Elodie Zana-Taïeb

Premedication for neonatal endotracheal intubation: results from the epidemiology of procedural pain in neonates study.

Objectives: To describe the frequency and nature of premedications used prior to neonatal endotracheal intubation; to confront observed practice with current recommendations; and to identify risk factors for the absence of premedication. Design, Setting, and Patients: Data concerning intubations were collected prospectively at the bedside as part of an observational study collecting around-the-clock data on all painful or stressful procedures performed in neonates during the first 14 days of their admission to 13 tertiary care units in the region of Paris, France, between 2005 and 2006. Intervention: Observational study. Measurements and Main Results: Specific premedication prior to endotracheal intubation was assessed. Ninety one intubations carried out on the same number of patients were analyzed. The specific premedicationrate was 56% and included mostly opioids (67%) and midazolam (53%). Compared with recent guidance from the American Academy of Pediatrics, used premedications could be classified as “preferred” (12%), “acceptable” (18%), “not recommended” (27%), and “not described” (43%). In univariate analysis, infants without a specific premedication compared with others were younger at the time of intubation (median age: 0.7 vs. 2.0 days), displayed significantly more frequent spontaneous breathing at the time of intubation (31% vs. 12%) and a higher percentage of analgesia for all other painful procedures (median values: 16% vs. 6%). In multivariate analysis, no factor remained statistically significant. Conclusions: Premedication use prior to neonatal intubation was not systematically used and when used it was most frequently inconsistent with recent recommendations. No patient- or center-related independent risk factor for the absence of premedication was identified in this study.

Impact of Common Treatments Given in the Perinatal Period on the Developing Brain

Background: Over the last decades, considerable progress has been made in the perinatal management of high-risk preterm neonates, changing the landscape of pathological conditions associated with neurological impairments. Major focal destructive lesions are now less common, and the predominant neuropathological lesion is diffuse white-matter damage in the most immature infants. Similarly, over the last few years, we have observed a trend towards a decrease in neurological impairment in the absence of treatments specifically aimed at neuroprotection. Objectives: We examined whether recent changes in treatment strategies in perinatal care during the perinatal period could have had an indirect beneficial impact on the occurrence of brain lesions and their consequences. Methods: Thus, we reviewed the effects of the most common treatments administered during the perinatal period to the mother or to very preterm infants on brain damage and neurocognitive follow-up. Results: Antenatal steroids and exogenous surfactant are the two main treatments capable of leading to neuroprotection in very preterm infants. Randomized controlled trials are currently investigating the effects of inhaled nitric oxide and erythropoietin, while antenatal magnesium sulphate and caffeine are also likely to provide some neuroprotection, but this needs to be further investigated. Finally, other common treatments against pain, haemodynamic failure and patent ductus arteriosus have conflicting or no effects on the developing brain. Conclusion: While specific neuroprotective drugs are still awaited, recent advances in perinatal care have been associated with an unexpected but significant decrease in the incidence of both severe brain lesions and neurological impairment.

Biological Impact of Recent Guidelines on Parenteral Nutrition in Preterm Infants.

Objectives: Recent guidelines for preterm neonates recommend early initiation of parenteral nutrition (PN) with high protein and relatively high caloric intake. This review considers whether these changes could influence homeostasis in very preterm infants during the first few postnatal weeks. Methods: This systematic review of relevant literature from searches of PubMed and recent guidelines was reviewed by investigators from several perinatal centers in France. Results: New recommendations for PN could be associated with metabolic acidosis via the increase in the amino acid ion gap, hyperchloremic acidosis, and ammonia acidosis. The introduction of high-intake amino acids soon after birth could induce hypophosphatemia and hypercalcemia, simulating a “repeat feeding–like syndrome” and could be prevented by the early intake of phosphorus, especially in preterm infants born after fetal growth restriction. Early high-dose amino acid infusions are relatively well tolerated in the preterm infant with regard to renal function. Additional studies, however, are warranted to determine markers of protein intolerance and to specify the optimal composition and amount of amino acid solutions. Conclusions: Optimal PN following new guidelines in very preterm infants, despite their demonstrated benefits on growth, may induce adverse effects on ionic homeostasis. Clinicians should implement appropriate monitoring to prevent and/or correct them.

Transcriptomic regulations in oligodendroglial and microglial cells related to brain damage following fetal growth restriction

Fetal growth restriction (FGR) is a major complication of human pregnancy, frequently resulting from placental vascular diseases and prenatal malnutrition, and is associated with adverse neurocognitive outcomes throughout life. However, the mechanisms linking poor fetal growth and neurocognitive impairment are unclear. Here, we aimed to correlate changes in gene expression induced by FGR in rats and abnormal cerebral white matter maturation, brain microstructure, and cortical connectivity in vivo. We investigated a model of FGR induced by low‐protein‐diet malnutrition between embryonic day 0 and birth using an interdisciplinary approach combining advanced brain imaging, in vivo connectivity, microarray analysis of sorted oligodendroglial and microglial cells and histology. We show that myelination and brain function are both significantly altered in our model of FGR. These alterations, detected first in the white matter on magnetic resonance imaging significantly reduced cortical connectivity as assessed by ultrafast ultrasound imaging. Fetal growth retardation was found associated with white matter dysmaturation as shown by the immunohistochemical profiles and microarrays analyses. Strikingly, transcriptomic and gene network analyses reveal not only a myelination deficit in growth‐restricted pups, but also the extensive deregulation of genes controlling neuroinflammation and the cell cycle in both oligodendrocytes and microglia. Our findings shed new light on the cellular and gene regulatory mechanisms mediating brain structural and functional defects in malnutrition‐induced FGR, and suggest, for the first time, a neuroinflammatory basis for the poor neurocognitive outcome observed in growth‐restricted human infants. GLIA 2016;64:2306–2320

