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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Hypertension. Author manuscript; available in PMC 2017 August 1.
Published in final edited form as:
PMCID: PMC4945429



Splanchnic venous pooling is a major hemodynamic determinant of orthostatic hypotension (OH), but is not specifically targeted by pressor agents, the mainstay of treatment. We developed an automated inflatable abdominal binder that provides sustained servo-controlled venous compression (40 mmHg) and can be activated only on standing. We tested the efficacy of this device against placebo and compared it to midodrine in nineteen autonomic failure patients randomized to receive either placebo, midodrine (2.5–10 mg) or placebo combined with binder on separate days in a single-blind, crossover study. Systolic blood pressure (SBP) was measured seated and standing before and 1-hour post-medication; the binder was inflated immediately before standing. Only midodrine increased seated SBP (31±5 vs. 9±4 placebo and 7±5 binder, P=0.003); whereas orthostatic tolerance (defined as area under the curve of upright SBP [AUCSBP]) improved similarly with binder and midodrine (AUCSBP, 195±35 and 197±41 vs. 19±38 mmHg*min for placebo, P=0.003). Orthostatic symptom burden decreased with the binder (from 21.9±3.6 to 16.3±3.1, P=0.032) and midodrine (from 25.6±3.4 to 14.2±3.3, P<0.001), but not with placebo (from 19.6±3.5 to 20.1±3.3, P=0.756). We also compared the combination of midodrine and binder, with midodrine alone. The combination produced a greater increase in orthostatic tolerance (AUCSBP, 326±65 vs. 140±53 mmHg*min for midodrine alone, P=0.028, n=21), and decreased orthostatic symptoms (from 21.8±3.2 to 12.9±2.9, P<0.001). In conclusion, servo-controlled abdominal venous compression with an automated inflatable binder is as effective as midodrine, the standard of care, in the management of OH. Combining both therapies produces greater improvement in orthostatic tolerance.

Keywords: autonomic failure, orthostatic hypotension, splanchnic circulation, midodrine, abdominal binder, orthostatic tolerance

Orthostatic hypotension (OH) is a significant medical problem; it occurs in about 6% of healthy elderly in the community, 18–54% of nursing home residents and up to 60% in hospitalized elderly.1 The incidence of OH increases exponentially after age 65, and its importance is likely to increase as our population ages.2 OH is not only a cause of disability and impaired quality of life, but it is also associated with a 2.6-fold increase in the risk of falls,3 and is an independent risk factor for the development of chronic kidney disease, comparable to having coronary artery disease, smoking, hypertriglyceridemia and other risk factors that receive more attention.4 Moreover, OH is an independent risk factor for increased mortality.5

Orthostatic hypotension is particularly disabling in patients with severe impairment of autonomic pathways (neurogenic OH), who cannot engage the hemodynamic mechanisms that normally prevent the drop in blood pressure (BP) on standing. Despite its clinical importance, there are only two drugs approved for the treatment of neurogenic OH, the α-1 agonist midodrine and the norepinephrine prodrug droxidopa. The use of these drugs, however, is often limited by the development or worsening of supine hypertension, a common comorbidity in these patients. It is also unlikely that these drugs will have a beneficial effect on the comorbidities associated with orthostatic hypotension, namely renal impairment, heart failure and increased risk of overall mortality. Finally, they do not specifically target a major hemodynamic mechanism of orthostatic hypotension, which is a reduction in stroke volume and venous return due to venous pooling, particularly in the splanchnic circulation. There is a need, therefore, to develop therapeutic approaches that address these limitations.

Compression of venous capacitance beds with lower body compression garments improve venous return and can be useful in treating orthostatic hypotension,6,7 The main advantages of this approach are that immediate pressor responses could be achieved only when required (i.e., standing); and that it can be safely combined with virtually any drug therapy. Nonetheless, compliance is low because they are difficult to use at compression levels that are effective. Therefore, we developed an automated inflatable binder that can be selectively activated in the upright posture to produce a sustained compression level of 40 mmHg, a level known to produce compression of the venous splanchnic circulation. In the present study, we present proof-of-concept studies showing that servo-controlled splanchnic venous compression with this inflatable binder is as effective as midodrine, the current standard of care, in improving orthostatic tolerance and reducing orthostatic symptoms in patients with primary autonomic failure. In addition, we evaluated whether the binder combined with midodrine provided additional improvement in orthostatic tolerance and symptoms, compared to midodrine alone.



