Enteral Nutrition Tolerance And REspiratory Support (ENTARES)
Condition: Very Low Birth Weight Infant; Respiratory Distress Syndrome in Premature Infant; Enteral Feeding Intolerance
MeSH terms: Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Birth Weight
Study type: Interventional

Summary: 
      This research study aims to evaluate the relation between non-invasive ventilation and
      feeding tolerance in preterms with respiratory distress syndrome (RDS).

      To this purpose a multicenter randomized controlled trial was designed. It will involve 13
      neonatal intensive care units (NICUs) in Italy and will be coordinated by the NICU of the
      University of Turin.

      The study focuses on the impact of two non-invasive respiratory support techniques (NCPAP and
      HHHFNC) on feeding intolerance and gastrointestinal complications to identify which technique
      is the most effective and safe in preterms with RDS. Further aim is to identify which
      technique could be the most suitable for full enteral feeding achievement and acquisition of
      oral feeding. Improving enteral feeding tolerance and promoting oral feeding could improve
      clinical outcomes and reduce risks and costs of prolonged hospital stay.

      Further aim is to evaluate the response to NCPAP and HHHFNC in the treatment of RDS, focusing
      on a population of extremely low preterms.
    

Detailed description: 
      BACKGROUND:

      Respiratory distress syndrome (RDS) is a common condition in premature infants and one of the
      major cause of neonatal mortality. For many years, preterm infants with RDS have been treated
      with mechanical ventilation increasing risks of acute lung injury and long-term morbidity, as
      bronchopulmonary dysplasia (BPD). Early nasal continuous positive airway pressure (NCPAP)
      treatment combined with surfactant replacement therapy decreases the need for mechanical
      ventilation and has been recommended as first line treatment for RDS. However, NCPAP has
      significant limitations, mainly related to the type of interface needed. Excessive leak
      around the prongs or mask and through the mouth can lead to inadequate support, whereas
      excessive pressure may result in pneumothorax and damage of the nose and face. Moreover, the
      bulky fixation devices obscure the infant's face both interfering with feeding and
      positioning. In recent years, heated humidified high-flow nasal cannula (HHHFNC) has been
      studied as an alternative non-invasive respiratory supports (NIReS). HHHFNC became popular
      partially thanks to some perceived advantages related to the type of interface used. Cannulae
      are easier to apply than NCPAP prongs or mask, may be more comfortable for infants, and may
      enable easier access to babies' faces, thus facilitating feeding and parental bonding.
      Whereas practical advantages seem to be established there is controversy about HHHFNC
      efficacy as respiratory support. Recent studies support that HHHFNC is as effective as NCPAP
      for the primary treatment of RDS, but evidences are still insufficient and data are still
      lacking, especially for the extremely preterm population (<28 weeks of gestation). A recent
      Cochrane comparing HHHFNC with other NIReS showed equivalent rates of treatment failure and
      similar rates of BPD when used as a post-extubation support in preterm infants. With
      equivalent effectiveness, the choice of the most adequate NIReS should consider the impact on
      the health status of the premature evaluating, above all, the effect on nutrition and growth.
      Along with RDS, feeding intolerance (FI) represents a relevant issue in preterm infants and
      the coexistence of the two represents a great challenge for the neonatologist. Because of
      gastrointestinal immaturity, almost 1:3 preterm infants develops clinical symptoms of FI
      causing interruptions of feeding which delays the establishment of adequate enteral nutrition
      and prolongs the need for parental nutrition thus increasing the risk of infections and
      prolonging hospital stay. Avoiding FI and its complication, as necrotizing enterocolitis
      (NEC), is a priority for the neonatologist, who often faces the challenge of interpreting the
      clinical and prognostic significance of common and aspecific signs of FI. Clear
      identification of the parameters that should be evaluated to identify FI is still lacking in
      literature, although, among controversy, the presence of gastric residuals, vomits and/or
      regurgitations, abdominal distension and the onset of crises of apnea/bradycardia are
      considered the most frequent signs. Literature and clinical practise suggest that a
      correlation between non-invasive ventilation and the occurrence of FI and NEC exists even if
      the mechanisms through which ventilation may induce FI and its incidence in ventilated
      infants are still unclear. Considering NIReS, the most common hypothesis is that pressurized
      gasses, that are not completely conveyed to the airways, could cause bowel distension. Bowel
      distension in infants on CPAP was described by Jaile et al. as CPAP belly syndrome but no
      inferences about feeding tolerance and risk of NEC was drawn. More recent studies evaluated
      the effect of CPAP on mesenteric flow and gastric emptying suggesting a role of CPAP as a
      risk factor for FI. No specific studies have been designed to evaluate the impact of
      different NIReS on FI and the occurrence of NEC, which are generally evaluated as secondary
      outcomes, susceptible to data analysis and patient selection biases. Our hypothesis is that
      different techniques of NIReS may have different impact on feeding issues in preterm infants.
      Therefore, our study will focus on the impact that the two most common NIReS (NCPAP and
      HHHFNC) have on feeding.

