DISEASEOF THE MONTH

Malignant

Hypertension
CHAGRIYA
Division

and Hypertensive
and
Hypertension.

Emergencies

KITIYAKARA
and

NICOLAS
Georgetown

J. GUZMAN
University Medical Center, Washington, DC.

of Nephrologv

Hypertensive
vere (1,2). BP elevation

crisis

refers
associated clinical

to a syndrome
with imminent and problem

characterized
risks accounts to the for

by sepatient 27.5%

infants

to the

elderly. populations

The

incidence has been

of malignant decreasing (6).

hypertension In Australia

in Caucasian

It is a common

and tension
sixfold

New

Zealand, as a cause
over the last the

the
25

annual
yr for (7).

incidence renal
This has

of malignant disease
been

hyperdecreased
to

of all
partment

medical
(3). and

emergencies
It is useful

presenting
to distinguish BP urgencies

to the
between should be 2),

emergency
hypertensive lowered in which

dewithin BP

of end-stage with
need (8). continue

has drugs

attributed

emergencies minutes,

(Table lowered
determinant

1 ), in which more slowly

for the

improved
understanding Indian-Asian malignant

BP

control
of patients

antihypertensive
treatment. to have

and
black incidence

better
and of

hypertensive

(Table several
of

However, a higher

can ration The

modest,

be

over
urgency

hours.
treatment

The

most

important

is detenio-

hypertension

of vital absolute
acute acute

organ level
increases

function of BP itself
in BP

secondary is less
may and (e.g. lead

to the important,
to critical (e.g. dissection

hypertension. because even

Etiology end-organ

Malignant plicate
sion. cause secondary Although malignant

hypertension primary
secondary hypertension may not causes

can

develop

de from 3), be the

novo any

or can
etiology on

comcan of clinical

damage
sia and

in previously medical
infarction).

normotensive condition

patients
in those

, pre-eclampan accomor acute

underlying

(essential)
hypertension (Table always

or secondary

hyperten-

glomerubonephritis)

with

panying
myocardial

, aortic
the has

identification

possible

Malignant Wagener celerated hypertension grade

hypertension IV retinal accompanied hypertension

denotes changes traditionally by grade

presence been used

of whereas

Keithac-

grounds, failure,
relative tension 30% essential of

especially since
frequency varies with

in cases pathology
of primary race, age.

presenting is not
and and period (6,9). predominant

with always

irreversible available.
malignant

renal The
hyper-

(papilbedema), III retinopathy

renal

to define (hemor-

secondary

of study.

rhages, cotton wool spots, edema). The two conditions and prognosis, and unless

and hard exudates without papillshare similar etiology, pathology, stated otherwise, both conditions

In white

subjects,
malignant hypertension

essential
hypertension is the

hypertension
In

accounts
blacks, cause of mortality and

for

20 to

however, malignant

will be referred to as malignant hypertension in this review. Malignant hypertension may develop in patients with preexisting hypertension or in previously nonmotensive patients. The
choice

hypertension,
(10). causes failure in U.S. such are

accounting
as threestroke,

for
end-stage

approximately
morbidity renal higher and

82%
disease,

of all cases
from cardiac than

Hypertension-related to fivefold

etiology

of hypertension of treatment,
used.

itself but

is less important have

in deciding on the and the

in African-Americans

the urgency The widespread reductions tension. presentation, sion and other This

it may

an influence agents to malignant

Caucasians interactions

and are often of

and

end results and socioeconomic

may

of uncontrolled status
predispose early

BP factors poor
to onset in early maof

of agents

( 1 1 ). The
of potent and will and antihypertensive have due resulted mortality outcome crises. appear
access lignant greater target

genetic
compliance

environmental with

development availability in morbidity review treatment,

to be important.
to health hypertension care

Low

of dialysis discuss

in significant hyperclinical hyperten-

( 1 2). In African-Americans,
increased
to

the pathophysiology, of malignant

hypertension,
organ

severity,
complications

inadequate
often

treatment,
result

and

susceptibility damage.

hypertensive

The

average
tends exception the

age
of

of

presentation
than atheromatous

for
that renal

essential
for secondary artery black

malignant
causes, (4). can stenosis subjects

Malignant
Incidence
Malignant

Hypertension
hypertension is relatively uncommon, occurring

hypertension with

to be higher

Secondary 2
presenting

causes
under

are
the

nearly
age of

always
30,

found

in white

subjects age. Renal

the

in 1 % of the hypertensive times more frequently than

population women,

(4,5). and

Men patients

are affected range from

whereas

present Renal for the

with

essential

malignant and accounts

pyebonephnitis

hypertension causes for

at a younger hypertension

parenchymal majority
with

renovascular

account

of secondary disease

in all populations. up to 80%

and glomerubonephnitis the cases of reflux

Correspondence to Dr. Nicolas J. Guzman, pertension, Georgetown University Medical PHC 6003. Washington, DC 20007.
1046-6673/0901 Journal Copyright of the 0 -01 33$03.00/0 American 1998 by the Society American of Nephrology Society

Division of Nephrology and HyCenter. 3800 Reservoir Road NW.

parenchymal
causes,

of all secondary disease

secondary and anal-

chronic

most
accounts
of Nephrology

common
for

diagnoses
approximately

(6,9,
with

1 3).
of

Tubulointerstitial

20%

malignant

hypertension,

vesico-ureteric

134

Journal

of the American

Society

of Nephrology

Table

I.

