Mild Intermittent Hypoxia for Spinal Cord Injury

(MIH and AD Trial)

Recruiting at 1 trial location

Overseen By Gino Panza, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: VA Office of Research and Development

Disqualifiers: Pregnant, Smoker, Drug addiction, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 9

Duration: 2 weeks

24 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing whether low oxygen exposure can help people with spinal cord injuries who have trouble controlling their blood pressure and breathing during sleep. The goal is to see if this treatment can improve their health and make daily activities easier for them.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment Mild Intermittent Hypoxia for Spinal Cord Injury?

Research shows that intermittent hypoxia, which involves brief periods of low oxygen, can improve physical function and walking ability in people with incomplete spinal cord injuries. It is considered a safe and effective way to enhance recovery by promoting changes in the nervous system that help restore movement. ^{1 2 3 4 5}

Is mild intermittent hypoxia safe for humans?

Research on intermittent hypoxia, including studies on animals and humans, suggests it can be safe, but it may cause oxidative stress (damage from free radicals) and inflammation. These effects are often managed with treatments like antioxidants or anti-inflammatory drugs, such as ibuprofen, to enhance safety. ^{6 7 8 9 10}

How is the treatment Mild Intermittent Hypoxia for Spinal Cord Injury different from other treatments?

Mild Intermittent Hypoxia (MIH) is unique because it involves brief, repeated exposures to low oxygen levels, which can enhance physical function and promote neuroplasticity (the brain's ability to reorganize itself) in people with spinal cord injuries. Unlike traditional exercise-based rehabilitation, MIH is a time-efficient and potentially more accessible approach that does not require extensive equipment or specialized facilities. ^{1 2 3 8 11}

Research Team

Gino Panza, PhD

Principal Investigator

John D. Dingell VA Medical Center, Detroit, MI

Eligibility Criteria

This trial is for individuals aged 18-60 with motor incomplete spinal cord injuries above the 6th thoracic vertebrae and signs of autonomic dysfunction. It's not for those with complete SCI, injuries below T6, disrupted sleep patterns, pregnancy, smokers, drug addiction, age outside the specified range or active skin sores.

Inclusion Criteria

I experience issues with involuntary body functions.

I am between 18 and 60 years old.

I have a partial spinal cord injury above my chest.

Exclusion Criteria

I have a complete spinal cord injury.

My spinal cord injury is below the middle of my back.

You work irregular hours that disrupt your sleep schedule.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive mild intermittent hypoxia (MIH) or sham air treatment for 8 days over a 2-week period, with concurrent CPAP treatment if diagnosed with sleep apnea

2 weeks

8 visits (in-person)

Follow-up

Participants are monitored for sustained impact of therapeutic MIH on autonomic function and SDB, with assessments conducted 4 weeks post-treatment

4 weeks

1 visit (in-person)

Treatment Details

Interventions

• Mild Intermittent Hypoxia
• Sham

Trial Overview The study tests mild intermittent hypoxia (MIH) as a preventive treatment for autonomic dysfunction in people with spinal cord injury. Participants will be exposed to MIH to see if it helps regulate blood pressure control and reduce complications related to sleep disordered breathing.

Participant Groups

Group I: Mild Intermittent Hypoxia Experimental Treatment 1 Intervention

This arm of the protocol will receive mild intermittent hypoxia (8% Oxygen) with end-tidal carbon dioxide maintained 1-3 millimeters of mercury above baseline, while in the laboratory. If diagnosed with sleep apnea, participants will be treated with continuous positive airway pressure for the duration of the intervention.

Group II: Sham Placebo Group 1 Intervention

This arm of the protocol will receive sham air (21 % Oxygen) while in the laboratory. No additional gases will be employed. If diagnosed with sleep apnea, participants will be treated with continuous positive airway pressure for the duration of the intervention.

