Research Summary (Stroke Medicine)

Research Interests of Professor Thompson G Robinson, Department of Cardiovascular Sciences, University of Leicester

Stroke is an important cause of morbidity and mortality; newly affecting nearly 100,000 individuals per annum in the United Kingdom. It is the third highest cause of UK mortality, and the single most important neurological cause of long-term disability; costing the UK economy approximately £8 billion per annum in health, social and indirect costs. Hypertension is the single most important modifiable risk factor in the primary and secondary prevention of ischaemic and haemorrhagic stroke. Therefore, my overall research interest relates to the study of cerebral haemodynamics, and in particular the impact of changes in cerebral haemodynamic control mechanisms on the management of blood pressure, blood pressure variability and other physiological perturbations following acute stroke through undertaking randomised controlled trials and other well-designed studies. There is also an exciting opportunity to extend the cerebral haemodynamic studies to other conditions, including cognitive impairment, which allies to another National Institute of Health Research priority research area.

My current research programme focuses around the following main areas:

(A) Acute stroke blood pressure management: individual patient meta-analysis and new clinical trials

As Chief Investigator of the Health Foundation and Stroke Association-funded Continue Or Stop post-Stroke Anithypertensives Collaborative Study (COSSACS, Lancet Neurol 2010) and the Department of Health Research and Development Health Technology Assessment Programme- funded Controlling Hypertension and Hypotension Immediately Post Stroke study (CHHIPS, Lancet Neurol 2009) trials, and UK Co-ordinating Investigator of the INTEnsive blood pressure Reduction in Acute intraCerebral haemorrhage Trial 2 (INTERACT2 trial, New Engl J Med 2013), my research has informed US (Jauch et al, Stroke 2013; Hemphill et al, Stroke 2015) and European (Steiner et al, Int J Stroke 2014) guidelines for the management of this common acute stroke management problem.
I am also part of the international Blood Pressure in Acute Stroke Collaboration. With the recent and forthcoming completion of a number of major acute stroke blood pressure trials, this collaboration plans a number of individual patient meta-analyses to inform international guidelines and outline future research priorities, and I am actively involved in the following areas: continue or stop pre- existing antihypertensive medication following acute stroke; effect of treatment delay, stroke type, and thrombolysis on the effect of glyceryl trinitrate, a nitric oxide donor, on outcome after acute stroke; blood pressure management in acute intracerebral haemorrhage; blood pressure management in acute ischaemic stroke; and blood pressure management in the context of acute reperfusion therapies including intravenous thrombolysis following acute ischaemic stroke.

I am the UK Co-ordinating Investigator of the Enhanced Control of Hypertension And Thrombolysis trial (ENCHANTED, internationally funded by the Australian National Health and Medical Research Council), as well as Principal Applicant on the Stroke Association grant funding the UK contribution to this international trial. This is an international, multicentre, quasifactorial, randomised controlled trial to explore the effects of low- versus standard-dose rtPA, and guideline versus intensive blood pressure-lowering in acute ischaemic stroke patients on 3-month death and dependency and 7-day symptomatic intracerebral haemorrhage rates. The thrombolysis dose arm was published in the New England Journal of Medicine in May 2015, and the blood pressure-lowering arm will continue until 2018 and is funded by the Australian National Health and Medical Research Council (Co-Applicant) and Stroke Association (Principal Applicant).

I am a Co-Applicant on the British Heart Foundation-funded Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial 2 (RIGHT2). This is a UK single-blind, randomised, multi- centre, parallel group study, designed to assessment the safety and efficacy of transdermal glyceryl trinitrate, a nitric oxide donor, in ultra-acute stroke by paramedic administration in an ambulance setting within 4 hours of stroke onset. A total of 825 patients will be recruited from up to eight UK Ambulance Trusts serving a minimum of six hyperacute stroke centres over a 3-year period; recruitment commencing 2015. Treatment with GTN or placebo will continue for a 4-day period, with the primary outcome of shift in death/ dependence/ independence on the Modified Rankin scale assessed at 90 days, and secondary outcomes assessed up to one year from randomisation.

(B) Studies assessing the manipulation of blood pressure and blood pressure variability for secondary stroke prevention

Hypertension is the single most important modifiable risk factor for first and recurrent stroke; the risk of recurrent stroke after transient ischaemic attack or minor non-disabling stroke being highest during the first few weeks. Therefore, another important strand to my research is to undertake primary and implementation research on blood pressure manipulation for secondary stroke prevention.

