Vascular endothelial growth factor in pulmonary lavage fluid from premature infants: effects of age and postnatal dexamethasone.

Corticosteroids are used to ameliorate bronchopulmonary dysplasia (BPD). They also affect normal development, including the expression of growth factors such as vascular endothelial growth factor (VEGF). Deep pulmonary lavage specimens were collected on days 1, 3, 7 and 28 of life in 40 infants of <34 weeks of gestation at birth during a randomized controlled trial of two doses of dexamethasone (DEX) at 12 and 24 h of age for BPD prophylaxis. VEGF was measured by enzyme-linked immunosorbent assay. The 18 DEX and 21 control subjects had similar gestations, birth weights and oxygen requirements at study entry. Lavage VEGF tripled between day 1 and 3 in both groups. The day 7 levels were higher in DEX subjects than in controls. DEX and control values were similar on day 28. Higher lavage VEGF levels on days 1 and 3 were also correlated with lower gestational age at birth. Lavage VEGF levels were not associated with the development of BPD. We speculate that these DEX- and age-associated changes in VEGF may affect pulmonary angiogenesis.     

Comparison of tracheal aspirate and bronchoalveolar lavage specimens from premature infants

Lung fluid obtained by tracheal aspiration (TA) or bronchoalveolar lavage (BAL) has been used to study bronchopulmonary dysplasia (BPD). These two sample collection methods have seldom been compared. Paired BAL and TA specimens were collected 1, 3, 7 and 28 days after birth in 40 infants <34 weeks' gestation during a randomized, controlled trial of dexamethasone for BPD prophylaxis. Interleukin 8 (IL-8) and cell counts were measured. Compared to subjects without BPD, those who developed BPD or died by 28 days had elevated IL-8 in epithelial lining fluid on day 1 in both BAL specimens (20 ng/ml vs. 2 ng/ml) and TA specimens (101 ng/ml vs. 18 ng/ml). IL-8 levels (r = 0.55) and neutrophil proportions (r = 0.51) were moderately correlated between BAL and TA samples. TA specimens may be suitable substitutes for BAL samples in some studies of newborn lung fluid.     

Surfactant protein A concentrations in tracheal aspirate fluid from infants requiring extracorporeal membrane oxygenation

To understand the lung abnormalities leading to respiratory failure in infants, we measured 35,000-dalton surfactant protein A concentrations in tracheal aspirate fluid collected daily from 25 infants receiving extracorporeal membrane oxygenation (ECMO). Surfactant protein A concentrations were standardized per milligrams of total protein present in the aspirate. Among the 23 survivors with complete data, the surfactant protein A concentration increased significantly with time (p less than 0.0001). Concurrent increases in lung compliance (p less than 0.0001) and radiographic scores (p less than 0.0001) were also observed. This increase in surfactant protein A content may reflect lung recovery from barotrauma and oxygen toxic effects or be a response to the primary pulmonary disease process. The two infants who did not survive extracorporeal membrane oxygenation failed to demonstrate these trends.     

Early postnatal growth in preterm infants

Changes in weight of 50 preterm infants (gestational age 32.7 +/- 0.3 weeks, birthweight 1772 +/- 49 g) were studied during the period of the 0-4 postnatal weeks. Intrauterine weight gain of fetuses with equivalent gestational age, weight percentile position and sex was calculated and used as a control. Study infants achieved significantly less weight by age of 4 weeks (116.2 +/- 1.2%) than it could have been expected theoretically (144.7 +/- 1.0%). Growth performance did not correlate significantly with calorie intake, but was closely related with gestational age.     

Haplotypes of tumor necrosis factor gene and tracheal aspirate fluid levels of tumor necrosis factor-alpha in preterm infants

Individual variability in the production of tumor necrosis factor-alpha (TNF-alpha) has been attributed to genetic factors. We examined whether alleles of TNF gene (lymphotoxin-alpha+250, TNF-alpha-308, and TNF-alpha-238) affect tracheal aspirate fluid (TAF) levels of TNF-alpha among preterm infants at risk of bronchopulmonary dysplasia. TAF samples were collected within 48 h of birth and 7, 14, 21, and 28 d later. Haplotypes [designated using the nucleotide bases in the chromosome order (lymphotoxin-alpha+250, TNF-alpha-308, TNF-alpha-238)] of TNF were correlated with levels of TNF-alpha. Diplotypes of TNF (genotypes of haplotypes) classified as high, intermediate, or low based on their relation to TAF TNF-alpha levels were also correlated with TNF-alpha levels. The most frequent (and reference haplotype) was AGG. The GGG haplotype was associated with the lowest TAF TNF-alpha levels on day 7 among African American infants (p < 0.008). Sequential changes in levels of TNF-alpha correlated with infants' diplotype status [high (HH), intermediate (HL), low (LL)]. Fetal chorioamnionitis but not bronchopulmonary dysplasia was associated with infants' diplotypes (p < 0.005). Haplotypes of the TNF gene influence TAF levels of TNF-alpha. Diplotypes of TNF are associated with fetal chorioamnionitis.     