We studied a total of 23 patients with neurogenic OH and severe autonomic failure (11 with pure autonomic failure [PAF], 5 with Parkinson disease [PD+OH], 5 with probable multiple system atrophy [MSA], 1 with dementia with Lewy bodies and 1 with autonomic failure of unknown etiology) recruited from referrals to Vanderbilt University Autonomic Dysfunction Center between November 2011 and October 2014 (Figure S1 in the online-only Data Supplement). Clinical diagnoses were defined using current diagnostic criteria.811 Orthostatic hypotension was defined as ≥20-mmHg decrease in systolic blood pressure (SBP) or ≥10 mmHg of diastolic blood pressure (DBP) within 3 minutes on standing.12 Patients were excluded if they were bedridden, if they had secondary causes of autonomic failure such as diabetes mellitus or amyloidosis, or if they had contraindications to administration of pressor agents (e.g. coronary artery disease) or to any increase in intra-abdominal pressure (e.g. severe gastroesophageal reflux, aortic aneurism). The Vanderbilt University Investigational Review Board approved this study, and written informed consent was obtained from each subject before initiating the study ( NCT00223691).

Screening Procedures

Patients were admitted to the Clinical Research Center at Vanderbilt University and were fed a low-monoamine, methylxanthine-free diet containing 150-mEq sodium and 60 to 80 mEq potassium per day. Medications affecting BP, blood volume and the autonomic nervous system were withheld for ≥5 half-lives before admission. All other medications were held constant during admission. The screening consisted of a medical history, physical examination, 12-lead ECG, laboratory assessments, and standardized autonomic function tests, including orthostatic stress test, Valsalva maneuver, hyperventilation, cold pressor test, isometric handgrip and sinus arrhythmia.13 BP and heart rate (HR) were obtained intermittently using an automated oscillometric sphygmomanometer (Dinamap ProCare, GE Healthcare), and continuously with finger photoplethysmographic volume-clamp BP device (Finometer, FMS, or Nexfin, BMEYE). HR was measured by continuous ECG. During the orthostatic test, blood samples were obtained for norepinephrine while patients were supine and upright, as described previously.14 Plasma norepinephrine was measured by high-performance liquid chromatography with electrochemical detection.15

General Protocol

Patients were studied on 4 separate days in a randomized, crossover manner to receive either a single oral dose of placebo, midodrine 2.5–10 mg (Shire Pharmaceuticals Inc., Wayne, PA), placebo combined with abdominal binder (40 mmHg), or midodrine 2.5–10 mg combined with abdominal binder (40 mmHg). The order of interventions was randomized using computer-generated random numbers. Medications were blinded to patients. The dose of midodrine was chosen based on their regular dose at home (standard of care), and was kept the same for both study days with midodrine. We used an abdominal compression level of 40 mmHg based on previous studies in autonomic failure patients showing that sustained abdominal compression of up to ~40 mmHg for short periods of time was safe, tolerable, and produced the greatest pressor effects on upright BP compared with lower compression levels (10–20 mmHg).6,7,1619 Lower compression levels ≥20 mmHg, however, were allowed if a patient could not tolerate 40 mmHg.

