Orthostatic Intolerance
Conditions
Brief summary
More than 78 million adults in the U.S. are obese. Bariatric surgery is the only modality that results in sustained weight loss along with reversal of diabetes mellitus, and a decrease in cardiovascular events. Obesity is associated with increased sympathetic nervous system (SNS) activity that contributes to blood pressure regulation; sympathetic vasoconstrictor activity is maximally activated upon standing and is fundamental for the maintenance of orthostatic tolerance. After bariatric surgery, there is a significant and sustained reduction in SNS activity at three and six months after the procedure, which is related to weight loss. Recently, multiple retrospective studies have reported an orthostatic intolerance (OI) syndrome after bariatric surgery characterized by chronic pre-syncopal symptoms, syncope and orthostatic hypotension. In the Vanderbilt University Medical Center bariatric surgical center, 741 post-bariatric surgery patients reported OI symptoms, 98 (13.2%) of these patients, progressed to chronic OI and in17 cases, the OI was so disabling that patients initiated treatment with pressor agents. More than 50% of OI cases in the cohort developed the condition during a weight-stable period. Hence, investigators propose the novel hypothesis that after bariatric surgery, the persistent reduction in SNS activity contributes to impaired orthostatic tolerance, which is independent of weight loss.
Detailed description
Considering that SNS vasoconstrictor activity depends on synaptic norepinephrine concentrations, investigators propose a proof-of-concept study to test the hypothesis that the norepinephrine transporter (NET) inhibitor, atomoxetine, which increases synaptic norepinephrine concentrations, will improve post-bariatric OI. Understanding the changes in SNS activity and its contribution to orthostatic tolerance after bariatric surgery is of utmost importance to unravel the mechanisms of a novel and unrecognized syndrome, post-bariatric OI. In 2014, nearly 200,000 individuals in the US underwent bariatric surgery, and the number of bariatric surgery procedures is expected to increase by 22% each year. It is projected, therefore, an increase in the incidence of post-bariatric OI. Participants with Roux-en-Y gastric bypass (RYGB) and Vertical sleeve gastrectomy (VSG) will be studied. OI is a chronic and disabling condition; treatment is challenging because current therapies have debatable efficacy. The proposed application will not only provide central knowledge on the pathophysiology of this new syndrome but also will fill an unmet therapeutic need by repurposing NET inhibitors for the treatment of OI.
Interventions
DRUGAtomoxetine
atomoxetine 0.5 mg/kg/day.
DRUGPlacebo
sugar pill
Sponsors
Vanderbilt University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Obese subjects that will undergo bariatric surgery or medical weight loss. * Age 18-60 years * BMI \>35 kg/m2 * Weight \< 400 lbs
Exclusion criteria
* Diabetes type 1 * Use of an alpha blockers, clonidine, beta-blockers. * Pregnancy or breast-feeding. Women of childbearing potential will be required to have undergone tubal ligation or to be using an oral contraceptive or barrier methods of birth control. * The use of any strong CYP2D6 inhibitor (e.g., fluoxetine, paroxetine, quinidine, tipranavir). * Use of selective NET inhibitors. * Use of monoamine oxidase inhibitors. * Cardiovascular disease such as myocardial infarction within six months prior to the study, presence of angina pectoris, significant arrhythmia, congestive heart failure (left ventricular hypertrophy acceptable), deep vein thrombosis, pulmonary embolism, second or third degree heart block, mitral valve stenosis, aortic stenosis or hypertrophic cardiomyopathy * History of serious neurologic disease such as cerebral hemorrhage, stroke, or transient ischemic attack * Hematocrit \< 34% * Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult * Mental conditions rendering a subject unable to understand the nature, scope and possible consequences of the study * Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, unlikelihood of completing the study, and investigator discretion
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Blood Pressure Measurements During Orthostatic Challenge With a Head up Tilt (HUT at 60 Degrees) Before and After Bariatric Surgery: at 2 Timepoints: After 10% Weight Loss and After 3 Months | 0- 3 months | To assess the hemodynamic (Blood Pressure) changes during an orthostatic challenge with a head up tilt (HUT at 60 degrees) before and after bariatric surgery, at two time-points: after 10% weight loss (10% WL) and after 3 months, in morbidly obese patients. Our primary endpoint (orthostatic tolerance, OT) is defined as the time between the start of the 60 degree HUT until pre-syncope Orthostatic hemodynamics were analyzed as the area under the curve (AUC) after baseline-correction during HUT. |
