The effect of lower limb strengthening exercise on orthostatic blood pressure and the skeletal muscle pump in older people with orthostatic hypotension.

INTRODUCTION: Activation of muscles during standing is recommended to activate the skeletal muscle pump, increasing venous return and increasing blood pressure (BP) in people with orthostatic hypotension (OH). AIM: The aim of this study is to determine if increasing the strength of the lower limb muscles can improve the effectiveness of the venous pump and postural BP in older people with OH. METHODS: Ten older people with OH underwent an 8-week lower limb strengthening intervention. Repeated measurements of orthostatic BP, calf venous ejection fraction (EF) and muscle strength took place before, during and after intervention. RESULTS: The intervention increased calf muscle strength by 21% (interquartile range: 18-28), p = 0.018, from a median baseline of 38 (34-45) kg. Participants had normal levels of venous EF 64% (51-75) at baseline, with little to no venous reflux. The median ejection volume at baseline was 44 (36-58) mL per calf. Despite increasing muscle strength, venous EF did not increase (percentage change -10% (-16 to 24), p = 0.8) and systolic BP drop did not improve (percentage change 0% (-17 to 16), p = 1.0). Similarly, visual analysis of individual case-series trends revealed increasing muscle strength with no clinically meaningful change in EF or orthostatic BP. CONCLUSIONS: Muscle strengthening exercise does not increase the effectiveness of the skeletal muscle pump and is not an efficacious intervention for OH. As there is little to no venous pooling in the calf during standing in older people with OH, below knee compression is unlikely to be clinically effective.

New horizons in the diagnosis and management of dehydration.

Hydration is a fundamental aspect of clinical practice and yet it is an under-researched topic, particularly in older people, leading to many areas of uncertainty. There are two types of dehydration; hypertonic, which is a water deficit, and isotonic, which is a deficit of both water and salt. Individual clinical signs and bedside tests are poor diagnostic tools, making dehydration difficult to identify. However, the diagnostic value of a holistic clinical approach is not known. The gold-standard clinical test for dehydration is serum osmolality, but this cannot diagnose isotonic dehydration and may delay diagnosis in acute situations. Salivary osmolality point-of-care testing is a promising and rapid new diagnostic test capable of detecting both hypertonic and isotonic dehydration in older people, but further evidence to support its clinical utility is needed. Daily fluid requirements may be less than previously thought in adults, but the evidence specific to older people remains limited. Hydration via the subcutaneous route is safer and easier to initiate than the intravenous route but is limited by infusion speed and volume. Prompting older adults more frequently to drink, offering a wider selection of drinks and using drinking vessels with particular features can result in small increases in oral intake in the short-term. The ongoing clinically-assisted hydration at end of life (CHELsea II) trial will hopefully provide more evidence for the emotive issue of hydration at the end of life.

The Effects of Noninvasive Vagus Nerve Stimulation on Fatigue in Participants With Primary Sjögren's Syndrome.

OBJECTIVES: Fatigue is one of the most important symptoms needing improvement in Primary Sjögren's syndrome (PSS). Previous data from our group suggest that noninvasive stimulation of the vagus nerve (nVNS) may improve symptoms of fatigue. This experimental medicine study uses the gammaCore device (electroCore) and a sham device to investigate the relationship between nVNS and fatigue in PSS, and to explore potential mechanisms involved. MATERIALS AND METHODS: Forty participants with PSS were randomly assigned to use active (n = 20) or sham (n = 20) nVNS devices twice daily for 54 days in a double-blind manner. Patient-reported measures of fatigue were collected at baseline and day 56: Profile of Fatigue (PRO-F)-Physical, PRO-F-Mental and Visual Analogue Scale of abnormal fatigue (fVAS). Neurocognitive tests, immunologic responses, electroencephalography alpha reactivity, muscle acidosis, and heart rate variability were compared between devices from baseline to day 56 using analysis of covariance. RESULTS: PRO-F-Physical, PRO-F-Mental, and fVAS scores were significantly reduced at day 56 in the active group only (p = 0.02, 0.02, and 0.04, respectively). Muscle bioenergetics and heart rate variability showed no change between arms. There were significant improvements in digit span and a neurocognitive test (p = 0.03), and upon acute nVNS stimulation, frontal region alpha reactivity showed a significant negative relationship with fatigue scores in the active group (p < 0.01). CONCLUSIONS: We observed significant improvements in three measures of fatigue at day 56 with the active device but not the sham device. Directly after device use, fatigue levels correlate with measures of alpha reactivity, suggesting modulation of cholinergic system integrity as a mechanism of action for nVNS.

