DISEASEOF THE MONTH

Malignant Hypertension and Hypertensive Emergencies

CHAGRIYA KITIYAKARA and NICOLAS J. GUZMANDivision of Nephrologv and Hypertension. Georgetown University Medical Center, Washington, DC.

Hypertensive crisis refers to a syndrome characterized by se-

vere BP elevation associated with imminent risks to the patient

(1,2). It is a common clinical problem and accounts for 27.5%

of all medical emergencies presenting to the emergency de-

partment (3). It is useful to distinguish between hypertensive

emergencies (Table 1 ), in which BP should be lowered within

minutes, and hypertensive urgencies (Table 2), in which BP

can be lowered more slowly over several hours. The most

important determinant for the urgency of treatment is detenio-

ration of vital organ function secondary to the hypertension.

The absolute level of BP itself is less important, because even

modest, acute increases in BP may lead to critical end-organ

damage in previously normotensive patients (e.g. , pre-eclamp-

sia and acute glomerubonephritis) and in those with an accom-

panying medical condition (e.g. , aortic dissection or acute

myocardial infarction).

Malignant hypertension denotes the presence of Keith-

Wagener grade IV retinal changes (papilbedema), whereas ac-

celerated hypertension traditionally has been used to define

hypertension accompanied by grade III retinopathy (hemor-

rhages, cotton wool spots, and hard exudates without papill-

edema). The two conditions share similar etiology, pathology,

and prognosis, and unless stated otherwise, both conditions

will be referred to as malignant hypertension in this review.

Malignant hypertension may develop in patients with pre-

existing hypertension or in previously nonmotensive patients.

The etiology of hypertension itself is less important in deciding

the urgency of treatment, but it may have an influence on the

choice of agents used.

The development of potent antihypertensive agents and the

widespread availability of dialysis have resulted in significant

reductions in morbidity and mortality due to malignant hyper-

tension. This review will discuss the pathophysiology, clinical

presentation, treatment, and outcome of malignant hyperten-

sion and other hypertensive crises.

Malignant HypertensionIncidence

Malignant hypertension is relatively uncommon, occurring

in 1% of the hypertensive population (4,5). Men are affected 2

times more frequently than women, and patients range from

Correspondence to Dr. Nicolas J. Guzman, Division of Nephrology and Hy-pertension, Georgetown University Medical Center. 3800 Reservoir Road NW.

PHC 6003. Washington, DC 20007.

1046-6673/0901 -01 33$03.00/0

Journal of the American Society of Nephrology

Copyright 0 1998 by the American Society of Nephrology

infants to the elderly. The incidence of malignant hypertension

in Caucasian populations has been decreasing (6). In Australia

and New Zealand, the annual incidence of malignant hyper-

tension as a cause of end-stage renal disease has decreased

sixfold over the last 25 yr (7). This has been attributed to

improved BP control with antihypertensive drugs and better

understanding of the need for treatment. However, black and

Indian-Asian patients continue to have a higher incidence of

malignant hypertension (8).

Etiology

Malignant hypertension can develop de novo or can com-

plicate underlying primary (essential) or secondary hyperten-

sion. Although secondary hypertension from any etiology can

cause malignant hypertension (Table 3), the identification of

secondary causes may not always be possible on clinical

grounds, especially in cases presenting with irreversible renal

failure, since renal pathology is not always available. The

relative frequency of primary and secondary malignant hyper-

tension varies with race, age. and period of study.

In white subjects, essential hypertension accounts for 20 to

30% of malignant hypertension (6,9). In blacks, however,

essential hypertension is the predominant cause of malignant

hypertension, accounting for approximately 82% of all cases

(10). Hypertension-related morbidity and mortality from

causes such as stroke, end-stage renal disease, and cardiac

failure are three- to fivefold higher in African-Americans than

in U.S. Caucasians and are often end results of uncontrolled BP

( 1 1 ). The interactions of genetic and environmental factors

appear to be important. Low socioeconomic status with poor

access to health care and compliance may predispose to ma-

lignant hypertension ( 1 2). In African-Americans, early onset of

hypertension, increased severity, inadequate treatment, and

greater susceptibility to complications often result in early

target organ damage.

The average age of presentation for essential malignant

hypertension tends to be higher than that for secondary causes,

with the exception of atheromatous renal artery stenosis (4).

