Curr Hypertens Rep (2014) 16:436

DOI 10.1007/s11906-014-0436-x

HYPERTENSIVE EMERGENCIES (BM BAUMANN, SECTION EDITOR)

Control of Blood Pressure in Hypertensive Neurological

Emergencies
Lisa Manning & Thompson G. Robinson & Craig S. Anderson

Published online: 26 April 2014

# Springer Science+Business Media New York 2014

Abstract Neurological hypertensive emergencies cause sig- Introduction

nificant morbidity and mortality. Most occur in the setting of
ischaemic stroke, spontaneous intracerebral hemorrhage Hypertensive emergencies are defined as large elevations in
(ICH), or subarachnoid hemorrhage (SAH), but other causes systolic and/or diastolic BP (usually >180 or >120 mmHg,
relate to hypertensive encephalopathy and reversible cerebral respectively) in association with impending or progressive
vasoconstriction syndrome (RCVS). Prompt and controlled cerebral and other end organ damage [1, 2•]. Most occur in
reduction of blood pressure (BP) is necessary, although there the setting of any of the major types of acute stroke, namely
remains uncertainty as to the optimal rate of decline and ideal ischemic stroke, spontaneous ICH, or SAH, but other causes
antihypertensive agent. There is probably no single treatment relate to hypertensive encephalopathy and a related disorder,
strategy that covers all neurological hypertensive emergen- RCVS or Call-Flemming syndrome. Prompt diagnosis of the
cies. Prompt diagnosis of the underlying disorder, recognition underlying disorder, recognition of its severity, and appropri-
of its severity, and appropriate targeted treatment are required. ate targeted treatment are required, although not all neurolog-
Lack of comparative-effectiveness data leaves clinicians with ical hypertensive emergencies require prompt lowering of BP,
limited evidence-based guidance in management, although as such treatment may increase the risk of cerebral ischemia.
significant developments have occurred recently in the field. Of the 1 billion people affected with hypertension world-
In this article, we review the management of specific neuro- wide, it is estimated that 1 to 2 % will have a hypertensive
logical hypertensive emergencies, with particular emphasis on emergency at some time in their life [2•, 3]. Of all the causes of
recent evidence. neurological hypertensive emergencies, the majority are due
to cerebral infarction (accounting for 25 % of all hypertensive
emergencies), with hypertensive encephalopathy (15 %) and
Keywords Hypertension . Emergencies . Critical care .
ICH (5 %) accounting for most of the rest [4]. The great
Neurological . Subarachnoid hemorrhage . Stroke .
majority of patients who present with a hypertensive emer-
Intracerebral hemorrhage . Encephalopathy
gency have prior known hypertension (80 – 90 %), often with
This article is part of the Topical Collection on Hypertensive Emergencies
poor adherence and/or inadequate treatment, and they are
more often of non-white background, elderly and male [2•,
L. Manning : T. G. Robinson
5, 6].
Department of Cardiovascular Sciences and NIHR Biomedical
Research Unit in Cardiovascular Disease, University of Leicester, Treatment recommendations depend on the type of associ-
Leicester, UK ated organ damage. If the patient has raised intracranial pres-
L. Manning sure (ICP) and/or neurological deterioration, they require
e-mail: [email protected] close monitoring in an intensive care or high dependency
T. G. Robinson setting to ensure careful control of BP. The lack of
e-mail: [email protected] comparative-effectiveness data leaves clinicians with limited
evidence-based guidance in their management of many hy-
C. S. Anderson (*)
pertensive emergencies [2•, 3]. Short-acting, titratable, intra-
The George Institute for Global Health, University of Sydney and
Royal Prince Alfred Hospital, Sydney, Australia venous antihypertensive agents are generally recommended,
e-mail: [email protected] where guideline recommendations are generally based on
 436, Page 2 of 11 Curr Hypertens Rep (2014) 16:436