A non-academic perspective on the future of lithium-based batteries.

In the field of lithium-based batteries, there is often a substantial divide between academic research and industrial market needs. This is in part driven by a lack of peer-reviewed publications from industry. Here we present a non-academic view on applied research in lithium-based batteries to sharpen the focus and help bridge the gap between academic and industrial research. We focus our discussion on key metrics and challenges to be considered when developing new technologies in this industry. We also explore the need to consider various performance aspects in unison when developing a new material/technology. Moreover, we also investigate the suitability of supply chains, sustainability of materials and the impact on system-level cost as factors that need to be accounted for when working on new technologies. With these considerations in mind, we then assess the latest developments in the lithium-based battery industry, providing our views on the challenges and prospects of various technologies.

Feasibility, reliability and safety of self-assessed orthostatic blood pressure at home.

BACKGROUND: A postural blood pressure assessment is required to diagnose Orthostatic Hypotension. With increasing remote consultations, alternative methods of performing postural blood pressure assessment are required. OBJECTIVE: Determine whether postural blood pressure measurement at home, without a clinician, is reliable, feasible and safe. DESIGN: Service improvement project within a falls and syncope service in Northeast England. SUBJECTS: Eligibility criteria: aged ≥60 years; postural blood pressure measurement is indicated and is physically and cognitively able to perform. Exclusion criteria: nursing home residents, attending clinic in person. METHODS: Postural blood pressure measurements were performed in patients' homes under clinical observation. Patient-led assessments were performed independent of the clinician, following written guidance. This was followed by a clinical-led assessment after 10-minute supine rest. OUTCOMES: Agreement between patient and clinician derived postural blood pressure values and diagnosis of Orthostatic Hypotension; intervention safety, feasibility and acceptability. RESULTS: Twenty-eight patients were eligible and 25 participated (mean age 75, median Clinical Frailty Score five).There was 95% agreement (Cohen's kappa 0.90 (0.70, 1.00)) between patient and clinician derived readings to diagnose orthostatic hypotension.Postural systolic blood pressure drop correlated strongly (r = 0.80), with patient derived readings overestimating by 1 (-6, 3) mmHg. Limits of agreement, determined via Bland Altman analysis, were +17 and -20 mmHg, greater than pre-determined maximum clinically important difference (±5 mmHg).Twenty participants performed valid postural blood pressure assessments without clinical assistance. CONCLUSIONS: Patient-led postural blood pressure assessment at home is a reliable, safe and acceptable method for diagnosing Orthostatic Hypotension.

Blood pressure and heart rate responses to orthostatic challenge and Valsalva manoeuvre in mild cognitive impairment with Lewy bodies.

OBJECTIVES: Orthostatic hypotension is a common feature of normal ageing, and age-related neurodegenerative diseases, in particular the synucleinopathies including dementia with Lewy bodies. Orthostatic hypotension and other abnormal cardiovascular responses may be early markers of Lewy body disease. We aimed to assess whether abnormal blood pressure and heart rate responses to orthostatic challenge and Valsalva manoeuvre would be more common in mild cognitive impairment with Lewy bodies (MCI-LB) than MCI due to Alzheimer's disease (MCI-AD). METHODS: MCI patients (n = 89) underwent longitudinal clinical assessment with differential classification of probable MCI-LB, possible MCI-LB, or MCI-AD, with objective autonomic function testing at baseline. Blood pressure and heart rate responses to active stand and Valsalva manoeuvre were calculated from beat-to-beat cardiovascular data, with abnormalities defined by current criteria, and age-adjusted group differences estimated with logistic models. RESULTS: Orthostatic hypotension and abnormal heart rate response to orthostatic challenge were not more common in probable MCI-LB than MCI-AD. Heart rate abnormalities were likewise not more common in response to Valsalva manoeuvre in probable MCI-LB. An abnormal blood pressure response to Valsalva (delayed return to baseline/absence of overshoot after release of strain) was more common in probable MCI-LB than MCI-AD. In secondary analyses, magnitude of blood pressure drop after active stand and 10-s after release of Valsalva strain were weakly correlated with cardiac sympathetic denervation. CONCLUSIONS: Probable MCI-LB may feature abnormal blood pressure response to Valsalva, but orthostatic hypotension is not a clear distinguishing feature from MCI-AD.

