Caffeine to Reduce Mechanical Ventilation in Preterm Infants

Study Overview
=================
Brief Summary
-----------------
Most premature infants require mechanical ventilation for prolonged periods of time and a significant proportion of them develop Bronchopulmonary Dysplasia (BPD). Caffeine is a stimulant of the respiratory center and has been used for the treatment of Apnea of Prematurity in infants not requiring mechanical ventilation or to facilitate weaning from mechanical ventilation by starting therapy shortly before extubation. Recently the use of Caffeine in ventilated infants has been initiated earlier because of the reported reduction in BPD. However there is paucity of data supporting this practice. Because protracted mechanical ventilation and supplemental oxygen increase the risk of developing BPD, a therapy that would facilitate the reduction of the respiratory support and shorten its duration is desirable. Therefore, it is of importance to evaluate the effects of early Caffeine initiation and administration during the course of mechanical ventilation in preterm infants by means of a randomized placebo-controlled trial. Hypothesis: The primary hypothesis of this study is that early use of caffeine in mechanically ventilated preterm infants will reduce the time to first elective extubation and secondarily, that this will reduce the total duration of mechanical ventilation and oxygen supplementation, and reduce the incidence and severity of BPD. Objective: The objective of this trial is to evaluate the effects of early caffeine use during mechanical ventilation on the time to first elective extubation, total duration of mechanical ventilation and oxygen supplementation, and the incidence of BPD. Study Design: This will be a single-center prospective, randomized, double-blind, placebo controlled clinical trial. Population: Premature neonates born between 23 and 30 completed weeks of gestation, who require mechanical ventilation within the first 5 days of life will be enrolled. Infants with major congenital anomalies or small for gestational age will be excluded. Methods: Infants will be randomized within the first 5 days to receive a study drug consisting of either blinded Caffeine citrate or blinded Placebo (equivalent volume of normal saline). Infants will continue to receive the study drug until the first elective extubation.

Official Title
-----------------
Use of Caffeine to Reduce Length of Mechanical Ventilation in Preterm Infants

Conditions
-----------------
Prematurity, Apnea, Respiratory Failure

Intervention / Treatment
-----------------
* Drug: Caffeine citrate
* Other: Normal saline


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Premature neonates born between 23 and 30 completed weeks of gestation. Requiring mechanical ventilation within the first 5 postnatal days Written-informed parental consent for the study Exclusion Criteria: Major congenital anomalies Small for gestational age

Ages Eligible for Study
-----------------
Minimum Age: 1 Day
Maximum Age: 5 Days

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Caffeine Arm<br>Subjects randomized to this arm will receive blinded Caffeine citrate. | Drug: Caffeine citrate<br>* Enrolled subjects will be randomized to receive a study drug consisting of either blinded Caffeine citrate. Randomization and study drug preparation will be done by the NICU pharmacy. Investigators and clinicians will be blinded to the assigned drug. After randomization, an initial loading dose of 20 mg/Kg of study drug will be followed by a 5 mg/Kg/day maintenance dose. The assigned study drug will be administered intravenous or orally as determined by the clinical team. Infants will continue to receive the study drug until 12 hours prior to the first elective extubation.<br>|
| Placebo Comparator: Placebo Arm<br>Subjects randomized to this arm will receive blinded Placebo (equivalent volume of normal saline). | Other: Normal saline<br>* Enrolled subjects will be randomized to receive a study drug consisting of blinded Placebo (equivalent volume of normal saline). Randomization and study drug preparation will be done by the NICU pharmacy. Investigators and clinicians will be blinded to the assigned drug. After randomization, an initial loading dose of 20 mg/Kg of study drug will be followed by a 5 mg/Kg/day maintenance dose. The assigned study drug will be administered intravenous or orally as determined by the clinical team. Infants will continue to receive the study drug until 12 hours prior to the first elective extubation.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Age at First Successful Extubation | Defined as age of extubation with infant remaining extubated for more than 24 hours. | From birth to until 36 weeks postmenstrual age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival |  | From the time of randomization up to 36 weeks corrected age, or until the time of discharge or death | 
| Total Duration of Mechanical Ventilation |  | From the time of first intubation until the last extubation, up to 36 weeks corrected age | 
| Total Duration of Oxygen Supplementation |  | From the time of first initiation until the last day of oxygen supplementation, up to 36 weeks corrected age | 
| Number of Infants With Bronchopulmonary Dysplasia (BPD) | BPD defined as need for oxygen for at least 28 days and at 36 weeks post-menstrual age. | Evaluated at 36 weeks corrected postmenstrual age | 
| Survival Without BPD | Discharge alive without BPD. BPD defined as need for oxygen for at least 28 days and at 36 weeks post-menstrual age. | From the time of randomization until 36 weeks corrected age, discharge or death | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Premature infants, Caffeine, Methylxanthines, Mechanical ventilation, Oxygen, Weaning, Bronchopulmonary dysplasia