Treatment of Supine Hypertension in Autonomic Failure
Condition: Hypertension
MeSH terms: Pure Autonomic Failure; Hypertension
Study type: Interventional
Phase: Phase 1

Summary: 
      Supine hypertension is a common problem that affects at least 50% of patients with primary
      autonomic failure. Supine hypertension can be severe, and complicates the treatment of
      orthostatic hypotension. Drugs used for the treatment of orthostatic hypotension (eg,
      fludrocortisone and pressor agents), worsen supine hypertension. High blood pressure may also
      cause target organ damage in this group of patients. The pathophysiologic mechanisms causing
      supine hypertension in patients with autonomic failure have not been defined.

      In a study, we, the investigators at Vanderbilt University, examined 64 patients with AF, 29
      with pure autonomic failure (PAF) and 35 with multiple system atrophy (MSA). 66% of patients
      had supine systolic (systolic blood pressure [SBP] > 150 mmHg) or diastolic (diastolic blood
      pressure [DBP] > 90 mmHg) hypertension (average blood pressure [BP]: 179 ± 5/89 ± 3 mmHg in
      21 PAF and 175 ± 5/92 ± 3 mmHg in 21 MSA patients). Plasma norepinephrine (92 ± 15 pg/mL) and
      plasma renin activity (0.3 ± 0.05 ng/mL per hour) were very low in a subset of patients with
      AF and supine hypertension. (Shannon et al., 1997).

      Our group has showed that a residual sympathetic function contributes to supine hypertension
      in patients with severe autonomic failure and that this effect is more prominent in patients
      with MSA than in those with PAF (Shannon et al., 2000). MSA patients had a marked depressor
      response to low infusion rates of trimethaphan, a ganglionic blocker; the response in PAF
      patients was more variable. At 1 mg/min, trimethaphan decreased supine SBP by 67 +/- 8 and 12
      +/- 6 mmHg in MSA and PAF patients, respectively (P < 0.0001). MSA patients with supine
      hypertension also had greater SBP response to oral yohimbine, a central alpha2 receptor
      blocker, than PAF patients. Plasma norepinephrine decreased in both groups, but heart rate
      did not change in either group. This result suggests that residual sympathetic activity
      drives supine hypertension in MSA; in contrast, supine hypertension in PAF.

      It is hoped that from this study will emerge a complete picture of the supine hypertension of
      autonomic failure. Understanding the mechanism of this paradoxical hypertension in the
      setting of profound loss of sympathetic function will improve our approach to the treatment
      of hypertension in autonomic failure, and it could also contribute to our understanding of
      hypertension in general.
    

Detailed description: 
      1. Overnight Medication Trials:

           Patients will be studied on the GCRC while in 150 mEq/day sodium balance and on a diet
           free of substances which interfere with catecholamine determination. Subjects will be
           asked to use the bathroom to empty their bladder at 8:00 PM. They will be given a
           randomly chosen medication aliskiren (Tekturna) 150-300mg po, bosentan (Tracleer) 62.5
           -125 mg po, captopril 25-50mg po, carbidopa 25-200mg po, clonidine 0.1-0.2mg po,
           desmopressin 0.2 - 0.6mg po (DDAVP), -diltiazem 30-60 mg po, dipyridamole 200 mg and
           aspirin 25 mg po (Aggrenox), eplerenone (Inspra) 50-100 mg po, guanfacine (Tenex) 1-3 mg
           po, hydralazine 10-50 mg po, hydrochlorothiazide 12.5-100 mg po, L- arginine 6-17 g po,
           losartan 25-100mg po, metoprolol tartrate (Lopressor) 25-100 mg po, nebivolol
           hydrochloride (Bystolic) 2.5-40 mg po, nitroglycerin-transdermal 0.05-0.2 mg patch,
           nifedipine (adalat) doses 10-30 mg, prazosin hydrochloride 0.5-1 mg po, sildenafil
           (Viagra) 25- 100 mg po, tamsulosin hydrochloride (Flomax) 0.4-0.8 mg po. The combination
           desmopressin 0.2 mg po (DDAVP) and nitroglycerin-transdermal 0.05-0.2 mg. The
           combinations desmopressin 0.2 mg po and nifedipine (10-30 mg). A placebo pill or skin
           patch will be done as a control to measure their supine blood pressure without
           medication intervention. They will then be asked to lie down with the head of the bed
           elevated 10 degrees. An automated blood pressure cuff (Dinamap) will be wrapped around
           an upper arm and blood pressure will be measured automatically 2 times in a row every 2
           hours. At 8 AM the following morning the study ends. The subjects will then stand at the
           bedside as motionless as possible for 30 minutes for blood pressure and heart rate
           determination.

