Integrative physiological assessment of cerebral hemodynamics and metabolism in acute ischemic stroke

Abstract

Restoring perfusion to ischemic tissue is the primary goal of acute ischemic stroke care, yet only a small portion of patients receive reperfusion treatment. Since blood pressure (BP) is an important determinant of cerebral perfusion, effective BP management could facilitate reperfusion. But how BP should be managed in very early phase of ischemic stroke remains a contentious issue, due to the lack of clear evidence. Given the complex relationship between BP and cerebral blood flow (CBF)—termed cerebral autoregulation (CA)—bedside monitoring of cerebral perfusion and oxygenation could help guide BP management, thereby improve stroke patient outcome. The aim of INFOMATAS is to ‘identify novel therapeutic targets for treatment and management in acute ischemic stroke’. In this review, we identify novel physiological parameters which could be used to guide BP management in acute stroke, and explore methodologies for monitoring them at the bedside. We outline the challenges in translating these potential prognostic markers into clinical use.

Introduction

Despite the growing burden of ischemic stroke worldwide, there are limited treatment options to improve stroke outcome, namely, reperfusion therapies such as thrombolysis and thrombectomy and acute stroke unit care. ¹ Blood pressure (BP) is a key determinant of cerebral blood flow (CBF), optimizing BP could improve patient outcome in acute stroke by enhancing reperfusion and rescuing salvageable ischemic tissue. Despite high BP being associated with poor stroke outcome, ² multi-center studies found the effects of antihypertensive treatment patient outcome to range from near-negative, ³ neutral^4–6 to near-positive. ⁷ Accordingly, there are still much controversies surrounding BP management following ischemic stroke. In acute stroke settings, neuroimaging plays a crucial role in stroke diagnosis, guiding treatment pathways and determining hemorrhagic transformation following reperfusion therapy. But there is no active bedside monitoring to determine the intricate relationship between BP and cerebral perfusion during acute stroke management (≤ 24 hours), nor how cerebral oxygen (O₂) status may be affected. Understanding how changes in BP affect the CBF and cerebral O₂ supply could improve how BP is managed following stroke. The aim of this review is to identify novel therapeutic targets that may improve BP management and advance our understanding of the pathophysiology surrounding stroke.

Despite the complexity of CBF regulation, the myriad of contributing factors is typically not accounted for in stroke management and treatment. Yet evaluating all the components of CBF regulation in the clinical setting would be a challenging, if not an impossible endeavor. Utilizing more simple models, such as examining BP stability, cerebral perfusion and O₂ status (i.e., brain tissue oxygenation) would be more suitable for clinical purposes. These variables could serve as prognostic markers for adverse outcomes, as well as therapeutic targets for restoring perfusion to variable penumbra. The ultimate goal would be to utilize these physiological markers at the bedside to actively guide BP management and modify treatment strategy when necessary in acute stroke. The Cerebral Autoregulation Network (CARNET, www.car-net.org) was initiated in 2011 to foster collaboration between clinicians and researchers to prioritize dynamic cerebral autoregulation (dCA) research. A new initiative titled ‘Identifying New targets FOr Management And Therapy in Acute Stroke’ (INFOMATAS) was launched in 2016 with the objective to set clinical trials to optimize BP management in acute stroke through a better understanding of dCA, ⁸ and identifying the best interventions to improve stroke outcome. INFOMATAS aim to achieve its goal through the following: 1) a critical reappraisal of the current literature to identify current knowledge-gaps; 2) meta-analyses of stroke studies to identify novel prognostic dCA markers and key outcome variables; and 3) perform clinical trials to examine the efficacy of therapeutic interventions guided by dCA status. Within the overarching goal of INFOMATAS, the purpose of this review is to identify novel physiological markers which may be used to guide BP management in acute ischemic stroke. In addition, we provide a critical reappraisal of the various methodologies for bedside monitoring in acute stroke management, and briefly outline the challenges in translating these assessments into clinical practice.

Acute ischemic stroke care

Before discussing potential therapeutic targets for BP management, we first provide a brief overview of the current guidelines for acute ischemic stroke. The tenet ‘Time is Brain’ underlies the current therapeutic approach to acute ischemic stroke. It emphasizes that the nervous tissue is rapidly and irreversibly lost as stroke progresses and therapeutic reperfusion interventions should be urgently carried out. It is estimated that the typical patient loses 1.9 million neurons each minute that stroke is untreated. ⁹ This time-ischemia relationship is modulated by the presence of collaterals, which slows infarct growth and prolongs the therapeutic window.^10,11 The penumbra is defined as a rim of hypoperfused parenchyma surrounding the irreversibly damaged core, which receives limited blood flow from leptomeningeal collateral arteries . As eloquently summarized by Hurford et al., ¹ the primary aim of acute ischemic stroke management is to salvage viable penumbra by restoring perfusion to the ischemic brain.

Diagnosis/neuroimaging

Following initial examination which includes patient history, neurological assessment, brachial BP and glucose status, patients with suspected stroke undergo diagnostic neuroimaging. The primary aim of neuroimaging in acute stroke is to: i) excluding intracranial hemorrhage, which preclude thrombolysis treatment; ii) identify early ischemia; iii) exclude other intracranial pathologies such as seizure, syncope, sepsis, migraine and brain tumors which may produce identical clinical presentations; and iv) determine whether there is a large vessel occlusion suitable for endovascular clot retrieval. Computed tomography (CT) is the most commonly used neuroimaging method for assessing cerebral perfusion and angiography in acute stroke settings. Non-contrast CT head scan is a quick, sensitive and cost-effective way of ruling out intracranial hemorrhage, which is usually sufficient for making thrombolysis decisions, and is well tolerated by most patients with few contraindications. ¹² Due to changes in net tissue water content, CT scanning has much lower sensitivity and specificity for acute ischemia. Magnetic resonance imagining (MRI) is an advanced neuroimaging tool with higher sensitivity for detecting tissue than CT, particularly in minor stroke ischemia in acute stroke. Ultimately, neuroimaging play a critical role in guiding initial stroke treatment strategy (thrombolysis, endovascular clot retrieval).