Azithromycin suppresses activation of nuclear factor-kappa B and synthesis of pro-inflammatory cytokines in tracheal aspirate cells from premature infants

Nuclear factor-kappaB (NF-kappaB) plays a central role in regulating key proinflammatory mediators. The activation of NF-kappaB is increased in tracheal aspirate (TA) cells from premature infants developing bronchopulmonary dysplasia (BPD). We studied the effect of azithromycin (AZM) on the suppression of NF-kappaB activation and the synthesis of pro-inflammatory cytokines IL-6 and IL-8 by TA cells obtained from premature infants. Tracheal aspirate cells were stimulated with tumor necrosis factor-alpha (TNF-alpha) and incubated with AZM. The nuclear NF-kappaB-DNA binding activity, the levels of inhibitory kappaB-alpha (IkappaB-alpha) in the cytoplasmic fraction and IL-6 and IL-8 release in the cell culture media were measured. Stimulation of TA cells by TNF-alpha increased the activation of NF-kappaB, which was suppressed by the addition of AZM. Increased activation of NF-kappaB was also associated with increased levels of pro-inflammatory cytokines (IL-6 and IL-8). AZM significantly reduced the IL-6 and IL-8 production to the levels similar to control. TNF-alpha stimulation also increased the degradation of IkappaB-alpha, which was restored with the addition of AZM. Our data suggest that AZM therapy may be an effective alternative to steroids in reducing lung inflammation and prevention of BPD in ventilated premature infants.     

Bronchopulmonary dysplasia and postnatal growth in extremely premature black infants

Bronchopulmonary dysplasia (BPD) may adversely affect the postnatal growth of the extremely premature infant; however, most studies have not controlled for birth weight. We studied 90 Black premature infants (mean birth weight 989 +/- 148 g). Weight was recorded biweekly until discharge and at 4, 8, and 12 months of age corrected for prematurity. Infants with BPD (N = 23) were contrasted with infants without BPD (N = 67). Data were modeled using the Count model: Stage I birth to term and Stage II term to 12 months. Birth weight was considered part of growth beginning in utero and multivariate analyses were used to control for BPD, gestational age, duration of hospitalization and socioeconomic status. After adjustment for birth weight, BPD did not explain the growth pattern. A lower gestational age was associated with a slower establishment of steady growth (P less than 0.01), while an increased duration of hospitalization was associated with a lower growth rate (P less than 0.05). Growth in stage II was not explained by study variables. 'Catch-up' growth was seen in both infants with and without BPD. We conclude that differences in growth among infants with BPD are mainly attributable to birth weight. We speculate that poorer growth may be seen in a sub-group of infants with severe BPD.     

Interleukin-16 in tracheal aspirate fluids of newborn infants

BACKGROUND: It is currently unknown if interleukin (IL)-16 exists in the lungs of ventilated infants, and because the predominant cells in the airways of infants with CLD are CD4+ macrophages, we hypothesized that IL-16 plays a role as a pro-inflammatory mediator in lung inflammation. AIMS: To examine if IL-16, a chemoattractant for CD4+ cells, is detectable in airway secretions of ventilated newborns. Its presence may be associated with lung inflammatory responses. STUDY DESIGN: Cohort cross-sectional study. SUBJECTS: Thirty-four mechanically ventilated newborn infants. MAIN OUTCOME MEASURES: Tracheal fluid (TF) specimens collected during the first month of life were examined for cell differentials determined from cytospin slides and supernatant was analyzed by ELISA for IL-16. RESULTS: Eighty-three cross-sectional tracheal fluid (TF) specimens were analyzed. Eleven of the 27 preterm but none of the 7 term infants developed chronic lung disease (CLD). IL-16, ranging from 203 to 42,073 pg/ml, was detected in 16 of the 46 specimens obtained from CLD infants, 1 of the 30 specimens from 16 non-CLD preterm and 2 of the 7 specimens from 7 term infants (p<0.001). Leukocyte counts (median 16.6 vs. 2.0 x 10(-9)/l, p<0.0001) and percentage neutrophils (median 93% vs. 73%, p<0.001) were higher in IL-16 positive specimens. CONCLUSION: IL-16 is detectable within the airway secretions of ventilated newborn infants and its presence is associated with a neutrophilic infiltration. Further studies are required to investigate its role in chronic inflammation in CLD.     

