mechanical ventilation with either high tidal volume (20 ml/kg) or low tidal volume (6 ml/kg) for 4 h while controlling for pH. RESULTS: Monocyte chemoattractant protein-1 level in the lungs of animals randomized to hyperoxia with high tidal volume ventilation was significantly elevated, compared to all other groups (p < 0.05). Myeloperoxidase assayed in lung homogenate was found to be significantly higher in nonventilated animals exposed to hyperoxia (p < 0.01). Only in animals previously exposed to hyperoxia did the addition of high tidal volume ventilation further increase the level of myeloperoxidase present (p < 0.05). Pulmonary vascular resistance was significantly elevated after 4 h of mechanical ventilation compared to 1 h (p < 0.001). CONCLUSIONS: We conclude that in neonatal piglets undergoing hyperoxic stress, superimposition of high tidal volume ventilation exacerbates the lung inflammation as assessed by lung monocyte chemoattractant protein-1 and level of myeloperoxidase.

Endogenous production of nitric oxide in endotoxemic piglets.

We sought to assess the relation between endotoxin-induced pulmonary hypertension and the production of nitric oxide (NO) in neonatal animals. Adult animals respond to endotoxin by increasing exhaled NO and plasma NO metabolites. The response of neonatal animals has not previously been reported. We administered 20 microg/kg of Escherichia coli lipopolysaccharide (LPS) to 12- to 18-day-old and to 5- to 7-week-old piglets. Pulmonary vascular resistance increased significantly in both age groups. Exhaled NO in the 12- to 18-day-old animals and in the 5- to 7-week-old piglets did not increase significantly. A similarly treated group of adult rats did show a significant increase in exhaled NO (2.6 +/- 1.0 to 109.5 +/- 54.3 ppb; p = 0.028). Plasma NO metabolite measurements followed the same pattern of no increase in both porcine groups, and a large increase in the rat group. However, immunostaining of lungs from 12- to 18-day-old piglets did reveal an increase in inducible NO synthase. These results suggest that piglets demonstrate a limited ability to modulate LPS-induced pulmonary hypertension by elevations in exhaled NO. They also demonstrate the differential response to LPS between species.

Interaction of endogenous endothelin-1 and inhaled nitric oxide in term and preterm infants.

The peptide endothelin-1 (ET-1) plays an unknown role in the pathogenesis and progression of two important neonatal pulmonary disorders, chronic lung disease (CLD) of prematurity and persistent pulmonary hypertension of the newborn (PPHN). Inhaled nitric oxide (INO) is a proven vasodilator therapy in PPHN and is an experimental therapy in CLD. We sought to determine the effects, if any, of the interaction of inhaled INO with ET-1 in these two separate disorders. Infants (n=21) with PPHN (mean gestation age, 39.4 weeks; mean birth weight, 3470 g) were treated with INO. All infants were <72 h of age at baseline. Plasma obtained at baseline and after 24 h of INO therapy was assessed for ET-1. The change in ET-1 levels with INO was inversely correlated with change in arterial partial pressure of O(2) (r=-0.71, P=0.0003). A separate group of 33 patients with CLD (mean gestational age, 27 weeks; mean birth weight, 740 g; mean age, 19 days) had tracheal aspirate levels of ET-1 obtained before, during, and after 7 days' administration of INO. Values were normalized by soluble secretory component of IgA. Tracheal aspirate ET-1 levels were detectable before INO therapy. There was no significant change during or after treatment with INO. There was not a significant correlation between baseline fractional inspired O(2) and ET-1 levels. There was a non-significant trend in the correlation between the change in ET-1 and the change in interleukin-8 levels in tracheal aspirate. This report confirms the presence of ET-1 in tracheal aspirate of premature infants who are developing CLD and reaffirms the presence of ET-1 in plasma of infants with PPHN. Short-term INO therapy was associated with a decrease in plasma ET-1 levels in PPHN, but did not affect tracheal aspirate ET-1 in CLD. Given the vasconstrictive, profibrotic, and proinflammatory properties of ET-1, specific ET-1 receptor antagonists could be considered as candidates for trials as adjunct therapy in either or both of these disorders.