Intratracheal administration of mesenchymal stem cell-derived extracellular vesicles reduces lung injuries in a chronic rat model of bronchopulmonary dysplasia.

Early therapeutic effect of intratracheally (IT)-administered extracellular vesicles secreted by mesenchymal stem cells (MSC-EVs) has been demonstrated in a rat model of bronchopulmonary dysplasia (BPD) involving hyperoxia exposure in the first 2 postnatal weeks. The aim of this study was to evaluate the protective effects of IT-administered MSC-EVs in the long term. EVs were produced from MSCs following GMP standards. At birth, rats were distributed in three groups: (a) animals raised in ambient air for 6 weeks (n = 10); and animals exposed to 60% hyperoxia for 2 weeks and to room air for additional 4 weeks and treated with (b) IT-administered saline solution (n = 10), or (c) MSC-EVs (n = 10) on postnatal days 3, 7, 10, and 21. Hyperoxia exposure produced significant decreases in total number of alveoli, total surface area of alveolar air spaces, and proliferation index, together with increases in mean alveolar volume, mean linear intercept and fibrosis percentage; all these morphometric changes were prevented by MSC-EVs treatment. The medial thickness index for <100 µm vessels was higher for hyperoxia-exposed/sham-treated than for normoxia-exposed rats; MSC-EV treatment significantly reduced this index. There were no significant differences in interstitial/alveolar and perivascular F4/8-positive and CD86-positive macrophages. Conversely, hyperoxia exposure reduced CD163-positive macrophages both in interstitial/alveolar and perivascular populations and MSC-EV prevented these hyperoxia-induced reductions. These findings further support that IT-administered EVs could be an effective approach to prevent/treat BPD, ameliorating the impaired alveolarization and pulmonary artery remodeling also in a long-term model. M2 macrophage polarization could play a role through anti-inflammatory and proliferative mechanisms.

Neonatal lymphocyte subpopulations analysis and maternal preterm premature rupture of membranes: a pilot study.

OBJECTIVES: Preterm premature rupture of membranes (pPROM) causes preterm delivery, and increases maternal T-cell response against the fetus. Fetal inflammatory response prompts maturation of the newborn's immunocompetent cells, and could be associated with unfavorable neonatal outcome. The aims were (1) to examine the effects of pPROM on the newborn's and mother's immune system and (2) to assess the predictive value of immune system changes in neonatal morbidity. METHODS: Mother-newborn pairs (18 mothers and 23 newborns) who experienced pPROM and controls (11 mothers and 14 newborns), were enrolled. Maternal and neonatal whole blood samples underwent flow cytometry to measure lymphocyte subpopulations. RESULTS: pPROM-newborns had fewer naïve CD4 T-cells, and more memory CD4 T-cells than control newborns. The effect was the same for increasing pPROM latency times before delivery. Gestational age and birth weight influenced maturation of the newborns' lymphocyte subpopulations and white blood cells, notably cytotoxic T-cells, regulatory T-cells, T-helper cells (absolute count), and CD4/CD8 ratio. Among morbidities, fewer naïve CD8 T-cells were found in bronchopulmonary dysplasia (BPD) (p=0.0009), and more T-helper cells in early onset sepsis (p=0.04). CONCLUSIONS: pPROM prompts maturation of the newborn's T-cell immune system secondary to antigenic stimulation, which correlates with pPROM latency. Maternal immunity to inflammatory conditions is associated with a decrease in non-major histocompatibility complex (MHC)-restricted cytotoxic cells.

Intratracheal administration of clinical-grade mesenchymal stem cell-derived extracellular vesicles reduces lung injury in a rat model of bronchopulmonary dysplasia.

