Diversity in Blood Flow to the Brain (Leicester)

The brain requires a constant supply of blood in order to maintain its function. Blood is under pressure in the arteries (tubes that take blood from the heart to the body) so that it can reach all parts of the body. When blood pressure drops, small arteries widen to bring back flow levels, and when pressure rises, they tighten to protect the most delicate blood vessels and avoid bleeding and swelling in the brain. Failure of this control system (called cerebral autoregulation) following injury to the brain can worsen health, and also influence how to control the changes happening in blood pressure. This project aims to improve methods for measuring cerebral autoregulation and to gain a deeper understanding of the complex relationship between blood pressure and blood flow in healthy individuals as well as in patients following stroke ( a "brain attack" that occurs when a blood clot blocks an artery). Using advanced data analysis methods we aim to estimate the damages that happen to this “control system” which keeps the blood flow and blood pressure controlled, with the hope to better understanding how this influences the management of an individual patient’s blood pressure in the acute (critical) and chronic (long term) phases following stroke.

Funding Body

This project has been funded by a project grant from the Engineering and Physical Sciences Research Council (EPSRC), which is the UK's main agency for funding research in engineering and the physical sciences, and is part of a three centre collaboration (see further project background). EPSRC invests around £800 million a year in research and postgraduate training, to help the nation handle the next generation of technological change.

Aims

The aim of this study is to investigate and evaluate the brain blood flow control (cerebral autoregulation - CA) by expanding the simple blood flow and blood pressure model into a broader framework of physiological regulation (specifically that of blood pressure regulation through the baroreflex), and to move it onto a personalised basis and hence progress towards an individualised/ personalised diagnosis and treatment of patients following brain injury, including stroke.

Specific objectives are:

  1. To propose and test simple bedside methods for the integrated multi-dimensional assessment of cardiovascular (baroreceptor) and cerebrovascular (cerebral autoregulation) control.
  2. To evaluate the diversity of autoregulatory responses of healthy subjects in anticipation that these reflect real individual differences in physiological strategies for brain blood flow control rather than random error.
  3. To evaluate the diversity of autoregulatory responses of a stroke population during the acute (<72 hours), subacute (2 weeks) and chronic (3 months) phases of stroke.
  4. To develop a grading system which takes into account the interaction of multiple individual cerebro- and cardiovascular parameters, using data collected from both populations, and therefore:
    1. To develop a scale to differentiate between a healthy and impaired system, based on the interaction between control systems.
    2. To extend these scales to patients with concomitant comorbidities (e.g. atrial fibrillation) that excluded them from previous studies in order to advance towards personalised care.
  5. To use this system to inform future management decisions in the acutely unstable stroke patient population and assess if these methods provide clinically meaningful results for the management of these patients. 

Protocol

This study is a prospective observational study. Each stroke patient (up to 40 patients recruited within 6 hours of symptom onset) will be required to participate for up to 3 months post stroke symptom onset, during which up to a total of 6 assessments will be made. The first four will be recorded whilst the patient is an in-patient under the care of the University Hospitals of Leicester NHS Trust Stroke Service (acute: within 72 hours of symptom onset), the next assessment will be within two weeks post stroke onset, and the final measurement will be between 2 weeks (subacute) and up to a period of 3 month post stroke onset (chronic).
Each healthy volunteer (up to 20) will be required to attend the University of Leicester’s Cardiovascular Research Laboratory for two assessments, spaced over a time period of two weeks.

Once informed consent has been obtained from each participant they will be required to provide basic information about their health and medications. Following which they will be able to continue with the lab based measurements. 

Baseline Assessments

For all subjects, initial assessments will be undertaken in a dedicated cardiovascular research laboratory, which is Setupat a controlled temperature (20-24o) and is free from distraction. Casual BP will be measured using a validated cuff device (UA 767). Beat-to-beat BP will be recorded continuously using the Finometer cuff device attached to the middle finger of the non-dominant hand (non-hemiparetic hand in stroke patients). R-R interval will be recorded using a 3-lead ECG, and End tidal CO2 (EtCO2) monitored using small nasal cannulae placed at the base of the nose (Salter Labs, ref 4000) attached to a capnograph (Capnocheck Plus) to monitor the breathing. Simultaneous bilateral recording of the middle cerebral artery (MCA) blood flow velocity will be performed using Transcranial Doppler (TCD) with 2MHz probes using a Viasys Companion ΙII, with the subject lying supine on a couch. The vessel will be located via the temporal bone window, and identified as the MCA by the waveform, its depth, velocity, and direction of flow. A head frame will be used to secure the ultrasound probes in position and to minimise their movement.

In healthy subjects (controls) and those patients who have not had a CUS scan, conventional duplex carotid CUSSultrasonography will also be performed with a 7.5- to 10-MHz linear-array probe to characterise atherosclerotic lesions and an ultrasound probe (similar to a pen) will be held against the neck (near the chin) to visualise the artery in the neck and measure the blood flow through the neck to measure blood flow velocity of the internal carotid arteries (ICA). Doppler shift is angle dependent, and since the probe cannot be parallel to the arteries in the neck, angle adjustment is required to obtain the velocity waveform. The subject’s head will be turned contralateral to the side being tested, a paper towel placed at the base of the neck to protect clothing, gel liberally applied to both the transducer and neck, and the scan will be started transversely from the proximal ICA to visualise the presence of any stenosis.

In the absence of a temporal window from which measurements of CBF can be made, the ICA will be used as a surrogate location to measure CBF. First colour Doppler mode will be used to identify flow within the artery and potential areas of high velocity, and assessment of the blood flow velocity in the ICA will be recorded.

After about 20 minutes the readings will have stabilised, then these parameters will be simultaneously recorded CBF waveformonto a computer software system (PHYSIDAS), providing data for subsequent analysis. We will make recordings for 15 to 20 minutes: at rest (5 minutes), when breathing a slightly higher than normal, but safe, concentration of waste gas (5% carbon dioxide) in addition to oxygen via a mask placed over the mouth and nose (5 minutes), and during a period when the arm will be flexed and extended at the elbow (hemiparetic arm in stroke patients and dominant arm in control subjects, 5 minutes; this will be repeated in control subjects with the non-dominant arm after the Finapres or Portapres device has been changed to the dominant hand).

Follow-up Assessments

In stroke patients up to 5 follow-up assessments will be made, up to 3 of these will be in the acute stroke phase within 72 hours from stroke onset (at 24, 48 and 72 hours, depending on how soon after stroke the patient was admitted and recruited). The last two assessments will carried out in the subacute phase (within 2 weeks) and in the chronic phase (at 3 months after stroke). At each assessment the protocol outlined above for baseline assessment will be repeated.

Sub-acute Phase

At this assessment, prior to the study specific assessment beginning (as outlined in the protocol for baseline assessments), extra information will be noted, including SAE review, NIHSS assessments.

Chronic phase

At the 3-month review, the assessment protocol of the sub-acute phase will be repeated, and in addition the modified Rankin Scale (mRS); a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability, to enable a dichotomised death or disability/ independent outcome to be applied.

Where are we up to now

Results and progress information will become available soon. 

Contact Details

Professor Tom Robinson

Professor Ronney Panerai

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