Effect of Lower Limb vs. Abdominal Compression on Mobility in Orthostatic Hypotension: A Single-Blinded,Randomized,Controlled,Cross-Over Pilot Study in Parkinson’s Disease

1 INTRODUCTION

The overall prevalence of orthostatic hypotension (OH) in patients with Parkinson’s disease (PD) is estimated to be between 30% and 52% [1, 2]. The pathophysiologic hallmarks comprise neurodegeneration with Lewy body pathology in sympathetic ganglia, hypothalamus, Locus coeruleus, rostral mesencephalon, and postganglionic sympathetic cardiac denervation leading to reduced vasoconstriction and cardiac sympathetic stimulation [3]. OH is defined as a sustained reduction of systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of 10 mm Hg within 3 min of standing or head-up tilt to at least 60° on a tilt table [4], leading to venous abdominal and femoral accumulation of intravasal blood and, consequently, to transient brain hypoperfusion [5]. Based on literature, it is reasonable to assume that OH not only leads to a change in mobility behavior in general, but also to a change in sit-to-stand (STS) behavior. First, on a performance level, OH is associated with decreased mobility, more frequent falls, and decreased activities of daily living in PD patients OH [1, 7]. Moreover, the extend of the blood pressure drops (BPD) is negatively associated with the ambulatory capacity measure, which is a surrogate of mobility performance and associated with Five Times Sit-to-Stand, Timed Up-and-Go, and Berg Balance Scale performances, as well as with gait speed [8]. These results argue in favor of a correlation between (severity of) OH and number of STS movements in daily life. Second, in a geriatric cohort with OH, the extent of systolic BPD was negatively associated with chair stand test performance [9], suggesting a close correlation between OH and speed/dynamic aspects of the STS maneuver. It is thus tempting to speculate that OH leads to reduced STS performance also in patients with PD, and, consequently, to decreased STS frequency in the usual environment (although we cannot rule out with absolute certainty that the relationship between STS and OH could also be the reverse, i.e., that reduced STS exacerbates OH, e.g., through increased venous stasis). STS frequency has also been shown to correlate positively with the number of steps per day [10] and negatively with frailty scores [11], suggesting that STS frequency can serve as an (OH-associated) marker of physical activity. This assumption may be— at least indirectly— supported by a recent meta-analysis that found an association between OH and reduced physical functioning in 16 out of 42 studies [12]. Since OH has great impact on quality of life and FDA and EMA require data on OH as part of clinical trials, appropriate studies are urgently needed.

So far, most PD patients with OH are treated with lower limb compression stockings (CS) and abdominal binder (AB) therapy, as a supplement to pharmacological treatment or as the stand-alone therapy. Both treatments were shown to be effective in reducing BPD and associated symptoms, such as dizziness and presyncopes. However, it remains unclear whether one of the two forms of therapy is more effective [5, 13–17]. We investigated the effect of these two treatments using a high-quality cross-over study design and— to the best of our knowledge, the first time ever in this form of trial— a digital mobility outcome (STS frequency) collected in the usual environment as a primary endpoint.

2 MATERIALS AND METHODS

2.1 Participants and study design

The study was registered at the German clinical trial register (DRKS00021597) and approved by the local ethics committee (D 508/17). Between 2018 and 2019, 149 PD patients were screened from the specialized Movement Disorder Center of the Department of Neurology of the University hospital Schleswig-Holstein, Campus Kiel, Germany. The screening was performed during patient’s regular clinical visits to the movement disorder outpatient clinic or inpatient treatment.