Reperfusion treatment

Due to the complexities of stroke neuropathology, only two therapies have successfully translated into clinical practice, namely thrombolysis and mechanical thrombectomy.^13–16 The clinical translation of these therapies are based on a well-established physiological paradigm: vascular occlusion decreases cerebral perfusion, so rapid reperfusion minimize neurological damage. While these therapies are effective in improving patient outcome and reduce long term disability following stroke, they are typically given to a small proportion of stroke patients worldwide due to delays in accessing diagnostic brain imaging and a narrow treatment window. Reperfusion therapy rates vary between countries, a recent survey of 44 European countries found the average rate of intravenous thrombolysis was ∼7.3%, while the average rate for endovascular treatment was ∼1.9%. ¹⁷ Thrombolysis treatment with intravenous or intra-arterial tissue plasminogen activator (rt-PA) is a common pharmacological strategies for the breakdown of blood clots (lysis) and to rapidly restore cerebral perfusion in acute ischemic stroke. Its therapeutic benefit is unaffected by baseline stroke severity or age.^18,19 The relatively low success of thrombolytic therapy for recanalization of large vessel occlusion prompted the development of mechanical thrombectomy, which was made possible due to technological advancements in endovascular neuroradiology. Mechanical endovascular thrombectomy involves a minimally invasive surgical procedure using a microcatheter and other thrombectomy devices to trap and remove the blood clot from an occluded artery. Whilst endovascular thrombectomy is limited to large-vessel occlusions, it can be delivered as a stand-alone treatment or in conjunction with systemic thrombolysis.

Acute stroke unit

Acute stroke unit care has been long recognized as the major component of stroke management for reducing death and disability after stroke, ²⁰ irrespective of age, stroke type (ischemic or hemorrhagic) or severity.^21,22 Acute stroke units typically consist of stroke-specific multidisciplinary care (neurology, physiotherapy, speech and language therapy, occupational therapy) and high nursing ratio. The primary goal of acute stroke unit is to prevent secondary brain insult by maintaining temperature, peripheral O₂ saturation, hydration, plasma glucose, BP as well as to manage dysphagia and monitor neurological status. ¹ Early neurological complications, such as recurrent ischemia, cerebral oedema or hemorrhagic transformation, and associated signs of neurological deterioration would prompt urgent repeat neuroimaging. While the role of routine follow-up neuroimaging is debatable, it is typically performed ∼24 hours after rt-PA administration to exclude intracerebral hemorrhage to aid in decision-making for anti-platelet therapy. The secondary role of follow-up neuroimaging is to assess infarct size. Given the importance of acute stroke units, it is ideal setting for bedside cerebral hemodynamic monitoring following stroke.

Integrative physiology in acute stroke

The physiological determinants of cerebral perfusion in acute ischemic stroke as well as the evolution of the ischemic penumbra have been extensively reviewed elsewhere,^23,24 thus will be briefly summarized here (Figure 1). CBF is determined by cerebral perfusion pressure (CPP) and the cerebrovascular resistance (CVR). CPP is the difference between central BP and cerebral venous pressure, the latter is assumed to be negligible unless there is an elevated intracranial pressure (ICP) or venous obstruction. CPP can be influenced by fluctuations in BP – termed BP variability (BPV), which is under baroreflex control. Meanwhile, CVR is determined by vessel radius and length and blood viscosity. Since vessel radius is the only amenable parameter to acute physiological stressors, CBF is determined by the caliber of the resistance vessels within the cerebral circulation under constant CPP. In the face of changes in CPP, there are two compensatory mechanism by which cerebral delivery of O₂ and nutrients can be maintained: 1) the intrinsic ability of the cerebral circulation to alter cerebrovascular resistance in response to dynamic changing BP to order to maintain CBF – termed cerebral autoregulation (CA); and 2) altering O₂ extraction fraction (OEF). ²⁵ Disruptions in either of these two compensatory mechanisms would result in a cascade of cellular events that may progress to neural cell death. In the face of impaired CA, accentuated BPV will directly result to fluctuations in cerebral perfusion, which destabilizes cerebral O₂ delivery. Yet despite their importance in determining the brain’s O₂ supply, BPV, CA and OEF are rarely monitored following stroke.

Figure 1.

Summary of penumbral hemodynamic and metabolism during acute stroke and following recanalization. CBF: cerebral blood flow; BPV: blood pressure variability; CA: cerebral autoregulation; OEF: oxygen extraction fraction. ↓ and ↑ denote relative decrease and increase from normative value, respectively. ↔ denotes normative values.