Assessment of autonomic symptoms may assist with early identification of mild cognitive impairment with Lewy bodies.

OBJECTIVES: Autonomic symptoms are a common feature of the synucleinopathies, and may be a distinguishing feature of prodromal Lewy body disease. We aimed to assess whether the cognitive prodrome of dementia with Lewy bodies, mild cognitive impairment (MCI) with Lewy bodies (MCI-LB), would have more severe reported autonomic symptoms than cognitively healthy older adults, with MCI due to Alzheimer's disease (MCI-AD) also included for comparison. We also aimed to assess the utility of an autonomic symptom scale in differentiating MCI-LB from MCI-AD. METHODS: Ninety-three individuals with MCI and 33 healthy controls were assessed with the Composite Autonomic Symptom Score 31-item scale (COMPASS). Mild cognitive impairment patients also underwent detailed clinical assessment and differential classification of MCI-AD or MCI-LB according to current consensus criteria. Differences in overall COMPASS score and individual symptom sub-scales were assessed, controlling for age. RESULTS: Age-adjusted severity of overall autonomic symptomatology was greater in MCI-LB (Ratio = 2.01, 95% CI: 1.37-2.96), with higher orthostatic intolerance and urinary symptom severity than controls, and greater risk of gastrointestinal and secretomotor symptoms. MCI-AD did not have significantly higher autonomic symptom severity than controls overall. A cut-off of 4/5 on the COMPASS was sensitive to MCI-LB (92%) but not specific to this (42% specificity vs. MCI-AD and 52% vs. healthy controls). CONCLUSIONS: Mild cognitive impairment with Lewy bodies had greater autonomic symptom severity than normal ageing and MCI-AD, but such autonomic symptoms are not a specific finding. The COMPASS-31 may therefore have value as a sensitive screening test for early-stage Lewy body disease.

Strategies to improve uptake and adherence of non-pharmacologic interventions for orthostatic hypotension in older people: a qualitative study.

PURPOSE: Non-pharmacologic therapies are a safe and effective treatment for orthostatic hypotension (OH) in older adults. However, adherence to non-drug therapies is challenging and may require specific behaviour change approaches to promote uptake and adherence. The study aim is to identify specific behavioural change techniques to promote uptake and adherence with non-pharmacologic interventions for older adults with OH. METHODS: Forty semi-structured, qualitative interviews were performed in 25 older adults with OH. Each participant experienced bolus-water drinking, physical counter-manoeuvres and compression garments during two efficacy studies. Emergent themes were identified through framework analysis, based on The Behaviour Change Technique Taxonomy. RESULTS: Several themes to encourage uptake and adherence arose. Motivation to adhere with an intervention may be improved by demonstrating its effectiveness, either through symptom monitoring or biofeedback. Practising or rehearsing how to use an intervention may improve self-efficacy and promote habit formation. Embedding therapies into daily life so that they become second nature was felt to be a useful strategy. Educating older adults about why they are being asked to use a therapy and demonstrating how to use it is important. More specific barriers may be overcome by encouraging a personal problem-solving approach. CONCLUSION: These specific behaviour change techniques, derived by older people with OH and based on evidence-based approaches, provide useful strategies to improve the uptake and adherence of non-drug therapies in the treatment of OH. TRIAL REGISTRATION: ISRCTN15084870.

The effects of caffeine in adults with neurogenic orthostatic hypotension: a systematic review.

