Current Diagnosis and Management of Hypertensive Emergency

CRITICAL CARE ISSUES FOR THE NEPHROLOGIST
Current Diagnosis and Management of Hypertensive
Emergency
Andrew R. Haas and Paul E. Marik
Division of Critical Care, Pulmonary, Allergy and Immunologic Disease, Jefferson Medical College of
Thomas Jefferson University, Philadelphia, Pennsylvania
ABSTRACT
The appropriate and timely evaluation and treatment of
patients with severely elevated blood pressure is essential to
avoid serious adverse outcomes. Most importantly, the distinction between a hypertensive emergency (crisis) and urgency
needs to be made. A sudden elevation in systolic (SBP) and/or
diastolic blood pressure (DBP) that is associated with acute
end organ damage (cardiovascular, cerebrovascular, or renal)
is defined as a hypertensive crisis or emergency. In contrast,
acute elevation in SBP and/or DBP not associated with evi-
dence of end organ damage is defined as hypertensive urgency.
In patients with a hypertensive emergency, blood pressure
control should be attained as expeditiously as possible with
parenteral medications to prevent ongoing and potentially permanent end organ damage. In contrast, with hypertensive
urgency, blood pressure control can be achieved with the use
of oral medications within 24–48 hours. This paper reviews the
management of hypertensive emergencies.
Hypertension is one of the most common chronic
medical conditions in the United States affecting close to
30% of the population over the age of 20 years (1,2).
While chronic hypertension is an established risk factor
for cardiovascular and cerebrovascular mortality and
end-stage renal disease, accelerated elevations in blood
pressure from various etiologies can result in acute end
organ damage and dysfunction. These acute blood pressure elevations are likely to be encountered by a wide
variety of clinicians and recognition and prompt evaluation and treatment are crucial to prevent permanent end
organ damage. Unfortunately, the impact of these clinical situations is often underappreciated such that appropriate and timely evaluation and treatment is delayed
leading to potentially serious adverse outcomes.
ciated with evidence of end organ damage is defined as
hypertensive urgency (7,8,11). To simplify the categorization of acute elevations in blood pressure, the term
‘‘malignant hypertension,’’ used to describe a syndrome
characterized by elevated blood pressure with encephalopathy or acute nephropathy, has been removed by the
National and International Blood Pressure Control
Guidelines and should be referred to as hypertensive
emergency or crisis instead (1,12).
Several points should be considered when distinguishing hypertensive emergency from hypertensive
urgency. The presence of end organ damage, not the
absolute blood pressure, is the differentiating factor
between hypertensive emergency and urgency. This
differentiation is critical, as how quickly and aggressively the quest for blood control is pursued is dictated
by the presence of end organ damage. Specifically, in
hypertensive emergency, blood pressure control should
be attained as expeditiously as possible with parenteral
medications to prevent ongoing and potentially permanent end organ damage. In contrast, with hypertensive urgency, blood pressure control can be achieved
with the use of oral medications within 24–48 hours
(7,8,11). This review will focus on the management of
hypertensive emergencies. Table 1 lists those clinical
conditions regarded as a hypertensive emergency.
The classification and approach to hypertension
undergoes periodic review by the Joint National
Committee (JNC) on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure with the
most recent report (JNC VII) having been released in
2003 (see Table 2) (1,12). Within this report, the classification of blood pressure was simplified compared with
previous JNC reports with the recognition of two stages
Definitions
The terminology applied to the clinical situations
associated with acute elevations in blood pressure has
been confusing and often misused. Most authorities concur that a sudden elevation in systolic (SBP) and/or diastolic blood pressure (DBP) that is associated with acute
end organ damage (cardiovascular, cerebrovascular, or
renal) is defined as hypertensive crisis or emergency (3–
11). In contrast, acute elevation in SBP or DBP not assoAddress correspondence to: Paul E. Marik, MD, Division of
Pulmonary and Critical Care Medicine, 834 Walnut Street,
Suite 650, Philadelphia, PA 19107, or e-mail: paul.marik@
jefferson.edu.
Seminars in Dialysis—Vol 19, No 6 (November–December)
2006 pp. 502–512
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HYPERTENSIVE EMERGENCY
TABLE 1. Hypertensive emergencies
Hypertensive encephalopathy
Acute aortic dissection
Acute myocardial infarction
Acute coronary syndrome
Pulmonary edema with respiratory failure
Severe pre-eclampsia, HELLP syndrome, eclampsia
Acute renal failure
Microangiopathic hemolytic anemia
HELLP, Hemolysis, elevated liver enzymes, low platelets.
TABLE 2. Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure categorization
of blood pressure (JNC VII) (1,12)
Blood Pressure Class Systolic BP (mmHg) Diastolic BP (mmHg)
Normal
Prehypertension
Stage I
Stage II
<120
121–139
140–159
>160
<80
80–89
90–99
>100
of hypertension (compared with the previous four stages
in JNC VI), but a new category called prehypertension
was added (13). Addition of this category was deemed
important to recognize that progression from this category to hypertension is often encountered, which subsequently puts patients at increased risk for the various
complications associated with chronic hypertension.
