The Randomized, Controlled Trial of Late Surfactant: Effects on Respiratory Outcomes at 1-Year Corrected Age.

OBJECTIVE: To determine the effects of late surfactant on respiratory outcomes determined at 1-year corrected age in the Trial of Late Surfactant (TOLSURF), which randomized newborns of extremely low gestational age (≤28 weeks' gestational age) ventilated at 7-14 days to late surfactant and inhaled nitric oxide vs inhaled nitric oxide-alone (control). STUDY DESIGN: Caregivers were surveyed in a double-blinded manner at 3, 6, 9, and 12 months' corrected age to collect information on respiratory resource use (infant medication use, home support, and hospitalization). Infants were classified for composite outcomes of pulmonary morbidity (no PM, determined in infants with no reported respiratory resource use) and persistent PM (determined in infants with any resource use in ≥3 surveys). RESULTS: Infants (n = 450, late surfactant n = 217, control n = 233) were 25.3 ± 1.2 weeks' gestation and 713 ± 164 g at birth. In the late surfactant group, fewer infants received home respiratory support than in the control group (35.8% vs 52.9%, relative benefit [RB] 1.28 [95% CI 1.07-1.55]). There was no benefit of late surfactant for No PM vs PM (RB 1.27; 95% CI 0.89-1.81) or no persistent PM vs persistent PM (RB 1.01; 95% CI 0.87-1.17). After adjustment for imbalances in baseline characteristics, relative benefit of late surfactant treatment increased: RB 1.40 (95% CI 0.89-1.80) for no PM and RB 1.24 (95% CI 1.08-1.42) for no persistent PM. CONCLUSION: Treatment of newborns of extremely low gestational age with late surfactant in combination with inhaled nitric oxide decreased use of home respiratory support and may decrease persistent pulmonary morbidity. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01022580.

Randomized Trial of Late Surfactant Treatment in Ventilated Preterm Infants Receiving Inhaled Nitric Oxide.

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.

Inhaled nitric oxide increases urinary nitric oxide metabolites and cyclic guanosine monophosphate in premature infants: relationship to pulmonary outcome.

OBJECTIVE: Inhaled nitric oxide (iNO) has been tested to prevent bronchopulmonary dysplasia (BPD) in premature infants, however, the role of cyclic guanosine monophosphate (cGMP) is not known. We hypothesized that levels of NO metabolites (NOx) and cGMP in urine, as a noninvasive source for biospecimen collection, would reflect the dose of iNO and relate to pulmonary outcome. STUDY DESIGN: Studies were performed on 125 infants who required mechanical ventilation at 7 to 14 days and received 24 days of iNO at 20-2 ppm. A control group of 19 infants did not receive iNO. RESULTS: In NO-treated infants there was a dose-dependent increase of both NOx and cGMP per creatinine (maximal 3.1- and 2-fold, respectively, at 10-20 ppm iNO) compared with off iNO. NOx and cGMP concentrations at both 2 ppm and off iNO were inversely related to severity of lung disease during the 1st month, and the NOx levels were lower in infants who died or developed BPD at term. NOx was higher in Caucasian compared with other infants at all iNO doses. CONCLUSION: Urinary NOx and cGMP are biomarkers of endogenous NO production and lung uptake of iNO, and some levels reflect the severity of lung disease. These results support a role of the NO-cGMP pathway in lung development.

Late administration of surfactant replacement therapy increases surfactant protein-B content: a randomized pilot study.

BACKGROUND: Surfactant dysfunction may contribute to the development of bronchopulmonary dysplasia (BPD) in persistently ventilated preterm infants. We conducted a multicenter randomized, blinded, pilot study to assess the safety and efficacy of late administration of doses of a surfactant protein-B (SP-B)-containing surfactant (calfactant) in combination with prolonged inhaled nitric oxide (iNO) in infants ≤1,000 g birth weight (BW). METHODS: We randomized 85 preterm infants ventilated at 7-14 d after birth to receive either late administration of surfactant (up to 5 doses) plus prolonged iNO or iNO alone. Large aggregate surfactant was isolated from daily tracheal aspirates (TAs) for measurement of SP-B content, total protein, and phospholipid (PL). RESULTS: Late administration of surfactant had minimal acute adverse effects. Clinical status as well as surfactant recovery and SP-B content in tracheal aspirate were transiently improved as compared to the controls; these effects waned after 1 d. The change in SP-B content with surfactant dosing was positively correlated with SP-B levels during treatment (r = 0.50, P = 0.02). CONCLUSION: Low SP-B values increased with calfactant administration, but the relationship of this response to SP-B levels suggests that degradation is a contributing mechanism for SP-B deficiency and surfactant dysfunction. We conclude that late therapy with surfactant in combination with iNO is safe and transiently increases surfactant SP-B content, possibly leading to improved short- and long-term respiratory outcomes.

