Enteral Nutrition Tolerance And REspiratory Support (ENTARES)

Study Overview
=================
Brief 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.

Official Title
-----------------
Enteral Nutrition Tolerance and Non-invasive Respiratory Support in Preterm Infants

Conditions
-----------------
Enteral Feeding Intolerance, Very Low Birth Weight Infant, Respiratory Distress Syndrome in Premature Infant

Intervention / Treatment
-----------------
* Device: HHHFNC
* Device: NCPAP


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: diagnosis of RDS stability on HHHFNC or NCPAP since at least 48 hours (SatO2 TC 90-95%, pCO2 ≤ 60 mmHg, FiO2 < 40%, Silverman score ≤ 6, ≤ 2 apnea episodes/hour with CPAP ≤ 7 cmH2O if on NCPAP and flow ≤ 6 L/min if on HHHFNC ) ≤ 7 days of life suitability to start enteral feeding (if not already started) parental written consent Exclusion Criteria: neurological or surgical diseases sepsis chromosomal abnormalities or major malformations

Ages Eligible for Study
-----------------
Minimum Age: 25 Weeks
Maximum Age: 29 Weeks

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: HHHFNC<br>Heated Humidified High Flow Nasal Cannulae | Device: HHHFNC<br>* 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).<br>|
| Active Comparator: NCPAP<br>Nasal Continuous Positive Air Pressure | Device: NCPAP<br>* 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).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Full Enteral Feeding (FEF) time | Time to reach Full Enteral Feeding, defined as an enteral intake of 150 mL/kg/die (n. of days) | From date of randomization until the date of hospital discharge or date of death, whichever came first, assessed up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Half Enteral Feeding (HEF) time | Time to reach Full Enteral Feeding/2, defined as an enteral intake of 75 mL/kg/die (n. of days) | From date of randomization until the date of hospital discharge or date of death, whichever came first, assessed up to 6 months | 
| Enteral feeding interruptions | Median number of feeding interruptions per day | From date of randomization until the date of hospital discharge or date of death, whichever came first, assessed up to 6 months | 
| Not given feeds | Median number of not given feeds per day | From date of randomization until the date of hospital discharge or date of death, whichever came first, assessed up to 6 months | 
| Pathologic gastric residuals | Median number of pathologic gastric residuals per day | From date of randomization until the date of hospital discharge or date of death, whichever came first, assessed up to 6 months | 
| Vomits and/or regurgitations | Median number of vomits and/or regurgitations per day | From date of randomization until the date of hospital discharge or date of death, whichever came first, assessed up to 6 months | 
| Abdominal distension | Median abdominal distension score per day | From date of randomization until the date of hospital discharge or date of death, whichever came first, assessed up to 6 months | 
| Beginning of oral feeding | Post-menstrual age when bottle- or breast-feeding is started | From date of randomization until the date of hospital discharge or date of death, whichever came first, assessed up to 6 months | 
| Full oral feeding time | Post-menstrual age when full bottle- or breast-feeding is achieved | From date of randomization until the date of hospital discharge or date of death, whichever came first, assessed up to 6 months | 
| Weight growth | Weight growth evaluated through Δ z-score analysis | From date of randomization until the date of hospital discharge or date of death, whichever came first, assessed up to 6 months | 
| Duration of respiratory support assigned at randomization | Time during which the non-invasive respiratory support device assigned at randomization is maintained | From date of randomization until the date of hospital discharge or date of death, whichever came first, assessed up to 6 months | 
| Total duration of respiratory support need | Time during which any kind of respiratory support is needed | From date of randomization until the date of hospital discharge or date of death, whichever came first, assessed up to 6 months | 
| Failure of the respiratory support assigned at randomization | Failure of the respiratory support assigned and need for mechanical ventilation or different kind of respiratory support (n. of days) | From date of randomization until the date of hospital discharge or date of death, whichever came first, assessed up to 6 months | 
| Length of hospital stay | Total duration of hospital stay (n. of days) | From date of randomization until the date of hospital discharge or date of death, whichever came first, assessed up to 6 months | 
| Complications | Occurrence of complications as NEC, bowel perforation, pneumothorax, BPD, retinopathy of the premature. | From date of randomization until the date of hospital discharge or date of death, whichever came first, assessed up to 6 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
RDS, Feeding Tolerance, HFNC, NCPAP, Preterm, NEC, Enteral Nutrition, Non Invasive Respiratory Support, Very Low Birth Weight Infant