Initial and delayed thyroid-stimulating hormone elevation in extremely low-birth-weight infants.

BACKGROUND: To determine the incidence, etiology, and outcomes of thyroid-stimulating hormone (TSH) elevation in extremely low-birth-weight infants (ELBWIs). METHODS: Newborn thyroid screening data of 584 ELBWIs (birth weight, < 1000 g; gestational age, ≥ 23 weeks) were retrospectively analyzed to identify initial (≤ 2 postnatal weeks) and delayed (> 2 weeks) TSH elevations. Growth and neurodevelopmental outcomes at 2 years' corrected age (CA) were assessed according to levothyroxine replacement. RESULTS: Initial and delayed TSH elevations were detected at CAs of 27 and 30 weeks, respectively, with incidence rates of 0.9 and 7.2%, respectively. All infants with initial TSH elevations had perinatal asphyxia, and 95% of those with delayed TSH elevation were exposed to various stressors, including respiratory support, drugs, and surgery within 2 weeks before diagnosis of TSH elevation. Free thyroxine (T4) levels were simultaneously reduced in 80 and 57% of infants with initial and delayed TSH elevations, respectively. Both initial and delayed TSH elevations were transient, regardless of levothyroxine replacement. Infants receiving levothyroxine replacement therapy had significantly higher TSH elevations, significantly lower free T4 levels, and significantly reduced mortality, compared to untreated infants. However, levothyroxine replacement had no significant effect on long-term growth and neurodevelopmental outcomes. CONCLUSIONS: The timing of insult superimposition on hypothalamic-pituitary-thyroid axis maturation is a major determinant of initial or delayed TSH elevation in ELBWIs. Levothyroxine replacement did not affect growth or neurodevelopmental outcomes in this population.

The level of extracellular superoxide dismutase in the first week of life in very and extremely low birth weight infants and the risk of developing bronchopulmonary dysplasia.

Background Antioxidant enzymes may play a significant role in the development of bronchopulmonary dysplasia (BPD). The aim of the study was to assess the relationship between the level of extracellular superoxide dismutase (SOD3) in the serum at days 1 and 7 of life and the risk of developing BPD. Methods The study comprised 103 neonates born before 32 weeks' gestation with a birth weight of ≤1500 g. Results In the investigated group, the median serum SOD3 level at day 1 of life was 4.01 ng/mL [interquartile range (IQR) 2.59-5.09 ng/mL] and at day 7 of life 3.13 ng/mL (IQR 2.49-4.34 ng/mL). A statistically significant decrease in the serum SOD3 level was found in the first week of life, P < 0.0001. No correlation was found between the serum SOD3 level at day 1 of life and gestational age R = 0.07, P = 0.4543 and birth weight R = 0.10, P = 0.3083. No statistically significant correlation was found between the dynamics of change in the SOD3 level in serum at days 1 and 7 of life and the risk of BPD development for the definition of BPD at day 28 of life, P = 0.8764 nor at 36 weeks' postmenstrual age, P = 0.6598. Conclusion The study revealed a statistically significant decrease in the serum SOD3 level in the first week of life in very and extremely low birth weight infants born before 32 weeks of gestation. In the clinical setting, no relationship was observed between the level of SOD3 in serum and the risk of developing BPD.

Pharmacometabolomics of Respiratory Phenotypic Response to Dexamethasone in Preterm Infants at Risk for Bronchopulmonary Dysplasia.

A prospective cohort study was performed in preterm infants less than 32 weeks gestation at birth who were treated with dexamethasone for developing or established bronchopulmonary dysplasia (BPD). Respiratory phenotype (Respiratory Severity Score (RSS)), serum, and urine metabolomics were assessed before and after treatment. Ten infants provided nine matched serum and nine matched urine samples. There was a significant decrease in RSS with steroid treatment. Serum gluconic acid had the largest median fold change (140 times decreased, P = 0.008). In metabolite set enrichment analysis, in both serum and urine, the urea cycle, ammonia recycling, and malate-aspartate shuttle pathways were most significantly enriched when comparing pretreatment and post-treatment (P value < 0.05). In regression analyses, 6 serum and 28 urine metabolites were significantly associated with change in RSS. Urine gluconic acid lactone was the most significantly correlated with clinical response (correlational coefficient 0.915). Pharmacometabolomic discovery of drug response biomarkers in preterm infants may allow precision therapeutics in BPD treatment.