Acute medication trials were performed in a post void state, and ≥2.5 hours after meals to avoid any confounding effects from postprandial hypotension. Participants were seated comfortably on a chair with their feet on the floor. BP and HR were recorded every 5 minutes with an automated brachial BP cuff (Dinamap ProCare, GE Healthcare). After 30 minutes of baseline measurements, patients were asked to stand for up to 10 minutes or until they developed symptoms of presyncope. BP and HR were measured at 1, 3, 5 and 10 minutes of standing (or as tolerated). The amount of time patients were able to stand was recorded by the study nurse using a timer. Immediately after sitting, the abdominal binder was placed (deflated) and/or the study medication was given. BP and HR were measured for the next 60 minutes. At the end of this period, the binder was inflated to 40 mmHg, and the 10-minute assessment of orthostatic tolerance was then repeated as described above, but this time with the binder inflated. Patients were asked to rate the severity of their orthostatic symptoms immediately after the orthostatic tolerance tests using the Orthostatic Hypotension Symptom Assessment (OHSA) Score.20 The questionnaire consisted of 6 items, including the following: (1) lightheadedness, dizziness, feeling faint or like passing out; (2) blurring vision, seeing spots, or tunnel vision; (3) trouble concentrating; (4) weakness; (5) fatigue; and (6) head, neck, or shoulder discomfort. Each item was scored on a 0 to 10 scale (with 0 reflecting absence of symptoms), and the total scores (range: 0–60) before and after treatment were used as a measure of symptom burden. We further tested the acute effect of the binder on standing BP by deflating the binder at the end of the post-intervention orthostatic tolerance test. Standing BP and HR were recorded for one more minute with the binder deflated.

Study Objectives

Our primary objective was to test the efficacy of abdominal compression with the inflatable binder against that of placebo in improving orthostatic tolerance in autonomic failure patients, and to compare it with midodrine, the standard of care. Orthostatic tolerance (primary outcome) was defined as the area under the curve of upright SBP (ΔAUCSBP; upright SBP multiplied by standing time).13 Secondary outcomes included orthostatic symptoms and seated SBP, as outlined in the Statistical Methods section. Comparisons were made between placebo, midodrine and placebo combined with binder, and included all patients who were able to complete these 3 treatment arms. Patients who were unable to stand in one of the study arms were not included in the final analysis.

A secondary objective of the study was to test the hypothesis that abdominal compression with the inflatable binder in combination with midodrine would produce a greater improvement in orthostatic tolerance compared to midodrine alone. Outcome measurements were compared in patients who completed these 2 treatment groups.

Description of the inflatable abdominal binder

We developed an inflatable abdominal binder from off-the-shelf components that applies a sustained servo-controlled compression pressure, programmable from 20 to 40 mmHg. The device consisted of a commercially available abdominal band or lumbar support garment (Airform back support, Ossur North America) made of polyester cloth with adjustable Velcro, and an inflatable cuff (commercially available BP cuff) placed underneath. The binder was attached to patients around the abdomen with the inflatable bladder placed at the level of the umbilicus. The inflatable bladder was pressurized by an automated inflator, which also monitored and maintained the compression level by inflating or deflating the bladder. We initially used a commercial inflator (Rapid Cuff Inflator E20, D.E. Hockason, Inc) and air pump (AG101 Air Source, D.E. Hockason, Inc) located in a cart next to the patient. We then developed a portable automated air pump and controller box that was attached to the binder. Both inflators were manually activated to provide a compression level of ~40 mmHg <2 minutes before the post-intervention orthostatic tolerance test. The inflation pressure was maintained constant by a servo-controlled circuit. The time taken to inflate or deflate the bladder with either pump was <30 seconds. A detailed description of the automated binder is available in the online-only Data Supplement.

