Treatment of Supine Hypertension in Autonomic Failure
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||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 Drug: captopril Drug: carbidopa Drug: losartan Drug: metoprolol tartrate Drug: nebivolol hydrochloride Drug: prazosin hydrochloride Drug: tamsulosin hydrochloride Other: Head-up tilt. Drug: aliskiren Other: Local heat stress||Phase 1|
|Study Design:||Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
|Official Title:||The Pathophysiology and Treatment of Supine Hypertension in Patients With Autonomic Failure|
- Decrease in supine systolic blood pressure [ Time Frame: 12 hours ]
- Decrease in pressure natriuresis [ Time Frame: 12 hours ]
|Study Start Date:||June 2001|
|Study Completion Date:||January 2017|
|Primary Completion Date:||January 2017 (Final data collection date for primary outcome measure)|
Experimental: 1: Active drug or intervention
Clonidine, Nitroglycerin transdermal, Dipyridamole/ Aspirin (Aggrenox), Desmopressin (DDAVP), Sildenafil, Nifedipine, Hydralazine, Hydrochlorothiazide, Bosentan, Diltiazem, Eplerenone, guanfacine, L-arginine, captopril, carbidopa, losartan, metoprolol tartrate, nebivolol hydrochloride, prazosin hydrochloride, tamsulosin hydrochloride, Head-up tilt, aliskiren, local heat stress
0.1-0.2mg po. Single dose.
Other Name: CatapresDrug: Nitroglycerin transdermal
0.05-0.2 mg patch. 1 application. Alone or in combination with DDAVP.
Other Name: Nitro-DurDrug: Dipyridamole/ Aspirin (Aggrenox)
dipyridamole 200 mg and aspirin 25 mg po. Single dose.
Other Name: AggrenoxDrug: Desmopressin (DDAVP)
0.2 - 0.6mg po. Single dose. Alone or in combination with nitroglycerin transdermal or nifedipine
Other Name: DDAVPDrug: Sildenafil
25- 100 mg po. Single dose.
Other Name: ViagraDrug: Nifedipine
10-30 mg po. Single dose.
Other Name: AdalatDrug: Hydralazine
10-50 mg po. Single doseDrug: Hydrochlorothiazide
12.5-100 mg po. Single dose.
Other Name: MicrozideDrug: Bosentan
62.5 -125 mg po. Single dose.
Other Name: TracleerDrug: Diltiazem
30-60 mg po. Single dose.
Other Name: CardizemDrug: Eplerenone
50-100 mg po. Single dose.
Other Name: InspraDrug: guanfacine
1-3 mg po. Single dose.
Other Name: TenexDietary Supplement: L-arginine
6-17 g po. Single doseDrug: captopril
25-50 mg PO. Single dose.
Other Name: capotenDrug: carbidopa
25-200 mg PO. Single dose.
Other Name: LodosynDrug: losartan
25-200 mg PO. Single dose.
Other Name: cozaarDrug: metoprolol tartrate
25-100 mg PO. Single dose.
Other Name: lopressorDrug: nebivolol hydrochloride
2.5-40 mg PO. Single dose.
Other Name: BystolicDrug: prazosin hydrochloride
0.5-1 mg PO. Single dose.
Other Name: MinipressDrug: tamsulosin hydrochloride
0.4-0.8 mg PO. Single dose.
Other Name: FlomaxOther: Head-up tilt.
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)
Other Name: HUTDrug: aliskiren
aliskiren (Tekturna) 150-300mg po single dose
Other Name: TekturnaOther: Local heat stress
Passive heat-stress using a commercial heating pad applied over the abdomen and part of the torso
Other Name: heating pad
Placebo Comparator: 2: Placebo
placebo pill or patch
Po or patch. Single dose.
Show Detailed Description
Please refer to this study by its ClinicalTrials.gov identifier: NCT00223717
|United States, Tennessee|
|Nashville, Tennessee, United States, 37232|
|Principal Investigator:||Italo Biaggioni, MD||Vanderbilt University|