Early dexamethasone decreases expression of activation markers on neutrophils and monocytes in preterm infants

AIM: To investigate the effects of early dexamethasone administration on activation of circulating neutrophils and monocytes in preterm infants with respiratory distress syndrome requiring treatment with surfactant. METHODS: Neonates (n = 30) with respiratory distress were randomized to receive dexamethasone (DEX group, 29.1 +/- 1.2 wk, 1223 +/- 156 g, n = 15) from the first postnatal day, or to serve as controls (control group, 29.2 +/- 1.4 wk, 1250 +/- 148 g, n = 15). Dexamethasone was given as a 4 d course (0.5 mg kg(-1) on postnatal days 1 and 2, and 0.25 mg kg(-1) on days 3 and 4). Polymorphonuclear leucocyte (PMN) and monocyte surface expression of CD11b, L-selectin and CD14 was quantified with flow cytometry, and plasma macrophage-inflammatory protein-1alpha (MIP-1alpha) with an enzyme-linked immunosorbent assay. Blood samples were collected on days 1, 2-3 and 5-7. RESULTS: In the DEX group 1/15, and in the control group 7/15 developed bronchopulmonary dysplasia (p < 0.04). PMN CD11b (median 100, range 70-190 vs 154, 96-213, p=0.01), monocyte CD14 (235, 102-433 vs 355, 219-533, p=0.01) and plasma MIP-1alpha (20 ng l(-1), 20-32 vs 37 ng l(-1), 20-70, p = 0.005) were lower in the DEX group at days 2-3. All adhesion molecule expression and plasma MIP-1alpha levels were comparable at days 5-7, with the exception of monocyte L-selectin expression levels, which remained lower in the DEX group. CONCLUSION: In preterm infants with respiratory distress syndrome, early dexamethasone causes downregulation of PMN and monocyte activation. This may attenuate pulmonary inflammation and improve pulmonary outcome.     

早产儿血清表皮生长因子测定的临床意义

目的：表皮生长因子与胎儿器官发育和功能成熟密切相关,该研究探讨早产儿窒息及早产儿坏死性小肠结肠炎患儿血清中表皮生长因子含量及其临床意义。方法：采用放射免疫方法检测10例足月新生儿和35例早产儿生后血清表皮生长因子浓度。结果：35～37周和28～34周早产儿血清表皮生长因子含量0.617±0.22μg/L,0.540±0.31μg/L明显低于足月新生儿0.723±0.18μg/L,差异有显著性(P<0.01);窒息早产儿与足月儿相比血清表皮生长因子水平降低更为明显0.446±0.24μg/Lvs0.723±0.18μg/L;坏死性小肠结肠炎早产儿与足月儿比较血清表皮生长因子浓度没有明显降低0.771±0.44μg/Lvs0.723±0.18μg/L,差异无显著性。结论：血清表皮生长因子水平与胎龄有关;窒息可使表皮生长因子水平降低。     

宫内发育迟缓早产儿生后生长迟缓对早期神经发育的影响

目的 探讨宫内发育迟缓(IUGR)早产儿生后生长迟缓对早期神经发育的影响。方法 回顾性分析2008 年5 月至2012 年5 月出生并定期随访至校正胎龄6 个月的171例早产儿的临床资料,其中IUGR早产儿40 例,早产适于胎龄儿(AGA)131 例。比较两组校正胎龄40 周、3个月、6个月的生长迟缓率及校正胎龄3 个月、6 个月时的神经发育情况。神经发育采用Gesell发育量表评估。结果 IUGR 组校正胎龄40 周、3个月、6个月的生长迟缓率均明显高于AGA 组;校正胎龄3 个月时Gesell 各项发育商(大运动、精细动作、语言、适应性及个人社交)均低于AGA 组;校正胎龄6 个月时,IUGR组精细动作及语言发育商低于AGA组,但两组大运动、适应性及个人社交发育商比较差异已无统计学意义。IUGR组6月龄时体重追赶落后的患儿各项发育商均明显低于追赶理想的IUGR 和AGA 患儿。结论 IUGR早产儿生后早期的生长迟缓可对早期神经发育产生不良影响。     

Early postnatal growth evaluation in full-term,preterm and small-for-dates infants

Postnatal growth patterns of weight, length/height and head circumference in full-term (FTI), preterm (PTI) and small-for-dates (SFDI) infants, are described by using distance and velocity data together with the concept of growth per unit of body weight. The study was performed in 112 healthy Caucasian infants, of a similar socioeconomic status, in Montevideo, Uruguay.Median growth velocity (MGV) and median growth velocity per unit (MGVU) of body size are defined. The authors stress that: (a) growth velocity is related to body mass, (b) a useful evaluation of growth is made by using two consecutive measures with a certain time interval independently of birthweight and gestational age, and (c) expressing growth per day per unit relates well to daily nutritional and other requirements.     

