Treatment of Orthostatic Hypotension in Autonomic Failure

This study is currently recruiting participants.
Verified June 2013 by Vanderbilt University
Sponsor:
Information provided by (Responsible Party):
Italo Biaggioni, Vanderbilt University
ClinicalTrials.gov Identifier:
NCT00223691
First received: September 14, 2005
Last updated: June 20, 2013
Last verified: June 2013

September 14, 2005
June 20, 2013
March 2002
May 2014   (final data collection date for primary outcome measure)
Increase in seated systolic blood pressure 1-hr post drug compared to baseline. [ Time Frame: 1.5-4 hours ] [ Designated as safety issue: No ]
Increase in seated systolic blood pressure 1-hr post drug compared to baseline.
Complete list of historical versions of study NCT00223691 on ClinicalTrials.gov Archive Site
Increase in standing time 1-hr post drug compared to baseline [ Time Frame: 1.5-4 hours ] [ Designated as safety issue: No ]
Increase in standing time 1-hr post drug compared to baseline
Not Provided
Not Provided
 
Treatment of Orthostatic Hypotension in Autonomic Failure
Evaluation and Treatment of Autonomic Failure.

The autonomic nervous system serves multiple regulatory functions in the body, including the regulation of blood pressure and heart rate, gut motility, sweating and sexual function. There are several diseases characterized by abnormal function of the autonomic nervous system. Medications can also alter autonomic function. Impairment of the autonomic nervous system by diseases or drugs may lead to several symptoms, including blood pressure problems (e.g., high blood pressure lying down and low blood pressure on standing), sweating abnormalities, constipation or diarrhea and sexual dysfunction. Because treatment options for these patients are limited. We propose to study patients autonomic failure and low blood pressure upon standing and determine the cause of their disease by history and examination and their response to autonomic testing which have already been standardized in our laboratory. Based on their possible cause, we will tests different medications that may alleviate their symptoms.

Subjects will be admitted to the Clinical Research Center at Vanderbilt University for the studies. The average inpatient stay is 7 days. Initially a complete history and physical will be performed and the patient will be placed on a low monamine, no methylxanthine, 150 mEq sodium, 60-80 mEq potassium diet.

The following tests will be performed:

  1. Meal challenge:

    We observed profound effects of diet on blood pressure in many patients with orthostatic hypotension. Some patients dropped their blood pressure by 40-60 mmHg during the postprandial period. Blood pressure will be monitored with an automated device (Dinamap) after feeding the patients with a standardized diet.

  2. Physiologic autonomic tests:

    Patients are studied supine, and blood pressure is monitored with a sphygmomanometer or an automated device (Dinamap, Finapres or tonometer).

    1. Orthostatic test: Blood pressure and heart rate are measured in the supine and standing positions. Orthostatic hypotension without an adequate heart rate increase is indicative of autonomic failure. On the other hand, orthostatic tachycardia in the absence of volume depletion is seen in "hyperadrenergic orthostatic hypotension".
    2. Standing time: The time the patient can stand motionless gives a very good indication of functional capacity.
    3. Deep breathing: Heart rate is monitored with an ECG and the patient is asked to breathe deeply 6 times each minute for two minutes. Heart rate variation due to respiration is an autonomic function. The loss of this respiratory arrhythmia is indicative of autonomic failure.
    4. Valsalva maneuver: The patient is asked to exhale against a 40 mmHg pressure. This produces transient changes in blood pressure and heart rate which are autonomically mediated, and can be monitored with an ECG. Failure to observe heart rate changes is indicative of autonomic failure.
    5. Hyperventilation: The patient is asked to hyperventilate for 30 seconds. The normal response is an increase in heart rate and no significant change in blood pressure. Patients with autonomic failure have profound reductions in blood pressure without compensatory heart rate increases.
    6. Handgrip: The patient is asked to maintain a handgrip for three minutes. Increases in heart rate and blood pressure are seen in normal subjects but not in patients with autonomic failure.
    7. Cold pressor test: The patient is asked to place an hand in ice cold water for one minute. The results are similar to the handgrip test.
    8. Supine hypertension screening: We will measure the blood pressure every two hours during one night to determine if the patient has supine hypertension or high blood pressure while lying down.
  3. Posture Study:

    Blood for catecholamine, bradykinins, plasma renin activity, aldosterone and plasma angiotensin II is drawn while the patient is supine and upright. Blood pressure is measured with a sphygmomanometer or an automated device (Dinamap). Normally, on assuming the upright posture, plasma norepinephrine and renin activity should double. Patients with autonomic failure typically show low supine levels of both norepinephrine and renin activity which failed to increase on assuming the upright posture. In contrast, patients with hyperadrenergic orthostatic hypotension typically have normal or exaggerated responses.

