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Cerebral autoregulation (CA) refers to the control of cerebral tissue blood flow (CBF) in response to changes in perfusion pressure. Due to the challenges of measuring intracranial pressure, CA is often described as the relationship between mean arterial pressure (MAP) and CBF. Dynamic CA (dCA) can be assessed using multiple techniques, with transfer function analysis (TFA) being the most common. A 2016 white paper by members of an international Cerebrovascular Research Network (CARNet) that is focused on CA strove to improve TFA standardization by way of introducing data acquisition, analysis, and reporting guidelines. Since then, additional evidence has allowed for the improvement and refinement of the original recommendations, as well as for the inclusion of new guidelines to reflect recent advances in the field. This second edition of the white paper contains more robust, evidence-based recommendations, which have been expanded to address current streams of inquiry, including optimizing MAP variability, acquiring CBF estimates from alternative methods, estimating alternative dCA metrics, and incorporating dCA quantification into clinical trials. Implementation of these new and revised recommendations is important to improve the reliability and reproducibility of dCA studies, and to facilitate inter-institutional collaboration and the comparison of results between studies.

Acute stroke is the leading cause of disability in the UK and a leading cause of mortality worldwide. The majority of patients with ischaemic stroke present with minor deficits or transient ischaemic attack (TIA), and are often first seen by patient-facing clinicians. Urgent evaluation and treatment are important as many patients are at high risk of major vascular events and death within hours to days after the index event. This narrative review summarises the evidence on four antiplatelet treatments for non-cardioembolic stroke prevention: aspirin, clopidogrel, dipyridamole and ticagrelor. Each of these drugs has a unique mechanism and has been tested as a single agent or in combination. Aspirin, when given early is beneficial and short-term treatment with aspirin and clopidogrel has been shown to be more effective in high-risk TIA / minor stroke. This review concludes by highlighting gaps in evidence, including scope for future trials that could potentially change clinical practice.

KEY POINTS We investigated the influence of arterial PCO2 ( PaCO2 ) with and without acute experimental metabolic alkalosis on neurovascular coupling (NVC). We assessed stepwise iso-oxic alterations in PaCO2 prior to and following intravenous NaHCO3 to acutely elevate arterial pH and [HCO3- ]. The NVC response was not altered following NaHCO3 between stepwise PaCO2 stages; therefore, NVC is acutely mediated by PaCO2 rather than the prevailing arterial [H+ ]/pH. The NVC response was attenuated by 27-38% with -10 mmHg PaCO2 and the absolute peak change was reduced by -19% with +10 mmHg PaCO2 irrespective of acutely elevated arterial pH/[HCO3- ]. The NVC kinetics (i.e. time to peak) were markedly slower with hypercapnia versus hypocapnia (24 ± 5 vs. 7 ± 5 s, respectively) likely indicating an influence of resting cerebrovascular tone on NVC responsiveness. ABSTRACT Elevations in cerebral metabolism necessitate appropriate coordinated and localized increases in cerebral blood flow (i.e. neurovascular coupling; NVC). Recent pre-clinical work indicates that arterial PCO2 ( PaCO2 ) mediates NVC independently of arterial/extracellular pH; this has yet to be experimentally tested in humans. The goal of this study was to investigate the hypotheses that: (1) the NVC response would be unaffected by acute experimentally elevated arterial pH; rather, PaCO2 would regulate any changes in NVC; and (2) stepwise respiratory alkalosis and acidosis would each progressively reduce the NVC response. Ten healthy males completed a standardized visual stimulus-evoked NVC test during matched stepwise iso-oxic alterations in PaCO2 (hypocapnia: -5, -10 mmHg; hypercapnia: +5, +10 mmHg) prior to and following intravenous NaHCO3 (8.4%, 50 mEq/50 ml) that elevated arterial pH (7.406 ± 0.019 vs. 7.457 ± 0.029; P 0.05) irrespective of the higher pH (P = 0.002) at each matched stage of PaCO2 (P = 0.417). The absolute peak change was reduced by -19 ± 41% with +10 mmHg PaCO2 irrespective of acutely elevated arterial pH/[HCO3- ] (stage post hoc: P = 0.022). The NVC kinetics (i.e. time to peak) were markedly slower with hypercapnia versus hypocapnia (24 ± 5 vs. 7 ± 5 s, respectively; stage effect: P

Instantaneous arterial pressure-flow (or velocity) relationships indicate the existence of a cerebral critical closing pressure (CrCP), with the slope of the relationship expressed by the resistance-area product (RAP). In 194 healthy subjects (20–82 years, 90 female), cerebral blood flow velocity (CBFV, transcranial Doppler), arterial blood pressure (BP, Finapres) and end-tidal CO2 (EtCO2, capnography) were measured continuously for five minutes during spontaneous fluctuations of BP at rest. The dynamic cerebral autoregulation (CA) index (ARI) was extracted with transfer function analysis from the CBFV step response to the BP input and step responses were also obtained for the BP-CrCP and BP-RAP relationships. ARI was shown to decrease with age at a rate of −0.025 units/year in men (p = 0.022), but not in women (p = 0.40). The temporal patterns of the BP-CBFV, BP-CrCP and BP-RAP step responses were strongly influenced by the ARI (p

The dynamic response of critical closing pressure (CrCP) and resistance-area product (RAP) of the cerebral circulation to a step change in mean arterial pressure can shed light on the nonstationary changes induced by paced hyperventilation and the effects of hypocapnia on the autoregulation of cerebral blood flow. Contrary to hypercapnia, where the response is dominated by CrCP, hypocapnia shows an initial depression of cerebral autoregulation, followed by improvements controlled by changes in RAP.

