Combined Therapeutic Air Mixture and Electrical Stimulation to Improve Breathing and Hand Function in Spinal Cord Injury

NCT06101199 | Terminated DMC

• 1 other identifier: iRISID-2023-1796
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this clinical trial is to determine whether people with paralysis due to a spinal cord injury can benefit from breathing short intermittent bouts of air with low oxygen (O2) combined with slightly higher levels of carbon dioxide (CO2), interspaced by breathing room air. The technical name for this therapeutic air mixture is 'acute intermittent hypercapnic-hypoxia,' abbreviated as AIHH. Following exposure to the gas mixture, participants will receive non-invasive electrical stimulation to the spinal cord paired with specific and targeted exercise training. The main question this trial aims to answer is: Can the therapeutic application of AIHH, combined with non-invasive electrical stimulation to the spinal cord plus exercise training, increase the strength of muscles involved in breathing and hand function in people with paralysis due to a spinal cord injury? Participants will be asked to attend a minimum of five study visits, each separated by at least a week. During these visits, participants will be required to:

• Answer basic questions about their health
• Receive exposure to the therapeutic air mixture (AIHH)
• Undergo non-invasive spinal electrical stimulation
• Complete functional breathing and arm strength testing
• Undergo a single blood draw
• Provide a saliva sample Researchers will compare the results of individuals without a spinal cord injury to those of individuals with a spinal cord injury to determine if the effects are similar.

Conditions

Cervical Spinal Cord Injury

Keywords

acute intermittent hypoxia; hypercapnia; hypercapnic; respiratory assessments; transcutaneous spinal cord stimulation; incomplete spinal cord injury; neuroplasticity; tetraplegia; respiratory function; combinatorial; upper extremity strength training; diaphragm motor evoked potentials; neurophysiology; surface electromyography; transcranial magnetic stimulation

Outcome Measures

Primary Outcomes (6)

• Change in Respiratory cortical and spinal drive in minutes of intervention

  Transcranial magnetic stimulation (TMS). Subjects will be seated comfortably with the neck slightly flexed. The vertex of the skull is identified by the intersection between nasion to inion and tragus to tragus. The region of the cortex responsible for diaphragm motor activation is located approximately 3 cm lateral and 2 cm anterior to the vertex. Single-pulse (1 Hz) stimuli are delivered using a handheld 70-mm figure-of-eight coil. Cervical Magnetic Stimulation (CMS). Single-pulse (1 Hz) stimuli will be delivered using a 90-mm handheld circular coil placed over the cervical spine (C3-C7). Recruitment curves are plotted by gradually increasing the intensity of stimulus from 40-100% of the maximal stimulator output in 5% increments \[72\]. Percent change in peak-to-peak amplitude will be used to measure neuroplasticity.

  Baseline

• Change in Upper extremity cortical and spinal drive in minutes of intervention

  Subjects will be seated comfortably with the neck slightly flexed. The vertex of the skull is identified by the intersection between nasion to inion and tragus to tragus. The hotspot region of the cortex responsible for hand or forearm muscles is located. Single-pulse (1 Hz) stimuli are delivered using a handheld 70-mm figure-of-eight coil. Neuroplasticity is measured as change in peak-to-peak % amplitude. Cervical Magnetic Stimulation (CMS). Single-pulse (1 Hz) stimuli will be delivered using a 90-mm handheld circular coil placed over the cervical spine (C3-C7). Recruitment curves are plotted by gradually increasing the intensity of stimulus from 40-100% of the maximal stimulator output in 5% increments \[72\]. Percent change in peak-to-peak amplitude will be used to measure neuroplasticity.

  Baseline

• Change in Maximum respiratory voluntary force production in minutes of intervention

  Maximal inspiratory and expiratory pressures. Inspiratory pressure generation is indicative of inspiratory strength and is associated with pulmonary health and infection risk. Expiratory pressure generation is reflective of expiratory respiratory strength and is associated with airway clearance and cough. Inspiratory and expiratory pressure generation improve following single-day sessions of AIH. Measurements will be obtained using a mouthpiece attached to a pneumotach (Hans Rudolph Inc.) to measure indices of ventilation.

