Amyotrophic Lateral Sclerosis (ALS), Neuromuscular Diseases
Conditions
Keywords
acute intermittent hypoxia (AIH), respiratory motor function, hypoxia, normoxia, EMG (electromyography)
Brief summary
This project seeks to investigate the effects of a single acute intermittent hypoxia (AIH) session on respiratory and non-respiratory motor function and EMG (electromyography) activity on patients with ALS (amyotrophic lateral sclerosis) and healthy controls.
Detailed description
Most ALS patients survive less than 5 years after diagnosis, and the main cause of death is respiratory failure. The investigators are interested in the therapeutic potential of acute intermittent hypoxia (AIH) for individuals with neuromuscular diseases, such as ALS. More than two decades of research indicates AIH elicits meaningful respiratory and non-respiratory motor recovery. Acute intermittent hypoxia (AIH) consists of alternating periods of breathing mildly hypoxic (lowered oxygen concentration) and normoxic (normal oxygen concentration) air. The investigators propose to study mechanisms of respiratory plasticity associated with a single presentation of mild AIH. The fundamental hypothesis guiding this proposal is that even a single AIH trial improves respiratory (and non-respiratory) motor function in ALS patients procedure. Participants will then be asked to breathe air with reduced oxygen for short periods of time, for a duration of 45 minutes. The activity of your muscles and your heart function will be monitored throughout the procedure.
Interventions
AIH entails continuous breathing as the level of oxygen in the air is decreased, then returned to normal. Participants will alternate between breathing normal air and breathing hypoxic air (air that has less oxygen). Participants will complete a single 45 minute session of acute intermittent hypoxia (AIH). Breathing, muscle activity and heart activity will be monitored before, during and after the procedure. The intervals will last 1 minute each.
Participants will complete the sham acute intermittent hypoxia, consisting of a single 45 minute session of breathing air with normal oxygen levels. All aspects of this procedure will otherwise be the same as for the AIH procedure. Breathing, muscle activity and heart activity will be monitored before, during and after the procedure.
Sponsors
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Masking description
Participants will be blind to the order of the AIH/sham AIH visits, but this information will be provided to the participant after completion of last visit.
Intervention model description
Participants will complete both the AIH and the sham AIH visits. The order of these visits will be randomized, but all subjects will complete both visits in the course of the study.
Eligibility
Sex/Gender
ALL
Age
21 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
* a healthy adult * clinical diagnosis of ALS * baseline FVC \>60% predicted for age, sex and height.
Exclusion criteria
* pregnant * diagnosed cardiovascular disease * a BMI \>35 kg/m2 * currently take selective serotonin reuptake inhibitors (SSRI) * history of seizures * history of hospitalization for sepsis * respiratory infection or took antibiotic medications within the past 4 weeks * use external respiratory support during any waking hours * participate in a pharmaceutical trial to treat ALS * have any other medical condition the PI or medical director identify would make it unsuitable to participate.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Maximal Inspiratory Pressure (MIP) | 3 Hours | MIP is a maximal voluntary static contraction of the inspiratory muscles against a closed valve, measured at the mouth. The test will be repeated until 3 measurements are obtained within 10% variability and an average of the three trials is reported. The change in MIP will be the percent difference in pressure between the averaged baseline MIP and the averaged follow-up measure, which is tested 60 minutes after the gas intervention. |
| Percent Change in Maximal Voluntary Grip Force | 3 Hours | Maximal static voluntary handgrip contractions will be evaluated in a seated position with the arm at the side and elbow flexed to 90 degrees. The test will be repeated until 3 measurements are obtained within 10% variability and then averaged. The change in grip will be the percent difference in force between the averaged baseline grip and the averaged follow-up grip measure, which is tested 60 minutes after the gas intervention. |