The population is ageing worldwide, thus increasing the burden of common age-related disorders to the individual, society and economy. Cerebrovascular diseases (stroke, dementia) contribute a significant proportion of this burden and are associated with high morbidity and mortality. Thus, understanding and promoting healthy vascular brain ageing are becoming an increasing priority for healthcare systems. In this review, we consider the effects of normal ageing on two major physiological processes responsible for vascular brain function: Cerebral autoregulation (CA) and neurovascular coupling (NVC). CA is the process by which the brain regulates cerebral blood flow (CBF) and protects against falls and surges in cerebral perfusion pressure, which risk hypoxic brain injury and pressure damage, respectively. In contrast, NVC is the process by which CBF is matched to cerebral metabolic activity, ensuring adequate local oxygenation and nutrient delivery for increased neuronal activity. Healthy ageing is associated with a number of key physiological adaptations in these processes to mitigate age-related functional and structural declines. Through multiple different paradigms assessing CA in healthy younger and older humans, generating conflicting findings, carbon dioxide studies in CA have provided the greatest understanding of intrinsic vascular anatomical factors that may mediate healthy ageing responses. In NVC, studies have found mixed results, with reduced, equivalent and increased activation of vascular responses to cognitive stimulation. In summary, vascular and haemodynamic changes occur in response to ageing and are important in distinguishing “normal” ageing from disease states and may help to develop effective therapeutic strategies to promote healthy brain ageing.

Limited data exist on the optimum level of SBP in thrombolyzed patients with acute ischemic stroke (AIS). We aimed to determine the effects of intensive blood pressure (BP) lowering, specifically in patients with severe AIS who participated in the international, Enhanced Control of Hypertension and Thrombolysis Stroke Study.Prespecificed subgroup analyzes of the BP arm of Enhanced Control of Hypertension and Thrombolysis Stroke Study, a multicenter, partial-factorial, open, blinded outcome assessed trial, in which 2227 thrombolysis-eligible and treated AIS patients with elevated SBP (150 mmHg) were randomized to intensive (target 130-140 mmHg) or guideline-recommended (180 mmHg) BP management. Severe stroke was defined by computed tomography or magnetic resonance angiogram confirmation of large-vessel occlusion, receipt of endovascular therapy, final diagnosis of large artery atheromatous disease, or high (10) baseline neurological scores on the National Institutes of Health Stroke Scale. The primary efficacy outcome was death or any disability (modified Rankin scale scores 2-6). The key safety outcome was intracranial hemorrhage (ICH). Treatment effects estimated in logistic regression models are reported as odds ratios (ORs) with 95% confidence intervals (CIs).There were 1311 patients [mean age 67 years; 37% female; median baseline National Institutes of Health Stroke Scale of 11 (range 6.0-15.0)] with severe AIS. Overall, there was no significant difference in the primary outcome of death or disability. However, intensive BP lowering significantly increased mortality (OR 1.52, 95% CI 1.09-2.13; P = 0.014) compared with guideline BP lowering, despite significantly lowering clinician-reported ICH (OR 0.63, 95% CI 0.43-0.92; P = 0.016).Intensive BP lowering is associated with increased mortality in patients with severe AIS despite lowering the risk of ICH. Further randomized trials are required to provide reliable evidence over the optimum SBP target in the most serious type of AIS.ClinicalTrials.gov Identifier: NCT01422616.

KEY POINTS Dynamic cerebral autoregulation (CA) is often expressed by the mean arterial blood pressure (MAP)-cerebral blood flow (CBF) relationship, with little attention given to the dynamic relationship between MAP and cerebrovascular resistance (CVR). In CBF velocity (CBFV) recordings with transcranial Doppler, evidence demonstrates that CVR should be replaced by a combination of a resistance-area product (RAP) with a critical closing pressure (CrCP) parameter, the blood pressure value where CBFV reaches zero due to vessels collapsing. Transfer function analysis of the MAP-CBFV relationship can be extended to the MAP-RAP and MAP-CrCP relationships, to assess their contribution to the dynamic CA response. During normocapnia, both RAP and CrCP make a significant contribution to explaining the MAP-CBFV relationship. Hypercapnia, a surrogate state of depressed CA, leads to marked changes in dynamic CA, that are entirely explained by the CrCP response, without further contribution from RAP in comparison with normocapnia. ABSTRACT Dynamic cerebral autoregulation (CA) is manifested by changes in the diameter of intra-cerebral vessels, which control cerebrovascular resistance (CVR). We investigated the contribution of critical closing pressure (CrCP), an important determinant of CVR, to explain the cerebral blood flow (CBF) response to a sudden change in mean arterial blood pressure (MAP). In 76 healthy subjects (age range 21-70 years, 36 women), recordings of MAP (Finometer), CBF velocity (CBFV; transcranial Doppler ultrasound), end-tidal CO2 (capnography) and heart rate (ECG) were performed for 5 min at rest (normocapnia) and during hypercapnia induced by breathing 5% CO2 in air. CrCP and the resistance-area product (RAP) were obtained for each cardiac cycle and their dynamic response to a step change in MAP was calculated by means of transfer function analysis. The recovery of the CBFV response, following a step change in MAP, was mainly due to the contribution of RAP during both breathing conditions. However, CrCP made a highly significant contribution during normocapnia (P

Objective Limited data exist to inform blood pressure (BP) thresholds for patients with atrial fibrillation prescribed direct oral anticoagulants (DOAC) therapy in the real world setting. Methods SBP was measured in 9051 primary care patients in England on DOACs for atrial fibrillation with postinitiation BP levels available within the Clinical Practice Research Datalink. The incidence rate for the primary outcome of the first recorded event (defined as a diagnosis of first stroke, recurrent stroke, myocardial infarction, symptomatic intracranial bleed, or significant gastrointestinal bleed) and of secondary outcomes all-cause mortality and cardiovascular mortality were calculated by postinitiation BP groups. Results The Cox proportional hazard ratio of an event [crude and adjusted hazard ratio 1.04 (95% confidence interval (CI) 1.00-1.08), P = 0.077 and 0.071, respectively] did not differ significantly with a 10 mmHg increase in SBP. The hazard of all-cause mortality [crude hazard ratio 0.83 (95% CI 0.80-0.86), P = 0.000; adjusted hazard ratio 0.84 (95% CI 0.81-0.87), P = 0.000] and cardiovascular mortality [crude hazard ratio 0.92 (95% CI 0.85-0.99), P = 0.021; adjusted hazard ratio 0.93 (95% CI 0.86-1.00), P = 0.041] demonstrated a significant inverse relationship with a 10 mmHg increase in SBP. Patients with a SBP within 161-210 mmHg had the lowest all-cause death rate, while patients with SBP within 121-140 mmHg had the lowest cardiovascular death rate. Conclusion SBP values below 161 mmHg are associated higher all-cause mortality, but lower event risk in patients with atrial fibrillation on DOAC therapy. The nadir SBP for lowest event rate was 120 mmHg, for lowest cardiovascular mortality was 130 mmHg and for lowest all-cause mortality was 160 mmHg. This demonstrates a need for a prospective interventional study of BP control after initiation of anticoagulation.

