BP mgt in stroke 2008

Neurol Clin 26 (2008) 565–583

Blood Pressure Management in Acute Stroke Victor C. Urrutia, MD*, Robert J. Wityk, MD Cerebrovascular Division, Department of Neurology, Johns Hopkins University School of Medicine, 601 N. Caroline Street, Suite 5073A, Baltimore, MD 21287, USA

The optimal management of arterial blood pressure in the setting of an acute stroke has not been defined [1–3]. Many articles have been published on this topic in the past few years, but definitive evidence from clinical trials continues to be lacking [4–7]. This situation is complicated further because stroke is a heterogeneous disease. The best management of arterial blood pressure may differ, depending on the type of stroke (ischemic or hemorrhagic) and the subtype of ischemic or hemorrhagic stroke [1,8].

This article reviews the relationship between arterial blood pressure and the pathophysiology specific to ischemic stroke, primary intracerebral hemorrhage (ICH), and aneurysmal subarachnoid hemorrhage (SAH), elaborating on the concept of ischemic penumbra and the role of cerebral autoregulation.

The article also examines the impact of blood pressure and its management on outcome. Finally, an agenda for research in this field is outlined.

Cerebral autoregulation Cerebral autoregulation is the mechanism by which cerebral blood flow (CBF) remains constant across a wide range of cerebral perfusion pressures (CPP), achieved by reflex vasoconstriction or vasodilation of the cerebral arterioles in response to changes in perfusion pressure. CPP is defined by the following relationship: CPP ¼ MAP ICP where MAP is mean arterial pressure and ICP is intracranial pressureIf ICP is constant and not elevated, MAP and CPP are proportional; they can be This is an updated version of an article that originally appeared in Critical Care Clinics, volume 22, issue 4. * Corresponding author.

E-mail address: vurruti1@jhmi.edu (V.C. Urrutia).

0733-8619/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ncl.2008.02.002 neurologic.theclinics.com

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used interchangeably when talking about autoregulation. CBF is determined by CPP and cerebrovascular resistance (CVR). CVR is governed primarily by arteriolar diameter, although larger vessels also may contribute. To maintain a constant CBF of approximately 50 mL/100 g/min, CVR increases through arteriolar constriction if CPP increases, and decreases by arteriolar dilation if CPP decreases. The autoregulatory system in the brain can maintain essentially constant CBF between a MAP of 50 to 60 mm Hg to 150 to 160 mm Hg. When MAP decreases to less than 50 to 60 mm Hg, maximum vasodilation is reached, and CBF decreases proportionally with the MAP, resulting in ischemia. On the other extreme, when MAP exceeds 150 to 160 mm Hg, arteriolar vasoconstriction is exhausted, and hydrostatic pressure increases continuously, resulting in cerebral edema and breakdown of the blood–brain barrier (ie, hypertensive encephalopathy or ICH) (Fig. 1).

Segmental vasodilation or a ‘‘sausage-string’’ appearance of the arteries comes first, followed by massive cerebrovascular dilation [9]. In chronically hypertensive individuals, the autoregulation curve is shifted as a result of the elevated MAP levels; the lower and upper inflection points are higher than in normal individuals. A normal CBF and oxygen consumption are maintained at the expense of a marked increase in the CVR [9]. These changes result in a decreased tolerance for relative hypotension because the capacity to maintain a constant CBF at the lower end of the blood pressure spectrum is impaired.

Evidence indicates that autoregulation is dysfunctional after a stroke. If capacity for autoregulation does not exist, CBF increases or decreases proportionally to the MAP, exposing the brain to ischemia from

Fig. 1. CBF remains constant across a wide range of CPP owing to cerebral autoregulation, achieved primarily through arteriolar vasoconstriction and vasodilation in response to changes in CPP. (Data from Rose JC, Mayer SA. Optimizing blood pressure in neurologic emergencies.

Neurocrit Care 2004;1:287–99.)

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hypoperfusion, or edema and hemorrhage in the case of hypertension (Fig. 2). Eames and colleagues [10] measured dynamic cerebral autoregulation by analyzing beat-to-beat, spontaneous blood pressure variability and CBF velocities with transcranial Doppler in 56 patients who had stroke and 56 matched controls. They found global impairment in dynamic autoregulation in patients who had stroke but not in controls, and this dysfunction occurred not only in the hemisphere ipsilateral to the infarct, but also contralaterally [10,11].

Ischemic penumbra CBF in the area of a cerebral infarction is not homogeneous. In animal experiments, Astrup and colleagues [12] showed a critical threshold of CBF, below which neurons cease to function but continue to survive for a time. These neurons can potentially return to a normal functional state with restoration of blood flow. Jones and colleagues [13] replicated these findings and suggested that the time window in which ischemia is reversible is in the range of several hours. The current concept of the ischemic penumbra is a region of brain with a gradient of decreased CBF. Tissue with the lowest CBF would be irreversibly damaged and constitute the core of the infarct [14,15]; this area will become an infarct even if CBF is restored.

The regions surrounding the core, the ‘‘penumbra’’ (Fig. 3), are ischemic and dysfunctional, but potentially salvageable. With timely reperfusion, the region of ischemic penumbra may be rescued from infarction. The length of time during which tissue in the ischemic penumbra remains viable is controversial, but is likely to depend on the location of the cerebral vessel

Fig. 2. In chronic hypertension, the autoregulatory curve is ‘‘shifted’’ to the right, maintaining constant CBF at higher CPP than normal and resulting in a decreased tolerance to relative hypotension. In the setting of cerebral ischemia, autoregulation is impaired, and CBF becomes proportional to CPP. (Data from Rose JC, Mayer SA. Optimizing blood pressure in neurologic emergencies. Neurocrit Care 2004;1:287–99.)

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Fig. 3. In an arterial bed distal to an acute occlusion, a ‘‘core’’ of irreversibly damaged tissue is surrounded by an area of decreased perfusion. The region of hypoperfusion associated with functional impairment that potentially can be salvaged by reperfusion is operationally considered the ‘‘ischemic penumbra.’’ (Adapted from Wityk RJ, Lewin JJ III. Blood pressure management during acute ischemic stroke. Expert Opin Pharmacother 2006;7:247–58; with permission.)

occlusion, the rapidity of occlusion, and the adequacy of collateral blood flow [14]. It widely believed that blood pressure is a crucial parameter in the setting of acute ischemic stroke and that its reduction may worsen hypoperfusion of the penumbra and hasten extension of the infarct [16].

