Speed of Lung Inflation During Ventilation of Extremely Preterm Infants

Official title

Longer Pressure Rise Time During Mechanical Ventilation of Extremely Preterm Infants: A Randomised Crossover Trial

Overview

Babies born extremely preterm (\<28 weeks of pregnancy) require support to breathe. Some babies require help to breathe from a breathing machine (mechanical ventilator). While this keeps babies alive, it may damage their lungs. To reduce this damage, doctors and nurses take particular care to try and provide the gentlest breathing support possible. However, evidence is still required to determine how to best support babies' breathing, whilst preventing lung damage and longer-term lung problems. This clinical trial aims to compare two ways of adjusting a common setting on the breathing machine. This setting is called the pressure rise time or PRT. The PRT determines how quickly the breathing machine inflates a premature baby's lungs. A short PRT quickly inflates the lungs. A long PRT inflates the lungs more slowly. Previous research suggests that more slowly inflating the baby's lungs may cause less lung damage and still allow oxygen to be delivered to and carbon dioxide to be cleared from the lungs. However, larger studies are required to determine whether this should become the standard treatment. This study investigates whether inflating the baby's lungs more slowly (long PRT) using the breathing machine is as effective as the PRT setting currently used (short PRT, more quickly inflating the lungs). The main question it aims to answer is: Does how quickly the breathing machine inflates an extremely preterm baby's lung impact their oxygen levels?

Detailed description

The FLOW-VENT trial will investigate if using a long pressure rise time (PRT; thereby reducing the speed of gas flow) compared to a short PRT, during synchronised, patient-triggered, volume-targeted conventional mechanical ventilation in extremely preterm infants within the first postnatal week impacts an infant's oxygenation.

All infants born extremely preterm (\<28 weeks' gestation) require breathing support to survive. However, this support can damage their lungs. Rates of bronchopulmonary dysplasia (BPD), the chronic lung disease of extreme prematurity, are increasing. This is despite 'lung protective' respiratory support and ventilation strategies that aim to minimise harm to the preterm lung.

Pre-clinical evidence suggests that gas flows lower than currently used during respiratory support of these infants may be a major, and easily modifiable way of reducing preterm lung injury (Tingay 2024; Bach 2012). Current guidelines lack evidence for suggested gas flow settings. Many ventilators now modulate ventilator gas flows by a setting known as pressure rise time (PRT).

FLOW-VENT is a prospective, multicentre, unblinded, randomised crossover trial enrolling 68 extremely preterm infants born \<28 weeks gestational age. A long PRT is defined as a PRT set at 75% of the inspiratory time (Ti). A short PRT is defined as a PRT set at 33% of the Ti.

Given the crossover design, infants will receive both the long and short PRT setting. Extremely preterm infants will be randomised to a 'sequence' which will determine the order in which they are exposed to the different PRTs; either:

* Long-Short PRT Sequence: Long PRT in the first treatment period and Short PRT in the second treatment period, OR * Short-Long PRT Sequence: Short PRT in the first treatment period and Long PRT in the second treatment period.

The trial crossover phase (\~10-12 hours) consists of: 1) Preparatory washout period (1 to 2 hours); 2) First treatment period (4-hours); 3) Washout period (1 to 2 hours); 4) Second treatment period (4-hours). Following this, there is a 12-hour follow-up period to monitor for adverse/safety events. The primary outcome (average S/F ratio) is assessed only during the 4-hour treatment periods.

Results from this trial will inform the decision to proceed to a larger randomised trial, powered for longer term respiratory outcomes (e.g. time to extubation from mechanical ventilation, BPD at 36 weeks' postmenstrual age).

Interventions

• Other Long PRT
  PRT (in seconds) set at 75% of inspiratory time (in seconds)
• Other Short PRT
  PRT (in seconds) set at 33% of inspiratory time (in seconds).

Primary outcome measures

• Change in peripheral oxygen saturation to fraction of inspired oxygen ratio (S/F Ratio) measured each minute during each treatment period (0 minutes to 4 hours) [Time frame: 0 minutes then each minute up to 4 hours for each of the Long PRT and Short PRT 4-hour treatment periods]

Secondary outcome measures (12)