experience and physiological rationale rather than hard evi- Conversely, persistently high BP may increase the risk of
dence, but there have been some significant recent develop- ongoing bleeding in SAH and ICH, promote hemorrhagic
ments [1, 7, 8]. In this review, we review the management of transformation of cerebral infarction in ischemic stroke, and
specific neurological hypertensive emergencies, with particu- increase the risk of cerebral edema in all neurological hyper-
lar emphasis on recent evidence. We begin with background tensive emergencies [15]. Mass effect related to hemorrhage
information on the regulation of cerebral blood flow and and cerebral edema in ICH, ischemic stroke, SAH and hyper-
potential implications for rapid BP lowering on the injured tensive encephalopathy, leads to elevations in ICP. In this
brain. setting cerebral perfusion pressure may be compromised by
high levels of MAP [16]. Whether the monitoring of cerebral
perfusion pressure in such situations improves outcomes is
uncertain, but this is often used to ensure that BP is not
Cerebral Autoregulation and Implications for Treatment
lowered disproportionate to maintaining adequate cerebral
perfusion [17, 18]. Hence, while lowering BP is essential in
An underlying hypothesis is that cerebral autoregulation is
hypertensive neurological emergencies, it is also a complex
altered in the context of hypertensive neurological emergen-
and potentially harmful therapy that necessitates careful
cies, which complicates the balance of potential benefits and
monitoring.
harms of BP-lowering treatment. Under normal circum-
stances, cerebral autoregulation is organized to maintain a
constant cerebral blood flow in the capillary bed to a mean
Specific Conditions
arterial pressure (MAP) of between 60 and 150 mmHg [9]. As
BP progressively increases, vasoconstriction occurs within
Acute Ischemic Stroke
cerebral arterioles resulting in BP exceeding the upper limit
of autoregulation,. This produces breakthrough vasodilatation
Stroke is the second leading cause of death and the leading
and increased cerebral blood flow, with disruption of the
cause of long-term disability worldwide, with acute ischemic
blood brain barrier and cerebral edema [10]. To complicate
stroke accounting for approximately 70 % of all strokes [19].
matters further, intracerebral pathology, for example, acute
Elevated BP is common in those presenting with acute stroke,
stroke, in itself may alter cerebral autoregulation (Fig. 1)
where approximately 75 % have a BP >140/90 mmHg, and
[12–14]. In an altered, and increasingly pressure dependant,
50 % and 15 % have systolic BP (SBP) >160 mmHg and
cerebral circulation, therapeutic reduction in BP may increase
>184 mmHg, respectively [20, 21]. The natural history is for
the risk of cerebral ischemia, particularly in ‘at risk’ penum-
BP to decline spontaneously over the subsequent several days
bral areas.
after the event. Elevated BP is associated with poor short- and
120 long-term outcomes [22–25]. Data from the first International
Stroke Trial suggested a U-shaped relationship between base-
100 line SBP (within 48 h of stroke) and short-term mortality and
Cerebral Blood Flow (ml/100g)

long-term death and dependency; the lowest risk of a poor

80 outcome was in patients with a SBP of 150 mmHg, with very
high and very low BP associated with worse outcome [26].
60 However, other studies have found a more linear relationship
between elevated in-hospital BP and poor outcomes [27–30].
40 Among patients receiving thrombolysis treatment, elevated
Normal BP is associated with a near linear increase in the risk of
20 Cerebral ischaemia
symptomatic ICH, with a U-shaped trend in the risk of death
and dependency at 3 months [22]. Based on these observa-
Chronic hypertension

0
tional data, the ideal SBP is 140-150 mmHg in the context of
0 50 100 150 200 250 acute ischemic stroke.
Cerebral Perfusion Pressure (mmHg) There is limited and conflicting evidence regarding the
Fig. 1 The cerebral autoregulation curve in normal individuals, and in
benefits of BP-lowering treatment in acute ischemic stroke,
patients with chronic hypertension and cerebral ischemia. The in part due to the heterogeneity of time to treatment, entry
autoregulatory curve is shifted to the right in chronic hypertension, criteria, type and severity of stroke, and degree and speed of
maintaining constant CBF at higher CPP than normal. Therefore, in those BP control across clinical trials. Table 1 describes important
with chronic hypertension, greater elevations in blood pressure than those
in non-hypertensive individuals, may be required before cerebral auto-
trials in this area and their key findings. The totality of the
regulation is overwhelmed. In the setting of cerebral ischemia, autoreg- evidence to date is that modest BP lowering with oral agents
ulation is impaired, and CBF becomes proportional to CPP [11] within the first 48 h after the onset of ischemic stroke is safe,
Table 1 Important Randomized, Controlled Trials of Intervention versus Control in BP Management Following Stroke. All trials included patients with ischaemic stroke and ICH