It has been suggested that diffusion-weighted and perfusion-weighted MRI (DWI and PWI) constitute a clinically useful analogy to the concept of ischemic penumbra. According to this view, DWI reveals areas of cerebral injury developing within minutes to hours after onset of ischemia; although reversible in exceptional circumstances, the DWI lesion represents, for practical purposes, the core of the infarct. PWI uses tracking of a bolus of gadolinium to generate relative CBF maps that can demonstrate regions of hypoperfusion. The subtraction of PWI and DWI volumes, the diffusion– perfusion mismatch, can be operationally used as a representation of the ischemic penumbra (Fig. 4) [17].

Ischemic stroke Natural history of blood pressure after ischemic stroke Increased blood pressure is common in patients presenting with acute stroke, particularly in patients who have pre-existing hypertension [18]. In most cases, blood pressure spontaneously declines in the first few days after stroke onset, but in about one third of patients, a significant decline can be seen even in the first few hours after onset [19]. Numerous studies have examined the relationship between admission or early changes in blood

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Fig. 4. An example of diffusion–perfusion mismatch and the concept of ‘‘penumbra.’’ The images labeled ‘‘before Rx’’ show a marked mismatch between a small DWI lesion (brighter signal) and a large area of hypoperfusion in PWI (darker signal). The area of hypoperfusion decreases after treatment with induced hypertension (‘‘during Rx’’), whereas the DWI lesion remains the same.

pressure and outcome after stroke [20–27]. These studies are contradictory.

Some studies note an association of poor outcome with patients who have high blood pressure on hospital admission [20,25]. Others have noted a decreased risk for neurologic deterioration from stroke with higher blood pressure [22] and worse outcomes in patients who have a decrease in blood pressure after admission [24]. The argument can be made that a higher blood pressure may reflect greater stroke severity, rather than causing worse outcomes [28]. Mattle and colleagues [27] reported a greater spontaneous decrease in blood pressure after admission in patients who recanalized after intra-arterial thrombolysis, compared with patients who had inadequate recanalization. Semplicini and colleagues [29] found that 77% of patients had an elevated blood pressure on admission and noted that in patients who had lacunar, large artery atherosclerotic, and cardioembolic strokes, higher blood pressures (systolic blood pressures [SBP] of 140–220 mm Hg

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and diastolic blood pressures [DBP] of 70–110 mm Hg) were associated with a better prognosis.

The International Stroke Trial, evaluating more than 17,000 patients, showed a ‘‘U-shaped’’ relationship between blood pressure and mortality, with low or high admission blood pressures linked to poor outcome [30]. In the first 48 hours, 54% of the patients had an SBP greater than 160 mm Hg. It was found that for every increase of SBP of 10 mm Hg over 150 mm Hg, early mortality increased by 3.8%, and for every decrease of 10 mm Hg below SBP of 150 mm Hg, mortality increased by 17.9% [30,31]. These findings were replicated subsequently in a hospital-based stroke registry [32].

These studies show a physiologic relationship between acute stroke and elevation of blood pressure; thus, elevated blood pressure may be a marker of stroke severity and not causally related to worse outcomes. They also suggest the possibility of a range of SBP that may be more favorable to patients who have stroke. It has been postulated that patients who have a significant ischemic penumbra may benefit from a higher blood pressure. Some patients may benefit from higher blood pressures, whereas in others, the opposite may be true. Studies evaluating the role of blood pressure modification (elevating or lowering it) in acute ischemic stroke are presented in the next section.

Modifying blood pressure in acute stroke Blood pressure reduction Only a few studies have examined the effect of blood pressure reduction in patients who have acute ischemic stroke [33–36]. In a Cochrane Review, five trials with a total of 218 subjects were identified [37]. The data were deemed insufficient to make a recommendation on lowering or elevating blood pressure in acute stroke. The most recent American Heart Association/American Stroke Association guidelines affirm that in most cases it is not imperative to lower blood pressure in the acute setting and that hypertension should only be treated carefully in cases were the blood pressure is markedly elevated (SBPR220 mm Hg or DBPR120 mm Hg). They have recommended a goal of a 15% reduction in the first 24 hours after a stroke [1]. However, these guidelines also state that a patient’s previous antihypertensive regimen can be safely restarted within 24 hours of stroke onset in patients who have mild-to-moderate stroke and are neurologically stable [1]. This apparent discrepancy is due to conflicting data from recent studies.

Numerous case reports and series describe neurologic worsening with excessive blood pressure lowering [38,39], whereas other studies have shown that antihypertensive therapy may be safe in patients who have acute stroke and may, in fact, be beneficial through mechanisms related and unrelated to the blood pressure–lowering effect.

The Intravenous Nimodipine West European Trial (INWEST) [40] was designed to test whether nimodipine had a neuroprotective effect in stroke.

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The target population was 600 subjects, but the trial was stopped after recruiting 295 subjects because of worse outcomes in the groups treated with nimodipine. Ahmed and colleagues [35] reanalyzed the data and found that the poorer outcome in the nimodipine groups was associated with lowering of blood pressure, even after adjusting for known risk factors for poor outcome. Willmot and collaborators [41] performed a study involving 18 patients, 12 randomized to transdermal glyceryl trinitrate (GTN) and 6 serving as controls. The patients were enrolled within 5 days of their stroke and were hypertensive (SBP 140–220 mm Hg), and the treatment continued for 7 days. The patients received a baseline xenon CT scan and the scan was repeated 1 hour after administration of GTN. Likewise, the blood pressure was measured before the first scan and after the second. GTN lowered SBP by 14% without any significant change in global, ipsilateral, or contralateral CBF, and 90-day outcomes were similar in both groups. Although the study population is small, the patients in this study, with the same blood pressure reduction, did not have an unfavorable outcome, as in the INWEST study.

This difference may be due to a drug- or class-specific differential effect on systemic blood pressure and CBF favoring GTN over nimodipine.

