Giovanni Vento

Plasma levels of interleukin-6 and interleukin-10 in preterm neonates evaluated for sepsis

Abstract In a prospective study, plasma interleukin-6 (IL-6) and interleukin-10 (IL-10) levels were measured by enzyme-linked immunosorbent assay in 45 premature neonates (25–34 weeks gestational age) with signs and symptoms of suspected sepsis at 0, 12 and 24 h; C-reactive protein (CRP) was measured at 0–24 h after enrolment. Six subjects were excluded due to insufficient blood sampling. The remaining 39 neonates were assigned to one of three groups: 25 newborns with sepsis (blood culture positive), seven with pneumonia (positive results on broncho-alveolar lavage fluid culture and characteristic chest radiography) and seven with necrotising enterocolitis (NEC) (characteristic intestinal and radiological signs according to the criteria of Bell et al.). A group of 20 healthy preterm neonates represented control subjects. On admission, higher levels of IL-6, IL-10 and CRP were observed in neonates with sepsis: IL-6 (median 1500 pg/ml, range 487–10000 pg/ml), IL-10 (median 113 pg/ml, range 70–196 pg/ml), CRP (median 22 mg/l, range 4–80 mg/l); pneumonia: IL-6 (median 1500 pg/ml, range 747–8000 pg/ml, IL-10 (median 84 pg/ml, range 76–92 pg/ml), CRP (median 10 mg/l, range 8–33 mg/l) and NEC: IL-6 (median 6650 pg/ml, range 1595–7950 pg/ml), IL-10 (median 80 pg/ml, range 61–147 pg/ml), CRP (median 3 mg/l, range 2.8–8 mg/l) as compared to controls (IL-6 median 208 pg/ml, range 198–349 pg/ml; IL-10 median 36 pg/ml, range 19–50 pg/ml; CRP median <2 mg/l) (P < 0.05). In neonates with sepsis, IL-6 levels were significantly correlated with IL-10 levels (r=0.65; P=0.04) at the time of the second sample. The highest IL-6 levels were observed at onset, while IL-10 was predominant 12 h later. On admission, IL-10 and CRP levels were significantly higher in non-survivors (IL-10 median 507 pg/ml, range 422–753 pg/ml; CRP median 123 mg/l, range 20–219 mg/l) than in survivors (IL-10 median 76 pg/ml, range 61–143 pg/ml; CRP median 8 mg/l range 3–46 mg/l), while IL-10 levels were significantly higher (P < 0.05) also 12 h after admission (non-survivors: IL-10 median 600 pg/ml, range 538–800 pg/ml; survivors: IL-10 median 74 pg/ml, range 53–161 pg/ml). IL-6 and IL-10 levels were significantly correlated with CRP levels on admission (r=0.45; P=0.05). Conclusion Preterm neonates with sepsis, pneumonia or necrotising enterocolitis showed increased interleukin-6, interleukin-10 and C-reactive protein levels. High interleukin-10 concentration was associated with mortality and could be an early indicator of prognosis.

Sustained Lung Inflation at Birth for Preterm Infants: A Randomized Clinical Trial

BACKGROUND: Studies suggest that giving newly born preterm infants sustained lung inflation (SLI) may decrease their need for mechanical ventilation (MV) and improve their respiratory outcomes. METHODS: We randomly assigned infants born at 25 weeks 0 days to 28 weeks 6 days of gestation to receive SLI (25 cm H2O for 15 seconds) followed by nasal continuous positive airway pressure (nCPAP) or nCPAP alone in the delivery room. SLI and nCPAP were delivered by using a neonatal mask and a T-piece ventilator. The primary end point was the need for MV in the first 72 hours of life. The secondary end points included the need for respiratory supports and survival without bronchopulmonary dysplasia (BPD). RESULTS: A total of 148 infants were enrolled in the SLI group and 143 in the control group. Significantly fewer infants were ventilated in the first 72 hours of life in the SLI group (79 of 148 [53%]) than in the control group (93 of 143 [65%]); unadjusted odds ratio: 0.62 [95% confidence interval: 0.38–0.99]; P = .04). The need for respiratory support and survival without BPD did not differ between the groups. Pneumothorax occurred in 1% (n = 2) of infants in the control group compared with 6% (n = 9) in the SLI group, with an unadjusted odds ratio of 4.57 (95% confidence interval: 0.97–21.50; P = .06). CONCLUSIONS: SLI followed by nCPAP in the delivery room decreased the need for MV in the first 72 hours of life in preterm infants at high risk of respiratory distress syndrome compared with nCPAP alone but did not decrease the need for respiratory support and the occurrence of BPD.

