Management of Blood Pressure During and After Recanalization Therapy for Acute Ischemic Stroke

So you acknowledge that there are no blood pressure management protocols but DO NOTHING to solve them. 

Management of Blood Pressure During and After Recanalization Therapy for Acute Ischemic Stroke

Jeffrey R. Vitt¹, Michael Trillanes² and J. Claude Hemphill III^1*

• ¹Department of Neurology, University of California, San Francisco, San Francisco, CA, United States
• ²Department of Pharmaceutical Services, University of California, San Francisco, San Francisco, CA, United States

Ischemic stroke is a common neurologic condition and can lead to significant long term disability and death. Observational studies have demonstrated worse outcomes in patients presenting with the extremes of blood pressure as well as with hemodynamic variability. Despite these associations, optimal hemodynamic management in the immediate period of ischemic stroke remains an unresolved issue, particularly in the modern era of revascularization therapies. While guidelines exist for BP thresholds during and after thrombolytic therapy, there is substantially less data to guide management during mechanical thrombectomy. Ideal blood pressure targets after attempted recanalization depend both on the degree of reperfusion achieved as well as the extent of infarction present. Following complete reperfusion, lower blood pressure targets may be warranted to prevent reperfusion injury and promote penumbra recovery however prospective clinical trials addressing this issue are warranted. (But lower blood pressure means less cerebral blow flow and less oxygen delivered to the brain, probably hastening the death of neurons in the penumbra.)

Introduction

Stroke is a common neurologic emergency worldwide with an overall growing incidence particularly in low to middle income countries where there has been over a 100% increase in stroke events over the past four decades (1). Approximately 85% are ischemic in origin and for the past two decades, intravenous tissue plasminogen activator (IV t-PA) has been the mainstay of treatment for patients with acute ischemic stroke (AIS) presenting within 3, and then expanded to 4.5, hours since last known well (2, 3). IV t-PA reduces the rate of functional dependence in up to one-third of individuals, but many AIS patients do not benefit from this treatment (2, 3). Over the past several years, multiple landmark studies have provided overwhelming evidence that intraarterial therapy (IAT) with mechanical thrombectomy, performed within 6 h of last known well in large vessel occlusion (LVO), leads to significantly improved functional outcomes and reduced mortality (4–7). More recently, the DEFUSE III and DAWN trials demonstrated that IAT can benefit patients treated out to 16 and 24 h if they have a favorable mismatch pattern on perfusion imaging (8, 9). While these breakthroughs have altered the paradigm of acute stroke management and can be considered as part of routine care, several unresolved issues remain regarding the optimal treatment of patients presenting with AIS, particularly regarding hemodynamic management. Though blood pressure (BP) elevation is common in AIS, the prognostic significance of this is unclear (10, 11). Some studies have found a correlation between hypertension and poor outcomes while others have reported inverse relationships (12–15). Furthermore, the guidelines for hemodynamic treatment following thrombolytic therapy in AIS are largely extrapolated from the IV t-PA trials as well as retrospective analyses (16). Thus, high quality evidence to guide management after IAT is lacking. The purpose of this review is to discuss the physiology and available data regarding hemodynamics in AIS with particular focus on how blood pressure might be optimally managed throughout the revascularization process.

Pathophysiology

In order to understand the principles of blood pressure management during AIS revascularization, it is useful to review fundamental aspects of blood flow in cerebral ischemia and infarction. Following complete cessation of cerebral blood flow (CBF) there is loss of normal neuronal electrical activity within seconds due to energy failure, disruption of ion homeostasis and membrane depolarization (17, 18). If perfusion is not restored within minutes, irreversible injury ensues leading to infarction (19). Ischemic stroke, however, is a focal process and there is rarely complete loss of CBF. Instead, surrounding the occluded vascular territory exist areas of mild hypoperfusion with intact function, ischemic tissue which remains salvageable but with dysregulated cellular processes (termed penumbra), and infarction with irreversible damage (17).