Secondary causes are nearly always found in white subjects

presenting under the age of 30, whereas black subjects can

present with essential malignant hypertension at a younger age.

Renal parenchymal and renovascular hypertension account

for the majority of secondary causes in all populations. Renal

parenchymal disease accounts for up to 80% of all secondary

causes, with chronic pyebonephnitis and glomerubonephnitis the

most common diagnoses (6,9, 1 3). Tubulointerstitial disease

accounts for approximately 20% of the cases of secondary

malignant hypertension, with vesico-ureteric reflux and anal-

134 Journal of the American Society of Nephrology

Table I. Hypertensive emergencies and treatment�’

. Alternative or . . -

Type of Emergency Drugs of Choice Second-Line Drug Relative Contraindications

Hypertensive Nitroprusside Labetalol Tnimethophan, cbonidine

encephabopathy

Intracranial hemorrhage Labetabol Nitroprusside Vasodilatorsb

Left ventricular failure and Nitropnusside ± Nitroglycerin Labetabol, beta-blockers,

pulmonary edema 1oop diuretics verapamib

± ACEI

Acute myocardial Nitroglycerin ± Nitropnusside. Vasodilatorsb

infarction, unstable beta-blockers labetalol

angina

Adrenergic crisis Nitroprusside ± Labetalol Monotherapy with beta-

beta-blockers, blockers

phentolamine

Dissecting aontic aneurysm Beta-blockers + Labetabol, Vasodilators”

nitroprusside, verapamil

trimethophan

Eclampsia Hydralazine, Nifedipinec ACEI, nitroprusside�’

labetalol

a ACEL, angiotensin-converting enzyme inhibitors.h Vasodilators with reflex sympathetic stimulation, e.g., hydralazine, minoxidil, diazoxide, and short-acting nifedipine.

C Hypotensive effects of magnesium may be potentiated by nifedipine.d Nitroprusside may be considered if BP cannot be controlled by other means.

Table 2. Hypertensive urgencies and treatment

. Alternative or RelativeType of Urgency Drugs of Choice . . .

Second-Line Drugs Contraindications

Uncomplicated Labetabol, ACE! Nifedipine,

malignant cbonidine

hypertension

Acute renal Labetalol, minoxidil + ACEI, diuretics, or Nitroprussideb

failure beta-blocker hemofiltrationa

Perioperative Nitroglycerin, Labetalob,

hypertension nitroprusside nicardipine

a Diuretics should be considered in patients with volume overload only. In obiguric patients, hemofiltration may be necessary.1� Nitnoprusside may be considered if no alternatives are available, but the dose and duration must be limited to avoid toxicity.

gesic nephropathy the commonest causes (9). Renovascular

hypertension is increasingly recognized as a cause of malignant

hypertension in white patients, with an estimated incidence of

17 to 53% of all patients with secondary malignant hypenten-

sion (9,13,14).

Pathology

The characteristic pathologic change of malignant hyperten-

sion represents endotheliab injury, arteriolar involvement, and

gbomerular ischemia ( 1 , 1 5, 16). Macroscopically, in the ab-

sence of prior underlying disease, the kidneys are often nor-

mal-sized and show cortical and subcapsular hemorrhages. The

medulla is usually hyperemic due to capillary engorgement,

resulting in streaks running parallel with the tubules. Under

bight microscopy, proliferative endartenitis in small arteries and

arterioles, arteniolar necrosis, and mucoid changes within

small- to medium-sized arteries are characteristically seen. The

arterioles typically show fibrinoid necrosis with fine subendo-

theliab lipid droplets and hyalin thrombi formation. Inflamma-

tory infiltrate is minimal, which distinguishes this condition

from necrotizing vasculitis. In the interbobular arteries, the

intima is infiltrated with eosinophilic-staining fibrin. Marked

intimal hyperplasia is accompanied by concentric layers of

collagen, resulting in changes often referred to as “onion skin.”

Taken together, these alterations may lead to near-total occlu-

sion of the arterial lumen and produce ischemia. Arcuate and

larger renal arteries are frequently normal or show only

changes of chronic hypertension.

