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

Study Overview
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Brief Summary
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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
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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: 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; severe apnoea. Enrolled infants will be evaluated from birth to day 7 of the hospital stay.

Official Title
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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.

Conditions
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Respiratory Distress Syndrome in Premature Infants

Intervention / Treatment
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* Procedure: INSURE
* Procedure: LISA
* Drug: Analgesic, Opioid


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 168 Days
Maximum Age: 223 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LISA-analgesic<br>Less Invasive Surfactant Administration (LISA) with remifentanil (0.5-2 micrograms/kg/dose) as the analgesic drug. | Procedure: LISA<br>* Surfactant (Poractant alfa) will be directly delivered into the lungs via a fine bore catheter inserted into the trachea and then patients will be extubated.<br>Drug: Analgesic, Opioid<br>* Remifentanil (0.5-2 micrograms/kg/dose)<br>|
| Experimental: LISA-no analgesic<br>Less Invasive Surfactant Administration (LISA) without an analgesic drug. | Procedure: LISA<br>* Surfactant (Poractant alfa) will be directly delivered into the lungs via a fine bore catheter inserted into the trachea and then patients will be extubated.<br>|
| Experimental: INSURE-analgesic<br>INtubation-SURfactant-Extubation (INSURE) with remifentanil (0.5-2 micrograms/kg/dose) as the analgesic drug. | Procedure: INSURE<br>* Patients will be intubated by endotracheal tube, exogenous surfactant (Poractant alfa) will be administered and then they will be extubated.<br>Drug: Analgesic, Opioid<br>* Remifentanil (0.5-2 micrograms/kg/dose)<br>|
| Experimental: INSURE-no analgesic<br>INSURE without an analgesic drug. | Procedure: INSURE<br>* Patients will be intubated by endotracheal tube, exogenous surfactant (Poractant alfa) will be administered and then they will be extubated.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cortisol concentrations | 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. | 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). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Galvanic Skin Responses | 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). | 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). | 
| Heart rate | 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. | 6 hours before and after surfactant therapy will be analyzed. | 
| Brain oxygenation | Brain oxygenation will be assessed by near-infrared spectroscopy (NIRS). | From the hospital admission to day 7 of the hospital stay. | 
| Oxygen saturation (SpO2) | 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. | From the hospital admission to day 7 of the hospital stay. | 
| Markers of oxidative stress | 8-isoprostane and nitrites/nitrates will be dosed on urine samples. | At the hospital admission and at 6 and 12 hours after surfactant therapy. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RDS, Preterm Infants, Surfactant, LISA, INSURE, Analgesia, Stress