Statistical Methods

The primary outcome was the change from baseline in orthostatic tolerance, defined as the area under the curve of upright SBP calculated by the trapezoidal rule (ΔAUCSBP; upright SBP multiplied by standing time). This is a composite score that integrates both the standing time and the upright SBP.13 Secondary outcomes included the change from baseline in the seated SBP at 60 minutes post drug (ΔSBP), and the orthostatic symptom burden, measured by the OHSA total score.20 For the primary objective, we compared the effects of placebo, midodrine and placebo combined with binder on the outcome measurements. Overall differences in ΔAUCSBP and ΔSBP among treatment groups were analyzed using repeated-measures analysis of variance (ANOVA). If a significant overall treatment difference was found, paired comparisons between treatment groups were performed using paired t tests with Bonferroni correction as post hoc test. For the secondary objective, differences in ΔAUCSBP and ΔSBP between midodrine and midodrine combined with binder were analyzed by paired t tests. Wilcoxon signed-rank test was used to test whether each treatment decreased the orthostatic symptom score compared with the baseline in both objectives. Power calculation was based on preliminary data from 3 patients. The difference in ΔAUCSBP mean values between placebo combined with binder and placebo alone 1 hour after drug administration was of 302 mmHg*min, with SD of difference of 188 mmHg*min. Assuming a minimally clinically significant effect size of 150 mmHg*min (~50% of the observed effect) with similar variance, a sample size of 19 patients would have 90% power to detect a difference in mean values between treatments with an α level of 0.05 using paired t test analysis (PS Dupont, Version 3.0.34). The study, however, was not powered for a non-inferiority comparison between midodrine and placebo combined binder. Data are presented as mean±SEM unless otherwise noted. All of the tests were 2-tailed, and a P value of <0.05 was considered significant. Analyses were performed with SPSS version 22.0 (IBM Corp).


Patient Characteristics and Autonomic Testing

We studied a total of 23 patients with severe autonomic failure (15 men; 67±2 years): 19 patients completed the three treatment arms required for the primary objective (placebo, midodrine and placebo combined with binder), and 21 patients completed the two treatment arms required for the secondary objective (midodrine and midodrine combined with binder; Figure S1 in the online-only Data Supplement). The presence of severe autonomic failure was evidenced by a profound decrease in SBP on standing (orthostatic hypotension), with an inadequate compensatory increase in HR, and by impaired autonomic reflexes (Table 1 and and2).2). Respiratory sinus arrhythmia was markedly reduced in all patients, suggesting parasympathetic dysfunction. Evidence of sympathetic dysfunction included blunted pressor responses to isometric handgrip and cold pressor tests, and an exaggerated decrease in SBP during Phase II and absence of BP overshoot during Phase IV of the Valsalva maneuver.

Table 1
Patient Characteristics
Table 2
Autonomic Function Tests and Orthostatic Stress Test

Primary Objective. Comparison of the Effects of the Inflatable Abdominal Binder with Placebo and Midodrine on Orthostatic Tolerance

Nineteen of the 23 patients completed the 3 treatment arms. In two patients we were unable to obtain upright BP during one of the treatment arms; in two other patients one of the study arms was not done for logistical reasons (Figure S1 in the online-only Data Supplement). The dose of midodrine previously determined to be effective in individual patients was used on this study: eight patients received a single dose of 10 mg of midodrine, ten patients 5 mg and one patient 2.5 mg. The compression level of 40 mmHg was well tolerated in all patients except for one, in whom a lower compression level (20 mmHg) was used. Average baseline seated SBP was similar among treatment groups (placebo 105±6 mmHg, placebo with binder 111±5 mmHg, and midodrine 105±4 mmHg; P=0.338 by repeated-measures ANOVA), suggesting that no significant carryover effects were present between treatment groups. One hour after drug administration, midodrine significantly increased seated SBP compared to placebo (31±5 vs. 9±4 mmHg respectively; P<0.001. Figure 1A), and to placebo and binder (7±5 mmHg; P=0.017). As expected, the binder combined with placebo had a similar effect on seated SBP to that of placebo alone, given that the binder was deflated while patients were seated.

Figure 1
Changes from baseline in seated systolic blood pressure (ΔSBP, Panel A), and areas under the curve of standing SBP (ΔAUCSBP, Panel B) after 1 hour postdrug, and orthostatic symptom scores (Panel C) at baseline (pre) and after 1 hour of ...