Blood pressure assessment

Pulse wave amplification

Under normal physiological conditions, changes in arterial BP is an important determinant of CPP (and therefore CBF). The current stroke guidelines are based on brachial BP as the primary macrovascular target for therapeutic treatment. This erroneously assumes that brachial BP reflects input pressure to the brain, and neglects to account for downstream pressures of the cerebral circulation, or the resistance of the cerebral vasculature. The major arteries supplying the brain are exposed to central pressure rather than brachial pressure. Yet in clinical practice, brachial BP is routinely used as the sole surrogate of CPP in acute stroke management. It has been known for over half a century that brachial pressure is a poor proxy for central pressure. Studies have found brachial BP overestimates central pressure within the ascending aorta by as much as 40 mmHg.^26,27 This disparity between brachial and central pressure – termed pulse wave amplification – is due to differing vessel properties through the arterial tree such as arterial stiffness and diameter, which lead to BP elevations at the brachial level through pulse wave reflection (Figure 2).

Figure 2.

Changes in contour in pressure wave (top) and flow wave (bottom) between ascending aorta and the saphenous artery. Reprinted with permission. ²⁸

Blood pressure variability

Blood pressure is a dynamic physiological parameter with oscillations in taking place across multiple time scales, such as very short-term (i.e., beat-to-beat), short-term (i.e., over 24 hours and day-to-day) and long‐term BPV which includes seasonal variations in BP (i.e., over months or years) between clinical visits.^29–31 Day-to-day variation in BP represents the sum of responses to extrinsic pressor stimuli, spontaneous and regulatory fluctuations associated with the central nervous system, respiration, humoral and local vasomotor related phenomena.^29–31 These diverse mechanisms ensure an adequate organ perfusion, adjusting BP in response to the varying demands of different organs. Evaluation of BPV across these multiple time scales could provide key insight into acute and long-term clinical outcomes such as stroke risk. ³² As suggested by Parati et al. ³⁰ changes in BP can be separated into those without regular structures (i.e., random or unpredictable changes) and those described by well‐defined patterns over time (i.e., rhythmic fluctuations, nocturnal fall in BP, morning BP surge and seasonal variations). Changes in BP are most commonly described using simple measures of dispersion such as standard deviation of average values over a specified time window (hours-to-months). More rapid assessment of beat-to-beat BPV (∼5 min) could be clinically useful in acute stroke settings, and can be obtained using sophisticated analytical methods such as spectral power density analysis (Figure 3).

Figure 3.

Main stages of transfer function analysis (TFA). In the time-domain, mean values of blood pressure (BP) and cerebral blood flow-velocity (CBFV) are obtained for each cardiac cycle and spectral analysis algorithm (FFT: Fast Fourier Transform) is used to obtain spectral estimates in the frequency domain. The auto- and cross-spectrum are then used to obtain estimates of the coherence function, amplitude (gain) and phase frequency responses. Courtesy of Dr JD Smirl ‘The relationship between arterial blood pressure and cerebral blood flow: insight into aging, altitude and exercise’, PhD Thesis, The University of British Columbia (Okanagan), June 2015. MAP: mean arterial pressure; MCAv: cerebral blood flow-velocity in the middle cerebral artery.

There is growing body of evidence which suggests that dramatic variations in BPV is an important risk factor for poor outcomes following stroke. Large cohort studies have found associations between increased systolic BPV with early stroke recurrence, and severe hemorrhagic transformation after ischemic stroke, and poorer clinical outcomes following acute ischemic stroke and hemorrhagic stroke.^33–38 The detrimental impact of high systolic BPV on long-term outcome appears to be independent of whether recanalization was successful with thrombolysis treatment. ³⁹ In addition, elevated diastolic BPV is associated with poor outcome following stroke,^35–37,40 while low diastolic BPV is a predictor of favorable outcome at 90 days following stroke. ⁴¹ In nonrecanalized patients, Delgado-Medero et al., ³⁹ found high short-term systolic BPV was associated with larger lesion volume at 36-48 hours post stroke. This relationship between systolic BPV and infarct volume is likely linked to cerebral autoregulatory failure within the ischemic brain, which is further exacerbated by the persistence of arterial occlusion. In contrast to these previous studies which assessed long-to-short term BPV, Allan et al., ⁴² assessed very short-term estimates of BPV and found it to be elevated BPV in acute ischemic stroke patients compared to age-matched controls. In a cohort of 405 transient ischemic attack and minor stroke patients, very-short term BPV has been shown as novel predictor of a patient’s long-term risk of recurrent stroke. ⁴³ These findings highlight the potential importance of assessing and dampening raised BPV in acute stroke management. Given the links between BPV and stroke outcome, infarction growth and stroke reoccurrence, rapid assessment of beat-to-beat BPV could serve as an important marker in acute stroke management. Yet despite the mounting evidence, the use of BPV as a novel prognostic marker in stroke has not been explored.

Dynamic cerebral autoregulation

The cerebral autoregulatory function represents the brain’s ability to maintain adequate blood flow in the face of acute changes in perfusion pressure. ⁴⁴ It is an important physiology marker of neurovascular integrity, with prognostic and therapeutic significance in acute stroke. It refers to the intrinsic mechanisms of the cerebral vessels to maintain relatively constant CBF during changes in BP. CA is often characterized into either static (i.e., > 5 min to hours) or dynamic (i.e., 4–5 s to 5 min) components. ²⁹ Rather than distinct physiological characteristics, static and dynamic CA are simply a continuum with static CA reflecting the ultra-low frequency (0–0.02 Hz), and dynamic CA (dCA) reflecting the very-low frequency (0.02–0.07 Hz), low frequency (0.07–0.20 Hz) and high frequency (0.20–0.35 Hz) ranges.^45,46 Several modelling techniques are utilized to quantify dCA with spontaneous or driven BP.^47,48