Hypertensive
Type

emergencies

and

treatment
.

of Emergency

Drugs

of Choice

Alternative Second-Line

or Drug

Relative

Contraindications

Hypertensive encephabopathy Intracranial hemorrhage Left ventricular pulmonary Acute myocardial unstable crisis failure edema and

Nitroprusside Labetabol Nitropnusside 1oop diuretics

ACEI

Labetalol Nitroprusside
Nitroglycerin

Tnimethophan, Vasodilatorsb
Labetabol,

cbonidine

beta-blockers,

verapamib Nitropnusside. labetalol Vasodilatorsb

Nitroglycerin beta-blockers Nitroprusside beta-blockers, phentolamine

infarction, angina Adrenergic

Labetalol

Monotherapy blockers

with

beta-

Dissecting

aontic

aneurysm

Beta-blockers nitroprusside,

Labetabol, verapamil

Vasodilators

trimethophan Eclampsia Hydralazine, labetalol

a h
C

Nifedipinec

ACEI,

nitroprusside

ACEL, angiotensin-converting enzyme inhibitors. Vasodilators with reflex sympathetic stimulation,

Hypotensive Nitroprusside effects may of magnesium be considered

e.g., hydralazine, minoxidil, may be potentiated by nifedipine. if BP cannot be controlled by other means.

diazoxide,

and

short-acting

nifedipine.

Table

2.

Hypertensive
of Urgency

urgencies

and

treatment
.

Alternative Second-Line
.

or Drugs

Relative Contraindications
. .

Type

Drugs

of Choice

Uncomplicated malignant hypertension Acute renal

Labetabol,

ACE!

Nifedipine, cbonidine

Labetalol, beta-blocker Nitroglycerin,

nitroprusside

minoxidil

ACEI,

diuretics,

or

Nitroprussideb

failure Perioperative
hypertension
a

hemofiltrationa Labetalob,
nicardipine

Diuretics
Nitnoprusside

should
may

be considered
be considered

in patients

with volume

overload

only.
but

In obiguric
the dose and

patients,
duration

hemofiltration
must be limited

may be necessary.
to avoid toxicity.

if no alternatives

are available,

gesic

nephropathy

the

commonest

causes

(9).

Renovascular

arterioles, small-

arteniolar to medium-sized typically

necrosis, arteries show fibrinoid

and are

mucoid characteristically necrosis with

changes seen. fine

within The subendo-

hypertension hypertension
17 to 53%

is increasingly in white
of all patients

recognized with
with secondary

as a cause an estimated
malignant

of malignant incidence
hypenten-

patients,

of

arterioles

theliab

lipid

droplets

and

hyalin

thrombi

formation.

Inflammathis condition arteries, the

fibrin. Marked

sion

(9,13,14).

tory infiltrate is minimal, from necrotizing vasculitis.

intima is infiltrated with

which distinguishes In the interbobular

eosinophilic-staining

Pathology The characteristic

sion sence represents of prior

pathologic
endotheliab injury, disease,

change

of malignant
involvement,

hypertenand

intimal ab-

hyperplasia

is accompanied

by

concentric

layers

of

arteriolar

gbomerular mal-sized medulla resulting

ischemia
underlying

( 1 , 1 5, 16). cortical hyperemic running proliferative

Macroscopically,
the kidneys are

in the
often

collagen, resulting in changes often referred Taken together, these alterations may lead
sion larger changes of the renal arterial arteries lumen are and produce frequently normal

to as onion to near-total
Arcuate or show

skin. occluand only

nor-

ischemia.

and show is usually in streaks

and subcapsular due parallel

hemorrhages.

The

to capillary with the

engorgement, tubules. Under arteries and

of chronic

hypertension.

Within the vascular

the

glomeruli, pole,

fibninoid This

necrosis, may be

usually

involving by

bight microscopy,

endartenitis

in small

is frequent.

accompanied

Malignant

Hypertension

and

Hypertensive

Emergencies

135

Table

3.

Causes

of malignant

hypertension

gbomerular cular lesions

scarring

and

progressive endartenitis the including and brain.

renal

failure. and focal

Similar necrosis heart,

vasare adrenal

of proliferative

Essential

hypertension etiologies nephritis

with renal involvement

Renal parenchymal glomerulonephritis tubulointerstitial

systemic systemic disorders sclerosis

seen in other organs, glands, intestine, liver,

pancreas,

Pat hophysiology The most important factor leading to the development of malignant hypertension is a severe, and frequently rapid, elevation of BP (1 ,l5, 16). Because there is considerable overlap
in the
(4),

HUS/TFP diabetes SLE vascubitides congenital renal Renovascular atheroma

fibromuscular Takayasus dysplasia arteritis

mellitus

BP

of patients

with

stable

and

malignant

hypertension

other

factors

seem

to be necessary

to initiate a triggermng followed and The to the the

the

the malignant factor superby a positive activation

of developing

disorders aplasia

phase. The rapidity of onset suggests imposed on pre-existing hypertension feedback 1oop the precipitating Elevation malignant denying
stress esis. on Under

leading factors of Blood

to higher (Figure Pressure. are and, related

BP 1).

