Critical Care October 2003 Vol 7 No 5Varon and Marik
Hypertension is an exceedingly common disorder in western
societies, and as such practitioners of most clinical special-
ties are likely to encounter patients with acute, severe eleva-
tions in blood pressure. In particular, hypertensive
emergencies and hypertensive urgencies (see the section on
Teminology, definitions, and misconceptions, below) are com-
monly encountered in the emergency department, operating
room, postanaesthesia care unit, and intensive care units
[1–8]. The most important factor that limits morbidity and
mortality from these disorders is prompt and carefully consid-
ered therapy . Unfortunately, hypertensive emergencies
and urgencies are among the most misunderstood and mis-
managed of acute medical problems seen today. Indeed, the
reflex of rapidly lowering an elevated blood pressure is asso-
ciated with significant morbidity and death. Clinicians dealing
with hypertensive emergencies and urgencies should be
familiar with the pathophysiology of the disease and the prin-
ciples of treatment. This article reviews current concepts, and
common misconceptions and pitfalls in the diagnosis and
management of patients with severe hypertension.
Terminology, definitions, and misconceptions
Efforts to classify hypertension on the basis of specific values
have existed for the past 100 years. In the USA, the Joint
National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure has classified hyperten-
sion according to the degree of elevation in blood pressure
[1,10]. According to the most recent report by this committee
(the JNC 7 Report ), patients with stage 1 hypertension
have a systolic blood pressure of 140–159mmHg or a dias-
tolic blood pressure of 90–99mmHg. Those patients with
stage 2 hypertension have a systolic blood pressure greater
than 160mmHg or a diastolic blood pressure greater than
100mmHg. Although not specifically addressed in the JNC7
Report, patients with a systolic blood pressure greater than
179mmHg or a diastolic blood pressure that is greater than
109mmHg are usually defined as having ‘severe or acceler-
A number of different terms have been applied to acute severe
elevations in blood pressure, and the current terminology is
somewhat confusing. However, most authorities have defined
hypertensive crises or emergencies as a sudden increase in
systolic and diastolic blood pressures associated with ‘acute
end-organ damage’ (i.e. cardiovascular, renal, central nervous
system) that requires immediate management. On the other
hand, the term ‘hypertensive urgency’ has been used for
patients with severely elevated blood pressure without acute
Clinical review: The management of hypertensive crises
Joseph Varon1and Paul E Marik2
1Associate Professor of Medicine, Pulmonary and Critical Care Section, Baylor College of Medicine, Clinical Associate Professor, The University of
Texas Health Science Center, Houston, Texas, USA
2Professor of Critical Care and Medicine, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
Correspondence: Paul Marik, email@example.com
Published online: 16 July 2003
This article is online at http://ccforum.com/content/7/5/374
© 2003 BioMed Central Ltd (Print ISSN 1364-8535; Online ISSN 1466-609X)
Critical Care 2003, 7:374-384 (DOI 10.1186/cc2351)
Hypertension is an extremely common clinical problem, affecting approximately 50 million people in the
USA and approximately 1 billion individuals worldwide. Approximately 1% of these patients will
develop acute elevations in blood pressure at some point in their lifetime. A number of terms have been
applied to severe hypertension, including hypertensive crises, emergencies, and urgencies. By
definition, acute elevations in blood pressure that are associated with end-organ damage are called
hypertensive crises. Immediate reduction in blood pressure is required only in patients with acute end-
organ damage. This article reviews current concepts, and common misconceptions and pitfalls in the
diagnosis and management of patients with acutely elevated blood pressure.
Keywords aortic dissection, β-blockers, calcium channel blockers, fenoldopam, hypertension, hypertensive crises,
hypertensive encephalopathy, labetalol, nicardipine, nitroprusside, pregnancy
Available online http://ccforum.com/content/7/5/374
end-organ damage [2–5,8,11,12]. It is important to emphasize
that the clinical distinction between hypertensive emergencies
(crises) and hypertensive urgencies depends on the presence
of acute target organ damage, rather than the absolute level of
blood pressure. Table 1 lists those clinical conditions that meet
the diagnostic criteria for hypertensive emergencies. The term
‘malignant hypertension’ has been used to describe a syn-
drome characterized by elevated blood pressure accompanied
by encephalopathy or acute nephropathy [1,13]. However, this
term has been removed from national and international blood
pressure control guidelines [1,10], and this condition is best
referred to as a hypertensive emergency or crisis.
The dynamic physiologic changes that occur in the early
postoperative period deserve special mention. Postoperative
hypertension has arbitrarily been defined as a systolic blood
pressure greater than 190mmHg and/or diastolic blood pres-
sure greater than 100mmHg on two consecutive readings
following surgery [14,15]. Postoperative hypertension may
have significant adverse sequelae in both cardiac and non-
cardiac patients . The transient but potentially life-threat-
ening nature of postoperative hypertension and the unique
clinical factors present in the postoperative period require
that this clinical syndrome be given individual consideration.
Another group of patients that requires special mention is
those pregnant patients who develop elevations in blood
pressure during, immediately before, or after delivery. The
presence of a systolic pressure greater than 169mmHg or a
diastolic pressure greater than 109mmHg in a pregnant
woman is considered a hypertensive emergency that requires
immediate pharmacologic management [3,17,18].
Hypertension is an extremely common clinical problem in
western countries. Hypertension affects approximately
50 million people in the USA and approximately 1 billion indi-
viduals worldwide [1,19,20]. Most of these patients have
essential hypertension and approximately 30% are undiag-
nosed [1,19,21]. Furthermore, only between 14% and 29%
of American patients with hypertension have adequate blood
pressure control . The incidence of hypertension
increases with age. In the Framingham heart study  the
incidence of hypertension increased in men from 3.3% at age
30–39 years to 6.2% at age 70–79 years. Overall, the preva-
lence and incidence of hypertension are slightly higher in men
than in women [19,20,22,23]. The incidence of hypertension
in African-Americans is about twofold higher than in whites
[19,20,22,23]. The prevalence and incidence of hypertension
in Mexican-Americans are similar to or lower than those in
non-Hispanic whites [19,23,24].
The syndrome of hypertensive emergency was first described
by Volhard and Fahr in 1914 and was characterized by
severe accelerated hypertension, accompanied by evidence
of renal disease and by signs of vascular injury to the heart,
brain, retina and kidney, and by a rapidly fatal course ending
in heart attack, renal failure, or stroke . The first large
study of the natural history of malignant hypertension was
published in 1939 before the widespread use of antihyper-
tensive agents . In that seminal report by Keith and col-
leagues, untreated malignant hypertension had a 1-year
mortality of 79% and a median survival of 10.5 months.
It has been estimated that approximately 1% of patients with
hypertension will develop a hypertensive crises at some point
during their lives [27,28]. Before the advent of antihyperten-
sive therapy, this complication occurred in up to 7% of the
hypertensive population . The epidemiology of hyperten-
sive crises parallels the distribution of essential hypertension
in the community, being much higher among African-Ameri-
cans and the elderly; however, men are affected two times
more frequently than are women [9,12,30,31]. Most patients
who present with a hypertensive crisis have previously been
diagnosed as hypertensive and many have been prescribed
antihypertensive therapy with inadequate blood pressure
control [9,12,30]. The lack of a primary care physician and
failure to adhere to prescribed antihypertensive regimens are
major risk factors for hypertensive emergencies . Tumlin
and colleagues  reported that only 51 out of 94 (54%)
patients presenting to an emergency room with a hyperten-
sive emergency had taken their hypertensive medication in
the preceding week. Illicit drug use has also been reported to
be a major risk factor for the development of hypertensive
Despite the development of increasingly effective antihyper-
tensive treatments over the past 4 decades, the incidence of
hypertensive crisis has increased. Hospital admissions for
hypertensive emergency more than tripled between 1983 and
1990, from 23000/year to 73000/year in the USA . The
reported incidence of postoperative hypertensive crisis varies
depending on the population examined, with most studies
reporting an incidence of between 4% and 35% [15,35,36].