The Acute Candesartan Cilexetil Therapy in Stroke Survivors Study (ACCESS) [33] used candesartan cilexetil, an angiotensin type 1 receptor antagonist, in patients who had ischemic stroke, with a goal of blood pressure reduction of 10% to 15% in the first 24 hours. Patients were included in the study if they had elevated blood pressures, as follows: SBP greater than or equal to 200 mm Hg; DBP greater than or equal to 100 mm Hg within the first 6 to 24 hours; SBP greater than or equal to 180 mm Hg; or DBP greater than or equal to 105 mm Hg 24 to 36 hours after stroke onset. Patients who had more than 70% carotid stenosis and were older than 85 years of age, and patients who had a decreased level of consciousness or signs of aortic dissection, acute coronary syndrome, or malignant hypertension, were excluded. No significant difference was found in blood pressure between candesartan cilexetil and placebo groups in the first week or the year of follow-up, and functional outcome assessed by the Barthel index at 3 months, which was the primary outcome of the study, was not significantly different between groups. Nevertheless, improved 1-year outcomes were observed in the candesartan cilexetil group, compared with placebo; mortality was 2.9% and 7.2% (P ¼ .07) and stroke recurrence was 9.8% and 18.7% (P ¼ .026) in the candesartan and placebo groups, respectively. This trial suggests that in patients who do not have evolving neurologic deficits, who have elevated blood pressures, treatment with an angiotensin II type 1 receptor antagonist may be safe and may improve survival and recurrence of stroke by mechanisms independent of blood pressure reduction.

Several animal studies support the notion that angiotensin II type 1 receptor antagonism may be beneficial in stroke [42,43]. Postulated mechanisms include increased CBF through stimulation of endothelial nitric oxide synthetase or direct activation of the angiotensin II type 2 receptor, or an

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anti-inflammatory effect. A recent meta-analysis found an association between antihypertensive agents that increase angiotensin II (angiotensin II type 1 receptor blockers, diuretics, and calcium channel blockers) and better cerebrovascular outcomes, compared with agents that decrease angiotensin II (beta blockers and angiotensin-converting enzyme [ACE] inhibitors) [44]. Studies showing a beneficial effect of ACE inhibitors in stroke may be explained by improved CBF despite a reduction of systemic blood pressure [31,45,46].

Elewa and collaborators [42] recently reported their experience with a temporary middle cerebral artery occlusion model in rats treated with candesartan, low- and high-dose enalapril, or hydralazine. Candesartan reduced infarct volumes and improved outcome when compared with saline.

Hydralazine and the higher dose enalapril produced a reduction in mean arterial pressure (MAP) and in infarct size but no functional improvement, whereas low-dose enalapril did not change MAP and had no impact on outcome measures.

Boutitie and collaborators [44] conducted a meta-analysis of 26 prospective randomized trials. They included trials testing antihypertensive agents that either increased or decreased angiotensin II levels. The total number of patients studied was 206,632, with 7,505 strokes. They found that the cumulative relative risk for stroke with angiotensin II–reducing agents was 0.87 (95% CI 0.80–0.95), compared with 0.67 (95% CI 0.60–0.74) with angiotensin II–increasing agents (P ¼ .00001).

Eveson and collaborators [45] conducted a phase II randomized placebocontrolled trial of lisinopril versus placebo in patients who had acute stroke.

They enrolled 40 patients within 24 hours of stroke onset and an SBP greater than or equal to 140 mm Hg or a DBP greater than or equal to 90 mm Hg. They excluded patients who had significant swallowing dysfunction, known carotid stenosis greater than 70%, history of Myocardial Infarction, congestive heart failure, or renal insufficiency, and ICH. The patients were randomized to receive lisinopril (5 mg daily) or placebo for 7 days; at that point, if they had an SBP greater than or equal to 140 mm Hg or a DBP greater than or equal to 90 mm Hg, enalapril was increased to 10 mg daily to complete 14 days. After 14 days, blood pressure management was at the discretion of the treating physician. Blood pressure reduction was significantly different between the groups, with the lisinopril group being lower. No adverse effects due to blood pressure lowering were observed, and functional outcomes at 14 days and 90 days showed no difference.

These studies suggest that blood pressure reduction in acute stroke may be safe and that a drug/class-specific effect may exist related to angiotensin II levels or angiotensin II type 1 receptor antagonist and outcome after stroke.

The mechanism of improved CBF is proposed to be related to inducing endothelial nitric oxide synthase and may be the final common mechanism for the effect observed with angiotensin receptor blockers, ACE inhibitors and GTN. Alternatively, the beneficial effect of antihypertensives may relate to

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the optimum blood pressure level. Data from the International Stroke Trial suggest a range of SBP of between 140 mm Hg and 180 mm Hg as being the optimum for patients who have stroke, whereas lower and higher SBP values increase mortality and morbidity, to a higher degree with lower blood pressure than with higher [30].

Currently, several clinical trials are attempting to resolve some of the persisting questions regarding blood pressure management in acute stroke [47]: Controlling Hypertension and Hypotension Immediately Post Stroke (CHHIPS) trial. This trial has a vasopressor arm where hypotensive patients (SBP%140 mm Hg) are randomized to phenylephrine versus placebo within 12 hours of onset, and a antihypertensive arm where hypertensive patients (SBPO180 mm Hg) are randomized to lisinopril, labetalol, or placebo.

Scandinavian Candesartan Acute Stroke Trial (SCAST). In this study, patients who have acute stroke within 30 hours of onset and an SBP greater than or equal to 140 mm Hg will be randomized to Candesartan versus placebo for 7 days.

Continue Or Stop post-Stroke Anti-hypertensives Collaborative Study (COSSACS). Patients who have acute stroke or ICH within 24 hours of onset and 24 hours from last dose of antihypertensives will be randomized to continuing antihypertensive therapy, versus not continuing, for 2 weeks.

Efficacy of Nitric Oxide in Stroke trial (ENOS). A randomized trial with factorial design, with the following interventions: GTN versus placebo and stopping or continuing antihypertensive therapy for 7 days in patients who have acute stroke within 48 hours of onset and an SBP greater than or equal to 140 mm Hg. Blood pressure augmentation Reports of induced hypertension to treat acute ischemic stroke date back to the 1950s. Shanbrom and Levy [48] reported on 2 patients (1 who had an internal carotid artery occlusion and 1 who had basilar artery thrombosis) who had fluctuating neurologic deficits followed by persistent neurologic deterioration. Both showed transient improvement in neurologic function after systemic blood pressure was elevated using intravenous norepinephrine.

