Abstract
Background
The objective of this study is to determine the effect of inspiratory resistance through an impedance threshold device (ITD) on orthostatic tolerance in patients with postural tachycardia syndrome (POTS). We hypothesized that the ITD would result in greater negative intrathoracic pressure to enhance cardiac venous return, improve stroke volume, and reduce heart rate in these patients.
Methods and Results
We compared the effect of a sham device (sham, no resistance) versus an ITD (increased inspiratory resistance), in 26 POTS patients in a randomized, single-blind, crossover study. Hemodynamic assessments were performed at baseline while supine and during head-up tilt (HUT) to 70 degrees for 10 minutes. We did not find differences in baseline hemodynamic parameters between the ITD and sham devices. After 10 minutes of HUT, the heart rate was lower with the ITD versus sham device (102±4 versus 109±4 beat/min, respectively; p=0.003). The ITD also improved stroke volume compared with the sham device (35±2 versus 26±1 mL, p=0.006).
Conclusions
These findings suggest that increasing negative intrathoracic pressure with ITD breathing improves heart rate control in POTS patients during upright posture.
Keywords: autonomic nervous system, tachycardia, stroke volume, postural tachycardia
Introduction
Postural tachycardia syndrome (POTS) is a common form of chronic orthostatic intolerance that primarily affects premenopausal women. This heterogeneous disorder is characterized by excessive sustained tachycardia upon standing, which is unrelated to medications or other medical conditions, and is accompanied by orthostatic symptoms such as lightheadedness, nausea, blurred vision, fatigue and mental clouding. While the underlying cause of POTS remains unclear, several mechanisms have been proposed including sympathetic activation, deconditioning, hypovolemia 1–4, and reduced stroke volume attributed to cardiac atrophy coupled with this hypovolemia 2, 5. While several pharmacologic and behavioral approaches have been tested in POTS, an optimal treatment strategy has not been identified for these patients.
The use of an impedance threshold device (ITD) has been proposed in the treatment of orthostatic intolerance 6, and was demonstrated to attenuate the fall in blood pressure with standing and to improve presyncopal symptoms in patients with orthostatic hypotension 7, 8. Breathing through the ITD increases negative intrathoracic pressure during spontaneous inspiration to improve venous return and ventricular preload through a thoracic suction effect 9. This suction effect increases blood pressure, cardiac output, and stroke volume in patients following cardiac arrest 10 and during central hypovolemia 11. The use of an ITD also blunted the fall in blood pressure during acute induction of orthostatic intolerance in healthy subjects 11, 12.
Given these findings, we hypothesized that breathing through an ITD would reduce tachycardia in POTS patients, by improving stroke volume. To test this hypothesis, we compared the effects of the ITD versus a sham device on heart rate in POTS patients in the supine position and during orthostatic stress test created by head-up tilt (HUT). As a secondary objective, we examined the hemodynamic mechanisms underlying any effect of the ITD on heart rate in these patients.
Methods
Standard Protocol Approvals, Registration, and Patient Consents
The Vanderbilt Institutional Review Board approved this study. Written informed consent was obtained from all participants. This study was registered at ClinicalTrials.gov (NCT00962728).
Study Participants
We enrolled 39 POTS patients admitted to the Vanderbilt Autonomic Dysfunction Center for evaluation between November 2008 and October 2011. Patients met all of the following criteria for POTS: (a) a heart rate increase ≥30 bpm within 10 minutes of standing or HUT; (b) absence of orthostatic hypotension (defined as a fall in blood pressure >20/10 mmHg) 4, 13, 14; (c) at least a 6-month history of orthostatic symptoms; and (d) absence of medications or an additional chronic medical condition known to cause tachycardia (e.g. bed-ridden, severe dehydration). All patients were at least 18 years of age and were not smokers, pregnant, or endurance-trained athletes.
General Protocol
POTS patients were studied on an inpatient basis and were placed on a low-monoamine, methylxanthine-free, fixed sodium (150mEq/day) and potassium (70 mEq/day) diet upon admission. Medications affecting the autonomic nervous system, blood pressure, or blood volume were withheld at least 5 half-lives before testing.
