Carl Bose

Risk factors for chronic lung disease in infants with birth weights of 751 to 1000 grams

We performed a multicenter, historical-cohort analysis to identify factors associated with chronic lung disease (CLD) in extremely low birth weight infants. The 235 infants who were born in 1984 with birth weights of 751 to 1000 gm and admitted to any of 10 participating neonatal intensive care units comprised the study population. We analyzed demographic characteristics, status at birth, severity of acute atelectasis, and early respiratory treatment in relation to CLD, which we defined as having received oxygen at age 30 days. By univariate analysis, CLD was associated with lower gestational age (p less than 0.001), male sex (p = 0.004), more severe acute atelectasis as indicated by a higher roentgenographic score (p less than 0.001), a higher ventilation rate at 96 hours (p = 0.012), and lower PaCO2 at 48 hours (p = 0.04). Infants receiving mechanical ventilation whose highest PaCO2 levels at 48 or 96 hour were less than 40 mm Hg were 1.45 times as likely to develop CLD as those whose highest PaCO2 levels were greater than 50 mm Hg (95% confidence interval 1.04 to 2.01). CLD rates by center were inversely related to mean PaCO2 levels in infants receiving mechanical ventilation at 48 and 96 hours (Spearman rank correlations 0.60 and 0.55; p less than 0.001). A logistic risk model that included sex, PaCO2 at 48 hours, roentgenographic score, gestational age, and race showed only male sex (p = 0.009) and lower PaCO2 at 48 hours (p = 0.04) to be independent predictors of CLD. We conclude that mechanical ventilation that results in PaCO2 levels above the physiologic range may decrease the risk of CLD in extremely low birth weight infants.

Very early surfactant without mandatory ventilation in premature infants treated with early continuous positive airway pressure: A randomized, controlled trial

BACKGROUND. Chronic lung disease is one of the most frequent and serious complications of premature birth. Because mechanical ventilation is a major risk factor for chronic lung disease, the early application of nasal continuous positive airway pressure has been used as a strategy for avoiding mechanical ventilation in premature infants. Surfactant therapy improves the short-term respiratory status of premature infants, but its use is traditionally limited to infants being mechanically ventilated. Administration of very early surfactant during a brief period of intubation to infants treated with nasal continuous positive airway pressure may improve their outcome and further decrease the need for mechanical ventilation. OBJECTIVE. Our goal was to determine if very early surfactant therapy without mandatory ventilation improves outcome and decreases the need for mechanical ventilation when used in very premature infants treated with nasal continuous positive airway pressure soon after birth. DESIGN/METHODS. Eight centers in Colombia participated in this randomized, controlled trial. Infants born between 27 and 31 weeks’ gestation with evidence of respiratory distress and treated with supplemental oxygen in the delivery room were randomly assigned within the first hour of life to intubation, very early surfactant, extubation, and nasal continuous positive airway pressure (treatment group) or nasal continuous airway pressure alone (control group). The primary outcome was the need for subsequent mechanical ventilation using predefined criteria. RESULTS. From January 1, 2004, to December 31, 2006, 279 infants were randomly assigned, 141 to the treatment group and 138 to the control group. The need for mechanical ventilation was lower in the treatment group (26%) compared with the control group (39%). Air-leak syndrome occurred less frequently in the treatment group (2%) compared with the control group (9%). The percentage of patients receiving surfactant after the first hour of life was also significantly less in the treatment group (12%) compared with the control group (26%). The incidence of chronic lung disease (oxygen treatment at 36 weeks’ postmenstrual age) was 49% in the treatment group compared with 59% in the control group. All other outcomes, including mortality, intraventricular hemorrhage, and periventricular leukomalacia were similar between the groups. CONCLUSIONS. In premature infants treated with nasal continuous positive airway pressure early after birth, the addition of very early surfactant therapy without mandatory ventilation decreased the need for subsequent mechanical ventilation, decreased the incidence of air-leak syndrome, and seemed to be safe. Reduction in the need for mechanical ventilation is an important outcome when medical resources are limited and may result in less chronic lung disease in both developed and developing countries.

Patent ductus arteriosus: lack of evidence for common treatments

Patent ductus arteriosus (PDA) is a common diagnosis among extremely premature infants, especially in those with lung disease. Treatments are often used to close the PDA. Despite nearly three decades of research, the question of whether the benefits of treatments to prevent ductal patency or promote closure outweigh the risks of these treatments remains unanswered. The authors rarely use treatments designed to close the PDA. This article reviews three considerations in support of this restrained approach: rates of spontaneous closure of the ductus arteriosus; adverse effect of persistent ductal patency; and benefits and risks of treatments for closure.

