Safety and biomarker signatures of adaptive response induction during personalized intermittent hypoxia-hyperoxia sessions in older adults: a pilot randomized placebo-controlled phase I study

INTRODUCTION: Preoperative intermittent hypoxia–hyperoxia (IHH) may be considered an organ-protective prehabilitation strategy for high-risk patients; however, the lack of personalized approaches to selecting optimal exposure modes limits its practical use. Near-infrared cerebral tissue oximetry (NIRS) may guide individualization of IHH protocols. OBJECTIVE: To evaluate the safety, tolerability, and biomarker signatures of adaptive response induction during NIRS-personalized IHH sessions. MATERIALS AND METHODS: This prospective single-blind randomized placebo-controlled study included 20 elderly volunteers randomized to the IHH group (n = 10) or the control group (n = 10). Participants underwent three daily 45-minute sessions consisting of five hypoxia-hyperoxia cycles or sham procedures. Personalization was achieved by individually titrating the fraction of inspired oxygen (FiO2) during the hypoxic phase to reduce cerebral tissue oxygen saturation (SctO2) by 20 % from baseline. The composite primary safety endpoint included individual intolerance, adverse events, and complications during sessions. Secondary endpoints assessed between-group differences in the dynamics of vital signs and FiO2. Biomarkers reflecting stress-adaptive responses and antioxidant activity were also evaluated. RESULTS: No cases of intolerance, adverse events, or complications were observed. Vital sign dynamics differed significantly between groups but remained within clinically safe ranges. Between the first and third sessions, a significant reduction in the FiO2 required to achieve a 20 % decrease in SctO2 was noted. The IHH group demonstrated significant increases in hypoxia-inducible factor-1α, nuclear factor erythroid 2-related factor 2, and catalase activity. CONCLUSIONS: Personalized NIRS-guided IHH sessions in elderly volunteers are safe and are associated with a reduction in the FiO2 required to decrease SctO2 to target levels, as well as activation of stress-adaptive and antioxidant pathways. These findings may be applicable to preoperative prehabilitation strategies and warrant confirmation in further clinical studies.