| Cardiac Output During Orthostatic Challenge With a Head up Tilt (HUT at 60 Degrees) Before and After Bariatric Surgery: at 2 Timepoints: After 10% Weight Loss and After 3 Months | 0- 3 months | To assess the hemodynamic (cardiac output \[CO\]) and cardiovascular autonomic changes during an orthostatic challenge with a head up tilt (HUT at 60 degrees) before and after bariatric surgery, at two time-points: after 10% weight loss (10% WL) and after 3 months, in morbidly obese patients. Our primary endpoint (orthostatic tolerance, OT) is defined as the time between the start of the 60 degree HUT until pre-syncope Orthostatic hemodynamics were analyzed as the area under the curve (AUC) after baseline-correction during HUT. |
| Stroke Volume Measurements During Orthostatic Challenge With a Head up Tilt (HUT at 60 Degrees) Before and After Bariatric Surgery: at 2 Timepoints: After 10% Weight Loss and After 3 Months | 0- 3 months | To assess the hemodynamic (stroke volume \[SV\]) and cardiovascular autonomic changes during an orthostatic challenge with a head up tilt (HUT at 60 degrees) before and after bariatric surgery, at two time-points: after 10% weight loss (10% WL) and after 3 months, in morbidly obese patients. Our primary endpoint (orthostatic tolerance, OT) is defined as the time between the start of the 60 degree HUT until pre-syncope Orthostatic hemodynamics were analyzed as the area under the curve (AUC) after baseline-correction during HUT. |
| Calculated Total Peripheral Resistance During Orthostatic Challenge With a Head up Tilt (HUT at 60 Degrees) Before and After Bariatric Surgery: at 2 Timepoints: After 10% Weight Loss and After 3 Months | 0- 3 months | To assess the hemodynamic ( total peripheral resistance \[TPR\]) and cardiovascular autonomic changes during an orthostatic challenge with a head up tilt (HUT at 60 degrees) before and after bariatric surgery, at two time-points: after 10% weight loss (10% WL) and after 3 months, in morbidly obese patients. Our primary endpoint (orthostatic tolerance, OT) is defined as the time between the start of the 60 degree HUT until pre-syncope |
Countries
United States
Participant flow
Recruitment details
A total of 10 morbid obese patients, scheduled for bariatric surgery, were enrolled in this study. 10 patients completed all 4 visits, which include a pre-surgical visit, a visit after 10% weight loss, and a visit after 3-months post-surgery. The demographic characteristics of these patients are shown in the table below. We could not enroll any patients, in Medical Weight loss category
Participants by arm
| Arm | Count |
|---|---|
| Baseline Characteristics Before Participants Underwent Bariatric Surgery for Weight Loss Participants underwent Bariatic surgery Roux-en-Y gastric bypass (RYGB) / Vertical sleeve gastrectomy (VSG) for weight loss . | 10 |
| Baseline of Participants Before They Underwent Non Surgical (Medical) Weight Loss Program Participants who underwent standard medical weight loss from the Vanderbilt Center for Weight Loss (VWL) | 0 |
| Total | 10 |
Baseline characteristics
| Characteristic | Baseline Characteristics Before Participants Underwent Bariatric Surgery for Weight Loss | Total | Baseline of Participants Before They Underwent Non Surgical (Medical) Weight Loss Program |
|---|---|---|---|
| Age, Continuous Age | 42 years STANDARD_DEVIATION 9.3 | 42 years STANDARD_DEVIATION 9.3 | — |
| Bariatric surgery type Roux-en-Y Gastric By-Pass procedures | 7 Participants | 7 Participants | — |
| Bariatric surgery type Vertical Sleeve Gastric By-Pass | 3 Participants | 3 Participants | — |
| BMI (Body Mass Index) | 51 kg/m2 STANDARD_DEVIATION 8.27 | 51 kg/m2 STANDARD_DEVIATION 8.27 | — |
| Diastolic Blood Pressure | 85 mm of Hg STANDARD_DEVIATION 4.69 | 85 mm of Hg STANDARD_DEVIATION 4.69 | — |
| Fat Mass | 73 Kg STANDARD_DEVIATION 12.18 | 73 Kg STANDARD_DEVIATION 12.18 | — |
| Heart rate | 93 beats per minute STANDARD_DEVIATION 7.93 | 93 beats per minute STANDARD_DEVIATION 7.93 | — |
| Height | 166 cm STANDARD_DEVIATION 8.6 | 166 cm STANDARD_DEVIATION 8.6 | — |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Red Blood Cell volume | 1973 ml STANDARD_DEVIATION 136.5 | 1973 ml STANDARD_DEVIATION 136.5 | — |
| Sex/Gender, Customized Gender Female | 9 Participants | 9 Participants | 0 Participants |
| Sex/Gender, Customized Gender Male | 1 Participants | 1 Participants | 0 Participants |
| Systolic Blood Pressure | 128 mm of Hg STANDARD_DEVIATION 3.69 | 128 mm of Hg STANDARD_DEVIATION 3.69 | — |
| Total Blood Volume | 316.1 Litres STANDARD_DEVIATION 6 | 316.1 Litres STANDARD_DEVIATION 6 | — |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 0 |
| other Total, other adverse events | 0 / 10 | 0 / 0 |
| serious Total, serious adverse events | 0 / 10 | 0 / 0 |
Outcome results
Primary
Blood Pressure Measurements During Orthostatic Challenge With a Head up Tilt (HUT at 60 Degrees) Before and After Bariatric Surgery: at 2 Timepoints: After 10% Weight Loss and After 3 Months
To assess the hemodynamic (Blood Pressure) changes during an orthostatic challenge with a head up tilt (HUT at 60 degrees) before and after bariatric surgery, at two time-points: after 10% weight loss (10% WL) and after 3 months, in morbidly obese patients. Our primary endpoint (orthostatic tolerance, OT) is defined as the time between the start of the 60 degree HUT until pre-syncope Orthostatic hemodynamics were analyzed as the area under the curve (AUC) after baseline-correction during HUT.
