acute ht response in patients with stroke

Acute Hypertensive Response in Patients With StrokePathophysiology and Management

Adnan I. Qureshi, MD

Acute hypertensive response is the elevation of bloodpressure (BP) above normal and premorbid values that

initially occurs within the first 24 hours of symptom onset inpatients with stroke. This phenomenon was reported in �60%of patients presenting with stroke in a nationally representa-tive study from the United States.1 With �980 000 patients2

admitted with stroke each year in the United States, theestimated annual prevalence of acute hypertensive response ismore than half a million patients. With �15 million patientsexperiencing stroke worldwide each year,3 the acute hyper-tensive response may be expected in �10 million patients peryear. The acute hypertensive response in stroke patients ismanaged by a diverse group of physicians, including emer-gency physicians, intensivists, internists, primary care physi-cians, neurologists, neurosurgeons, and cardiologists. Previ-ous audits suggest that antihypertensive agents andmanagement strategies vary considerably and are not alwaysconsistent with recommended guidelines.4 Data from 1181acute ischemic stroke patients enrolled in the Project forImprovement of Stroke Care Management suggested thatadministration of antihypertensive medication within 24hours in 56% of the patients was inconsistent with guidelinesprovided by the American Stroke Association (ASA).5 Thepresent review article summarizes the current concepts per-taining to treatment of the acute hypertensive responsederived from recent guidelines provided by professionalorganizations and “best available” evidence derived fromexperimental and clinical studies and discusses incorporationof these concepts into clinical practice. Randomized trials,nonrandomized controlled studies, and selected observationalstudies were identified with multiple searches on Medlinefrom 1980 to 2007 by cross-referencing the key words ofstroke, acute hypertension, antihypertensive agents, acutestroke, and hypertension. Pertinent articles identified frombibliographies of selected articles were also reviewed. Treat-ment targets and strategies were identified by review ofexisting guidelines from professional organizations.

Definition of Acute Hypertensive ResponseThe 2003 World Health Organization (WHO)/InternationalSociety of Hypertension (ISH) statement6 and the SeventhReport of the Joint National Committee on Prevention,Detection, Evaluation, and Treatment of High Blood Pressure

(JNC 7)7 define hypertension on the basis of the presence ofconsistent BP �140/90 mm Hg (multiple readings on sepa-rate days). This definition of hypertension is a threshold forthe use of long-term antihypertensive treatment that is sup-ported by evidence derived from randomized trials and clinic-or population-based data that demonstrate reduction in car-diovascular events with this threshold for treatment. Thesame definition cannot be applied in the case of acutehypertensive response, because the above-mentioned ascer-tainment criteria and rationale are not valid. The executivesummary of the ISH statement8 on management of BP inacute stroke stated that high BP (�140/90 mm Hg) is verycommon early after ischemic stroke (occurring in �75% ofcases) and intracerebral hemorrhage (ICH; �80%) and isindependently associated with a poor functional outcome. Tomaintain consistency with the ISH statement, acute hyperten-sive response is defined as ”systolic BP �140 mm Hg ordiastolic BP of �90 mm Hg demonstrated on 2 recordingstaken 5 minutes apart within 24 hours of symptom onset.”This definition predominantly serves to provide a uniformstandard for measuring prevalence and not for setting treat-ment thresholds for antihypertensive treatment, which mayvary depending on stroke subtype and other considerations.

Prevalence of Acute Hypertensive ResponseThe reported prevalence of the acute hypertensive responsedepends on patient selection, study design, referral patterns,and the definition used. In a systematic review of 18 studies,9

52% of patients with stroke were reported to have an acutehypertensive response at the time of admission. The criteriaused to define high BP varied considerably: Systolic BPcriteria ranged from 150 to 200 mm Hg and diastolic BPcriteria from 90 to 115 mm Hg. In one of the largest studiesin the United States using the National Hospital AmbulatoryMedical Care Survey,1 systolic BP �140 mm Hg was ob-served in 63% of the 563 704 adult stroke patients, diastolicBP �90 mm Hg in 28%, and mean arterial pressure (MAP)�107 mm Hg in 38%. In the International Stroke Trial,10

17 398 patients were randomized within 48 hours of strokeonset (median time 20 hours) from 467 hospitals in 36countries. Mean systolic BP at enrollment was 160.1 mm Hg,and 82% of patients had high BP based on the WHOdefinition of hypertension (systolic BP �140 mm Hg).

From the Zeenat Qureshi Stroke Research Center, University of Minnesota, Minneapolis.Correspondence to Adnan I. Qureshi, MD, University of Minnesota, MMC 295, 420 Delaware St SE, Minneapolis, MN 55455.(Circulation. 2008;118:176-187.)© 2008 American Heart Association, Inc.

Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.107.723874

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Characteristics of Acute Hypertensive ResponseThe acute hypertensive response in stroke is characterized byits high prevalence, self-limiting nature, and prognostic sig-nificance. With the definition of hypertension provided by theWHO6 and JNC 7,7 the age-, sex-, and ethnicity-adjusted rateswere 61% among stroke patients and 14% in the US popu-lation in 1999 to 2000.1,11 New-onset high BP in patientswithout a previous history of hypertension has been observedin 20% of patients with stroke12 and 8% of the generalpopulation.11 A crude comparison suggests that these propor-tions are higher than expected on the basis of premorbidhypertension among stroke patients. There is also spontane-ous reduction of BP (by an average of 20/10 mm Hg) within10 days after the acute event without any specific antihyper-tensive therapy.13 Among the 1455 patients from the GlycineAntagonist in Neuroprotection International Trial14 evaluatedwithin 6 hours of symptom onset, MAP declined graduallyover the next 60 hours regardless of initial MAP value, witha prominent reduction observed within 10 hours of the firstmeasurement. The prognostic significance is highlighted in asystematic review of 18 studies9 that demonstrated thatpatients with stroke and high initial BP were at a 1.5- to5.0-fold increased risk of death or dependency and clinicaldeterioration.