On standing, inflation of the abdominal binder and midodrine produced a similar significant increase in AUCSBP (i.e. improved orthostatic tolerance) compared with placebo (195±35 and 197±41 vs. 19±38 mmHg*min on the placebo day, P=0.019 and P=0.010 respectively; Figure 1B). This represents an average increase in SBP of 19.5 mm Hg over the 10-minute standing period for the binder group vs. 1.9 mm Hg for the placebo group. The same number of patients in the binder and midodrine groups (n=14) was able to stand for the full 10 minutes of the post-intervention orthostatic test, while only 10 did in the placebo group. The increase in 1-minute standing SBP from pre-intervention was 5±4 mmHg in the placebo day, 12±4 mmHg in the placebo combined with binder day, and 16±3 mmHg in the midodrine day. Compared with placebo, the group averaged SBP at 3, 5, and 10 minutes of standing was significantly higher with midodrine and with placebo combined with binder while it was similar between these two groups (P=0.001 for drug effect, P<0.001 for time effect, and P=0.191 for inter action; 2-way ANOVA; Figure S3 in the online-only Data Supplement). Orthostatic symptom scores were obtained at baseline and 1 hour after placebo (n= 18), placebo and binder (n=17), and midodrine (n=18). Compared with the baseline values, the total orthostatic symptom burden after 1 hour post-intervention significantly decreased with inflation of the abdominal binder (21.9± 3.6 versus 16.3±3.1, respectively; P=0.032; Figure 1C) and with midodrine (25.6±3.4 versus 14.2±3.3, respectively; P<0.001), but not with placebo (19.6±3.5 versus 20.1±3.3, respectively; P=0.756). Similar results were obtained if the analysis was restricted to patients with orthostatic symptom scores in all of the treatment arms.

Individual responses and a responder analysis are included in the online-only Data Supplement (Figure S4). Compared with placebo, midodrine and the binder had a lower proportion of nonresponders at all response levels (ΔAUCSBP; Figure S4B). If we arbitrarily assign an increase from baseline in upright SBP of 15 mm Hg over the 10 minute standing period as a clinically significant improvement (ΔAUCSBP ≥150 mmHg*min, Figure S4A and S4B), 63% (n=12) of patients were responders to the binder vs. 16% (n=3) for placebo (P=0.016 by McNemar’s test, Figure S4B and S4C). There was no difference in the percentage of responders between the binder and midodrine (68%[n=13], P=1.000 by McNemar’s test; Figure S4B and S4C). The number of non-responders was too small to determine if they differed in any clinical characteristic.

Acute Pressor Effect of the Inflatable Abdominal Binder

Fourteen patients were able to stand until the end of the orthostatic test with the binder inflated. In 13 of them, we deflated the binder while they were still standing, and measured standing SBP for an additional minute. Figure 2 shows the standing SBP at 1 minute without the binder (“No Binder”), at 1 and 10 minutes with the binder inflated, and after 1 minute with the binder deflated. Abdominal compression with the binder significantly increased upright SBP at 1 minute, from 81±6 mmHg with no binder to 93±7 mmHg (P=0.017 by paired t test). After 10 minutes standing with the binder inflated, SBP remained the same (93±5 mmHg), and significantly decreased to baseline levels (82±5 mmHg; P=0.001 by paired t tests) when the binder was deflated. In 9 of the 13 patients, SBP remained ≥90 mmHg after 10 minutes standing, above the threshold pressure below which cerebral blood flow autoregulation fails in these patients and triggers symptoms of cerebral hypoperfusion.21

Figure 2
Standing systolic blood pressure (SBP) without the binder (No Binder, measured at 1 minute of standing), and with the binder inflated (Binder inflated, measured at 1 and 10 minutes of standing) or deflated (Binder deflated, measured at 11 minute of standing). ...

Secondary Objective. Comparison of the Effects of the Inflatable Abdominal Binder in Combination with Midodrine versus Midodrine Alone on Orthostatic Tolerance

