Lung conservation LIquid VEntilation for acute RESPiratory distress syndrom – LIVE-RESP

The Acute Respiratory Distress Syndrome (ARDS) is the most severe form of acute respiratory failure. It is currently highlightened by the Covid-19 crisis but, independently from this specific pandemic, it represents a constant public health issue. Despite precise recommendations for the implementation of mechanical ventilation (MV) in those patients, mortality is still very high and dramatic sequels can be observed in survivors. Accordingly, there is an unmet need for alternative approaches of MV. Here, we propose to use the liquid ventilation of the lungs with a breathable liquid to reduce pulmonary stress. Beyond a very high solubility for O2 and CO2, this breathable liquid has a very low surface tension and high spreading coefficient, replacing the gas-liquid interface with a liquid-liquid interface at the alveolar surface. This increases alveolar recruitment and reduces transpulmonary pressure, as well as ventilation / perfusion mismatch. In addition, those breathable liquids were shown to exert anti-inflammatory effects that could further improve lung recovery during ARDS. More precisely, we propose a safe and efficient strategy of liquid ventilation using a patented and clinically-relevant technology of “lung conservative liquid ventilation” (LCLV). We initially developed this technique for hypothermia induction in patients resuscitated after cardiac arrest. We obtained a very solid proof of concept of its safety and benefits for cooling induction, leading to the creation of the company Orixha and aiming at producing and testing the LCLV device as a new ultra-rapid cooling method for the post-cardiac arrest syndrom. A clinical trial is planned in 2022 to test the benefits in cardiac arrest patients. Beyond this initial medical application, whether LCLV can also provide direct pulmonary benefits during ARDS is a still-opened question that we propose to address in the present project.
Accordingly, the goal of the present project is to develop and test a novel device of LCLV dedicated to ARDS. It will include technological challenges along with pathophysiological questions, in order to determine the ideal LCLV settings in ARDS conditions, which involves a normothermic LCLV as compared to the hypothermic LCLV that was previously investigated for cardiac arrest. Beyond a coordination work package (WP0), the present project will be divided into three WP. The first one (WP1) will be dedicated to technological challenges and conception of a new LCLV device dedicated to ARDS. The second one (WP2) will be dedicated to performance and safety evaluation in “healthy” swine submitted to prolonged LCLV. The last one (WP3) will be dedicated to the pre-clinical evaluation in a porcine model of ARDS. We will test two conditions of ARDS severity, i.e., LCLV vs gas MV during moderate ARDS, or in combination with extra-corporeal membrane of oxygenation (ECMO) during very severe ARDS (P/F <80 mmHg). All procedures will fit to the French official regulations and agreements regarding animal use for experimental research will be obtained before project kick-off. We already have all the know-how and material for ARDS experiments, large animals investigation, ECMO evaluation and LCLV investigation.
Our consortium gathers the complementary skills required to conduct this ambitious project regarding pathophysiological implications (Partner 1), industrial challenge (Partner 2) and clinical perspective (Partner 3). The ability of the different partners to collaborate with each other was demonstrated by previously successful projects and publications. It will provide a proof of concept of the benefits of LCLV in ARDS. A clinical trial with an up-graded Medical Device for ARDS is realistic soon after the end of the present project. If the benefits are confirmed in humans, the European market for LCLV in ARDS will represent at least 1 000 LCLV devices and the treatment of more than 10 000 patients/year.