Hypertensive Emergencies On The Cutting Edge

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Hy pe r t e n s ive E m ergencies – On The Cu t t ing Edge

Hypertensive Emergencies – On The Cutting These data have important implications for clinicians in
Edge the emergency department (ED) where elevated BP and
Phillip D. Levy, MD, MPH its associated consequences are commonly encountered. 5
Associate Professor of Emergency Medicine According to the National Hospital Ambulatory Medical
Associate Director of Clinical Research, Department of Care Survey, 2.9% of the 115 million ED visits in 2005 were
Emergency Medicine related to chronic HTN, up from 2.1% in 1995. In 2006,
Wayne State University School of Medicine 16.2% of those treated in EDs across the US, approximately
Detroit, MI 15 million patients, had an initial BP that was “severely high”,
for example ≥ 160/100 mm Hg.6,7 The vast majority of patients
Objectives: with substantially elevated BP in the ED are asymptomatic
and, untreated, their BP will often diminish within a few
1. Describe severe blood pressure elevation in the emergency
hours of ED arrival. 8,9 Yet ED management is frequently
department, highlighting features which distinguish true
directed towards pharmacological reduction of the numerical
hypertensive emergencies from other conditions
BP value.10-12 This may be attributable to confusion regarding
2. Describe the basic pathophysiology which contributes to the risk proﬁle of patients with HTN and a consequent failure
and results from a hypertensive emergency to differentiate true hypertensive emergencies which warrant
3. Describe hypertensive emergency management guided by immediate intervention to arrest potentially fatal acute end-
target-organ speciﬁc therapeutic intervention and blood organ damage13 from simple BP elevations that portend long-
pressure reduction goals term risk but carry a low likelihood of near-term adverse
events.14,15

Introduction What Is a Hypertensive Emergency?

Hypertension (HTN) is one of the most important chronic While the term “hypertensive crisis” has been used to
medical conditions, affecting close to 75 million Americans1 and categorize any patient whose BP exceeds a certain threshold,
2
approximately 1 billion people worldwide. The current burden often systolic BP ≥ 180 or diastolic BP ≥ 110-120 mm
of HTN reﬂects a steady rise in disease prevalence over the past Hg, 16-18 there is limited evidence to suggest that BP alone
two decades, which, at least in the United provides sufﬁcient granularity to direct
States, has been accompanied by greater emergent decision making. Moreover,
levels of awareness, treatment and blood According to the National Hospital as noted by Shayne and Pitts in their
pressure (BP) control. Hypertension Ambulatory Medical Care Survey, comprehensive review, use of this term
is defined by the 7 th Joint National is misleading as most with a severely
Committee on Prevention, Detection, 2.9% of the 115 million ED visits elevated BP in the ED are not at risk for
Evaluation, and Treatment of High acute, or even subacute, development
3
Blood Pressure [JNC 7] as a BP > 140/90 in 2005 were related to chronic of pressure-mediated consequences.19
mm Hg for most and > 130/80 mm Hg
HTN, up from 2.1% in 1995. In Alternative terminology (Table 1)
for individuals with diabetes mellitus focused on the presence or absence
or chronic kidney disease. Despite the 2006, 16.2% of those treated in of signs or symptoms attributable to
4

trend towards an increase in BP control, acute target-organ damage within the
overall rates of HTN remain suboptimal EDs across the US, approximately context of severe HTN has been widely
with persistent elevation in nearly 50%.4 promulgated and serves to distinguish
15 million patients, had an initial those with active vasculopathy from
Among those with poorly controlled
HTN, almost 1 in 5 (11.5% overall) BP that was “severely high”, for those without. 10,19-22 As so defined,
have exceedingly high BPs, deﬁned as > hypertensive emergencies constitute
160/100 mm Hg, the JNC 7 cut-off for example ≥ 160/100 mm Hg. the subset of patients who present
Stage II HTN, a circumstance which is with acute end-organ damage and
particularly concerning considering that evidence of organ system dysfunction
the independent risk of pressure-related cardiovascular mortality (Table 2). Though still used by some, often inappropriately,
is known to double with each 20/10 mm Hg rise in BP above the the terms “accelerated” and “malignant” HTN are applicable
‘‘ideal’’ level of 115 ⁄ 75 mm Hg. 3 only to those patients with acute BP elevations which are

Hypertensive Emergencies – On The Cutting Edge 19
Advancing the Standard of Care: Cardiovascular and
Neurovascular Emergencies

