Blood Pressure Managementin Acute Stroke

Victor C. Urrutia, MD*, Robert J. Wityk, MDCerebrovascular 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 anacute stroke has not been defined [1–3]. Many articles have been publishedon this topic in the past few years, but definitive evidence from clinical trialscontinues to be lacking [4–7]. This situation is complicated further becausestroke is a heterogeneous disease. The best management of arterial bloodpressure may differ, depending on the type of stroke (ischemic or hemor-rhagic) and the subtype of ischemic or hemorrhagic stroke [1,8].

This article reviews the relationship between arterial blood pressure andthe pathophysiology specific to ischemic stroke, primary intracerebral hemor-rhage (ICH), and aneurysmal subarachnoid hemorrhage (SAH), elaboratingon the concept of ischemic penumbra and the role of cerebral autoregulation.The article also examines the impact of blood pressure and its managementon outcome. Finally, an agenda for research in this field is outlined.

Neurol Clin 26 (2008) 565–583

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 cerebralarterioles in response to changes in perfusion pressure. CPP is defined bythe following relationship:

CPP ¼MAP� ICP

where MAP is mean arterial pressure and ICP is intracranial pressureIf ICPis 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 � 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 isdetermined by CPP and cerebrovascular resistance (CVR). CVR is governedprimarily by arteriolar diameter, although larger vessels also may contrib-ute. To maintain a constant CBF of approximately 50 mL/100 g/min, CVRincreases through arteriolar constriction if CPP increases, and decreases byarteriolar dilation if CPP decreases. The autoregulatory system in the braincan maintain essentially constant CBF between a MAP of 50 to 60 mm Hgto 150 to 160 mm Hg. When MAP decreases to less than 50 to 60 mm Hg,maximum vasodilation is reached, and CBF decreases proportionally withthe MAP, resulting in ischemia. On the other extreme, when MAP exceeds150 to 160 mm Hg, arteriolar vasoconstriction is exhausted, and hydrostaticpressure increases continuously, resulting in cerebral edema and breakdownof the blood–brain barrier (ie, hypertensive encephalopathy or ICH) (Fig. 1).Segmental vasodilation or a ‘‘sausage-string’’ appearance of the arteriescomes first, followed by massive cerebrovascular dilation [9]. In chronicallyhypertensive individuals, the autoregulation curve is shifted as a result ofthe elevated MAP levels; the lower and upper inflection points are higherthan in normal individuals. A normal CBF and oxygen consumption aremaintained at the expense of a marked increase in the CVR [9]. These changesresult in a decreased tolerance for relative hypotension because the capacityto maintain a constant CBF at the lower end of the blood pressure spectrumis impaired.

Evidence indicates that autoregulation is dysfunctional after a stroke. Ifcapacity for autoregulation does not exist, CBF increases or decreasesproportionally 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 autoregula-tion by analyzing beat-to-beat, spontaneous blood pressure variability andCBF velocities with transcranial Doppler in 56 patients who had strokeand 56 matched controls. They found global impairment in dynamic autor-egulation in patients who had stroke but not in controls, and this dysfunc-tion occurred not only in the hemisphere ipsilateral to the infarct, but alsocontralaterally [10,11].

Ischemic penumbra

CBF in the area of a cerebral infarction is not homogeneous. In animalexperiments, Astrup and colleagues [12] showed a critical threshold ofCBF, below which neurons cease to function but continue to survive fora time. These neurons can potentially return to a normal functional statewith restoration of blood flow. Jones and colleagues [13] replicated thesefindings and suggested that the time window in which ischemia is reversibleis in the range of several hours. The current concept of the ischemic penum-bra is a region of brain with a gradient of decreased CBF. Tissue with thelowest CBF would be irreversibly damaged and constitute the core of theinfarct [14,15]; this area will become an infarct even if CBF is restored.The regions surrounding the core, the ‘‘penumbra’’ (Fig. 3), are ischemicand dysfunctional, but potentially salvageable. With timely reperfusion,the region of ischemic penumbra may be rescued from infarction. The lengthof time during which tissue in the ischemic penumbra remains viable iscontroversial, 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.)

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 consid-

ered the ‘‘ischemic penumbra.’’ (Adapted from Wityk RJ, Lewin JJ III. Blood pressure manage-

ment during acute ischemic stroke. Expert Opin Pharmacother 2006;7:247–58; with permission.)

