par Annoni, Filippo
Président du jury Schiffmann, Serge N.
Promoteur Taccone, Fabio
Co-Promoteur Creteur, Jacques
Publication Non publié, 2025-01-06
Thèse de doctorat
Résumé : Even when resuscitation efforts achieve return of spontaneous circulation (ROSC), a largeproportion of patients die in the following days after a cardiac arrest (CA) due to cardiac andespecially brain injury or survive with important disability.In the first part of this work, I have developed a reliable model of CA (ventricular fibrillation,)in large animals (swine) that is characterized by the application of a comprehensive neuromonitoringtechnique.In parallel, I conducted a review of the literature to build the theoretical framework behindthe possible use of hypertonic sodium lactate (HSL) and ß-hydroxybutyrate (BHB) in the context ofCA. Such energetic substrates solutions can be useful after ROSC, as they could decrease reactiveoxygen species (ROS) production, modulate excitotoxicity, reduce intracranial pressure, increaseorgan perfusion, improve cardiac performance, and increase pH.In the third part of this work, I conducted a series of experiments to explore the impact of 0.5M HSL infusion (30µmol/Kg*min) started either during cardiopulmonary resuscitation (CPR, 10mmol) and after ROSC (Intra-arrest group) or only after ROSC (post-ROSC group) for 12 hours.Animals treated with HSL had increased pH, lactate, and Na plasmatic concentrations (p=<0.001),and lower K (p=0.004). In both intra-arrest and post-ROSC groups, the norepinephrine requirementwas lower compared with controls (p=0.005 for interaction,). Treated animals had lower circulatingbiomarkers of brain injury (glial fibrillary acid protein or GFAP, p<0.05 at 6 and 12 hours) and cardiacinjury (Troponin I, p<0.05 at 6 and 12 hours), compared to controls. Similarly, animals treated withNa-BHB (0.18 g/Kg*h, 1189 mOsm/L) had higher circulating BHB, Na and osmolarity (all p<0.05),lower plasma biomarkers of brain injury at 6 (GFAP and neuron specific enolase, NSE, p<0.05) and12 hours (neurofilament light chain, NFL, GFAP and NSE, p<0.01) compared to controls.In the fourth part, I developed the protocol for a human randomized, controlled, phase II, openlabel, investigator initiated clinical trial that will hopefully translate these findings to the bedside.

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