Solving the mystery of blood pressure in acute stroke.

In acute ischemic stroke, the most intuitive therapeutic approach is to restore perfusion to the ischemic territory, typically downstream from an occluded artery. Hemodynamic variables such as systemic blood pressure are seemingly obvious factors that may influence the evolution of ischemic injury and neurologic outcome. The impact of systemic blood pressure and subsidiary maintenance of cerebral perfusion pressure are basic elements of stroke pathophysiology, yet colossal research efforts have been diverted toward the more elusive goal of identifying critical molecular targets in the ischemic cascade. Augmentation of blood pressure in acute stroke may theoretically diminish cerebral ischemia, yet hypertension may also aggravate cerebral edema or precipitate hemorrhagic transformation. Such influential effects may play a pivotal role in acute stroke, yet the clinician has scant data to guide management of such patients. In a clinical scenario where every second lost may be equated with increasing brain damage, measurement of systemic blood pressure is a basic and universal step yet clinicians are paradoxically paralyzed with regard to management of this critical variable. A litany of reports has documented the typical pattern of elevated blood pressure during incipient stages of ischemic stroke and many have addressed the prognostic role of blood pressure in acute stroke, yielding only conflicting conclusions. We still do not know the answer to this obvious, and perhaps complex, question that has been addressed in simple analyses of stroke data sets. Few studies have endeavored to ask why blood pressure is elevated.

After more than half a century of unsuccessful clinical trials in acute ischemic stroke, hemodynamic variables remain neglected. (1) Baseline blood pressure measures have been used to provide data for numerous prognostic studies; however, other hemodynamic factors such as volume status and fluid management have been omitted. Furthermore, the relationship of blood pressure with other vascular correlates such as patency of the proximal arteries and the extent of compensatory collateral circulation has been largely ignored. (2) More recent studies have attempted to discern whether specific parameters such as the systolic or diastolic component are more important, or whether other aspects such as pulse pressure or blood pressure variability are paramount. An exhaustive review of deliberate manipulation of blood pressure in acute stroke demonstrated a dearth of data to guide clinical management of stroke patients. (3) Guidelines for the treatment of acute ischemic stroke have formulated Grade C recommendations for management of blood pressure, principally relying on level III clinical evidence. (4,5)

Against this backdrop of uncertainty, Underwood et al investigated the management of blood pressure in a series of acute ischemic stroke patients treated at a single institution, with respect to adherence to published guidelines and neurologic outcome. (6) They discovered poor compliance with guidelines for the management of blood pressure and excessive use of antihypertensive therapy to reduce baseline pressure readings in this cohort. Only 22% of patients met criteria for treatment of arterial hypertension, yet 98% of the cohort was administered antihypertensive therapy. In addition, blood pressure was reduced excessively in all cases that met criteria for intervention. Although a potential association with clinical outcome was sought, no such relationship could be established between overzealous blood pressure reduction and worsened neurologic outcomes. This paper underscores the clinical quagmire that envelops the routine management of stroke patients on a daily basis throughout the country. Several questions abound, including the motivating factors leading physicians to ignore published guidelines and aggressively lower blood pressure. As the authors suggest, perhaps the relatively weak level of evidence behind published guidelines has inspired an inadequate sense of confidence. Some clinicians may be more concerned about the worrisome complications of evolving cerebral edema or hemorrhagic transformation. It remains to be seen whether the practices described in this study are reflected in larger stroke cohorts and whether such blood pressure management varies with the use of thrombolytics or in the realm of clinical trials.

The nebulous recommendations for blood pressure management and conflicting reports with respect to outcome that are rife in the literature emphasize the case that something is missing. There remains a paucity of studies that address why blood pressure is elevated acutely and subsequently diminishes. Prior suggestions have implicated the role of a full bladder, pain, or even stress in acute stroke patients. More direct pathophysiologic explanations have included tissue-related events such as hypoxia or increased intracranial pressure. Such explanations are particularly unlikely during the very first minutes or hours after stroke onset. Vascular correlates, including the presence of large artery occlusion or status of collaterals may be involved. Acute hypertension may be a marker of insufficient collateral flow rather than a disorder itself. Endogenous pathophysiologic mechanisms for hypertension in acute ischemic stroke warrant further investigation. Prior analyses of blood pressure in acute stroke have considered only limited aspects, relating blood pressure trends with treatment and subsequent clinical outcome in trials of investigational agents. These statistical calculations have failed to enlighten or reveal novel pathophysiologic correlates. Dedicated studies of hemodynamic factors in acute ischemic stroke, including detailed imaging with angiographic features and characterization of stroke subtypes, consideration of baseline comorbidities, and delineation of serologic mediators will be required to answer these critical questions. Unfortunately, such potentially costly studies are devoid of funding resources due to the nonproprietary nature of the topic. Until such studies ensue, the clinician is left without a clear answer as to how and why to manage the blood pressure in acute ischemic stroke. The onus is on the stroke research community to address these fundamental aspects of stroke pathophysiology and answer this mysterious, and yet so important question in clinical practice.

References

1. Kidwell CS, Liebeskind DS, Starkman S, et al. Trends in acute ischemic stroke trials through the 20th century. Stroke 2001;32:1349-1359.

2. Liebeskind DS. Collateral circulation. Stroke 2003;34:2279-2284.

3. Interventions for deliberately altering blood pressure in acute stroke. Cochrane Database Syst Rev 2006:CD000039.

4. Adams HP Jr, Adams RJ, Brott T, et al. Guidelines for the early management of patients with ischemic stroke: A scientific statement from the Stroke Council of the American Stroke Association. Stroke 2003:34:1056-1083.

5. Adams H, Adams R, Del Zoppo G, et al. Guidelines for the early management of patients with ischemic stroke: 2005 guidelines update a scientific statement from the Stroke Council of the American Heart Association/American Stroke Association. Stroke 2005;36:916-923.

6. Underwood M, et al. Overuse of hypertension treatment in acute ischemic stroke. South Med J 2006;99:1230-1233.

Courage is not simply one of the virtues, but the form of every virtue
at the testing point.
--C. S. Lewis

David S. Liebeskind, MD

From the UCLA Stroke Center and Department of Neurology, University of California, Los Angeles, CA.

Reprint requests to David S. Liebeskind, MD, UCLA Stroke Center, 710 Westwood Plaza, Los Angeles, CA 90095. Email: [e-mail]

Accepted September 7, 2006.