Pilot trial of late booster doses of surfactant for ventilated premature infants.

OBJECTIVE: Many premature infants at risk for bronchopulmonary dysplasia experience episodes of surfactant dysfunction with reduced surfactant protein B (SP-B). In this study, we investigated the safety and responses to booster doses of surfactant. STUDY DESIGN: A total of 87 infants, 500 to 1250 g birth weight, who were ventilated at 7 to 10 days received 2 or 3 doses of Infasurf (Calfactant, Forest Pharmaceuticals, St Louis, MO, USA) within a 1-week period. RESULT: For 184 doses, occurrence rates of transient bradycardia (13) and plugged endotracheal tube (5) were low, and no other adverse effects were noted. Treatment transiently improved the respiratory severity score (FiO(2) × mean airway pressure), SP-B content (+75%) and surface properties of isolated surfactant. Levels of eight proinflammatory cytokines in tracheal aspirate were interrelated and unchanged from baseline after surfactant treatment. CONCLUSION: Booster doses of surfactant for premature infants with lung disease are safe and transiently improve respiratory status as well as composition and function of endogenous surfactant.

The effect of inhaled nitric oxide on pulmonary function in preterm infants.

OBJECTIVE: Bronchopulmonary dysplasia (BPD) in preterm infants is associated with impaired alveolar growth, inflammation and airway hyperreactivity. In animal models of BPD, inhaled nitric oxide (NO) improves alveolar growth and inhibits airway smooth muscle proliferation. This study was designed to assess the effect of inhaled NO on resistance and compliance in ventilated preterm infants with evolving BPD. STUDY DESIGN: Expiratory resistance and compliance of the respiratory system were measured in 71 ventilated preterm infants, < or = 32 weeks gestation, randomized to NO (n=34) versus placebo (n=37) for > or = 24 days at 7 to 21 days of life. RESULT: At baseline expiratory resistance (231+/-71 versus 215+/-76 cm H(2)O l(-1) s(-1)) and compliance (0.49+/-0.14 versus 0.53+/-0.13 ml cm H(2)O(-1) kg(-1)) were comparable between placebo and NO groups, respectively. There was no effect of NO on expiratory resistance or compliance at 1 h, 1 week or 2 weeks of study gas administration. CONCLUSION: NO had no short- or medium-term effect on expiratory resistance or compliance in ventilated preterm infants.

HIV-1 infection of placental cord blood monocyte-derived dendritic cells.

Dendritic cells (DC), the most potent antigen-presenting cells (APC), have been implicated as the initial targets of HIV infection in skin and mucosal surfaces. DC can be generated in vitro from blood-isolated CD14(+) monocytes or CD34(+) hematopoietic progenitor cells in the presence of various cytokines. In this study, we investigated whether monocytes obtained from placental cord blood are capable of differentiation into dendritic cells when cultured with a combination of cytokines - granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-4 (IL-4), and tumor necrosis factor-alpha (TNF-alpha). We then examined HIV infection, HIV receptor (CD4, CCR5) expression, and beta-chemokine [macrophage inflammatory protein-1alpha and -1beta (MIP-1alpha, MIP-1beta)] production by placental cord monocyte-derived dendritic cells (MDDC) as compared to that of autologous cord monocyte-derived macrophages (MDM). Monocytes isolated from placental cord blood differentiate into DC after 7 days in culture with the mixture of cytokines, as demonstrated by development of characteristic DC morphology, loss of CD14 expression, and gain of CD83, a marker for mature DC. Mature cord MDDC had significantly lower susceptibility to M-tropic ADA (CCR5-dependent) envelope-pseudotyped HIV infection in comparison to autologous placental cord MDM, whereas there was no significant difference in virus replication in cord MDDC and MDM infected with murine leukemia virus envelope-pseudotyped HIV (HIV receptor-independent). This limited susceptibility of cord MDDC to M-tropic HIV infection may be due to lower expression of CD4 and CCR5 on the cell membrane and higher production of MIP-1alpha and MIP-1beta. These data provide important information toward our understanding of the biological properties of cord MDDC in relation to HIV infection.

Association of plasma cortisol and chronic lung disease in preterm infants.

BACKGROUND: It has been suggested that preterm infants may have developmental immaturity of the hypothalamic-pituitary-adrenal axis, and that decreased cortisol response to stress increases risk of chronic lung disease (CLD) secondary to inflammatory lung injury. METHODS: To investigate the relationship between endogenous corticosteroid and CLD, we measured plasma cortisol during the first 28 days of life in a subset of neonates in the North American Thyrotropin-Releasing Hormone (TRH) Collaborative Trial. Analyses were performed on 314 infants, 24 to 32 weeks' gestation, whose mothers received 1 or 2 courses of antenatal corticosteroids plus TRH or placebo. RESULTS: Mean cortisol was 3.1 microg/dL (range: 0.1-17.9) at birth, reached maximal levels at 24 hours (19.4 microg/dL, range: 0.8-124.6), and decreased to 5.9 microg/dL (range: 0.2-24.7) at 14 to 28 days of age; levels during the first week were not associated with gestational age. The Clinical Risk Index for Babies (CRIB), a neonatal assessment tool that is correlated with risk of mortality, was positively associated with cortisol level on days 1 and 3 through 7. TRH versus placebo treatment did not influence cortisol levels at any time point. To examine the relationship between cortisol and adverse outcome of death or CLD at 36 weeks' postmenstrual age (CLD36), logistic regression models adjusting for known contributing clinical factors (gestational age and CRIB score) were fit. There was a statistically borderline negative association between median cortisol level at 3 to 7 days and CLD36. After adjusting for gestational age and CRIB score, the predicted probability of CLD36 was only minimally influenced by the cortisol concentration. CONCLUSION: In preterm infants, basal plasma cortisol concentration during the first week is a weak predictor for CLD36. Possible benefits as well as risks of supplemental, low-dose cortisol treatment of high-risk preterm infants remain to be determined.

