Caffeine Treatment in in the Delivery Room
Condition: Respiratory Distress Syndrome
MeSH terms: Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn
Study type: Interventional

Summary: 
      Background. In recent years, particular attention has been paid to all interventions that
      could help reduce the need for mechanical ventilation MV and, therefore, the risk of BPD.
      However, early application of non-invasive respiratory supports and early treatment with
      surfactant fail in 45-50% of cases. Failure frequently depends on the onset of apnea episodes
      and, therefore, it has been proposed to treat very preterm infants with caffeine already in
      the delivery room in the first min of life.

      Hypothesis and objectives of the study. Our aim is to verify the hypothesis that it is
      possible to administer caffeine in the delivery room intravenously and enterally via an
      orogastric tube.

      Study design. Infants 25-29 weeks of gestational age will be enrolled and will be randomized
      to receive 20 mg/kg of caffeine citrate intravenously, via the umbilical vein, or enterally,
      through an orogastric tube, within 10 min of birth. The dosage of plasma caffeine
      concentration will be performed 60+15 min after administration to measure its peak and 60+15
      min before the next dose (5 mg/kg/day i.v.).

      Endpoints. The primary endpoint will be the evaluation of the success rate of intravenous or
      enteral administration of caffeine in the delivery room. Secondary endpoints will be the
      evaluation of: number of infants in whom caffeine will be successfully administered by
      intravenous versus enteral route; number of infants where caffeine will be successfully
      administered that reached the therapeutic plasmatic range the first dose, confirming the
      success of the administration; comparison of caffeine blood level obtained with intravenous
      and enteral administration; frequency of successes in obtaining the therapeutic range after
      the second dose; frequency of MV within the first 72 hours of life in studied infants.

      Statistical analysis. In the absence of previous studies to use as a reference and this study
      being a feasibility study, it was decided arbitrarily to study 20 infants treated in the
      delivery room with caffeine administered intravenously and 20 infants treated in the delivery
      room with caffeine administered enterally. The clinical characteristics of the two groups
      will be described by calculating the mean value and the standard deviation or the rate and
      percentage. The primary endpoint will be evaluated by calculating the percentage of cases in
      which caffeine will be successfully administered. The comparison between the number of
      infants in which caffeine will be successfully administered intravenously versus the enteral
      route and the comparison between the caffeine plasma level obtained with intravenous and
      enteral administration will be performed using the Student "t" test for continuous parametric
      variables, the Wilcoxon rank sum test for non-parametric continuous variables and the χ2 test
      for categorical variables. A p <0.05 will be considered as statistically significant.
    

Detailed description: 
      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.

      MATERIALS AND METHODS Patients. The study will be conducted in 2 Third Level Neonatal
      Intensive Care Units after approval by local ethics committees.

      Inclusion criteria. Once the written informed consent of the parents or legal guardians has
      been obtained, inborn infants of 25+0-29+6 weeks of gestational age at high risk of
      developing "respiratory distress syndrome" (RDS), who do not require MV in the delivery room,
      will be enrolled in the study.

      Exclusion criteria. Exclusion criteria will be: maternal consumption of caffeine before
      giving birth (> 2 cups of coffee in the 6 hours before birth), major congenital
      malformations, chromosomal syndromes, fetal hydrops, and inherited metabolic disorders.

      Design of the study. Infants will be electronically randomized to receive 20 mg/kg (1 mL=20
      mg) of caffeine citrate (Peyona®, Chiesi Farmaceutici Spa, Parma, Italy) intravenously, via
      the umbilical vein, or enterally, through an orogastric tube, within 10 min of birth.

      Intravenous administration may take place via an umbilical venous catheter or a "butterfly"
      needle inserted into the umbilical vein. The bolus of caffeine will be followed by the
      administration of a 2 mL "flush" of saline both in the case of administration by venous and
      enteral route. Successes and failures of the administration with the two different methods
      will be recorded.

      The level of plasma caffeine concentration will be measured 60+15 min after the
      administration to evaluate its peak and 60+15 min before the administration of the second
      dose (5 mg/kg/day i.v.) which will be given after admission in neonatal intensive care unit
      10. The plasma level will be measured using the "dried blood spots" method with spectrometry
      and "tandem-mass" liquid chromatography 11 in the Laboratory of Clinical Chemistry and
      Pharmacology of the A. Meyer Pediatric Hospital of Florence. Blood samples will be collected
      with heel punctures commonly performed for monitoring these patients and stored at -80°C
      until to analysis.

      If necessary, resuscitation in the delivery room will be performed following the guidelines
      of the AAP/ AAH 12. After admission in neonatal intensive care, infants who have not required
      VM in the delivery room will be assisted with the following non-invasive respiratory
      supports: nasal continuous positive airway pressure (NCPAP), "bi-level" NCPAP (BiPAP), nasal
      intermittent mandatory ventilation (N-IMV) using a CDP/ PEEP of 5-8 cmH2O. Surfactant
      (Curosurf ®, Chiesi, Parma, Italy) will be given (200 mg/kg) according to the INSURE
      (Intubation-SURfactant-Extubation) or LISA (Less-Invasive-Surfactant-Administration)
      technique in infants requiring FiO2 >0.30 to maintain a SpO2 90-95% and in all infants who
      will need MV.

