Dose‐related propofol resistance in COVID‐19 patients: Altered drug plasma levels, mechanistic insights from neuronal‐derived extracellular vesicles and miRNA analysis

Aim: Critical care for COVID-19 patients presents unique challenges, particularly in sedation management. Patients demonstrate notable dose-related resistance to propofol, potentially due to complex pharmacokinetic alterations. Emerging evidence suggests that plasma extracellular vesicle-associated miRNA represents valuable predictive biomarkers for drug response and may help elucidate the mechanism underlying altered propofol activity. Methods: A comparative study was conducted at ASUGI, Trieste, involving 27 COVID-19 and 14 non-COVID-19 patients. Propofol was administered through bolus and continuous infusion. Comprehensive analyses included plasma propofol concentration measurement (HPLC-UV), neuron-derived extracellular vesicle characterization, GABRB2 protein level assessment (ELISA) and miRNA sequencing. Statistical analysis utilized t-test and logistic regression. Results: COVID-19 patients required substantially higher propofol doses. Plasma propofol levels were significantly lower in COVID-19 patients (600.49 ng/mL vs. 4018.44 ng/mL, p =.0008). Elevated GABRB2 protein levels were observed, and five upregulated miRNAs were identified, potentially targeting 247 genes in the thalamus and cortex, mainly involved in inflammation and oxidative stress pathways. Discussion: The increased propofol dose requirement observed in COVID-19 patients appears to result from inflammation-driven metabolic changes that accelerate drug clearance. miRNA regulatory networks suggest complex interactions affecting metabolic enzymes and oxidative stress, providing insights into altered drug pharmacokinetics.