deMISTify: The Impact of Ventilator Pressure Levels During Minimally Invasive Surfactant Therapy on Lung Aeration in Preterm Infants

deMISTify: The Impact of CPAP Levels During Minimally Invasive Surfactant Therapy on Regional Patterns of Ventilation in Preterm Infants

Infants born preterm (before 36 weeks' gestation age) have immature lungs and struggle to breathe on their own. They are supported via respiratory machines like ventilators, as well as pharmaceutical aids like surfactant replacement therapy. Surfactant replacement therapy is an established therapy for the treatment of respiratory distress syndrome, which is a common illness in infants born preterm.

Surfactant replacement therapy can be delivered to an infant's lungs a few ways, including via a small tube that is briefly placed down an infant's throat. This is considered the least invasive method currently available, and is becoming more popular. It is referred to as minimally invasive surfactant therapy (MIST). A baby can receive surfactant via MIST if they are receiving non-invasive respiratory support, like from a continuous positive airway pressure (CPAP) machine.

Doctors and researchers are looking for simple ways to make MIST more effective. This clinical trial will investigate if briefly increasing the air pressure delivered by a CPAP machine before giving MIST therapy will make MIST more effective. This strategy is called a lung recruitment manoeuvre (LRM), because it opens up more of the lungs - 'recruits' them - to help with oxygenation. The CPAP setting that is briefly changed is called positive end expiratory pressure (PEEP) - it increases the amount of air left in the lungs at the end of a breath. This stops parts of the lung collapsing when exhaling, which commonly occurs in the lungs of infants born preterm as they are immature.

The goal of this clinical trial is to investigate if a LRM prior to MIST improves ventilation and lung aeration in preterm infants born 24-32 weeks' gestation. The main question it aims to answer is: How a LRM prior to MIST might impact patterns of ventilation and lung aeration in preterm infants, compared to no LRM prior to MIST.

The current standard of care is no LRM before MIST. Researchers will compare this current standard against a LRM before MIST to see if it potentially improves patterns of ventilation.

Participants will be randomly placed (by chance) to receive either no LRM before MIST (control) or a LRM before MIST (intervention). Participants will be randomised once their treating clinical team have decided to give MIST.

Infants born preterm (before 36 weeks' gestation age) have immature lungs and struggle to breathe on their own. They are supported via respiratory machines like ventilators, as well as pharmaceutical aids like exogenous surfactant. Exogenous surfactant is an established therapy for the treatment of respiratory distress syndrome and may reduce the risk of an infant developing bronchopulmonary dysplasia.

Exogenous surfactant therapy can be administered via an endotracheal tube which is either permanent, or transiently placed, but can now also be administered via less-invasive techniques. Minimally Invasive Surfactant Therapy (MIST) uses a thin catheter that is passed through the vocal cords to deliver exogenous surfactant directly into the lungs when an infant is on non-invasive respiratory support. MIST is becoming increasing popular in neonatal practice as more infants are managed on non-invasive respiratory support, and it is considered lower-risk compared to techniques that transiently place an endotracheal tube for surfactant therapy as there is no risk of extubation failure.

To further improve surfactant therapy, optimisations of delivery techniques have been explored. One optimisation that has been investigated with the transient endotracheal tube method of delivery surfactant is adding a lung recruitment manoeuvre (LRM) prior to surfactant delivery. This demonstrated a reduced need for mechanical ventilation within 72 hours following a LRM compared to infants which did not receive the LRM before surfactant via a transient endotracheal tube. By adding a lung recruitment component to MIST, the benefits of this more invasive method may be replicated without increasing risk of extubation failure.

deMISTify is a blinded, randomised, controlled trial of preterm infants, 24-32 weeks' gestation, receiving continuous positive airway pressure (CPAP) respiratory support and MIST. The primary aim of the study is to investigate the impact of a LRM prior to MIST on the mean ventro-dorsal centre of ventilation. Infants will receive a transient increase in CPAP Positive End-Expiratory Pressure (PEEP) levels, known as a LRM, prior to the administration of MIST. Infants who do not receive a LRM will act as the control group. The primary outcome will be change in centre of ventilation (ventro-dorsal) from a pre-MIST baseline as a measure of air distribution in the lungs, 1 hour after MIST, assessed using electrical impedance tomography (EIT).

Arm 1: Control - Patients randomised to Control will receive no LRM prior to MIST and no changes to baseline PEEP will be made. In all participating sites the standard PEEP level during CPAP is 7-8 cmH2O.

Arm 2: Intervention

- PEEP will be transiently increased to 10 cmH2O 20 minutes before MIST is scheduled to occur. PEEP will remain at this setting for the duration of MIST. Following MIST, PEEP will be decreased to baseline.

Inclusion Criteria:

• Born between 24 to 31+6 weeks' gestation, by best obstetric estimate
• Admitted to a participating NICU
• A parent/guardian who can provide informed consent
• Receiving CPAP respiratory support
• Planned to receive MIST by clinicians as standard clinical care
• Clinically stable (as determined by clinical team)
• Infant less than 72 hours of age
• MIST can be administered within 90 min of allocating assigned interventional arm

Exclusion Criteria:

• Receiving any form of respiratory support other than CPAP
• Receiving more than 8 cmH2O PEEP via CPAP in the 4 hours prior to surfactant administration (except in the Delivery Room as part of resuscitation at birth)
• The infant's clinical team has concern regarding clinical stability and tolerability of EIT
• The infant's skin integrity will not tolerate the EIT belt and gel
• Refusal of informed consent by their parent/guardian/legally acceptable representative
• The infant does not have a parent/guardian who can provide informed consent.
• Major congenital anomaly involving the cardiac, respiratory, gastrointestinal systems, or a known genetic syndrome or diagnosis that might affect respiratory course and outcomes
• Severe pulmonary hypoplasia due to anhydramnios or oligohydramnios before 24 weeks in which the neonatal clinician anticipates that pulmonary hypoplasia related respiratory failure will be the major respiratory problem in early post-natal life
• Suspected or confirmed air leak or pneumothorax
• Previous treatment with surfactant or mechanical ventilation via an endotracheal tube
• Urgent need for intubation and mechanical ventilation as determined by the treating clinician
• Not receiving full active intensive care (i.e. palliative/comfort care)