Mesenchymal stem cells (MSCs) prevent the onset of bronchopulmonary dysplasia (BPD) in animal models, an effect that seems to be mediated by their secreted extracellular vesicles (EVs). The aim of this study was to compare the protective effects of intratracheally (IT) administered MSCs versus MSC-EVs in a hyperoxia-induced rat model of BPD. At birth, rats were distributed as follows: animals raised in ambient air for 2 wk ( n = 10), and animals exposed to 60% oxygen for 2 wk and treated with IT-administered physiological solution ( n = 10), MSCs ( n = 10), or MSC-EVs ( n = 10) on postnatal days 3, 7, and 10. The sham-treated hyperoxia-exposed animals showed reductions in total surface area of alveolar air spaces, and total number of alveoli ( Nalv), and an increased mean alveolar volume (Valv). EVs prompted a significant increase in Nalv ( P < 0.01) and a significant decrease in Valv ( P < 0.05) compared with sham-treated animals, whereas MSCs only significantly improved Nalv ( P < 0.05). Small pulmonary vessels of the sham-treated hyperoxia-exposed rats also showed an increase in medial thickness, which only EVs succeeded in preventing significantly ( P < 0.05). In conclusion, both EVs and MSCs reduce hyperoxia-induced damage, with EVs obtaining better results in terms of alveolarization and lung vascularization parameters. This suggests that IT-administered EVs could be an effective approach to BPD treatment.

Preventing bronchopulmonary dysplasia: new tools for an old challenge.

Bronchopulmonary dysplasia (BPD) is the most prevalent chronic lung disease in infants and presents as a consequence of preterm birth. Due to the lack of effective preventive and treatment strategies, BPD currently represents a major therapeutic challenge that requires continued research efforts at the basic, translational, and clinical levels. However, not all very low birth weight premature babies develop BPD, which suggests that in addition to known gestational age and intrauterine and extrauterine risk factors, other unknown factors must be involved in this disease's development. One of the main goals in BPD research is the early prediction of very low birth weight infants who are at risk of developing BPD in order to initiate the adequate preventive strategies. Other benefits of determining the risk of BPD include providing prognostic information and stratifying infants for clinical trial enrollment. In this article, we describe new opportunities to address BPD's complex pathophysiology by identifying prognostic biomarkers and develop novel, complex in vitro human lung models in order to develop effective therapies. These therapies for protecting the immature lung from injury can be developed by taking advantage of recent scientific progress in -omics, 3D organoids, and regenerative medicine.

Lipopolysaccharide-induced chorioamnionitis and postnatal lung injury: The beneficial effects of L-citrulline in newborn rats.

AIM OF THE STUDY: The lung architecture of newborns appears to be affected by an inflammatory reaction to maternal choriodecidual layer infection. L-citrulline (L-Cit) was administered to pregnant rats exposed to intra-amniotic lipopolysaccharide (LPS)-induced chorioamnionitis to investigate its effect on neonatal lung injury. MATERIALS AND METHODS: The pups were assigned to four experimental groups: 1- pups exposed to intra-amniotic NaCl but not to postnatal L-Cit (Controls); 2 - pups exposed to intra-amniotic NaCl as well as to postnatal L-Cit treatment (L-Cit group); 3 - pups exposed to prenatal LPS but not to postnatal (LPS); 4- pups exposed to prenatal LPS as well as to postnatal L-Cit treatment (LPS + L-Cit). Some pups in each group were sacrificed on postnatal (P) day 3 and others on day 7. The pups' lungs were harvested for morphometric analysis; cytokine, arginase 1, and VEGF values were quantified. Serum arginine, citrulline, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine, NG-monomethyl arginine, and homoarginine levels were determined using UPLC-MS/MS. RESULTS: L-Cit attenuated the disruption of alveolar growth in the LPS + L-Cit group. Arginine, homo-arginine, and ADMA levels fell in the LPS treated groups. Arginine and ADMA rose at P7 in the L-Cit group whose members also showed higher VEGF levels with respect to the Controls. The Controls, instead, showed higher IL-10 and IL-1ß values with respect to the L-Cit group at P7. Arginase 1 was higher in the LPS groups with respect to the Controls at P7. CONCLUSIONS: L-Cit improved alveolar and vascular growth diminishing the lung inflammatory response in the newborn rats exposed to intra-amniotic LPS. The ADMA/DDAH/NO pathway appeared to counteract proinflammatory cytokine production and to sustain macrophage migration.