Underlying Causes of AcuteHypertensive Response

In at least a portion of these patients, the acute hypertensiveresponse is merely a reflection of inadequately treated orundetected chronic hypertension15; however, spontaneousreduction in the initial BP over the next few days in mostpatients13,14 supports the role of other transient and stroke-specific mechanisms. Spontaneous reduction of BP aftervessel recanalization in patients with ischemic stroke alsoimplies stroke-specific mechanisms.16 Stroke involves tran-sient or permanent damage to the areas involved in the brainregulation of cardiovascular functioning, including BP. Theparasympathetic and sympathetic nervous systems are later-alized to the left and right cerebral hemispheres, respective-ly.17 Prefrontal18 and insular19 cortices provide inhibitory andexcitatory input, respectively, through pathways that connectto the nuclei in the brainstem, particularly in nucleus tractussolitarius and ventrolateral medulla.20 Further modulation isprovided by cingulated cortex, amygdala, and hypothalamus.Because of the widespread distribution of these areas, moststroke lesions involve these areas to a varied extent.

Increased sympathoadrenal tone21 with subsequent releaseof renin and vasoconstriction of arterioles results from (1)direct injury to inhibitory or modulatory brain regions or (2)indirect effects of reduced parasympathetic activity,22 whichleads to impaired cardiac baroreceptor sensitivity in patientswith stroke.23 Although direct injury is the most likelyexplanation, an indirect effect of muscle paralysis24 or therelease of neurotransmitters such as nitric oxide25 duringischemia may be contributing factors to altered activity ofthese nuclei. Other stress responses to hospitalization, head-ache, urinary retention, or concomitant infection26 may leadto abnormal autonomic activity and raised levels of circulat-ing catecholamines27 and inflammatory cytokines12 and sub-

sequently may contribute to the hypertensive response. Pre-sumably, these abnormal autonomic responses normalizeover a few hours owing to spontaneous or therapeuticrecanalization and resolution of the ischemia and perhapsbecause of other neural compensatory mechanisms.28

An increase in systemic BP associated with increasedintracranial pressure (ICP), particularly in the presence ofbrainstem compression,29–31 has particular relevance for pa-tients with intracerebral and subarachnoid hemorrhages. El-evated ICP can result in a systemic BP increase32; however,the elevation in systemic BP does not appear to demonstratea clear relationship to the presence of cerebral ischemia,32,33

ICP values, transtentorial herniation,32,33 or response to hy-perosmotic treatment.32,33 This suggests that the primarycause of the acute hypertensive response is damage orcompression of specific regions in the brain that mediateautonomic control. Hypertensive responses to other factorsmentioned above are exaggerated and additive because ofimpaired parasympathetic activity and baroreceptorsensitivity.

Cerebrovascular Physiology and Implicationsfor Treatment

Under normal circumstances, changes in precapillary arterio-lar diameter (�400 �m) maintain constant cerebral bloodflow in the capillary bed between MAPs of 60 and150 mm Hg.34 A fast dynamic response to changes in pres-sure pulsations is followed by a slow static response thatrestores cerebral blood flow after the initial dynamic responsehas settled35 by myogenic (mechanogenic) and metabolic(chemogenic) mechanisms.36 With decreasing BP, there isvasodilation of arterioles until maximal vasodilation occurs,and subsequently, there is reduction of blood flow. Withincreasing BP, there is progressive vasoconstriction of arte-rioles until the BP exceeds the upper limit of autoregulation,followed by breakthrough vasodilation, increase in cerebralblood flow,36 blood-brain barrier dysfunction, and cerebraledema.

In chronic hypertension, the lower end of the autoregula-tion curve is shifted toward high pressure,37 presumablybecause vessel wall thickening and luminal narrowing limitthe capacity of the resistance vessels for dilation. In acutestroke, autoregulation may be impaired in regions surround-ing an acute lesion and even in the hemisphere contralateralto the lesion because of dilation of cerebral resistance vesselsin an attempt to increase blood flow in response to tissueischemia and acidosis.38 More recently, it has been shownthat autoregulation is impaired for rapid changes (dynamicautoregulation) in systemic BP even when it is preserved forcontrolled changes.39 Other conditions, such as cerebralvasospasm in subarachnoid hemorrhage,40 also cause arterio-lar constriction, which shifts the autoregulatory range towardhigher values.

In the presence of elevated ICP, MAPs �60 mm Hg maynot be adequate to maintain constant cerebral blood flow inthe capillary bed. Ascertainment of the difference betweenMAP and ICP is recommended as an index of cerebralperfusion pressure. The standard, global measure of cerebralperfusion pressure can underestimate the localized pressure

Qureshi Acute Hypertensive Response in Stroke Patients 177



and perfusion changes in focal stroke lesions but is still usefulin the absence of another, more sensitive measure. The BrainTrauma Foundation41 recommends maintenance of a cerebralperfusion pressure �70 mm Hg to enhance perfusion toischemic regions of the brain after severe traumatic injury. Instroke, such treatment thresholds have been extrapolated fromglobal cerebral perfusion data derived from traumatic braininjury patients in the absence of any other pertinent data.

