Acute Intermittent Hypoxia for Traumatic Brain Injury

Overseen By Alicia Vose, Ph.D.

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of Florida

Disqualifiers: Neurological, Psychiatric, Pulmonary, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

Duration: 1 week

5 Participants Needed

Trial Summary

What is the purpose of this trial?

Acute intermittent hypoxia (AIH) involves 1-2min of breathing low oxygen air to stimulate neuroplasticity. Animal and human studies show that AIH improves motor function after neural injury, particularly when paired with task-specific training. Using a double blind cross-over study we will test whether AIH and task-specific airway protection training improves airway protection more than training alone in individuals with chronic mild-moderate traumatic brain injury (TBI).

Do I need to stop my current medications for the trial?

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.

Is Acute Intermittent Hypoxia (AIH) safe for humans?

Acute Intermittent Hypoxia (AIH) is considered a safe and non-invasive treatment approach, as it involves brief, repetitive periods of breathing reduced oxygen air alternated with normal oxygen levels. ^{1 2 3 4 5}

How is the treatment Acute Intermittent Hypoxia (AIH) different from other treatments for traumatic brain injury?

Acute Intermittent Hypoxia (AIH) is unique because it involves exposing patients to short periods of low oxygen levels, which may help the brain adapt and recover after injury. This approach is different from other treatments like hyperbaric oxygen therapy, which uses high oxygen levels to aid recovery. ^{6 7 8 9 10}

Research Team

Alicia Z Vose, Ph.D.

Principal Investigator

University of Florida

Eligibility Criteria

This trial is for individuals with chronic mild to moderate traumatic brain injury (TBI) who may benefit from a new therapy. Participants should be stable and not have other medical conditions that could interfere with the study.

Inclusion Criteria

I am not pregnant and can provide a negative pregnancy test.

I am between 21 and 80 years old.

A Glasgow Coma Scale score between 9-15

Exclusion Criteria

Severe aphasia preventing a participant from understanding the protocol and consent form

I have a lung condition that causes low oxygen levels.

I have a history of serious lung problems like COPD or severe asthma.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive daily AIH or sham AIH followed by task-specific airway protection training over 5-day intervention blocks

1 week

5 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 week

1 visit (in-person)

Treatment Details

Interventions

• Acute Intermittent Hypoxia (AIH)
• Task specific Airway Protection Training

Trial Overview The study tests if breathing low oxygen air in short bursts (Acute Intermittent Hypoxia or AIH) combined with special training can improve airway protection better than training alone after TBI, using a double-blind cross-over design.

Participant Groups

Group I: AIH + TST Active Control 2 Interventions

Participants will complete a 5-day intervention blocks where they receive daily AIH followed by task specific airway protection training 60 minutes after the AIH exposure. Each exposure involves a 1-minute delivery of low oxygen (9-11% inspired O2), followed by a 1.5-min interval of room air breathing (21% O2). This method of waiting 45-60 minutes after the delivery of AIH and prior to engaging in task-specific training/rehabilitation enables sufficient time to increase brain derived neurotrophic factor (BDNF) following AIH, thereby augmenting the impact of task-specific training.

Group II: Sham AIH + TST Placebo Group 2 Interventions

Participants will complete a 5-day intervention blocks where they receive sham AIH followed by task specific airway protection training 60 minutes after the AIH sham exposure. Sham AIH will be delivered using methods identical to AIH, except a normoxic gas mixture (\~21% O2) will be delivered. The gas mixture with normoxic air will effectively serve as a sham.

Acute Intermittent Hypoxia (AIH) is already approved in United States for the following indications:

Approved in United States as Acute Intermittent Hypoxia for:

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

Who Is Running the Clinical Trial?

University of Florida

Lead Sponsor

Trials

1,428

Recruited

987,000+

Findings from Research

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]

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]

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]

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]

High-altitude intracerebral hemorrhage (ICH) leads to more severe neurological deficits and brain damage compared to ICH at lower altitudes, as indicated by lower brain tissue oxygen levels and higher markers of metabolic distress in minipigs.