Name (year) Number of Initial median Time to Treatment Outcome measures Key findings
participants SBP (mmHg) treatment
(hours)

SCAST (2013) 2,029 171 17.8 Candesartan PO* Composite endpoint of vascular death, No beneficial effect seen in treatment group
[31•] myocardial infarction, or stroke
during the first 6 months
Curr Hypertens Rep (2014) 16:436

Functional outcome at 6 months

COSSACS 763 150 23.5 Previously taken Death or dependency at 2 weeks No differences between groups in primary
(2010) [32] antihypertensive agents outcome, vascular events or serious adverse
events.
CHHIPS (2009) 179 181 17.4 – 20.5 Labetalol PO, IV† Lisinopril Death and dependency at 2 weeks No difference in primary outcome between
[33] PO, SL‡ groups (numbers small).
Reduced 3 month mortality in treatment group.
Active treatment not associated with increased
early neurological deterioration.
IMAGES (2004) 2,589 MAP 108 7 Magnesium IV Death and disability at 90 days Non-significant trend toward better outcome in
[34] treatment group.
Significant trend toward better outcome in
subgroup with high BP (MAP > 108)
INWEST (1994) 295 159 – 161 10.5 – 11.5 Nimodipine IV Neurological outcome at day 21 Increased rate of poor outcome in treatment group
[35] Functional outcome at day 21
BEST (1988) 302 Not published 22 – 25.3 Atenolol, propranolol PO Mortality, neurological and functional Increased mortality in treatment group (though
[36] state at day 8, 1 month and 6 months. groups unbalanced in terms of stroke severity)
CATIS (2013) 4,091 167 15 Stepped agent protocol enalapril Mortality and major disability at 14 days; No difference between groups in the primary or
[37•] (first-line), calcium channel mortality and major disability at 90-days secondary outcomes;
blocker (second-line), diuretic
(third-line)

* PO: Per Os
† IV: Intravenous
‡ SL: Sub-lingual
SCAST: The angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): a randomised, placebo-controlled, double-blind trial
COSSACS: Continue or Stop post-Stroke Antihypertensives Collaborative Study
CHHIPS: Controlling Hypertension and Hypotension Immediately Post Stroke
IMAGES: Intravenous Magnesium Efficacy in Acute Stroke
INWEST: Intravenous Nimodipine West European Stroke Trial
BEST: Low dose beta blockade in acute stroke
CATIS: China Antihypertensive Trial in Acute Ischemic Stroke
Page 3 of 11, 436
436, Page 4 of 11 Curr Hypertens Rep (2014) 16:436