Management of Acute Hypertensive Responsein Stroke Subtypes

Despite the high prevalence of acute hypertensive responsesobserved in all stroke subtypes, differences in underlyingpathophysiology mandate different management strategies(Figure).7,42–47 BP responses can be categorized as (1) spon-taneous decline without medication; (2) no clear decline, oreven an elevation, despite administration of antihypertensivemedication; (3) modest decline with antihypertensive medi-cation (�10% to 15% from baseline value); and (4) intensedecline with antihypertensive medication (�20% from base-line value). The studies presented below are confounded byoverlap of the 4 categories of responses in varying propor-tions and require interpretation with this understanding.Another important issue in management is the identificationof intravascular volume depletion (dehydration)48 in thesepatients, which may result in a natural hypertensive or

hypotensive response or an exaggerated hypotensive responseto antihypertensive medication.49,50 Early identification andappropriate fluid repletion before pharmacological interven-tion ensures a controlled response to treatment.

Patients With Acute Ischemic StrokeIschemic stroke results from occlusion of an artery withsubsequent reduction in regional cerebral blood flow, demar-cated into regions of severe reduction (core) and moderatereduction (penumbra).51 The penumbra remains viable forhours because some degree of blood flow is sustained throughcollateral supply; however, it is theoretically vulnerable tofurther ischemic injury with systemic BP reduction52 becauseof impaired regional autoregulation,38 particularly duringrapid BP reduction. Conversely, in an experimental model offocal cerebral ischemia and reperfusion, BP reduction re-duced infarct size and deficits.53 Therefore, a period ofvulnerability to progression of ischemic deficits may existafter which there may be benefit from BP reduction. A higherrate of death or dependency was observed in patients withinitially high or low systolic BP (U-shaped relationship)among 17 398 ischemic stroke patients randomized in theInternational Stroke Trial.10 The relationship appeared to bemediated in part by increased rates of early recurrence anddeath that resulted from presumed cerebral edema in patientswith high BP and increased coronary heart disease events in

Intracerebral hemorrhage

Ischemic stroke

Candidate for thrombolysis

Not a candidate for thrombolysis

Suspect high ICP

Do not suspect high ICP

Reduce BP if >185/110 mm Hg using short acting IV medication. α

Reduce BP if >220/120 mm Hg using short acting

IV medication. Avoid and treat

hypotension (<100/70 mm Hg).α

Reduce BP if SBP >180 mm Hg

or MAP >130 mm Hg using short acting

IV medication; ICP monitoring recommended to

maintain CPP >60 mm Hg. β

Reduce BP if SBP >180 mm Hg

or MAP >130 mm Hg using short acting

IV medication. Monitor neurological

examination every 15 minutes. β

Treat with thrombolysis.

Maintain BP <180/105 mm Hg using short acting IV medication or

infusions for 24 h. α Oral antihypertensive agents may be considered after 24 hours; BP goal ≈160/110 mm Hg.

Titrate to more aggressive goals after neurological stability is achieved. α

Reduce BP if >185/110 mm Hg using short acting IV medication*

Emergent computed tomographic scan

Clinical diagnosis of acute stroke

Figure. Algorithm for treatment of acute hypertensive response among patients with stroke and stroke subtypes. IV indicates intrave-nous; SBP, systolic BP; DBP, diastolic BP; and CPP, cerebral perfusion pressure. *Based on the NINDS rtPA prethrombolytic proto-col42 for patients with acute ischemic stroke, for short-term BP management by Emergency Medical Services without delaying earlydiagnosis and differentiation. The Emergency Medical Services BP management practices vary considerably in the absence of distinc-tion between ischemic stroke and ICH.43 �Based on recommendations of the ASA, Stroke Council,44,46 and/or European Stroke Initia-tive.45 �The recommended BP treatment threshold is similar to the existing ASA and European Stroke Initiative recommendations forpatients with ICH.44,45 �Based on recommendations of JNC 77 and the ACCESS protocol.47

178 Circulation July 8, 2008



those with low BP. Recent data suggest that wide fluctuations(not initial values) of BP in the first few hours in patients withacute ischemic stroke may be associated with an increasedrisk of death at 90 days.14,54

The Low Dose Beta Blockade in Acute Stroke (BEST)study55 (Table 142,47,55–60) revealed greater mortality amongpatients in whom �-blocker therapy was begun within 48hours of symptom onset. An analysis of data from the Intrave-nous Nimodipine West European Stroke Trial (INWEST)found a significant correlation between diastolic BP reductionwith nimodipine and worsening of neurological status (within24 hours of symptom onset).61 Patients with a diastolic BPreduction �20% or a diastolic BP drop to �60 mm Hg had asignificantly higher risk of death or dependency at 21 days. Asubsequent meta-analysis58 evaluating the use of oral orintravenous calcium channel blockers initiated at 6 hours to 5days after symptom onset in acute ischemic stroke patientsfound that intravenous administration, higher doses, andadministration within 12 hours of symptom onset wereassociated with an increased risk of poor outcomes. Theeffect may be mediated in part by alterations of regionalcerebral blood flow.62 This susceptibility varies with strokesubtype and evolution stage, showing higher tolerance toBP lowering in patients with total anterior circulationinfarction63 and in those treated after 12 hours of symptomonset.58

New data suggest that the increased risk of poor out-comes is probably limited to patients treated very aggres-sively or to specific antihypertensive agents (Table 1). TheAcute Candesartan Cilexetil Evaluation in Stroke Survivors(ACCESS)47 trial initiated treatment with either the angioten-sin receptor antagonist candesartan or placebo in patientswith ischemic stroke and a BP measurement �200/100 mm Hg 6 to 24 hours after admission or �180/105 mm Hg at 24 to 36 hours. The target reduction in BP was10% to 15% within 24 hours. If patients in the candesartangroup displayed a hypertensive profile on day 7 (meandaytime BP �135/85 mm Hg), candesartan was increased oran additional antihypertensive drug was added. In placebo-treated patients with a hypertensive profile on day 7, cande-sartan was begun. Both the cumulative 12-month mortalityrate (2.9% versus 7.2%) and the incidence of vascular events(9.8% versus 18.7%) were lower in the candesartan-treatedgroup; however, the primary outcome of disability measuredby Barthel index at 3 months was not different between the 2treatment groups.