Fractal analysis of alveolarization in hyperoxia-induced rat models of bronchopulmonary dysplasia.

No papers are available about potentiality of fractal analysis in quantitative assessment of alveolarization in bronchopulmonary dysplasia (BPD). Thus, we here performed a comparative analysis between fractal [fractal dimension (D) and lacunarity] and stereological [mean linear intercept (Lm), total volume of alveolar air spaces, total number of alveoli, mean alveolar volume, total volume and surface area of alveolar septa, and mean alveolar septal thickness] parameters in experimental hyperoxia-induced models of BPD. At birth, rats were distributed between the following groups: 1) rats raised in ambient air for 2 wk; 2) rats exposed to 60% oxygen for 2 wk; 3) rats raised in normoxia for 6 wk; and 4) rats exposed to 60% hyperoxia for 2 wk and to room air for further 4 wk. Normoxic 6-wk rats showed increased D and decreased lacunarity with respect to normoxic 2-wk rats, together with changes in all stereological parameters except for mean alveolar volume. Hyperoxia-exposed 2-wk rats showed significant changes only in total number of alveoli, mean alveolar volume, and lacunarity with respect to equal-in-age normoxic rats. In the comparison between 6-wk rats, the hyperoxia-exposed group showed decreased D and increased lacunarity, together with changes in all stereological parameters except for septal thickness. Analysis of receiver operating characteristic curves showed a comparable discriminatory power of D, lacunarity, and total number of alveoli; Lm and mean alveolar volume were less discriminative. D and lacunarity did not show significant changes when different segmentation thresholds were applied, suggesting that the fractal approach may be fit to automatic image analysis.

Association of Rewarming Rate on Neonatal Outcomes in Extremely Low Birth Weight Infants with Hypothermia.

OBJECTIVE: To explore the possible association between rewarming rate and neonatal outcomes in extremely low birth weight infants (ELBWIs) with hypothermia. STUDY DESIGN: All ELBWIs with hypothermia (temperature < 36.0°C) on neonatal intensive care unit (NICU) admission were retrospectively evaluated. Rewarming rate was analyzed as both a dichotomous (≥ 0.5°C/h rapid group; < 0.5°C/h slow group) and a continuous variable. Multivariable analysis was performed to explore the relation between rewarming rate and several outcomes, adjusting for clinically relevant confounders. RESULTS: Hypothermia on NICU admission was present in 182 out of 744 ELBWIs (24.5%). The rewarming rate was slow in 109 subjects (59.9%) and rapid in 73 subjects (40.1%), with a median rewarming rate of 0.29°C/h (IQR 0.2-0.35) and 0.76°C/h (IQR 0.61-1.09), respectively (P < .0001). The median rewarming time was 340 minutes (IQR 250-480) and 170 minutes (IQR 110-230), respectively (P < .0001). After adjusting for clinically relevant confounders, we did not find significant associations between rewarming rate group (≥ 0.5°C/h vs < 0.5°C/h) and neonatal outcomes. When we considered the rewarming rate as continuous variable, a higher rewarming rate was identified as a protective factor for respiratory distress syndrome (OR 0.39, 95% CI 0.17-0.87; P = .02). CONCLUSIONS: In ELBWIs with hypothermia upon NICU admission, there were no significant differences between rapid or slow rewarming rate and major neonatal outcomes. A higher rewarming rate was associated with a reduced incidence of respiratory distress syndrome.

Analysis and interpretation of acylcarnitine profiles in dried blood spot and plasma of preterm and full-term newborns.