but there is uncertainty about whether this improves long-term necessary. Other agents (for example, nitroglycerin, hydral-
outcomes (Table 1) [31•, 33, 38, 39]. Whilst the Controlling azine, urapidil [not available in the US] and enalaprilat) may
Hypertension and Hypotension Immediately Post Stroke also be considered [1, 45–47]. Though guidelines recommend
(CHHIPS) trial showed that early treatment (within 36 h) a cautious approach to BP lowering, the available evidence
was safe and halved mortality compared to placebo at suggest potentially greater benefits may be derived from more
3 months, Scandinavian Candesartan Acute Stroke Trial aggressive BP lowering in the context of thrombolysis. The
(SCAST) concluded that there was no benefit of treatment ongoing Enhanced Control of Hypertension and Thromboly-
with an angiotensin-receptor blocker and potential harm on sis Stroke Study (ENCHANTED, ClinicalTrials.gov:
the basis of a non-significant trend towards increased poor NCT01422616), which compares intensive (systolic target
functional outcome at 6 months [31•, 33]. Most recently, the 130 – 140 mmHg) versus guideline recommended BP reduc-
large-scale China Antihypertensive Trial in Acute Ischemic tion (systolic target <180 mmHg), as well as low dose
Stroke (CATIS) showed no beneficial (or adverse) effects of (0.6 mg/kg) versus standard dose (0.9 mg/kg) recombinant
an angiotensin converting enzyme inhibitor (ACE-I) based tissue plasminogen activator (rtPA), in thrombolysis eligible
regime of BP lowering within 48 h of acute ischemic stroke patients, will provide solid evidence regarding BP manage-
[37•]. However, all of these studies may be limited by the ment in the peri- and immediate post-thrombolysis period
treatment being initiated relatively late (12 – 24 h) after the [48].
onset of symptoms in relatively mild cases of stroke, and in
achieving relatively modest BP reductions to target over 24 h. Acute ICH
Effects of BP lowering may depend on initial BP level, time
to treatment, stroke severity, history of hypertension, intensity ICH accounts for 10 to 15 % of all strokes in high-income
of treatment, and the agents used. There is no clear answer as to Western countries, but between 20 – 50 % of those in low- to
the ideal agent (Table 1). More positive outcomes were found middle-income developing countries [19, 49, 50]. Elevated
in other trials where BP lowering was commenced earlier after BP is a frequent occurrence, often to markedly elevated levels,
stroke onset, although the use of nimodipine was shown to in patients with acute ICH [21, 51]. As in ischemic stroke, BP
have an adverse effect [33, 35]. In particular, secondary anal- generally falls spontaneously within several days after onset.
yses of the Intravenous Nimodipine West European Stroke Elevated BP following ICH is associated with poor outcomes,
Trial INWEST and SCAST suggest that rapid and large de- though the exact pathophysiological mechanisms remain un-
creases in BP are associated with poor outcome, whereas rapid clear [51–54]. While some studies report a link between SBP
but moderate early BP reduction appears to be safe [35, 40]. and hematoma growth, others do not [52, 54, 55]. There has
Further data on BP lowering are expected from the Efficacy in been an extrapolation from the penumbra of ischemic stroke to
Nitric Oxide (ENOS) trial, where nitric oxide was compared a risk of inducing cerebral ischemia in the perihematomal
with placebo (and continuing versus stopping current antihy- edematous region from rapid lowering of BP, though recent
pertensive therapy), which has completed recruitment of over careful studies with advanced cerebral imaging are more
4,000 patients within 48 h of stroke onset [41]. reassuring against such hazard [56]. A systematic review,
Cochrane systematic reviews and several international and a large multicenter study in China show that a SBP greater
guidelines report ongoing uncertainty as to the optimal man- than 140 – 150 mmHg within 12 h of ICH is associated with a
agement of BP in the context of acute ischemic stroke [8, more than doubling in the risk of subsequent death or depen-
42–46]. Both American and European guidelines recommend dency [51, 57]. In contrast to the U-shaped relationship be-
against lowering BP in most patients during the initial 24 h of tween SBP and outcome in ischemic stroke, only one study in
acute ischemic stroke unless the BP levels are extreme, that is, ICH has shown a poor outcome at very low levels of SBP
systolic >200 mmHg, or there is a concomitant specific situ- [58].
ation that would warrant such treatment. When BP manage- Current guidelines for BP management in ICH are outlined
ment is indicated, targets are based on best clinical judgment in Table 2, although these were published prior to the com-
and observational data, with cautious lowering of SBP by pletion of two important recent studies [60••, 61]. Their rec-
15 % and close monitoring for neurological deterioration [1, ommendations were based mainly on observational studies
9, 45–47]. Arterial monitoring of BP should be considered in which suggest that a reduction in MAP by 15 % was associ-
critically ill patients who require frequent titration of intrave- ated with decreased CBF [62]; reducing SBP to <160 mmHg
nous BP-lowering agents. within 6 h of onset is associated with a trend toward improved
More specific guidance is available for patients who are outcome [63]; higher baseline SBP is associated with growth
candidates for thrombolytic therapy (BP >180/110 mmHg of ICH [52]; and rapid BP lowering may be hazardous [64].
being a contraindication to thrombolysis). If BP is >185/ Most recently, three studies have demonstrated safety, fea-
110 mmHg, intravenous labetalol (10 to 20 mg) or nicardipine sibility and potential efficacy of early intensive BP lowering in
(5 mg/h) are popular agents given with dose titration used as acute ICH: The Antihypertensive Treatment of Acute Cerebral
Curr Hypertens Rep (2014) 16:436 Page 5 of 11, 436

Table 2 Summary of Current International Guidance on Management of Elevated BP Following ICH