  Baseline

• Change in Airway occlusion pressure (P0.1) in minutes of intervention

  Airway occlusion pressure (P0.1). P0.1 is the pressure generated at the mouth in the first 0.1 second of inspiration, when the airway is unexpectedly occluded at the end of an expiration. The negative pressure generation in 0.1 seconds reflects respiratory motor drive without time for modification by sensory systems (lung stretch, visual, etc.). In essence, the P0.1 reflects the spontaneous (automatic) functional activity of inspiratory muscles at rest. Mouth occlusion pressure at this time is often regarded as an index of inspiratory neuromuscular drive. This measure will be obtained while participants breathe through a mouthpiece connected to a 2-way valve in a closed circuit. The inspiratory valve will be occluded without participant awareness during expiration and maintained until the subsequent inspiratory effort. Negative pressure generation will be recorded using a pressure transducer (Hans Rudolph Inc.).

  Baseline

• Change in Forced vital capacity in minutes of intervention

  Forced vital capacity (FVC). FVC is the volume of air displaced during a forced expiration to residual volume, following a full inspiration to total lung capacity. Forced vital capacity will be measured using a mouthpiece attached to the a pneumotach (Hans Rudolph Inc.). The signal will be recorded using PowerLab (AD Instruments Inc.). Impairments in pulmonary function are associated with higher risks of respiratory illness and higher mortality rate.

  Baseline

• Change in Upper extremity functional assessment in minutes of intervention

  We will use Graded Refined Assessment of Strength, Sensibility and Prehension (GRASSP) to assess gain in upper extremity grasp and prehension strength. The GRASSP is a clinical impairment measure specific to the upper limb for use after tetraplegia. It is a multimodal test that measures sensorimotor and prehension function in three domains important in describing arm and hand function (strength, sensibility and prehension) comprising five subtests for each upper limb: strength, dorsal sensation, palmar sensation, prehension ability and prehension performance. These numerical scores provide a comprehensive profile of upper-limb function.

  Baseline

Secondary Outcomes (1)

• Change in Cardiovascular Response in minutes of intervention

  Baseline

Study Arms (4)

AIHH + tSCS-paired Strength Training

ACTIVE COMPARATOR

Participants will receive exposure to AIHH followed by transcutaneous spinal cord stimulation-paired respiratory and upper extremity strength training.

Other: Acute Intermittent Hypercapnic Hypoxia; Other: Transcutaneous spinal cord stimulation

SHAM AIHH + tSCS-paired Strength Training

EXPERIMENTAL

Participants will receive exposure to SHAM AIHH followed by transcutaneous spinal cord stimulation-paired respiratory and upper extremity strength training.

Other: Transcutaneous spinal cord stimulation; Other: SHAM Acute Intermittent Hypercapnic Hypoxia

SHAM AIHH + SHAM tSCS-paired Strength Training

SHAM COMPARATOR

Participants will receive exposure to SHAM AIHH followed by SHAM transcutaneous spinal cord stimulation-paired respiratory and upper extremity strength training.

Other: SHAM Acute Intermittent Hypercapnic Hypoxia; Other: SHAM Transcutaneous spinal cord stimulation

AIHH + SHAM tSCS-paired Strength Training

EXPERIMENTAL

Participants will receive exposure to AIHH followed by SHAM transcutaneous spinal cord stimulation-paired respiratory and upper extremity strength training.

Other: Acute Intermittent Hypercapnic Hypoxia; Other: SHAM Transcutaneous spinal cord stimulation

Interventions

Acute Intermittent Hypercapnic Hypoxia OTHER

15 x \[1 min 9% O2, 4% CO2, and balance N2, followed by 1.5 min normoxia\];

Also known as: AIHH

AIHH + SHAM tSCS-paired Strength Training; AIHH + tSCS-paired Strength Training

Transcutaneous spinal cord stimulation OTHER

Open-loop, continuous, high-frequency electrical stimulation at 150 Hz with a tolerable current amplitude of \~25-35 mA and a pulse width of 400 µsec, using a biphasic symmetric waveform. Paired with Respiratory Resistance Training and Hand Grip Strength Training.

Also known as: tSCS

AIHH + tSCS-paired Strength Training; SHAM AIHH + tSCS-paired Strength Training

SHAM Acute Intermittent Hypercapnic Hypoxia OTHER

Normoxia for the amount of time AIHH is delivered.

Also known as: SHAM AIHH

SHAM AIHH + SHAM tSCS-paired Strength Training; SHAM AIHH + tSCS-paired Strength Training

SHAM Transcutaneous spinal cord stimulation OTHER

Open-loop, continuous, high-frequency electrical stimulation at 150 Hz with a tolerable current amplitude of 0mA and a pulse width of 400 µsec,using a biphasic symmetric waveform. Paired with Respiratory Resistance Training and Hand Grip Strength Training.

Also known as: SHAM tSCS

AIHH + SHAM tSCS-paired Strength Training; SHAM AIHH + SHAM tSCS-paired Strength Training

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female age 18-65 years old 113
• Non-progressive or central cord spinal cord injury from C2-T1 inclusive
• American Spinal Injury Association (ASIA) Impairment Scale or AIS classification B, C, or D
• \>20% impairment in maximal inspiratory or expiratory pressure generation, relative to established normative values.
• Able to participate in physical and occupational therapy rehabilitation programs
• Minimum 12 months post SCI
• Capable of providing informed consent
• Has adequate caregiver support to facilitate participation in study
• Willingness to undergo non-deidentifiable audio and/or visual recording

You may not qualify if:

• Has uncontrolled cardiopulmonary disease or cardiac symptoms based on medical records and/or abnormal response to intervention
• Has diffuse lower motor neuron injury rendering majority of muscles not excitable
• Has any unstable or significant medical condition that is likely to interfere with study procedures or likely to confound study endpoint evaluations (neuropathic pain, depression, mood disorders, cognitive disorders, etc.)
• Has autonomic dysreflexia that is severe, unstable, or uncontrolled
• Has uncontrolled orthostatic hypotension that may interfere with rehabilitation
• Requires ventilator support
• Has spasms that limit participation in study training as determined by the medical record and/or abnormal response to experimental treatment intervention
• Has skin breakdown in areas that will come in contact with electrodes or pressure injuries that prevent participation in physical functioning activities
• Has any active implanted medical device, such as cardiac pacemaker
• Has no EMG activity, observed via surface e-stim, in phrenic nerve nor at least three (3) hand/forearm muscles
• Pregnant, planning to become pregnant, or currently breastfeeding
• Concurrent participation in another drug or device trial that may interfere with this study
• Has other traumatic injuries, such as peripheral nerve injuries, sever musculoskeletal injuries (e.g., shattered pelvis, long bone fractures) that prevent evaluation of response to or participation in rehabilitation
• Non-English speaker

Sponsors & Collaborators

• Thomas Jefferson University: lead

Study Sites (1)

Thomas Jefferson University

Philadelphia, Pennsylvania, 19107, United States

Location

MeSH Terms

Conditions

Hypercapnia; Quadriplegia; Respiratory Aspiration

Condition Hierarchy (Ancestors)

Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Paralysis; Neurologic Manifestations; Nervous System Diseases; Respiration Disorders; Respiratory Tract Diseases; Pathologic Processes

Study Officials

• Justine Dee, PT

  Thomas Jefferson University

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor, Department of Physical Therapy, Thomas Jefferson University

Study Record Dates

• First Submitted: October 2, 2023
• First Posted: October 26, 2023
• Study Start: October 16, 2023
• Primary Completion: June 30, 2025
• Study Completion: June 30, 2025
• Last Updated: August 17, 2025

Record last verified: 2025-08

Locations

US (1)