ences 261 (2007) 74–79www.elsevier.com/locate/jns

Journal of the Neurological Sci

Acute hypertension in intracerebral hemorrhage:Pathophysiology and treatment

Qaisar A. Shah a,⁎, Mustapha A. Ezzeddine b, Adnan I. Qureshi a

a Zeenat Qureshi Stroke Research Center, Department of Neurology, University of Minnesota, Minneapolis, MN, United Statesb Department of Neurology, University of Medicine and Dentistry of New Jersey, Newark, NJ, United States

Available online 5 June 2007

Abstract

Non-traumatic or spontaneous intracerebral hemorrhage (ICH) is defined as intra-parenchymal bleeding with or without extension into theventricles and rarely into the subarachoid space. Primary ICH in most cases is associated with chronic hypertension. Acute hypertension isassociated with hematoma expansion, and poor neurological outcome. The treatment of hypertension in acute ICH is a topic of controversy.Experiments have shown an area of ischemia around the hematoma, with the reduction of regional cerebral blood flow (CBF) secondary tocompression of microvasculature. Not all scientific results agree with the above findings. Recent studies have shown that CBF decreases inthe perihematoma region but with concomitant reduction of cerebral metabolism, which would argue against an area of ischemia in theperihematoma region. Based on the above result, there have been several clinical trials looking at clinical outcome and decrease in hematomaexpansion rates with reduction of blood pressure acutely after ICH. The parameters for the blood pressure control are still under investigation.The American Heart Association has put forward guidelines for blood pressure control which have been adopted in the centers around thecountry. We have described the protocol we use at our center for the blood pressure control in patients with acute ICH.© 2007 Elsevier B.V. All rights reserved.

Keywords: Intracerebral hemorrhage; Mean arterial pressure; Hypertension; Nicardipine; American Heart Association; Hematoma expansion; Cerebral bloodflow; Intracranial pressure

1. Epidemiology

Non-traumatic or spontaneous ICH is defined as intra-parenchymal bleeding with or without extension into theventricles and rarely into the subarachoid space. Sponta-neous ICH accounts for 10–15% of all cases of stroke andcould be classified as primary or secondary [1]. Primary ICHis mostly the result of chronic hypertension and amyloidangiopathy, and accounts for almost 78–88% of cases [2].Secondary ICH could be the result of underlying vascularmalformation, coagulation abnormalities, or intracranialtumors. Worldwide incidence of ICH ranges from 10 to 20cases per 100,000 population [3], and is estimated to affect

⁎ Corresponding author. University of Minnesota, 420 Delaware StreetSE, Minneapolis, MN 55455, United States. Tel.: +1 612 626 6519; fax: +1612 625 7950.

E-mail address: qaisarshah@gmail.com (Q.A. Shah).

0022-510X/$ - see front matter © 2007 Elsevier B.V. All rights reserved.doi:10.1016/j.jns.2007.04.036

approximately 37,000 to 52,000 people every year in theUnited States [4]. The mortality from ICH within the firstmonth ranges from 44% to 51% and at 2 years post-ictusfrom 56% to 61% [5,6].

Elevated blood pressure is common after stroke particu-larly ICH. Wallace and Levy [7] reported elevated bloodpressure in two-thirds of the study patients with acute strokeand spontaneous reduction within 10 days without anyantihypertensive treatment [7,8]. Subsequent studies haveconfirmed the high prevalence of elevated blood pressureamong patients with acute stroke [9,10]. In a large cross-sectional study, Qureshi et al. [11] reported elevated systolicblood pressure (SBP) ≥140 mm Hg in 63% of strokepatients, in stroke subtypes the proportion of patients withelevated SBP≥140 mm Hg were as follows: ischemic stroke67%, ICH 75% and subarachnoid hemorrhage 100%.Prevalence of various blood pressure in ICH were asfollows; SBP between 140 and 184 mm Hg were 50%,

75Q.A. Shah et al. / Journal of the Neurological Sciences 261 (2007) 74–79

SBP between 185 and 219 mm Hg were 17%, SBPN220 mm Hg were 3%.