BP level (mmHg) Treatment Options Monitoring

*SBP>200 or †MAP >150 Consider aggressive BP lowering with IV infusion of short Monitor BP every 5 min
acting antihypertensive, e.g. labetalol/nicardipine
SBP >180 or MAP >130 with Consider monitoring ICP and reducing BP with IV infusion Maintain ICP ≥60 mmHg
possible raised ‡ICP
SBP >180 or MAP >130 with Consider modest reduction in BP with IV infusion Re-examine patient and monitor
no evidence of raised ICP BP every 15 min
Target BP = 160/90 mmHg

[17, 47, 59]

*SBP = Systolic blood pressure
†MAP = Mean Arterial Pressure
‡ICP = Raised Intracranial Pressure

Hemorrhage trial (ATACH), Intensive Blood Pressure Reduc- Hypertensive Encephalopathy

tion in Acute Cerebral Hemorrhage Trial (INTERACT) and
the Intracerebral Haemorrhage Acutely Decreasing Arterial Hypertensive encephalopathy accounts for 16 % of all hyper-
Pressure Trial (ADAPT), [61, 65]. The pilot phase INTER- tensive emergencies [5]. When MAP significantly exceeds the
ACT, which was undertaken in 404 patients who could be upper limit of cerebral autoregulation, vasodilation occurs
treated within 6 h of ICH onset, showed a trend towards resulting in over perfusion. While this reaction may occur at
attenuation in hematoma growth in the intensive treatment BP levels as low as 160/100 mmHg, higher BP levels may be
group, with no excess of neurological deterioration or other needed to overwhelm autoregulation in those with chronic
adverse events. The ATACH study demonstrated safety of a hypertension. The pathogenesis of this disorder is poorly
nicardipine-based BP-lowering regime in acute ICH, while understood, though dysfunction of cerebral endothelium and
the ADAPT randomized trial showed that BP lowering to a blood brain barrier are likely to be instrumental, with in-
target SBP of <150 versus <180 mmHg within 24 h of onset creased permeability leading to microhemorrhages and cere-
did not produce any clinically meaningful change in CBF bral edema, which give rise to clinical symptoms of headache,
within the immediate perihematomal region or hemispheres, vomiting, confusion, visual disturbance, and seizures [66]. If
as measured by CT perfusion [56]. not treated promptly, progressive cerebral edema and ICH can
The definitive, main phase INTERACT2 trial, randomly lead to raised ICP and ultimately, death.
assigned 2,839 patients with spontaneous ICH and elevated There is no randomized evidence to guide the most appro-
SBP (≥150 and ≤220 mmHg) to a strategy of intensive (SBP priate drug or optimal manner of BP lowering in this condi-
<140 mmHg within 1 h) versus guideline-recommended (SBP tion. Patients should be monitored in an intensive care or high
<180 mmHg) lowering of BP within 6 h [60••]. In those dependency setting to allow close monitoring, with consider-
assigned to intensive treatment, intravenous and oral antihy- ation given to arterial BP and ICP monitoring. Treatment
pertensive agents were given, according to pre-specified pro- recommendations are for SBP to be reduced cautiously by
tocols based on local availability. The results showed a bor- 20 to 25 %, or a DBP to 100 – 110 mmHg in the first 1 – 2 h,
derline significant reduction in poor outcome at 90 days, using titratable intravenous agents [8, 66]. More rapid BP
defined by death or major disability (odds ratio [OR] 0.87, reduction may lead to cerebral hypoperfusion. Particular cau-
95 % confidence interval [CI] 0.75–1.01; P=0.06), with a tion is necessary in older patients and in those with pre-
significant favourable shift in an ordinal analysis of the distri- existing hypertension, as they appear at increased risk of
bution of scores on the modified Rankin Scale (pooled OR for hypoperfusion and stroke [66, 67]. Nicardipine and labetalol
shift 0.87, 95 % CI 0.77–1.00; P=0.04). Moreover, intensive are commonly used, whereas sodium nitroprusside has the
BP lowering was shown to be safe, and resulted in signifi- potential to raise ICP and is reserved for resistant cases
cantly better health-related quality of life. [67–69]. The use of anticonvulsive therapy to control seizures
In conclusion, current evidence suggests that early inten- may also help reduce BP [70].
sive BP lowering is safe and may improve outcome from ICH.
The ongoing randomized ATACH2 trial and the Field Admin- SAH
istration of Stroke Therapy - Magnesium (FAST-Mag) trials
will provide further information on the role of early BP SAH, most often due to rupture of an intracranial aneurysm,
lowering, while guidelines are currently being updated to accounts for 5 – 10 % of all strokes, but with devastating
reflect these advances. consequences due to having an early case fatality near 45 %
436, Page 6 of 11 Curr Hypertens Rep (2014) 16:436

