The Effects Of Bronchodilator Therapy On Respiratory And Autonomic Function In Patients With Familial Dysautonomia
Condition: Familial Dysautonomia
MeSH terms: Primary Dysautonomias; Autonomic Nervous System Diseases; Dysautonomia, Familial
Study type: Interventional
Phase: Phase 3

Summary: 
      Evaluate the effects of bronchodilator therapy on respiratory function. Our overall goal is
      to determine whether, in patients with familial dysautonomia (FD), there is a component of
      airway obstruction that is reversible. To this end, we will evaluate airway resistance before
      and after receiving the anti-cholinergic ipratropium (Atrovent ®) and the beta-2-agonist
      albuterol (ProVentil®/Ventolin®). We predict that the response to either drug will depend on
      the underlying level of sympathetic and parasympathetic activity and airway tone. We will
      then determine the cardiovascular effects of inhaled ipratropium and albuterol in patients
      with FD. Because patients with FD have fewer sympathetic neurons and denervation
      supersenstivity, we predict that following albuterol inhalation, there will be non-selective
      activation of alpha-1-adrenergic receptors. Furthermore, because of a congenital defect in
      the afferent baroreceptor neurons that sense blood pressure, we suspect that the resulting
      vasoconstriction will be unopposed leading to a pressor effect. We hypothesize that
      inhalation of the anti-cholinergic ipratopium will produce little rise in heart rate, due to
      the extent of parasympathetic denervation to the heart.
    

Detailed description: 
      Familial dysautonomia (FD) is a rare fatal autosomal recessive disease caused by a deficiency
      of the protein IKAP.1 This results in a selective developmental defect that affects mostly
      afferent (sensory) neurons including those in the dorsal root ganglia and cranial nerves.2, 3
      We have shown recently that the protein deficiency impairs the development of afferent
      baroreceptor pathways, leaving the sympathetic efferent neurons reduced in number but
      functionally active. This results in the complete failure to detect and buffer fluctuations
      in blood pressure leading to volatile hypertension. In addition to the afferent baroreflex
      pathways, the deficiency of IKAP during embroyogenesis also affects the function of the
      chemoreflex pathways. As a result, patients fail to increase ventilation adequately in
      response to hypoxia and hypercapnia.4 As well as the impairment of the neurological
      mechanisms that regulate breathing, patients with FD also have a combination of obstructive,
      restrictive and probably also neuromuscular lung disease. Failure to coordinate swallowing
      results in recurrent bouts of aspiration pneumonia occurring from birth.5, 6 Imaging studies
      show that almost all patients with FD have bronchial wall thickening, atelectasis and almost
      30% have bronchiectasis7. Pulmonary function tests show air flow limitation and associated
      lung restriction with reduction in diffusion capacity12. Sudden attacks of asthma like
      wheezing are common 8 and frequently associated with emotional upset,5 a time when
      sympathetic outflow to the vasculature is increased heightened.3 There is also a component of
      restrictive lung disease, with a very high incidence of scoliosis, which frequently begins at
      an early age. Complicating matters further, many patients opt to undergo spine fusion
      surgery, 9 which could potentially worsen further chest wall compliance.10 Patients with FD
      also lack muscle spindles, 2 making it likely that they have neuromuscular abnormalities
      arising from the absence of proprioceptive feedback from the respiratory muscles involved in
      the coordination of breathing.

      Severe respiratory disease is a leading cause of death in patients with FD and many are
      treated empirically with inhaled bronchodilators. It is not known, however, whether these
      drugs are effective at reversing increased airway resistance. Hence, there is an urgent need
      to understand if the short acting beta-2-adrenergic agonist albuterol and the anticholinergic
      ipratropium, are effective bronchodilators. Furthermore, because treatment with these agents
      has potential cardiovascular side effects, we will also analyze their effects on blood
      pressure, heart rate and cardiac output.
    

Intervention name(s): Albuterol-sulphate; Ipratropium-bromide; placebo
Intervention type(s): Drug; Drug; Other
Intervention description(s): Beta-2-adrenergic agonist 2.5 mg 3 cc inhalation Peak effect 15 - 30 mins. Mean duration of effect 3 hours; Anti-cholinergic 500 mcg 3 cc inhalation Peak effect 30 - 90 mins. Duration of effect 2 - 4 hours.; Saline solution 3 cc NA
Other intervention name(s): (Proventil ®); (Atrovent ®)
Intervention MeSH terms: Bromides; Albuterol; Ipratropium
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: familial dysautonomia