As mentioned previously, hypertension is an extremely common medical problem in the United States
with an ever-increasing incidence given increasing
obesity rates and the metabolic syndrome affecting the
nation (14–16). A striking increase in hypertension in
young adults and children because of obesity and sedentary lifestyles is also occurring (17,18). Most of these
patients have essential hypertension; however, only
68.9% were reported to be aware of their blood pressure problem, only 58.4% were under pharmacologic
treatment, and adequate blood pressure control was
achieved in only 30–50% of patients depending on the
population studied (2,19–25). Interestingly, even with
these poor statistics on blood pressure recognition,
treatment, and control, only 1% of these patients will
develop a true hypertensive emergency (26,27). As
would be expected, most patients who present with
hypertensive emergency have previously received a
diagnosis of hypertension with many of them having
inadequate blood pressure control on oral therapy. Of
note, because of many factors including access to
healthcare, economic demographics, and age and ethnic responses to various medications, the elderly and
African Americans are at higher risk of developing a
hypertensive emergency (11,28–30).
Pathophysiology
The pathophysiology of hypertensive emergency is
multifactorial and includes such factors as mechanical
stress and injury, endothelial damage, renin–angiotensin
system activation, and oxidative stress. The initial insult
is often difficult to ascertain, but abrupt release of
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humoral vasoconstrictors increase systemic vascular
resistance (31,32). The subsequent increase in blood
pressure generates mechanical stress and endothelial
injury leading to increased permeability, activation of
the coagulation cascade and platelets, and deposition of
fibrin. This process results in ischemia and the release
of additional vaso-active mediators generating a vicious
cycle of ongoing injury. The renin–angiotensin system is
often activated leading to further vasoconstriction and
the production of proinflammatory cytokines such as
IL-6 (33,34). Furthermore, NADPH oxidase activity is
increased and generates reactive oxygen species (35).
These collective mechanisms can culminate in end organ
hypoperfusion, ischemia, and dysfunction that manifest
as hypertensive emergency.
Initial Diagnostic Evaluation
Patients with hypertensive emergency usually present
for evaluation as a result of a new symptom complex
related to their elevated blood pressure. Patient triage
and physician evaluation should proceed expeditiously
to prevent ongoing end organ damage. A focused medical history that includes the use of any prescribed or
over-the-counter medications should be obtained. If
the patient is known to have hypertension, their hypertensive history, previous control, current antihypertensive medications with dosing, compliance, and time
from last dose are important facts to know as subsequent treatment decisions are made. Inquiry into use
of recreational drugs (amphetamines, cocaine, and
phencyclidine) or monoamine oxidase inhibitors
should be made. Confirmation of the blood pressure
should be obtained in both arms by a physician using
a blood pressure cuff of appropriate size. The appropriate size cuff is particularly important as the use of a
cuff too small for the arm size has been shown to artificially elevate blood pressure readings in obese
patients (36,37). As mentioned previously, it is important to note that the rate of blood pressure elevation
may be more important than the absolute value (38–
41). Patients with long-standing hypertension may
tolerate SBP > 200 mmHg or DBP > 150 mmHg
without developing clinical signs or symptoms of end
organ damage; however, in postoperative or pregnancy
patients a much lower but more rapidly progressive
increase in blood pressure may result in end organ
damage.
The physical examination should attempt to identify
evidence of end organ damage by assessing pulses in all
extremities, auscultating the lungs for evidence of pulmonary edema, the heart for murmurs or gallops, the
renal arteries for bruits, and performing a focused neurologic and fundoscopic examination. Headache and
altered levels of consciousness are the usual manifestations of hypertensive encephalopathy (38,42). Focal
neurological findings, especially lateralizing signs, are
uncommon in hypertensive encephalopathy, being more
suggestive of a cerebrovascular accident. Subarachnoid
hemorrhage should be considered in patients with a
sudden onset of a severe headache. The ocular examination may show evidence of advanced retinopathy with
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Haas and Marik
arteriolar changes, exudates, hemorrhages, or papilledema assisting in the identification of hypertensive encephalopathy. Cardiac evaluation should aim to identify
angina or myocardial infarction with the focus on clarifying any atypical symptoms such as dyspnea, cough, or
fatigue that may be overlooked (28,43). Severe renal
injury may result in hematuria or oliguria. On the basis
of this evaluation, the clinician should be able to distinguish between a hypertensive emergency and an urgency
and to formulate the subsequent plan for further diagnostic tests and treatment.
