Download Hypertensive Emergencies – On The Cutting Edge

Hy p e r t e n s ive E m ergencies – On The Cu t t ing Edge
Hypertensive Emergencies – On The Cutting
Edge
Phillip D. Levy, MD, MPH
Associate Professor of Emergency Medicine
Associate Director of Clinical Research, Department of
Emergency Medicine
Wayne State University School of Medicine
Detroit, MI
Objectives:
1. Describe severe blood pressure elevation in the emergency
department, highlighting features which distinguish true
hypertensive emergencies from other conditions
2. Describe the basic pathophysiology which contributes to
and results from a hypertensive emergency
3. Describe hypertensive emergency management guided by
target-organ specific therapeutic intervention and blood
pressure reduction goals
Introduction
These data have important implications for clinicians in
the emergency department (ED) where elevated BP and
its associated consequences are commonly encountered. 5
According to the National Hospital Ambulatory Medical
Care Survey, 2.9% of the 115 million ED visits in 2005 were
related to chronic HTN, up from 2.1% in 1995. In 2006,
16.2% of those treated in EDs across the US, approximately
15 million patients, had an initial BP that was “severely high”,
for example ≥ 160/100 mm Hg.6,7 The vast majority of patients
with substantially elevated BP in the ED are asymptomatic
and, untreated, their BP will often diminish within a few
hours of ED arrival. 8,9 Yet ED management is frequently
directed towards pharmacological reduction of the numerical
BP value.10-12 This may be attributable to confusion regarding
the risk profile of patients with HTN and a consequent failure
to differentiate true hypertensive emergencies which warrant
immediate intervention to arrest potentially fatal acute endorgan damage13 from simple BP elevations that portend longterm risk but carry a low likelihood of near-term adverse
events.14,15
What Is a Hypertensive Emergency?
While the term “hypertensive crisis” has been used to
Hypertension (HTN) is one of the most important chronic
categorize any patient whose BP exceeds a certain threshold,
medical conditions, affecting close to 75 million Americans1 and
2
often systolic BP ≥ 180 or diastolic BP ≥ 110-120 mm
approximately 1 billion people worldwide. The current burden
Hg, 16-18 there is limited evidence to suggest that BP alone
of HTN reflects a steady rise in disease prevalence over the past
provides sufficient granularity to direct
two decades, which, at least in the United
emergent decision making. Moreover,
States, has been accompanied by greater
According
to
the
National
Hospital
as noted by Shayne and Pitts in their
levels of awareness, treatment and blood
pressure (BP) control. Hypertension Ambulatory Medical Care Survey, comprehensive review, use of this term
is misleading as most with a severely
is defined by the 7 th Joint National
Committee on Prevention, Detection, 2.9% of the 115 million ED visits elevated BP in the ED are not at risk for
acute, or even subacute, development
Evaluation, and Treatment of High
in
2005
were
related
to
chronic
3
of pressure-mediated consequences.19
Blood Pressure [JNC 7] as a BP > 140/90
mm Hg for most and > 130/80 mm Hg
HTN, up from 2.1% in 1995. In Alternative terminology (Table 1)
focused on the presence or absence
for individuals with diabetes mellitus
4
or chronic kidney disease. Despite the 2006, 16.2% of those treated in of signs or symptoms attributable to
acute target-organ damage within the
trend towards an increase in BP control,
overall rates of HTN remain suboptimal EDs across the US, approximately context of severe HTN has been widely
promulgated and serves to distinguish
with persistent elevation in nearly 50%.4
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,
hypertensive emergencies constitute
have exceedingly high BPs, defined as >
the subset of patients who present
160/100 mm Hg, the JNC 7 cut-off for example ≥ 160/100 mm Hg.
with acute end-organ damage and
Stage II HTN, a circumstance which is
evidence of organ system dysfunction
particularly concerning considering that
(Table 2). Though still used by some, often inappropriately,
the independent risk of pressure-related cardiovascular mortality
the terms “accelerated” and “malignant” HTN are applicable
is known to double with each 20/10 mm Hg rise in BP above the
3
only to those patients with acute BP elevations which are
‘‘ideal’’ level of 115 ⁄ 75 mm Hg.