[71–73]. Hypertension is an established risk factor [74]. Stud- bleeding, and the maintenance of cerebral perfusion pressure.
ies of the frequency and significance of elevated BP in SAH When BP remains elevated (SBP 160 – 180 mmHg), despite
are lacking. As cerebral autoregulation is often disturbed in administration of nimodipine (given for neuroprotection and
SAH, rapid BP lowering has the potential for inducing cere- vasospasm) and analgesia, a short-acting continuous-infusion
bral ischemia [14]. One observational study reported that intravenous agent is most appropriate. No robust evidence is
elevated BP on admission with SAH was an independent poor available regarding drug type, though agents with a reliable
prognostic factor [75], but another found no association be- dose-response relationship and favorable safety profile in-
tween BP and prognosis [76]. Indeed, a recent observational clude nicardipine, labetalol, and esmolol. The magnitude of
study on the prognostic significance of admission BP in SAH BP lowering has not been determined but a target SBP of 140
concluded that a lower MAP was associated with a poor – 160 mmHg (i.e. maintain MAP >90 mmHg) seems reason-
prognosis and increased mortality [77]. able. Centrally acting BP medication should be avoided (e.g.
Recurrent hemorrhage (or re-bleeding) remains a serious sodium nitroprusside) because of its tendency to raise ICP [76,
consequence of SAH, with case fatality around 70 %. It affects 87].
9 – 17 % of patients in the first 72 h [78]. Higher initial BP is a
potential risk factor. One retrospective review found that re-
bleeding occurred less frequently in those treated for high BP RVCS
following SAH, and another reported that re-bleeding was
more common in those with SBP >160 mmHg [79, 80]. A RVCS is a rare condition characterized by recurrent acute-
further large retrospective study, however, found no relation- onset severe headaches and reversible cerebral vasoconstric-
ship between re-bleeding risk and BP [81]. Relative change in tion with or without neurological deficits or seizure. It can
BP may be important with one review reporting that an acute occur spontaneously, or be evoked by pregnancy or use of a
BP increase occurred immediately prior to re-bleeding [82]. vasoactive drug. The major complication is stroke due to
Interpretation of these findings is limited by their retrospective ischemia, ICH or SAH [88]. The pathophysiology is unknown
nature, confounding variables, and cause and effect relation- but it is generally considered a transient disturbance in the
ships. Cerebral ischemia in the days following SAH may control of cerebral vascular tone. Around a third of all patients
contribute to poor outcome. Traditionally, this has been attrib- with RCVS have an SBP ≥160 or DBP ≥90 mmHg during
uted to cerebral vasospasm, though recent studies have shown their acute headaches [88]. There are no large, prospective
that treatment of vasospasm does not necessarily translate to trials to guide BP or indeed of overall management, and no
better neurological outcome [83]. Rapid BP lowering in the pharmacological treatment has proven efficacy. Data from
presence of impaired cerebral autoregulation may be implicat- small open-labelled trials in patients with thunderclap head-
ed in adverse outcomes, though data are lacking. Thus, robust ache (including RCVS) suggests that headaches may respond
evidence related to the prognostic significance of elevated BP to nimodipine given orally or IV (dose adjusted according to
in SAH, and of the association between elevated BP (or its degree of vasoconstriction) [89]. However, in a more recent
treatment) and re-bleeding or delayed ischemia, are urgently case series of 67 patients with RCVS, 30 % of those treated
required. with the drug had recurrent headaches [90]. In those with
Evidence regarding the optimal approach to hypertensive ischemic or hemorrhagic complications, caution should be
treatment in SAH is sparse. A 1960s study of 1,005 patients exercised with dose escalation of nimodipine, as BP reduction
with SAH who were randomized to one of four treatment may have deleterious effects. Nicardipine, verapamil and
modalities – one arm of drug-induced BP lowering, another intra-arterial milrinone have been used with success in case
of bed rest alone, and the other two arms were carotid ligation reports, but no higher level evidence on efficacy and safety
and intracranial surgery – showed no effect of BP lowering on exists [89–91].
case fatality or re-bleeding at 6 months compared with bed rest
[84, 85]. An observational study in the 1980s found that
patients with treated hypertension had a higher rate of cerebral
infarction but lower rate of re-bleeding compared to normo- Individual Antihypertensive Agents
tensive control patients, and a later observational study sug-
gests that avoiding antihypertensive medication and increas- A wide range of agents exist for the treatment of hyperten-
ing fluid intake may reduce the risk of cerebral infarction [79, sive neurological emergencies, but the lack of clinical
86]. outcome controlled trials and comparative-effectiveness
It is not too surprising, then, that current guidelines state studies means there is no one ideal drug specific to each
that BP management in SAH remains controversial [87]. A neurological condition. Available agents, and evidence and
cautious approach to BP lowering should be considered, with prescribing guidelines related to each, are discussed in the
close patient monitoring for stroke, hypertension-related re- following sections.
Curr Hypertens Rep (2014) 16:436 Page 7 of 11, 436