A post hoc analysis of hypertensive patients in the NationalInstitutes of Neurological Disorders and Stroke (NINDS)recombinant tissue plasminogen (rtPA) trial42 who receivedantihypertensive therapy (intravenous labetalol and/or nitro-prusside in selected patients) but no rtPA therapy within 24hours of randomization showed no difference in rates ofdeterioration or death at 24 hours or in rates of favorableoutcome at 3 months compared with hypertensive patientswho received neither antihypertensive medication nor rtPA.The results from various studies suggest somewhat contra-dictory consequences of antihypertensive treatment inacute ischemic stroke: INWEST showed a detrimentaleffect; ACCESS, a favorable effect; and post hoc analysis of

NINDS rtPA study showed no effect. The mean systolic BPin the ACCESS trial was higher than in INWEST (196versus 162 mm Hg), and the mean value during the first 2days was also higher (�150 versus �145 mm Hg). Theaverage maximum MAP in the NINDS placebo group (thosenot given rtPA) who received antihypertensive medication(133 mm Hg) and the average lowest value during the first 24hours (�110 mm Hg) also appear higher than those observedin INWEST. The difference in aggressiveness of BP reduc-tion between the studies was also evident from the 60%incidence of diastolic BP values of �60 mm Hg duringnimodipine treatment in INWEST. These differences stressthe importance of BP thresholds and treatment targets indetermining tolerability of antihypertensive treatment inacute ischemic stroke.

Another aspect that requires further consideration is thepotential for differential benefit or harm between classes ofantihypertensive medication. The differences in results be-tween trials such as the BEST, INWEST, ACCESS, andNINDS rtPA studies may be related to the properties of theantihypertensive medication used. A systematic review64 of 7randomized, controlled trials involving patients with priorstroke or transient ischemic attack demonstrated heterogene-ity in outcomes that were related in part to the class ofantihypertensive drugs used. Angiotensin-converting enzymeinhibitors and diuretics, separately and in combination, butnot �-blockers, reduced vascular events. Another estimate ofstroke reduction with different antihypertensive medications(angiotensin-converting enzyme inhibitors, calcium antago-nists, angiotensin receptor blockers, and diuretics or�-blockers) using data from 29 randomized trials65 directedtoward primary prevention suggested that the greatestreduction was observed with angiotensin receptor block-ers, with small (borderline significance) differences be-tween the other different classes of antihypertensive med-ication. Conclusive evidence for differential effects ofdifferent antihypertensive medications in the acute periodis not available.

The management of high BP in acute ischemic stroke ishighly controversial because of a lack of reliable evidencefrom randomized, controlled trials. The current recommen-dations regarding BP management in acute ischemic stroke46

are based on 2 observations. BP reduction is associated withan increased risk of neurological deterioration and worseoutcome in patients with ischemic stroke in some studies,59,66

although a causal relationship has not been demonstratedconclusively. The benefit of acute BP lowering (unlikechronic treatment) in patients with ischemic stroke remainsunclear.46 There may be a reduction of cardiovascular eventswith early institution of angiotensin receptor antagonists;however, the benefit is not conclusively related to BPreduction.47 Therefore, in the absence of definitive benefit,both the ASA and the European Stroke Initiative are consis-tent in not recommending routine lowering of BP unless it isrepeatedly exceeds 200 to 220 mm Hg systolic or 120 mm Hgdiastolic in the acute period.46,67,68 However, with the antic-ipated completion of several large clinical trials42,47,55–60 inthe next 5 years (Table 1), these recommendations may bemodified.




Table 1. Summary of Completed and Ongoing Prospective Clinical Trials That Evaluated or Are Evaluating Various Aspects ofAntihypertensive Treatment in the Acute Period of Stroke

Trial(s) Design Patients Included Intervention Primary OutcomeNo. of

Patients Comments

Interventions fordeliberatelyaltering BP inacute stroke56

Meta-analysis(5 trials)

Any stroke within 2 wkof symptom onset

Nimodipine (n�66), nicardipine(n�5), captopril (n�3),

clonidine (n�2), nitroglycerin(n�16), perindopril (n�14), and

placebo/control (n�92)

BP reduction andcase fatality

218 Oral calcium channel blockersreduced SBP (weighted meandifference 10.9 mm Hg) at 48

h, ACEI reduced SBP(weighted mean difference

15.0 mm Hg) at 24 h;Nitroglycerin showed a

nonsignificant reduction in BPat 24 h

Low Dose BetaBlockade inAcute Stroke(BEST)55

Randomized trial Hemispheric strokepresenting within 48 h

of symptom onset

Atenolol (50 mg/d), slow-releasepropranolol (80 mg/d), or

matching placebo capsules for 3wk or until discharge

Neurologicalassessment at

entry, day 8, and1 and 6 mo

302 Deaths more common amongpatients taking �-blockers.Neurological recovery and

functional outcome at 6 modid not differ

AcuteCandesartanCilexetilEvaluation inStroke Survivors(ACCESS)47

Double-blind,randomized

multicenter trial

Initial BP�200/110 mm Hg,

acute cerebralischemia and motor

paresis

Candesartan or placebo for 7 dinitiated over a mean period of

30 h after symptom onset

Functional statusassessed by

mRS and BarthelIndex and

mortality ratesafter 3 mo

339 Total mortality, cerebralcomplications, and

cardiovascular complicationsreduced by 47.5% with

candesartan initiated within24 h of admission

Nitroglycerin foracute stroke57

Meta-analysis(2 studies)