Orthostatic Stress Testing
All patients underwent standardized orthostatic stress testing, in the morning at 8:00 AM following an overnight fast. Patients remained supine after overnight rest and then were asked to stand for 30 minutes, or as long as tolerated. Blood pressure and heart rate were measured in the supine and upright positions using an automated sphygmomanometer cuff. Blood samples were collected at the end of the supine and standing periods via an antecubital vein catheter that was placed at least 30 minutes before testing. Supine and standing plasma norepinephrine and epinephrine levels were measured by HPLC with electrochemical detection as previously described 15.
Study Design
We performed a randomized, single-blind (patient blinded to intervention), crossover study assessing the effects of the ITD versus sham device on heart rate during HUT to 70 degrees in POTS patients. The primary outcome was defined a priori as the heart rate after 10 minutes of HUT. As a secondary objective, we compared the effects of the ITD versus sham device on stroke volume, cardiac output, blood pressure and total peripheral resistance. The order of interventions was randomized using computer generated random numbers, and a 20-minute washout period was allowed between interventions.
Protocol
All testing was performed in the afternoon, and at least 2 hours after a meal. Patients were strapped into a tilt table (Medical Positioning Inc., Kansas City, MO) and allowed to rest in the supine position for 30 minutes prior to data collection. Baseline blood pressure and heart rate were recorded for 5 minutes, and then patients were instrumented with a low resistance mouthpiece connected to a bag to measure cardiac output using the Innocor inert gas rebreathing technique (Innovision, Denmark). Patients were asked to breath spontaneously for at least 5 minutes in the supine position through the active (ITD, ResQGARD, Advanced Circulatory Systems Inc.) or sham resistance devices. Patients were tilted head-up to 70 degrees for 10 minutes, or as long as tolerated (Figure 1). Blood pressure (oscillometric device, Vital Guard 450, IVY Biomedical Systems Inc.) and cardiac output (Innocor) were measured at baseline, and every 5 minutes during testing. Heart rate was measured by continuous ECG. Stroke volume was calculated as cardiac output divided by heart rate (CO/HR). Total peripheral resistance was calculated as 80 times the mean blood pressure divided by cardiac output ((80 × mean BP)/CO) and reported in SI units (dyne × seconds × cm−5).
Figure 1.
Study Design. A. Top Panel - Schematic diagram of the study protocol. On the study day, subjects were tilted head-up to 70 degrees, twice in a randomized manner, either with the active impedance threshold device (ITD) or the sham device. Lower panel - A typical continuous tracing of blood pressure and heart rate during head up tilt is shown. B. Picture showing the apparatus setup for both sham (left side) and ITD devices (right side), connected in sequence with the Innocor device used to measure cardiac output.
Symptoms
Patients were asked to self-report symptom burden immediately after being tilted back to the supine position using the validated Vanderbilt POTS Symptom Score 16, 17. Patients were asked to rate the severity of 9 symptoms on a 0 to 10 scale, with 0 reflecting absence of symptoms. The sum of the scores at each time point was used as a measure of overall symptom burden. The symptoms evaluated were: mental clouding, blurred vision, shortness of breath, rapid heartbeat, tremulousness, chest discomfort, headache, lightheadedness, and nausea.
Statistical Analysis
We tested the null hypothesis that the heart rate at 10 minutes following HUT, the primary outcome, would not be different between ITD and sham devices in POTS patients. Secondary outcomes included stroke volume, cardiac output, blood pressure, and total peripheral resistance. Outcomes were compared using paired t-tests. A two-tailed p value <0.05 was defined as statistically significant. Data are presented as mean ± SEM. They were also analyzed with linear mixed-effects models. Each variable in Table 2 was regressed against indicator covariates for whether a devise was used and whether this was a sham or ITD device. An interaction term for these two covariates was included in these models. The device, ITD and interaction covariates were treated as fixed effects. Data from each patient was treated as a random effect. This analysis was restricted to data collected from supine patients. Analogous analyses were run for the data in Table 3 only here data collected without any device was excluded and the dependent variable was regressed against position (supine or tilted) and ITD. These analyses were run using Stata’s mixed command (Version 13.1, StataCorp LP, College Station TX). Tests of contrasts from these analyses gave results that were comparable to those of analogous t-tests in Tables 2 and 3. We only present the t-tests because the regression analyses, while theoretically more powerful also make assumptions that are not required by the t-tests. Other analyses were performed using SPSS (Version 22.0, IBM Corp). GraphPad Prism (Version 6.03, GraphPad Software, San Diego, CA) was used to generate figures.