  4. Twelve hour urine collections for catecholamines, urinalysis, protein, glucose, creatinine, osmolality, electrolytes and F2-isoprostanes will be collected to analyze for catecholamine excretion (hormones produces by the autonomic nervous system) oxidative stress markers and to assess the patient's kidney function.
  5. Blood will be collected in the fasted state through and intravenous catheter to analyze for PAI-1, CRP, F2-isoprostanes, proinflammatory cytokines and renal function.
  6. EKG will be recorded while the patient is lying down and while the patient is standing.
  7. Orthostatic vital signs will be measured several times a day. This testing consists of blood pressure and heart rate measured while the patient is lying down and then repeated after standing quietly for 10 minutes. Several readings are measured in sequence using an automated blood pressure monitor (Dinamap).
  8. Tilt table test: This test uses a tilt table, which is a motorized table with a footboard. The participant rests quietly on the table while the monitoring equipment is assembled. EKG electrodes are applied to the chest to monitor heart rate and rhythm. Blood pressure will be measured with a cuff applied to a finger. Blood pressure will also be checked periodically using a traditional blood pressure cuff wrapped around an upper arm. Safety straps are used to secure the patient to the table to prevent falling or unsteadiness when the table is moved to an upright position. Gradual head up tilt will be performed until a systolic blood pressure of 70 mm Hg is reached or the appearance of symptoms related to hypotension. Changes in cardiac output (heart's pumping capacity) will be measured by analyzing the air that is breathed ("rebreathing test", Innocor). This will be done through a mouthpiece connected to a bag full of air and small concentrations of the inactive gases SF6 and N2O. Subjects will breathe normally through a mouthpiece connected to a bag for about 5 minutes at baseline, at 30º and at the maximum head up tilt. Innocor is FDA approved for inert gases cardiac output measurement.

    This test may or may not be performed. Some patients may have already undergone this test or it may not be pertinent to a particular patient. The principal investigator will decide whether this test is performed or not.

  9. Therapeutic Drug Trials:

We will try different medications to determine if blood pressure improves upon standing. For all these tests, blood pressure is monitored with a sphygmomanometer and heart rate with an ECG. The procedures are detailed below.

Patients will be in the fasted state in the seated position throughout the study. They will be connected to an automated blood pressure monitor (Dinamap). Thirty minutes after baseline blood pressure and heart rate measurements, they will be given a dose of the medicine to be tested. Blood pressure will be monitored every 5 to 15 minutes for up to four additional hours. Upright blood pressure, heart rate and the standing time will be measure periodically throughout the study. The patients will be asked to rate their symptoms at various time during the study.

This study has been designed to determine optimal candidate drugs and therapy for the treatment of orthostatic hypotension. Potential pressor agents have been selected for this study because of their different mechanism of action. We propose also to use the combination of different therapeutic agents.

For some of these tests,we will do the following:

  1. we will determine the effect of the medication on catecholamines and/or markers of inflammation and/or oxidative stress. We will draw a blood sample at baseline and after the medication has taken effect. A saline lock or small flexible intravenous catheter will be placed for this purpose. For each medication trial, the amount of blood drawn would be up to 6 teaspoons. The total blood drawn for all the medication trials would not exceed 36 teaspoons.
  2. We will measure changes in cardiac output (heart's pumping capacity) by analyzing the air that is breathed ("rebreathing test", Innocor). This will be done through a mouthpiece connected to a bag full of air and small concentrations of the inactive gases SF6 and N2O. Subjects will breathe normally through a mouthpiece connected to a bag for about 5 minutes before and after the medication. Innocor is FDA approved for inert gases cardiac output measurement.
  3. We will measure the cerebral blood flow to determine if it can be improved with the medication. A middle cerebral artery will be continuously insonated by transcranial Doppler ultrasonography. The transducer will be affixed with head straps.
  4. We will apply eleven sticky patches to the front of the body to measure the impedance (electrical resistance). This will allow us to determine fluid shifts between body segments and obtain a continuous measurement of cardiac output and peripheral resistance.
Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Single Blind (Subject)
Primary Purpose: Treatment
  • Autonomic Failure
  • Orthostatic Hypotension
  • Drug: Atomoxetine
    10-50 mg, PO. Single dose. Alone or in combination with Yohimbine or Mestinon.
    Other Name: Strattera
  • Drug: Acarbose
    25-100 mg, PO. Single dose.
    Other Name: Precose
  • Drug: Pyridostigmine Bromide
    30 mg-180 mg PO. Single dose. Alone or in combination with Yohimbine or atomoxetine.
    Other Name: Mestinon
  • Drug: Yohimbine
    2.7, 5.4 or 10.8 mg PO. Single dose. Alone or in combination with Atomoxetine or Pyridostigmine.
    Other Name: Yocon
  • Drug: Midodrine HCl
    2.5, 5.0, 7.5, 10 mg PO. Single dose
    Other Name: ProAmatine
  • Drug: placebo
    PO.Single dose.
  • Drug: Modafinil
    50-400 mg PO. Single dose
    Other Name: Provigil
  • Drug: Octreotide
    5-50 µg, S.C. Single dose.
    Other Name: Sandostatin
  • Other: water intake
    Tap water 2 onz., 8 oz., 16 oz. PO, alone or in combination with any of the above medications. Single dose.
  • Drug: Diphenhydramine Hydrochloride
    12.5 mg-100 mg PO. Single dose. Alone or in combination with Ranitidine
    Other Name: Benadryl
  • Drug: Ranitidine HCL
    150-300 mg PO. Single dose. Alone or in combination with Diphenhydramine.
    Other Name: zantac
  • Drug: Tranylcypromine
    5 - 40 mg PO. Single dose
    Other Name: Parnate
  • Drug: Ergotamine/ Caffeine
    Ergotamine: 1.0 mg PO. Single dose. Caffeine 100 mg PO.Single dose
    Other Name: Cafergot
  • Drug: Celecoxib
    50-200 mg PO. Single dose
    Other Name: Celebrex
  • Drug: Pseudoephedrine
    15, 30 or 60 mg, PO. Single dose.
    Other Name: Sudafed
  • Drug: Methylphenidate
    5 or 10 mg PO. Single dose.
    Other Name: Ritalin
  • Drug: Indomethacin
    25, 50 or 75 mg, PO. Singe dose.
    Other Name: Indocin
  • Drug: Ibuprofen
    300, 600 or 900 mg, PO. Single dose.
    Other Name: Advil, Motrin
  • Drug: Oxymetazoline 0.05% nasal solution
    1-2 sprays/ nostril. Single dose.
    Other Name: Afrin
  • Dietary Supplement: Bovril
    6-10 g, PO. Single dose.
  • Drug: Acetazolamide
    125-1000 mg PO. Single dose. Alone or in combination with yohimbine or midodrine
    Other Name: Diamox
  • Drug: Rivastigmine tartrate
    1.5-6 mg PO. Single dose.
    Other Name: Exelon
  • Drug: Carbidopa/levodopa
    10mg/100mg or 25mg/100mg. 1-2 tab PO. Single dose. Alone or in combination with carbidopa (Lodosyn) 25-175 mg
    Other Name: Sinemet, Lodosyn
  • Device: Inflatable abdominal binder
    External abdominal compression (20-40 mm Hg) with an inflatable abdominal binder applied after a pressor agent (e.g. midodrine, yohimbine).
    Other Name: external abdominal compression
  • Device: inflatable abdominal binder (sham)
    External abdominal compression (5 mm Hg) with an inflatable abdominal binder applied after a pressor agent (e.g. midodrine, yohimbine).
    Other Name: external abdominal compression (sham)
  • Experimental: 1: active intervention
    atomoxetine, pyridostigmine bromide, yohimbine, midodrine hcl, modafinil, octreotide, water intake, ranitidine hcl, diphenhydramine hydrochloride, tranylcypromine, ergotamine/ caffeine, celecoxib, pseudoephedrine, methylphenidate, indomethacin, ibuprofen, Oxymetazoline 0.05% nasal solution, acarbose, Rivastigmine tartrate, acetazolamide, carbidopa/levodopa, inflatable abdominal binder or bovril
    Interventions:
    • Drug: Atomoxetine
    • Drug: Acarbose
    • Drug: Pyridostigmine Bromide
    • Drug: Yohimbine
    • Drug: Midodrine HCl
    • Drug: Modafinil
    • Drug: Octreotide
    • Other: water intake
    • Drug: Diphenhydramine Hydrochloride
    • Drug: Ranitidine HCL
    • Drug: Tranylcypromine
    • Drug: Ergotamine/ Caffeine
    • Drug: Celecoxib
    • Drug: Pseudoephedrine
    • Drug: Methylphenidate
    • Drug: Indomethacin
    • Drug: Ibuprofen
    • Drug: Oxymetazoline 0.05% nasal solution
    • Dietary Supplement: Bovril
    • Drug: Acetazolamide
    • Drug: Rivastigmine tartrate
    • Drug: Carbidopa/levodopa
    • Device: Inflatable abdominal binder
  • Placebo Comparator: 2: Placebo or sham device
    placebo pill or inflatable abdominal binder (sham)
    Interventions:
    • Drug: placebo
    • Device: inflatable abdominal binder (sham)

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
500
May 2014
May 2014   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Patients referred for evaluation of their autonomic function
  • Ages 18-85

Exclusion Criteria:

  • Pregnancy
Both
18 Years to 85 Years
No
Contact: Bonnie Black, RN adcresearch@vanderbilt.edu
United States
 
NCT00223691
000814, HL46681
No
Italo Biaggioni, Vanderbilt University
Vanderbilt University
Not Provided
Principal Investigator: Italo Biaggioni, MD Vanderbilt University
Vanderbilt University
June 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP