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Review

Blood Pressure Management in Acute Stroke: A Long-Standing Debate

Spengos K.a · Tsivgoulis G.a · Zakopoulos N.b

Author affiliations

aDepartment of Neurology, University of Athens School of Medicine, Eginition Hospital, and bDepartment of Clinical Therapeutics, University of Athens School of Medicine, Alexandra Hospital, Athens, Greece

Corresponding Author

Konstantinos¦Spengos¦Vasilissis Sofias 82¦11528¦Athens¦0030 6946 4662 16¦0030 210 674 2604¦spengos@hol.gr¦Greece

Related Articles for ""

Eur Neurol 2006;55:123–135

Abstract

Although elevated blood pressure (BP) levels are a common complication of acute stroke, whether of ischaemic or haemorrhagic type, a long-standing debate exists regarding the management of post-stroke hypertension. In the absence of solid, randomised data from controlled trials, the current observational evidence allows different approaches, since theoretical arguments exist for both lowering BP in the setting of acute stroke (reduce the risk of stroke recurrence, of subsequent oedema formation, of rebleeding and haematoma expansion in patients with cerebral bleeding) as well as leaving raised BP levels untreated (avoid reduction in cerebral perfusion pressure and blood flow to viable ischaemic tissue in the absence of normal autoregulation). The present review will summarize the evidence for and against the therapeutic manipulation of BP in acute stroke provided by the currently available observational studies and randomised trials, consider the ongoing clinical trials in this area and address the present recommendations regarding this conflicting issue.

© 2006 S. Karger AG, Basel


Keywords

Acute stroke · Blood pressure · Hypertension ·


Introduction

Elevated blood pressure (BP) as defined by the World Health Organization and the International Society of Hypertension (systolic BP >140 mm Hg and/or diastolic BP >90 mm Hg) is established as the most prevalent modifiable risk factor for stroke. Large-scale observational studies have demonstrated that BP values are positively and continuously associated with the risk of stroke in a log-linear fashion [1]. Significant advances in primary and secondary stroke prevention using various antihypertensive agents have been achieved recently. There is now clear evidence that BP reduction protects against first-ever, as well as recurrent stroke independent of baseline BP levels [2,3,4]. More specifically, systemic reviews of 17 primary prevention trials involving a total of 47,000 participants showed that lowering systolic BP (SBP) by 10–12 mm Hg and diastolic BP (DBP) by 5–6 mm Hg leads to a 38% reduction in the risk of stroke [2]. Furthermore, a recent meta-analysis of 7 secondary prevention trials involving 15,527 participants demonstrated that the use of BP-lowering agents reduced the risk of recurrent stroke by 24% [4].

Elevated BP values (>140/90 mm Hg) are present in up to 80% of patients with acute stroke [5, 6], while almost every fourth patient presents with markedly raised SBP values >180 mm Hg. There is no single explanation for the elevation of BP in acute stroke. The main contributing factors include pre-existing hypertension [7], activation of neuro-endocrine systems [8, 9], the stress of hospitalisation [10], infarct topography [11], stroke subtype [7, 12, 13], stroke severity [14] and the reactive increases in systemic BP in response to raised intracranial pressure [15].

Despite its high prevalence, the optimal management of arterial hypertension during the acute stroke stage has not been established and remains an issue of long-lasting debate and little consensus [15, 16]. Notably, the results of numerous observational studies, which investigated the relationship of admission BP levels with stroke outcome in patients with ischaemic stroke (IS; table 1) and intracerebral haemorrhage (ICH; table 2) are conflicting and data from randomised controlled studies are still missing [17, 18]. Aim of this review was not to answer this still open question, but to present a critical overview of all arguments pro and contra lowering BP in the acute setting of stroke on the basis of current observational and randomised evidence, consider the ongoing clinical trials in this area and address the present recommendations regarding this conflicting issue.

Table 1

Observational studies investigating the relationship between initial blood pressure (BP) values and short-term outcome (≤3 months) in patients with acute ischaemic stroke (IS)

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Table 2

Observational studies investigating the relationship between initial blood pressure (BP) values and short-term outcome (≤3 months) in patients with acute intracerebral haemorrhage (ICH)

http://www.karger.com/WebMaterial/ShowPic/277465

Search Criteria

Observational Studies

Systemic searches of PUBMED electronic database for published observational studies that reported baseline BP and early (<3 months) outcome (death, dependency, death or dependency, recurrent stroke, early neurological deterioration) were made by K.S. and G.T. The search strategy included the following key words: blood pressure, hypertension, acute, stroke, outcome, prognosis, death, mortality, intracerebral haemorrhage. Additional studies were also sought from references of identified studies and reviews [15,16,17,18,19,20]. Functional status in the identified studies was typically assessed by the modified Rankin Scale (mRS) and the Barthel Index (BI). Early neurological deterioration in the identified studies was invariable measured with the National Institutes of Health Stroke Scale (NIHSS), the Canadian Stroke Scale (CSS) and the Canadian Neurological Score (CNS). Published reports that presented insufficient data, used other outcome measures or were duplicate articles were excluded. Decisions on inclusion and exclusion of the observational studies were made by consensus of the three authors

Intervention Trials

Intervention trials (pilot preliminary trials, safety and feasibility studies and randomised controlled trials) that assessed the effect of BP-lowering medications during the first 2 weeks after stroke onset on early (<3 months) outcome were identified through systematic searches of PUBMED and Cochrane electronic databases by K.S. and G.T. The search strategy included the following key words: blood pressure, hypertension, acute, stroke, intracerebral haemorrhage, blood pressure lowering, blood pressure reduction, blood pressure elevation, induced hypertension, pilot trial, safety study, randomised controlled trial. Additional studies were also sought from references of identified studies and reviews [15,16,17,18,19,20]. Studies that evaluated the impact of BP reduction after the second week of ictus on secondary prevention of stroke and other vascular events were excluded. Published reports that were duplicate articles were not included in the present review. Decisions on inclusion and exclusion of the interventional trials were made by consensus of the three authors.