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

It has been suggested that diffusion-weighted and perfusion-weightedMRI (DWI and PWI) constitute a clinically useful analogy to the conceptof ischemic penumbra. According to this view, DWI reveals areas ofcerebral 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 bolusof gadolinium to generate relative CBF maps that can demonstrate regionsof hypoperfusion. The subtraction of PWI and DWI volumes, the diffusion–perfusion mismatch, can be operationally used as a representation of theischemic penumbra (Fig. 4) [17].

Ischemic stroke

Natural history of blood pressure after ischemic stroke

Increased blood pressure is common in patients presenting with acutestroke, particularly in patients who have pre-existing hypertension [18]. Inmost cases, blood pressure spontaneously declines in the first few days afterstroke onset, but in about one third of patients, a significant decline can beseen even in the first few hours after onset [19]. Numerous studies haveexamined the relationship between admission or early changes in blood

Fig. 4. An example of diffusion–perfusion mismatch and the concept of ‘‘penumbra.’’ The im-

ages 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.

569BLOOD PRESSURE MANAGEMENT IN ACUTE STROKE

pressure and outcome after stroke [20–27]. These studies are contradictory.Some studies note an association of poor outcome with patients who havehigh blood pressure on hospital admission [20,25]. Others have noted a de-creased risk for neurologic deterioration from stroke with higher blood pres-sure [22] and worse outcomes in patients who have a decrease in bloodpressure after admission [24]. The argument can be made that a higher bloodpressure may reflect greater stroke severity, rather than causing worseoutcomes [28]. Mattle and colleagues [27] reported a greater spontaneousdecrease in blood pressure after admission in patients who recanalized afterintra-arterial thrombolysis, compared with patients who had inadequaterecanalization. Semplicini and colleagues [29] found that 77% of patientshad an elevated blood pressure on admission and noted that in patientswho 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 witha 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]. Inthe 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 mmHg belowSBP of 150mmHg, mortality increased by 17.9% [30,31]. These findings werereplicated subsequently in a hospital-based stroke registry [32].

These studies show a physiologic relationship between acute stroke andelevation of blood pressure; thus, elevated blood pressure may be a markerof stroke severity and not causally related to worse outcomes. They also sug-gest the possibility of a range of SBP that may be more favorable to patientswho have stroke. It has been postulated that patients who have a significantischemic penumbra may benefit from a higher blood pressure. Some patientsmay benefit from higher blood pressures, whereas in others, the opposite maybe true. Studies evaluating the role of blood pressure modification (elevatingor 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 reductionin 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 weredeemed insufficient to make a recommendation on lowering or elevatingblood pressure in acute stroke. The most recent American Heart Associa-tion/American Stroke Association guidelines affirm that in most cases it isnot imperative to lower blood pressure in the acute setting and that hyper-tension should only be treated carefully in cases were the blood pressure ismarkedly elevated (SBPR220 mm Hg or DBPR120 mm Hg). They haverecommended 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 antihyper-tensive regimen can be safely restarted within 24 hours of stroke onset inpatients 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 exces-sive blood pressure lowering [38,39], whereas other studies have shown thatantihypertensive therapy may be safe in patients who have acute stroke andmay, in fact, be beneficial through mechanisms related and unrelated to theblood pressure–lowering effect.

