Determinants of the dynamic cerebral critical closing pressure response to changes in mean arterial pressure

Objective. Cerebral critical closing pressure (CrCP) represents the value of arterial blood pressure (BP) where cerebral blood flow (CBF) becomes zero. Its dynamic response to a step change in mean BP (MAP) has been shown to reflect CBF autoregulation, but robust methods for its estimation are lacking. We aim to improve the quality of estimates of the CrCP dynamic response. Approach. Retrospective analysis of 437 healthy subjects (aged 18–87 years, 218 males) baseline recordings with measurements of cerebral blood velocity in the middle cerebral artery (MCAv, transcranial Doppler), non-invasive arterial BP (Finometer) and end-tidal CO2 (EtCO2, capnography). For each cardiac cycle CrCP was estimated from the instantaneous MCAv-BP relationship. Transfer function analysis of the MAP and MCAv (MAP-MCAv) and CrCP (MAP-CrCP) allowed estimation of the corresponding step responses (SR) to changes in MAP, with the output in MCAv (SRVMCAv) representing the autoregulation index (ARI), ranging from 0 to 9. Four main parameters were considered as potential determinants of the SRVCrCP temporal pattern, including the coherence function, MAP spectral power and the reconstruction error for SRVMAP, from the other three separate SRs. Main results. The reconstruction error for SRVMAP was the main determinant of SRVCrCP signal quality, by removing the largest number of outliers (Grubbs test) compared to the other three parameters. SRVCrCP showed highly significant (p < 0.001) changes with time, but its amplitude or temporal pattern was not influenced by sex or age. The main physiological determinants of SRVCrCP were the ARI and the mean CrCP for the entire 5 min baseline period. The early phase (2–3 s) of SRVCrCP response was influenced by heart rate whereas the late phase (10–14 s) was influenced by diastolic BP. Significance. These results should allow better planning and quality of future research and clinical trials of novel metrics of CBF regulation

Frailty and cerebrovascular disease: Concepts and clinical implications for stroke medicine.

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

Lipid-lowering pretreatment and outcome following intravenous thrombolysis for acute ischaemic stroke: a post hoc analysis of the enhanced control of hypertension and thrombolysis stroke study trial

Background: Debate exists as to whether statin pretreatment confers an increased risk of 90-day mortality and symptomatic intracranial haemorrhage (sICH) in acute ischaemic stroke (AIS) patients treated with intravenous thrombolysis. We assessed the effects of undifferentiated lipid-lowering pretreatment on outcomes and interaction with low-dose versus standard-dose alteplase in a post hoc subgroup ­analysis of the Enhanced Control of Hypertension and Thrombolysis Stroke Study. Methods: In all, 3,284 thrombolysis-eligible AIS patients (mean age 66.6 years; 38% women), with information on lipid-lowering pretreatment, were randomly assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) intravenous alteplase within 4.5 h of symptom onset. Of the total number of patients, 615 (19%) received statin or other lipid-lowering pretreatment. The primary clinical outcome was combined endpoint of death or disability (modified Rankin Scale scores 2–6) at 90 days. Results: Compared with patients with no lipid-lowering pretreatment, those with lipid-lowering pretreatment were significantly older, more likely to be non-Asian and more likely to have a medical history including vascular co-morbidity. After propensity analysis assessment and adjustment for important baseline variables at the time of randomisation, as well as imbalances in management during the first 7 days of hospital admission, there were no significant differences in mortality (OR 0.85; 95% CI 0.58–1.25, p = 0.42), or in overall ­90-day death and disability (OR 0.85, 95% CI 0.67–1.09, p = 0.19), despite a significant decrease in sICH among those with ­lipid-lowering pretreatment according to the European Co-operative Acute Stroke Study 2 definition (OR 0.49, 95% CI 0.28–0.83, p = 0.009). No differences in key efficacy or safety outcomes were seen in patients with and without lipid-lowering pretreatment between low- and standard-dose alteplase arms. Conclusions: Lipid-lowering pretreatment is not associated with adverse outcome in AIS patients treated with intravenous alteplase, whether assessed by 90-day death and disability or death alone

Neurovascular coupling methods in healthy individuals using transcranial Doppler ultrasonography: A systematic review and consensus agreement