Blood pressure (BP) elevations often complicate the management of intracerebral hemorrhage and aneurysmal subarachnoid hemorrhage, the most serious forms of acute stroke. Despite consensus on potential benefits of BP lowering in the acute phase of intracerebral hemorrhage, controversies persist over the timing, mechanisms, and approaches to treatment. BP control is even more complex for subarachnoid hemorrhage, where there are rationales for both BP lowering and elevation in reducing the risks of rebleeding and delayed cerebral ischemia, respectively. Efforts to disentangle the evidence has involved detailed exploration of individual patient data from clinical trials through meta-analysis to determine strength and direction of BP change in relation to key outcomes in intracerebral hemorrhage, and which likely also apply to subarachnoid hemorrhage. A wealth of hemodynamic data provides insights into pathophysiological interrelationships of BP and cerebral blood flow. This focused update provides an overview of current evidence, knowledge gaps, and emerging concepts on systemic hemodynamics, cerebral autoregulation and perfusion, to facilitate clinical practice recommendations and future research.

Frailty is a distinctive health state in which the ability of older people to cope with acute stressors is compromised by an increased vulnerability brought by age-associated declines in physiological reserve and function across multiple organ systems. Although closely associated with age, multimorbidity, and disability, frailty is a discrete syndrome that is associated with poorer outcomes across a range of medical conditions. However, its role in cerebrovascular disease and stroke has received limited attention. The estimated rise in the prevalence of frailty associated with changing demographics over the coming decades makes it an important issue for stroke practitioners, cerebrovascular research, clinical service provision, and stroke survivors alike. This review will consider the concept and models of frailty, how frailty is common in cerebrovascular disease, the impact of frailty on stroke risk factors, acute treatments, and rehabilitation, and considerations for future applications in both cerebrovascular clinical and research settings.

The relationship between cerebral blood flow and blood pressure is a critical part of investigation of cerebral autoregulation. Conventionally, cerebrovascular resistance (CVR) has been used to describe this relationship, but the underlying principles used for this method is flawed in real-world application for several reasons. Despite this, the use of CVR remains entrenched within current literature. This ‘Point/Counterpoint’ review provides a summary of the flaws in using CVR and explains the benefits of calculating the more accurate critical closing pressure (CrCP) and resistance-area product (RAP) parameters, with support of real-world data.

Introduction: Studies indicate a 13–27% mortality rate following a transient ischaemic attack (TIA). However, outcomes following TIA/minor stroke since the introduction of rapid-access TIA clinics and prompt vascular risk factor intervention are not known. Specifically, there is paucity of data comparing outcomes between people who are diagnosed with an “acute cerebrovascular” (CV) event or an alternative non-cardiovascular diagnosis (non-CV) in a rapid-access TIA clinic. We aimed to assess the mortality in such a setting. Methods: A retrospective observational study was undertaken at the Leicester rapid-access secondary care TIA clinic. Data included information collected at the first clinic visit (including comorbidities, and primary diagnosis, categorized as CV and non-CV) and the date of death for people dying during follow-up. Results: 11,524 subjects were included with 33,164 years of follow-up data; 4,746 (41.2%) received a CV diagnosis. The median follow-up time was 2.75 years (interquartile range 1.36–4.32). The crude mortality rate was 37.3 (95% CI: 35.3–39.5) per 1,000 person-years (PTPY). The mortality rate was higher following a CV diagnosis (50.8 [47.2–54.7] PTPY) compared to a non-CV diagnosis (27.9 [25.7–30.4] PTPY), and for males, older people, those of white ethnicity, and people with orthostatic hypotension (OH). Discussion: This study identified possible risk factors associated with a higher mortality in TIA clinic attendees, who may benefit from specific intervention. Future research should explore the underlying causes and the effect of specific targeted management strategies.

Brain tissue pulsates with each cardiac cycle, however the effect of disease on this natural motion is still unclear. Current literature mainly focuses on healthy brain tissue, with only limited studies looking at disease states such as Chiari malformation and acute ischemic stroke. This case report advances on recent literature by describing the case of a patient with an acute intracerebral hemorrhage and demonstrating an amplified MRI cine of the brain's motion. A clearer understanding of the effects of disease on brain motion may guide clinical application of pulsation measurement.

Background and Purpose: In thrombolysis-eligible patients with acute ischemic stroke, there is uncertainty over the most appropriate systolic blood pressure (SBP) lowering profile that provides an optimal balance of potential benefit (functional recovery) and harm (intracranial hemorrhage). We aimed to determine relationships of SBP parameters and outcomes in thrombolyzed acute ischemic stroke patients. Methods: Post hoc analyzes of the ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study), a partial-factorial trial of thrombolysis-eligible and treated acute ischemic stroke patients with high SBP (150–180 mm Hg) assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) alteplase and intensive (target SBP, 130–140 mm Hg) or guideline-recommended (target SBP Results: Among 4511 included participants (mean age 67 years, 38% female, 65% Asian) lower attained SBP and smaller SBP variability were associated with favorable shift on the modified Rankin Scale (per 10 mm Hg increase: odds ratio, 0.76 [95% CI, 0.71–0.82]; P P =0.025) respectively, but not for magnitude of SBP reduction (0.98, [0.93–1.04]; P =0.564). Odds of intracranial hemorrhage was associated with higher attained SBP and greater SBP variability (1.18 [1.06–1.31]; P =0.002 and 1.34 [1.11–1.62]; P =0.002) but not with magnitude of SBP reduction (1.05 [0.98–1.14]; P =0.184). Conclusions: Attaining early and consistent low levels in SBP Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01422616.