Table 2.
Effect of breathing devices on supine hemodynamic parameters at baseline
| Without device | With device | p value | |
|---|---|---|---|
| Sham | |||
| Systolic blood pressure (mmHg) | 102 ± 13 | 100 ± 13 | 0.302 |
| Diastolic blood pressure (mmHg) | 63 ± 8 | 64 ± 9 | 0.066 |
| Mean arterial pressure (mmHg) | 76 ± 9 | 76 ± 10 | 0.454 |
| Heart rate (beats/min) | 76 ± 13 | 76 ± 13 | 0.773 |
| Cardiac Output (L/min) | 6.1 ± 1.2 | 5.9 ± 1.5 | 0.474 |
| Stroke volume (mL) | 82 ± 25 | 81 ± 30 | 0.808 |
| Total peripheral resistance (dyne×sec×cm−5) | 1041 ± 5 | 1087 ± 11 | 0.146 |
| ITD | |||
| Systolic blood pressure (mmHg) | 100 ± 3 | 105 ± 4 | 0.016 |
| Diastolic blood pressure (mmHg) | 65 ± 2 | 64 ± 2 | 0.554 |
| Mean arterial pressure (mmHg) | 77 ± 2 | 78 ± 2 | 0.212 |
| Heart rate (beats/min) | 77 ± 2 | 78 ± 3 | 0.155 |
| Cardiac Output (L/min) | 6.3 ± 0.3 | 5.6 ± 0.2 | 0.005 |
| Stroke volume (mL) | 86 ± 6 | 75 ± 4 | 0.002 |
| Total peripheral resistance (dyne×sec×cm−5) | 1010 ± 9 | 1143 ± 11 | 0.002 |
Values are expressed as mean ± SEM. P value represents paired t-test comparisons between without device and with device
Table 3.
Hemodynamic effects of ITD and sham devices during head-up tilt
| Sham | ITD | p value | |
|---|---|---|---|
| Supine | |||
| Systolic blood pressure (mmHg) | 100 ± 3 | 105 ± 4 | 0.016 |
| Diastolic blood pressure (mmHg) | 64 ± 2 | 64 ± 2 | 1.000 |
| Mean arterial pressure (mmHg) | 76 ± 2 | 78 ± 2 | 0.200 |
| Heart rate (beats/min) | 76 ± 3 | 78 ± 3 | 0.013 |
| Cardiac Output (L/min) | 5.9 ± 0.3 | 5.6 ± 0.2 | 0.300 |
| Stroke volume (mL) | 81 ± 6 | 75 ± 4 | 0.091 |
| Total peripheral resistance (dyne×sec×cm−5) | 1087 ± 56 | 1143 ± 57 | 0.164 |
| 10 minute HUT at 70 degrees | |||
| Systolic blood pressure (mmHg) | 105 ± 2 | 108 ± 3 | 0..233 |
| Diastolic blood pressure (mmHg) | 71 ± 2 | 73 ± 2 | 0.333 |
| Mean arterial pressure (mmHg) | 83 ± 2 | 84 ± 2 | 0.164 |
| Heart rate (bpm) | 109 ± 4 | 102 ± 4 | 0.007 |
| Cardiac Output (L/min) | 3.3 ± 0.2 | 3.4 ± 0.2 | 0.538 |
| Stroke volume (mL) | 31 ± 2 | 35 ± 2 | 0.026 |
| Total peripheral resistance (dyne×sec×cm−5) | 2082 ± 104 | 2109 ± 138 | 0.750 |
Values are expressed as mean ± SEM. P value represents paired t-test comparisons between sham and ITD groups
Sample Size
This study was powered to detect a difference in tilt-induced heart rate of 10 bpm between ITD and sham interventions, which would reflect a clinically meaningful reduction. Assuming that the pooled standard deviation in upright heart rate will be 15 bpm 18, a final sample size of 26 patients would provide 90% power to detect this difference with an alpha level of 0.05 using a paired sample t-test (PS software, version 3.0.43) 19.
