MANAGEMENT OF HYPERTENSION

IN ACUTE STROKE

SMF SARAF RSUD BANGLI

FAKULTAS KEDOKTERAN UNIVERSITAS ISLAM AL-AZHAR
2018
 Hypertension is commonly seen in the setting of an acute
stroke. Although hypertension is the most important
modifiable risk factor for both ischemic and hemorrhagic
stroke, the immediate management of elevated blood
pressure in this setting is controversial.
 Questions remain to be definitively answered, such as when
to start lowering blood pressure, by how much to lower
pressure, which pharmaceutical agents to use and
whether to continue or stop previous antihypertensive
medications.
 Recently, pilot studies have been initiated in an attempt to
answer these questions and will hopefully lay the foundation
for larger definitive studies.
 Stroke is one of the leading causes of morbidity and mortality in
the USA. It is well recognized that hypertension is the leading
modifiable risk factor for stroke and extensive research has
linked hypertension and risk of stroke in multiple patient
populations [1] .
 Epidemiological evidence suggests that a 5 mm lower diastolic
blood pressure (DBP) together with a 9 mm lower systolic blood
pressure (SBP) confers a 33% lower risk of stroke, and a 10 mm
lower DBP together with a 18–19 mm lower SBP confers more
than a 50% reduction in stroke risk [2].
 Combined data from well-designed, randomized trials of
antihypertensive drugs have also shown that a 5–6 mmHg
reduction in DBP reduces stroke incidence by 42%
 . The results of the Perindopril Protection against Recurrent
Stroke Study (PROGRESS) showed that, fol- lowing a stroke, an
average reduction in blood pressure (BP) by 9/4 mmHg
translates to a reduc- tion of total stroke by 28% and a
reduction of major cardiovascular events by 26% over a 4-
year period [4] . However, the management of hyper- tension
immediately after an acute stroke remains a controversial
and less well-studied subject.
Cerebrovascular physiology
Normal cerebral autoregulation
 Under normal circumstances, the cerebral blood flow (CBF) of
the adult brain is maintained at approximately 50 ml/100
g/min, despite varia- tions in systemic BP, by a physiological
regu- latory mechanism termed autoregulation. The normal
range for autoregulation is a cerebral perfusion pressure (CPP;
the difference between the mean arterial pressure [MAP] and
venous pressure) of approximately 50–160 mmHg . In this
range, when the CPP decreases, the blood vessels dilate to
decrease cerebrovascular resis- tance. The inverse is observed
when the CPP increases and the arterioles constrict to
increase cerebrovascular resistance (Figur e 1) .
 Above the upper limit of autoregulation, there may be,
‘breakthrough’ vasodilation leading to vasogenic cerebral
edema. A BP below the lower limit of autoregulation can
result in a decrease in CBF and, potentially, cerebral
ischemia.
Autoregulation in stroke

 The phenomenon of autoregulation can be perturbed in

several ways in patients with stroke.
1. Effect of increased intracranial pressure
2. Effect of chronic hypertension
3. Effect of cerebral ischemia
 Penumbra iskemik
 It has been suggested that focal cerebral ischemia leads to a
central ‘core’ of severely ischemic tissue with failure of electrical
activity and ionic pumps. Surrounding this core is an area of
ischemic tissue with flow between the thresholds of electrical
and ion pump failure. This region of structurally viable but
function- ally impaired tissue has been termed the ‘penumbra’
(Figur e 2) . The ability of the penumbra to survive depends not
only on the degree of flow reduction, but also on the duration of
reduction. This tissue is potentially salvageable with restoration of
flow, but further decrease in CBF to this area might lead to
irreversible neuronal death.
Prevalence, mechanisms & natural history of
hypertension after stroke
Prevalence of hypertension after acute stroke
 Prevention, Detection, Evaluation and Treatment of High
Blood Pressure (JNC 7) guidelines [7] . A study of 563,704 adult
patients in the National Hospital Ambulatory Medical Care
Survey showed that SBP greater than 140 mmHg was noted in
63% of the patients [8] . In the International stroke trial, 17,398
patients with acute stroke were studied. The mean SBP was
160.1 mmHg at the time of admission and 82% of the patients
enrolled had SBP greater than 140 mmHg [9] . These data
demonstrate that an elevated BP is common in acute stroke
and its causes, effect and treatment should be addressed.
Natural history of
hypertension
 There is a spontaneous reduction of BP in most
acute stroke patients even without any specific
antihypertensive treatment. Wallace and Levy
reported that patients with acute stroke had a
significant decrease in BP within 10 days of the
acute stroke [12] . Another study reported that a
significant decline in BP was seen within the first
few hours of the stroke onset [13] . A significant
drop in BP in patients with ischemic stroke after
the blocked vessel is recanalized has also been
reported [14] .
Management of hypertension in stroke
subtypes Ischemic stroke

