Acute intermittent hypoxia and respiratory muscle recruitment in people with amyotrophic lateral sclerosis: A preliminary study

Abstract

Respiratory failure is the main cause of death in amyotrophic lateral sclerosis (ALS). Since no effective treatments to preserve independent breathing are available, there is a critical need for new therapies to preserve or restore breathing ability. Since acute intermittent hypoxia (AIH) elicits spinal respiratory motor plasticity in rodent ALS models, and may restore breathing ability in people with ALS, we performed a proof-of-principle study to investigate this possibility in ALS patients. Quiet breathing, sniff nasal inspiratory pressure (SNIP) and maximal inspiratory pressure (MIP) were tested in 13 persons with ALS and 10 age-matched controls, before and 60 min post-AIH (15, 1 min episodes of 10% O2, 2 min normoxic intervals) or sham AIH (continuous normoxia). The root mean square (RMS) of the right and left diaphragm, 2nd parasternal, scalene and sternocleidomastoid muscles were monitored. A vector analysis was used to calculate summated vector magnitude (Mag) and similarity index (SI) of collective EMG activity during quiet breathing, SNIP and MIP maneuvers. AIH facilitated tidal volume and minute ventilation (treatment main effects: p < 0.05), and Mag (ie. collective respiratory muscle activity; p < 0.001) during quiet breathing in ALS and control subjects, but there was no effect on SI during quiet breathing. SNIP SI decreased in both groups post-AIH (p < 0.005), whereas Mag was unchanged (p = 0.09). No differences were observed in SNIP or MIP post AIH in either group. Discomfort was not reported during AIH by any subject, nor were adverse events observed. Thus, AIH may be a safe way to increase collective inspiratory muscle activity during quiet breathing in ALS patients, although a single AIH presentation was not sufficient to significantly increase peak inspiratory pressure generation. These preliminary results provide evidence that AIH may improve breathing function in people with ALS, and that future studies of prolonged, repetitive AIH protocols are warranted.

Keywords: AIH; ALS; Acute intermittent hypoxia; Amyotrophic lateral sclerosis; Control of breathing; Respiratory muscle activity; Respiratory plasticity; Surface EMG.

Copyright © 2021. Published by Elsevier Inc.

Figures

Figure 1.. Experimental protocol.

The study consisted of two randomly assigned visits. During the sham visit (A), the intervention sequence lasted for approximately 45 minutes and room air (21% oxygen) was delivered the entire time (with all other procedures simulating AIH test days). The AIH visit (B) consisted of delivering 15 60 second episodes of 10% oxygen, separated by 120 seconds of room air breathing (21% oxygen). Quiet breathing, MIP and SNIP tests, as well as sEMG recordings, were performed before (baseline) and 60 min after interventions.

Figure 2.

AIH effects on quiet breathing and maximal respiratory pressure in ALS patients and controls. (A) Tidal volume was greater 60 minutes after AIH in both patients and controls as compared to Sham (p=0.04). (B) Individual tidal volume data during Sham treatment. (C) Individual tidal volume data points during AIH protocols. (D) Minute ventilation increased following AIH versus Sham (p=0.03). (E) Individual minute ventilation data during sham treatment. (F) Individual minute ventilation data points during AIH. (G) No group or treatment main effects were detected for respiratory rate. (H) Changes in SNIP did not differ based on treatment, but tended to be greater for controls (p=0.07). (I) MIP was not different between groups (p=0.36). MV= minute ventilation, VT= tidal volume, *p<0.05.

Figure 3.

EMG recordings of the right diaphragm, parasternal, scalene and sternocleidomastoid muscles during quiet breathing, SNIP and MIP at baseline in a control participant. Note the changes in the amplitude and duration of muscle recruitment between maneuvers.

Figure 4.

Collective respiratory muscle activity (response vector Mag) and recruitment pattern (SI) during quiet breathing in ALS patients and controls. (A) Response vector Mag was significantly greater in ALS patients and controls, following AIH versus sham (treatment main effect: p<0.001). (B) Individual Mag data in response to SHAM. (C) Individual Mag data points in response to AIH. (D) The difference in SI between sham vs. AIH sessions was not different between groups (p=0.15). (E) Individual SI data in response to SHAM. (F) Individual SI data in response to AIH. RV Mag= response vector magnitude, SI= similarity index, ***p<0.001.

Figure 5.

Similarity index (SI) and response vector magnitude (Mag) during SNIP and MIP tests. (A) SNIP response vector Mag trended upward for most subjects, following AIH (p=0.09), and the increase in Mag was greater in controls (p=0.01). (B) Individual Mag data in response to SHAM. (C) Individual Mag data in response to AIH. (D) SI during SNIP decreased in both groups 60 minutes post-AIH (treatment main effect: p=0.003). SI was significantly lower post-treatment in controls (p=0.03). (E) Individual SI data in response to SHAM. (F) Individual SI data in response to AIH. (G) No significant group or treatment differences in response vector Mag were observed for MIP. (H) Individual Mag data in response to SHAM. (I) Individual Mag data in response to AIH. (J) No significant group or treatment differences in SI were observed for MIP. (K) Individual SI data in response to SHAM. (L) Individual SI data in response to AIH. Mag= response vector magnitude, SI= similarity index,*p<0.05, **p<0.005.

Figure 6.

Muscle facilitation response to AIH is highly variable between individuals and tasks. % of change between sham and AIH session in the right and left; scalene, SCM, para sternal, and diaphragm muscles during quiet breathing, SNIP and MIP are presented in four ALS participants. While some muscles show strong AIH facilitation, others show no facilitation. Note: During quiet breathing, zero activity was recorded in a few of the muscles in ALS001, ALS004, and ALS005, possibly due to limitations of surface EMG recordings from deeply situated muscles, such as the diaphragm and parasternal during non-forceful maneuvers in individuals with higher percentage of subcutaneous fat.