PURPOSE: To systematically review the evidence base for the effectiveness and safety of caffeine for the treatment of neurogenic orthostatic hypotension in adults. METHODS: Eight electronic databases were searched in January 2021. Original research studies or case reports involving adults with neurogenic orthostatic hypotension were included if caffeine was an intervention and outcomes included symptoms, blood pressure or adverse effects. Relevant studies were screened and underwent qualitative analysis. Insufficient reporting precluded meta-analysis. RESULTS: Five studies were identified: four crossover studies and one case report summation. Study size ranged from 5 to 16 participants. Participants had neurogenic orthostatic hypotension, with a mean standing systolic blood pressure of 86 mmHg. Two studies evaluated caffeine alone. Three studies administered caffeine in combination with ergotamine. Caffeine dose ranged from 100 to 300 mg. Nature and timing of outcomes measured varied between studies, with measurements being recorded from 30 to 480 min after intervention. Caffeine/ergotamine improved symptoms in one study and reduced orthostatic blood pressure drop in two studies. Caffeine/ergotamine increased seated blood pressure in three studies, whilst the results for caffeine alone were inconsistent. No serious adverse events were reported. All studies demonstrated high risk of bias. CONCLUSION: Caffeine should only be considered as a treatment for adults with neurogenic orthostatic hypotension when evidence-based treatments have been exhausted. SYSTEMATIC REVIEW REGISTRATION: PROSPERO ID: CRD42020124589. Date of registration: 30/10/2020.

Orthostatic hypotension: a pragmatic guide to diagnosis and treatment.

Topics for DTB review articles are selected by DTB's editorial board to provide concise overviews of medicines and other treatments to help patients get the best care. Articles include a summary of key points and a brief overview for patients. Articles may also have a series of multiple choice CME questions.

The Prevalence of Orthostatic Hypotension: A Systematic Review and Meta-Analysis.

BACKGROUND: Orthostatic hypotension (OH) is associated with increased risk of falls, cognitive impairment and death, as well as a reduced quality of life. Although it is presumed to be common in older people, estimates of its prevalence vary widely. This study aims to address this by pooling the results of epidemiological studies. METHODS: MEDLINE, EMBASE, PubMed, Web of Science, and ProQuest were searched. Studies were included if participants were more than 60 years, were set within the community or within long-term care and diagnosis was based on a postural drop in systolic blood pressure (BP) ≥20 mmHg or diastolic BP ≥10 mmHg. Data were extracted independently by two reviewers. Random and quality effects models were used for pooled analysis. RESULTS: Of 23,090 identified records, 20 studies were included for community-dwelling older people (n = 24,967) and six were included for older people in long-term settings (n = 2,694). There was substantial variation in methods used to identify OH with differing supine rest duration, frequency and timing of standing BP, measurement device, use of standing and tilt-tables and interpretation of the diagnostic drop in BP. The pooled prevalence of OH in community-dwelling older people was 22.2% (95% CI = 17, 28) and 23.9% (95% CI = 18.2, 30.1) in long-term settings. There was significant heterogeneity in both pooled results (I2 > 90%). CONCLUSIONS: OH is very common, affecting one in five community-dwelling older people and almost one in four older people in long-term care. There is great variability in methods used to identify OH.

Combination non-pharmacologic intervention for orthostatic hypotension in older people: a phase 2 study.

BACKGROUND: orthostatic hypotension (OH) is highly prevalent in older populations and is associated with reduced quality of life and increased mortality. Although non-pharmacologic therapies are recommended first-line, evidence for their use is lacking. OBJECTIVE: determine the efficacy of combination non-pharmacologic therapy for OH in older people. METHODS: a total of 111 orthostatic BP responses were evaluated in this prospective phase 2 efficacy study in 37 older people (≥60 years) with OH. Primary outcome was the proportion of participants whose systolic BP drop improved by ≥10 mmHg. Secondary outcomes include standing BP and symptoms. Comparison is made to the response rate of the most efficacious single therapy (bolus water drinking 56%). Therapeutic combinations were composed of interventions with known efficacy and tolerability: Therapy A- Bolus water drinking + physical counter-manoeuvres (PCM); Therapy B- Bolus water drinking + PCM + abdominal compression. RESULTS: the response rate to therapy A was 38% (95% confidence interval - CI 24, 63), with standing systolic BP increasing by 13 mmHg (95% CI 4, 22). Therapy B was efficacious in 46% (95% CI 31, 62), increasing standing systolic BP by 20 mmHg (95% CI 12, 29). Neither therapy had a significant effect on symptoms. There were no adverse events. CONCLUSIONS: in comparison to single therapy, there is little additional benefit to be gained from combination non-pharmacologic therapy. Focussing on single, efficacious therapies, such as bolus water drinking or PCM, should become standard first-line therapy.