Labetalol ischemic stroke patients receiving thrombolysis, and it is safe

in all neurological hypertensive emergencies.
Labetalol is a combined selective alpha-1 adrenergic and non-
selective beta adrenergic. It has a rapid onset (2 to 5 min) after Sodium Nitroprusside
intravenous administration and effects last 2 to 4 h [92]. It can
be given by IV bolus or continuous infusion without the need Sodium nitroprusside is an arterial and venous vasodilator.
for invasive BP monitoring. It reduces total systemic vascular Though easily titratable with reversible effects, sodium nitro-
resistance but maintains cerebral blood flow [93]. A recent prusside decreases cerebral perfusion with increasing ICP, so
systematic review of nicardipine versus labetalol in hyperten- it should be used cautiously in neurological hypertensive
sive crises found 10 comparative studies [2•]. Four were emergencies. Invasive BP monitoring is required [98]. It is
concerned specifically with hypertension in stroke patients. cited as an agent to consider in the management of hyperten-
Comparable efficacy and safety data were reported, but sive emergencies in recent European stroke and hypertension
nicardipine appeared to provide more predictable and consis- guidelines.
tent control of BP. Main adverse events were hypotension
(17 %) and arrhythmia (20 %). Clevidipine
In a stroke population, the use of labetalol within 36 h of
onset is safe, and effectively reduces BP [33]. There are no Clevidipine is a new, third generation dihydropyridine calci-
specific data in hypertensive encephalopathy or SAH. um channel blocker. It has a rapid onset (<1 min), is easily
Labetalol can be used for all neurological hypertensive emer- titratable, and does not require invasive monitoring [99].
gencies, is recommended by the American Stroke Association Clevidipine was safe and effective in reducing BP in 126
for the management of hypertension for thrombolysis in is- patients presenting to the emergency department or intensive
chemic stroke, and is cited in European and American guide- care with hypertensive crisis [100]. Further studies have con-
lines as an appropriate agent to use in the management of firmed its safety in hypertensive emergencies in the cardiac
aneurysmal SAH. surgery population, and direct comparisons have demonstrat-
ed similar efficacy and safety with nitroglycerin, sodium
Nicardipine nitroprusside, and nicardipine in the perioperative setting
[101]. The recently published Clevidipine in the Treatment
Nicardipine is a second generation dihydropyridine calcium of Patients with Acute Hypertension and Intracerebral Hem-
channel blocker. It has cerebral and coronary arterial orrhage (ACCELERATE) trial in 35 hypertensive patients
vasodilatory properties, and may improve cerebral perfusion with acute ICH [102•], clevidipine alone quickly and safely
[94]. It has an onset of action of 5 to 10 min. In a retrospective achieved control of SBP. There are no data specific to other
study comparing nicardipine with labetalol in patients with neurological hypertensive emergencies, and it is not cited in
ICH, SAH and ischemic stroke, those allocated nicardipine current guidelines.
had less variable reductions in MAP, were more likely to
achieve their target BP within 1 h, and were less likely to need Esmolol
dose adjustments or additional antihypertensive agents. Safety
was comparable [95]. A prospective, randomized trial found Esmolol is a cardio-selective beta blocker (given as an IV
significantly less BP variability with nicardipine, but compa- bolus or infusion) with an onset of action within 1 min, and
rable rates of adverse events compared with other agents [96]. duration of 10 to 20 min. It is not dependent on renal or
Among hypertensive patients in an intensive care setting, hepatic function, therefore may be useful in those with renal
those who received nicardipine were less likely to require a or hepatic impairment [7]. There are no specific trials in
second agent and had significantly shorter lengths of hospital hypertensive neurological emergencies. It is cited as agent to
stay as compared to those receiving other antihypertensive consider in European SAH guidelines.
agents (including 44 % on labetalol as the “other antihyper-
tensive agent”) [97]. Nitroglycerin
A small, prospective study found that a reduction of MAP
with nicardipine or labetalol in those with ICH and severe Nitroglycerin is a venodilator that reduces preload. The onset
hypertension did not reduce cerebral blood flow [62]. This of action is immediate, and the duration of action 3 to 5 min.
may be of clinical importance given the concerns regarding Preload reduction is followed by a decrease in cardiac output
potential for iatrogenic end organ damage. Main adverse that can potentially be detrimental to patients who already
effects are hypotension (15 %) and arrhythmia (20 %) [2•]. have compromised cerebral or renal blood flow [3]. It can be
According to European and American Guidelines, nicardipine given IV or as a transdermal patch. Large trial data are scarce.
is recommended as a first line agent (along with labetalol) in A meta-analysis of two previous trials in acute stroke found no
436, Page 8 of 11 Curr Hypertens Rep (2014) 16:436