Twenty-one patients completed the two study arms required for the secondary objective; in the other two patients one of the study days were not done for logistical reasons (Figure S1 in the online-only Data Supplement). Eight patients received a 10 mg dose of midodrine, eleven patients 5 mg and two patients 2.5 mg. An abdominal compression level of 20 mmHg was used in one patient. Baseline seated SBP was similar between groups (midodrine 105±4 mmHg, and midodrine combined with binder 108±6 mmHg; P=0.691). As expected, the change from baseline in seated SBP after 1 hour post-drug did not differ between midodrine alone and midodrine combined with the binder deflated (30±5 vs. 32±5 mmHg, P=0.808; Figure 3A). On standing, the combination of midodrine and binder produced a greater increase in AUCSBP (improved orthostatic tolerance) compared with midodrine alone (326±65 vs. 140±53 mmHg*min, respectively, P=0.028; Figure 3B). Seventeen patients with the combination were able to stand for the full 10 minutes of the post-intervention orthostatic test compared with 14 in the midodrine group. The increase in standing SBP at 1 minute from pre-intervention was greater with the combination than with midodrine alone, but the difference did not reach statistical significance (23±4 vs. 14±3 mmHg, respectively; P=0.068). Orthostatic symptom scores were obtained at baseline and 1 hour post-intervention in 20 patients with midodrine alone and in 19 patients with the combination. Total symptom burden was significantly reduced with midodrine alone (from 26.0±3.1 to 16.7±3.2; P=0.005; Figure 3C), and with midodrine combined with binder (from 21.8±3.2 to 12.9±2.9; P<0.001).

Figure 3
Changes from baseline in seated systolic blood pressure (ΔSBP, Panel A), and areas under the curve of standing SBP (ΔAUCSBP, Panel B) after 1 hour postdrug, and orthostatic symptom scores (Panel C) at baseline (pre) and after 1 hour of ...

Adverse Events

One subject reported mild abdominal discomfort with a compression level of 40 mmHg, but deflation to a lower compression level (20 mmHg) improved the discomfort, and allowed the patient to complete the studies. All other patients tolerated the procedure and no other adverse events were reported with the binder.


We found that servo-controlled splanchnic venous compression, using an inflatable automated abdominal binder at a compression level of 40 mmHg, was as effective as midodrine, the current standard of care, in improving upright BP and reducing orthostatic symptoms. Greater beneficial effects were obtained when both treatments were applied simultaneously. Abdominal compression has been previously used for the treatment of orthostatic hypotension, but the use of a servo-controlled automated inflatable binder that can be activated only when required (i.e. standing) is a novel approach.

Despite the clinical importance of OH, there are few available options for its treatment. Midodrine and droxidopa are the only drugs approved by the FDA for the treatment of neurogenic OH. Both are prodrugs that are activated through their conversion, respectively, to desglymidodrine, a selective α1-adrenoreceptor agonist, and norepinephrine.22 Fludrocortisone is also commonly used in the treatment of OH, and is generally regarded as a volume expander. The increase in plasma volume, however, is transient and its long-term pressor effect relies on an increase in peripheral resistance.23,24

Not only are treatment options scarce, but current therapies for neurogenic OH have limitations. Midodrine and other pressor agents can induce or worsen supine hypertension, given that these drugs increase both supine and standing BP, so that orthostatic hypotension (the difference between supine and standing BP) is often not selectively improved. Thus, it is less likely that these drugs help to reduce the risk of renal disease, heart failure, and overall mortality associated with OH, and they may be contraindicated in patients with significant cardiovascular disease. Moreover, side effects of these drugs (e.g. urinary retention and piloerection for midodrine, exaggerated fluid retention and hypokalemia for fludrocortisone) further limit their use. Finally, direct vasoconstrictors like midodrine do not specifically target a major hemodynamic mechanism responsible for neurogenic orthostatic hypotension, the reduction in venous return due to failure of sympathetically mediated contraction of capacitance beds.

On standing, there is normally an orthostatic shift of 500–700 mL of blood from the chest to the venous capacitance system below the diaphragm, and most of this venous pooling occurs in the splanchnic circulation.25 The splanchnic circulation contains a large and highly compliant venous bed which normally stores ~25% of the blood volume at rest,26 and receives up to 25% of the resting cardiac output.27 Splanchnic veins are highly innervated by sympathetic nerves, and represent the largest blood volume reservoir in the human body. Veins of the extremities, on the other hand, are less compliant and have relatively insignificant sympathetic innervation; thus, their role as blood volume reservoir is relatively minor.27 This is consistent with the observation that patients who underwent selective bilateral splanchnic sympathectomy often developed OH, whereas those with sympathetic denervation of lower limbs by bilateral lumbar sympathectomy did not.28 Taken together, these observations support the notion that splanchnic capacitance vessels play an important role in the regulation of upright BP.

