24hr Effects of Tiotropium Bromide in Tetraplegia
| Status: | Enrolling by invitation |
|---|---|
| Conditions: | Hospital, Orthopedic |
| Therapuetic Areas: | Orthopedics / Podiatry, Other |
| Healthy: | No |
| Age Range: | 18 - 65 |
| Updated: | 4/17/2018 |
| Start Date: | July 2014 |
| End Date: | December 2018 |
A Randomized, Double-blind, Placebo-controlled Trial to Determine the Effects and Duration of Action of Tiotropium Bromide on Pulmonary Function in Persons With SCI
Respiratory complications are the leading cause of death during the initial year after acute
SCI, and the third leading cause of death thereafter. Complete or partial loss of respiratory
muscle innervations in individuals with cervical and high thoracic injuries leads to
inadequate ventilation and inability to effectively clear secretions, often prompting
supportive ventilation following initial injury. Development of atelactasis, pneumonias and
respiratory failure are the most common respiratory complications observed during the acute
phase of injury. It is well known that a restrictive ventilatory defect, dependent upon the
level and completeness of injury, is apparent in individuals with chronic cervical SCI.
Respiratory functional impairment might be further compromised in these individuals, the
majority of whom share many aspects of obstructive airway physiology commonly associated with
asthma. The asthma-like features that individuals with chronic cervical SCI demonstrate have
been hypothesized to be due to overriding cholinergic airway tone carried by intact vagal
(parasympathetic) nerve fibers arising from the brainstem, whereas sympathetic innervations
is interrupted at the level of the upper thoracic spinal cord. Whether airway narrowing and
AHR in chronic cervical SCI is also related to chronic airway inflammation is unknown,
although it is conceivable that repeated respiratory infections or, possibly, a neurogenic
component, could contribute to chronic airway inflammation.
Therefore, the investigators aim to assess how long-acting bronchodilator (tiotropium
bromide) affects various indices of lung function, including: pulmonary function tests,
levels of inflammation and cough strength across 24 hours after receiving study drug. Results
will be analyzed for baseline, 1 hour, 3 hours, 20 hours and 24 hours post drug inhalation
for both active medication and non-active placebo.
SCI, and the third leading cause of death thereafter. Complete or partial loss of respiratory
muscle innervations in individuals with cervical and high thoracic injuries leads to
inadequate ventilation and inability to effectively clear secretions, often prompting
supportive ventilation following initial injury. Development of atelactasis, pneumonias and
respiratory failure are the most common respiratory complications observed during the acute
phase of injury. It is well known that a restrictive ventilatory defect, dependent upon the
level and completeness of injury, is apparent in individuals with chronic cervical SCI.
Respiratory functional impairment might be further compromised in these individuals, the
majority of whom share many aspects of obstructive airway physiology commonly associated with
asthma. The asthma-like features that individuals with chronic cervical SCI demonstrate have
been hypothesized to be due to overriding cholinergic airway tone carried by intact vagal
(parasympathetic) nerve fibers arising from the brainstem, whereas sympathetic innervations
is interrupted at the level of the upper thoracic spinal cord. Whether airway narrowing and
AHR in chronic cervical SCI is also related to chronic airway inflammation is unknown,
although it is conceivable that repeated respiratory infections or, possibly, a neurogenic
component, could contribute to chronic airway inflammation.
Therefore, the investigators aim to assess how long-acting bronchodilator (tiotropium
bromide) affects various indices of lung function, including: pulmonary function tests,
levels of inflammation and cough strength across 24 hours after receiving study drug. Results
will be analyzed for baseline, 1 hour, 3 hours, 20 hours and 24 hours post drug inhalation
for both active medication and non-active placebo.
