Management of blood pressure in acute stroke

Philip Bath

DEFINITIONS

HYPERTENSION

Essential hypertension is defined by the World Health Organization as a systolic blood pressure >140 mmHg and, as such, includes around 40% of populations (depending on age) in the western world.¹ However, more than three-quarters of patients presenting with acute stroke have a blood pressure which exceeds this (Table 8.1); hence, this cutoff can be considered non-discriminatory and too low. A recent survey of stroke-interested physicians suggested a boundary of 200/110 mmHg in acute stroke,² a figure which would include less than 10% of patients (Table 8.1) and is therefore too high to be useful. Since the risk of a poor outcome after stroke starts to rise at blood pressure levels above 180/100 mmHg (see below^3–5), this may be an appropriate and clinically useful working definition.

HYPOTENSION

Less attention has been paid to the issue of low blood pressure in acute stroke. Taking the pragmatic view used for defining hypertension above, a poor outcome after stroke appears to be associated with admission blood pressure levels below 120/80 mmHg, although this is present in less than 5% of patients (see Table 8.1).

INCIDENCE AND NATURAL HISTORY OF BLOOD PRESSURE IN ACUTE STROKE

HYPERTENSION

Blood pressure is elevated in 70–94% of patients with acute stroke,^4–7 depending on the definition used and population studied. Rapid falls in blood pressure occur over the first hours⁸ and normotension is achieved in two-thirds of individuals over the first week.^6,9,10 In spite of this downward trend during the acute and subacute phase of stroke, great variations can occur from moment to moment (Fig. 8.1). As with most aspects related to blood pressure, the magnitude of decline is proportional to the initial level.¹¹ Persisting hypertension should be treated, e.g. with a diuretic or angiotensin-converting enzyme (ACE) inhibitor,^12–14

for the purposes of secondary stroke prevention; drug therapy should not be initiated or restarted for at least a week when stable levels are achieved.

Table 8.1 Frequency of systolic blood pressure at enrollment into acute stroke trials Systolic blood pressure (mmHg) International Stroke Trial⁴ (%) (n=17

398)

Blood Pressure in Acute Stroke Collaboration⁵ (%) (n=3470)

<120 4.2 4.7

120–139 14.2 17.5

140–159 27.9 29.4

160–179 26.1 25.9

180–199 16.9 14.7

>200 10.7 7.8

HYPOTENSION

A low blood pressure (systolic blood pressure <120 mmHg) is present in less than 5% of patients.^4,5 Although its natural history is not known, this is most likely to be determined by the underlying cause (see next section).

CAUSES OF HYPERTENSION AND HYPOTENSION IN ACUTE STROKE

Many factors are associated with hypertension, in particular stroke type (primary intracerebral hemorrhage, PICH) and a prior history of hypertension (Table 8.2).¹⁵ Some factors are likely to be causative—such as activation of neurohormonal systems (corticotropic, sympathetic, renin- angiotensin) or reduced vascular Figure 8.1 Incidence of blood pressure in acute stroke.

nitric oxide synthesis—and therefore offer potential and selective targets for treatment. Blood pressure control is modulated by a number of brain centers and it has been proposed that damage to one or more of these, especially the right insular cortex, might alter blood pressure;¹⁶ more recent data suggest that this is not the case.¹⁷

Hypotension most commonly seems to be associated with the presence of concurrent conditions which themselves cause low blood pressure, especially heart disease or infection (Table 8.2).

BLOOD PRESSURE AND OUTCOME AFTER ACUTE STROKE

HYPERTENSION

Many studies,^3,18–22 but not all,^23–25 have shown that hypertension during the acute phase of ischemic or hemorrhagic stroke is associated with a poor outcome. Analysis of two large datasets, together involving almost 21 000 patients with acute ischemic stroke, reveals that a curvilinear relationship exists such that blood pressure above 180/100 mmHg is associated with a worse outcome assessed either as early

Table 8.2 Associations and possible causes of hypertension and hypotension in acute stroke Hypertension

Age¹¹ Race—black⁸⁹

Primary intracerebral hemorrhage⁸⁹ Previous hypertension^11,15,90

Damage to vasomotor modulatory centers, e.g. insular cortex¹⁶ Stress of hospitalization (‘white coat hypertension’)

