Background. It has been suggested that preterm infants may have developmental immaturity of the hypothalamic-pituitary-adrenal axis, and that decreased cortisol response to stress increases risk of chronic lung disease (CLD) secondary to inflammatory lung injury. Methods. To investigate the relationship between endogenous corticosteroid and CLD, we measured plasma cortisol during the first 28 days of life in a subset of neonates in the North American Thyrotropin-Releasing Hormone (TRH) Collaborative Trial. Analyses were performed on 314 infants, 24 to 32 weeks' gestation, whose mothers received 1 or 2 courses of antenatal corticosteroids plus TRH or placebo. Results. Mean cortisol was 3.1 μg/dL (range: 0.1–17.9) at birth, reached maximal levels at 24 hours (19.4 μg/dL, range: 0.8–124.6), and decreased to 5.9 μg/dL (range: 0.2–24.7) at 14 to 28 days of age; levels during the first week were not associated with gestational age. The Clinical Risk Index for Babies (CRIB), a neonatal assessment tool that is correlated with risk of mortality, was positively associated with cortisol level on days 1 and 3 through 7. TRH versus placebo treatment did not influence cortisol levels at any time point. To examine the relationship between cortisol and adverse outcome of death or CLD at 36 weeks' postmenstrual age (CLD36), logistic regression models adjusting for known contributing clinical factors (gestational age and CRIB score) were fit. There was a statistically borderline negative association between median cortisol level at 3 to 7 days and CLD36. After adjusting for gestational age and CRIB score, the predicted probability of CLD36 was only minimally influenced by the cortisol concentration. Conclusion. In preterm infants, basal plasma cortisol concentration during the first week is a weak predictor for CLD36. Possible benefits as well as risks of supplemental, low-dose cortisol treatment of high-risk preterm infants remain to be determined.
Inflammation leading to alveolar and airway damage is a significant contributing factor to the development of bronchopulmonary dysplasia (BPD). Preterm infants, who may have developmental immaturity of their hypothalamic-pituitary-adrenal axis and decreased cortisol response to stress, could be particularly vulnerable to the effects of inflammatory injury. For these reasons, using anti-inflammatory agents such as dexamethasone to prevent BPD has appeared to be reasonable.
Clinical studies have demonstrated decreased inflammatory markers and suppression of cytokine-mediated inflammatory reactions in the bronchoalveolar lavage fluid of preterm infants treated with dexamethasone. (1) In addition, corticosteroids have been associated with numerous potential physiologic benefits on the lung, including increased surfactant synthesis, enhanced beta-adrenergic activity, increased antioxidant production, stabilization of cell and lysosomal membranes, and inhibition of prostaglandin and leukotriene synthesis. (1) Acute improvement in lung function, with increased dynamic compliance and decreased pulmonary resistance, has also been demonstrated within 12 hours of treatment with dexamethasone. (2)
Likely because of this acute improvement in lung function, which facilitates weaning from mechanical ventilation, postnatal steroids have been widely used. In the recent multicenter North American Thyrotropin-releasing Hormone Trial for the prevention of lung disease in preterm infants, 72% of infants weighing less than 1,500 g who were ventilated at 14 days received postnatal steroids in an effort to prevent BPD (personal communication, Dr Roberta Ballard, June, 2001). However, the long-term effects of dexamethasone on pulmonary outcome, survival, and neurodevelopmental outcome in preterm infants has raised some questions about its use.
The following criteria for assessing the benefit of postnatal steroids have been proposed:
1. Decreased mortality.
2. Decreased outcome of BPD or death at 36 weeks’ postmenstrual age (PMA).
3. No significant acute adverse effects.
4. No long-term effects on growth or neurodevelopmental outcome.
5. No increased occurrence of disease, such as cardiac disease or diabetes, throughout life.
In this review and …
Background. 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. Methods. 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. Findings. 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. Interpretation. 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.
Objective. Premature infants are susceptible to bronchopulmonary dysplasia (BPD), a chronic lung disease of infancy that appears to be caused in part by oxidative stress from hyperoxia. To investigate the possible role of nitric oxide-derived oxidants such as peroxynitrite in the etiology of BPD, we measured levels of plasma 3-nitrotyrosine, which is produced by the reaction of peroxynitrite with proteins. Patients and Methods. Ten premature infants who developed BPD, defined as requiring supplemental oxygen beyond 36 weeks' postmenstrual age, were identified retrospectively from a group of subjects enrolled in a clinical trial of antenatal therapy. Serial plasma samples had been collected on these infants during the first month of life as part of the trial. Sixteen comparison premature infants were identified from the same population: 5 had no lung disease, 6 had respiratory distress syndrome that resolved, and 5 had residual lung disease at 28 days of life that resolved by 36 weeks' postmenstrual age. Plasma 3-nitrotyrosine levels were measured using a solid phase immunoradiochemical method. Results. All 3-nitrotyrosine values in infants without BPD were <0.25 ng/mg protein, and levels did not change with postnatal age. Plasma 3-nitrotyrosine concentrations were significantly higher in infants with BPD, increasing approximately fourfold during the first month of life. For the 20 infants who had blood samples available at 28 days of life, plasma 3-nitrotyrosine levels correlated with the fraction of inspired oxygen that the infant was receiving (r = 0.7). Conclusion. Plasma 3-nitrotyrosine content is increased during the first month of life in infants who develop BPD. This suggests that peroxynitrite-mediated oxidant stress may contribute to the development of this disease in premature infants and that 3-nitrotyrosine may be useful as an early plasma indicator of infants at risk for developing BPD.
