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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.
Hypertension
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Drug: BQ123
Drug: Trimethaphan
Drug: 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
Dietary Supplement: L-arginine
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Phase I
Phase II
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U.S. FDA Resources
| Study Type: |
Interventional |
| Study Design: |
Treatment, Randomized, Single Blind (Subject), Placebo Control, Crossover Assignment, Efficacy Study |
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| Official Title: |
Pathophysiology and Treatment of Supine Hypertension |
Primary Outcome Measures:
- Decrease in supine systolic blood pressure [ Time Frame: 12 hours ] [ Designated as safety issue: No ]
Secondary Outcome Measures:
- Decrease in pressure natriuresis [ Time Frame: 12 hours ] [ Designated as safety issue: No ]
| Estimated Enrollment: |
160 |
| Study Start Date: |
June 2001 |
| Estimated Study Completion Date: |
April 2008 |
| Estimated Primary Completion Date: |
April 2008 (Final data collection date for primary outcome measure) |
| 1: Experimental |
Drug: BQ123
10-3000 nmol min, IV infusion at rate of 1 ml min-1 for 15 minutes . Single dose. Drug: Trimethaphan
The IV infusion will be initiated at 0.5 or 1 mg/min and increased by 1.0 mg/minute in 6-minute intervals to one of the following end points: presyncopal symptoms, no further decrease in blood pressure with increased infusion rates, or an infusion rate of 12 mg/min Drug: Clonidine
0.1-0.2mg po. Single dose. Drug: Nitroglycerin transdermal
0.05-0.2 mg patch. 1 application. Alone or in combination with DDAVP. Drug: Dipyridamole/ Aspirin (Aggrenox)
dipyridamole 200 mg and aspirin 25 mg po. Single dose. Drug: Desmopressin (DDAVP)
0.2 - 0.6mg po. Single dose. Drug: Sildenafil
25- 100 mg po. Single dose. Drug: Nifedipine
10-30 mg po. Single dose. Drug: Hydralazine
10-50 mg po. Single dose Drug: Hydrochlorothiazide
12.5-100 mg po. Single dose. Drug: Bosentan
62.5 -125 mg po. Single dose. Drug: Diltiazem
30-60 mg po. Single dose. Drug: Eplerenone
50-100 mg po. Single dose. Drug: guanfacine
1-3 mg po. Single dose. Dietary Supplement: L-arginine
6-17 g po. Single dose |
| 2: Placebo Comparator |
Drug: Placebo
Po or patch. Single dose. |
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| Ages Eligible for Study: |
18 Years to 80 Years |
| Genders Eligible for Study: |
Both |
| Accepts Healthy Volunteers: |
No |
Inclusion Criteria:
- Patients with autonomic failure and with supine hypertension from all races
Exclusion Criteria:
- 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00223717
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| Vanderbilt University |
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| Nashville, Tennessee, United States, 37232 |
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| Contact: Bonnie Black, RN adcresearch@vanderbilt.edu |
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| Principal Investigator: Italo Biaggioni, MD |
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| Sub-Investigator: David Robertson, MD |
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| Sub-Investigator: Satish Raj, MD |
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| Sub-Investigator: Alfredo Gamboa, MD |
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| Sub-Investigator: Cyndya Shibao, MD |
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| Sub-Investigator: Andre Diedrich, MD |
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| Sub-Investigator: Luis E Okamoto, MD |
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| Principal Investigator: |
Italo Biaggioni, MD |
Vanderbilt University |
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| Vanderbilt University |
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| Nashville, Tennessee, United States, 37232 |
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| Contact: Bonnie Black, RN adcresearch@vanderbilt.edu |
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| Principal Investigator: Italo Biaggioni, MD |
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| Sub-Investigator: David Robertson, MD |
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| Sub-Investigator: Satish Raj, MD |
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| Sub-Investigator: Alfredo Gamboa, MD |
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| Sub-Investigator: Cyndya Shibao, MD |
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| Sub-Investigator: Andre Diedrich, MD |
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| Sub-Investigator: Luis E Okamoto, MD |
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| Principal Investigator: |
Italo Biaggioni, MD |
Vanderbilt University |
Publications of Results:
Shibao C, Gamboa A, Diedrich A, Biaggioni I. Management of hypertension in the setting of autonomic dysfunction. Curr Treat Options Cardiovasc Med. 2006 Apr;8(2):105-9.