Farhat and Schneider [49] reported clinical improvement with induced hypertension in 4 patients who had stroke secondary to large vessel occlusion from various causes (eg, tumor compression of the internal carotid artery and occlusion of the internal carotid artery for treatment of an intracranial aneurysm). Patients seemed to have a blood pressure threshold below which neurologic deficits returned. Wise [50] reported on the use of induced hypertension in 2 patients who had acute ischemic stroke complicating angiography. In the first patient, induced hypertension was discontinued after 5 hours without recurrence of neurologic deficit. The second patient was

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treated for 2 days, until he could undergo carotid endarterectomy. Wise and collaborators [51] reported on 13 patients who had acute ischemic stroke whose blood pressure was augmented within several hours of onset of symptoms. Rapid clinical improvement (eg, within 1 hour of induced hypertension) was noted in 5 of 13 patients, and improvement was maintained in 3 of 5 patients when assessed 24 hours later. In many of these patients, neurologic deficits returned when hypertensive treatment was stopped, and improved again when reinstated. Baseline MAP was 65 to 100 mm Hg in the 5 responders, and a clinical response was seen after MAP elevation of 13 to 30 mm Hg above baseline. No systemic complications were reported. Olsen and collaborators [11] and Agnoli and colleagues [52] examined the effects of induced hypertension on CBF using intracarotid tracer injection methods. Areas of cerebral hypoperfusion showed improved perfusion with elevation of systemic blood pressure, demonstrating the loss of autoregulation in ischemic brain [11,52]. Despite these early positive reports, induced hypertension did not achieve widespread use because of concerns of a high risk for ICH and worsening of brain edema.

Several groups have reported on patients who had ischemic stroke who were treated with induced hypertension in the neurologic intensive care setting. Rordorf and collaborators [53] reviewed 30 patients who had ischemic stroke treated with induced hypertension and compared them with 30 similar patients who had stroke treated with standard therapy. Intravenous phenylephrine was used to increase blood pressure until neurologic deficits improved.

Treatment was started within 24 hours of stroke onset and was continued for a mean of 110 hours (range 7–576 hours). Neurologic improvement occurred in 10 of the 30 treated patients and occurred at an SBP threshold of 130 to 180 mm Hg. Improvements in neurologic deficits occurred within 2 to 30 minutes of raising blood pressure. At follow-up, 4 of the 10 patients who responded had no neurologic deficit and no infarct on brain imaging, despite the fact that they had had an average of 10 hours of neurologic deficit before improvement. No overall difference was seen in neurologic or cardiac complications between the patients treated with and without induced hypertension.

In contrast, the group assigned to standard therapy had higher rates of ICH and cerebral edema on CT scan. Because this review was nonrandomized and retrospective, it is possible that CT findings biased patient selection.

The same investigators subsequently performed a prospective study of induced hypertension in 13 subjects who had acute ischemic stroke within 12 hours of onset of symptoms [54]. Exclusion criteria included recent cardiac ischemia, congestive heart failure, ICH, or cerebral edema on initial head CT scan. All patients had admission SBP of less than 200 mm Hg. The goal was to increase SBP to at least 160 mm Hg or to 20% above the admission SBP, with a maximum allowed SBP of 200 mm Hg. Neurologic improvement was defined as a reduction by at least two points in the National Institutes of Health stroke scale (NIHSS) performed by two independent examiners. To avoid misinterpretation of spontaneous improvement as treatment-related improvement,

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phenylephrine was discontinued in all responders. After SBP returned to baseline for 20 minutes, the patient was examined for neurologic deterioration. A beneficial neurologic response was seen in 7 of 13 patients who had blood pressure elevation. Induced hypertension therapy was continued for 1 to 6 days and eventually weaned successfully in all patients. In the responders, the neurologic deficit did not worsen between discontinuation of induced hypertension and time of discharge. At the time of discharge, the mean NIHSS was 7.4 (range 2–15) among responders compared with an NIHSS of 10 (range 5–15) among nonresponders. Despite the presence of multiple cardiovascular risk factors in the patients enrolled, no cardiac or neurologic complications were associated with treatment.

Hillis and colleagues [55,56] have used DWI and PWI to study the neural basis of aphasia and cognitive function in patients who had acute stroke.

One patient studied was a 55-year-old, right-handed man who had a left carotid artery occlusion and a left middle cerebral artery territory infarct primarily involving the frontal lobe [57]. Neurologic examination revealed a transcortical motor aphasia with telegraphic speech and frequent paraphasias. DWI revealed a large region of restricted diffusion in the left frontal lobe, but PWI showed an even larger area of hypoperfusion also involving the anterior left temporal lobe (Wernicke’s area). On serial testing, it was noted that his language ability worsened with a relative decrease in blood pressure. When his MAP was increased from a baseline of 88 mm Hg to a maximum of 100 mm Hg using phenylephrine, PWI showed reperfusion of Wernicke’s area, and a marked improvement in word and sentence comprehension was noted. The patient eventually was transitioned from intravenous phenylephrine to oral medications (fludrocortisone, salt tablets, and midodrine) to maintain an elevated MAP. By 2 months after stroke onset, these oral medications had been tapered without worsening of aphasia and with return to his normal blood pressure. A repeat PWI at that time showed normal perfusion to Wernicke’s area and no expansion of the infarct beyond the original DWI abnormality. A remarkable feature of this case was that induced hypertension resulted in partial, but objective, neurologic improvement when started 7 days after onset of stroke. Similar findings were subsequently reported in 5 other patients treated with induced hypertension 1 to 9 days after ischemic stroke [58].

With this preliminary experience, Hillis and colleagues [59] went on to perform a prospective, unblinded study of induced hypertension in 15 subjects who were randomly assigned in a 2:1 ratio to receive induced hypertension or standard stroke care. Patients were included if they had acute ischemic stroke presenting within 1 and 7 days of onset of symptoms, a quantifiable neurologic deficit, and a diffusion–perfusion mismatch of 20% or greater on baseline MRI scan. Exclusion criteria included recent cardiac ischemia, congestive heart failure, hemorrhage on CT scan, or contraindication to intravenous phenylephrine use. MAP was increased initially by discontinuing antihypertensive medications, then with intravascular

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volume expansion, and finally with intravenous phenylephrine. MAP was increased in increments of 10% to 20% above baseline with a goal of improving NIHSS by two or more points. The maximum allowed MAP was 140 mm Hg. All patients treated with induced hypertension were admitted to the neurologic ICU. Nine patients were randomly assigned to induced hypertension and 6 to standard care. The two groups were similar in terms of age, baseline NIHSS, and volume of DWI and PWI lesions on baseline MRI scan. By day 3, patients in the induced hypertension treatment arm had a significantly better mean NIHSS (5.6 versus 12.3; P!.02) compared with the standard treatment group, and this difference persisted until follow-up at 6 to 8 weeks (mean NIHSS 2.8 versus 9.7; P!.04). No patient in the study experienced a serious adverse event. Six of 9 patients treated with induced hypertension were classified as responders (ie, they showed a reduction of more than two points on the NIHSS, which was associated with an increase in MAP of between 14 and 27 mm Hg [13%–30%]). Neither treatment group showed a significant difference in the volume of DWI lesion, whereas patients treated with induced hypertension had a significant reduction in PWI lesion volume (from mean 132 mL to 58 mL; P!.02) and a significant reduction in the volume of diffusion–perfusion mismatch (from mean 83 mL to 53 mL; P!.005). Independent of treatment, improvements in NIHSS seemed to correlate with a significant reduction in hypoperfused volume in PWI on serial scans [60].