• Change in pressure rise time (PRT) measured each minute during each treatment period (0 minutes to 4 hours). [Time frame: Measured during each of the Long PRT and Short PRT 4-hour treatment periods.]
• Change in mean airway pressure (MAP) measured each minute during each treatment period (0 minutes to 4 hours). [Time frame: Measured during of the Long PRT and Short PRT 4-hour treatment periods.]
• Change in positive end expiratory pressure (PEEP) measured each minute during each treatment period (0 minutes to 4 hours). [Time frame: Measured during each of the Long PRT and Short PRT 4-hour treatment periods.]
• Change in peak inspiratory pressure (PIP) measured each minute during each treatment period (0 minutes to 4 hours). [Time frame: Measured during each of the Long PRT and Short PRT 4-hour treatment periods.]
• Change in tidal volume (VT) measured each minute during each treatment period (0 minutes to 4 hours). [Time frame: Measured during each of the Long PRT and Short PRT 4-hour treatment periods.]
• Change in respiratory rate measured each minute during each treatment period (0 minutes to 4 hours). [Time frame: Measured during each of the Long PRT and Short PRT 4-hour treatment periods.]
• Change in minute ventilation measured each minute during each treatment period (0 minutes to 4 hours). [Time frame: Measured during each of the Long PRT and Short PRT 4-hour treatment periods.]
• Change in endotracheal tube leak measured each minute during each treatment period (0 minutes to 4 hours) [Time frame: Measured during each of the Long PRT and Short PRT 4-hour treatment periods.]
• Change in inspiratory time (Ti) measured each minute during each treatment period (0 minutes to 4 hours) [Time frame: Measured during each of the Long PRT and Short PRT 4-hour treatment periods.]
• Change in inspiratory gas flows measured each minute during each treatment period (0 minutes to 4 hours). [Time frame: Measured during each of the Long PRT and Short PRT 4-hour treatment periods.]
• Change in peripheral oxygen saturation (SpO2) measured each minute during each treatment period (0 minutes to 4 hours). [Time frame: Measured during each of the Long PRT and Short PRT 4-hour treatment periods.]
• Change in fraction of inspired oxygen (FiO2) measured each minute during each treatment period (0 minutes to 4 hours). [Time frame: Measured during each of the Long PRT and Short PRT 4-hour treatment periods.]

Eligibility criteria

Inclusion criteria

• Admitted to participating neonatal intensive care unit
• Born between 22+0 to 27+6 weeks' gestation
• Current weight ≥400 grams
• Receiving synchronised, patient-triggered, volume-targeted (all breaths) conventional mechanical ventilation (Pressure Control-Assist Control + Volume Guarantee \[PC-AC+VG\] mode on Dräger Babylog VN500/800 ventilators) initiated within 72-hours post birth
• Postnatal age ≥6 hours and ≤7 days
• Received surfactant therapy
• Clinically stable (as per treating and research team consensus)
• Parent(s)/legal guardian provides prospective informed consent.

Exclusion criteria

• Major congenital anomaly involving the cardiac, respiratory or 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 22 weeks in which the neonatal consultant anticipates that pulmonary hypoplasia related respiratory failure will be the major respiratory problem in early postnatal life
• Receiving (or expected to receive within the next 12 hours) any other mode of mechanical ventilation including synchronised intermittent mandatory ventilation (SIMV), pressure support ventilation (PSV) or high-frequency oscillatory ventilation
• Planned for extubation from mechanical ventilation within the next 12 hours.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Crossover

Masking

Open label

Primary purpose

Treatment

Study locations

Australia · 3 centers

• Mercy Hospital for Women — Heidelberg
• The Royal Women's Hospital — Parkville
• Joan Kirner Women's and Children's Hospital — Saint Albans

Publications

• Tingay DG, Fatmous M, Kenna K, Chapman J, Douglas E, Sett A, Poh QH, Dahm SI, Quach TK, Sourial M, Fang H, Greening DW, Pereira-Fantini PM. Speed of lung inflation at birth influences the initiation of lung injury in preterm lambs. JCI Insight. 2024 Aug 6;9(18):e181228. doi: 10.1172/jci.insight.181228. PMID 39106107
• Bach KP, Kuschel CA, Patterson N, Skwish H, Huth S, Phua HH, Bloomfield FH. Effect of Bias Gas Flow on Tracheal Cytokine Concentrations in Ventilated Extremely Preterm Infants: A Randomized Controlled Trial. Neonatology. 2021;118(3):332-339. doi: 10.1159/000515364. Epub 2021 Apr 7. PMID 33827091
• Bach KP, Kuschel CA, Oliver MH, Bloomfield FH. Ventilator gas flow rates affect inspiratory time and ventilator efficiency index in term lambs. Neonatology. 2009;96(4):259-64. doi: 10.1159/000220765. Epub 2009 May 27. PMID 19478530
• Bach KP, Kuschel CA, Hooper SB, Bertram J, McKnight S, Peachey SE, Zahra VA, Flecknoe SJ, Oliver MH, Wallace MJ, Bloomfield FH. High bias gas flows increase lung injury in the ventilated preterm lamb. PLoS One. 2012;7(10):e47044. doi: 10.1371/journal.pone.0047044. Epub 2012 Oct 8. PMID 23056572
• Chong D, Kayser S, Szakmar E, Morley CJ, Belteki G. Effect of pressure rise time on ventilator parameters and gas exchange during neonatal ventilation. Pediatr Pulmonol. 2020 May;55(5):1131-1138. doi: 10.1002/ppul.24724. Epub 2020 Mar 9. PMID 32150670

Identifiers

NCT: NCT07101419 · 117784

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