Clinical Trial: The Effects Of Bronchodilator Therapy On Respiratory And Autonomic Function In Patients With Familial Dysautonomia

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: The Effects of Bronchodilator Therapy On Respiratory and Autonomic Function in Patients With Familial Dysautonomia

Brief 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 Summary:

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 ne
Sponsor: New York University School of Medicine

Current Primary Outcome:

• Change From Baseline of Forced Vital Capacity [ Time Frame: Pre and 30 minutes post study drug administration ]
  FVC is a measure of the amount of air exhaled, and is measured in liters of air per second. The percentage in the change in the amount of air exhaled from baseline, measured in liters of air per second. Increase in the percentage of air exhaled from baseline indicates improvement in respiratory function.
• Change in Respiratory Function (Airway Resistance at 5 Hz) From Baseline [ Time Frame: Pre and 30 minutes post study drug administration ]
  The percentage change in respiratory function from baseline is measured in percentage change in Resistance, kPa/(L/s).

Original Primary Outcome:

• respiratory Function (airway resistance, R5HZ) [ Time Frame: Pre and 30 minutes post study drug administration ]
  Our overall goal is to evaluate whether there is a component of airway obstruction that is reversible. To address this goal, we will compare the effects of a short acting, inhaled beta-2-adrenergic receptor agonist (albuterol) and an antagonist of acetylcholine (ipratropium) on airway resistance. Using pulse oscillometry, we will compare airway resistance before and after the brochodilators are administered. The variables that measure airway resistance are R5HZ and R20HZ.
• respiratory function (airway resistance, R20HZ) [ Time Frame: Pre and 30 minutes post study drug administration ]
  Our overall goal is to evaluate whether there is a component of airway obstruction that is reversible. To address this goal, we will compare the effects of a short acting, inhaled beta-2-adrenergic receptor agonist (albuterol) and an antagonist of acetylcholine (ipratropium) on airway resistance. Using pulse oscillometry, we will compare airway resistance before and after the brochodilators are administered. The variables that measure airway resistance are R5HZ and R20HZ.

Current Secondary Outcome:

• Change in Forced Expiratory Volume (FEV) From Baseline [ Time Frame: Pre and 30 post study drug admistration ]
  Forced expiratory volume is measured in liters of air per second. FEV was measured during the first second of exhalation.
• Change in Forced Expiratory Flow Between 25-75% (FEF25-75) [ Time Frame: pre and 30 minutes post intervention ]
  FEF25-75 is measured in liters of air per second at 25-75%

Original Secondary Outcome:

• Cardiac function (blood pressure) [ Time Frame: Pre and 30 post study drug admistration ]
  Our second aim is to evaluate the effects of both bronchodilators on cardiovascular function. Relative change in BP ,RR intervals and CO from baseline after receiving albuterol or ipratropium will be calculated.
• RR interval [ Time Frame: pre and 30 minutes post intervention ]
  Our second aim is to evaluate the effects of both bronchodilators on cardiovascular function. Relative change in BP ,RR intervals and CO from baseline after receiving albuterol or ipratropium will be calculated.
• Cardiac Output (CO) [ Time Frame: pre and post 30 minutes intervention ]
  Our second aim is to evaluate the effects of both bronchodilators on cardiovascular function. Relative change in BP ,RR intervals and CO from baseline after receiving albuterol or ipratropium will be calculated.

Dates:
Date Received: November 5, 2013
Date Started: March 2013
Date Completion:
Last Updated: April 26, 2016
Last Verified: April 2016