RESUMEN
STUDY OBJECTIVE: The effect of volatile anesthetics on postoperative recovery in older adults is still not entirely clear. Thus, we evaluated the effect of desflurane versus sevoflurane anesthesia on speed of postoperative recovery in older adults eligible for same-day discharge. We further evaluated the incidence of postoperative nausea and vomiting (PONV), bispectral index (BIS) values, and S100B concentrations. DESIGN: Single-center, prospective, observer-blinded, randomized clinical trial. SETTING: Operating room. PATIENTS: 190 patients ≥65 years of age and scheduled for minor- to moderate-risk noncardiac surgeries. INTERVENTIONS: Goal-directed administration of desflurane versus sevoflurane for maintenance of anesthesia with an intraoperative goal of BIS 50 ± 5. MEASUREMENTS: The primary outcome was the time to anesthesia recovery, which was defined as the time between arrival at the post-anesthesia care unit (PACU) and reaching criteria for discharge from PACU, based on modified Aldrete score ≥ 12 points. Modified Aldrete scores were assessed at PACU arrival and thereafter in five-minute intervals. PONV was evaluated during PACU stay and the first three postoperative days, BIS values were recorded during PACU stay, and S100B values were measured before and after surgery, and on the second postoperative day. MAIN RESULTS: 95 patients were randomized to receive desflurane, and 95 patients to receive sevoflurane. We did not observe a significant difference in median duration of postoperative recovery between the groups (desflurane: 0 min [0;0]; sevoflurane: 0 min [0;0]; p = 0.245). 77 patients (81.1%) in the desflurane group and 84 patients (88.4%) in the sevoflurane group already had Aldrete scores ≥12 points upon arrival at PACU (p = 0.277). There was also no significant difference in the incidences of PONV (p = 0.606), postoperative BIS values (p = 0.197), and postoperative maximum S100B concentrations (p = 0.821) between the groups. CONCLUSIONS: Despite previous reports, we did not observe significant faster recovery times after desflurane anesthesia. Both volatile anesthetics may be appropriate for same-day discharge in older adults.
RESUMEN
Ferroptosis is evolving as a highly promising approach to combat difficult-to-treat tumour entities including therapy-refractory and dedifferentiating cancers1-3. Recently, ferroptosis suppressor protein-1 (FSP1), along with extramitochondrial ubiquinone or exogenous vitamin K and NAD(P)H/H+ as an electron donor, has been identified as the second ferroptosis-suppressing system, which efficiently prevents lipid peroxidation independently of the cyst(e)ine-glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis4-6. To develop FSP1 inhibitors as next-generation therapeutic ferroptosis inducers, here we performed a small molecule library screen and identified the compound class of 3-phenylquinazolinones (represented by icFSP1) as potent FSP1 inhibitors. We show that icFSP1, unlike iFSP1, the first described on-target FSP1 inhibitor5, does not competitively inhibit FSP1 enzyme activity, but instead triggers subcellular relocalization of FSP1 from the membrane and FSP1 condensation before ferroptosis induction, in synergism with GPX4 inhibition. icFSP1-induced FSP1 condensates show droplet-like properties consistent with phase separation, an emerging and widespread mechanism to modulate biological activity7. N-terminal myristoylation, distinct amino acid residues and intrinsically disordered, low-complexity regions in FSP1 were identified to be essential for FSP1-dependent phase separation in cells and in vitro. We further demonstrate that icFSP1 impairs tumour growth and induces FSP1 condensates in tumours in vivo. Hence, our results suggest that icFSP1 exhibits a unique mechanism of action and synergizes with ferroptosis-inducing agents to potentiate the ferroptotic cell death response, thus providing a rationale for targeting FSP1-dependent phase separation as an efficient anti-cancer therapy.