Activation of corticotropic (ACTH, cortisol) system^91–94 Activation of sympathetic nervous system⁹¹

Activation of renin-angiotensin system Low plasma nitric oxide levels⁹⁵ Increased cardiac output³⁶

Secondary to raised intracranial pressure (Cushing reflex) Hypotension

Large cortical stroke (total anterior circulation syndromes)⁴ Heart disease (myocardial infarction, heart failure)^4,11 Infection (septicemia, respiratory tract, urinary tract)

death, or late death, or dependency.^3–5 This link is independent of standard prognostic factors, including age, gender, stroke severity, stroke position (cortical vs lacunar), time to randomization, level of consciousness, and atrial fibrillation.⁴

These disparate findings have at least two explanations. First, the three neutral studies were all small and are likely to have suffered from a type 2 error (false-negative result). Secondly, studies employing both casual and beat-to-beat or 24-hour blood pressure readings have found that the first are relatively insensitive to the blood pressure-outcome relationship,^20,22 presumably because they suffer from considerable variation. The latter explanation would be particularly relevant to small studies.

Little research has been preformed on why a high blood pressure causes a worse outcome, but a number of putative explanations have been proposed (Table 8.3).²⁶ Of these, the most obvious is the relationship between hypertension and early recurrent stroke after cerebral infarction,²⁷ which mirrors the relationship between blood pressure and both first and recurrent stroke.^28,29

Table 8.3 Mechanisms which may link blood pressure with outcome Hypertension

Ischemic stroke Recurrent ischemia^4,27 Hemorrhagic transformation²⁶ Cerebral edema^4,26

Hemorrhagic stroke Recurrent bleeding³¹ Hypotension Recurrent ischemia⁴

Heart disease (myocardial infarction, heart failure)⁴ Infection (septicemia, respiratory tract, urinary tract)

Hypertension may also promote cerebral edema in patients with ischemic stroke,⁴ and rebleeding in intracerebral hemorrhage.^30,31

HYPOTENSION

Few studies have reported a link between hypotension and a poor outcome after ischemic stroke for two reasons: first, the proportion of patients with blood pressure below 120/80 is small, meaning that studies must be large; and, secondly, most investigators have assumed a pseudo-linear relationship based on the concept that outcome improves with lower blood pressure. Where investigators have allowed for three states (hypertension, normotension, and hypotension) it has become clear that hypotension is also associated with a poor outcome.³² This is most apparent in data from the International Stroke Trial⁴ and ‘Blood Pressure in Acute Stroke Collaboration’,⁵ which suggest that outcome is worst in patients with systolic blood pressure

<120 mmHg and/or diastolic blood pressure <70 mmHg.^3–5 The relationship between hypotension and outcome in primary intracerebral hemorrhage is unknown.

OTHER HEMODYNAMIC MEASURES

Functional outcome after stroke is not just related to absolute blood pressure levels but also to other hemodynamic measures, including beatto-beat blood pressure, blood pressure variability, pulsatility index, and heart rate.^22,33

RELATIONSHIP BETWEEN BLOOD PRESSURE AND CEREBRAL PERFUSION

Cerebral perfusion is normally determined by local brain metabolic demands and is independent of systemic blood pressure except at very low or high levels, so-called cerebral autoregulation. Chronic hypertension is associated with a right shift of the perfusion/pressure curve so that perfusion is maintained at higher blood

pressures.³⁴ Following acute ischemic stroke or PICH, autoregulation is lost and perfusion becomes, all other things being equal, pressure-dependent.³⁵ This dysautoregulation usually settles over a period of a few weeks.³⁵

In view of the above, it is commonly held that raising blood pressure will improve perfusion, and therefore potentially improve outcome, and lowering blood pressure will reduce it, thereby possibly worsening outcome. Unfortunately, this view is simplistic and takes no account of many factors, including the pathophysiological response to raising blood pressure, the magnitude and rate of blood pressure change, pial blood flow, and the agent being used. Co-morbid factors which alter hemodynamic function are also likely to be important, including cardiac output, atrial fibrillation, diabetes mellitus, and pyrexia.^26,36

Evidence is also accruing that it is possible to lower blood pressure without compromising cerebral blood flow following acute ischemic or hemorrhagic stroke.^37–39

MEASUREMENT OF BLOOD PRESSURE

Blood pressure is one of the most common physiological measures in clinical medicine and yet it is also one which is performed very poorly. Review of existing trials of vasoactive drugs in acute stroke reveals that little if no thought was given to the measurement of blood pressure, and that study reports rarely provide any information.⁴⁰ It is vital that current and future studies rectify this point through careful design and reporting. Important considerations need to be given to the following information:

• Measurer: who (nurse, doctor, technician), training, assessment, retraining and reassessment (and their interval).