Like other forms of accelerated hypertension, patients with
postoperative hypertensive crisis usually have a prior history
of poorly controlled hypertension . Pregnancy-related
Dissecting aortic aneurysm
Acute left ventricular failure with pulmonary edema
Acute myocardial ischemia
Acute renal failure
Symptomatic microangiopathic hemolytic anemia
Critical Care October 2003 Vol 7 No 5 Varon and Marik
hypertension (pre-eclampsia) is a form of hypertension that
deserves special mention. Pre-eclampsia occurs in about 7%
of all pregnancies but the incidence varies according to the
patient population, with 70% being nulliparous and 30%
Etiology and pathophysiology
Malignant hypertension can develop de novo or can compli-
cate underlying essential or secondary hypertension
(Table 2). In white patients, essential hypertension accounts
for 20–30% of malignant hypertension. In blacks, however,
essential hypertension is the predominant cause of malig-
nant hypertension, accounting for approximately 80% of all
cases [38,39]. Renal parenchymal disease accounts for up
to 80% of all secondary causes, with chronic pyelonephritis
and glomerulonephritis being the most common diagnoses
. The average age of presentation of essential malignant
hypertension tends to be higher than that for secondary
causes. Secondary causes are almost always found in white
patients presenting under the age of 30 years, whereas
black patients can present with essential hypertension at a
The factors that lead to the severe and rapid elevation of
blood pressure in patients with malignant hypertension are
poorly understood. The rapidity of onset suggests a trigger-
ing factor superimposed on pre-existing hypertension. The
risks for developing malignant hypertension are related to
the severity of the underlying hypertension, and therefore
the role of mechanical stress on the vessel wall appears to
be critical in its pathogenesis. The release of humoral vaso-
constrictor substances from the stressed vessel wall is
thought to be responsible for the initiation and perpetuation
of the hypertensive crisis [40,41]. Increased blood pressure
results in endothelial damage, with local intravascular acti-
vation of the clotting cascade, fibrinoid necrosis of small
blood vessels, and release of vasoconstrictor substances
[40,41]. This leads to a vicious cycle of further vascular
injury, tissue ischemia, and release of vasoconstrictor sub-
stances [40,41]. The volume depletion that results from
pressure natriuresis further simulates the release of vaso-
constrictor substances from the kidney. The release of vaso-
constrictor substances from the kidney has long been
postulated to play a central role in the pathophysiology of
malignant hypertension .
renin–angiotensin system has been strongly implicated in
the initiation and perpetuation of the vascular injury associ-
ated with malignant hypertension [29,43–45]. In addition to
activation of the renin–angiotensin system, vasopressin,
endothelin, and catecholamines are postulated to play
important roles in the pathophysiology of hypertensive
Activation of the
Clinical manifestations of hypertensive crises
The clinical manifestations of hypertensive crises are those
associated with end-organ dysfunction (Table 1). Organ dys-
function is uncommon with diastolic blood pressures less
than 130mmHg (except in children and in pregnancy) .
However, the absolute level of blood pressure may not be as
important as the rate of increase [7,50,51]. In patients with
longstanding hypertension a systolic blood pressure of
200mmHg or elevations in diastolic pressure up to
150mmHg may be well tolerated without the development of
hypertensive encephalopathy, whereas children or pregnant
women may develop encephalopathy with a diastolic blood
pressure of only 100mmHg .
The symptoms and signs of hypertensive crises vary from
patient to patient. Headache, altered level of consciousness,
and/or focal neurologic signs are seen in patients with hyper-
tensive encephalopathy [6,7]. On physical examination, these
patients may have retinopathy with arteriolar changes, hemor-
rhages and exudates, as well as papilledema. In other
patients, the cardiovascular manifestations of hypertensive
crises may predominate, with angina, acute myocardial infarc-
tion, or acute left ventricular failure [9,52]. In some patients,
severe injury to the kidneys may lead to acute renal failure
with oliguria and/or hematuria.
In pregnant patients, the acute elevations in blood pressure
may range from a mild to a life-threatening disease process.
The clinical features vary but may include visual field defects,
severe headaches, seizures, altered mental status, acute
cerebrovascular accidents, severe right upper quadrant
Secondary causes of malignant hypertension
Renal parenchymal Chronic pyelonephritis
Systemic disorders with
Systemic lupus erythematosus
Conn’s syndrome (primary
Coarctation of the aorta
abdominal pain, congestive heart failure, and oliguria. In the
vast majority of cases, this process can only be terminated by
delivery. The decision to continue the pregnancy or to deliver
should be made following consultation between medical and
obstetric personnel [18,37,53,54].
One syndrome that warrants special consideration is aortic
dissection. Approximately 2000 new cases occur in the USA
each year [55,56]. Aortic dissection should be considered a
likely diagnostic possibility in patients presenting to the emer-
gency department with acute chest pain and elevated blood
pressure. Left untreated, about three-quarters of patients with
type A dissection die within 2 weeks of an acute episode, but
with successful initial therapy the 5-year survival rate
increases to 75% [55,56]. Hence, timely recognition of this
disease entity coupled with urgent and appropriate manage-
ment is the key to a successful outcome in a majority of
patients. It is important to understand that the propagation of
the dissection is dependent not only on the elevation in blood
pressure itself but also on the velocity of left ventricular ejec-
tion [55–58]. For this reason, the aim of antihypertensive
therapy is to lessen the pulsatile load or aortic stress by low-
ering the blood pressure. Specific targets are the blood pres-
sure and rate of pressure rise.
Evaluation and management of hypertensive
A targeted medical history and physical examination sup-
ported by appropriate laboratory evaluation is required in
patients presenting with a possible hypertensive crisis [7,28].
The patient’s hypertensive history and prior blood pressure
control should be ascertained, as should any history of renal
and cardiac disease. The use of prescribed or nonprescribed
medications, and recreational drugs should be determined.
The blood pressure in both arms should be measured by the
physician. In obese patients appropriately sized cuffs should
be used. Physical examination should include palpation of
pulses in all extremities, auscultation for renal bruits, a focused
neurologic examination, and a funduscopic examination.
A complete blood count and smear (to exclude a microangio-
pathic anemia), electrolytes, blood urea nitrogen, creatinine,
urinalysis, and electrocardiogram should be obtained in all
patients. A chest radiograph should be obtained in patients
with shortness of breath or chest pain, and a head computed
tomography scan should be obtained in patients with neuro-
logic symptoms [7,28]. In patients with unequal pulses and/or
evidence of a widened mediastinum on the chest radiograph,
a chest computed tomography or magnetic resonance
imaging scan should be considered [55,56]. Patients in
whom an aortic dissection is considered should not undergo
transesophageal echocardiography until the blood pressure
has been adequately controlled. One the basis of the clinical
evaluation, the physician should be able to make the distinc-
tion between a hypertensive emergency/crisis and a hyper-
tensive urgency .
Initial therapeutic approach
The majority of patients with severe hypertension (diastolic
pressure >109mmHg) will have no acute end-organ damage
(hypertensive urgencies). In these patients the blood pres-
sure should be lowered gradually over a period of
24–48 hours, usually with oral medication. Rapid reduction in
blood pressure in these patients may be associated with sig-
nificant morbidity [59–61]. In patients with true hypertensive
emergencies, rapid but controlled lowering of blood pressure
is indicated to limit and prevent further organ damage
[2,27,28,58,61]. However, the blood pressure should not be
lowered to normal levels [3–5,11,12]. Most patients with
hypertensive emergencies are chronically hypertensive and
will have a rightward shift of the pressure–flow (cerebral,
renal, and coronary) autoregulation curve (Fig.1) . Rapid
reduction in blood pressure below the cerebral, renal, and/or
coronary autoregulatory range will result in a marked reduc-
tion in organ blood flow, leading to ischemia and infarction
. For this reason all patients with a hypertensive emer-
gency should be managed in an intensive care unit, where the
patient can be closely monitored. Intra-arterial blood pressure
monitoring may be required in patients with blood pressure
that is labile and difficult to control.