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

571BLOOD PRESSURE MANAGEMENT IN ACUTE STROKE

The target population was 600 subjects, but the trial was stopped afterrecruiting 295 subjects because of worse outcomes in the groups treatedwith nimodipine. Ahmed and colleagues [35] reanalyzed the data and foundthat the poorer outcome in the nimodipine groups was associated withlowering of blood pressure, even after adjusting for known risk factors forpoor outcome. Willmot and collaborators [41] performed a study involving18 patients, 12 randomized to transdermal glyceryl trinitrate (GTN) and6 serving as controls. The patients were enrolled within 5 days of their strokeand were hypertensive (SBP 140–220 mm Hg), and the treatment continuedfor 7 days. The patients received a baseline xenon CT scan and the scan wasrepeated 1 hour after administration of GTN. Likewise, the blood pressurewas measured before the first scan and after the second. GTN lowered SBPby 14% without any significant change in global, ipsilateral, or contralateralCBF, and 90-day outcomes were similar in both groups. Although the studypopulation is small, the patients in this study, with the same blood pressurereduction, did not have an unfavorable outcome, as in the INWEST study.This difference may be due to a drug- or class-specific differential effect onsystemic 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 an-tagonist, in patients who had ischemic stroke, with a goal of blood pressurereduction of 10% to 15% in the first 24 hours. Patients were included in thestudy if they had elevated blood pressures, as follows: SBP greater than orequal to 200 mm Hg; DBP greater than or equal to 100 mm Hg within thefirst 6 to 24 hours; SBP greater than or equal to 180 mm Hg; or DBP greaterthan or equal to 105 mm Hg 24 to 36 hours after stroke onset. Patients whohad 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 aorticdissection, acute coronary syndrome, or malignant hypertension, wereexcluded. No significant difference was found in blood pressure betweencandesartan cilexetil and placebo groups in the first week or the year of fol-low-up, and functional outcome assessed by the Barthel index at 3 months,which was the primary outcome of the study, was not significantly differentbetween groups. Nevertheless, improved 1-year outcomes were observed inthe 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 thatin patients who do not have evolving neurologic deficits, who have elevatedblood pressures, treatment with an angiotensin II type 1 receptor antagonistmay be safe and may improve survival and recurrence of stroke by mecha-nisms independent of blood pressure reduction.

Several animal studies support the notion that angiotensin II type 1 recep-tor antagonism may be beneficial in stroke [42,43]. Postulated mechanismsinclude increased CBF through stimulation of endothelial nitric oxidesynthetase 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 be-tween antihypertensive agents that increase angiotensin II (angiotensin IItype 1 receptor blockers, diuretics, and calcium channel blockers) and bettercerebrovascular outcomes, compared with agents that decrease angiotensinII (beta blockers and angiotensin-converting enzyme [ACE] inhibitors)[44]. Studies showing a beneficial effect of ACE inhibitors in stroke may beexplained by improved CBF despite a reduction of systemic blood pressure[31,45,46].

Elewa and collaborators [42] recently reported their experience witha temporary middle cerebral artery occlusion model in rats treated withcandesartan, low- and high-dose enalapril, or hydralazine. Candesartanreduced infarct volumes and improved outcome when compared with saline.Hydralazine and the higher dose enalapril produced a reduction in meanarterial pressure (MAP) and in infarct size but no functional improvement,whereas low-dose enalapril did not change MAP and had no impact onoutcome measures.

Boutitie and collaborators [44] conducted a meta-analysis of 26 prospec-tive randomized trials. They included trials testing antihypertensive agentsthat either increased or decreased angiotensin II levels. The total numberof patients studied was 206,632, with 7,505 strokes. They found that thecumulative relative risk for stroke with angiotensin II–reducing agentswas 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 placebo-controlled trial of lisinopril versus placebo in patients who had acute stroke.They enrolled 40 patients within 24 hours of stroke onset and an SBP greaterthan 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, knowncarotid stenosis greater than 70%, history of Myocardial Infarction, conges-tive heart failure, or renal insufficiency, and ICH. The patients were random-ized to receive lisinopril (5 mg daily) or placebo for 7 days; at that point, ifthey had an SBP greater than or equal to 140 mm Hg or a DBP greater thanor equal to 90 mm Hg, enalapril was increased to 10 mg daily to complete14 days. After 14 days, blood pressure management was at the discretionof the treating physician. Blood pressure reduction was significantly differentbetween the groups, with the lisinopril group being lower. No adverse effectsdue to blood pressure lowering were observed, and functional outcomes at 14days and 90 days showed no difference.

These studies suggest that blood pressure reduction in acute stroke may besafe and that a drug/class-specific effect may exist related to angiotensin IIlevels or angiotensin II type 1 receptor antagonist and outcome after stroke.The mechanism of improved CBF is proposed to be related to inducing en-dothelial nitric oxide synthase and may be the final common mechanism forthe effect observed with angiotensin receptor blockers, ACE inhibitors andGTN. Alternatively, the beneficial effect of antihypertensives may relate to

573BLOOD PRESSURE MANAGEMENT IN ACUTE STROKE

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

Currently, several clinical trials are attempting to resolve some of the per-sisting 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 hypotensivepatients (SBP%140 mm Hg) are randomized to phenylephrine versusplacebo within 12 hours of onset, and a antihypertensive arm wherehypertensive 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 SBPgreater than or equal to 140 mm Hg will be randomized to Candesar-tan versus placebo for 7 days.

