Cooling the body through total liquid ventilation – COOLIVENT

Out-of-hospital cardiac arrest is a leading cause of death worldwide. Therapeutic hypothermia (32-34°C) was proposed to improve the outcomes of patients after their resuscitation but it does not afford enough benefit with current techniques. Here, we propose a new paradigm for temperature management using ultra-fast cooling of the whole body through total liquid ventilation (TLV) of the lungs with temperature-controlled liquid perfluorocarbons. This unique technique can use the lungs as a heat exchanger while maintaining normal gas exchanges. After experimental cardiac arrest, hypothermic TLV (HTLV) was shown to improve survival as well as neurological, cardiac and renal outcomes, as compared to conventional cooling techniques. Recently, we developed and tested a fully functional and robust ventilator prototype for HTLV with an accurate control of liquid pressures and volumes within the lungs in a real-time responsive manner. The aim of the present project is to complete the final research steps of this work before its clinical translation. To achieve this goal, we need to assess the conformity and safety of the previously developed prototype of liquid ventilator to support its clinical and further industrial transfers. This implies conformity assessment to European directives/guidelines and safety evaluation of the final procedure in animals. We also need to evaluate the relevance of previously identified biomarkers that could be ultimately used for the clinical evaluation of HTLV (i.e., markers of inflammation and innate immunity mediators). These markers will not be sufficient for the full clinical evaluation of HTLV but they will contribute to identify and weight clinical endpoints for further evaluation of this technology in humans. To achieve these goals, the project is divided into 4 work packages (WP). The first (WP1) will be dedicated to project coordination. The second (WP2) will correspond to the regulatory steps before further evaluation of HTLV. It includes an evaluation of the liquid ventilation device by a certification company and establishment of the regulatory requirement/regulatory pathway roadmap by an external independent experts’ cabinet. This is crucial for the conformity assessment to the European directive on medical devices and an essential step before the clinical use approval and further steps such as registration. The goal of the third WP (WP3) will be to demonstrate the safety and cooling efficiency of HTLV in human-sized pigs with this final HTLV ventilator device. If technological improvements are done in WP2, safety experiments will be done using the final version of the HTLV prototype. Finally, the last WP4 will allow to determine whether a transcriptomic signature could be observed in human survivors of cardiac arrest using the real population that will be investigated when HTLV will be used in humans (i.e., just after the present project). Globally, this project can be considered as highly original as it opens a unique personalized medicine and disruptively positive perspectives for the treatment of cardiac arrest. With ultrafast cooling and HTLV, we could offer a new and unique solution to change the paradigm of hypothermia induction following cardiac arrest. Once transferred to the clinical arena, HTLV will be a real medical breakthrough with many other possible applications. In addition, we will assess an important tool for patient prognostication survival after cardiac arrest through transcriptomic analyses. All these findings will allow us to be ready for the clinical evaluation of HTLV at the end of the present project (2020). This will be supported by the creation of a start-up company in Q2/Q3 in 2017, in full agreement with the public supervising bodies and technological transfer organizations. Beyond contributing to a medical breakthrough, this company will contribute to the French economy and competitiveness by being the leader in healthcare industry.