 Large, randomized trials have confirmed the significant role of

lowering BP in the primary and secondary prevention of stroke
and lowering BP seems to benefit not only hypertensive
individuals but also patients with a normal BP after stroke [4] .
Impact of hypertension on
stroke
 While there seems to be convincing evidence
that lowering BP improves outcome in patients
with stroke in the long run, the impact of lowering
BP in the short term is controversial. There are
several theoretical reasons both in favor and
against immedi- ate pharmacological lowering of
BP in this setting and these are summarized in Box
2.
 An increased risk of hemorrhagic trans-formation of the
infarction with higher BPs has also been reported. However,
the risk of hemorrhagic transformation was independent of BP
in the International Stroke Trial [9]. Hypertension has also been
considered to be a risk factor for intracerebral hemorrhage
(ICH) after thrombolytic treatment.
 In the National Institute of Neurological Disorders
and Stroke (NINDS) trial of tissue plasminogen
activator after ischemic stroke and the European–
Australasian Acute Stroke Study (ECASS) II trial,
elevated BP was a risk factor for hemorrhagic
transformation. However, other studies have not
been able to confirm this association.
 There are also several arguments against
immediate lowering of BP in the setting of acute
cerebral ischemia. As indicated earlier, BP
spontaneously declines after a stroke. Cerebral
ischemia can be worsened by lowering BP in
chronic hypertensives where the autoregulatory
curve is shifted to the right [19] . An ischemic area
with autoregulatory impairment can be
converted into irreversible ischemia if a lower BP
leads to a decrease in CBF.
 Lowering BP might decrease flow distal to a
vascular stenosis or promote the propagation of
an intraluminal thrombus. Lastly, there are several
anecdotal case reports of worsening neurodeficit
in patients with ischemic stroke in whom BP was
acutely lowered [20] .
Controlled trials studying BP
reduction & stroke outcomes
 While the association between hypertension and outcome in
ischemic stroke is debatable, in order to definitively answer the
question, ‘should BP be lowered acutely after an ischemic stroke
?
 one needs to look at the results of large, randomized clinical
trials of BP lowering in this setting. Unfortunately, no adequately
powered trials have been conducted that can answer this
question.
 However, efforts are under way to design and conduct such
studies.
 Several small studies have examined strategies to lower BP and
their outcomes in acute stroke.
 A recent Cochrane review of 1153 patients enrolled in 12
randomized, controlled trials of BP manipulation (11 trials
lowering BP, one increasing BP) within 1 week of an ischemic or
hemorrhagic stroke was published.
 The authors found insuf ficient evidence to evaluate the effects
of altering BP on outcome during the acute phase of stroke [21]
.
 There have been very few studies of BP-lowering
in computer tomography-proven ischemic stroke
patients where the sample size was moderately
large. These studies are summarized in Table 1. A
post hoc analysis of NINDS tissue plasminogen
activator trial showed no difference in outcome
between patients in the placebo arm who
received antihypertensive therapy compared
with those who did not [22] .
 The Acute Candesartan Cilexitil Evaluation in Stroke Survivors
(ACCESS) trial randomized 339 patients with acute stroke and a
BP of more than 200/110 mmHg to receive candesartan cilexitil
or placebo.
 The trial was stopped prematurely when a 47.5% reduction in
mortality and cardio- vascular events was noted in the
treatment group [23] .
 However, there was no significant difference in BP between the
two groups and, hence, the benefit cannot be attributed to BP
reduction.
 The Intravenous Nimodipine West European Stroke Trial
(INWEST) randomized patients with acute strokes presenting
within 24 h of symptoms into three treatment arms.
 One arm received placebo while the other two arms
received low-dose (1 mg/h) and high-dose (2 mg/h)
nimodipine. This trial noted worsening of clinical outcomes
with lower DBPs [24] .
 Recently, the Controlling Hypertension and Hypotension
Immediately Post-Stroke Trial (CHHIPS) pilot trial results were
published. In this trial, 179 patients with an acute stroke (25
patients had ICH) were randomized to treatment with
placebo or antihypertensives (b-blockers or angiotensin-
converting enzyme inhibi- tors).
 Antihypertensive treatment appeared to be safe and there
was a borderline significant reduction in mortality at 90 days
in the actively treated group [25] .