Multiple courses of antenatal corticosteroids and outcome of premature neonates. North American Thyrotropin-Releasing Hormone Study Group.

OBJECTIVES: We sought to examine outcome for premature neonates after multiple courses of antenatal corticosteroids compared with a single course. STUDY DESIGN: We performed a post hoc nonrandomized analysis on 710 neonates of 25-32 weeks' gestation who were born to mothers enrolled in the North American Thyrotropin-Releasing Hormone Trial and who received 1, 2, or >/=3 courses of antenatal corticosteroids. RESULTS: There was no detectable clinical difference in incidence of respiratory distress syndrome, chronic lung disease, and intraventricular hemorrhage related to courses of antenatal corticosteroids, and outcome was similar for infants delivered at 7-13 days compared with those delivered at 1-6 days after receiving antenatal corticosteroids. Compared with those who received a single course, neonates who received >/=2 courses had lower birth weights (-39 g, P =.02), and those receiving >/=3 courses had increased risk of death (adjusted odds ratio, 2.8; 95% confidence interval, 1.3-5.9; P =.01) and lower levels of plasma cortisol at age 2 hours. CONCLUSION: In this retrospective analysis multiple courses of antenatal corticosteroids did not improve outcome and were associated with increased mortality, decreased fetal growth, and prolonged adrenal suppression.

A new pattern of cerebellar hemorrhages in preterm infants.

OBJECTIVE: Posterior fossa hemorrhages may be underdiagnosed in surviving neonates, with cerebellar hemorrhage discovered in 10% to 25% of autopsy specimens from very low birth weight infants. Posterior fossa lesions have been difficult to visualize by the traditional ultrasonography approach through the anterior fontanelle. Late in 1994, routine posterior fossa imaging through the posterolateral fontanelle was instituted to improve the ultrasonographic visualization of the posterior fossa in neonates. METHODS: Infants identified with posterior fossa hemorrhage by cranial ultrasonography between 1994 and 1996 were followed prospectively through discharge and their clinical courses reviewed. Infants diagnosed with posterior fossa hemorrhage between 1991 and 1994 were identified retrospectively from a comprehensive radiology database to use in comparison. All infants surviving to discharge were entered into neurodevelopmental follow-up using standard developmental assessments. RESULTS: Approximately 525 infants underwent cranial sonography during the study period between October 1994 and September 1996, including 250 infants weighing <1500 g. Thirteen infants were identified with posterior fossa hemorrhage using the posterolateral fontanellar approach. In contrast, only 2 infants were identified with posterior fossa hemorrhage between 1991 and 1994 using traditional anterior fontanellar views. Six very low birth weight infants were identified with cerebellar hemorrhages not associated with supratentorial, intraventricular hemorrhage. Each hemorrhage had a clinically silent presentation and, in 5 infants, was not well-appreciated by anterior fontanellar images. Magnetic resonance imaging studies were performed on 5 of the 6 infants and confirmed a cerebellar lesion in the area of previous echo density on ultrasonography. No infant is exhibiting motor abnormalities on neurologic examination, although 4 infants are demonstrating cognitive, developmental delay. Follow-up, however, is limited to a corrected age of

Antenatal hormone therapy for fetal lung maturation.

In summary, several agents have been studied, but only CS and thyroid hormones have been found to accelerate fetal lung maturation in animal studies. Thirty years of research has documented the beneficial effect of antenatal CS on fetal lung maturation, and antenatal steroid in combination with postnatal surfactant remains the mainstay of prevention and therapy for RDS in preterm infants. The efficacy and safety of postnatal steroids have yet to be demonstrated. Unfortunately, the addition of antenatal TRH to this regimen has not provided further benefit to the neonatal outcome of preterm infants as evidenced by the recently completed multicenter trials. In addition, the optimal number of courses of antenatal CS for lung maturation remains unclear.

Characterization of natural killer and antibody-dependent cellular cytotoxicity of preterm infants against human immunodeficiency virus-infected cells.

The odds risk of vertical transmission of human immunodeficiency virus (HIV) to preterm infants is almost four times that of term infants and may relate to maternal and neonatal factors. We characterized the competence of early nonspecific cellular immunity, namely natural killer cytotoxicity (NKC) and antibody-dependent cellular cytotoxicity (ADCC), of peripheral blood mononuclear cells (PBMC) from preterm (n = 20) and term neonates (n = 28) versus adult controls against a T cell line infected with the human T cell lymphotrophic virus-III(B) using a chromium-51 release assay. PBMC from term neonates exhibited levels of NKC activity equal to adults against HIV-infected targets, yet the NKC capacity of preterm neonatal PBMC was significantly diminished. The ADCC activity of both term and preterm neonatal PBMC against HIV-infected targets was significantly less than that of adult PBMC. Overnight stimulation of a subset of samples with IL-12 augmented the NKC activity of both infant groups and adults, whereas the ADCC activity remained unchanged. These findings demonstrate that term neonates are deficient in ADCC against HIV-infected targets, whereas preterm infants are deficient in both NKC and ADCC, which may relate, in part, to the increased risk of transmission of HIV with preterm delivery. In addition, IL-12 has the potential to augment both term and preterm neonatal antiviral defense.