Cynthia H. Cole

Prophylaxis of Early Adrenal Insufficiency to Prevent Bronchopulmonary Dysplasia: A Multicenter Trial

Background. Infants developing bronchopulmonary dysplasia (BPD) show decreased cortisol response to adrenocorticotropic hormone. A pilot study of low-dose hydrocortisone therapy for prophylaxis of early adrenal insufficiency showed improved survival without BPD at 36 weeks’ postmenstrual age, particularly in infants exposed to histologic chorioamnionitis. Methods. Mechanically ventilated infants with birth weights of 500 to 999 g were enrolled into this multicenter, randomized, masked trial between 12 and 48 hours of life. Patients received placebo or hydrocortisone, 1 mg/kg per day for 12 days, then 0.5 mg/kg per day for 3 days. BPD at 36 weeks’ postmenstrual age was defined clinically (receiving supplemental oxygen) and physiologically (supplemental oxygen required for O2 saturation ≥90%). Results. Patient enrollment was stopped at 360 patients because of an increase in spontaneous gastrointestinal perforation in the hydrocortisone-treated group. Survival without BPD was similar, defined clinically or physiologically, as were mortality, head circumference, and weight at 36 weeks. For patients exposed to histologic chorioamnionitis (n = 149), hydrocortisone treatment significantly decreased mortality and increased survival without BPD, defined clinically or physiologically. After treatment, cortisol values and response to adrenocorticotropic hormone were similar between groups. Hydrocortisone-treated infants receiving indomethacin had more gastrointestinal perforations than placebo-treated infants receiving indomethacin, suggesting an interactive effect. Conclusions. Prophylaxis of early adrenal insufficiency did not improve survival without BPD in the overall study population; however, treatment of chorioamnionitis-exposed infants significantly decreased mortality and improved survival without BPD. Low-dose hydrocortisone therapy did not suppress adrenal function or compromise short-term growth. The combination of indomethacin and hydrocortisone should be avoided.

Blood Gases and Retinopathy of Prematurity: The ELGAN Study

Objective: This study tested the hypothesis that preterm infants who had a blood gas derangement on at least 2 of the first 3 postnatal days are at increased risk for more severe retinopathy of prematurity (ROP). Method: 1,042 infants born before 28 weeks’ gestational age (GA) were included. An infant was considered to be exposed if his/her blood gas measure was in the highest or lowest quartile for GA on at least 2 of the first 3 postnatal days. Results: Multivariable models adjusting for confounders indicate that exposure to a PCO2 in the highest quartile predicts ROP (stage 3, 4 or 5: OR = 1.6, 95% CI = 1.1–2.3); zone 1: 2.0, 1.1–3.6; prethreshold/threshold: 1.9, 1.2–3.0; plus disease: 1.8, 1.1–2.9). Estimates are similar for a low pH for zone 1 (2.1, 1.2–3.8), prethreshold/threshold (1.8, 1.1–2.8), but did not quite achieve statistical significance for ROP stage 3, 4, or 5 (1.4, 0.9–2.0) and plus disease (1.5, 0.9–2.4). A PaO2 in the highest quartile for GA on at least 2 of the first 3 postnatal days was associated with a doubling of the risk of ROP in zone 1 (2.5, 1.4–4.4) and of prethreshold/threshold disease (2.1, 1.4–3.3), a 70% risk increase for plus disease (1.7, 1.04–2.8), while a 40% risk increase for ROP stage 3 or higher did not achieve statistical significance (1.4, 0.96–2.0). Conclusion: Infants exposed to high PCO2, low pH and high PaO2 appear to be at increased risk of more severe ROP.

Effects of early inhaled beclomethasone therapy on tracheal aspirate inflammatory mediators IL‐8 and IL‐1ra in ventilated preterm infants at risk for bronchopulmonary dysplasia

We tested the hypothesis that inhaled beclomethasone therapy for prevention of bronchopulmonary dysplasia (BPD) reduces pulmonary inflammation. As part of a randomized, placebo‐controlled trial, interleukin‐8 (IL‐8) and interleukin‐1 receptor antagonist (IL‐1ra) concentrations in tracheal aspirates were measured as markers of pulmonary inflammation. On study days 1 (baseline), 8, 15, and day 28 of age, samples were obtained from enrolled infants (birth weights <1,251 g, gestational age <33 week, 3 to 14 days of age) who remained ventilated and had not received systemic glucocorticoid therapy. Cytokine levels (pg/μg of free secretory component of immunoglobulin A) were compared between groups. We determined whether baseline cytokine levels modified treatment effect regarding subsequent need for systemic glucocorticoid therapy or occurrence of BPD (age 28 days).