further
risks

of

hypertension hypertension
the vessel normal wall

severity role
in its

of the
pathogen-

un-

acute PAN
Endocrine

occlusion

therefore,

of mechanical
endothelium is

appears

to be critical vascular

circumstances,

pheochromocytoma Conns Cushing Drugs cocaine

clonidine

protected

from

an increase

in BP by the blood

vessels

ability hyperand damand

walls wall

syndrome 5 syndrome

to vasoconstrict. With tension, autoregulation transmission age leads

deposition

severe mechanical injury from fails, resulting in focal vasodilation BP to the endothelium. vascular permeability
proteins and hypertension fibrinogen

of high to enhanced
of plasma with

Endothelial with leakage

in vessel

amphetamines
withdrawal

and
tion.

activation
Patients

of mediators
chronic

of coagulation the transmission

are relatively

and
develop protected

cell

proliferato the
the de-

MAOI

interactions

arterial from

erythropoietin

hypertrophy
capillary

that
circulation

minimizes
and

of pressure

cycbosporine Tumor-rebated renal Wilms lymphoma Coarctation cell carcinoma tumor of the aorta

vebopment Endocrine
tensin system

of malignant and
is greatly

hypertension. Mediators.
in malignant

Paracrine
activated

The

renin-angiohypertension.

Pre-eclampsia/ecbampsia
a

Hyper-reninnemia may be primary or secondary emia produced by arteriolar occlusion. Increased production leads to further renal vasoconstriction
syndnome/thrombotic SLE, systemic lupus erythematosus;

to renal ischangiotensin II and isch-

HUS/TTP,

hemolytic-uremic purpura;

thrombocytopenic

emia. further

Volume renin

depletion due to pressure natniuresis stimulates release and worsens malignant hypertension. In

PAN,

polyarteritis

nodosa;

MAOI,

monoamine

oxidase

inhibitor.
Critical degree

focal plication

mesangial of the cells atrophy

cell

proliferation glomeruli

and,

less commonly, show wrinkling of interstitium

with

crescent and reduof the jux-

of hypertension

formation. taglomerular granular

hemorrhage

Less-damaged basement can

and

membrane. with be
chronic

Enlargement The

Endotheiiai

damage

Increase in vasoconstrictors s (renin-angiotensin,vasopressin catecholamines)

apparatus also
patchy

proliferation seen.
inflammation

renin-secreting may show Acute and

Intravascular hemolysis Platelet and fibrin deposition

fibrosis.

////

Further pressure

blood increase

Tubular tubular fibrin

may

develop,

in part,

due

to ischemia.

necrosis may also can be demonstrated and 1gM changes of renal of renal

be present. in the

On immunofluorescence, glomeruli, arterioles,

Pressure

natriuresis

small arteries, The vascular the development by the occlusion

and C3 can be seen in the mesangium. within the kidney correlate well with failure vessels (4). Impaired leading perfusion to ischemic caused damage

Hypovolemia Fibrinoid necrosis intimal proliferation

and

/
Further release of vasoconstrictors

\
I
Increase pressure in blood

V
____________________________

and renal scarring is the critical factor in determining outcome. Renal ischemia may persist after treatment and may lead to

1
Figure

and isehemia

1. Mechanisms

of malignant

hypertension.

136

Journal

of the American

Society

of Nephrology

some and Local platelets, produces

emia

instances, reverse the

restoration malignant

of plasma phase.

volume

may

reduce

BP

tients common the

with and

malignant was found

hypertension. in 1 of 89

Aortic patients

dissection at autopsy

is (4).

less

intravascular activation of the clotting cascade and in the setting of microangiopathic hemolytic anemia, a vicious cycle of fibnin deposition and tissue ischto fibninoid necrosis. Increased local production

Neurologic
presenting

Symptoms.
complaint

Neurobogic
in malignant

symptoms
hypertension.

are
More

often
than in focal

60%
7%

of patients
of patients ischemia, hypertensive

have

headaches
(4,6).

at presentation,
Cerebrovascular and and include subarachnoid is now

and
events transient

up to 28%
occur or hemorrhage

leading

complain

of dizziness and

of

cytokines

and

growth

factors

stimulates

proliferation

of levels a de-

at presentation cerebral encephabopathy

medial smooth of vasopressin,

crease smoking; in and

muscle cells. An increase endothelin, cortisob, and

of prostacyclin system as immune

in circulating catecholamines;
a result have of all

cerebral

production

cigarette been

(6,8). True
complication ache,

an

uncommon by headwith

abnormalities

of malignant vomiting,

hypertension and visual

characterized blurring, together

implicated their roles

in the pathogenesis remain undefined.

of malignant

hypertension,

but

nausea,

impaired
blindness

cognitive
(1 ,2 1).

function,
Occasionally,

generalized
focal of rise

seizures,
neurologic

or cortical
symptoms

may Clinical The

the

occur.