Use of whole exome sequencing in the NICU: Case of an extremely low birth weight infant with syndromic features.

Single gene (Mendelian) disorders are one of the leading causes of neonatal morbidity and mortality. However, in the setting of preterm birth phenotypic features of genetic diseases are often undifferentiated and are clinically very difficult to interpret based on the wide range of differential diagnoses. We report an extremely low birth weight infant (ELBW) born prematurely at 23 + 0 gestational weeks after twin pregnancy with a novel clinical manifestation with persistent hyperglycaemia as well as the known manifestations of disease-associated hypokinesia, renal salt wasting, and multifocal atrial tachycardia. The patient died of heart failure on the 72nd day of life. Whole exome sequencing (WES) revealed a previously well established, disease-causing heterozygous likely pathogenic variant in the Harvey rat sarcoma viral oncogene homolog (HRAS)-gene (c.35G > C, p. G12A, rs104894230), which implied the clinical diagnosis of Costello syndrome (CS; OMIM#190020.0004). The twin brother merely had complications related to preterm birth and did not show any CS symptoms. In conclusion, our case illustrated that CS should be considered in ELBW infants showing a life-threatening combination of complex cardiac arrhythmia and hypokinesia. If a syndromic disorder is suspected in the neonatal intensive care unit (NICU) setting, rapid WES is a useful, non-invasive diagnostic tool in critically ill ELBW infants.

Evaluation of dynamic thiol-disulfide homeostasis in very low-birth-weighted preterms.

BACKGROUND: Thiols are organic compounds containing sulfhydryl groups which exert antioxidant effects via dynamic thiol-disulfide homeostasis. The shift towards disulfides indicates the presence of oxidative environment. Thiol-disulfide homeostasis has not been evaluated in neonates. We aimed to evaluate dynamic thiol-disulfide homeostasis in preterm infants. METHODS: Preterm infants with birth weight less than 1500 g (25-32 weeks of gestation) were included. Infants with major congenital anomaly, perinatal asphyxia, twin to twin transfusion and infants who were mechanically ventilated and nil by mouth for more than 3 days or fed with formula, had intraventricular hemorrhage ≥ grade 2 or sepsis, received blood/blood product transfusion or inotrope treatment and developed bronchopulmonary dysplasia or retinopathy of prematurity (≥ stage 3), and died were excluded thereafter. Serum thiol-disulfide homeostasis was evaluated for three times: (Baseline, first week, third week). Serum native thiol, total thiol and disulfide were measured (µmol/Lt), disulfide:native thiol, disulfide:total thiol, and native thiol:total thiol ratios were calculated. Wilcoxon's test was used to analyze the significance of change in measurements. Baseline results were analyzed for gender and mode of delivery. RESULTS: Eighty preterm infants [1255 (1080-1415) grams] were included. Baseline values were native thiol: 209.54 ± 41.83 µmol/L; total thiol: 251.70 ± 45.82 µmol/L; disulfide: 21.08 ± 7.43 µmol/Lt; disulfide:native thiol: 10.49 ± 4.62; disulfide:total thiol: 8.45 ± 2.93; native thiol:total thiol: 83.10 ± 5.87. Thiol levels increased in each measurement, disulfide and disulfide/thiol ratios increased in the first week, decreased in the third week, ratio of native/total thiol decreased in the first week, increased in the third week. No effect of gender or mode of delivery on baseline thiol-disulfide homeostasis was detected. CONCLUSIONS: The shift in the thiol-disulfide equilibrium towards disulfides in the first week can be attributed to subjection of infants to many oxidative insults. Furthermore, the thiol predominance in the third week could be explained by the decrease in oxidative events and increase in feeding as a supply of antioxidants. This study, displaying the levels of the dynamic thiol-disulfide homeostasis in preterm infants without obvious risks for increased oxidative stress, may provide acceptable range for thiol-disulfide homeostasis in recovering preterm infants.

Serum glutathione S-transferase Pi as predictor of the outcome and acute kidney injury in premature newborns.

