Early Detection of Ventilation-Induced Brain Injury Using Magnetic Resonance Spectroscopy and Diffusion Tensor Imaging: An In Vivo Study in Preterm Lambs

Skiöld, Béatrice; Wu, Qisong; Hooper, Stuart B.; Davis, Peter G; McIntyre, Richard; Tolcos, Mary; Pearson, James T.; Vreys, Ruth; Egan, Gary F.; Barton, Samantha K.; Cheong, Jeanie L.Y.; Polglase, Graeme R.

doi:10.1371/journal.pone.0095804

Cited by 29 publications

(59 citation statements)

References 47 publications

(54 reference statements)

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“…This is of importance as it is well established that the onset of ventilation is sufficient to exacerbate pathways already involved in preterm injury: altered pulmonary and cardiovascular hemodynamics [27,28] and profound pulmonary and systemic inflammation [27][28][29][30] . These pathways of injury have downstream effects including cerebral hemodynamic fluctuations and localized inflammation in the brain [5,6,18] . Cerebral inflammation has been associated with abnormal neurodevelopmental outcomes [31] , diagnoses of cerebral palsy [32] , increased incidences of periventricular leukomalacia [33] , as well as magnetic resonance-defined cerebral white matter injury [34] in neonates.…”

Section: Discussionmentioning

confidence: 99%

“…in 5% dextrose; Jurox, NSW, Australia) to prevent spontaneous breathing. Injurious ventilation was initiated with a high tidal volume (V T ) targeting 10-12 mL/kg (peak inspiratory pressure adjusted to an upper limit of 50 cm H 2 O) to cause ventilation-induced brain pathology as described previously [5,6] . After 15 min, the lambs were ventilated in volume-guarantee mode (V T 7 mL/kg, peak end expiratory pressure 5 cm H 2 O, inspiratory time 0.5 s, expiratory time 0.5 s) for a further 105 min.…”

Section: Instrumentation and Deliverymentioning

confidence: 99%

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Optimizing the Dose of Erythropoietin Required to Prevent Acute Ventilation-Induced Cerebral White Matter Injury in Preterm Lambs

et al. 2017

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Erythropoietin (EPO) is being trialed in preterm neonates for neuroprotection. We have recently demonstrated that a single high bolus dose (5,000 IU/kg) of recombinant human EPO amplified preterm lung and brain ventilation-induced injury. We aimed to determine the optimal dose of EPO to reduce ventilation-induced cerebral white matter inflammation and injury in preterm lambs. Lambs (0.85 gestation) were ventilated with an injurious strategy for 15 min followed by conventional ventilation for 105 min. Lambs were randomized to no treatment (VENT; n = 8) or received a bolus dose of EPO (EPREX®): 300 IU/kg (EPO 300; n = 5), 1,000 IU/kg (EPO 1,000; n = 5), or 3,000 IU/kg (EPO 3,000; n = 5). Physiological parameters were measured throughout the study. After 2 h, brains were collected for analysis; real-time quantitative polymerase chain reaction and immunohistochemistry were used to assess inflammation, cell death, and vascular leakage in the periventricular and subcortical white matter (PVWM; SCWM). Molecular and histological inflammatory indices in the PVWM were not different between groups. EPO 300 lambs had higher IL-6 (p = 0.006) and caspase-3 (p = 0.025) mRNA expression in the SCWM than VENT lambs. Blood-brain barrier (BBB) occludin mRNA levels were higher in EPO 3,000 lambs in the PVWM and SCWM than VENT lambs. The number of blood vessels with protein extravasation in the SCWM was lower in EPO 1,000 (p = 0.010) and EPO 3,000 (p = 0.025) lambs compared to VENT controls but not different between groups in the PVWM. Early administration of EPO at lower doses neither reduced nor exacerbated cerebral white matter inflammation or injury. 3,000 IU/kg EPO may provide neuroprotection by improving BBB integrity.

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Section: Discussionmentioning

confidence: 99%

Section: Instrumentation and Deliverymentioning

confidence: 99%

Optimizing the Dose of Erythropoietin Required to Prevent Acute Ventilation-Induced Cerebral White Matter Injury in Preterm Lambs

et al. 2017

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“…Prophylactic administration of hAECs did not exert a potent protective effect within the brain WM of preterm lambs that were ventilated in a manner known to cause lung and brain inflammation and injury [7,13,29]. Of the two pathways of injury characteristic of ventilation-induced brain injury [7], the hAECs did not appear to have an effect on physiology but did have an effect on the inflammatory pathway.…”

Section: Discussionmentioning

confidence: 99%

“…However, even at this relatively mature stage of development, the ovine brain is still vulnerable to WM damage [13,29], particularly after the ventilation-induced lung injury that would be apparent after high V T ventilation of such immature lungs [45]. …”