Elevation of the blood pressure has been associatedwith poorclinical outcomes including death or dependency [10].Dandapani et al. [12] in their retrospective review of 87 patientswith ICH showed marked elevation of blood pressure onadmission and persistent inadequate blood pressure controlwereassociated with poor clinical outcome. There was significantlyhigher mortality in patients with SBP N145 mm Hg.

2. Pathophysiology

Under normal circumstances, brain can tolerate widerange of variations in blood pressure. The change inarteriolar diameter is responsible for autoregulation. Thearterioles usually vasoconstrict during increase in bloodpressure and vasodilate during decrease in blood pressure.This change in vessel diameter maintains normal CBF underwide cerebral perfusion pressure (CPP) ranges. The auto-regulatory range for mean arterial pressure (MAP) isconsidered to range from 50 to 150 mm Hg. With chronichypertension there is a shift in the curve to the right. Thus,there is a potential risk of ischemic brain injury with suddendecrease in CPP below the lower limit of autoregulationparticularly in patients with chronic untreated hypertension.

The underlying reason for high blood pressure in strokepatients is not absolutely clear. There have been severaldifferent explanations. Majority of stroke patients, particu-larly patients with ICH have chronic hypertension andelevation at the time of admission is merely a reflection ofthe untreated hypertension [13]. It could also be a reactionfrom compression of the brain stem, also known asCushing–Kocher response, in order to maintain cerebralperfusion [4,14]. Stress response leading to abnormalsympathetic activity, altered parasympathetic activity, raisedlevels of circulating catecholamines [15], and brain natriure-tic peptide may also contribute to hypertension acutely [16].

3. Theoretical principles for blood pressure management

The treatment of acute hypertension in patients with ICHis highly controversial, as the effect of pharmacologicalreduction of MAP on CBF is unclear. It has been shown inthe animal studies by Nath et al. [17] and Bullock et al. [18]that there is a transient decrease in CBF in all brain regions,with lowest CBF recorded in the perihematoma region. Thiswas postulated to be the result of compression effect on theneighboring microvasculature, leading to local ischemia andacidosis. Auto-regulation may be disrupted in the perihema-toma, thus decreasing the blood pressure and impairing theCBF, and subsequently provoke ischemia. Also autoregula-tory vasodilation of cerebral vessels as a reaction to systemicblood pressure reduction may increase intracranial pressure(ICP) ultimately reducing the CPP [19].

Although not all experiments agrees with the abovefindings, Qureshi et al. [20] demonstrated no change in CBF,

cerebral metabolic rate of oxygen (CMRO2), and oxygenextraction fraction (OEF) in dogs despite elevation of bothICP and MAP after ICH. Subsequent studies by Hirano et al.[21] and Carhuapoma et al. [22] has shown no ischemia in theperihematoma region by using positron emission tomogra-phy (PET) and diffusion weighted image (DWI), respec-tively. Zazulia et al. [23] studied patients within the first 24 hafter ICH onset using positron emission tomography (PET)scan, and were able to demonstrate no significant reductionof CBF, CMRO2, or OEF. The above studies argue againstthe possibility of ischemia in the perihematoma region. Theexplanation of the reduced blood flow and reducedmetabolism in the perihematoma is unclear; one explanationinvolves toxic effect of the blood to the perihematomacausing decrease in the metabolism [17,24,25].

There have been three phases described for CBF andmetabolic changes in the peri-hematoma region based onrecent laboratory and clinical studies [26]. A hibernationphase is seen during the first 48 h. This phase is described bya reduction in CBF and metabolism, in both ipsilateral andcontralateral hemispheres. This has also been proven byusing PET scan, demonstrating decrease CBF and OEF [23].A reperfusion phase is seen between 48 h and 14 days. Thisconsists of a heterogeneous pattern, including areas ofnormal, hypo- and hyper-cerebral perfusion. The normal-ization phase is observed after 14 days and consists ofnormal blood flow except in non-viable tissue (Fig. 1). Basedon this assumption, blood pressure reduction in the period ofhibernation should be relatively safe.

