Treatment of Supine Hypertension in Autonomic Failure
Information source: Vanderbilt University
ClinicalTrials.gov processed this data on November 27, 2014
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Hypertension
Intervention: Clonidine (Drug); Nitroglycerin transdermal (Drug); Dipyridamole/ Aspirin (Aggrenox) (Drug); Desmopressin (DDAVP) (Drug); Sildenafil (Drug); Nifedipine (Drug); Hydralazine (Drug); Hydrochlorothiazide (Drug); Placebo (Drug); Bosentan (Drug); Diltiazem (Drug); Eplerenone (Drug); guanfacine (Drug); L-arginine (Dietary Supplement); captopril (Drug); carbidopa (Drug); losartan (Drug); metoprolol tartrate (Drug); nebivolol hydrochloride (Drug); prazosin hydrochloride (Drug); tamsulosin hydrochloride (Drug); Head-up tilt. (Other); aliskiren (Drug); Local heat stress (Other)
Phase: Phase 1/Phase 2
Sponsored by: Vanderbilt University
Official(s) and/or principal investigator(s):
Italo Biaggioni, MD, Principal Investigator, Affiliation: Vanderbilt University
Bonnie Black, RN, Email: email@example.com
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.
Official title: The Pathophysiology and Treatment of Supine Hypertension in Patients With Autonomic Failure
Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Single Blind (Subject), Primary Purpose: Treatment
Primary outcome: Decrease in supine systolic blood pressure
Secondary outcome: Decrease in pressure natriuresis
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
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
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.
Minimum age: 18 Years.
Maximum age: 80 Years.
- Patients with autonomic failure and with supine hypertension from all races
- All medical students
- Pregnant women
- High-risk patients (e. g. heart failure, symptomatic coronary artery disease, liver
impairment, history of stroke or myocardial infarction)
- History of serious allergies or asthma.
Locations and Contacts
Bonnie Black, RN, Email: firstname.lastname@example.org
Vanderbilt University, Nashville, Tennessee 37232, United States; Recruiting
Bonnie Black, RN, Email: email@example.com
Italo Biaggioni, MD, Principal Investigator
David Robertson, MD, Sub-Investigator
Satish Raj, MD, Sub-Investigator
Alfredo Gamboa, MD, Sub-Investigator
Cyndya Shibao, MD, Sub-Investigator
Andre Diedrich, MD, Sub-Investigator
Luis E Okamoto, MD, Sub-Investigator
Amy C Arnold, PhD, Sub-Investigator
Cindy A Dorminy, MEd, LPN, Sub-Investigator
Autonomic Dysfunction Center Website
Shibao C, Okamoto L, Biaggioni I. Pharmacotherapy of autonomic failure. Pharmacol Ther. 2012 Jun;134(3):279-86. doi: 10.1016/j.pharmthera.2011.05.009. Epub 2011 Jun 12. Review.
Starting date: June 2001
Last updated: September 24, 2014