Breathing Therapy for Spinal Cord Injury

Overseen By Hannah Snyder, M.S.

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of Florida

Must not be taking: Seizure threshold-lowering

Disqualifiers: Multiple sclerosis, Stroke, Cardiovascular disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 8

62 Participants Needed

Trial Summary

What is the purpose of this trial?

Acute intermittent hypoxia (AIH) involves brief (1 min), repeated episodes (\~15) of breathing low oxygen air to stimulate spinal neuroplasticity. Animal and human studies show that AIH improves motor function after spinal cord injury, particularly with slightly increased carbon dioxide (hypercapnic AIH; AIHH) and task-specific training. Using a double blind cross-over design, the study will test whether AIHH improves breathing more than AIH and whether specific genetic variations are related to individuals' intervention responses.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you are on medications that lower the seizure threshold, you may be excluded from certain parts of the study.

What data supports the effectiveness of the treatment Acute Intermittent Hypoxia (AIH) for spinal cord injury?

Research shows that AIH can improve breathing function and increase maximal inspiratory pressure in people with spinal cord injuries, suggesting potential benefits for respiratory recovery. Additionally, AIH is considered a promising strategy for enhancing motor recovery in spinal cord injuries and neurodegenerative diseases, although individual responses can vary. ^{1 2 3 4 5}

Is breathing therapy for spinal cord injury generally safe for humans?

Acute intermittent hypoxia (AIH), a type of breathing therapy, is considered safe and non-invasive for humans, as it involves brief periods of breathing low oxygen air alternated with normal air. However, individual responses can vary significantly. ^{1 2 3 5 6}

How does the treatment Acute Intermittent Hypoxia (AIH) differ from other treatments for spinal cord injury?

Acute Intermittent Hypoxia (AIH) is unique because it uses controlled episodes of low oxygen levels to stimulate the body's natural ability to adapt and improve breathing and motor functions after a spinal cord injury. This approach leverages the body's neuroplasticity (the ability of the brain and spinal cord to reorganize and form new connections) to potentially enhance recovery, which is different from traditional treatments that may not focus on this mechanism. ^{1 2 3 4 7}

Research Team

Emily Fox

Principal Investigator

University of Florida & Brooks Rehabilitation

Eligibility Criteria

This trial is for adults aged 18-70 with chronic spinal cord injury (SCI) at or below C-3 to T-12, who have had the condition for over a year and show some impairment in breathing strength. It's not open to those with other neurological conditions, severe pain, major illness, certain metal implants, or uncontrolled medical issues like hypertension.

Inclusion Criteria

Your ability to breathe in or out is 20% lower than normal.

Medically stable with physician clearance

I have some feeling or movement below my spinal injury.

Exclusion Criteria

I do not have severe illness or uncontrolled conditions like heart disease, lung disease, or high blood pressure.

I don't have seizures, uncontrolled migraines, a pacemaker, skull implants, or take seizure-lowering meds.

I experience severe and repeated episodes of autonomic dysreflexia.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Single-session Testing Days

Participants complete baseline testing, receive AIH, AIHH, or sham AIH interventions, and undergo post-testing on three separate days.

3 days

3 visits (in-person)

Respiratory Strength Training Blocks

Participants undergo 5 days of AIH, AIHH, or sham AIH combined with respiratory strength training, followed by post-testing 1, 3, and 7 days after the intervention.

5 days of intervention + 7 days of follow-up

5 visits (in-person) for intervention, 3 visits (in-person) for follow-up

Follow-up

Participants are monitored for changes in maximal inspiratory and expiratory pressure, and motor evoked potential.

7 days

Treatment Details

Interventions

• Acute Intermittent Hypercapnic-Hypoxia (AIHH)
• Acute Intermittent Hypoxia (AIH)
• Sham AIH

Trial Overview The study tests two types of breathing treatments: AIH which uses low oxygen air and AIHH that adds slightly more carbon dioxide. Participants will also do task-specific training. The goal is to see if these can improve respiratory function after SCI and if genetics affect the outcome.

Participant Groups

Group I: Single-session testing days Experimental Treatment 3 Interventions

Participants will complete three separate single-session testing days. Baseline testing will be performed, then on each day, participants will receive AIH, AIHH, and sham AIH in random order. Post-testing will occur after each intervention.

Group II: Respiratory strength training blocks Experimental Treatment 3 Interventions

Participants will complete three separate respiratory strength training blocks. In each block, participants will receive 5 days of AIH, 5 days of AIHH, and 5 days of sham AIH in random order, followed by respiratory strength training. Each block will include 5 days of intervention and training, and post-testing 1, 3, and 7 days after intervention and training has concluded.

Acute Intermittent Hypercapnic-Hypoxia (AIHH) is already approved in United States, Canada for the following indications:

Approved in United States as Acute Intermittent Hypoxia (AIH) for:

• Respiratory recovery in spinal cord injury
• Improvement in motor function after spinal cord injury

Approved in Canada as Therapeutic Acute Intermittent Hypoxia for:

• Respiratory recovery in spinal cord injury

Who Is Running the Clinical Trial?