Time frame: 0- 3 months
Population: Orthostatic hemodynamics (SBP, DBP, HR) were analyzed as the area under the curve (AUC) after baseline-correction during HUT
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pre- Bariatric Participants | Blood Pressure Measurements During Orthostatic Challenge With a Head up Tilt (HUT at 60 Degrees) Before and After Bariatric Surgery: at 2 Timepoints: After 10% Weight Loss and After 3 Months | Systolic Blood pressure: analyze as Area under the curve (AUC) after baseline-correction during HUT. | 113 mmHg*hr | Standard Deviation 72.41 |
| Pre- Bariatric Participants | Blood Pressure Measurements During Orthostatic Challenge With a Head up Tilt (HUT at 60 Degrees) Before and After Bariatric Surgery: at 2 Timepoints: After 10% Weight Loss and After 3 Months | Diastolic Blood pressure:analyze as Area under the curve (AUC) after baseline-correction during HUT | 303.7 mmHg*hr | Standard Deviation 93.74 |
| Participants After 10% of Weight Loss | Blood Pressure Measurements During Orthostatic Challenge With a Head up Tilt (HUT at 60 Degrees) Before and After Bariatric Surgery: at 2 Timepoints: After 10% Weight Loss and After 3 Months | Systolic Blood pressure: analyze as Area under the curve (AUC) after baseline-correction during HUT. | 56.02 mmHg*hr | Standard Deviation 30.68 |
| Participants After 10% of Weight Loss | Blood Pressure Measurements During Orthostatic Challenge With a Head up Tilt (HUT at 60 Degrees) Before and After Bariatric Surgery: at 2 Timepoints: After 10% Weight Loss and After 3 Months | Diastolic Blood pressure:analyze as Area under the curve (AUC) after baseline-correction during HUT | 60.98 mmHg*hr | Standard Deviation 29.54 |
| Participants After 3 Months of the Surgery | Blood Pressure Measurements During Orthostatic Challenge With a Head up Tilt (HUT at 60 Degrees) Before and After Bariatric Surgery: at 2 Timepoints: After 10% Weight Loss and After 3 Months | Systolic Blood pressure: analyze as Area under the curve (AUC) after baseline-correction during HUT. | 39.4 mmHg*hr | Standard Deviation 28.53 |
| Participants After 3 Months of the Surgery | Blood Pressure Measurements During Orthostatic Challenge With a Head up Tilt (HUT at 60 Degrees) Before and After Bariatric Surgery: at 2 Timepoints: After 10% Weight Loss and After 3 Months | Diastolic Blood pressure:analyze as Area under the curve (AUC) after baseline-correction during HUT | 39.44 mmHg*hr | Standard Deviation 28.53 |
Primary
Calculated Total Peripheral Resistance During Orthostatic Challenge With a Head up Tilt (HUT at 60 Degrees) Before and After Bariatric Surgery: at 2 Timepoints: After 10% Weight Loss and After 3 Months
To assess the hemodynamic ( total peripheral resistance \[TPR\]) and cardiovascular autonomic changes during an orthostatic challenge with a head up tilt (HUT at 60 degrees) before and after bariatric surgery, at two time-points: after 10% weight loss (10% WL) and after 3 months, in morbidly obese patients. Our primary endpoint (orthostatic tolerance, OT) is defined as the time between the start of the 60 degree HUT until pre-syncope
Time frame: 0- 3 months
Population: Orthostatic hemodynamics (SBP, DBP, HR) were analyzed as the area under the curve (AUC) after baseline-correction during HUT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pre- Bariatric Participants | Calculated Total Peripheral Resistance During Orthostatic Challenge With a Head up Tilt (HUT at 60 Degrees) Before and After Bariatric Surgery: at 2 Timepoints: After 10% Weight Loss and After 3 Months | 9.162 mmHg*L/min | Standard Deviation 5.995 |
| Participants After 10% of Weight Loss | Calculated Total Peripheral Resistance During Orthostatic Challenge With a Head up Tilt (HUT at 60 Degrees) Before and After Bariatric Surgery: at 2 Timepoints: After 10% Weight Loss and After 3 Months | 7.239 mmHg*L/min | Standard Deviation 6.245 |