Plasma biomarkers of oxidative stress: relationship to lung disease and inhaled nitric oxide therapy in premature infants.

OBJECTIVES: Inhaled nitric oxide treatment for ventilated premature infants improves survival without bronchopulmonary dysplasia. However, there has been no information regarding possible effects of this therapy on oxidative stress. We hypothesized that inhaled nitric oxide therapy would not influence concentrations of plasma biomarkers of oxidative stress. PATIENTS AND METHODS: As part of the Nitric Oxide Chronic Lung Disease Trial, we collected blood samples at specified intervals from a subpopulation of 100 infants of <1250 g birth weight who received inhaled nitric oxide (20 ppm, weaned to 2 ppm) or placebo gas for 24 days. Plasma was assayed for total protein and for 3-nitrotyrosine and carbonylation by using immunoassays. RESULTS: The demographic characteristics and primary outcome for the infants were representative of the entire group of infants who were in the Nitric Oxide Chronic Lung Disease Trial. For all infants at baseline, before receiving study gas, the concentration of total protein was inversely correlated with the respiratory severity score, and plasma carbonyl was positively correlated with severity score, supporting an association between oxidative stress and severity of lung disease. Infants who survived without bronchopulmonary dysplasia had 30% lower protein carbonylation concentrations at study entry than those who had an adverse outcome. At each of 3 time points (1-10 days) during exposure to study gas, there were no significant differences between control and treated infants for concentrations of plasma protein, 3-nitrotyrosine, and carbonylation. CONCLUSIONS: Inhaled nitric oxide treatment for premature infants who are at risk for bronchopulmonary dysplasia does not alter plasma biomarkers of oxidative stress, which supports the safety of this therapy.

Surfactant function and composition in premature infants treated with inhaled nitric oxide.

OBJECTIVES: We hypothesized that inhaled nitric oxide treatment of premature infants at risk for bronchopulmonary dysplasia would not adversely affect endogenous surfactant function or composition. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Inflammatory markers and mediators in tracheal fluid of premature infants treated with inhaled nitric oxide.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Inhaled nitric oxide, as administered in this study, seemed to be safe. Its use was not associated with any increase in airway inflammatory substances.

Inhaled nitric oxide in preterm infants undergoing mechanical ventilation.

BACKGROUND: Bronchopulmonary dysplasia in premature infants is associated with prolonged hospitalization, as well as abnormal pulmonary and neurodevelopmental outcome. In animal models, inhaled nitric oxide improves both gas exchange and lung structural development, but the use of this therapy in infants at risk for bronchopulmonary dysplasia is controversial. METHODS: We conducted a randomized, stratified, double-blind, placebo-controlled trial of inhaled nitric oxide at 21 centers involving infants with a birth weight of 1250 g or less who required ventilatory support between 7 and 21 days of age. Treated infants received decreasing concentrations of nitric oxide, beginning at 20 ppm, for a minimum of 24 days. The primary outcome was survival without bronchopulmonary dysplasia at 36 weeks of postmenstrual age. RESULTS: Among 294 infants receiving nitric oxide and 288 receiving placebo birth weight (766 g and 759 g, respectively), gestational age (26 weeks in both groups), and other characteristics were similar. The rate of survival without bronchopulmonary dysplasia at 36 weeks of postmenstrual age was 43.9 percent in the group receiving nitric oxide and 36.8 percent in the placebo group (P=0.042). The infants who received inhaled nitric oxide were discharged sooner (P=0.04) and received supplemental oxygen therapy for a shorter time (P=0.006). There were no short-term safety concerns. CONCLUSIONS: Inhaled nitric oxide therapy improves the pulmonary outcome for premature infants who are at risk for bronchopulmonary dysplasia when it is started between 7 and 21 days of age and has no apparent short-term adverse effects. (ClinicalTrials.gov number, NCT00000548 [ClinicalTrials.gov] .).

Urinary metabolites of oxidative stress and nitric oxide in preterm and term infants.

