Sylvie Bélanger

Deleterious Effect of Tracheal Obstruction on Type II Pneumocytes in Fetal Sheep

It was previously shown that tracheal obstruction accelerated fetal lung growth and eventually reversed the pulmonary hypoplasia in experimental diaphragmatic hernia. We have successfully developed a reversible tracheal obstruction technique in fetal sheep using balloon occlusion and showed that 3 wk of obstruction induced significant lung growth of the same magnitude as the tracheal ligation. The purpose of this study was to examine the effects of 1 and 3 wk of tracheal occlusion on the alveolar cell population with specific attention to the type II pneumocytes. We first showed that 1 wk of occlusion induced a significant increase in lung weight and in alveolar surface area. We then used the surfactant protein C (SP-C) mRNA as a specific marker of differentiated type II pneumocytes. Total RNA was isolated from fetal sheep lung with or without tracheal occlusion, and Northern blots were hybridized with a cDNA probe specific for the sheep SP-C. The results show a dramatic decrease in SP-C mRNA expression (8.8-fold, p < 0.01). In situ hybridization showed a marked decrease in the density of cells expressing SP-C, as well as the amount of SP-C mRNA expressed by the cells. The effect was present as early as 1 wk of occlusion. The sparseness of type II pneumocytes was further confirmed by electron microscopy. We thus conclude that tracheal obstruction causes a profound decrease in the number of type II pneumocytes in the lungs. Given the crucial role of type II pneumocytes in surfactant production, we could speculate that, if tracheal occlusion is able to accelerate lung growth, the final product is probably surfactant-deficient.

Fluticasone Inhalation in Moderate Cases of Bronchopulmonary Dysplasia

Objective.This randomized, controlled trial was designed to determine the efficacy of inhaled fluticasone propionate on oxygen therapy weaning in a population of preterm infants who were born at <32 weeks of gestation and experienced moderate bronchopulmonary dysplasia (BPD). Methods.Thirty-two infants who were ≤32 weeks of gestation, had moderate BPD that required supplemental oxygen (fraction of inspired oxygen ≥0.25), and were aged between 28 and 60 days were randomized. Fluticasone propionate 125 μg twice daily for 3 weeks and once daily for a fourth week was delivered to infants who weighed between 500 and 1200 g. The dosage was doubled for infants who weighed ≥1200 g. Results.Compared with placebo, treatment had no effect on either duration of supplemental O2 therapy or ventilatory support as assessed by survival analysis. At 28 days, a trend toward a lower cortisol/creatinine ratio in the treatment group was noted compared with placebo (25.1 ± 18.9 vs 43 ± 14.4). In the fluticasone group at 28 days, the systolic arterial pressure (78 ± 3 vs 68 ± 3 mm Hg) and diastolic arterial pressure (43 ± 3.4 mm Hg vs 38 ± 2.0 mm Hg) were higher compared with baseline fluticasone values. The chest radiograph score was lower than baseline (2.8 ± 1.4 vs 3.7 ± 2.2) in the fluticasone group at 28 days. This study has a statistical power of 1.0 to detect a significant difference in the duration of oxygen supplementation of >21 days between the study groups. Conclusion.We conclude that fluticasone propionate reduces neither supplemental O2 use nor the need for ventilatory support in this patient population. However, fluticasone does have a positive radiologic effect in lowering chest radiograph scores. In addition, our data point to a possible association among inhaled fluticasone treatment and higher arterial blood pressure. Thus, the results of this investigation do not support the use of inhaled corticosteroids in the treatment of oxygen-dependent infants who have established moderate BPD.

Use of Antenatal Steroids to Counteract the Negative Effects of Tracheal Occlusion in the Fetal Lamb Model

Tracheal occlusion (TO) in fetal lambs induces pulmonary hyperplasia but has negative effects on type II cells. The purpose of this study was to determine whether antenatal steroids could reverse the adverse effects of TO on lung maturation in fetal lambs. Sixteen time-dated pregnant ewes (term, 145 d) and 24 of their fetuses were divided into six groups:1) TO at 117 d gestation;2) TO at 117 d with a single maternal intramuscular injection of 0.5 mg/kg betamethasone 24 h before delivery;3) TO at 117 d and release of the occlusion 2 d before delivery;4) TO and release of the occlusion with maternal steroids;5) unoperated controls without antenatal steroid treatment; and 6) unoperated controls, littermates of groups 1–4, treated with antenatal steroids. All fetuses were killed at 137 d gestation. Outcome measurements consisted of lung weight-to-body weight ratio; lung morphometry determined by mean terminal bronchial density; and assessment of type II pneumocytes by in situ hybridization to the mRNA of surfactant proteins B and C. Lung weight-to-body weight ratio and mean terminal bronchial density were significantly different among groups with TO and controls, indicating increased lung growth and structural maturation. The density of type II pneumocytes was markedly decreased by TO. Release 2 d before sacrifice significantly increased the density and surfactant activity of type II pneumocytes, but to levels still far from controls. Steroids alone had an effect similar to release. An additive effect was noted with steroids and 2-d release resulting in type II cell density comparable to controls. After fetal TO, a single maternal intramuscular dose of 0.5 mg/kg of betamethasone 24 h before delivery allows partial recuperation of the type II pneumocytes, an effect that is potentiated by 2-d release.

