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Trends in Anaesthesia and Critical Care 3 (2013) 31e36

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Trends in Anaesthesia and Critical Care

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REVIEW

Antihypertensive therapy in acute cerebral haemorrhage

Edoardo De Robertis*, Giovanni Marco Romano, Geremia Zito Marinosci, Giuseppe Servillo,Rosalba TufanoDepartment of Surgical, Anaesthesiological, Intensive Care Medicine, and Emergencies Sciences, University of Naples Federico II, 80131 Naples, Italy

Keywords:Blood pressureHypertensionIntracerebral haemorrhageICH growthOutcome

* Corresponding author. Dept. of Anaesthesia, UniveS. Pansini 5, 80131 Naples, Italy. Tel.: þ39 081 746355

E-mail address: ederober@unina.it (E. De Robertis

2210-8440/$ e see front matter � 2012 Elsevier Ltd.http://dx.doi.org/10.1016/j.tacc.2012.12.001

s u m m a r y

Spontaneous intracerebral haemorrhage (ICH) is one of the most serious and devastating neurologicalemergencies inflicting both a social and economic burden on modern society. Despite having a highmorbidity and mortality, the treatment available is mainly supportive and the outcome remains poor.The acute hypertensive response following ICH appears to be detrimental due to the possible contri-bution of high blood pressure (BP) in rebleeding and haematoma enlargement. Early antihypertensivetherapy is believed to limit haematoma growth and improve patient outcome, but the effectiveness andsafety of this treatment are still debated. However, we are starting to collect enough evidence on theimportance of a strict control of BP after acute ICH.

� 2012 Elsevier Ltd. All rights reserved.

1. Introduction

Stroke is the third largest cause of death after cardiovascular andcancer diseases in the US and it is the leading cause of serious, long-term disability.1 It represents a major public health issue due tohealthcare costs, such as inpatient care, rehabilitation, follow-upand the loss of patients from the workforce.2 Stroke is caused byischaemia, haemorrhage and subarachnoid haemorrhage. Intrace-rebral haemorrhage (ICH) is recognised as the least treatable formof stroke and by virtue of this fact, it carries the highest risk ofmortality and poor long-term outcome.3 Primary ICH is defined asspontaneous bleeding in the brain parenchyma which may extendto the ventricles though rarely into the subarachnoid space. It is theconsequence of a rupture in small, penetrating vessels, usuallycaused by chronic hypertension and less frequently by amyloidangiopathy. Intracranial tumours, vascular malformation, trauma,or coagulopathy account for most cases of secondary ICH.4 Hyper-tension represents a significant risk factor for primary ICH,5 and itappears to influence negatively the outcome in patients affected byacute ICH.6 At the same time, there is much uncertainty about theusefulness and safety of an early use of antihypertensive therapy inthe acute phase of the bleeding, attributable to a lack of strongevidence demonstrating a real benefit from this treatment. Thepurpose of this review is to focus on the role of high BP in acutespontaneous ICH, particularly the effect of the hypertensive

rsity of Naples Federico II, Via0.).

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response on haematoma enlargement and outcome, and it willanalyse the current evidence concerning antihypertensive therapy.

2. Epidemiology and risk factors

Primary ICH is responsible for 6.5e19.6% of all stroke cases,7

with lower proportional frequency in high-income countries(where ICH represents approximately 10% of all strokes) than inlow-/middle-income countries (where ICH is about 20% of allstrokes).8 Overall, the ICH incidence is reported to be 24.6 per100,000 personeyears (95% CI 19.7e30.7),9 with a tendency toincrease progressively with each decade of life.7 There was nodecrease in the incidence rate between 1980 and 2006 and thisactually increased for east and southeast Asian people.9 Currently,1-month case fatalities are estimated to be between 25 and 35%for high-income countries and 30e48% for low-/middle-incomecountries.8 ICH imposes an enormous economic burden onhealthcare costs, in terms of direct costs, consequential to patientsmedical care, and indirect costs, associated with lost workproductivity.2 Hypertension is the most important and powerfulmodifiable risk factor for spontaneous ICH5,10 and recurrence11;high alcohol intake, low serum cholesterol, current smoking, dia-betes and waist-to-hip ratio have been shown to increase the risk.12

Non-modifiable risk factors include age andmale gender.13 Patientswith untreated or uncontrolled hypertension have a significantlyhigher risk of intracerebral bleeding.14,15 Chronic hypertensionleads to a weakening, degeneration and fibrinoid necrosis of smalland penetrating vessels, which can be subjected to a spontaneousrupture.16 Hypertensive ICH typically occurs in the basal ganglia

Table 1Independent predictors of haematoma expansion.