           Urine will be collected for 24 hours for determination of volume and sodium, potassium
           and catecholamines (for some medication trials) in 12 hour segments, from 8 a.m. to 8
           p.m. and 8 p.m. to 8 a.m. to ascertain how the medications affect urine production.

           For medication trials affecting renal Na and/or water regulation (e.g. desmopressin,
           carbidopa), blood samples will be collected (5 mL, 1 teaspoon) at 8 PM and 8 AM for
           determination of a basic metabolic panel.

           Raising the head of the bed during the night is a non-pharmacologic measure that may
           reduce supine blood pressure, nocturnal natriuresis and improve orthostatic hypotension
           the following morning in autonomic failure patients with supine hypertension. However,
           it is not known if tilting the bed with the head up is better than raising only the head
           of the bed. To compare the effect of these two ways of raising the head of the bed on
           nighttime blood pressure and nocturnal natriuresis, some patients will undergo two
           additional tests. On two separate nights (either consecutive or not), patients will
           receive the placebo and will be assigned by simple randomization to lie down in one of
           two different bed positions:

             1. The head of the bed elevated 10 degrees (~ 7 inches); or

             2. The whole bed tilted head-up 5 degrees in reverse trendelenburg (head of the bed
                elevated ~7 inches).

           Blood pressure, orthostatic tolerance at 8 AM and urine collections will be performed as
           described above.

        2. Blood Pressure Lowering Effect of Local Heat Stress in Supine Hypertension:

           Heat stress due to high environmental temperatures lowers blood pressure in autonomic
           failure patients. The mechanisms underlying this phenomenon are not fully understood but
           it could be associated with 2 factors: First, heart stress is more likely to increase
           core temperature in this patient population because heat dissipation is impaired due to
           inability to sweat. Second, autonomic failure patients lack the compensatory sympathetic
           splanchnic vasoconstriction and tachycardia that normally maintain blood pressure in
           response to heat stress in healthy subjects. We hypothesize, therefore, that even
           moderate levels of local heat stress will lower blood pressure in patients with
           autonomic failure and supine hypertension. We propose a pilot study to evaluate the
           effect of local (abdominal) heat stress on blood pressure in autonomic failure patients,
           something that has not been previously done, and to assess its potential use in the
           treatment of supine hypertension

           This pilot study is optional and will be conducted in patients already enrolled in the
           "Evaluation and Treatment of Autonomic Failure" and the medication trial part of this
           protocol. Subjects will be studied in the supine position on two study days (with and
           without heat stress). Each study day will last ~3 hours. Core body and skin temperature
           will be monitored throughout the study using an ingestible telemetry pill and dermal
           patches. Blood pressure and heart rate will be measured intermittently with an automated
           blood pressure sphygmomanometer wrapped around an upper arm. Segmental body fluid shifts
           will be estimated using bioelectrical Impedance and hemodynamic parameters using body
           impedance and the rebreathing test (Innocor). After obtaining normothermic baseline
           measurements, we apply passive heat-stress with a commercial heating pad that covers all
           the abdomen and part of the torso to provide local heating at ~44ºC continuously for 2
           hr. Outcome measurements are obtained at 1 and 2 hours after passive heat-stress, or
           when the CBT increases ~1ºC above baseline, whichever occurs first. For the control
           (non-heating) study day, the heating pad will be applied on patients but we will not
           turn it on, and data collection will be performed at the one-hour intervals for 2 hours,
           to provide a time control.