Any stroke within 4 dof symptom onset

Nitroglycerin (5–10 mg/d) bytransdermal patch

BP change onday 1

127 No clear effect onend-of-treatment death,

combined death ordeterioration, or end-of-trialdeath, combined death, or

dependency

Calciumantagonists foracute ischemicstroke58

Meta-analysis(28 trials)

Any stroke 6 h to 5 dafter symptom onset(ischemic stroke only

in 23 trials)

IV isradipine (1 trial); oralnimodipine (16 trials); IVnimodipine (5 trials); IV

flunarizine (3 trials); oralPY108-608 (1 trial); and IV and

oral nimodipine (2 trials)

Poor outcome,defined as deathor dependency inactivities of daily

living

7521 No overall effect on outcomeat the end of follow-up. IV

administration, higher doses,and administration within 12

h of symptom onset wereassociated with an increased

rate of poor outcome

NINDS rt-PAStroke Trial42

Post hoc analysisof randomized

trial

Ischemic stroke within3 h of symptom onset

and BP�180/105 mm Hg

after receiving IV rt-PAor placebo

IV labetalol or nitroprussideinfusion if DBP �140 mm Hg or

inadequate response tolabetalol; treatment for 24 h;

80/195 placebo-treated patientsand 65/177 rtPA-treated

patients receivedantihypertensive treatment

Neurologicaldeterioration,ICH, and good

outcome(multiple scales

at 3 mo)

372 All outcome measures similarfor those patients who

received postrandomizationantihypertensive therapy and

those who did not amongplacebo-treated patients;

among rtPA patients, thosewho received antihypertensivetherapy had worse outcomes

than those who did not

ControllingHypertensionand HypotensionImmediatelyPost-Stroke Trial(CHHIPS)59

Prospective,multicenter,randomized,double-blind,

titrated-dose trial

(1) Hypotensive (SBP�140 mm Hg)

nonhemorrhagic strokepatients treated within

12 h of symptomonset; (2) Hypertensive(SBP �160 mm Hg),nondysphagic within36 h of stroke onset;

(3) Hypertensive,dysphagic within 36 h

of stroke onset

(1) IV phenylephrine at 80�g/min titrated to target SBP

150 mm Hg or 15 mm Hgincrease above baseline;(2) oral lisinopril 5 mg or

labetalol 50 mg to target SBP150 mm Hg or 15 mm Hg

reduction from baseline; (3)sublingual lisinopril 5 mg and/orIV labetalol 50 mg to target SBP

150 mm Hg or 15 mm Hgreduction from baseline

Death ordependency(mRS �3) at

14 d

2050 Ongoing

(Continued )




Table 1. Continued

Trial(s) Design Patients Included Intervention Primary OutcomeNo. of

Patients Comments

Efficacy of NitricOxide in StrokeTrial (ENOS)59

Prospective,international,multicenter,randomized,

parallel-group,double-blind,

placebo-controlled trial

Any stroke treatedwithin 48 h

Transdermal nitroglycerin orplacebo for 7 d. Patients takingantihypertensive drugs will be

randomized to continue ordiscontinue their medication

for 7 d

Mortality rateand mRS at

3 mo

5000 Ongoing

ScandinavianCandesartanAcute StrokeTrial (SCAST)59

Randomized,controlled

multicenter trial

Acute stroke within 30h and SBP

�140 mm Hg

Candesartan (dose increasingfrom 4 to 16 mg/d) or placebo

for 7 d

Death ordisability at 6

mo; combinationof vascular

death,myocardial

infarction, orstroke during

first 6 mo

2500 Ongoing

Continue OrStop post-StrokeAntihypertensivesCollaborativeStudy(COSSACS)59

Multicenter,prospective,randomized,

open, blindedend-point

ascertainmentstudy

Any stroke within 24 hof symptom onset

Patients will receiveantihypertensive therapy for a

2-wk period

Death ordisability (mRS�2) at 14 dafter stroke

2900 Ongoing

AntihypertensiveTreatment inAcute CerebralHemorrhage(ATACH)60

Prospective,open-label,multicentersafety and

tolerability study

Supratentorial ICHwithin 6 h of symptom

onset and SBP�200 mm Hg

Stepwise, interventional designto test 3 tiers of SBP reduction:

170–200 mm Hg,140–170 mm Hg and110–140 mm Hg with

IV nicardipine

Ability to achieveand maintain

treatment goals(SBP range forthe 18–24-h

period) and anyneurologicaldeterioration

60 Recruitment complete; nosafety concerns

Intensive BloodPressureReduction inAcute CerebralHemorrhage –(INTERACT) PilotStudy59

Randomized,open-label,

active-control,parallel-

assignment,safety/efficacy

study

ICH within 6 h ofsymptom onset and

SBP �150 mm Hg and�200 mm Hg

Intensive SBP lowering; controlgroup receives ASAguideline-based BP

management

Mortality anddependency

(mRS of 3 to 5)at 3 mo

400 Recruitment complete; nosafety concerns

IntracerebralHemorrhageAcutelyDecreasingArterial PressureTrial (ICHADAPT)59

Multicenter,randomized,open-label,

blinded-pointtrial

Primary ICH and SBP�150 mm Hg

IV labetalol to reduce SBP to�150 mm Hg within 1 h of

treatment; control groupreceives ASA guideline-based

BP management

PerihematomalrCBF measuredwith CT scanperfusion 2 h

after treatment

82 Ongoing

Nicardipine forthe Treatmentof Hypertensionin Patients withIschemic Stroke,IntracerebralHemorrhage orSubarachnoidHemorrhage(CARING)59

Phase IV,prospective,

open-label study

Ischemic stroke, ICH,or SAH patients who

require BP control

25 Patients will receivedouble-concentrate dose; 25 willreceive triple-concentrate dose

Rate ofperipheral IV

phlebitis, time,and dosageadjustment

needed to reachtarget BP range

50 Double-concentrated IVnicardipine can be given

safely

SBP indicates systolic BP; ACEI, ACE inhibitor; mRS, modified Rankin scale; DBP, diastolic BP; ASA, American Stroke Association; rCBF, regional cerebral blood flow;and SAH, subarachnoid hemorrhage.




