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Few medications are available and well tested to treat infants who already have developed or inevitably will develop severe bronchopulmonary dysplasia (sBPD). Infants who develop sBPD clearly have not benefited from decades of research efforts to identify clinically meaningful preventive therapies for very preterm infants in the first days and weeks of their postnatal lives. This review addresses challenges to individualized approaches to medication use for sBPD. Specific challenges include understanding the combination of an individual infant’s postmenstrual and postnatal age and the developmental status of drug-metabolizing enzymes and receptor expression. This review will also explore the reasons for the variable responsiveness of infants to specific therapies, based on current understanding of developmental pharmacology and pharmacogenetics. Data demonstrating the remarkable variability in the use of commonly prescribed drugs for sBPD are presented, and a discussion about the current use of some of these medications is provided. Finally, the potential use of antifibrotic medications in late-stage sBPD, which is characterized by a profibrotic state, is addressed.

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 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.

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-1β, interleukin-8, transforming growth factor-β, N-acetylglucosaminidase, 8-epi-prostaglandin F2α, 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 F2α 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.

After completing this article, readers should be able to: 1. Describe the benefits and difficulties inherent in conducting randomized clinical trials (RCTs). 2. Describe the results of recent trials of therapies to prevent chronic lung disease (CLD). 3. Describe the trends in risk and resulting prevalence of the adverse effects of CLD in recent years. 4. Describe the limitations of RCTs in examining methods of reducing CLD. This review summarizes results of definitive interventional randomized clinical trials (RCTs) designed to reduce the incidence of, or the severity of, chronic lung disease (CLD) of prematurity. The mostly modest results understate the considerable energy expended to accomplish such studies. Included in the efforts to complete successful RCTs are inspiration, design, securing of funding, enrollment, analysis of results, and achievement of publication. This review is wholly dependent on the publication of results, both those in which the patients in the experimental arm fared better (few) and those reporting no differences in the primary outcome of CLD (many). All completed and published studies contributed to providing guidance for current and future therapy. The review focuses on definitive, preferably multicenter, and, when possible, blinded studies. Randomized trials have been embraced relatively recently but now exuberantly by neonatologists. Nonetheless, testing of putative interventions against CLD could occur more quickly with a coordinated effort to enroll a higher proportion of the very low-birthweight (VLBW) (

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.

Bronchopulmonary dysplasia is a chronic, sometimes fatal lung disease, which primarily affects premature infants and often leads to a dependence on mechanical ventilation lasting many months. To identify prognostic factors of mortality at 1 and 2 months of age, the authors reviewed the medical records of the 144 neonates admitted to two neonatal intensive care units in Seattle from January 1, 1986, through December 31, 1988, who required mechanical ventilation throughout the first month of life. Likely predictors of mortality were tested by logistic regression analysis. The calculated mean airway pressure at 30 days of age (MAP30) and the diagnosis of bacterial sepsis at any time during the first month of life (Bact0-30) were statistically significant predictors of mortality (P < .001 and P = .018, respectively) and had the lowest deviance in the regression model. The probability of mortality was estimated by 1/(1 + e-x, where x = -6.510 + 0.4588 (MAP30) + 1.475 (Bact0-30), and where MAP30 is expressed as centimeters of water pressure (1 cm H2O = 0.0978 kPa) and the presence or absence of bacteremia is 1 and 0, respectively. The records of the 57 infants who still required mechanical ventilation at 60 days of age were reanalyzed with clinical data available during the first 2 months of life. Mean airway pressure (MAP60) and the fraction of inspired oxygen (F60) at 60 days of age combined to form the best predictors of mortality, where x = -7.668 + 0.2940 (MAP60) + 5.935 (F60). The occurrence of bacterial sepsis during the first 2 months of life, the degree of hypochloremia, and the duration of chronic sedative use were also significant predictors of survival, even controlling of MAP60 and F60. These regression equations allow more accurate estimation of the likelihood of survival for chronically ventilated infants and may facilitate decisions regarding withdrawal or continuation of life support.

The modern era of surfactant-replacement therapy (SRT) is almost 30 years old. Capitalizing on the then-new understanding of surfactant composition and function,1 Fujiwara et al2 opened a new decade and a new era in neonatal medicine with their January 12, 1980, report in the Lancet . Their 10-patient phase II open-label single-center study demonstrated physiologic efficacy of exogenous bovine-derived surfactant in infants with respiratory distress syndrome (RDS). On the heels of this report, multiple studies followed. These studies included single-dose safety trials, efficacy trials, dose-ranging trials, and optimal timing trials, all aimed at preventing or treating RDS. Later trials sought to identify term and preterm infants with disorders other than RDS who might benefit from SRT. These later efforts met with more limited success.3–5 More recently, lucinactant, a synthetic surfactant containing a 21 amino acid peptide, sinapultide, has been tested against other surfactants in the management of RDS.6 Against this bright background of remarkable improvement in mortality rates for very low birth weight infants, the shadow of bronchopulmonary dysplasia (BPD) has lengthened. … Address correspondence to William E. Truog, MD, Children's Mercy Hospitals and Clinics, Section of Neonatology, Department of Pediatrics, 2401 Gillham Road, Kansas City, MO 64108. E-mail: wtruog{at}cmh.edu

To the Editor. — In their recent review article in Pediatrics , “Inhaled Nitric Oxide for Preterm Infants: A Systematic Review,”1 Barrington and Finer report on meta-analyses of nitric-oxide (NO) studies in premature infants. They include our NO CLD study2 as 1 of 2 studies testing the effect of inhaled NO (iNO) started beyond the first 3 days of life with the primary outcome of improving survival without bronchopulmonary dysplasia (BPD) measured at 36 weeks' postmenstrual age. In their article, Barrington and Finer stated that “[t]he study by Ballard et al reported a significant benefit of iNO in improving rates of survival without BPD. However, the figures given in the article (165 of 294 vs 182 of 288 patients) were not significant when RevMan software was used to calculate the [relative risk] and its CIs [confidence intervals] … or when SPSS software was used to perform a simple χ2 test … or unadjusted, logistic regression analysis. The reason for this discrepancy is not clear.” On the basis of this analysis, they stated in their abstract that “[l]ater use of inhaled nitric oxide to prevent …

Adult respiratory distress syndrome, commonly seen in adults, is not well recognized in children. A retrospective chart review was carried out to determine the relative incidence, predisposing conditions, clinical course, and outcome of children with adult respiratory distress syndrome. Fifteen patients were identified. The most common predisposing conditions were near-drowning and near-strangulation with a noticeable absence of major trauma. Mortality was 60%. Death was most often secondary to central nervous system complications. Air leak was the most common complication of treatment. Two of six survivors suffered major neurologic handicaps. Long-term pulmonary sequelae were minimal.

Chronic lung disease in prematurely born infants, defined as the need for increased inspired oxygen at 28 days of age, was thought to be more common in some institutions than in others. To test this hypothesis, we surveyed the experience in the intensive care nurseries at Columbia and Vanderbilt Universities, the Universities of Texas at Dallas, Washington at Seattle, and California at San Francisco, the Brigham and Women's Hospital in Boston, Texas Children's Hospital in Houston, and Mt Sinai Hospital in Toronto. The survey included 1,625 infants with birth weights of 700 to 1,500 g. We confirmed the relationship of risk to low birth weight, white race, and male sex. Significant differences in the incidence of chronic lung disease were found between institutions even when birth weight, race, and sex were taken into consideration through a multivariate logistic regression analysis. Columbia had one of the best outcomes for low birth weight infants and the lowest incidence of chronic lung disease.