 Thus, the currently available evidence is insufficient to provide
accurate guidance on the management of BP immediately
after a stroke and treatment of this condition is largely
empirical.
 Hopefully, the results of planned large studies will provide
evidence to guide the management of this common
problem. Important ongoing studies in this area are
summarized in Table 2.
GUIDELINES FOR BP
MANAGEMENT IN ACUTE
ISCHEMIC STROKE

 Current guidelines from the American Heart Association and

American Stroke Association recommend acautious
approach to lowering BP.
 In patients treated with thrombolytic treatment, they
recommend lowering of BP to a SBP of not more than 185
mmHg and DBP no greater than 110 mmHg prior to treatment,
and keeping the SBP below 180 mmHg and the DBP below
105 mmHg for 24 h.
 The guidelines also recommend withholding antihyperten-
sives during the acute period unless SBP exceeds 220 mmHg
or DBP exceeds 120 mmHg.
 If BP is to be lowered, the guidelines recommend cautious
lowering of BP by 15% in the first 24 h. A class IIa
recommendation also notes that antihypertensive treatment
should be restarted at 24 h in previously hypertensive patients
who are neurologically stable if there are no other
contraindications
 European Stroke Organization guide- lines recommend
lowering SBP to less than 185 mmHg and DBP less than 110
mmHg prior to thrombolysis.
 They do not recommend acute BP lowering in the setting of
an acute ischemic stroke but recommend cautious lowering if
the BP is extremely high (>220/120 mmHg) on repeated
measurements, or with severe cardiac failure, aortic dissection
or hypertensive encephalopathy [27] .
 Hemorrhagic stroke
 Approximately 10–15% of first-ever strokes are due to intracere-
bral hemorrhage [28] .
 The mortality and morbidity associated with this disease is quite
significant.
 The 30-day mortality of patients with ICH is approximately 37%,
and only 20% regain functional independence by 6 months.
 In the PROGRESS trial, long-term treatment of hypertension with
perindopril (an angiotensin-con- verting enzyme inhibitor)
with/without indapamide (a diuretic) in patients with ICH
decreased recurrent strokes by 49% over a mean period of 3.9
years [29]
Impact of hypertension on outcome
after intracerebral hemorrhage