        3. Circadian Hemodynamic Changes in Autonomic Failure Patients with Supine Hypertension:

      This study is optional and will be conducted in patients already enrolled in the "Evaluation
      and Treatment of Autonomic Failure" and the medication trial part of this protocol. A
      separate consent form (addendum) will be provided. In the present study, we propose the
      following:

        1. Monitor BP and HR in patients with AF and supine hypertension during a 24-hour period,
           which includes fixed periods of supine rest during the day, with strict control of
           physical activities, meals, water ingestion and other confounding factors. This will
           allow us to learn more about the intrinsic circadian variation of BP in our patients
           without the influence of "external factors".

        2. Characterize the hemodynamic changes underlying the dipping phenomenon and the morning
           BP surge, and

        3. Assess changes in plasma volume (measured by changes in hematocrit), calculated plasma
           osmolality and hormones that regulate blood pressure and blood volume, in order to learn
           more about the mechanisms responsible for the dipping phenomenon and morning BP surge in
           autonomic failure patients with supine hypertension.

      These parameters will be compared with the circadian rhythm of body temperature, a marker of
      the central circadian rhythm, to determine whether these diurnal changes are synchronized to
      the circadian pacemaker.

      The duration of the study day will be 24 hours and can start any time during the day.
      Typically, the study will start ~ 8AM. Therapeutic trials for orthostatic hypotension and/or
      supine hypertension as well as other study procedures related to the above mentioned
      protocols may be performed while participating in this study. If an overnight medication
      trial is performed during the study, patients may be offered to participate in a second study
      day without any medication.
    

Intervention name(s): Clonidine; Nitroglycerin transdermal; Dipyridamole/ Aspirin (Aggrenox); Desmopressin (DDAVP); Sildenafil; Nifedipine; Hydralazine; Hydrochlorothiazide; Placebo; Bosentan; Diltiazem; Eplerenone; guanfacine; L-arginine; captopril; carbidopa; losartan; metoprolol tartrate; nebivolol hydrochloride; prazosin hydrochloride; tamsulosin hydrochloride; Head-up tilt.; aliskiren; Local heat stress
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Dietary Supplement; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Other; Drug; Other
Intervention description(s): 0.1-0.2mg po. Single dose.; 0.05-0.2 mg patch. 1 application. Alone or in combination with DDAVP.; dipyridamole 200 mg and aspirin 25 mg po. Single dose.; 0.2 - 0.6mg po. Single dose. Alone or in combination with nitroglycerin transdermal or nifedipine; 25- 100 mg po. Single dose.; 10-30 mg po. Single dose.; 10-50 mg po. Single dose; 12.5-100 mg po. Single dose.; Po or patch. Single dose.; 62.5 -125 mg po. Single dose.; 30-60 mg po. Single dose.; 50-100 mg po. Single dose.; 1-3 mg po. Single dose.; 6-17 g po. Single dose; 25-50 mg PO. Single dose.; 25-200 mg PO. Single dose.; 25-200 mg PO. Single dose.; 25-100 mg PO. Single dose.; 2.5-40 mg PO. Single dose.; 0.5-1 mg PO. Single dose.; 0.4-0.8 mg PO. Single dose.; Head of the bed elevated 10 degrees (7 inch) or whole bed tilted head-up 5 degrees in reverse trendelenburg (head of the bed elevated 7 inches); aliskiren (Tekturna) 150-300mg po single dose; Passive heat-stress using a commercial heating pad applied over the abdomen and part of the torso
Other intervention name(s): Catapres; Nitro-Dur; Aggrenox; DDAVP; Viagra; Adalat; Microzide; Tracleer; Cardizem; Inspra; Tenex; capoten; Lodosyn; cozaar; lopressor; Bystolic; Minipress; Flomax; HUT; Tekturna; heating pad
Intervention MeSH terms: Aspirin; Losartan; Metoprolol; Hydrochlorothiazide; Clonidine; Eplerenone; Nebivolol; Bosentan; Diltiazem; Guanfacine; Prazosin; Captopril; Hydralazine; Nifedipine; Deamino Arginine Vasopressin; Sildenafil Citrate; Nitroglycerin; Dipyridamole; Carbidopa; Aspirin, Dipyridamole Drug Combination; Tamsulosin
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Participant)
Primary purpose: Treatment
Keywords: Supine Hypertension; Hypertension; Treatment; Autonomic failure; Pure autonomic failure; Multiple System Atrophy; Shy-Drager Syndrome