Acute stroke is associated with high morbidity and mortality. In the last decades, new therapies have been investigated with the aim of improving clinical outcomes in the acute phase post stroke onset. However, despite such advances, a large number of patients do not demonstrate improvement, furthermore, some unfortunately deteriorate. Thus, there is a need for additional treatments targeted to the individual patient. A potential therapeutic target is interventions to optimize cerebral perfusion guided by cerebral hemodynamic parameters such as dynamic cerebral autoregulation (dCA). This narrative led to the development of the INFOMATAS (Identifying New targets FOr Management And Therapy in Acute Stroke) project, designed to foster interventions directed towards understanding and improving hemodynamic aspects of the cerebral circulation in acute cerebrovascular disease states. This comprehensive review aims to summarize relevant studies on assessing dCA in patients suffering acute ischemic stroke, intracerebral haemorrhage, and subarachnoid haemorrhage. The review will provide to the reader the most consistent findings, the inconsistent findings which still need to be explored further and discuss the main limitations of these studies. This will allow for the creation of a research agenda for the use of bedside dCA information for prognostication and targeted perfusion interventions.

RationaleDisturbances in dynamic cerebral autoregulation after ischemic stroke may have important implications for prognosis. Recent meta-analyses have been hampered by heterogeneity and small samples.Aim and/or hypothesisThe aim of study is to undertake an individual patient data meta-analysis (IPD-MA) of dynamic cerebral autoregulation changes post-ischemic stroke and to determine a predictive model for outcome in ischemic stroke using information combined from dynamic cerebral autoregulation, clinical history, and neuroimaging.Sample size estimatesTo detect a change of 2% between categories in modified Rankin scale requires a sample size of ∼1500 patients with moderate to severe stroke, and a change of 1 in autoregulation index requires a sample size of 45 healthy individuals (powered at 80%, α = 0.05). Pooled estimates of mean and standard deviation derived from this study will be used to inform sample size calculations for adequately powered future dynamic cerebral autoregulation studies in ischemic stroke.Methods and designThis is an IPD-MA as part of an international, multi-center collaboration (INFOMATAS) with three phases. Firstly, univariate analyses will be constructed for primary (modified Rankin scale) and secondary outcomes, with key co-variates and dynamic cerebral autoregulation parameters. Participants clustering from within studies will be accounted for with random effects. Secondly, dynamic cerebral autoregulation variables will be validated for diagnostic and prognostic accuracy in ischemic stroke using summary receiver operating characteristic curve analysis. Finally, the prognostic accuracy will be determined for four different models combining clinical history, neuroimaging, and dynamic cerebral autoregulation parameters.Study outcome(s)The outcomes for this study are to determine the relationship between clinical outcome, dynamic cerebral autoregulation changes, and baseline patient demographics, to determine the diagnostic and prognostic accuracy of dynamic cerebral autoregulation parameters, and to develop a prognostic model using dynamic cerebral autoregulation in ischemic stroke.DiscussionThis is the first international collaboration to use IPD-MA to determine prognostic models of dynamic cerebral autoregulation for patients with ischemic stroke.

Intracerebral haemorrhage is relatively common and has devastating consequences. Furthermore, non-invasive and invasive strategies to manage raised intracranial pressure remain limited and associated with high morbidity and mortality. We report a case of a 72-year-old male with intracerebral haemorrhage with ventricular extension, hydrocephalus and intracranial hypertension, who was evaluated by transcranial Doppler ultrasound and optic nerve sheath diameter. This case demonstrates that beyond pharmacological and surgical interventions, simple manipulation of arterial carbon dioxide has the propensity to improve cerebral haemodynamic parameters. Our results demonstrate the negative effects of hypercapnia on cerebral autoregulation and the benefits of having transcranial Doppler ultrasound available in the intensive care unit point of care.

Summary With an ageing population and increasing incidence of cerebrovascular disease, an increasing number of patients presenting for routine and emergency surgery have a prior history of stroke. This presents a challenge for pre-, intra-, and postoperative management as the neurological risk is considerably higher. Evidence is lacking around anaesthetic practice for patients with vascular neurological vulnerability. Through understanding the pathophysiological changes that occur after stroke, insight into the susceptibilities of the cerebral vasculature to intrinsic and extrinsic factors can be developed. Increasing understanding of post-stroke systemic and cerebral haemodynamics has provided improved outcomes from stroke and more robust secondary prevention, although this knowledge has yet to be applied to our delivery of anaesthesia in those with prior stroke. This review describes the key pathophysiological and clinical considerations that inform clinicians providing perioperative care for patients with a prior diagnosis of stroke.

Orthostatic hypotension (OH) and atrial fibrillation (AF) are both regarded as independent risk factors for transient ischemic attack (TIA). However, the clinical implication of OH in the presence of AF is unclear. This study investigates, for the first time, the association between blood pressure (BP), OH and mortality in a cohort of patients with AF and TIA symptoms. To investigate the incidence of the association between OH, AF and TIA. This retrospective observational study utilised the Leicester one-stop transient TIA clinic patient database to consider the initial systolic and diastolic BP of 688 patients with a diagnosis of AF. The primary outcome was time until death. Covariant measures included status of AF diagnosis (known or new AF), cardiovascular risk factors, and primary clinic diagnosis [cerebrovascular (CV) versus non-cerebrovascular (non-CV)]. Statistical models adjusted for sex, age, previous AF diagnosis. Mortality rate was higher in the over 85 age group [191.5 deaths per 1000 person years (py) (95% CI 154.0–238.1)] and lower in the aged 75 and younger age group [40.0 deaths per 1000 py (95% CI 27.0–59.2)] compared to intermediate groups. A 10 mmHg increase in supine diastolic BP was associated with a significant reduction in the hazard of mortality for patients suspected of TIA with AF [adjusted HR 0.79 (95% CI 0.68–0.92), p