Early clinical studies using carotid clamping revealed that the risk of transitioning from ischemic to infarcted tissue depends on both the magnitude and duration of hypoperfusion (17). Furthermore, if CBF is reestablished in a timely manner the ischemic tissue may be salvaged and restored to normal function. Neurons within the penumbra are highly vulnerable to changes in local perfusion pressure, either from edema, alterations in systemic BP, or changes in cerebral vasoreactivity, and maintain a relatively preserved oxygen consumption despite lower CBF due to an increase in the oxygen extraction fraction (20, 21). While the infarction threshold largely depends on the duration and extent of hypoperfusion, individual factors including vascular compliance and collateral vessels between both intracranial and extracranial circulations can influence the resilience of the penumbra (17). Following acute vessel occlusion, the perfusion pressure distal to the clot falls leading to a pressure gradient in which retrograde flow commences through collaterals thereby achieving a sufficient level of CBF to maintain penumbra viability (22). In this setting, drops in BP or increases in tissue pressure from local mass effect can lead to an attenuation of the collateral gradient and exacerbate ischemia (23). This is demonstrated clinically in AIS as patients with more robust collaterals often have a lower BP, likely from adequate perfusion to the penumbra, and improved clinical outcomes relative to those with poor collateralization (24, 25). Furthermore, the presence of a robust collateral circulation predicts a higher likelihood of recanalization following IAT and, in cases where the procedure is unsuccessful, there is a reduced infarct volume compared to patients with poor collateralization (26, 27).

In the healthy brain, CBF is tightly regulated to meet regional metabolic demand and this is accomplished through the process of cerebral autoregulation whereby resistance-level blood vessels constrict or dilate across a range of systemic pressures (typically a mean arterial pressure [MAP] between 50 and 150 mmHg) in order to maintain a more constant flow (28). When pressures fall below the lower limit of autoregulation, surrounding brain parenchyma becomes ischemic and eventually infarcted unless CBF is rapidly restored. Conversely, when MAP rises above the capacity of cerebral autoregulation, a linear increase in CBF occurs leading to edema and hemorrhage. In AIS, the disruption of blood flow results in dysregulation of multiple cellular processes which may include autoregulatory mechanisms within the penumbra, thus making CBF directly dependent on systemic pressures (28, 29). Though early studies using radiotracer injection confirmed changes in CBF within the ischemic hemisphere in proportion to alterations in MAP, the resolution of these techniques did not allow for differentiation of penumbra from core infarct (28). Newer studies have had various findings, with reports of impaired autoregulation both globally and within the ischemic hemisphere contrasting with a recent study that found no change in regional CBF following alterations in MAP using high resolution positron emission tomography (PET) (30, 31). While these conclusions were derived from measures of static autoregulation, in which regional changes in CBF were assessed at a single time point after BP manipulation, recent focus has shifted toward dynamic autoregulation using techniques such as transcranial doppler to track instantaneous changes in blood flow in response to BP fluctuations (28, 30). In contrast to static autoregulation, which is often preserved in AIS, recent studies have revealed that dynamic autoregulation may be particularly vulnerable to ischemic insult and can remain abnormal for several weeks after presentation (30, 32). Though impairments in dynamic autoregulation appear common across a spectrum of stroke subtypes and may indicate selective damage to central autonomic control networks, the clinical relevance remains unclear and is the subject of ongoing investigation (30, 33).

While reestablishing CBF is essential for survival of ischemic tissue, reperfusion itself can contribute to significant neurologic injury in the form of infarction, edema and hemorrhagic transformation (34, 35). Reperfusion injury is a complex and incompletely understood process however several important underlying pathophysiologic mechanisms have been identified. Immediately following recanalization there often is a dramatic increase in CBF, likely as a result of impaired autoregulation as well as release of vasodilatory substances, which leads to hyperperfusion and the potential for secondary cellular injury (18, 36). The magnitude of cerebral hyperemia seems to be influenced in part by the duration of ischemia and in MRI studies, hyperperfusion following thrombolysis was most commonly observed in areas of pretreatment hypoperfusion and was an independent predictor of eventual infarction (36). After recanalization there can also exist a paradoxical hypoperfusion state, termed no-reflow phenomenon, which can lead to permanent infarction and is thought to result from microvascular dysfunction related to astrocyte and endothelial cell swelling as well as increased inflammation and platelet aggregation (37, 38). On a cellular level, reperfusion after prolonged ischemia leads to mitochondrial overproduction of toxic reactive oxygen species causing inflammation and triggering the release of extracellular matrix metalloproteinases (MMP) which enzymatically degrade the endothelial basal lamina and increase microvascular permeability (39, 40). Loss of blood brain barrier (BBB) integrity in turn leads to vasogenic cerebral edema formation and in clinical studies is a strong predictor for hemorrhagic transformation and poor neurologic outcome following revascularization (41).