Early postnatal growth of Basotho infants in the Mantsonyane area, Lesotho

The records of 814 infants born in a rural hospital in Lesotho were analysed. It was calculated that on average Basotho infants regained their birthweight between 3 and 4 days of age and the average weight loss amounted to 3%. Compared with Caucasian infants, Basotho infants regained their birthweight sooner. Of 289 infants in whom the gestational age was assessed, small-for-dates infants showed an increased mean growth rate compared with pre-term and appropriate-for-dates full-term infants.     

Early life factors predict abnormal growth and bone accretion at prepuberty in former premature infants with/without neonatal dexamethasone exposure

Growth, bone, and body composition were studied at prepuberty in former very low birth weight (VLBW) infants who received dexamethasone (DEX) for bronchopulmonary dysplasia (BPD) compared with VLBW infants without DEX and term-born infants (TERM) to identify early life risk factors for later low bone mass. Children (56 girls/63 boys, 5-10 y) previously studied in neonatal life were recruited into three groups: VLBW + DEX, VLBW - DEX, and TERM children. Anthropometry and whole body bone, fat, and lean mass were measured. At prepuberty, the average height and weight for VLBW + DEX group were significantly lower than that for VLBW - DEX and TERM. Both VLBW groups had lower bone mass even adjusted for height and lean mass than TERM children and lower lean mass both total and adjusted for height. Z-scores for whole body bone mineral content below -1.5 occurred in 27.9% of VLBW + DEX children. The key factors for low bone mass were earlier gestational age and having BPD with DEX in neonatal life. In former VLBW infants, growth and bone mass attainment before puberty can be predicted from early life variables. VLBW + DEX children may be protected from overweight, but are at risk for short stature and low bone mass.     

Early physiotherapy intervention in premature infants

Preterm infants are more likely to have disabling cerebral palsy (CP) than term infants. It has been reported that early therapeutic approaches may be appropriate for infants at risk of neuromotor dysfunction, to minimize the degree of future handicaps. Two hundred and twenty-nine infants born at less than 34 weeks' gestation, with birth weight < or = 2,000 g, cared for in the neonatal intensive care unit of Hacettepe University Hospital between January 1997-June 1999 were included in this study. Of the 229 infants initially included, 39 (17%) were dropped from the study within the first 12 months' assessment, due to lack of participation from the families. Thirty of the remaining 190 infants were found to have perinatal hypoxia or abnormal neurosonography, and were taken as the group at risk of development of CP, thus receiving early intervention therapy; these are listed as "premature at risk". The study group consisted of 160 infants not considered at risk. These were randomly paired into two groups of 80 infants, one that was given early interventional therapy, and the control group that received no program. Eleven of the 30 infants at risk, 2 of the 80 infants from the intervention group, and 4 of the 80 from the control group were diagnosed as having CP within the first six months of life. There was no difference in the age of loss or acquisition of reflexes and general abilities between the intervention and control groups. There was no difference in the prevalence of CP between the intervention and control groups. In conclusion this study showed no effect of early intervention in premature babies without risk of CP other than prematurity.     

Catabolic effect in premature infants with early dexamethasone treatment

To evaluate the catabolic effects of dexamethasone therapy on protein metabolism, amino acid concentrations and urinary 3-methylhistidine (3MH) were measured in 28 premature infants who were included in a double-blind controlled study using early dexamethasone therapy in the prevention of bronchopulmonary dysplasia. Fifteen infants received dexamethasone (0.5mg/kg/day i.v.) and 13 infants received normal saline as control. Heparinized venous blood samples for amino acid analysis were obtained before the study and again at day 5 after starting the study. Urinary 3MH was measured on days 1, 3, 5, 7, 14, 21, and 28 of treatment. A substantial increase in amino acid concentrations was observed in infants receiving dexamethasone. Alanine, glutamine, citrulline, ornithine and cystine concentrations increased twofold or more. The 3MH:creatinine ratio was increased in the treated group. These metabolic effects were most likely due to an increase in protein catabolism.