• Patient: position (supine, sitting, standing), time of day, environment (ward, outpatient clinic).

• Blood pressure equipment: manufacturer, model, type (mercury, oscillometric), use (manual, semiautomatic).

EXPERIMENTAL STUDIES

ALTERING BLOOD PRESSURE

Inducing arterial hypertension in experimental animals may, in some situations, worsen cerebral edema associated with focal ischemia.^41,42

CANDIDATE DRUGS

Several drugs which are candidates for treating stroke are vasoactive and have been tested in experimental models of ischemia. Nitric oxide donors (including sodium nitroprusside) reduce infarct lesion size although dramatic falls in blood pressure must be avoided, either by giving a pressor agent in parallel or by using low doses.^43–45 Similarly, some of these agents, as well as other vasoactive drugs such as propentofylline, maintain or improve cerebral blood flow in spite of their hypotensive effects.^44,46,47 In contrast, a systematic review of nimodipine in experimental stroke found no evidence of benefit,⁴⁸ mirroring the results of clinical studies.⁴⁹

ARGUMENTS FOR RAISING BLOOD PRESSURE

Lost autoregulation and the possibility that raising blood pressure will improve perfusion, and thus outcome, is the main argument for this approach. Four case series, involving a total of 49 patients, have reported that elevating blood pressure—with noradrenaline (norepinephrine), metaraminol, levarterenol, or phenylephrine—can be beneficial.^50–53 Vasopressor therapy was also reported to be effective in reversing hemiplegia complicating cerebral arteriography in two patients.⁵⁴ Unfortunately, no published data from randomized controlled trials (RCTs) exists on the efficacy of raising blood pressure in acute ischemic stroke or PICH.^40,55 Indirect support for this approach comes from the observation that ‘triple H’ therapy, which includes inducing hypertension,⁵⁶ may be beneficial in patients with subarachnoid hemorrhage, although the overall effectiveness of this approach in this form of stroke has yet to be confirmed.⁵⁷ However, trials in acute ischemic stroke where hypervolemic hemodilution was induced (and where blood pressure is likely to have increased) did not find benefit for this intervention.⁵⁸

ARGUMENTS AGAINST RAISING BLOOD PRESSURE

Severe hypertension is associated with forced vasodilation, cerebral edema, capillary vasoconstriction, and ultimately in hypoperfusion, thereby presenting clinically as infarct extension or reinfarction. This sequence of pathophysiological events is found in hypertensive encephalopathy and could occur if blood pressure is elevated during acute ischemic stroke. Hypertension could also promote bleeding, manifest as hemorrhagic transformation in ischemic stroke, and rebleeding or hematoma enlargement in patients with PICH.^30,31

Acute stroke is associated with a raised cardiac output³⁶and the propensity for cardiac dysrhythmias.

Inotropes will exacerbate these, and thence the risk of myocardial ischemia and heart failure.

Two agents which raise blood pressure, although this was not their intended effect, have been assessed in RCTs in acute ischemic stroke and had unfavorable effects on outcome. Diaspirin cross-linked hemoglobin (DCLHb), a hemoglobin-based oxygen carrier, raised blood pressure and increased early death.⁵⁹ Similarly, the development of aptiganel, an NMDA antagonist which raises blood pressure,⁶⁰ has ceased in stroke; the exact reasons are unclear since phase III data have yet to be published.

