Acute Intermittent Hypoxia With High-Intensity Gait Training in Chronic Stroke: A Phase II Randomized Crossover Trial

Abstract

Background: Studies in individuals with chronic stroke indicate high-intensity training (HIT) focused on walking improves locomotor function, which may be due to repeated activation of locomotor circuits and serotonin-dependent modulation of motor output. Separate studies in animals and individuals with spinal cord injury suggest acute intermittent hypoxia (AIH) can augment the effects of locomotor interventions through similar serotonin-dependent mechanisms, although no studies have coupled AIH with HIT in individuals poststroke. The goal of this study was to evaluate the safety and efficacy of AIH+HIT versus HIT alone in individuals with chronic stroke.

Methods: This phase II double-blind randomized, crossover trial recruited individuals between 18 and 85 years old, >6 months poststroke, and self-selected speeds <1.0 m/s. Participants received up to 15 sessions of AIH for 30 minutes using 15 cycles of hypoxia (60-90 seconds; 8%-9% O₂) and normoxia (30-60 seconds; 21% O₂), followed by 1 hour of HIT targeting >75% heart rate reserve. The control condition received normoxia for 30 minutes before HIT. Following the first training phase, participants performed the second phase >1 month later. The primary outcomes were self-selected speed and fastest speed, a 6-minute walk test, and peak treadmill speed. A 3-way mixed-model ANOVA assessed the effects of time, training, and order of interventions.

Results: Of 55 individuals screened, 35 were randomized to AIH+HIT or normoxia+HIT first, and 28 individuals completed both interventions, revealing greater gains in self-selected speeds (0.14 [0.08-0.18] versus 0.05 [0.01-0.10] m/s), fastest speed (0.16 [0.10-0.21] versus 0.06 [0.02-0.10] m/s), and peak treadmill speed (0.21 [0.14-0.29] versus 0.11 [0.06-0.16] m/s) following AIH+HIT versus normoxia+HIT (P<0.01) with no order effects. Greater gains in spatiotemporal symmetry were observed with AIH+HIT, with worse outcomes for those prescribed serotonin-mediated antidepressant medications.

Conclusions: AIH+HIT resulted in greater gains in locomotor function than normoxia+HIT. Subsequent phase III trials should further evaluate the efficacy of this intervention.

Registration: URL: https://clinicaltrials.gov/; Unique identifier: NCT04472442.

Keywords: heart rate; hypoxia; serotonin; stroke; walking.

Figure 1.

CONSORT diagram of enrollment.

Figure 2.

Changes in SSS (2A), FS (2B), 6MWT (2C), and peakTM (2D) in AIH+HIT first (squares; n=17) and normoxia+HIT first (triangles; n=11) groups at each assessment (mean and 95% CIs).

Figure 3.

A-B. Scatter plot of changes in SSS and FS with AIH+HIT and S_PO₂ achieved during AIH delivery prior to HIT. C-E. Mean changes in SSS and FS with and without history of sleep apnea (3C), with or without use of anti-depressants (primarily SSRIs); 3D), and with and without use of anti-spasticity medications (3E). (* p<0.05; ** p<0.01)