Results

Lowering Blood Pressure in Acute Stroke

Contras

Ischaemic Stroke

There is a series of arguments against treating hypertension in IS: (1) In the natural course of the disease BP values tend to normalise spontaneously within hours or days after IS onset[7, 13, 21, 22]. (2) Since the rescue of tissue at risk remains the main goal of acute IS treatment, keeping tissue perfusion pressure above a critical level within the ischaemic penumbra becomes of crucial importance. It is well known that cerebral autoregulation normally maintains perfusion over a wide range of systemic BP (fig. 1) and its curve is shifted towards higher BP values in chronic hypertensive individuals. During the acute phase of IS, cerebral autoregulation becomes dysfunctional and perfusion tends to be passively dependent on perfusion pressure [23]. Hence, it has been reasoned that BP should not be actively lowered in order to avoid any further reduction of the cerebral blood flow, with the possible sequelae of infarct extension and worsening of outcome [15, 24]. The degree of BP reduction in the first 24 h after stroke onset was independently associated with poor outcome in a series of patients with IS, who received antihypertensive treatment (59%) in the emergency department [25]. Moreover, it has been recently reported that a BP drop >20 mm Hg during the first hours of ictus, followed by the use of BP-lowering medications, was the most important prognostic factor for early neurological deterioration, increased infarct volume and mortality at 3 months [26]. Furthermore, the investigators of Intravenous Nimodipine West European Trial have demonstrated that aggressive BP reduction with high-dose intravenous nimodipine was associated with neurological worsening of acute stroke patients [27, 28]. The authors assumed that the profound DBP drop (>20%) in patients with already altered autoregulation may cause a further decrease in cerebral perfusion pressure and regional blood flow with deterioration of collateral supply below the lethal thresholds in the area of the ischaemic penumbra. (3) The course of elevated systolic BP in patients undergoing intra-arterial thrombolysis is inversely associated with the degree of vessel recanalisation. In a recent study, Mattle et al.[ 29] reported that, in patients where thrombolysis succeeded to reopen the occluded vessel, which was responsible for tissue ischaemia, SBP declined significantly faster in comparison to cases where recanalisation had failed. Based on the former observations it may be postulated that BP elevation might be a compensatory reaction to persistent vessel occlusion.

Fig. 1

Relationship between cerebral blood flow and mean arterial pressure under normal conditions and in ischaemia.

http://www.karger.com/WebMaterial/ShowPic/277461

Intracerebal Haemorrhage

The following arguments are in favour of not treating hypertension in the acute stage of ICH: (1) In the natural course of the disease increased BP declines to baseline values within the first days after ICH onset [7, 30]. (2) A zone of hypoperfusion in brain surrounding acute ICH has been reported in positron emission tomography (PET) studies [31, 32]. Consequently, it has been argued that overaggressive BP reduction has the potential to further decrease the cerebral perfusion pressure and theoretically worsen brain injury particularly in the setting of increased intracranial pressure [23]. The findings of a single-photon emission CT (SPECT) study demonstrating that drug-induced reductions of mean arterial pressure (MAP) in excess of 20% during the acute period of the ICH resulted in a decrease of regional cerebral blood flow (rCBF) are in keeping with the former hypothesis [33].

Pros

Ischaemic Stroke

The following arguments support the therapeutic manipulation of BP in the acute IS stage: (1) High BP levels in acute IS have been associated with subsequent death or dependency in a recent meta-analysis of observational studies investigating the association of BP with outcome [19]. (2) Sustained high BP values, assessed by means of ambulatory blood pressure monitoring have been associated with subsequent oedema formation [34], whereas casually documented elevated BP values have also been related to death resulting from presumed cerebral oedema in acute IS patients according to the results of the International Stroke Trial (IST) [35]. (3) Data from observational studies have suggested that increased admission BP values are related to early [35, 36] and late [37, 38] stroke recurrence.

Intracerebal Haemorrhage

Antihypertensive treatment is considered in patients with acute ICH on the basis of the subsequent arguments: (1) High BP levels in acute ICH have been associated with subsequent death, death or dependency and death or deterioration in a recent meta-analysis of observational studies investigating the association of BP with outcome [19]. (2) Increased acute BP values assessed by means of ambulatory blood pressure monitoring have been associated with cerebral oedema in ICH patients [14]. (3) Elevated BP values during the acute stroke stage have been shown to increase the risk of haematoma enlargement in patients with ICH [19, 39, 40]. (4) High admission BP values during the acute stage of ICH have been related to an increased rate of recurrent haemorrhagic stroke [41].