Patients With Acute Ischemic StrokeReceiving Thrombolysis

The acute hypertensive response among patients with ische-mic stroke receiving thrombolysis is frequently transient69

and resolves after recanalization70; however, elevated BPbefore receipt of thrombolysis has been associated with anincreased risk of ICH. In the Australian Streptokinase Trial,71

baseline systolic BP �165 mm Hg resulted in a 25% in-creased risk of major ICHs among patients with ischemicstroke treated with streptokinase. In a multicenter retrospec-tive and prospective investigation72 of individual data from1205 patients treated in routine clinical practice with intra-venous rtPA within 3 hours of stroke symptom onset, ele-vated pretreatment MAP was associated with an increasedrate of ICH. In a large audit of practices and outcomes in 29hospitals in the Cleveland, Ohio, area,73 BP parametersrecommended by the NINDS rtPA trial were not followed in52% of the 70 patients treated with intravenous thrombolysis.The result was a 16% rate of symptomatic ICHs. A quality-improvement program in 9 of these hospitals74 decreased therate of noncompliance to BP recommendations to 6% in 47patients subsequently treated with rtPA. The rate of symp-tomatic ICH dropped to 6%, which indirectly supports thebeneficial value of BP control in reducing rtPA-related ICHs.

Both the ASA and European Stroke Initiative guidelinesrecommend the reduction of BP according to the eligibilitythresholds for inclusion in the NINDS rtPA efficacy trial42

(Figure7,42–47) before thrombolytics are administered.46,67,68

In the NINDS rtPA efficacy trial,42 patients were not eligibleif they required aggressive antihypertensive therapy, definedas use of intravenous nitroprusside or repeated intravenousinfusions of other medications. A post hoc analysis reportedthe frequency, course, and treatment of hypertension (�185/110 mm Hg before randomization or �180/105 mm Hgwithin the first 24 hours after randomization).42 Antihyper-tensive treatment before and after treatment with rtPA wasused in 9% and 24%, respectively, of the patients treated withrtPA. Prethrombolysis use of antihypertensive treatment didnot adversely affect the rate of favorable outcomes at 3months. Postthrombolysis hypertension and use of antihyper-tensive treatment correlated with a lower rate of favorableoutcome at 3 months. It remains unclear whether this adverseeffect was related to more severe ischemic injury, persistentvascular occlusion, or pronounced reduction in BP. Patientstreated with thrombolytics and antihypertensive therapy weremore likely to have an abrupt decline in BP than those whowere not treated. The higher susceptibility to hypotensionassociated with antihypertensive treatment after thrombolyticuse (not seen in the placebo group) may be related torecanalization or reperfusion; however, the rate of ICHamong patients with acute hypertension with appropriatecontrol was similar to that observed in nonhypertensivepatients. Another study75 reported that postthrombolytic acutehypertension occurred predominantly within 6 hours of re-ceipt of thrombolysis, and if treated adequately, is notassociated with an increased risk of ICH. Therefore, early BPreduction with rapidly acting antihypertensive treatment ap-pears paramount for safe and beneficial thrombolysis amongpatients with acute ischemic stroke. Frequent BP monitoring

and titration with short-acting intravenous agents are prefer-able to avoid uncontrolled decline in BP. The data abouttreating the acute hypertensive response after thrombolyticuse are limited, because most studies excluded patients withdifficult-to-control BP and did not use some of the newerantihypertensive agents. With the increasing use ofthrombolytics and other endovascular treatment in acuteischemic stroke, new studies are required to address theseissues.

Patients With ICHOne third of subjects presenting with ICH continue todemonstrate hematoma expansion (with subsequent deterio-ration and death) in the first few hours after onset.76 An initialsystolic BP �200 mm Hg is associated with hematomaexpansion77 and increased mortality78 among patients withICH. Persistently higher systolic BP is also associated withperihematoma brain edema formation.79 Reducing BP mayreduce the rate of hematoma expansion, although conclusiveevidence of this is not available.29 Recent studies suggest thatreduction of BP may be tolerated because of reduced metab-olism (hibernation)80 and preserved autoregulation in theperihematoma region.81

A multicenter prospective observational study82 reportedthe use of intravenous labetalol, hydralazine, and/or nitro-prusside for maintaining BP �160/90 mm Hg within 24hours of symptom onset among patients with ICH. Low ratesof neurological deterioration and hematoma expansion wereobserved in treated patients. Patients treated within 6 hours ofsymptom onset were more likely to be functionally indepen-dent at 1 month than patients who were treated between 6 and24 hours. Another study83 evaluated the tolerability and safetyof intravenous nicardipine infusion within 24 hours of symp-tom onset to reduce and maintain MAP �130 mm Hg,consistent with previous ASA guidelines. The primary out-come of tolerability was achieved in 86% of the patients. Lowrates of neurological deterioration and hematoma expansionwere observed among treated patients. Indirect comparisonssuggest that intermittent intravenous bolus regimens of anti-hypertensive agents have greater variability in BP controlthan continous infusion regimens.83

