Asthma, Tetraplegia
Conditions
Keywords
Tetraplegia, Mild asthma, Exhaled Nitric Oxide, NOS inhibitor, Spinal cord injury, Pulmonary Function
Brief summary
Previously it was observed that individuals with tetraplegia have reduced baseline airway caliber and exhibit non-specific airway hyperresponsiveness (AHR). In persons with tetraplegia we have suggested that this is due to overriding cholinergic airway tone. In asthma, the mechanisms underlying bronchoconstriction and AHR are more closely tied to airway inflammation. Whether AHR in tetraplegia is also related to chronic airway inflammation is unknown. Recently, a non-invasive technique for assessing airway inflammation has been established in asthma that involves measurement of nitric oxide (NO) concentrations (FeNO) in expired air. FeNO is elevated in asthma likely due to excess NO production by inflammatory cells within the airway Measurement of FeNO in persons with tetraplegia would help in assessing the role of airway inflammation in this population. This may have therapeutic significance in such individuals. NO in the lung is felt to be the principal inhibitory neurotransmitter of the non-adrenergic, non-cholinergic (NANC) system. It is thought that inhalation of NO has no effect on airway tone in healthy individuals but reduces methacholine responsiveness while having weak direct bronchodilatory effect in asthmatics. The primary purpose of this study is to determine the levels of exhaled NO (FeNO) in individuals with chronic cervical spinal cord injury (SCI), and to compare them with those obtained in age and sex matched able-bodied individuals and subjects with stable mild to moderate asthma. If the FeNO levels are high and comparable to those found in asthmatic subjects, this will imply the role of chronic inflammation in reduced baseline airway caliber and non-specific airway hyper-responsiveness (AHR) exhibited by individuals with chronic cervical SCI. If the FeNO levels are comparable with those found in able-bodied controls, this will support our previous statement that unopposed cholinergic innervation is responsible for low baseline airway caliber and AHR in individuals with chronic tetraplegia. Further scientific conclusions about NO and its role in control of airway tone, pulmonary resistances and blood pressure will be drawn upon intravenous and inhaled administration of L-NAME. This compound has been shown promising results for the treatment and prevention of orthostatic hypotension in individuals with tetraplegia. Knowing its effects on airways and potential of easier mode of delivery (inhalation vs. intravenous) is of utmost importance.
Detailed description
The study requires a maximum of five study visits in the following order: 1. nebulized normal saline, 2. nebulized 1mg/kg of L-NAME (see below), 3. intravenous normal saline, 4. intravenous 1 mg/kg L-NAME, 5. intravenous 2 mg/kg L-Name.
Interventions
A non-specific inhibitor of the nitric oxide synthase enzyme.
Sponsors
VA Office of Research and Development
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
1. Written informed consent. 2. Age between 18 and 65 years. 3. Able-bodied individuals, persons with mild asthma or individuals with tetraplegia for at least one year of duration. 4. Able to perform acceptable pulmonary function tests and follow procedures.
Exclusion criteria
1. coronary artery disease; 2. active cigarette smokers or previous smokers who stopped \<5 years ago; 3. MI or stroke within 3 months; 4. moderate to severe reduction in lung function defined as FEV1 \< 70 % predicted (except in individuals with tetraplegia); 5. hypertension; 6. medications known to affect the cardiovascular system; 7. pregnancy 8. current use of cholinesterase medication; and 9. lack of mental capacity to give informed consent Group specific
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Exhaled Levels of Nitric Oxide | Exhaled NO reported during visit, before intervention at baseline, post intervention at 60 minutes and 120 minutes | Nitric Oxide was measured applying a real time technique for measurement of Nitric Oxide in Exhaled Breath Condensate. Elevated Nitric Oxide in exhalate is a measure of elevated production of NO in conditions such as underlying inflammation and/or oxidative stress. Exhaled NO was reported as the mean of three values within 10% of each other. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Specific Airway Conductance (sGaw) as Measured by Plethysmography | Specific airway conductance reported during visit, before intervention at baseline, post intervention at 60 minutes and 120 minutes | Specific airway conductance (sGaw) is the airway conductance relative to lung volume because it takes into account the important effect of lung volume on airway resistance, it is a useful index of bronchomotor tone. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from SCI service of James J. Peters VAMC as well as from SCI outpatient clinics. Participants in the asthma group were recruited through medicine clinic at James J. Peters VAMC. Healthy able-bodied controls were recruited from the group of able-bodied controls that has been doing studies with our center in the past.
