LISA/MIST: Complex clinical problems almost never have easy solutions

Over the last 10 years, new techniques to administer surfactant have been promoted, based on their presumed lesser invasiveness and they have been generally called LISA (less invasive surfactant administration). We believe that the clinical potential of LISA techniques is currently overestimated. LISA lacks biological and pathophysiological background justifying its potential benefits. Moreover, LISA has been investigated in clinical trials without previous translational data and these trials are affected by significant flaws. The available data from these trials only allow to conclude that LISA is better than prolonged, unrestricted invasive ventilation with loosely described parameters, a mode of respiratory support that should be anyway avoided in preterm infants. We urge the conduction of high-quality studies to understand how to choose and titrate analgesia/sedation and optimize surfactant administration in preterm neonates. We offer a comprehensive, evidence-based review of the clinical data on LISA, their biases and the lack of physiopathology background

Effect of cooling on lung secretory phospholipase A2 activity in vitro, ex vivo, and in vivo

Hypothermia can modify surfactant composition and function. Secretory phospholipase A2 (sPLA2) hydrolyses surfactant phospholipids and is important in the pathobiology of several critical respiratory disorders. We hypothesize that sPLA2 activity might be influenced by the temperature partially explaining surfactant changes. This study aims to evaluate comprehensively the effect of hypothermia on sPLA2 activity. We measured sPLA2 activity at different temperatures, alone or combined with bile acids, in vitro (incubating human recombinant sPLA2-IIA and porcine sPLA2-IB), ex vivo (by cooling bronchoalveolar lavage samples from neonates with respiratory distress syndrome or no lung disease), and in vivo (using lavage samples obtained before and after 72 h of whole body cooling in neonates with hypoxic-ischemic encephalopathy). We also measured concentrations of various sPLA2 subtypes and natural sPLA2 inhibitors in in vivo cooled samples. Results were corrected for protein content and dilution. In vitro cooling did not show any effect of hypothermia on sPLA2. Ex vivo cooling did not alter total sPLA2 activity, and the addition of bile acids increased sPLA2 activity irrespective of the temperature and the type of sampled patient. In vivo hypothermia reduced median sPLA2 activity from 16.6 [15.2–106.7] IU/mg to 3.3 [2.7–8.5] IU/mg (P = 0.026) and mean sPLA2-IIA from 1.1 (0.8) pg/μg to 0.6 (0.4) pg/μg (P = 0.047), whereas dioleylphosphatidylglycerol increased from 8.3 (3.9)% to 12.8 (5.1)% (P = 0.02). Whole body hypothermia decreases in vivo global sPLA2 activity in bronchoalveolar lavage fluids through the reduction of sPLA2-IIA and increment of dioleylphosphatidylglycerol. This effect is absent during in vitro or ex vivo hypothermia

Natural evolution of patent ductus arteriosus in the extremely preterm infant

International audienceObjective The persistence of the patent ductus arteriosus (PDA) is frequently encountered in very preterm infants. Neither preventive nor curative treatments of PDA have been shown to improve the outcome of these infants. Since no consensus on optimal treatment of PDA is established, we evaluated the rate of spontaneous PDA closure in infants born before 28 weeks of gestation.Patients and methods We studied a retrospective cohort of 103 infants (gestational age 24-27 weeks) admitted to our neonatal intensive care unit from 1 June 2008 to 31 July 2010. Maternal and neonatal characteristics were collected. The PDA was defined by the persistence of ductal patency after 72 h and was followed up by regular echocardiography.Results Twelve infants died within the first 72 h and were excluded from the analysis. Among 91 infants analysed, 8 (9%) closed their ductus arteriosus before 72 h and the ductus could not be determined patent in 13. Of the 70 infants with a PDA still persistent, one underwent surgical ligation and echocardiography showed spontaneous closure in 51 (73%) of them. In the remaining 18 infants, the date of PDA closure could not be determined either because of their death (n=11) or due to discharge (n=7). Overall, a spontaneous closure of the ductus arteriosus was observed in 59 of the 91 infants.Conclusions We have to question whether exposure to the risks of therapeutic interventions targeted for ductal closure is warranted since a PDA closes spontaneously in at least 73% of infants born before 28 wee

Breast milk in neonate oral care: oropharyngeal effects in extremely preterm infants