Transfer function analysis is a popular analytical technique used to characterized dCA. ⁴⁸ By decomposing arterial BP and blood velocity recordings into their diverse oscillatory components, transfer functions can describe the relationships between BP (model input) and CBF (model output) in terms of their linear statistical dependence (coherence), magnitude (gain), and timing (phase) as a function of the frequency component of interest (Figure 3). ⁴⁶ While there is no consensus on which modelling approach can be considered the gold standard, the assessment of dCA using spontaneous BP is the most logical quantification of dCA at the bedside as it imposes a low burden for patients.^49,50 Under normal conditions, assessment of dCA with spontaneous BP oscillations is associated with low coherence (see Tzeng and Panerai ⁴⁹ as well as Simpson and Claassen ⁵¹ for crosstalk). Since BP variations is elevated with stroke, ⁴² coherence is likely to be improved in this cohort. Wavelet decomposition analysis is an alternative analytical approach to characterize the nonlinear and non-stationary relationship between BP and CBF.^52,53 A supplementary advantage of this analytical approach is it can account for the influence of partial pressure of arterial carbon dioxide (PaCO₂) on dCA.^54,55 Briefly, wavelet phase synchronization utilizes portions of continuous recordings (i.e., wavelets) of varied duration to fit to both BP and CBF. This allows for analysis of phase (i.e. timing) between input (i.e., BP) and output (i.e., CBF). This analytical method can produce information from spectral and temporal domains of nonstationary signals. ⁵³

The presence or absence of CA in acute stroke is critical for maintenance of stable perfusion in the ischemic penumbra and for avoiding excessive hyperperfusion. The effect of stroke on dCA has previously been summarized,^56,57 along with a systemic review. ⁸ In brief, irrespective of stroke sub-types, dCA appears to be impaired 24-72 hours following stroke.^58–61 With ischemic stroke of the middle cerebral artery territory, dCA impairment has been observed in the ipsilateral hemisphere, while lacunar ischemic stroke results in bilateral CA impairment. ⁶² Ipsilateral dCA continues to worsen during the first 5 days following major ischemic stroke and after unsuccessful thrombolysis, while bilateral CA appears to be preserved following minor strokes.^57,63 Impaired CA was associated with neurological deterioration, the necessity of decompressive surgery and poor outcome. ⁵⁷ The magnitude of dCA impairment during acute stroke was associated with the degree of stroke severity (as assessed by the National Institute of Health Stroke Scale), hemorrhagic transformation, cerebral oedema as well as long-term outcome.^60,61 In chronic ischemic stroke, better dCA was associated with less temporal lobe gray matter atrophy on the infarcted side and better functional status. ⁶⁴

Cerebral oxygen status

Both ischemic and hemorrhagic stroke fundamentally involve brain tissue ischemia. Thus, the ultimate goal in stroke treatment is to improve O₂ tension at the level of the brain tissue. Brain tissue O₂ tension (PbtO₂) can be described as the balance between total O₂ delivery and cerebral metabolic rate of O₂ (CMRO₂), but the precise relationship between the two have not been well characterized. Mass cerebral O₂ delivery is the product of CBF and CaO₂. Assuming the rate of O₂ accumulation in brain tissue is negligible, ⁶⁵ CMRO₂ can be calculated with the following equations:

$$\mathrm{CMR}{\mathrm{O}}_2=\mathrm{CBF}\times {\text{a-jvDO}}_2$$

where arterio–jugular venous O₂ difference (a-jvDO₂) is:

$$\text{a}-{\text{jvDO}}_{\text{2}}={\text{CaO}}_{\text{2}}-{\text{CjvO}}_{\text{2}}$$

where CjvO₂ is the jugular-venous O₂ content. However, recent data indicate that O₂ accumulation in the brain tissue is not zero during physiological challenges. ⁶⁶ There is little existing data to shed light on the relationships between PbtO₂, BP, CBF, cerebral O₂ delivery and CMRO₂ in the context of stroke. While the sparse literature has been primarily focused on patients with traumatic brain injury (TBI), there is considerable potential for transferred learning into acute stroke. In TBI, PbtO₂ is a stronger predictor of patient survival than ICP or even CPP, ⁶⁷ and has been shown to be most closely related to CBF and a-jvDO₂ rather than direct measures of cerebral O₂ delivery or CMRO₂. ⁶⁶ Accordingly, PbtO₂ can be obtained using the formula:

$${\mathrm{P}}_{\mathrm{bt}}{\mathrm{O}}_2=\mathrm{CBF}\times {\text{a-jvDO}}_2$$

While PbtO₂ may not necessarily be a direct indicator of O₂ delivery or cerebral O₂ metabolism, it is nevertheless clinically very useful as it is closely related to both CBF and partial pressure of arterial O₂ (PaO₂).^68–71 Monitoring PbtO₂ thus provides a continuous index of low arterial O₂ tension or low cerebral perfusion, allowing for timely interventions to correct these abnormalities which are known to be associated with poor outcome. In the context of low CBF, increasing PaO₂ with hyperoxia has very little impact on PbtO₂, which suggests that improving CBF would be more effective method of improving PbtO₂ rather than hyperoxia therapy. ⁶⁸

Oxygen extraction fraction

In the face of reduced cerebral O₂ delivery, the amount of O₂ extracted from the blood can be elevated to ensure normal cerebral O₂ metabolism.^72–74 The cerebral OEF is the net balance between cerebral O₂ delivery and consumption, which can be summarized by the formula:

$$\mathrm{OEF}=\frac{{\mathrm{CMRO}}_2}{\mathrm{C}{\mathrm{aO}}_2\times \mathrm{CBF}}$$

where, CMRO₂ is the cerebral metabolic rate for O₂, CaO₂ is the arterial O₂ content, and CBF is cerebral blood flow. OEF therefore serves as an effective metric for determining metabolic reserve in chronic cerebral ischemia. When cerebral O₂ delivery is disrupted, the OEF can be elevated to maintain CMRO₂. During normal physiological condition, a slight decrease in CBF would result in a compensatory increase in in OEF.^75,76 When CBF is dramatically reduced, such as following ischemic stroke, OEF dramatically increases until maximal O₂ extraction is reached. Beyond this limit of O₂ extraction, any further reduction in CBF will result in reduced CMRO₂, which increases in oxidative stress and mitochondrial damage, resulting in necrosis and apoptosis-mediated neuronal cell death.