Effect of Two Models of Intrauterine Growth Restriction on Alveolarization in Rat Lungs: Morphometric and Gene Expression Analysis

Intrauterine growth restriction (IUGR) in preterm infants increases the risk of bronchopulmonary dysplasia, characterized by arrested alveolarization. We evaluated the impact of two different rat models (nitric oxide synthase inhibition or protein deprivation) of IUGR on alveolarization, before, during, and at the end of this postnatal process. We studied IUGR rat pups of dams fed either a low protein (LPD) or a normal diet throughout gestation and pups of dams treated by continuous infusion of Nω-nitro-L-arginine methyl ester (L-NAME) or its diluent on the last four days of gestation. Morphometric parameters, alveolar surface (Svap), mean linear intercept (MLI) and radial alveolar count (RAC) and transcriptomic analysis were determined with special focus on genes involved in alveolarization. IUGR pups regained normal weight at day 21 in the two treated groups. In the LPD group, Svap, MLI and RAC were not different from those of controls at day 4, but were significantly decreased at day 21, indicating alveolarization arrest. In the L-NAME group, Svap and RAC were significantly decreased and MLI was increased at day 4 with complete correction at day 21. In the L-NAME model, several factors involved in alveolarization, VEGF, VEGF-R1 and –R2, MMP14, MMP16, FGFR3 and 4, FGF18 and 7, were significantly decreased at day 4 and/or day 10, while the various factors studied were not modified in the LPD group. These results demonstrate that only maternal protein deprivation leads to sustained impairment of alveolarization in rat pups, whereas L-NAME impairs lung development before alveolarization. Known growth factors involved in lung development do not seem to be involved in LPD-induced alveolarization disorders, raising the question of a possible programming of altered alveolarization.

Clinical Utility and Safety of a Model-Based Patient-Tailored Dose of Vancomycin in Neonates

ABSTRACT Pharmacokinetic modeling has often been applied to evaluate vancomycin pharmacokinetics in neonates. However, clinical application of the model-based personalized vancomycin therapy is still limited. The objective of the present study was to evaluate the clinical utility and safety of a model-based patient-tailored dose of vancomycin in neonates. A model-based vancomycin dosing calculator, developed from a population pharmacokinetic study, has been integrated into the routine clinical care in 3 neonatal intensive care units (Robert Debré, Cochin Port Royal, and Clocheville hospitals) between 2012 and 2014. The target attainment rate, defined as the percentage of patients with a first therapeutic drug monitoring serum vancomycin concentration achieving the target window of 15 to 25 mg/liter, was selected as an endpoint for evaluating the clinical utility. The safety evaluation was focused on nephrotoxicity. The clinical application of the model-based patient-tailored dose of vancomycin has been demonstrated in 190 neonates. The mean (standard deviation) gestational and postnatal ages of the study population were 31.1 (4.9) weeks and 16.7 (21.7) days, respectively. The target attainment rate increased from 41% to 72% without any case of vancomycin-related nephrotoxicity. This proof-of-concept study provides evidence for integrating model-based antimicrobial therapy in neonatal routine care.

Lung microRNA deregulation associated with impaired alveolarization in rats after intrauterine growth restriction

Intrauterine growth restriction (IUGR) was recently described as an independent risk factor of bronchopulmonary dysplasia, the main respiratory sequelae of preterm birth. We previously showed impaired alveolarization in rat pups born with IUGR induced by a low-protein diet (LPD) during gestation. We conducted a genome-wide analysis of gene expression and found the involvement of several pathways such as cell adhesion. Here, we describe our unbiased microRNA (miRNA) profiling by microarray assay and validation by qPCR at postnatal days 10 and 21 (P10 and P21) in lungs of rat pups with LPD-induced lung-alveolarization disorder after IUGR. We identified 13 miRNAs with more than two-fold differential expression between control lungs and LPD-induced IUGR lungs. Validated and predicted target genes of these miRNAs were related to “tissue repair” at P10 and “cellular communication regulation” at P21. We predicted the deregulation of several genes associated with these pathways. Especially, E2F3, a transcription factor involved in cell cycle control, was expressed in developing alveoli, and its mRNA and protein levels were significantly increased at P21 after IUGR. Hence, IUGR affects the expression of selected miRNAs during lung alveolarization. These results provide a basis for deciphering the mechanistic contributions of IUGR to impaired alveolarization.