The Surprising Composition of the Salivary Proteome of Preterm Human Newborn

Saliva is a body fluid of a unique composition devoted to protect the mouth cavity and the digestive tract. Our high performance liquid chromatography (HPLC)-electrospray ionization-MS analysis of the acidic soluble fraction of saliva from preterm human newborn surprisingly revealed more than 40 protein masses often undetected in adult saliva. We were able to identify the following proteins: stefin A and stefin B, S100A7 (two isoforms), S100A8, S100A9 (four isoforms), S100A11, S100A12, small proline-rich protein 3 (two isoforms), lysozyme C, thymosins β4 and β10, antileukoproteinase, histone H1c, and α and γ globins. The average mass value reported in international data banks was often incongruent with our experimental results mostly because of post-translational modifications of the proteins, e.g. acetylation of the N-terminal residue. A quantitative label-free MS analysis showed protein levels altered in relation to the postconceptional age and suggested coordinate and hierarchical functions for these proteins during development. In summary, this study shows for the first time that analysis of these proteins in saliva of preterm newborns might represent a noninvasive way to obtain precious information of the molecular mechanisms of development of human fetal oral structures.

Bile acid-induced lung injury in newborn infants: a bronchoalveolar lavage fluid study.

OBJECTIVES. Neonatal respiratory distress syndrome is associated with intrahepatic cholestasis of pregnancy, and bile acids may play a major role in neonatal bile acid pneumonia. Our aim was to demonstrate the bile acid presence in the bronchoalveolar lavage fluid of neonates affected by respiratory distress syndrome who were born from intrahepatic cholestasis of pregnancy and to investigate bile acid mechanisms of action in acute lung injury. METHODS. In this prospective study, we enrolled 10 neonates delivered from intrahepatic cholestasis of pregnancy, affected by respiratory distress syndrome requiring mechanical ventilation (intrahepatic cholestasis of pregnancy group) and 2 control groups. The first group consisted of 20 infants with respiratory distress syndrome delivered from pregnancies without any sign of intrahepatic cholestasis of pregnancy (respiratory-distress-syndrome group), and the second group included 20 neonates with no lung disease who were ventilated for extrapulmonary reasons (no-lung-disease group). We measured bile acid and pH in the bronchoalveolar lavage fluid and serum bile acid levels in the first 24 hours of life. RESULTS. Bile acids were measurable in the bronchoalveolar lavage fluid of all of the infants in the intrahepatic cholestasis of pregnancy group but were absent in the 2 control groups. Bronchoalveolar lavage fluid pH was not different among the 3 groups. Infants in the intrahepatic-cholestasis-of-pregnancy group had significantly higher serum bile acid levels compared with those in both of the control groups. CONCLUSIONS. Bile acids are detectable in the bronchoalveolar lavage fluid of newborns from intrahepatic cholestasis of pregnancy affected by respiratory distress syndrome. Elevated serum bile acid levels in these infants allow us to hypothesize that bile acid reaches the lung after an uptake from the circulation. These findings strongly support a role for bile acid in causing bile acid pneumonia.

Thymosin β4 and β10 Levels in Pre-Term Newborn Oral Cavity and Foetal Salivary Glands Evidence a Switch of Secretion during Foetal Development

