Diffusion tensor imaging detects ventilation-induced brain injury in preterm lambs

Abstract

PurposeInjurious mechanical ventilation causes white matter (WM) injury in preterm infants through inflammatory and haemodynamic pathways. The relative contribution of each of these pathways is not known. We hypothesised that in vivo magnetic resonance imaging (MRI) can detect WM brain injury resulting from mechanical ventilation 24 h after preterm delivery. Further we hypothesised that the combination of inflammatory and haemodynamic pathways, induced by umbilical cord occlusion (UCO) increases brain injury at 24 h.MethodsFetuses at 124±2 days gestation were exposed, instrumented and either ventilated for 15 min using a high tidal-volume (VT) injurious strategy with the umbilical cord intact (INJ; inflammatory pathway only), or occluded (INJ+UCO; inflammatory and haemodynamic pathway). The ventilation groups were compared to lambs that underwent surgery but were not ventilated (Sham), and lambs that did not undergo surgery (unoperated control; Cont). Fetuses were placed back in utero after the 15 min intervention and ewes recovered. Twenty-four hours later, lambs were delivered, placed on a protective ventilation strategy, and underwent MRI of the brain using structural, diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) techniques.ResultsAbsolute MRS concentrations of creatine and choline were significantly decreased in INJ+UCO compared to Cont lambs (P = 0.03, P = 0.009, respectively); no significant differences were detected between the INJ or Sham groups and the Cont group. Axial diffusivities in the internal capsule and frontal WM were lower in INJ and INJ+UCO compared to Cont lambs (P = 0.05, P = 0.04, respectively). Lambs in the INJ and INJ+UCO groups had lower mean diffusivities in the frontal WM compared to Cont group (P = 0.04). DTI colour mapping revealed lower diffusivity in specific WM regions in the Sham, INJ, and INJ+UCO groups compared to the Cont group, but the differences did not reach significance. INJ+UCO lambs more likely to exhibit lower WM diffusivity than INJ lambs.ConclusionsTwenty-four hours after injurious ventilation, DTI and MRS showed increased brain injury in the injuriously ventilated lambs compared to controls. DTI colour mapping threshold approach provides evidence that the haemodynamic and inflammatory pathways have additive effects on the progression of brain injury compared to the inflammatory pathway alone.

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

“…Using these techniques, the intact placental circulation manages nutrition and gas exchange of the fetus, allowing subtle mechanisms of respiratory support to be examined. In the headout approach, the fetal head and chest are exteriorized, the fetus is intubated and ventilation with various strategies altering delivered volume, pressures, respiratory frequencies, or oxygen content, and then returned to the uterus (74)(75)(76)(77)(78). In utero ventilation (IUV) studies require the fetus to be exteriorized and instrumented with ventilation tubes and equipment required for monitoring prior to being returned to the uterus.…”

“…Importantly, pathology resultant from injurious ventilation can be visualized using non-invasive imaging such as magnetic resonance imaging (MRI) (72,77,91) and correlated with histopathology (89). Magnetic resonance spectroscopy (MRS) detected acute changes in brain metabolite peak-area ratios (Lactate/Creatine and Lactate/Choline) in preterm lambs that received high V T although macroscopic injury was absent in structural MR images (T1, T2) (72).…”

“…Notably, these MRS changes were observed within 90 min of ventilation onset (72). Recent findings suggest that MRS-detectable changes persist 24 h after injurious ventilation (77). Diffusion tensor imaging (DTI) perhaps offers the most sensitive measures of early brain injury.…”

“…Several explanations have been put forward to link ventilation and brain injury. Studies in ventilated preterm lambs have identified two major pathways of acute VIBI: cerebral inflammation and hemodynamic instability (13,15,16,77). Both pathways are proposed to be downstream effects of the pulmonary consequences following ventilation (13,15,16).…”

“…The relative contribution of each pathway toward the progression of white matter injury discussed in section Animal Studies That Investigate Pathology of VIBI is unknown although a recent study suggests that the hemodynamic pathway has an additive effect on the inflammatory pathway on injury progression, but the inflammatory pathway seems to dominate (77).…”