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

Efficacy of Nitric Oxide in Stroke trial (ENOS). A randomized trial withfactorial design, with the following interventions: GTN versus placeboand stopping or continuing antihypertensive therapy for 7 days inpatients who have acute stroke within 48 hours of onset and an SBPgreater than or equal to 140 mm Hg.

Blood pressure augmentation

Reports of induced hypertension to treat acute ischemic stroke date backto the 1950s. Shanbrom and Levy [48] reported on 2 patients (1 who had aninternal carotid artery occlusion and 1 who had basilar artery thrombosis)who had fluctuating neurologic deficits followed by persistent neurologic de-terioration. Both showed transient improvement in neurologic function aftersystemic blood pressure was elevated using intravenous norepinephrine.Farhat and Schneider [49] reported clinical improvement with induced hy-pertension in 4 patients who had stroke secondary to large vessel occlusionfrom various causes (eg, tumor compression of the internal carotid arteryand occlusion of the internal carotid artery for treatment of an intracranialaneurysm). Patients seemed to have a blood pressure threshold below whichneurologic deficits returned. Wise [50] reported on the use of inducedhypertension in 2 patients who had acute ischemic stroke complicating an-giography. In the first patient, induced hypertension was discontinued after5 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 andcollaborators [51] reported on 13 patients who had acute ischemic strokewhose blood pressure was augmented within several hours of onset of symp-toms. Rapid clinical improvement (eg, within 1 hour of induced hyperten-sion) was noted in 5 of 13 patients, and improvement was maintained in3 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 Hgin the 5 responders, and a clinical response was seen after MAP elevationof 13 to 30 mm Hg above baseline. No systemic complications were re-ported. Olsen and collaborators [11] and Agnoli and colleagues [52] exam-ined the effects of induced hypertension on CBF using intracarotid tracerinjection methods. Areas of cerebral hypoperfusion showed improvedperfusion with elevation of systemic blood pressure, demonstrating theloss of autoregulation in ischemic brain [11,52]. Despite these early positivereports, induced hypertension did not achieve widespread use because ofconcerns of a high risk for ICH and worsening of brain edema.

Several groups have reported on patients who had ischemic stroke whowere treated with induced hypertension in the neurologic intensive care set-ting. Rordorf and collaborators [53] reviewed 30 patients who had ischemicstroke treated with induced hypertension and compared them with 30 similarpatients who had stroke treated with standard therapy. Intravenous phenyl-ephrinewas used to increase bloodpressure until neurologic deficits improved.Treatment was started within 24 hours of stroke onset and was continued fora mean of 110 hours (range 7–576 hours). Neurologic improvement occurredin 10 of the 30 treated patients and occurred at an SBP threshold of 130 to180 mm Hg. Improvements in neurologic deficits occurred within 2 to30 minutes of raising blood pressure. At follow-up, 4 of the 10 patients whoresponded had no neurologic deficit and no infarct on brain imaging, despitethe fact that they had had an average of 10 hours of neurologic deficit beforeimprovement. No overall difference was seen in neurologic or cardiac compli-cations between the patients treated with and without induced hypertension.In contrast, the group assigned to standard therapy had higher rates of ICHand cerebral edema on CT scan. Because this review was nonrandomizedand retrospective, it is possible that CT findings biased patient selection.The same investigators subsequently performed a prospective study ofinduced hypertension in 13 subjects who had acute ischemic stroke within12 hours of onset of symptoms [54]. Exclusion criteria included recent cardiacischemia, congestive heart failure, ICH, or cerebral edema on initial head CTscan. All patients had admission SBP of less than 200mmHg. The goal was toincrease SBP to at least 160 mm Hg or to 20% above the admission SBP, withamaximum allowed SBP of 200mmHg.Neurologic improvement was definedas a reduction by at least two points in theNational Institutes ofHealth strokescale (NIHSS) performed by two independent examiners. To avoid misinter-pretation of spontaneous improvement as treatment-related improvement,