Patients were included if they met the following inclusion criteria: Diagnosis of PD according to the UK Brain Bank Criteria [18] and Hoehn & Yahr stage 1–4, symptomatic OH (OHQ symptom assessment item 1≥1 [19]), and at least moderate OH (systolic/diastolic BPD of at least 20/10 mmHg within 3 min of standing or head-up tilt to at least 60° on a tilt table) [20]. Exclusion criteria were OH due to medication side effects (diuretics, alpha adrenergics (e.g., for bladder disorder), sympatholytics, vasadilatators, antidepressants, antihypertensives; as defined by anamnestic evidence that OH symptoms occurred or worsened with start of intake of medication, cognitive deficits (Non-motor symptom scale domain attention/memory>24/36 points [21–23]), other severe neurological, psychiatric, cardiac or vascular diseases, severe diabetes mellitus, severe peripheral neuropathy as determined by examination findings, pregnancy/breast feeding, and changes of the medical therapy in the 4 weeks prior to enrollment. Judgment of disease severity with respect to exclusion criteria 1–6 was made by an experienced movement disorder specialist (SP). Pharmacological antihypotensive treatment was not an exclusion criterion.

All participants gave written informed consent. After an observation period of one week (T1-T2: baseline assessment without any OH compression therapy), participants were randomized to wear CS or AB for one week (T2-T3: treatment phase 1). Participants then crossed over to the other treatment arm, respectively (T3-T4: treatment phase 2). Drug therapy was continued unchanged through the study. Investigators were single-blinded, which means that the assessment and therapy monitoring were carried out by two different persons and the examiner did not get a chance to see the type of OH compression therapy during the assessment.

Primary, secondary, and exploratory endpoints are described in detail below. Study details are provided in Fig. 1.

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Fig. 1

Study flow chart. Compression stock., compression stockings; IMU, inertial measurement unit; OH, orthostatic hypotension; PD, Parkinson’s disease.

3 RESULTS

3.2 Primary endpoint

Real-life STS frequency was not significantly different between the two interventions (F(1.2, 16.2)=4.5, p = 0.6, ω² = 0.0). Baseline assessment over 1 week (T1-T2) showed 3.6±1.8 STS/h (±SD). During AB therapy, participants performed 3.6±2.2 STS/h (p against baseline = 1.0), and during CS therapy 4.4±4.1 STS/h (p against baseline = 1.0; p against AB = 1.0. Details are provided in Fig. 2 and Supplementary Table 3).

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Fig. 2

Sit-to-stand movements (STS) per hour during control, abdominal binder (AB) and compression stockings (CS) conditions. No significant difference could be observed between the three groups. (n.s., not significant. Data given as mean±SD).

A total of 1,768.9 h and 5,710 STS movements were recorded with the sensors over all three measurement weeks. Per participant, an average of 43.2±21.7 h/week were recorded. The analysis of variance showed no differences between the three conditions baseline, AB and CS treatment (p = 0.73).

3.3 Secondary endpoints

T1 and T2 (control conditions) did not significantly differ concerning MAP drops. Concerning AB treatment, MAP drops were comparable between AB+ and T1 and AB+ and AB– but were higher in AB– compared to T1 (p = 0.007). Concerning CS treatment, MAP drops were comparable between CS+ and CS– but were higher in CS+ (p = 0.014) and in CS– (p = 0.005), compared to T1. Moreover, the intervention groups differed with an F(3.4,51.2)=5.2, p < 0.0022, ω² = 0.072. The direct comparison between AB and CS showed no significant differences, especially no differences between AB+ and CS+ (details are provided in Fig. 3, Supplementary Tables 1 and 2).

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Fig. 3

Mean arterial blood pressure (MAP) drops (calculated by subtracting 5^th minute supine mean blood pressure from mean blood pressure at third minute of head-up tilt) at baseline (T1) and after abdominal binder (AB) and compression stockings (CS) therapies. T2, control assessment one week after T1. Assessments performed with the respective devices (AB+, CS+) and after 15 min washout (AB–, CS–). Data are given as mean±SE. *p<0.05, n.s., not significant.

Treatment with AB but not with CS reduced OH-associated symptoms as assessed with the OHQ (F(1.4,21.1)=5.7, p = 0.018, ω² = 0.082, see Fig. 4 and Table 2). Post-hoc testing showed a reduction of 8 points by AB (SE±2.5, p_bonf against baseline = 0.0062) and 5 point by CS therapy (SE±2.5, p_bonfagainst baseline = 0.4) without significant differences in direct comparison between AB and CS treatment (Table 2).