Blood Pressure in Acute Stroke

Elevated BP is common in patients presenting with AIS, with one study involving more than 250,000 patients demonstrating a systolic blood pressure (SBP) > 140 mmHg in approximately three-fourths of patients (10). Severe hypertension is also relatively common with nearly 10% of patients presenting with SBP > 200 mmHg (42). Multiple observational studies have identified elevated BP as a risk factor for cerebral edema, hemorrhage and generally worse clinical outcomes following AIS (43–45). However, this association does not necessarily indicate a causative relationship. Instead, hypertension may be a marker of stroke severity, such as in the case of carotid terminus occlusion or poor collateralization, where spontaneously elevated blood pressure may serve as a compensatory mechanism to maintain cerebral perfusion (25, 46). Under which circumstances these mechanisms become maladaptive and contribute directly to cerebral injury remains uncertain and requires further clarification through clinical trials.

In several cohorts, a U-shaped relationship exists between BP and outcome in AIS in which both extremes of BP have prognostic significance for death and disability. In a retrospective analysis of the International Stroke Trial, patients presenting with SBP 140–179 mmHg had the lowest likelihood of death or dependency at 6 months with a nadir at around 150 mmHg (42). For every 10 mmHg above a SBP of 150 mmHg, patients had a 3.6% increase in the risk of death and a 4.2% increased risk of recurrent stroke within the next 6 months. For patients with a SBP > 200 mmHg there was more than a 50% increase in the risk of stroke. Conversely, relative hypotension was also detrimental with a 17.9% increased risk of death for every 10 mmHg drop below 150 mmHg; patients with SBP < 120 mmHg had the worst outcomes and a higher incidence of coronary events. Similar findings have been reported in other studies with slightly different BP thresholds conferring the most favorable outcomes. In work done by Vemmos and colleagues, the best outcomes were observed with SBP values around 130 mmHg while in a study from the Mayo Clinic, the optimal threshold for SBP seemed to be in the range of 156–220 mmHg with a nearly two-fold increase in risk of mortality with episodes of hypotension (47). Similarly, in work done by Castillo et al. patients had lower mortality and more functional independence when presenting with a SBP near 180 mmHg, with final infarct volumes being highest among patients with SBP well above or below this value (15). Interestingly, abrupt declines in SBP (>20 mmHg) were identified as the strongest predictor of poor outcome and were associated with a larger final infarct volume of over 60 ml, suggesting that dynamic BP changes may be particularly injurious to vulnerable ischemic tissue.

In clinical studies, dynamic fluctuations in BP have been identified as a strong prognostic marker in AIS and increase the risk of intracranial hemorrhage following IV t-PA (12). BP variability may be particularly harmful in the setting of large territory infarcts, where it has been independently linked to worse clinical outcomes (12, 48). In one study, patients with BP variability seemed to have worse outcomes in the presence of robust collaterals despite otherwise similar hemodynamic profiles (48). The reasons behind these findings are not entirely clear, however it may be related to increased transmission of fluctuating pressures to the ischemic penumbra. While the impact of BP variability seems to be more apparent in the initial stages of ischemia, one study found day-to-day variability over the course of 1 week was higher in patients with poor outcomes at 1 year (14). Overall, it appears that ischemic tissue may be particularly susceptible to fluctuations in systemic BP, likely as a result of impaired autoregulation and narrow ischemic thresholds, leading to either hypoperfusion with infarction or surges in perfusion with resulting edema (15, 28). Table 1 summarizes results from several observational studies related to blood pressure and ischemic stroke outcome.

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