Initial objective evaluation should include a metabolic panel to assess electrolytes, creatinine, and blood
urea nitrogen; a complete blood count (and smear if
microangiopathic hemolytic anemia is suspected); a
urinalysis to look for proteinuria or microscopic
hematuria; and an electrocardiogram to assess for
cardiac ischemia (27). Supportive radiographic studies
such as a chest radiograph in a patient with dyspnea or
chest pain or a head computed tomography scan in a
patient with neurologic symptoms should be obtained
in the appropriate clinical scenario. If the physical
examination or clinical picture is consistent with aortic
dissection (unequal pulses and widened mediastinum),
a contrast-computed tomography scan or MRI of the
chest should be obtained promptly to rule out aortic
dissection. Although trans-esophageal echocardiography has excellent sensitivity and specificity for aortic
dissection, this study should not be performed until
adequate blood control has been achieved. In patients
presenting with pulmonary edema it is important to
obtain an echocardiogram to distinguish between diastolic dysfunction, transient systolic dysfunction, or mitral regurgitation (44). Many patients, particularly the
elderly, have a normal ejection fraction and in such
patients heart failure is caused by isolated diastolic dysfunction (44). The management of these patients differs
from those patients with predominant systolic dysfunction and those with transient mitral regurgitation (see
Table 3).
The unique clinical situation of pregnancy and
eclampsia is worth noting. Pre-eclampsia can range from
mild to life threatening, with features in severe disease
consistent with multiorgan damage (45,46). Patients
may have severe headache, seizures, acute delirium,
visual defects, right upper quadrant pain, oliguria, and
congestive heart failure. Intracerebral hemorrhage is a
devastating and often fatal complication (45,47). While
antihypertensive agents are used to control blood pressure, rapid assessment and decisions regarding risk to
mother and fetus need be considered as the only definitive therapy is delivery of the fetus (45,46).
Initial Management
The majority of patients in whom severe hypertension
(SBP > 160, DBP > 100 mmHg) is identified on initial evaluation will not have evidence of end organ damage and thus have hypertensive urgency. As no acute
end organ damage is present, these patients may present
for evaluation of another complaint, and the elevated
blood pressure may represent an acute recognition of
chronic hypertension. In these patients, utilizing oral
medications to lower the blood pressure gradually over
24–48 hours is the best approach to management
(7,8,11). In fact, rapid reduction of blood pressure may
be associated with significant morbidity in hypertensive
urgency because of a rightward shift in the pressure/flow
auto-regulatory curve in critical arterial beds (cerebral,
coronary, and renal) (48). Rapid correction of severely
elevated blood pressure below the autoregulatory range
of these vascular beds can result in a marked reduction
in perfusion causing ischemia and infarction (39,49–51).
Therefore, although the blood pressure must be reduced
in these patients, it must be lowered in a slow and controlled fashion to prevent this impaired autoregulatory
hypoperfusion problem.
This autoregulatory problem also occurs in patients
with hypertensive emergency; and as end organ damage
is already present, rapid and excessive correction of the
blood pressure can further reduce perfusion and propagate the ongoing injury. Therefore, patients with a
hypertensive emergency are best managed with a
continuous infusion of a short-acting, titratable antihypertensive agent. Because of unpredictable pharmacodynamics, the sublingual and intramuscular route
should be avoided. Patients with a hypertensive emergency should be managed in an intensive care unit with
close monitoring. For those patients with the most
severe clinical manifestations or with the most labile
blood pressure, intra-arterial blood pressure monitoring
may be prudent.
TABLE 3. Recommended antihypertensive agents for hypertensive crises
Condition
Acute pulmonary edema-systolic dysfunction
Acute pulmonary edema-diastolic dysfunction
Acute myocardial ischemia
Hypertensive encephalopathy
Acute aortic dissection
Pre-eclampsia, eclampsia
Acute renal failure/microangiopathic anemia
Sympathetic crisis/cocaine overdose
Preferred antihypertensive agent
Nicardipine, fenoldopam, or nitroprusside in combination
with nitroglycerin and a loop diuretic
Esmolol, metoprolol, labetalol, or verapamil in combination
with low-dose nitroglycerin and a loop diuretic
Labetalol or esmolol in combination with nitroglycerin
Labetalol, nicardipine, or fenoldopam
Labetalol or combination of nicardipine or fenoldopam and
esmolol or combination of nitroprusside with either esmolol
or IV metoprolol
Labetalol or nicardipine
Fenoldopam or nicardipine
Verapamil, diltiazem, or nicardipine in combination with a
benzodiazepine
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HYPERTENSIVE EMERGENCY
There are a variety of rapid-acting intravenous agents
that are available for use in patients with hypertensive
emergency, and the agent of choice depends on which
manifestation of end organ damage is present and the
available monitored setting (see Table 3). As mentioned
previously, rapid-acting intravenous agents should not
be used outside of an intensive care unit monitored setting to prevent a precipitous reduction of blood pressure,
which may have significant morbidity or mortality. The
immediate goal is to reduce DBP by 10–15% or to about
110 mmHg over a period of 30–60 minutes. In aortic
dissection, this goal should be achieved within 5–10 minutes. Once there is a stable blood pressure with intravenous agents and end organ damage ceased, oral therapy
can be initiated as the intravenous agents are slowly
titrated down.
One very important consideration prior to initiating
intravenous therapy is to assess the patient’s volume
status. Because of pressure natriuresis, patients with
hypertensive emergencies may be volume depleted and
restoration of intravascular volume with intravenous
saline will serve to restore organ perfusion and prevent a
precipitous fall in blood pressure when antihypertensive
regimens are initiated.
