Fast Assessment of Surfactant Deficiency to Speed up Treatment (FAST)

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?

Study Overview

• Status: Completed
• Conditions: RDS of Prematurity; Prematurity
• Intervention / Treatment: Diagnostic test: LS-ratio

Detailed Description

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.

• Study Type: Observational
• Enrollment (Actual): 72

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Department of Neonatology, Rigshospitalet

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 1 year (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Preterm newborn babies that have gastric/oral secretions sampled before 45 minutes of age

Description

Inclusion Criteria:

Inclusion criteria:

• Have GAS obtained within 45 minutes from birth via:

  • a naso- or orogastric tube inserted in the delivery room if clinically indicated as part of resuscitation or
  • a nasogastric tube inserted as part of routine management of preterm infants.
• Written informed consent has been obtained

Exclusion Criteria:

• Intubated and treated with surfactant before obtaining GAS
• Diagnosis of lethal malformations
• Antenatal diagnosis of lung hypoplasia
• Therapeutic infusion given in the amniotic cavity
• GAS unavailable or significantly contaminated by meconium/pus
• Sepsis

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
observational group; Infants born 24-32 weeks. Inclusion criteria: Have gastric aspirate and oral secretions obtained within 45 minutes from birth via:a naso- or orogastric tube inserted in the delivery room if clinically indicated as part of resuscitation ora nasogastric tube inserted as part of routine management of preterm infants.; Written informed consent has been obtained	Diagnostic test: LS-ratio; Accurately predict RDS using Lecithin/Sphingomyelin ratio (L/S ratio determined by a rapid FTIR test on fresh gastric aspirates) using retrospective analysis

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
development of RDS	5 days from delivery

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Collaborators: Odense University Hospital; Aarhus University Hospital; Hvidovre University Hospital; Herlev Hospital; Aalborg University Hospital; Holbaek Sygehus; Kolding Sygehus

Publications and helpful links

Helpful Links

• Publication of the completed study

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2017
• Primary Completion (Actual): April 26, 2019
• Study Completion (Actual): April 26, 2019

Study Registration Dates

• First Submitted: July 27, 2017
• First Submitted That Met QC Criteria: July 27, 2017
• First Posted (Actual): August 1, 2017

Study Record Updates

• Last Update Posted (Actual): March 16, 2020
• Last Update Submitted That Met QC Criteria: March 12, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: Prematurity; Respiratory distress syndrome; Lung surfactant; Mid-infrared spectroscopy; gastric aspirate
• Additional Relevant MeSH Terms: Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Premature Birth
• Other Study ID Numbers: H-17013993

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No