Neurally Adjusted Ventilatory Assist for Neonates With Congenital Diaphragmatic Hernias (NAN-C)

Congenital Diaphragmatic Hernias (CDH) are typically repaired surgically in the first few days of a neonate's life. Following surgical repair, infants usually require ventilatory support to ensure adequate oxygenation. Traditionally assist control ventilation (ACV) has been used to support neonates with CDH. Due to delivering a fixed pressure of oxygen, ACV has been associated with barotrauma and long-term lung damage. A more recent approach to ventilation is non-invasive neurally adjusted ventilatory assist (NIV-NAVA). NIV-NAVA uses electrical signals of the diaphragm to deliver a proportional pressure of oxygen. Our dual-centre randomised cross-over trial aims to investigate the efficacy of NIV-NAVA compared to ACV for supporting neonates with CDH.

Study Overview

• Status: Active, not recruiting
• Conditions: Congenital Diaphragmatic Hernia
• Intervention / Treatment: Device: Assist Control Ventilation; Device: Neurally Adjusted Ventilatory Assist

Detailed Description

Background:

Congenital Diaphragmatic Hernias (CDH) are typically repaired surgically in the first few days of a neonate's life. Following surgical repair, infants usually require ventilatory support to ensure adequate oxygenation. Traditionally assist control ventilation (ACV) has been used to support neonates with CDH. Due to delivering a fixed pressure of oxygen, ACV has been associated with barotrauma and long-term lung damage. A more recent approach to ventilation is non-invasive neurally adjusted ventilatory assist (NIV-NAVA). NIV-NAVA uses electrical signals of the diaphragm to deliver a proportional pressure of oxygen. Evidence suggests that NAVA may reduce physiological parameters associated with lung pressure and hence reduce the risk of iatrogenic lung injury.

Aims:

Our aim is to compare the oxygenation index (OI) of neonates with CDH, ventilated with ACV and NIV-NAVA. The OI is calculated as the fractured of inspired oxygen x mean airway pressure x partial pressure of oxygen/100. The oxygenation index is used as a marker of hypoxic respiratory failure in infants with CDH and forms the basis of the criteria to administer nitric oxide.

Methods:

Our investigation is a dual-centre randomised cross-over trial. Infants will be identified and parents counselled in the first few days following delivery. Neonates that meet inclusion criteria will be randomised to receive either NIV-NAVA or ACV first, followed by the other method of ventilation. Infants will be stabilised on ACV one-hour prior to entering the trial. On entry into the trial, they will receive 4-hours of each ventilatory method with a 20-minute stabilisation break in between.

• Study Type: Interventional
• Enrollment (Estimated): 18
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Anne Greenough, Professor; Phone Number: 020 3299 3105; Email: anne.greenough@kcl.ac.uk

Study Locations

• United Kingdom
  • London, United Kingdom
    • Kings College Hospital
  • London, United Kingdom
    • St. George's University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Infants born with congenital diaphragmatic hernia more than 34-weeks gestation

Exclusion Criteria:

• Receiving Nitric Oxide
• Requiring an FIO2 more than 80% to maintain SpO2: 85-95%.
• Severe chromosomal abnormality
• Severe cardiac anomalies requiring corrective surgery
• Renal anomalies
• Skeletal deformities suspected to impede thoracic or lung development
• Severe central nervous system anomalies suspected to impede diaphragmatic signalling
• Use of neuromuscular blocking agents
• Contraindication to nasogastric tube insertion