BACKGROUND: Acylcarnitines are biomarkers of fatty acid metabolism, and examining their patterns in preterm newborn may reveal metabolic changes associated with particular conditions related to prematurity. Isomeric acylcarnitines in dried blood spots (DBS) and plasma have never been assessed in preterm infants. METHODS: We studied 157 newborn divided into four groups by weeks of gestational age (GA), as follows: 22-27 wk in group 1; 28-31 wk in group 2; 32-36 wk in group 3; and 37-42 wk in group 4. Samples were collected on the third day of life. Acylcarnitines were separated and quantified using ultra-performance liquid chromatography tandem mass spectrometry. RESULTS: Acylcarnitine concentrations correlated significantly with GA and birth weight in both DBS and plasma samples. Concentrations were lower in preterm newborn, except for acylcarnitines derived from branched-chain amino acids, which were higher and correlated with enteral feeding. On day 3 of life, no correlations emerged with gender, respiratory distress syndrome, bronchopulmonary dysplasia, surfactant administration, or mechanical ventilation. CONCLUSION: We established GA-based reference ranges for isomeric acylcarnitine concentrations in preterm newborn, which could be used to assess nutritional status and the putative neuroprotective role of acylcarnitines.

L-citrulline prevents alveolar and vascular derangement in a rat model of moderate hyperoxia-induced lung injury.

BACKGROUND: Moderate normobaric hyperoxia causes alveolar and vascular lung derangement in the newborn rat. Endogenous nitric oxide (NO), which promotes lung growth, is produced from the metabolism of L-arginine to L-citrulline in endothelial cells. We investigated whether administering L-citrulline by raising the serum levels of L-arginine and enhancing NO endogenous synthesis attenuates moderate hyperoxia-induced lung injury. METHODS: Newborn rats were exposed to FiO(2) = 0.6 or room air for 14 days to induce lung derangement and then were administered L-citrulline or a vehicle (sham). Lung histopathology was studied with morphometric features. Lung tissues and bronchoalveolar lavage fluid (BALF) were collected for analysis. Lung vascular endothelial growth factor (VEGF), nitric oxide synthase (eNOS), and matrix metalloproteinase 2 (MMP2) gene and protein expressions were assessed. RESULTS: Serum L-arginine rose in the L-citr + hyperoxia group (p = 0.05), as well as the Von Willebrand factor stained vessels count (p = 0.0008). Lung VEGF immune staining, localized on endothelial cells, was weaker in the sections under hyperoxia than the L-citr + hyperoxia and room air groups. This pattern was comparable with the VEGF gene and protein expression profiles. Mean alveolar size increased in the untreated hyperoxia and sham-treated groups compared with the groups reared in room air or treated with L-citrulline under exposure to hyperoxia (p = 0.0001). Lung VEGF and eNOS increased in the L-citrulline-treated rats, though this treatment did not change MMP2 gene expression but regulated the MMP2 active protein, which rose in BALF (p = 0.003). CONCLUSIONS: We conclude that administering L: -citrulline proved effective in improving alveolar and vascular growth in a model of oxygen-induced pulmonary damage, suggesting better lung growth and matrix regulation than in untreated groups.

Present and Future of Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) is the most common respiratory disorder among infants born extremely preterm. The pathogenesis of BPD involves multiple prenatal and postnatal mechanisms affecting the development of a very immature lung. Their combined effects alter the lung's morphogenesis, disrupt capillary gas exchange in the alveoli, and lead to the pathological and clinical features of BPD. The disorder is ultimately the result of an aberrant repair response to antenatal and postnatal injuries to the developing lungs. Neonatology has made huge advances in dealing with conditions related to prematurity, but efforts to prevent and treat BPD have so far been only partially effective. Seeing that BPD appears to have a role in the early origin of chronic obstructive pulmonary disease, its prevention is pivotal also in long-term respiratory outcome of these patients. There is currently some evidence to support the use of antenatal glucocorticoids, surfactant therapy, protective noninvasive ventilation, targeted saturations, early caffeine treatment, vitamin A, and fluid restriction, but none of the existing strategies have had any significant impact in reducing the burden of BPD. New areas of research are raising novel therapeutic prospects, however. For instance, early topical (intratracheal or nebulized) steroids seem promising: they might help to limit BPD development without the side effects of systemic steroids. Evidence in favor of stem cell therapy has emerged from several preclinical trials, and from a couple of studies in humans. Mesenchymal stromal/stem cells (MSCs) have revealed a reparatory capability, preventing the progression of BPD in animal models. Administering MSC-conditioned media containing extracellular vesicles (EVs) have also demonstrated a preventive action, without the potential risks associated with unwanted engraftment or the adverse effects of administering cells. In this paper, we explore these emerging treatments and take a look at the revolutionary changes in BPD and neonatology on the horizon.