Introduction It has long been suggested that ultrasound could be used to measure brain tissue pulsations in humans, but potential clinical applications are relatively unexplored. The aim of this systematic review was to explore and synthesise available literature on ultrasound measurement of brain tissue motion in humans. Methods Our systematic review was designed to include predefined study selection criteria, quality evaluation, and a data extraction pro-forma, registered prospectively on PROSPERO (CRD42018114117). The systematic review was conducted by two independent reviewers. Results Ten studies were eligible for the evidence synthesis and qualitative evaluation. All eligible studies confirmed that brain tissue motion over the cardiac cycle could be measured using ultrasound; however, data acquisition, analysis, and outcomes varied. The majority of studies used tissue pulsatility imaging, with the right temporal window as the acquisition point. Currently available literature is largely exploratory, with measurements of brain tissue displacement over a narrow range of health conditions and ages. Explored health conditions include orthostatic hypotension and depression. Conclusion Further studies are needed to assess variability in brain tissue motion estimates across larger cohorts of healthy subjects and in patients with various medical conditions. This would be important for informing sample size estimates to ensure future studies are appropriately powered. Future research would also benefit from a consistent framework for data analysis and reporting, to facilitate comparative research and meta-analysis. Following standardisation and further healthy participant studies, future work should focus on assessing the clinical utility of brain tissue pulsation measurements in cerebrovascular disease states.

Background The importance of junior doctor morale is increasingly being recognised. We aimed to identify and explore the factors affecting junior doctor morale in a UK teaching hospital. Methods We carried out an online survey asking junior doctors to rate their morale, rank the top five factors that positively affected morale and offer free-text comments. Results Nine hundred and forty three junior doctors were approached, 402 (42.6%) responded. Overall morale was rated 6 [interquartile range (IQR): 5-8], and how valued 6 (IQR: 4-8), supported 7 (IQR: 6-9) and autonomous 7 (IQR: 6-8) they felt [median ratings using a scale of 0 (low)-10 (high)]. When comparing the four domains of feeling supported, feeling valued, having autonomy and overall morale, respondents felt most supported overall (n = 402, X2 = 85.6, p < 0.0001). Key themes were identified: team working and relationships, feedback, training and education, resources, wellbeing and pastoral support, staffing and workload, senior clinician support, and autonomy. The most common factors positively affecting morale were ‘feeling part of a team’ (66.4%) and ‘being recognised for good practice’ (56.7%). Conclusion We identified a number of diverse themes affecting junior doctor morale. Doctors felt more supported than valued or autonomous, with complex relationships between these domains.

KEY POINTS Dynamic cerebral autoregulation (CA) is expressed by the temporal pattern of cerebral blood flow (CBF) recovery following a sudden change in arterial blood pressure (BP). Transfer function analysis of BP as input and CBF velocity as output can express dynamic CA through its amplitude (or gain) and phase frequency responses. The upper frequency limit (FupLim ) at which dynamic CA can operate is of considerable physiological interest and can also provide additional information about worsening CA due to disease processes. In healthy subjects FupLim was strongly dependent on arterial PCO2 changes induced by four different breathing manoeuvres. The considerable intersubject variability in FupLim suggests that fixed frequency bands should not be adopted for averaging values of gain and phase in studies of dynamic CA. ABSTRACT Dynamic cerebral autoregulation (CA) can be expressed in the frequency domain by the amplitude and phase frequency responses calculated by transfer function analysis of arterial blood pressure (BP) and cerebral blood flow velocity (CBFV). We studied the effects of arterial PCO2 ( PaCO2 ) on the upper frequency limit (FupLim ) of these responses and its intersubject variability. Twenty-four healthy subjects (11 female, age 36.0 ± 13.4 years) were recruited. Recordings of CBFV (transcranial Doppler ultrasound), BP (Finometer) and end-tidal CO2 ( PETCO2 , capnography) were performed during 5 min at rest (normocapnia) and during four breathing manoeuvres: 5% and 8% CO2 in air and hyperventilation targeting reductions of 5 and 10 mmHg compared to normocapnia. FupLim was determined by the break point of the autoregulation index (ARI) curve as a function of frequency when the phase response was gradually set to zero. The five breathing conditions led to highly significant differences in PETCO2 (p

Purpose: Carbon dioxide (CO2) is a potent cerebral vasomotor agent. Despite reduction in CO2 levels (hypocapnia) being described in several acute diseases, there is no clear data on baseline CO2 values in acute stroke. The aim of the study was to systematically assess CO2 levels in acute stroke. Material and methods: Four online databases, Web of Science, MEDLINE, EMBASE and CENTRAL, were searched for articles that described either partial pressure of arterial CO2 (PaCO2) and end-tidal CO2 (EtCO2) in acute stroke. Results: After screening, based on predefined inclusion and exclusion criteria, 20 studies were retained. There were 5 studies in intracerebral hemorrhage and 15 in ischemic stroke, totalling 660 stroke participants. Acute stroke was associated with a significant decrease in CO2 levels compared to controls. Cerebral haemodynamic studies using transcranial Doppler ultrasonography demonstrated a significant reduction in cerebral blood flow velocities and cerebral autoregulation in acute stroke patients. Conclusion: The evidence from this review suggests that acute stroke patients are significantly more likely than controls to be hypocapnic, supporting the value of routine CO2 assessment in the acute stroke setting. Further studies are required in order to evaluate the clinical impact of these findings.