The
and

critical
the rapidity

precipitating

factor
in BP. develops may

appears
The absolute may such as not

to be the
BP be very with from rise is mainin at

Presentation clinical presentation

of the

suddenness

of malignant
high BP effects

hypertension
on target

reflects
organs.

which high,

hypertensive and hypertensive without Hypertensive

encephabopathy retinopathy previous in cerebral encephalopathy

consequences

be absent, is likely due

particularly those to arise

which previously
ditions.

in turn

depend

on the level hypertension, In patients mmHg

several

and rate and with systolic hypertension

before

of rise of the BP, medical hypertension,

the con-

in patients eclampsia. loss

hypertension vessels

existing Pressure. of presenting to 180

for

underlying malignant with diastolic BP

the

of autoregulation

to a severe

Blood the range from mmHg

always,

BP is wide, and stable

years

BP ranging 150
of

BP. Under normal circumstances, tamed constant despite fluctuations perfusion

processes perfusion

cerebral over
to be

blood flow a moderate subjects,

at

range adaptive
a higher against

in

100 (9).

from
onset

to 290 but
the

pressure.
allow pressure the

In chronic
blood and thereby flow

hypertensive
provide some

Pre-existing

is often,

not
ma-

maintained protection

present

lignant phase (4). Optic Fundi. marks of malignant

is a presenting

the Grades III and

in 35 to

development

of hypertensive

encephalopathy bevels This

during

sud-

IV retinopathy (1 7, 18). Impairment

60% of patients

are

the
with

hallthis

hypertension
symptom

of vision

den BP, when

tensive

increases in BP. However, at very high a breakdown in autoregubation occurs. the BP is no greater patients. encephalopathy or greater. The
breakdown focal cerebral arterioles, and

of systemic may occur in previously hyper-

than

160/100

mmHg

condition (4,6). In malignant hypertension, the development of hard exudates and hemorrhages is preceded by loss of autoregulation with development of areas of narrowing and dilatation in retinal vessels ( I , 18). Retinal hemorrhages necrosis of the capillary and precapiblary arteriolar dothelial proteins region, exudates usually
ing tion, of the

normotensive mmHg
perfusion, tion,

In chronic rarely result

of edema.

hypertensive

patients,

develops until the BP is 200/120 is cerebral vasodilation. hyperbarrier, Pathologic plasma findings edema. As the exudainclude

result from walls. Enof plasma In the macula star. nerve

Early of

blood-brain

damage this are near

optic

leads form

to leakage retina a radiating by ischemic head.

obliteration nerve head,

and pattern, infarct

deposition exudates. of
cup. blurring

cerebral
crosis

microinfarctions,
of cerebral

petechial
and

hemorrhages,
cerebral

fibninoid
BP

neis

in the posterior may caused the optic

disc of

as hard

the macula the denotes of venous

Soft fiber, swell-

lowered,

fluid

extravasation

decreases

and

cerebral

autoregu-

nerve
with the

Papilledema
of the

signs

of disc

lation returns. In patients with chronic hypertension, autoregulation may take time to re-establish. Therefore, BP should be lowered slowly in severely hypertensive subjects to avoid
precipitating cerebral ischemia.

papilledema
hyperemia

are overfilling the

of the veins,
and

loss

pulsathe

Kidneys.
verity.

Renal

involvement

is common

but

varies
seen.

in sePa-

margins. Although tients with extremely

(17), with current

finding of papilbedema poor prognosis in the

therapy,

identified pretreatment
the differences

paera
in

Non-nephrotic-range

proteinunia

is frequently

antihypertensive

outcome longer reversed Heart. ure Heart

with

between apparent and lead

patients (19). With

with

and without

papilledema lesions acute

are no can heart be fail-

treatment,

retinal

tients with higher levels of proteinunia tend to have higher serum creatinine levels (8). Overt nephrotic syndrome is uncommon. Although there is a large overlap, proteinunia tends to be higher in those with underlying gbomerubonephnitis than in
those with essential hypertension (4). The urinalysis usually

vision Malignant
is the

often returns hypertension edema

(8).

to normal. can cause due

reflects

any

underlying

renal

disease.

Elevation

in serum

cre-

and

to pulmonary presenting
hypertension

to pressure
left

overload.
ventricular

failure
malignant

complication
Underlying

in 1 1 % of patients of patients at presen-

atinine (>2.3 mg/dl) occurs (8), with median creatinine than

mic activity

in 31% of patients at presentation levels higher in blacks (2.7 mg/dl) (20). Abnormalities.
develop increased as in a result most,

in whites
metabolic

(1.7 and

mg/dl)

hypertrophy

is found

in as many

as 75%

Electrolyte depletion and

and

Hematologic
may are

Hypokaleof but volume

tation (20), but may be absent when the rise in BP is sudden. Ischemic heart disease is also common at presentation. Angina is present in 4.1% and myocardial infarction in 3.7% of pa-

alkabosis

secondary
aldosterone

hyperaldosteronism

( 1 ). Plasma
not

renin
all,

Malignant

Hypertension

and Hypertensive

Emergencies

I 37

patients. the levels

With

treatment,

there aldosterone,

may

be a dissociation which may remain

between elevated more and

bid

will

usually unless
in renal

restore specifically
parenchymal

organ

perfusion. for
or disease

Diuretics volume
coexisting

should overload,
pulmonary

be as

of plasma

for months, and plasma renin activity, which decreases rapidly. These findings of suppressed plasma renin activity aldosterone hypersecretion may hemolytic mimic anemia fibrin the findings (with red hyperaldosteronism. Microangiopathic ments, ucts, cyte failure thrombocytopenia, and increased sedimentation and anemia

avoided occurs edema. Once causes guided

ondany

indicated

of primary cell fragprodEnythroto renal faalso for

the patient of malignant by presenting

cause

is more stable. hypertension clinical

in the

investigations should be laboratory

of white

for secondary performed, as findings.

subjects

and
majority

A secand in

increased

degradation

is found

fibninogen) is frequently present. rate is frequently elevated due (4).

