Clinical trial NCT04073173: Stress Assessment With and Without Analgesia During Surfactant Therapy in Preterm Infants.
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.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Respiratory Distress Syndrome in Premature Infants
Keywords: RDS
Preterm Infants
Surfactant
LISA
INSURE
Analgesia
Stress
Lead sponsor: Ospedali Riuniti Ancona
Sponsor class: OTHER
Collaborators: name: Fondazione Cassa di Risparmio di Verona Vicenza Belluno e Ancona
name: Istituto di Ricerca Pediatrica Città della Speranza
First posted: 2019-08-29
Enrollment: 80
Sex: ALL
Minimum age (years): 168
Maximum age (years): 223
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Cortisol concentrations
timeFrame: 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 outcomes:
measure: Galvanic Skin Responses
timeFrame: 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).
measure: Heart rate
timeFrame: 6 hours before and after surfactant therapy will be analyzed.
measure: Brain oxygenation
timeFrame: From the hospital admission to day 7 of the hospital stay.
measure: Oxygen saturation (SpO2)
timeFrame: From the hospital admission to day 7 of the hospital stay.
measure: Markers of oxidative stress
timeFrame: At the hospital admission and at 6 and 12 hours after surfactant therapy.
Other outcomes:
Locations:
Study officials:
affiliation: Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona
name: Virgilio Carnielli, MD, PHD
role: STUDY_DIRECTOR
affiliation: Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona
name: Clementina Rondina, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sweet DG, Carnielli V, Greisen G, Hallman M, Ozek E, Plavka R, Saugstad OD, Simeoni U, Speer CP, Vento M, Visser GH, Halliday HL. European Consensus Guidelines on the Management of Respiratory Distress Syndrome - 2016 Update. Neonatology. 2017;111(2):107-125. doi: 10.1159/000448985. Epub 2016 Sep 21.
citation: Okamura H, Kinoshita M, Saitsu H, Kanda H, Iwata S, Maeno Y, Matsuishi T, Iwata O. Noninvasive surrogate markers for plasma cortisol in newborn infants: utility of urine and saliva samples and caution for venipuncture blood samples. J Clin Endocrinol Metab. 2014 Oct;99(10):E2020-4. doi: 10.1210/jc.2014-2009. Epub 2014 Jul 31.
citation: Lago P, Benini F, Agosto C, Zacchello F. Randomised controlled trial of low dose fentanyl infusion in preterm infants with hyaline membrane disease. Arch Dis Child Fetal Neonatal Ed. 1998 Nov;79(3):F194-7. doi: 10.1136/fn.79.3.f194.
citation: Guinsburg R, Kopelman BI, Anand KJ, de Almeida MF, Peres Cde A, Miyoshi MH. Physiological, hormonal, and behavioral responses to a single fentanyl dose in intubated and ventilated preterm neonates. J Pediatr. 1998 Jun;132(6):954-9. doi: 10.1016/s0022-3476(98)70390-7.
citation: Guinsburg R, Kopelman BI, de Almeida MF, Miyoshi MH. [Pain in intubated and ventilated preterm neonate: multidimensional assessment and response to fentanyl analgesia]. J Pediatr (Rio J). 1994 Mar-Apr;70(2):82-90. doi: 10.2223/jped.727. Portuguese.
citation: Badiee Z, Vakiliamini M, Mohammadizadeh M. Remifentanil for endotracheal intubation in premature infants: A randomized controlled trial. J Res Pharm Pract. 2013 Apr;2(2):75-82. doi: 10.4103/2279-042X.117387.