Can Ultrasound-Guided Xenon Delivery Provide Neuroprotection in Traumatic Brain Injury?

Abstract

Traumatic brain injury (TBI) is associated with high mortality and morbidity in children and adults. Unfortunately, there is no effective management for TBI in the acute setting. Rodent studies have shown that xenon, a well-known anesthetic gas, can be neuroprotective when administered post-TBI. Gas inhalation therapy, however, the approach typically used for administering xenon, is expensive, inconvenient, and fraught with systemic side effects. Therapeutic delivery to the brain is minimal, with much of the inhaled gas cleared by the lungs. To bridge major gaps in clinical care and enhance cerebral delivery of xenon, this study introduces a novel xenon delivery technique, utilizing microbubbles, in which a high impulse ultrasound signal is used for targeted cerebral release of xenon. Briefly, an ultrasound pulse is applied along the carotid artery at the level of the neck on intravenous injection of xenon microbubbles (XeMBs) resulting in release of xenon from microbubbles into the brain. This delivery technique employs a hand-held, portable ultrasound system that could be adopted in resource-limited environments. Using a high-fidelity porcine model, this study demonstrates the neuroprotective efficacy of xenon microbubbles in TBI for the first time.

Keywords: microbubbles; neuroprotection; traumatic brain injury; ultrasound; xenon.

FIG. 1.

Neuroprotective efficacy of xenon microbubbles in the porcine model of traumatic brain injury. There is marked decrease in edema from Day 1 magnetic resonance imaging (MRI) (A) to Day 5 MRI (B) in the xenon-treated group. On the right, graph is showing percentage change in volumes (cm³) from Day 1 MRI to Day 5 MRI of edema, core, and total volume in the perfluorobutane (PFB)-treated (gray) and xenon-treated groups (n = 3 each). The statistical significance of the difference in the percentage change between PFB-treated versus xenon-treated groups is assigned as * for p ≤ 0.03, ** for p ≤ 0.01, and ns (not significant).

FIG. 2.

Histology in xenon microbubbles treated group versus perfluorobutane (PFB) microbubble treated group. Vessels (black arrows) adjacent to the site of injury (asterisks) in the xenon condition showed less endothelial proliferation and perivascular inflammation (including neutrophils, lymphocytes, and macrophages) compared with the PFB-treated group. Hematoxylin and eosin stain. Scale bar applies to all images. On the right, graphs are showing the difference in endothelial proliferation score (A) and perivascular inflammation score (B) between the PFB-treated (n = 2) and xenon-treated groups (n = 3). The statistical significance of the difference in scores between control vsversusxenon-treated groups is assigned as * for p ≤ 0.02 and ns (not significant).