Marzan and colleagues [61] used norepinephrine to induce hypertension in 34 patients who had ischemic stroke, in a study that included patients who would have been excluded from most of the other published investigations [62]. Among the 34 subjects, 14 had infarcts on baseline CT involving more than one third of the middle cerebral artery territory, 8 were concomitantly treated with thrombolytic agents, and 17 received intravenous heparin. Nine of 34 patients (26%) were responders (more than a two-point improvement in NIHSS); however, among patients not treated with thrombolytic therapy, 5 of 26 (19%) were responders. Serious complications potentially related to induced hypertension occurred in 2 patients (cardiac arrhythmia and symptomatic ICH). The investigators believed this rate of complications was acceptable, particularly given the severity of stroke and the aggressive nature of the interventions. Koenig and colleagues [62] reviewed the outcomes and adverse events associated with the use of any form of blood pressure elevation in patients who had acute ischemic stroke who had baseline DWI and PWI studies and were treated within 7 days of onset of symptoms. Forty-six treated patients were compared with 54 patients from the same time period who received ‘‘standard therapy.’’ Treated patients were more likely to have a larger volume of diffusion–perfusion mismatch and the presence of large-artery atherosclerosis and were more likely to be treated in the neurologic ICU. Treated patients had a decrease in median NIHSS by the time of discharge, but it was not statistically significant. Serious adverse events occurred in 4 patients in each group.

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Several other approaches to blood pressure manipulation in patients who have stroke have been reported. In a study of diaspirin cross-linked hemoglobin (DCLHb), a hemoglobin-based oxygen carrier, in patients who had acute stroke, a dose-dependent elevation of MAP was noted in the DCLHb-treated subjects [63]. The treated group showed no excess of hemorrhagic transformation, cerebral edema, or hypertensive encephalopathy. The overall clinical outcome was not improved, however, in the treated patients. Finally, Campbell and associates [64] reported on the use of intra-aortic balloon pumps placed above and below the renal arteries, causing partial aortic obstruction and resulting in increased cerebral perfusion, sometimes with no systemic blood pressure elevation. CBF assessed by transcranial Doppler, angiography, or positron emission tomography (PET)/single-photon emission computed tomography (SPECT) improved in 12 of 16 patients.

Summary: blood pressure and acute ischemic stroke Currently, the optimal management of blood pressure in acute stroke remains poorly defined. From a review of the literature, the following conclusions can be made: (1) At the onset of acute stroke, most patients have an elevated blood pressure, and this elevated blood pressure tends to return to prestroke levels in approximately 7 days. (2) No conclusive evidence supports lowering the blood pressure in acute stroke. However, findings in animal studies and small clinical trials suggest that blood pressure can be lowered safely in the acute setting and that it may have a beneficial effect. Large randomized clinical trials are currently underway to help answer these questions.

Moreover, the early use of angiotensin II type 1 receptor blocking agents may be beneficial because of a mechanism not directly related to reducing blood pressure (ie, their effects on CBF) and the induction of endothelial nitric oxide. (3) In selected cases, blood pressure augmentation may be beneficial and safe in the management of acute ischemic stroke. (4) More research is needed to identify effective strategies for blood pressure management in acute ischemic stroke. It is possible that patients may benefit from active management to maintain blood pressure within a specified range. Clinical trials such as the proposed CHHIPS may help answer these questions, specifically whether achieving a target blood pressure by reducing or augmenting blood pressure is beneficial [31]. Until such data are available, the guidelines of the American Heart Association provide a reasonable approach to this problem [1].

Hemorrhagic stroke Intracerebral hemorrhage The role of blood pressure management in the acute phase of primary ICH is equally not well defined. Elevated blood pressure is seen in 46% to 56% of patients presenting with ICH [65]. Outcomes after ICH are closely related to

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hematoma size and hematoma expansion [66,67]. Ohwaki and colleagues [68] studied 76 patients and used a multiple logistic regression model to show that SBP of more than 160 mm Hg was independently associated with hematoma growth. Studies have shown that hematoma expansion occurs early within the first 24 hours in 38% of patients [69]. The hypothesis has been advanced that lowering blood pressure in the acute setting may decrease the hematoma expansion rate and improve prognosis, yet this theory remains to be tested in clinical trials. The concept of decreasing blood pressure after ICH has been opposed because of concerns about reducing CBF and promoting ischemia in the perihematomal brain tissue. This concept has been studied in a few patients using SPECT, PET, and DWI. Recent results suggest that in the acute setting, regional CBF is reduced around the hematoma, with a matching decrease in the cerebral metabolic rate of oxygen. The oxygen extraction fraction remains low, indicating no region of ischemia [70–72]. Stages of CBF have been proposed in the perihematomal area, as follows [73]: Hibernation: decreased CBF, decreased cerebral metabolic rate of oxygen, and decreased oxygen extraction fraction (0–48 hours) Reperfusion: blood flow is heterogeneous and can be decreased, normal, or augmented (48 hours to 14 days) Normalization (O14 days) In a study by Powers and colleagues [71], 14 patients who had ICH were evaluated with a baseline PET scan 6 to 22 hours after onset of symptoms.

Blood pressure was lowered by 15%, from a MAP of 143 to 119 mm Hg with either nicardipine or labetalol, and repeat PET showed that the CBF remained stable in the perihematomal area. Studies such as this and the one done by Ohwaki and colleagues [68,71] suggest that reducing blood pressure in the first 24 hours after ICH is safe. In a study by Qureshi and coworkers [65], 27 patients who had ICH were treated to reduce SBP to less than 160 mm Hg and DBP to less than 110 mm Hg. Only 2 of 27 patients deteriorated neurologically, and only 9.1% had hematoma expansion (defined as a growth of the hematoma of O33%).