Innate immunity ascertained from blood and tracheal aspirates of preterm newborn provides new clues for assessing bronchopulmonary dysplasia.

AIM: The study aimed to establish how granulocytes, monocytes and macrophages contribute to the development of bronchopulmonary dysplasia (BPD). MATERIALS AND METHODS: Study A: samples of blood and tracheal aspirates (TAs) collected from preterm newborn infants during the first 3 days of life were investigated by flow cytometry, and testing for white blood cells (WBCs), neutrophils and neutrophil extracellular traps (NETs). Maternal blood samples were also collected. Study B: data from previously-tested samples of TAs collected from preterm newborn infants were re-analyzed in the light of the findings in the new cohort. RESULTS: Study A: 39 preterm newborn infants were studied. A moderate correlation emerged between maternal WBCs and neutrophils and those of their newborn in the first 3 days of life. WBCs and neutrophils correlated in the newborn during the first 8 days of life. Decision rules based on birth weight (BW) and gestational age (GA) can be used to predict bronchopulmonary dysplasia (BPD). Neutrophil levels were lower in the TAs from the newborn with the lowest GAs and BWs. Study B: after removing the effect of GA on BPD development, previously-tested newborn were matched by GA. Monocyte phenotype 1 (Mon1) levels were lower in the blood of newborn with BPD, associated with a higher ratio of Monocyte phenotype 3 (Mon3) to Mon1. Newborn infants from mothers with histological chorioamnionitis (HCA) had lower levels of classically-activated macrophages (M1) and higher levels of alternatively-activated macrophages (M2) in their TAs than newborn infants from healthy mothers. CONCLUSION: Immune cell behavior in preterm newborn infants was examined in detail. Surprisingly, neutrophil levels were lower in TAs from the newborn with the lowest GA and BW, and no correlation emerged between the neutrophil and NET levels in TAs and the other variables measured. Interestingly, monocyte phenotype seemed to influence the onset of BPD. The rise in the ratio of Mon 3 to Mon 1 could contribute to endothelial dysfunction in BPD.

Comparison between the perinatal risk inventory and the nursery neurobiological risk score for predicting development in high-risk newborn infants.

BACKGROUND: The availability of a score for predicting neonatal outcome prior to discharge may help us to define the risk of developmental disorders in very low birth weight infants. AIM: To compare Scheiner's Perinatal Risk Inventory (PERI) with Brazy's Neurobiological Risk Score (NBRS) when applied at discharge, in predicting developmental delay at 24 months of age. STUDY DESIGN: To evaluate the predictive power of the two tests, we measured their sensitivity and specificity in predicting outcome (Mental Development Index, MDI, Psychomotor Development Index, PDI, and Amiel-Tison Neurological Examination) in an observational study. SUBJECTS: 102 very low birth weight infants (BW <1,500 g) admitted to our NICU at the Pediatric Department of Padova University. RESULTS: In the cohort studied, 75.5% of the patients had a normal MDI, while 24.5% showed a delayed performance (8.8% mildly and 15.7% severely so); the PDI was normal in 74.5% patients, whilst 25.5% had a delayed performance (9.8% mildly and 15.7% severely so). According to the Amiel-Tison test, neurological performance was normal in 66% patients, impaired without disability in 19% and impaired with disability in 15%. NBRS showed a sensitivity and specificity respectively of 0.96 and 0.23 (MDI), 0.96 and 0.24 (PDI), 0.94 and 0.25 (Amiel-Tison test); for PERI were 0.88 and 0.54 (MDI), 0.77 and 0.51 (PDI), 0.82 and 0.57 (Amiel-Tison test). The PERI and NBRS can predict the MDI with an AUC >0.8 and the PDI or Amiel-Tison findings with an AUC of 0.7-0.8. No significant differences were found between the areas under the ROC curves using the NBRS and the PERI. CONCLUSIONS: : In assessing the prognosis for individual babies, the physician can choose either the PERI or the NBRS to predict PDI, MDI or Amiel-Tison performance.