Neuroradiological predictors Reduced time interval from symptomonset to the first CT scan27,28

Haematoma volume on presentation27

Intraventricular invasion27

Heterogeneity of haematoma densityon admission CT29

Contrast extravasation seen onCT-angiography (CT-A spot sign)30

Clinical predictors Early neurological deterioration31

Laboratory parameterspredictors

Elevated interleukin-632

Reduced platelet activity33

E. De Robertis et al. / Trends in Anaesthesia and Critical Care 3 (2013) 31e3632

(putamen, thalamus, or caudate) and less frequently in the pons,cerebellum, or within the deep hemispheric white matter.4 Anti-hypertensive treatment is probably the most effective way of pre-venting ICH. The incidence of hypertension-associated ICH inOxfordshire has fallen over the past 25 years (but not in the overallnumber of cases in older age-groups, in part due to a rise in theantithrombotic-related ICH) in association with increased use ofpreventive treatments.17 The Systolic Hypertension in the ElderlyProgram (SHEP) study18 reported that treatment of isolated systolichypertension in the elderly decreased the risk of ICH by approxi-mately 50%; such a protective effect was more marked for hae-morrhagic stroke than for ischaemic stroke. Moreover, theperindopril protection against recurrent stroke study (PROGRESS)19

investigated the effect of a blood pressure lowering regimen, basedon an angiotensin-converting enzyme inhibitor (perindopril)associated with or without a diuretic (indapamide), to preventrecurrent strokes in hypertensive and non-hypertensive patients.Compared to placebo, patients treated with the antihypertensivetherapy showed a reduction in the overall relative risk (RR) ofrecurrent stroke of 28% (95% CI 17e38), whilst the RR of recurrenceof ICH in patients treated with the antihypertensive therapy wasreduced by 50% (95% CI 26e67), with a lower risk for combinationtherapy (perindopril þ indapamide). Benefits in hypertensive andnon-hypertensive participants were similar. The PROGRESS trialshowed that the antihypertensive treatment had protective andbeneficial effects particularly against haemorrhagic stroke,providing evidence of the important role of high BP in ICHrecurrence.

3. Pathophysiology and outcome predictors

ICH is adynamicallyevolvingprocess. Tissue dissection andbrainherniation represent the primary mechanism of brain injury; peri-haematomal oedema (PHE), haematoma enlargement and cellulartoxicity of blood products act as secondary mechanisms ofdamage.20 Outcome and clinical deterioration of patients with ICHare mostly influenced by haematoma growth,21,22 whilst the role ofPHE is less clear.23 Other independent predictors for 30 daymortality include large ICH volume, Glasgow Coma Scale score,older age, intraventricular haemorrhage, and infratentorial loca-tion.24 Haematoma expansion (HE), which is defined as an increaseof 33e50% in the haematoma volume or an absolute change inhaematoma volume of 12.5e20 ml on repeat CT,25 occurs withina few hours after symptom onset or within the next 24 h.26 HErepresents a common and severe complication of ICH whichcontributes to midline shift, accelerates neurological deterioration,and is associated with poor outcome.23 The mechanisms leading tohaematoma growth are not fully understood; it has been proposedthat a sudden increase in intracranial pressure (ICP), which causesa local tissue distortion and vascular engorgement, associated witha bloodebrain barrier disruption, leads to a multifocal bleedingprocess from the periphery of the existing clot, resulting in HE.25

Davis et al.22 performed a pooled individual patient meta-analysisdefining the role of HE in predicting outcome. The authors re-ported that any HE occurred in about 73% of patients and a signifi-cant growth (�33% volume increase) occurred in about 30%. Foreach 10% increase in ICH growth, the hazard rate of dying increasedby 5% and patients were 18% more likely to worsen from indepen-dence to assisted independence or from assisted independence topoor outcome. Certain independent predictors seem to correlatewith HE (Table 1), whilst the relationship between the latter and BPis controversial. The INTERACT (Intensive blood pressure reductionin acute cerebral haemorrhage) trial34 is the largest randomised andmulti-centre trial which compared intensive (target systolic BP:140 mmHg) versus standard guideline-based (target systolic BP:

180 mmHg) blood pressure reduction within the first 6 h in 404patients with acute ICH. Patients were randomly assigned to eachgroup and treated with a stepped intravenous protocol to lower BP.The primary efficacy endpoint was a proportional change in hae-matomavolume at 24h; secondaryefficacy outcomeswere absoluteand substantial growth of the haematoma and of the haematomaplus any intraventricular haemorrhage. The INTERACT trial hasshown that an intensive lowering of blood pressure is feasible andsafe, and has a positive impact on reducing HE, but at the same timedoes not affect the outcome34; however, it was not powered todetect clinical outcomes. On the other hand, a post-hoc analysis35 ofthe data from the ATACH (Antihypertensive Treatment of AcuteCerebral Hemorrhage) trial36 has shown no significant relationshipbetween systolic BP (SBP) reduction and HE. This trial was notdesigned to assess HE as the primary endpoint and was not suffi-ciently powered to analyse it.37 The Cincinnati study21 failed toprovide anyevidence of baseline BP elevations inpredictingHE. Alsoan exploratory analysis from a randomised study of the rFVIIa didnot find any association between BP and haematoma growth.27 Onthe other hand, a retrospective study38 demonstrated that high SBPincreased the risk of haematoma growth, whilst two studies39,40

reported no association (Table 2). Accordingly, there is no clearevidence concerning whether elevated BP is the cause or conse-quence of HE: in fact, high BP could be an attempt to maintaincerebral blood flow (CBF) in the presence of raised ICP. Peri-haematomal brain oedema develops early and tends to evolve overtime. Early PHE is due to the vasogenic effect of osmotic activesubstances (proteins, electrolytes) from the clot. It begins immedi-ately after bleeding and peaks at 4e5 days.41 Delayed oedemadevelops a few days post-ictus, involving the activation of thecoagulation cascade and thrombin production,42 which is followedby erythrocyte lysis and haemoglobin mediated neurotoxiceffects.43 The role of PHE in predicting outcome in patients withintracerebral bleeding is still controversial.25 In the INTERACT trial,the PHE was strongly related to the size of the underlying haema-toma but at the same time did not appear to have any independenteffect in determining the outcome.44 Moreover, an analysis of theINTERACT study,45 showed that an early intensive BP-lowering didnot have any appreciable effects on PHE reduction. In another study,relative oedema (oedemavolumedividedbyhaematomavolume) inthe first few hours after ICH predicted good outcome (odds ratio,0.09; 95% CI, 0.01e0.64).46 Elevated SBP valueswithin 24 h from ICHonset seem to be associated with subsequent brain oedemaformation.47 A post-hoc analysis36 of the data from the ATACH trial(with the limitations aforementioned) failed to provide a relation-ship between SBP lowering andperihaematomal oedema reduction.

4. Effect of elevated blood pressure on outcome: acutehypertensive response

Elevated blood pressure is a common physiological responseafter stroke.48 The acute hypertensive response (BP � 140/

Table 3High blood pressure and outcome.

Reference Year ofpublication

Number ofpatients

Association between BPand outcome

Zhang et al.51 2008 1760 Combined death and disability/dependency (during hospitalisation)was associated with high BP (forSBP between 160 and 179 mmHgOR was 1.42; 95% CI, 1.00e2.03)

Okumura et al.53 2005 1097 Relative risk of death within30 days for SBP between 170and 189 mmHg was 1.65(95% CI, 0.98e2.77%)

Willmot et al.6 2004 10,892 Combined death or dependencywas associated with SBP >

150 mmHg (OR, 2.69; 95% CI,1.13e6.40)

Vemmos et al.54 2004 121 A U-shaped relationship wasfound between outcome (1 month,12 months mortality rates) andadmission SBP. The nadir SBPlevel ranged between141 and 160 mmHg

Fogelholm et al.55 1997 425 High first-day MAP (especiallyif >145 mmHg) worsened the28-day survival rate

Dandapani et al.52 1995 87 Patients with marked elevationof BP (defined as an MAP>145 mmHg) had higher mortalityrate and severe morbidity thanthose patients with lesser degreesof BP elevation

BP: blood pressure; SBP: systolic blood pressure; MAP; mean arterial pressure.

Table 2Relationship between high blood pressure and haematoma growth.

Reference (year ofpublication)

Number ofpatients

Definition of HEin relation tobaseline volume

Baseline CT (hoursfrom symptomsonset to first CT)

Second CT (hoursfrom baseline CT)

Relationship betweenhigh BP and HE

Type of study

Brott et al.21 (1997) 103 >33% �3 1 No association was demonstratedbetween HE and BP

Prospective observationalstudy

Kazui et al.28 (1997) 186 �12.5 cm3 �24 �96 SBP at admission �200 mmHg wasassociated with HE

Retrospective study

Ohwaki et al.38 (2004) 76 �140% or �12.5 cm3 NS �24 Maximum SBP between the baselineand second CTs was the factor mostsignificantly associated with HE