Hyperbaric oxygen (HBO) therapy administered shortly after ICH significantly improved brain oxygenation and reduced metabolic disturbances, brain edema, and neurological deficits, suggesting it may be an effective acute treatment for high-altitude ICH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyperbaric oxygen therapy ameliorates acute brain injury after porcine intracerebral hemorrhage at high altitude. Zhu, HT., Bian, C., Yuan, JC., et al.[2018]

In a study of 103 patients with severe traumatic brain injury, longer durations of brain hypoxia (Pbto(2) < 15 mm Hg) were linked to worse outcomes, indicating that brain hypoxia is a significant predictor of prognosis.

Even when controlling for factors like intracranial pressure and cerebral perfusion pressure, brain hypoxia remained independently associated with poorer outcomes, suggesting that improving brain oxygen levels could be a crucial therapeutic target in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain hypoxia is associated with short-term outcome after severe traumatic brain injury independently of intracranial hypertension and low cerebral perfusion pressure. Oddo, M., Levine, JM., Mackenzie, L., et al.[2012]

In a study of 3699 critically ill patients with traumatic brain injury (TBI), hyperoxia (PaO2 ≥ 300 mmHg) in the first 24 hours of ICU care did not lead to worse long-term neurological outcomes compared to normoxia (PaO2 60-299 mmHg).

The research found no significant differences in functional outcomes at 6, 12, and 24 months between patients who experienced hyperoxia and those who maintained normoxia, suggesting that hyperoxia may be safe for TBI patients in the ICU.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Functional Outcomes in Patients Admitted to the Intensive Care Unit with Traumatic Brain Injury and Exposed to Hyperoxia: A Retrospective Multicentre Cohort Study. Weeden, M., Bailey, M., Gabbe, B., et al.[2021]

Traumatic brain injury (TBI) combined with hypoxia significantly worsens brain cell death and increases the size of brain contusions, indicating that hypoxia exacerbates the effects of TBI.

The study found that hypoxia delays the expression of neuronal apoptosis inhibitor proteins (NAIPs) after TBI, suggesting that these proteins may play a crucial role in the brain's vulnerability to damage following injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypoxia alters the expression of inhibitor of apoptosis proteins after brain trauma in the mouse. Mikrogianakis, A., Shaye, RE., Griffin, P., et al.[2016]

In a study involving 42 patients with severe traumatic brain injury, the combination of hyperbaric oxygen (HBO2) and normobaric hyperoxia (NBH) significantly increased brain tissue oxygen levels and improved markers of cerebral metabolism compared to standard care.

The combined HBO2/NBH treatment resulted in a 26% reduction in mortality and a 36% improvement in favorable outcomes, indicating its potential as an effective therapeutic strategy for severe TBI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A prospective, randomized Phase II clinical trial to evaluate the effect of combined hyperbaric and normobaric hyperoxia on cerebral metabolism, intracranial pressure, oxygen toxicity, and clinical outcome in severe traumatic brain injury. Rockswold, SB., Rockswold, GL., Zaun, DA., et al.[2015]

References

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

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

2. England pubmed.ncbi.nlm.nih.gov

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

3. Germany pubmed.ncbi.nlm.nih.gov

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

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

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

5. 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]

6. England pubmed.ncbi.nlm.nih.gov

Hyperbaric oxygen therapy ameliorates acute brain injury after porcine intracerebral hemorrhage at high altitude. [2018]

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

Brain hypoxia is associated with short-term outcome after severe traumatic brain injury independently of intracranial hypertension and low cerebral perfusion pressure. [2012]

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

Functional Outcomes in Patients Admitted to the Intensive Care Unit with Traumatic Brain Injury and Exposed to Hyperoxia: A Retrospective Multicentre Cohort Study. [2021]

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

Hypoxia alters the expression of inhibitor of apoptosis proteins after brain trauma in the mouse. [2016]

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

A prospective, randomized Phase II clinical trial to evaluate the effect of combined hyperbaric and normobaric hyperoxia on cerebral metabolism, intracranial pressure, oxygen toxicity, and clinical outcome in severe traumatic brain injury. [2015]