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Background: Intrauterine inflammation and the requirement for mechanical ventilation independently increase the risk of perinatal brain injury and adverse neurodevelopmental outcomes. We aimed to investigate the effects of mechanical ventilation for 24h, with and without prior exposure to intrauterine inflammation, on markers of brain inflammation and injury in the preterm sheep brain. Methods: Chronically instrumented fetal sheep at ~115 days of gestation were randomly allocated to receive a single intratracheal dose of 1 mg lipopolysaccharide (LPS) or isovolumetric saline, then further randomly allocated 1 h after to receive mechanical ventilation with room air or no mechanical ventilation (unventilated control + saline [UVC, n = 7]; in utero mechanical ventilation + saline [VENT, n = 8], unventilated control + intratracheal LPS [UVC + LPS, n = 7]; in utero ventilation + intratracheal LPS [VENT + LPS, n = 7]). Serial fetal blood and plasma samples were collected throughout the experimental protocol for assessment of blood biochemistry and plasma interleukin (IL)-6 levels. After 24 h of mechanical ventilation, fetal brains were collected for RT-qPCR and immunohistochemical analyses. Results: LPS exposure increased numbers of microglia and upregulated pro-inflammatory related genes within the cortical gray matter (GM) and subcortical white matter (SCWM) (pLPS < 0.05). Mechanical ventilation alone increased astrocytic cell density in the periventricular white matter (PVWM) (pVENT = 0.03) but had no effect on pro-inflammatory gene expression. The combination of ventilation and LPS increased plasma IL-6 levels (p < 0.02 vs. UVC and VENT groups), and exacerbated expression of pro-inflammatory-related genes (IL1β, TLR4, PTGS2, CXCL10) and microglial density (p < 0.05 vs. VENT). Conclusion: This study demonstrates that 24 h of mechanical ventilation after exposure to intrauterine inflammation increased markers of systemic and brain inflammation and led to the upregulation of pro-inflammatory genes in the white matter. We conclude that 24 h of mechanical ventilation following intrauterine inflammation may precondition the preterm brain toward being more susceptible to inflammation-induced injury. [ABSTRACT FROM AUTHOR]

Initiation of respiratory support in the delivery room increases the risk and severity of brain injury in preterm neonates through two major pathways: an inflammatory pathway and a haemodynamic pathway. The relative contribution of each pathway on preterm brain injury is not known. We aimed to assess the role of the inflammatory and haemodynamic pathway on ventilation-induced brain injury (VIBI) in the preterm lamb. Fetal lambs (125 ± 1 day gestation) were exteriorised, instrumented and ventilated with a high tidal-volume (VT) injurious strategy for 15 min either with placental circulation intact to induce the inflammatory pathway only (INJINF; n = 7) or umbilical cord occluded to induce both the inflammatory and haemodynamic pathways (INJINF+HAE; n = 7). Sham controls were exteriorised but not ventilated (SHAM; n = 5) while unoperated controls (UNOP; n = 7) did not undergo fetal instrumentation. Fetuses were returned in utero following intervention and the ewe allowed to recover. Arterial blood gases and plasma were sampled periodically. Twenty-four hours following intervention, lambs were delivered and maintained on non-injurious ventilation for ~40 min then brains were collected postmortem for immunohistochemistry and RT-qPCR to assess inflammation, vascular pathology and cell death within white matter regions. Compared to INJINF lambs, INJINF+HAE lambs achieved a consistently higher VT during injurious ventilation and carotid blood flow was significantly lower than baseline by the end of ventilation. Throughout the 24 h recovery period, systemic arterial IL-6 levels of INJINF+HAE lambs were significantly higher than SHAM while there was no difference between INJINF and SHAM animals. At 24 h, mRNA expression levels of pro-inflammatory cytokines, tight junction proteins, markers of cell death, and histological injury indices of gliosis, blood vessel protein extravasation, oligodendrocyte injury and cell death were not different between groups. Injurious ventilation, irrespective of strategy, did not increase brain inflammation or injury 24 h later when compared to control animals. However, the haemodynamic pathway did influence carotid blood flow adaptations during injurious ventilation and increased systemic arterial IL-6 that may underlie long-term pathology. Future studies are required to further characterise the pathways and their long-term effects on VIBI. [ABSTRACT FROM AUTHOR]

Respiratory distress is relatively common in infants born at or near-term, particularly in infants delivered following elective cesarean section. The pathophysiology underlying respiratory distress at term has largely been explained by a failure to clear airway liquid, but recent physiological evidence has indicated that it results from elevated airway liquid at the onset of air-breathing. We have investigated the effect of elevated airway liquid volumes at birth on cardiorespiratory function in preterm and near-term lambs. Preterm (130 ± 0 days gestation, term °147 days gestation; n = 12) and near-term (139 ± 1 days gestation; n = 13) lambs were instrumented (to measure blood pressure, blood flow, and blood gas status) and, at delivery, airway liquid volumes were adjusted to mimic levels expected following vaginal delivery (Controls; °7 mL/kg) or elective cesarean section with no labor (elevated liquid (EL); 37 mL/kg). Lambs were delivered, mechanically ventilated, and monitored for blood gas status, oxygenation, ventilator requirements, blood flows (carotid artery and pulmonary artery), and blood pressure during the first few hours of life. Preterm and near-term EL lambs had poorer gas exchange and required greater ventilatory support to maintain adequate oxygenation. Pulmonary blood flow was reduced and carotid artery blood flow, mean arterial blood pressure, and heart rate were reduced in EL near-term but not preterm lambs. These data provide further evidence that greater airway liquid volumes at birth adversely affect newborn cardiorespiratory function, with the effects being greater in near-term newborns. NEW & NOTEWORTHY We provide evidence for adverse effects of elevated airway liquid volumes at birth on pulmonary blood flow and gas exchange in both preterm and near-term lambs, although the effects were greatest in near-term newborns. Our study is an important step toward understanding the fundamental physiology underlying the cardiorespiratory morbidity associated with near-term newborns with elevated airway liquid volumes leading to respiratory distress soon after birth. [ABSTRACT FROM AUTHOR]

