Early Caffeine in Preterm Neonates

Caffeine is routinely administered to extremely preterm neonates as a respiratory stimulant
to prevent or treat apnea of prematurity, or prolonged pauses in breathing in preterm babies.
Caffeine, a methylxanthine, is an adenosine receptor antagonist that has the effects of
relaxing smooth muscle in the airways, stimulating the central nervous system and cardiac
muscle, and acting as a diuretic. The mode of action in apnea of prematurity could be from
several mechanisms, including stimulation of respiratory drive, enhancement of minute
ventilation, increased response to hypercapnia, increase in skeletal muscle tone, and
decrease in diaphragmatic fatigue.

The timing of caffeine administration is highly variable, ranging from the first hours of
life to several days after birth. In the Caffeine for Apnea of Prematurity (CAP) trial, in
which the average day of initial caffeine dose was 3 days of life, the incidence of
bronchopulmonary dysplasia (BPD) was significantly reduced in the caffeine group compared to
the placebo group (47% vs 36%, p<0.001). Neonates in the caffeine group also had fewer days
of mechanical ventilation and oxygen exposure, both of which are known risk factors in the
development of BPD. Further studies have demonstrated greater benefit of caffeine given in
the first 2-3 days of life versus later. These studies suggest that caffeine administered
earlier in life may be beneficial in terms of respiratory outcomes. However, the effects of
caffeine administered shortly after birth are unknown and need to be studied with a
randomized, placebo-controlled trial.

The investigators postulate that by giving caffeine as soon as possible after birth,
intrinsic respiratory function will be supported sufficiently to avoid intubation altogether,
thus eliminating a major risk factor for BPD. Intravenous caffeine reaches therapeutic level
almost immediately, typically within thirty minutes of administration. However, the majority
of infants who require invasive ventilation are intubated within the first few hours of life,
usually before the infant has received caffeine. Additionally, many centers utilize minimally
invasive administration of surfactant, a medication that helps keep lungs open by lowering
surface tension, to treat respiratory distress syndrome of the newborn in attempt to avoid
intubation, as preterm neonates who do not require immediate intubation and instead receive
non-invasive continuous positive airway pressure (CPAP) at birth have decreased risk of BPD.
These techniques require spontaneous, effective breathing, and early caffeine administration
may aid in this process. This study aims to deliver caffeine to preterm infants immediately
after birth to determine whether intubation can be avoided.

While the primary outcome of this study is aimed at reducing intubation rates and thus
affecting rates of BPD, beneficial cardiovascular effects may also be noted. The incidence of
hypotension in preterm infants <28 weeks is as high as 78%.This study will also be using
non-invasive technologies to continuously monitor hemodynamic parameters including cardiac
function, output, blood flow, oxygenation to the brain surrounding the administration of
caffeine. Very early caffeine therapy may improve cardiovascular function in this early
transitional period, potentially decreasing the risk of devastating complications of
prematurity such as intraventricular hemorrhage.

This is a double-blinded, randomized, placebo-controlled clinical trial which will
investigate whether administration of caffeine to preterm neonates (<32 weeks' gestation)
within the first 2 hours of life compared to 12 hours of life will decrease the rate of
intubation during the first 12 hours of life. This study will also investigate whether
caffeine administration to preterm neonates (<32 weeks' gestation) increases cardiac output.
A total of 88 infants will be included in this study, randomized to two study arms. One arm
will receive intravenous caffeine citrate within 2 hours of life and placebo (normal saline)
at 12 hours of life, and the other arm will receive placebo within 2 hours of life and
caffeine citrate at 12 hours of life. Therefore, all participants will receive caffeine by 12
hours of life, and the only variable is the timing of caffeine.

Inclusion Criteria:

- Neonates <32 weeks' gestational age born at LAC+USC Medical Center or Hollywood
Presbyterian Medical Center will be considered for enrollment

Exclusion Criteria:

- Exclusions are major congenital anomalies, major cardiac defects (other than patent
ductus arteriosus, patent foramen ovale, small atrial septal defect, and small
ventricular septal defect), and intubation in the delivery room

- If intravenous access is not obtained within the first 2 hours of life (either through
peripheral IV or central venous catheter), then the neonate will no longer be eligible
for the study.