A variety of different antihypertensive agents are available for
use in patients with hypertensive crises. The agent(s) of
choice will depend on the end-organ involved as well as the
monitoring environment (Table 3). Rapid acting intravenous
agents should not be used outside the intensive care unit
because a precipitous and uncontrolled fall in blood pressure
may have lethal consequences. Reductions in diastolic blood
pressure by 10–15% or to about 110mmHg is generally rec-
ommended. This is best achieved by an continuous infusion
of a short acting, titratable, parenteral antihypertensive agent
. In patients with a dissecting aneurysm this goal should
Available online http://ccforum.com/content/7/5/374
Cerebral autoregulation in normotensive and chronically hypertensive
Cerebral blood flow
Mean arterial pressure
60 mmHg 120 mmHg160 mmHg
be achieved within 5–10 min. In all other patients, this end-
point should be achieved within 1 hour. Once the end-points
of therapy have been reached, the patient can be started on
oral maintenance therapy and the intravenous agent weaned
off. It should be noted that most patients with hypertensive
emergencies are volume depleted. Volume repletion with
intravenous crystalloid will serve to restore organ perfusion
and prevent the precipitous fall in blood pressure that may
occur with antihypertensive therapy.
It should be emphasized that only patients with hypertensive
emergencies require immediate reduction in markedly ele-
vated blood pressure. In all other patients the elevated blood
pressure can be lowered slowly using oral agents. Lowering
the blood pressure in patients with ischemic strokes may
reduce cerebral blood flow, which because of impaired
autoregulation may result in further ischemic injury. The
common practice of ‘normalizing’ blood pressure following a
cerebrovascular accident is potentially dangerous. When a
proximal arterial obstruction results in a mild stroke, a fall in
blood pressure may result in further infarction involving the
entire territory of that artery. The current recommendation of
the American Heart Association is that hypertension in the
setting of acute ischemic stroke should only be treated ‘rarely
and cautiously’ [63,64]. It is generally recommended that
antihypertensive therapy be reserved for patients with a dias-
tolic pressure greater than 120–130mmHg, aiming to reduce
the pressure by no more than an arbitrary figure of 10–15%
in the first 24 hours. This approach is supported by a study
reported by Semplicini and colleagues . Those investiga-
tors demonstrated that a higher initial blood pressure was
associated with a better neurologic outcome following an
acute ischemic stroke. They suggested that hypertension may
be protective during an acute ischemic stroke and that lower-
ing the blood pressure may be potentially harmful. In patients
with intracerebral hematomas there is almost always a rise in
intracranial pressure with reflex systemic hypertension. There is
no evidence that hypertension provokes further bleeding in
patients with intracranial hemorrhage. However, a precipitous
fall in systemic blood pressure will compromise cerebral perfu-
sion. The controlled lowering of the blood pressure is currently
recommended only when the systolic blood pressure is greater
than 200mmHg or the diastolic pressure is greater than
110mmHg [66–68]. This recommendation is supported by a
recent study that demonstrated that the rapid decline in blood
pressure within the first 24 hours after presentation was asso-
ciated with increased mortality in patients with an intracranial
hemorrhage . The rate of decline in blood pressure was
independently associated with increased mortality.
Pregnant patients with hypertensive crises represent a
special group of patients. In these patients, intravenous drug
therapy is reserved for those patients with systolic blood
pressure persistently greater than 180mmHg or diastolic
blood pressure persistently greater than 110mmHg
(105mmHg in some institutions) . Before delivery it is
desirable to maintain the diastolic blood pressure greater
than 90mmHg because this pressure allows for adequate
utero-placental perfusion. If the diastolic blood pressure
decreases to below 90mmHg, then decreased uteroplacen-
tal perfusion may precipitate acute fetal distress progressing
to an in utero death or to perinatal asphyxia .
Pharmacologic agents used in the treatment
of hypertensive crises
The ideal pharmacologic agent for the management of hyper-
tensive crises would be fast-acting, rapidly reversible, and
titratable without significant side effects. Although no single
ideal agent exists, a growing number of drugs are available
for the management of hypertensive crises. The agent of
choice in any particular situation will depend upon the
patient’s clinical presentation. The preferred agents include
esmolol, labetalol, fenoldopam, and nicardipine. 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. pheochromo-
cytoma) [3,7,27,50,51,57]. Sodium nitroprusside may be
used in patients with acute pulmonary edema and/or severe
left ventricular dysfunction and in patients with aortic dissec-
tion. However, because sodium nitroprusside is extremely
rapid acting and a potent antihypertensive agent, intra-arterial
blood pressure monitoring is required; in addition, sodium
nitroprusside requires special handling to prevent its degra-
dation by light. These factors limit the use of this drug in the
emergency department . Oral and sublingual nifedipine
are potentially dangerous in patients with hypertensive crises
and are not recommended. Clonidine and angiotensin-con-
Critical Care October 2003 Vol 7 No 5Varon and Marik
Recommended antihypertensive agents for hypertensive crises
ConditionPreferred antihypertensive agent
Acute pulmonary edema Fenoldopam or nitroprusside in
combination with nitroglycerin
(up to 60 µg/min) and a loop
Acute myocardial ischemia Labetalol or esmolol in combination
with nitroglycerin (up to 60 µg/min)
Hypertensive encephalopathyLabetalol, nicardipine, or fenoldopam
Acute aortic dissectionLabetalol or combination of
nicardipine or fenoldopam and
esmolol or combination of
nitroprusside with either esmolol or
EclampsiaLabetalol or nicardipine. Hydralazine
may be used in a non-ICU setting
Acute renal failure/
Fenoldopam or nicardipine
Verapamil, diltiazem, or nicardipine in
combination with a benzodiazepine
ICU, intensive care unit.
verting enzyme inhibitors are long acting and poorly titratable,
but these agents are particularly useful in the management of
hypertensive urgencies [71–75]. Angiotensin-converting
enzyme inhibitors are contraindicated in pregnancy [73,76].
The recommended intravenous antihypertensive agents are
reviewed briefly below.
Esmolol is an ultra-short-acting, cardioselective, β-adrenergic
blocking agent [77–79]. The onset of action of this agent is
within 60s, with a duration of action of 10–20 min [77–79].
The metabolism of esmolol is via rapid hydrolysis of ester link-
ages by red blood cell esterases and is not dependant upon
renal or hepatic function. Because of its pharmacokinetic
properties, some authors consider it an ‘ideal beta-adrenergic
blocker’ for use in critically ill patients . This agent is avail-
able for intravenous use both as a bolus and as an infusion.
Esmolol is particularly useful in severe postoperative hyper-
tension [80–86]. It is a suitable agent in situations in which
the cardiac output, heart rate, and blood pressure are
increased. It has proven safe in patients with acute myocar-
dial infarction, even those who have relative contraindications
to β-blockers . Typically, the drug is given as a
0.5–1mg/kg loading dose over 1 min, followed by an infusion
starting at 50µg/kg per min and increasing up to 300µg/kg
per min as necessary.
Fenoldopam has recently been approved for the management
of severe hypertension in the USA. It is a dopamine agonist
(DA1 agonist) that is short acting and has the advantages of
increasing renal blood flow and sodium excretion [88,89].
Fenoldopam has relatively unique actions and represents a
new category of antihypertensive medication. Although the
structure of fenoldopam is similar to that of dopamine,
fenoldopam is highly specific for only DA1 receptors and is
10 times more potent than dopamine as a renal vasodilator
. Fenoldopam is rapidly and extensively metabolized by
conjugation in the liver, without the participation of
cytochrome P450 enzymes. The onset of action is within
5 min, with the maximal response being achieved by 15 min
[91–93]. The duration of action is between 30 and 60 min,
with the pressure gradually returning to pretreatment values
without rebound once the infusion is stopped [91–93]. No
adverse effects have been reported . The dose rate of
fenoldopam must be individualized according to body weight
and according to the desired rapidity and extent of the phar-
macodynamic effect. An initial starting dose of 0.1µg/kg per
min is recommended. Fenoldopam has been demonstrated to
cause a consistent dose-related decrease in blood pressure
in the dose range 0.03–0.3µg/kg per min . Fenoldopam
has been demonstrated to improve creatinine clearance,
urine flow rates, and sodium excretion in severely hyperten-
sive patients with both normal and impaired renal function
[89,94,95]. It may therefore be the drug of choice in severely
hypertensive patients with impaired renal function .
