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SYSTEMATIC REVIEW

Effectiveness of non-pharmacological interventions to treat orthostatic hypotension in elderly people and people with a neurological condition: a systematic review

Logan, Angela1,2,3; Freeman, Jennifer1,3; Pooler, Jillian4; Kent, Bridie3,5; Gunn, Hilary1; Billings, Sarah6; Cork, Emma7; Marsden, Jonathan1,3

Author Information
doi: 10.11124/JBISRIR-D-18-00005
  • Open

Abstract

Summary of Findings

Introduction

Orthostatic (postural) hypotension (OH) is a common clinical phenomenon in elderly people and people with a neurological condition.1-4 The consensus definition is a sustained drop of at least 20 mmHg in systolic blood pressure (sBP) and/or at least 10 mmHg in diastolic blood pressure (dBP) within three minutes of moving from supine to standing, or following head-up tilt to at least 60 degrees.5,6

Orthostatic hypotension has both non-neurogenic and neurogenic causes and can be acute or chronic.6 Non-neurogenic causes fall into three categories: hypovolemia (reduced blood volume), cardiac pump failure, and venous pooling. Neurogenic OH is associated with neurological diseases and can be caused by abnormalities in either the central nervous system (eg, stroke, spinal cord injury, Parkinson's disease) or peripheral nervous system (eg, Guillain Barré syndrome, diabetic neuropathy).7

Orthostatic hypotension can cause a variety of symptoms and is a common cause of syncope (transient loss of consciousness, rapid onset, and short duration) that may contribute to morbidity, disability, and even death because of the potential risk of substantial injury.5 Other characteristic symptoms include dizziness/light-headedness and pre-syncope; weakness, fatigue, and lethargy; palpitations and sweating; visual disturbances (including blurring, enhanced brightness, and tunnel vision); hearing disturbances (including impaired hearing, crackles, and tinnitus); and neck pain (occipital/para-cervical and shoulder region), low back pain, or precordial pain.8,9 These symptoms relate to the degree of the fall in blood pressure and hypoperfusion (reduced blood flow) of the brain and other organs, and can vary in severity.

The prevalence of OH in elderly people (defined for this review as age 50 years and older10) is high, both in the United Kingdom (UK) and internationally, but varies depending on the characteristics of the population studied. It is more prevalent in elderly people who are hospitalized and institutionalized (up to 68%)11 than in those living in the community (30%),12 likely a reflection of the multiple disease processes, including neurological and cardiac conditions, as well as the type and number of prescribed medications. In addition, orthostatic changes in blood pressure (BP) become more exaggerated after prolonged immobilization.13 The prevalence of OH in people with neurological conditions is also high. Systematic reviews have concluded that OH occurs in approximately 40% of people with Parkinson's disease2 and 50% to 82% of people with spinal cord injury, depending on the level of lesion.3 It is also common in people with stroke,14 occurring in up to 52%.4 Given that stroke predominantly occurs in elderly people, it is possible that the prevalence of OH post-stroke may be much higher. This aligns with current European guidelines, which highlight that OH is under-diagnosed.5

The presence of OH can interfere with and limit rehabilitation, especially after stroke and spinal cord injury where early mobilization (out-of-bed activities such as sitting, standing, and walking within 48 hours) is recommended.15-18 Early mobilization has demonstrated improved functional outcomes17; however, studies of early mobilization in people with acute stroke excluded participants from the intervention arm if they had OH on three consecutive occasions.18,19 Given the high incidence of OH in this population, this exclusion criterion could impact recruitment rates and generalizability of the findings of trials of early mobilization interventions, and ultimately influence the number of people potentially benefitting from these interventions.

The risk of harm with OH must be acknowledged and addressed. In acute and sub-acute stroke, OH has the potential to cause additional brain damage both in the area surrounding the stroke (penumbra) and throughout the brain due to hypoperfusion, a consequence of impaired cerebral autoregulation.20 This may result in increased disability and mortality. Considering this risk of harm, it is surprising that current guidelines for the management of people with stroke15,21,22 do not provide guidance on managing OH.

The goal of managing OH is to increase the patient's standing BP without also increasing their resting BP, and specifically to reduce OH symptoms, increase the time the patient can stand, and improve the patient's ability to perform activities of daily living.23 Currently, there is no specific intervention that achieves all of these goals, despite the multitude of pharmacological and non-pharmacological interventions available. A recent systematic review highlighted that although there were multiple pharmacological interventions available in the UK, Europe, and the United States of America (USA), there is little high-quality data as to which intervention is the best.24 Furthermore, the review concluded that there are limited data on the benefits of long-term pharmacological interventions in people with OH in terms of the effects on postural BP changes as well as symptom relief. The burden of pharmacological interventions also warrants consideration. People with stroke and elderly people are more likely to have multimorbidity25 and thus are at risk of polypharmacy (taking five medications or more).26 Therefore, identifying non-pharmacological interventions to treat OH in elderly people and people with stroke is paramount.

Reviews27 and guidelines5,28 from the USA and Europe for the management of OH recommend non-pharmacological interventions as first-line treatment before progressing to pharmacological interventions. However, people with neurological conditions often have complex needs and severe disability, which means that some non-pharmacological interventions may not be appropriate. For example, undertaking physical maneuvers requires a specific level of mobility and balance, and functional electrical simulation may be contraindicated due to other medical conditions or skin frailty. Therefore, these guideline recommendations cannot be automatically translated to people with neurological conditions, which underpins the rationale for this review. Non-pharmacological interventions for OH, such as compression garments, are used to treat OH in elderly people and those with spinal cord injury and Parkinson's disease,29,30 and could be applicable to people with stroke. However, non-pharmacological interventions are not commonly used, and there is a lack of clear guidance on their use. In line with this, previous reviews of standing in people with neurological conditions31 have highlighted this as a research priority for people with OH, for elderly people, and adults with a neurological disease.32

An initial search of the literature in MEDLINE, Embase, CINAHL, Cochrane Database of Systematic Reviews, and PROSPERO identified one systematic review from Canada examining studies that evaluated non-pharmacological interventions to treat OH.33 However, this review was broad, covering various patient populations and not restricted to elderly people or people with a neurological condition. Furthermore, the review did not focus on any specific outcomes, such as impact on mobilization or functional ability, thus identifying the need for a systematic review in this area. This review, together with a systematic review of pharmacological interventions,24 will allow the development of a protocol to enable the assessment and treatment of OH in elderly people and people with neurological conditions.

Review question

What is the evidence base for non-pharmacological interventions in treating orthostatic hypotension (OH) in elderly people and people with a neurological condition?

Review objectives

The objectives of the review are to determine the effectiveness of non-pharmacological interventions for OH in elderly people and people with a neurological condition.

Inclusion criteria

Participants

The current review considered studies that included participants who were:

  • Diagnosed with OH by a medical professional using criteria such as the International Classification of Diseases and Related Health Problems, 10th revision (ICD-10)34
  • AND
  • Classified as elderly (defined as 50 years or over). Currently, there is no consensus definition of “elderly,” “older,” or “old people,” with 50 years accepted as the definition of elderly people based on the World Health Organization Older Adult Health and Ageing in Africa project10
  • AND/OR
  • Aged 18 years and over with progressive or sudden, non-progressive neurological condition of the central nervous system; peripheral nervous system conditions were excluded.

Participants receiving treatment for acute or chronic OH were included, which encompassed treatment carried out in hospitals, outpatient clinics, in-patient rehabilitation units, and the community (either in their own homes, or in a residential or nursing home setting).

Interventions

The review considered studies that evaluated non-pharmacological interventions to treat OH. These included compression garments (eg, lower limb compression stockings or abdominal corset); neuromuscular stimulation; physical maneuvers (eg, squatting and bending at the waist), and isometric exercises (muscle contractions against a resistant that are not associated with any movement of the limb) for arms, lower limbs, and abdominal muscles during standing; raising the head of bed at night time; or increasing fluid and salt intake. However, a full systematic search identified additional interventions that were considered (eg, frequency and size of meals). Interventions of any duration, frequency, or intensity were considered.

Comparators

The review considered studies that compared the non-pharmacological interventions listed previously with usual care, no intervention, pharmacological interventions, and/or other non-pharmacological interventions.