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 targetorgan damage manifest
by clinical sequelae or
diagnostic test
abnormalities
Requires immediate intervention with
parenteral therapy and admission to a
monitored setting
Presence of chronic
target-organ damage
without evidence of acute
deterioration
Requires re-initiation or up-titration of oral
antihypertensive therapy; acute blood
pressure reduction with parenteral or rapid
acting oral agents should be avoided; may
necessitate serial testing in an observation
setting
Hypertensive urgency
Uncomplicated hypertension
with poor control
Asymptomatic without
evidence of acute or
chronic end-organ
damage
Although some hypertensive
emergency patients will
present de novo with
elevated blood pressure,
most episodes are triggered
Requires arrangement of timely follow-up
with reinforcement of the need for life-long
dietary and medication compliance; initiation
(for new onset), re-initiation or up-titration
(for chronic hypertensives) of oral
antihypertensive therapy may be needed if
follow-up is uncertain; acute blood pressure
reduction is unnecessary and may be
detrimental
by an acute rise in systemic
vascular
resistance
superimposed on underlying
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 targetorgan damage and can be aptly described
using more generalizable terminology like
hypertensive emergency.
Pathophysiology
Although some hypertensive emergency
patients will present de novo with elevated
blood pressure, most episodes are triggered by
an acute rise in systemic vascular resistance
superimposed on underlying chronic HTN.23 In
either case, the etiology is usually idiopathic,
such as “primary” or “essential” HTN, with an
identifiable cause, such as “secondary” HTN,
in fewer than 10% (Table 3).
From a macrocirculatory standpoint,
hypertensive emergencies resemble
uncomplicated instances of uncontrolled
chronic HTN but on a microcirculatory
level, they differ greatly. This is due in
large part to the rate of BP rise, which is
more abrupt in those with a hypertensive
emergency and neurohormonal activation,
20
Table 2. Target-organ involvement in hypertensive emergencies
Injury Pattern by Target-Organ
Estimated Incidence* (%)
Brain
Acute ischemic stroke
Hypertensive encephalopathy
Intracerebral or subarachnoid bleed
37-45
6-25
8-16
5-23
Heart
Acute heart failure syndromes
Acute coronary syndrome
27-49
14-37
11-12
Blood vessels
Aortic dissection
1-2
Kidney
Acute renal insufficiency
Acute glomerulonephritis
?
22
?
Other
Eclampsia
Retinal hemorrhage or papilledema
Microangiopathic hemolytic anemia
1.5-2
2
0.9
0.6
* Incidence estimates represent a range based on percentages compiled from Zampaglione (60)
and Katz (21)
Hypertensive Emergencies – On The Cutting Edge
Hy p e r t e n s ive E m ergencies – On The Cu t t ing Edge
PATIENT EVALUATION:
General Approach
specifically, the sympathetic nervous and renin-angiotensinaldosterone systems, which often precipitates the acute event.
The net result is an overwhelming of vascular autoregulation,
which serves to maintain a relatively constant blood flow
when confronted by changing pressure dynamics, with local
mechanical stress and endothelial injury. The latter leads to
reduced endothelial nitric-oxide synthase (eNOS) function
and a drop in nitric-oxide mediated vascular smooth muscle
relaxation. 24 This, coupled with excess release of endothelin,
causes a profound increase in systemic vascular resistance
through arteriolar constriction. The cycle is thus selfperpetuating with an initial inciting factor setting off a cascade
of effects that functionally maintains BP at severely elevated
levels. Without interruption of microcirculatory dysfunction,
perfusion distal to the arterioles begins to decrease and a
proinflammatory, hypercoagulable state with fibrinoid necrosis
and regional ischemia develops.23
At the macrocirculatory level, sustained elevations in systemic
vascular resistance cause the central aortic pressure and left
ventricular (LV) load to rise, which, in turn, requires greater
contractile force to maintain cardiac output and forward
flow.25,26 This manifests as an increase in both the rate and
magnitude of LV pressure (dp/dt) which, in the absence of
cardiac dysfunction, imparts greater mechanical stress and
shear force on the aorta. However, when underlying LV
remodeling or overt cardiac dysfunction are present, the
ventricle may be too weak to generate sufficient pumping
force (systolic dysfunction) or too stiff to accommodate the
necessary increase in LV pressure (diastolic dysfunction).