The U-Shaped Relationship between Acute BP Values and Stroke Outcome

Ischaemic Stroke

Some of the former pathophysiological facts and study findings support on the one hand the thesis of not applying – or even discontinuing previously initiated – antihypertensive treatment in the acute phase of stroke in order to avoid further infarct expansion and tissue necrosis. On the other hand, there is solid evidence suggesting that moderate BP lowering might be beneficial by reducing the risk of oedema formation, haematoma enlargement and stroke recurrence, improving this way survival and clinical outcome. Because of these conflicting issues and the lack of unambiguous data, the appropriate evidence-based approach to post-stroke hypertension remains to be settled [42, 43].

The U-shaped relationship between acute BP values and IS outcome might be an explanation for the discrepancy of findings and arguments. The IST was the first to demonstrate a U-shaped relationship between baseline SBP and both early death and late death or dependency in patients with IS [35]. Both high and low SBP values were independent prognostic factors for poor clinical outcome. This seemed to be attributed to the higher rates of early recurrence and cerebral oedema among patients with high BP, while low BP values (SBP <120 mm Hg) in the acute stroke setting have been associated with a severe clinical stroke (total anterior circulation syndrome) and an excess of deaths due to coronary heart disease [35]. Additionally, both low and high admission SBP and DBP values have been related to increased infarct volume [26]. A similar U-shaped relationship between admission SBP and DBP levels and early mortality among patients with acute IS has also been documented by two recent studies [44, 45]. The best outcome was observed in patients with normal or mildly elevated admission SBP (U point or nadir of the curve: 121–170 mm Hg) and DBP values (U point or nadir of the curve: 81–110 mm Hg), suggesting that both extremely high and low admission BP values are likely to affect outcome adversely.

Intracerebal Haemorrhage

The U-shaped curve relating acute BP values with outcome has also been confirmed in patients with ICH according to the results of a Greek [44] and a Japanese [45] hospital-based study, which demonstrated that both lower and higher BP levels following ICH were predictors for poor early prognosis.

Interpretation of Existing Trial Data

Ischaemic Stroke

Unfortunately, solid data from randomised controlled trials (RCTs) are limited and inconclusive when considering whether lowering BP during the first hours of ictus is beneficial or not in IS patients. More specifically no randomised data exist for central acting agents, alpha adrenergic receptor blockers or other vasodilators, such as hydralazine. The efficacy and safety of transdermal nitric oxide donors has been demonstrated by a small RCT that studied transdermal glyceryl trinitrate and found that it lowered BP by 5–8% in a stroke population that mainly consisted of patients with recent IS (33 of the 37 cases) [46]. A recent pilot RCT concluded that following acute IS, oral benflurazide, a thiazide diuretic, did not lower systemic BP levels over the subsequent 7-day period [47].

Though the Perindopril Protection Against Recurrent Stroke Study [48] and the Heart Outcomes Prevention Evaluation-HOPE [49] have evaluated the efficacy of perindopril and ramipril, respectively, in the risk reduction of recurrent stroke in patients with cerebrovascular disease, neither of these studies provides information that might help us to determine how acutely following stroke the angiotensin-converting enzyme inhibitors can be commenced safely. One small RCT found that oral perindopril reduced BP values by 11% without altering global cerebral blood flow or middle cerebral artery (MCA) blood flow velocity [50]. The Acute Candesartan Cilexetil Therapy in Stroke Survivors – ACCESS, a prospective double-blind, placebo-controlled, randomised phase II trial, evaluated the use of an angiotensin II receptor blocker in acute IS patients with severely elevated BP levels (SBP >180 mm Hg and/or DBP >105 mm Hg). Preliminary data from 342 patients demonstrated that oral candesartan reduced a composite secondary outcome (all-cause mortality and vascular events) by 52.5% [51]. It should be noted though that the trial was stopped prematurely with a neutral finding for its primary outcome (total mortality and disability at 3 months). Moreover, this preliminary observation remains to be confirmed by a larger phase III RCT [52].

In contrast, beta-blockers, such as propranolol and atenolol achieve a greater BP fall compared to placebo, but are characterised by a trend towards a worse outcome [20, 53]. The safety and feasibility of labetalol, a combined beta- and alpha-adrenergic antagonist, in rapidly and effectively reducing BP has been demonstrated in the NINDS thrombolysis trial [54]. Finally, the application of calcium channel antagonists during the acute stage of IS has no positive or negative effect on functional outcome or survival, according to a review of 29 RCTs [55] and the conclusions of a review from the Blood Pressure in Acute Stroke Collaboration (BASC) [20]. In addition, the INWEST trial demonstrated that the functional outcome was worsened in parallel with the degree by which BP was reduced [27, 28].