Background Thymosin β4, its sulfoxide, and thymosin β10 were detected in whole saliva of human pre-term newborns by reversed-phase high performance chromatography coupled to electrospray ion-trap mass spectrometry. Methodology/Principal Findings Despite high inter-individual variability, concentration of β-thymosins increases with an inversely proportional trend to postmenstrual age (PMA: gestational age plus chronological age after birth) reaching a value more than twenty times higher than in adult whole saliva at 190 days (27 weeks) of PMA (thymosin β4 concentration: more than 2.0 µmol/L versus 0.1 µmol/L). On the other hand, the ratio between thymosin β4 and thymosin β10 exhibits a constant value of about 4 along all the range of PMA (190–550 days of PMA) examined. In order to investigate thymosin β4 origin and to better establish the trend of its production as a function of gestational age (GA), immunohistochemical analysis of major and minor salivary glands of different pre-term fetuses were carried out, starting from 84 days (12 weeks) of gestational age. Reactive granules were seen in all glands with a maximum of expression around 140–150 days of GA, even though with high inter- and intra-individual variability. In infants and adults reactive granules in acinar cells were not observed, but just a diffuse cytoplasmatic staining in ductal cells. Significance This study outlines for the first time that salivary glands during foetal life express and secrete peptides such as β-thymosins probably involved in the development of the oral cavity and its annexes. The secretion increases from about 12 weeks till to about 21 weeks of GA, subsequently it decreases, almost disappearing in the period of expected date of delivery, when the gland switches towards the secretion of adult specific salivary peptides. The switch observed may be an example of further secretion switches involving other exocrine and endocrine glands during foetal development.

Effect on growth of two different dexamethasone courses for preterm infants at risk of chronic lung disease. A randomized trial.

A randomized study was designed to evaluate the effects of two different dexamethasone courses on the growth of preterm infants. The first phase included 30 preterm infants at high risk for chronic lung disease (CLD). 15 babies (moderately early dexamethasone group) were treated with dexamethasone for 14 days, from the 10th day of life, and received a total dose of 4.75 mg/kg; 15 babies were assigned to the control group. The second phase included 30 preterm infants at high risk for CLD. 15 babies (early dexamethasone group) were treated with dexamethasone for 7 days, from the 4th day of life, and received a total dose of 2.38 mg/kg; 15 babies were assigned to the control group. All the main clinical baseline characteristics were similar between the groups both in the first and in the second phase. Infants given the two dexamethasone courses showed significantly reduced weight gain during the period of treatment when compared to the respective control group, but they had a weight catch-up soon after the end of treatment. At 30 days of life the weight and length gain of each treated group were similar to those of control infants, but the moderately early dexamethasone group showed a significantly poorer head growth. No differences between the groups were observed at discharge. Dexamethasone treatment induces a slower weight gain which is time-limited to the period of treatment and is followed by a body weight catch-up. However, the poorer head growth detected at 30 days of life in the infants who received a higher dose of dexamethasone could indicate important adverse effects, possibly dose-related, on postnatal brain growth and development.

A scoring system to predict the evolution of respiratory distress syndrome into chronic lung disease in preterm infants

Objective: The purpose of this study was to develop and validate an empirical scoring system to predict the evolution of neonatal respiratory distress syndrome (RDS) into chronic lung disease (CLD) in preterm infants, by comparing it with a more complicated logistic regression model. Design: Clinical study. Setting: Neonatal intensive care unit. Patients: The retrospective analysis of a 3-year experience showed that a gestational age (GA) of less than 30 weeks, a birth weight (BW) of less than 1000 g, the diagnosis of hyaline membrane disease (HMD) and pulmonary interstitial emphysema (PIE) during the first 72 h of life, the peak inspiratory pressure (PIP) and the fraction of inspired oxygen (FIO2) were the highest relative risk factors correlated with the evolution of CLD. On this basis an empirical and a statistical scoring system were defined and prospectively applied at 3 and 5 days of life to 228 neonates with BW less than 1250 g. The results obtained with both scoring systems were then compared. Results: Of the 149 infants surviving at 28 days of life, 67 (GA: 29.9 ± 2.3 weeks; BW: 1058 ± 143 g) were normal and 82 (GA: 27.5 ± 3.9 weeks; BW: 838 ± 200 g) had CLD. Using a cut-off value of 4.0, the empirical scoring system showed a specificity of 97.0 % and a sensitivity of 92.7 % on the 3rd day of life; on the 5th day of life the specificity was still 95.5 %, while sensitivity remained 92.7 %. The areas under the ROC curves plotted with both scoring systems tested were similar. Conclusions: The proposed empirical scoring system is easy to use and is highly reliable. The application of this scoring system provides the opportunity to direct aggressive treatment for CLD toward only very high risk patients between the 3rd and 5th days of life.