      PROJECT AIMS AND DESIGN:

      Aim of the study is to evaluate the effects on feeding tolerance of different NIReS
      techniques (NCPAP vs HHHFNC) in preterm infants with RDS and to evaluate their impact on full
      enteral feeding achievement and acquisition of oral feeding. Further aim is to evaluate the
      response to NCPAP and HHHFNC as treatment for RDS in extremely preterm infants. To these
      purposes a multicenter randomized controlled trial was designed. The research project will
      involve 13 neonatal intensive care units (NICU) in Italy and will be coordinated by the NICU
      of the University of Turin.

      PATIENTS:

      Basing on a population of infants with a gestational age <30 weeks and consecutively admitted
      to the NICUs of each research unit from January to June 2017 (mean time of FEF: 19.6 days,
      delta: 5.7) and considering a ratio between the subjects of the two arms of 1:1, the sample
      size to observe a difference of 30% between the 2 arms has been set at 141 patients per arm.

      PROTOCOL:

      After randomization each infant will be subsequently enrolled into the study and treated with
      NCPAP or HHHFNC as per randomization. Each research unit will refer to its own protocols for
      ventilation and nutrition, although respecting some minimal standard criteria and
      indications, common and approved by all research units. Common criteria for ventilation
      regard the suggested initial setup of NCPAP and HHHFNC and the indications suggested to try
      weaning and define failure and are listed below:

      Suggested initial setup:

      CPAP between 5 and 7 cmH2O if on NCPAP and flow between 4 and 7 L/min if on HHHFNC; FiO2 is
      set as to reach pO2 = 50 - 60 mmHg and SatO2 TC = 90 - 95%.

      Criteria to try weaning:

      CPAP < 4 cmH2O if on NCPAP and flow < 2 if on HHHFNC with FiO2 < 25% to maintain pO2 = 50 -
      60 mmHg and SatO2 TC = 90 - 95%.

      Failure criteria:

        -  FiO2 > 40%

        -  pH < 7.2

        -  pCO2 > 65 mmHg

        -  ≥ 3 episodes of desaturations (SatO2 TC ≤ 80%) per hour

        -  ≥ 3 episodes of apnea (> 20 sec) and/or bradycardia (FC ≤ 80 bpm) per hour

        -  Silverman score > 6

      The indications for the interruption of feeding are based on abdominal examination, on the
      occurrence of vomits/regurgitations and crises of apnea/bradycardia and on the evaluation of
      alvus and gastric residual volumes, if required by the protocol of the unit. The maximum
      cut-off for feeding progression is set at 30 mL/Kg/day. Data on ventilation, nutrition,
      growth and clinical events will be collected from enrollment to discharge.

      DATA ANALYSIS:

      Data will be analysed according to an intention-to-treat model. Therefore, data from all
      infants enrolled into the study will be considered for the analysis. Death and transfer to
      another hospital, before reaching full enteral feeding, are the only two reasons for
      exclusion. The primary outcome will be evaluated by a survival analysis with non-parametric
      distribution. Secondary outcomes will be evaluated by Fisher's exact test or appropriate
      generalized linear models.

      EXPECTED RESULTS AND IMPACT ON CLINICAL PRACTICE:

      The identification of the most suitable NIReS for preterm infants with RDS and FI could
      reduce gastrointestinal complications, improve growth and reduce hospital stay, thus
      improving quality of life of infants and their family and reducing health costs. The
      evaluation of the timing of oral feeding could be useful to understand the influence that
      NIReS techniques have on the development of sucking-swallowing coordination. The evaluation
      of the response to NCPAP and HHHFNC could clarify their efficacy as treatment for RDS in
      extremely preterm infants.
    

Intervention name(s): HHHFNC; NCPAP
Intervention type(s): Device; Device
Intervention description(s): Application to HHHFNC to treat respiratory distress syndrome in preterm infants previously demonstrated to be stable on a non-invasive respiratory support (HHHFNC or NCPAP).; Application to NCPAP to treat respiratory distress syndrome in preterm infants previously demonstrated to be stable on a non-invasive respiratory support (HHHFNC or NCPAP).
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Two arms multicenter randomized controlled trial designed according to the intention-to-treat model. The assignement to one of the two arms (NCPAP or HHHFNC) is by block randomization. The randomization program is designed to obtain, in each research unit, a balance between the two arms according to gestation age (GA <28 weeks and GA ≥ 28 weeks).
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Feeding Tolerance; RDS; HFNC; NCPAP; Preterm; NEC; Enteral Nutrition; Non Invasive Respiratory Support; Very Low Birth Weight Infant