Healthy ageing has been associated with lower cerebral blood flow velocities (CBFVs); however, the behaviour of hemodynamic parameters associated with cerebrovascular tone (critical closing pressure, CrCP) and cerebrovascular resistance (resistance-area product, RAP) remains unclear. Specifically, evidence supports ageing being associated with greater cerebrovascular tone and resistance during exercise with elevated CrCP and RAP in older individuals at rest and during exercise. Comprehensive hemodynamic assessment of CrCP and RAP during hyperventilation-induced hypocapnia in two distinct age groups (young ≤ 49 and old > 50) has not been described. CBFV in the middle cerebral artery (CBFV, transcranial Doppler), blood pressure (BP, Finometer) and end-tidal CO2 (EtCO2, capnography) were recorded in 104 healthy individuals (43 young [age 33.8 (9.3) years], 61 old [age 64.1 (8.5) years]) during a minimum of 60 s of metronome-driven hyperventilation-induced hypocapnia. Autoregulation index was calculated as a function of time, using a moving window autoregressive-moving average model. CBFV was reduced in response to age (p

Background: Transcranial Doppler Ultrasonography (TCD) can be utilised to measure the tight coupling of cerebral blood flow velocity (CBFv) in response to cognitive demand by task activation, termed neurovascular coupling. Aims: To investigate the differences in neurovascular coupling between healthy older (>50 years) and younger (18-49 years) adults in response to cognitive testing. Methods: Fifty-four older (n=25) and younger (n=29) adults underwent continuous bilateral TCD, beat-to-beat blood pressure (MAP; Finapres), heart rate (HR; electrocardiogram), and end-tidal CO2 (ETCO2; capnography) monitoring. After a 5-min baseline period, memory (M1-4: recalling three learned words, learning a name and address, recalling US presidents and UK prime ministers, and recalling the previously learned name and address) and visuospatial (V1-4: drawing a cube and infinity diagram, drawing a clock face, counting dots, and recognising obscured letters) tasks from the Addenbrooke's Cognitive Examination (ACE-III) were performed. Data are mean (standard deviation). Results: In the memory paradigms, the peak percentage change in CBFv differed significantly between younger and older groups only in the dominant hemisphere during the M1 task, (2.17 (9.16)% vs. 8.38 (9.27)%, respectively, p=0.017). In the visuospatial paradigm, there were also significant differences in peak percentage change in CBFv between younger and older groups in the V1 (5.87 (8.32)% vs. 11.89 (6.60)%, p=0.005) and V2 tasks (6.30 (8.72)% vs. 11.30 (7.77)%, p=0.032). Conclusion: Healthy older adults demonstrate augmented cerebrovascular physiology in response to cognitive challenge compared to younger adults. The impact of abnormal ageing on cerebrovascular physiology, for example, related to cognitively impaired states, requires further investigation.

The Head Positioning in Acute Stroke Trial (HeadPoST) is a pragmatic, international, cluster crossover randomized trial of 11,093 patients with acute stroke assigned to a lying-flat (0°) or sitting-up (head elevated ≥30°) position. This post hoc analysis aimed to determine the association between blood pressure variability (BPV) and outcomes for patients from a wide range of international clinical settings and how the association was modified by randomized head position. BPV was defined according to the standard criteria, with the key parameter considered the coefficient of variation (CV) of systolic BP (SBP) over 24 h. Outcome was ordinal 90-day Modified Rankin Scale (mRS) score. The association was analyzed by ordinal, logistic regression, hierarchical, mixed models with fixed intervention (lying flat vs. sitting up), and fixed period, random cluster, and random cluster-period, effects. Nine thousand one hundred and fifty six (8324 acute ischemic stroke and 817 intracerebral hemorrhage; mean age 68.1 years; 39.2% women) were included in the analysis. CV of SBP had a significant linear association with unfavorable shift of mRS at 90 days (adjusted odds ratio 1.06, 95% confidence interval 1.02–1.11; P = 0.01). There was no heterogeneity of the association by randomized head positioning. In addition, CV of diastolic BP (DBP) (1.08, 1.03–1.12; P = 0.001) over 24 h post stroke was significantly associated with 3-month poor outcome. The association was more apparent in sitting-up position (1.12, 1.06–1.19) compared with lying-flat position (1.03, 0.98–1.09) (P interaction = 0.005). BPV was associated with adverse stroke outcome, and the magnitude of the association was greater with sitting-up head positioning in terms of DBP variability.

The regulation and defense of intracellular pH is essential for homeostasis. Indeed, alterations in cerebrovascular acid-base balance directly affect cerebral blood flow (CBF) which has implications for human health and disease. For example, changes in CBF regulation during acid-base disturbances are evident in conditions such as chronic obstructive pulmonary disease and diabetic ketoacidosis. The classic experimental studies from the past 75+ years are utilized to describe the integrative relationships between CBF, carbon dioxide tension (PCO2 ), bicarbonate (HCO3 - ), and pH. These factors interact to influence 1) the time course of acid-base compensatory changes and the respective cerebrovascular responses (due to rapid exchange kinetics between arterial, extracellular fluid, and intracellular brain tissue). We propose that alterations in arterial [HCO3 - ] during acute respiratory acidosis/alkalosis contribute to cerebrovascular acid-base regulation; and 2) the regulation of CBF by direct changes in arterial versus extravascular/ interstitial PCO2 and pH - the latter recognized as the proximal compartment which alters vascular smooth muscle cell regulation of CBF. Taken together, these results substantiate two key ideas: first, that the regulation of CBF is affected by the severity of metabolic/respiratory disturbances, including the extent of partial/full acid-base compensation. Second, that the regulation of CBF is independent of arterial pH and that diffusion of CO2 across the blood-brain barrier is integral to altering perivascular extracellular pH. Overall, by realizing the integrative relationships between CBF, PCO2 , HCO3 - , and pH, experimental studies may provide insights to improve CBF regulation in clinical practice with treatment of systemic acid-base disorders. This article is protected by copyright. All rights reserved.