 One of the arguments in favor of acutely lowering BP is the

observation in some studies that high BP in the setting of
acute ICH is associated with increased mortality. However,
other studies have not been able to confirm this association.
 Similarly, there are conflicting reports on whether
hypertension in the setting of acute ICH is associated with a
poor clinical outcome independent of mortality.
 Most recently, in a pooled analysis of 218 patients enrolled in
a total of four clinical trials, presenting within 3 h of onset of
symptoms and prospectively studied, elevated BP did not
predict increased mortality or poor outcome [30].
 Perhaps the most compelling theoretical argument in favor of acutely lowering BP is
that high BP might promote expansion of the hematoma and lowering BP acutely
might prevent or lessen the degree of expansion of the hematoma.
 Significant hematoma expansion (>33% increase in volume) within the first 24 h is seen
in approximately a third of all patients with ICH presenting within 3 h of onset of
symptoms [31].
 It is a major cause of secondary injury after ICH and associated with clinical
deterioration and increased mortality after ICH [30]. Early observations suggested
that there may be an association between hematoma expansion and acute
hypertension.
 However, more recent observations contradict this assumption. In a study of 65
prospectively observed patients presenting within 3 h of onset of symptoms, neither
baseline nor peak BP was significantly associated with hematoma expansion [32].
 Another argument in favor of lowering BP is that high BP might
promote edema around ICH by increasing the capillary
hydrostatic pressure. Perihematomal edema is seen on day 1
and in the 2nd and 3rd weeks after ICH [33].
 However, it is unclear whether edema is responsible for clinical
deterioration or worse outcomes in ICH.
 Preliminary evidence suggest that early edema is not
associated with hypertension but the association of
hypertension with late edema remains to be studied in detail
[34].
 Other arguments for lowering BP include the presence of
systemic complications that might warrant BP lowering.
 For example, 18% of patients with ICH have elevated serum
markers of cardiac injury that are associated with higher
mortality [35].
 Reducing BP in order to reduce after-load and improve
cardiac function might be a reasonable approach in such
patients.
 The major argument against immediate lowering of BP is the possibility that
lowering BP might lead to cerebral ischemia. There are several possible
theoretical explanations for this.
 Patients with increased ICP in whom a normal CPP is being maintained by a high
MAP will have low CPP and possibly decreased CBF if the MAP is lowered to
‘normal levels’.
 The exact incidence and predictors of increased ICP in patients with ICH is not
known, but is reasonable to assume that patients with significant hydrocephalus
or large hematoma volumes could have high ICP and would be at risk of
developing cerebral ischemia if BP is reduced acutely.
 Another argument that has been put forth is that there may be a rim of
‘perihematomal ischemia’ in patients with ICH due to compression of capillaries
by the blood clot. This was based on early CBF studies using single photon
emission CT scans that demonstrated an area of low CBF around the
hematoma.
 Lowering BP in this setting might lead to further secondary injury in the
perihematomal region.
 However, more recent studies with PET and MRI scans suggest that the lowered
CBF in the perihematomal region is most likely due to metabolic suppression of
the tissue rather than ischemia [36]. Therefore, keeping the BP high in order to
avoid exacerbation of perihematomal ischemia may not be justified.
 Other arguments to avoid acute lowering of BP, such as the
shifting of the autoregulatory curve in chronic hypertensives, have
been discussed in the section on ischemic stroke and the same
principles apply to ICH as well.
 The pros and cons of lowering BP in the setting of an acute ICH
are summarized in Box 2
Treatment of hypertension
after ICH
 Similar to the situation in ischemic stroke, there are no definitive
studies that conclusively demonstrate the harm or benefit of
lowering BP acutely after an ICH.
 Studies have attempted to study the effect of lowering BP on
mortality, clinical outcome, ICP, CPP, cerebral edema and CBF.
 Most of these studies are retrospective and small, and it is
difficult to make definitive conclusions based on these studies.
 The effect of lowering BP on cerebral autoregulation in the
perihematomal region has also been studied.
 Recently, three pilot clinical trials on the treatment of acute
hypertension after ICH (Control of Hypertension In Pregnancy
Study [CHIPPS], Antihypertensive Treatment of Acute Cerebral
Hemorrhage [ATACH] and Intensive Blood Pressure Reduction in
Acute Cerebral Hemorrhage Trial [INTERACT]) have been
concluded and the results presented or published.
 All three trials were safety and efficacy trials and not powered to
assess clinical outcome (summarized in TaBle 1).
 The CHIPPS trial has been discussed earlier. Notably, CHIPPS
included 25 patients with ICH, of whom eight were treated
with placebo, nine with labetalol and nine with lisinopril.
 The primary end point of death or dependency at 2 weeks
(modified Rankin scale score > 3) was seen in three patients in
the placebo group, eight in the labetalol group and six in the
lisinopril group.
 At 3 months, one patient each in the labetalol and lisinopril
group and no patients in the placebo group had died [25]
 The ATACH study was a multicenter US study that addressed the
tolerability and safety of intravenous nicardipine infusion for 18–
24 h post-ictus in patients with ICH, with a SBP of over 200 mmHg
presenting within 6 h of symptoms.
 Three SBP goals (170–200, 140–170 and 110–140 mmHg) were
targeted and the lower treatment targets were studied if there
were no safety concerns at the higher target.
 In total, 58 patients (18, 20 and 20 in each target group,
respectively) with relatively small hematomas (mean volume < 20
ml) were enrolled.
 There was no difference in 3-month mortality between the
groups and there were no safety concerns in any tier.
 Of note, BP in patients assigned to the lowest tier were often
above the threshold, indicating that it might be difficult to
achieve this degree of BP control in these patients [37].
 The INTERACT was a multicenter, randomized trial of BP
reduction that enrolled patients primarily from China.
 Hypertensive patients (SBP 150–220 mmHg) with an acute ICH
within 6 h of symptom onset were randomized to
antihypertensive treatment to a target of 140 mmHg
(intensive group; n = 203) or 180 mmHg (guideline group; n =
201) for 7 days or until hospital discharge.
 Most of the patients were in a good clinical grade (median
Glasgow Coma Scale: 14) with small, deep ganglionic
hematomas.
 Compared with the guideline group, the intensive group
showed lower mean proportional hematoma growth at 24 h
(13.7 vs 36.3%; p = 0.04).
 However, this difference was not significant after adjustment
for initial hematoma volume and time from onset of ICH to CT
scan.
 In addition, there was no significant difference in adverse
event rate or outcome at 90 days [38].
 While none of these trials were powered to detect a
difference in clinical outcome, the results indicate that
acute BP reduction in ICH may be safe and that larger
studies designed to test the efficacy of this therapeutic
approach could be initiated.
 A few such studies are already underway (TaBle 2).
GUIDELINES FOR BP MANAGEMENT IN
CEREBRAL HEMORRHAGE