BACKGROUND: Many neonatal diseases have been associated with oxidative stress and altered nitric oxide status. OBJECTIVE: To determine the effects of clinical interventions on the levels of urinary peroxides, a marker of oxidative stress, and urinary nitrate/nitrites, indices of nitric oxide production and metabolism, in the first 72 h of life in premature infants. METHODS: A single, spot urine sample was collected from 82 premature and 20 healthy term infants within the first 72 h of life. The peroxide levels were quantified using a fluorometric method, and nitrate/nitrite levels were quantified by chemiluminescence. RESULTS: Premature infants had a median peroxide level of 10.0 micromol/mmol creatinine (Cr) (interquartile range 4.8-20.0 micromol/mmol Cr). These values were significantly higher than term infants (median 5.0 micromol/mmol Cr, interquartile range 2.7-10.0 micromol/mmol Cr). Urinary nitrate/nitrite levels were not significantly different between preterm (220.5 micromol/mmol Cr, interquartile range 161-287 micromol/mmol Cr) and healthy term infants (244 micromol/mmol Cr, interquartile range 194-316 micromol/mmol Cr). For urinary peroxides, infants on TPN had significantly higher urinary peroxide levels than infants who were not on TPN at the time of urine collection (p = 0.006). Administration of indomethacin was associated with lower levels of urinary nitrate/nitrites (p = 0.0003). Both effects remained significant after controlling for gestational age, degree of respiratory distress and day of urine collection. CONCLUSION: Monitoring the level of both peroxides and nitrate/nitrite may offer added information about the degree of oxidative stress experienced by a newborn but needs to account for clinical and therapeutic interventions.

Dysfunction of pulmonary surfactant in chronically ventilated premature infants.

Infants of <30 wk gestation often require respiratory support for several weeks and may develop bronchopulmonary dysplasia (BPD), which is associated with long-term pulmonary disability or death in severe cases. To examine the status of surfactant in infants at high risk for BPD, this prospective study analyzed 247 tracheal aspirate samples from 68 infants of 23-30 wk gestation who remained intubated for 7-84 d. Seventy-five percent of the infants had one or more surfactant samples with abnormal function (minimum surface tension 5.1-21.7 mN/m by pulsating bubble surfactometer), which were temporally associated with episodes of infection (p = 0.01) and respiratory deterioration (p = 0.005). Comparing normal and abnormal surfactant samples, there were no differences in amount of surfactant phospholipid, normalized to total protein that was recovered from tracheal aspirate, or in relative content of phosphatidylcholine and phosphatidylglycerol. Contents of surfactant proteins (SP) A, B, and C, measured in the surfactant pellet by immunoassay, were reduced by 50%, 80%, and 72%, respectively, in samples with abnormal surface tension (p < or = 0.001). On multivariable analysis of all samples, SP-B content (r = -0.58, p < 0.0001) and SP-C content (r = -0.32, p < 0.001) were correlated with surfactant function. We conclude that most premature infants requiring continued respiratory support after 7 d of age experience transient episodes of dysfunctional surfactant that are associated with a deficiency of SP-B and SP-C.

Risk factors for extended-spectrum beta-lactamase-producing Enterobacteriaceae in a neonatal intensive care unit.

Risk factors for colonization or infection with extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae during an outbreak in a neonatal intensive care unit (NICU) included low gestational age and exposure to third-generation cephalosporins. We also reviewed the existing medical literature regarding the clinical epidemiology of ESBLs in NICUs .

Low levels of tissue inhibitors of metalloproteinases with a high matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio are present in tracheal aspirate fluids of infants who develop chronic lung disease.

OBJECTIVE: The pathogenesis of chronic lung disease (CLD) involves inflammation with proteolytic damage to lung extracellular matrix. Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that, acting in concert with their tissue inhibitors, tightly orchestrate extracellular matrix morphogenesis and repair after injury. Imbalances in their levels relative to that of their inhibitors have been implicated in diseases characterized by matrix disruption and remodeling. We investigated the possibility that imbalances in MMP-9 and MMP-2 relative to their tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2, respectively, in tracheal aspirates of preterm infants may be involved in the development of CLD. METHODS: Serial tracheal aspirates collected from birth until extubation in 49 ventilated preterm infants (24-32 weeks' gestations) were analyzed for MMP-2, MMP-9, TIMP-1, and TIMP-2. Data normalized by TA values of free secretory component of immunoglobulin A were compared for CLD (n = 22) versus no CLD (n = 27). Also, known clinical predictors of CLD (gestational age, birth weight, and sex) were assessed for both groups. Association of predictors with the outcome CLD was assessed by logistic regression. RESULTS: Mean gestational age was lower in CLD infants, but birth weight and gender were comparable for both groups. CLD infants had significantly lower TIMP-1 level with higher MMP-9/TIMP-1 ratio during the first 2 weeks of life and low TIMP-2 and MMP-2 levels during the first 3 days of life compared with no-CLD infants. Logistic regression analysis indicated that the findings are predictive of CLD. CONCLUSIONS: We conclude that low tracheal aspirate levels of TIMPs, with a high MMP-9/TIMP-1 ratio early in life, are associated with subsequent development of CLD.

