BackgroundIntermittent hypoxia (IH) is emerging as a cost-effective nonpharmacological method for vital organ protection. We aimed to assess the effects of a short-term moderate intermittent hypoxia preconditioning protocol (four cycles of 13% hypoxia lasting for 10 min with 5-min normoxia intervals) on acute hypoxic injury induced by sustained hypoxic exposure (oxygen concentration of 11.8% for 6 h).MethodsOne hundred healthy volunteers were recruited and randomized to the IH group and the control group to receive IH or sham-IH preconditioning for 5 days, respectively, and then were sent to a hypoxic chamber for simulated acute high-altitude exposure (4500 m).ResultsThe overall incidence of acute mountain sickness was 27% (27/100), with 14% (7/50) in the IH group and 40% (20/50) in the control group (p = 0.003). After 6-h simulated high-altitude exposure, the mean Lake Louise Score was lower in the IH group as compared to controls (1.30 +/- 1.27 vs. 2.04 +/- 1.89, p = 0.024). Mean peripheral oxygen saturations (SpO2) and intracranial pressure (ICP) measures after acute hypoxic exposure exhibited significant differences, with the IH group showing significantly greater SpO2 values (85.47 +/- 5.14 vs. 83.10 +/- 5.15%, p = 0.026) and lower ICP levels than the control group (115.59 +/- 32.15 vs. 130.36 +/- 33.83 mmH2O, p = 0.028). IH preconditioning also showed greater effects on serum protein gene product 9.5 (3.89 vs. 29.16 pg/mL; p = 0.048) and C-reactive protein (-0.28 vs. 0.41 mg/L; p = 0.023).ConclusionThe short-term moderate IH improved the tolerance to hypoxia and exerted protection against acute hypoxic injury induced by exposure to sustained normobaric hypoxia, which provided a novel method and randomized controlled trial evidence to develop treatments for hypoxia-related disease. In this trial, an intermittent hypoxia preconditioning protocol of four cycles of 13% hypoxia lasting for 10 min with 5-min normoxia intervals was found to exert protective effects on acute hypoxic injury. Intermittent hypoxia preconditioning has the potential to reduce the occurrence and severity of acute mountain sickness in hypoxic condition, improve peripheral oxygen saturation, reserve intracranial pressure, and lessen elevation of inflammatory and brain injury biomarkers. The figure of Graphical Abstract was created with .image