Perfusion and Antihypertensive Therapy in Acute Ischemic Stroke

Overview

The purpose of this study is to provide a description of blood flow changes in the brain after blood pressure lowering drugs are given. This information will be used by physicians to guide blood pressure lowering therapy in stroke patients in the future.

Objective: To elucidate the inter-relationships between blood pressure (BP), cerebral blood flow (CBF) and oxygen metabolism in acute ischemic stroke in order to establish rational acute hypertension treatment thresholds. Background: Management of acute hypertension in the first 48 hours after stroke is controversial and lends itself to competing rationales. Early reduction of BP may improve outcome by reducing the rate of hemorrhagic transformation and edema formation in early infarcts. Conversely, early BP reduction might reduce CBF and extend the infarct. Natural history studies have demonstrated that patients with higher BP at presentation have elevated early mortality rates, but causality has not been established. Consensus-based guidelines for acute BP management are not based on physiological data or sound evidence. The investigators propose to start addressing this clinical dilemma with a non-randomized controlled study of serial measurements of CBF and oxygen metabolism in acute stroke patients with 3 different levels of acute blood pressure representing 3 different potential treatment thresholds. Hypothesis: The investigators hypothesize that the volume and severity of oligemia in at risk tissue will not increase with BP reduction in acute stroke patients. Specific Aims: 1. Determine the effect of mean arterial pressure (MAP) decreases on CBF. 2. Determine the relationship between infarct volume change over time and MAP. 3. Determine the frequency of hemorrhagic transformation and its relationship to MAP. Study Design: A 3 group non-randomized controlled study. After informed consent, all patients will undergo MRI scanning including diffusion and perfusion-weighted imaging (DWI and PWI). Patients with MAP \<100 mmHg will not receive hypertension treatment. Patients with moderate hypertension (MAP 100-120 mmHg) will be treated with transdermal nitroglycerin (0.2 mg/h) for 48 hours. Patients with severe hypertension (MAP \>120 mmHg) will also be treated with intravenous labetalol, to a target of \<120 mmHg. Two hours after the baseline scan, MRI will be repeated. Any clinical or radiographic evidence of exacerbated oligemia associated with BP reduction will result in immediate discontinuation of all anti-hypertensive therapy. The effectiveness of BP control will be evaluated using a weighted mean average of MAP over 72 hours. All patients will be re-imaged with MRI on day 3 to assess for hemorrhagic transformation. The primary endpoint is the change in objectively measured hypoperfused tissue volume between the baseline and 2 hour scans. Hypoperfused tissue will be determined as the volume of voxels with CBF ≤18 ml/100g/min, a previously validated measurement independent of observer variability. Sample size is based on power calculations required to detect a 10% change in oligemic tissue volume (which would be sufficient to result in exacerbation of ischemic injury) following MAP reduction. Preliminary Work: First, the investigators surveyed Canadian stroke neurologists about their current BP management practices. Indications for acute BP therapy in acute stroke varied from 180 to 240 mmHg systolic, and few clinicians even considered diastolic or MAP treatment thresholds. Physicians based a generally conservative approach on the absence of evidence. Second, the investigators assessed the feasibility of serial MRI and MAP treatment protocols. To date, 9 patients have been imaged with repeat MRI, within 2 hours of the initial exam, confirming that the CBF≤18 ml/100g/min measures of at risk tissue volume can be used to monitor cerebral perfusion. Four patients were treated with our BP management protocol and imaged serially. MAP decreased in all 4 patients 2 hours after treatment. Increases in hypoperfused tissue volume (CBF≤18 ml/100g/min) following MAP reduction were generally mild (\<10%). Of note, after BP reduction, the patient with the lowest initial MAP (96 mmHg) had a marked decline in CBF and large increase in volume of at risk tissue. Third, the investigators determined that decreases in CBF were always associated with increases in oxygen extraction, which appeared to protect tissue from infarct expansion because DWI lesion volumes remained stable. The variations in current practice and demonstration that reductions in MAP can lead to decreases CBF, potentially increasing the risk of adverse stroke-related outcomes justifies studies to determine appropriate treatment thresholds. Significance: The precise relationship between CBF and MAP in acute stroke must be elucidated prior to developing treatment thresholds for testing in a large randomized controlled trial. A serial perfusion study, with careful monitoring of MAP is a critical step in developing a rational BP management protocol. These findings will also help elucidate the mechanisms for poor outcome in patients with both high and low MAP at onset.

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Outcomes