Section: Discussionmentioning

confidence: 99%

Human Amnion Epithelial Cells Modulate Ventilation-Induced White Matter Pathology in Preterm Lambs

et al. 2015

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Background: Preterm infants can be inadvertently exposed to high tidal volumes (V_T) during resuscitation in the delivery room due to limitations of available equipment. High V_T ventilation of preterm lambs produces cerebral white matter (WM) pathology similar to that observed in preterm infants who develop cerebral palsy. We hypothesized that human amnion epithelial cells (hAECs), which have anti-inflammatory and regenerative properties, would reduce ventilation-induced WM pathology in neonatal late preterm lamb brains. Methods: Two groups of lambs (0.85 gestation) were used, as follows: (1) ventilated lambs (Vent; n = 8) were ventilated using a protocol that induces injury (V_T targeting 15 ml/kg for 15 min, with no positive end-expiratory pressure) and were then maintained for another 105 min, and (2) ventilated + hAECs lambs (Vent+hAECs; n = 7) were similarly ventilated but received intravenous and intratracheal administration of 9 × 10⁷ hAECs (18 × 10⁷ hAECs total) at birth. Oxygenation and ventilation parameters were monitored in real time; cerebral oxygenation was measured using near-infrared spectroscopy. qPCR (quantitative real-time PCR) and immunohistochemistry were used to assess inflammation, vascular leakage and astrogliosis in both the periventricular and subcortical WM of the frontal and parietal lobes. An unventilated control group (UVC; n = 5) was also used for qPCR analysis of gene expression. Two-way repeated measures ANOVA was used to compare physiological data. Student's t test and one-way ANOVA were used for immunohistological and qPCR data comparisons, respectively. Results: Respiratory parameters were not different between groups. Interleukin (IL)-6 mRNA levels in subcortical WM were lower in the Vent+hAECs group than the Vent group (p = 0.028). IL-1β and IL-6 mRNA levels in periventricular WM were higher in the Vent+hAECs group than the Vent group (p = 0.007 and p = 0.001, respectively). The density of Iba-1-positive microglia was lower in the subcortical WM of the parietal lobes (p = 0.010) in the Vent+hAECs group but not in the periventricular WM. The number of vessels in the WM of the parietal lobe exhibiting protein extravasation was lower (p = 0.046) in the Vent+hAECs group. Claudin-1 mRNA levels were higher in the periventricular WM (p = 0.005). The density of GFAP-positive astrocytes was not different between groups. Conclusions: Administration of hAECs at the time of birth alters the effects of injurious ventilation on the preterm neonatal brain. Further studies are required to understand the regional differences in the effects of hAECs on ventilation-induced WM pathology and their net effect on the developing brain.

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“…These pathways are amplified when the initiation of ventilation encompasses a high V T [10]. Whilst improving ventilation strategies can minimize some aspects of ventilation-induced lung and brain injury, it is not sufficient to mitigate injury [10,16]. Thus, IPPV, irrespectively of the strategy, can increase brain injury and inflammation from as early as its initiation.…”

Section: Preterm Birth Brain Injury and Ventilation Requirementmentioning

confidence: 99%

Ventilation-Induced Brain Injury in Preterm Neonates: A Review of Potential Therapies

Barton

Tolcos²,

Miller

et al. 2016

Neonatology

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Mechanical ventilation is a risk factor for cerebral inflammation and brain injury in preterm neonates. The risk increases proportionally with the intensity of treatment. Recent studies have shown that cerebral inflammation and injury can be initiated in the delivery room. At present, initiation of intermittent positive pressure ventilation (IPPV) in the delivery room is one of the least controlled interventions a preterm infant will likely face. Varying pressures and volumes administered shortly after birth are sufficient to trigger pathways of ventilation-induced lung and brain injury. The pathways involved in ventilation-induced brain injury include a complex inflammatory cascade and haemodynamic instability, both of which have an impact on the brain. However, regardless of the strategy employed to deliver IPPV, any ventilation has the potential to have an impact on the immature brain. This is particularly important given that preterm infants are already at a high risk for brain injury simply due to immaturity. This highlights the importance of improving the initial respiratory support in the delivery room. We review the mechanisms of ventilation-induced brain injury and discuss the need for, and the most likely, current therapeutic agents to protect the preterm brain. These include therapies already employed clinically, such as maternal glucocorticoid therapy and allopurinol, as well as other agents, such as erythropoietin, human amnion epithelial cells and melatonin, already showing promise in preclinical studies. Their mechanisms of action are discussed, highlighting their potential for use immediately after birth.

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Early Detection of Ventilation-Induced Brain Injury Using Magnetic Resonance Spectroscopy and Diffusion Tensor Imaging: An In Vivo Study in Preterm Lambs

Cited by 29 publications

References 47 publications

Optimizing the Dose of Erythropoietin Required to Prevent Acute Ventilation-Induced Cerebral White Matter Injury in Preterm Lambs

Optimizing the Dose of Erythropoietin Required to Prevent Acute Ventilation-Induced Cerebral White Matter Injury in Preterm Lambs

Human Amnion Epithelial Cells Modulate Ventilation-Induced White Matter Pathology in Preterm Lambs

Ventilation-Induced Brain Injury in Preterm Neonates: A Review of Potential Therapies

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