Retrospective study

Jauch et al.40 (2006) 98 �33% �3 1 BP was not associated with HE Post-hoc analysisBroderick et al.27 (2007) 399 �33% or �12.5 ml �3 �24 HE was not related to baseline BP Exploratory analysisMartí-Fàbregas et al.39

(2008)60 �33% �6 �42 No association between BP and HE

within the first 24 h after an acute ICHObservational study

Anderson et al.34 (2008) 404 �33% or �12.5 ml �6 �24 A rapid management of BP-loweringseemed to attenuate HE

Randomised pilot trial

Qureshi et al.35 (2010) 60 �33% �6 �24 No significant relationship betweenSBP reduction and HE

Post-hoc analysis

BP: blood pressure; HE: haematoma enlargement; ICH: intracerebral haemorrhage; SBP: systolic blood pressure; MAP: mean arterial pressure; NS: not specified.

E. De Robertis et al. / Trends in Anaesthesia and Critical Care 3 (2013) 31e36 33

90 mmHg) in stroke patients tends to attenuate in a few hours/days, with high BP values associated with a worse outcome.49 Ina large cross-sectional study, Qureshi et al.50 reported elevated SBP(�140 mmHg), with 75% of the patients presenting with ICH in theemergency department. However, patients with primary ICHfrequently show a history of longstanding chronic hypertensionand consequently, elevated BP at admission could merely bea reflection of the untreated hypertension.49 Perhaps, elevated BPin acute ICH has multifactorial aetiology and mechanisms such asa compensatory response to increased ICP (Cushing reflex), a stressresponse leading to an abnormal sympathetic activity, an alteredparasympathetic activity, raised levels of circulating catechol-amines and brain natriuretic peptide, could contribute to thehypertensive response.50 The effect of elevated BP on outcome inpatients affected by ICH seems to be supposedly remarkable. Maybe, high BP contributes to HE formation as well as the developmentof perihaematomal cerebral oedema. A recent systematic review6

involving 32 studies and 10,892 patients has shown that high BPvalues at admission in the acute phase of ICH are associated witha poor outcome, assessed either as death or as combined death ordisability. In this study, patients with high SBPwere almost twice aslikely to have HE. Furthermore, a positive and significant associa-tion between admission BP and outcome (death and/or disability)has been shown in acute haemorrhagic stroke patients in InnerMongolia, China.51 A retrospective study52 involving 87 patientswith ICH found that marked elevation of BP (defined asa MAP > 145 mmHg) was associated with higher mortality andsevere morbidity than a lesser degree of BP elevation; an effectiveBP-lowering in the acute phase of ICH appeared to have a favour-able effect on prognosis. Okumura et al.53 in a retrospective studyinvolving 1097 patients with brain haemorrhage found a J-shapedrelationship between admission SBP levels and mortality(unchanged after adjustments for age, sex, consciousness andhaemorrhage), with a nadir SBP level ranging between 150 and169 mmHg. On the other hand, a prospective study54 conducted inGreece involving a total of 1121 patients admitted within 24 h fromstroke onset (of whom 191 had ICH), has shown a U-shaped rela-tionship between early (1 month)/late (12 months) mortality ratesand admission SBP values in patients with ICH. The nadir SBP levelranged between 141 and 160 mmHg. A poor outcome was alsoobservable for SBP levels �140 mmHg. Most probably, certainpotential confounding factors, such as premorbid BP status, drugtherapy, age, patient eligibility, criteria for defining high BP andmethods for its measurement, represent a limitation in all the

aforementioned studies (Table 3), highlighting the need forprospective randomised controlled studies to investigate thismatter.

5. Antihypertensive therapy

Despite active and considerable research, the treatment of ICHremains mainly supportive, in as much as there is still nosubstantial evidence demonstrating a real benefit from anymedicalor surgical treatment. In such a context, patient outcome isgenerally poor. The STICH (Surgical Trial in IntraCerebral Haemor-rhage) trial56 has failed to provide any overall benefit of an early

E. De Robertis et al. / Trends in Anaesthesia and Critical Care 3 (2013) 31e3634

surgical clot evacuation compared with initial conservative treat-ment in patients with ICH (except for lobar clots>30 ml and within1 cm of the cortical surface), showing disappointing results of thesurgical approach. Results from the phase II of a randomised,placebo-controlled trial showed that treatment with the haemo-static agent rFVIIa, not only led to a reduction in HE, but alsosignificantly reduced mortality and improved functional outcomewith a modest increase in the risk of thromboembolic complica-tions.57 However, the phase 3 study of the Factor Seven for AcuteHaemorrhagic Stroke Treatment (FAST) trial58 despite showinga statistically significant reduction in HE in patients treated withrFVIIa, did not provide any beneficial effect on the primaryendpoint (death or severe disability). A post-hoc analysis of theFAST data suggested a potential benefit of rFVIIa in a subset of ICHpatients.59 Current American Heart Association/American StrokeAssociation (AHA/ASA) guidelines for the management of sponta-neous ICH60 do not recommend the use of rFVIIa or the surgicalremoval of clots in unselected patients. On the other hand, thepossible presence of a perihaematomal ischaemic zone has beena major issue of concern against using antihypertensive therapy.61

