Many extremely low gestational age neonates (≤ 28 wk, ELGANS) continue to require intubation and mechanical ventilation beyond the first week of life and many experience episodes of dysfunctional surfactant associated with low surfactant protein B content and clinically significant respiratory decompensations (Pediatr Res 2004;56:918-26). We hypothesized that booster surfactant treatment (booster) given during week 2-3 to these infants is safe and improves pulmonary outcome. Infants were enrolled in one of two booster pilot trials. ELGANS requiring ventilation at 7 to 10 days of life received one to two doses of “prophylactic” surfactant (Infasurf®, 3 mL/kg) 1 week apart. In a separate “Rescue” pilot trial, ventilated ELGANS at 5 to 21 days of life with respiratory decompensation received two doses of Infasurf over 12 to 24 hours. Tracheal aspirate (TA) samples were analyzed for minimum surface tension (STmin) in a pulsating bubble surfactometer and for concentrations of cytokines, growth factors, and chemokines. Clinical data including respiratory severity score (SS = mean airway press × FiO2) were collected. Twenty-six infants have been enrolled in the ongoing pilot trials. Mean GA and BW were 25.5 ± 1.3 week and 718.3 ± 151.8 g, respectively. Surfactant instillation was tolerated by infants in both trials. Changes in SS, as an index of initial clinical response, are shown as the number of infants with lower SS score/number with same SS score/number with higher SS score compared to the pr-treatment value (mean and range SS): Following treatment, there was an initial decrease in STmin for most infants, indicating improved function. Analysis of concentrations of IL-1α, IL-1β, IL-6, IL-8, TNFα, IL-10, RANTES, MIP-1α, TGF-β1, and VEGF after treatment revealed no significant changes as compared with pretreatment. These preliminary results support the safety of booster surfactant administration in ventilated ELGANS beyond 7 days of age and indicate a favorable initial response in respiratory status. This therapy will be tested for safety and prevention of bronchopulmonary dysplasia in a multicenter, randomized, controlled trial.
We induced beta-adrenergic receptor blockade at 28 days gestation in the fetal rabbit with an irreversible beta-antagonist, bromace-tylalprenolomenthane (BrAlp). There was a marked decrease in concentration of available receptors in lung with increasing doses of BrAlp. BrAlp treatment decreased isoproterenol, but not prostaglandin, stimulated adenosine 3′,5′-cyclic monophosphate (cAMP) generation in lung minces, and had no effect on activation of adenylate cyclase through non-beta-receptor-mediated components of the cyclase system in particulate preparations. Phospholipid recovery via lung lavage was significantly less from treated fetuses than from controls in groups delivered by cesarean section at 30 days (-31%) or vaginally at 31 days (-34%) and not allowed to air breathe. However, if fetuses from either group were allowed to air breathe, the difference was abolished. BrAlp treatment did not affect the phospholipid composition in lavage fluid, the rate of phosphatidylcholine synthesis, or tissue content of total or saturated phosphatidylcholine. Beta-adrenergic receptor blockade did not produce a significant change in lung water content either at or after birth regardless of the route of delivery. These data indicate that endogenous catecholamines play a role in surfactant secretion in both the fetal and newborn rabbit. We found no effects of BrAlp treatment on lung water, suggesting perhaps a less important role of endogenous catecholamines or that fewer receptors are required for this response than remained after treatment.
Bronchopulmonary dysplasia (BPD) is a major complication of prematurity, but the ability to predict which infants with a given birth weight or gestational age will experience this morbidity remains poor. We consider whether a physiologic marker of respiratory status between 4 and 10 days after birth, the PRSS (mean airway pressure × FiO2), can also serve as an early predictor of BPD.
Methods
We studied infants <32 weeks gestational age requiring CPAP or ventilation who were enrolled in two multicenter trials, the NO CLD trial (infants randomized to either postnatal nitric oxide or placebo at 20 centers) and the North American Thyrotropin-Releasing Hormone study (TRH) (Ballard RA, NEJM, 1998). Peak respiratory severity score (PRSS) was collected from bedside flowsheet data. Logistic regression models were developed to determine the association of the PRSS between 4 and 10 days after birth and the development of BPD, defined as an oxygen requirement at 36 weeks postmenstrual age. Birth weight and gestational age were included in separate models to control for baseline risk of BPD.
Results
332 patients from the NO CLD trial and 194 from the TRH trial required CPAP or mechanical ventilation between days 4 and 10 after birth. The mean birth weight was 748 6 124 g and gestational age was 25 6 2.5 weeks. 308 (59%) developed BPD. Logistic regression models including birth weight and PRSS showed that the PRSS between 4 and 10 days was significantly associated with BPD using thresholds of both 3.5 [OR 2.0, 95% CI 1.4-2.8] and 4.0 [OR 2.1, 95% CI 1.5-3.0]. Although birth weight alone was significantly associated with BPD (p=0.03), when PRSS was added to the model, birth weight was no longer significant. When gestational age was substituted for birth weight in the predictive models, PRSS remained significantly associated with the development of BPD. Both PRSS thresholds remained significantly associated with BPD when each trial was analyzed separately.
Conclusions
The PRSS that a ventilated infant reaches between 4 and 10 days after birth is a significant risk factor for occurrence of BPD. This finding emphasizes the role of early postnatal lung disease in the development of BPD. PRSS may be a useful clinical and research tool to identify infants at increased risk for BPD.
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