Thus, non-pharmacologic approaches targeting capacitance vessels, particularly splanchnic veins, not only may be effective in increasing standing BP, but also may address the limitations of pressor agents. Indeed, mechanical compression of venous capacitance beds in the lower body has been shown to improve upright BP and orthostatic symptoms by increasing stroke volume and cardiac output in patients with primary autonomic failure.6 Compression of the abdominal vascular bed was by far the most effective site to improve standing BP, whereas leg compression alone was much less effective presumably because it is a much smaller volume reservoir.6,7,29 For it to be effective, however, compression of the abdomen has to be sustained and intense enough to produce a measurable effect on OH while being tolerable to patients. In this study, we used a maximal compression level of 40 mmHg based on our pilot studies and the literature. Smit et al., has shown that abdominal compression with air-pressurized antigravity suits increased standing SBP by 11–17 mmHg at a compression level of 15–20 mmHg, whereas higher compression levels (40 mmHg) had greater pressor effects.6 Furthermore, several acute studies have documented that abdominal compression up to ~40 mmHg was safe, tolerable and did not increase supine BP. 6,7,1619 More important, abdominal compression of 40 mmHg provides selective venous compression without affecting aortic blood flow.30

Unfortunately, current compression garments suffer from low patient compliance. Waist-high compression stockings require substantial time and significant effort to put on, and once on it is impractical for patients to take them off even for periods when they are no longer needed. Elastic abdominal binders are easier to put on and off, but are difficult to apply at the required compression level for them to be effective (20–40 mmHg). Most patients may require assistance applying them, making it difficult to selectively use abdominal compression only while standing. Furthermore, applying abdominal compression while patients are supine results in a reduction in cardiac preloading and stroke volume,6 suggesting that compression garments should be used only in the upright posture. Thus, abdominal binders are effective treatments in laboratory settings, but their effectiveness is limited by difficulty of use and low compliance. The automated abdominal binder was developed to overcome these limitations. The main advantages of this device would be that (a) it can apply effective abdominal compression (manually or automatically) only when needed (when the patient stands), and (b) our servo-controlled design ensures a pre-defined sustained compression level by inflating and deflating the bladder. This latter feature would avoid excessive, and potentially harmful, increases in intra-abdominal pressure when performing physiologic maneuvers such coughing, sneezing, breathing deeply, etc.; or while bending over or lifting heavy objects.

Our results indicate that the automated abdominal binder improved standing BP and reduced orthostatic symptoms in a magnitude similar to that of midodrine, the standard of care. Furthermore, the abdominal binder provides a greater increase in orthostatic tolerance when added to midodrine compared to midodrine alone (Figure 3B). This suggests that the binder and midodrine have complimentary hemodynamic effects (venous compliance and arterial vasoconstriction, respectively) so that combination therapy would be additive. Desglymidodrine, the active metabolite of midodrine, constricts peripheral human veins in vitro and in healthy volunteers.31,32 Thus, in theory, midodrine could reduce splanchnic capacitance. However, selective α1-adrenoreceptor stimulation with systemic infusion of phenylephrine failed to increase venous return and cardiac output in normal subjects,3335 and in autonomic failure patients midodrine 10 mg did not decrease calf venous compliance.36 Taken together, these observations suggest that the pressor effects of midodrine are mediated predominantly by resistance vessels, whereas its effect on capacitance vessels, particularly those in the splanchnic circulation, is less important. This also agrees with our observation that selective splanchnic venous compression with the binder produced additional improvement in orthostatic tolerance when combined with midodrine.