Pressor agents such as phenylephrine, ephedrine, and phenylpropanolamine are sympathomimetic amines and therefore promote vasoconstriction (the mechanism by which they elevate blood pressure) and platelet aggregation. Neither property would seem beneficial in acute ischemic stroke, since both could cause reinfarction, and yet this class of drugs have been used to elevate blood pressure in stroke patients.^50–53 Nevertheless, they may cause stroke (subarachnoid hemorrhage, intracerebral hemorrhage, ischemic stroke and transient ischemic attack) as has already been shown in fit subjects when used as appetite suppressants or decongestants.^61,62

ARGUMENTS FOR LOWERING BLOOD PRESSURE

Hypertension at admission is an independent prognostic factor for death or a poor functional outcome, as detailed above. Furthermore, hypertensive patients with acute ischemic stroke are at increased risk of suffering early recurrence and cerebral edema according to observational data from the International Stroke Trial.^4,27 Several case series, describing either ischemic stroke (481 patients) or primary intracerebral hemorrhage (254 patients) suggest that lowering blood pressure (with a large variety of agents) may be beneficial.^19,63,64 Indirect evidence comes from the NINDS trial of alteplase,⁶⁵ where blood pressure was lowered in some patients either before, during, or immediately after thrombolysis, as thought clinically

relevant. However, it remains unclear what effect this strategy might have had on the positive findings of this trial.^66,67

No large RCTs have assessed the safety and efficacy of lowering blood pressure^40,55 and there are only a handful of phase II trials which have tested, or are testing, the effect of vasodepressors (Table 8.4).^37,40,68

ARGUMENTS AGAINST LOWERING BLOOD PRESSURE

Since cerebral autoregulation is lost during acute stroke and perfusion becomes, at least in part, pressure dependent, lowering blood pressure might be expected to worsen outcome (see above). Case series, involving 8 patients, have suggested that blood pressure reduction is associated with a worsening in outcome.^69,70 However, the strongest arguments against lowering blood pressure come from some trials in acute stroke involving vasoactive drugs, in particular calcium antagonists and beta-receptor antagonists (see next section).

Table 8.4 Drugs for elevating and lowering blood pressure in acute stroke

Drug Potential detrimental effects Effect on outcome

Lower BP

Alpha blockers Not known

Angiotensin II receptor antagonists (candesartan, losartan)

Two ongoing studies^78,96

Angiotensin-converting enzyme Maintain global CBF³⁷ inhibitor (captopril, perindopril)

Beta-receptor antagonists (atenolol, propranolol)

Negative inotropes Neutral/worse⁷²

Calcium channel blockers (nimodipine, lifarizine)

May reduce regional CBF.⁸⁵ Significant BP lowering associated with a worse outcome after ischemic stroke^73–75,97

Neutral/worse⁴⁹

Diuretics Can cause hemoconcentration and

dehydration

Not known

Nitric oxide (glyceryl trinitrate, sodium nitroprusside)

Maintains regional CBF.³⁸ Donors may, or may not, have antiplatelet effects.^38,68 Used in alteplase trials.^65,66,98

Not known

Dextrorphan Induces adverse central events, e.g. stupor, apnoea⁹⁹

Trafermin Leucocytosis Neutral¹⁰⁰

Raise BP

Corticosteroids Complicated by hyperglycemia, infection, gastrointestinal bleeding¹⁰¹

Neutral¹⁰¹

Hemodilution Used in SAH⁵⁷ Neutral⁵⁸

Sympathomimetics (levarterenol, metaraminol, noradrenaline (norepinephrine), phenylephrine)

Inotropes can induce cardiac ischemia and dysrhythmias. Activate platelets.

Vasoconstrictors might worsen cerebral perfusion

No trials

BP, blood pressure; CBF, cerebral blood flow; SAH, subarachnoid hemorrhage.

WHICH DRUGS SHOULD WE USE TO ALTER BLOOD PRESSURE

RAISING BLOOD PRESSURE

Pressor agents which could in principle be used for raising blood pressure include, amongst others, sympathomimetics, angiotensin, endothelin, and nitric oxide synthase inhibitors (Table 8.4). These drugs are either positive inotropes, vasoconstrictors, or both. Whether they should be used to raise blood pressure in ischemic stroke is, however, questionable for several reasons. First, they will tend to promote cardiac ischemia, an important cause of death after stroke, in a population who are already likely to have clinical or occult ischemic heart disease. Secondly, positive chronotropic agents will tend to facilitate cardiac dysrhythmias. Thirdly, vasoconstrictors with cerebral activity may reduce perfusion. Lastly, many sympathomimetics promote platelet activation. If blood pressure must be raised, it may make most sense to use chrononeutral vasodilating inotropic agents such as dobutamine, dopexamine, or low-dose dopamine, although even these are not totally immune from the above problems. We are currently performing a phase II trial with dobutamine in acute ischemic stroke.⁴⁰

