Respiratory Effect of the LISA Method With Sedation by Propofol Versus Absence of Sedation.

Study Overview
=================
Brief Summary
-----------------
The investigators propose to evaluate premedication with Propofol compared to a control strategy including a placebo with a possible rescue treatment with ketamine to ensure pain control before LISA Procedure . Investigators hypothesize that sedation with Propofol is safe and non-inferior to placebo for the risk of Mechanical Ventilation in the 72 hours following the procedure.

Detailed Description
-----------------
Non-inferiority trial comparing Propofol versus placebo during the intra tracheal Less Invasive Surfactant Administration (LISA) in preterm babies < 32 weeks of gestation for the need for mechanical ventilation after the procedure. An open-label ketamine treatment as rescue is possible in each group. In each participating unit, information will be given to parents of preterm babies <32 wGA upon their admission to the delivery room or to the NICU (neonatal intensive care unit), and informed consent will be sought as soon as possible. Eligible babies presenting a RDS (respiratory distress syndrome) will be included and randomized to the control (placebo) group or Propofol group. While benefiting from Nasal Intermittent Positive Pressure Ventilation (NIPPV) the newborn will be prepared as usual for tracheal intubation. Trialists will be blinded to treatment allocation. The drug administration in the two groups will be titrated according to weight (0.5mg/kg per dose of Propofol or a similar volume of placebo). After each dose, a pain score (FANS) will be quickly evaluated within 2 minutes of the injection, to assess the need for a supplementary dose (up to a predefined limit) or rescue treatment by Ketamine. After the steps of sedation, the LISA procedure will be performed, with detailed data collection of per procedure events up to 72 hours of life. Babies will be subsequently managed as usual in each NICU and data will be collected about respiratory, neurological and hemodynamic outcomes during the hospital stay, and especially at discharge, 28 days, and 36 weeks. At two years of corrected age, a final examination will be performed to evaluate neurodevelopmental outcomes.

Official Title
-----------------
Respiratory Effect of the LISA (Less Invasive Surfactant Administration) Method With Sedation by Propofol Versus Absence of Sedation: Double-blind Comparative Randomized Clinical Trial.

Conditions
-----------------
Respiratory Distress Syndrome in Premature Infant

Intervention / Treatment
-----------------
* Drug: Propofol-Lipuro
* Drug: Placebos