Either may produce a relative decrease in preload recruitable
stroke work, and thus stroke volume, precipitating back-flow
of fluid into the lungs and rapid onset of acute heart failure.
This has often been termed “flash pulmonary edema”.27, 28
Hypertensive Emergencies – On The Cutting Edge
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
on the degree of associated papilledema, uremia, acidosis
or hyperkalemia, present with defining clinical features
such as blurred vision, obtundation, Kussmaul respirations,
palpitations or ventricular dysrhythmias.
The work-up of a hypertensive emergency should be guided
by symptoms and signs identifiable on clinical examination
which should include funduscopy. Depending on the case,
the evaluation of HTN can involve the use of one or more
of the following modalities: plain film radiography (chest
x-ray), computed tomography, magnetic resonance imaging,
electrocardiography, or echocardiography. Laboratory testing
for renal dysfunction including a urinalysis and a basic
metabolic panel is recommended for most patients regardless
of their presentation. More sensitive novel biomarkers of
acute renal injury such as cystatin-c, neutrophil-gelatinase
associated lipocalin (NGAL), and kidney injury molecule-1
(KIM-1)29 may be incorporated in the future.
Asymptomatic Hypertension
The necessity for testing is to identify occult target-organ
damage in patients who have profound yet asymptomatic HTN
is not clear. In a recent multicenter study of 109 such patients,
clinically meaningful unanticipated test abnormalities were
detected in only 6%. None of these tests were felt by the
treating physician to be definitively attributable to HTN.30
Chest x-ray and electrocardiography in particular have
poor sensitivity for detection of subclinical cardiac disease,
especially LV hypertrophy, and a low likelihood of altering
clinical management.31 Investigation of other approaches to
detect clinically silent target-organ cardiac damage such as
measurement of serum natriuretic peptide (NP) biomarkers
such b-type NP (BNP) and n-terminal pro-BNP (NT-proBNP)
concentration have yielded conflicting results.32,33 Based on
21
Advancing the Standard of Care: Cardiovascular and
Neurovascular Emergencies
the findings of a recent study using echocardiography, the
prevalence of subclinical target-organ cardiac damage among
those with asymptomatic, severely elevated BP in the ED may
be far greater (approximately ~75%) than previously thought.34
Such data highlight the underlying risk for pressure-mediated
consequences of poor BP control among these patients and
suggest a potential benefit from more extensive screening
particularly in the outpatient setting.
vasodilators and dopamine agonists, concluded that despite
minor differences in the degree of BP lowering with one
antihypertensive class versus another, there was insufficient
evidence to determine which agent is most effective at reducing
morbidity or mortality.39 More recent data from The ECLIPSE
(Evaluation of CLevidipine In the Perioperative Treatment
of Hypertension Assessing Safety Events) trial, 40 which
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
options can facilitate utilization, enhance the ability to
Antihypertensive Therapy
direct intervention towards the appropriate precipitant, and
help avoid potentially harmful application. As shown in the
While some oral or sublingual medications have a relatively
following equation, mean arterial pressure (MAP) can be
quick onset of action, a more predictable, controlled
reduced by lowering any of the following parameters: systemic
antihypertensive effect can be achieved with parenteral agents
vascular resistance (SVR) which stems largely from regulation
making them preferable in the setting of a true hypertensive
of vasogenic tone in the arterioles, cardiac output (CO) which
emergency. According to data from the Studying the
is the pumping force of the heart, or central venous pressure
Treatment of Acute hyperTension (STAT) registry, labetalol
(CVP) which represents intravascular volume and, more
is the most common IV antihypertensive medication used for
roughly, hydrostatic force in the circulatory system. As with
management of severely elevated BP, defined in the registry
most physiology, these parameters do not work in isolation
as BP > 180/110 mm Hg, and nitroglycerin is the infusion
and perturbations in one may affect the other. For example
used most frequently.38 Direct comparison data are scant with
reducing CVP causes, by the Frank-Starling principle, a
regard to the relative efficacy of differing agents. A Cochrane
decrease in CO:
Review of 15 randomized controlled trials (n = 869) involving
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 p e 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,
specific
their effect directly either through and existing evidence,
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
in systemic (vs. cerebral) vascular
therapy is often administered simply of endogenous vasoconstrictors.