575BLOOD PRESSURE MANAGEMENT IN ACUTE STROKE

phenylephrine was discontinued in all responders. After SBP returned to base-line for 20 minutes, the patient was examined for neurologic deterioration. Abeneficial neurologic responsewas seen in 7 of 13 patientswho had blood pres-sure elevation. Induced hypertension therapy was continued for 1 to 6 daysand eventually weaned successfully in all patients. In the responders, theneurologic deficit did not worsen between discontinuation of induced hyper-tension and time of discharge. At the time of discharge, the mean NIHSSwas 7.4 (range 2–15) among responders comparedwith anNIHSSof 10 (range5–15) among nonresponders. Despite the presence of multiple cardiovascularrisk factors in the patients enrolled, no cardiac or neurologic complicationswere associated with treatment.

Hillis and colleagues [55,56] have used DWI and PWI to study the neuralbasis 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 leftcarotid artery occlusion and a left middle cerebral artery territory infarctprimarily involving the frontal lobe [57]. Neurologic examination revealeda transcortical motor aphasia with telegraphic speech and frequent parapha-sias. DWI revealed a large region of restricted diffusion in the left frontallobe, but PWI showed an even larger area of hypoperfusion also involvingthe anterior left temporal lobe (Wernicke’s area). On serial testing, it wasnoted that his language ability worsened with a relative decrease in bloodpressure. When his MAP was increased from a baseline of 88 mm Hg toa maximum of 100 mm Hg using phenylephrine, PWI showed reperfusionof Wernicke’s area, and a marked improvement in word and sentence com-prehension was noted. The patient eventually was transitioned from intrave-nous phenylephrine to oral medications (fludrocortisone, salt tablets, andmidodrine) to maintain an elevated MAP. By 2 months after stroke onset,these oral medications had been tapered without worsening of aphasiaand with return to his normal blood pressure. A repeat PWI at that timeshowed normal perfusion to Wernicke’s area and no expansion of the infarctbeyond the original DWI abnormality. A remarkable feature of this casewas that induced hypertension resulted in partial, but objective, neurologicimprovement when started 7 days after onset of stroke. Similar findings weresubsequently reported in 5 other patients treated with induced hypertension1 to 9 days after ischemic stroke [58].

With this preliminary experience, Hillis and colleagues [59] went on toperform a prospective, unblinded study of induced hypertension in 15 sub-jects who were randomly assigned in a 2:1 ratio to receive induced hyperten-sion or standard stroke care. Patients were included if they had acuteischemic stroke presenting within 1 and 7 days of onset of symptoms,a quantifiable neurologic deficit, and a diffusion–perfusion mismatch of20% or greater on baseline MRI scan. Exclusion criteria included recentcardiac ischemia, congestive heart failure, hemorrhage on CT scan, or con-traindication to intravenous phenylephrine use. MAP was increased initiallyby discontinuing antihypertensive medications, then with intravascular

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volume expansion, and finally with intravenous phenylephrine. MAP wasincreased in increments of 10% to 20% above baseline with a goal of im-proving NIHSS by two or more points. The maximum allowed MAP was140 mm Hg. All patients treated with induced hypertension were admittedto the neurologic ICU. Nine patients were randomly assigned to induced hy-pertension and 6 to standard care. The two groups were similar in terms ofage, baseline NIHSS, and volume of DWI and PWI lesions on baseline MRIscan. By day 3, patients in the induced hypertension treatment arm had a sig-nificantly better mean NIHSS (5.6 versus 12.3; P!.02) compared with thestandard treatment group, and this difference persisted until follow-up at6 to 8 weeks (mean NIHSS 2.8 versus 9.7; P!.04). No patient in the studyexperienced a serious adverse event. Six of 9 patients treated with inducedhypertension were classified as responders (ie, they showed a reduction ofmore than two points on the NIHSS, which was associated with an increasein MAP of between 14 and 27 mm Hg [13%–30%]). Neither treatmentgroup showed a significant difference in the volume of DWI lesion, whereaspatients treated with induced hypertension had a significant reduction inPWI lesion volume (from mean 132 mL to 58 mL; P!.02) and a significantreduction in the volume of diffusion–perfusion mismatch (from mean 83 mLto 53 mL; P!.005). Independent of treatment, improvements in NIHSSseemed to correlate with a significant reduction in hypoperfused volumein PWI on serial scans [60].

