24hr Effects of Tiotropium Bromide in Tetraplegia
Condition: Spinal Cord Injury
MeSH terms: Spinal Cord Injuries
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Tiotropium Bromide; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Tiotropium bromide is an anticholinergic used to study bronchodilatation and improvement of pulmonary function in tetraplegic patients; Placebo is a non-active inhalation capsule .
Other intervention name(s): Anticholinergic
Intervention MeSH terms: Bromides; Tiotropium Bromide; Cholinergic Antagonists
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: tiotropium bromide