Early versus late cord clamping: effects on peripheral blood flow and cardiac function in term infants.

BACKGROUND: In the debate on the best cord clamping time in newborn infants, we hypothesized that late cord clamping enables an increased volemia due to blood transfer to the newborn from the placenta. AIM: To assess whether clamping time can affect limb perfusion and heart hemodynamics in a group of 22 healthy term newborn infants. STUDY DESIGN: A case-control study. SUBJECTS: Eleven early-clamped (at 30 s) vaginally-delivered newborn infants were compared with eleven late-clamped (at 4 min) newborns. OUTCOME MEASURES: The two groups were studied using near-infrared spectroscopy and M-mode echocardiography. RESULTS: Late cord clamping coincided with a higher hematocrit (median 62% versus 54%) and hemoglobin concentration (median 17.2 versus 15 g/dL), whilst there were no changes in bilirubin level. Echocardiography showed a larger end-diastolic left ventricle diameter (1.7 cm median value versus 1.5) coupled with unvaried shortening and ejection fraction values. There were no changes in calf blood flow, oxygen delivery, oxygen consumption or fractional oxygen extraction calculated from the NIRS measurements, or in foot perfusion index. CONCLUSIONS: Our results demonstrated that late cord clamping coincides with an increased placental transfusion, expressed by higher hematocrit and hemoglobin values, and larger left ventricle diameter at the end of the diastole, with no changes in peripheral perfusion or oxygen metabolism.

Can tissue oxygenation index (TOI) and cotside neurophysiological variables predict outcome in depressed/asphyxiated newborn infants?

BACKGROUND: Diagnostic tools of birth asphyxia provide only an uncertain prediction of neurological outcome. AIMS: To assess whether TOI and DeltaCBV, combined with a set of biochemical and neurophysiological variables, have any diagnostic and prognostic value in birth depression or asphyxia. STUDY DESIGN: Case control study at the nursery and NICU of the Padova University Children's Hospital. SUBJECTS: 22 term neonates with an Apgar score < or = 6 at 5', a 1-h umbilical artery pH value < or = 7.25 with an increased base deficit and a gestational age > or = 36 weeks; 15 healthy term infants with an Apgar score > or = 9 at 5'. OUTCOME MEASURES: Troponin I and NIRS measurements (TOI and DeltaCBV) were assessed in both groups. Blood gases, neurological evaluation, US, NIRS, EEG and SEP were evaluated in the infants with depression or asphyxia. RESULTS: Troponin I was higher in the study group than in controls (p=0.04), showing a correlation with base excess values. In the depressed/asphyxiated neonates with an abnormal outcome at 1 year, TOI rose to 80.1% vs 66.4% in controls (p=0.04) and 74.7% in infants with a normal 1-year outcome. A multiple regression model showed a significant multiple correlation coefficient, R=0.79, p<0.001, where the predictive variables significantly associated with outcome were SEP and BE. CONCLUSIONS: Troponin I is a useful short-term index of birth asphyxia or perinatal depression. An increased TOI suggests a risk of abnormal neurological outcome at 1 year. Among the cotside variables, BE and evoked potential abnormalities were the best predictors of abnormal outcome in this study.

Does helmet CPAP reduce cerebral blood flow and volume by comparison with Infant Flow driver CPAP in preterm neonates?