Within the glomeruli, fibninoid necrosis, usually involving

the vascular pole, is frequent. This may be accompanied by

Table 3. Causes of malignant hypertension�’

Essential hypertension

Renal parenchymal etiologies

glomerulonephritis

tubulointerstitial nephritis

systemic disorders with renal involvement

systemic sclerosis

HUS/TFP

diabetes mellitus

SLE

vascubitides

congenital disorders

renal aplasia

Renovascular

atheroma

fibromuscular dysplasia

Takayasu’s arteritis

acute occlusion

PAN

Endocrine

pheochromocytoma

Conn’s syndrome

Cushing’ 5 syndrome

Drugs

cocaine

amphetamines

clonidine withdrawal

MAOI interactions

erythropoietin

cycbosporine

Tumor-rebated

renal cell carcinoma

Wilms’ tumor

lymphoma

Coarctation of the aorta

Pre-eclampsia/ecbampsia

a HUS/TTP, hemolytic-uremic syndnome/thrombotic

thrombocytopenic purpura; SLE, systemic lupus erythematosus;

PAN, polyarteritis nodosa; MAOI, monoamine oxidase inhibitor.

focal mesangial cell proliferation and, less commonly, crescent

formation. Less-damaged glomeruli show wrinkling and redu-

plication of the basement membrane. Enlargement of the jux-

taglomerular apparatus with proliferation of renin-secreting

granular cells can also be seen. The interstitium may show

hemorrhage and patchy chronic inflammation with fibrosis.

Tubular atrophy may develop, in part, due to ischemia. Acute

tubular necrosis may also be present. On immunofluorescence,

fibrin can be demonstrated in the glomeruli, arterioles, and

small arteries, and 1gM and C3 can be seen in the mesangium.

The vascular changes within the kidney correlate well with

the development of renal failure (4). Impaired perfusion caused

by the occlusion of renal vessels leading to ischemic damage

and renal scarring is the critical factor in determining outcome.

Renal ischemia may persist after treatment and may lead to

Critical degree

of hypertension

_ � _, Endotheiiai damage Increase in vasoconstrictors s

(renin-angiotensin,vasopressin

catecholamines)

Platelet and fibrin deposition Further blood/�///� pressure increase

Intravascular

hemolysis Pressure natriuresis

� Hypovolemia

Fibrinoid necrosis and /intimal proliferation Further release of vasoconstrictors

\ VI Increase in blood ____________________________

�1 pressure and isehemia

Figure 1. Mechanisms of malignant hypertension.

Malignant Hypertension and Hypertensive Emergencies 135

gbomerular scarring and progressive renal failure. Similar vas-

cular lesions of proliferative endartenitis and focal necrosis are

seen in other organs, including the pancreas, heart, adrenal

glands, intestine, liver, and brain.

Pat hophysiology

The most important factor leading to the development of

malignant hypertension is a severe, and frequently rapid, ele-

vation of BP (1 ,l5, 16). Because there is considerable overlap

in the BP of patients with stable and malignant hypertension

(4), other factors seem to be necessary to initiate the malignant

phase. The rapidity of onset suggests a triggermng factor super-

imposed on pre-existing hypertension followed by a positive

feedback 1oop leading to higher BP and further activation of

the precipitating factors (Figure 1).

Elevation of Blood Pressure. The risks of developing

malignant hypertension are related to the severity of the un-

denying hypertension and, therefore, the role of mechanical

stress on the vessel wall appears to be critical in its pathogen-

esis. Under normal circumstances, the vascular endothelium is

protected from an increase in BP by the blood vessels’ ability

to vasoconstrict. With severe mechanical injury from hyper-

tension, autoregulation fails, resulting in focal vasodilation and

transmission of high BP to the endothelium. Endothelial dam-

age leads to enhanced vascular permeability with leakage and

deposition of plasma proteins and fibrinogen in vessel walls

and activation of mediators of coagulation and cell prolifera-

tion. Patients with chronic hypertension develop arterial wall

hypertrophy that minimizes the transmission of pressure to the

capillary circulation and are relatively protected from the de-

vebopment of malignant hypertension.

Endocrine and Paracrine Mediators. The renin-angio-

tensin system is greatly activated in malignant hypertension.