Results
Study Participants
Thirty-nine POTS patients were enrolled in this study (Figure 2). Two patients were excluded prior to randomization (1 diagnosed with pseudosyncope and 1 withdrew consent to participate). The remaining 37 patients were randomized to ITD versus sham devices. Of these, 11 patients were excluded because they did not tolerate HUT for 10 minutes with both interventions. There were 5 patients that could not tolerate tilt with the sham device, 4 with the ITD, and 2 could not tolerate the tilt with either device. Thus, 26 patients completed the study and were included in the final analysis.
Figure 2.
Enrollment and Randomization of Study Participants
Baseline Patient Characterization
The clinical characteristics of POTS patients in this study are shown in Table 1. All but one patient was female, reflecting the strong gender predominance of this disorder. During orthostatic stress testing (Table 1), POTS patients exhibited a significant increase in heart rate upon standing (43±4 bpm; p<0.001), with no differences in systolic (3±4 mm Hg) or diastolic (6±3 mm Hg) blood pressure. This orthostatic tachycardia was accompanied by a significant increase in plasma norepinephrine (174±16 supine versus 656±59 pg/mL standing; p<0.001) and epinephrine (18±4 supine versus 100±28 pg/mL standing; p<0.001) levels.
Table 1.
Clinical Characteristics of POTS patients
| Parameter | POTS Patients (n=26) |
|---|---|
| Female, n (%) | 25 (96%) |
| Age (years) | 30 ± 2 |
| Height (cm) | 166 ± 2 |
| Weight (kg) | 65 ± 3 |
| Body Mass Index (kg/m2) | 23 ± 1 |
| Supine | |
| Heart rate (beats/min) | 69 ± 2 |
| Systolic blood pressure (mmHg) | 107 ± 3 |
| Diastolic blood pressure (mmHg) | 66 ± 2 |
| Norepinephrine (pg/mL) | 173 ± 16 |
| Epinephrine (pg/mL) | 21 ± 4 |
| Standing | |
| Heart rate (beats/min) | 112 ± 4 |
| Systolic blood pressure (mmHg) | 110 ± 4 |
| Diastolic blood pressure (mmHg) | 72 ± 3 |
| Norepinephrine (pg/mL) | 654 ± 61 |
| Epinephrine (pg/mL) | 101 ± 28 |
| Change from supine to standing | |
| Heart rate (beats/min) | 43 ± 4 |
| Systolic blood pressure (mmHg) | 3 ± 4 |
| Diastolic blood pressure (mmHg) | 6 ± 3 |
| Norepinephrine (pg/mL) | 482 ± 27 |
| Epinephrine (pg/mL) | 82 ± 51 |
Values are expressed as mean ± SEM. POTS, postural tachycardia syndrome
Effect of ITD versus Sham device on Supine Hemodynamics
There were two supine baseline periods in this study without devices: (1) prior to the first tilt test and (2) between the two tilt tests. When compared to the first baseline period, POTS patients had decreased stroke volume (86±4 versus 82±6 mL; p=0.001) and cardiac output (6.4±0.2 versus 6.0±0.3 L/min; p=0.002), with no difference in heart rate (77±2 and 76±2 bpm; p=0.581) during the second baseline period. When stratified by intervention (ITD versus sham), this pattern was similar in both groups, suggesting the randomization was effective in equalizing hemodynamic carryover effects. In the supine position, the ITD did not change HR or MAP, but resulted in a decrease in SV (p=0.002) and an increase in TPR (p=0.002, Table 2, Figure 3). There was no effect of the sham device on supine hemodynamic function when compared with baseline (Table 2, Figure 3). At the end of the supine breathing period, systolic blood pressure (105±4 versus 100±3 mmHg; p=0.016) and heart rate (78±13 versus 76±13 bpm; p=0.013) were higher with the ITD compared with sham device, with no differences in other hemodynamic measures (Table 3).