OBJECTIVE: We compared neonatal helmet continuous positive airway pressure (CPAP) and the conventional nasal Infant Flow driver (IFD) CPAP in the noninvasive assessment of absolute cerebral blood flow (CBF) and relative cerebral blood volume changes (DeltaCBV) by near-infrared spectroscopy. DESIGN AND SETTING: A randomized crossover study in a tertiary referral NICU. PATIENTS AND INTERVENTIONS: Assessment of CBF and DeltaCBV in 17 very low birth weight infants with respiratory distress (median age 5 days) treated with two CPAP devices at a continuous distending pressure of 4 mbar. MEASUREMENTS AND RESULTS: Neonates were studied for two consecutive 60-min periods with helmet CPAP and with IFD CPAP. Basal chromophore traces enabled DeltaCBV changes to be calculated. CBF was calculated in milliliters per 100 grams per minute from the saturation rise integral and rate of rise O(2)Hb-HHb. Median (range) CBF with helmet CPAP was 27.37 (9.47-48.20) vs. IFD CBF 34.74 (13.59-60.10)(p=0.049) and DeltaCBV 0.15 (0.09-0.28) with IFD and 0.13 (0.07-0.27) with helmet CPAP (NS). Using helmet and IFD CPAP, the neonates showed no difference in mean physiological parameters (transcutaneous carbon dioxide and oxygen tension, pulse oximetry saturation, heart rate, breathing rate, mean arterial blood pressure, desaturation rate, axillary temperature). CONCLUSION: Assessing CBF and DeltaCBV measured by near-infrared spectroscopy with two CPAP devices revealed no differences in relative blood volume, but CBF was lower with helmet CPAP. Greater active vasoconstriction and/or passive capillary and/or venous vessel compression seem the most likely reason, due to a positive pressure around the head, neck, and shoulders by comparison with the airway pressure.

Untargeted Metabolomic Analysis of Amniotic Fluid in the Prediction of Preterm Delivery and Bronchopulmonary Dysplasia.

OBJECTIVE: Bronchopulmonary dysplasia (BPD) is a serious complication associated with preterm birth. A growing body of evidence suggests a role for prenatal factors in its pathogenesis. Metabolomics allows simultaneous characterization of low molecular weight compounds and may provide a picture of such a complex condition. The aim of this study was to evaluate whether an unbiased metabolomic analysis of amniotic fluid (AF) can be used to investigate the risk of spontaneous preterm delivery (PTD) and BPD development in the offspring. STUDY DESIGN: We conducted an exploratory study on 32 infants born from mothers who had undergone an amniocentesis between 21 and 28 gestational weeks because of spontaneous preterm labor with intact membranes. The AF samples underwent untargeted metabolomic analysis using mass spectrometry combined with ultra-performance liquid chromatography. The data obtained were analyzed using multivariate and univariate statistical data analysis tools. RESULTS: Orthogonally Constrained Projection to Latent Structures-Discriminant Analysis (oCPLS2-DA) excluded effects on data modelling of crucial clinical variables. oCPLS2-DA was able to find unique differences in select metabolites between term (n = 11) and preterm (n = 13) deliveries (negative ionization data set: R2 = 0.47, mean AUC ROC in prediction = 0.65; positive ionization data set: R2 = 0.47, mean AUC ROC in prediction = 0.70), and between PTD followed by the development of BPD (n = 10), and PTD without BPD (n = 11) (negative data set: R2 = 0.48, mean AUC ROC in prediction = 0.73; positive data set: R2 = 0.55, mean AUC ROC in prediction = 0.71). CONCLUSIONS: This study suggests that amniotic fluid metabolic profiling may be promising for identifying spontaneous preterm birth and fetuses at risk for developing BPD. These findings support the hypothesis that some prenatal metabolic dysregulations may play a key role in the pathogenesis of PTD and the development of BPD.

Neurologic outcome in children after extracorporeal membrane oxygenation: prognostic value of diagnostic tests.