Hyper-reninnemia may be primary or secondary to renal isch-

emia produced by arteriolar occlusion. Increased angiotensin II

production leads to further renal vasoconstriction and isch-

emia. Volume depletion due to pressure natniuresis stimulates

further renin release and worsens malignant hypertension. In

136 Journal of the American Society of Nephrology

some instances, restoration of plasma volume may reduce BP

and reverse the malignant phase.

Local intravascular activation of the clotting cascade and

platelets, in the setting of microangiopathic hemolytic anemia,

produces a vicious cycle of fibnin deposition and tissue isch-

emia leading to fibninoid necrosis. Increased local production

of cytokines and growth factors stimulates proliferation of

medial smooth muscle cells. An increase in circulating levels

of vasopressin, endothelin, cortisob, and catecholamines; a de-

crease in production of prostacyclin as a result of cigarette

smoking; and immune system abnormalities have all been

implicated in the pathogenesis of malignant hypertension, but

their roles remain undefined.

Clinical Presentation

The clinical presentation of malignant hypertension reflects

the consequences of the high BP effects on target organs.

which in turn depend on the level and rate of rise of the BP, the

previously existing hypertension, and underlying medical con-

ditions.

Blood Pressure. In patients with malignant hypertension,

the range of presenting BP is wide, with diastolic BP ranging

from 100 to 180 mmHg and systolic BP from 150 to 290

mmHg (9). Pre-existing stable hypertension is often, but not

always, present for several years before the onset of the ma-

lignant phase (4).

Optic Fundi. Grades III and IV retinopathy are the hall-

marks of malignant hypertension (1 7, 18). Impairment of vision

is a presenting symptom in 35 to 60% of patients with this

condition (4,6). In malignant hypertension, the development of

hard exudates and hemorrhages is preceded by loss of auto-

regulation with development of areas of narrowing and dilata-

tion in retinal vessels ( I , 18). Retinal hemorrhages result from

necrosis of the capillary and precapiblary arteriolar walls. En-

dothelial damage leads to leakage and deposition of plasma

proteins in the posterior retina as hard exudates. In the macula

region, this may form a radiating pattern, the macula star. Soft

exudates are caused by ischemic infarct of the nerve fiber,

usually near the optic nerve head. Papilledema denotes swell-

ing of the optic disc with obliteration of the cup. Early signs of

papilledema are overfilling of the veins, loss of venous pulsa-

tion, hyperemia of the nerve head, and blurring of the disc

margins. Although the finding of papilbedema identified pa-

tients with extremely poor prognosis in the pretreatment era

(17), with current antihypertensive therapy, the differences in

outcome between patients with and without papilledema are no

longer apparent (19). With treatment, retinal lesions can be

reversed and vision often returns to normal.

Heart. Malignant hypertension can cause acute heart fail-

ure and lead to pulmonary edema due to pressure overload.

Heart failure is the presenting complication in 1 1 % of patients

with malignant hypertension (8). Underlying left ventricular

hypertrophy is found in as many as 75% of patients at presen-

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-

tients with malignant hypertension. Aortic dissection is less

common and was found in 1 of 89 patients at autopsy (4).

Neurologic Symptoms. Neurobogic symptoms are often

the presenting complaint in malignant hypertension. More than

60% of patients have headaches at presentation, and up to 28%

complain of dizziness (4,6). Cerebrovascular events occur in

7% of patients at presentation and include transient or focal

cerebral ischemia, and cerebral and subarachnoid hemorrhage

(6,8).

