Treatment of Orthostatic Hypotension in Autonomic Failure
Condition: Autonomic Failure; Orthostatic Hypotension
MeSH terms: Hypotension, Orthostatic; Pure Autonomic Failure; Hypotension
Study type: Interventional
Phase: Phase 1

Summary: 
      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.
    

Detailed description: 
      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 apply external abdominal compression (up to 40mm Hg) to evaluate the ability of
           this counterpressure method in combination with a pressor agent to improve orthostatic
           tolerance. For this purpose, we will use an abdominal binder with an inflatable cuff
           placed underneath, which will be inflated to exert pressure at the level of the
           umbilicus while patients are standing. Patients may be randomly assigned to 5mm Hg (sham
           treatment) and/or 20-40mm Hg external abdominal compression with an abdominal binder
           applied at baseline of some of the therapeutic trials described above. The principal
           investigator will decide which medication will be used in each trial.

        3. 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.

        4. 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.

        5. 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.
    

Intervention name(s): Atomoxetine; Acarbose; Pyridostigmine Bromide; Yohimbine; Midodrine HCl; placebo; Modafinil; Octreotide; water intake; Diphenhydramine Hydrochloride; Ranitidine HCL; Tranylcypromine; Ergotamine/ Caffeine; Celecoxib; Pseudoephedrine; Methylphenidate; Indomethacin; Ibuprofen; Oxymetazoline 0.05% nasal solution; Bovril; Acetazolamide; Rivastigmine tartrate; Carbidopa/levodopa; Inflatable abdominal binder; inflatable abdominal binder (sham)
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Other; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Dietary Supplement; Drug; Drug; Drug; Device; Device
Intervention description(s): 10-50 mg, PO. Single dose. Alone or in combination with Yohimbine or Mestinon.; 25-100 mg, PO. Single dose.; 30 mg-180 mg PO. Single dose. Alone or in combination with Yohimbine or atomoxetine.; 2.7, 5.4 or 10.8 mg PO. Single dose. Alone or in combination with Atomoxetine or Pyridostigmine.; 2.5, 5.0, 7.5, 10 mg PO. Single dose; PO.Single dose.; 50-400 mg PO. Single dose; 5-50 µg, S.C. Single dose.; Tap water 2 onz., 8 oz., 16 oz. PO, alone or in combination with any of the above medications. Single dose.; 12.5 mg-100 mg PO. Single dose. Alone or in combination with Ranitidine; 150-300 mg PO. Single dose. Alone or in combination with Diphenhydramine.; 5 - 40 mg PO. Single dose; Ergotamine: 1.0 mg PO. Single dose. Caffeine 100 mg PO.Single dose; 50-200 mg PO. Single dose; 15, 30 or 60 mg, PO. Single dose.; 5 or 10 mg PO. Single dose.; 25, 50 or 75 mg, PO. Singe dose.; 300, 600 or 900 mg, PO. Single dose.; 1-2 sprays/ nostril. Single dose.; 6-10 g, PO. Single dose.; 125-1000 mg PO. Single dose. Alone or in combination with yohimbine or midodrine; 1.5-6 mg PO. Single dose.; 10mg/100mg or 25mg/100mg. 1-2 tab PO. Single dose. Alone or in combination with carbidopa (Lodosyn) 25-175 mg; External abdominal compression (20-40 mm Hg) with an inflatable abdominal binder applied after a pressor agent (e.g. midodrine, yohimbine).; External abdominal compression (5 mm Hg) with an inflatable abdominal binder applied after a pressor agent (e.g. midodrine, yohimbine).
Other intervention name(s): Strattera; Precose; Mestinon; Yocon; ProAmatine; Provigil; Sandostatin; Benadryl; zantac; Parnate; Cafergot; Celebrex; Sudafed; Ritalin; Indocin; Advil, Motrin; Afrin; Diamox; Exelon; Sinemet, Lodosyn; external abdominal compression; external abdominal compression (sham)
Intervention MeSH terms: Acarbose; Diphenhydramine; Promethazine; Ibuprofen; Celecoxib; Indomethacin; Octreotide; Phenylephrine; Acetazolamide; Midodrine; Pseudoephedrine; Ephedrine; Oxymetazoline; Ergotamine; Bromides; Levodopa; Carbidopa; Carbidopa, levodopa drug combination; Tranylcypromine; Caffeine; Methylphenidate; Modafinil; Rivastigmine; Ranitidine; Yohimbine; Pyridostigmine Bromide; Atomoxetine Hydrochloride
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Participant)
Keywords: orthostatic hypotension; autonomic failure