Treatment of Orthostatic Hypotension in 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 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.

Eligibility Criteria:
Inclusion Criteria:

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

Exclusion Criteria:

* Pregnancy