Spinal Cord Injuries
Conditions
Keywords
Pulmonary Function Test, Buspirone Hydrochloride, Oxygen Consumption
Brief summary
The purpose of this study is to find out if taking the drug Buspar will increase breathing capacity in individuals with spinal cord injuries.
Detailed description
Chemoreceptive regulatory feedback is crucial for precise ventilatory control, especially during exercise. However, individuals with high-level SCI have a reduced chemoreceptive drive to breathe. Studies have shown lesser increases in minute ventilation and mouth pressure during hypercapnia in those with tetraplegia. Peripheral factors rather than central factors appear to cause the reduction of the ventilatory response to hypercapnia. This reduced ventilatory drive may have functional impact on exercise ventilation in patients with high level SCI and enhancing ventilatory drive may improve exercise ventilation in high-level SCI. Currently, there are no treatments to overcome these functional deficits that affect daily activity and exercise-based rehabilitation recovery. However, previous work in an animal model of SCI has found that that a serotonin agonist markedly increases respiratory responses to carbon dioxide. Treatment with a serotonin 5HT1A agonist effectively improved the ventilatory drive after both acute and chronic spinal cord injuries in rats. One potential mechanism is increased excitability of the ventral motoneurons that have survived the spinal cord injury. 5-HT1A receptors do exist on these neurons, and when activated, amplify the excitatory output. Another mechanism resides at the intercostal and abdominal muscle afferents which influence supraspinal respiratory group neurons in the brainstem and motor output to the muscles of breathing. Hence, serotonin agonists may act on neural pathways in the spinal cord responsible for transferring afferent information from intercostal muscles to supraspinal centers. Lastly, 5-HT1A receptors may also be involved in functional plasticity of neural respiratory pathways, in particular ipsilateral phrenic nerve activity. Up regulation of 5-HT1A receptors due to denervation supersensitivity could result in postsynaptic hyperresponsivity due to loss of descending input. BuSpar/Buspirone is a serotonin 5HT1A agonist and used as an anxiolytic in humans. It does not cause sedation, has minimal effects on psychomotor performance or cognition, and has low threshold for abuse potential or dependence liability. Prior studies have found Buspirone to be well tolerated. It has been used safely in spinal cord injury, but not for respiratory purposes. (Though there is one clinical trial in process: Role of Enhancing Serotonin Receptors Activity for Sleep Apnea Treatment in Patients with SCI.) However, Buspirone up to 60 mg daily has been used to treat disturbed respiratory rhythms in multiple sclerosis, brain cancer, and brainstem infarction. Interestingly, in patients with COPD, a 14-day oral administration of buspirone (20 mg) found improved anxiety and depression as well as increased exercise tolerance with lesser sensations of dyspnea. Hence, buspirone may offer a treatment to improve hypercapnic ventilatory drive. Given that oral administration of 30 mg results in peak plasma levels at one hour and that the average elimination half life is about 2 to 3 hours, buspirone is an attractive and safe approach to exploring the ability to improve respiratory responses to exercise and/or hypercapnia exposure in those with high level spinal cord injury that limits breathing capacity.
Interventions
DRUGBuspirone
Subjects take 30 mg buspirone HCl (15 mg twice a day) for 14 Days.
DRUGPlacebo
Subjects take placebo pills (twice a day) for 14 Days.
Sponsors
Spaulding Rehabilitation Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
* Chronic high-level SCI (at least 24-months post injury) * Age 18 to 50 years. * Medically stable * Spinal Cord Injury ≥T3 * American Spinal Injury Association grade A or B or C. * Able to perform arm crank exercise.
