Control of Blood Pressure in Hypertensive Neurological Emergencies
Control of Blood Pressure in Hypertensive Neurological Emergencies
Control of Blood Pressure in Hypertensive Neurological Emergencies
DOI 10.1007/s11906-014-0436-x
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)
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
* 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
*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
[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
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
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