Table 1. Terminology for patients with severely elevated blood pressure

Term Description Implications *
Hypertensive emergency Presence of acute target- Requires immediate intervention with
Although some hypertensive
organ damage manifest parenteral therapy and admission to a
by clinical sequelae or monitored setting emergency patients will
diagnostic test
abnormalities
present de novo with
Hypertensive urgency Presence of chronic Requires re-initiation or up-titration of oral
target-organ damage antihypertensive therapy; acute blood
without evidence of acute pressure reduction with parenteral or rapid elevated blood pressure,
deterioration acting oral agents should be avoided; may
necessitate serial testing in an observation
setting most episodes are triggered
Uncomplicated hypertension Asymptomatic without Requires arrangement of timely follow-up
with poor control evidence of acute or with reinforcement of the need for life-long by an acute rise in systemic
chronic end-organ dietary and medication compliance; initiation
damage (for new onset), re-initiation or up-titration
(for chronic hypertensives) of oral
vascular resistance
antihypertensive therapy may be needed if
follow-up is uncertain; acute blood pressure superimposed on underlying
reduction is unnecessary and may be
detrimental
chronic HTN.
* Should also prompt a search for potential medications which may increase blood pressure including
non-steroidal anti-inflammatory drugs, steroids, decongestants, appetite suppressants, over-the-counter
stimulants, oral contraceptives, and tricyclic antidepressants.

accompanied by retinal hemorrhage or
papilledema, respectively. Regardless, such
ocular findings are still considered target-
organ damage and can be aptly described Table 2. Target-organ involvement in hypertensive emergencies
using more generalizable terminology like Injury Pattern by Target-Organ Estimated Incidence* (%)
hypertensive emergency.
Brain 37-45
Pathophysiology Acute ischemic stroke 6-25
Hypertensive encephalopathy 8-16
Intracerebral or subarachnoid bleed 5-23
Although some hypertensive emergency
patients will present de novo with elevated Heart 27-49
blood pressure, most episodes are triggered by Acute heart failure syndromes 14-37
Acute coronary syndrome 11-12
an acute rise in systemic vascular resistance
superimposed on underlying chronic HTN.23 In Blood vessels
either case, the etiology is usually idiopathic, Aortic dissection 1-2
such as “primary” or “essential” HTN, with an Kidney ?
identiﬁable cause, such as “secondary” HTN, Acute renal insufficiency 22
in fewer than 10% (Table 3). Acute glomerulonephritis ?

Other 1.5-2
From a macrocirculatory standpoint, Eclampsia 2
hypertensive emergencies resemble Retinal hemorrhage or papilledema 0.9
Microangiopathic hemolytic anemia 0.6
uncomplicated instances of uncontrolled
chronic HTN but on a microcirculatory * Incidence estimates represent a range based on percentages compiled from Zampaglione (60)
level, they differ greatly. This is due in and Katz (21)

large part to the rate of BP rise, which is
more abrupt in those with a hypertensive
emergency and neurohormonal activation,

20 Hypertensive Emergencies – On The Cutting Edge
Hy pe r t e n s ive E m ergencies – On The Cu t t ing Edge

PATIENT EVALUATION:

General Approach

Hypertensive emergencies are generally accompanied by
symptoms related to the target-organ that is acutely involved.
Focal neurological deﬁcit or altered mentation point to brain
injury while chest pain or shortness of breath are indicative
of cardiac or vascular involvement. Though frequently
encountered, and potentially worrisome depending on the
scenario, symptoms such as headache or dizziness do not, in
and of themselves, serve as criterion from which a diagnosis of
hypertensive emergency can be established. Retinal or kidney
involvement tends to be more cryptic but can, depending
speciﬁcally, the sympathetic nervous and renin-angiotensin- on the degree of associated papilledema, uremia, acidosis
aldosterone systems, which often precipitates the acute event. or hyperkalemia, present with defining clinical features
The net result is an overwhelming of vascular autoregulation, such as blurred vision, obtundation, Kussmaul respirations,
which serves to maintain a relatively constant blood flow palpitations or ventricular dysrhythmias.
when confronted by changing pressure dynamics, with local
mechanical stress and endothelial injury. The latter leads to The work-up of a hypertensive emergency should be guided
reduced endothelial nitric-oxide synthase (eNOS) function by symptoms and signs identiﬁable on clinical examination
and a drop in nitric-oxide mediated vascular smooth muscle which should include funduscopy. Depending on the case,
relaxation. 24 This, coupled with excess release of endothelin, the evaluation of HTN can involve the use of one or more
causes a profound increase in systemic vascular resistance of the following modalities: plain film radiography (chest
through arteriolar constriction. The cycle is thus self- x-ray), computed tomography, magnetic resonance imaging,
perpetuating with an initial inciting factor setting off a cascade electrocardiography, or echocardiography. Laboratory testing
of effects that functionally maintains BP at severely elevated for renal dysfunction including a urinalysis and a basic
levels. Without interruption of microcirculatory dysfunction, metabolic panel is recommended for most patients regardless
perfusion distal to the arterioles begins to decrease and a of their presentation. More sensitive novel biomarkers of
proinﬂammatory, hypercoagulable state with ﬁbrinoid necrosis acute renal injury such as cystatin-c, neutrophil-gelatinase
and regional ischemia develops.23 associated lipocalin (NGAL), and kidney injury molecule-1
(KIM-1)29 may be incorporated in the future.
At the macrocirculatory level, sustained elevations in systemic
vascular resistance cause the central aortic pressure and left Asymptomatic Hypertension
ventricular (LV) load to rise, which, in turn, requires greater
The necessity for testing is to identify occult target-organ
contractile force to maintain cardiac output and forward
damage in patients who have profound yet asymptomatic HTN
ﬂow.25,26 This manifests as an increase in both the rate and
is not clear. In a recent multicenter study of 109 such patients,
magnitude of LV pressure (dp/dt) which, in the absence of
clinically meaningful unanticipated test abnormalities were
cardiac dysfunction, imparts greater mechanical stress and
detected in only 6%. None of these tests were felt by the
shear force on the aorta. However, when underlying LV
treating physician to be deﬁnitively attributable to HTN.30
remodeling or overt cardiac dysfunction are present, the
Chest x-ray and electrocardiography in particular have
ventricle may be too weak to generate sufficient pumping
poor sensitivity for detection of subclinical cardiac disease,
force (systolic dysfunction) or too stiff to accommodate the
especially LV hypertrophy, and a low likelihood of altering
necessary increase in LV pressure (diastolic dysfunction).
clinical management.31 Investigation of other approaches to
Either may produce a relative decrease in preload recruitable
detect clinically silent target-organ cardiac damage such as
stroke work, and thus stroke volume, precipitating back-ﬂow
measurement of serum natriuretic peptide (NP) biomarkers
of ﬂuid into the lungs and rapid onset of acute heart failure.
such b-type NP (BNP) and n-terminal pro-BNP (NT-proBNP)
This has often been termed “ﬂash pulmonary edema”.27, 28
concentration have yielded conﬂicting results.32,33 Based on

Hypertensive Emergencies – On The Cutting Edge 21
Advancing the Standard of Care: Cardiovascular and
Neurovascular Emergencies