Exclusion criteria
* Cardiomyopathy * High blood pressure( \>140/90 mmHg or you are taking high blood pressure medication) * Significant irregular heartbeat * Heart disease * Chronic lung disease (COPD, bronchitis) * Current use of cardioactive or antidepressant drugs * Family history of significant irregular heart beat or sudden cardiac death * Orthostatic hypotension (symptomatic fall in blood pressure \>30 mmHg when upright) * Current grade 2 or greater pressure ulcers at relevant contact site * Neurological disease (stroke, peripheral neuropathy, myopathy) * Arm or shoulder conditions that limit ability to perform arm crank exercise * History of bleeding disorder, diabetes, kidney disease, cancer, other neurological disease * Recent weigh change (greater than 10 pounds) * Regular use of tobacco * Intrathecal baclofen pump, * Current use of cardioactive, antidepressant, other sedating agents * Suicidal ideation * Pregnant and/or breastfeeding women. In addition, subjects must have no known hypersensitivity to Buspar and must not be taking a monoamine oxidase inhibitor.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pulmonary Function | 14 Days | Forced expiratory volume over 1 second (FEV1). |
| Hypercapnic Ventilatory Response | 14 Days | A change in the drive to breathe with a change in carbon dioxide |
| Sleep Quality | 14 Days | Sleep apneas and hypopneas per hour. |
| Exercise Pulmonary Capacity | 14 Days | Change in peak oxygen consumption during exercise |
Countries
United States
Participant flow
Recruitment details
Individuals with a medically stable spinal cord injury at neurological level \>T3 and AIS A, B, or C were recruited 2021-22 to participate in the study.
Pre-assignment details
Excluded if they have cardiovascular disease, diabetes, other neurological disease, renal disease, or cancer. Also excluded with current use of tobacco, cardioactive medications, antidepressants, or sedating agents.
Participants by arm
| Arm | Count |
|---|---|
| All Participants If eligible, all participants were studied at baseline before being randomly assigned to a 14 days of treatment (placebo or busrpirone) before crossing over to the other arm. | 8 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Baseline | Withdrawal by Subject | 1 | 0 |
| Treatment 1 (14 Days) | Adverse Event | 1 | 0 |
| Treatment 1 (14 Days) | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 33.1 Years STANDARD_DEVIATION 8.54 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Exercise Pulmonary Capacity | 15.32 ml/kg of O2 STANDARD_DEVIATION 7.01 |
| Hypercapnic Ventilatory Response | 0.725 L /min/mmHg of CO2 STANDARD_DEVIATION 0.525 |
| Pulmonary Function | 3.15 L STANDARD_DEVIATION 1.06 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 7 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 8 Participants |
| Sleep Quality | 2.85 apneas + hypopneas per hour STANDARD_DEVIATION 7.01 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 6 |
| other Total, other adverse events | 0 / 5 | 1 / 6 |
| serious Total, serious adverse events | 0 / 5 | 0 / 6 |
Outcome results
Primary
Exercise Pulmonary Capacity
Change in peak oxygen consumption during exercise
Time frame: 14 Days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Exercise Pulmonary Capacity | 18.28 ml/kg of O2 | Standard Deviation 8.2 |
| Buspirone | Exercise Pulmonary Capacity | 17.69 ml/kg of O2 | Standard Deviation 7.29 |
Primary
Hypercapnic Ventilatory Response
A change in the drive to breathe with a change in carbon dioxide
Time frame: 14 Days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Hypercapnic Ventilatory Response | 0.659 L /min/mmHg of CO2 | Standard Deviation 0.32 |
| Buspirone | Hypercapnic Ventilatory Response | 0.566 L /min/mmHg of CO2 | Standard Deviation 0.133 |
Primary
Pulmonary Function
Forced expiratory volume over 1 second (FEV1).
Time frame: 14 Days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Pulmonary Function | 3.59 L | Standard Deviation 1.07 |
| Buspirone | Pulmonary Function | 3.77 L | Standard Deviation 1.12 |
Primary
Sleep Quality
Sleep apneas and hypopneas per hour.
Time frame: 14 Days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Sleep Quality | 4.26 counts per hour | Standard Deviation 2.11 |
| Buspirone | Sleep Quality | 6.18 counts per hour | Standard Deviation 2.97 |