John M. Fiascone

Infection, Oxygen, and Immaturity: Interacting Risk Factors for Retinopathy of Prematurity

Background: Interactions among known risk factors for retinopathy of prematurity (ROP) remain to be clarified. Objectives: The aim of this study was to identify risk factors associated with ROP and to explore the interrelationships between prominent risk factors for ROP. Methods: From an institutional cohort of 1,646 very preterm newborns with gestational age <30 weeks or birth weight <1,501 g, we selected infants with a gestational age <30 weeks who met the criteria for ROP screening (n = 622) for a nested case-control analysis. Results: Of the 622 eligible newborns, 293 (47%) were diagnosed with ROP. From multivariable analyses, gestational age <26 weeks (OR 2.9, CI 1.7–4.9), oxygen exposure at 28 days (OR 1.7, CI 1.0–2.7), and neonatal sepsis (OR 2.1, CI 1.4–3.2) emerged as prominent risk factors for ROP. Oxygen- associated ROP risk was more prominent among infants of 23–25 weeks’ gestational age, while infection-associated ROP risk was higher among infants born at 28–29 weeks. The OR for the joint effect of all 3 risk factors (23.5) was higher than would have been expected under the additive (8.6) and the multiplicative (16.5) patterns of interaction. Conclusions: Our study suggests that neonatal sepsis, oxygen exposure, and low gestational age are not only independently associated with a significantly increased risk of ROP, but also interact beyond additive and even multiplicative patterns.

Betamethasone increases pulmonary compliance in part by surfactant-independent mechanisms in preterm rabbits.

ABSTRACT. Antenatal exposure to corticosteroids is known to increase the pulmonary compliance of preterm animals. We wished to determine whether this was due solely to alteration in lung surfactant content. Rabbit does were injected with either vehicle alone or betamethasone on days 25 and 26 of gestation. Fetuses were delivered at 27 days and given either 50% lactated Ringers or intratracheal natural surfactant prior to their first breath. Fetuses were mechanically ventilated at a tidal volume of 12 ml/kg for 60 min with periodic compliance measurements. Following ventilation an alveolar lavage was collected for phosphatidylcholine determination. Some fetuses did not undergo ventilation but had saline compliance studies instead. Fetuses given intratracheal surfactant had a higher dynamic compliance than fetuses exposed to antenatal corticosteroids (0.55 ± 0.01 versus 0.48 ± 0.02 ml/cm H2O/kg, respectively). Fetuses exposed to antenatal corticosteroids and given intratracheal surfactant had a dynamic compliance (0.66 ± 0.02) that was greater than those exposed to either single therapy. This was found despite an alveolar surfactant content equal to that in fetuses receiving intratracheal surfactant alone. Saline compliance at birth was significantly greater for fetuses exposed antenatally to steroids. These data imply the existence of a nonsurfactant mechanism by which antenatal corticosteroids increase fetal pulmonary compliance.

Implementation of safe sleep practices in the neonatal intensive care unit

Objective:To increase the percentage of eligible infants engaging in safe sleep practices (SSP) in two level III neonatal intensive care units (NICUs) in the Boston, Massachusetts area.Study design:On the basis of eligibility criteria (⩾34 weeks or ⩾1800 g without acute medical conditions), all infants were eligible for two sleep practices: SSP or NICU therapeutic positioning (NTP) depending on their gestational age, weight, clinical illness and need for therapeutic interventions. Compliance with SSP was defined as: (1) supine positioning, (2) in a flat crib with no incline, (3) without positioning devices and (4) without toys, comforters or fluffy blankets. NTP comprised usual NICU care. Nursing education was comprised of a web-based learning module and in-person teaching sessions with a study team member. Double-sided crib cards (SSP one side and NTP on the other) were attached to the bedside of every infant. Pre- and postintervention audits of all infants were carried out at both study sites. We compared compliance across all time points using generalized estimating equations to account for correlated data (SAS v9.3, Cary, NC, USA).Result:Of 755 cases, 395 (52.3%) were assessed to be eligible for SSP. From the pre- to post-intervention period, there was a significant improvement in overall compliance with SSP (25.9 to 79.7%; P-value<0.001). Adherence to each component of SSP also improved significantly following the intervention.Conclusion:Safe infant sleep practices can be integrated into the routine care of preterm infants in the NICU. Modeling SSP to families far in advance of hospital discharge may improve adherence to SSP at home and reduce the risk of sleep-related morbidity and mortality in this vulnerable population of infants.