International audienceVentilator-associated pneumonia (VAP) is a frequent nosocomial infection in neonatal intensive care units (NICU). Extremely preterm infants are at highest risk of developing VAP. Several studies indicate that oral care included in a preventive protocol effectively reduces neonatal VAP incidence. We investigated the effects of oral care with breast milk on oral immune defenses and microbiota in extremely preterm infants. Thirty infants born ≤ 30 weeks gestation hospitalized at our NICU were selected and divided into three groups: oral care with breast milk, formula, or sterile water. Effects on oral immune defenses in vivo were studied using ELISA to measure lactoferrin (LF) and secretory immunoglobulin A (sIgA) in pharyngeal aspirates before and after oral care. Different LF concentrations were tested in vitro to assess their effects on loads of selected bacterial species by culture. Effects on selected bacteria potentially responsible for VAP in vivo were studied by real-time PCR detection in pharyngeal aspirates before and after oral care. Oral care with breast milk significantly increases LF concentrations to 69.8 × 103 ng/ml (p = 0.012) and sIgA to 36.8 × 103 ng/ml (p = 0.017) in vivo. These LF concentrations considerably reduce loads of E. coli, S. epidermidis, S. aureus, and P. aeruginosa, in vitro. However, contrary to our expectation, no effect on colonization of bacteria most commonly responsible for VAP was found in vivo.Conclusion: In extremely preterm infants, oral care with breast milk increases local immune defense markers (LF, sIgA), which combat bacterial infections. Further clinical trials should be conducted to evaluate their effects on VAP prevention in neonates.What is known: • The population at higher risk to develop VAP are preterm infants. • Several studies indicate oral care within a preventive bundle is effective in reducing neonatal VAP incidence.What is new: • In extremely premature infants, oral care with breast milk causes a significant increase in local immune defences in terms of lactoferrin (LF) and secretory immunoglobulin A (sIgA). • LF concentrations obtained after oral care with breast milk decreased loads of bacteria most commonly responsible for VAP in premature infants under experimental in-vitro

Lung Ultrasound Score Predicts Surfactant Need in Extremely Preterm Neonates

There are several lung ultrasound scores (LUS) for evaluating lung aeration in critically ill adults with restrictive lung disorders. A modified LUS adapted for neonates correlates well with oxygenation and is able to be used to predict the need for surfactant in preterm neonates with respiratory distress syndrome (RDS). However, no data are available for extremely preterm neonates for whom timely surfactant administration is especially important. We hypothesized that LUS might be reliable in extremely preterm neonates with RDS who are treated with continuous positive airway pressure. We aimed to determine the diagnostic accuracy of LUS in predicting the need for surfactant treatment and re-treatment in this population

Surfactant injury in the early phase of Severe Meconium Aspiration Syndrome

Rationale. No in vivo data are available about the effect of meconium on human surfactant in the early stages of severe meconium aspiration syndrome (MAS). Objectives. To characterize the changes in surfactant composition, function and structure during the early phase of meconium injury. Methods. We designed a translational, prospective, cohort study on nonbronchoscopic bronchoalveolar lavages of neonates with severe MAS (n=14) or no lung disease (n=18). Surfactant lipids have been analysed by liquid chromatography-high resolution mass spectrometry. Secretory phospholipases A2 subtype-IB,-V and -X and surfactant protein-A were assayed by ELISA. Surfactant protein-B and -C were analysed by Western Blot both under non-reducing and reducing conditions. Surfactant function was assessed by adsorption test and captive bubble surfactometry, while lung aeration was evaluated by semi-quantitative lung ultrasound. Surfactant nanostructure was studied with cryo-electron and atomic force microscopy. Main Results. Several changes in phospholipid subclasses were detected during MAS. Lysophosphatidylcholine species released by the sPLA2 hydrolysis were increased. Protein-B and -C were significantly increased together with some shorter immature forms of proteinB. Surfactant function was impaired and correlated with poor lung aeration. Surfactant nanostructure was significantly damaged in terms of vesicles size, tridimensional complexity and compactness. Conclusions. Various alterations of surfactant phospholipids and proteins were detected in the early phase of severe meconium aspiration, due to hydrolysis and inflammation and as a defensive response. This impairs both surfactant structure and function, finally resulting in a reduced lung aeration. These findings support the development of new surfactant protection and anti-inflammatory strategies for severe MAS

Small for Gestational Age Preterm Neonates Exhibit Defective GH/IGF1 Signaling Pathway

International audienceTo investigate the impact of fetal growth restriction (FGR) on hormonal regulation of post-natal growth and glucose metabolism [via insulin and growth hormone (GH)/Insulin-like Growth factor 1 (IGF1) axis pathways] in small for gestational age (SGA) neonates. We conducted a monocentric observational prospective comparative study on 73 singleton babies born with a weight inferior to 2,000 g. We analyzed auxological (weight, height and head circumference), and hormonal (GH, IGF1, and insulin plasma concentrations) data comparing SGA and appropriate for gestational age (AGA) neonates, between day 1 and 60.One third (23/73) of the neonates were SGA. Twenty-five percent (18/73) required insulin for idiopathic hyperglycemia of prematurity and were smaller in weight and head circumference at discharge. In the SGA group compared with the AGA group, GH plasma concentrations were higher at day 3 (70.1 vs. 38.0 mIU/L) and IGF1 plasma concentrations were higher at day 10 (29.0 vs. 18.7 ng/ml). SGA neonates displayed resistance to GH and IGF1, concomitant to insulin resistance. This could partially explain the initial defective catch-up growth and, later in life, the higher prevalence of metabolic syndrome in this population