Outcomes

Outcomes considered included sBP and/or dBP (both sBP and/or dBP in lying and standing using manual or automated device); time to symptoms and time to recovery; resting heart rate (HR) using manual or automatic device; cerebral blood flow using transcranial Doppler or correlation spectroscopy and others; observed and/or perceived symptoms; duration of standing or sitting in minutes; tolerance of therapy (eg, ability to participate in therapy as measured by length and frequency of sessions); function/activities of daily living; other outcomes not previously identified; and adverse events/effects where this information was provided.

Types of studies

This review considered experimental and epidemiological study designs including randomized controlled trials (RCTs), non-RCTs, quasi-experimental, before and after studies, prospective and retrospective cohort studies, and case-control studies. In addition, descriptive epidemiological study designs, including case series, and individual case reports were also considered.

Methods

This systematic review was conducted in accordance with the JBI methodology for systematic reviews of effectiveness35 and according to an a priori protocol (PROSPERO CRD42020167022).36

Search strategy

The initial search was carried out in January 2017 and updated in April 2018, and aimed to find both published and unpublished studies. A three-step search strategy was utilized. An initial limited search of MEDLINE, AMED, CINAHL, and Embase was undertaken, followed by analysis of the text words contained in the title and abstract, and of the index terms used to describe the articles. A second search using all identified keywords and index terms was then undertaken across all included databases. Third, the reference lists of all studies that met the inclusion criteria were searched for additional studies. The search was restricted to studies published in English, as team members were unable to translate other languages. There were no date limits.

Information sources

Databases that were searched included MEDLINE (Ovid), Embase (Ovid), Cochrane Central Register of Controlled Trials, CINAHL, AMED (EBSCO), PEDro, ClinicalTrials.gov, and OpenGrey. A search for unpublished studies was carried out in Google Scholar and Conference Papers Index. Appendix I provides the search strategy from all databases.

Study selection

Following the search, all identified citations were uploaded into EndNote X8 (Clarivate Analytics, PA, USA) bibliographic software37 and duplicates removed. Titles and abstracts were screened by two independent reviewers for assessment against the inclusion criteria for the review. The full text of potentially eligible studies was retrieved and assessed in detail against the inclusion criteria by two independent reviewers. The details of studies that met the inclusion criteria were imported into the JBI System for the Unified Management, Assessment and Review of Information (JBI SUMARI; JBI, Adelaide, Australia).38 Any disagreements that arose between the reviewers were resolved through discussion, or with a third reviewer.

Assessment of methodological quality

Selected studies were critically appraised by two independent reviewers for methodological quality using the standardized critical appraisal instruments from JBI for the following study types: randomized controlled trials, quasi-experimental studies, case control studies, and case reports.39 Disagreements were resolved through discussions, negating the requirement for a third reviewer. In accordance with the aim to be as comprehensive as possible, all studies meeting the inclusion criteria were included in the review, regardless of the quality score.

Data extraction

Quantitative data were extracted from papers using the standardized data extraction tool available in JBI SUMARI39 by two independent reviewers (AL, JM, JP, JF, SB, and EC). The data extracted included specific details about the interventions, populations, study methods, outcomes of significance, and specific objectives.

Authors of papers were contacted to request missing or additional data where required. Thirteen authors were contacted, and responses were received from five.

Data synthesis

Due to the variability and heterogeneity in the parameters of the papers presented, it was not possible to include all papers in the meta-analyses. For papers not included in the meta-analyses, data are presented as mean +/- standard deviation (SD) unless otherwise stated, alongside the narrative summary.

Outcomes for papers included in the meta-analyses were as follows: the change in mean arterial BP between supine and maximum upright stand or tilt (depending on what the studies measured) at the earliest measurement point (eg, selecting measurements at one minute rather than two minutes, if both available). Where mean arterial pressure was not available, it was calculated with constant proportions between dBP and sBP: mean arterial pressure = 1/3 sBP + 2/3 dBP (mmHg).40 Where dBP data were not available, the change in sBP was used. The change in systolic blood pressure from supine to stand or tilted (depending on what the studies measured) at the earliest measurement point was also pooled.

Results were pooled with statistical meta-analysis using RevMan V5.4 (Copenhagen: The Nordic Cochrane Centre, Cochrane). Effect sizes were expressed as standardized mean differences (Hedges g) and their 95% confidence intervals calculated for analysis.41,42 Heterogeneity was assessed statistically using the standard chi-squared and I2 tests. The choice of random effects model and methods for meta-analysis were based on the guidance by Tufanaru et al.43 There were insufficient individualized data to conduct subgroup analyses,39 and insufficient number of studies to generate a funnel plot.44

Assessing certainty in the findings

A Summary of Findings was created using GRADEpro software (McMaster University, ON, Canada) for all studies included in the meta-analysis. The GRADE approach for grading the quality of evidence was followed.45 The Summary of Findings presents the following information, where appropriate: absolute risks for treatment and control, estimates of relative risk, and a ranking of the quality of the evidence based on study limitations (risk of bias), indirectness, inconsistency, imprecision, and publication bias.45-48 The following outcomes were considered critical and were included in the Summary of Findings: mean arterial blood pressure and systolic blood pressure.

Results

Study inclusion

The results of the search and study selection process are presented in Figure 1.49 A total of 4481 potentially relevant studies were identified. Table 1 shows the total number of relevant studies identified for each database. Of those, 1080 were duplicates. From the remaining 3401 records, 3316 were excluded after title and abstract assessment. The eligibility of 85 full-text articles were assessed, 42 of which were excluded. The methodological quality of the remaining 43 studies were assessed, which included 13 randomized control trials, 28 quasi-experimental studies, one case-control study, and one case report.

Figure 1
Figure 1:
PRISMA flowchart of the study selection and inclusion process49
Table 1 - Number of relevant studies identified for each main database
Database Relevant studies identified
MEDLINE (Ovid) 1394
CINAHL (EBSCO) 993
Embase (Ovid) 1401
AMED (EBSCO) 693
Total 4481

Methodological quality

Methodological quality in all studies varied, but were included to provide a comprehensive review.

Table 2 presents the critical appraisal of the 13 RCTs included in the systematic review. True randomization was not used in one study, unclear in six studies, and used in six studies (Q1). Concealed allocation to treatment was used in five studies and unclear in four studies (Q2). Quality criteria relating to blinding of participants, clinicians, and researchers scored poorly in most studies (Q4 and Q5). Follow-up was either complete, or strategies to address incomplete follow-up were utilized in nine studies (Q8), and nine studies analyzed participants in the groups to which they were randomized (Q9).

Table 2 - Critical appraisal of eligible randomized controlled trials
Study Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10 Q11 Q12 Q13
Faghri and Yount70 N N N N N N Y N Y Y Y Y N
Fan et al.54 U U Y N U U Y N Y Y Y Y N
Fanciulli et al.66 U N Y U N N Y Y U Y Y Y Y
Figueroa et al.71 U U Y N N U Y Y N Y Y Y Y
Kanegusuku86 Y Y Y N N N Y Y Y Y Y Y Y
Gorelik et al.80 U U Y N N U Y Y U Y Y Y Y
Luther et al.64 Y N Y N N N Y N Y Y Y Y Y
Phillips et al.83 Y Y U Y Y Y Y Y Y Y Y Y Y
Podoleanu et al.62 Y Y Y Y N N Y Y Y Y Y Y Y
Rocca et al.68 Y Y N N N U Y Y Y Y Y Y Y
Takahagi et al.85 U U Y N U U Y Y Y Y Y Y Y
Taveggia et al.63 Y N Y N N N Y Y Y Y Y Y Y
Vijayakumar et al.87 U Y Y U U U Y U U Y U Y Y
Total % 46 38 77 15 8 8 100 69 69 100 92 100 85
Y = Yes; N = No; U = Unclear; JBI critical appraisal checklist for randomized controlled trialsQ1 = Was true randomization used for assignment of participants to treatment groups?Q2 = Was allocation to treatment groups concealed?Q3 = Were treatment groups similar at baseline?Q4 = Were participants blind to treatment assignment?Q5 = Were those delivering treatment blind to treatment assignment?Q6 = Were outcome assessors blind to treatment assignment?Q7 = Were treatment groups treated identically other than the intervention of interest?Q8 = Was follow-up complete, and if not, were strategies to address incomplete follow-up utilized?Q9 = Were participants analyzed in the groups to which they were randomized?Q10 = Were outcomes measured in the same way for treatment groups?Q11 = Were outcomes measured in a reliable way?Q12 = Was appropriate statistical analysis used?Q13 = Was the trial design appropriate, and any deviations from the standard RCT design (individual randomization, parallel groups) accounted for in the conduct and analysis of the trial?