 The American Heart Association/American Stroke Association

2007 guidelines recommend that “the optimal level of a
patient’s BP should be based on individual factors such as
chronic hypertension, ICP, age, presumed cause of
hemorrhage, and interval since onset”.
 Aggressive BP reduction is recommended if SBP is greater than
200 mmHg or MAP is greater than 150 mmHg.
 If the SBP is greater than 180 mmHg or MAP is greater than 130
mmHg, BP management depends on the index of suspicion for
increased ICP.
 If increased ICP is suspected, it is recommended to
monitor ICP and treat BP to maintain CPP between 60–80
mmHg.
 If not, a modest reduction of BP (i.e., MAP of 110 mmHg or
target BP of 160/90 mmHg) is recommended [26] .
 The European Stroke Initiative 2006 guidelines recommend an
upper level of 180/105 mmHg and a target of 160/100 mmHg
(or M AP of 120 mmHg) in hypertensive patients.
 In non hypertensives, an upper level of 160/95 mmHg and a
target of 150/90 mmHg (or MAP of 110 mmHg) is suggested.
 In patients with suspected increased ICP, a CPP of at least 60–
70 mmHg is recommended [39] .
Choice of antihypertensive
agents
 In the setting of an acute ischemic stroke, it would be
preferable to use an agent that has a rapid and short duration
of action without significant neurological effects such as
sedation or increase in intracranial pressure.
 Intravenously administered agents are preferred. In the USA,
preferred agents include labetalol, hydralazine, esmolol,
nicardipine, nitroglycerine, nitroprusside and enalapril. Urapidil
and fenoldopam are also used in Europe.
 It has been suggested that vasodilators should be avoided in
the setting of increased intracranial pressure
 However, there are no randomized, controlled trials
comparing the efficacy and side-effect profile of different
agents in the setting of stroke.
Terimakasih