These data indicate that treatment of hypertension could be beneficial to reduce hematoma expansion and clinical deterioration in the acute period after ICH. The recent guidelines from the American Heart Association/ American Stroke Association, published in 2007 [8], recognize that the evidence is still not sufficient to guide management of blood pressure in ICH; the recommendation is to treat patients aggressively with an SBP greater than 200 mm Hg or MAP greater than150 mm Hg; to consider ICP monitoring to guide therapy, with the goal of maintaining a CPP between 60 and 80 mm Hg in patients who have suspected elevation of ICP and an SBP greater than 180 mm Hg or MAP greater than 130 mm Hg; and to consider treatment to a goal of SBP of 160 mm Hg or MAP of 110 mm Hg in patients who have an SBP greater than 160 mm Hg or MAP greater than 130 mm Hg without suspicion of elevated ICP.

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Two trials are currently underway to evaluate these questions. In the Antihypertensive Treatment in Acute Cerebral Hemorrhage (ATACH) study, patients are randomly assigned to three treatment groups with a specified target blood pressure level [47]. In the INTEnsive blood pressure Reduction in Acute Cerebral hemorrhage Trial (INTERACT), patients are randomized to a protocol of intensive blood pressure lowering versus ASA guideline blood pressure management as control [47].

Aneurysmal subarachnoid hemorrhage Aneurysmal SAH occurs in more than 30,000 individuals per year in the United States, and 30-day mortality is 25% to 50% [74]. Management of SAH is governed by different priorities and paradigms, depending on the time after onset of the hemorrhage. The biggest concern in the first few days after rupture is rebleeding, which occurs in 9% to 30% of patients.

The risk is 20% in the first 2 weeks and 30% in the first month if the aneurysm remains untreated. Mortality in patients who rebleed increases to 50% to 80% [75,76]. After the aneurysm has been secured by clipping or coiling, the next major concern is vasospasm. Symptomatic vasospasm occurs in 30% of patients and is a major cause of morbidity and mortality in SAH. Its incidence peaks between days 10 and 14 after SAH [74].

Blood pressure may be an important determinant of rebleeding and vasospasm. The risk for rebleeding is highest in the first 24 hours after SAH [75,77]. Ohkuma and colleagues [75] studied 273 patients and found aneurysmal rerupture in 13.6% within the first 24 hours. In the same study, they found a statistically significant higher risk for rebleeding in patients who had SBP greater than 160 mm Hg. Claassen and coworkers [78] found, in a group of 467 patients who had SAH studied within the first 3 days, that MAP less than 70 mm Hg, or greater than 130 mm Hg, was an independent predictor of death and disability at 3 months. Hypotension with MAP of less than 70 mm Hg is seen in 4% of all patients who have SAH in the acute period, whereas 33% to 50% of patients present with elevated blood pressure. In this study, however, hypertension was not independently associated with rerupture.

In patients within days 1 to 4 of the onset of a SAH and without vasospasm, hydrocephalus, or ICH, PET shows a decrease in the cerebral metabolic rate of oxygen, CBF, and cerebral blood volume with normal oxygen extraction fraction. Metabolism and CBF show a coupled reduction [70], which is similar to the pattern in the perihematomal region in an ICH, discussed earlier. One could postulate, based on the experience with ICH, that lowering blood pressure would not cause an increase in ischemia if the criteria mentioned earlier are met. Early studies of blood pressure management after SAH, which were completed before the adoption of early aneurysm surgery as a standard of care, suggested that patients who benefited from treatment of hypertension to prevent rebleed subsequently

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had a higher rate of ischemic stroke later in the course when vasospasm was more prevalent [79]. This change in priority as the patient evolves from a situation of high rebleed risk to a high vasospasm risk makes interpretation of these studies difficult. Wijdicks and colleagues [79] studied 134 patients enrolled in a trial of tranexamic acid in which 80 (60%) were treated with antihypertensive medication. Rebleeding occurred in 12 of 80 (15%) patients treated with antihypertensives, compared with 18 of 54 patients (33%) who did not receive antihypertensives. Cerebral infarction occurred in 43% of patients who had antihypertensive treatment versus 22% in those who did not [79].

A randomized controlled trial of blood pressure management in early SAH has not been conducted. Data from observational studies suggest a benefit in avoiding the extremes of blood pressure. Also, in the absence of vasospasm, hydrocephalus, or ICH with increased ICP, blood pressure reduction may be safe. Based on expert opinion and accumulated experience, it seems reasonable to maintain SBP at less than 160 mm Hg before treatment of the aneurysm, provided that the conditions outlined earlier are met [74]. A well-designed, randomized, controlled trial is needed to address this important question. After definitive aneurysm treatment by clipping or coiling, a strategy of permissive or induced hypertension is commonly implemented to improve CBF in the setting of vasospasm; however, clinical trials are also needed to support this practice.

References [1] Adams HP Jr, Del ZG, Alberts MJ, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists.

Stroke 2007;38(5):1655–711.

[2] Adams H, Adams R, Del ZG, 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(4):916–23.

[3] 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(4):1056–83.

[4] Markus H. Acute stroke. Int Psychogeriatr 2003;(15 Suppl 1):161–6.

[5] Goldstein LB. Blood pressure management in patients with acute ischemic stroke. Hypertension 2004;43(2):137–41.

[6] Wityk RJ, Lewin JJ III. Blood pressure management during acute ischaemic stroke. Expert Opin Pharmacother 2006;7(3):247–58.

[7] Verstappen A, Thijs V. What do we (not) know about the management of blood pressure in acute stroke? Curr Neurol Neurosci Rep 2004;4(6):505–9.

[8] Broderick J, Connolly S, Feldmann E, et al. Guidelines for the management of spontaneous intracerebral hemorrhage in adults: 2007 update: a guideline from the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research

BLOOD PRESSURE MANAGEMENT IN ACUTE STROKE

[9]

[10]

[11]

[12] [13] [14] [15]

[16] [17] [18] [19] [20] [21] [22] [23]

[24] [25] [26] [27] [28]

[29] [30] [31]

581

Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group. Circulation 2007;116(16):e391–413.

Chillon J-M, Baumbach G. Autoregulation: arterial and intracranial pressure. In: Edvinsson L, Krause DN, editors. Cerebral blood flow and metabolism. 2nd edition. Philadelphia: Lippincott, Williams, Wilkins; 2002. p. 395–406.

Eames PJ, Blake MJ, Dawson SL, et al. Dynamic cerebral autoregulation and beat to beat blood pressure control are impaired in acute ischaemic stroke. J Neurol Neurosurg Psychiatry 2002;72(4):467–72.

Olsen TS, Larsen B, Herning M, et al. Blood flow and vascular reactivity in collaterally perfused brain tissue. Evidence of an ischemic penumbra in patients with acute stroke. Stroke 1983;14(3):332–41.

Astrup J, Siesjo BK, Symon L. Thresholds in cerebral ischemia - the ischemic penumbra.