In addition to a restrictive ventilatory defect stemming for respiratory muscle paralysis,
cervical SCI (tetraplegia) is associated with obstructive airway physiology similar to that
associated with asthma. The investigators hypothesize that these aspects of obstructive
physiology stem from unopposed increases in cholinergic airway tone as a result of autonomic
imbalance; where vagal innervation (cholinergic neurotransmission) to the lungs is intact,
and the bronchodilating adrenergic influences of sympathetic pathways are interrupted. The
investigators demonstrated using spirometric criteria, significant bronchodilator responses
in approximately 50% of subjects with tetraplegia following inhalation of short acting beta-2
agonists (albuterol sulfate) and anticholinergic agents (ipratropium bromide). When specific
airway conductance (sGaw), a more sensitive indicator of bronchodilation, was assessed via
whole body plethysmography, significant bronchodilation and restoration of normal airway
caliber was noted in all subjects.
Intuitively, one might expect that through bronchodilation susceptible individuals with
tetraplegia who already have compromised respiratory muscle strength and weakened cough might
benefit from better airway clearance, and via increases in lung volumes improve the
length-tension relationship of residual expiratory muscles for initiation of more forceful
coughs. Based upon a comparative study of the bronchodilator effects of ipratropium bromide
versus albuterol in persons with tetraplegia (in publication), it appears that ipratropium
bromide elicited greater bronchodilation, perhaps because of the specificity of action in
blocking acetylcholine binding to the muscarinic-3 (M3) airway smooth muscle receptor. The
investigators purpose in this preliminary study is to assess whether salutary effects upon
pulmonary function, cough strength, and airway inflammation are observed across a twenty-four
hour period following inhalation of a single dose of tiotropium bromide 18 mcg inhalational
capsule versus placebo utilizing a double-blind crossover design in persons with chronic
stable tetraplegia.
cervical SCI (tetraplegia) is associated with obstructive airway physiology similar to that
associated with asthma. The investigators hypothesize that these aspects of obstructive
physiology stem from unopposed increases in cholinergic airway tone as a result of autonomic
imbalance; where vagal innervation (cholinergic neurotransmission) to the lungs is intact,
and the bronchodilating adrenergic influences of sympathetic pathways are interrupted. The
investigators demonstrated using spirometric criteria, significant bronchodilator responses
in approximately 50% of subjects with tetraplegia following inhalation of short acting beta-2
agonists (albuterol sulfate) and anticholinergic agents (ipratropium bromide). When specific
airway conductance (sGaw), a more sensitive indicator of bronchodilation, was assessed via
whole body plethysmography, significant bronchodilation and restoration of normal airway
caliber was noted in all subjects.
Intuitively, one might expect that through bronchodilation susceptible individuals with
tetraplegia who already have compromised respiratory muscle strength and weakened cough might
benefit from better airway clearance, and via increases in lung volumes improve the
length-tension relationship of residual expiratory muscles for initiation of more forceful
coughs. Based upon a comparative study of the bronchodilator effects of ipratropium bromide
versus albuterol in persons with tetraplegia (in publication), it appears that ipratropium
bromide elicited greater bronchodilation, perhaps because of the specificity of action in
blocking acetylcholine binding to the muscarinic-3 (M3) airway smooth muscle receptor. The
investigators purpose in this preliminary study is to assess whether salutary effects upon
pulmonary function, cough strength, and airway inflammation are observed across a twenty-four
hour period following inhalation of a single dose of tiotropium bromide 18 mcg inhalational
capsule versus placebo utilizing a double-blind crossover design in persons with chronic
stable tetraplegia.
Inclusion Criteria:
1. Chronic Spinal Cord Injury (>1 year post-injury)
2. Stable tetraplegia (level of injury C3-C8, non-ventilator dependent)
3. Male or female between the ages 18-65
Exclusion Criteria:
1. Smoking, active or history of smoking during last 6 months;
2. Ventilator dependent;
3. Known history of asthma, COPD or inflammatory disease during lifetime;
4. Active or recent (within 3 months) respiratory infection;
5. Use of medications known to affect the respiratory system;
6. Use of medications known to alter airway caliber
7. Uncontrolled hypertension;
8. Glaucoma or cataracts;
9. History of milk protein allergy
10. Pregnant or trying to become pregnant
11. Lack of mental capacity to give informed consent
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