Estimation of Early Life Endogenous Surfactant Pool and CPAP Failure In
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Raschetti et al. Respiratory Research (2019) 20:75 https://doi.org/10.1186/s12931-019-1040-z RESEARCH Open Access Estimation of early life endogenous surfactant pool and CPAP failure in preterm neonates with RDS Roberto Raschetti1†, Roberta Centorrino1†, Emmanuelle Letamendia1,2,3, Alexandra Benachi2, Anne Marfaing-Koka3 and Daniele De Luca1,4* Abstract Background: It is not known if the endogenous surfactant pool available early in life is associated with the RDS clinical course in preterm neonates treated with CPAP. We aim to clarify the clinical factors affecting surfactant pool in preterm neonates and study its association with CPAP failure. Methods: Prospective, pragmatic, blind, cohort study. Gastric aspirates were obtained (within the first 6 h of life and before the first feeding) from 125 preterm neonates with RDS. Surfactant pool was measured by postnatal automated lamellar body count based on impedancemetry, without any pre-analytical treatment. A formal respiratory care protocol based on European guidelines was applied. Clinical data and perinatal risk factors influencing RDS severity or lamellar body count were real-time recorded. Investigators performing lamellar body count were blind to the clinical data and LBC was not used in clinical practice. Results: Multivariate analysis showed gestational age to be the only factor significantly associated with lamellar body count (standardized β:0.233;p = 0.023). Lamellar body count was significantly higher in neonates with CPAP success (43.500 [23.750–93.750]bodies/μL), than in those failing CPAP (20.500 [12.250–49.750] bodies/μL;p = 0.0003). LBC had a moderate reliability to detect CPAP failure (AUC: 0.703 (0.615–0.781);p < 0.0001; best cut-off: ≤30,000 bodies/μL). Upon adjustment for possible confounders, neither lamellar body count, nor its interaction factor with gestational age resulted associated with CPAP failure. Conclusions: Early postnatal lamellar body count on gastric aspirates in CPAP-treated preterm neonates with RDS is significantly influenced only by gestational age. Lamellar bodies are not associated with CPAP failure. Thus, the endogenous surfactant pool available early in life only has a moderate reliability to predict CPAP failure. Keywords: Lamellar bodies, Preterm neonate, Respiratory distress syndrome, Continuous positive airway pressure Background is recommended when CPAP fails [3, 4] and, if per- Antenatal corticosteroid prophylaxis and early applica- formed within the first 3 h of life, reduces death and/or tion of continuous positive airway pressure (CPAP) are bronchopulmonary dysplasia [5]. Surfactant is com- considered the gold standard for, respectively, the pre- monly administered based on inspired oxygen fraction vention and treatment of respiratory distress syndrome (FiO2)[3], however, the suggested FiO2 thresholds are (RDS) in preterm neonates [1, 2]. Surfactant replacement arbitrary, they can be reached beyond the optimal 3 h-time window and they lack of any physiopathological background. Moreover, contemporaneous measurement * Correspondence: [email protected] † Roberto Raschetti and Roberta Centorrino have contributed equally and of oxygen saturation or PaO2 might be needed to accur- both are to be considered as first authors ately describe oxygenation. The CPAP level may also in- 1 “ ” Division of Pediatrics and Neonatal Critical Care, Medical Center A.Béclère , fluence oxygenation, through its effect on the lung South Paris University Hospitals, AP-HP, Paris, France 4Physiopathology and Therapeutic Innovation Unit-UNSERM U999, South aeration. In fact, both recent pediatric and neonatal Paris-Saclay University, Paris, France Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Raschetti et al. Respiratory Research (2019) 20:75 Page 2 of 8 acute respiratory distress syndrome (ARDS) definitions presence of meconium-stained amniotic fluid and airway include these variables in appropriate indexes [6, 7]. secretions, occurrence of respiratory failure early from The available endogenous surfactant also influences birth and typical lung imaging; [21] 7) blood aspiration lung aeration and, therefore, assessing the surfactant syndrome, defined as respiratory distress and blood- pool available early in life could be interesting to better stained amniotic fluid and airway secretions, onset of re- understand the clinical picture and eventually guide sur- spiratory