the findings of a recent study using echocardiography, the vasodilators and dopamine agonists, concluded that despite
prevalence of subclinical target-organ cardiac damage among minor differences in the degree of BP lowering with one
those with asymptomatic, severely elevated BP in the ED may antihypertensive class versus another, there was insufﬁcient
be far greater (approximately ~75%) than previously thought.34 evidence to determine which agent is most effective at reducing
Such data highlight the underlying risk for pressure-mediated morbidity or mortality.39 More recent data from The ECLIPSE
consequences of poor BP control among these patients and (Evaluation of CLevidipine In the Perioperative Treatment
suggest a potential benefit from more extensive screening of Hypertension Assessing Safety Events) trial, 40 which
particularly in the outpatient setting. compared clevidipine to nitroglycerin, sodium nitroprusside,
and nicardipine in 1512 cardiac surgery patients with acute
While the current approach to routine testing may not impact HTN and the CLUE (Evaluation of Intravenous niCardipine
acute care in asymptomatic hypertensives, there is value in and Labetalol Use in the Emergency Department)41 study,
knowing information such as baseline renal function and which included 226 ED patients with severely elevated
electrolyte levels prior to initiation of antihypertensive therapy. BP, suggest superiority but within class equivalence of IV
Accordingly, the JNC 7 recommends dihydropyridine calcium channel
that a basic metabolic panel be obtained blockers for BP reduction, such as more
before prescribing oral BP lowering While some oral or sublingual rapid lowering and greater time spent
medications. 3 It is most appropriate within prespeciﬁed target range, versus
to have such medications initiated or medications have a relatively quick alternative therapy. Although mortality
restarted by the patient’s primary care was also slightly lower in ECLIPSE with
physician. When follow-up cannot be onset of action, a more predictable, use of clevidipine compared to sodium
ensured, this responsibility may fall on controlled antihypertensive effect nitroprusside only, generalizability of
the ED provider.35 Based on existing this ﬁnding is limited by virtue of the
evidence, first-line therapy for nearly can be achieved with parenteral select patient population enrolled.
all hypertensive individuals should Because the focus of the CLUE study
involve the use of thiazide or thiazide- agents making them preferable in was immediate BP lowering effects,
like diuretics like chlorthalidone with
the setting of a true hypertensive outcomes beyond 30 minutes were
the addition of a second agent, usually not assessed. Consequently, the “hard”
an angiotensin converting enzyme emergency. clinical meaning of observed group-wise
inhibitor (ACE-I) or a calcium channel differences in BP reduction is unclear.
blocker, if the patient has chronic HTN
which is poorly controlled on monotherapy.36,37 Given existing data limitations, deciding which parenteral
medication is best for an individual patient can be challenging.
MANAGEMENT: Understanding the pharmacology of differing therapeutic
Antihypertensive Therapy options can facilitate utilization, enhance the ability to
direct intervention towards the appropriate precipitant, and
While some oral or sublingual medications have a relatively help avoid potentially harmful application. As shown in the
quick onset of action, a more predictable, controlled following equation, mean arterial pressure (MAP) can be
antihypertensive effect can be achieved with parenteral agents reduced by lowering any of the following parameters: systemic
making them preferable in the setting of a true hypertensive vascular resistance (SVR) which stems largely from regulation
emergency. According to data from the Studying the of vasogenic tone in the arterioles, cardiac output (CO) which
Treatment of Acute hyperTension (STAT) registry, labetalol is the pumping force of the heart, or central venous pressure
is the most common IV antihypertensive medication used for (CVP) which represents intravascular volume and, more
management of severely elevated BP, deﬁned in the registry roughly, hydrostatic force in the circulatory system. As with
as BP > 180/110 mm Hg, and nitroglycerin is the infusion most physiology, these parameters do not work in isolation
used most frequently.38 Direct comparison data are scant with and perturbations in one may affect the other. For example
regard to the relative efﬁcacy of differing agents. A Cochrane reducing CVP causes, by the Frank-Starling principle, a
Review of 15 randomized controlled trials (n = 869) involving decrease in CO:
7 different drug classes including nitrates, ACE-I, diuretics,
MAP = (CO x SVR) + CVP
calcium channel blockers, α1-adrenergic antagonists, direct

22 Hypertensive Emergencies – On The Cutting Edge
Hy pe r t e n s ive E m ergencies – On The Cu t t ing Edge

Most intravenous (IV) antihypertensive agents exert their and the acute consequences of elevated BP rather than
effect directly either through receptor-mediated activation the BP itself. As indicated in Table 2, the vast majority of
or inhibition or indirectly through a decrease in production hypertensive emergencies involve the brain or heart and
or release of endogenous vasoconstrictors. As shown in Table treatment goals should reﬂect the speciﬁc problems caused
4, the specific hemodynamic response is a function of the by high pressures. For instance, in acute coronary syndromes
pathway being interrupted. For the complicated by HTN, the primary
most part, all IV antihypertensives goal beyond reperfusion is a reduction
produce some decrease in SVR. The M o s t i n t r a v e n o u s ( I V ) in cardiac work-load and an increase
magnitude of BP reduction is largely a in coronary artery perfusion. Based on
reﬂection of the mechanism of action. antihypertensive agents exert respective pharmacodynamic profiles
42,43
Intrinsic dose response relationships,
their effect directly either through and existing evidence, specific
which often change with aging, are agents can be aligned with indication
important to consider when using any receptor-mediated activation or driven goals to develop an approach
agent clinically.42 to management which is likely to yield
inhibition or indirectly through a optimal outcomes (Table 5). While few
Speciﬁc Indications
decrease in production or release absolute contraindications exist, nitric
oxide donors do cause greater reduction
In clinical practice, antihypertensive
therapy is often administered simply of endogenous vasoconstrictors. in systemic (vs. cerebral) vascular
resistance resulting in relatively greater
to control elevated BP with clinicians
intracranial pressure and the potential
using medications with which they
for shunting of blood flow to the peripheral circulation.44
are most familiar. For treatment of a true hypertensive
Similar effects may also occur with hydralazine and both
emergency however, therapeutic intervention is best directed
classes should be used with caution or avoided in neurologic
towards the precipitant of speciﬁc target-organ dysfunction
hypertensive emergencies.45,46