The current ASA44 and European Stroke Initiative45 guide-lines recommend lowering BP in patients with an ICH tomaintain systolic BP below 180 mm Hg. Both guidelinesacknowledge that there may be a subset of patients who cantolerate more aggressive BP reduction, such as those withgood neurological status or those without chronic hyper-tension. A recent observational study suggested that moreaggressive BP reduction may have greater benefit in reducingthe rate of hematoma expansion. One study assessed theresults of lowering systolic BP below targets of 140, 150, or160 mm Hg.84 The rate of hematoma expansion was 9% inpatients with systolic BP �150 mm Hg and 30% amongpatients treated to maintain systolic BP �160 mm Hg or ahigher threshold. Several ongoing trials (Table 1) are pro-spectively evaluating whether more aggressive BP loweringis safe and reduces the rate of hematoma expansion. TheNINDS-funded Antihypertensive Treatment of Acute Cere-bral Hemorrhage (ATACH)60 trial is presently determining




the exact threshold of BP lowering (systolic BP�140 mm Hg, �170 mm Hg, or �200 mm Hg) for patientswith ICH within 6 hours of symptom onset. Another pilotrandomized study, Intensive Blood Pressure Reduction inAcute Cerebral Hemorrhage (INTERACT), is comparingclinical outcomes in patients treated with intensive BP low-ering (systolic BP �140 mm Hg) versus those treated accord-ing to ASA guidelines within 6 hours of symptom onset. Bothtrials recently reported preliminary results that suggested thataggressive BP reduction to a target of �140 mm Hg probablydecreases the rate of substantial hematoma enlargement84a

without increasing adverse events.84b

A new consideration is the combination of intravenoushemostatic treatment and aggressive BP control. In an explor-atory analysis from a study of recombinant activated factorVII85 in ICH, initial systolic BP �170 mm Hg was associatedwith a trend toward lower hematoma expansion rates. Inanother study,86 a total of 188 patients admitted within 24hours of symptom onset were treated with a combination ofrapidly administered antifibrinolytic agents and systolic BPmaintained �150 mm Hg. Hematoma enlargement was ob-served in only 4.3% of patients, which supports furtherevaluation of this approach.

Antihypertensive Agents and RegimensThe agents that are recommended by the ASA for acutehypertensive response are either intravenous or transdermal

agents with rapid onset and short duration of action to allowprecise titration (Table 242,53,58,81–83,87–96). BP can be moni-tored adequately with an inflatable cuff in most patients withacute hypertensive response, whereas intra-arterial monitor-ing should be considered in patients who require frequenttitration with intravenous antihypertensive agents and inpatients whose neurological status is deteriorating. ICP mon-itoring may be necessary in patients with a suspected in-creased ICP, to measure and preserve cerebral perfusionpressure during systemic BP lowering. Patients with a poorlevel of consciousness, midline shift, or compression of basalcisterns on computed tomographic scan may be consideredfor ICP monitoring when being treated with antihypertensiveagents. Of note, cerebral perfusion pressure may overestimateregional perfusion because of its inability to measure regionalpressure and autoregulatory disturbances.

Management of Chronic Hypertension in theImmediate Poststroke Period

Approximately 50% of patients are admitted with strokewhile taking regular antihypertensive therapy.8 The abruptdiscontinuation of antihypertensive medication may lead toenhanced sympathetic activity, rebound hypertension, and aconsequent increase in cardiovascular events97,98 in patientswith coronary artery disease using �-adrenergic blockers orthose using high doses of centrally acting antiadrenergicdrugs. In studies conducted in nonstroke patients, a slow

Table 2. Pharmacological Characteristics of Antihypertensive Agents Recommended in the Stroke Council, American HeartAssociation’s Statements for Healthcare Professionals

AgentMechanism of

Action CBF ICP AutoregulationPlateletActivity‡

CardiacContractility‡ Dose

Onset ofAction Half-Life

IschemicStroke ICH

Labetalol �- and�-Adrenergic

blocker

� � � � � � � � � � � � � 5–20-mg bolusevery 15 min up

to 300 mg

5–10min

3–6 h SS,CS,42

ES87

SS, CS,82,88

ES89

Hydralazine Direct relaxation ofarteriolar smooth

muscle

�� 5–20-mg bolusevery 15 min

10–20min

1–4 h SS, ES53 SS, CS82

Nitroprusside Releases nitricoxide

�� Infusion of 0.2 to10

�g � kg�1 � min�1

Withinseconds

2–5 min SS,CS,42

ES90

SS, CS82

Nitroglycerine Releases nitricoxide

� � � � � � � � � � � 20 to 400�g/min

1–2 min 3–5 min SS, CS91

Nitropaste Releases nitricoxide

� � � � � � � � � � � 0.2–0.4 mg/h upto 0.8 mg/h

1–2 min 3–5 min SS, CS92 SS, CS92

Nicardipine Calcium channelblocker

� � � � � � � � � 5–15 mg/h 5–10min

0.5–4 h SS, CS58 SS, CS81,83

Esmolol† �-Adrenergicblocker

� � � � � � � � � � � 250 �g/kg bolusfollowed by 25

to 300�g � kg�1 � min�1

5 min 9 min SS

Enalapril* ACE inhibitor � � � � � � �� 1.25–5 mg every6 h

15 min 1–4 h CS,93

ES53SS, ES94

CBF indicates cerebral blood flow; SS, scientific statement; CS, clinical study; ES, experimental study; ACE, angiotensin-converting enzyme; �, increase or favorableeffects; ��, substantial increase or favorable effects; �, decrease or negative effects; and . . . , no documented direct effect.