A Pulmonary Score for Assessing the Severity of Neonatal Chronic Lung Disease

Background. Limited data are available to describe the spectrum of severity of neonatal chronic lung disease. In the multicenter Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity trial, all infants had some degree of pulmonary dysfunction, because eligibility required a median oxygen saturation of ≤94% with room air. Infants randomized to the supplemental oxygen group (oxygen saturation target of 96–99%) had more pulmonary morbidity than did those in the conventional group (oxygen saturation target of 88–94%). This prompted the retrospective development of a pulmonary severity score to compare the baseline status of the 2 groups. Objectives. To describe a pulmonary score that reflects the severity of neonatal lung disease and to evaluate the association of the score and its components with subsequent pulmonary morbidity through 3 months of corrected age. Design and Methods. A pulmonary score was developed empirically by a consensus panel of 3 neonatologists and was defined as the fraction of inspired oxygen (Fio2) × (support) + (medications), where Fio2 is the actual or “effective” (for nasal cannula) Fio2; support is 2.5 for a ventilator, 1.5 for nasal continuous positive airway pressure, or 1.0 for nasal cannula or hood oxygen; and medications is 0.20 for systemic steroids for bronchopulmonary dysplasia, 0.10 each for regular diuretics or inhaled steroids, and 0.05 each for methylxanthines or intermittent diuretics. The scores could range from 0.21 to 2.95. Pulmonary morbidity was defined as any of the following occurring from randomization at a mean of 35.4 weeks’ postmenstrual age through 3 months of corrected age: death or rehospitalization with a pulmonary cause; an episode of pneumonia/sepsis/exacerbation of chronic lung disease; or continued hospitalization, supplemental oxygen therapy, diuretic treatment, or systemic steroid therapy at 3 months. Between-group differences were tested with the Kruskal-Wallis or χ2 test. Results. Data through death or the 3-month corrected age examination were available for 588 infants. Enrolled infants represented a wide spectrum of severity of chronic lung disease, with baseline pulmonary scores at randomization ranging from 0.21 to 2.6. The median pulmonary score at enrollment did not differ between the conventional and supplemental groups (0.42 and 0.45, respectively). However, higher baseline pulmonary scores were observed for infants who did versus did not develop subsequent pulmonary morbidity (0.48 vs 0.38). The pulmonary score was associated with subsequent pulmonary morbidity. Regression analyses adjusting for Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity group assignment, gestational age at birth, race, gender, and postmenstrual age at randomization revealed that the score was a significant independent predictor of subsequent pulmonary morbidity (odds ratio: 7.2; 95% confidence interval: 3.6-14.4). Conclusions. The pulmonary score, calculated near term, reflects a wide spectrum of bronchopulmonary dysplasia severity and is associated with subsequent pulmonary morbidity through corrected age of 3 months. This simple score could prove useful in clinical and research settings. Validation of the score requires additional study.

Meta‐analysis of dexamethasone therapy started in the first 15 days of life for prevention of chronic lung disease in premature infants

We performed a systematic review of randomized controlled trials to determine whether the use of dexamethasone therapy in the first 15 days of life is beneficial for prevention of chronic lung disease in prematurely born infants. Studies were identified by conducting a literature search using the Medline database (1970–1997) and supplemented by a search of the Cochrane Library (1998, issue 4). Inclusion criteria were: 1) prospective randomized design with initiation of dexamethasone therapy within the first 15 days of life; 2) report of outcome of interest; and 3) less than 20% cross‐over between treatment and control group during the study period. Our primary outcomes were mortality at hospital discharge and the development of chronic lung disease at 28 days of life and 36 weeks postconceptional age. The secondary outcomes were the presence of a patent ductus arteriosus and treatment side effects. The overall baseline event rate in the control group and pooled risk ratio (RR) of event reduction with 95% confidence interval (CI) were calculated.

