The goal of this clinical trial is to determine whether a higher dose of caffeine citrate can improve breathing and reduce health complications in extremely premature infants, specifically those born before 28 weeks of pregnancy, known as ELGAN infants. These babies often struggle with breathing due to underdeveloped lungs, and caffeine is commonly used to help support their respiratory function. However, the most effective and safest dose has not yet been clearly established. The study aims to answer two main questions: Does a higher maintenance dose of caffeine (10 mg/kg) lead to better oxygenation, as measured by the Oxygen Saturation Index (OSI), compared to the standard dose (5 mg/kg)? And does the higher dose reduce the risk of serious complications such as lung disease, brain injury, or death-without causing more side effects like fast heart rate, high blood pressure, or poor growth? To answer these questions, researchers will compare two groups of infants: one receiving the high-dose caffeine treatment and the other receiving the standard dose. This comparison will help determine if the higher dose leads to better outcomes without increased risk. Participants will begin caffeine treatment once they have regained their birth weight and are at least seven days old. They will be randomly assigned to receive either the high or standard caffeine dose and will be followed until caffeine is stopped or they are discharged from the hospital. During this time, researchers will monitor each infant's oxygenation levels, need for breathing support, signs of common complications, growth and feeding progress, and any side effects. Before discharge, each infant's motor development will also be assessed using a tool called the Test of Infant Motor Performance (TIMP). This study could help define the most effective caffeine dosing strategy for supporting extremely premature infants and improving their short-term health outcomes.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
40
High Dose Group: Caffeine citrate administered as a 20 mg/kg loading dose followed by a 10 mg/kg/day maintenance dose starting at 7 days of life. Dose escalation up to 12.5 mg/kg/day may be performed based on clinical indications. The drug is administered either intravenously or orally in a blinded fashion. Standard Dose Group: Caffeine citrate administered as a 20 mg/kg loading dose followed by a 5 mg/kg/day maintenance dose starting at 7 days of life. Dose escalation up to 7.5 mg/kg/day may be performed based on clinical indications. The drug is administered either intravenously or orally in a blinded fashion.
Average Oxygen Saturation Index (OSI) per Patient Over First 56 Days
The OSI is calculated as (FiO₂ × MAP × 100) / SpO₂. The average OSI per patient will be calculated from randomization through the first 56 days or until caffeine is discontinued or the patient is discharged. Higher OSI values indicate worse oxygenation.
Time frame: From Randomization to Day 56 or Caffeine Discontinuation
Total Duration of Respiratory Support
Total number of days each patient receives any respiratory support, including invasive ventilation, CPAP, or supplemental oxygen.
Time frame: From Randomization to 1 year
Total Incidence of Severe Bronchopulmonary Dysplasia (BPD)
Number of infants diagnosed with severe BPD based on NICHD criteria.
Time frame: From Randomization to 1 year
Total Incidence of Severe Intraventricular Hemorrhage or Periventricular Leukomalacia (IVH/PVL)
Number of infants diagnosed with severe IVH (Grade III/IV) or PVL based on cranial imaging.
Time frame: From Randomization to 1 year
Total Length of NICU Stay
Total number of days each infant remains in the NICU from birth until discharge.
Time frame: Birth to 1 year
Total Number of Infant Deaths
Number of infants who die before NICU discharge.
Time frame: From Randomization to 1 year
Total Test of Infant Motor Performance (TIMP) Score Prior to Discharge
TIMP is a 42-item motor development assessment. Each item scores from 0 to 6. Total scores range from 0 to 252. Higher scores indicate better motor performance.
Time frame: Prior to NICU Discharge
Total Duration of SpO₂ Below Threshold (Intermittent Hypoxia)
Cumulative minutes with SpO₂ below target threshold, derived from Neo-DReAMS repository.
Time frame: From Randomization through Day 56
Total Time with Heart Rate >180 bpm (Tachycardia)
Total minutes with heart rate exceeding 180 bpm recorded via monitor.
Time frame: From Randomization to 1 year
Total Growth Parameter Z-Scores (Length, Weight, Head Circumference)
Growth will be assessed using Fenton z-scores. Higher scores reflect better growth relative to gestational norms.
Time frame: From Randomization to 1 year
Total Osteopenia Markers (Alkaline Phosphatase, Calcium, Phosphorus)
Osteopenia assessed by abnormal lab values: alkaline phosphatase \>500 IU/L, abnormal calcium or phosphorus. Abnormal values per infant will be summed.
Time frame: From Randomization to 1 year
Total Incidence of Hypertension (>95th Percentile)
Number of days with blood pressure \>95th percentile for gestational age.
Time frame: From Randomization to 1 year
Total Time to Full Enteral Feeds
Days from birth until the infant reaches 120 mL/kg/day enteral nutrition.
Time frame: From Randomization to 1 year
Total Number of NPO Periods >24 Hours
Number of times infant is NPO (nothing by mouth) for more than 24 hours.
Time frame: From Randomization through NICU Discharge
Total Incidence of Necrotizing Enterocolitis (NEC)
Number of infants diagnosed with NEC (Bell's stage II or higher).
Time frame: From Randomization to 1 year
Total Incidence of Spontaneous Intestinal Perforation (SIP)
Number of infants with radiographically or surgically confirmed SIP.
Time frame: From Randomization to 1 year
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