Bronchopulmonary dysplasia and inflammatory biomarkers in the premature neonate

Bronchopulmonary dysplasia (BPD) is the most common, serious sequela of premature birth. Inflammation is a major contributor to the pathogenesis of BPD. Often initiated by a pulmonary fetal inflammatory response, lung inflammation is exacerbated by mechanical ventilation and exposure to supplemental oxygen. In response to these initiators of injury, a complex interaction occurs between proteins that attract inflammatory cells (ie, chemokines), proteins that facilitate the transendothelial migration of inflammatory cells from blood vessels (ie, adhesion molecules), proteins that promote tissue damage (ie, pro-inflammatory cytokines and proteases), and proteins that modulate the process (eg, anti-inflammatory cytokines, binding proteins and receptor antagonists). In addition, during recovery from inflammatory injury, growth factors and other substances that control normal lung growth and mediate repair influence subsequent lung structure. In this review, we discuss the role of each aspect of the inflammatory process in the development of BPD. This discussion will include data from measurements of biomarkers in samples of fluid aspirated from the airways of human infants relevant to each phase of inflammation. Despite their limitations, these measurements provide some insight into the role of inflammation in the development of BPD and may be useful in identifying infants at risk for the disease.

Fetal Growth Restriction and Chronic Lung Disease Among Infants Born Before the 28th Week of Gestation

OBJECTIVE: Improvement in survival of extremely premature infants over the past several decades has resulted in an increase in the number of infants with chronic lung disease (CLD). Historical neonatal exposures associated with CLD now less frequently precede the disease. There is now increasing interest in exposures and events before delivery that predict CLD. The objective of this study was to identify current prenatal predictors of CLD. METHODS: We collected data about prenatal, placental, and neonatal characteristics of 1241 newborns who were delivered before completion of the 28th week of gestation. Associations between prenatal factors, microbiologic and histologic characteristics of the placenta, and selected neonatal characteristics and CLD risk were first evaluated in univariate analyses. Subsequent multivariate analyses investigated the contribution of prenatal factors, particularly fetal growth restriction (FGR), to CLD risk. RESULTS: Among the prenatal factors, birth weight z scores, used as a marker of FGR, provided the most information about CLD risk. Indicators of placental inflammation and infection were not associated with increased risk of CLD. Within nearly all strata of prenatal, placental, and neonatal variables, growth-restricted infants were at increased CLD risk, compared with infants who were not growth-restricted. FGR was the only maternal or prenatal characteristic that was highly predictive of CLD after adjustment for other risk factors. CONCLUSIONS: FGR is independently associated with the risk of CLD. Thus, factors that control fetal somatic growth may have a significant impact on vulnerability to lung injury and in this way increase CLD risk.

Patency of the ductus arteriosus in the premature infant: is it pathologic? Should it be treated?

Purpose of review The ductus arteriosus is a vessel that connects the pulmonary artery to the aorta and provides a pulmonary-to-systemic diversion during fetal life. In the vast majority of infants, the ductus arteriosus closes by 3 days of life. In some infants, especially preterm infants with lung disease, there is delayed closure of the ductus arteriosus. There has been controversy as to whether or when the ductus arteriosus should be closed by either pharmacologic or surgical methods. Recent findings There have been several epidemiologic studies describing an association between a patent ductus arteriosus and the development of morbidities, such as chronic lung disease. These associations have suggested to some that a causal relationship exists between patency of the ductus arteriosus and chronic lung disease and other morbidities. However, recent metaanalyses of randomized, controlled trials of the use of indomethacin for the prevention and treatment of the patent ductus arteriosus have not documented a decrease in the incidence of these morbidities after treatment, despite success in closure of the patent ductus arteriosus. Summary In preterm infants, patency of the ductus arteriosus may represent a normal physiologic adaptation to allow shunting from either systemic-to-pulmonary circulation (eg, in the first day of life) or from pulmonary-to-systemic circulation (eg, in the presence of severe lung disease). Therapies designed to close the ductus arteriosus are contraindicated in some settings and should not be considered a standard of care at any time until these therapies are proven to decrease long-term clinical morbidities in randomized, placebo-controlled trials.

Hypothermia and other treatment options for neonatal encephalopathy: an executive summary of the Eunice Kennedy Shriver NICHD workshop.

HIE is not a single disease from a single cause, and is characterized by great diversity in the timing and magnitude of brain injury. It is therefore unreasonable to expect any single intervention to provide uniformly favorable outcome. The known heterogeneity in neuropathological changes after perinatal HIE combined with potential regional heterogeneity of treatment effects will lead to marked differential effects on outcomes among survivors of HIE (e.g. physical disability versus cognitive deficits). This underscores the need for longer term follow up of all infants with HIE undergoing any treatment. In spite of rapidly accumulating clinical and laboratory data related to hypothermia as a neuroprotective strategy for HIE, the speakers and discussants at the workshop underscored numerous gaps in knowledge in this field summarized in the Table, which compares the gaps identified at the 2005 NICHD workshop8 with current gaps. The participants noted that with only six completed studies1-6 providing information on follow-up for up to 18 months of age, the longer-term neurodevelopmental impact of hypothermia for HIE are pending.23,24 This, they concluded, should lead to an overall measure of caution in applying the new therapy of hypothermia indiscriminately for all cases of HIE. Table 1 Comparison of Categories of Gaps in Knowledge and Change from 2005 to 2010 Based on the available data and large knowledge gaps, the expert panel suggested that although hypothermia is unequivocally a promising therapy for HIE, a substantial proportion of infants still suffer from death or disability despite treatment. Further analysis of existing trial data, development of adjuvant therapies to hypothermia, development of biomarkers and further refinements of hypothermia therapy for use in infants suffering from HIE and clinical trials of therapeutic hypothermia in mid resource settings with different risk factors but adequate facilities and infrastructure are all urgently needed and were identified as areas of high priority for study.

