Stress Assessment With and Without Analgesia During Surfactant Therapy in Preterm Infants.

Stress Assessment in Preterm Infants With Respiratory Distress Syndrome Treated or Not With an Analgesic Drug During the Traditional or the Less Invasive Method of Surfactant Therapy.

This study will compare stress, changes in oxygenation and oxidative damage in preterm infants with respiratory distress syndrome (RDS) randomized to receive or not remifentanil as an analgesic drug during the administration of porcine surfactant (poractant alfa, Curosurf®) through the traditional (INSURE) or the less invasive (LISA) method.

At present, LISA and INSURE are both used for surfactant therapy in infants as comparable methods. However, a clear policy of using analgesics during surfactant therapy is still lacking: some neonatologists use analgesics to reduce stress and pain scores, whereas others do not approve their use due to interference with spontaneous breathing.

In this open-label, randomized, phase 4 clinical trial, infants admitted to our neonatal intensive unit care (NICU) will be evaluated according to the selection criteria and then randomized to receive or not remifentanil as an analgesic drug during the administration of porcine surfactant (poractant alfa, Curosurf®) via the INSURE or LISA method: Group-1) LISA-analgesic; Group 2) LISA-no analgesic; Group-3) INSURE-analgesic; Group-4) INSURE-no analgesic. Study patients will be stratified by gestational age at birth: Block A) 23.0-27.6 weeks of gestation; Block B) 28.0-31.6 weeks of gestation.

Early caffeine administration will be provided according to our NICU guidelines shortly after birth. Infants with adequate respiratory drive will be stabilized on nasal continuous positive airway pressure (CPAP; 4-8 cm of water) right after birth. Oxygen saturation targets will be 90-94%; moderate degrees of hypercarbia (PaCO2 < 60 mmHg, provided arterial pH >7.22) will be tolerated. Conditions mimicking respiratory distress syndrome (RDS; i.e. sepsis, air leaks, aspiration pneumonia, congenital heart disease) will be ruled out. RDS diagnosis will be clinical according to the European Guidelines. Nasal CPAP, bi-level CPAP or nasal intermittent positive pressure ventilation (synchronized or not) will be used at the discretion of the attending physician to stabilize the patients. Intubation criteria according to our NICU guidelines will be:

1. severe acidosis (defined as arterial pH<7.20 with a partial pressure of carbon dioxide (PaCO2) > 55 mmHg and partial pressure of oxygen (PaO2) < 50 mmHg) with a fraction of inspired oxygen (FiO2) > 0.50;
2. severe apnoea.

Enrolled infants will be evaluated from birth to day 7 of the hospital stay.

Inclusion Criteria:

• gestational age at birth between 168 and 223 days,
• respiratory distress syndrome (diagnosed on the basis of clinical and/or radiological grounds) with a fraction of inspired oxygen ≥0.30 (for infants born ≤26 weeks' gestational age) or ≥0.40 (for infants born >26 weeks' gestational age) to achieve a peripheral oxygen saturation of 90-94% within 24 hours of life and good respiratory drive,
• written informed consent.

Exclusion Criteria:

• major malformations,
• late admission (after 24 hours of life),
• intubation in the delivery room,
• severe birth asphyxia,
• prolonged rupture of membranes,
• air leaks,
• no informed consent.