Labetalol is a combined selective α1- and nonselective
β-adrenergic receptor blocker with an α to β blocking ratio of
1:7 . Labetalol is metabolized by the liver to form an inac-
tive glucuronide conjugate . The hypotensive effect of
labetalol begins within 2–5 min after its intravenous adminis-
tration, reaching a peak at 5–15 min after administration and
lasting for about 2–4 hours [98,99]. Because of its β-blocking
effects, the heart rate is either maintained or slightly reduced.
Unlike pure β-adrenergic blocking agents, which decrease
cardiac output, labetalol maintains cardiac output .
Labetalol reduces the systemic vascular resistance without
reducing total peripheral blood flow. In addition, the cerebral,
renal, and coronary blood flows are maintained [100–103].
This agent has been used in the setting of pregnancy-induced
hypertensive crisis because little placental transfer occurs,
mainly due to the drug’s negligible lipid solubility .
Labetalol may be given as a loading dose of 20mg, followed
by repeated incremental doses of 20–80mg given at 10-min
intervals until the desired blood pressure is achieved. Alterna-
tively, after the initial loading dose, an infusion commencing at
1–2mg/min and uptitrated until the desired hypotensive
effect is achieved is particularly effective. Bolus injections of
1–2mg/kg have been reported to produce precipitous falls in
blood pressure and should therefore be avoided .
Nicardipine is a second generation dihydropyridine derivative
calcium channel blocker with high vascular selectivity and
strong cerebral and coronary vasodilatory activities. It is
100 times more water soluble than is nifedipine, and there-
fore it can be administered intravenously, making nicardipine
an easily titratable intravenous calcium channel blocker
[105,106]. The onset of action of intravenous nicardipine is
between 5 and 15 min with a duration of action of 4–6 hours.
Once administered intravenously, nicardipine crosses the
blood–brain barrier and reaches the nervous tissue, where it
binds to calcium-channels of the L-type, acting primarily at
the level of the hippocampus . Intravenous nicardipine
has been shown to reduce both cardiac and cerebral
ischemia . The appropriate dosage of nicardipine is
independent of the patient’s weight, with an initial infusion
rate of 5mg/hour, increasing by 2.5mg/hour every 5 min to a
maximum of 30mg/hour until the desired blood pressure
reduction is achieved .
Sodium nitroprusside is an arterial and venous vasodilator
that decreases both afterload and preload [109–113]. Nitro-
prusside decreases cerebral blood flow while increasing
intracranial pressure – effects that are particularly disadvanta-
geous in patients with hypertensive encephalopathy or follow-
ing a cerebrovascular accident [114–117]. Nitroprusside is a
very potent agent, with onset of action within seconds, a
duration of action of 1–2min, and a plasma half-life of
Available online http://ccforum.com/content/7/5/374
3–4 min [109–113,118]. In patients with coronary artery
disease a significant reduction in regional blood flow (coro-
nary steal) can occur . In a large randomized, placebo-
controlled trial, nitroprusside was shown to increase mortality
when infused in the early hours after acute myocardial infarc-
tion (mortality at 13 weeks, 24.2% versus 12.7%) .
Nitroprusside contains 44% cyanide by weight . Cyanide
is released nonenzymatically from nitroprusside, the amount
generated being dependent on the dose of nitroprusside
administered. Cyanide is metabolized in the liver to thiocyanate
. Thiosulfate is required for this reaction [112,121]. Thio-
cyanate is 100 times less toxic than cyanide. The thiocyanate
generated is excreted largely through the kidneys. Cyanide
removal therefore requires adequate liver function, adequate
renal function, and adequate bioavailability of thiosulfate.
Nitroprusside may cause cytotoxicity because of the release
of cyanide with interference with cellular respiration
[122,123]. Cyanide toxicity has been documented to result in
‘unexplained cardiac arrest’, coma, encephalopathy, convul-
sions, and irreversible focal neurologic abnormalities
[113,124]. The current methods of monitoring for cyanide
toxicity are insensitive. Metabolic acidosis is usually a preter-
minal event. In addition, a rise in serum thiocyanate levels is a
late event and not directly related to cyanide toxicity. Red
blood cell cyanide concentrations (although not widely avail-
able) may be a more reliable method of monitoring for
cyanide toxicity . A red blood cell cyanide concentration
above 40nmol/ml results in detectable metabolic changes.
Levels above 200nmol/ml are associated with severe clinical
symptoms and levels greater than 400nmol/ml are consid-
ered lethal . Data suggest that nitroprusside infusion
rates in excess of 4µg/kg per min for as little as 2–3 hours
may lead to cyanide levels that are within the toxic range
. The recommended doses of nitroprusside of up to
10µg/kg per min result in cyanide formation at a far greater
rate than human beings can detoxify. Sodium nitroprusside
has also been demonstrated to cause cytotoxicity through the
release of nitric oxide, with hydroxyl radical and peroxynitrite
generation leading to lipid peroxidation [122,125–127].
Recently, Khot and colleagues  reported the use of nitro-
prusside in 25 normotensive patients with severe aortic steno-
sis and left ventricular dysfunction. After 24 hours of
nitroprusside infusion (mean dose of 128µg/min) there was a
significant increase in the mean cardiac index to
2.52±0.55l/min per m2
from a baseline value of
1.60±0.35l/min per m2; this was associated with a significant
increase in stroke volume and a significant fall in the systematic
vascular resistance and pulmonary capillary wedge pressure.
The nitroprusside was well tolerated, had minimal side effects,
and was associated with an improvement in renal function. It
should be emphasized that, in this study, the patients received
the nitroprusside infusion for no longer than 24 hours and the
maximum dose did not exceed 2µg/kg per min.
Considering the potential for severe toxicity with nitroprus-
side, this drug should only be used when other intravenous
antihypertensive agents are not available and then only in
specific clinical circumstances and in patients with normal
renal and hepatic function . The duration of treatment
should be as short as possible and the infusion rate should
not exceed 2µg/kg per min. An infusion of thiosulfate should
be used in patients receiving higher dosages (4–10µg/kg
per min) of nitroprusside . It has also been demon-
strated that hydroxocobalamin (vitamin 12a) is safe and effec-
tive in preventing and treating cyanide toxicity associated with
the use of nitroprusside. This may be given as a continuous
infusion at a rate of 25mg/hour. Hydroxocobalamin is unsta-
ble and should be stored dry and protected from light.
Cyanocobalamin (vitamin B12), however, is ineffective as an
antidote and is not capable of preventing cyanide toxicity.
Nifedipine, nitroglycerin, and hydralazine
Nifedipine, nitroglycerin, and hydralazine are not recom-
mended in the management of hypertensive emergencies.
The bases of these recommendations are discussed below.
Nifedipine has been widely used via oral or sublingual admin-
istration in the management of hypertensive emergencies,
severe hypertension associated with chronic renal failure,
perioperative hypertension, and pregnancy induced hyperten-
sion [72,129–136]. Although nifedipine has been given via
the sublingual route, the drug is poorly soluble and is not
absorbed through the buccal mucosa. However, it is rapidly
absorbed from the gastrointestinal tract after the capsule is
broken/dissolved . This mode of administration has not
been approved by the US Food and Drug Administration. A
significant decrease in blood pressure is usually observed
5–10 min after nifedipine administration, with a peak effect at
between 30 and 60 min and a duration of action of approxi-
mately 6–8 hours .