Marzan and colleagues [61] used norepinephrine to induce hypertensionin 34 patients who had ischemic stroke, in a study that included patientswho would have been excluded from most of the other published investiga-tions [62]. Among the 34 subjects, 14 had infarcts on baseline CT involvingmore than one third of the middle cerebral artery territory, 8 were concom-itantly treated with thrombolytic agents, and 17 received intravenousheparin. Nine of 34 patients (26%) were responders (more than a two-pointimprovement in NIHSS); however, among patients not treated with throm-bolytic therapy, 5 of 26 (19%) were responders. Serious complicationspotentially related to induced hypertension occurred in 2 patients (cardiacarrhythmia and symptomatic ICH). The investigators believed this rate ofcomplications was acceptable, particularly given the severity of stroke andthe aggressive nature of the interventions. Koenig and colleagues [62] re-viewed the outcomes and adverse events associated with the use of anyform of blood pressure elevation in patients who had acute ischemic strokewho had baseline DWI and PWI studies and were treated within 7 days ofonset of symptoms. Forty-six treated patients were compared with 54 pa-tients from the same time period who received ‘‘standard therapy.’’ Treatedpatients were more likely to have a larger volume of diffusion–perfusionmismatch and the presence of large-artery atherosclerosis and were morelikely to be treated in the neurologic ICU. Treated patients had a decreasein median NIHSS by the time of discharge, but it was not statistically signif-icant. Serious adverse events occurred in 4 patients in each group.

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Several other approaches to blood pressure manipulation in patients whohave stroke have been reported. In a study of diaspirin cross-linked hemoglo-bin (DCLHb), a hemoglobin-based oxygen carrier, in patients who had acutestroke, a dose-dependent elevation of MAP was noted in the DCLHb-treatedsubjects [63]. The treated group showed no excess of hemorrhagic transfor-mation, cerebral edema, or hypertensive encephalopathy. The overall clinicaloutcome was not improved, however, in the treated patients. Finally, Camp-bell and associates [64] reported on the use of intra-aortic balloon pumpsplaced above and below the renal arteries, causing partial aortic obstructionand resulting in increased cerebral perfusion, sometimes with no systemicblood pressure elevation. CBF assessed by transcranial Doppler, angio-graphy, or positron emission tomography (PET)/single-photon emissioncomputed 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 re-mains poorly defined. From a review of the literature, the following conclu-sions can be made: (1) At the onset of acute stroke, most patients have anelevated blood pressure, and this elevated blood pressure tends to return toprestroke levels in approximately 7 days. (2) No conclusive evidence supportslowering the blood pressure in acute stroke. However, findings in animalstudies and small clinical trials suggest that blood pressure can be loweredsafely in the acute setting and that it may have a beneficial effect. Large ran-domized clinical trials are currently underway to help answer these questions.Moreover, the early use of angiotensin II type 1 receptor blocking agents maybe beneficial because of a mechanism not directly related to reducing bloodpressure (ie, their effects on CBF) and the induction of endothelial nitric ox-ide. (3) In selected cases, blood pressure augmentation may be beneficial andsafe in the management of acute ischemic stroke. (4) More research is neededto identify effective strategies for blood pressure management in acute ische-mic stroke. It is possible that patients may benefit from active management tomaintain blood pressure within a specified range. Clinical trials such as theproposed CHHIPS may help answer these questions, specifically whetherachieving a target blood pressure by reducing or augmenting blood pressureis beneficial [31]. Until such data are available, the guidelines of the AmericanHeart 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 ICHis equally not well defined. Elevated blood pressure is seen in 46% to 56% ofpatients 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 thatSBP of more than 160 mm Hg was independently associated with hematomagrowth. Studies have shown that hematoma expansion occurs early withinthe first 24 hours in 38% of patients [69]. The hypothesis has been advancedthat lowering blood pressure in the acute setting may decrease the hematomaexpansion rate and improve prognosis, yet this theory remains to be tested inclinical trials. The concept of decreasing blood pressure after ICH has beenopposed because of concerns about reducing CBF and promoting ischemiain the perihematomal brain tissue. This concept has been studied in a fewpatients using SPECT, PET, and DWI. Recent results suggest that in theacute setting, regional CBF is reduced around the hematoma, with amatchingdecrease in the cerebral metabolic rate of oxygen. The oxygen extractionfraction remains low, indicating no region of ischemia [70–72]. Stages ofCBF 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 wereevaluated 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 Hgwith either nicardipine or labetalol, and repeat PET showed that the CBFremained stable in the perihematomal area. Studies such as this and theone done by Ohwaki and colleagues [68,71] suggest that reducing bloodpressure in the first 24 hours after ICH is safe. In a study by Qureshi andcoworkers [65], 27 patients who had ICH were treated to reduce SBP toless than 160 mm Hg and DBP to less than 110 mm Hg. Only 2 of 27 pa-tients 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 toreduce hematoma expansion and clinical deterioration in the acute periodafter ICH. The recent guidelines from the American Heart Association/American Stroke Association, published in 2007 [8], recognize that the evi-dence is still not sufficient to guide management of blood pressure in ICH;the recommendation is to treat patients aggressively with an SBP greaterthan 200 mm Hg or MAP greater than150 mm Hg; to consider ICP moni-toring to guide therapy, with the goal of maintaining a CPP between 60 and80 mm Hg in patients who have suspected elevation of ICP and an SBPgreater than 180 mm Hg or MAP greater than 130 mm Hg; and to considertreatment to a goal of SBP of 160 mm Hg or MAP of 110 mm Hg in patientswho have an SBP greater than 160 mm Hg or MAP greater than 130 mm Hgwithout suspicion of elevated ICP.