BACKGROUND: The incidence of acute kidney injury (AKI) among the neonates treated at the Neonatal Intensive Care Unit is high with high mortality rates. Glutathione S-transferase (GST) class Pi plays an important role in the protection of cells from cytotoxic and oncogenic agents. The aim of the study was to examine whether the levels of serum glutathione S-transferase Pi (GST Pi) determined after birth have any predictive value for the outcome and development of AKI in premature neonates. METHODS: The prospective study included 36 premature neonates. The data about morbidity was gathered for all the neonates included in the study. The blood samples were taken in the first 6 h of life and GST Pi levels were measured. RESULTS: The mean values and standard deviations of GST Pi among the neonates who died and who survived were 1.904 ± 0.4535 vs 1.434 ± 0.444 ng/ml (p = 0.0128). Logistic regression revealed a statistically significant, positive correlation between GST Pi levels and death (p = 0.0180, OR7.5954; CI 1.4148-40.7748).The mean value of GST Pi levels in the neonates with AKI was higher than in neonates without AKI (p = 0.011). CONCLUSIONS: The conclusion of our study is that high levels of serum GST Pi in the first 6 h after birth are associated with an increased mortality and development of AKI in prematurely born neonates.

Early Elevation in Interleukin-6 is Associated with Reduced Growth in Extremely Low Birth Weight Infants.

Objective To determine whether reduced growth velocity (GV) in extremely low birth weight infants is preceded by elevated inflammatory cytokines. Study Design GV was determined at 36 weeks' postmenstrual age (PMA) in 768 infants 401 to 1,000 g birth weight (BW). Association between blood cytokines measured through day of life 21 and GV was explored using linear regression models that adjusted for late-onset sepsis (LOS), BW, small for gestational age (SGA), gender, race, energy intake, and center. Results Serum interleukin-6 (IL-6) was increased at days 14 and 21 in LOS infants. LOS was associated with reduced energy intake and GV for weight (weight-GV) at 36 weeks' PMA. Linear regression analysis controlling for LOS and energy intake showed significant relationships between increased IL-6 at days 14 and 21 with reduced weight-GV at 36 weeks' PMA (p < 0.0001). The relationship between day 21 IL-6 and weight-GV was not associated with LOS (p = 0.12) when controlling for BW and energy intake. Both BW (p = 0.02) and energy intake (p = 0.003) influenced the relationship between day 14 IL-6 and weight-GV. Conclusion IL-6 elevation during the first month of life is associated with lower weight-GV at 36 weeks' PMA and may have a direct effect upon energy balance and postnatal growth.

Serum α-fetoprotein concentration in extremely low-birthweight infants.

BACKGROUND: Extremely low-birthweight infants (ELBWI) are at greater risk of developing hepatoblastoma than are normal-weight infants. Serum α-fetoprotein (AFP) plays an important role as a tumor marker in the diagnosis of hepatoblastoma, therefore the aim of this study was to determine the changes in serum AFP concentration after birth in ELBWI. METHODS: Data were obtained for infants born between January 2005 and March 2008 with birthweight <1000 g who were followed up at Gunma Children's Medical Center with clinical examinations, including monitoring of the development of hepatoblastoma. The relationship between serum AFP concentration and age was analyzed up to 730 days after birth. RESULTS: Overall, 95 serum AFP measurements were obtained from 23 infants 30-730 days of age, with gestational age 24-32 weeks, and birthweight 498-982 g. Log10 (AFP [ng/mL]) was significantly correlated with log10 (age [days]) (r = -0.961, P = 0.000, n = 95), with the following regression formula: log10 (AFP [ng/mL]) = 11.063 - 3.752 log10 (age [days]) (adjusted R2  = 0.923, n = 95). The standard error of the estimate, mean log10 (age [days]), and the sum of squares for log10 (age [days]) were 0.363, 2.503, and 10.579, respectively. CONCLUSIONS: A correlation was found between serum AFP concentration and age in ELBWI, and the 95%CI of serum AFP concentration was determined for ELBWI up to 2 years after birth.

Risk factors vary early preterm birth and perinatal complications after assisted reproductive technology.

We conducted a study of markers of endothelial dysfunction and angiogenesis regulation, as well as the identification of the main lymphocyte populations, activated CD3 + CD95+-cells and cytokine-producing CD4 + IFN-γ+-, CD4 + IL-4+ -lymphocytes in the 1st trimester of gestation in women with ART-induced pregnancy and spontaneous pregnancy. We used the same indicators to assess the immune status of ELBW infants at birth and at the post-conceptual age of 38-40 weeks. It was determined that the risk factors of very early preterm delivery are: threatened miscarriage, chronic placental insufficiency, endothelial dysfunction, increased spontaneous production of intracellular cytokines. Adverse perinatal outcomes in ELBW infants from ART-induced pregnancy are associated with lower anthropometric measures, low Apgar scores high level of inflammatory infections (pneumonia), grade II intraventricular hemorrhage, movement disorders in the form of lower paraparesis. Immune status of those infants is characterized by the increase in the number of CD8+- and CD3-CD16 + CD56+ -lymphocytes, the expression level of Fas-receptor by T-cells, and the increased production of intracellular and serum IFNγ against the decrease in the number of CD4+-cells, which indicates enhancing of cytotoxic effector potential and proinflammatory orientation of cell responses.