Pharmacologic Agents Available for
Treatment of Hypertensive Emergency
Given the aforementioned problem related to an
abnormal autoregulatory response in many patients
with hypertensive emergency, the ideal agent for these
situations would be fast acting and rapidly reversible to
allow for optimal titration of blood pressure control.
Intravenous antihypertensive agents available for the
management of hypertensive emergencies fall into the
broad categories of arterial vasodilators (hydralazine,
fenoldopam, nicardipine, clevidipine, and enalaprilat);
venous vasodilators (nitroglycerin); mixed venous and
arterial vasodilators (sodium nitroprusside); negative inotropic/chronotropic agents with (labetalol) or without
vasodilator properties (esmolol); and alpha-adrenergic
receptor blockers for increased sympathetic activity
(phentolamine). At this time the preferred agents for the
management of hypertensive emergency include labetalol, esmolol, nicardipine, and fenoldopam. Phentolamine and trimethaphan camsylate are less commonly used
today; however, they may be useful in particular situations such as catecholamine-induced hypertensive crises
(i.e., pheochromocytoma) (26,38–40,52,53). The preferred antihypertensive for each hypertensive emergency
is listed in Table 3. The antihypertensive agents that have
been used for the treatment of a hypertensive emergency
are reviewed individually and alphabetically below. The
dosage and adverse effects of these agents are summarized in Table 4.
Clevidipine. Clevidipine is a relatively new agent
under investigation for management of postanesthesia
hypertension and possibly hypertensive emergencies
(54). It is an ultrashort acting vaso-selective calcium
channel antagonist with rapid onset and very short halflife (<1 min). Similar to esmolol, it is rapidly metabolized by red blood cell esterases; thus its metabolism is
not affected by renal or hepatic function. Clevidipine
reduces blood pressure by a direct and selective effect on
arterioles, thereby reducing afterload without affecting
cardiac filling pressures or causing reflex tachycardia
(54). In fact, it increases stroke volume and cardiac output. Moreover, it has been shown to protect against
ischemia/reperfusion injury in an animal model of myocardial ischemia and to maintain renal function and
splanchnic blood flow when compared with nitroprusside (55–57).
Several small trials have compared clevidipine with
nitroprusside in the management of anesthetized
patients with postoperative hypertension. These studies
report similar findings: clevidipine is as effective at blood
pressure control as nitroprusside, but it has less effect on
cardiac filling pressures and heart rate (58,59). Although
no studies have investigated the role of clevidipine in
hypertensive emergency, its profile of excellent blood
pressure control, fewer hemodynamic and cardiac side
effects, and a short half-life, make it a potentially ideal
drug for the treatment of hypertensive emergency. At
TABLE 4. Recommended antihypertensive agents for hypertensive crises dosage and adverse effects of commonly used parenteral
antihypertensive medications
Agent
Enalaprilat
Esmolol
Fenoldopam
Labetalol
Nicardipine
Nitroglycerin
Nitroprusside
Phentolamine
Dosage
1.25 mg over 5 min every 4–6 hr, titrated by 1.25 mg
increments at 12- to 24-hr intervals to a maximum
of 5 mg every 6 hr
500 lg/kg loading dose over 1 min, infusion at
25–50 lg/kg/min, increased by 25 lg/kg/min every
10–20 min to maximum of 300 lg/kg/min
0.1 lg/kg/min initial dose, 0.05–0.1 lg/kg/min
increments to a maximum of 1.6 lg/kg/min
20 mg initial bolus, 20–80 mg repeat boluses or
start infusion at 2 mg/min with a maximum
24 hr dose of 300 mg
5 mg/hr, increased at 2.5 mg/hr increments
every 5 min to a maximum of 15 mg/hr
5 ug/min, titrated by 5 ug/min every
5–10 min to a maximum of 100 ug/min
0.5 lg/kg/min, increased to a maximum
of 2 lg/kg/min to avoid toxicity
1–5 mg boluses, maximum 15-mg dose
Adverse effects
Variable response, potential hypotension in high rennin
states, headache, dizziness
Nausea, flushing, first degree heart block, infusion
site pain
Nausea, headache, flushing
Hypotension, dizziness, nausea/vomiting, paresthesias,
scalp tingling, bronchospasm
Headache, dizziness, flushing, nausea, edema, tachycardia
Headache, dizziness, tachyphylaxis
Thiocyanate and cyanide toxicity, headache, nausea/vomiting,
muscle spasm, flushing
Flushing, tachycardia, dizziness nausea/vomiting
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Haas and Marik
this time clevidipine is not available in the United States
for use outside of clinical trials.