When the delivery of O₂ falls, the amount of available O₂ extracted from the blood can increase in order to maintain normal O₂ metabolism. In patients with carotid stenosis or occlusion, increased OEF is a significant predictor of stroke.⁷⁸ In ischemic stroke patients, an increased OEF is often associated with decreases in CBF and CMRO₂ in the affected hemisphere 2‐24 hours after ictus – termed misery perfusion,^79,80 and increased risk of stroke reoccurrence.^79,81,82 Elevated OEF is a known hallmark of threatened yet potentially salvageable tissue following stroke (i.e., ischemic penumbra). In the penumbral tissue, regions of reduced perfusion and elevated OEF and variable CMRO₂ have been observed up to 16 hours post‐ictus (see Lin and Powers⁸³ for review). In the penumbra, spontaneous reperfusion results in a concurrent decline in regional OEF below normal values, as well as further decline in CMRO₂ – termed luxury perfusion, which has been observed in up to a third of stroke patients by 48 hours post‐ictus.^84,85 This luxury perfusion signifies a mismatch of cerebral perfusion to metabolism, which peaks at around two weeks.⁸⁶ Changes in OEF is therefore one of the key variables of interest in penumbral development as it reflects the perfusion‐metabolism balance within the ischemic tissue.²⁴

Intracranial pressure and critical closing pressure

Intracranial pressure is a parameter often considered in the context of CA, particularly in TBI patients, where ICP is typically elevated. In pathological states such as cerebral hemorrhage, head trauma and hydrocephalus, ICP can increase profoundly, due to direct bleeding into the parenchyma, ventricles or subarachnoid space, cerebral oedema or hydrocephalus. ⁸⁶ This uncontrolled intracranial hypertension can cause severe brain damage or death. The ‘gold standard’ for ICP measurement is ventricular cerebrospinal fluid pressure or lumbar CSF pressure, using a line inserted into the CSF space connected to a pressure transducer. Non-invasive measures have proven difficult to validate and thus invasive methods remain the preferred option, thus limiting their applicability in stroke predominantly to subarachnoid hemorrhage rather than ischemic stroke.

Critical closing pressure (CrCP) is a concept first proposed by Burton in 1951; ⁸⁷ it describes the BP at which blood flow in collapsible vessels approaches zero. In the cerebral circulation, CrCP equals the sum of ICP and a component proportional to the active tension of the vascular smooth muscle. It has been postulated that the ‘virtual’ driving pressure is BP–CrCP rather than BP–ICP. ⁸⁸ Therefore, in the absence of changes in BP, changes in CrCP reflect changes in effective CPP. Studies have shown CrCP to be approximately ∼30 mmHg in healthy adults,^89,90 and is strongly associated with changes in PaCO₂ across diverse populations.^90,91 Specifically, hypercapnia directly reduce CrCP, whilst the opposite effect is observed during hypocapnia. ⁸⁸ This close relationship between CrCP and PaCO₂ is likely due to the change in cerebrovascular tone associated with changes in PaCO₂. Similarly, there is a direct association between CrCP and BP. ⁹² This likely reflects the autoregulation of CBF, where increases in BP produce concurrent increases in active wall tension, thereby increasing CrCP. ⁸⁸ These observations highlight the roles of PaCO₂ and BP on determining CrCP by directly altering the properties of the cerebral vessels, and thus have potential implications for both PaCO₂ and CA on CrCP. Since both ICP and CrCP are rarely measured in the acute stroke setting, the true perfusion pressure to the brain is not known.

Bedside physiological monitoring

Bedside monitoring of central BP, beat-to-beat BPV, dCA and OEF have the potential to better guide BP management, serve as prognostic markers and improve our understanding of the pathophysiology underlying stroke (Figure 4). The need for continuous hemodynamic assessment, along with specialist online analyses pose significant investment and technological challenges. Therefore, these measurements should ideally be non-invasive – to reduce infection risk and patient discomfort, and can be reproducibly performed by the treating physician and/or nurse with relative ease – to minimize burden on the medical staff. As previously mentioned, impairment and worsening of dCA has been observed between 1-5 days following stroke onset,^57,58–61 which provides a framework within which TCD assessment of dCA could be periodically performed. Here, we provide an overview of methodologies for continuous bedside monitoring of beat-to-beat BPV, CBF and OEF.

Figure 4.