Blood Pressure Goals

The long-standing approach to
antihypertensive medication use is to target
a maximal reduction in MAP of 25% within
the ﬁrst hour and a goal BP of 160/100 mm
Hg by 2-6 hours.3,16 This treatment is based
on existing understanding of the cerebral
pressure-flow autoregulation curve, which
shifts to the right in chronic HTN. An
excessive decrease in BP may lead to a
precipitous decline in cerebral blood ﬂow.19
Given the heterogeneity of acute target-
organ dysfunction, the use of as a singular
goal for BP control in all hypertensive
emergencies makes little physiologic sense.
This is particularly true for conditions such
as aortic dissection, where more aggressive
targets such as a systolic BP < 110 mm Hg
have been recommended to decrease on-
going injury and reduce the likelihood of
perioperative adverse events. 47 Similarly,
reductions in MAP which exceed 30% have
been associated with more rapid symptom
resolution and improved outcomes in acute

Hypertensive Emergencies – On The Cutting Edge 23
Advancing the Standard of Care: Cardiovascular and
Neurovascular Emergencies

state that “aggressive” reduction is warranted
when systolic BP is > 200 mm Hg or MAP
is > 150 mm Hg and more modest decreases
are indicated with target BP 160/90 mm Hg
or MAP 110 mm Hg when lesser elevations,
defined as systolic BP > 180 mm Hg or
MAP > 130 mm Hg, are present.53 The
persistent BP elevation in the setting of acute
intracerebral hemorrhage is associated with
hematoma expansion and worse outcomes
prompted the recent study of the target and
timing of antihypertensive therapy. The
Intensive Blood Pressure Reduction in Acute
Cerebral Hemorrhage Trial (INTERACT; n
= 404) and the Antihypertensive Treatment
of Acute Cerebral Hemorrhage study
(ATACH; n = 60) compared differing BP
goals, finding a strong signal that earlier
intervention with lower BP targets (systolic
BP approximately 140 mm Hg) may attenuate
hematoma expansion without an excess of
adverse events.54-57 To achieve such targets,
nicardipine may be more effective than other
agents including labetalol.58

Disposition

With little exception, patients with
heart failure patients with a hypertensive phenotype.48,49 A hypertensive emergency should be admitted to a monitored
recent subanalysis of 302 patients with acute heart failure in setting. By virtue of the presenting clinical picture and the
the STAT registry found that adverse events were increased corresponding use of IV antihypertensive medications, some
when systolic BP was lowered beyond 120 mm Hg within 12 of which can produce precipitous drops in blood pressure,
hours. This underscores the need for continued vigilance many will require on-going treatment in a step-down or
when managing this condition.50 intensive care unit. In certain circumstances, such as chest
pain with elevated BP or acute deterioration of chronic kidney
Understanding the importance of BP goals may be most
disease, short-term management in an observation unit may
critical when treating neurologic hypertensive emergencies.
be appropriate. This presumes that timely reassessment and
This is evident on review of the current American Heart
expeditious completion of the diagnostic work-up can be
Association/American Stroke Association (AHA/ASA)
assured in this setting.59
guidelines for acute ischemic stroke, which call for a BP
reduction to < 185/110 mm Hg when thrombolysis is planned. Prognosis
Otherwise, antihypertensive therapy is only indicated when
BP is markedly elevated (> 220/120 mm Hg) with a goal to Outcomes associated with a given hypertensive emergency
decrease by approximately 15% at 24 hours post-onset.51 This are largely a function of underlying target-organ damage. Data
is supported by a meta-regression of BP control in stroke from STAT suggest that severe HTN is a high-risk condition
which suggests an association between large falls or increases with in-hospital and 30-day mortality rates of 6.9% and 11%,
in BP and worse outcome and modest reductions with a respectively, and a 90-day readmission rate of nearly 40%.21
decrease in death and/or dependency.52 Updated in 2010, the When associated with moderate to severe acute kidney injury,
AHA/ASA guidelines for acute intracerebral hemorrhage mortality is even greater (odds ratio = 1.05; p=0.03 per 10-
mL/min decline).60

24 Hypertensive Emergencies – On The Cutting Edge
Hy pe r t e n s ive E m ergencies – On The Cu t t ing Edge

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26 Hypertensive Emergencies – On The Cutting Edge