The hematoma expansion is a dynamic process and bothfrom animal and human studies it has been shown toprogress for first 24 h, with the greatest expansion being inthe first 6 h [27–29]. The initial elevated blood pressure hasbeen clearly associated with poor clinical outcome but itsrelationship with hematoma expansion is still unclear. Therehas been some limited clinical studies showing increasedrisk of hematoma expansion in patients having elevatedinitial blood pressures [30], but it is unclear whether theelevated blood pressure predisposes patients to the expan-sion of the hematoma or is a consequence of this event. Theblood pressure control for the prevention of hematomaexpansion is currently under study. The current clinical trialwith the use of ultra-early hemostatic therapy withrecombinant activated factor VII (rFVIIA) has shown toreduce the hematoma expansion, reduce mortality andimprove clinical outcome at 3 months [31]. But this studydid not specifically look at the change in blood pressure andits effect on hematoma expansion. Overall, the literature issupporting controlled reduction of blood pressure in theacute period of ICH.

4. American Heart Association guidelines

The American Heart Association (AHA) guidelinesrecommend controlling of the blood pressure tailored tothe individual factors, such as chronic hypertension, ICP,

Fig. 1. Different phases of the cerebral blood flow and metabolism in the perihematoma. rCBF: regional cerebral blood flow. Reprinted with permission fromElsevier. Qureshi et al. [26].

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age, mechanism of hemorrhage, and time interval sinceonset. MAP should be maintained between 90 and130 mm Hg [32]. In patients with elevated ICP who havean ICP monitor, CPP should be kept N70 mm Hg.

5. Clinical trials and experimental studies

What we know about ICH from the current status ofpreclinical and clinical trials is that blood pressure is elevatedin majority of patients with ICH. Elevated blood pressure isassociated with hematoma expansion and poor neurologicaloutcome, and there is no perihematoma ischemic region.Thus, based on the above evidence, it is reasonable to treatelevated blood pressure in patients presenting acutely in theemergency department. The adequate blood pressure para-meters, in order to sustain an adequate CPP as well toimprove the clinical outcome, are unknown. There have beenseveral small clinical trials and there is one ongoing largemulticenter clinical trial to answer this question.

In 1962, Meyer and Bauer [33] first demonstratedimprovement in mortality with the use of antihypertensivemedication in patients with ICH in their prospective, non-randomized trial. The data was limited because of the factthat the treated group had less severe symptoms thanuntreated group. Dandapani et al. [12] in 1995, retro-spectively studied blood pressure control within first 2 to 6 hafter presentation. Improved mortality and morbidity wereobserved with blood pressure reduction. However, the studydid not consider variables such as ICH volume, ventricularblood, and initial Glasgow coma scale (GCS) that confound

the results. Qureshi et al. [34] in 1999, in an animal studyshowed that the pharmacologic reduction of MAP had noadverse effects on ICP and rCBF in regions around anddistant to the hematoma. The study was limited by the factthat all the experimental animals were normotensive, asoppose to the majority of the patients who have longstandinghypertension which changes the cerebral flow dynamics.Powers et al. [35] in 2001, studied 14 patients within 6 to22 h with small- to medium-sized acute ICH. The CBF weremeasured before and after treatment with PET scan. Therewas no change in CBF either globally or in the perihematomaregion with a 15% reduction in MAP. The patients wererandomized to receive either nicardipine or labetalol.

In 2004, in a prospective multicenter study [36], safetyand feasibility of early antihypertensive treatment in 27patients showed low rates of neurological deterioration andhematoma expansion. Patients who were treated within 6 hwere more likely to be independent at one month thanpatients who were treated between 6 and 24 h. There weresome limitations to the study, including unmatched controlwith variable characteristics, and that not every patientunderwent 24-h follow-up computed tomography (CT).Therefore, asymptomatic hematoma expansion could havebeen missed. In a single-center, prospective registry in2006 [37], 29 patients were treated with nicardipine toachieve MAP goal b130 mm Hg within first 24 h, asrecommended by AHA guidelines. The study was uniquein several aspects. First, the AHA guidelines were used asa guiding principle for the management of the bloodpressure for the first time. Second, nicardipine was selected

Graph 1. Systolic blood pressure control with intravenous labetalol and hydralazine. Reprinted with permission from SAGE. Qureshi et al. [36].