Schematic representation of the proposed on integrative hemodynamic assessment in ischemic stroke. Abrupt elevations in blood pressure is a hallmark of acute ischemic stroke, but this rise may be overestimated at the brachial artery due to pulse wave amplification. Increases in blood pressure variability, coupled with reduced cerebral autoregulation following stroke accentuates hyper- and hypoperfusion insults to the brain. While the driving cerebral pressure has traditionally been view as blood pressure minus intracranial pressure, it has been postulated that the ‘virtual’ driving pressure is in fact blood pressure minus critical closing pressure (shaded green). Cerebral autoregulation (shaded red) represents the relationship between perfusion pressure, vascular resistance and blood flow in the brain. In order to maintain cerebral metabolism, decreases in cerebral blood flow will elicit compensatory increases in cerebral oxygen extraction fraction (shaded blue). Cerebral tissue oxygenation is the net balance of cerebral oxygen delivery and oxygen consumption. Finally, changes in partial pressure of arterial carbon dioxide (CO₂) would directly influence cerebral autoregulation via its effects on cerebrovascular tone.

Oscillometric-based BP

From a physiological standpoint, and given the complexities of the cerebral circulation, conventional brachial BP targets are unlikely to provide meaningful insights about CPP and CBF. While it is unclear how pulse wave amplification affects perfusion pressure within the cerebral circulation, recent studies have found central BP is more strongly related to future cardiovascular events than brachial BP,^93–96 and responds differently to certain drugs.^97,98 Several new oscillometric-based BP devices are readily available, which allows for non-invasive and relatively cost-effective monitoring of central BP (e.g., Arteriograph, WatchBP Office). These findings provide a compelling argument for implementing and exploring the use of central BP monitoring in routine clinical stroke management.

Finger photoplethysmography

Techniques for measuring beat-to-beat BP can be either invasive or non-invasive. The former requires the insertion of an arterial line, with a cannula needle placed in an artery and connected to a pressure transducer. Although accurate and being considered as the ‘gold standard’, this technique cannot be routinely used and thus non-invasive measurements are much more common, despite the compromise that this entails in terms of measurement accuracy. In the context of CA, finger photoplethysmography has been shown to be a valid method of assessing dynamic beat-to-beat BP.^99,100 Commercial devices such Finapres and Finometer (Finapres Medical Systems, Netherlands) and Nexfin (BMEYE, Irvine, CA, USA) are commonly used, along with a number of other devices on the market using similar principles. These have been widely used for over 30 years and are based on the vascular unloading technique. A cuff is applied to a peripheral artery (typically the index finger) which provides a continuous measurement at a very high temporal resolution. However, BP measurements performed in the finger are limited, as it is not possible to assume that BP is the same as in the major arteries supplying the brain. However, it has been shown that the biases in estimating dCA metrics with non-invasive BP assessment are negligible.^101,102 While finger photoplethysmography has been extensively used in cardiovascular research, its utility in clinical settings is less well-known. Continuous inflation of the finger cuff can cause discomfort, which makes it unsuitable for prolonged use.

Transcranial Doppler ultrasound

Transcranial Doppler ultrasound (TCD) was first successfully used by Aaslid et al., ¹⁰³ to measure cerebral blood velocity in the middle cerebral artery, opening up the whole field of dCA research. It has since become the most commonly used technique for measuring CBF in the context of both static CA and dCA.^47,104 The utility of TCD for the integrative assessment of cerebrovascular function has been reviewed in-depth,^105–107 thus will be briefly summarized herein. TCD is performed using low-frequency transducer (≤ 2 mHz) placed on the scalp at the four sonographic windows of the cranium, which permits insonation of all major vessels in the circle of Willis. The temporal window allows insonation of the middle, anterior, proximal posterior cerebral arteries, and proximal internal carotid artery. The occipital window permits insonation of the vertebral and basilar arteries, while the submandibular window is used for external internal carotid artery. And the orbital window for the ophthalmic artery. For intracranial arteries, the transducer is securely fixed to the head and held in place with commonly available headbands, while insonation of internal carotid artery requires the probes to be hand-held, which subject the recorded signals to potential artefacts. While the use of TCD to identify the desired vessels require special operator training to ensure reliable signal detection, there are automated TCD systems such as The Presto 1000 (PhysioSonics) and Delica EMS 9 D robotic TCD device (Shenzen Delica Medical Equipment Co. Ltd) which can identify intracranial vessels without the need for a trained ultrasound technician. ¹⁰⁸

Since TCD assess artery blood velocity per se, rather than blood flow, TDC-derived measure of CBF rests on the assumption that vessel diameter remains constant. Several studies have investigated the sensitivity of vessel diameter to BP, arterial O₂ saturation (SaO₂) and PaCO₂, showing that there is some variability between different vessels.^109–115 In general, vessel diameters of major conduit cerebral arteries appear to remain constant during modest steady-state changes in BP, SaO₂ and PaCO₂. It should be noted that the dynamic response of vessel diameter to these stimuli remains unexplored. There have also been recent attempts to develop ultrafast ultrasound techniques to map full dynamic 3 D velocity fields in individual vessels.^116,117 Such techniques have not yet been used in the context of CA but show considerable promise.

Since ICP and CrCP are rarely measured in the acute stroke, the true perfusion pressure to the brain is not known. Monitoring CrCP in conjunction with central BP, would greatly improve our understanding of changes in CPP during stroke. With the introduction of transcranial Doppler ultrasonography, it is now possible to derive estimates of CPP non-invasively by comparing the waveforms of BP and cerebral blood velocity (i.e., BP–CrCP).^88,92,118 However, clinical validations of CrCP as a surrogate measure of CPP have thus far been limited to TBI patients. Rapid and non-invasive measures of CrCP could be used to guide therapeutic treatment and restore perfusion to ischemic tissues in acute stroke.

