Prematurity Clinical Trial
Official title:
Fast Assessment of Surfactant Deficiency to Speed up Treatment: Assessment of Lung Maturity and Prediction of RDS by Determination of L/S-ratio in Fresh Gastric Aspirates by FTIR Spectroscopy
The aim is to validate a FTIR spectroscopy test for measuring lung maturity/Respiratory
Distress Syndrome (RDS) in terms of safety, usability, and efficacy.
The purpose is to accurately predict RDS using Lecithin/Sphingomyelin ratio (L/S ratio
determined by a rapid FTIR test on fresh gastric aspirates) using retrospective analysis.
Research question:
"In very preterm newborn infants with (risk of) respiratory distress who have not received
prophylactic surfactant: does analysis of L/S-ratio in fresh gastric aspirates using a rapid
FTIR test predict RDS requiring exogenous surfactant with sufficient specificity and
sensitivity to be clinical useful?
Respiratory distress syndrome (RDS) remains a major cause of mortality and morbidity in
premature infants despite the increased use of antenatal steroids and early nasal continuous
positive airway pressure (nCPAP) in addition to exogenous surfactant replacement
therapy(1,2). In recent years, there have been several improvements in treatment, reducing
the incidence and severity of RDS and bronchopulmonary dysplasia (BPD) including early
treatment with nCPAP, early targeted surfactant replacement therapy, increased used of lung
protective ventilation together with an overall reduced use of mechanical ventilation(1,3,4).
However, the majority of premature infants with a gestational age of less than 30 weeks have
immature lungs and approximately half still require treatment with exogenous surfactant(2).
Timing of surfactant treatment seems crucial. Prophylactic surfactant treatment followed by
mechanical ventilation has been widely used, but has now been shown to increase the combined
mortality and incidence of BPD, as opposed to early targeted rescue treatment, especially
when combined with nCPAP and avoidance of mechanical ventilation using the "Intubation,
surfactant, extubation (INSURE) or "Less Invasive Surfactant Administration " (LISA)
approach(5-8). In addition, evidence shows that very early targeted surfactant treatment is
associated with a better outcome compared to later treatment(9).
Consequently, it is necessary to treat with surfactant selectively and very soon after birth,
preferably even before classical symptoms of RDS are present, in order to further improve
outcome from RDS. To be able to do so, we need a bedside test that can quickly identify which
infants have surfactant deficiency to target treatment effectively(1).
Biomarkers expressing lung maturity have been identified in amniotic fluid, gastric aspirate,
and oropharyngeal secretions(10-12). These fluids are partially produced in the foetal lungs
as well as in the kidneys and the amniotic sac and therefore contain lung surfactant(13). The
classic method to determine surfactant in amniotic fluid has been measuring
lecithin/sphingomyelin ratio (L/S) with thin-layer chromatography(10,14). Sphingomyelin
secretion remains fairly constant during pregnancy, whereas lecithin secretion increases in
parallel with lung maturation. Consequently, L/S-ratio reflects lung maturity independently of
dilution sampling effects(10)
Gastric aspirate (GAS) and oropharyngeal (OPS) secretion are easier to obtain and measure
than amniotic fluid, and can be obtained within minutes from birth using routine neonatal care
measures(15,16). Previously, we have measured the surfactant content in gastric aspirate with
microbubble stability tests and with lamellar body counts(17,18). In a recent randomized
clinical trial in very preterm infants we compared early surfactant treatment guided by
lamellar body counts in gastric aspirate with traditional surfactant treatment, and found a
significant reduction in the need of oxygen at six hours of age and by day 28, in addition to
reduced duration of oxygen-dependency and a trend towards a lower incidence of
bronchopulmonary dysplasia(19).
However, both the microbubble stability test and lamellar body counts are work and laboratory
intensive and require a minimum of two to three hours for analysis.
The investigators have developed a fast method based on Fourier Transform Infrared (FTIR)
Spectroscopy for determining the L/S ratio in gastric aspirate and secretion from the
oropharynx. In a recent study, the algorithms for FTIR L/S analyses were developed and
improved 20). Concentrations were measured of the most surface-active lung phospholipid
dipalmitoylphosphatidylcholine and sphingomyelin in frozen gastric aspirates from 89
premature infants expressed as lecithin/sphingomyelin ratio (L/S) by mass spectrometry as the
reference method. The same aspirates were analyzed with FTIR spectroscopy. An L/S algorithm
was developed based on the 89 aspirates. Subsequently gastric aspirates were sampled in 136
infants of 24-31 weeks of gestation. L/S was measured in these frozen gastric aspirates using
FTIR spectroscopy and the results were compared with RDS development. Of 136 infants 61 (45%)
developed RDS. The cut-off value of L/S was 2.2, sensitivity was 92% and specificity was 73%.
The FTIR spectroscopy analysis required 10 μL of aspirate and took 10 minutes.
In an effort to increase accuracy and reproducibility, the investigators have continued to
improve the FTIR spectroscopy method and algorithms by making comparative measurements with
mass spectrometry using fresh non-frozen aspirates from newborn infants. These improvements
may also have affected the optimal cut-off value in our test.
The investigators are in the process of planning a large multicenter randomized clinical
trial of FTIR spectroscopy guided surfactant treatment using a point of care (POC) device
based on the FTIR algorithms and techinique using fresh aspirates that can be analyzed
immidiately in birth suite or the NICU. Before embarking on an interventional study however,
it is needed to re-validate the updated and improved FTIR spectroscopy test by again
comparing clinical appearance of RDS with L/S-ratio measured by FTIR spectroscopy on fresh
non-frozen gastric aspirates froma new population of preterm infants.
Hypothesis: Fast determination of Lecithin/Sphingomyelin-ratio (L/S-ratio) in gastric
aspirates by FTIR Spectroscopy, can accurately and consistently predict RDS based on clinical
criteria.
Trial design The trial is designed as prospective non-intervention observational cohort
study, with the aim to assess the efficacy in predicting RDS by a LS-test on fresh gastric
aspirates and oral secretions based on FTIR spectroscopy, by comparing clinical progress with
the LS-ratio. Included infants will be treated according to routine guidelines and at the
discretion of the attending neonatologist. No interventions are planned to be based on the
result of the L/S test.
AMMENTMENT:
We have ammended the project with an attempt to use the same method and AI combined with
clinical data to predict development of BPD, defined as continued requirements for
supplemental oxygen to DOL28. Spectroscopic measurements were done again using stored gastric
aspirate from the first part of the study.
This amendment has been approved by HREC and measurements were only done after parents gave
informed consent for participation of this additional part of the study.
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