Figure 3.
Effect of ITD breathing on supine hemodynamic parameters. All panels show supine hemodynamic parameters at baseline breathing without any device (WO, blank bars) or using a breathing device (With, black bars). The left side of each panel shows the change with the impedance threshold device (ITD) and the right side with the Sham device. Breathing with the ITD did not change heart rate (HR; Panel A) or mean arterial pressure (MAP; Panel B), but decreased stoke volume (SV; Panel C) and increased total peripheral resistance (TPR; Panel D). Breathing with the sham device did not alter any of the hemodynamic parameters studied. The heart rate at the end of the supine period, however, was significantly higher while breathing with the ITD compared with the sham device (Panel A).
Effect of ITD versus Sham device on Hemodynamics during Orthostatic Challenge
The HUT elicited similar hemodynamic changes with the ITD versus sham devices. As shown in Figure 4, HUT with the ITD resulted in increased heart rate (23±4 bpm; p<0.001), mean arterial pressure (7±2 mmHg; p<0.001) and total peripheral resistance (967±105 dyne×sec×cm−5; p<0.001), and decreased stroke volume (40±3 ml; p<0.001). Similarly, HUT with the sham device increased heart rate (33±3 bpm; p<0.001), mean arterial pressure (6±2 mmHg; p<0.001), and total peripheral resistance (992±78 dyne×sec×cm−5; p<0.001), and decreased stroke volume (50±4 mL; p<0.001). The ITD, however, attenuated these hemodynamic changes to HUT when compared with the sham device (Table 3, Figure 4). At 10 minutes following HUT, heart rate was lower (p=0.007) and stroke volume was higher (p=0.026) with the ITD versus sham device, with no differences in mean arterial pressure or total peripheral resistance (Table 3, Figure 4).
Figure 4.
Hemodynamic changes during head up tilt with the ITD or sham device. Changes in hemodynamic parameters from baseline (white bars for ITD, gray bars for Sham) to 70 degrees of head up tilt (black bars for ITD and checkered bars for Sham). Breathing through both the ITD and sham devices resulted in an increase in heart rate (HR; Panel A), mean arterial pressure (MAP; Panel B) and total peripheral resistance (TPR; Panel D) and a decrease in stroke volume (SV; Panel C). At 10 minutes following head-up tilt, however, heart rate was lower (Panel A) and stroke volume was higher (Panel C) with the ITD versus sham device.
Effect of Interventions on Symptom Scores
The overall symptom scores were similar between the ITD and sham interventions (18±2 versus 19±2; p=0.897). Interestingly, even though the ITD could potentially make it harder to breath, the “shortness of breath” symptom was rated equally between interventions (4.1±0.6 ITD versus 3.5±0.6 sham; p=0.382).
Discussion
We assessed the effects of increased inspiratory resistance using an ITD on orthostatic tolerance and symptoms in POTS patients in a randomized, crossover study. The main finding is that increased negative intrathoracic pressure reduces upright heart rate in POTS. This attenuation in orthostatic tachycardia was associated with increased stroke volume and maintenance of cardiac output and blood pressure, perhaps reflecting improved cardiac venous return through a thoracic suction effect. These overall findings suggest that an ITD could be used as a non-pharmacological approach to help restrain upright heart rate in POTS patients.
Hemodynamic Adaptations to Standing in POTS
The assumption of upright posture requires rapid cardiovascular adaptations to maintain blood pressure including activation of afferent autonomic neural pathways to induce reflex-mediated increases in efferent sympathetic outflow, vasoconstriction, and subsequently venous return. While the underlying cause of POTS remains unclear, many patients have low blood volume 1, 16, 20, which can reduce venous return and stroke volume even in the supine position 5, 20. This reduction in stroke volume is thought to elicit tachycardia as a compensatory mechanism to maintain cardiac output and blood pressure in these patients.
