Effects of Flow Magnitude on Cardiorespiratory Stability During Nasal High Flow Therapy in Preterm Infants

Study Overview
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Brief Summary
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Premature babies often need help breathing for a longer period of time. Traditionally, this is done with a breathing aid called NCPAP (nasal continuous positive airway pressure). This treatment is safe and effective, but it is very time-consuming and can sometimes have side effects. In the present research project, the investigators want to find out whether another type of breathing aid called NHF (nasal high flow therapy) is just as effective for stable premature babies. The investigators suspect that NHF is just as effective, but easier to use and more comfortable.

Detailed Description
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This is a single center parallel group three arm randomized controlled clinical trial investigating cardiorespiratory stability in stable preterm infants receiving NHF. Currently, NCPAP remains the gold standard for administration of prolonged non-invasive ventilatory support in very preterm infants. NHF is a promising method for tailored, less invasive long-term ventilatory support for preterm infants. If ventilatory support with NHF is similarly effective to conventional NCPAP in stable preterm infants, clinicians are likely to adopt this method for widespread clinical use because of its improved comfort and potential other benefits. Primary aim of this trial is to examine cardiorespiratory stability in preterm infants treated with two commonly used NHF flowrates (Interventional group 1 and 2) in comparison to NCPAP (Comparator). Secondary aim is to examine potential comfort-related beneficial effects of NHF.

Official Title
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Effects of Flow Magnitude on Cardiorespiratory Stability During Nasal High Flow Therapy in Preterm Infants (MASTER Trial)

Conditions
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Respiratory Distress Syndrome

Intervention / Treatment
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* Other: NHF high
* Other: NHF low
* Other: NCPAP


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion if all apply. Preterm infants up to 31+6 weeks GA admitted to the Division of Neonatology at Inselspital Bern (inborn or outborn) >2nd day of life (defined as date day) Stable on NCPAP 6 cm H2O for ≥ 24 hours, defined as: ≤ 2 apneas with concomitant bradycardias (<100/min) per hour for the previous 6 hours FiO2 ≤ 0.3 and not increasing No significant chest recessions (Silverman Score < 5) Respiratory rate ≤ 60/min No need for intermittent positive pressure ventilation Parents with an age 18+ years Written parental informed consent (or other legal representative) Exclusion Criteria: Exclusion if any applies. Significant fetal anomalies Primary palliative care Stable on NCPAP 6 cm H2O according to stability criteria for more than 120 hours