| Percent Change in Sniff Nasal Inspiratory Pressure | 3 Hours | Maximal voluntary contractions of the inspiratory muscles measured with a pressure sensor placed in the nare. The test will be repeated until 3 measurements are obtained within 10% variability and then averaged. The change in sniff nasal inspiratory pressure will be the percent difference in pressure between the averaged baseline sniff nasal inspiratory pressure and the averaged follow-up measure, which is tested 60 minutes after the gas intervention. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Minute Ventilation | 3 Hours | Minute ventilation is measured using a pneumotachograph connected to the face mask to record breath-by-breath volume and breathing rate, which is then multiplied to calculate minute ventilation. After achieving a stable tidal volume, 5 minutes of resting minute ventilation will be recorded and then averaged. The change in minute ventilation will be the percent difference in volume between the averaged baseline ventilation and the averaged follow-up ventilation, which is tested 60 minutes after the gas intervention. |
| Occlusion Pressure (P0.1) | 3 Hours | P0.1 is measured with a pressure transducer connected to a face mask and represents the pressure generated against a transiently occluded airway in the first 0.1 sec of inspiration. The generated during this initial period of inspiration is resistant to learning or sensory bias and is considered a clinical estimate of inspiratory drive. Five measurements will be conducted and then averaged, with 5-15 un-occluded breaths between each P0.1 measurement. The averaged pressures at baseline and 60 minutes post-gas intervention will be reported and will be expressed in cm H2O. |
| Percentage Change in Respiratory EMG Vector Magnitude | 3 Hours | EMG vector magnitude represents the composite surface EMG activity expressed from eight respiratory muscles (bilateral scalene, sternocleidomastoid, 2nd parasternal, and 8th external intercostal/diaphragm). The vector magnitude was calculated for each participant from the root mean square (RMS) values from each EMG channel, as the square root of the sum of the individual squared EMG channel amplitudes. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ALS Group Participants will complete a single 45 minute session of acute intermittent hypoxia (AIH), as well as, the 45 minute sham AIH session, consisting of breathing air with normal oxygen levels. Breathing, muscle activity and heart activity will be monitored before, during and after both procedures.
Acute Intermittent Hypoxia: AIH entails continuous breathing as the level of oxygen in the air is decreased, then returned to normal. Participants will alternate between breathing normal air and breathing hypoxic air (air that has less oxygen). Participants will complete a single 45 minute session of acute intermittent hypoxia (AIH). Breathing, muscle activity and heart activity will be monitored before, during and after the procedure. The intervals will last 1 minute each.
Sham Acute Intermittent Hypoxia: Participants will complete the sham acute intermittent hypoxia, consisting of a single 45 minute session of breathing air with normal oxygen levels. All aspects of this procedure will otherwise be the same as for the AIH procedure. Breathing, muscle activity and heart activity will be monitored before, during and after the procedure. | 13 |
| Healthy Control Group Participants will complete a single 45 minute session of acute intermittent hypoxia (AIH), as well as, the 45 minute sham AIH session, consisting of breathing air with normal oxygen levels. Breathing, muscle activity and heart activity will be monitored before, during and after both procedures.
Acute Intermittent Hypoxia: AIH entails continuous breathing as the level of oxygen in the air is decreased, then returned to normal. Participants will alternate between breathing normal air and breathing hypoxic air (air that has less oxygen). Participants will complete a single 45 minute session of acute intermittent hypoxia (AIH). Breathing, muscle activity and heart activity will be monitored before, during and after the procedure. The intervals will last 1 minute each.