LOWERING BLOOD PRESSURE

No significant differences exist between antihypertensive drug classes in the primary prevention of stroke and myocardial infarction.⁷¹ In contrast, it appears that all classes are not equal in acute stroke. Both calcium channel blockers and beta-receptor antagonists have been tested, although not for their hypotensive properties, and been associated with a worse outcome (see Table 8.4).^72–75 The INWEST trial found that outcome was worst in those patients treated at a higher dose of nimodipine and who had a 20% or greater fall in blood pressure.^74,76

Limited data suggest that ACE inhibitors and nitric oxide donors can lower blood pressure without compromising cerebral blood flow.^37,38,68 Interestingly, these results do not fit in with a theoretical argument that cerebral vasodilators (nitric oxide donors but not ACE inhibitors) should not be given since they may compromise cerebral perfusion by increasing intracranial pressure.⁷⁷ Furthermore, it can be argued that cerebroactive drugs might be especially useful if they improved penumbral perfusion.

No published data exist for alpha-adrenergic receptor antagonists, angiotensin receptor antagonists,⁷⁸ diuretics, or centrally acting drugs such as methyldopa or moxonidine. Many antihypertensive agents are probably unsuitable for use in PICH since they have antiplatelet properties, e.g. calcium channel blockers and sodium nitroprusside.³⁸

CONTINUING OR STOPPING PRE-STROKE ANTIHYPERTENSIVE MEDICATION?

Around 50% of patients with acute stroke are admitted on antihypertensive medication and the question arises as to what should be done with this. In a recent survey, almost three-quarters of responders reported that they continued such medication with the other one-quarter stopping it.² This variation is also reflected by practice in clinical studies where some patients continue medication,⁷⁹ while others stop it.^37,68 No completed trials have yet addressed whether outcome is altered by stopping or continuing antihypertensive drugs,⁸⁰ although the ENOS trial has factored this question into its design.^81,82

WITHDRAWING ANTIHYPERTENSIVE THERAPY DURING THE SUBACUTE PHASE

Only one trial has assessed the effect of withdrawing antihypertensive therapy once it has been initiated following stroke onset.⁸³ Nifedipine, clonidine, furosemide, and/or acetazolamide were given to 112 hypertensive patients with acute ischemic stroke. They were then randomized to continue or stop this medication after 3 days. No difference in functional outcome or death were observed at 1 month⁸³ although the trial was underpowered to answer this question. However, the relevance of this question has largely disappeared since it is now known that lowering blood pressure in the chronic phase after ischemic and hemorrhagic stroke is an important form of secondary prevention.^12–14

RANDOMIZED CONTROLLED TRIALS

In comparison with other areas of acute stroke management, the question of how to manage blood pressure has attracted little interest. Nevertheless, several RCTs have been completed, and others are underway or planned (Table 8.5). Some of these studies are large enough to provide information on the effect of altering blood pressure on outcome and should inform future practice. However, these trials have largely focussed on lowering blood pressure, leaving one issue underresearched—namely, whether blood pressure should ever be elevated, especially if it is low.

EFFECTS OF CHANGING BLOOD PRESSURE ON SURROGATE MEASURES OF OUTCOME AND EFFICACY

It is evident that any trials of vasoactive drugs in acute stroke should be paralleled by studies assessing the effect of these agents on regional cerebral perfusion, assessed using semiquantitative techniques such as position emission tomography (PET), single-photon emission computed tomography (SPECT), perfusion magnetic resonance (MR), or xenon computed tomography (CT). Few studies have been performed to date⁸⁴ but perindopril (an ACE inhibitor) and sodium nitroprusside (a nitric oxide donor), given at doses which reduce blood pressure by 10%, do not appear to reduce perfusion in ischemic stroke.^37,38 In contrast, calcium channel blockers may worsen cerebral blood flow in parallel with their hypotensive effect.⁸⁵ No assessment of the effect of pressor agents on cerebral perfusion have been reported in acute stroke.⁸⁴

Since almost all vasoactive drugs have collateral effects (see Table 8.3), it is also vital that these are also assessed in future studies. Of particular importance is hemostasis, since drugs with antiplatelet activity (e.g.

sodium nitroprusside³⁸) should not be used in PICH, whereas those which activate platelets (e.g. sympath-omimetics) should be used cautiously, if at all, in any type of stroke.