Table 3 presents the results of the critical appraisal for eligible quasi-experimental studies. Cause and effect was clear in all but one study (Q1). In five studies, Q2 and Q3 were not applicable because there were no comparisons made. There was no control group in nine of the 28 studies (Q4). Question 7 was deemed not applicable to one study because no comparisons were made.

Table 3 - Critical appraisal of eligible quasi-experimental studies
Study Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9
Bouvette et al.72 N N N N Y Y U U Y
Brilla et al.73 Y N/A N/A N Y Y Y Y Y
Denq et al.74 Y Y Y Y Y Y Y Y Y
Elokda et al.75 Y Y Y Y Y N Y Y Y
Faghri et al.76 Y Y Y Y Y N Y Y Y
Gorelik et al.81 Y U U Y Y Y Y Y Y
Gorelik et al.82 Y Y Y Y Y Y Y Y Y
Hamzaid et al.88 Y N/A N/A N Y Y Y Y Y
Henry et al.50 Y N/A N/A N N U Y Y U
Humm et al.51 Y Y Y Y Y Y Y Y Y
Kuznetsov et al.89 Y Y Y Y Y Y Y Y Y
Loew et al.69 Y Y Y Y Y Y Y Y Y
Lopes et al.77 Y Y U Y Y Y Y Y Y
Lucas et al.90 Y Y Y Y Y Y Y Y Y
Mader78 Y Y Y Y Y Y Y Y Y
Puvi-Rajasingham & Mathias52 Y Y Y Y Y Y Y Y Y
Rimaud et al.67 Y Y Y Y Y Y Y Y Y
Shannon et al.65 Y Y Y N Y Y Y Y Y
Smit55 Y Y Y N Y N/A Y Y Y
Smit56 Y Y Y Y Y Y Y Y Y
Ten Harkel et al.58 Y Y Y Y Y Y Y N Y
Ten Harkel et al.57 Y Y U N Y Y Y Y Y
Tutaj et al.92 Y N/A N/A N N Y Y Y Y
van Lieshout et al.59 Y Y N Y Y Y Y U Y
Wadsworth et al.91 Y Y Y Y Y Y Y Y Y
Yoshida et al.84 Y Y Y Y Y Y Y Y Y
Young & Mathias53 Y Y Y Y Y Y Y Y Y
Zion et al.79 Y N/A N/A N Y Y N/A Y Y
Total % 96 91 78 68 93 89 96 89 96
Y = Yes; N = No; U = Unclear; N/A = not applicable; JBI critical appraisal checklist for quasi-experimental studiesQ1 = Is it clear in the study what is the ’cause’ and what is the ’effect’ (i.e., there is no confusion about which variable comes first)?Q2 = Were the participants included in any comparisons similar?Q3 = Were the participants included in any comparisons receiving similar treatment/care, other than the exposure or intervention of interest?Q4 = Was there a control group?Q5 = Were there multiple measurements of the outcome both pre and post the intervention/exposure?Q6 = Was follow up complete and if not, were differences between groups in terms of their follow up adequately described and analyzed?Q7 = Were the outcomes of participants included in any comparisons measured in the same way?Q8 = Were outcomes measured in a reliable way?Q9 = Was appropriate statistical analysis used?

Confounding factors were not identified (Q6) and no strategies to deal with confounding factors were present (Q7) in the case-control study. All other aspects of methodological quality were met (Table 4).

Table 4 - Critical appraisal of eligible case-control study
Study Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10
Galizia et al.61 Y Y Y Y Y N N Y Y Y
Y = Yes; N = No; U = Unclear; JBI critical appraisal checklist for case-control studiesQ1 = Were the groups comparable other than the presence of disease in cases or the absence of disease in controls?Q2 =Were cases and controls matched appropriately;Q3 = Were the same criteria used for identification of cases and controls?Q4 = Was exposure measured in a standard, valid and reliable way?Q5 = Was exposure measured in the same way for cases and controls?Q6 = Were confounding factors identified?Q7 = Were strategies to deal with confounding factors stated?Q8 = Were outcomes assessed in a standard, valid and reliable way for cases and controls?Q9 = Was the exposure period of interest long enough to be meaningful?Q10 = Was appropriate statistical analysis used?

Table 5 presents the critical appraisal results for the eligible case report. The post-intervention clinical condition was not clearly described (Q5), but all other aspects of methodological quality were reported.

Table 5 - Critical appraisal of eligible case report
Study Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8
Helmi60 Y Y Y Y N Y Y Y
Y = Yes; N = No; U = Unclear; JBI critical appraisal checklist for case reportsQ1 = Were patient's demographic characteristics clearly described?Q2 = Was the patient's history clearly described and presented as a timeline?Q3 = Was the current clinical condition of the patient on presentation clearly described?Q4 = Were diagnostic tests or assessment methods and the results clearly described?Q5 = Was the intervention(s) or treatment procedure(s) clearly described?Q6 = Was the post-intervention clinical condition clearly described?Q7 = Were adverse events (harms) or unanticipated events identified and described?Q8 = Does the case report provide takeaway lessons?

Characteristics of included studies

Date of publication of studies ranged from 1984 to 2018, and all were published in English. In the following sections, the main features of these studies are summarized. Detailed information about the settings, participants, methods, interventions, outcomes, and results are provided in Appendix II.

Study settings

Twenty of the included studies were undertaken in Europe (four in United Kingdom,50-53 one in Ireland,54 six in the Netherlands,55-60 three in Italy,61-63 two in Germany,64,65 one in Austria,66 one in France,67 and two in Switzerland68,69). Of the remaining 23 studies, 10 were undertaken in the USA,70-79 three in Israel,80-82 two in Canada,83,84 two in Brazil,85,86 one in India,87 one in Malaysia,88 one in Russia,89 one in New Zealand,90 one in Australia,91 and it was unclear in which country one study was undertaken.92 The interventions described were undertaken in hospital settings,52,53,60,62,68,69,77,80-82,91 rehabilitation facilities,61,63,64,67,75,76,87-89 outpatient clinics or centers,50,54,57,70,74,84,85 laboratories,51,55,56,58,59,65,71,78,83,90 or community settings.66,72,73,79,86 It was unclear in which setting one study was conducted.92

Participants

The 43 studies analyzed included a total of 1069 participants, ranging from one (case report study60) to 128 (quasi-experimental study89). The age range of all participants was reported in 20 studies50,52,55-60,66-68,71,74,75,78,79,83,84,88,91 and was from 18 to 89 years. Twenty-two studies51,53,54,61-64,69,70,72,73,76,77,80-82,85-87,89,90,92 reported mean age. One study reported the age range for participants with autonomic failure and the mean age for nine participants with idiopathic OH.65 There was a total of 440 elderly (≥50 years) participants.

Approximately 48% of all participants were male. Six studies included only males,60,67,75,77,88,90 16 studies included more males than females,50,52,57,63,64,66,68,71,76,78,83,84,86,87,91,92 two studies had an equal number of males and females,53,58 two studies reported the gender of participants with OH/neurological conditions but did not report gender for control participants.59,70

Studies in this systematic review included participants with OH (n = 362), stroke (n = 170), spinal cord injury (n = 86), Parkinson's disease (n = 57), brain injury (n = 28), brain hemorrhage (n = 18), syncope (n = 21), familial dysautonomia (n = 17), primary autonomic/autonomic failure (n = 52), multi-system atrophy (n = 31), cardiac arrhythmias (n = 10), dizziness/palpitations (n = 27), infectious diseases (n = 21), pulmonary edema (n = 10), acute coronary syndrome (n = 11), decompensated heart failure (n = 18), other conditions (n = 39), and also healthy control participants (n = 91). Four of the 1069 participants had both spinal cord injury and OH, and others had multiple conditions.

