Comparing CPAP Titration Strategies in very preterm infants at birth

Continuous positive airway pressure (CPAP) is routinely used in the delivery
room to support spontaneous breathing of preterm infants. Although
international guidelines currently recommend 5-8 cm H2O CPAP in the delivery
room, data to support this recommendation is limited and the optimal CPAP
strategy is unknown. In preterm rabbit and lamb models we demonstrated that
using a dynamic CPAP strategy is more effective for supporting spontaneous
breathing. Using an initially high CPAP-level of 15 cm H2O promoted lung liquid
clearance and lung aeration. Once lung aeration and breathing has been
established CPAP level can be lowered as a CPAP level of 8 cm H2O will be
enough to prevent lung liquid return and maintain lung volume. This high-level
CPAP strategy (HCPAP) has shown to improve breathing effort and oxygenation. We
hypothesize that this dynamic high CPAP strategy of 15-8 cm H2O is more
effective in supporting preterm infants at birth than the currently used
low-level CPAP 5-8 cm H2O (LCPAP). Before performing a large clinical trial we
will perform a small clinical trial to verify the preclinical findings of HCPAP
in preterm infants at birth.

To compare the effect of a HCPAP with LCPAP on oxygenation in the first 5
minutes during stabilization in preterm infants at birth.

Single center randomized controlled study

HCPAP vs low LCPAP strategy.

Infants allocated to the HCPAP (intervention group) will start on 15 or 8 cm
H2O CPAP depending on their breathing effort directly after birth. Infants with
poor breathing effort will initially receive 15 cm H2O CPAP which will be
titrated to 8 cm H2O (in steps of 2-2-3 cm H2O per minute) after the infant i)
is breathing on CPAP ii) reached a SpO2 * 85% with FiO2 * 0.4 and iii) heart
rate * 100 bpm. Infants with good breathing effort will start with 8 cm H2O
CPAP directly.

Infants allocated to the LCPAP (control group) will receive initially 5 cm H2O
CPAP, but can be titrated to up to 8 cmH2O depending on their breathing and
oxygenation. This is conform local guideline.

The burden and risk are expected to be equal between the groups based on
preclinical experiments. The optimal CPAP strategy to support breathing of
preterm infants at birth is currently unknown and the current recommendation
of 5-8 cm H2O is largely based on dogma. CPAP of 5-8 cm H2O CPAP may be
insufficient to support breathing increasing the need of positive pressure
ventilation, supplemental oxygen and intubation, which have the potential to
injure the preterm lungs and brain. Initiating respiratory support with high
CPAP and down-titration after lung aeration fits more with the changing lung
characteristics during the cardiopulmonary transition at birth and is supported
by animal data. Animal research showed that high CPAP improves the oxygenation
while reducing the supplemental oxygen requirement. If successful, this
strategy could reduce the need for invasive respiratory support.

The burdens associated with participation are minimal as all infants born
before 30 weeks gestational age already receive CPAP at birth. We also expect
the risks to be minimal as none of the animal studies in spontaneous breathing
lambs and sheep shown an increased risk when using 15 cm H2O CPAP. Also, a
retrospective study in the LUMC has shown that circa 80% of the preterm infants
receive ventilation directly at birth when they are supported with 5-8 cm H2O
CPAP. During ventilation the mean airway pressure is already 15 cm H2O CPAP,
thus the CPAP of 15 cm H2O will not be higher than the pressure that the
majority of the infants already receive as standard of care.

The results of this pilot study will directly be translated to a protocol for a
larger clinical trial using clinically important outcomes. As most preterm
infants born need stabilization and respiratory support at birth, this trial
will affect treatment of many preterm infants.