The low-cost, excellent temporal resolution and bedside availability of TCD make it an ideal tool for clinical assessment of CBF. TCD could provide valuable bedside monitoring of hemispheric CBF, but lack specificity to assess regional perfusion. As a non-invasive modality, TCD can easily be used to track the progression of an occlusion both before, during and after treatment. ¹¹⁹ In acute stroke setting, the use of TCD has been shown to provide additional useful information to standard non-contrast CT, CT angiography and MRI diffusion imaging, by identifying collateral flow, active micro-emboli, vessel patency, and occlusion detection missed on CT angiography. ¹²⁰ Patient care was accordingly modified, ranging from endovascular rescue after failed intravenous thrombolysis, suspended angiography, and aggressive neurocritical care. Using TCD, the CLOTBUST trial found that the presence of residual flow signal, dampened waveform, and microembolic signals prior to thrombolysis was associated with increased likelihood of complete recanalization after thrombolysis. ¹²¹ Collectively, these findings support the use of TCD to evaluate the efficacy of intravenous rt-PA in real time, determine whether recanalization was successful, and any need for subsequent mechanical thrombectomy in acute stroke settings.

Near-infrared spectroscopy

Positron emission tomography and MRI are the two most widely used imaging modalities for obtaining quantitative measures of cerebral O₂ status. Since these methods have been adeptly reviewed by Lin et al., ⁸² and are impractical modalities for bedside monitoring, we will instead focus on the potential utility of near-infrared spectroscopy (NIRS). NIRS methods have a long history in the context of CBF research, having been first performed in vivo by Jöbsis et al., ¹²² as a non-invasive method of assessing cerebral tissue oxygenation. Utilizing light in the near-infrared region from 700 to 2500 nm, NIRS can be used to monitor concentration changes in oxygenated (O₂Hb) and deoxygenated hemoglobin (HHb) in the human brain. This capability is due to the varying absorption spectra with the oxygenated vs. deoxygenated state of Hb, and the redox state of the cytochrome c oxidase in the mitochondria. From these two signals, regional cortical tissue O₂ saturation (SctO₂, also commonly known as tissue oxygenation index) can be calculated using the formula:

$$\mathrm{Sct}{\mathrm{O}}_2=\frac{{\mathrm{O}}_2\mathrm{H}\mathrm{b}}{{\mathrm{O}}_2\mathrm{H}\mathrm{b}+\mathrm{HHb}}\times 100$$

From the formula, an increase in O₂ extraction at the level of the brain tissue will result in a decrease in O₂Hb, an increase in HHb, and a subsequent decrease in SctO₂. A decrease in O₂ delivery (i.e., reduced flow) with a constant cerebral metabolic rate will also elicit a decrease in SctO₂. As such, simultaneous assessment of both CBF and cerebral metabolic status are necessary to accurately interpret NIRS-derived signals. NIRS systems can exhibit temporal resolution comparable with TCD, but also can be used to obtain spatial information using multiple measurement points, unlike TCD. More commonly, NIRS-derived CA assessment can be obtained from O₂Hb and HHb values using multiple probes, together with a mathematical model to quantify autoregulation.^123–127 However, unlike other imaging methods such as MRI, the results are limited to a relatively small penetration depth and comprise mixed signals from skin, subcutaneous fat, the skull, cerebrospinal fluid and brain tissue. Interpretation of the recorded signals thus has to be performed with caution, with assessment of CA requiring the removal of extra-cranial components through the use of multiple detector lengths or mathematical modelling.^128,129

Given the theoretical importance of the collateral blood supply and penumbral perfusion, NIRS-derived O₂ saturation might be a sufficient indicator of severe collateral circulatory compromise in clinical stroke management. Despite its limited depth penetration, NIRS is linked to changes in cerebral blood velocity and cortical activation, and has been used to provide indices of regional and global cerebral tissue oxygenation, and reflects peripheral O₂ saturation during acute hypoxic exposure in healthy humans.^130–133 Compared to MRI and PET, NIRS presents a low-cost, bedside compatible method of assessing cerebral oxygenation status. In acute stroke settings, NIRS has considerable potential as a bedside monitoring tool for assessing the severity of cerebral ischemia, changes in cerebral metabolic and dCA status, thrombolysis and tissue reperfusion. Petersen et al., ¹³⁴ recently demonstrated the feasibility for NIRS-derived dCA to guide BP management in large vascular occlusion patients undergoing thrombectomy. Using dCA to derive a personalized upper threshold of BP for each patient, they found significant association between percentage time mean BP above threshold and worst 90-day outcome, whilst no significant associations were observed when 140 mmHg and 160 mmHg thresholds were used. Findings from this study supports the use of personalized, dCA-based approach on BP management in patients undergoing reperfusion treatment.

The use of NIRS to continuously monitor regional tissue oxygenation has been increasing adopted in the field of intensive care, cardiac surgery and neonatology.^{127,135–138} In clinical practice, interventions to preserve cerebral tissue oxygenation with NIRS in patients undergoing coronary artery bypass surgery lowered incidence of adverse clinical events,^139,140 while cerebral tissue desaturation predicts cognitive decline and longer hospital stay following cardiac surgery. ¹⁴¹ In a cohort of 43 anesthetized stroke patients undergoing endovascular therapy, Hametner et al., ¹⁴² found lower interhemispheric difference in NIRS-derived SctO₂ predicted with death at 90-day following treatment, while higher SctO₂ variability was associated with poorer patient outcome. While the assessment of prefrontal cortical SctO₂ limited the use of NIRS for posterior circulation strokes, the authors concluded that NIRS monitoring in acute ischemic stroke patients is feasible and may serve as prognostic marker for long-term patient outcome. In the context of stroke, the use of spatially-resolved NIRS-derived dCA and SctO₂ could provide crucial insight into penumbra evolution.