Trial of vitamin A supplementation in very low birth weight infants at risk for bronchopulmonary dysplasia

We performed a randomized, double-blind, controlled trial to determine whether vitamin A supplementation in a group of very low birth weight infants would reduce the incidence of bronchopulmonary dysplasia. Forty-nine infants (birth weight 700 to 1100 gm) requiring mechanical ventilation and supplemental oxygen at 96 hours age were randomly assigned to receive either 2000 IU retinyl palmitate (n = 27) or saline placebo (n = 22) intramuscularly every other day for up to 14 doses. There were no differences between treatment groups in the incidences of bronchopulmonary dysplasia at 31 days of postnatal age (vitamin A group 48%, placebo group 55%; p = 0.776), supplemental oxygen requirement at 34 weeks of postconceptional age, or other complications of prematurity. The vitamin A group had higher mean plasma vitamin A concentrations than the placebo group, but mean plasma vitamin A concentrations were greater than 20 micrograms/dl (suggesting sufficiency) in both groups after the first study week. By study day 28, only one fourth of the infants in either group had plasma vitamin A concentrations less than 20 micrograms/dl. In contrast to an earlier report, we found no change in the incidence of BPD with vitamin A supplementation. Our findings may reflect a low baseline incidence of vitamin A deficiency in the study population and recent changes in the respiratory care of very low birth weight infants. The latter may have lessened the potential impact of vitamin A deficiency on lung disease.

Factors associated with treatment for hypotension in extremely low gestational age newborns during the first postnatal week.

OBJECTIVE. The goals were to identify the blood pressures of extremely low gestational age newborns that prompt intervention, to identify other infant characteristics associated with receipt of therapies intended to increase blood pressure, and to assess the interinstitutional variability in the use of these therapies. METHODS. The cohort included 1507 extremely low gestational age newborns born at 23 weeks to 27 weeks of gestation, at 14 institutions, between March 2002 and August 2004; 1387 survived the first postnatal week. Blood pressures were measured as clinically indicated. Interventions were grouped as any treatment (ie, vasopressor and/or fluid boluses of >10 mL/kg) and vasopressor treatment, and logistic regression analyses were performed. RESULTS. At each gestational age, the lowest mean arterial pressures in treated and untreated infants tended to increase with advancing postnatal age. Infants who received any therapy tended to have lower mean arterial pressures than infants who did not, but uniform thresholds for treatment were not apparent. The proportion of infants receiving any treatment decreased with increasing gestational age from 93% at 23 weeks to 73% at 27 weeks. Treatment nearly always began during the first 24 hours of life. Lower gestational age, lower birth weight, male gender, and higher Score for Neonatal Acute Physiology–II values were associated with any treatment and vasopressor treatment. Institutions varied greatly in their tendency to offer any treatment and vasopressor treatment. Neither the lowest mean arterial pressure on the day of treatment nor other characteristics of the infants accounted for center differences in treatment. CONCLUSIONS. Blood pressure in extremely premature infants not treated for hypotension increased directly with both increasing gestational age and postnatal age. The decision to provide treatment was associated more strongly with the center where care was provided than with infant attributes.

Rising birth prevalence of gastroschisis

OBJECTIVE: Gastroschisis is a congenital anomaly that has been reported to be increasing in frequency. The objective of this study was to determine the birth prevalence of gastroschisis using two large databases.STUDY DESIGN: We reviewed data from a statewide database and a national database from a neonatal health care provider, abstracting cases of gastroschisis.RESULTS: In North Carolina, the birth prevalence of gastroschisis increased from 1.96 per 10,000 births in 1997 to 4.49 per 10,000 births in 2000 (p=0.0007). The overall increase was almost entirely because of the increase in infants born to mothers less than 20 years old. Among infants receiving care from the national neonatal provider, the prevalence of gastroschisis increased from 2.9 per 1000 patients in 1997 to five per 1000 patients in 2001 (p=0.044).CONCLUSION: The birth prevalence of gastroschisis is increasing in North Carolina, and this trend may be occurring nationally. The rapid change in the birth prevalence in the subset of population most at risk for gastroschisis implicates environmental or pharmacologic teratogens rather than changing population characteristics as a causal factor in the development of gastroschisis.