Serum eotaxin-1 is increased in extremely-low-birth-weight infants with bronchopulmonary dysplasia or death.

BACKGROUND: Early systemic inflammation in extremely-low-birth-weight (ELBW) infants is associated with an increased risk of bronchopulmonary dysplasia (BPD). Our objective was to identify circulating biomarkers and develop prediction models for BPD/death soon after birth. METHODS: Blood samples from postnatal day 1 were analyzed for C-reactive protein (CRP) by enzyme-linked immunosorbent assay and for 39 cytokines/chemokines by a multiplex assay in 152 ELBW infants. The primary outcome was physiologic BPD or death by 36 wk. CRP, cytokines, and clinical variables available at ≤24 h were used for forward stepwise regression and Classification and Regression Tree (CART) analysis to identify predictors of BPD/death. RESULTS: Overall, 24% developed BPD and 35% died or developed BPD. Regression analysis identified birth weight and eotaxin (CCL11) as the two most significant variables. CART identified FiO2 at 24 h (11% BPD/death if FiO2 ≤28%, 49% if >28%) and eotaxin in infants with FiO2 > 28% (29% BPD/death if eotaxin was ≤84 pg/ml; 65% if >84) as variables most associated with outcome. CONCLUSION: Eotaxin measured on the day of birth is useful for identifying ELBW infants at risk of BPD/death. Further investigation is required to determine if eotaxin is involved in lung injury and pathogenesis of BPD.

Permissive hypercapnia in extremely low birthweight infants (PHELBI): a randomised controlled multicentre trial.

BACKGROUND: Tolerating higher partial pressure of carbon dioxide (pCO2) in mechanically ventilated, extremely low birthweight infants might reduce ventilator-induced lung injury and bronchopulmonary dysplasia. We aimed to test the hypothesis that higher target ranges for pCO2 decrease the rate of bronchopulmonary dysplasia or death. METHODS: In this randomised multicentre trial, we recruited infants from 16 tertiary care perinatal centres in Germany with birthweight between 400 g and 1000 g and gestational age 23-28 weeks plus 6 days, who needed endotracheal intubation and mechanical ventilation within 24 h of birth. Infants were randomly assigned to either a high target or control group. The high target group aimed at pCO2 values of 55-65 mm Hg on postnatal days 1-3, 60-70 mm Hg on days 4-6, and 65-75 mm Hg on days 7-14, and the control target at pCO2 40-50 mmHg on days 1-3, 45-55 mm Hg on days 4-6, and 50-60 mm Hg on days 7-14. The primary outcome was death or moderate to severe bronchopulmonary dysplasia, defined as need for mechanical pressure support or supplemental oxygen at 36 weeks postmenstrual age. Cranial ultrasonograms were assessed centrally by a masked paediatric radiologist. This trial is registered with the ISRCTN registry, number ISRCTN56143743. RESULTS: Between March 1, 2008, and July 31, 2012, we recruited 362 patients of whom three dropped out, leaving 179 patients in the high target and 180 in the control group. The trial was stopped after an interim analysis (n=359). The rate of bronchopulmonary dysplasia or death in the high target group (65/179 [36%]) did not differ significantly from the control group (54/180 [30%]; p=0·18). Mortality was 25 (14%) in the high target group and 19 (11%; p=0·32) in the control group, grade 3-4 intraventricular haemorrhage was 26 (15%) and 21 (12%; p=0·30), and the rate of severe retinopathy recorded was 20 (11%) and 26 (14%; p=0·36). INTERPRETATION: Targeting a higher pCO2 did not decrease the rate of bronchopulmonary dysplasia or death in ventilated preterm infants. The rates of mortality, intraventricular haemorrhage, and retinopathy did not differ between groups. These results suggest that higher pCO2 targets than in the slightly hypercapnic control group do not confer increased benefits such as lung protection. FUNDING: Deutsche Forschungsgemeinschaft.