True hypertensive encephabopathy is now an uncommon

complication of malignant hypertension characterized by head-

ache, nausea, vomiting, and visual blurring, together with

impaired cognitive function, generalized seizures, or cortical

blindness (1 ,2 1). Occasionally, focal neurologic symptoms

may occur. The critical precipitating factor appears to be the

suddenness and the rapidity of rise in BP. The absolute BP at

which hypertensive encephabopathy develops may not be very

high, and hypertensive retinopathy may be absent, particularly

in patients without previous hypertension such as those with

eclampsia. Hypertensive encephalopathy is likely to arise from

loss of autoregulation in cerebral vessels due to a severe rise in

BP. Under normal circumstances, cerebral blood flow is main-

tamed constant despite fluctuations over a moderate range in

perfusion pressure. In chronic hypertensive subjects, adaptive

processes allow the blood flow to be maintained at a higher

perfusion pressure and thereby provide some protection against

the development of hypertensive encephalopathy during sud-

den increases in BP. However, at very high bevels of systemic

BP, a breakdown in autoregubation occurs. This may occur

when the BP is no greater than 160/100 mmHg in previously

normotensive patients. In chronic hypertensive patients, hyper-

tensive encephalopathy rarely develops until the BP is 200/120

mmHg or greater. The result is cerebral vasodilation. hyper-

perfusion, breakdown of blood-brain barrier, plasma exuda-

tion, and focal cerebral edema. Pathologic findings include

cerebral microinfarctions, petechial hemorrhages, fibninoid ne-

crosis of cerebral arterioles, and cerebral edema. As the BP is

lowered, fluid extravasation decreases and cerebral autoregu-

lation returns. In patients with chronic hypertension, autoreg-

ulation may take time to re-establish. Therefore, BP should be

lowered slowly in severely hypertensive subjects to avoid

precipitating cerebral ischemia.

Kidneys. Renal involvement is common but varies in se-

verity. Non-nephrotic-range proteinunia is frequently seen. Pa-

tients with higher levels of proteinunia tend to have higher

serum creatinine levels (8). Overt nephrotic syndrome is un-

common. 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

reflects any underlying renal disease. Elevation in serum cre-

atinine (>2.3 mg/dl) occurs in 31% of patients at presentation

(8), with median creatinine levels higher in blacks (2.7 mg/dl)

than in whites (1.7 mg/dl) (20).

Electrolyte and Hematologic Abnormalities. Hypokale-

mic metabolic alkabosis may develop as a result of volume

depletion and secondary hyperaldosteronism ( 1 ). Plasma renin

activity and aldosterone are increased in most, but not all,

Malignant Hypertension and Hypertensive Emergencies I 37

patients. With treatment, there may be a dissociation between

the levels of plasma aldosterone, which may remain elevated

for months, and plasma renin activity, which decreases more

rapidly. These findings of suppressed plasma renin activity and

aldosterone hypersecretion may mimic the findings of primary

hyperaldosteronism.

Microangiopathic hemolytic anemia (with red cell frag-

ments, thrombocytopenia, increased fibrin degradation prod-

ucts, and increased fibninogen) is frequently present. Enythro-

cyte sedimentation rate is frequently elevated due to renal

failure and anemia (4).

General Features. Generalized weakness, malaise, fa-

tigue, and weight loss are common symptoms (4,6). There also

may be severe salt and water depletion that may account for

some weight loss in the accelerated phase.

Management

A thorough history, physical examination, and a few diag-

nostic tests will identify patients with malignant hypertension

and help determine whether emergent intensive care unit treat-

ment with invasive monitoring of BP is needed even before

diagnostic tests are completed ( I .2). Initial assessment should

be focused on signs of cardiovascular, neurologic, renal, and

ocular damage. Accompanying medical conditions such as

stroke, myocardial infarction, and aortic dissection should be

immediately identified. Baseline investigations should include

a complete blood count and smear; determination of serum

electrolyte, blood urea nitrogen, and creatinine levels; urinal-

ysis, chest x-ray: and electrocardiogram. Renal ultrasound with

Doppler may be useful if there is suspicion of renal artery

stenosis and to determine renal size. If there are neurologic

changes, brain computed tomography or magnetic resonance

imaging is necessary to rule out focal lesions. In the presence

of renal dysfunction, intravenous contrast should be avoided if

possible to avoid precipitating acute renal failure.

Careful monitoring of BP, fluid balance, electrolytes, and

renal function is necessary, but invasive monitoring is not

required in all cases. In most instances, rapid normalization of

BP is not necessary and should be avoided because this may

precipitate cerebral or cardiac ischemia. The risks of imminent

end-organ damage must be balanced against the risks of rapid

BP lowering. In malignant hypertension complicated by organ

failure or other hypertensive emergencies (Table I ), it is nec-

essany 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 ab-

normal cerebral autoregulatory capacity and are at greater risk

if BP is reduced too fast. In the elderly. underlying heart or

cerebrovascular disease and increased sensitivity to antihyper-

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 perfu-

sion. Similarly, volume depletion is common in patients with

malignant hypertension and may bead to an excessive fall in BP

during treatment. Volume repletion with intravenous crystal-

bid will usually restore organ perfusion. Diuretics should be

avoided unless specifically indicated for volume overload, as

occurs in renal parenchymal disease or coexisting pulmonary

edema.