No conclusive evidence is present at this point to avoid any particular class of antihypertensive medication (including �-blockers95). In general, medications withslow onset of action, long half-lives, or those known to cause precipitous BP reduction (sublingual nifedipine96) should be avoided in the first 24 hours because theycannot be titrated to ensure controlled BP reduction.

*Data predominantly derived from other ACE inhibitors; †limited data available; ‡not derived from studies performed in acute stroke settings and unclear directrelevance.




increase in systemic BP99 and a low rate of cardiovascularevents100 follows discontinuation of antihypertensive treat-ment. A small randomized trial101 was unable to demonstrateany difference in the rate of death or disability after discon-tinuation of antihypertensive treatment in patients with ische-mic stroke within 72 hours of symptom onset. New multi-center trials are addressing this question (Table 1). In theinterim, the decision to continue or discontinue antihyperten-sive agents must be made on a case-by-case basis with theintent to avoid hypotension, excessive hypertension, andmyocardial ischemia. Reduction of the dose of the currentagent or a change to a short-acting intravenous antihyperten-sive agent may be considered.

Another issue is the timing of initiation or aggressivetitration of oral antihypertensive treatment in patients withstroke who have chronic hypertension or undetected hyper-tension. In the California Acute Stroke Prototype Registry,102

great variability in practices between hospitals and consider-able room for improvement was noted among two thirds ofpatients with acute ischemic cerebrovascular events dis-charged from the hospital who were given 1 or moreantihypertensive medications. The heterogeneity in practicedespite the definitive benefit demonstrated in clinical tri-als103–105 is concerning. Theoretically, oral hypertensiveagents can be initiated at 24 to 48 hours after symptom onset,because most of the acute processes, such as ischemicpenumbra and hematoma expansion, are uncommon after thefirst 24 hours. In the ACCESS trial47 (discussed above),treatment was started with daily candesartan or placebo onday 1. On day 2, the dosage was increased 2- or 4-fold if BPwas �160/100 mm Hg. If patients in the candesartan groupshowed a hypertensive profile on day 7 (mean daytime BP�135/85 mm Hg), candesartan was increased or an additionalantihypertensive drug was added. The results support earlyinitiation of antihypertensive treatment with gradual titrationto more aggressive BP treatment targets.

The JNC 7 report7 recommends that BP be maintained atintermediate levels (around 160/100 mm Hg) until neurolog-ical stability is achieved. Special circumstances such aselevated ICP, progressive cerebral edema, ongoing cerebralischemia due to occlusive vessel disease or symptomaticcerebral vasospasm, and postoperative cerebral changes re-quire individualized management. After the first week, orwhen neurological stability is achieved, a more aggressivetreatment can be initiated for secondary prevention of recur-rent stroke.7,106 The ASA107 recommends that antihyperten-sive therapy be considered for all patients with ischemicstroke or transient ischemic attack, because benefit is seen inpersons with and without a history of hypertension. Specialconsideration may be necessary for patients with bilateralsevere carotid stenoses,108 who may bear a high risk of strokewith aggressive BP lowering until carotid revascularization isperformed.

ConclusionsDifferent strategies are required to manage the acute hyper-tensive response in different subtypes of stroke. Therefore,early diagnosis and differentiation are critically important fortimely institution of the appropriate strategy. The manage-

ment of high BP in acute ischemic stroke is highly contro-versial because of a lack of reliable evidence from random-ized, controlled trials. Aggressive BP reduction is currentlynot recommended in patients with ischemic stroke in theacute phase because of potentially deleterious effects ob-served in some observational studies and absence of adocumented benefit of acute BP lowering. A reduction in BPbefore administration of thrombolytics in patients with ische-mic stroke is important to reduce the risk of secondary ICHs.Reduction of BP in patients with ICH requires furtherevaluation for efficacy given recent studies that have docu-mented clinical tolerability due to reduced metabolism (hi-bernation) with preserved autoregulation in the perihematomaregion.

Further studies are required to demonstrate the clinicalbenefits of treating the acute hypertensive response in pa-tients with stroke and to determine whether these benefits areagent specific. Imaging modalities need to be developed thatallow bedside measurement of regional cerebral blood flowand metabolism so that titration of antihypertensive treatmentcan be based on critical variables. Most recommendations arebased on expert opinions and general principles defined byobservational studies and small clinical trials. With theanticipated completion of several large clinical trials in thenext 5 years, these recommendations can be established onthe basis of superior levels of scientific evidence.

AcknowledgmentThe author wishes to thank Donald Quick, PhD, for his carefulreview of the manuscript and helpful comments.

Sources of FundingDr Qureshi was supported in part by the National Institute ofNeurological Diseases and Stroke, National Institutes of Health, asPrincipal Investigator of the Antihypertensive Treatment in AcuteCerebral Hemorrhage (ATACH; R01-NS44976-01A2), medicationfor which was provided by Protein Design Labs. Dr Qureshi is alsothe recipient of an Established Investigator Award from the Ameri-can Heart Association as principal investigator of Innovative Strat-egies for Treating Cerebral Hemorrhage (American Heart Associa-tion grant No. 0840053N).

DisclosuresDr Qureshi was the recipient of an honorarium from the EmergencyMedicine Cardiac Research Education Group.

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KEY WORDS: stroke � hypertension � blood pressure � cerebralinfarction � cerebral ischemia � hemorrhage � thrombolysis




Adnan I. QureshiAcute Hypertensive Response in Patients With Stroke: Pathophysiology and Management

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