Orthostatic blood pressure changes and physical, functional and cognitive performance: the MELoR study.

PURPOSE: Consensus definitions currently define initial orthostatic hypotension (IOH) as ≥ 40 mmHg systolic (SBP) or ≥ 20 mmHg in diastolic blood pressure (DBP) reductions within 15 s of standing, while classical orthostatic hypotension (COH) is defined as a sustained reduction ≥ 20 mmHg SBP or ≥ 10 mmHg SBP within 3 min of standing. The clinical relevance of the aforementioned criteria remains unclear. The present study aimed to determine factors influencing postural blood pressure changes and their relationship with physical, functional and cognitive performance in older adults. METHODS: Individuals aged ≥ 55 years were recruited through the Malaysian Elders Longitudinal Research (MELoR) study and continuous non-invasive BP was monitored over 5 min of supine rest and 3 min of standing. Physical performance was measured using the timed-up-and-go test, functional reach, handgrip and Lawton's functional ability scale. Cognition was measured with the Montreal Cognitive Assessment. Participants were categorized according to BP responses into four categories according to changes in SBP/DBP reductions from supine to standing: < 20/10 mmHg within 3 min (no OH), ≥ 20/10 mmHg from 15 s to 3 min (COH), ≥ 40/20 mmHg within 15 s and ≥ 20/10 mmHg from 15 s to 3 min (COH + IOH) and ≥ 40/20 mmHg within 15 s and < 20/10 mmHg within 3 min (IOH). RESULTS: A total of 1245 participants were recruited, COH + IOH 623 (50%), IOH 165 (13%) and COH 145 (12%). Differences between groups existed in age, gender, hypertension, diabetes, use of alpha-blocker and/or beta-blocker, ACE-inhibitors, diuretics, biguanides, and baseline systolic BP. In univariate analyses, differences between groups were present in physical performance and cognition. Multivariate comparisons revealed better physical performance in IOH compared to no OH, better physical and cognitive performance in COH + IOH compared to no OH, and cognition in COH than no OH. CONCLUSION: Our findings suggest that older adults who fulfil current consensus definitions for IOH had better physical performance and cognitive scores. This indicates that an initial postural BP drop in people aged ≥ 55 years may not necessarily be associated with increased frailty, as suggested by previously published literature.

Fatigue and cognitive impairment in immune thrombocytopenic purpura remain stable over time: short report from a longitudinal study.

Immune thrombocytopenic purpura (ITP) is an autoimmune disorder characterised by low platelet counts and increased bleeding risk. In 2009, two cross-sectional studies determined that fatigue and cognitive impairment (CI) were common in ITP. Here, we report the results from a longitudinal study of 34 people with ITP. Fatigue severity remained unchanged over 7 years, and CI significantly improved. Future fatigue and CI severity could be predicted using baseline severity scores. These findings may be reassuring for ITP patients, as symptoms remain stable over time. Furthermore, using baseline scores to predict future severity could aid the clinical management of ITP.

Acceptability of non-drug therapies in older people with orthostatic hypotension: a qualitative study.

BACKGROUND: Orthostatic hypotension (OH) is highly prevalent in older populations. It is associated with a reduced quality of life and an increased risk of dementia, stroke and death. Non-pharmalogical therapies are the recommended first-line therapy and are preferred to drug treatments by older people. However, uptake and adherence is low and evidence for their use is lacking. OBJECTIVE: Determine the acceptability of non-pharmalogical interventions for OH in older people. METHODS: This qualitative study, nested within a phase II efficacy study, recruited 25 people aged over 60 years from a Falls and Syncope Clinic. All participants had experienced the following non-pharmalogical therapies within a phase II study: bolus water drinking, compression stockings, abdominal compression, physical counter-manoeuvres. Individual semi-structured qualitative interviews were recorded and transcribed verbatim. Emergent themes were identified through framework analysis of transcripts. RESULTS: Physical counter-manoeuvres were considered the most acceptable therapy as no equipment is required, they can be performed discreetly and are only required during postural change. Bolus water drinking was mostly considered as an acceptable therapy, although there were significant concerns around urinary frequency. The idea of bolus water drinking was a barrier to its uptake, but once experienced it was easier than anticipated. Participants had mixed views on acceptability of abdominal compression whereas compression stockings were considered unacceptable by the majority of participants. This was due to the practicalities of applying/removing the compression and the stigma attached to their appearance. CONCLUSIONS: Current first-line treatment with compression stockings is largely unacceptable to older people with OH, challenging current guidelines. In order to promote uptake and adherence, first line therapy should focus on bolus-water drinking and physical counter-manoeuvres.