Bronchopulmonary dysplasia: A review for the pediatrician

In this review we have attempted to introduce bronchopulmonary dysplasia as a new chronic lung disease of infancy and childhood. The major risk factors for this illness are preterm birth and the respiratory distress syndrome. The precise etiology of BPD is not understood but trauma from mechanical ventilation and toxicity from exposure to supplemental oxygen are thought to be important. Problems in diagnosis and diagnostic criteria have been discussed as have the details of the unfavorable pulmonary mechanics. We have mentioned some of our own practices in regard to a large and successful home oxygen therapy program. Suggestions have been made for establishing readiness for discharge and for follow-up of these children. Medical management of these patients presently suffers from a lack of prospective and controlled studies. Medical care draws heavily from experience with pediatric asthma. What is known about the long-term outcome of these children has been reviewed with an attempt to highlight controversies between published reports and underscore the need for further investigation. The greatest future success in this area would be the prevention of premature birth. Prior to this, we must await the completion of future controlled and prospective studies.

Predictors of ductal closure and intestinal complications in very low birth weight infants treated with indomethacin.

Objective: To describe factors associated with failure of patent ductus arteriosus closure and development of gastrointestinal complications in subjects treated with indomethacin. Study Design: Infants ≤30 weeks and <1,500 g delivered between 1997–2003 with patent ductus arteriosus treated with indomethacin were included in this single-center retrospective study. Risk factors for failed ductal closure rates and gastrointestinal complications were identified with uni- and multivariable analyses. Results: Among 210 subjects treated with indomethacin, ductal closure increased from 43% at 23 weeks to 87% at 27 weeks (OR 1.51 per week gestation, 95% CI 1.14–2.01, p = 0.004) and was unchanged thereafter. Gastrointestinal complications decreased with increasing gestational age (OR 0.67/week, 95% CI 0.52–0.84) but increased with male gender (OR 2.41, 95% CI 1.07–5.45). SNAP-II (Score for Neonatal Acute Physiology-II) scores at birth and at the time of first indomethacin therapy were not associated with likelihood of closure or with gastrointestinal complications. Duration of ductal patency was not associated with risk of necrotizing enterocolitis or intestinal perforation after adjusting for gestational age and gender. Conclusions: Ductal closure with indomethacin is linearly associated with gestational age in infants ≤27 weeks. Illness severity at the time of treatment is not predictive of treatment outcome or gastrointestinal complications. The duration of ductal patency is not associated with an increase in adjusted risk of necrotizing enterocolitis or intestinal perforation in patients treated with indomethacin.

Reutilization of surfactant phosphatidylglycerol and lysophosphatidylcholine by adult rabbits

Adult rabbits reutilize the phosphatidylcholine (PC) of surfactant much less efficiently than developing rabbits (22% vs. 95%). Comparisons of reutilization efficiency of other components of surfactant in adult rabbits have not been determined. We injected adult rabbits intratracheally with [3H]dipalmitoylphosphatidylcholine (DPPG) mixed with [14C]lysophosphatidylcholine (lysoPC) and natural surfactant or [14C]DPPC mixed with [3H]dipalmitoylphosphatidylglycerol (DPPG) and natural surfactant. Recovery in the alveolar wash and lamellar bodies of labelled DPPC, lysoPC and DPPG was determined at different times after injection. By plotting the ratio of [3H]DPPG to [14C]DPPC in the alveolar wash versus time after injection we found that phosphatidylglycerol was reutilized with an efficiency of only 0-7% which was much less than the reutilization of PC in these animals. At early times after injection, adult rabbits injected with [14C]lysoPC had a ratio of [14C]PC in their alveolar wash to lamellar bodies that was larger than 1.0. By comparison, 3-day old rabbits injected intratracheally with [14C]lysoPC had a ratio of [14C]PC in alveolar wash to lamellar bodies less than 1.0 at the earliest times measurable. Thus adult rabbits demonstrate a pathway for accumulation of PC in their alveolar space prior to its appearance in lamellar bodies. This was not detected in developing rabbits. As in developing rabbits, adult rabbits reutilize the phosphatidylglycerol of surfactant less efficiently than the PC of surfactant.