Intracerebal Haemorrhage

The existing trial data in the ICH subgroup is even scarcer. In a small survey of 10 critically ill haemorrhagic stroke patients (7 cases with ICH and 3 cases of subarachnoid haemorrhage) treated in a surgical intensive unit labetalol infusion produced a rapid and mild BP-lowering effect (SBP reduction ranging between 6 and 19%, DBP reduction ranging between 3 and 26%). This response did not worsen perceived mental status or stroke-induced neurologic deficits [56]. Nishiyama et al.[ 57] determined the effect of nicardipine infusion (titrated to maintain SBP levels between 120–160 mm Hg) on intracranial pressure, MCA flow velocity as well as the presence of brain oedema and haematoma rebleeding in 22 patients with putaminal ICH after surgical evacuation. Intracranial pressure decreased during the infusion without any change in MCA velocity or any evidence of rebleeding and exacerbation of cerebral oedema. Powers et al.[ 58] had also evaluated the impact of BP reduction in 14 patients with acute (6–22 h after onset) supratentorial ICH on rCBF measured by means of PET scan. MAP was reduced by 15% using either nicardipine or labetalol infusions. Interestingly, no significant difference in the perihaematomal rCBF or global CBF before and after treatment was observed. Lastly, Qureshi et al.[ 59] performed a multicenter prospective observational study to evaluate the feasibility and safety of intravenous antihypertensive protocol (infusion of labetalol and/or hydralazine and/or nitroprusside) for controlling SBP and DBP levels below 160 and 90 mm Hg, respectively, in 27 patients with acute ICH. The investigators documented a low rate of neurological deterioration (7.4%) and haematoma expansion (9.1%) in the treated patients. Furthermore, they noted that patients treated within 6 h from symptom onset were more likely to be functionally independent at 1 month compared with cases who were treated during the time window between 6 and 24 h.

Ongoing Trials

The results of currently ongoing trials may provide some answers to some of the former unresolved issues. The Control of Hypertension and Hypotension Immediately Post-Stroke Trial [60] is a randomised double-blind placebo-controlled study using stepwise angiotensin-converting enzyme inhibitors. Death and dependency at 2 weeks after stroke will be the primary outcome measure. The transdermal application of glyceryl trinitrate is evaluated in the Efficacy of Nitric Oxide in Stroke – ENOS – study [61]. Useful data about stroke patients who are already on antihypertensive medication are expected from the Continue or Stop Post-Stroke Antihypertensive Collaborative Study [62].

Raising Blood Pressure in Acute Stroke

Ischaemic Stroke

Feasibility, Safety and Preliminary Results of Induced BP Elevation. If BP lowering in the acute setting of stroke could have detrimental results, it could than be theoretically assumed that raising BP might be beneficial, especially in terms of saving tissue in the ischaemic penumbra. However, there is scarce randomised or observational evidence to support this practice. Rodorf et al.[ 63, 64] have reported that intravenous application of phenylephrine is safe and feasible based on the findings of two small pilot studies. Moreover, the investigators noted that the responders to vasopressors scored better in the NIHSS at discharge [64]. Norepinephrine infusion has also been used to induce hypertension in 19 acute IS patients with complete or subtotal MCA stroke and was associated with enhanced cerebral perfusion without any detrimental increases in intracranial pressure [65].

Selection of Candidate Patients for Induced BP Elevation. The results of a preliminary study showed that patients who were most likely to display functional gains with pressor therapy, were those with severe stenosis or occlusion of an internal carotid artery (ICA) and/or a MCA [64]. It is conceivable that induced BP elevation could be more beneficial in such cases, since the former stroke subgroup is the most likely to present with the largest perfusion-diffusion mismatch during the first hours of ictus. Furthermore, in an ambulatory BP-monitoring study that evaluated the early spontaneous time course of BP in IS subgroups of different etiology, a substantially steeper BP decline was documented in the large-artery-atherosclerotic stroke subgroup [14]. Finally, according to a recent pilot RCT pharmacological BP elevation in patients with acute IS and large perfusion-diffusion mismatch caused by occlusion or stenosis of ICA and/or MCA resulted in smaller tissue lesions, as these were visualised by means of perfusion weighted MRI on the third day after stroke onset [66]. The previous encouraging findings warrant a full-scale double-blind clinical trial to investigate the efficacy and risks of this type of intervention specifically in the subgroup of patients with carotid artery disease.

Intracerebal Haemorrhage

To the best of our knowledge no study had previously addressed the issue of raising low or normal BP levels in the setting of acute ICH.

Discussion

Limitations and Shortcomings of Observational Studies

The discrepancies between the results of the various observational studies may reflect underlying methodological problems such as BP levels measured by different observers, retrospective BP documentation and lack of data on how BP was recorded. As illustrated in tables 1 and 2, the variation in the time of BP measurements (ranging from a few hours to several days after stroke onset) may also account in part for the conflicting results. In addition, certain reports did not investigate the relationship of acute BP levels with stroke outcome separately in the IS and the ICH subgroup, others used highly selected patient groups participating in clinical trials [27, 28], while some investigators continued or initiated BP-lowering medications following admission [25, 26]. Furthermore, the study protocol of certain reports did not include CT scans routinely in all stroke patients [7, 67], while in a number of studies unconscious stroke patients and cases with atrial fibrillation were excluded [67,68,69]. Besides, functional disability and neurological impairment were evaluated by different outcome measures in the majority of the observational studies (tables 1, 2). Finally, in the IST, which is the study that involved by far the largest cohort of patients (n = 17,398), only a single measure of SBP was available for each patient [35]. Consequently, the relationship of DBP and its derivatives (MAP, pulse pressure) with outcome could not be evaluated.