First, I am leading a collaborative UK-wide research group to assess a non-pharmacological approach, isometric exercise, as an adjunct to pharmacological therapy in preventing stroke and other cardiovascular events in an older, at risk of stroke, population. Isometric exercise has a potent effect in healthy young people; with as little as 20 minutes per week over four weeks producing a 5mmHg systolic blood pressure reduction. However, there are no robust studies of its effects in an older, at risk of stroke, population, though its use is potentially attractive, as it is simple to undertake at home, encourages patient participation in exercise, and may reduce the number of prescribed medications. A systematic review of the effects of isometric exercise programme on blood pressure reduction is being finalised; with plans to submit a feasibility study to optimise an appropriate isometric exercise ‘prescription’ for a TIA/ stroke population at high risk of recurrent stroke and other cardiovascular events. This will result in a patient-friendly isometric exercise programme to be assessed in a future randomised controlled trial of BP reduction, and stroke and other cardiovascular events prevention.

Secondly, I am involved in two collaborative projects concerned with blood pressure management following intracerebral haemorrhage; the most devastating form of stroke with high mortality, disability and risk of recurrence. The Triple therapy prevention of Recurrent Intracerebral Disease EveNts Trial (TRIDENT) involves colleagues in Edinburgh, New York, Sydney and Vancouver, and is an investigator-initiated and conducted, international collaborative, multi-centre, double-blind, placebo-controlled, parallel-group, randomised controlled trial to assess cardiovascular outcomes following treatment with a fixed low-dose combination blood pressure lowering pill strategy on top of standard care in subjects with a history of stroke due to spontaneous intracerebral haemorrhage. We are planning grant applications across major national medical research funding bodies. The second is a UK collaborative project that is being developed following a successful National Institute of Health Research Stroke Writing Group application. The Prevention of Hypertensive Injury to the Brain using Intensive Treatment (PROHIBIT-ICH) will determine whether a strategy of intensive treatment guided by telemetric monitoring versus standard treatment of blood pressure in survivors of spontaneous intracerebral haemorrhage attributed to small vessel disease is feasible, safe, and associated with reduced cerebral injury (including incident cerebral microbleeds, white matter changes, brain atrophy, diffusion tensor imaging changes) magnetic resonance imaging.

Finally, there is increasing scientific interest in blood pressure variability; with increased blood pressure variability being reported to be associated with vascular risk independent of mean blood pressure. In addition, commonly used antihypertensive agents have different class effects on blood pressure variability, which may, in part, explain the overall differential effects on stroke risk for similar absolute reductions in mean blood pressure in a hypertensive population. I am in the early stages of a British Heart Foundation/ Stroke Association-funded Programme Grant to determine the definition and measurement, natural history and prognostic significance of blood pressure variability (not blood pressure per se) following acute stroke. To date, we have completed a systematic review of blood pressure variability and outcome following acute stroke; concluding that systolic blood pressure variability, if captured within the first few hours after stroke onset, may predict both functional outcome in acute stroke, and risk of intracranial haemorrhage on repeat brain imaging in those with acute ischaemic stroke treated with thrombolytic therapy (Manning et al, Stroke 2015). In addition, we have completed additional analyses of the association of blood pressure variability and outcome in completed trials of blood pressure manipulation in acute intracerebral haemorrhage (Manning et al, Lancet Neurol 2014) and all stroke subtypes (Manning et al, Stroke 2015). The second phase of the Programme Grant is currently being undertaken: a multi-centre (Leicester, Norwich, Oxford), prospective observational study assessing blood pressure variability with beat- to-beat, casual, 24-hour and Home blood pressure monitoring techniques in acute stroke, including measurement failure rates and acceptability to patients. In addition to assessing the most appropriate device(s) to measure blood pressure and the most appropriate statistical technique to define variability in acute stroke, patients will be followed-up over a 12-month period with blood pressure variability measurements repeated at 1 week or hospital discharge, and at 1, 3 and 12 months to determine the natural history and prognostic significance of blood pressure variability. The Research Programme will conclude with a feasibility, prospective, randomised, open, blinded-endpoint trial to compare the effects of a calcium channel blocker versus angiotensin converting enzyme/ angiotensin receptor blocker-based regime on blood pressure variability in first-ever TIA and minor ischaemic stroke patients at high risk of recurrent TIA/ stroke recruited within 24 hours of symptom onset. These studies will form the basis of a clinical trial application to reduce the risk of recurrent stroke and other cardiovascular events by the implementation of a novel therapeutic strategy based on the reduction of increased blood pressure variability following TIA and stroke.