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Shibao C, Gamboa A, Abraham R, Raj SR, Diedrich A, Black B, Robertson D, Biaggioni I. Clonidine for the treatment of supine hypertension and pressure natriuresis in autonomic failure. Hypertension. 2006 Mar;47(3):522-6. Epub 2006 Jan 3.
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Shibao C, Gamboa A, Diedrich A, Biaggioni I. Management of hypertension in the setting of autonomic failure: a pathophysiological approach. Hypertension. 2005 Apr;45(4):469-76. Epub 2005 Feb 28.
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Diedrich A, Jordan J, Tank J, Shannon JR, Robertson R, Luft FC, Robertson D, Biaggioni I. The sympathetic nervous system in hypertension: assessment by blood pressure variability and ganglionic blockade. J Hypertens. 2003 Sep;21(9):1677-86. Erratum in: J Hypertens. 2003 Nov;21(11):2204-5.
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Biaggioni I, Robertson RM. Hypertension in orthostatic hypotension and autonomic dysfunction. Cardiol Clin. 2002 May;20(2):291-301, vii. Review.
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Jordan J, Biaggioni I. Diagnosis and treatment of supine hypertension in autonomic failure patients with orthostatic hypotension. J Clin Hypertens (Greenwich). 2002 Mar-Apr;4(2):139-45.
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Shannon JR, Jordan J, Diedrich A, Pohar B, Black BK, Robertson D, Biaggioni I. Sympathetically mediated hypertension in autonomic failure. Circulation. 2000 Jun 13;101(23):2710-5.
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Jordan J, Shannon JR, Pohar B, Paranjape SY, Robertson D, Robertson RM, Biaggioni I. Contrasting effects of vasodilators on blood pressure and sodium balance in the hypertension of autonomic failure. J Am Soc Nephrol. 1999 Jan;10(1):35-42.
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Shannon J, Jordan J, Costa F, Robertson RM, Biaggioni I. The hypertension of autonomic failure and its treatment. Hypertension. 1997 Nov;30(5):1062-7.
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| Responsible Party: |
Vanderbilt University ( Italo Biaggioni ) |
| Study ID Numbers: |
010189 |
| First Received: |
September 14, 2005 |
| Last Updated: |
February 7, 2008 |
| ClinicalTrials.gov Identifier: |
NCT00223717 |
| Health Authority: |
United States: Food and Drug Administration |
Keywords provided by Vanderbilt University:
| Supine Hypertension |
| Hypertension |
| Treatment |
| Autonomic failure | |
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| Pure autonomic failure |
| Multiple System Atrophy |
| Shy-Drager Syndrome | | Study placed in the following topic categories:
| Multiple system atrophy |
| Hypotension, Orthostatic |
| Hydralazine |
| Nifedipine |
| Bosentan |
| Trimethaphan |
| Arginine Vasopressin |
| Nitroglycerin |
| Trimethaphan camsylate |
| Aspirin | |
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| Guanfacine |
| Vasopressins |
| Cyclo(Trp-Asp-Pro-Val-Leu) |
| Shy-Drager Syndrome |
| Multiple system atrophy (MSA) with orthostatic hypotension |
| Clonidine |
| Vascular Diseases |
| Sildenafil |
| Hydrochlorothiazide |
| Eplerenone | | Additional relevant MeSH terms:
| Anti-Inflammatory Agents |
| Neurotransmitter Agents |
| Vasodilator Agents |
| Adrenergic Agents |
| Cholinergic Antagonists |
| Molecular Mechanisms of Pharmacological Action |
| Coagulants |
| Hormone Antagonists |
| Nicotinic Antagonists |
| Sodium Chloride Symporter Inhibitors | |
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| Diuretics |
| Physiological Effects of Drugs |
| Hematologic Agents |
| Hormones, Hormone Substitutes, and Hormone Antagonists |
| Calcium Channel Blockers |
| Fibrinolytic Agents |
| Reproductive Control Agents |
| Cholinergic Agents |
| Adrenergic Agonists |
| Membrane Transport Modulators | |
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