579BLOOD PRESSURE MANAGEMENT IN ACUTE STROKE

Two trials are currently underway to evaluate these questions. In the An-tihypertensive Treatment in Acute Cerebral Hemorrhage (ATACH) study,patients are randomly assigned to three treatment groups with a specifiedtarget blood pressure level [47]. In the INTEnsive blood pressure Reductionin Acute Cerebral hemorrhage Trial (INTERACT), patients are randomizedto a protocol of intensive blood pressure lowering versus ASA guidelineblood pressure management as control [47].

Aneurysmal subarachnoid hemorrhage

Aneurysmal SAH occurs in more than 30,000 individuals per year in theUnited States, and 30-day mortality is 25% to 50% [74]. Management ofSAH is governed by different priorities and paradigms, depending on thetime after onset of the hemorrhage. The biggest concern in the first fewdays 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 aneu-rysm 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 in30% 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 vaso-spasm. The risk for rebleeding is highest in the first 24 hours after SAH[75,77]. Ohkuma and colleagues [75] studied 273 patients and found aneu-rysmal rerupture in 13.6% within the first 24 hours. In the same study,they found a statistically significant higher risk for rebleeding in patientswho 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, thatMAP less than 70 mm Hg, or greater than 130 mm Hg, was an independentpredictor of death and disability at 3 months. Hypotension with MAP ofless than 70 mm Hg is seen in 4% of all patients who have SAH in the acuteperiod, whereas 33% to 50% of patients present with elevated blood pres-sure. In this study, however, hypertension was not independently associatedwith rerupture.

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

580 URRUTIA & WITYK

had a higher rate of ischemic stroke later in the course when vasospasm wasmore prevalent [79]. This change in priority as the patient evolves from a sit-uation of high rebleed risk to a high vasospasm risk makes interpretation ofthese studies difficult. Wijdicks and colleagues [79] studied 134 patientsenrolled in a trial of tranexamic acid in which 80 (60%) were treated withantihypertensive 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 occurredin 43% of patients who had antihypertensive treatment versus 22% in thosewho did not [79].

A randomized controlled trial of blood pressure management in earlySAH has not been conducted. Data from observational studies suggesta benefit in avoiding the extremes of blood pressure. Also, in the absenceof vasospasm, hydrocephalus, or ICH with increased ICP, blood pressurereduction may be safe. Based on expert opinion and accumulated experi-ence, it seems reasonable to maintain SBP at less than 160 mm Hg beforetreatment of the aneurysm, provided that the conditions outlined earlierare met [74]. A well-designed, randomized, controlled trial is needed toaddress this important question. After definitive aneurysm treatment byclipping or coiling, a strategy of permissive or induced hypertension is com-monly implemented to improve CBF in the setting of vasospasm; however,clinical trials are also needed to support this practice.

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