Inhaled Glucocorticoid Therapy in Infants at Risk for Neonatal Chronic Lung Disease

The primary impetus for the study of inhaled glucocorticoid therapy in the treatment and prevention of neonatal chronic lung disease (CLD) was to achieve effective anti-inflammatory therapy with few adverse effects. Initial reports of inhaled glucocorticoid therapy in infants with established CLD suggest modest improvement in neonatal respiratory outcomes. Recent randomized trials also indicate that inhaled glucocorticoid therapy may provide some benefit, but have not demonstrated a reduction in CLD. Some studies suggest that the pulmonary response to systemic glucocorticoid may be greater and faster than response to inhaled glucocorticoid therapy. Few adverse effects have been noted with inhaled glucocorticoid therapy. One limitation of studies of inhaled glucocorticoid therapy is the uncertainty of the dose delivered and deposited in peripheral airways and regions of the lungs. Experience with and systematic study of inhaled glucocorticoid therapy is still in its early stages. The role of inhaled glucocorticoid therapy in the treatment and prevention of CLD is evolving. Advances in delivery devices and new developments of drug formulations should improve aerosol delivery and deposition in infants. Given the clinical

Postnatal glucocorticosteroid therapy for treatment and prevention of neonatal chronic lung disease

Neonatal chronic lung disease (CLD) is a persistent complication, primarily of premature infants. Postnatal glucocorticoid therapy is widely used in the treatment and prevention of CLD. Most studies reveal acute improvement in the pulmonary status of infants treated with postnatal glucocorticoid therapy. Recent studies of ‘earlier’ intervention (<< 14 days of age) demonstrated a reduction in mortality and in the occurrence of CLD between 28 days of age and 36 weeks postmenstrual age. Great concern remains, however, regarding the potential adverse outcomes, including growth inhibition, infection, catastrophic GI complications and CNS injury. Therefore, the use of postnatal glucocorticoid therapy remains controversial with respect to the clinical indications for initiating therapy, the dose, duration, onset and route of administration, as well as potential benefits and risks. Inhaled glucocorticoid therapy is increasingly used to treat and prevent CLD in order to avoid adverse effects of high dose systemic glucocorticoid therapy. Recent studies with inhaled glucocorticoid therapy show promise. Further work, however, for improving aerosol delivery and deposition, will be needed to refine their role in the prevention and treatment of CLD. Future studies enabling early, accurate identification of infants at greatest risk for CLD, coupled with a more comprehensive understanding of the different pathogeneses, will provide information regarding appropriate timing of onset, dosing, route of therapy and duration of intervention.

Effect of Beclomethasone Therapy on Tracheal Aspirate Interleukin-8 and Interleukin-1 Receptor Antagonist in Preterm Ventilated Infants at Risk for Bronchopulmonary Dysplasia (BPD)

Effect of Beclomethasone Therapy on Tracheal Aspirate Interleukin-8 and Interleukin-1 Receptor Antagonist in Preterm Ventilated Infants at Risk for Bronchopulmonary Dysplasia (BPD)

UTILIZATION OF AEROSOL THERAPY IN NEONATES IN USA NICUS. † 1954

Due to the apparent widespread use of aerosol therapy in neonates, we surveyed the current use of aerosol therapy in Level III Neonatal Units in the USA. The indications, the methods of delivery, and the medications aerosolized were assessed. 190 of 287 (66%) NICUs responded to the survey. 186/190 (98%) NICUs indicated they use aerosol therapy. Clinical reasons for using aerosol therapy include bronchospasm (98%); antiinflammation (68%); diuresis (8%); antibiotic administration (17%); mucolysis (4%); pulmonary toilet (3%); hemostasis in pulmonary hemorrhage (2%). For intubated neonates, 84% of respondents utilize nebulization (neb), 16% use metered dose inhalers (MDI). For nonintubated infants, 95% of respondents use neb, 5% use MDI. With respect to medications aerosolized in NICU patients, all 186 NICUs that practice aerosol therapy use beta adrenergic agents; 59% use Na cromoglycate; 44% corticosteroids; 9% diuretics; 20% ipratropium; 9% racemic epinephrine; 4% mucomyst. 12% indicated use of aminoglycosides. 3 NICUs indicated use of either cocaine or epinephrine for hemostasis in pulmonary hemorrhage. Of survey responders who use corticosteroids, 50% nebulize steroids despite existing evidence that the respirable particle size for steroids is more effectively achieved by MDI. Conclusion: Despite a paucity of data on aerosol drug delivery, clinical efficacy, and safety, the majority of NICUs responding to the survey do use aerosol therapy. Given the widespread use, varying clinical indications, methods of delivery, and types of drugs it is critical to document optimal dosing, delivery, safety, and efficacy.

Effect of Early Inhaled Glucocorticord Therapy on Tracheobronchial Lesions in Mechanically Ventilated Preterm Infants

Effect of Early Inhaled Glucocorticord Therapy on Tracheobronchial Lesions in Mechanically Ventilated Preterm Infants