Limitations and Shortcomings of Intervention Trials

Ischaemic Stroke

Certain limitations of the pilot trials that assessed antihypertensive treatment strategies in acute IS patients are worth pondering. For one, the time window for randomisation ranged from 24 [51] to 120 h[ 46] following stroke onset in these preliminary intervention studies. Consequently, the different degrees of BP reduction documented in the various antihypertensive drug classes should be acknowledged after taking into account the former confounder. Moreover, only in the ACCESS study all subjects received carotid ultrasound examination before randomisation, which resulted in the exclusion of subjects with severe stenosis and occlusion of the ICA [51]. Since patients with carotid artery disease present the highest perfusion-diffusion mismatch, even moderate BP reductions may result in substantial reductions in CBF and cause infarct expansion [24]. This safety issue should be taken into consideration in the design of future phase III trials. It is also noteworthy that during the placebo-controlled phase of the ACCESS study in the first 7 days following recruitment, BP levels were similar in patients treated with angiotensin II receptor blockers and patients receiving placebo. Consequently, the authors assumed that the beneficial effect of candesartan could be attributed to its neurohumoral inhibiting effects [51]. Further research is needed to resolve the underlying mechanisms by which angiotensin receptor blockers affect the cerebrovascular system. Finally, Doppler data in the majority of intervention trials [47, 50] support the hypothesis that a number of BP-lowering medications does not adversely affect CBF or alter cerebral haemodynamics in a clinically significant way. Other forms of brain imaging techniques such as SPECT or PET scanning are needed to further validate the previous findings and provide additional information on the effects of BP-lowering treatment on regional perfusion, particularly in the area surrounding the cerebral infarct.

Limited preliminary trials seem to support the alternative therapeutic approach of induced hypertension in specific subgroups of acute IS patients. Nevertheless, there are important arguments against raising BP during the acute IS stage. Although, drug-induced hypertension holds promise, this therapy may be associated with increased risk of brain oedema or haemorrhagic transformation of the cerebral infarction, while additional vasopressor-related complications may include cardiac ischaemia or arrhythmias [52]. Furthermore, it should be acknowledged that sympathomimetic agents tend to induce platelet activation, while it is noteworthy that the use of such drugs within nasal decongestants and in weight reduction programmes has been associated with the development of stroke and other vascular diseases [70]. Lastly, certain agents which raise BP (although this was not their intended effect) had unfavourable effects on stroke outcome in RCTs during the acute stroke period. More specifically, the administration of diaspirin cross-linked haemoglobin has been associated with raised BP levels during the first three days of ictus and worse outcome [71].

Intracerebal Haemorrhage

Certain important methodological issues should be addressed before interpreting the results of the trials that investigated the feasibility of BP-lowering medications in the setting of acute ICH. First, the rates of neurological deterioration and haematoma expansion were compared to unmatched patients with variable characteristics. Therefore, no direct comparisons can be made. Second, the small number of patients enrolled in the former studies raises concerns regarding the safety of aggressive pharmacological treatment of acute hypertension, especially after taking into consideration that nicardipine infusion was associated with decreased cerebral perfusion pressure in one trial [57], although the former reduction did not correlate with a poorer outcome. Third, there is a possibility that asymptomatic haematoma expansion may be undetected in certain cases, since repeat CT scans were not acquired consistently but at the discretion of treating physicians and were usually performed only in patients with clinical deterioration [59].

Recommendations – Conclusions

Ischaemic Stroke

The European Stroke Initiative (EUSI) [72] and the Stroke Council of the American Stroke Association [43, 52] have released updated scientific statements and guidelines regarding the management of hypertension in the setting of acute IS. Both authorities recommend that BP should not be lowered in IS patients who are not otherwise candidates for thrombolysis (grade C recommendation; supported by data from non-randomised concurrent cohort studies with historical controls or anecdotal case series). Threshold BP values demanding immediate medical interventions are recommended by consensus (table 3). More specifically, pharmacological intervention is indicated if repeated BP readings reveal SBP values >220 mm Hg and DBP >120 mm Hg. In patients eligible for thrombolytic therapy SBP values >185 mm Hg or DBP values >110 mm Hg should be actively treated and maintained at desired levels (<185/110 mm Hg) during and after rt-PA infusion. Situations that might require urgent antihypertensive therapy independent of BP levels include acute myocardial infarction, severe left ventricular heart failure, aortic dissection, acute renal failure, acute pulmonary oedema and hypertensive encephalopathy (table 4).

Table 3

Current guidelines for the management of blood pressure in the acute phase of ischaemic stroke

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Table 4

Indications for urgent antihypertensive therapy in patients with acute ischaemic stroke according to current guidelines

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In cases where acute therapeutic manipulation of BP is indicated, BP lowering should be done cautiously at a clinically significant and relevant degree (target of BP reduction ranging from 10 to 15%), in order to avoid profound (>20%) BP reductions that have been associated with neurological and functional worsening [27]. Parenteral agents such as labetalol, nicardipine or uradipil that are easily titrated and have minimal vasodilatory effects on cerebral blood flow are preferred (table 3). In certain cases with excessive DBP levels (>140 mm Hg), intravenous administration of sodium nitroprusside is recommended for adequate BP control, despite possible major adverse effects, such as reflex tachycardia and coronary artery ischaemia. The use of sublingual nifedipine should be avoided because of the risk of abrupt BP reduction and possible ischaemic steel [43, 72]. Finally, at present, drug-induced hypertension cannot be recommended for the treatment of most patients with IS [52].