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Assist Control Ventilation (ACV); Infants will first be ventilated with ACV for four hours. Following this, they will undergo a 20-minute stabilisation period prior to ventilating with non-invasive neurally adjusted ventilatory assist.	Device: Assist Control Ventilation; ACV delivers fixed oxygen pressure set by the clinician at the start of each inspiratory breath.; Device: Neurally Adjusted Ventilatory Assist; NAVA uses electrical signals of the diaphragm to deliver a proportional pressure of oxygen, to which proportion is set by the clinician as the NAVA level.; Other Names: Assist Control Ventilation
Experimental: Neurally Adjusted Ventilatory Assist; Infants will first be ventilated with NAVA for four hours. Following this, they will undergo a 20-minute stabilisation period prior to ventilating with assist control ventilation (ACV).	Device: Assist Control Ventilation; ACV delivers fixed oxygen pressure set by the clinician at the start of each inspiratory breath.; Device: Neurally Adjusted Ventilatory Assist; NAVA uses electrical signals of the diaphragm to deliver a proportional pressure of oxygen, to which proportion is set by the clinician as the NAVA level.; Other Names: Assist Control Ventilation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Oxygenation Index (OI)	Oxygenation Index is calculated as MAP x FIO2 x PaO2/100. MAP is the mean airway pressure. FIO2 represents the concentration of inspired oxygen and PAO2 is the partial pressure of oxygen. The OI is a reliable indicator of lung function, previous research has shown its use in the prognostication of neonates with CDH.	Infants will receive each mode of ventilation for four hours. OI will be recorded every 5-minutes for the final 30-minutes of each ventilation period. The OI will be averaged over the 30-minute time frame. This average OI will then be compared.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Respiratory Severity Score (RSS)	The respiratory severity score is calculated as RSS = FIO2 x MAP. Where FIO2 represents the fraction of inspired oxygen and MAP is the mean airway pressure. In one multivariate analysis of 59 infants with CDH, RSS was an effective prognostic marker.	RSS will be recorded every 5-minutes for the final 30-minutes that the infant is on each ventilation mode. This will be compared to their baseline 30-minutes pre-randomisation and between ventilation modes.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Morphine Equivalent Use	Analgesic medication will be used with a basal-bolus regimen with the option for as required analgesia based on perceived pain and agitation.	The cumulative total of morphine used during the four-hour period on each ventilation mode will be calculated. This will be compared between ventilation modes.
Midazolam Equivalent Use	Cumulative midazolam use on each ventilatory method will be calculated.	The cumulative total of midazolam, or equivalent benzodiezapine, used during the four-hour period on each ventilation mode will be calculated. This will be compared between ventilation modes
Mean Airway Pressure (MAP)	The MAP is mean pressure the lungs are exposed to during inspiration and expiration. Mean airway pressure is one of the main determinants of oxygenation.	MAP will be recorded every 5-minutes for the final 30-minutes that the infant is on each ventilation mode. This will be compared to their baseline 30-minutes pre-randomisation and between ventilation modes.
Fraction of Inspired Oxygen (FIO2)	The FIO2 is the concentration of oxygen delivered expressed as a percentage.	FIO2 will be recorded every 5-minutes for the final 30-minutes that the infant is on each ventilation mode. This will be compared to their baseline 30-minutes pre-randomisation and between ventilation modes.
Peak Inspiratory Pressure (PIP)	Peak Inspiratory Pressure is defined as the pressure reached at the end of inspiration.	PIP will be recorded every 5-minutes for the final 30-minutes that the infant is on each ventilation mode. This will be compared to their baseline 30-minutes pre-randomisation and between ventilation modes.

Collaborators and Investigators

• Sponsor: King's College Hospital NHS Trust
• Collaborators: St George's, University of London

Study record dates

Study Major Dates

• Study Start (Actual): May 26, 2023
• Primary Completion (Estimated): June 1, 2024
• Study Completion (Estimated): June 1, 2024

Study Registration Dates

• First Submitted: April 7, 2023
• First Submitted That Met QC Criteria: April 20, 2023
• First Posted (Actual): May 3, 2023

Study Record Updates

• Last Update Posted (Actual): June 1, 2023
• Last Update Submitted That Met QC Criteria: May 31, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Congenital Abnormalities; Pathological Conditions, Anatomical; Internal Hernia; Hernia; Hernias, Diaphragmatic, Congenital; Hernia, Diaphragmatic
• Other Study ID Numbers: 319769

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Requests for individual participant data will be reviewed by the principal investigator. On request, data will be made available to other researchers 6-months following trial cessation. Parents will be consented to share their child's data for research purposes. All data will be anonymised on entry into the trial so no individual data point will be recognisable.

IPD Sharing Time Frame

It is our intent that the NAN-C protocol will be published, following SPIRIT guidelines, following the start of the trial.

At present, there are no plans to grant public access to the full protocol, participant-level data set or statistical code. For 6-months following publication of the final study results, investigators will be granted priority for secondary data analyses. Following this period, requests for de-identified data will be considered. Requests for data presented in the final paper should be submitted via email to Professor Anne Greenough.

• IPD Sharing Access Criteria: Requests for data presented in the final paper should be submitted via email to Professor Anne Greenough.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No