Treatment With Caffeine of Very Preterm Infant in the Delivery Room: the CAFROOM Feasibility Study

INTRODUCTION Background Mechanical ventilation (MV) is one of the most important risk factors for the development of bronchopulmonary dysplasia (BPD) in the preterm infant, due to the early pulmonary inflammation from volume- and baro-trauma and the secondary 1. Despite this, around 80% of infants born with gestational age <27 weeks must be treated with MV 2 for a respiratory distress syndrome (RDS), and in about 65% of cases it starts already in the delivery room in the first min of life 3.

Therefore, in recent years particular attention has been paid to all interventions that could help reduce the need of MV, thus reducing the risk of BPD. Among these interventions, the early application of non-invasive continuous positive airway pressure (CPAP), the use of sustained lung inflation (SLI), and early treatment with surfactant with INSurE (Intubation- Surfactant-Extubation) or LISA (less invasive surfactant administration) 1,4. These interventions have the common objective of promoting lung recruitment by promoting the development and maintenance of alveolar residual functional capacity (CFR), improving pulmonary compliance, reducing work of breathing and favoring gas exchange 1,4. Unfortunately, these treatments are not always effective and recent studies have shown that CPAP in combination or not with surfactant administration fails to prevent MV in about 45-50% of treated infants 3; similarly the SLI strategy in association with non-invasive CPAP and with the possible administration of surfactant fails to prevent MV in approximately 60% of treated infants 5. In fact, in many cases the failure of MV prevention does not depend on severity of RDS, which also remains a very important factor, but especially in mild-moderate forms of RDS is due to the onset of relapsing episodes of apnea. Therefore, it has been proposed to treat very preterm infants with caffeine in the delivery room already in the first min of life. This drug is very effective in the preterm infant in whom it has been shown to decrease the frequency of apnea, the risk of BPD, the duration of non-invasive respiratory supports, and the risk of re-intubation 6, also in infants without previous crisis of apnea 7.In fact, caffeine stimulates spontaneous respiratory activity, improves lung compliance and minute volume, reduces airway resistance, and increases diaphragm contractility, together with a good safety profile and without significant side effects at current doses 6. In a recent pilot study, Katheria et al. randomized 21 infants with gestational age <29 weeks to receive 20 mg/kg of caffeine citrate within 2 h of life or at 12 hours of life obtaining in treated infants a decrease, although not statistically significant, of the need of VM (27 vs. 70%) in association with an overall hemodynamic improvement 8. Subsequently, Dekker et al. randomized 23 infants of 24-29 gestational weeks to receive 10 mg/kg of caffeine in the delivery room or immediately after arrival in neonatal intensive care unit (4.4 vs. 48 min of life) demonstrating that early treatment is associated with a significant increase in tidal volume and a lower need for oxygen-therapy 9. Although the results were promising, neither study measured the plasma concentration of caffeine or had sufficient statistical power to assess whether caffeine administered in the delivery room is effective in reducing the risk of mechanical ventilation.

Study hypothesis The present feasibility study aims to evaluate the possibility of administering caffeine in the delivery room intravenously and enterally through an orogastric tube during the postnatal stabilization of the preterm infant. It is preliminary to the planning of a subsequent randomized controlled trial of adequate size, which will aim to assess whether caffeine administered so early can actually reduce the risk of MV in preterm infants.

Objectives of the study Primary objectives of the study. The primary objective will be the evaluation of the feasibility of the administration of intravenous or enteral caffeine in the very preterm infant in the delivery room during assistance for cardiorespiratory stabilization of the infant.

Secondary objectives of the study. The secondary objectives will be to compare the feasibility of administering caffeine intravenously vs. enteral and evaluation of the need for MV in treated infants.