Influence of energy substrates on respiratory gas exchange during conventional mechanical ventilation of preterm infants

OBJECTIVE The purpose of this study was to determine the optimal parenteral feeding regimen for infants with compromised respiratory function. METHODS We studied the influence of varying the source of energy on respiratory gas exchange in 10 infants who were supported by mechanical ventilation and who received intravenous feedings. Two isoenergetic parenteral regimens were infused consecutively; the level of fat intake was varied inversely with that of glucose. Under similar ventilator settings, transcutaneous partial pressures of oxygen and carbon dioxide, as well as indirect calorimetry were measured during each regimen. RESULTS Despite the higher carbon dioxide production during the glucose-rich regimen (8.9 +/- 0.7 vs 7.9 +/- 0.4 ml/kg per minute, p < 0.05 by analysis of variance), transcutaneous partial pressure of carbon dioxide remained unaffected, suggesting ventilatory compensation as documented by the increased (p < 0.002) alveolar ventilation. This was not associated with a detectable rise in oxygen consumption, but with a significant change in partial pressure of oxygen (77 +/- 5 vs 66 +/- 3 mm Hg, p < 0.05). CONCLUSIONS Ventilator-dependent infants with early and mild bronchopulmonary dysplasia, who receive intravenous feedings of a moderate load of glucose-based energy, can compensate for enhanced carbon dioxide production by increasing their respiratory drive, with a beneficial effect on oxygenation compared with that observed when energy is derived from lipid-based solutions.

Interleukin-1 expression during hyperoxic lung injury in the mouse.

An important component of the pathophysiologic response to hyperoxia (O2) is pulmonary inflammation, although the roles of specific inflammatory mediators during pulmonary O2 toxicity are not completely known. Interleukin-1 (IL-1) is an early inflammatory mediator and is sufficient to elicit many of the responses associated with acute injury. The IL-1 family comprises two bioactive proteins, IL-1alpha and IL-1beta, and their natural antagonist IL-1ra. Here we report studies of IL-1 regulation during hyperoxic lung injury in the adult mouse. When assayed by Northern blot, increases in IL-1beta mRNA were seen after 2 days of hyperoxia. In contrast, IL-1alpha mRNA was barely detectable before 4 days of hyperoxia. To further understand the cellular origin of IL-1beta expression in lungs, in situ hybridization and immunohistochemical analyses were performed. IL-1beta mRNA or protein was not detected in the lungs of unexposed animals. At 3 days, we observed the accumulation of IL-1beta transcripts in pulmonary interstitial macrophages and in a subset of neutrophils, and immunodetectable IL-1beta protein was co-localized in adjacent sections. At 4 days of exposure, IL-1beta transcripts were widespread in lung tissue, but many areas rich in IL-1beta mRNA were devoid of immunodetectable IL-1beta. However, it is not known whether increased synthesis of IL-1beta or the uncoupling of IL-1beta protein and mRNA accumulation has a role in pathophysiology of pulmonary O2 toxicity.

Body Composition in Very Preterm Infants: Role of Neonatal Characteristics and Nutrition in Achieving Growth Similar to Term Infants

Background: The identification of factors involved in the postnatal growth of preterm infants will help achieve growth similar to that of term infants. Objectives: As per protocol: to compare body composition in very preterm infants at term-corrected age (TCA) with that in term infants, and to explore relationships between neonatal characteristics and body composition in preterm infants. Methods: Anthropometry, nutritional characteristics, and neonatal outcomes were prospectively collected in 26 preterm (<29 weeks) and 33 term (37-40 weeks) infants. Body composition using dual-energy X-ray absorptiometry (DXA) was measured at TCA in preterm infants and between days 7 and 10 in term infants. Results: Parenteral nutrition in preterm infants provided a mean of 2.9 ± 0.2 and 2.1 ± 0.5 g/kg/day of intravenous amino acids and lipids, respectively, during the first week of life. The mean weight gain velocity from birth to DXA assessment was 12.1 ± 1.4 g/kg/day. Compared with term infants, preterm infants at TCA were shorter and lighter, with a smaller head circumference, a lower weight estimated by DXA (2,960 ± 552 vs. 3,843 ± 377 g), and increased skinfold thicknesses. Fat mass percent (13.9 ± 5.4%) and lean mass percent (84.7 ± 5.6%) in preterm infants were similar to those in term infants (14.7 ± 3.5 and 83.5 ± 3.6%, respectively). Neonatal weight gain velocity in preterm infants was positively associated with lean mass (grams). Conclusion: Subcutaneous fat is increased in preterm infants. Higher protein intake in preterm infants might increase weight gain velocity and achieve a lean mass comparable to that of term infants.