A prospective, randomized, double blind study comparing lutein to placebo for reducing occurrence and severity of retinopathy of prematurity

Lutein has been shown to have antioxidant functions in newborns and with zeaxantin selectively taken up into the macula of the eye. We hypothesize that lutein administration may contribute to reducing the incidence of Retinopathy of Prematurity (ROP). This was a single center, double-blind randomized controlled study. Preterm infants with gestational age (GA) ≤32 weeks able to tolerate minimal enteral feeding before the seventh day of life (DOL) were enrolled; lutein and zeaxantin plasma concentrations and ROP occurrence and severity were evaluated. Sixty-three newborns were enrolled, 31 in the lutein group and 32 in the placebo group (one died before ROP assessment). The mean GA was 29.9 (±1.9) weeks and the mean birth weight was 1331 (±415) grams. There were no differences in the incidence of ROP at any stage between groups. Oxidative injury is probably an additional mechanism of damage of the developing retinal vessels, and it probably plays only a minor role in the pathogenesis of ROP. Supplementation with antioxidant substances might have beneficial effects noticeable only on larger samples of high risk neonates or at very high dosage. Further investigations would be needed to evaluate whether lutein supplementation can influence functional rather than anatomical outcomes in preterm infants.

Spontaneous minute ventilation is a predictor of extubation failure in extremely-low-birth-weight infants

Objective: To validate the percentage of time spent below a target value of spontaneous expiratory minute ventilation (<125 ml/min per kg) during a 2-h period of continuous positive airway pressure (CPAP) via an endotracheal tube (ETT) as a predictor of failed extubation in preterm infants.Methods: Forty-one infants intubated for at least 24 h, with birth weight between 500 and 1000 g, who were clinically stable and at ventilator setting compatible with an extubation attempt, were studied during a 2-h period of ETT CPAP. Dynamic lung compliance and total lung resistance were measured during a period of quiet breathing, while tidal volume (Vt), respiratory rate and the corresponding spontaneous expiratory minute ventilation values were calculated for the complete recording period of 2 h using a customized computer program. The time each patient spent below the target spontaneous expiratory minute ventilation value was reported as a percentage of the total recorded time (% spontaneous expiratory minute ventilation <125 ml/min per kg). Extubation failure was defined as the need for reintubation within 72 h.Results: Eleven out of 41 babies (26.8%) experienced failure of extubation (failure group) while 30 infants (73.2%) were successfully extubated (success group). There were no significant differences in dynamic lung compliance and lung resistance between the two groups, but the mean values of respiratory rate and spontaneous expiratory minute ventilation were significantly lower in the failure group than in the success group: 43 (37–56) breaths/min and 240 (160–353) ml/min per kg vs. 53 (28–67) breaths/min and 309 (223–434) ml/min per kg, respectively (p=0.0129 and p=0.0039). Moreover, the babies in whom extubation failed spent a longer time below the target value of spontaneous expiratory minute ventilation when compared with successfully extubated babies (p<0.0001). Percentage of time spent with spontaneous expiratory minute ventilation <125 ml/min per kg had a larger area than transcutaneous (Tc)PCO2, TcPO2and pulse oxymetry saturation (SpO2) under the receiver operator characteristic curves.Conclusion: The measurement of spontaneous expiratory minute ventilation prior to extubation could be useful in identifying those babies who are not ready for spontaneous ventilation.

Analysis of risk factors for progression to treatment-requiring ROP in a single neonatal intensive care unit: is the exposure time relevant?

Objective: Retinopathy of prematurity (ROP) is a multifactorial disease whose pathogenesis is organized in two phases. We hypothesized that postnatal risk factors may differently exert their effect in a phase dependent way. Methods: Data obtained from medical records of 93 very low birth weight neonates with stage ≥ 3 ROP were analyzed. Perinatal ROP risk factors were compared between infants with stage 3 ROP not requiring surgery and infants with treatment-requiring ROP with relation to newborn’s lifetime exposure. Results: In the first two weeks and in the whole first month of life length of oxygen administration was an independent risk factor for treatment-requiring ROP. In the first month of life also sepsis was identified as independent risk factor for surgical ROP. Sepsis and Candida pneumonia in the time frame from birth to ROP diagnosis and prolonged mechanical ventilation from diagnosis to prethreshold ROP were associated to treatment-requiring ROP. Blood transfusions are the only risk factor for treatment-requiring ROP identified in all the periods analyzed. Conclusion: Risk factors for ROP play their role since birth. Beside scrupulous oxygen-administration monitoring and prevention of infections, blood transfusions are of primary importance in the development of treatment-requiring ROP.