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Preterm Infants < 32 wGA (weeks of gestational age) Presenting a RDS (respiratory distress syndrome) in the first 48 hours of life treated by CPAP (continuous positive airway pressure) or BiPAP (Bilevel Positive Airway Pressure) requiring surfactant : FIO2 : (fraction of inspired oxygen) if 28 - 31 SA : FiO2 ≥30% for a duration ≥ 10mn if <28 SA FIO2 ≥25% for a duration ≥10mn SpO2 (arterial oxygen saturation) : to obtain a SpO2 between ≥88 and ≤ 95% Available IntraVenous line (peripheral, umbilical or central catheter) Recipient of the French Social Security Informed consent form signed Exclusion Criteria: Congenital and/or major malformations FIO2 >60% Silverman score >6 Contraindication to the use of Propofol : Low Blood Pressure with 2 successive measurements (Mean < Gestational Age expressed in Weeks of Gestation) persisting after one volume expansion, Use of inotropic medication to maintain a normal blood pressure. Use of sedative or analgesic drugs (except paracetamol and ibuprofen) in the previous 24h Coma, convulsions, areactivity at neurological examination
Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Propofol<br>Propofol (Propofol LIPURO 1% 100mL), Pharmacologic form: 10mg/ml. Considering the birthweight of most preterm babies, Propofol will be diluted to a final concentration of 1mg/ml by the nurse. Treatment initiation: the 1st dose will be injected following usual management of LISA procedure included the installation of the newborn and the atropine and caffeine injections and sugar solution administration Dose per administration: 0.5mg/kg per dose of Propofol. Number of administrations: Several administrations of 0.5 mg/kg are possible, according the level of sedation achieved, as evaluated by the FANS score. If the FANS score is ≥6, a new dose will be injected up to a total of two (before 28 wGA) or 3 (between 28 - 31 wGA) administrations of the drug. (See paragraph 5.3) | Drug: Propofol-Lipuro<br>* sedation of babies < 32wGA with propofol / placebo before a LISA Procedure<br>|
| Placebo Comparator: medialipide<br>Name of treatment for placebo: Medialipide® (B. BRAUN) Pharmacological form: 20g/100ml Medialipide 20% will be used as the placebo. This is an emulsion of medium and long triglycerides based on soya oil and having same appearance organoleptic characteristics as Propofol. Dose per administration: Same volume as for the Propofol administration Number of administrations: according the same protocol that for the Propofol administration. Modalities of preparation : The same dilution procedure as Propofol lipuro 1% SPC (Summary of Product Characteristics):1 part of Medialipide 20% with 9 parts of 5% w/v glucose solution or 0.9% w/v sodium chloride solution as shown in parenteral nutrition which is in accordance with medialipide 20% SPC | Drug: Placebos<br>* injected to babies < 32wGA with propofol / placebo before a LISA Procedure<br>* Other names: medialipide;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| need for mechanical ventilation after the procedure | Rate of mechanical ventilation from the start of the LISA procedure up to 72 hours of life. | 72hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of MV (mechanical ventilation ) in each class of GA (<28, 28-31wGA) | Rate of MV (mechanical ventilation ) from the start of the LISA procedure up to 72 hours of life in each class of GA (<28, 28-31wGA) | 72hours | 
| FANS during LISA and 1h after LISA | Faceless acute neonatal pain scale (FANS) assessed during LISA and 1 hour after the procedure by an independent operator. | 1hour | 
| number of ketamine administrations for rescue | Number of ketamine administrations for rescue in order to obtain a FANS score <6 and to be able to proceed to LISA. | before LISA Procedure | 
| Number of laryngoscopies | Number of laryngoscopies needed to perform LISA | during LISA Procedure (T0) | 
| Tolerance and efficacy (Per procedure events): Apnea | Apnea requiring bag mask ventilation | during LISA Procedure (T0) | 
| Tolerance and efficacy (Per procedure events): emergency intubation | Emergency intubation after the drug injection before the LISA procedure can be performed or within 1h following the drug injection | from drug injection to 1hour after | 
| Tolerance and efficacy (Per procedure events): Viby Mogensen score | Clinician's satisfaction during laryngoscopy with the Viby Mogensen score : Item Score 1 Score 2 Score 3 Score 4 Laryngoscopy Easy Fair Difficult Impossible Vocal cords Open Moving Closing Closed Coughing None Slight Moderate Severe Jaw relaxation Complete Slight Stiff Rigid Limb movements None Slight Moderate Severe the total score is calculated adding each item scores. min score = 5. max score = 20. An easy intubation would obtain a low score and a difficult intubation would have a high score. | during LISA Procedure | 
| BPD (bronchopulmonary dysplasia) at 36 weeks of Gestational Age | Broncho Pulmonary Dysplasia at 36 weeks of Gestational Age | equivalent to 36 weeks of Gestational Age | 
| In-hospital morbidity and mortality: pneumothorax | Pneumothorax within 72hours | 72hours post LISA Procedure | 
| In-hospital morbidity and mortality: Necrotizing Enterocolitis | necrotizing enterocolitis during hospitalization | the day of discharge from hospital (the day depends to each participant : between 36-45 weeks of Gestational Age) | 
| In-hospital morbidity and mortality : sepsis | proven sepsis during hospitalization | the day of discharge from hospital (the day depends to each participant : between 36-45 weeks of Gestational Age) | 
| In-hospital morbidity and mortality: retinopathy | retinopathy of prematurity during hospitalization | the day of discharge from hospital (the day depends to each participant : between 36-45weeks of gestational ageGA) | 
| In-hospital morbidity and mortality | periventricular leukomalacia or grade 3 or 4 intraventricular hemorrhage during hospitalization | the day of discharge from hospital (the day depends to each participant : between 36-45weeks of Gestational Age) | 
| In-hospital morbidity and mortality: patent ductus arteriosus | treatment of a patent ductus arteriosus during hospitalization | the day of discharge from hospital (the day depends to each participant : between 36-45 weeks of Gestational Age) | 
| In-hospital morbidity and mortality: death 36weeks of Gestational Age | Death at 36 weeks of Gestational Age | equivalent to 36 weeks of Gestational Age | 
| In-hospital morbidity and mortality: death during hospitalization | in-hospital mortality | the day of discharge from hospital (the day depends to each participant : between 36-45weeks of Gestational Age) | 
| At two years of corrected age: ASQ (Ages and Stages Questionnaire) | ASQ (Ages and Stages Questionnaire) questionnaire is a general developmental screening tool (5 areas are evaluated: Communication, gross motor, fine motor, problem solving, and personal-social). Total score is the sum of each of the 5 area scores (wich are between 0-60. Total score is between 0 and 300. The higher the score is, the best developed the children is. | 2 years (corrected age) | 
| At two years of corrected age: motor function | Gross Motor Function Classification Scale (GMFCS) looks at movements such as sitting, walking and use of mobility devices. It is helpful because it provides families and clinicians with a clear description of a child's current motor function, and an idea of what equipment or mobility aids a child may need in the future, e.g. crutches, walking frames or wheelchairs. Participant will be assignated to one of the 5 levels by the clinicians : a patient who is in level 5 has more motor impairments than a patient in level 1. | 2 years (corrected age) | 
| At two years of corrected age: vision | Visual functions : a clinical examination will conclude if the participant has a visual deficit or not. And in the deficit case, what kind of vision pathology. | 2 years (corrected age) | 
| At two years of corrected age: audition | Hearing functions : a clinical examination will conclude if the participant has a hearing deficit or not. And in the deficit case, what kind of audition pathology. | 2 years (corrected age) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
LISA, propofol, medialipide, ketamin, sedation, premature infant, surfactant