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

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ClinicalTrials.gov Identifier: NCT04073173
Recruitment Status : Not yet recruiting
First Posted : August 29, 2019
Last Update Posted : August 29, 2019
Sponsor:
Collaborator:
Fondazione Cassa di Risparmio di Verona Vicenza Belluno e Ancona
Information provided by (Responsible Party):
Virgilio Paolo Carnielli, Ospedali Riuniti Ancona

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.

Condition or disease Intervention/treatment Phase
Respiratory Distress Syndrome in Premature Infants Procedure: INSURE Procedure: LISA Drug: Analgesic, Opioid Phase 4

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, monocentric, randomized phase 4 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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Masking Description: Participants and data analyst will be masked.
Primary Purpose: Treatment
Official Title: 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.
Estimated Study Start Date : November 1, 2019
Estimated Primary Completion Date : October 31, 2021
Estimated Study Completion Date : October 31, 2021


Arm Intervention/treatment
Experimental: LISA-analgesic
Less Invasive Surfactant Administration (LISA) with remifentanil (0.5-2 micrograms/kg/dose) as the analgesic drug.
Procedure: LISA
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.

Drug: Analgesic, Opioid
Remifentanil (0.5-2 micrograms/kg/dose)

Experimental: LISA-no analgesic
Less Invasive Surfactant Administration (LISA) without an analgesic drug.
Procedure: LISA
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.

Experimental: INSURE-analgesic
INtubation-SURfactant-Extubation (INSURE) with remifentanil (0.5-2 micrograms/kg/dose) as the analgesic drug.
Procedure: INSURE
Patients will be intubated by endotracheal tube, exogenous surfactant (Poractant alfa) will be administered and then they will be extubated.

Drug: Analgesic, Opioid
Remifentanil (0.5-2 micrograms/kg/dose)

Experimental: INSURE-no analgesic
INSURE without an analgesic drug.
Procedure: INSURE
Patients will be intubated by endotracheal tube, exogenous surfactant (Poractant alfa) will be administered and then they will be extubated.




Primary Outcome Measures :
  1. Cortisol concentrations [ Time Frame: 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 :
  1. Galvanic Skin Responses [ Time Frame: 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).

  2. Heart rate [ Time Frame: 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.

  3. Brain oxygenation [ Time Frame: From the hospital admission to day 7 of the hospital stay. ]
    Brain oxygenation will be assessed by near-infrared spectroscopy (NIRS).

  4. Oxygen saturation (SpO2) [ Time Frame: 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.

  5. Markers of oxidative stress [ Time Frame: At the hospital admission and at 6 and 12 hours after surfactant therapy. ]
    8-isoprostane and nitrites/nitrates will be dosed on urine samples.



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Ages Eligible for Study:   161 Days to 223 Days   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • gestational age at birth between 161 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04073173


Contacts
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Contact: Clementina Rondina, MD +390715962368 clementina.rondina@ospedaliriuniti.marche.it
Contact: Virgilio Carnielli, MD, PHD +390715962045 virgilio.carnielli@ospedaliriuniti.marche.it

Sponsors and Collaborators
Virgilio Paolo Carnielli
Fondazione Cassa di Risparmio di Verona Vicenza Belluno e Ancona
Investigators
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Study Director: Virgilio Carnielli, MD, PHD Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona
Principal Investigator: Clementina Rondina, MD Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona

Publications:

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Responsible Party: Virgilio Paolo Carnielli, Director of Neonatology, Ospedali Riuniti Ancona
ClinicalTrials.gov Identifier: NCT04073173     History of Changes
Other Study ID Numbers: StrAAS
2019-002923-13 ( EudraCT Number )
First Posted: August 29, 2019    Key Record Dates
Last Update Posted: August 29, 2019
Last Verified: August 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Virgilio Paolo Carnielli, Ospedali Riuniti Ancona:
RDS
Preterm Infants
Surfactant
LISA
INSURE
Analgesia
Stress
Additional relevant MeSH terms:
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Respiratory Distress Syndrome, Newborn
Respiratory Distress Syndrome, Adult
Syndrome
Respiratory Tract Diseases
Infant, Newborn, Diseases
Disease
Pathologic Processes
Lung Diseases
Respiration Disorders
Infant, Premature, Diseases
Remifentanil
Analgesics, Opioid
Pulmonary Surfactants
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Narcotics
Central Nervous System Depressants
Respiratory System Agents