[Anthropometric and biochemical indices in the nutritional assessment of the newborn with extremely low weight]. / Índices antropométricos y bioquímicos en la valoración nutricional del neonato de peso muy bajo.

OBJECTIVE: To evaluate anthropometric and biochemical indices of the nutritional status of newborn with extremely low weight. METHODS: It was carried out a cohort study with 10 patients included, of both sexes, and weight at birth between 700-1200 g, who were under treatment with parenteral nutrition (PN), and/or minimal enteric stimulus (MES). RESULTS: Nine patients (90 %) received PN plus MES. One patient received only oral or enteric nutrition. Daily increase in weight was 7-23.8 g with an average of 15.6 g. In size, weekly increase was 0.30-1.5 cm with an average of 0.78 cm. In cephalic perimeter, the weekly increase was between 0.1-1.1 cm weekly with an average of 0.57 cm. Once the PN treatment was stopped and the patients were managed only with oral feeding, the weigh increases ranged between 12.5-35 g per day with an average of 22.7 g/day; height increased weekly from 0.45 to 1.1 cm, with an average of 0.89 cm/week; cephalic perimeter increased weekly from 0.45 to 1.3 cm, with an average of 0.80 cm. All the patients (100 %) had a positive nitrogen balance. CONCLUSIONS: The treatment of PN and MES is a useful strategy in order to keep a positive nitrogen balance and promote the increase in weight, size and cephalic perimeter so that the newborn could get the rate of growth in utero.

OBJETIVO: evaluar los índices antropométricos y bioquímicos del neonato de peso extremadamente bajo. MÉTODOS: estudio de cohorte en el que se evaluaron 10 pacientes con peso al nacer entre 700 y 1200 g, a quienes se les proporcionó nutrición parenteral y enteral. RESULTADOS: 90 % de los recién nacidos recibió nutrición parenteral más estímulo enteral mínimo, con los que registró un incremento diario de peso de 7 a 23 g, con una media de 15.6 g; en la talla, el incremento fue de 0.30 a 1.5 cm semanales, con una media de 0.78 cm; y en el perímetro cefálico, entre 0.1 y 1.1 cm semanales, con una media de 0.57 cm. Al suspender la nutrición parenteral y administrar vía oral exclusiva, el incremento del peso osciló entre 12.5 y 35 g diarios, con una media de 22.7 g; la talla aumentó de 0.45 a 1.1 cm semanales, con una media de 0.89 cm; el perímetro cefálico, de 0.45 a 1.3 cm semanales, con una media de 0.80 cm. Todos los neonatos tuvieron balance nitrogenado positivo. CONCLUSIONES: se debe iniciar la nutrición parental total desde el primer contacto con el paciente y, de ser posible, el estímulo enteral mínimo para mantener un balance nitrogenado positivo y favorecer el aumento de peso, talla y perímetro cefálico para alcanzar la tasa de crecimiento in utero.

Tobacco smoke exposure during pregnancy increases maternal blood lead levels affecting neonate birth weight.

To assess the effect of lead exposure from cigarette smoke on fetal growth, blood lead concentrations were measured using inductively coupled plasma mass spectrometry in 150 healthy pregnant women. Mean lead concentrations in plasma and whole blood were significantly higher in the smoking group compared with the nonsmoking group in each trimester of pregnancy (p < 0.001). Logistic regression analysis showed the highest impact of the number of cigarettes smoked per day for serum lead concentration (ß = 0.238; p < 0.05), while in whole blood, it was duration of smoking before conception (ß = 0.297; p < 0.001). Birth weight of the smoking mothers' infants was significantly lower (mean ± SEM, 3,192 ± 50.8 and 3,569 ± 49.6 g, respectively; p < 0.001) and negatively correlated with lead levels in plasma (r = -0.38; p < 0.001) and in whole blood (r = -0.27; p < 0.001). Therefore, it is suggested that smoking during pregnancy increases lead concentrations in maternal blood. Fetal exposure to low doses of lead in utero may be a serious risk factor causing lower birth weight.

Vitamin A supplementation in extremely low-birth-weight infants: subgroup analysis in small-for-gestational-age infants.