77Q.A. Shah et al. / Journal of the Neurological Sciences 261 (2007) 74–79

in order to maintain an even and effective reduction in theblood pressure, instead of previous protocols with acombination of boluses of labetalol and hydralazine,(Graphs 1 and 2). The study demonstrated that 86% ofpatients tolerated nicardipine, neurological deteriorationwas observed in 13% of patients and that hematomaexpansion was seen in 18% of patients.

6. New clinical trials

Antihypertensive treatment of acute cerebral hemorrhage(ATACH) trial [38] is designed to determine the tolerabilityof the treatment as assessed by achieving and maintainingthree different SBP goals with intravenous nicardipineinfusion for 18 to 24 h post-ictus in subjects with ICHwho present within 6 h of symptom onset. The neurologicaldeterioration during the treatment and any serious adverseevents will also be monitored. The patients are being

Graph 2. Mean arterial pressure control with intravenous nicardipine. Printed w

recruited if they have initial SBP greater than 200 mm Hg.The study is divided into three tiers; in the first tier the SBPbeing kept between 170 and 200 mm Hg, in the second tierbetween 140 and 170 mm Hg, and in the third tier between110 and 140 mm Hg. The current study will be able to helpincrease our understanding of the principles of bloodpressure control in acute ICH. Currently, we use AHAguidelines to maintain MAP between 90 and 130 mm Hg atour institution with intravenous nicardipine infusion usingthe above mentioned protocol (see Table 1).

7. Initiation of oral antihypertensive medications

A high proportion of the ICH patients have chronichypertension. After 24 h, blood pressure should bemaintained at intermediate levels (below 160/100) and oralantihypertensive medications can be initiated. In clinicaltrials, antihypertensive medication has shown to reduce the

ith permission from Lippincott Williams & Wilkins. Qureshi et al. [37].

Table 1Nicardipine infusion

MAP: mean arterial pressure.aTarget MAP: 90 mm Hg–130 mm Hg.

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mean incidence of stroke by 35–40%, myocardial infarctionby 20% to 25%; and more than 50% in heart failure [39].“The Seventh Report of the Joint National Committee onPrevention, Detection, Evaluation, and Treatment of HighBlood Pressure, provides a new guideline for hypertensionprevention and management. The following are the keymessages: (a) In persons older than 50 years, SBP of morethan 140 mm Hg is a much more important cardiovasculardisease (CVD) risk factor than diastolic BP. (b) The risk ofCVD, beginning at 115/75 mm Hg, doubles with eachincrement of 20/10 mm Hg; individuals who are normoten-sive at 55 years of age have a 90% lifetime risk fordeveloping hypertension. (c) Individuals with a SBP of 120to 139 mm Hg or a diastolic BP of 80 to 89 mm Hg shouldbe considered as prehypertensive and require health-

promoting lifestyle modifications to prevent CVD. (d)Thiazide-type diuretics should be used in drug treatmentfor most patients with uncomplicated hypertension, eitheralone or combined with drugs from other classes. Certainhigh-risk conditions are compelling indicators for the initialuse of other antihypertensive drug classes (angiotensin-converting enzyme inhibitors, angiotensin-receptor block-ers, β-blockers, calcium channel blockers). (e) Most patientswith hypertension will require 2 or more antihypertensivemedications to achieve goal BP (b140/90 mm Hg, or b130/80 mm Hg for patients with diabetes or chronic kidneydisease). (f) If BP is more than 20/10 mm Hg above the goalBP, consideration should be given to initiating therapy with2 agents, 1 of which usually should be a thiazide-typediuretic” [40].

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