Inclusion criteria for studies varied. Fourteen studies had OH as an inclusion criterion with a specific definition: 10 studies defined OH as a decrease in sBP of >20mmHg or a decrease in dBP >10mmHg after a change in posture.54,61,66,73,79-82,87,88 Other definitions were a decrease in sBP >30mmHg or a decrease in dBP >15mmHg71; sBP decrease by at least 40mmHg or dBP decrease by at least 30mmHg92; a decrease in sBP of >30mmHg or a decrease in dBP >20mmHg,74 and progressive decrease in BP below a value of 90mmHg.62 Eleven studies had OH as an inclusion criterion but did not provide a definition of OH.50-53,55-59,65,72 Nine studies had an age inclusion criterion of elderly people: ≥50 years,86 ≥60 years,54,79,81,82 or ≥65 years61,69,80 or specified an age range73 (60 to 85 years). Nineteen studies had neurological conditions as an inclusion criterion.60,63,64,66-71,75-77,83,84,86-89,91

Interventions/comparators

Eight non-pharmacological interventions for OH were identified under two general categories: physical modalities (exercise, electrical stimulation, compression, physical counter-maneuvers, compression and physical counter-maneuvers, and sleeping with head up) and dietary measures (food and fluid intake), which aim to treat OH by raising standing blood pressure without raising supine blood pressure to increase the time people can stand and improve their ability to perform activities of daily living.

Physical modalities

Exercise

Exercise included aerobic training using a cycle ergometer, resistance/strength training using resistance bands or weights, passive stepping using robotic tilt tables, and upper limb exercises. Nine studies included in this systematic review evaluated the effects of exercise on OH. Participants included in these studies had spinal cord injury,77 brain injury,61,63,64,68,73,79,85,86 brain haemorrhage,68 stroke,68 neurocardiogenic syncope,85 Parkinson's disease,86 and OH.61,73,79

Four studies63,64,77,85 used tilt tables, three of which63,64,85 used robotic tilt tables where participants with brain injury undertook passive stepping while being tilted up to 65 degrees63,64 and 70 degrees.85 Duration of intervention periods were different: two sessions of sequential testing64 (intended duration of testing in minutes not reported) and 24 sessions, each 30 minutes, three times per week.63 The fourth study77 used a tilt table and included participants with spinal cord injury who performed upper limb exercises while being tilted up to 70 degrees.

The effect of aerobic physical training was used in one study85 for participants with neuro-cardiogenic syncope. Participants undertook a 12-week supervised program of moderate aerobic intensity training using a cycle ergometer. Training took place twice a week and lasted for 35 minutes, and patients were instructed to perform two additional unsupervised sessions.

One study68 examined the effect of passive stepping at 30, 50, and 70 degrees using a robotic tilt table, automated cycling in supine versus standard care (defined as mobilization with physiotherapist), for patients with severe brain injury.

Four studies61,73,79,86 examined the effects of resistance training on elderly people with OH. In one study,61 participants performed 10 full extensions of the ankle, knee, and hip joints of both limbs starting from 60 degrees flexion of hips and 90 degrees flexion of knee and ankle joints against a resistance band (6 kg load) that participants positioned under the soles of their forefeet and firmly held at both ends while supine in bed prior to standing up. Participants in the three remaining studies73,79,86 undertook a home-based resistance program, which incorporated exercises for both upper and lower limbs. These three studies were included in a meta-analysis (Figures 2–4).77

Figure 2
Figure 2:
Change in systolic blood pressure (mmHg) from supine to one-minute standing or 60 degrees head-up tilt following resistance exercise compared with no intervention
Figure 3
Figure 3:
Change in mean arterial blood pressure when moving from supine to one-minute standing or a vertical position on a tilt table following electrical stimulation
Figure 4
Figure 4:
Change in mean arterial blood pressure when moving from supine to one-minute sitting following compression bandaging compared with no intervention

Six studies61,63,68,77,85,86 in the exercise category had a control group that consisted of tilting only,61,63,77 standard care,68,86 and stretching and light walking.85 In one study,64 participants acted as their own controls in a randomized crossover design. Two did not include a control group.73,79

Electrical stimulation

Electrical stimulation is a technique that uses low energy electrical pulses to artificially generate a muscle contraction of paralyzed muscles. When used in a functional context to elicit patterns of movement, it is also referred to as functional electrical stimulation. The studies included in this review used electrical stimulation of upper limbs, lower limbs, and abdomen.

Seven studies examined the effects of electrical stimulation on OH.70,75,76,83,84,88,89 Participants in one study89 had a stroke; the other six studies included people with spinal cord injury. Two papers70,76 reporting on the same study included the same sample and examined the same experimental interventions, differing slightly in the measured outcomes. They compared upright stationary standing versus upright dynamic standing using functional electrical stimulation, both using a standing apparatus for 30 minutes on the same day. Another repeated measures study75 positioned participants in multiple tilt angles (0, 15, 30, 45, and 60 degrees), four minutes at each angle followed by four minutes recovery, repeated with and without electrical stimulation to the lower limb (bilateral knee extensors and ankle plantar flexor muscles). One study88 included two participants who underwent four weeks of electrical stimulation to trunk and lower-limb muscles (rectus abdominis, quadriceps, hamstrings, and gastrocnemius muscles), four times per week for one hour per day. One study83 tested the capacity of electrical stimulation, applied transcutaneously over the spinal cord (approximately corresponding to the T8 spinal segment) to manage OH in participants with spinal cord injury. Two studies84,89 used a robotic tilt table and electrical stimulation to compare passive stepping and passive stepping combined with electrical stimulation.

Use of control group varied: three studies included a control group,48,65,71 two studies55,68 had no control group, and participants acted as their own controls in one study.64,86

Compression

Compression involves using various types of bandages and garments on different body parts, commonly the lower limbs and abdomen. Fourteen studies50,56,60,62,66,67,71,74,80-82,87,90,91 examined the effect of compression on OH. Participants were elderly with OH,50,62,71,80-82 had acute stroke,87 Parkinson's disease,66 neurogenic OH,62,74 autonomic dysfunction,56 spinal cord injury,60,67,91 and healthy older and younger adults.90

Two studies,62,87 both RCTs, examined the effect of compression to both the abdomen and lower limbs. In one study,62 elderly participants with OH wore ankle to thigh bandages for 10 minutes, then an abdominal bandage was added for a further 10 minutes. Participants then wore leggings, which covered from the mid foot to the abdomen, for one month at home. Authors reported that these were worn daily but did not report any recommendations or report usage from follow-up data. In the other study,87 participants with acute stroke wore a pneumatic abdominal binder and pneumatic calf compression for six consecutive sessions for approximately 15 minutes during progressive incline on a tilt table.

Four studies56,66,71,91 examined the effect of abdominal compression on OH. Participants with Parkinson's disease66 were enrolled in a randomized crossover trial. They wore an abdominal binder or placebo binder. Participants then wore an abdominal binder every day (time not specified) for four weeks. The second study,71 a randomized crossover trial, assessed the effects of a conventional or patient-controlled adjustable abdominal binder on OH. Binders were worn for approximately 10 minutes during the testing period. The third study56 tested the effect of abdominal compression (maximal pressure protocol 1 and graded compression protocol 2) of participants with autonomic dysfunction. The fourth study91 enrolled participants with spinal cord injury into a randomized crossover trial. Participants wore an abdominal binder (pressure not reported) daily (time not specified) for six months.

Three studies examined the effect of lower limb compression during tilt tabling,50,60,74 all of which used different compression garments and different pressures on different body parts. In one study,74 participants with neurogenic OH underwent tilt testing with and without compression applied to calves, thighs, and abdomen using an inflatable G-suit to evaluate the impact of compression of different body parts on orthostatic BP and tolerance. Another study,60 a case report, tested one participant with spinal cord injury on a tilt table with and without inflatable external leg compression to bilateral lower limbs. The third study50 tested elastic compression hosiery (tights covering the legs and abdomen) fitted to bilateral lower limbs in elderly participants.

One study67 examined the effects of a wheelchair ergometer with and without graduated compression stockings. Participants with spinal cord injury used the wheelchair ergometer twice: once with garment compression stockings and once without a week later. Additional details are presented in Appendix II.

One study90 examined the effect of compression leggings at normal body temperature and a long-sleeved and legged, two piece, tube-lined perfusion suit at elevated body temperature in healthy elderly people and younger adults.

