Blood Pressure Management After Endovascular Thrombectomy

 

What research is your doctor and hospital initiating to remove the uncertainty of blood pressure management? Doing nothing should be cause for firing up to and including the board of directors.

Blood Pressure Management After Endovascular Thrombectomy

 

Teng J. Peng¹, Santiago Ortega-Gutiérrez², Adam de Havenon³ and Nils H. Petersen^1*

• ¹Department of Neurology, Yale University School of Medicine, New Haven, CT, United States
• ²Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA, United States
• ³Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT, United States

Endovascular thrombectomy (EVT) has changed the landscape of acute stroke therapy and has become the standard of care for selected patients presenting with anterior circulation large-vessel occlusion (LVO) stroke. Despite successful reperfusion, many patients with LVO stroke do not regain functional independence. Particularly, patients presenting with extremes of blood pressure (BP) or hemodynamic variability are found to have a worse clinical recovery, suggesting blood pressure optimization as a potential neuroprotective strategy. Current guidelines acknowledge the lack of randomized trials to evaluate the optimal hemodynamic management during the immediate post-stroke period. Following reperfusion, lower blood pressure targets may be warranted to prevent reperfusion injury and promote penumbral recovery, but adequate BP targets adjusted to individual patient factors such as degree of reperfusion, infarct size, and overall hemodynamic status remain undefined. This narrative review outlines the physiological mechanisms of BP control after EVT and summarizes key observational studies and clinical trials evaluating post-EVT BP targets. It also discusses novel treatment strategies and areas of future research that could aid in the determination of the optimal post-EVT blood pressure.

Introduction

Large vessel occlusions (LVO) account for approximately one third of ischemic strokes but contribute to more than half of all stroke-related mortality and severe disability (1–3). Over the last several years, LVO strokes are increasingly recognized as unique entities with distinct cerebrovascular pathophysiology and treatment strategies. Acute stroke interventions have traditionally focused on the rapid recanalization of the occluded vessel to restore blood flow to the ischemic tissue. This may be achieved, in a small percentage, by administering intravenous alteplase or, much more effectively, with the use of endovascular thrombectomy (EVT) (4–6). Despite successful reperfusion, LVO stroke patients may continue to have infarct growth, and half do not regain their functional independence, evidencing a need for adjunctive therapies to further improve outcomes (7, 8). Recent evidence suggests that hemodynamic management may play an important role in post-EVT care. While optimal BP targets remain unknown, clinicians must balance the need for sufficient post-thrombectomy blood flow to prevent further infarct growth with the risk of reperfusion injury and hemorrhagic transformation.

This narrative review aims to describe the physiological mechanisms of how BP influences outcome after EVT, provide an overview of observational studies, and discuss completed and ongoing clinical trials of BP management after EVT. We will also discuss recent advances in personalized blood pressure management approaches and suggest potential areas of future research.

Cerebral Autoregulation and Physiologic Considerations of BP Management After EVT

To understand the importance and relevance of blood pressure in acute ischemic stroke, it is helpful to review normal brain vascular physiology and how it can become impaired during ischemia. In a healthy brain, cerebral blood flow (CBF) depends on the pressure gradient between the cerebral arteries and veins. The cerebral arterial pressure is equivalent to the systemic arterial blood pressure (ABP), while the cerebral venous pressure is equivalent to the intracranial pressure (ICP) (9, 10). Cerebral autoregulation is the process in which the brain is able to maintain a steady CBF despite fluctuations in ABP and ICP (9, 11). The mechanisms of autoregulation are not entirely understood but have been shown to involve changes in arteriolar diameter, which directly affects cerebral vascular resistance (CVR) (11). CBF is directly related to ABP and inversely related to CVR, such that CBF = ABP/CVR (12, 13).

Following vessel occlusion, there is a reduction in CBF to the dependent vascular territory. Below a critical threshold of ~10 ml/100 g brain tissue/min, disruption of ion homeostasis and membrane depolarization lead to a loss of neuronal electrical activity (14, 15). Unless blood flow is rapidly restored, the damage becomes irreversible, and cell death occurs. Surrounding the infarct core, there is a zone of hypoperfused, functionally impaired but still viable tissue known as the “ischemic penumbra” (14, 16). The low perfusion pressure in the penumbra creates a pressure gradient that promotes retrograde flow to the ischemic territory (17). The rate of ischemic core growth depends on the duration of ischemia and the degree of collateral blood flow (18).