Prenatal mild pyelectasis: evaluating the thresholds of renal pelvic diameter associated with normal postnatal renal function.

OBJECTIVE: To determine the threshold of the renal pelvic anteroposterior (AP) diameter that predicts normal postnatal renal outcome in the follow-up of cases with mild pyelectasis. METHODS: A retrospective review of our sonography database was conducted over a 3-year period for cases of mild pyelectasis diagnosed between 18 and 30 weeks. Cases were evaluated for the association between different thresholds of renal pelvic anteroposterior diameter and normal postnatal function after 32 weeks' gestation and also for the initial renalpelvic anteroposterior diameter at 18 to 30 weeks. RESULTS: In the 3-year period, 7416 women were evaluated, and 150 cases with a diagnosis of pyelectasis (2%) were identified. Among the 115 women meeting our inclusion criteria, complete outcomes were available for 66. Persistent postnatal renal anomalies were seen in 20 cases (30%). On the basis of receiver operating characteristic curves, the renal threshold that best predicted normal postnatal outcome was an anteroposterior diameter of less than 7.0 mm after 32 weeks, yielding sensitivity and specificity of 87% and 85%, respectively (odds ratio, 0.31; 95% confidence interval, 0.11-0.86; P < .02). CONCLUSIONS: In the follow-up of fetuses with a diagnosis of mild pyelectasis between 18 and 30 weeks, a renal pelvic anteroposterior diameter of less than 7.0 mm after 32 weeks is highly predictive of normal postnatal renal function. Therefore, only those with an anteroposterior diameter of greater than 6 mm after 32 weeks deserve follow-up.

Surfactant protein profile of pulmonary surfactant in premature infants.

Although premature infants are known to be deficient in pulmonary surfactant, there is limited information regarding surfactant protein (SP) composition. To assess the postnatal profile of SPs, tracheal aspirate samples were collected from 35 intubated infants of 23-31 weeks of gestation between 8 and 80 days of age. In 71 large aggregate surfactant samples that had normal in vitro function (minimum surface tension of less than 1 mN/m by pulsating bubble surfactometry), mean +/- SEM contents of SP-A, SP-B, and SP-C (3.7 kD) were 7.1 +/- 1.4%, 1.8 +/- 0.2%, and 4.6 +/- 0.6%, respectively, of phospholipid. To assess SPs in the 1st week of life, we analyzed samples from additional infants receiving only synthetic replacement surfactant. On the 2nd day of life, contents of SP-A, SP-B, and SP-C were 13.4%, 8.4%, and 0.1%, respectively, of the mean levels for Day 8-80 samples. The major postnatal increases for SP-A, SP-B, and SP-C occurred during the 1st, 2nd, and 3rd weeks, respectively. We conclude that surfactant of newborn premature infants is markedly deficient in SPs, in particular SP-C. Despite continuing lung disease, some infants who are more than 1 week of age have surfactant with normal in vitro function that contains SPs at levels comparable to adult surfactant.

Morphine enhances HIV infection of neonatal macrophages.

Perinatal transmission of HIV accounts for almost all new HIV infections in children. There is an increased risk of perinatal transmission of HIV with maternal illicit substance abuse. Little is known about neonatal immune system alteration and subsequent susceptibility to HIV infection after morphine exposure. We investigated the effects of morphine on HIV infection of neonatal monocyte-derived macrophages (MDM). Morphine significantly enhanced HIV infection of neonatal MDM. Morphine-induced HIV replication in neonatal MDM was completely suppressed by naltrexone, the opioid receptor antagonist. Morphine significantly up-regulated CCR5 receptor expression and inhibited the endogenous production of macrophage inflammatory protein-1beta in neonatal MDM. Thus, morphine, most likely through alteration of beta-chemokines and CCR5 receptor expression, enhances the susceptibility of neonatal MDM to HIV infection, and may have a cofactor role in perinatal HIV transmission and infection.

Plasma 3-nitrotyrosine and outcome in neonates with severe bronchopulmonary dysplasia after inhaled nitric oxide.