OBJECTIVE: Preterm infants with intrauterine growth restriction are at increased risk of respiratory distress syndrome and bronchopulmonary dysplasia (BPD). A randomized clinical trial by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network demonstrated that vitamin A supplementation in extremely low-birth-weight (ELBW) preterm infants requiring early respiratory support decreased the risk of developing BPD. STUDY DESIGN: A subgroup analysis of small-for-gestational-age (SGA) infants from the original NICHD trial was performed to test the hypothesis that in infants requiring early respiratory support, vitamin A supplementation decreases the relative risk of BPD or death in premature SGA infants to a greater extent than in gestational age-equivalent vitamin A-treated appropriate-for-gestational-age (AGA) infants. RESULTS: Although vitamin A supplementation significantly increased serum retinol concentrations in AGA ELBW infants (median [5th percentile, 95th percentile]: 16.3 [-7.0, 68.8] versus 2.4 [-13.9, 55.1]; p < 0.001), no increases were noted in SGA ELBW infants. CONCLUSIONS: Given the limited power of this analysis due to a low number of SGA infants, these data did not provide evidence to support the hypothesis that vitamin A supplementation in preterm SGA infants requiring early respiratory support decreases the relative risk of BPD or death as compared with preterm AGA infants.

Cytokines and neurodevelopmental outcomes in extremely low birth weight infants.

OBJECTIVE: To determine if selected pro-inflammatory and anti-inflammatory cytokines and/or mediators of inflammation reported to be related to the development of cerebral palsy (CP) predict neurodevelopmental outcome in extremely low birth weight infants. STUDY DESIGN: Infants with birth weights ≤1000 g (n = 1067) had blood samples collected at birth and on days 3 ± 1, 7 ± 1, 14 ± 3, and 21 ± 3 to examine the association between cytokines and neurodevelopmental outcomes. The analyses were focused on 5 cytokines (interleukin [IL] 1ß; IL-8; tumor necrosis factor-α; regulated upon activation, normal T-cell expressed, and secreted (RANTES); and IL-2) reported to be most predictive of CP in term and late preterm infants. RESULTS: IL-8 was higher on days 0-4 and subsequently in infants who developed CP compared with infants who did not develop CP in both unadjusted and adjusted analyses. Other cytokines (IL-12, IL-17, tumor necrosis factor-ß, soluble IL rα, macrophage inflammatory protein 1ß) were found to be altered on days 0-4 in infants who developed CP. CONCLUSIONS: CP in former preterm infants may, in part, have a late perinatal and/or early neonatal inflammatory origin.

Transcutaneous blood gas monitoring during neonatal intensive care.

AIM: To evaluate the accuracy in transcutaneous (Tc) blood gas monitoring in newborn infants, including extremely low birth weight infants, during neonatal intensive care. METHODS: Tc PO(2) /PCO(2) was monitored in the neonatal intensive care unit (NICU) during stable infant conditions. In comparison, simultaneous arterial PO(2) and PCO(2) was measured. Sixty measurements were taken in 46 infants with median (range) birth weight of 0.93 (0.53-4.7) kg and at median (range) age of 8.5 (1-44) days. Comparison of measurements was performed using Bland-Altman plots, and the mean (95% CI) of the difference was calculated. Comparison was also performed in relation to body weight, postnatal age and oxygen requirement. RESULTS: The mean (95% CI) difference in PO(2) (TcPO(2)-aPO(2)) was 0.3 (-0.2-0.9) kPa, and the corresponding difference in PCO(2) (TcPCO(2)-aPCO(2)) was 0.4 (0.03-0.8, p < 0.05) kPa. Some differences were related to body weight, age and oxygen requirement, but these differences were small. CONCLUSION: There was good agreement between TcPO(2)/TcPCO(2) and corresponding arterial measurements. The mean difference between the methods was small and clinically acceptable in a current NICU. Tc blood gas monitoring could be recommended as a valuable complement for blood gas monitoring also in extremely low birth weight infants.

T cell cytokines and the risk of blood stream infection in extremely low birth weight infants.