Ischemia-induced vasoparalysis in the penumbra leads to loss of intrinsic autoregulatory function (19, 20). The decrease in downstream perfusion pressure distal to the occluded vessel, with compensatory dilation of brain arterioles, further impairs autoregulation and causes the CBF to become passively dependent on the ABP (21). The loss of autoregulation after LVO can persist even after revascularization is achieved, rendering the brain vulnerable to fluctuations in perfusion pressure (22, 23). Low ABP can exacerbate cerebral hypoperfusion and cause further ischemic core growth, particularly among patients with incomplete reperfusion. In contrast, elevated ABP may cause excessive flow, cerebral edema, and hemorrhagic conversion (22, 23). Advanced age, greater stroke severity, hyperglycemia, large infarct volume, treatment with alteplase, and poor collateral status have been associated with the development of hemorrhagic transformation and may further increase the risk of reperfusion injury with elevated BP (24, 25). After thrombectomy, the optimal BP requires a careful balance of these opposing concerns to provide the ideal environment for penumbral recovery while avoiding secondary injury from hypo- or hyperperfusion.

Targeted BP therapies aim to maintain BP below or above a fixed threshold. However, BP is one of the most dynamic physiologic variables with significant changes during the early phase after LVO stroke. Sustained increases in BP variability (BPV) may reflect alterations in the mechanisms responsible for cardiovascular homeostasis and represent a potentially modifiable contributor to end-organ damage and poor neurological recovery after LVO stroke (26–30). Although the exact mechanism by which BPV may exert a negative influence remains unknown, direct exposure of the vulnerable oligemic brain tissue to perfusion fluctuations created by elevated systemic BPV may play a critical role. Short-term BP fluctuations can occur due to various internal and external factors, including central sympathetic drive, arterial tone, cardiopulmonary reflexes, humeral mechanisms, blood viscosity, volume status, and medications (31).

Relevant Observational Studies

Current guidelines by the American Heart Association released in 2019 recommend maintaining a BP goal of ≤ 180/105 for the first 24 h after mechanical thrombectomy (32). These guidelines are based on limited evidence and do not account for individual patient factors such as reperfusion status or infarct volume. Sustained elevations of systolic blood pressure (SBP) have been associated with higher rates of symptomatic intracerebral hemorrhage (sICH) and poor functional outcomes (33–36). The Blood pressure After Endovascular Stroke Therapy (BEST) multicenter prospective cohort study of 485 patients found that a peak post EVT SBP of >158 mmHg best discriminated between favorable (mRS 0–2) from unfavorable (mRS 3–6) (37), confirming the results of a smaller, previously published study (33). To further characterize BP trajectories during the first 72 h after thrombectomy, Kodali et al. used a person-centered modeling approach to identify subgroups of patients with similar BP patterns (38). Patients with high and high-to-moderate SBP trajectories had significantly greater odds of an unfavorable outcome compared to those with persistently low SBP post-EVT.

Several studies have suggested that the optimal BP target may depend on the degree of recanalization (35, 39, 40). Mistry et al. retrospectively evaluated a group of 228 patients with LVO stroke and found that higher peak values of systolic blood pressure in the first 24 h after EVT independently correlated with worse 90-day outcomes (41). Interestingly, hemorrhagic complications, a marker of reperfusion injury, were observed at lower mean peak SBP levels among recanalized patients compared to non-recanalized patients (41). However, others consistently found that the best outcomes in patients with successful recanalization occurred at lower blood pressures (36, 39, 40, 42, 43). Recanalized patients (TICI 2b-3) demonstrate a significant spontaneous decrease in SBP over 24 h after EVT (36). The relationship between post-EVT BP and functional outcomes becomes linear, with the most favorable outcomes at an SBP of 110 mmHg (35, 36). In contrast, non-recanalized patients (TICI 0-2a) show a diminished decline in post-EVT BP, and the relationship with functional outcomes is U or J-shaped. Both high and low average post EVT SBP are associated with worse outcomes.