| Participants After 3 Months of the Surgery | Calculated Total Peripheral Resistance During Orthostatic Challenge With a Head up Tilt (HUT at 60 Degrees) Before and After Bariatric Surgery: at 2 Timepoints: After 10% Weight Loss and After 3 Months | 9.167 mmHg*L/min | Standard Deviation 4.458 |
Primary
Cardiac Output During Orthostatic Challenge With a Head up Tilt (HUT at 60 Degrees) Before and After Bariatric Surgery: at 2 Timepoints: After 10% Weight Loss and After 3 Months
To assess the hemodynamic (cardiac output \[CO\]) and cardiovascular autonomic changes during an orthostatic challenge with a head up tilt (HUT at 60 degrees) before and after bariatric surgery, at two time-points: after 10% weight loss (10% WL) and after 3 months, in morbidly obese patients. Our primary endpoint (orthostatic tolerance, OT) is defined as the time between the start of the 60 degree HUT until pre-syncope Orthostatic hemodynamics were analyzed as the area under the curve (AUC) after baseline-correction during HUT.
Time frame: 0- 3 months
Population: Orthostatic hemodynamics (Cardiac Output ) were analyzed as the area under the curve (AUC) after baseline-correction during HUT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pre- Bariatric Participants | Cardiac Output During Orthostatic Challenge With a Head up Tilt (HUT at 60 Degrees) Before and After Bariatric Surgery: at 2 Timepoints: After 10% Weight Loss and After 3 Months | 9.124 L/min | Standard Deviation 8.066 |
| Participants After 10% of Weight Loss | Cardiac Output During Orthostatic Challenge With a Head up Tilt (HUT at 60 Degrees) Before and After Bariatric Surgery: at 2 Timepoints: After 10% Weight Loss and After 3 Months | 3.562 L/min | Standard Deviation 2.522 |
| Participants After 3 Months of the Surgery | Cardiac Output During Orthostatic Challenge With a Head up Tilt (HUT at 60 Degrees) Before and After Bariatric Surgery: at 2 Timepoints: After 10% Weight Loss and After 3 Months | 4.916 L/min | Standard Deviation 3.652 |
Primary
Stroke Volume Measurements During Orthostatic Challenge With a Head up Tilt (HUT at 60 Degrees) Before and After Bariatric Surgery: at 2 Timepoints: After 10% Weight Loss and After 3 Months
To assess the hemodynamic (stroke volume \[SV\]) and cardiovascular autonomic changes during an orthostatic challenge with a head up tilt (HUT at 60 degrees) before and after bariatric surgery, at two time-points: after 10% weight loss (10% WL) and after 3 months, in morbidly obese patients. Our primary endpoint (orthostatic tolerance, OT) is defined as the time between the start of the 60 degree HUT until pre-syncope Orthostatic hemodynamics were analyzed as the area under the curve (AUC) after baseline-correction during HUT.
Time frame: 0- 3 months
Population: Orthostatic hemodynamics (Stroke volume) were analyzed as the area under the curve (AUC) after baseline-correction during HUT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pre- Bariatric Participants | Stroke Volume Measurements During Orthostatic Challenge With a Head up Tilt (HUT at 60 Degrees) Before and After Bariatric Surgery: at 2 Timepoints: After 10% Weight Loss and After 3 Months | 116.2 mL | Standard Deviation 56.5 |
| Participants After 10% of Weight Loss | Stroke Volume Measurements During Orthostatic Challenge With a Head up Tilt (HUT at 60 Degrees) Before and After Bariatric Surgery: at 2 Timepoints: After 10% Weight Loss and After 3 Months | 148 mL | Standard Deviation 78.61 |
| Participants After 3 Months of the Surgery | Stroke Volume Measurements During Orthostatic Challenge With a Head up Tilt (HUT at 60 Degrees) Before and After Bariatric Surgery: at 2 Timepoints: After 10% Weight Loss and After 3 Months | 105.6 mL | Standard Deviation 60.04 |