Sudden uncontrolled and severe reductions in blood pres-
sure accompanying the administration of nifedipine may pre-
cipitate cerebral, renal, and myocardial ischemic events,
which have been associated
[72,108,130–133,137–140]. Elderly hypertensive patients
with underlying organ impairment and structural vascular
disease are more vulnerable to the rapid and uncontrolled
reduction in arterial pressure . Given the seriousness of
the reported adverse events and the lack of any clinical docu-
mentation attesting to a benefit, the use of nifedipine
capsules for hypertensive emergencies and ‘pseudo-
emergencies’ should be abandoned . The Cardiorenal
Advisory Committee of the US Food and Drug Administration
has concluded that the practice of administering sublingual/
oral nifedipine should be abandoned because this agent is
neither safe nor efficacious .
with fatal outcomes
Critical Care October 2003 Vol 7 No 5 Varon and Marik
Available online http://ccforum.com/content/7/5/374
Nitroglycerin, hydralazine, and diuretics
Nitroglycerin is a potent venodilator, and only at high doses
does it affect arterial tone . It causes hypotension and
reflex tachycardia, which are exacerbated by the volume
depletion characteristic of hypertensive emergencies. Nitro-
glycerin reduces blood pressure by reducing preload and
cardiac output, which are undesirable effects in patients with
compromised cerebral and renal perfusion. Low dose
(60mg/min) nitroglycerin may, however, be used as an
adjunct to intravenous antihypertensive therapy in patients
with hypertensive emergencies associated with acute coro-
nary syndromes or acute pulmonary edema.
Hydralazine is a direct acting vasodilator. Following intramuscu-
lar or intravenous administration there is an initial latency period
of 5–15 min followed by a progressive and often precipitous
fall in blood pressure that can last up to 12 hours [143,144].
Although hydralazine’s circulating half-life is only about 3 hours,
the half-time of its effect on blood pressure is about 100 hours
[145–148]. Because of hydralazine’s prolonged and unpre-
dictable antihypertensive effects and the inability to titrate the
drug’s hypotensive effect effectively, hydralazine is best
avoided in the management of hypertensive crises.
Volume depletion is common in patients with malignant
hypertension, and the administration of a diuretic together
with a hypertensive agent can lead to a precipitous drop in
blood pressure. Diuretics should be avoided unless specifi-
cally indicated for volume overload as occurs in renal
parenchymal disease or coexisting pulmonary edema.
Patients with hypertensive crises may require immediate
reduction in elevated blood pressure to prevent and arrest
progressive end-organ damage. The best clinical setting in
which to achieve this blood pressure control is in the inten-
sive care unit, with the use of titratable intravenous hypoten-
sive agents. There are several antihypertensive agents
available for this purpose, including esmolol, nicardipine,
labetalol, and fenoldopam. Although sodium nitroprusside is a
rapid acting and potent antihypertensive agents, it may be
associated with significant toxicity and should therefore only
be used in select circumstances and at a dose that should
not exceed 2µg/kg per min. The appropriate therapeutic
approach in each patient will depend on the clinical presenta-
tion. Agents such as nifedipine and hydralazine should be
abandoned because these agents are associated with signifi-
cant toxicities and/or side effects.
The sixth report of the Joint National Committee on preven-
tion, detection, evaluation, and treatment of high blood pres-
sure. Arch Intern Med 1997, 157:2413-2446.
2.Calhoun DA, Oparil S: Treatment of hypertensive crisis. N Engl
J Med 1990, 323:1177-1183.
Gifford RW Jr: Management of hypertensive crises. JAMA
Ferguson RK, Vlasses PH: Hypertensive emergencies and
urgencies. JAMA 1986, 255:1607-1613.
Reuler JB, Magarian GJ: Hypertensive emergencies and urgen-
cies: definition, recognition, and management. J Gen Intern
Med 1988, 3:64-74.
Hickler RB: ‘Hypertensive emergency’: a useful diagnostic cat-
egory. Am J Public Health 1988, 78:623-624.
Garcia JYJ, Vidt DG: Current management of hypertensive
emergencies. Drugs 1987, 34:263-278.
Bertel O, Marx BE: Hypertensive emergencies. Nephron 1987,
Bennett NM, Shea S: Hypertensive emergency: case criteria,
sociodemographic profile, and previous care of 100 cases.
Am J Public Health 1988, 78:636-640.
10. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA,
Izzo JL, Jones DW, Materson BJ, Oparil S, Wright JT, Roccella EJ:
The Seventh Report of the Joint National Committee on Pre-
vention, Detection, Evaluation, and Treatment of High Blood
Pressure. The JNC 7 Report. JAMA 2003, 289:2560-2572.
11. Rahn KH: How should we treat a hypertensive emergency?
Am J Cardiol 1989, 63:48C-50C.
12. Kaplan NM: Treatment of hypertensive emergencies and
urgencies. Heart Dis Stroke 1992, 1:373-378.
13. Joint National Committee for the Detection, Evaluation and
Treatment of high blood pressure: the 1984 Report. Arch
Intern Med 1984, 114:1045-1057.
14. Halpern NA, Goldberg M, Neely C, Sladen RN, Goldberg JS,
Floyd J, Gabrielson G, Greenstein RJ: Postoperative hyperten-
sion: a multicenter, prospective, randomized comparison
between intravenous nicardipine and sodium nitroprusside.
Crit Care Med 1992, 20:1637-1643.
15. Gal TJ, Cooperman LH: Hypertension in the immediate postop-
erative period. Br J Anaesth 1975, 47:70-74.
16. Goldman L, Caldera DL: Risks of general anesthesia and elec-
tive operation in the hypertensive patient. Anesthesiol 1979,
17. Rey E, LeLorier J, Burgess E, Lange IR, Leduc L: Report of the
Canadian Hypertension Society Consensus Conference: 3.
Pharmacologic treatment of hypertensive disorders in preg-
nancy. CMAJ 1997, 157:1245-1254.
18. Glock JL, Morales WJ: Efficacy and safety of nifedipine versus
magnesium sulfate in the management of preterm labor: a
randomized study. Am J Obstet Gynecol 1993, 169:960-964.
19. Burt VL, Whelton P, Roccella EJ, Brown C, Cutler JA, Higgins M,
Horan MJ, Labarthe D: Prevalence of hypertension in the US
adult population. Results from the Third National Health and
Nutrition Examination Survey, 1988–1991. Hypertension 1995,
20. Dannenberg AL, Garrison RJ, Kannel WB: Incidence of hyper-
tension in the Framingham Study. Am J Public Health 1988,
21. Varon J, Marik PE: The diagnosis and management of hyper-
tensive crises. Chest 2000, 118:214-227.
22. Kearse LA, Rosow C, Zaslavsky A, Connors P, Dershwitz M,
Denman W: Bispectral analysis of the electroencephalogram
predicts conscious processing of information during propofol
sedation and hypnosis. Anesthesiol 1998, 88:25-34.
23. Burt VL, Cutler JA, Higgins M, Horan MJ, Labarthe D, Whelton P,
Brown C, Roccella EJ: Trends in the prevalence, awareness,
treatment, and control of hypertension in the adult US popula-
tion. Data from the health examination surveys, 1960 to 1991.
Hypertension 1995, 26:60-69.
24. Haffner SM, Mitchell BD, Valdez RA, Hazuda HP, Morales PA,
Stern MP: Eight-year incidence of hypertension in Mexican-
Americans and non-Hispanic whites. The San Antonio Heart
Study. Am J Hypertens 1992, 5:147-153.
25. Volhard F, Fahr T: Die brightsche Nierenkranbeit: Klinik, Patholo-
gie und Atlas. Berlin: Springer; 1914.
26. Keith NM, Wagener HP, Barker NW: Some different types of
essential hypertension: their course and prognosis. Am J Med
Sci 1939, 197:332-343.
27. McRae RPJ, Liebson PR: Hypertensive crisis. Med Clin North
Am 1986, 70:749-767.
