Impact of Post-ARDS Covid Sedation on Persistent Neuroinflammation (PET-DEXDOCOVID)

COVID-19 is responsible of a pandemic since December 31 2019, which began in China and spread rapidly. Confirmed Covid positive patients worlwide is estimated at 179 M in June 2021. The infection started in France at the beginning of 2020 and causes severe pneumonia with 130,519 confirmed cases, including 2,712 (2.1%) hospitalizations in intensive care units. COVID-19 emerges as a poorly understood systemic disease that affects several organs, especially the lungs. The first reason for worsening and hospitalization in intensive care is acute respiratory distress syndrome (ARDS) that requires heavy and long care management with orotracheal intubation and mechanical ventilation, as well as prolonged sedation and curarization. Patients who survived this critical phase should then be weaned from this invasive monitoring as quickly as possible to limit risk of morbidity and mortality. It therefore appears essential to do everything possible to reduce the duration of mechanical ventilation and the period of ventilatory weaning, a real daily challenge in intensive care, for both medical and socio-economic sides.

Beside COVID-19 infection, the ventilatory weaning phase is a long and difficult period that can last more than 40 to 60% of the time spent under mechanical ventilation and can be more complicated as the duration of sedation is prolonged. This phase is correlated with the duration of mechanical ventilation, as well as with respiratory, cardiac and neuromuscular diseases. Considering all the risk factors for prolonged ventilatory weaning, one of these is the intensive care delirium.

Delirium in intensive care is a serious event, possibly leading to mortality or acute and late complications (self-extubation, catheter removal, ...) since 30% of delirium patients develop cognitive sequelae. The incidence of this post-ARDS delirium is approximately 20% according to the studies and is found predominantly in patients with severe sepsis. The academic tool to access delirium in intensive care is the CAM-ICU (Confusion Assessment Mehod - ICU) scale; the RASS score (Richmond Agitation-Sedation Scale) is also usable to access patients with a hyperactive form (RASS score greater than 2).

Several drug strategies based on the use of sedating agents such as dexmedetomidine or certain neuroleptics such as loxapine or haloperidol have been developed to reduce this incidence. Dexmedetomidine is a selective adrenergic receptor agonist and has hypnotic and analgesic properties.

At the same time, dexmedetomidine exhibits neuroprotective effects. In experimental models such as intraperitoneal injection of lipopolysaccharide or LPS, marrow lesions or ischemia-reperfusion models, dexmedetomidine reduces cerebral inflammation with a direct action on the microglial phenotype. The impacted signaling pathway is still unclear, however several studies show an action of dexmedetomidine on the AMPK pathway. The use of dexmedetomidine to prevent and treat delirium is not uniform within intensive care units in France and is not administered systematically.