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 targetorgan 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 ongoing 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
heart failure patients with a hypertensive phenotype.48,49 A
recent subanalysis of 302 patients with acute heart failure in
the STAT registry found that adverse events were increased
when systolic BP was lowered beyond 120 mm Hg within 12
hours. This underscores the need for continued vigilance
when managing this condition.50
Understanding the importance of BP goals may be most
critical when treating neurologic hypertensive emergencies.
This is evident on review of the current American Heart
Association/American Stroke Association (AHA/ASA)
guidelines for acute ischemic stroke, which call for a BP
reduction to < 185/110 mm Hg when thrombolysis is planned.
Otherwise, antihypertensive therapy is only indicated when
BP is markedly elevated (> 220/120 mm Hg) with a goal to
decrease by approximately 15% at 24 hours post-onset.51 This
is supported by a meta-regression of BP control in stroke
which suggests an association between large falls or increases
in BP and worse outcome and modest reductions with a
decrease in death and/or dependency.52 Updated in 2010, the
AHA/ASA guidelines for acute intracerebral hemorrhage
24
With little exception, patients with
hypertensive emergency should be admitted to a monitored
setting. By virtue of the presenting clinical picture and the
corresponding use of IV antihypertensive medications, some
of which can produce precipitous drops in blood pressure,
many will require on-going treatment in a step-down or
intensive care unit. In certain circumstances, such as chest
pain with elevated BP or acute deterioration of chronic kidney
disease, short-term management in an observation unit may
be appropriate. This presumes that timely reassessment and
expeditious completion of the diagnostic work-up can be
assured in this setting.59
Prognosis
Outcomes associated with a given hypertensive emergency
are largely a function of underlying target-organ damage. Data
from STAT suggest that severe HTN is a high-risk condition
with in-hospital and 30-day mortality rates of 6.9% and 11%,
respectively, and a 90-day readmission rate of nearly 40%.21
When associated with moderate to severe acute kidney injury,
mortality is even greater (odds ratio = 1.05; p=0.03 per 10mL/min decline).60
Hypertensive Emergencies – On The Cutting Edge
Hy p e r t e n s ive E m ergencies – On The Cu t t ing Edge
Conclusion
Severe BP elevations in the ED are common. Differentiating
a true hypertensive emergency from poorly controlled chronic
HTN is critical to enable appropriate application of resources.
When indicated, therapeutic intervention should be driven
by condition-specific goals using agents appropriate for the
disease manifestations. Understanding the pharmacology of
antihypertensive medications can facilitate management and
better prepare the emergency physician to provide care for this
important group of patients.
14. Effects of treatment on morbidity in hypertension. Results in patients
with diastolic blood pressures averaging 115 through 129 mm Hg. JAMA
1967;202:1028-34.
15. Vlcek M, Bur A, Woisetschlager C, Herkner H, Laggner AN, Hirschl
MM. Association between hypertensive urgencies and subsequent
cardiovascular events in patients with hypertension. J Hypertens
2008;26:657-62.
16. Grossman E, Ironi AN, Messerli FH. Comparative tolerability profile of
hypertensive crisis treatments. Drug Saf 1998;19:99-122.
17. Varon J, Marik PE. The diagnosis and management of hypertensive crises.
Chest 2000;118:214-27.
18. Varon J. The diagnosis and treatment of hypertensive crises. Postgrad Med
2009;121:5-13.
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Hypertensive Emergencies – On The Cutting Edge