Critical Care October 2003 Vol 7 No 5Varon and Marik
28. Vidt DG: Current concepts in treatment of hypertensive emer-
gencies. Am Heart J 1986, 111:220-225.
29. Laragh J: Laragh’s lessons in pathophysiology and clinical
pearls for treating hypertension. Am J Hypertens 2001, 14:
30. Smith CB, Flower LW, Reinhardt CE: Control of hypertensive
emergencies. Postgrad Med 1911, 89:111-116.
31. Lip GY, Beevers M, Potter JF, Beevers DG: Malignant hyperten-
sion in the elderly. QJM 1995, 88:641-647.
32. Shea S, Misra D, Ehrlich MH, Field L, Francis CK: Predisposing
factors for severe, uncontrolled hypertension in an inner-city
minority population. N Engl J Med 1992, 327:776-781.
33. Tumlin JA, Dunbar LM, Oparil S, Buckalew V, Ram CV, Mathur V,
Ellis D, McGuire D, Fellmann J, Luther RR: Fenoldopam, a
dopamine agonist, for hypertensive emergency: a multicenter
randomized trial. Fenoldopam Study Group. Acad Emerg Med
34. National Center for Health Statistics: Vital and Health Statistics:
Detailed Diagnoses and Procedures for Patients Discharged
from Short-stay Hospitals: United States, 1983–1990. Hyattsville,
MD: National Center for Health Statistics; 1997.
35. Halpern NA, Alicea M, Krakoff LR, Greenstein R: Postoperative
hypertension: a prospective, placebo-controlled, randomized,
double-blind trial, with intravenous nicardipine hydrochloride.
Angiology 1990, 41:992-1004.
36. Prys-Rroberts C: Anaesthesia and hypertension. Br J Anaesth
37. Sibai BM: Preeclampsia-eclampsia. Curr Prob Obstet Gynecol
Infert 1990, 13:3-45.
38. Yu SH, Whitworth JA, Kincaid-Smith PS: Malignant hyperten-
sion: aetiology and outcome in 83 patients. Clin Exp Hypertens
39. Milne FJ, James SH, Veriava Y: Malignant hypertension and its
renal complications in black South Africans. S Afr Med J 1989,
40. Ault MJ, Ellrodt AG: Pathophysiological events leading to the
end-organ effects of acute hypertension. Am J Emerg Med
41. Wallach R, Karp RB, Reves JG, Oparil S, Smith LR, James TN:
Pathogenesis of paroxysmal hypertension developing during
and after coronary bypass surgery: a study of hemodynamic
and humoral factors. Am J Cardiol 1980, 46:559-565.
42. Goldblatt H: Studies on experimental hypertension: Produc-
tion of malignant phase of hypertension. J Exp Med 1938, 67:
43. Stefansson B, Ricksten A, Rymo L, Aurell M, Herlitz H:
Angiotensin-converting enzyme gene I/D polymorphism in
malignant hypertension. Blood Pressure 2000, 9:104-109.
44. Montgomery HE, Kiernan LA, Whitworth CE, Fleming S, Unger T,
Gohlke P, Mullins JJ, McEwan JR: Inhibition of tissue
angiotensin converting enzyme activity prevents malignant
hypertension in TGR(mREN2)27. J Hypertens 1998, 16:635-
45. Fleming S. Malignant hypertension: the role of the paracrine
renin–angiotensin system. J Pathol 2000, 192:135-139.
46. Kohno M, Yokokawa K, Yasunari K, Kano H, Minami M, Ueda M,
Tatsumi Y, Yoshikawa J: Renoprotective effects of a combined
endothelin type A/type B receptor antagonist in experimental
malignant hypertension. Metab Clin Exp 1997, 46:1032-1038.
47. Vacher E, Richer C, Cazaubon C, Fornes P, Nisato D, Giudicelli
JF: Are vasopressin peripheral V1 receptors involved in the
development of malignant hypertension and stroke in SHR-
SPs? Fundam Clin Pharmacol 1995, 9:469-478.
48. Hiwatari M, Abrahams JM, Saito T, Johnston CI: Contribution of
vasopressin to the maintenance of blood pressure in deoxy-
corticosterone-salt induced malignant hypertension in spon-
taneously hypertensive rats. Clin Sci 1986, 70:191-198.
49. Filep J, Frolich JC, Fejes-Toth G: Effect of vasopressin blockade
on blood pressure in conscious rats with malignant two-
kidney Goldblatt hypertension. Clin Exp Hypertens 1985, 7:
50. Prisant LM, Carr AA, Hawkins DW: Treating hypertensive emer-
gencies. Controlled reduction of blood pressure and protec-
tion of target organs. Postgrad Med 1990, 93:92-96.
51. Ziegler MG: Advances in the acute therapy of hypertension.
Crit Care Med 1992, 20:1630-1631.
52. Fromm RE, Varon J, Gibbs L: Congestive heart failure and pul-
monary edema for the emergency physician. J Emerg Med
53. Roberts JM, Redman CWG: Pre-eclampsia: more than preg-
nancy-induced hypertension. Lancet 1993, 341:1447-1454.
54. Cunningham FG, Lindheimer MD: Hypertension in pregnancy. N
Engl J Med 1992, 326:927-932.
55. Khan IA, Nair CK: Clinical, diagnostic, and management per-
spectives of aortic dissection. Chest 2002, 122:311-328.
56. Kouchoukos NT, Dougenis D: Surgery of the thoracic aorta. N
Engl J Med 1997, 336:1876-1888.
57. Cohn LH: Aortic dissection: new aspects of diagnosis and
treatment. Hosp Pract (Off Ed) 1994, 29:47-56.
58. Chen K, Varon J, Wenker OC, Judge DK, Fromm RE, Sternbach
GL: Acute thoracic aortic dissection: the basics. J Emerg Med
59. Bannan LT, Beevers DG, Wright N: ABC of blood pressure
reduction. Emergency reduction, hypertension in pregnancy,
and hypertension in the elderly. BMJ 1980, 281:1120-1122.
60. Bertel O, Marx BE, Conen D: Effects of antihypertensive treat-
ment on cerebral perfusion. Am J Med 1987, 82:29-36.
61. Reed WG, Anderson RJ: Effects of rapid blood pressure reduc-
tion on cerebral blood flow. Am Heart J 1986, 111:226-228.
62. Strandgaard S, Olesen J, Skinhoj E, Lassen NA: Autoregulation
of brain circulation in severe arterial hypertension. BMJ 1973,
63. Emergency Cardiac Care Committee and Subcommittees,
American Heart Association. Guidelines for Cardiopulmonary
resuscitation and emergency cardiac care. Part IV, special
resuscitation situations: stroke. JAMA 1992, 268:2242-2244.
64. Adams HP, Brott TG, Crowell RM, Furlan AJ, Gomez CR, Grotta J,
Helason CM, Marler JR: Guidelines for the management of
patients with acute ischemic stroke. A statement for the
healthcare professionals from a special writing group of the
stroke council, American Hear Association. Circulation 1994,
65. Semplicini A, Maresca A, Boscolo G, Sartori M, Rocchi R, Giantin
V, Forte PL, Pessina AC: Hypertension in acute ischemic
stroke: a compensatory mechanism or an additional damag-
ing factor? Arch Intern Med 2003, 163:211-216.
66. Lavin P: Management of hypertension in patients with acute
stroke. Arch Intern Med 1986, 146:66-68.
67. Hirschl MM: Guidelines for the drug treatment of hypertensive
crises. Drugs 1995, 50:991-1000.
68. O’Connell J, Gray C: Treating hypertension after stroke. BMJ
69. Qureshi AI, Bliwise DL, Bliwise NG, Akbar MS, Uzen G, Frankel
MR: Rate of 24-hour blood pressure decline and mortality
after spontaneous intracerebral hemorrhage: A retrospective
analysis with a random effects regression model. Crit Care
Med 1999, 27:480-485.
70. Boldt J, Zickmann B, Rapin J, Hammermann H, Dapper F, Hempel-
mann G: Influence of volume replacement with different HES-
solutions on microcirculatory blood flow in cardiac surgery.