Sham Acute Intermittent Hypoxia: Participants will complete the sham acute intermittent hypoxia, consisting of a single 45 minute session of breathing air with normal oxygen levels. All aspects of this procedure will otherwise be the same as for the AIH procedure. Breathing, muscle activity and heart activity will be monitored before, during and after the procedure. | 10 |
| Total | 23 |
Baseline characteristics
| Characteristic | ALS Group | Healthy Control Group | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 7 Participants | 7 Participants | 14 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 3 Participants | 9 Participants |
| Age, Continuous | 65.3 years | 67.4 years | 66.2 years |
| Amyotrophic Lateral Sclerosis Functional Rating Scale- Revised (ALS-RFS-R) | 38.8 units on a scale | — | 38.8 units on a scale |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 10 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 13 Participants | 8 Participants | 21 Participants |
| Region of Enrollment United States | 13 Participants | 10 Participants | 23 Participants |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 7 Participants |
| Sex: Female, Male Male | 10 Participants | 6 Participants | 16 Participants |
| Vital capacity (% predicted) | 83.3 Percentage | 105.2 Percentage | 92.8 Percentage |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 11 | 0 / 14 | 0 / 11 |
| other Total, other adverse events | 2 / 14 | 1 / 11 | 4 / 14 | 0 / 11 |
| serious Total, serious adverse events | 0 / 14 | 0 / 11 | 0 / 14 | 0 / 11 |
Outcome results
Primary
Percent Change in Maximal Inspiratory Pressure (MIP)
MIP is a maximal voluntary static contraction of the inspiratory muscles against a closed valve, measured at the mouth. The test will be repeated until 3 measurements are obtained within 10% variability and an average of the three trials is reported. The change in MIP will be the percent difference in pressure between the averaged baseline MIP and the averaged follow-up measure, which is tested 60 minutes after the gas intervention.
Time frame: 3 Hours
Population: Individuals with an ALS diagnosis and age matched healthy controls.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ALS Group | Percent Change in Maximal Inspiratory Pressure (MIP) | Sham Hypoxia | 0.3 percentage change in MIP from baseline | Standard Error 2.9 |
| ALS Group | Percent Change in Maximal Inspiratory Pressure (MIP) | AIH | -4.8 percentage change in MIP from baseline | Standard Error 1.6 |
| Healthy Control Group | Percent Change in Maximal Inspiratory Pressure (MIP) | Sham Hypoxia | -3.1 percentage change in MIP from baseline | Standard Error 2.3 |
| Healthy Control Group | Percent Change in Maximal Inspiratory Pressure (MIP) | AIH | -5.0 percentage change in MIP from baseline | Standard Error 3.2 |
Primary
Percent Change in Maximal Voluntary Grip Force
Maximal static voluntary handgrip contractions will be evaluated in a seated position with the arm at the side and elbow flexed to 90 degrees. The test will be repeated until 3 measurements are obtained within 10% variability and then averaged. The change in grip will be the percent difference in force between the averaged baseline grip and the averaged follow-up grip measure, which is tested 60 minutes after the gas intervention.
Time frame: 3 Hours
Population: Individuals with an ALS diagnosis and age matched unaffected controls.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ALS Group | Percent Change in Maximal Voluntary Grip Force | AIH | -8.2 percent change in grip forcfrom baseline | Standard Error 0.26 |
| ALS Group | Percent Change in Maximal Voluntary Grip Force | SHAM | 14.5 percent change in grip forcfrom baseline | Standard Error 0.11 |
| Healthy Control Group | Percent Change in Maximal Voluntary Grip Force | AIH | -11.2 percent change in grip forcfrom baseline | Standard Error 0.24 |
| Healthy Control Group | Percent Change in Maximal Voluntary Grip Force | SHAM | 18.2 percent change in grip forcfrom baseline | Standard Error 0.07 |
Primary
Percent Change in Sniff Nasal Inspiratory Pressure
Maximal voluntary contractions of the inspiratory muscles measured with a pressure sensor placed in the nare. The test will be repeated until 3 measurements are obtained within 10% variability and then averaged. The change in sniff nasal inspiratory pressure will be the percent difference in pressure between the averaged baseline sniff nasal inspiratory pressure and the averaged follow-up measure, which is tested 60 minutes after the gas intervention.