Participants by arm
| Arm | Count |
|---|---|
| Chronic Tetraplegia Individuals with chronic tetraplegia
N-Nitro L-arginine-methylester (L-NAME) : A non-specific inhibitor of the nitric oxide synthase enzyme. | 9 |
| Mild Asthma Individuals with diagnosed mild asthma
N-Nitro L-arginine-methylester (L-NAME) : A non-specific inhibitor of the nitric oxide synthase enzyme. | 7 |
| Healthy Controls Neurologically intact, otherwise healthy, age-matched control
N-Nitro L-arginine-methylester (L-NAME) : A non-specific inhibitor of the nitric oxide synthase enzyme. | 7 |
| Total | 23 |
Baseline characteristics
| Characteristic | Mild Asthma | Healthy Controls | Chronic Tetraplegia | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 7 Participants | 9 Participants | 23 Participants |
| Age, Continuous | 42 years STANDARD_DEVIATION 9 | 37 years STANDARD_DEVIATION 10 | 42 years STANDARD_DEVIATION 10 | 40 years STANDARD_DEVIATION 10 |
| Region of Enrollment United States | 7 Participants | 7 Participants | 9 Participants | 23 Participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 6 Participants | 6 Participants | 8 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 9 | 0 / 7 | 0 / 7 |
| serious Total, serious adverse events | 0 / 9 | 0 / 7 | 0 / 7 |
Outcome results
Primary
Exhaled Levels of Nitric Oxide
Nitric Oxide was measured applying a real time technique for measurement of Nitric Oxide in Exhaled Breath Condensate. Elevated Nitric Oxide in exhalate is a measure of elevated production of NO in conditions such as underlying inflammation and/or oxidative stress. Exhaled NO was reported as the mean of three values within 10% of each other.
Time frame: Exhaled NO reported during visit, before intervention at baseline, post intervention at 60 minutes and 120 minutes
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Chronic Tetraplegia | Exhaled Levels of Nitric Oxide | 120 minutes (post intervention) | 3.04 ppb (parts per bilion) | Standard Deviation 2.23 |
| Chronic Tetraplegia | Exhaled Levels of Nitric Oxide | Baseline (before intervention) | 17.27 ppb (parts per bilion) | Standard Deviation 4.96 |
| Chronic Tetraplegia | Exhaled Levels of Nitric Oxide | 60 minutes (post intervention) | 3.70 ppb (parts per bilion) | Standard Deviation 3.14 |
| Mild Asthma | Exhaled Levels of Nitric Oxide | 60 minutes (post intervention) | 5.56 ppb (parts per bilion) | Standard Deviation 2.93 |
| Mild Asthma | Exhaled Levels of Nitric Oxide | 120 minutes (post intervention) | 5.73 ppb (parts per bilion) | Standard Deviation 3.7 |
| Mild Asthma | Exhaled Levels of Nitric Oxide | Baseline (before intervention) | 19.83 ppb (parts per bilion) | Standard Deviation 8.15 |
| Healthy Controls | Exhaled Levels of Nitric Oxide | Baseline (before intervention) | 15.025 ppb (parts per bilion) | Standard Deviation 9.75 |
| Healthy Controls | Exhaled Levels of Nitric Oxide | 120 minutes (post intervention) | 3.71 ppb (parts per bilion) | Standard Deviation 3.46 |
| Healthy Controls | Exhaled Levels of Nitric Oxide | 60 minutes (post intervention) | 4.07 ppb (parts per bilion) | Standard Deviation 3.47 |
Secondary
Specific Airway Conductance (sGaw) as Measured by Plethysmography
Specific airway conductance (sGaw) is the airway conductance relative to lung volume because it takes into account the important effect of lung volume on airway resistance, it is a useful index of bronchomotor tone.
Time frame: Specific airway conductance reported during visit, before intervention at baseline, post intervention at 60 minutes and 120 minutes
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Chronic Tetraplegia | Specific Airway Conductance (sGaw) as Measured by Plethysmography | 60 minutes (post intervention) | 0.218 L/sec/cmH20/L | Standard Deviation 0.093 |
| Chronic Tetraplegia | Specific Airway Conductance (sGaw) as Measured by Plethysmography | Baseline (before intervention) | 0.164 L/sec/cmH20/L | Standard Deviation 0.071 |
| Chronic Tetraplegia | Specific Airway Conductance (sGaw) as Measured by Plethysmography | 120 minutes (post intervention) | 0.207 L/sec/cmH20/L | Standard Deviation 0.094 |
| Mild Asthma | Specific Airway Conductance (sGaw) as Measured by Plethysmography | 60 minutes (post intervention) | 0.315 L/sec/cmH20/L | Standard Deviation 0 |
| Mild Asthma | Specific Airway Conductance (sGaw) as Measured by Plethysmography | Baseline (before intervention) | 0.336 L/sec/cmH20/L | Standard Deviation 0 |
| Mild Asthma | Specific Airway Conductance (sGaw) as Measured by Plethysmography | 120 minutes (post intervention) | 0.345 L/sec/cmH20/L | Standard Deviation 0 |
| Healthy Controls | Specific Airway Conductance (sGaw) as Measured by Plethysmography | Baseline (before intervention) | 0.197 L/sec/cmH20/L | Standard Deviation 0.043 |
| Healthy Controls | Specific Airway Conductance (sGaw) as Measured by Plethysmography | 120 minutes (post intervention) | 0.197 L/sec/cmH20/L | Standard Deviation 0.043 |
| Healthy Controls | Specific Airway Conductance (sGaw) as Measured by Plethysmography | 60 minutes (post intervention) | 0.196 L/sec/cmH20/L | Standard Deviation 0.047 |