Potential Benefits of ITD in POTS
Given the heterogeneity of POTS, this disorder is challenging to treat and there are currently limited therapeutic options for these patients. The primary treatment approaches in POTS patients involve either attempting to restrain heart rate (e.g. beta-blockers or pyridostigmine) or increasing circulating blood volume (e.g. increased dietary salt and water, fludrocortisone, DDAVP). As with many medications, potential side effects may limit their use. In this regard, non-pharmacologic interventions have an intuitive appeal, as they do not produce off-target pharmacologic adverse effects. In this study, we tested a non-pharmacologic intervention that has the potential to increase venous return and stroke volume, and by partially reversing these abnormal hemodynamic responses, to reduce upright heart rate in POTS patients.
Venous return is a passive process that is determined by a pressure gradient (venous-right atrial pressure) and venous resistance. During inspiration, the intrathoracic pressure is negative while abdominal pressure is positive. The resulting increase in the pressure gradient pulls blood towards the right atrium to increase venous return. With deeper inspiration or with use of ITD, both of which increase intrathoracic negative pressure, there could be an enhancement of venous return due to the larger negative pressure generated. In fact, breathing through an ITD has been shown to increase stroke volume and improve orthostatic tolerance in healthy subjects during hypovolemic challenges. It has also been recently shown that slow breathing can improve orthostatic tolerance, and the proposed mechanism being through the generation of negative intrathoracic pressure 21. The ITD can force an increase in the depth of breathing by generating increased respiratory resistance. We hypothesized that this would increase stroke volume to decrease tachycardia in POTS patients.
In the supine position, the ITD produced a modest increase in systolic blood pressure, an increase in total peripheral resistance and a decrease in stroke volume, without altering heart rate. We speculate that the bigger respiratory effort required by the ITD caused an increase in sympathetic tone and total peripheral resistance, with a resultant decrease in venous return and stroke volume d. During orthostatic stress, the ITD effectively reduced heart rate and increased stroke volume during in POTS patients when compared with the sham device. Importantly, there were no differences in self-reported symptom scores between devices, even though breathing through an ITD requires more effort. Given these findings, it is possible that the ITD could be used as a rescue measure or as a co-adjuvant to other therapies to acutely reduce orthostatic tachycardia in POTS, without worsening symptoms.
Limitations
This study has some potential limitations. First, we only tested responses to the ITD during an acute tilt protocol. This was designed as a “proof of concept” study to show that the ITD could favorably restrain heart rate and alter hemodynamics and in POTS. The results are reported after 10 minutes of head up tilt. We actually see a trend towards a restraining effect of the ITD on the continuous increase in heart rate during tilt, but the study was not adequately powered to study such a pattern of effect. Further studies are needed to assess the practical use of ITD for treatment of POTS, and to study its long-term efficacy. It is possible that the ITD could be used as a rescue therapy for patients when they are feeling symptomatic while upright. Second, we focused on the hemodynamic mechanisms of the ITD, but did not examine for neurohormonal changes or other potential mechanisms that could contribute to its beneficial effects. Finally, our patients were enrolled at a specialized care center for treatment of autonomic disorders and therefore may not reflect the broader, and perhaps less severe, POTS population.
Conclusions
Breathing through an ITD device can acutely restrain upright heart rate and increase stroke volume in patients with POTS. Further studies are needed to explore the chronic effects of ITD breathing, but these data suggest that it may be an effective rescue therapy for some POTS patients to reduce tachycardia during orthostatic stress.
Acknowledgments
We are very grateful to all the volunteers, and the nurses form Vanderbilt clinical research center.
Funding Sources: Supported in part by NIH grants K23HL95905, R01HL102387, P01HL056693, 5U54NS065736 and UL1TR000445.
Dr. Gamboa is supported by NIH Grant K23 HL95905. Dr. Arnold is supported by a Scientist Development Grant from the American Heart Association (14SDG19710011). Dr. Robertson is supported by NIH grants U54RR032646 and P01 HL056693. Dr. Raj was supported by NIH Grant R01HL102387 and is involved in expert medical consulting for law firms regarding POTS. Dr. Raj is a consultant for Medtronic (<$5000), Lundbeck (>$5000) and GE Healthcare (<$5000), although none of the consulting relates to either breathing devices or POTS.
Footnotes
Conflict of Interest Disclosures:
All others have none.
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