This report presents the long-term (36 months) neurologic outcome in 12 neonates and 9 children who survived after extracorporeal membrane oxygenation and attempts to identify its prognostic indicators through a prospective study in the pediatric intensive care unit of a university hospital. Outcome assessment, neurodevelopmental tests, electroencephalogram, auditory evoked potentials, visual evoked potentials, and somatosensory evoked potentials, cerebral sonography, or cerebral tomography were evaluated at the end of bypass and at 6, 12, 24, and 36 months after extracorporeal membrane oxygenation. "Before extracorporeal membrane oxygenation" variables (oxygenation index, pH, oxygen arterial partial pressure) and "during extracorporeal membrane oxygenation" variables (pH, oxygen arterial partial pressure, duration of bypass, clotting activated time, electroencephalogram) were also analyzed. A negative neurologic outcome (Glasgow Outcome Score different from "good recovery" or neurodevelopmental score less than 70) 12 months after extracorporeal membrane oxygenation was documented in 8.3% of neonates and in 30% of children who survived. There was no further change in subsequent evaluations (24 and 36 months follow-up). The most abnormal electroencephalogram during extracorporeal membrane oxygenation, the first electroencephalogram, neuroimaging score, and somatosensory evoked potentials after extracorporeal membrane oxygenation treatment were associated with negative neurologic outcome. The study documented that neonates and children treated with extracorporeal membrane oxygenation require long-term follow-up; electroencephalogram, neuroimaging score, and somatosensory evoked potentials have prognostic value for abnormal neurologic outcome.

Foot pulse oximeter perfusion index correlates with calf muscle perfusion measured by near-infrared spectroscopy in healthy neonates.

OBJECTIVE: In critically ill neonates, peripheral perfusion and oxygenation assessment may provide indirect information on the circulatory failure of vital organs during circulatory shock. The development of pulse oximetry has recently made it possible to calculate the perfusion index (PI), obtained from the ratio between the pulsatile and nonpulsatile signals of absorbed light. The main goals of this study were: (1) to study foot PI; and (2) to evaluate the relationship between foot PI, obtained continuously by pulse oximetry, and a number of variables, i.e. blood flow (BF), oxygen delivery (DO(2)), oxygen consumption (VO(2)), and fractional oxygen extraction (FOE), measured indirectly by near-infrared spectroscopy (NIRS) on the calf in 43 healthy term neonates (weight 3474.6 +/- 466.9 g; gestational age 39.1 +/- 1.4 weeks). STUDY DESIGN: Calf BF, DO(2) and VO(2) were assessed by NIRS on short-lived venous and arterial occlusion maneuvers. PI was measured on the contralateral foot. RESULTS: Foot PI was 1.26 +/- 0.39. There was a positive correlation between foot PI and both calf BF (r = 0.32, p = 0.03) and DO(2) (r = 0.32, p = 0.03), but no correlation was found between foot PI and calf FOE and between foot PI and VO(2). CONCLUSIONS: In the neonatal intensive care unit, continuously measuring foot PI by pulse oximetry seems clinically more feasible for peripheral perfusion monitoring than spot measurements of the calf BF and/or VO(2) by indirect NIRS.

Exstrophy-Epispadias Complex in a Newborn: Case Report and Review of the Literature.

Aim The aim of this report is to present a brief review of the current literature on the management of EEC. Case Report A term male neonate presented at birth with classic bladder exstrophy, a variant of the exstrophy-epispadias complex (EEC). The defect was covered with sterile silicon gauzes and waterproof dressing; at 72 hours of life, primary closure without osteotomy of bladder, pelvis, and abdominal wall was successfully performed. Discussion EEC incidence is approximately 2.15 per 1,00,000 live births; several urological, musculocutaneous, spinal, orthopedic, gastrointestinal, and gynecological anomalies may be associated to EEC. Initial medical management includes use of occlusive dressings to prevent air contact and dehydration of the open bladder template. Umbilical catheters should not be positioned. Surgical repair stages include initial closure of the bladder and abdominal wall with or without osteotomy, followed by epispadias repair at 6 to 12 months, and bladder neck repair around 5 years of life. Those who fail to attain continence eventually undergo bladder augmentation and placement of a catheterizable conduit. Conclusion Modern-staged repair of EEC guarantees socially acceptable urinary continence in up to 80% of cases; sexual function can be an issue in the long term, but overall quality of life can be good.