Ignite Creation Date:
2024-05-05 @ 12:03 PM
Last Modification Date:
2024-10-26 @ 9:19 AM
Study NCT ID:
NCT00223717
Status:
COMPLETED
Last Update Posted:
2017-10-13
First Post:
2005-09-14
Brief Title:
Treatment of Supine Hypertension in Autonomic Failure
Sponsor:
Vanderbilt University
Organization:
Vanderbilt University Medical Center
Study Overview
Official Title:
The Pathophysiology and Treatment of Supine Hypertension in Patients With Autonomic Failure
Status:
COMPLETED
Status Verified Date:
2017-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 179 589 3 mmHg in 21 PAF and 175 592 3 mmHg in 21 MSA patients Plasma norepinephrine 92 15 pgmL and plasma renin activity 03 005 ngmL 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 mgmin trimethaphan decreased supine SBP by 67 - 8 and 12 - 6 mmHg in MSA and PAF patients respectively P 00001 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
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 179 589 3 mmHg in 21 PAF and 175 592 3 mmHg in 21 MSA patients Plasma norepinephrine 92 15 pgmL and plasma renin activity 03 005 ngmL 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 mgmin trimethaphan decreased supine SBP by 67 - 8 and 12 - 6 mmHg in MSA and PAF patients respectively P 00001 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 mEqday 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 800 PM They will be given a randomly chosen medication aliskiren Tekturna 150-300mg po bosentan Tracleer 625 -125 mg po captopril 25-50mg po carbidopa 25-200mg po clonidine 01-02mg po desmopressin 02 - 06mg 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 125-100 mg po L- arginine 6-17 g po losartan 25-100mg po metoprolol tartrate Lopressor 25-100 mg po nebivolol hydrochloride Bystolic 25-40 mg po nitroglycerin-transdermal 005-02 mg patch nifedipine adalat doses 10-30 mg prazosin hydrochloride 05-1 mg po sildenafil Viagra 25- 100 mg po tamsulosin hydrochloride Flomax 04-08 mg po The combination desmopressin 02 mg po DDAVP and nitroglycerin-transdermal 005-02 mg The combinations desmopressin 02 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 am to 8 pm and 8 pm to 8 am to ascertain how the medications affect urine production
For medication trials affecting renal Na andor water regulation eg 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 andor 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
Patients will be studied on the GCRC while in 150 mEqday 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 800 PM They will be given a randomly chosen medication aliskiren Tekturna 150-300mg po bosentan Tracleer 625 -125 mg po captopril 25-50mg po carbidopa 25-200mg po clonidine 01-02mg po desmopressin 02 - 06mg 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 125-100 mg po L- arginine 6-17 g po losartan 25-100mg po metoprolol tartrate Lopressor 25-100 mg po nebivolol hydrochloride Bystolic 25-40 mg po nitroglycerin-transdermal 005-02 mg patch nifedipine adalat doses 10-30 mg prazosin hydrochloride 05-1 mg po sildenafil Viagra 25- 100 mg po tamsulosin hydrochloride Flomax 04-08 mg po The combination desmopressin 02 mg po DDAVP and nitroglycerin-transdermal 005-02 mg The combinations desmopressin 02 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 am to 8 pm and 8 pm to 8 am to ascertain how the medications affect urine production
For medication trials affecting renal Na andor water regulation eg 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 andor 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None