Stroke 1981;12(6):723–5.

Jones TH, Morawetz RB, Crowell RM, et al. Thresholds of focal cerebral ischemia in awake monkeys. J Neurosurg 1981;54(6):773–82.

Fisher M, Garcia JH. Evolving stroke and the ischemic penumbra. Neurology 1996;47(4): 884–8.

Marchal G, Beaudouin V, Rioux P, et al. Prolonged persistence of substantial volumes of potentially viable brain tissue after stroke: a correlative PET-CT study with voxel-based data analysis. Stroke 1996;27(4):599–606.

Hakim AM. Ischemic penumbra: the therapeutic window. Neurology 1998;51(3 Suppl 3): S44–6.

Fisher M, Albers GW. Applications of diffusion-perfusion magnetic resonance imaging in acute ischemic stroke. Neurology 1999;52(9):1750–6.

Wallace JD, Levy LL. Blood pressure after stroke. JAMA 1981;246(19):2177–80.

Broderick J, Brott T, Barsan W, et al. Blood pressure during the first minutes of focal cerebral ischemia. Ann Emerg Med 1993;22(9):1438–43.

Carlberg B, Asplund K, Hagg E. The prognostic value of admission blood pressure in patients with acute stroke. Stroke 1993;24(9):1372–5.

Demchuk AM, Tanne D, Hill MD, et al. Predictors of good outcome after intravenous tPA for acute ischemic stroke. Neurology 2001;57(3):474–80.

Jorgensen HS, Nakayama H, Raaschou HO, et al. Effect of blood pressure and diabetes on stroke in progression. Lancet 1994;344(8916):156–9.

Aslanyan S, Fazekas F, Weir CJ, et al. Effect of blood pressure during the acute period of ischemic stroke on stroke outcome: a tertiary analysis of the GAIN International Trial.

Stroke 2003;34(10):2420–5.

Oliveira-Filho J, Silva SC, Trabuco CC, et al. Detrimental effect of blood pressure reduction in the first 24 hours of acute stroke onset. Neurology 2003;61(8):1047–51.

Willmot M, Leonardi-Bee J, Bath PM. High blood pressure in acute stroke and subsequent outcome: a systematic review. Hypertension 2004;43(1):18–24.

Vemmos KN, Tsivgoulis G, Spengos K, et al. Pulse pressure in acute stroke is an independent predictor of long-term mortality. Cerebrovasc Dis 2004;18(1):30–6.

Mattle HP, Kappeler L, Arnold M, et al. Blood pressure and vessel recanalization in the first hours after ischemic stroke. Stroke 2005;36(2):264–8.

Christensen H, Meden P, Overgaard K, et al. The course of blood pressure in acute stroke is related to the severity of the neurological deficits. Acta Neurol Scand 2002; 106(3):142–7.

Semplicini A, Maresca A, Boscolo G, et al. Hypertension in acute ischemic stroke: a compensatory mechanism or an additional damaging factor? Arch Intern Med 2003;163(2):211–6.

Leonardi-Bee J, Bath PM, Phillips SJ, et al. Blood pressure and clinical outcomes in the International Stroke Trial. Stroke 2002;33(5):1315–20.

Potter J, Robinson T, Ford G, et al. CHHIPS (Controlling Hypertension and Hypotension Immediately Post-Stroke) pilot trial: rationale and design. J Hypertens 2005;23(3):649–55.

582

URRUTIA & WITYK

[32] Vemmos KN, Tsivgoulis G, Spengos K, et al. U-shaped relationship between mortality and admission blood pressure in patients with acute stroke. J Intern Med 2004;255(2):257–65.

[33] Schrader J, Luders S, Kulschewski A, et al. The ACCESS study: evaluation of Acute Candesartan Cilexetil Therapy in Stroke Survivors. Stroke 2003;34(7):1699–703.

[34] Bath PM, Pathansali R, Iddenden R, et al. The effect of transdermal glyceryl trinitrate, a nitric oxide donor, on blood pressure and platelet function in acute stroke. Cerebrovasc Dis 2001;11(3):265–72.

[35] Ahmed N, Nasman P, Wahlgren NG. Effect of intravenous nimodipine on blood pressure and outcome after acute stroke. Stroke 2000;31(6):1250–5.

[36] Lisk DR, Grotta JC, Lamki LM, et al. Should hypertension be treated after acute stroke? A randomized controlled trial using single photon emission computed tomography. Arch Neurol 1993;50(8):855–62.

[37] Blood Pressure in Acute Stroke Collaboration (BASC). Interventions for deliberately altering blood pressure in acute stroke (Cochrane Review). Cochrane Database Syst Rev 2001;(3). Available at: http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/ CD000039/frame.html. Accessed May 13, 2006.

[38] Graham DI. Ischaemic brain damage of cerebral perfusion failure type after treatment of severe hypertension. Br Med J 1975;4(5999):739.

[39] Fischberg GM, Lozano E, Rajamani K, et al. Stroke precipitated by moderate blood pressure reduction. J Emerg Med 2000;19(4):339–46.

[40] Wahlgren NG, MacMahon DG, Keyser JD, et al, for the INWEST Study Group. The Intravenous Nimodipine West European Trial of Nimodipine in the Treatment of Acute Ischemic Stroke. Cerebrovasc Dis 1994;4:204–10.

[41] Willmot M, Ghadami A, Whysall B, et al. Transdermal glyceryl trinitrate lowers blood pressure and maintains cerebral blood flow in recent stroke. Hypertension 2006;47(6):1209–15.

[42] Elewa HF, Kozak A, Johnson MH, et al. Blood pressure lowering after experimental cerebral ischemia provides neurovascular protection. J Hypertens 2007;25(4):855–9.

[43] Sigurdsson ST, Strandgaard S. Blood pressure lowering in acute ischaemic stroke: an update on the role of angiotensin receptor blockers. J Hypertens 2007;25(4):743–5.

[44] Boutitie F, Oprisiu R, Achard JM, et al. Does a change in angiotensin II formation caused by antihypertensive drugs affect the risk of stroke? A meta-analysis of trials according to treatment with potentially different effects on angiotensin II. J Hypertens 2007;25(8):1543–53.

[45] Eveson DJ, Robinson TG, Potter JF. Lisinopril for the treatment of hypertension within the first 24 hours of acute ischemic stroke and follow-up. Am J Hypertens 2007;20(3):270–7.

[46] Walters MR, Bolster A, Dyker AG, et al. Effect of perindopril on cerebral and renal perfusion in stroke patients with carotid disease. Stroke 2001;32(2):473–8.