nearly should
vasculitis

all white

patients

under

the age of 30. A kidney

biopsy or renal size and

be performed is suspected

when acute glomerulonephritis on the basis of normal kidney In these soon as artery cases, possible stenosis

General Features. Generalized weakness, malaise, tigue, and weight loss are common symptoms (4,6). There may be severe salt and water depletion that may account some weight loss in the accelerated phase.

nephnitic urinary sediment. need to be performed as brought cluded kidney under control. in elderly size, renal

renal biopsy may once the BP is should be exwith asymmetric of atherosclerotic

Renal

patients, and in patients bruits, or other evidence

Management

A thorough

history,

physical

examination,

and

a few

diag-

nostic tests will identify patients with malignant and help determine whether emergent intensive ment with invasive tests damage. myocardial identified. blood blood
x-ray:

hypertension care unit treateven renal, such should include before should and as be

disease. Endocrine causes such as pheochromocytoma and Conns syndrome are rare but should be excluded. If secondary causes are found, these should be appropriately corrected. In the long-term. advice on lifestyle modifications. such as cessation of smoking together with close follow-up and aggressive management of hypertension. is indicated.

monitoring

of BP ( I .2).

is needed neurologic, conditions dissection

diagnostic be focused ocular stroke,

are completed Accompanying infarction, Baseline

Initial

assessment

on signs

of cardiovascular, medical and aortic

Outcome

immediately a complete electrolyte,

ysis, chest

investigations

should

count and smear; urea nitrogen, and

and electrocardiogram.

determination of serum creatinine levels; urinalRenal ultrasound with

The tremely

outcome poor,

of with

untreated malignant hypertension is exb-year survival of only 65% in patients

presenting with grade III retinopathy and 2 1% in those with grade IV retinopathy (I 7). In the early series, uremia was the major cause ofdeath (50 to 60%) (4). Heart failure and cerebral with only and aortic of improved vascular disease one death each dissection. if More accounted attributed recently, for 30 to 40% of deaths, to myocardial infarction with the availability

Doppler stenosis changes, imaging of renal

possible

may be useful and to determine

if there renal

is suspicion size. If there

of renal artery are neurologic

brain computed tomography is necessary to rule out focal dysfunction,

to avoid

or magnetic resonance lesions. In the presence should

failure.

intravenous
precipitating

contrast
acute renal

be avoided

Careful monitoring of BP, fluid balance, renal function is necessary, but invasive required BP is not precipitate end-organ BP lowering. in all cases. necessary cerebral damage In most instances, rapid and should be avoided or cardiac ischemia. The must be balanced hypertension against

electrolytes, monitoring normalization

and is not of

antihypertensive therapy and dialysis, the prognosis has improved and differences between patients with grades Ill and IV retinopathy are no longer apparent. ( I 9). Median survival time has improved during between patients do not each decade and is 144 months for those survival is BP control Black and a failure 10%. as the presenting longer for and who 1980 and 1989 (20). Median who have adequate follow-up have end-organ damage such

because this may risks of imminent the risks of rapid by organ

as proteinunia,

In malignant

complicated

renal failure, or left ventricular subjects have higher mortality. greater

still

hypentrophy ( 13, 19,20). higher follow-up BP, In one

with

failure or other hypertensive emergencies (Table I ), it is necessany to reduce the BP rapidly. In uncomplicated malignant hypertension or other hypertensive urgencies (Table 2), BP need not be reduced by greater than 20%. or to a target of BP of 160 to 170/100 to I 10 mmHg in 24 h. Chronic hypertensive patients and the elderly have an abnormal cerebral autoregulatory capacity and are at greater risk if BP is reduced too disease fast. and In the elderly. underlying heart to antihyperor cerebrovascular increased sensitivity

degree
accounted

of renal
for 40%

impairment.
of deaths

series,
stroke,

renal 1 1, and

myocardial

infarction. respectively

and

heart An

failure, increase

accounting in myocardial

for 24.

(20).

infarction

cause of death compared due to more prolonged sequent development

with the pretreatment survival in high-risk of coronary artery

era is probably patients and sub-

disease.

tensive medications may be present. Concurrent use of other antihypertensive agents may impair compensatory reflexes and lead to a precipitous fall in BP and reduced end-organ perfusion. Similarly, volume depletion is common in patients with malignant hypertension and may bead to an excessive during treatment. Volume repletion with intravenous fall in BP crystal-

Drugs of Choice and Urgencies

The ical are safer choice when of agent condition

for

Hypertensive
largely agents

Emergencies
on the associated act more because rapidly the medand dose is

depends Intravenous

( I ,2).
given

as a constant

infusion

can be titrated recommended

to avoid hypotension. Invasive BP monitoring when intravenous therapy is used in continuous

138

Journal

of the American

Society

of Nephrology

infusion. introduced Generally, hypertensive nifedipine with with other

Once and oral

the agents

BP

is controlled, agents act more However, may cause nervous should slowly

oral and

agents can

should weaned. be used

be in

Nitroprusside equally diac fected and preboad but

decreases reduces and may

both myocardial

systemic oxygen Cardiac

arterial output with

and venous and is generally

tone carunafReflex

intravenous

be gradually

consumption heart failure.