Intracerebal Haemorrhage

Current recommendations for treatment of elevated BP levels in patients with acute ICH are more aggressive than those for cases with IS [42]. Accordingly, SBP and DBP levels should be maintained below 180 and 105 mm Hg, respectively (table 5). If antihypertensive treatment is indicated during the acute stage of ICH, then BP should be lowered carefully in a monitored setting with close and continuous observation of BP values and using an easily titrable, short-acting agent (such as labetalol, esmolol, enalapril or nicardipine). Theoretical concerns regarding the vasodilatory effects of sodium nitroprusside and its potential detrimental impact on intracranial pressure [73] limit its use only in patients with excessively high SBP (>230 mm Hg) and DBP (>140 mm Hg) levels. Extreme (>20%) reductions in BP levels ought to be avoided [32] and if SBP falls below 90 mm Hg the use of pressors is indicated [42].

Table 5

Current guidelines for the management of blood pressure in the acute phase of intracerebral haemorrhage [42]

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Perspectives

In the absence of solid data supporting the elevation or reduction of BP in patients with acute stroke, it is clear that evidence from RCTs is urgently required. These trials should have sufficient power and size to take into account: (1) different patient groups according to age, gender, stroke subtypes; comorbidities; (2) different treatment paradigms (increase or decrease BP, drug class, timing and route of therapeutic BP manipulation, continue or temporarily stop prior antihypertensive medications); (3) different treatment effects of antihypertensive drug classes (BP reduction, neurohumoral inhibitory effects); (4) other acute stroke treatment strategies (thrombolysis); (5) strict, clinically meaningful outcome measures, and (6) safety issues. Smaller studies are also needed to investigate the impact of vasoactive drugs in pathophysiological mechanisms underlying stroke, such as cerebral perfusion and haemostasis. The anticipated results of the currently ongoing phase III trials may clarify certain of the former issues regarding the optimal BP management in acute stroke and provide adequate scientific basis for more evidence-based treatment decisions in the moderately near future.


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    External Resources
  28. Ahmed N, Nasman P, Wahlgren NG: Effect of intravenous nimodipine on blood pressure and outcome after acute stroke. Stroke 2000;31:1250–1255.
  29. Mattle HP, Kappeler L, Arnold M, et al: Blood pressure and vessel recanalization in the first hours after ischemic stroke. Stroke 2005;36:264–268.
  30. Morfis L, Schwartz RS, Poulos R, Howes LG: Blood pressure changes in acute cerebral infarction and hemorrhage. Stroke 1997;28:1401–1405.
  31. Zazulia AR, Diringer MN, Videen TO, et al: Hypoperfusion without ischemia surrounding acute intracerebral hemorrhage. J Cereb Blood Flow Metab. 2001;21:804–810.
  32. Videen TO, Dunford-Shore JE, Diringer MN, Powers WJ: Correction for partial volume effects in regional blood flow measurements adjacent to hematomas in humans with intracerebral hemorrhage: implementation and validation. J Comput Assist Tomogr 1999;23:248–256.
  33. Kuwata N, Kuroda K, Funayama M, Sato N, Kubo N, Ogawa A: Dysautoregulation in patients with hypertensive intracerebral hemorrhage: a SPECT study. Neurosurg Rev 1995;18:237–245.
  34. Vemmos K, Tsivgoulis G, Spengos K, et al: Association between 24-h blood pressure monitoring variables and oedema formation in patients with hyperacute stroke. J Hypertens 2003;21:2167–2173.
  35. Leonardi-Bee J, Bath PM, Phillips SJ, Sandercock PA, IST Collaborative Group: Blood pressure and clinical outcomes in the International Stroke Trial. Stroke 2002;33:1315–1320.
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  39. Kazui S, Minematsu K, Yamamoto H, Sawada T, Yamaguchi T: Predisposing factors to enlargement of spontaneous intracerebral hematoma. Stroke 1997;28:2370–2375.
  40. Ohwaki K, Yano E, Nagashima H, Hirata M, Nakagomi T, Tamura A: Blood pressure management in acute intracerebral hemorrhage: relationship between elevated blood pressure and hematoma enlargement. Stroke 2004;35:1364–1367.
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  46. Bath PMW, Pathansali R, Iddenden R, Bath FJ: The effect of transdermal glyceryl trinitrate, a nitric oxide donor, on blood pressure and platelet function in acute stroke. Cerebrovasc Dis 2001;11:265–272.
  47. Eames PJ, Robinson TG, Panerai RB, Potter JF: Bendrofluazide fails to reduce elevated blood pressure levels in the immediate post-stroke period. Cerebrovasc Dis 2005;19:253–259.
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  50. Dyker AG, Grosset DG, Lees K: Perindopril reduces blood pressure but not cerebral blood flow in patients with recent cerebral ischemic stroke. Stroke 1997;28:580–583.
  51. Schrader J, Luders S, Kulschewski A, et al: Acute Candesartan Cilexetil Therapy in Stroke Survivors Study Group (2003). The ACCESS Study: evaluation of acute candesartan cilexetil therapy in stroke survivors. Stroke 2003;34:1699–1703.
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    External Resources
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  58. Powers WJ, Zazulia AR, Videen TO, et al: Autoregulation of cerebral blood flow surrounding acute (6 to 22 hs) intracerebral hemorrhage. Neurology 2001;57:18–24.
  59. Qureshi AI, Mohammad YM, Yahia AM, et al: A prospective multicenter study to evaluate the feasibility and safety of aggressive antihypertensive treatment in patients with acute intracerebral hemorrhage. J Intens Care Med 2005;20:34–42.
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  62. COSSACS Trial Group: COSSACS (Continue or Stop Post-Stroke Antihypertensives Collaborative Study): rationale and design. J Hypertens 2005;23:455–458.
  63. Rordorf G, Cramer SC, Efird JT, Schwamm LH, Buonanno FS, Koroshetz WJ: Pharmacological elevation of blood pressure in acute stroke: clinical effects and safety. Stroke 1997;28:2133–2138.
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  67. Robinson T, Waddington A, Ward-Close S, Taub N, Potter J: The predictive role of 24-hour compared to casual blood pressure levels on outcome following acute stroke. Cerebrovasc Dis 1997;7:264–272.
    External Resources
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Author Contacts

