Astrocyte preservation after cardiac arrest treated by hypothermic liquid ventilation – ASTRAL

Cardiac arrest is a major health issue with very low survival rate. In order to improve the neurological prognosis and the survival rate of resuscitated patients, the laboratory is developing a breakthrough technology for the induction of ultra-rapid hypothermia after cardiac arrest by hypothermic Total Liquid Ventilation (hTLV). This consists in filling the lungs with oxygenated perfluorocarbons and it can use the lungs as heat exchanger while maintaining normal gas exchanges during the procedure. Due to its very rapid cooling speed (<15min), the device has been experimentally shown to provide considerably higher survival rate and neurological function than conventional, but slower cooling. Recently, the laboratory received an ANR Grant for the development of a liquid ventilator and a start-up Orixha has been created for supporting the first-in-man study. Yet, one major issue remains, which is related to the mechanism of action of hTLV. Indeed, despite the strong proof-of-concept, there is no mechanistic hypothesis to explain the superiority of ultra-rapid cooling by hTLV over conventional cooling. The goal of this project is then to decipher the mechanism behing hTLV and to describe the window of susceptibility (therapeutic window) of patients to hypothermia. This would speed-up, optimize the clinical translation of the device, and define the way in which hTLV fits into the current post-cardiac arrest cares. Additionally, this would also lead to technological choices in order to better correspond to the therapeutic window.
During preliminary studies, the laboratory demonstrated that cardiac arrest is followed by an early pathophysiological phase characterised by metabolic and vascular cerebral crisis. These crises are sensitive to hTLV, and our results suggest that astrocytes play a pivotal role in the mechanism of action of hTLV and in the duration of the therapeutic window. Astrocytes are indeed know for controlling the brain hemodynamic as well as to support the metabolism of neurons. During preliminary experiment, we were able to evidence an implication of this particular cell type in post-cardiac arrest physiopathology. The aim here is then to decipher the role of astrocytes after cardiac arrest, as well as their susceptibility to hTLV. The secondary objective would be to determine a pharmacological strategy for specific protection of astrocytes, in order to be used in synergy with hTLV.
We defined two different workpackages. Workpackage 1 will evaluate the role of hTLV on the post-cardiac arrest astrocyte dyfunction, both in vivo and in vitro. This will allow to characterize the post-cardiac arrest activation of astrocytes (astrogliosis), the benefit of hTLV on this activation and, in vitro to determine several potential therapeutic target. The second workpackage (WP2) will aim determine the in vivo consequences of astrocyte pharmacological protection. First in a rabbit model of cardiac arrest for evaluation of cerebral metabolic alterations by microdialysis. Second in a model of cardiac arrest in pigs, in conjunction with hTLV for investigate the overall neuroprotection.
The project will help to rationalize and to optimize the clinical translation of the medical device of hTLV. It will allow a better understanding of the role of astrocytes and the pathophysiology of post-cardiac arrest in order to develop new therapeutic or prognostication tools.