afterboad. improve

urgencies. or captopril agents central

short-acting hypotension of volume system

drugs such as when combined depletion. effects Drugs such as

in patients

or in the presence

significant

sympathetic nerve stimulation, increases in myocardial contractility and heart rate, and coronary steal may occur in the absence of left ventricular failure. Nitroprusside is nonenzymatically maticalby toxicity, blurred per mm monitored converted to cyanide, which is then converted enzyto thiocyanate and excreted in the urine. Thiocyanate which vision, for usually manifests as confusion, at a rate hyper-reflexia, below 3 j.tgfkg
should be levels

cbonidine and methyldopa hypertensive encephalopathy. reflex sympathetic activity, minoxidil, tion. The summarized can worsen details of specific in Table 4.

should be avoided Drugs that can such as diazoxide, ischemia are drugs

in patients with result in marked hydralazine, and and aortic dissecand below

myocardial

and tinnitus,

is unusual,

discussed

up to 72 h. Blood thiocyanate during high-dose or prolonged

administration

of

Sodium Nitroprusside Sodium nitroprusside tensive duration

artenial

is the because with almost

is required

drug it has

of choice a rapid
for titration

in most onset
of

hypera short Intraeffects.

nitroprusside or if the drug is used in patients with renal impairment. The levels should be maintained below 10 mg/dl to avoid thiocyanate toxicity. Cyanide toxicity is unusual until the total dose exceeds
300

emergencies of action
BP monitoring

and
its

mg

or when

the

infusion

rate

is

universal

effectiveness.

above 20 /.Lgfkg per mm. Nitroprusside in eclampsia because it crosses the

is not a drug of choice placenta. In renal failure,

Table

4. Drug

Drugs

used Route I.V.I. I.V. I.V.I. P.O.

in the treatment
Inltlal
. .

of hypertensive

crises5
Dose Range Onset-Peak Effects Duration
.

Dose

Comments

Nitroprusside Labetalol

0.5

p.g/kg

per

mm

o.s

to 10 p.g/kg

per

mm

1 to 2 mm
5 mm

2 to 3 mm
2 to 6 h

Thiocyanate toxicity
Stop if no response 300

20 mg 0.5 mg/mm 200 to 400

20 to 80 mg every 10 to 15 mm mg 0.5 to 2 mg/mm 200 to 400 mg every

2 to 4 h (maximum 2.4 g)

after 5 to 30 mm 0.5 to 4 h 2 to 6 h 8 to I 2 h Avoid

total in

mg

contraindications

to

beta-blocker
2 to 5 mm 5 to

Nitroglycerin

I.V.I.

5 to

10 p.g/min

5 to

100 g/min

10 mm

Tolerance develop prolonged Autonomic dysfunction Reflex

may with use

Tnimethaphan Hydrabazine

I.V.I. I.V.

0.5

mg/mm

0.5

to 5 mg/mm

1 to 5 mm 5 to 15 mm

5 to

15 mm

10 mg

5 to 20 mg every
20 to 30

2 to 6 h

tachycardia

mm
50 mg)
5 mm 6 mg)

(maximum Propranobol I.V. 0.5 to 1 mg 0.5 mg every (maximum

1 to 2 mm

4 to 12 h

Phentobamine Enalaprilat

I.V.I. I.V.

0.5 to 1 mg bobus 1 mg/mm I.V.I. 0.625 to 1.25 mg

or

1 to 5 mg/mm 1 to 25 mg every 6 h

1 to 5 mm 10 to 60 mm

15 to 60 mm 2 to 6 h

Avoid in contraindications beta-blocker Tachycardia Caution in bilateral

to

RAS or volume depletion Captopnil Nifedipine P.O. P.O. 6.25 to 12.5 10 mg mg 12.5 to 50 mg every 8 h 10 to 20 mg every 15 mm
5 mg

30 to 90 mm 2 to 10 mm

4 to 6 h 3 to 6 h

Same

as enalaprilat and

Avoid in cerebral cardiac ischemia, and Reflex heart failure tachycardia

Minoxidil

P.O.

2.5 to 5 mg

every 4 h (up to 20 mg) infusion; IV.,

0.5

to 4 h

8 to 24 h

All drugs

can cause

hypotension.

b.V.I.,

intravenous

intravenous;

P.O.,

oral;

RAS,

renal

artery

stenosis.

Malignant

Hypertension

and Hypertensive

Emergencies

I 39

prolonged be avoided, monitored. Labetalol Labetabol urgencies states. tive This

or high and

dose the

administration bevels of thiocyanate

of nitroprusside should

should be closely

fall in BP. Additionally, sympathetic activation

diazoxide and sodium

can cause retention.

pronounced For these

reflex reasons, in myo-

diazoxide is now rarely used and is contraindicated cardial ischemia and aortic dissection. can be used and drug may be in most particularly and with hypertensive useful some emergencies in hyperadrenergic competivasodilating efdirect and Trimethaphan This tension
is limited

Camnsylate blocker effects is useful in the aortic treatment aneurysm, blockade of hyperbut and its use conby dissecting

ganglion complicated

is an alpha blocker

noncardioselective

beta-adrenergic

by its side

of autonomic

fects. It reduces peripheral vascular resistance without reflex stimulation of cardiac output. Labetabob can be given as a small intravenous peated patient total required continuous mm. Large infusions effective urgencies. appropriate cated and heart before bobus, and incrementally larger doses can be reThe after a is not as a IS is every 10 mm until is unlikely to respond dose of 300 in this mg setting. the desired BP is achieved. if no response is observed Invasive can BP monitoring also be given Labetalol

fusion. Phentolamine and Phenoxvbenzamine caused cocaine inhibitor frequently in these and is used blocking agents by catecholamine and crisis. used conditions. in the amphetamine The shorterbecause niPhenoxyfor are