Enalaprilat. As the intravenous form of the oral
angiotensin converting enzyme (ACE) inhibitor enalapril, enalaprilat has gained popularity in use in some
hypertensive emergencies. It has an onset of action
within 15 minutes, but its peak effect may not be seen
for up to 4 hours and its duration of action can last from
12 to 24 hours. The response to enalaprilat can be variable and unpredictable as a result of variable plasma volume and plasma rennin activity present in patients with
hypertensive emergency (60). Hypovolemic patients with
high plasma rennin activity may have an excessive and
deleterious hypotensive response. Because of these factors, the delayed peak effect, and its long duration of
action, enalaprilat is not ideal for rapid titration of blood
pressure in hypertensive emergency. Importantly, this
agent is contraindicated in pregnancy (61,62).
Esmolol. Esmolol is a cardioselective, beta-adrenergic blocking agent with an almost immediate onset of
action, a short half-life of approximately 9 minutes, and
a duration of action of 10–30 minutes (63–65). Its short
half-life is because of rapid hydrolysis by red blood cell
esterases and thus is not dependent on renal or hepatic
function for metabolism. These pharmacokinetic and
dynamic properties make esmolol an ideal agent for use
in critically ill patients with supraventricular dysrhythmias, patients with postoperative hypertension, and in
patients with hypertensive emergency (66,67). Esmolol
can be administered via bolus or continuous infusion.
The recommended bolus dose is 0.5–1.0 lg/kg with an
infusion rate at 50–200 lg/kg/min. Because of its short
duration of action, the main side effects of bradycardia
and excessive hypotension because of negative chronotropic and inotropic effects are rapidly reversed by slowing or discontinuing the infusion. For hypertensive
emergency, esmolol often must be combined with a
vasodilating agent to achieve optimal blood pressure
control.
Fenoldopam. Fenoldopam is unique among the
parenteral blood pressure agents as it mediates peripheral vasodilation by acting on peripheral dopamine-1
receptors. Interestingly, it has the distinct advantage of
mediating renal arterial vasodilation by activating dopamine receptors on the proximal and distal tubules (10
times more potent than dopamine), and it inhibits
sodium reabsorption, thereby promoting natriuresis and
diuresis (68). The onset of action is within 5 minutes
with a maximal response achieved by 15 minutes (69–
71). The duration of action is 30–60 minutes without
rebound hypertension when the infusion is discontinued.
It is quickly and extensively metabolized by conjugation
in the liver without the participation of the P450-cytochrome complex. After a starting dose of 0.1 lg/kg/min,
the dose can be titrated every 15 minutes depending on
the blood pressure response. It has been demonstrated
to have a dose-dependent decrease in blood pressure
in the infusion range of 0.03–0.3 lg/kg/min (72). No
adverse effects have been noted with its use.
In a prospective, randomized, open-label, multicenter
clinical trial, fenoldopam was as effective as nitroprusside for the treatment of hypertensive emergency. However, fenoldopam has been demonstrated to improve
creatinine clearance, urine flow rates, and sodium excretion in severely hypertensive patients with both normal
and impaired renal function (73–75). Consequently, fenoldopam may be particularly beneficial in patients with
impaired renal function with hypertensive emergency
(76). Of note, fenoldopam is contraindicated in patients
with glaucoma.
Hydralazine. Hydralazine is a direct arteriolar
vasodilator with little or no effect on the venous circulation and often causes reflex sympathetic stimulation.
Hydralazine should therefore be used with caution in
patients with coronary artery disease or aortic dissection
unless a beta-blocking agent is used concomitantly. Furthermore, although hydralazine has a rapid onset within
5–15 minutes, there can be an unpredictable and often
precipitous drop in blood pressure that can last up to
12 hours. Therefore, it can be very difficult to titrate the
blood pressure response, and it is best to avoid hydralazine for the management of hypertensive emergency.
Traditionally, because of limited crossing of the uteroplacental circulation, hydralazine has been the drug of
choice for the treatment of pre-eclampsia or eclampsia.
Labetalol. Labetalol is a combined selective
alpha-1 and nonselective beta-adrenergic receptor blocker with an alpha- to beta-blocking ratio of 1:7 (77). Labetalol is metabolized by the liver to form an inactive
glucuronide conjugate (78). Of note, labetalol reduces
afterload without reducing cerebral, coronary, or renal
blood flow (79–82). Labetalol has a rapid onset of action
(5 min or less), reaches it peak action by 5–15 minutes,
and persists for 2–4 hours (78,83). The initial bolus dose
is 20 mg followed by repeat doses of 20–80 mg at
10-minute intervals to a total dose of 300 mg until the
therapeutic blood pressure goal is achieved. Alternatively, after the initial oral loading dose of 20 mg, an infusion of 0.5–2 mg/min of labetalol could be commenced
and titrated to achieve blood pressure goals.
Labetalol is safe in patients with acute coronary syndromes with systemic hypertension, but should be avoided in patients with asthma, chronic obstructive
pulmonary disease (COPD), systolic heart failure, bradycardia, or greater than first degree heart block. Labetalol has been used in pregnancy-related hypertensive
emergency as little placental transfer occurs (79). The
drug is effective and well-tolerated in patients with all
grades of hypertension, but is of particular value in special subgroups such as black patients, the elderly, and
patients with renal hypertension.