Three studies80-82 examined the effect of lower limb compression bandages from ankle to thigh on OH. All three studies included elderly participants who were hospitalized due to acute medical conditions,80 decompensated heart failure,81 and OH.82 In all three studies, compression bandages were applied along both legs from ankle to thigh before sitting without compression and repeated with compression. In one study,80 compression was approximately 30 mmHg at the ankle. The remaining two studies used 40 mmHg compression81 and 30 mmHg to 40 mmHg compression82 at the ankle.

In 10 studies, participants acted as their own controls,50,56,66,67,71,74,80-82,90 two studies had a control group,62,87 and two studies had no control group.60,91

Physical counter-maneuvers

Physical counter-maneuvers are specific movements or exercises such as squatting, leg crossing, or tensing specific muscles with the aim of increasing standing BP and reducing OH. Five studies55,57,59,72,92 were identified in the literature search that examined the effect of physical counter-maneuvers on OH, varying in the number and type of maneuvers performed. Participants in these studies had OH due to pure autonomic failure,55,57,59 neurogenic OH,72 and familial dyautomonia.92

One study72 examined the use of multiple physical counter-maneuvers for three to four months following a training period. Training consisted of four training sessions in the laboratory performing the physical counter-maneuvers. Participants were then asked to perform the three selected maneuvers at home for three to four months when symptomatic.

In one study,59 all participants performed leg-crossing and squatting in a fixed order. Participants stood for 10 minutes maximum or until symptoms occurred, then performed leg-crossing in standing for 30 seconds then resumed normal standing. When BP dropped again, participants squatted for 30 seconds then resumed the normal standing position.

In one study,55 participants performed nine different maneuvers, each for one minute serially, separated by 30 to 60 seconds of standing. Participants were asked to sit on seats of varying heights (48 cm, 38 cm, 20 cm), with or without leg-crossing, squatting, and standing in a crossed-leg position with or without additional contraction of the lower limb muscles. All maneuvers were repeated twice and performed in a random order.

One study92 examined the effect of four physical counter-maneuvers (bending forward, squatting, and leg crossing in a random order) in 17 participants with familial dysautonomia. Participants also completed a fourth physical counter-maneuver using abdominal compression.

One study57 compared leg muscle pumping or tensing for one minute, commencing after two minutes of active standing, compared to active standing only.

Three studies did not include a control group,55,72,92 and two studies included a control group.57,59

Physical counter-maneuvers and compression

Two studies used a combination of physical counter-maneuvers and compression. One study56 examined the effects of abdominal compression and physical maneuvers in participants with neurogenic hypotension. Participants maintained a standing position with the abdominal binder and then performed physical maneuvers standing while wearing an anti-gravity suit. For nine participants, the duration of standing was extended (duration not specified) by standing without crossed legs or abdominal compression. As soon as a stable low BP was obtained for 30 seconds, the counter-maneuvers were repeated for 90 seconds, followed by a short period of normal standing. Nine participants (unclear if it was the same nine who undertook extended standing) performed two active standing maneuvers; external abdominal compression was applied by elastic binder.

Another study71 compared the effect of physical counter-maneuvers, one of which was abdominal compression. Participants performed four counter-maneuvers (bending forward, squatting, leg crossing, abdominal compression) in a randomized order and abdominal compression using an inflatable belt. Outcomes were measured before and after.

Sleeping head-up tilt

One study54 examined the effect of sleeping with the head of the bed elevated by 6 inches for six weeks. The control group received no intervention. Another study58 examined the effect of sleeping with the head of the bed elevated with and without pharmacological intervention and 2000 mL water per day. There was no control group, but there was a control period during the first week.

Dietary measures

Food intake

Studies in this category examined the size and frequency of meals and their effect on OH. Three studies52,69,78 examined the effect of food intake on OH.

One study69 tested participants with Parkinson's disease and 10 age-matched controls over two consecutive days to examine the change in sBP induced by meals. They also compared the impact of orthostatic sBP response in participants with Parkinson's disease with that of control participants.

One study78 examined the effect of meal size and the time of day on OH in elderly and young healthy participants.

The final study52 examined the effect of meal size and number of meals in people with autonomic failure. All participants underwent the same conditions: the first day participants ate three meals versus the second day (at least one day apart) when participants ate six meals. Total calorie intake was the same over both days.

Participants acted as their own controls in two studies,52,69 and one study did not include a control group.78

Fluid intake

Ingesting water to increase BP and attenuate OH was examined in three studies.51,53,65 Participants in all three studies drank 480 mL of fluid; however, additional variables such as food intake and exercise were also studied.

One study51 examined the effect of ingesting water before exercise on OH. All participants had severe pre-exercise OH and underwent the same testing using a cycle ergometer. Testing was undertaken on two separate occasions, one in which participants drank 480 mL distilled water.

A second study65 examined the effect of water ingestion and food intake. All participants underwent two protocols. In protocol 1, participants drank 480 mL of tap water; in protocol 2, participants drank 480 mL of water immediately before eating the test meal.

The final study53 in the category examined the effects of drinking 480 mL distilled water. All participants had autonomic failure and underwent the same testing: standing BP was measured before, and 15 and 35 minutes after ingesting of 480 mL distilled water.

Two studies51,65 did not include a control group, and in the third study87 participants acted as their own controls.

Follow-up and measurement intervals

Follow-up periods varied: 30 days,71 one month,56 four weeks,50,68 eight weeks,62,88,59 12 weeks,52,58 three to four months,61 and 14 months.81

Outcomes

A wide variety of outcome measures were used in the included studies. Several outcomes included in this review were not identified a priori and have been highlighted in the limitations section. The most common objective outcomes were sBP and/or dBP, (used in all 43 studies) and HR,51-58,60-65,67-74,77-80,83,85-92 cardiac output,51,53-57,67,70,74,76,90,92 and stroke volume.51,53-57,60,67,70,76,83,84,89,90,92 Other objective outcomes included the following: total peripheral resistance,51,53-56,70,76,90,92 mean arterial pressure,54,70,76,83,88,90-92 mean BP,55,57-59,66,68,72,84,92 oxygen saturations,60,80,81 respiratory rate,68 resistance index,72,89 HR variability,67 stroke index,72 cardiac index,60,72,74 maximum power output,67 maximum systolic velocity,89 minimum diastolic velocity,89 end diastolic index,72 peripheral resistance index,74 end diastolic volume index,74 pulsatility index,89 systemic vascular resistance,57 inferior caval vein,56 femoral vein,56 rate pressure product,76 perfusion index,60 cerebral blood flow,68,89 blood velocity of middle and posterior cerebral artery,83 cerebral vascular resistance,90 calf impedence,92 electrocardiographic RR-intervals,86,92 Valsalva maneuvers,65,86 hyperventilation test,65 cold pressor test,51,65 oxygen uptake,67 end-tidal partial pressure of carbon dioxide,90 peak expiratory flow,91 forced expiratory flow,91 forced vital capacity,91 voice measures,91 interruption of verticalization,64 maximal cardiopulmonary exercise test,85 fluid balance,54,58 esophageal temperature,90 venous blood and plasma samples,68 and edema.54,49

Observed or perceived orthostatic symptoms were measured using a variety of methods. The most common method was self-report,52-55,58,59,75,80-82,84,88 where participants described their symptoms. One study83 asked participants to rank their symptoms from one to 10. Other studies used formal outcome measures: Specific Symptom Scale Questionnaire for Orthostatic Intolerance,62 global symptomatic improvement score,72 Orthostatic Symptom Scale,71 severity of OH symptoms,74 orthostatic tolerance,58 Symptom Change Scale,71 Orthostatic Hypotension Questionnaire,66 OH Daily Activity Scale,66 and OH Symptom Assessment.66

Two studies measured maximum standing time.51,58 Three studies used measures of disability and function: Timed Up and Go Test,79 Barthel Index89 and modified Rankin Scale.87 Other measures were measures of muscle strength,51,65,79,86,89 one repetition maximum,73,86 and electromyography of leg muscles.84

Review findings

Physical modalities

Exercise interventions delivered during tilt tabling demonstrated mixed results. Greater tolerance of verticality and reduced occurrence of OH was observed in three studies.63,64,77 Passive stepping using robotic tilt tables was effective at reducing the number of OH symptoms,63,64 and this was also observed when performing upper limb exercises during verticalization.77 A 12-week aerobic training program85 resulted in an increase in orthostatic tolerance and reduction of positive head-up tilt tests. Lower limb resistance exercises61 were the least effective, resulting in minimal reduction in an initial fall in sBP when moving from supine to standing. No significant absolute or relative difference was observed in any of the BP components with passive cycling or passive stepping.68 However, there was a higher difference in arterial BP in both the intervention groups compared with standard physiotherapy. Three studies73,79,86 investigating the effects of resistance exercise training compared with no intervention were included in a meta-analysis which showed a statistically non-significant difference (SMD = −0.86, 95% CI −2.34, 0.63) (Figure 2). There was substantial heterogeneity (I2 = 90%) and confidence intervals were wide.