These nonsebective abpha-adrenergic most effective in hypertensive states excess such as pheochromocytoma, overdose, and monoamine oxidase acting phentolamine is now less troprusside is equally effective benzamine is longer-acting surgery of pheochromocytoma. Angiotensin-Converting Angiotensin-converting captopril such scberoderma unpredictable plasma renin and enalapnilat renal and activity. crisis. depends as malignant

is given.

intravenous doses given

infusion, with as intravenous

onset of action in bolus or continuous Oral labetabob in hypertensive and bronchospasm, occur is contraindi-

may be associated with hypotension. within 1 to 3 h and may be useful However, for failure. medical with hence, is given it has a variable emergencies. bradycardia, alpha-blockade if this condition heart hypertension dose-response Labetalol block, may should

preparation

is not Enzyme enzyme are The useful and response on a patients patients hypertension Inhibitors inhibitors are (ACEI) drugs plasma and of such urgencies choice in and and with is variable volume patients as in hypertensive to ACEI

in patients

Paradoxical

in pheo-

chromocytoma; labetalol

be established

is suspected.

Nitroglycerin Intravenous nitroglycerin oxygen consumption, and lowers improves afterload coronary and myocardial artery perfusion.

Hypovolemic

bilateral renal or a decrease nancy. Hydralazine Hydralazine sia. It may

tachycardia.

artery stenosis in GFR. ACEI

may have a precipitous are also contraindicated

fall in BP in preg-

Hypotension and reflex tachycardia ence of volume depletion. Prolonged

may develop in the presuse may result in toler-

ance. Nitroglycerin is the drug of choice in hypertensive crisis complicated by myocardial ischemia because it can improve coronary perfusion better than nitroprusside. On the other hand, hence, situations. its effectiveness it should is less predictable as first-line than nitroprusside; therapy in other not be considered

is a direct vasodilator used primarily in eclampcause a rapid fall in BP and significant reflex
Hydrabazine is contraindicated in ischemic heart

disease Minoxidil

and

aortic

dissection.

Beta-Adrenergic Propranobol initial shear treatment stress

Blockers (intravenously) of dissecting vessel wall. in the is the aortic Esmobol drug aneurysm of choice for the the B 1of an
j.tg/kg

Minoxidil is a potent, orally lator that is useful in malignant renal failure. It may cause marked retention blockers. chemia
Calcium

active, direct hypertension reflex with

arteniolar vasodiassociated with and fluid and betacardiac is-

to reduce

tachycardia diuretics in acute

is a short-acting

selective intravenous

beta-blocker that bolus injection.

is effective within 5 mm Esmolol (loading dose 500

and needs Minoxidil and aortic

to be combined is contraindicated dissection.

Blockers

in 1 mm; maintenance useful as an adjunctive in hypertension angina, induced in BP. associated

dose, 50 to 300 p.g/kg per mm) may be therapy aimed at lowering the heart rate with myocardial infarction, unstable be avoided in cocainecause a paradoxical rise

Channel

The ers BP

dihydropyridine mainly by BP

class causing effectively and reflex

of calcium vasodibation.

channel Oral

blockers short-acting crises, activation but (22).

bownisemay For in

and thyrotoxicosis. It should hypertension because it may

fedipine lowers vere hypotension develop and lead these reasons, the treatment

in hypertensive sympathetic

to stroke

or myocardial

infarction

Diazoxide Diazoxide is a potent arterial vasodilator within a few minutes. It is given as small (50 to 100 mg) every desired BP is achieved.

with onset intravenous

of action boluses

short-acting of hypertensive

nifedipine is not emergencies.

recommended

10 to 15 mm up to 600 mg or until the Larger doses can produce a profound

Nondihydropyridine verapamil, appear hypertension (23).

calcium channel blockers, particularly to be safe in the treatment of postinfarction Verapamil can also be used in aortic dis-

140

Journal

of the American

Society

of Nephrology

section nifedipine

when

beta-blockers preparations and

are

contraindicated.

Slow-release dihydropyri-

Hypertensive Hypertensive

Encephalopathy encephalopathy
).

second-generation

is an emergency

that

requires

dines such as nicardipine cause less reflex sympathetic activation and are useful in the treatment of malignant hypertension complicated by renal failure. Intravenous nicardipine (2.5 to 15 mg/h) appears to be as effective ment of postoperative hypertension Further evaluation is necessary, nifedipine ommended cerebral and second-generation for hypertensive ischemia. crises as nitroprusside and has fewer however, before dihydropyridines complicated in the treatside effects. slow-release can be necby cardiac or

rapid reduction in BP ( I ,2 I Caution is needed in patients with chronic hypertension and the elderly because too rapid BP reduction may worsen cerebral ischemia. Nitroprusside is the drug of choice for this complication. Invasive intensive care unit BP monitoring is indicated. Mean BP should be lowered by a maximum of 20% or to a diastolic BP of 100 to 1 10 mmHg within the first hour. After rapid reduction of BP, clinical resolution is usually seen and BP can be reduced more gradually over the next 48 to 72 h.