Once the patient is more stable. investigations for secondary

causes of malignant hypertension should be performed, as

guided by presenting clinical and laboratory findings. A sec-

ondany cause is found in the majority of white subjects and in

nearly all white patients under the age of 30. A kidney biopsy

should be performed when acute glomerulonephritis or renal

vasculitis is suspected on the basis of normal kidney size and

nephnitic urinary sediment. In these cases, renal biopsy may

need to be performed as soon as possible once the BP is

brought under control. Renal artery stenosis should be ex-

cluded in elderly patients, and in patients with asymmetric

kidney size, renal bruits, or other evidence of atherosclerotic

disease. Endocrine causes such as pheochromocytoma and

Conn’s 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 ces-

sation of smoking together with close follow-up and aggressive

management of hypertension. is indicated.

Outcome

The outcome of untreated malignant hypertension is ex-

tremely poor, with b-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

vascular disease accounted for 30 to 40% of deaths, with only

one death each attributed to myocardial infarction and aortic

dissection. More recently, with the availability of improved

antihypertensive therapy and dialysis, the prognosis has im-

proved and differences between patients with grades Ill and IV

retinopathy are no longer apparent. ( I 9). Median survival time

has improved during each decade and is 144 months for those

presenting between 1980 and 1989 (20). Median survival is

longer for patients who have adequate follow-up BP control

and who do not have end-organ damage such as proteinunia,

renal failure, or left ventricular hypentrophy ( 1 3, 19,20). Black

subjects have higher mortality. higher follow-up BP, and a

greater degree of renal impairment. In one series, renal failure

still accounted for 40% of deaths with stroke, myocardial

infarction. and heart failure, accounting for 24. 1 1, and 10%.

respectively (20). An increase in myocardial infarction as the

cause of death compared with the pretreatment era is probably

due to more prolonged survival in high-risk patients and sub-

sequent development of coronary artery disease.

Drugs of Choice for Hypertensive Emergenciesand Urgencies

The choice of agent depends largely on the associated med-

ical condition ( I ,2). Intravenous agents act more rapidly and

are safer when given as a constant infusion because the dose

can be titrated to avoid hypotension. Invasive BP monitoring is

recommended when intravenous therapy is used in continuous

138 Journal of the American Society of Nephrology

a All drugs can cause hypotension. b.V.I., intravenous infusion; IV., intravenous; P.O., oral; RAS, renal artery stenosis.

infusion. Once the BP is controlled, oral agents should be

introduced and intravenous agents should be gradually weaned.

Generally, oral agents act more slowly and can be used in

hypertensive urgencies. However, short-acting drugs such as

nifedipine or captopril may cause hypotension when combined

with other agents or in the presence of volume depletion. Drugs

with significant central nervous system effects such as

cbonidine and methyldopa should be avoided in patients with

hypertensive encephalopathy. Drugs that can result in marked

reflex sympathetic activity, such as diazoxide, hydralazine, and

minoxidil, can worsen myocardial ischemia and aortic dissec-

tion. The details of specific drugs are discussed below and

summarized in Table 4.

Sodium Nitroprusside

Sodium nitroprusside is the drug of choice in most hyper-

tensive emergencies because it has a rapid onset and a short

duration of action with almost universal effectiveness. Intra-

artenial BP monitoring is required for titration of its effects.

Table 4. Drugs used in the treatment of hypertensive crises5

Nitroprusside decreases both systemic arterial and venous tone

equally and reduces myocardial oxygen consumption and car-

diac preboad and afterboad. Cardiac output is generally unaf-

fected but may improve in patients with heart failure. Reflex

sympathetic nerve stimulation, increases in myocardial con-

tractility and heart rate, and coronary steal may occur in the

absence of left ventricular failure. Nitroprusside is nonenzy-

matically converted to cyanide, which is then converted enzy-

maticalby to thiocyanate and excreted in the urine. Thiocyanate

toxicity, which usually manifests as confusion, hyper-reflexia,

blurred vision, and tinnitus, is unusual, at a rate below 3 j.tgfkg

per mm for up to 72 h. Blood thiocyanate levels should be

monitored during high-dose or prolonged administration of

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 mg or when the infusion rate is

above 20 /.Lgfkg per mm. Nitroprusside is not a drug of choice

in eclampsia because it crosses the placenta. In renal failure,

Drug Route. .