Plasma protein levels of 3-nitrotyrosine and 3-chlorotyrosine were measured by LC-MS/MS at 0 and 72 h after the initiation of inhaled nitric oxide (INO) at 20 ppm in 22 prematurely born infants with clinically documented bronchopulmonary dysplasia. Infants were classified at the time of hospital discharge as either "off mechanical ventilation," "on mechanical ventilation," or "expired/organ failure." These outcomes were tested for association with changes in plasma levels of 3-nitrotyrosine and 3-chlorotyrosine and selected clinical risk factors. Infants whose 3-nitrotyrosine levels decreased over the 72 h period were more likely to wean off of mechanical ventilation (p =.03). There was no significant association between changes in 3-chlorotyrosne levels and outcome. After controlling for other variables, an odds ratio of 8.3 (95% CI: 1.3-54.4) for improved outcomes was observed if the 3-nitrotyrosine levels decreased. These data suggest that nitrative and oxidative stress may be related to the severity of lung disease and, consequentially, the overall outcome in this select group of infants with severe bronchopulmonary dysplasia.

CCR5 expression and beta-chemokine production during placental neonatal monocyte differentiation.

The stage of maturation of monocytes affects their susceptibility to HIV infection. The beta-chemokines and their receptor CCR5 play a crucial role in inflammatory reactions and HIV infection. We therefore examined the correlation between the expression of CCR5 and beta-chemokine production and the susceptibility to HIV infection during cord monocyte (CM) differentiation into macrophages. CM and CM-derived macrophages (CMDM) were examined for beta-chemokine and CCR5 expression. The susceptibility of the CM cultured in vitro at different time points to HIV infection was also determined. Although the levels of CCR5 mRNA expression in freshly isolated CM are comparable to those in CMDM, CM had significantly lower levels of CCR5 protein on the cell surface than CMDM did. Steady increase of CCR5 protein expression on the cell surface was observed during CM differentiation into macrophages. The CCR5 expression correlated with the increased susceptibility to HIV infection by CMDM. Although there was no significant difference in endogenous beta-chemokine production between CM and CMDM, HIV infection of CMDM significantly enhanced production of macrophage inflammatory protein-1alpha and -1beta. CCR5 receptor plays a critical role in HIV infection of neonatal blood monocyte/macrophages.

Pulmonary surfactant for neonatal respiratory disorders.

Surfactant therapy has revolutionized neonatal care and is used routinely for preterm infants with respiratory distress syndrome. Recent investigation has further elucidated the function of surfactant-associated proteins and their contribution toward surfactant and lung immune defense functions. As the field of neonatology moves away from intubation and mechanical ventilation of preterm infants at birth toward more aggressive use of nasal continuous positive airway pressure, the optimal timing of exogenous surfactant therapy remains unclear. Evidence suggests that preterm neonates with bronchopulmonary dysplasia and prolonged mechanical ventilation also experience surfactant dysfunction; however, exogenous surfactant therapy beyond the first week of life has not been well studied. Surfactant replacement therapy has been studied for use in other respiratory disorders, including meconium aspiration syndrome and pneumonia. Commercial surfactant preparations currently available are not optimal, given the variability of surfactant protein content and their susceptibility to inhibition. Further progress in the treatment of neonatal respiratory disorders may include the development of "designer" surfactant preparations.

Multiple courses of antenatal corticosteroids are associated with early severe lung disease in preterm neonates.

OBJECTIVE: Determine whether the increased neonatal mortality following repeated courses of antenatal corticosteroids (ANCS), observed in the Thyrotropin-Releasing Hormone (TRH) Trial, was related to confounding maternal risk factors or specific preterm morbidities. STUDY DESIGN: A post hoc analysis of 595 TRH trial neonates, 26 to 32 weeks' gestation, studied the association between > or =3 courses ANCS and mortality. Potential confounding maternal factors and preterm morbidities were evaluated using logistic regression and log likelihood modeling. RESULTS: Mortality was 9.2% after > or =3 courses (13/141) vs. 4.8% after 1 or 2 courses (22/454). This association was not explained by maternal factors, or other common preterm morbidities. However, 15/141 infants receiving > or =3 courses (10.6%) had early severe lung disease (ESLD) with 10 deaths, compared to 16/454 of the 1- to 2-course infants (3.5%) with 7 deaths (odds ratio 3.5, p<0.001). CONCLUSIONS: ESLD, but not maternal risk factors, was associated with increased mortality in preterm infants after > or =3 courses ANCS.