Older people are often taking several medications for a number of different medical conditions. Although physicians prescribe medications to treat diseases and symptoms, there may be also harmful side effects, especially so in older people taking several medications. Unfortunately, regular review of the benefits or risks of prescribed medications is as of yet not part of standard care. Also, data on how and in whom to stop medications in older people are scarce. The reason this is an important area of work is that medication related issues in older people are a common cause of harm, including both expected and unexpected effects of medications. Research to date tells us that to ensure successful implementation of structured and appropriate deprescribing, careful planning within hospital systems is needed. This includes involving different members of the team to ensure the patients truly benefit. The themed collection published on the Age and Ageing journal website offers key articles providing tools to assist decision-making, implementation strategies and multidisciplinary interventions—all with the aim of improving patient outcome and sustainability of deprescribing approaches.

Over the last two decades, there have been a number of major landmark clinical trials, classified as “major” as they sought to address clear clinical practice driven questions, in a pragmatic yet robust trial design, using a large powered sample size (n > 1000), in order to help improve patient outcome through informing guidelines. A commonality across all stroke sub-types included in these trials is the tendency to acute hypertensive crises within the acute stroke period. This phenomenon is associated with greater stroke complications and worsened overall prognosis. Multiple trials have attempted to address the issue of acute blood pressure management during the acute stroke period, with consideration for timing, magnitude of lowering, agent and relationship to other interventions. This review will consider the major clinical trials performed in ischaemic and haemorrhagic stroke that test the hypothesis that acute BP reduction improves clinical outcomes.

We investigated the influence of arterialElevations in cerebral metabolism necessitate appropriate coordinated and localized increases in cerebral blood flow (i.e. neurovascular coupling; NVC). Recent pre-clinical work indicates that arterial

In this review we will examine the role of the autonomic nervous system in the control of cerebral blood flow (CBF) in dementia. Worldwide, 55 million people currently live with dementia, and this figure will increase as the global population ages. Understanding the changes in vascular physiology in dementia could pave the way for novel therapeutic approaches. Reductions in CBF have been demonstrated in multiple dementia sub-types, in addition to increased cerebrovascular resistance and reduced vasoreactivity. Cerebral autoregulation (CA) is a key mechanism for the maintenance of cerebral perfusion, but remains largely intact in cognitive disorders, despite reductions in global and regional CBF. However, the tight coupling between neuronal activity and CBF (neurovascular coupling - NVC) is lost in dementia, which may be a key driver of cognitive dysfunction. Despite numerous studies investigating disturbances in the control of CBF in dementia, less is known about the specific mechanisms responsible for the observed changes. Disturbances could be related to one of a number of pathways and mechanisms including disruption of the autonomic component. In this review we will explore clinical and animal studies, which specifically investigated the autonomic component of CBF control in dementia, drawing on the clinical implications and potential for novel biomarker and therapeutic targets.

The Covid-19 pandemic has had an unprecedented effect on surgical practice and healthcare delivery globally. We compared the impact of the care pathways which segregate Covid-19 Positive and Negative patients into two geographically separate sites, on hip fracture patients in our high-volume trauma center in 3 distinct eras - the pre-pandemic period, against the first Covid-19 wave with dual-site service design, as well as the subsequent surge with single-site service delivery. In addition, we sought to invoke similar experiences of centres worldwide through a scoping literature review on the current evidence on "Dual site" reconfigurations in response to Covid-19 pandemic.We prospectively reviewed our hip fracture patients throughout the two peaks of the pandemic, with different service designs for each, and compared the outcomes with a historic service provision. Further, a comprehensive literature search was conducted using several databases for articles discussing Dual-site service redesign.In our in-house study, there was no statistically significant difference in mortality of hip fracture patients between the 3 periods, as well as their discharge destinations. With dual-site reconfiguration, patients took longer to reach theatre. However, there was much more nosocomial transmission with single-site service, and patients stayed in the hospital longer. 24 articles pertaining to the topic were selected for the scoping review. Most studies favour dual-site service reorganization, and reported beneficial outcomes from the detached care pathways.It is safe to continue urgent as well as non-emergency surgery during the Covid-19 pandemic in a separate, geographically isolated site.

INTRODUCTION: Intracerebral haemorrhage (ICH) is associated with high morbidity and mortality. Blood pressure (BP) control is one of the main management strategies in acute ICH. Limited data currently exist regarding intracranial pressure (ICP) in acute ICH. The relationship between BP lowering and ICP is yet to be fully elucidated.METHODS: We conducted a systematic review to investigate the effects of BP lowering on ICP in acute ICH. The study protocol was registered on PROSPERO (CRD42019134470).RESULTS: Following PRISMA guidelines, MEDLINE, EMBASE and CENTRAL were searched for studies on ICH with BP and ICP or surrogate measures. 1096 articles were identified after duplicates were removed; 18 studies meeting the inclusion criteria. Dihydropyridine calcium channel blockers (CCBs) were the most common agent used to lower BP, but had a varying effect on ICP. Other BP-lowering agents used also had a varying effect on ICP.DISCUSSION AND CONCLUSION: Further work, including large observational or randomized interventional studies, is needed to develop a better understanding of the effect of BP lowering on ICP in acute ICH, which will assist the development of more effective management strategies.TRIAL REGISTRATION: The study protocol was registered on PROSPERO (CRD42019134470) on 29/05/2019.

Simulation-based education (SBE) has become a mainstay in medical education. It is a versatile educational technique that can be applied not only to refine psychomotor skills, but also to develop the care pathways, inter-professional behavior, and clinical decision-making needed for practice as a stroke clinician.

Intracerebral haemorrhage (ICH) is associated with high morbidity and mortality. Blood pressure (BP) control is one of the main management strategies in acute ICH. Limited data currently exist regarding intracranial pressure (ICP) in acute ICH. The relationship between BP lowering and ICP is yet to be fully elucidated.We conducted a systematic review to investigate the effects of BP lowering on ICP in acute ICH. The study protocol was registered on PROSPERO (CRD42019134470).Following PRISMA guidelines, MEDLINE, EMBASE and CENTRAL were searched for studies on ICH with BP and ICP or surrogate measures. 1096 articles were identified after duplicates were removed; 18 studies meeting the inclusion criteria. Dihydropyridine calcium channel blockers (CCBs) were the most common agent used to lower BP, but had a varying effect on ICP. Other BP-lowering agents used also had a varying effect on ICP.Further work, including large observational or randomized interventional studies, is needed to develop a better understanding of the effect of BP lowering on ICP in acute ICH, which will assist the development of more effective management strategies.The study protocol was registered on PROSPERO (CRD42019134470) on 29/05/2019.