Inltlal Dose Dose RangeOnset-Peak

Effects.

Duration Comments

Nitroprusside I.V.I. 0.5 p.g/kg per mm o.s to 10 p.g/kg per mm 1 to 2 mm 2 to 3 mm Thiocyanate

toxicity

Labetalol I.V. 20 mg 20 to 80 mg every

10 to 15 mm

5 mm 2 to 6 h Stop if no response

after total 300 mg

I.V.I.

P.O.

0.5 mg/mm

200 to 400 mg

0.5 to 2 mg/mm

200 to 400 mg every

2 to 4 h (maximum

2.4 g)

5 to 30 mm

0.5 to 4 h

2 to 6 h

8 to I 2 h Avoid in

contraindications to

beta-blocker

Nitroglycerin I.V.I. 5 to 10 p.g/min 5 to 100 �g/min 2 to 5 mm 5 to 10 mm Tolerance may

develop with

prolonged use

Tnimethaphan I.V.I. 0.5 mg/mm 0.5 to 5 mg/mm 1 to 5 mm 5 to 15 mm Autonomic

Hydrabazine I.V. 10 mg 5 to 20 mg every

20 to 30 mm(maximum 50 mg)

5 to 15 mm 2 to 6 h

dysfunction

Reflex tachycardia

Propranobol I.V. 0.5 to 1 mg 0.5 mg every 5 mm

(maximum 6 mg)

1 to 2 mm 4 to 12 h Avoid in

contraindications to

beta-blocker

Phentobamine I.V.I. 0.5 to 1 mg bobus or

1 mg/mm I.V.I.

1 to 5 mg/mm 1 to 5 mm 15 to 60 mm Tachycardia

Enalaprilat I.V. 0.625 to 1.25 mg 1 to 25 mg every 6 h 10 to 60 mm 2 to 6 h Caution in bilateral

RAS or volume

depletion

Captopnil P.O. 6.25 to 12.5 mg 12.5 to 50 mg every 8 h 30 to 90 mm 4 to 6 h Same as enalaprilat

Nifedipine P.O. 10 mg 10 to 20 mg every 15

mm

2 to 10 mm 3 to 6 h Avoid in cerebral and

cardiac ischemia,

and heart failure

Minoxidil P.O. 2.5 to 5 mg 5 mg every 4 h

(up to 20 mg)

0.5 to 4 h 8 to 24 h Reflex tachycardia

Malignant Hypertension and Hypertensive Emergencies I 39

prolonged or high dose administration of nitroprusside should

be avoided, and the bevels of thiocyanate should be closely

monitored.

Labetalol

Labetabol can be used in most hypertensive emergencies and

urgencies and may be particularly useful in hyperadrenergic

states. This drug is an alpha and noncardioselective competi-

tive beta-adrenergic blocker with some direct vasodilating ef-

fects. It reduces peripheral vascular resistance without reflex

stimulation of cardiac output. Labetabob can be given as a small

intravenous bobus, and incrementally larger doses can be re-

peated every 10 mm until the desired BP is achieved. The

patient is unlikely to respond if no response is observed after a

total dose of 300 mg is given. Invasive BP monitoring is not

required in this setting. Labetalol can also be given as a

continuous intravenous infusion, with onset of action in IS

mm. Large doses given as intravenous bolus or continuous

infusions may be associated with hypotension. Oral labetabob is

effective within 1 to 3 h and may be useful in hypertensive

urgencies. However, it has a variable dose-response and is not

appropriate for medical emergencies. Labetalol is contraindi-

cated in patients with bradycardia, heart block, bronchospasm,

and heart failure. Paradoxical hypertension may occur in pheo-

chromocytoma; hence, alpha-blockade should be established

before labetalol is given if this condition is suspected.

Nitroglycerin

Intravenous nitroglycerin lowers afterload and myocardial

oxygen consumption, and improves coronary artery perfusion.

Hypotension and reflex tachycardia may develop in the pres-

ence of volume depletion. Prolonged use 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, its effectiveness is less predictable than nitroprusside;

hence, it should not be considered as first-line therapy in other

situations.

