Cerebral Autoregulation in Subarachnoid Hemorrhage

 Don't have this type of stroke, treatment knowledge seems extremely limited.

Cerebral Autoregulation in Subarachnoid Hemorrhage

Darcy Lidington^1,2, Hoyee Wan^1,2 and Steffen-Sebastian Bolz^1,2,3*

• ¹Department of Physiology, University of Toronto, Toronto, ON, Canada
• ²Toronto Centre for Microvascular Medicine at the Ted Rogers Centre for Heart Research Translational Biology and Engineering Program, University of Toronto, Toronto, ON, Canada
• ³Heart & Stroke/Richard Lewar Centre of Excellence for Cardiovascular Research, University of Toronto, Toronto, ON, Canada

Subarachnoid hemorrhage (SAH) is a devastating stroke subtype with a high rate of mortality and morbidity. The poor clinical outcome can be attributed to the biphasic course of the disease: even if the patient survives the initial bleeding emergency, delayed cerebral ischemia (DCI) frequently follows within 2 weeks time and levies additional serious brain injury. Current therapeutic interventions do not specifically target the microvascular dysfunction underlying the ischemic event and as a consequence, provide only modest improvement in clinical outcome. SAH perturbs an extensive number of microvascular processes, including the “automated” control of cerebral perfusion, termed “cerebral autoregulation.” Recent evidence suggests that disrupted cerebral autoregulation is an important aspect of SAH-induced brain injury. This review presents the key clinical aspects of cerebral autoregulation and its disruption in SAH: it provides a mechanistic overview of cerebral autoregulation, describes current clinical methods for measuring autoregulation in SAH patients and reviews current and emerging therapeutic options for SAH patients. Recent advancements should fuel optimism that microvascular dysfunction and cerebral autoregulation can be rectified in SAH patients.

Introduction

Cerebral aneurysms are common [1–5% prevalence (1, 2)] and pose a “silent risk” of severe brain injury. When an aneurysm ruptures, blood rapidly enters into the subarachnoid space: this event is termed aneurysmal subarachnoid hemorrhage (SAH) (1, 3, 4). In severe cases, intracranial pressure (ICP) elevates to levels that cause cerebrovascular arrest and death quickly ensues. As one might expect, SAH has a high case fatality rate (32–67%); of those that survive the initial bleed, 30-50% will suffer long-term disability as a result of serious brain injury (3–5). In terms of productive life years lost, SAH closely rivals more common forms of stroke due to its early age of onset (1, 6): thus, SAH incurs a disproportionately heavy cost (7), despite being a relatively rare form of stroke (~10 in 100,000 persons per year) (8–10). The interventions to halt ruptured aneurysm bleeding and prevent subsequent re-bleeds are frequently successful: thus, if the patient survives the initial bleeding event, which depends on the severity of bleeding and how quickly emergency medical attention is initiated, most of the treatable mortality and morbidity in SAH occurs during neurointensive care. In this regard, a pronounced secondary ischemic event, termed “delayed cerebral ischemia (DCI)” emerges 3–14 days following SAH. DCI is a significant cause of death and disability in SAH patients who survive the initial aneurysm rupture (1, 11, 12).

Until recently, DCI was attributed to radiographically visible large artery constriction, known as angiographic vasospasm, as this common complication often occurs concomitantly with the ischemic event (13). Consequently, the majority of research efforts focused on developing therapeutic interventions to curtail angiographic vasospasm, in the hopes that this would significantly improve patient outcome (4, 14). These efforts culminated in the disappointing CONSCIOUS clinical trials involving the endothelin-1 receptor antagonist clazosentan, which successfully reduced the incidence of large artery constriction, but failed to improve clinical outcome (15–18). This failure necessitated a shift in attention from the radiographically visible angiographic vasospasm to the radiographically invisible cerebral microcirculation. Indeed, given that the microcirculation is the primary determinant of cerebrovascular resistance (19), microcirculatory dysfunction is more aptly positioned to drive ischemic injury than large artery vasoconstriction. There are an extensive number of processes governed by the microcirculation; of these processes, the “automated” control of cerebral perfusion, termed “cerebral autoregulation,” appears to be an important aspect of SAH-induced brain injury, as it is clearly impaired following SAH (20–24) and it is a strong independent predictor of both DCI and negative outcome (22–24).

For physicians caring for SAH patients, this review summarizes the key clinical aspects of cerebral autoregulation and its disruption in the context of SAH. Our review is segmented into three primary subsections: (1) an overview of cerebral autoregulation, its mechanistic basis and predictions on how SAH alters autoregulatory function, (2) clinical measures of autoregulation and their relationship to patient outcomes, and (3) current therapeutic interventions for SAH in the context of autoregulation, which explains why alternative approaches are desperately required. In our subsequent discussion, we will examine some emerging therapeutic options that may be capable of correcting dysfunctional autoregulation in SAH.

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