In fact, the pharmacological lowering of BP has been hamperedby the belief that a further decrease in cerebral perfusion pressurewould have adversely affected the ischaemic penumbra. Neuro-imaging studies62,63 have shown that perihaematomal hypo-perfusion is linked to a reduced metabolic demand64 rather thantissue ischaemia, providing evidence against a perihaemorrhagicpenumbra. Even though the autoregulation of CBF could beimpaired by an increased ICP and by the brain insult in patientswith ICH, a pharmacologic reduction of mean arterial pressure(MAP) does not seem to negatively influence CBF in regions aroundor distant to the haematoma.65 Thus, these findings linked to theexistence of a peri-clot zone with reduced metabolic demand,allows for a less risky use of antihypertensive treatment in patientswith spontaneous ICH. Moreover, reducing BP can be accomplishedwithout increasing the risk of neurological deterioration and itmight improve the outcome.66 The ATACH trial36 has investigatedthe feasibility and acute safety of three tiers of SBP reduction (tier 1:target SBP 170e200 mmHg, tier 2: target SBP 140e170 mmHg, tier3: target SBP 110e140 mmHg) with nicardipine infusion, in 60patients with supratentorial intracerebral haemorrhage within 6 hof symptom onset. The observed proportions of neurologicaldeterioration and serious adverse events were below the pre-specified safety thresholds, and the 3-month mortality rate waslower than expected in all SBP tiers. However, the incidence ofneurological deterioration increased progressively across the threetiers (6%, 10%, and 18%, respectively), with tier 3 showing thehighest incidence of neurological deterioration, serious adverseevents and symptomatic HE. The INTERACT trial34 has shown thefeasibility and safety of an intensive BP-lowering regimen; thelatter led to a significant reduction in HE without an increase in therate of neurological complications. Certainly, many questionsremain unresolved and some perplexities can arise concerning thesafety and utility of reducing BP. Is there any real benefit gainedfrom reducing the BP? What is the best time to start the antihy-pertensive therapy, and for how long should it be maintained?What is the ideal BP we need to achieve? The ATACH267 andINTERACT268 trials are currently underway and could answer someof these questions. In the meantime, it is prudent to follow AHA/ASA guidelines,60 which suggest:

� if SBP is >200 mmHg or MAP is >150 mmHg, consideraggressive reduction of BP with continuous infusion of drugs,and monitor BP frequently (every 5 min).

� if SBP is >180 mmHg or MAP is >130 mmHg and there isevidence or suspicion of elevated ICP, consider monitoring ICP

and reduce BP using intermittent or continuous infusion ofmedications to keep CPP �60 mmHg.

� if SBP is >180 mmHg or MAP is >130 mmHg and there is noevidence or suspicion of elevated ICP, consider a modestreduction in BP (e.g. MAP of 110 mmHg or target BP of 160/90 mmHg) using intermittent or continuous infusions ofmedication to control it and clinically re-examine the patientevery 15 min.

� in patients presenting a systolic BP of 150e220 mmHg, acutelowering of systolic BP to 140 mmHg is probably safe.

Drugs which may be considered for reducing BP are labetalol,hydralazine, nitroglycerine, sodium nitroprusside, nicardipine,esmolol and enalapril.69 New intravenous medications have beendeveloped for the control of high BP: Clevidipine is the first third-generation dihydropyridine calcium channel blocker under studyfor the treatment of severe hypertension, with selectivity for arte-riolar vasodilatation. The molecule presents favourable pharma-cokinetic characteristics: extremely rapid onset of effect, ultrashortaction, ease of titration, metabolism via blood and tissue esterases,without the need for dose adjustment in patients with renal orhepatic impairment.70 Studies are needed to confirm its safety andeffectiveness in patients with ICH.

6. Conclusion

Reducing BP earlymay be beneficial in preventing complicationssuch as rebleeding and haematoma growth. Moreover, it seems thatthere is a direct relationship between BP values at admission andoutcome in patients affected by ICH. Finally, there are still somequestions about the efficacy and safety of antihypertensive therapywhose answers could be given by randomised trials currentlyunderway.

Conflict of interest

No conflicts of interest declared.

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