Treatment of Supine Hypertension in Autonomic Failure

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.

Conditions

• Hypertension

Interventions

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. Alone or in combination with nitroglycerin transdermal or nifedipine

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

Placebo

Po or patch. 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

DRUG

captopril

25-50 mg PO. Single dose.

DRUG

carbidopa

25-200 mg PO. Single dose.

DRUG

losartan

25-200 mg PO. Single dose.

DRUG

metoprolol tartrate

25-100 mg PO. Single dose.

DRUG

nebivolol hydrochloride

2.5-40 mg PO. Single dose.

DRUG

prazosin hydrochloride

0.5-1 mg PO. Single dose.

DRUG

tamsulosin hydrochloride

0.4-0.8 mg PO. Single dose.

OTHER

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)

DRUG

aliskiren

aliskiren (Tekturna) 150-300mg po single dose

OTHER

Local heat stress

Passive heat-stress using a commercial heating pad applied over the abdomen and part of the torso

Sponsors & Collaborators

• Vanderbilt University

  lead OTHER

Principal Investigators

• Italo Biaggioni, MD · Vanderbilt University

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

SINGLE

Model

CROSSOVER

Eligibility

Min Age

18 Years

Max Age

80 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2001-01-31

Primary Completion

2017-01-31

Completion

2017-01-31

Countries

• United States

Study Locations