Neurodevelopmental Outcomes of Infants Born at <29 Weeks of Gestation Admitted to Canadian Neonatal Intensive Care Units Based on Location of Birth

Objective To compare mortality and neurodevelopmental outcomes of outborn and inborn preterm infants born at <29 weeks of gestation admitted to Canadian neonatal intensive care units (NICUs). Study design Data were obtained from the Canadian Neonatal Network and Canadian Neonatal Follow‐up Network databases for infants born at <29 weeks of gestation admitted to NICUs from April 2009 to September 2011. Rates of death, severe neurodevelopmental impairment (NDI), and overall NDI were compared between outborn and inborn infants at 18‐21 months of age, corrected for prematurity. Results Of 2951 eligible infants, 473 (16%) were outborn. Mean birth weight (940 ± 278 g vs 897 + 237 g), rates of treatment with antenatal steroids (53.9% vs 92.9%), birth weight small for gestational age (5.3% vs 9.4%), and maternal college education (43.7% vs 53.9%) differed between outborn and inborn infants, respectively (all P values <.01). The median Score for Neonatal Acute Physiology‐II (P = .01) and Apgar score at 5 minutes (P < .01) were higher in inborn infants. Severe brain injury was more common among outborn infants (25.3% vs 14.7%, P < .01). Outborn infants had higher odds of death or severe NDI (aOR 1.7, 95% CI 1.3‐2.2), death or overall NDI (aOR 1.6, 95% CI 1.2‐2.2), death (aOR 2.1, 95% CI 1.5‐3.0), and cerebral palsy (aOR 1.9, 95% CI 1.1‐3.3). Conclusions The composite outcomes of death or neurodevelopmental impairment were significantly higher in outborn compared with inborn infants admitted to Canadian NICUs. Adverse outcomes were mainly attributed to increased mortality and cerebral palsy in outborn neonates.

Association of Resident Duty Hour Restrictions, Level of Trainee, and Number of Available Residents with Mortality in the Neonatal Intensive Care Unit

Objective This article assesses the effect of reducing consecutive hours worked by residents from 24 to 16 hours on yearly total hours worked per resident in the neonatal intensive care unit (NICU) and evaluates the association of resident duty hour reform, level of trainee, and the number of residents present at admission with mortality in the NICU. Study Design This is a 6‐year retrospective cohort study including all pediatric residents working in a Level 3 NICU (N = 185) and infants admitted to the NICU (N = 8,159). Adjusted odds ratios (aOR) were estimated for mortality with respect to Epoch (2008‐2011 [24‐hour shifts] versus 2011‐2014 [16‐hour shifts]), level of trainee, and the number of residents present at admission. Results The reduction in maximum consecutive hours worked was associated with a significant reduction of the median yearly total hours worked per resident in the NICU (381 hour vs. 276 hour, p < 0.01). Early mortality rate was 1.2% (50/4,107) before the resident duty hour reform and 0.8% (33/4,052) after the reform (aOR, 0.57; 95% confidence interval [CI], 0.33‐0.98). Neither level of trainee (aOR, 1.22; 95% CI, 0.71‐2.10; junior vs. senior) nor the number of residents present at admission (aOR, 2.08; 95% CI, 0.43‐10.02, 5‐8 residents vs. 0‐2 residents) were associated with early mortality. Resident duty hour reform was not associated with hospital mortality (aOR, 0.73; 95% CI, 0.50‐1.07; after vs. before resident duty hour reform). Conclusion Resident duty hour restrictions were associated with a reduction in the number of yearly hours worked by residents in the NICU as well as a significant decrease in adjusted odds of early mortality but not of hospital mortality in admitted neonates.

Fetal Tracheal Occlusion : Antenatal Steroid Potentiates the Effect of Occlusion Release on Lung Maturation

Fetal Tracheal Occlusion : Antenatal Steroid Potentiates the Effect of Occlusion Release on Lung Maturation