Mild Intermittent Hypoxia is already approved in United States, European Union for the following indications:

Approved in United States as Mild Intermittent Hypoxia for:

• Obstructive Sleep Apnea (OSA)
• Cardiovascular dysfunction
• Exercise performance fatigue

Approved in European Union as Intermittent Hypoxia-Hyperoxia Treatment for:

• Obstructive Sleep Apnea (OSA)
• Cardiovascular conditions
• Respiratory conditions

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

John D. Dingell VA Medical Center

Collaborator

Trials

10

Recruited

1,100+

Findings from Research

Acute intermittent hypoxia (IH) is a promising and safe method to improve physical function in individuals with chronic spinal cord injury (SCI), offering a time-efficient alternative to traditional exercise rehabilitation.

IH involves brief sessions of low oxygen exposure followed by normal breathing, which has shown efficacy in enhancing health and physical function without the need for extensive resources or specialized training.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Acute Intermittent Hypoxia on Physical Function and Health Status in Humans with Spinal Cord Injury: A Brief Review. Astorino, TA., Harness, ET., White, AC.[2018]

Acute intermittent hypoxia has shown promise as a therapeutic strategy to improve respiratory function in individuals with cervical spinal cord injuries, based on studies that demonstrate its potential to induce neuroplasticity and functional recovery.

Research in animal models has laid the groundwork for exploring the effects of acute intermittent hypoxia in human clinical studies, highlighting its potential to restore breathing function after spinal cord injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intermittent hypoxia and respiratory recovery in pre-clinical rodent models of incomplete cervical spinal cord injury. Gonzalez-Rothi, EJ., Lee, KZ.[2021]

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]

A 4-week treatment combining intermittent hypoxia (IH) with body weight-supported treadmill training (BWSTT) significantly improved walking speed and endurance in individuals with incomplete spinal cord injuries (iSCI), as shown by better performance on the 10-meter walk test and 6-minute walk test.

The benefits of daily IH were maintained with a reduced frequency of treatment (3 times a week), suggesting that IH could be a safe and effective long-term therapy to enhance recovery in individuals with iSCI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repetitive Intermittent Hypoxia and Locomotor Training Enhances Walking Function in Incomplete Spinal Cord Injury Subjects: A Randomized, Triple-Blind, Placebo-Controlled Clinical Trial. Navarrete-Opazo, A., Alcayaga, J., Sepúlveda, O., et al.[2022]

Therapeutic acute intermittent hypoxia (tAIH) shows promise in improving both respiratory and non-respiratory motor functions in individuals with neuromuscular disorders, particularly those with chronic spinal cord injuries, as highlighted in recent workshops aimed at clinical translation.

Key recommendations for advancing tAIH include enhancing our understanding of its mechanisms, optimizing treatment protocols, identifying effective combinatorial therapies, and ensuring long-term safety, which are essential for its potential routine clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic acute intermittent hypoxia: A translational roadmap for spinal cord injury and neuromuscular disease. Vose, AK., Welch, JF., Nair, J., et al.[2023]

Intermittent hypoxic training (IHT) has been shown to improve several health markers in COPD patients, including increased exercise capacity and lung function, making it a promising therapeutic strategy for this group.

Currently, there is no strong evidence that IHT provides health benefits for patients with bronchial asthma, indicating a need for further research to explore its potential in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of intermittent hypoxia in the treatment of bronchial asthma and chronic obstructive pulmonary disease. Vogtel, M., Michels, A.[2016]

Intermittent hypobaric hypoxia (IHH) effectively protects the brain from injury caused by acute severe hypoxia (ASH) in rats, as shown by reduced oxidative stress and apoptosis-related damage.

The neuroprotective effects of IHH are linked to the downregulation of NF-κB and an increase in erythropoietin (EPO) levels, suggesting a mechanism that prevents oxidative injury and promotes cell survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intermittent Hypobaric Hypoxic Preconditioning Provides Neuroprotection by Increasing Antioxidant Activity, Erythropoietin Expression and Preventing Apoptosis and Astrogliosis in the Brain of Adult Rats Exposed to Acute Severe Hypoxia. Coimbra-Costa, D., Garzón, F., Alva, N., et al.[2021]

Acute intermittent hypoxia (AIH) significantly improved lower extremity muscle strength in adults with chronic incomplete spinal cord injury, with torque increasing by approximately 20% at 30 minutes and 30% at 60 minutes post-AIH.