Neurovascular coupling (NVC) is the perturbation of cerebral blood flow (CBF) to meet varying metabolic demands induced by various levels of neural activity. NVC may be assessed by Transcranial Doppler ultrasonography (TCD), using task activation protocols, but with significant methodological heterogeneity between studies, hindering cross-study comparisons. Therefore, this review aimed to summarise and compare available methods for TCD-based healthy NVC assessments. Medline (Ovid), Scopus, Web of Science, EMBASE (Ovid) and CINAHL were searched using a predefined search strategy (PROSPERO: CRD42019153228), generating 6006 articles. Included studies contained TCD-based assessments of NVC in healthy adults. Study quality was assessed using a checklist, and findings were synthesised narratively. 76 studies (2697 participants) met the review criteria. There was significant heterogeneity in the participant position used (e.g., seated vs supine), in TCD equipment, and vessel insonated (e.g. middle, posterior, and anterior cerebral arteries). Larger, more significant, TCD-based NVC responses typically included a seated position, baseline durations >one-minute, extraneous light control, and implementation of previously validated protocols. In addition, complementary, combined position, vessel insonated and stimulation type protocols were associated with more significant NVC results. Recommendations are detailed here, but further investigation is required in patient populations, for further optimisation of TCD-based NVC assessments

Is It Feasible To Manipulate Arterial Carbon Dioxide Levels To Improve Impaired Cerebral Autoregulation In Acute Haemorrhagic Stroke?

Background: Cerebral Autoregulation (CA) is usually defined as the tendency of cerebral blood flow (CBF) to remain approximately constant despite changes in arterial blood pressure (BP) within the range of 50 to 170mmHg. Dynamic CA (dCA) can be estimated from the transient response of CBF to rapid changes in BP. Spontaneous acute intracerebral haemorrhage (ICH) presents a devastating cerebral event with high morbidity and mortality. The mainstay of treatment remains BP control, which relies on a functioning CA. CA has been shown to be impaired in acute ICH. Arterial partial pressure of carbon dioxide (PaCO2) has a strong influence on dCA and other cardio- and cerebro-vascular variables. Understanding the dynamic CA response to physiological manoeuvres, such as exercise and changes in respiratory patterns, has often been confounded by simultaneous changes in PaCO2. Hypercapnia leads to vasodilation of cerebral vessels and overall causes deterioration in CA. Conversely, hypocapnia has a vasoconstrictive effect, improving CA. Aim: The aim of this thesis is to comprehensively model the cerebral haemodynamic response to the entire physiological range of PaCO2 in order to safely permit the assessment of feasibility of clinical translation of a CO2-based intervention into a cohort of acute ICH patients with impaired autoregulation. Objectives: This thesis objectives are to: i) determine the natural history and prognostic implications of CA impairment in acute ICH; ii) determine if the use of current CO2 measurement techniques leads to significant differences in CO2-related systemic and cerebrovascular parameters; iii) determine the most appropriate method of initiating and maintaining hypocapnia; iv) determine if key cerebral haemodynamic parameters including autoregulation index (ARI), arterial BP (BP), heart rate (HR), critical closing pressure (CrCP) and resistance-area product (RAP) follow a logistic non-linear model similar to those described for cerebral blood flow velocity (CBFV); v) investigate sex differences in cerebral haemodynamics across the physiological range of PaCO2 and vi) determine whether hypocapnia (via hyperventilation) in acute ICH may improve CA and consequently clinical outcome. Methods: CA was measured in healthy and acute ICH patients by transcranial Doppler ultrasound assessment of middle cerebral artery velocities alongside continuous non-invasive monitoring of BP. Results: 45 healthy volunteers underwent a multi-step protocol inducing hypo- and hyper-capnia and 12 acute ICH patients underwent a metronome based hypocapnic intervention at <48 hours and 10-14 days. The thesis results demonstrated i) the aforementioned parameters follow a logistic curve relationship; ii) CBFV is lower and dCA is impaired in acute ICH as compared to healthy controls; iii) different EtCO2 measurement techniques do lead to physiological changes and differences in parameter values; iv) dysautoregulation can be minimised by continuous metronome use during hyperventilation-induced hypocapnia; v) logistic curve parameters are influenced by sex and vi) dCA can be improved in acute ICH using a CA targeted CO2-based interventional manoeuvre. Conclusion: This thesis presents a new paradigm for assessment of the interaction of CO2 and dCA and its potential clinical applications. In addition, original findings include improved understanding of CO2 focussed physiological measurement protocol design, comprehensive clarification of cerebral haemodynamics in ICH, optimisation of hypocapnia induction, demonstration of novel sex differences during PaCO2 change and via accumulation of the aforementioned knowledge, the safety and feasibility of a novel CA targeted CO2-based interventional manoeuvre in acute ICH

Review of major trials of acute blood pressure management in stroke

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 \u3e 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

Appropriate deprescribing in older people: a challenging necessity Commentary to accompany themed collection on deprescribing

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