Nicardipine. Nicardipine is a second generation
dihydropyridine calcium channel blocker with high vascular selectivity and strong cerebral and coronary vasodilatory activity; consequently, it has been shown to
reduce both cardiac and cerebral ischemia in patients
with a hypertensive emergency (84). It can be given as
an intravenous infusion and is readily titratable. Its
HYPERTENSIVE EMERGENCY
onset of action is between 5 and 15 minutes, with a
duration of action of 4–6 hours. The initial dose is
5 mg/hr increasing the infusion rate by 2.5 mg/hr every
5 minutes to a maximum of 15 mg/hr until the desired
blood pressure is attained.
Several studies have investigated the role of nicardipine when administered to patients with severe hypertension (85,86). In two multicenter, prospective randomized
trials comparing nicardipine with nitroprusside in
patients with severe postoperative hypertension, Halpern et al. and Neuteal et al. reported that nicardipine is as
effective as nitroprusside (87,88). In a recent prospective
study comparing nicardipine with nitroprusside in
patients who presented to the emergency department
with hypertensive emergency and acute pulmonary
edema, nicardipine, and nitroprusside were equally
effective at controlling blood pressure without significant
differences in heart rate, respiratory rate, or oxygen saturation, but there were greater declines in serum norepinephrine levels in the nicardipine group compared with
nitroprusside (89). This fact may suggest that nicardipine
may be advantageous over nitroprusside to prevent the
cycle of perpetual vascular injury by decreasing norepinephrine levels. A useful therapeutic benefit of nicardipine is that the agent has been demonstrated to increase
both stroke volume and coronary blood flow with a favorable effect on myocardial oxygen balance (84,90–93).
This property is useful in patients with coronary artery
disease and systolic heart failure. In addition, nicardipine
has been shown to reduce cerebral ischemia (84).
Nifedipine. Oral or sublingual nifedipine has been
widely used in many clinical situations associated with
elevated blood pressure. Although it is not absorbed
through the buccal mucosa, it is rapidly absorbed
through the gastrointestinal tract after the capsule is dissolved and causes direct arteriole vasodilation (94). A
rapid and significant decrease in blood pressure occurs
within 5–10 minutes, peaks at 30–60 minutes, and lasts
up to 6 hours (95). As effective as nifedipine is at vasodilation, sudden and dramatic declines in blood pressure
may precipitate cerebral, renal, and cardiac ischemic
events that have been associated with fatal outcomes
(84,94,95). Because of the difficulty in controlling the
response to nifedipine, this drug should not be used for
blood pressure control in hypertensive emergencies.
Nitroglycerin. For blood pressure control, nitroglycerin is administered as an intravenous infusion mediating its blood pressure effect primarily by causing
venodilation and decreased preload and cardiac output.
It is an ineffective arteriolar vasodilator and as such is
not an effective agent for use in hypertensive emergency;
however, it is a valuable therapy for patients with severe
hypertension and symptomatic acute coronary syndromes or pulmonary edema and in postcoronary artery
bypass surgery. The initial dose of nitroglycerin is 5 lg/
min, which can be titrated to a maximum of 100 lg/min.
The onset of action is 2–5 minutes with a duration of
action of 5–10 minutes. Headache because of cerebral
vasodilation and tachycardia resulting from reflex sympathetic activation are the primary side effects.
507
Phentolamine. Phentolamine is a pure alphaadrenergic antagonist utilized for the management of
catecholamine-induced hypertensive emergencies (e.g.,
pheochromocytoma or tyramine ingestion in a
patient being treated with a monoamine oxidase
inhibitor) (26,38–40,52,53). It is administered intravenously in 1–5 mg boluses with an immediate effect
that can last up to 15 minutes. Continuous infusion
can be done if necessary, but phentolamine may
cause tachydysrhythmias or angina. Once initial catecholamine-induced hypertension is under control,
oral phenoxybenzamine, a long-acting alpha-adrenergic antagonist should be administered.
Sodium Nitroprusside. Sodium nitroprusside is
considered by many to be the most effective parenteral
drug for the treatment of most hypertensive emergencies
as it is an effective arterial and venous vasodilator,
thereby decreasing afterload and preload. It has an
extremely rapid onset (within seconds) and a duration of
action of 1–2 minutes with a plasma half-life of 3–4 minutes. Consequently, abrupt cessation of infusion will
cause blood pressure to rise almost immediately and
return to preinfusion levels within 1–10 minutes.
Even though nitroprusside has an ideal pharmacokinetic and pharmacodynamic profile for the treatment of
hypertensive emergency, it has many limitations. It is
light sensitive and requires special handling to prevent
drug degradation (72). It requires intra-arterial monitoring to prevent excessive blood pressure correction. Cerebral blood flow may decrease in a dose-dependent
manner and both clinical and experimental evidence has
demonstrated that it may increase intracranial pressure
(98–101). Furthermore, in patients with coronary artery
disease, the significant afterload reduction may reduce
coronary arterial flow (coronary steal phenomenon)
(102). Interestingly, in a randomized, placebo-controlled
trial, nitroprusside increased mortality (mortality at
13 weeks, 24.2% vs. 12.7%) when infused in early hours
after acute myocardial infarction (103).