Clonidine Clonidine, not a first-line occurs within some patients

Cerebrovascular The optimal a centrally acting alpha 2 adrenergic agonist, is of cerebrovascular arachnoid drug for hypertensive crisis. Its onset of action 30 to 60 mm, but its effects are variable and suffer an extreme fall in BP. Cbonidine can cause and should be avoided in patients

Accidents treatment of severe accidents, and such cerebral

hypertension infarction,

in the presence and remains rebleeding the risks subto be and/or of wors-

as intracerebrab

hemorrhage

determined. The risks of elevated BP causing cerebral edema need to be weighed against ening cerebral (I ,2,21 ,27,28). BP >
20% or care 130 to

somnolence and confusion with encephabopathy.

ischemia In patients
mean level

with too with severely

BP of should be

rapid BP reduction. elevated BP (diastolic

lowered cautiously by

mmHg), a diastolic unit settings.

100

to

1 10 mmHg of labetabol
can also be

during under
used, but

the intenit

Special
Acute Renal related function be with
covery

Situations
Renal to the high with as 4% Failure in malignant renal Although in patients survival
with adequate

initial
sive

24 h, with further

continuous intracranial channel

infusion

Nitroprusside

survival

hypertension disorder with appear over

treatment

appears the renal level survival

to

be can

may used rhage

increase calcium

pressure. blocker

Recently, nimodipine

the cerehas been hemor-

underlying 60% renal

and essential

of renal

broselective to reduce (27). Ventricular

at presentation.

the S-yr

cerebral

vasospasm

in subarachnoid

as

hypertension, much (24). worse, Renal

particularly

patients only

gbomerubonephnitis

to fare
of BP,

18 months is not with may for

re-

Left

Failure

and

Pulmonary

Edema of an acute left ventricular rise in com-

is possible

if renal

impairment

at presentation

severe.

Progressive

Acute systemic pliance

side signs are and

heart failure occurs as a result vascular resistance and reduced

deterioration is more likely in patients above 3.4 mg/dl (6,9). Renal recovery
in dialysis-dependent patients over

a serum creatinine occasionally occur

ranging from I wk

( 1,2). Vasodilators
indicated, symptoms

and
of

such as nitroglycerin their doses should be

heart failure subside.

and nitroprusadjusted until

Loop diuretics

a period

to 2 yr (25). function, protect caution

Because

of the

potential

recovery

of renal

can ACEI tabol should

be

used

once

the

arterial may

resistance

has

been

reduced. Labeand

urgent antihypertensive the kidney from further is necessary to maintain blood flow with for this situation

treatment injury. At euvobemia and

is necessary to the same time, to avoid comtherapy. parenteral

and and

hydralazine beta-blockers

be considered may worsen

subsequently. cardiac function

be avoided. Infarction and conditions and may and labetalol has little acute Unstable of choice because improve Angina for severe it reduces coronary be hypertension myocardiab blood flow used. effect Betabut is

promising renal Drugs of choice labetabol, minoxidil extremely derma glomenular

particularly

the antihypertensive include oral and

Myocardial Nitroglycerin

and oral combined effective renal

if

agents such as short-acting nifedipine and with beta-blockers. ACEI can also be and rate
is

is the agent

are and

specifically temporarily

indicated treatment worsen

volume

in scleromay renal reduce failure,

(26)

complicated by these oxygen consumption (1 ,2).

blockade

crisis. filtration
there

Antihypertensive
concomitant

Nitroprusside
generally

may also antihypertensive

depletion.

Under these conditions, volume replacement with intravenous crystalboids may be indicated to improve renal perfusion. Conversely, in patients with nephrogenic edema or end-stage renal failure, dramatically
use

useful in reducing rate. Vasodilator

ity. such

myocardial oxygen consumption and heart drugs that stimulate reflex sympathetic activhydralazine, short-acting nifedipine, and

as diazoxide,

minoxidib,
Dissecting

should
Aortic

be avoided.
Aneurysm

fluid

removal reduce BP.

with
membranes

loop

diuretics term,
dialysis, for

or by dialysis strict BP control,

and avoidance

may the
of

In the long

of biocompatible

The

goal

of therapy

in this

condition

is to reduce

the

shear of BP with is retreat-

nephrotoxins the greatest should be recovery

and intradialysis chance for renal postponed until of renal function

hypotensive episodes may allow recovery. Finally, transplantation at least 12 months because late can occur.

forces on the aortic wall ( 1 ,2,29). Emergency reduction to the lowest tolerated level (systolic, 100 to I 10 mmHg) drugs that do not increase heart rate and contractility quired. Propranolol combined with nitroprusside is the

Malignant

Hypertension

and Hypertensive

Emergencies

141

ment lished

of choice. It is imperative that beta-blockade is estabbefore the introduction of nitroprusside. Labetabol and
are useful alternatives. If beta-blockers are

2.

Mann sion:

SI,

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SA:

Hypertensive Diagnosis

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In: Hvperten2nd Ed.,

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Zampaglione pertensive presentation. 4. Kincaid-Smith urgencies

IH, Brenner

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Gudbrandsson hypertension: Scand Stewart end-stage Lip GY, 206: IH,

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M, Beevers A survey in England. and 1986 SH, Veriava outcome

Postoperative Postoperative tone after nary cautious labetabol and vascular coronary ischemia. can volume may

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