Time frame: 3 Hours
Population: Individuals with an ALS diagnosis and age matched healthy controls.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ALS Group | Percent Change in Sniff Nasal Inspiratory Pressure | Sham | 2.5 Percent Change from Baseline | Standard Deviation 4.1 |
| ALS Group | Percent Change in Sniff Nasal Inspiratory Pressure | AIH | 4.9 Percent Change from Baseline | Standard Deviation 5 |
| Healthy Control Group | Percent Change in Sniff Nasal Inspiratory Pressure | Sham | 7.4 Percent Change from Baseline | Standard Deviation 5.9 |
| Healthy Control Group | Percent Change in Sniff Nasal Inspiratory Pressure | AIH | 5.8 Percent Change from Baseline | Standard Deviation 5.5 |
Secondary
Occlusion Pressure (P0.1)
P0.1 is measured with a pressure transducer connected to a face mask and represents the pressure generated against a transiently occluded airway in the first 0.1 sec of inspiration. The generated during this initial period of inspiration is resistant to learning or sensory bias and is considered a clinical estimate of inspiratory drive. Five measurements will be conducted and then averaged, with 5-15 un-occluded breaths between each P0.1 measurement. The averaged pressures at baseline and 60 minutes post-gas intervention will be reported and will be expressed in cm H2O.
Time frame: 3 Hours
Population: Individuals with an ALS diagnosis and age matched healthy controls who completed a single exposure to acute intermittent hypoxia. P0.1 during sham hypoxia presentations were not collected due to an oversight by study staff and cannot be reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ALS Group | Occlusion Pressure (P0.1) | Baseline | -0.80 cm H2O | Standard Deviation 0.58 |
| ALS Group | Occlusion Pressure (P0.1) | 60 minutes post-AIH | -0.83 cm H2O | Standard Deviation 0.72 |
| Healthy Control Group | Occlusion Pressure (P0.1) | Baseline | -0.60 cm H2O | Standard Deviation 0.41 |
| Healthy Control Group | Occlusion Pressure (P0.1) | 60 minutes post-AIH | -0.47 cm H2O | Standard Deviation 0.53 |
Secondary
Percentage Change in Respiratory EMG Vector Magnitude
EMG vector magnitude represents the composite surface EMG activity expressed from eight respiratory muscles (bilateral scalene, sternocleidomastoid, 2nd parasternal, and 8th external intercostal/diaphragm). The vector magnitude was calculated for each participant from the root mean square (RMS) values from each EMG channel, as the square root of the sum of the individual squared EMG channel amplitudes.
Time frame: 3 Hours
Population: Individuals with an ALS diagnosis and age matched controls.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ALS Group | Percentage Change in Respiratory EMG Vector Magnitude | Sham hypoxia | -24.5 percentage change from baseline | Standard Error 4.1 |
| ALS Group | Percentage Change in Respiratory EMG Vector Magnitude | AIH | 179.8 percentage change from baseline | Standard Error 45.9 |
| Healthy Control Group | Percentage Change in Respiratory EMG Vector Magnitude | Sham hypoxia | 7.4 percentage change from baseline | Standard Error 13.1 |
| Healthy Control Group | Percentage Change in Respiratory EMG Vector Magnitude | AIH | 352.3 percentage change from baseline | Standard Error 99.4 |
Secondary
Percent Change in Minute Ventilation
Minute ventilation is measured using a pneumotachograph connected to the face mask to record breath-by-breath volume and breathing rate, which is then multiplied to calculate minute ventilation. After achieving a stable tidal volume, 5 minutes of resting minute ventilation will be recorded and then averaged. The change in minute ventilation will be the percent difference in volume between the averaged baseline ventilation and the averaged follow-up ventilation, which is tested 60 minutes after the gas intervention.
Time frame: 3 Hours
Population: Individuals with an ALS diagnosis and age matched controls.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ALS Group | Percent Change in Minute Ventilation | Sham hypoxia | 5.7 percentage change from baseline | Standard Error 7.3 |
| ALS Group | Percent Change in Minute Ventilation | AIH | 19.5 percentage change from baseline | Standard Error 6 |
| Healthy Control Group | Percent Change in Minute Ventilation | Sham hypoxia | -5.6 percentage change from baseline | Standard Error 5.4 |
| Healthy Control Group | Percent Change in Minute Ventilation | AIH | 2.6 percentage change from baseline | Standard Error 7.2 |