failure early from birth and typical lung factant replacement. Lamellar bodies are intracellular, imaging; [22] 8) pulmonary haemorrhage, defined as re- easily measurable, surfactant storage granules released spiratory distress suddenly occurring together with from type II-pneumocytes [8, 9]. Once in the alveolar bright blood-stained airway secretions, presence of space, lamellar bodies are subjected to the breathing left-to-right ductal shunting and typical lung imaging; cycle and form the surfactant layer adsorbed at the gas/ [23] 9) any kind of neonatal ARDS, defined according to liquid interface [9, 10]. Thus, lamellar body count (LBC) criteria described earlier [6]. is an estimation of the available endogenous surfactant. All pregnancies received full prenatal care: gestational LBC correlates with lung aeration evaluated by a age was estimated based on the postmenstrual date and semi-quantitative lung ultrasound score [11, 12]. LBC early gestation ultrasound findings; antenatal betametha- can be realized on amniotic fluid and is used as prenatal sone was administered as two 12-mg doses 24 h apart, lung maturity test, as it has a good reliability to predict whenever delivery was expected to occur before 34 the RDS occurrence [13, 14], but is also doable postna- weeks. Steroid prophylaxis was considered complete tally (at the delivery or using gastric aspirates obtained when the second dose was given at least 24 h before the before the first feeding) [15–17]. delivery. Small for gestational age (SGA) babies were Despite this physiopathological background, the link classified according to Fenton’s curves [24]. Chorioam- between the available surfactant pool and the CPAP fail- nionitis and obstetric cholestasis were clinically defined ure has never been investigated. Our purposes are: 1) to as described elsewhere [25, 26]. Gestational diabetes and clarify what are the clinical factors affecting early post- pre-eclampsia were diagnosed as per current inter- natal LBC in CPAP-treated preterm neonates with RDS; national guidelines [27, 28]. and 2) to investigate reliability of postnatal LBC and its association to CPAP failure. Respiratory protocol We use a formal respiratory care protocol derived from Methods European guidelines for RDS management [3]. Delivery Patients room intubation was performed only on persistently We designed a pragmatic, observational, blind, prospect- apnoeic or bradycardic babies, unresponsive to ive cohort study. The study was conducted during face-mask ventilation, according to international guide- 2014–2015 in an academic tertiary referral neonatal lines on neonatal resuscitation [29]. Neonates are started intensive care unit (NICU). All inborn preterm neonates with variable or continuous flow-CPAP if they were ≤ (< 37 weeks’ gestation) with RDS treated with nasal or > 32 weeks’ gestation, respectively. This choice aims to CPAP were eligible for the study. In detail, RDS was di- reduce the work of breathing as much as possible in the agnosed when the following criteria [6] were met: 1) smallest preterm neonates [30]. Appropriately sized occurrence of respiratory distress within the first 24 h of nasal masks were used and particular care was applied life; 2) presence of typical lung ultrasound or chest to minimize CPAP interruptions. CPAP was set at 6 X-rays findings; [18, 19] 3) complete, sustained and cmH2O and oxygen was added only if CPAP was not prompt oxygenation improvement after surfactant re- enough to maintain peripheral oxygen saturation within placement or significant improvement under CPAP 90 and 95% [31]. Pacifiers of adequate size with drops of which prevented surfactant administration; 4) no other 30% glucose solution were used to reduce leaks and respiratory disorders, as detailed below. provide sedation, if needed [31]. CPAP was started in Exclusion criteria were: 1) chromosomal abnormalities the delivery room just after stabilization or upon NICU or complex congenital malformations; 2) congenital lung admission for babies with gestational age ≤ or > 32 weeks, diseases; 3) need for surgery in the first week of life; respectively [12]. 4) early onset severe sepsis/septic shock, as defined CPAP failure was defined as need for surfactant elsewhere; [20] 5) transient tachypnea of the neonate, replacement to treat RDS in the first 48 h of life. Surfac- defined as mild (Silverman score ≤ 3) respiratory distress tant was administered as poractant-α (Chiesi Farmaceu- occurring in a neonate of more than 34 weeks’ gestation