      MV will be started in the case of pCO2 >65 mmHg and pH <7.20, or pO2 <50 mm Hg with FiO2
      >0.50 after surfactant administration or in case of apnea (> 4 episodes in 1 hour or> 2
      episodes in 1 hour requiring manual ventilation), and will be conducted with the aim of
      maintaining a pCO2 of 55-65 mmHg and a SpO2 of 90-95% 9, using synchronized VM (patient
      triggered ventilation: PTV), or the volume controlled VM, or high frequency ventilation
      (HFV).

      Collected data. For each infant will be recorded: gestational age; birth weight; birth weight
      <10th percentile; gender; type of delivery; Apgar score at 5 min; main disorders of pregnancy
      (pre-eclampsia, premature rupture of membranes, clinical chorioamniositis, placental
      abruption); RDS, whose diagnosis will be based on the occurrence of oxygen-dependence,
      tachypnea, dyspnea, exclusion of other causes of respiratory failure, and the presence of a
      typical radiological pattern; treatment with surfactant and nitric oxide; need, type and
      duration of respiratory assistance (oxygen therapy, NCPAP, BiPAP, N-IMV, PTV, HFV); prenatal
      and postnatal steroid treatment. In addition, common complications of prematurity will be
      recorded: patency of the ductus arteriosus (PDA) requiring drug therapy, bronchopulmonary
      dysplasia (BPD), intraventricular hemorrhage (ICH) of 3-4 grade 13, periventricular
      leukomalacia (LPV) 14, retinopathy of prematurity (ROP) of grade >3 15, necrotizing
      enterocolitis (NEC) <2 grade 16, and sepsis. In addition, mortality and the duration of
      hospitalization will be reported.

      Permitted concomitant pharmacological treatments. The enrolled patients can be treated with
      the following drugs: surfactant, caffeine, doxapram, ibuprofen, paracetamol, indomethacin,
      dopamine, dobutamine, milrinone, adrenaline, diuretics, antibiotics, glucocorticoids,
      immunoglobulins, antiepileptics, nitric oxide, analgesics, sedatives.

      List of participating centers. Patients will be enrolled at the neonatal intensive care units
      of Careggi University Hospital of Florence and of IRCCS Foundation - Ospedale Maggiore
      Policlinico Mangiagalli and Regina Elena of Milan.

      ENDPOINTS Primary endpoint. The primary endpoint will be the evaluation of the number of
      infants in whom the administration of caffeine intravenously or enterally will occur
      successfully in the delivery room delivery within 10 min of life.

      Secondary endpoints. Secondary endpoints will be the evaluation of: number of infants in whom
      caffeine will be successfully administered by intravenous versus enteral route; number of
      infants where caffeine will be successfully administered that reached the therapeutic
      plasmatic range the first dose, confirming the success of the administration; comparison of
      caffeine blood level obtained with intravenous and enteral administration; frequency of
      successes in reaching the therapeutic range after the second dose; frequency of VM within the
      first 72 hours of life in studied infants.

      STATISTICAL ANALYSIS Sample size. In the absence of previous studies to use as a reference
      and this study being a feasibility study, it was decided arbitrarily to study 20 infants
      treated in the delivery room with caffeine administered intravenously and 20 infants treated
      in the delivery room with caffeine administered enterally.

      Description and analysis of data. The clinical characteristics of the two groups will be
      described by calculating the mean value and the standard deviation or the rate and
      percentage.

      The primary endpoint will be evaluated by calculating the percentage of cases in which
      caffeine will be successfully administered. Similarly, the secondary endpoints, represented
      by the number of cases in which the therapeutic plasmatic range will be reached after the
      first and the second dose of caffeine and the frequency of VM within the first 72 hours of
      life, will be evaluated. The comparison between the number of infants in which caffeine will
      be successfully administered intravenously versus the enteral route and the comparison
      between the caffeine plasma level obtained with intravenous and enteral administration will
      be performed using the Student "t" test for continuous parametric variables, the Wilcoxon
      rank sum test for non-parametric continuous variables and the χ2 test for categorical
      variables. A p <0.05 will be considered as statistically significant.
    

Intervention name(s): Caffeine Citrate
Intervention type(s): Drug
Intervention description(s): Infants will receive 20 mg/kg of caffeine citrate intravenously, via the umbilical vein, or enterally, through an orogastric tube, within 10 min of birth.
Other intervention name(s): Caffeine
Intervention MeSH terms: Caffeine; Caffeine citrate
Intervention model: Single Group Assignment
Intervention model description: A cohort of preterm infants will be given caffeine in the delivery room
Masking: None (Open Label)
Primary purpose: Supportive Care
Keywords: Caffeine; delivery room; preterm infant