Using polyoxometalates to enhance the capacity of lithium-oxygen batteries.

The Keggin-type polyoxometalate α-SiW12O404- increases the discharge capacity and potential of lithium-oxygen batteries, by facilitating the reduction of O2 to Li2O2, as confirmed by in situ electrochemical pressure measurements and XRD. Compared to organic redox mediators, polyoxometalates have higher chemical and structural stability, which could lead to longer cycling lithium-oxygen batteries.

The efficacy of nonpharmacologic intervention for orthostatic hypotension associated with aging.

OBJECTIVE: To determine the efficacy and safety of nonpharmacologic interventions for orthostatic hypotension (OH) secondary to aging. METHODS: A total of 150 orthostatic challenges were performed in 25 older people (age 60-92 years) to determine cardiovascular responses to bolus water drinking, compression stockings, abdominal compression, and physical countermaneuvers. Primary outcome was response rate as assessed by proportion of participants whose systolic blood pressure (SBP) drop improved by ≥10 mm Hg. RESULTS: The response rate to bolus water drinking was 56% (95% confidence interval [CI] 36.7-74.2), with standing SBP increasing by 12 mm Hg (95% CI 4-20). Physical countermaneuvers were efficacious in 44% (95% CI 25.8-63.3) but had little effect on standing SBP (+7.5 mm Hg [95% CI -1 to 16]). Abdominal compression was efficacious in 52% (95% CI 32.9-70.7) and improved standing SBP (+10 mm Hg [95% CI 2-18]). Compression stockings were the least efficacious therapy (32% [95% CI 16.1-51.4]) and had little effect on standing SBP (+6 mm Hg [95% CI -1, 13]). No intervention improved symptoms during standing. There were no adverse events. CONCLUSIONS: Bolus water drinking should become the standard first-line nonpharmacologic intervention, whereas compression stockings should be disregarded in this population. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for older people with OH, bolus water drinking is superior to other nonpharmacologic interventions in decreasing SBP drop.

The Effect of Water on Quinone Redox Mediators in Nonaqueous Li-O2 Batteries.

The parasitic reactions associated with reduced oxygen species and the difficulty in achieving the high theoretical capacity have been major issues plaguing development of practical nonaqueous Li-O2 batteries. We hereby address the above issues by exploring the synergistic effect of 2,5-di-tert-butyl-1,4-benzoquinone and H2O on the oxygen chemistry in a nonaqueous Li-O2 battery. Water stabilizes the quinone monoanion and dianion, shifting the reduction potentials of the quinone and monoanion to more positive values (vs Li/Li+). When water and the quinone are used together in a (largely) nonaqueous Li-O2 battery, the cell discharge operates via a two-electron oxygen reduction reaction to form Li2O2, with the battery discharge voltage, rate, and capacity all being considerably increased and fewer side reactions being detected. Li2O2 crystals can grow up to 30 µm, more than an order of magnitude larger than cases with the quinone alone or without any additives, suggesting that water is essential to promoting a solution dominated process with the quinone on discharging. The catalytic reduction of O2 by the quinone monoanion is predominantly responsible for the attractive features mentioned above. Water stabilizes the quinone monoanion via hydrogen-bond formation and by coordination of the Li+ ions, and it also helps increase the solvation, concentration, lifetime, and diffusion length of reduced oxygen species that dictate the discharge voltage, rate, and capacity of the battery. When a redox mediator is also used to aid the charging process, a high-power, high energy density, rechargeable Li-O2 battery is obtained.

Improving Na-O2 batteries with redox mediators.

A new route to enhance the performance of Na-O2 cells is demonstrated. Redox mediators (such as ethyl viologen) are shown to facilitate the discharge reaction, producing an increased capacity (due to suppressed electrode passivation), higher discharge potential (due to faster kinetics) and stable cycling.