The greatest limitation to the prolonged use of nitroprusside is the risk of developing fatal cyanide or thiocyanate toxicity. Nitroprusside contains 44% cyanide by
weight, which is released nonenzymatically in a dosedependent manner from nitroprusside. Cyanide is then
metabolized in the liver in a reaction that requires thiosulfate to generate thiocyanate, which is 100 times less
toxic than cyanide and is excreted largely by the kidney.
Therefore, cyanide removal requires the bioavailability
of thiosulfate and adequate liver and renal function
(104,105). Coma, encephalopathy, convulsions, unexplained cardiac arrest, and irreversible neurologic abnormalities have been documented as a result of cyanide
toxicity (106,107). The current methods of monitoring
for cyanide toxicity are insensitive and not widely available and the clinical manifestations of cyanide toxicity
often present too late for effective treatment to be initiated (104). Data suggests that infusion rates of 4 lg/kg/
min for as little as 2–3 hours may lead to toxic cyanide
levels (104).
Given the potential for potentially fatal toxicity with
nitroprusside, this drug should only be used when
508
Haas and Marik
other parenteral antihypertensive agents are not
available. As the risk of developing cyanide toxicity is
increased with higher doses (>2 lg/kg/min), longer
infusion times (>24–48 hr), and with liver and renal
insufficiency, treatment should be as brief as possible
with the lowest dose (should not exceed 2 lg/kg/min)
and in patients with normal liver and renal function. If
doses between 4 and 10 lg/kg/min are being used, an
infusion of thiosulfate should be used to prevent the
accumulation of cyanide (105). Similarly, it has been
shown that a continuous infusion of hydroxycobalamin is safe and effective in preventing and treating cyanide toxicity associated with nitroprusside (108).
Considering the limitations associated with the use of
nitroprusside, its use should be avoided if other agents
are available.
Special Circumstances Regarding
Management
Acute Aortic Dissection. Patients who present to
the emergency department with the presumptive diagnosis of aortic dissection should be started on parenteral
antihypertensives as soon as possible. The objective of
treatment is to lower the pulsatile load and aortic stress
by lowering cardiac output and blood pressure in the
hopes of retarding the propagation of dissection and
preventing aortic rupture. A vasodilator alone is not
ideal as this can promote reflex tachycardia, increase
aortic ejection velocity, and promote dissection propagation; therefore, the combination of a beta-adrenergic
antagonist and a vasodilator is the standard approach to
treatment. Esmolol is the beta-adrenergic antagonist
of choice with metoprolol as a suitable alternative
(109,110). Although nitroprusside has traditionally been
used as the vasodilator of choice, nicardipine or fenoldopam are less toxic, equally effective alternatives
(110,111). All patients with aortic dissection require cardiovascular surgical consultation to determine if surgical
management is necessary. Unless significant medical
comorbidities are present, surgery is indicated for all
patients with ascending aorta type A dissection
(112,113). Patients with type B dissections and distal aortic dissections can be managed with aggressive blood
pressure control as outcomes have been shown to be the
same with either medical or surgical treatment unless
complications such as leak, rupture, or impaired flow to
vital organs supervene (114).
Stroke. Stroke is the number one cause of permanent disability in adults in the United States. Most
patients who present with acute ischemic or hemorrhagic
stroke will present with elevated blood pressure likely as
an adaptive mechanism to maintain blood flow to the
affected area (115). In these clinical situations, the elevated systemic blood pressure is not a manifestation of
hypertensive emergency, but rather a protective physiologic response to maintain cerebral perfusion pressure to
the vascular territory affected by ischemia. Because of
impaired cerebral autoregulation from chronic hypertension, rapid blood pressure correction can reduce cerebral perfusion and extend the ischemic penumbra to
the entire arterial territory with catastrophic consequences. There is no evidence that this elevated blood
pressure affects the outcome during the acute phase of
an ischemic stroke (39,116,117).
The American Heart Association currently recommends that hypertension in the setting of acute ischemic stroke be treated ‘‘rarely and cautiously’’ (118,119).
Most experts agree that a 10–15%, but not greater
than 20%, reduction in blood pressure during the first
24 hours is an acceptable goal in patients with severe
elevations of blood pressure (DBP > 120 mmHg)
following an acute ischemic stroke (39,116,117,120).
Interestingly, Semplicini et al. demonstrated a better
neurologic outcome in patients with higher presenting
systemic blood pressure, suggesting that lowering the
blood pressure could be harmful in these situations
(121). Furthermore, induced hypertension may be
beneficial in patients with an acute ischemic stroke. In
fact, Rordorf et al. used phenylephrine to increase the
SBP by 20% (but not to exceed 200 mmHg) in patients
with an acute stroke and demonstrated signs of neurologic improvement in seven out of 13 patients (122).