Electrical stimulation was favorable but not statistically significant in the five studies not included in the meta-analysis. In these studies, participants using electrical stimulation could stand for longer and had reductions in OH,70,76 demonstrated a longer tolerance time during head-up tilt,88 and had normalized BP.75,83 Meta-analysis of two studies84,89 comparing robotic stepping and electrical stimulation (ROBO-FES) with robotic stepping alone (ROBO) demonstrated a small statistically non-significant effect in favor of ROBO-FES (SMD −0.32, 95% CI −0.80, 0.17). Robotic stepping combined with electrical stimulation (ROBO-FES) compared to control also showed a small non-significant effect in favor of ROBO-FES (SMD −0.44, 95% CI −0.92, 0.04); however, it should be noted that data for this comparison were from one study only (Figure 3).

Compression demonstrated positive results for elderly people with OH and people with neurogenic OH. Two studies62,87 concluded that combined lower limb and abdominal compression improved orthostatic stability in elderly people and people with stroke.

Abdominal compression56,66,71 was shown to reduce OH in elderly people with neurogenic OH. Abdominal compression significantly reduced BP fall upon tilting66 compared to placebo. Symptoms of OH decreased significantly at the four-week follow-up. Abdominal compression was effective at attenuating OH compared with no abdominal compression,71 and symptoms were not affected by type of binder. There was no statistically significant difference with or without abdominal binder91; however, mean arterial BP was higher with the abdominal binder at six weeks and at six months.

Three lower limb compression studies reported positive results. Maximum improvement was observed with all three combinations of compression (calves, thighs, and abdomen),74 and abdominal compression alone significantly reduced OH (P<0.005). Similarly, a significant improvement was observed in elderly people with OH wearing elastic hosiery tights,50 with a reduction of OH at one minute (P<0.01) and at two minutes (P < 0.005). The spinal cord injury case report60 demonstrated that the individual was able to remain in the upright position for longer, allowing improved mobilization during physiotherapy while wearing the inflatable external leg compression. The inflatable external leg compression succeeded in improving pre-syncope symptoms and preventing OH for several hours.

Participants with spinal cord injury demonstrated an increase in sympathetic activity and a decrease in parasympathetic activity after maximal exercise while wearing graduated compression stockings using the wheelchair cycle ergometer.67

Lower limb compression stockings90 caused a passive physical resistance that, upon standing, delayed the maximal drop in mean arterial pressure in both younger adults and elderly people. The authors of the study concluded that compression stockings appeared to reduce venous pooling; however, the total peripheral resistance increased in elderly participants in minute six. There were no differences between groups when heat and orthostatic stress were combined.

Lower limb compression bandages80 decreased OH symptoms in participants who were medically unwell, including 14 with stroke. Approximately 55% of participants experienced symptoms in the un-bandaged group. Significant changes were observed in the un-bandaged group compared to the bandaged group, with significantly greater incidence of palpitations, tachycardia, and decline of oxygen saturation over time (P < 0.04, P < 0.03, P < 0.03, respectively). The authors did not report results for sBP or dBP. Results from the two studies81,82 included in the meta-analysis (Figure 4) indicated a small effect in favor of compression bandaging, however, it was statistically non-significant (SMD −0.16, 95% CI −0.41, 0.09).

Overall, lower limb and abdominal compression,50,62,87 lower limb compression,50,60,67,80-82,90 and abdominal compression56,66,71,91 may be effective in improving OH; however, not all studies were statistically significant.

Physical counter-maneuvers were deemed effective in reducing OH in people with neurogenic OH, if performed correctly.72 Squatting produced the most dramatic change in arterial BP, resulting in longer standing time improved. The follow-up survey identified that the use of the maneuvers varied from once to 11 times per day (3.83 ±3.1 maneuvers per day). However, the follow-up survey was conducted via telephone; therefore, it was unknown whether participants were performing maneuvers correctly.

Leg crossing and squatting59 improved standing BP in people with autonomic failure. After leg crossing, all participants stood for 10 minutes or more (pre-intervention standing times not provided). Time in standing after squatting was not reported.

Leg crossing and leg muscle contractions55 resulted in higher standing BP than without leg muscle contraction. Leg crossing while sitting on 48 cm and 38 cm chairs demonstrated an increase in sitting BP in people with pure autonomic failure.

Leg muscle pumping (tiptoeing and leg crossing)57 had different effects on OH in people with autonomic failure. Tiptoeing did not change BP after one minute in the patient group, but the normative group showed an increase in BP. Leg-crossing increased BP in both groups initially, which was more pronounced in the normative group.

Physical maneuvres92 that significantly increased mean BP included bending forward (P < 0.005), squatting (P < 0.002), and abdominal compression (P < 0.04), but not leg crossing. Squatting and abdominal compression also induced a significant increase in cardiac output during squatting (P < 0.02) and during abdominal compression (P < 0.014).

In summary, physical counter-maneuvers,59,72,92 leg crossing,55,59,92 leg muscle pumping/contractions,55 squatting and bending forward92 improved OH, while tiptoeing did not.57 Leg crossing while sitting on 48 cm and 38 cm chairs demonstrated an increase in sitting BP.55

A combination of abdominal compression and physical counter-maneuvers had a significant effect on standing BP in one study (P < 0.0556) and significant increase in cardiac output in another study (P = 0.0271). However, there were no significant differences in the effect of abdominal compression on the diameter of caval or femoral veins, or compression and arterial pressure response.56

Sleeping with head up reduced BP after one minute of standing (P < 0.01 for sBP).58 Four of the six participants adopted this intervention. Combined treatment (sleeping with head up and pharmacological treatment using fludrocortisone) was most effective, significantly reducing OH symptoms in all patients (P < 0.001) and increasing the maximal standing period to at least 10 minutes compared to 35 to 170 seconds pre-treatment. Sleeping with head up at 6 inches for six weeks had no effect on OH symptoms and BP.54

Dietary measures

Food intake had a negative effect on BP in elderly people and people with neurogenic OH. Participants with Parkinson's disease had a significant (P < 0.01) postprandial sBP drop in supine position compared to healthy controls.69 There was a greater fall in sBP with passive versus active standing in both groups, with a greater postprandial fall in the group with Parkinson's disease. The authors reviewed one meal (lunch) and did not look at all meals throughout an entire day or collect data on the size of meals participants usually ate compared with those provided in the study.

Post-meal BP was lower in all positions52 (lying sBP P < 0.005, lying dBP P < 0.02, sitting dBP P < 0.07, standing dBP P < 0.06) after three large meals. Compared to six meals, sBP and dBP between meals reached lower levels on the three-meal study day. Fewer symptoms were reported during the six-meal study day.

Post-meal supine BP was significantly lower (P < 0.02) in elderly participants.78 Supine sBP and dBP were significantly higher (P < 0.15 and P < 0.001) in the elderly group, but standing sBP and dBP were similar between groups.

Overall, eating smaller, more frequent meals as opposed to larger, less frequent meals resulted in significantly higher supine, sitting, and standing BP and improved OH symptoms in people with autonomic failure, people with neurogenic OH, elderly people, and people with Parkinson's disease.

Fluid intake prior to standing had a positive effect on OH in various positions. Five minutes after drinking water, there was a significant rise in BP in the supine position (P < 0.05).51 With exercise there was a clear fall in BP, which occurred even after water ingestion. Blood pressure remained low after exercise but was significantly higher (P < 0.05) after water intake, resulting in better tolerance of post-exercise standing. Drinking water improved orthostatic tolerance post-exercise. Standing prior to water ingestion caused a significant fall (P < 0.01) in BP in all participants.65 After water ingestion, there was a rise in seated BP. Seated and standing BP at 15 and 35 minutes after water ingestion was significantly higher (P < 0.01 and P < 0.001) than before water, with an improvement in orthostatic symptoms.