Acta Anaesthesiol Scand 1994, 38:432-438.
71. Strauss R, Gavras I, Vlahakos D, Gavras H: Enalaprilat in hyper-
tensive emergencies. J Clin Pharmacol 1986, 26:39-43.
72. Komsuoglu SS, Komsuoglu B, Ozmenoglu M, Ozcan C, Gurhan
H: Oral nifedipine in the treatment of hypertensive crises in
patients with hypertensive encephalopathy. Int J Cardiol 1992,
73. DiPette DJ, Ferraro JC, Evans RR, Martin M: Enalaprilat, an intra-
venous angiotensin-converting enzyme inhibitor, in hyperten-
sive crises. Clin Pharmacol Ther 1985, 38:199-204.
74. Angeli P, Chiesa M, Caregaro L, Merkel C, Sacerdoti D, Rondana
M, Gatta A: Comparison of sublingual captopril and nifedipine
in immediate treatment of hypertensive emergencies. A ran-
domized, single-blind clinical trial. Arch Intern Med 1991, 151:
75. Ceyhan B, Karaaslan Y, Caymaz O, Oto A, Oram E, Oram A,
Ugurlu S: Comparison of sublingual captopril and sublingual
nifedipine in hypertensive emergencies. Jpn J Pharmacol
76. Hirschl MM, Binder M, Bur A, Herkner H, Woisetschlager C,
Bieglmayer C, Laggner AN: Impact of the renin–angiotensin-
aldosterone system on blood pressure response to intra-
venous enalaprilat in patients with hypertensive crises. J Hum
Hypertens 1997, 11:177-183.
Available online http://ccforum.com/content/7/5/374
77. Gray RJ: Managing critically ill patients with esmolol. An ultra
short-acting beta-adrenergic blocker. Chest 1988, 93:398-403.
78. Lowenthal DT, Porter RS, Saris SD, Bies CM, Slegowski MB,
Staudacher A: Clinical pharmacology, pharmacodynamics and
interactions with esmolol. Am J Cardiol 1985, 56:14F-18F.
79. Reynolds RD, Gorczynski RJ, Quon CY: Pharmacology and
pharmacokinetics of esmolol. J Clin Pharmacol 1986, Suppl
80. Balser JR, Martinez EA, Winters BD, Perdue PW, Clarke AW,
Huang W, Tomaselli GF, Dorman T, Campbell K, Lipsett P,
Breslow MJ, Rosenfeld BA: Beta-adrenergic blockade acceler-
ates conversion of postoperative supraventricular tach-
yarrhythmias. Anesthesiol 1998, 89:1052-1059.
81. Platia EV, Michelson EL, Porterfield JK, Das G: Esmolol versus
verapamil in the acute treatment of atrial fibrillation or atrial
flutter. Am J Cardiol 1989, 63:925-929.
82. Stumpf JL: Drug therapy of hypertensive crises. Clin Pharm
83. Smerling A, Gersony WM: Esmolol for severe hypertension fol-
lowing repair of aortic coarctation. Crit Care Med 1990, 18:
84. Gray RJ, Bateman TM, Czer LS, Conklin C, Matloff JM: Use of
esmolol in hypertension after cardiac surgery. Am J Cardiol
85. Gray RJ, Bateman TM, Czer LS, Conklin C, Matloff JM: Compari-
son of esmolol and nitroprusside for acute post-cardiac surgi-
cal hypertension. Am J Cardiol 1987, 59:887-891.
86. Muzzi DA, Black S, Losasso TJ, Cucchiara RF: Labetalol and
esmolol in the control of hypertension after intracranial
surgery. Anesth Analg 1990, 70:68-71.
87. Mooss AN, Hilleman DE, Mohiuddin SM, Hunter CB: Safety of
esmolol in patients with acute myocardial infarction treated
with thrombolytic therapy who had relative contraindications
to beta-blocker therapy. Ann Pharmacother 1994, 28:701-703.
88. Shi Y, Zalewski A, Bravette B, Maroko AR, Maroko PR: Selective
dopamine-1 receptor agonist augments regional myocardial
blood flow: comparison of fenoldopam and dopamine. Am
Heart J 1992, 124:418-423.
89. Shusterman NH, Elliott WJ, White WB: Fenoldopam, but not
nitroprusside, improves renal function in severely hyperten-
sive patients with impaired renal function. Am Heart J 1993,
90. Tiberi M, Caron MG: High agonist-independent activity is a dis-
tinguishing feature of the dopamine D1B receptor subtype. J
Biol Chem 1994, 269:27925-27931.
91. Bodmann KF, Troster S, Clemens R, Schuster HP: Hemody-
namic profile of intravenous fenoldopam in patients with
hypertensive crisis. Clin Invest 1993, 72:60-64.
92. Munger MA, Rutherford WF, Anderson L, Hakki AI, Gonzalez FM,
Bednarczyk EM, Emmanuel G, Weed SG, Panacek EA, Green JA:
Assessment of intravenous fenoldopam mesylate in the man-
agement of severe systemic hypertension. Crit Care Med
93. White WB, Radford MJ, Gonzalez FM, Weed SG, McCabe EJ,
Katz AM: Selective dopamine-1 agonist therapy in severe
hypertension: effects of intravenous fenoldopam. J Am Coll
Cardiol 1988, 11:1118-1123.
94. Elliott WJ, Weber RR, Nelson KS, Oliner CM, Fumo MT, Gretler
DD, McCray GR, Murphy MB: Renal and hemodynamic effects
of intravenous fenoldopam versus nitroprusside in severe
hypertension. Circulation 1990, 81:970-977.
95. White WB, Halley SE: Comparative renal effects of intra-
venous administration of fenoldopam mesylate and sodium
nitroprusside in patients with severe hypertension. Arch Intern
Med 1989, 149:870-874.
96. Reisin E, Huth MM, Nguyen BP, Weed SG, Gonzalez FM: Intra-
venous fenoldopam versus sodium nitroprusside in patients
with severe hypertension. Hypertension 1990, 15:I59-I62.
97. Lund-Johansen P: Pharmacology of combined alpha-beta-
blockade. II. Haemodynamic effects of labetalol. Drugs 1984,
98. Kanot J, Allonen H, Kleimola T, Mantyla R: Pharmacokinetics of
labetalol in healthy volunteers. Int J Clin Pharmacol Ther
Toxicol 1981, 19:41-44.
99. Goldberg ME, Clark S, Joseph J, Moritz H, Maguire D, Seltzer JL,
Turlapaty P: Nicardipine versus placebo for the treatment of
postoperative hypertension. Am Heart J 1990, 119:446-450.
100.Pearce CJ, Wallin JD: Labetalol and other agents that block
both alpha- and beta-adrenergic receptors. Cleve Clin J Med
101.Wallin JD: Adrenoreceptors and renal function. J Clin Hyper-
tens 1985, 1:171-178.
102.Marx PG, Reid DS: Labetalol infusion in acute myocardial
infarction with systemic hypertension. Br J Clin Pharmacol
1979, Suppl 2:233S-238S.
103.Olsen KS, Svendsen LB, Larsen FS, Paulson OB: Effect of
labetalol on cerebral blood flow, oxygen metabolism and
autoregulation in healthy humans. Br J Anaesth 1995, 75:51-
104.Rosei EA, Trust PM, Brown JJ: Intravenous labetalol in severe
hypertension. Lancet 1975, 2:1093-1094.
105.Turlapaty P, Vary R, Kaplan JA: Nicardipine, a new intravenous
calcium antagonist: a review of its pharmacology, pharmaco-
kinetics, and perioperative applications. J Cardiothorac Anesth
106.IV Nicardipine Study Group: Efficacy and safety of intravenous
nicardipine in the control of postperative hypertension. Chest
107.Sabbatini M, Strocchi P, Amenta F: Nicardipine and treatment
of cerebrovascular diseases with particular reference to
hypertension-related disorders. Clin Exp Hypertens 1995, 17:
108.Schillinger D: Nifedipine in hypertensive emergencies: a
prospective study. J Emerg Med 1987, 5:463-473.