(C) Studies of cerebral haemodynamic impairments following stroke: from individualised modelling towards personalised treatment of the injured brain, impact of therapeutic strategies to improve cerebral perfusion, and association with cognitive impairment

Over many years, my research, in collaboration with Professor Ronney Panerai, has been at the forefront of the development of non-invasive assessments of cerebral autoregulation, demonstrating impaired autoregulation in the acute stroke period, as well as refining methods of cerebral autoregulation assessment. Cerebral autoregulation is an important mechanism whereby cerebral perfusion is normally maintained at a constant level, over a relatively wide blood pressure range, and it is well established that dynamic cerebral autoregulation is impaired, particularly following moderate to severe stroke. As a consequence, cerebral perfusion is pressure-dependent, and this has implications for hypertension management, a common pathophysiological complication of acute stroke. However, there remain significant research opportunities, particularly to explore further the integration of cardiovascular and cerebrovascular control mechanisms, especially to examine individual variability in health and disease, and how this impacts on a personalised cardiovascular management strategy in acute stroke; the impact of various techniques to improve cerebral perfusion and how these might be impacted upon by impairments in cerebral haemodynamic control mechanisms; and finally to develop the literature on the association between abnormalities in cerebral haemodynamics in association with cognitive impairment, and therapeutic strategies to improve cerebral haemodynamics and the potential benefit on delaying the progression of cognitive impairment.

I am the Principal Applicant of an Engineering and Physical Sciences Research Council grant to develop a simple bedside test for the integrated multi-dimensional assessment of cardiovascular (baroreceptor) and cerebrovascular (cerebral autoregulation) control, which will develop a grading system to differentiate between healthy and impaired systems, including in patients with concomitant co-morbidity (e.g. atrial fibrillation) that are currently typically excluded from assessments, and therefore inform management decisions in the acutely unstable stroke population. We have established a database of the diversity of cardiovascular and cerebral haemodynamic responses, including baroreceptor sensitivity, autoregulatory indices, cerebrovascular reactivity and neurovascular coupling, of healthy subjects in anticipation that these reflect real individual differences in physiological strategies for brain blood flow control rather than random error. We will also evaluate the diversity of autoregulatory responses of a hyperacute (<9 hours), acute (<72 hours), subacute (<2 weeks) and chronic (<3 months) stroke population, as well as in other types of acquired brain injury (e.g. subarachnoid haemorrhage) through collaboration with colleagues at Oxford University and the University of Southampton. These studies will inform future research to develop personalised strategies for cardio- and cerebrovascular management decisions in an acutely unstable stroke patient population.

Importantly, there are other pathophysiological consequences of acute stroke that may adversely impact on cerebral haemodynamics. My Group has secured funding from an industrial partner to undertake an exploratory study to non-invasively measure global and regional changes in brain tissue pulsatility using ultrasound, as a means of detecting cerebral oedema. If successful, this would significantly add to the non-invasive assessment of cerebral haemodynamics in an acute stroke population, providing an early means of distinguishing cerebral oedema from other causes of neurological deterioration. Its impact on management of acute stroke patients in a standard hyperacute stroke ward setting (rather than an intensive or high dependency care setting) would be explored in studies funded through further industrial partnerships and/ or research grants. Furthermore, partial pressures of carbon dioxide impact significantly on cerebral haemodynamics; with hypercapnia emulating a state of impaired dynamic cerebral autoregulation, and conversely hypocapnia one of improved dynamic cerebral autoregulation. Acute stroke is a physiologically unstable period, where changes in respiratory rate as a consequence of neurological damage and/ or cardiorespiratory complications may alter carbon dioxide tensions, with the potential to have an additional adverse impact on cerebral haemodynamic parameters. An Academic Clinical Fellow attached to my Group will be undertaking a preliminary study to define a carbon dioxide ‘dose-response’ curve on dynamic cerebral autoregulation. This will provide further input to the personalised medicine project.