Cytokines mediate the host immune response to infectious micro-organisms. The objective of this study was to determine whether immune regulatory interleukins (IL-4, IL-5, IL-6, and IL-10) and inflammatory cytokines (Interferon-γ [INF-γ], tumor necrosis factor-ß [TNF-ß], IL-2, and IL-17) are associated with an increased risk of developing blood stream bacterial/fungal infection (BSI) in extremely low birth weight (ELBW) infants. ELBW infants from 17 NICHD Neonatal Research Network centers without early onset sepsis were studied. Cytokines were measured from blood on days 1, 3, 7, 14, and 21 after birth. 996 ELBW infants contributed a minimum of 4080 unique measurements for each cytokine during the five sampling periods. Infants with BSI had lower levels of the inflammatory cytokines IL-17 (p=0.01), and higher levels of the regulatory cytokines, IL-6 (p=0.01) and IL-10 (p<0.001). Higher levels of regulatory cytokines relative to pro-inflammatory cytokines were associated with increased risk of BSI even after adjusting for confounding variables. In ELBW infants, the ratio of immune regulatory cytokines to inflammatory cytokines was associated with development of BSI. Altered maturation of regulatory and inflammatory cytokines may increase the risk of serious infection in this population.

Clara cell secretory protein in tracheobronchial aspirates and umbilical cord serum of extremely premature infants with systemic inflammation.

BACKGROUND: A systemic fetal inflammatory response, reflected by chorioamnionitis with funisitis, is a risk factor for bronchopulmonary dysplasia. Clara cell secretory protein (CC10), a product of pulmonary Clara cells, has anti-inflammatory properties. Local down-regulation of CC10 has been associated with inflammatory lung disease. Increased serum levels of CC10 can indicate injury to alveolar-capillary integrity. OBJECTIVE: We hypothesized that extremely premature infants with a systemic fetal inflammatory response would have decreased concentrations of CC10 in tracheobronchial aspirates and that CC10 concentrations in umbilical cord serum of these infants would be increased, reflecting alveolar epithelial damage. METHODS: We measured CC10 concentrations in tracheobronchial aspirates of 42 ventilated extremely premature infants during their first week of life and in umbilical cord serum of 24 of them by ELISA. Standardized histological examination of the placenta, membranes and umbilical cord was used to identify infants with funisitis. RESULTS: Seventeen infants with funisitis had lower CC10 concentrations in tracheobronchial aspirates on days 1 (p < 0.01) and 3 (p < 0.05) than the remaining 25. Exogenous surfactant treatment was associated with higher CC10 concentrations on day 1 (p < 0.05). Initial leukocyte count correlated inversely with CC10 in tracheobronchial aspirates on days 1-5. Umbilical cord serum concentrations of CC10 did not differ between the infants with funisitis and the controls. CONCLUSIONS: Reduced anti-inflammatory CC10 concentrations in airways of extremely premature infants with a fetal inflammatory response might make their lungs susceptible for further postnatal injuries. Umbilical cord serum CC10 is not an indicator for a fetal systemic inflammatory reaction.

Systematic underestimation of oxygen delivery in ventilated preterm infants.

BACKGROUND: Emerging evidence indicates that hyperoxia is a risk factor for bronchopulmonary dysplasia, a common multifactorial long-term complication of prematurity. To date, the equivalence between set and delivered oxygen (O(2)) in ventilated preterm infants has not been rigorously studied. OBJECTIVES: To test the hypothesis of systematic underestimation of O(2) delivery in extremely low birth weight (ELBW) infants during long-term ventilation. METHODS: Actually achieved O(2) concentrations were measured and compared to the set inspired oxygen fraction (FiO(2)). A total of 108 O(2) measurements were carried out during the ventilation of 54 ELBW infants: O(2)-Delta error (i.e., the difference between O(2) concentrations achieved by the ventilator and set FiO(2)) was the main study outcome measure. RESULTS: Systematic O(2)-Delta errors were found, with mean values of +9.52% (FiO(2) 0.21-0.40), +2.10 (FiO(2) 0.41-0.60), +2.86% (FiO(2) 0.61-0.80), and +0.016% (FiO(2) 0.81-1.0; p < 0.0001). Theoretical simulations from the observed data indicate that, if not corrected, systematic O2-Delta errors would lead to a non-intentional total O(2) load of 1,202.9 (FiO(2) 0.21-0.40), 252.46 (FiO(2) 0.41-0.60), 342.85 (FiO(2) 0.61-0.80), and 2 (FiO(2) 0.81-1.0) extra liters/kg body weight/100 ventilation hours. CONCLUSIONS: Systematic underestimation of the O(2) delivered by infant ventilators can potentially lead to surprisingly large increases in total O(2) load during long-term ventilation of ELBW infants, especially in the lower FiO(2) range (i.e., 0.21-0.40). Underestimation of true O(2) delivery can potentially lead to unrecognized high O(2) loads, and more pronounced and prolonged hyperoxia.