Konstantinos¦Spengos¦Vasilissis Sofias 82¦11528¦Athens¦0030 6946 4662 16¦0030 210 674 2604¦spengos@hol.gr¦Greece

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Published online: June 23, 2006
Issue release date: June 2006

Number of Print Pages: 13
Number of Figures: 1
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ISSN: 0014-3022 (Print)
eISSN: 1421-9913 (Online)

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  27. Wahlgren NG, MacMahon DG, de Keyser J, Indredavik B, Ryman T, INWEST Study Group: Intravenous Nimodipine West European Stroke Trial (INWEST) of nimodipine in the treatment of acute ischaemic stroke. Cerebrovasc Dis 1994;4:204–210.
    External Resources
  28. Ahmed N, Nasman P, Wahlgren NG: Effect of intravenous nimodipine on blood pressure and outcome after acute stroke. Stroke 2000;31:1250–1255.
  29. Mattle HP, Kappeler L, Arnold M, et al: Blood pressure and vessel recanalization in the first hours after ischemic stroke. Stroke 2005;36:264–268.
  30. Morfis L, Schwartz RS, Poulos R, Howes LG: Blood pressure changes in acute cerebral infarction and hemorrhage. Stroke 1997;28:1401–1405.
  31. Zazulia AR, Diringer MN, Videen TO, et al: Hypoperfusion without ischemia surrounding acute intracerebral hemorrhage. J Cereb Blood Flow Metab. 2001;21:804–810.
  32. Videen TO, Dunford-Shore JE, Diringer MN, Powers WJ: Correction for partial volume effects in regional blood flow measurements adjacent to hematomas in humans with intracerebral hemorrhage: implementation and validation. J Comput Assist Tomogr 1999;23:248–256.
  33. Kuwata N, Kuroda K, Funayama M, Sato N, Kubo N, Ogawa A: Dysautoregulation in patients with hypertensive intracerebral hemorrhage: a SPECT study. Neurosurg Rev 1995;18:237–245.
  34. Vemmos K, Tsivgoulis G, Spengos K, et al: Association between 24-h blood pressure monitoring variables and oedema formation in patients with hyperacute stroke. J Hypertens 2003;21:2167–2173.
  35. Leonardi-Bee J, Bath PM, Phillips SJ, Sandercock PA, IST Collaborative Group: Blood pressure and clinical outcomes in the International Stroke Trial. Stroke 2002;33:1315–1320.
  36. Sacco RL, Foulkes MA, Mohr JP, Wolf PA, Hier DB, Price TR: Determinants of early recurrence of cerebral infarction. The Stroke Data Bank. Stroke 1989;20:983–989.
  37. Hier DB, Foulkes MA, Swiontoniowski M, et al: Stroke recurrence within 2 years after ischaemic infarction. Stroke 1991;22:155–161.
  38. Tsivgoulis G, Spengos K, Zakopoulos N, Manios E, Vassilopoulos D, Vemmos K: Twenty-four-hour pulse pressure predicts long-term recurrence in acute stroke patients. J Neurol Neurosurg Psychiatry 2005;76:1360–1365.
  39. Kazui S, Minematsu K, Yamamoto H, Sawada T, Yamaguchi T: Predisposing factors to enlargement of spontaneous intracerebral hematoma. Stroke 1997;28:2370–2375.
  40. Ohwaki K, Yano E, Nagashima H, Hirata M, Nakagomi T, Tamura A: Blood pressure management in acute intracerebral hemorrhage: relationship between elevated blood pressure and hematoma enlargement. Stroke 2004;35:1364–1367.
  41. Arakawa S, Saku Y, Ibayashi S, Nagao T, Fujishima M: Blood pressure control and recurrence of hypertensive brain hemorrhage. Stroke 1998;29:1806–1809.
  42. Broderick JP, Adams HP Jr, Barsan W, et al: Guidelines for the management of spontaneous intracerebral hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke 1999;30:905–915.
  43. Adams HP Jr, Adams RJ, Brott T, et al: Stroke Council of the American Stroke Association. Guidelines for the early management of patients with ischemic stroke: A scientific statement from the Stroke Council of the American Stroke Association. Stroke 2003;34:1056–1083.
  44. Vemmos KN, Tsivgoulis G, Spengos K, et al: U-shaped relationship between mortality and admission blood pressure in patients with acute stroke. J Intern Med 2004;255:257–265.
  45. Okumura K, Ohya Y, Maehara A, Wakugami K, Iseki K, Takishita S: Effects of blood pressure levels on case fatality after acute stroke. J Hypertens 2005;23:1217–1223.
  46. Bath PMW, Pathansali R, Iddenden R, Bath FJ: The effect of transdermal glyceryl trinitrate, a nitric oxide donor, on blood pressure and platelet function in acute stroke. Cerebrovasc Dis 2001;11:265–272.