Recombinant tissue plasminogen activator is the only approved hyperacute treatment for acute ischaemic stroke, other than aspirin, though its use is significantly limited to eligible patients presenting within 4.5 hours of symptom onset. Thrombolytic therapy aims to restore blood supply as quickly as possible, thereby limiting any brain damage. However, early reperfusion may be detrimental in the presence of cererbral dysautoregulation and blood pressure-dependent cerebral blood flow, potentially contributing to reperfusion injuries, including post-ischaemic oedema and/ or intracerebral haemorrhage. In addition, there is evidence from animal models that tissue plasminogen activator administration peer se may impair myogenic reactivity, further impairing cerebral autoregulation. With the advent of alternative thrombolytic agents (e.g. desmoteplase, tenecteplase), alternative reperfusion strategies (clot extraction, stents) and the use of advanced neuroimaging to extend treatment times (up to 9 to 12 hours), it is important to assess whether these have less detrimental effects on cerebral haemodynamic parameters than conventional thrombolysis with intravenous recombinant tissue plasminogen activator.

As well as attempts to treat major vessel occlusion, improving cerebral blood flow, particularly to the penumbral area, through collateral arteries and leptomeningeal recruitment is another potential therapeutic approach in acute ischaemic stroke. Though general blood pressure augmentation therapies, most commonly phenylephrine, and non-invasive mechanical therapies, including partial aortic occlusion and external counterpulsation, have been evaluated in a number of small studies, there is a need for a more widely applicable therapy. A simple way of increasing cerebral blood flow in the collateral circulation and of augmenting blood flow into the ischaemic penumbra might be to lower the head of patients into a ‘lying flat’ (0o) position. Several observational studies have investigated the effects of head positioning on cerebral blood flow in a healthy population; reporting significant reduction in middle cerebral artery blood flow with 30o head-up tilt compared to the supine position. However, there are few studies on the effect of head positioning following acute ischaemic stroke, with a systematic review concluding that there was insufficient evidence to make any recommendation. Therefore, the Australian National Health and Medical Research Council-funded, multi-centre, prospective, cluster randomised, cross-over, blinded outcome assessment HEAD Position in Stroke Trial (HEADPoST; Co-Applicant, Joint UK Co- ordinating Investigator) will compare the effects of ‘lying flat’ (0o) with ‘sitting up’ (>30o) head position applied in the first 24 hours of hospital admission for patients presenting within 12 hours of acute ischaemic stroke onset (commenced 2015). However, the trial provides an exciting opportunity to undertake more detailed, mechanistic sub-studies of the effect of head positioning on cerebral blood flow, including the effects of complete or partial re-canalisation versus persistent occlusion, the importance and extent of collateral blood flow, the potential differential effects on the affected and unaffected hemipsheres, the additional influence of cerebral oedema and/ or raised intracranial pressure, and the effect of stroke subtype (including large vessel versus lacunar stroke syndrome).

(D) Studies of disabling co-morbidity in an ageing population

Finally, my other area of research expertise relates to the prediction of disability in an ageing population and its impact on other co-morbidities. In particular, I am undertaking collaborative work to inform best management decisions for older female patients with breast cancer, including the design of an assessment and management tool, as part of an ongoing NIHR Programme Grant.

In addition, cognitive impairment associated with TIA and stroke disease, as well as other neurodegenerative conditions associated with ageing, is an important cause of morbidity and mortality. Impaired cerebral haemodynamic control mechanisms, exacerbated by critically low levels of cerebral blood flow, and associated with the low levels of physical activity typically seen in disabled stroke survivors, have further adverse consequences on cognitive performance. Preliminary studies have shown that breaking up sedentary periods by low-intensity physical activity produces beneficial effects on cerebral perfusion in patients with cognitive impairment associated with Alzheimer’s Disease. Therefore, there is an exciting opportunity to investigate the effects of low-intensity physical activity on cerebral haemodynamics, and cognitive performance, both in terms of disease progression but also in delaying disease onset, in a broad spectrum of cognitively impaired subjects including vascular causes. This will build on the preliminary work in my Group investigating cerebral haemodynamic changes in patients with idiopathic Parkinson’s disease, both in the medicated and ‘off’ states.

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