Whether the association between lower post-EVT BP and better functional outcome in patients with successful recanalization is causal or just a reflection of other stroke-related factors, such as better collaterals, remains unclear. However, physiological consideration and the results mentioned above have led many stroke centers to adopt a tiered approach to BP management after thrombectomy stratified by reperfusion status. An online survey regarding BP management post EVT performed across StrokeNet sites in the United States found that most institutions (39%) used a target SBP of 120–139 mmHg on recanalized patients and permissive hypertension on non-recanalized patients (44). However, the complexity of location of vessel occlusion, degree of recanalization, and final infarct volume suggest that a more nuanced approach may be necessary.

Several observational studies have investigated the effect of differing BP treatment protocols after thrombectomy on radiographic and clinical outcomes. Goyal et al. separated patients into three groups based on post-EVT achieved SBPs of <140, <160, and <180 mmHg. Actual BP targets varied and depended on the treating physician's preference and the patient's clinical status. The investigators found that achieving an SBP goal of <160 mmHg during the first 24 h post-EVT was associated with lower odds of mortality than permissive hypertension (34). This study did not find any significant functional outcome differences at 3 months, but results may have been underpowered due to the small sample size. A more recent large multicenter study by Anadani et al. showed that SBP targets of <140 mmHg after successful reperfusion were associated with lower odds of unfavorable outcome and need for hemicraniectomy than SBP targets of <180 mmHg (36, 42).

Besides BP targets, BPV has emerged as an important aspect of post-EVT hemodynamic management. Studies found that BPV is elevated in patients with larger strokes and associated with higher rates of death and disability in stroke patients that did not undergo EVT (30, 45). Furthermore, antihypertensive drug classes have differing effects on interindividual variation in blood pressure. Calcium-channel blockers such as amlodipine (oral) and nicardipine (intravenous) have been shown to reduce BPV, while b-blocker may increase it (46, 47). Several recent studies have focused on the relationship between BPV and outcome in patients receiving EVT. While there was significant heterogeneity in the frequency and duration of measurements as well as BPV parameters, high BPV was consistently associated with a reduced likelihood of neurological recovery (29, 30, 48).

The effect of reperfusion status on the relationship between BPV and outcome is more controversial. After incomplete reperfusion, higher infarct volumes with surrounding ischemic tissue may make patients more vulnerable to BP fluctuations. Conversely, successful recanalization exposes friable brain tissue to changes in perfusion pressure, potentially increasing the risk of reperfusion injury. While one of the early studies showed the association between BPV and unfavorable outcome appeared strongest among patients with incomplete recanalization (29), others found the opposite effect (49–51). In a post-hoc analysis of the BEST study, patients were stratified by recanalization status (TICI 0-2a, 2b, and 3), and high BPV was associated with poor outcomes for patients with TICI 3 exclusively (37). Similarly, another study showed that the effects of higher BPV on outcomes were more pronounced among patients with better reperfusion status (52). A link between higher BP variability and an increased risk of reperfusion injury is supported by Kim et al. They found that high BP variability in the first 24 h following successful EVT was associated with an increased risk of symptomatic intracerebral hemorrhage (53). However, other investigators could not confirm this association (51).

Whether the relationship between high BPV and outcome is causative or an epiphenomenon of stroke-related factors and associated physiologic stressors remains unknown. Chang et al. demonstrated an inverse relationship between BPV parameters and the degree of recanalization (28). They hypothesized that lower recanalization success might increase the chances of insular and adjacent tissue destruction resulting in sympathetic overactivity. However, despite solid conceptual reasons to support a link between BPV and infarct location, other investigators found no association between BPV and injury to the structures of the central autonomic network, arguing against a central origin (51).

While evidence suggests that maintaining a stable BP with low variability after successful thrombectomy may be as important as controlling mean peak BP values, there has not been a clinical trial dedicated to reducing BPV in stroke patients. A summary of observational trials can be found in Table 1.