Abstract Background Bronchopulmonary dysplasia (BPD) is closely associated with ventilator-induced lung injury (VILI) in very preterm infants. The greatest risk of VILI may be in the immediate period after birth, when the lungs are surfactant deficient, still partially filled with liquid and not uniformly aerated. However, there have been very few studies that have examined this immediate post-birth period and identified the initial injury-related pathways that are activated. We aimed to determine if the early response genes; connective tissue growth factor (CTGF), cysteine rich-61 (CYR61) and early growth response 1 (EGR1), were rapidly induced by VILI in preterm lambs and whether ventilation with different tidal volumes caused different inflammatory cytokine and early response gene expression. Methods To identify early markers of VILI, preterm lambs (132 d gestational age; GA, term ~147 d) were resuscitated with an injurious ventilation strategy (VT 20 mL/kg for 15 min) then gently ventilated (5 mL/kg) for 15, 30, 60 or 120 min (n = 4 in each). To determine if early response genes and inflammatory cytokines were differentially regulated by different ventilation strategies, separate groups of preterm lambs (125 d GA; n = 5 in each) were ventilated from birth with a VT of 5 (VG5) or 10 mL/kg (VG10) for 135 minutes. Lung gene expression levels were compared to levels prior to ventilation in age-matched control fetuses. Results CTGF, CYR61 and EGR1 lung mRNA levels were increased ~25, 50 and 120-fold respectively (p < 0.05), within 30 minutes of injurious ventilation. VG5 and VG10 caused significant increases in CTGF, CYR61, EGR1, IL1-β, IL-6 and IL-8 mRNA levels compared to control levels. CTGF, CYR61, IL-6 and IL-8 expression levels were higher in VG10 than VG5 lambs; although only the IL-6 and CYR61 mRNA levels reached significance. Conclusion CTGF, CYR61 and EGR1 may be novel early markers of lung injury and mechanical ventilation from birth using relatively low tidal volumes may be less injurious than using higher tidal volumes.

Objective: Umbilical cord milking (UCM) at birth may benefit preterm infants, but the physiological effects of UCM are unknown. We compared the physiological effects of two UCM strategies with immediate umbilical cord clamping (UCC) and physiological-based cord clamping (PBCC) in preterm lambs.Methods: At 126 days' gestational age, fetal lambs were exteriorised, intubated and instrumented to measure umbilical, pulmonary and cerebral blood flows and arterial pressures. Lambs received either (1) UCM without placental refill (UCMwoPR); (2) UCM with placental refill (UCMwPR); (3) PBCC, whereby ventilation commenced prior to UCC; or (4) immediate UCC. UCM involved eight milks along a 10 cm length of cord, followed by UCC.Results: A net volume of blood was transferred into the lamb during UCMwPR (8.8 mL/kg, IQR 8-10, P=0.01) but not during UCMwoPR (0 mL/kg, IQR -2.8 to 1.7) or PBCC (1.1 mL/kg, IQR -1.3 to 4.3). UCM had no effect on pulmonary blood flow, but caused large fluctuations in mean carotid artery pressures (MBP) and blood flows (CABF). In UCMwoPR and UCMwPR lambs, MBP increased by 12%±1% and 8%±1% and CABF increased by 32%±2% and 15%±2%, respectively, with each milk. Cerebral oxygenation decreased the least in PBCC lambs (17%, IQR 13-26) compared with UCMwoPR (26%, IQR 23-25, P=0.03), UCMwPR (35%, IQR 27-44, P=0.02) and immediate UCC (34%, IQR 28-41, P=0.02) lambs.Conclusions: UCMwoPR failed to provide placental transfusion, and UCM strategies caused considerable haemodynamic disturbance. UCM does not provide the same physiological benefits of PBCC. Further review of UCM is warranted before adoption into routine clinical practice. [ABSTRACT FROM AUTHOR]

Objective: While delayed umbilical cord clamping (UCC) is thought to facilitate placental to infant blood transfusion, the physiological factors regulating flow in the umbilical arteries and veins during delayed UCC is unknown. We investigated the effects of gravity, by changing fetal height relative to the placenta, and ventilation on umbilical blood flows and the cardiovascular transition during delayed UCC at birth.Methods: Catheters and flow probes were implanted into preterm lambs (128 days) prior to delivery to measure pulmonary, carotid, umbilical artery (UaBF) and umbilical venous (UvBF) blood flows. Lambs were placed either 10 cm below or 10 cm above the ewe. Ventilation commenced 2-3 min before UCC and continued for 30 min after UCC.Results: Gravity reduced umbilical and cerebral flows when lambs were placed below the midline, but the reduction in UaBF and UvBF was similar. Ventilation during delayed UCC reduced UvBF and UaBF by similar amounts, irrespective of the lamb's position, such that flows into and out of the placenta remained balanced. The effects of ventilation on umbilical flows were much greater than the effects of gravity, but no net placental to lamb blood transfusion could be detected under any condition. Cardiovascular parameters, cerebral oxygen kinetics and final blood volumes were similar in both groups 5 min after UCC.Conclusions: Gravity caused small transient effects on umbilical and cerebral flow, but given changes were similar in umbilical arteries and veins, no net placental transfusion was detected. Ventilation during delayed UCC has a markedly greater influence on cardiovascular function in the newborn. [ABSTRACT FROM AUTHOR]