Ages Eligible for Study
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Minimum Age: 23 Weeks
Maximum Age: 31 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NHF high<br>Nasal high flow therapy 8L/min | Other: NHF high<br>* Nasal high flow therapy 8L/min.<br>|
| Experimental: NHF low<br>Nasal high flow therapy 6L/min | Other: NHF low<br>* Nasal high flow therapy 6L/min.<br>|
| Active Comparator: NCPAP<br>Nasal continuous positive airway pressure 6 cm H20 | Other: NCPAP<br>* Nasal continuous positive airway pressure 6 cm H20<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment failure | Treatment failure is a composite outcome defined as meeting one of the following treatment failure criteria within 24 hours of starting of intervention: >2 apneas with concomitant bradycardias (<100/min) per hour for > 1 hour or FiO2 > 0.3 consistently for > 1 hour or Significant chest recessions (Silverman Score ≥ 5) for > 1 hour or Respiratory rate > 60/min consistently for > 1 hour or Any need for intermittent positive pressure ventilation The presence of Treatment failure within 24 hours of starting of intervention will be documented (dichotomous outcome; yes/no). | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Apneas and bradycardias | The total frequency of apneas and bradycardias (<100/min) within 24 hours of starting of intervention will be documented. | 24 hours | 
| Respiratory rate (RR) | The mean RR within 24 hours of starting of intervention will be documented. | 24 hours | 
| Heart rate (HR) | The mean HR within 24 hours of starting of intervention will be documented. | 24 hours | 
| Oxygen saturation (SpO2) and fraction of inspired oxygen (FiO2) | The mean SpO2/FiO2 ratio within 24 hours of starting of intervention will be documented. | 24 hours | 
| Frequency of any treatment failure | Treatment failure is a composite outcome (see Outcome 1). The frequency of any treatment failure during the duration of the study will be documented. | Individual study duration: estimated to be between a minimum of 7 days to an (estimated) maximum of 10 weeks. | 
| Rescue NCPAP | Rescue NCPAP is defined as NCPAP >6 cm H2O. The frequency of need for Rescue NCPAP during the duration of the study will be collected. | Individual study duration: estimated to be between 7 days to 10 weeks. | 
| Postmenstrual age (PMA) off positive pressure support | The investigators will document the PMA when the infant is off positive pressure support. | Estimated to be at a PMA of approximately 29 to 34 weeks. | 
| Postmenstrual age (PMA) off FiO2 > 0.21 | The investigators will document the PMA when the infant is off FiO2 > 0.21 | Estimated to be at a PMA between approximately 28 to 34 weeks. | 
| Postmenstrual age (PMA) at discharge | The investigators will document the PMA when the infant is being discharged from the hospital. | Estimated to be at a PMA of approximately 38-40 weeks. | 
| Cerebral oxygen saturation (cRSO2) 1 hour before until 3 hours after start of the intervention | The cerebral oxygen saturation (cRSO2) in [%] 1 hour before until 3 hours after start of the intervention will be measured by using Near-infrared spectroscopy (NIRS). | 4 hours | 
| Time spent <55% cRSO2 1 hour before until 3 hours after start of the intervention | The time spent <55% cRSO2 in [min] 1 hour before until 3 hours after start of the intervention will be measured by using Near-infrared spectroscopy (NIRS). | 4 hours | 
| Cerebral oxygen saturation (cRSO2) 1 hour before until 3 hours after cessation of the intervention | The cerebral oxygen saturation (cRSO2) in [%] 1 hour before until 3 hours after cessation of the intervention will be measured by using Near-infrared spectroscopy (NIRS). | 4 hours | 
| Time spent <55% cRSO2 1 hour before until 3 hours after cessation of the intervention | The time spent <55% cRSO2 in [min] 1 hour before until 3 hours after cessation of the intervention will be measured by using Near-infrared spectroscopy (NIRS). | 4 hours | 
| Change in end-expiratory lung impedance (ΔEELI) | The change Δ in end-expiratory lung impedance (ΔEELI) will be measured using electrical impedance tomography (EIT) at 8 different timepoints during the first 48 hours after starting of intervention. One measurement will last 6 minutes. The measurements will take place: within 2 hours before starting of intervention within 30 minutes after starting of intervention 2, 6, 12, 24, 36, and 48 hours after starting of intervention | 48 hours | 
| Change in global inhomogeneity (ΔGI) index | The change Δ in global inhomogeneity (ΔGI) index will be measured using electrical impedance tomography (EIT) at 8 different timepoints during the first 48 hours after starting of intervention. One measurement will last 6 minutes. The measurements will take place: within 2 hours before starting of intervention within 30 minutes after starting of intervention 2, 6, 12, 24, 36, and 48 hours after starting of intervention | 48 hours | 
| Change in variability of tidal volume (ΔTV) | The change Δ in variability of tidal volume (ΔTV) will be measured using electrical impedance tomography (EIT) at 8 different timepoints during the first 48 hours after starting of intervention. One measurement will last 6 minutes. The measurements will take place: within 2 hours before starting of intervention within 30 minutes after starting of intervention 2, 6, 12, 24, 36, and 48 hours after starting of intervention | 48 hours | 
| Change in ratio of tidal volume anterior/posterior (ΔRatio TV ap) | The change Δ in ratio of tidal volume anterior/posterior (ΔRatio TV ap) will be measured using electrical impedance tomography (EIT) at 8 different timepoints during the first 48 hours after starting of intervention. One measurement will last 6 minutes. The measurements will take place: within 2 hours before starting of intervention within 30 minutes after starting of intervention 2, 6, 12, 24, 36, and 48 hours after starting of intervention | 48 hours | 
| Incidence of Bronchopulmonary dysplasia (BPD) | The incidence with specification of severity of BPD at 36 weeks PMA will be documented. BPD is a form of chronic lung disease (CLD). BPD is classified into 3 levels of severity according to the internationally used definition of Jobe and Bancalari (1). FiO2 >0.21 for ≥ 28 days and Breathing room air (mild) FiO2 <0.3 (moderate) FiO2 ≥ 0.3 and/or positive pressure support (severe) (1) Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2001;163(7):1723-9. | At 36 weeks PMA | 
| Urinary cortisol | A 24-hour-urine-sample will be collected on the third study day. The urinary production rates of cortisol and the most important metabolites will be documented as an indicator for infant stress. | 24 hours | 
| COMFORTneo score | The COMFORTneo score will be documented on the third, fourth and fifth study day. The score measures comfort and chronic pain by observation. | 72 hours | 
| Revised Bernese Pain Scale for Neonates (BSN-R) score | The BSN-R score will be documented on the third, fourth and fifth study day. The score measures pain. | 72 hours | 
| Parental assessment of comfort | The parents will be asked 3 predefined questions concerning their infants' comfort on the on the third, fourth and fifth study day. | 72 hours | 
| NASA Task Load Index (NASA-TLX) | The NASA-TLX will be filled out by the participants' nurses on the third, fourth and fifth study day. The NASA-TLX is a questionnaire that measures workload. | 72 hours | 
| Nasal trauma score | The nasal trauma score is measured daily as a part of routine care. The highest Nasal trauma score during the duration of the study will be documented. Measuring nasal trauma using the Nasal trauma score takes approximately 20 seconds. | Individual study duration: estimated to be between 7 days to 10 weeks. | 
| Behavioral Sleep stage classification for Preterm Infants (BeSSPI) | Sleep-wake cycles as determined by the BeSSPI on the fourth study day will be documented. The BeSSPI identifies sleep stages by observation and takes approximately 2.5 hours. | 24 hours | 
| Parental Bonding Questionnaire (PBQ) | The score of the PBQ will be documented at 36 weeks PMA. The PBQ investigates infant-parental bonding. | At 36 weeks PMA | 
| Age at initiating breastfeeds | The postmenstrual age (PMA) at initiating breastfeeds will be documented. This refers to the PMA at which the first successful breastfeeding attempt takes place. | Estimated to be between 30-34 weeks PMA. | 
| Age at reaching full breastfeeds | The postmenstrual age (PMA) at reaching full breastfeeds will be documented. This corresponds to 100% nutrition per breastfeeds for 24 consecutive hours. | Estimated to be between 34-40 weeks PMA. | 
| Weight | The weight in [g] at 36 weeks postmenstrual age (PMA) will be documented. | At 36 weeks PMA | 
| Head circumference | The head circumference in [cm] at 36 weeks postmenstrual age (PMA) will be documented. | At 36 weeks PMA | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Nasal high flow therapy, Continuous positive airway pressure