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

Phase 4

• Conditions: Respiratory Distress Syndrome in Premature Infants
• Interventions: Procedure: INSURE; Procedure: LISA; Drug: Analgesic, Opioid

• Registration Number: NCT04073173
• Lead Sponsor: Virgilio Paolo Carnielli

Brief Summary

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.

Detailed Description

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.

Study Timeline

• Study First Submitted: 2019-08-27
• Study First Submitted QC: 2019-08-27
• Study First Posted: 2019-08-29
• Status Verified: 2020-09
• Last Update Submitted: 2020-09-01
• Last Update Posted: 2020-09-03
• Study Start: 2020-11-01
• Primary Completion: 2022-10-31
• Study Completion: 2022-10-31

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 80

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
INSURE-no analgesic	INSURE	INSURE without an analgesic drug.
LISA-analgesic	LISA	Less Invasive Surfactant Administration (LISA) with remifentanil (0.5-2 micrograms/kg/dose) as the analgesic drug.
LISA-analgesic	Analgesic, Opioid	Less Invasive Surfactant Administration (LISA) with remifentanil (0.5-2 micrograms/kg/dose) as the analgesic drug.
LISA-no analgesic	LISA	Less Invasive Surfactant Administration (LISA) without an analgesic drug.
INSURE-analgesic	INSURE	INtubation-SURfactant-Extubation (INSURE) with remifentanil (0.5-2 micrograms/kg/dose) as the analgesic drug.
INSURE-analgesic	Analgesic, Opioid	INtubation-SURfactant-Extubation (INSURE) with remifentanil (0.5-2 micrograms/kg/dose) as the analgesic drug.

Primary Outcome Measures

Name	Time	Method
Cortisol concentrations	At 1, 3, 6 12, 24 hours after surfactant administration and then daily in the first week at the same time of the day (to avoid circadian variations).	Cortisol concentrations will be assessed in saliva, as salivary cortisol levels have been shown to be useful surrogate markers for plasma cortisol levels in neonates. Saliva samples will be collected using an absorbent swab stick, centrifuged at 4000 rpm for 10 minutes and kept at -80°C until assayed (minimum sample volume 25 µl). Enzyme immunoassay (ELISA kit) will be used. Basal samples will be obtained at the hospital admission and right before surfactant.

Secondary Outcome Measures

Name	Time	Method
Heart rate	6 hours before and after surfactant therapy will be analyzed.	Cardiac monitoring will assess heart rate. Traces will be saved onto a computer with a sampling frequency of 1 Hertz. Average heart rate, periods of tachycardia (\>160 bpm for ≥5 seconds) and bradycardia (\<100 bpm for ≥5 seconds) will be recorded. These parameters may be correlated with stress and hemodynamic instability during the procedures.
Brain oxygenation	From the hospital admission to day 7 of the hospital stay.	Brain oxygenation will be assessed by near-infrared spectroscopy (NIRS).
Galvanic Skin Responses	At 1, 3, 6 12, 24 hours after surfactant administration and then daily in the first week at the same time of the day (to avoid circadian variations).	An instrumental stress-test device measuring galvanic skin conductance will be used (Pain Monitor, Med-Storm, Norway): three electrodes will be attached to the infant's foot (sole and sides of the ankle); skin conductance is measured in micro Siemens (µS).
Oxygen saturation (SpO2)	From the hospital admission to day 7 of the hospital stay.	High precision oxygenation assessment will be attained by high frequency (1 Hz) sampling of SpO2 data from the cardio monitor to a computer, possibly by using multiple pulse oximeters in the same patient.
Markers of oxidative stress	At the hospital admission and at 6 and 12 hours after surfactant therapy.	8-isoprostane and nitrites/nitrates will be dosed on urine samples.