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Fig. 4

Symptoms associated with orthostatic hypotension (OH) as reported in the OH Questionnaire (OHQ) are reduced by treatment with abdominal binders (AB) (–8.4; SE: 2.5; p_bonf < 0.01) but not compression stockings (CS) (–4.0; SE: 2.5; p_bonf = 0.4). **p < 0.01. Data given as mean±SE.

The SCOPA-AUT showed an improvement by AB therapy (F(1.6,24.5)=4.2, p = 0.033, ω² = 0.08; post hoc testing: reduction of 3 points, SE±1.2, p_bonf = 0.046, Table 2). The reduction of the SCOPA-AUT by compression therapy approached significance (–3, SE±1.2, p_bonf = 0.059). Both AB and CS therapies reduced the non-motor symptoms assessed via the NMSS (F(2,30)=9.5, p = 0.0064, ω² = 0.1, Table 2). Post hoc testing showed significant differences between both, no therapy and AB (mean difference = 10.2, SE±2.6, p_bonf = 0.0037) and between no therapy and CS (mean difference = 9.2, SE±2.6, p_bonf = 0.0013). No significant differences were observed comparing AB and CS treatment, neither for the SCOPA-AUT nor for the NMSS. The evaluation of the other secondary endpoints (PDQ-39, MDS-UPDRS, part I-IV, ADL/iADL, and STS duration) showed no significant differences between the three conditions (no therapy, AB and CS; Table 2, Supplementary Table 3).

The evaluation of the STS duration showed no significant differences between no therapy, therapy with abdominal binder and therapy with compression stockings (detailed results are provided in Supplementary Table 3).

4 DISCUSSION

Treating OH with AB and CS was not associated with increase in continuously assessed, objective real-life surrogate markers of physical activity, and these parameters did not differ between the two interventions. More specifically, the primary outcome measure of this single blinded cross-over trial, real-life STS frequency, was not significantly changed by the interventions. The results of the secondary and exploratory physical activity endpoints argue against a relevant change in quality of STS (and turning) movements, and the amount of overall physical activity.

The following reasons may explain, at least partly, this “negative” result. The participants included in this trial were already at a relatively high physical activity level at inclusion, which may make it difficult to further increase this parameter. Already under control conditions, our patient population performed about twice as many STS/h as the study participants of an earlier, in some parts comparable study [30]. Interestingly, the population of the latter was even younger, less severely affected and had a shorter duration of illness, than our cohort, which suggests that no reliable predictions about daily activity and mobility can be made from a person’s demographic and gross clinical data. Similar results were obtained in a review comparing mobility parameters under supervised with mobility parameters under unsupervised conditions [31]. Moreover, an increase in physical activity also requires a change in habits. Although the home measurements were taken over 1 week, a longer observation period (e.g., 1–2 months) could possibly show an effect. Moreover, as expected in a cohort with advanced PD patients, also these participants suffered from multiple PD-associated symptoms beyond OH (i.e., akinesia, rigidity, and postural instability) that might have prevented them from increasing their physical activity significantly due to an (efficient) OH treatment. Therefore, future trials in this field should also assess the participants’ satisfaction with their existing mobility and their general desire to improve mobility (if they are satisfied with their current mobility, it will not improve as a result of an improvement in a symptom), as well as the effective restriction of mobility due to the symptom to be treated. A recent systematic review presents a conceptual framework for walking experience from the perspective of patients [32]. It can be assumed that the similar applies to STS.

As already mentioned, this is possibly the first trial worldwide that has used a specific digital endpoint of mobility as the primary endpoint for the evaluation of a (potentially) mobility-influencing symptom and can therefore provide preliminary but important insights for the design of such future trials in the field.