While ¹⁵O₂-positron emission tomography is considered the gold-standard method of assessing OEF in humans, ¹⁴³ but requires an on-site cyclotron and complex procedures to administer short half-life tracers. NIRS presents a relatively cheaper, bedside alternative PET for assessing OEF, and has been extensively used in neonatal research. ¹⁴⁴ Since NIRS-derived SctO₂ shows good agreement with jugular venous O₂ saturation (SjvO₂) in certain clinical populations,^145–147 it can be used to calculate OEF using the formula:

$$\mathrm{OEF}=\frac{\mathrm{Sa}{\mathrm{O}}_2-\mathrm{Sct}{\mathrm{O}}_2}{\mathrm{Sa}{\mathrm{O}}_2}$$

NIRS-derived estimates of OEF could provide immediate information on the cerebral metabolic status in acute stroke. In new-born piglets, Naulaers et al., ¹⁴⁸ reported good agreement between NIRS-derived cerebral OEF estimates with invasive measures of OEF obtained from arterial blood gas calculations. ¹⁴⁸ The authors nevertheless stressed that NIRS-derived OEF measures should only be used as trends rather than absolute values. Currently, there is currently little NIRS data in stroke patients, and how NIRS-derived values relate to BP, CBF and focal cerebral ischemia. Moreover, since the agreement between NIRS-derived SctO₂ and direct SjvO₂ values in stroke patients has not been determined, the validity of NIRS-derived OEF for this clinical group is currently unknown. The field of cerebral oximetry is still relatively new, there is much work to be done to address how NIRS monitoring could be used to guide clinical practice in stroke management.

Carbon dioxide

Changes in PaCO₂ and associated arterial hydrogen ion concentration are potent stimuli for altering cerebrovascular resistance (thus CBF). In healthy individuals, variations in partial pressure of end-tidal CO₂ (P_ETCO₂) directly influence dCA measures,^52,149,150 while OEF has been shown to be is inversely correlated with P_ETCO₂, accounting for half of the inter-subject variables in OEF. ¹⁵¹ Therefore variations of PaCO₂ need to be accounted for when assessing cerebral hemodynamics. PaCO₂ can be measured either invasively or non-invasively. Invasive techniques are normally based on intravascular electrodes. More commonly, P_ETCO₂ is measured via capnography as a surrogate for PaCO₂. This is achieved using an infrared gas analyzer placed within a ventilator circuit (for ventilated subjects) and via a facemask or nasal prongs (for non-ventilated subjects). Studies have found good correlation between P_ETCO₂ and PaCO₂ in certain clinical settings,^152–154 with the equivalence breaking down in the presence of respiratory disease or dysfunction.^155–157

Future perspectives

Despite recent advances in acute stroke care, there is much uncertainty around BP management due to the lack of information. Since the goal is to restore cerebral perfusion and O₂ supply, bedside monitoring of cerebral perfusion and tissue oxygenation could help guide BP treatment following stroke. In the ideal scenario, continuous and/or recurrent BPV, dCA and OEF monitoring could be carried out in the acute stroke unit (Figure 5). In acute stroke care, brachial BP is routinely used as the sole surrogate of cerebral perfusion pressure, which erroneously assumes that brachial BP equals central BP, and neglects to account of the relationship between BP and CBF (i.e., dCA). While non-invasive measures of central BP, BPV and dCA and cerebral tissue oxygenation could improve BP management in acute ischemic stroke, there are several challenges to overcome before their use in clinical settings. Firstly, there is a lack of normative values and pathologically relevant thresholds for central BP, BPV, dCA and OEF measures for acute stroke. Experimental, pre-clinical and translational studies are clearly needed to establish normative values, determine relevant pathological thresholds and establish optimal BP treatment strategies to restore these parameters. Secondly, these complex hemodynamic information needs to be summarized and presented to medical staff in a manner that alerts them to development of various pathological processes. There are commercially available analysis software such as ICM+ (Cambridge Enterprise) which have been used to monitor indices such as ICP, CPP and dCA in TBI patients. These software integrate raw signals from bedside monitoring devices and provide online trending of complex parameters, and their clinical utility are currently been explored in neonatal care and acute stroke. Each of these issues pose significant hurdles to overcome. Ultimately, the use of these novel prognostic markers rest upon their capacities to improve BP management and patient outcome in acute stroke.

Figure 5.

Schematic representation of acute stroke care with integrative physiological assessment. Ideally, bedside monitoring would take place in the acute stroke unit to guide blood pressure (BP) management. With the goal of BP management to optimize central BP, blood pressure variability (BP), dynamic cerebral autoregulation (dCA) and oxygen extraction traction (OEF) during the first 5 days following stroke onset.

Summary

Despite the complexity of CBF control, clinical monitoring in acute stroke has been largely limited to peripheral BP, at the level of the brachial artery. However, cerebral perfusion is determined by a myriad of physiological parameters, which are often overlooked in both stroke management and research. There is emerging evidence that accentuated BPV, impaired dCA and elevated OEF are harbingers of poor penumbra recovery and patient outcome, yet their utility in BP management is limited due to the lack of established normative and pathological values, as well as intervention strategies to restore them. Would individualized BP threshold, guided by dCA parameters, lead to better BP management and patient outcome? If so, then how do we establish reference values for dCA indices that could be used guide BP management? And what intervention strategies could be used to restore dCA in acute stroke? These are some of the key questions that the INFOMATAS initiative strives to answer.