clear effect on end-of-treatment death, combined death or or where there is raised ICP; the latter also prompts consider-
deterioration with the transdermal patch [103]. The recently ation of cerebral perfusion pressure monitoring. Randomized
completed ENOS trial, designed to test the safety and efficacy data in patients with ICH suggests that early intensive lower-
of transdermal glyceryl trinitrate in acute stroke, may add to ing of BP is safe and effective, whereas for those with ische-
our understanding [41]. mic stroke, early and more modest BP lowering is safe and
may improve outcomes. In SAH and hypertensive encepha-
Enalaprilat lopathy, data for the effect of BP lowering is scarce. Ongoing
large trials are likely to inform future clinical practice
Enalaprilat is currently the only ACE-I that is commercially guidelines.
available in a parenteral formulation. It has an onset of action
of 15 min and duration of action of 12 to 24 h. This property
Compliance with Ethics Guidelines
makes titration difficult, and hypotension can develop [104]. It
is not often used in hypertensive neurological emergencies Conflict of Interest Lisa Manning declares that she has no conflict of
and data are limited. interest.
Thompson G. Robinson has received grants from ANHMRC
Urapidil Heath Foundation/The Stroke Association (Grant Funding for IN-
TERACT2 Grant Funding for COSSACS) and The Stroke Associ-
ation NIHR British Heart Foundation. He has also received advi-
Urapidil is a vasodilator acting on peripheral vessels by alpha- sory board consultancy fees and payments for lectures from
1 adrenoceptor blockade, and on central nervous system by Boehringer Ingelhelm. Dr. Robinson has also received paid travel
alpha adrenoceptor blockade. It has an onset of action of 2 to accommodations from Boehringer Ingelhelm, Educational Grant to
attend European Stroke Conference).
5 min and duration of 3 h. Wide individual variations in doses Craig S. Anderson has received a research fellowship grant from the
are observed. One systematic review of treatment of hyper- National Health & Medical Research Council of Australia.
tensive emergencies suggested that intravenous urapidil gave
Human and Animal Rights and Informed Consent This article does
the most desirable number needed to treat compared to other not contain any studies with human or animal subjects performed by any
available agents [104]. A head to head study comparing it to of the authors.
sodium nitroprusside in hypertensive crises, showed it to be
equally as effective and safe [105]. Given the large contribu-
tion of Chinese patients, urapidil was the most popular agent
used in the INTERACT2 trial of ICH. It is an effective References
treatment of hypertensive crises, perioperative hypertension,
and pre-eclampsia [106]. It is not explicitly mentioned in Papers of particular interest, published recently, have been
current international guidelines on stroke, ICH or SAH and highlighted as:
is not currently available in the US • Of importance
•• Of major importance

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