Concerning clinical and PRO-related endpoints, our analysis showed favorable effects of AB, compared to CS therapy. Especially the OHQ, a questionnaire focusing on orthostatic symptoms (OHSA) and associated activities (OHDAS), showed a significant and, based on Frith and Newton [33] a clinically relevant reduction of symptoms by AB but not by CS. A positive effect of AB on OH-associated symptoms has already been reported by use of the OHQ in a 4-week open-label follow up study [15]. While in an older study with 14 patients superiority of AB over CS stockings for BPD was demonstrated, this was evident in our study only for subjectively reported symptoms [17].

In addition, autonomic dysfunction assessed with the SCOPA-AUT was significantly improved only in the AB intervention but failed to reach significance with CS therapy. Finally, the AB and CS both improved non-motor symptoms (NMSS) compared to no therapy. These results show 1) that the interventions investigated here have indeed an effect that most probably translates into real life but may be detectable/relevant only in the “non-physical activity” area, and 2) that AB therapy may achieve even more effect, compared to CS therapy. Future studies should investigate these aspects on a more granular level, and also test whether the combination of both therapies may lead to additional benefit for the patients.

This trial shows additional, to our best knowledge not yet published results: We observed that continuous compression therapy, somehow contrary to the above-mentioned positive effects patients reported, did not decrease BPD but even increased it. This was significant after one week of treatment with CS (CS+), but not with AB (AB+). This result also tends to speak for the superiority of AB therapy over CS therapy.

Most interestingly, mean BPD increased even further when compression therapy was stopped, even after a short washout phase of 15 min, and reached now significance in both treatment arms compared to baseline. It is conceivable that AB and CS treatment lead to an accelerated decompensation of the blood pressure-regulating system. To our knowledge, this paradox effect of permanent compression therapy has not been described before. All previous studies consistently report positive effects of compression therapy on BPD [5]. There are some possible explanations for this discrepancy. First, permanent compression therapy might reduce physiologic self-regulation of vaso-compression and sympathetic activation as venous pooling and return is taken over by compression of the abdominal splanchnic veins (AB) or femoral veins (CS). This functional loss might result in an even more pronounced BPD in extreme situations as in tilting table tests where additional compensatory mechanisms like activation of the muscle pump cannot be used. However, such situations do rarely occur in daily life. Second, there is evidence that BPD and clinical symptoms may be relatively independent from each other. A study reported that only 23 of 37 patients with a moderate BPD (>20/10 mmHg) had OH-associated symptoms but 14 had not [1], which was confirmed in another, more recent and independent study [34]. The reason(s) for the low association between OH and clinical symptoms are not completely understood, but effective compensation to the variable (peripheral) pressures on the cerebral blood flow level might play a role [35, 36]. Third, a compression therapy might affect the overall feeling of safety which could attenuate OH-associated symptoms reported by patients. Long-term studies with compression therapy are needed to examine a possible habituation effect (on subjective patient reported outcomes). Fourth, in previous studies effects of compression therapy were evaluated after wearing AB or CS just a few hours. Washout times between baseline and compression therapy differed between 20 min [14, 17], 1 h [13] and 1 day [15]. The key difference is the length of time wearing the compression therapy which was 7 days for each device in our study instead of just a few hours. All other factors are less likely to explain the differences. In particular, the applied compression pressures are almost identical to the previous studies [13–17].

Our study has limitations. First, the evaluation was performed in a small patient collective with some heterogeneity that cannot be avoided in such groups, e.g., with regard to medication. A larger case number of participants may have provided more insight, including results from correlation analyses that are not possible with such a small N. However, we consider this a thoroughly performed pilot trial for hypothesis generation, especially as it is, to our best knowledge, the first trial investigating a neurological cohort that used a digital real-life parameter as a primary endpoint. Second, our trial shows surprising results especially concerning BPD, which requires further investigation into the pathophysiology of OH treatment. In subsequent studies, possible discrepancies between patient self-assessment and objective measurement of physical activity should be considered.