Daily intermittent hypoxia enhances walking after chronic spinal cord injury: a randomized trial

Abstract

Objectives: To test the hypothesis that daily acute intermittent hypoxia (dAIH) and dAIH combined with overground walking improve walking speed and endurance in persons with chronic incomplete spinal cord injury (iSCI).

Methods: Nineteen subjects completed the randomized, double-blind, placebo-controlled, crossover study. Participants received 15, 90-second hypoxic exposures (dAIH, fraction of inspired oxygen [Fio2] = 0.09) or daily normoxia (dSHAM, Fio2 = 0.21) at 60-second normoxic intervals on 5 consecutive days; dAIH was given alone or combined with 30 minutes of overground walking 1 hour later. Walking speed and endurance were quantified using 10-Meter and 6-Minute Walk Tests. The trial is registered at ClinicalTrials.gov (NCT01272349).

Results: dAIH improved walking speed and endurance. Ten-Meter Walk time improved with dAIH vs dSHAM after 1 day (mean difference [MD] 3.8 seconds, 95% confidence interval [CI] 1.1-6.5 seconds, p = 0.006) and 2 weeks (MD 3.8 seconds, 95% CI 0.9-6.7 seconds, p = 0.010). Six-Minute Walk distance increased with combined dAIH + walking vs dSHAM + walking after 5 days (MD 94.4 m, 95% CI 17.5-171.3 m, p = 0.017) and 1-week follow-up (MD 97.0 m, 95% CI 20.1-173.9 m, p = 0.014). dAIH + walking increased walking distance more than dAIH after 1 day (MD 67.7 m, 95% CI 1.3-134.1 m, p = 0.046), 5 days (MD 107.0 m, 95% CI 40.6-173.4 m, p = 0.002), and 1-week follow-up (MD 136.0 m, 95% CI 65.3-206.6 m, p < 0.001).

Conclusions: dAIH ± walking improved walking speed and distance in persons with chronic iSCI. The impact of dAIH is enhanced by combination with walking, demonstrating that combinatorial therapies may promote greater functional benefits in persons with iSCI.

Classification of evidence: This study provides Class I evidence that transient hypoxia (through measured breathing treatments), along with overground walking training, improves walking speed and endurance after iSCI.

Figures

Figure 1. Trial recruitment flowchart and experimental protocol

Flowchart showing recruitment, randomization, and data collection from subjects in blocks 1 and 2. In block 1, subjects received a breathing intervention consisting of 15 episodes of breathing mild hypoxia (fraction of inspired oxygen [Fio2] = 0.09) for 90 seconds alternating with 60-second normoxia (Fio2 = 0.21). This intervention was repeated once daily for 5 days. Alternatively, subjects received 5 days of continuous normoxia. Overground walking speed and endurance were quantified by the 10-Meter Walk Test and 6-Minute Walk Test, respectively, at baseline (BL), within 60 minutes after acute intermittent hypoxia (AIH) on the first (D1) and fifth (D5) exposure days, and in follow-ups (F/U) at 1 week (F1, i.e., D8) and 2 weeks (F2, i.e., D15). In block 2, subjects received a combinatorial intervention of daily AIH and overground walking (dAIH + walking). After the breathing intervention and a 35- to 45-minute rest period, subjects walked overground at maximal exertion for 30 minutes each day. Overground walking speed and endurance were quantified at BL, D1, D5, F1, and F2. dSHAM = daily normoxia.

Figure 2. dAIH-induced increases in overground walking speed in persons with chronic incomplete spinal cord injury

(A) Bars represent mean ± 1 standard error changes in 10-Meter Walk Test (10MWT) times (seconds) across all subjects at each time point for daily acute intermittent hypoxia (dAIH) (black) and daily normoxia (dSHAM) (white). Asterisks indicate significance relative to baseline (BL) (repeated-measures linear mixed model, p < 0.05) and brackets with asterisks indicate significant differences between interventions dAIH and dSHAM (repeated-measures linear mixed model, p < 0.05). (B) Subject changes in 10MWT times (seconds) relative to BL across days 1 (D1) and 5 (D5) and follow-ups 1 (F1) and 2 (F2) during dAIH intervention (B.1) and during dSHAM intervention (B.2). Decreases in time represent increases in walking speed. (C) Same mean comparisons as in panel A for dAIH + walking (black) and dSHAM + walking (white). (D) Same subject trends as in panel B for dAIH + walking (D.1) and dSHAM + walking (D.2).

Figure 3. dAIH-induced sustained increases in overground walking endurance in persons with chronic incomplete spinal cord injury

(A) Bars represent mean ± 1 standard error changes in 6-Minute Walk Test (6MWT) distances (meters) across all subjects at each time point for either daily acute intermittent hypoxia (dAIH) (black) or daily normoxia (dSHAM) (white). Asterisks indicate significance relative to baseline (BL) (repeated-measures linear mixed model, p < 0.05) and brackets with asterisks indicate significant differences between interventions dAIH and dSHAM (repeated-measures linear mixed model, p < 0.05). (B) Subject changes in 6MWT distances (meters) relative to baseline (BL) across days 1 (D1) and 5 (D5) and follow-ups 1 (F1) and 2 (F2) during dAIH intervention (dAIH, B.1) and during dSHAM intervention (dSHAM, B.2). (C) Same mean comparisons as in panel A for dAIH with daily overground walking (dAIH + walking, black) and dSHAM + walking (white). (D) Same subject trends as in panel B for dAIH + walking (D.1) and dSHAM + walking (D.2).

Figure 4. dAIH with daily overground walking produces greater improvements in walking compared with dAIH alone

(A) Bars represent mean ± 1 standard error changes in 10-Meter Walk Test (10MWT) times (seconds) across all subjects at days 1 (D1) and 5 (D5) and follow-ups 1 (F1) and 2 (F2) for daily acute intermittent hypoxia (dAIH) (black) or the combinatorial intervention of dAIH with daily overground walking (white). (B) Same trends as in panel A for mean ± 1 standard error changes in 6-Minute Walk Test (6MWT) distances (meters). Brackets with asterisks indicate significant differences between interventions dAIH and dAIH + walking (repeated-measures linear mixed model, p < 0.05). BL = baseline.