Drinking 480 mL of water at room temperature in less than five minutes improved standing BP and orthostatic tolerance in people with autonomic failure.53 The response was similar in patients with multiple system atrophy and those with pure autonomic failure. Water ingested before a meal attenuated postprandial hypotension in these patients. Drinking water also attenuated orthostatic tachycardia in people with idiopathic orthostatic intolerance. Ingestion of water increased BP in supine,70 sitting,78 and standing.78,87 Water ingested prior to a meal also attenuated postprandial hypotension.87

Discussion

This review set out to examine the effectiveness of non-pharmacological interventions to treat OH in elderly people and people with a neurological condition.

Although the literature contained many non-pharmacological interventions to treat OH in these populations, the review highlighted a heterogeneity of methods. The inclusion criteria included some participants who did not have a formal diagnosis of OH prior to entering a study. Many studies included participants with neurological conditions such as Parkinson's disease, brain injury, stroke, and spinal cord injury, but did not specify OH as an inclusion criterion. This may be because OH in neurological conditions is associated with central autonomic dysfunction or the absence of vein blood pump related to lower limb paralysis. Additionally, periods of immobility or prolonged bed rest, which can cause physiological changes such as diminished sympathetic activity,93 in combination with hypovolemia, may also predispose some individuals with neurological conditions to OH. However, the authors did not explicitly provide this as a rationale for their chosen sample.

Thirty-one percent of studies specified OH in their inclusion criteria, but there was heterogeneity in the definitions used, and only 26% provided a definition, which makes meaningful comparison difficult. The most commonly used definition was a sustained drop in sBP of at least 20 mmHg and/or dBP of at least 10 mmHg following a change of posture, which was applied to various postures (standing, tilting [ranging from 15 to 90 degrees tilt angles], or sitting). Other variations used a higher threshold.71,74,92 Using higher thresholds could result in participants being missed during screening. It also raises the question as to whether the lack of standardization observed in these studies is mirrored in clinical practice. The time points at which BP was measured also varied from immediately61,62 to up to 10 minutes73,89 of being upright. Further, the definition of “being upright” varied from 60 to 90 degrees on a tilt table or self-initiated standing, and authors did not acknowledge or discuss the differences between active and passive standing. Verticalization using a tilt table does not fully replicate the physiology of active standing because the exercise reflex and the mechanical squeeze on the venous capacitance and arterial resistance vessels are less.94 Therefore, OH may occur more frequently with tilt-table testing.95

Cerebral hypoperfusion is acknowledged in clinical guidelines5,28 as a common cause of syncope or transient loss of consciousness,96 which is likely to impact standing time and symptoms experienced. Monitoring cerebral blood flow is important in people with acute or sub-acute stroke, because autoregulation is impaired following stroke.20 Two recent meta-analyses97,98 concluded that OH was independently associated with a significantly higher risk of developing coronary heart disease, cardiovascular disease, and heart failure. Despite the relative importance of maintaining cerebral blood flow when standing upright, it was measured in only two studies. One study68 monitored cerebral blood flow, but only in participants with sub-arachnoid hemorrhage and not in participants with ischemic stroke or severe brain trauma. The authors acknowledged the potential risk of impairing cerebral blood flow during mobilization but did not provide a rationale for only monitoring participants with sub-arachnoid hemorrhage. Additionally, they did not provide any data on cerebral blood flow. The second study89 included 104 participants with stroke (128 recruited but 28 dropped out), all of whom had cerebral blood flow measured pre- and post-training. Cerebral blood flow was reduced ≤10%, but participants were asymptomatic. Asymptomatic OH is more common than symptomatic OH,99 which means clinicians may be unaware of the potential risk of further brain damage when these patients are being mobilized or undergoing therapy. As well as measuring cerebral blood flow, future work should investigate what is a clinically important drop in cerebral blood flow.

Which interventions worked?

Overall, the results were mixed. Although effect sizes often favored the intervention in individual studies, meta-analyses of three interventions were statistically non-significant. The effect size for resistance exercise was large, however, confidence intervals were wide and there was substantial heterogeneity. There was a small statistically non-significant effect in favor of electrical stimulation and compression bandaging. It is important to note that in general the sample sizes were small, which may have influenced results. A minimally clinically important difference for mmHg does not exist in relation to OH. However, it is important to acknowledge that small changes in mmHg may result in an important change for individual patients. For example, alleviation of symptoms and ability to undertake activities of daily living. Conversely, for some patients changes in mmHg may be negligible. Of the additional interventions reviewed, physical counter-maneuvers and fluid intake produced favorable results. It is important to consider the feasibility and practicality of these interventions if they are to be implemented into clinical practice.

Physical counter-maneuvers were favorable in reducing OH, for example, but people with balance and mobility problems may find many of the physical maneuvers challenging, and their risk of falling increased. Additionally, performing these physical maneuvers requires the ability to stand and move between sitting and standing, and people with moderate and severe disability would often not be able to perform these movements without mechanical or physical assistance. The resistance training programs may also be unsuitable for people with moderate to severe disability. Several studies used robotic tilt tables and automated cycle ergometers to passively move lower limbs during verticalization, which may be more suitable for people with neurological conditions who have moderate to severe disability. When considering implementation into practice, it is important to consider how accessible this equipment is; robotic tilt tables, for instance, are not routinely available in clinical practice.

Other interventions that may be suitable for people with moderate to severe disability are compression and electrical stimulation. Compression garments, such as compression stockings, may allow repeated safe standing or sitting. They can be used in conjunction with tilt tables and standing frames to facilitate orthostatic tolerance, and are commonly used in spinal cord rehabilitation.100 In stroke, current clinical guidelines recommend intermittent pneumatic compression or graded compression stockings of lower limbs as thromboembolism prophylaxis.101 Therefore, abdominal binders may make it more appropriate as they would not interfere with this. Furthermore, abdominal binders may make it easier for health care providers to monitor skin integrity, and they provide less risk of skin damage. However, abdominal binders are contraindicated for people receiving nutritional support via a gastrostomy tube, because the binder would compress the tube and may cause pain and skin damage. Additionally, people with moderate to severe disability may need assistance to don and doff compression garments.

Electrical stimulation is an adjunctive intervention commonly used in clinical practice to treat muscle impairment.102 Contraindications for electrical stimulation include poor skin integrity, significant autonomic dysreflexia in incomplete spinal cord injury above T6, and uncontrolled epilepsy.103 Only one study provided this information.88 None of the studies discussed the contraindications of using electrical stimulation in clinical practice. However, contractions induced by electrical stimulation of lower limb muscles may activate the skeletal muscle pump as effectively as voluntary contractions of these muscles in people without weakness or disability as a result of stroke or neurological impairment. This may allow patients to stand earlier or for longer during rehabilitation sessions or performing activities of daily living.

Water ingestion had a positive effect on OH and would be suitable for many people. However, stroke and degenerative neurological conditions can cause swallow impairments104; therefore, ingesting water quickly may be unsafe or challenging for these people due to risk of aspiration and aspiration pneumonia. Further, people who have incontinence or reduced mobility that affects their ability to get to the toilet may be reluctant to undertake this intervention. This intervention would also be unsuitable for people who have fluid restriction due to other medical conditions. All three studies tested water ingestion on a one-off basis making the accumulative effects unknown.

Long-term follow-up and prolonged intervention regimes were lacking in most studies. Therefore, it is unknown whether OH improves over time with repeated application of a specific non-pharmacological intervention and whether improvements are sustained, alleviating the need for further intervention over the longer term. None of the studies evaluated instantaneous versus training effects (eg, repeated interventions) of the different OH interventions. For example, an abdominal binder improved OH when it was worn for four weeks,66 but because there was no follow-up beyond this point, it was not known if symptoms returned once it was no longer worn. This warrants different trial designs with longer follow-up periods.

