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.
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Background
Antenatal corticosteroid prophylaxis and early application of continuous positive airway pressure (CPAP) are considered the gold standard for, respectively, the prevention and treatment of respiratory distress syndrome (RDS) in preterm neonates [1, 2]. Surfactant replacement is recommended when CPAP fails [3, 4] and, if performed within the first 3 h of life, reduces death and/or bronchopulmonary dysplasia [5]. Surfactant is commonly administered based on inspired oxygen fraction (FiO2) [3], however, the suggested FiO2 thresholds are arbitrary, they can be reached beyond the optimal 3 h-time window and they lack of any physiopathological background. Moreover, contemporaneous measurement of oxygen saturation or PaO2 might be needed to accurately describe oxygenation. The CPAP level may also influence oxygenation, through its effect on the lung aeration. In fact, both recent pediatric and neonatal acute respiratory distress syndrome (ARDS) definitions include these variables in appropriate indexes [6, 7].
The available endogenous surfactant also influences lung aeration and, therefore, assessing the surfactant pool available early in life could be interesting to better understand the clinical picture and eventually guide surfactant replacement. Lamellar bodies are intracellular, easily measurable, surfactant storage granules released from type II-pneumocytes [8, 9]. Once in the alveolar space, lamellar bodies are subjected to the breathing cycle and form the surfactant layer adsorbed at the gas/liquid interface [9, 10]. Thus, lamellar body count (LBC) is an estimation of the available endogenous surfactant. LBC correlates with lung aeration evaluated by a semi-quantitative lung ultrasound score [11, 12]. LBC can be realized on amniotic fluid and is used as prenatal lung maturity test, as it has a good reliability to predict the RDS occurrence [13, 14], but is also doable postnatally (at the delivery or using gastric aspirates obtained before the first feeding) [15,16,17].
Despite this physiopathological background, the link between the available surfactant pool and the CPAP failure has never been investigated. Our purposes are: 1) to clarify what are the clinical factors affecting early postnatal LBC in CPAP-treated preterm neonates with RDS; and 2) to investigate reliability of postnatal LBC and its association to CPAP failure.
Methods
Patients
We designed a pragmatic, observational, blind, prospective cohort study. The study was conducted during 2014–2015 in an academic tertiary referral neonatal intensive care unit (NICU). All inborn preterm neonates (< 37 weeks’ gestation) with RDS treated with nasal CPAP were eligible for the study. In detail, RDS was diagnosed when the following criteria [6] were met: 1) occurrence of respiratory distress within the first 24 h of life; 2) presence of typical lung ultrasound or chest X-rays findings; [18, 19] 3) complete, sustained and prompt oxygenation improvement after surfactant replacement or significant improvement under CPAP which prevented surfactant administration; 4) no other respiratory disorders, as detailed below.
Exclusion criteria were: 1) chromosomal abnormalities or complex congenital malformations; 2) congenital lung diseases; 3) need for surgery in the first week of life;
4) early onset severe sepsis/septic shock, as defined elsewhere; [20] 5) transient tachypnea of the neonate, defined as mild (Silverman score ≤ 3) respiratory distress occurring in a neonate of more than 34 weeks’ gestation presenting with typical lung ultrasound or chest X-rays findings and resolving within the first 72 h of life; [6, 18, 19] 6) meconium aspiration syndrome, defined as the presence of meconium-stained amniotic fluid and airway secretions, occurrence of respiratory failure early from birth and typical lung imaging; [21] 7) blood aspiration syndrome, defined as respiratory distress and blood-stained amniotic fluid and airway secretions, onset of respiratory failure early from birth and typical lung imaging; [22] 8) pulmonary haemorrhage, defined as respiratory distress suddenly occurring together with bright blood-stained airway secretions, presence of left-to-right ductal shunting and typical lung imaging; [40]. Thus, we used a quick assay to estimate surfactant pool, in a homogeneous population of preterm babies with RDS without any other respiratory disorders and subjected to good perinatal care and a formal, modern, respiratory care protocol. This is representative of the usual neonatal care in developed countries. We cannot evaluate the effect of maternal diabetes or hypothyroidism, as few or no cases presented with these disorders. Nonetheless, we have been able to evaluate all other major clinical factors influencing endogenous surfactant pool and clinical picture of RDS in preterm neonates. It would have been interesting to deeply study the reliability of LBC in different classes of gestational age and, particularly, in extremely preterm neonates who are more likely to need a “guided” surfactant therapy. However, we did not have a large enough population and a preliminary subgroup analysis did not seem to show any difference. This analysis could have been biased and may need to be repeated in larger populations. However, the availability of more accurate tools (such as semiquantitative lung ultrasound and the surfactant adsorption or microbubble tests) reduces the interest in this regard [11, 12, 38, 41]. Finally, ours is a relatively small population but comparable to those of other studies in the field [14].
Conclusion
Early life LBC on gastric aspirates in CPAP-treated preterm neonates with RDS is significantly influenced by gestational age. LBC is not associated with CPAP failure. Thus, the endogenous surfactant pool available early in life only has a moderate reliability to predict CPAP failure. Further studies are needed to better clarify the biological factors associated to CPAP failure in similar populations.
Abbreviations
- aRR:
-
Adjusted relative risks
- AUC:
-
Area under the curve
- CPAP:
-
Continuous positive airway pressure
- FiO2 :
-
Inspired oxygen fraction
- LBC:
-
Lamellar body count
- NICU:
-
Neonatal intensive care unit
- RDS:
-
Respiratory distress syndrome
- ROC:
-
Receiver operating characteristic
- SGA:
-
Small for gestational age
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The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
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RR and RC, prepared the databases and collected all the data, coordinated the sample transfer, drafted the initial manuscript, they contributed equally to and reviewed and revised the manuscript. EL, AB and AMK designed the data and sample collection procedures, analysed samples and reviewed and revised the manuscript. DDL conceptualized and designed the study, coordinated and supervised it, performed the statistical analysis, and critically reviewed the manuscript for important intellectual content. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
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This study is a part of a project on surfactant and respiratory support in neonates approved by the Ethical Committee at the South Paris University Hospital (n.CPP13–046) and consent to participation was obtained from parents or guardian upon NICU admission.
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Competing interests
DDL has received grants for research and educational projects from Chiesi Pharmaceuticals spa and ABBVIE inc. He also received travel grants from ABBVIE inc. He served as consultant and lecturer for both Chiesi Pharmaceuticals spa and ABBVIE inc. Finally, he has been the Chair of the external advisory board for Chiesi Pharmaceuticals spa and a member of the ABBVIE inc. These companies produce two surfactants, but they had no role in design, preparation, review, approval of the manuscript or decision to submit it for publication. The other authors have no conflicts of interest to disclose.
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Raschetti, R., Centorrino, R., Letamendia, E. et al. Estimation of early life endogenous surfactant pool and CPAP failure in preterm neonates with RDS. Respir Res 20, 75 (2019). https://doi.org/10.1186/s12931-019-1040-z
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DOI: https://doi.org/10.1186/s12931-019-1040-z