109.Francis GS: Vasodilators in the intensive care unit. Am Heart J
110.Friederich JA, Butterworth JF: Sodium nitroprusside: twenty
years and counting. Anesth Analg 1995, 81:152-162.
111.Fung HL: Clinical pharmacology of organic nitrates. Am J
Cardiol 1993, 72:9C-13C.
112.Pasch T, Schulz V, Hoppenshauser G: Nitroprusside-induced
formation of cyanide and its detoxication with thiosulphate
during deliberate hypotension. J Cardiovasc Pharmacol 1983,
113.Robin ED, McCauley R: Nitroprusside-related cyanide poison-
ing. Time (long past due) for urgent, effective interventions.
Chest 1992, 102:1842-1845.
114.Hartmann A, Buttinger C, Rommel T, Czernicki Z, Trtinjiak F:
Alteration of intracranial pressure, cerebral blood flow,
autoregulation and carbondioxide-reactivity by hypotensive
agents in baboons with intracranial hypertension. Neurochirur-
gia 1989, 32:37-43.
115.Kondo T, Brock M, Bach H: Effect of intra-arterial sodium nitro-
prusside on intracranial pressure and cerebral autoregulation.
Jpn Heart J 1984, 25:231-237.
116.Griswold WR, Reznik V, Mendoza SA: Nitroprusside-induced
intracranial hypertension [letter]. JAMA 1981, 246:2679-2680.
117.Anile C, Zanghi F, Bracali A, Maira G, Rossi GF: Sodium nitro-
prusside and intracranial pressure. Acta Neurochir (Wien)
118.Murphy C: Hypertensive emergencies. Emerg Med Clin N Am
119.Mann T, Cohn PF, Holman LB, Green LH, Markis JE, Phillips DA:
Effect of nitroprusside on regional myocardial blood flow in
coronary artery disease. Results in 25 patients and compari-
son with nitroglycerin. Circulation 1978, 57:732-738.
120.Cohn JN, Franciosa JA, Francis GS, Archibald D, Tristani F,
Fletcher R, Montero A, Cintron G, Clarke J, Hager D, Saunders R,
Cobb F, Smith R, Loeb H, Settle H: Effect of short-term infusion
of sodium nitroprusside on mortality rate in acute myocardial
infarction complicated by left ventricular failure: results of a
Veterans Administration cooperative study. N Engl J Med
121.Hall VA, Guest JM: Sodium nitroprusside-induced cyanide
intoxication and prevention with sodium thiosulphate prophy-
laxis. Am J Crit Care 1992, 2:19-27.
122.Niknahad H, O’Brien PJ: Involvement of nitric oxide in nitro-
prusside-induced hepatocyte cytotoxicity. Biochem Pharmacol
123.Izumi Y, Benz AM, Clifford DB, Zorumski CF: Neurotoxic effects
of sodium nitroprusside in rat hippocampal slices. Exp Neurol
124.Vesey CJ, Cole PV, Simpson PJ: Cyanide and thiocyanate con-
centrations following sodium nitroprusside infusion in man.
384 Download full-text
Critical Care October 2003 Vol 7 No 5Varon and Marik
Br J Anaesth 1976, 48:651-659.
125.Nakamura Y, Yasuda M, Fujimori H, Kiyono M, Pan-Hou H: Cyto-
toxic effect of sodium nitroprusside on PC12 cells. Chemos-
phere 1997, 34:317-324.
126.Gobbel GT, Chan TY, Chan PH: Nitric oxide- and superoxide-
mediated toxicity in cerebral endothelial cells. J Pharmacol
Exp Ther 1997, 282:1600-1607.
127.Rauhala P, Khaldi A, Mohanakumar KP, Chiueh CC: Apparent
role of hydroxyl radicals in oxidative brain injury induced by
sodium nitroprusside. Free Radic Biol Med 1998, 24:1065-
128.Khot UN, Novaro GM, Popovic ZB, Mills RM, Thomas JD, Tuzcu
EM, Hammer D, Nissen SE, Francis GS: Nitroprusside in criti-
cally ill patients with left ventricular dysfucntion and aortic
stenosis. N Engl J Med 2003, 348:1756-1763.
129.Huysmans FT, Sluiter HE, Thien TA, Koene RA: Acute treatment
of hypertenisve crisis with nifedipine. Br J Clin Pharmacol
130.Spah F, Grosser KD: Treatment of hypertensive urgencies and
emergencies with nitrendipine, nifedipine, and clonidine:
effect on blood pressure and heart rate. J Cardiovasc Pharma-
col 1988, Suppl 4:S154-S156.
131.Gonzalez-Carmona VM, Ibarra-Perez C, Jerjes-Sanchez C:
Single-dose sublingual nifedipine as the only treatment in
hypertensive urgencies and emergencies. Angiology 1991, 42:
132.Diker E, Erturk S, Akgun G: Is sublingual nifedipine administra-
tion superior to oral administration in the active treatment of
hypertension? Angiology 1992, 43:477-481.
133.Haft JI, Litterer WE: Chewing nifedipine to rapidly treat hyper-
tension. Arch Intern Med 1984, 144:2357-2359.
134.Puri GD, Batra YK, Singh H: Efficacy of sublingual nifedipine in
the relief of immediate post-opertive hypertension. Indian J
Med Res 1987, 86:624-628.
135.Wu SG, Lin SL, Shiao WY, Huang HW, Lin CF, Yang YH: Com-
parison of sublingual captopril, nifedipine and prazosin in
hypertensive emergencies during hemodialysis. Nephron
136.Glock JL, Morales WJ: Efficacy and safety of nifedipine versus
magnesium sulphate in the management of preterm labor: a
randomized study. Am J Obstet Gynecol 1993, 169:960-964.
137.van Harten J, Burggraaf K, Danhof M, van Brummelen P, Breimer
DD: Negligible sublingual absorption of nifedipine. Lancet
138.Grossman E, Messerli FH, Grodzicki T, Kowey P: Should a mora-
torium be placed on sublingual nifedipine capsules given for
hypertensive emergencies and pseudoemergencies? JAMA
139.Woodmansey P, Channer KS: Nifedipine and hypotension
[letter]. Lancet 1991, 338:763-764.
140.Peters FP, de Zwaan C, Kho L: Prolonged QT interval and ven-
tricular fibrillation after treatment with sublingual nifedipine
for malignant hypertension [letter]. Arch Intern Med 1997, 157:
141.Levy JH: Treatment of perioperative hypertension. Anesthesiol
Clin North Am 1999, 17:569-570.
142.Bussmann WD, Kenedi P, von Mengden HJ, Nast HP, Rachor L:
Comparison of nitroglycerin with nifedipine in patients with
hypertensive crisis or severe hypertension. Clin Investig 1992,
143.Schroeder HA: Effects on hypertension of sulfhydryl and
hydrazine compounds. J Clin Invest 1951, 30:672-673.
144.Shepherd AM, Ludden TM, McNay JL, Lin MS: Hydralazine
kinetics after single and repeated oral doses. Clin Pharmacol
Ther 1980, 28:804-811.
145.O’Malley K, segal JL, Israili ZH, Boles M, McNay JL, Dayton PG:
Duration of hydralazine action in hypertension. Clin Pharmacol
Ther 1975, 18:581-586.
146.Reece PA, Cozamanis I, Zacest R: Kinetics of hydralazine and
its main metabolites in slow and fast acetylators. Clin Pharma-
col Ther 1980, 28:769-778.
147.Ludden TM, Shepherd AM, McNay JL, Lin MS: Hydralazine
kinetics in hypertensive patients after intravenous administra-
tion. Clin Pharmacol Ther 1980, 28:736-742.
148.Moore-Jones D, Perry HM Jr: Radioautographic localization of
hydralazine-1-C-14 in arterial walls. Proc Soc Exp Biol Med