Determining long-term effects is important because studies suggest the cardiovascular system can adapt over time to develop orthostatic tolerance. In spinal cord injury, for example, these adaptations may be due to changes in Rennin–angiotensin–aldosterone activity.105,106 Further, adaptations in the central control of autonomic functions have been identified in healthy animals with prolonged exercise training and may occur over time and with training in people with OH.107

There may be a difference in the short- and long-term effects of the interventions between conditions. Where there is direct damage to autonomic centers, such as in multiple system atrophy108 and Parkinson's disease,109 the potential for adaptive changes may be limited. In contrast, there may be greater potential for central and neuro-hormonal adaptive changes in the elderly and in people after stroke, where causes may be more linked to paralysis and long-term immobility. This highlights the need for future studies to stratify participants according to both their condition and stage or severity of disease. Different conditions have different pathophysiological mechanisms underlying OH110-112 and thus potentially different short- and long-term effects of an intervention.

Limitations

The primary limitation of this review was the heterogeneity of methods of the studies included.

There was significant variability between studies. Most studies had small sample sizes, which limits generalizability of the results. The methodological quality of the included studies varied. For RCTs, randomization was not used or unclear, and blinding in most RCTs was low. Some quasi-experimental studies did not include a comparator or control group. The number of participants included in the meta-analyses varied: electrical stimulation (n = 3889 and n = 1084), compression (n = 5381 and n = 7382), and exercise (n = 5373, n = 1486, and n = 879). The certainty of the evidence was very low for all studies included in the meta-analysis, thus any translation into practice must be tentative. Subgroup analysis was not possible due to insufficient number of studies included in the meta-analysis, as well as inconsistency of reported demographics, medications, and severity of neurological condition using disease-specific validated outcome measures.

Outcomes not previously identified in the protocol development were identified through this systematic review process, and the authors recognize this as a protocol deviation: cardiac output51,53-57,67,70,74,76,90,92 and stroke volume.51,53-57,60,67,70,76,83,84,89,90,92 Other objective outcomes included the following: total peripheral resistance,51,53-56,70,76,90,92 mean arterial pressure,54,70,76,83,88,90-92 mean BP,55,57-59,66,68,72,84,92 oxygen saturations,60,80,81 respiratory rate,68 resistance index,72,89 HR variability,67 stroke index,72 cardiac index,60,72,74 maximum power output,67 maximum systolic velocity,89 minimum diastolic velocity,89 end diastolic index,72 peripheral resistance index,74 end diastolic volume index,74 pulsatility index,89 systemic vascular resistance,57 inferior caval vein,56 femoral vein,56 rate pressure product,76 perfusion index,60 cerebral blood flow,68,89 blood velocity of middle and posterior cerebral artery,83 cerebral vascular resistance,90 calf impedence,92 electrocardiographic RR-intervals,86,92 Valsalva maneuvers,65,86 hyperventilation test,65 cold pressor test,51,65 oxygen uptake,67 end-tidal partial pressure of carbon dioxide,90 peak expiratory flow,91 forced expiratory flow,91 forced vital capacity,91 voice measures,91 interruption of verticalization,64 maximal cardiopulmonary exercise test,85 fluid balance,54,58 esophageal temperature,90 venous blood and plasma samples,68 and edema.54

This review was further limited by the inclusion of only English-language studies.

Conclusion

This review found mixed results for the effectiveness of non-pharmacological interventions to treat OH in people 50 years and older and people with a neurological condition. The settings, participants, outcomes, study designs, and intervention types were heterogeneous, resulting in an inability to include all studies in a meta-analysis. For those interventions that underwent meta-analysis (resistance exercise, electrical stimulation, and compression bandaging), all produced statistically non-significant results. There are several non-pharmacological interventions that may be effective in treating OH but have not resulted in clinically meaningful changes in outcome.

Some interventions may not be suitable for people with moderate to severe disability (eg, they may be unable to stand to perform physical maneuvers or perform resistance training due to weakness). Thus, it is important for clinicians to consider a patient's abilities and impairments when choosing which non-pharmacological interventions to implement.

Recommendations for practice

The findings of this systematic review have several implications for clinicians working with people with neurological conditions and elderly people in both inpatient and community settings. Although meta-analyses were not statistically significant and the GRADE certainty of evidence was very low, on a practical level, physical modalities such as electrical stimulation, lower limb compression, and resistance exercise training could be implemented into rehabilitation sessions for people with stroke, people with neurological conditions, and elderly people with relatively minimal effort.

Many rehabilitation units have cycle ergometers (eg, MOTOmed, Thera Trainers), which patients could use while sitting out, even in specialist wheelchairs. However, depending on the severity of disability, some patients may need supervision to optimize safety. Additionally, many rehabilitation units also have access to functional electrical stimulation (eg, Microstim), which could be incorporated into standing practice to increase the duration of standing and optimize physical activity during rehabilitation sessions. Clinicians need to check whether patients have any contraindications (eg, spinal cord injury above T6, uncontrolled epilepsy, poor skin integrity, cognitive problems).

When OH is problematic, lower limb compression and abdominal binders could be used, both within and outside of rehabilitation sessions, to optimize physical activity. Abdominal binders are easier to don and doff than lower limb compression stockings, making them easier for patients to use independently. For those who require assistance with compression, education of clinicians, carers, and family members is required so that patients can use them within and outside of rehabilitation sessions, and in the community setting.

The applicability of water ingestion for people with neurological conditions has been acknowledged. If patients have been screened by speech and language therapists and deemed to have no swallow impairment, sipping water may be a useful way of managing OH during standing practice.

This review suggests a range of non-pharmacological interventions may be effective in managing OH. Most do not require specialist equipment and training; therefore, the cost of implementation is likely to be minimal. Importantly, from a practical perspective, many of these interventions can be implemented inside or outside of rehabilitation sessions. However, the patient's physical abilities and impairments (eg, cognitive impairment, severity of disability, swallow impairment) should be considered when selecting a non-pharmacological intervention.

Recommendations for future research

This systematic review highlighted heterogeneity in measurement of non-pharmacological interventions to treat OH. Lack of a standardized approach to measurement in OH trials makes consolidation of the body of knowledge difficult, which may negatively impact effective interventions being implemented into clinical practice. A consensus is required when measuring BP at specific time points during standing or verticalization. Further, a consensus is required for measuring OH in people with neurological conditions who have impaired mobility and reduced standing times. Additionally, a core set of outcome measures and standardized time points would facilitate pooling of results in meta-analyses to enable more accurate conclusions to be drawn.

Standardization of inclusion criteria is required to ensure that all participants enrolled in OH intervention studies have OH, either by testing during screening or from a formal diagnosis. Improved consistency of methodology reporting, as recommended by the Consolidated Standards of Reporting Trials guidelines,113 is also recommended. Consistency of reporting demographics, medications, and severity of neurological condition using disease-specific validated outcome measures would allow subgroup analysis.

Funding

This systematic review presents independent research funded by the National Institute for Health Research (NIHR) (Integrated Clinical Academic, Clinical Doctoral Research Fellowship- 2015-01-044). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.

Appendix I: Search strategy

Each of the databases listed below were searched individually as part of one search in January 2017. The search was repeated on April 26 and 27, 2018, to update the search prior to submission for publication. Limiters for all searches: English language. The number of relevant studies identified in each database is shown in Table 1. The number of records identified (number of hits for each search formula) for each database is shown in the results column on the right-hand side of each table. Advice was sought from an information scientist and guidance given to report it in the following ways:

MEDLINE (Ovid)

CINAHL (EBSCO)

Embase (Ovid)

AMED (EBSCO)

PEDro (Physiotherapy Evidence Database)

Cochrane Central Register of Controlled Trials

Clinical Trials Register

OpenGrey

Appendix II: Characteristics of included studies

Eight non-pharmacological interventions for orthostatic hypotension were identified under two general categories: physical modalities (exercise, electrical stimulation, compression, compression and physical counter-maneuvers, physical counter-maneuvers, and sleeping with head up) and dietary measures (food and fluid intake).

Physical modalities

Exercise
Electrical stimulation

Compression

Physical counter-maneuvers
Physical counter-maneuvers and compression
Sleeping with head up

Dietary measures

Food intake

Fluid intake

Fluid intake and exercise

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Keywords:

elderly, older adults; neurological condition; non-pharmacological treatment; orthostatic hypotension

© 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of JBI