GUIDELINES

Until definitive trial (level 1) data become available, guidelines built on expert opinion and the limited results of case series and observational studies should inform clinical practice. Nevertheless, these are, as a group, inconsistent with each other, as shown in Table 8.6.

CONCLUSIONS

If the past few years have seen the treatment of acute stroke focus on thrombolysis and neuroprotection, a future emphasis will be on the management of physiological variables, especially blood pressure. Repeated

calls have been made for large trials in this area and yet these are now only just starting. The design of such trials is complex since blood pressure could be raised or lowered on the basis of opposing pathophysiological arguments. Parallel studies will need to assess collateral effects of vasoactive drugs, especially on cerebral perfusion and hemostasis. While such trials are underway, blood pressure should be managed according to published guidelines.

ACKNOWLEDGMENTS

Philip Bath is UK Stroke Association Professor of Stroke Medicine. I thank Dr Parveen Rashid, Table 8.5 Completed, ongoing, and planned trials assessing the effect of altering blood pressure in acute or subacute stroke

Intervention, treatment period, trial acronym

Patients/

centers

Stroke type, time window

BP inclusion (mmHg)

Prior

antihypertensi ve

hypertensive medication

Aim, outcome Status

Candesartan 7 days (or longer if BP remains high), ACCESS

500/60–70 Ischemic, SBP>200 and/

or DBP>110

? Lower BP,

MRS at 12 months

Ongoing^78,108

Dobutamine (intravenous) 2 hours

24/1 Ischemic, <96 hours

100<SBP<18 0

60<DBP<110

Stop Raise BP, BP

at 2 hours

Ongoing⁴⁰

Glyceryl trinitrate (transdermal) 12 days

37/1 Ischemic,

PICK <120 hours

Any Stop Lower BP, BP

at day 1

Completed⁶⁸

Glyceryl trinitrate (transdermal) 10 days

90/1 Ischemic,

PICH <72 hours

Any Stop Lower BP, BP

at 7 days

Completed⁴⁰

Glyceryl trinitrate (transdermal) 7 days, ENOS

5000/100+ Ischemic, PICH <48 hours

140<SBP<22 0

Randomize to stop or continue

Lower BP, MRS>2 at 3 months

Ongoing^81,82

Losartan (?) (?)

24/1 Ischemic 36–

168 hours

DBP>90 ? Lower BP,

Cerebral perfusion, renal function

Completed⁹⁶

Perindopril (oral)

24/1 Ischemic 48–

168 hours

170<SBP<25 0

95<DBP<120

Stop Lower BP,

Global cerebral blood flow

Completed³⁷

BP, blood pressure; DBP, diastolic blood pressure; MRS, modified Rankin score; PICH, primary intracerebral hemorrhage; SBP, systolic blood pressure.

Table 8.6 Published guidelines for the management of blood pressure in acute ischemic stroke

Patient group Recommendation Guideline (Ref)

Coexisting hypertensive encephalopathy, heart failure or ischemia, aortic dissection, or continued intracerebral bleeding

Reduce blood pressure 102–105

Other stroke patients Do not lower BP 86,103

Other stroke patients Reduce BP if SBP>200 or SBP>220, MBP>130, or DBP>120–130

69,70,104,106

Other stroke patients Do not reduce SBP below 160 mmHg 107

Other stroke patients Do not reduce MBP by more than 20% 70

Other stroke patients Do not reduce DBP below 110 mmHg 105

Previously normotensive stroke patients Reduce MBP to <120 mmHg 102 Previously hypertensive stroke patients Reduce MBP to 130–140 mmHg 102 SBP, systolic blood pressure; DBP, diastolic blood pressure; MBP, mean blood pressure=DBP+((SBP−DBP)/3).

Dr Mark Willmot, and Mrs J Leonardi-Bee for commenting on the manuscript of this chapter.