Respiratory Support of the Preterm Neonate: Lessons About Ventilation-Induced Brain Injury From Large Animal Models

Abstract

Many preterm neonates require mechanical ventilation which increases the risk of cerebral inflammation and white matter injury in the immature brain. In this review, we discuss the links between ventilation and brain injury with a focus on the immediate period after birth, incorporating respiratory support in the delivery room and subsequent mechanical ventilation in the neonatal intensive care unit. This review collates insight from large animal models in which acute injurious ventilation and prolonged periods of ventilation have been used to create clinically relevant brain injury patterns. These models are valuable resources in investigating the pathophysiology of ventilation-induced brain injury and have important translational implications. We discuss the challenges of reconciling lung and brain maturation in commonly used large animal models. A comprehensive understanding of ventilation-induced brain injury is necessary to guide the way we care for preterm neonates, with the goal to improve their neurodevelopmental outcomes.

Investigating Pathways of Ventilation Induced Brain Injury on Cerebral White Matter Inflammation and Injury After 24 h in Preterm Lambs

“…The experimental design used in this study was intended to isolate the consequences of the initial volutrauma from any subsequent inflammation and injury by returning placental circulation after ventilation ( Hillman et al, 2007 ; Chan et al, 2020 ). Other preterm lamb studies that utilised the same injurious ventilation strategy (15 min of high V T ventilation) have reported detectable brain injury by ∼2 h (i.e., increased mRNA expression of pro-inflammatory cytokines, compromised BBB, increased microgliosis, astrogliosis, and markers of cell death in the PVWM and SCWM) ( Polglase et al, 2012 ; Barton et al, 2015b ; Barton et al, 2016 ).…”

“…The occluder cuff was deflated and removed at the end of the 15 min injurious ventilation and placental blood flow was restored. The “fetal head-out ventilation” model which involves returning the fetus to the uterus following ventilation was utilized in this study to isolate the effects of ventilation alone, allows for sufficient development of inflammation and injury pathways to manifest into gross lung/brain injury, and perform ventilation strategies at a gestational age in which the sheep’s structural lung development is comparable to that of a very preterm human infant ( Alcorn et al, 1981 ; Chan et al, 2020 ).…”

“…The inflammatory pathway of VIBI is postulated to be a downstream consequence of ventilation-induced lung injury ( Barton et al, 2015a ; Chan et al, 2020 ). In the delivery room, inadvertent excessive tidal volume (V T ; volutrauma) applied during PPV initiates a pulmonary inflammatory response that can subsequently induce systemic and cerebral inflammation.…”

Advantages of a Centrifugal Pump in the Development of a Swine Model of an Artificial Placenta

“…By contrast, fetal minipigs delivered at 93-107 days GA weighing 0.39-0.82 kg are in their canalicular and saccular stages of lung development and comparable to preterm human fetuses delivered at 22-28 weeks GA. Thus, fetal pigs delivered at 95 days GA would therefore be equivalent in body weight and lung maturity to human fetuses born at 22-25 weeks GA, and may represent a more appropriate model for the development of an AP system 27,33,34 .…”

“…Although cannulation was technically feasible, one study reported the development of hydrops fetalis following 5-8 days of support 32 , whereas the other required the use of aggressive pharmacological interventions in order to achieve hemodynamic stability 19 . Although fetal sheep delivered at 85-95 days GA share similar body weight to human fetuses delivered at the biological limit of viability, they are developmentally immature and their pulmonary development is analogous to a human fetus delivered at 18 weeks GA 10,26,33,34 . By contrast, fetal minipigs delivered at 93-107 days GA weighing 0.39-0.82 kg are in their canalicular and saccular stages of lung development and comparable to preterm human fetuses delivered at 22-28 weeks GA.…”