In the setting of hemorrhagic stroke with intracerebral hematoma, blood pressure control is recommended when SBP is greater than 200 mmHg and/or DBP
is greater than 110 mmHg (116,117,123). However, a
rapid decline in blood pressure within 24 hours of
presentation has been demonstrated to be independently associated with increased mortality in patients
with intracranial hemorrhage (124). Judicious restraint
in controlling blood pressure in the setting of ischemic
or hemorrhagic stroke is therefore warranted.
Pre-eclampsia and Eclampsia. The presentation of a patient with pregnancy-induced hypertension
may range from a mild to a life-threatening disease
process (46). Most pre-eclamptic patients are vasoconstricted and hemoconcentrated. Initial therapy of
pre-eclampsia includes volume expansion, magnesium
sulfate (MgSO4) for seizure prophylaxis, and blood
pressure control (125–127). Delivery is the definitive
treatment for pre-eclampsia and eclampsia.
Magnesium sulfate is usually given as a loading dose
of 4–6 grams in 100 cc D5 1/4 NS over 15–20 minutes
followed by a constant infusion of 1–2 g of MgSO4 per
hour depending on urine output and deep tendon
reflexes, which are checked on an hourly basis. The
next step in the management of pre-eclampsia is to
reduce the blood pressure to a safe range being diligent
to avoid significant hypotension. The objective of treating severe hypertension is to prevent intracerebral hemorrhage and cardiac failure without compromising
cerebral perfusion or jeopardizing uteroplacental blood
flow, which is already reduced in many women with
eclampsia (46). Most authorities and the current guidelines from the American College of Obstetricians and
Gynecologists recommend keeping the SBP between
140 and 160 mmHg and the DBP between 90 and
105 mmHg (45,46,128,129). This recommendation is
supported by a recent study, which demonstrated that
a SBP > 160 mmHg was the most important factor
associated with a cerebrovascular accident in patients
509
HYPERTENSIVE EMERGENCY
with severe pre-eclampsia and eclampsia (47). This
would suggest that a SBP between 155 and 160 mmHg
should be the primary trigger to initiate antihypertensive therapy in a patient with severe pre-eclampsia or
eclampsia (47,130).
Hydralazine has been recommended as the drug of
choice to treat severe pre-eclampsia and eclampsia since
the early 1970s (131). However, hydralazine has a number of properties that make it unsuitable for this indication. Its side effects (such as headache, nausea, and
vomiting) are common and mimic symptoms of deteriorating pre-eclampsia. Most importantly, however, it
has a delayed onset of action, an unpredictable hypotensive effect, and a prolonged duration of action. These
properties may result in a precipitous hypotensive overshoot compromising both maternal cerebral blood flow
and uteroplacental blood flow. Indeed, in a meta-analysis published by Magee et al. hydralazine was associated
with an increased risk of maternal hypotension, which
was associated with an excess of cesarean sections, placental abruptions, and low APGAR scores (132). Based
on the available data, we suggest that hydralazine should
not be used as first line treatment of severe hypertension
in pregnancy. Similarly, sublingual or oral nifedipine
should be avoided in this setting. Our preference is intravenous labetalol or nicardipine, which are easier to
titrate and have a more predictable dose response than
hydralazine. Both agents appear to be safe and effective
in hypertensive pregnant patients (133–137).
Sympathetic Crises. The most commonly
encountered sympathetic crises revolve around the recreational use of sympathomimetic drugs such as cocaine,
amphetamine, or phencyclidine. Rarely, these crises may
be seen with pheochromocytoma, a patient taking a
monoamine oxidase inhibitor who ingests a tyraminecontaining food, or patients who abruptly stop
antihypertensive medications such as clonidine or
beta-adrenergic antagonists.
In the clinical situations characterized by sympathetic overstimulation, beta-adrenergic antagonists
should be avoided to prevent vascular beta-receptor
antagonism resulting in unopposed alpha-adrenergic
activity and potential increase in blood pressure. In
fact, in cocaine-induced hypertensive emergency, the
use of beta-adrenergic blockade can increase coronary
vasoconstriction, fail to control heart rate, increase
blood pressure, and decrease survival (138–140). Interestingly, although labetalol is traditionally considered
as the ideal agent because of its alpha- and beta-adrenergic antagonism, experimental studies do not support
its use in this clinical setting (63,141–144). Blood
pressure control is best achieved with nicardipine, fenoldopam, or verapamil in combination with a benzodiazepine (140,145,146). Phentolamine is an alternative
agent (147).
Conclusions
Hypertensive emergency represents a serious medical
condition with the potential for permanent end organ
damage and significant morbidity and mortality. Recognition of elevated blood pressure with evidence of end
organ damage should prompt initiation of timely and
appropriate parenteral antihypertensive regimens to prevent on-going end organ damage. With the development
of pharmacologic agents in the last decade, the traditional agent, nitroprusside, should be utilized significantly less given that the other agents such as esmolol,
nicardipine, and fenoldopam are now available and are
equally effective with fewer adverse effects. It should be
stressed that the use of oral or sublingual nifedipine
should be avoided to prevent increased mortality.
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