  47. Eames PJ, Robinson TG, Panerai RB, Potter JF: Bendrofluazide fails to reduce elevated blood pressure levels in the immediate post-stroke period. Cerebrovasc Dis 2005;19:253–259.
  48. PROGRESS Collaborative Group: Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet 2001;358:1033–1041.
  49. Bosch J, Yusuf S, Pogue J, et al: HOPE Investigators. Heart outcomes prevention evaluation: use of ramipril in preventing stroke: double blind randomised trial. Br Med J 2002;324:699–702.
  50. Dyker AG, Grosset DG, Lees K: Perindopril reduces blood pressure but not cerebral blood flow in patients with recent cerebral ischemic stroke. Stroke 1997;28:580–583.
  51. Schrader J, Luders S, Kulschewski A, et al: Acute Candesartan Cilexetil Therapy in Stroke Survivors Study Group (2003). The ACCESS Study: evaluation of acute candesartan cilexetil therapy in stroke survivors. Stroke 2003;34:1699–1703.
  52. Adams H, Adams R, Del Zoppo G, Goldstein LB: Stroke Council of the American Heart Association; American Stroke Association (2005). Guidelines for the early management of patients with ischemic stroke: 2005 guidelines update a scientific statement from the Stroke Council of the American Heart Association/American Stroke Association. Stroke 2005;36:916–923.
  53. Barer DH, Cruickshank JM, Ebrahim SB, Mitchell JR: Low dose beta blockade in acute stroke (‘BEST’ trial): an evaluation. Br Med J 1998;296:737–741.
    External Resources
  54. Brott T, Lu M, Kothari R, et al: Hypertension and its treatment in the NINDS rt-PA Stroke Trial. Stroke 1998;29:1504–1509.
  55. Horn J, Limburg M: Calcium antagonists for ischemic stroke: a systematic review. Stroke 2001;32:570–576.
  56. Patel RV, Kertland HR, Jahns BE, Zarowitz BJ, Mlynarek ME, Fagan SC: Labetalol: response and safety in critically ill hemorrhagic stroke patients. Ann Pharmacother 1993;27:180–181.
  57. Nishiyama T, Yokoyama T, Matsukawa T, Hanaoka K: Continuous nicardipine infusion to control blood pressure after evacuation of acute cerebral hemorrhage. Can J Anaesth 2000;47:1196–1201.
  58. Powers WJ, Zazulia AR, Videen TO, et al: Autoregulation of cerebral blood flow surrounding acute (6 to 22 hs) intracerebral hemorrhage. Neurology 2001;57:18–24.
  59. Qureshi AI, Mohammad YM, Yahia AM, et al: A prospective multicenter study to evaluate the feasibility and safety of aggressive antihypertensive treatment in patients with acute intracerebral hemorrhage. J Intens Care Med 2005;20:34–42.
  60. Potter J, Robinson T, Ford G, et al: The CHHIPS Trial Group. CHHIPS (Controlling Hypertension and Hypotension Immediately Post-Stroke) Pilot Trial: rationale and design. J Hypertens 2005;23:649–655.
  61. Bath PM, Willmot MR, Weaver C, Leonardi-Bee J: Efficacy of nitric oxid in stroke (ENOS) trial – a prospective randomised controlled trial in acute stroke. Cerebrovasc Dis 2002;13(suppl 3):79.
  62. COSSACS Trial Group: COSSACS (Continue or Stop Post-Stroke Antihypertensives Collaborative Study): rationale and design. J Hypertens 2005;23:455–458.
  63. Rordorf G, Cramer SC, Efird JT, Schwamm LH, Buonanno FS, Koroshetz WJ: Pharmacological elevation of blood pressure in acute stroke: clinical effects and safety. Stroke 1997;28:2133–2138.
  64. Rordorf G, Koroshetz WJ, Ezzeddine MA, Segal AZ, Buonanno FS: A pilot study of drug induced hypertension for treatment of acute stroke. Neurology 2001;56:1210–1213.
  65. Schwarz S, Georgiadis D, Aschoff A, Schwab S: Effects of induced hypertension on intracranial pressure and flow velocities of the middle cerebral arteries in patients with large hemispheric stroke. Stroke 2002;33:998–1004.
  66. Hillis AE, Ulatowski JA, Barker BP, et al: A pilot randomized trial of induced blood pressure elevation: effects on function and focal perfusion in acute and subacute stroke. Cerebrovasc Dis 2003;16:236–246.
  67. Robinson T, Waddington A, Ward-Close S, Taub N, Potter J: The predictive role of 24-hour compared to casual blood pressure levels on outcome following acute stroke. Cerebrovasc Dis 1997;7:264–272.
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