[47] Stroke Trials Registry. The Internet Stroke Center. 2007. Ref Type: Internet Communication.

[48] Shanbrom E, Levy L. The role of systemic blood pressure in cerebral circulation in carotid and basilar artery thromboses. Am J Med 1957;23:197–204.

[49] Farhat SM, Schneider RC. Observations on the effect of systemic blood pressure on intracranial circulation in patients with cerebrovascular insufficiency. J Neurosurg 1967; 27(5):441–5.

[50] Wise GR. Vasopressor-drug therapy for complications of cerebral arteriography. N Engl J Med 1970;282(11):610–2.

[51] Wise G, Sutter R, Burkholder J. The treatment of brain ischemia with vasopressor drugs.

Stroke 1972;3(2):135–40.

[52] Agnoli A, Fieschi C, Bozzao L, et al. Autoregulation of cerebral blood flow. Studies during drug-induced hypertension in normal subjects and in patients with cerebral vascular diseases.

Circulation 1968;38(4):800–12.

[53] Rordorf G, Cramer SC, Efird JT, et al. Pharmacological elevation of blood pressure in acute stroke. Clinical effects and safety. Stroke 1997;28(11):2133–8.

[54] Rordorf G, Koroshetz WJ, Ezzeddine MA, et al. A pilot study of drug-induced hypertension for treatment of acute stroke. Neurology 2001;56(9):1210–3.

BLOOD PRESSURE MANAGEMENT IN ACUTE STROKE

583

[55] Hillis AE, Barker PB, Beauchamp NJ, et al. MR perfusion imaging reveals regions of hypoperfusion associated with aphasia and neglect. Neurology 2000;55(6):782–8.

[56] Hillis AE, Wityk RJ, Tuffiash E, et al. Hypoperfusion of Wernicke’s area predicts severity of semantic deficit in acute stroke. Ann Neurol 2001;50(5):561–6.

[57] Hillis AE, Barker PB, Beauchamp NJ, et al. Restoring blood pressure reperfused Wernicke’s area and improved language. Neurology 2001;56(5):670–2.

[58] Hillis AE, Kane A, Tuffiash E, et al. Reperfusion of specific brain regions by raising blood pressure restores selective language functions in subacute stroke. Brain Lang 2001;79(3):495–510.

[59] Hillis AE, Ulatowski JA, Barker PB, et al. A pilot randomized trial of induced blood pressure elevation: effects on function and focal perfusion in acute and subacute stroke. Cerebrovasc Dis 2003;16(3):236–46.

[60] Hillis AE, Wityk RJ, Beauchamp NJ, et al. Perfusion-weighted MRI as a marker of response to treatment in acute and subacute stroke. Neuroradiology 2004;46(1):31–9.

[61] Marzan AS, Hungerbuhler HJ, Studer A, et al. Feasibility and safety of norepinephrineinduced arterial hypertension in acute ischemic stroke. Neurology 2004;62(7):1193–5.

[62] Koenig MA, Geocadin RG, de GM, et al. Safety of induced hypertension therapy in patients with acute ischemic stroke. Neurocrit Care 2006;4(1):3–7.

[63] Saxena R, Wijnhoud AD, Koudstaal PJ, et al. Induced elevation of blood pressure in the acute phase of ischemic stroke in humans. Stroke 2000;31(2):546–8.

[64] Campbell MS, Grotta JC, Gomez CR, et al. NeuroFlo Investigators. Abstract presented at the 29th International Stroke Conference, San Diego, CA, 2004. Stroke 2004;35:291.

[65] Qureshi AI, Mohammad YM, Yahia AM, et al. A prospective multicenter study to evaluate the feasibility and safety of aggressive antihypertensive treatment in patients with acute intracerebral hemorrhage. J Intensive Care Med 2005;20(1):34–42.

[66] Hallevy C, Ifergane G, Kordysh E, et al. Spontaneous supratentorial intracerebral hemorrhage. Criteria for short-term functional outcome prediction. J Neurol 2002;249(12):1704–9.

[67] Kazui S, Naritomi H, Yamamoto H, et al. Enlargement of spontaneous intracerebral hemorrhage. Incidence and time course. Stroke 1996;27(10):1783–7.

[68] Ohwaki K, Yano E, Nagashima H, et al. Blood pressure management in acute intracerebral hemorrhage: relationship between elevated blood pressure and hematoma enlargement.

Stroke 2004;35(6):1364–7.

[69] Aronowski J, Hall CE. New horizons for primary intracerebral hemorrhage treatment: experience from preclinical studies. Neurol Res 2005;27(3):268–79.

[70] Powers WJ, Zazulia AR. The use of positron emission tomography in cerebrovascular disease. Neuroimaging Clin N Am 2003;13(4):741–58.

[71] Powers WJ, Zazulia AR, Videen TO, et al. Autoregulation of cerebral blood flow surrounding acute (6 to 22 hours) intracerebral hemorrhage. Neurology 2001;57(1):18–24.

[72] Zazulia AR, Diringer MN, Videen TO, et al. Hypoperfusion without ischemia surrounding acute intracerebral hemorrhage. J Cereb Blood Flow Metab 2001;21(7):804–10.

[73] Qureshi AI, Hanel RA, Kirmani JF, et al. Cerebral blood flow changes associated with intracerebral hemorrhage. Neurosurg Clin N Am 2002;13(3):355–70.

[74] Ropper AH, Gress DR, Diringer MN, et al. Neurological and neurosurgical intensive care.

4th edition. Philadelphia: Lippincot Williams & Wilkins; 2003. p. 231–42.

[75] Ohkuma H, Tsurutani H, Suzuki S. Incidence and significance of early aneurysmal rebleeding before neurosurgical or neurological management. Stroke 2001;32(5):1176–80.

[76] Rose JC, Mayer SA. Optimizing blood pressure in neurological emergencies. Neurocrit Care 2004;1(3):287–99.

[77] Fujii Y, Takeuchi S, Sasaki O, et al. Ultra-early rebleeding in spontaneous subarachnoid hemorrhage. J Neurosurg 1996;84(1):35–42.

[78] Claassen J, Vu A, Kreiter KT, et al. Effect of acute physiologic derangements on outcome after subarachnoid hemorrhage. Crit Care Med 2004;32(3):832–8.

[79] Wijdicks EF, Vermeulen M, Murray GD, et al. The effects of treating hypertension following aneurysmal subarachnoid hemorrhage. Clin Neurol Neurosurg 1990;92(2):111–7.