University of Florida

Lead Sponsor

Trials

1,428

Recruited

987,000+

U.S. Army Medical Research Acquisition Activity

Collaborator

Trials

26

Recruited

10,500+

Findings from Research

Acute intermittent hypoxia (AIH) is a safe and effective therapy that can enhance strength, walking speed, endurance, and dynamic balance in individuals with chronic, incomplete spinal cord injury (SCI).

AIH shows promise for promoting walking recovery through neuroplasticity mechanisms, but more research is needed to determine its effectiveness across larger groups and to identify optimal treatment protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute intermittent hypoxia as a potential adjuvant to improve walking following spinal cord injury: evidence, challenges, and future directions. Tan, AQ., Barth, S., Trumbower, RD.[2022]

Patients with cervical spinal cord injury (SCI) showed significantly higher minute ventilation (V̇e) after acute intermittent hypoxia (AIH) compared to able-bodied controls, indicating a potential for enhanced respiratory recovery.

While heart rate variability responses to hypoxia were observed in all groups, individuals with cervical SCI did not exhibit the same recovery patterns as those with thoracic SCI or able-bodied individuals, suggesting unique cardiovascular responses in cervical SCI patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tetraplegia is associated with enhanced peripheral chemoreflex sensitivity and ventilatory long-term facilitation. Sankari, A., Bascom, AT., Riehani, A., et al.[2022]

The study found that individuals with the APOE 4 genotype showed lower diaphragm motor-evoked potential (MEP) enhancements in response to acute intermittent hypercapnic-hypoxia (AIHH), indicating that genetic factors can influence the effectiveness of this rehabilitation strategy.

Additionally, the research revealed that males had a greater enhancement in diaphragm MEP compared to females, and that age negatively affected respiratory motor plasticity, highlighting the importance of biological factors in individual responses to AIHH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

APOE4, Age & Sex Regulate Respiratory Plasticity Elicited By Acute Intermittent Hypercapnic-Hypoxia. Nair, J., Welch, JF., Marciante, AB., et al.[2023]

A single session of acute intermittent hypoxia (AIH) significantly increased maximal inspiratory pressure (MIP) in 17 adults with chronic spinal cord injury (SCI), suggesting potential for enhancing respiratory function.

While AIH improved MIP, other breathing functions like maximal expiratory pressure (MEP) and forced vital capacity (FVC) did not show significant changes, indicating that AIH may selectively affect certain respiratory muscles and highlighting the need for further research into its therapeutic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-session effects of acute intermittent hypoxia on breathing function after human spinal cord injury. Sutor, T., Cavka, K., Vose, AK., et al.[2022]

In a study of 17 healthy adults, it was found that individuals with the APOE4 genotype showed lower respiratory motor plasticity in response to acute intermittent hypercapnic-hypoxia (AIHH), suggesting genetic factors can influence the effectiveness of this rehabilitation strategy.

Additionally, males demonstrated greater improvements in diaphragm motor function compared to females, and older age was associated with reduced respiratory response, highlighting the importance of sex and age as biological determinants in AIHH outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

APOE4, Age, and Sex Regulate Respiratory Plasticity Elicited by Acute Intermittent Hypercapnic-Hypoxia. Nair, J., Welch, JF., Marciante, AB., et al.[2023]

Acute intermittent hypoxia (AIH) is a safe treatment that involves alternating between low and normal oxygen levels, but in this study, it did not significantly change the excitability of the primary motor cortex in healthy participants.

Despite a notable drop in arterial oxygen saturation during AIH, there were no measurable effects on corticospinal excitability or intracortical circuits, suggesting that AIH may need to be adjusted in severity or tailored to individuals for potential benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of acute intermittent hypoxia on corticospinal excitability within the primary motor cortex. Radia, S., Vallence, AM., Fujiyama, H., et al.[2022]

Individuals with cervical spinal cord injury (SCI) showed a significantly higher short-term hypoxic ventilatory response (HVR) during acute intermittent hypoxia (AIH) compared to those with thoracic SCI, indicating a potentially different respiratory response mechanism in cervical SCI patients.

Despite the increased short-term HVR, there was no evidence of long-term ventilatory facilitation following AIH in either cervical or thoracic SCI groups, suggesting that while acute responses may differ, long-term adaptations in ventilation are not observed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tetraplegia is associated with increased hypoxic ventilatory response during nonrapid eye movement sleep. Vaughan, S., Sankari, A., Carroll, S., et al.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

Acute intermittent hypoxia as a potential adjuvant to improve walking following spinal cord injury: evidence, challenges, and future directions. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Tetraplegia is associated with enhanced peripheral chemoreflex sensitivity and ventilatory long-term facilitation. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

APOE4, Age & Sex Regulate Respiratory Plasticity Elicited By Acute Intermittent Hypercapnic-Hypoxia. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Single-session effects of acute intermittent hypoxia on breathing function after human spinal cord injury. [2022]

5. England pubmed.ncbi.nlm.nih.gov

APOE4, Age, and Sex Regulate Respiratory Plasticity Elicited by Acute Intermittent Hypercapnic-Hypoxia. [2023]

6. Germany pubmed.ncbi.nlm.nih.gov

Effects of acute intermittent hypoxia on corticospinal excitability within the primary motor cortex. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Tetraplegia is associated with increased hypoxic ventilatory response during nonrapid eye movement sleep. [2023]