Finally, the ideal treatment for orthostatic hypotension would preferentially increase upright BP while having less of an effect in supine or seated BP. This concept is shown graphically in Figure 4; i.e., the increase in BP produced by an ideal agent would fall above the line of identity. We found, however, that pressor agents like midodrine increase seated BP to a greater degree than standing BP (Figure 4), so that symptoms are improved by an increase in standing BP rather than a true improvement in orthostatic hypotension (difference between standing and seated BP). By contrast, the binder selectively improves upright BP by design, a characteristic of the ideal treatment for orthostatic hypotension that avoids worsening of supine hypertension. It also improved the response to midodrine, by “shifting” it towards the line of identity (Figure 4, arrows).

Figure 4
Changes from baseline in seated SBP (ΔSBP) and standing SBP (1 min standing) after 1 hour of the intervention. The binder, either alone or in combination with midodrine, produced a selective increase in upright SBP (arrows). Values are expressed ...

There are some potential limitations to this study. First, we only tested responses to the inflatable binder during ≤10 minutes of standing. This was designed as a proof-of-concept study to show acute effects of the binder in BP and symptoms in autonomic failure patients. Further studies are needed to assess the long-term efficacy, tolerability and practical use of the inflatable binder for the treatment of neurogenic OH. Second, a sham binder was not used as a control because adequate blinding of patients wearing a sham device would not have been possible given our crossover study design. To overcome this limitation, we further tested the pressor effects of the binder by deflating it at the end of orthostatic tolerance test. As shown in Figure 2, standing BP decreased to baseline levels after 1 minute of abdominal decompression. Future parallel-group studies are needed to compare the efficacy of the binder with a sham device control group, and between the automated binder with a manually applied one. Third, a relatively small number of patients were included in this study. Autonomic failure is a rare disease, and our sample size is similar to other clinical studies for OH in these patients. 6,7,13,19 Finally, we enrolled patients with severe autonomic failure referred to a tertiary care center, who may not reflect the broader and less severe disease population. Nonetheless, the results of our proof-of-concept studies suggest that our inflatable binder is as effective as midodrine, the current standard of care, in the treatment of orthostatic hypotension.


The inflatable binder we report has several potential advantages over currently available therapies. Venous pooling is a mayor hemodynamic determinant of orthostatic hypotension, and the inflatable binder specifically targets the venous splanchnic circulation. It can be activated (manually or with an automated posture detector) only when needed (when patients stand). The servo controller ensures a pre-defined sustained compression level. It does not worsen supine hypertension (a common comorbidity of other treatment options). Its effects have immediate onset and off-set (compared to short acting pressor agents that have a peak effect of one hour and last several hours). It can be combined with pressor agents (to produce a greater effect on upright BP). It relies less on patient compliance or their ability to apply an effective compression level. Further studies are needed to determine the long-term effectiveness, safety and tolerability of this approach, particularly in comparison to pressor agents and conventional compression garments (e.g. elastic abdominal binders).

Novelty and Significance

1. What is New

  • Abdominal venous compression with a servo-controlled automated abdominal binder is as effective as midodrine, the standard of care, in improving orthostatic tolerance in patients with neurogenic orthostatic hypotension.
  • Combining the automated abdominal binder with midodrine provides additional improvement in orthostatic tolerance.

2. What is Relevant

  • Splanchnic venous pooling is a mayor hemodynamic determinant of orthostatic hypotension, but is not specifically targeted by current treatment approaches.
  • The autonomic abdominal binder has the advantage of immediate onset and offset of action, and lack of adverse effects inherent to pressor agents such as supine hypertension.

3. Summary

In this proof of concept study the automated inflatable abdominal binder acutely improved orthostatic tolerance. Longer term studies are required to assess the effectiveness, safety and tolerability of this device.

Supplementary Material

Online Supplement


We acknowledge the patients who volunteered for these studies and the Clinical Research Center nurses who made this study possible.

Sources of Funding

This work was supported by National Institutes of Health (NIH) grants PO1 HL56693, U54 NS065736, R01 HL122847 and UL1 TR000445 (National Center for Advancing Translational Sciences). Additional support was provided by American Heart Association grant 14CRP20380211. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Advancing Translational Sciences or the NIH.


Conflicts of Interest/Disclosures

LEO, AD, FJB, RH and IB have submitted a patent application for the use of an automated inflatable abdominal binder as a medical device


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