Corticosteroids and intratracheal surfactant both alter the distribution between the airways and lung tissue of intratracheally administered radiolabeled phosphatidylcholine in the preterm rabbit

Developmental differences exist regarding quantitative aspects of surfactant phosphatidylcholine clearance from the alveolar space and its subsequent reutilization. We wished to further extend observations of this nature to prematurely delivered rabbits undergoing mechanical ventilation. In addition we tested the hypothesis that prenatal corticosteroid exposure and/or intratracheal surfactant at birth would produce alterations in the lungs clearance of phosphatidylcholine from the airways. Pregnant does were injected with either Ringers lactate or betamethasone on days 25 and 26 of gestation. Fetuses were delivered at 27 days and given by intratracheal injection either surfactant or one-half strength Ringers lactate, both of which were trace labeled with [3H]phosphatidylcholine. Fetuses then underwent mechanical ventilation for periods of time ranging from 10 to 120 min. Following ventilation, alveolar lavage and lung tissue were examined to determine the distribution of [3H]phosphatidylcholine between these two compartments. Antenatal corticosteroid exposure was associated with decreased recovery of the radiolabel from the alveolar space and increased recovery of the label from the lung tissue in comparison to control fetuses. Intratracheal surfactant was associated with persistence of the radiolabel within the alveolar space. Therapy with both of these modalities produced a radiolabel distribution that resembled that seen in fetuses receiving intratracheal surfactant alone.

STEROID EFFECTS ON LUNG COLLAGEN (C) AND ELASTIN (E) ARE DEPENDENT ON GESTATIONAL AGE

C and E, the major lung structural proteins, increase as a fraction of dry lung weight throughout development. Since connective tissue metabolism is known to be effected by corticosteroids, we sought to determine the effect of antenatal exposure to betamethasone (B) on the C and E content of the lungs of prematurely delivered fetal rabbits. Pregnant does were injected with either saline (control) or B (0.2 mg/kg) at 48 and 24 hours prior to sacrifice which was at 24, 27, or 29 days gestation (term = 31). Fetuses were delivered by hysterotomy and weighed, after which their lungs were removed and lyophilized. E was isolated from aliquots of dried lungs by hot alkali digestion. Total lung hydroxyproline (OH-PRO) and E OH-PRO were determined by a colorometric assay and expressed as ug OH-PRO/100 mg dry lung. The difference between these two values was taken as a measure of lung C. C (ug OH-PRO/100 tag dry lung) in control fetuses increased from a mean of 262 at 24 days to 375 at 29 days (p<.01). Over the same period, E (ug OH-PRO/100 mg dry lung) increased from a mean of 4 to 11 (p<.01). Note that a steroid effect was demonstrated at 24, 27, and 29 days by a decrease in body weight (vs. controls) of 25%, 34%, and 33% respectively. At 24 days B increased C by 25% and E by 100%; at 27 days B increased C by 20% but had little effect on E; at 29 days B had little effect on C or E. These preliminary results suggest that steroid effects on lung connective tissue are significant but only at certain gestational ages.

Terbutaline does not improve lung function in preterm rabbits

OBJECTIVE We used the premature rabbit model of surfactant deficiency to test the hypothesis that perinatal administration of terbutaline would lead to increased secretion of surfactant into the alveolar space and increase lung compliance during mechanical ventilation. STUDY DESIGN Fetuses underwent delivery at a gestational age of 28 days (term 31 days) followed by mechanical ventilation. Fetuses were subdivided into four treatment protocols: control, fetuses given terbutaline at birth, fetuses of mothers given terbutaline 1 hour before delivery, and fetuses of mothers given terbutaline intramuscularly 12 hours before delivery. Dynamic compliance was determined. After this, alveolar lavage fluid was obtained for phosphatidylcholine content determination. Some fetuses were killed at birth and their alveolar lavage phosphatidylcholine was determined. RESULTS Among the fetuses undergoing mechanical ventilation, perinatal terbutaline exposure did not alter either dynamic compliance or alveolar lavage phosphatidylcholine. Mechanical ventilation was associated with large increases in alveolar lavage phosphatidylcholine content. CONCLUSION Perinatal beta-adrenergic agonist exposure does not alter in vivo lung function following preterm delivery.

A Regional Evaluation of Survival of Infants with End-Stage Renal Disease

Background: Information regarding morbidity and mortality of infants born with end-stage renal disease (ESRD) requiring dialysis early in life is critical to optimize patient care and better counsel families. Objective: We evaluated outcomes of infants born regionally with ESRD, and those within our broader catchment area referred for dialysis. Study Design: We screened deaths at 5 regional referral hospitals, identifying infants with ESRD who did not survive to transfer for dialysis. We also screened all infants <8 weeks old seen at our institution over a 7-year period with ESRD referred for dialysis. We evaluated factors associated with survival to dialysis and transplant. Results: We identified 14 infants from regional hospitals who died prior to transfer and 12 infants at our institution who were dialyzed. Because of the large burden of lethal comorbidities in our regional referral centers, overall survival was low, with 73% dying at birth hospitals. Amongst dialyzed infants, 42% survived to transplant. Conclusion: This study is unusual in reporting survival of infants with ESRD including those not referred for dialysis, which yields an expectedly lower survival rate than reported by dialysis registries.