Pretreatment with ibuprofen did not enhance the effects of AIH on muscle strength, indicating that while AIH is effective for improving leg strength, systemic inflammation management with ibuprofen may not be necessary for its benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of acute intermittent hypoxia on motor function in individuals with chronic spinal cord injury following ibuprofen pretreatment: A pilot study. Lynch, M., Duffell, L., Sandhu, M., et al.[2018]

Intermittent hypoxia training (IHT) significantly improved oxygen saturation levels in rats during extreme hypoxia exposure, indicating enhanced acclimatization to low oxygen environments.

IHT reduced oxidative stress markers and inflammatory responses in the lungs of trained rats compared to untrained rats, suggesting that this training helps maintain better physiological balance during high-altitude conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Physiological and oxidative stress responses to intermittent hypoxia training in Sprague Dawley rats. Nimje, MA., Patir, H., Tirpude, RK., et al.[2022]

In a study involving adult mice, 35 days of intermittent hypoxia (simulating sleep apnea) led to significant liver damage characterized by oxidative stress, lipid peroxidation, and DNA damage.

No significant oxidative stress was observed after 21 days of intermittent hypoxia, indicating that prolonged exposure is necessary to induce these harmful effects on the liver.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hepatic oxidative stress in an animal model of sleep apnoea: effects of different duration of exposure. Rosa, DP., Martinez, D., Picada, JN., et al.[2023]

Moderate acute intermittent hypoxia (mAIH) can enhance sympathetic nerve activity (sympLTF) and respiratory function (pLTF) in rats, but spinal cord injuries (cSCI) can impair these responses due to increased tissue hypoxia, especially after complete spinal injuries.

Despite the impairment of respiratory pLTF and splanchnic sympLTF following complete C2 spinal hemisection, renal sympLTF remains intact, suggesting that mAIH could still provide therapeutic benefits for managing blood pressure in individuals with chronic spinal cord injuries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cervical spinal hemisection effects on spinal tissue oxygenation and long-term facilitation of phrenic, renal and splanchnic sympathetic nerve activity. Perim, RR., Vinit, S., Mitchell, GS.[2023]

References

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

Efficacy of Acute Intermittent Hypoxia on Physical Function and Health Status in Humans with Spinal Cord Injury: A Brief Review. [2018]

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

Intermittent hypoxia and respiratory recovery in pre-clinical rodent models of incomplete cervical spinal cord injury. [2021]

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

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

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

Repetitive Intermittent Hypoxia and Locomotor Training Enhances Walking Function in Incomplete Spinal Cord Injury Subjects: A Randomized, Triple-Blind, Placebo-Controlled Clinical Trial. [2022]

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

Therapeutic acute intermittent hypoxia: A translational roadmap for spinal cord injury and neuromuscular disease. [2023]

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

Role of intermittent hypoxia in the treatment of bronchial asthma and chronic obstructive pulmonary disease. [2016]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Intermittent Hypobaric Hypoxic Preconditioning Provides Neuroprotection by Increasing Antioxidant Activity, Erythropoietin Expression and Preventing Apoptosis and Astrogliosis in the Brain of Adult Rats Exposed to Acute Severe Hypoxia. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Effect of acute intermittent hypoxia on motor function in individuals with chronic spinal cord injury following ibuprofen pretreatment: A pilot study. [2018]

9. England pubmed.ncbi.nlm.nih.gov

Physiological and oxidative stress responses to intermittent hypoxia training in Sprague Dawley rats. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Hepatic oxidative stress in an animal model of sleep apnoea: effects of different duration of exposure. [2023]

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

Cervical spinal hemisection effects on spinal tissue oxygenation and long-term facilitation of phrenic, renal and splanchnic sympathetic nerve activity. [2023]