In the COVID-19 pandemic, patients who are older and residents of long-term care facilities (LTCF) are at greatest risk of worse clinical outcomes. We reviewed discharge criteria for hospitalised COVID-19 patients from 10 countries with the highest incidence of COVID-19 cases as of 26 July 2020. Five countries (Brazil, Mexico, Peru, Chile and Iran) had no discharge criteria; the remaining five (USA, India, Russia, South Africa and the UK) had discharge guidelines with large inter-country variability. India and Russia recommend discharge for a clinically recovered patient with two negative reverse transcription polymerase chain reaction (RT-PCR) tests 24 h apart; the USA offers either a symptom based strategy—clinical recovery and 10 days after symptom onset, or the same test-based strategy. The UK suggests that patients can be discharged when patients have clinically recovered; South Africa recommends discharge 14 days after symptom onset if clinically stable. We recommend a unified, simpler discharge criteria, based on current studies which suggest that most SARS-CoV-2 loses its infectivity by 10 days post-symptom onset. In asymptomatic cases, this can be taken as 10 days after the first positive PCR result. Additional days of isolation beyond this should be left to the discretion of individual clinician. This represents a practical compromise between unnecessarily prolonged admissions and returning highly infectious patients back to their care facilities, and is of particular importance in older patients discharged to LTCFs, residents of which may be at greatest risk of transmission and worse clinical outcomes.

Hypocapnia is known to affect patients with acute stroke and plays a key role in governing cerebral autoregulation. However, the impact of hypocapnia on brain tissue pulsations (BTPs) is relatively unexplored. As BTPs are hypothesised to result from cerebrovascular resistance to the inflow of pulsatile arterial blood, it has also been hypothesised that cerebral autoregulation changes mediated by hypocapnia will alter BTP amplitude. This healthy volunteer study reports measurements of BTPs obtained using transcranial tissue Doppler (TCTD). Thirty participants underwent hyperventilation to induce mild hypocapnia. BTP amplitude, EtCO2, blood pressure, and heart rate were then analysed to explore the impact of hypocapnia on BTP amplitude. Significant changes in BTP amplitude were noted during recovery from hypocapnia, but not during the hyperventilation manoeuvre itself. However, a significant increase in heart rate and pulse pressure and decrease in mean arterial pressure were also observed to accompany hypocapnia, which may have confounded our findings. Whilst further investigation is required, the results of this study provide a starting point for better understanding of the effects of carbon dioxide levels on BTPs. Further research in this area is needed to identify the major physiological drivers of BTPs and quantify their interactions with other aspects of cerebral haemodynamics.

Key points We investigated the influence of arterial P C O 2 ( P aC O 2 ) with and without acutely elevated arterial pH and bicarbonate ([HCO3 - ]) on cerebral blood flow (CBF) regulation in the internal carotid artery and vertebral artery. We assessed stepwise iso-oxic alterations in P aC O 2 (i.e. cerebrovascular CO2 reactivity) prior to and following i.v. sodium bicarbonate infusion (NaHCO3 - ) to acutely elevate arterial pH and [HCO3 - ]. Total CBF was unchanged irrespective of a higher arterial pH at each matched stage of P aC O 2 , indicating that CBF is acutely regulated by P aC O 2 rather than arterial pH. The cerebrovascular responses to changes in arterial H+ /pH were altered in keeping with the altered relationship between P aC O 2 and H+ /pH following NaHCO3 - infusion (i.e. changes in buffering capacity). Total CBF was ∼7% higher following NaHCO3 - infusion during isocapnic breathing providing initial evidence for a direct vasodilatory influence of HCO3 - independent of P aC O 2 levels. Abstract Cerebral blood flow (CBF) regulation is dependent on the integrative relationship between arterial P C O 2 ( P aC O 2 ), pH and cerebrovascular tone; however, pre-clinical studies indicate that intrinsic sensitivity to pH, independent of changes in P aC O 2 or intravascular bicarbonate ([HCO3 - ]), principally influences cerebrovascular tone. Eleven healthy males completed a standardized cerebrovascular CO2 reactivity (CVR) test utilizing radial artery catheterization and Duplex ultrasound (CBF); consisting of matched stepwise iso-oxic alterations in P aC O 2 (hypocapnia: -5, -10 mmHg; hypercapnia: +5, +10 mmHg) prior to and following i.v. sodium bicarbonate (NaHCO3 - ; 8.4%, 50 mEq 50 mL-1 ) to elevate pH (7.408 ± 0.020 vs. 7.461 ± 0.030; P P aC O 2 (P = 0.927). Neither hypocapnic (3.44 ± 0.92 vs. 3.44 ± 1.05% per mmHg P aC O 2 ; P = 0.499), nor hypercapnic (7.45 ± 1.85 vs. 6.37 ± 2.23% per mmHg P aC O 2 ; P = 0.151) reactivity to P aC O 2 were altered pre- to post-NaHCO3 - . When indexed against arterial [H+ ], the relative hypocapnic CVR was higher (P = 0.019) and hypercapnic CVR was lower (P = 0.025) following NaHCO3 - , respectively. These changes in reactivity to [H+ ] were, however, explained by alterations in buffering between P aC O 2 and arterial H+ /pH consequent to NaHCO3 - . Lastly, CBF was higher (688 ± 105 vs. 732 ± 89 mL min-1 , 7% ± 12%; P = 0.047) following NaHCO3 - during isocapnic breathing providing support for a direct influence of HCO3 - on cerebrovascular tone independent of P aC O 2 . These data indicate that in the setting of acute metabolic alkalosis, CBF is regulated by P aC O 2 rather than arterial pH.