Beta-Adrenergic Blockers

Propranobol (intravenously) is the drug of choice for the

initial treatment of dissecting aortic aneurysm to reduce the

shear stress in the vessel wall. Esmobol is a short-acting B 1 -

selective beta-blocker that is effective within 5 mm of an

intravenous bolus injection. Esmolol (loading dose 500 j.tg/kg

in 1 mm; maintenance dose, 50 to 300 p.g/kg per mm) may be

useful as an adjunctive therapy aimed at lowering the heart rate

in hypertension associated with myocardial infarction, unstable

angina, and thyrotoxicosis. It should be avoided in cocaine-

induced hypertension because it may cause a paradoxical rise

in BP.

Diazoxide

Diazoxide is a potent arterial vasodilator with onset of action

within a few minutes. It is given as small intravenous boluses

(50 to 100 mg) every 10 to 15 mm up to 600 mg or until the

desired BP is achieved. Larger doses can produce a profound

fall in BP. Additionally, diazoxide can cause pronounced reflex

sympathetic activation and sodium retention. For these reasons,

diazoxide is now rarely used and is contraindicated in myo-

cardial ischemia and aortic dissection.

Trimethaphan Camnsylate

This ganglion blocker is useful in the treatment of hyper-

tension complicated by dissecting aortic aneurysm, but its use

is limited by its side effects of autonomic blockade and con-

fusion.

Phentolamine and Phenoxvbenzamine

These nonsebective abpha-adrenergic blocking agents are

most effective in hypertensive states caused by catecholamine

excess such as pheochromocytoma, cocaine and amphetamine

overdose, and monoamine oxidase inhibitor crisis. The shorter-

acting phentolamine is now less frequently used because ni-

troprusside is equally effective in these conditions. Phenoxy-

benzamine is longer-acting and is used in the preparation for

surgery of pheochromocytoma.

Angiotensin-Converting Enzyme Inhibitors

Angiotensin-converting enzyme inhibitors (ACEI) such as

captopril and enalapnilat are useful in hypertensive urgencies

such as malignant hypertension and are drugs of choice in

scberoderma renal crisis. The response to ACEI is variable and

unpredictable and depends on a patient’s plasma volume and

plasma renin activity. Hypovolemic patients and patients with

bilateral renal artery stenosis may have a precipitous fall in BP

or a decrease in GFR. ACEI are also contraindicated in preg-

nancy.

Hydralazine

Hydralazine is a direct vasodilator used primarily in eclamp-

sia. It may cause a rapid fall in BP and significant reflex

tachycardia. Hydrabazine is contraindicated in ischemic heart

disease and aortic dissection.

Minoxidil

Minoxidil is a potent, orally active, direct arteniolar vasodi-

lator that is useful in malignant hypertension associated with

renal failure. It may cause marked reflex tachycardia and fluid

retention and needs to be combined with diuretics and beta-

blockers. Minoxidil is contraindicated in acute cardiac is-

chemia and aortic dissection.

Calcium Channel Blockers

The dihydropyridine class of calcium channel blockers bow-

ers BP mainly by causing vasodibation. Oral short-acting ni-

fedipine lowers BP effectively in hypertensive crises, but se-

vere hypotension and reflex sympathetic activation may

develop and lead to stroke or myocardial infarction (22). For

these reasons, short-acting nifedipine is not recommended in

the treatment of hypertensive emergencies.

Nondihydropyridine calcium channel blockers, particularly

verapamil, appear to be safe in the treatment of postinfarction

hypertension (23). Verapamil can also be used in aortic dis-

140 Journal of the American Society of Nephrology

section when beta-blockers are contraindicated. Slow-release

nifedipine preparations and second-generation dihydropyri-

dines such as nicardipine cause less reflex sympathetic activa-

tion 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 as nitroprusside in the treat-

ment of postoperative hypertension and has fewer side effects.

Further evaluation is necessary, however, before slow-release

nifedipine and second-generation dihydropyridines can be nec-

ommended for hypertensive crises complicated by cardiac or

cerebral ischemia.

Clonidine

Clonidine, a centrally acting alpha 2 adrenergic agonist, is

not a first-line drug for hypertensive crisis. Its onset of action

occurs within 30 to 60 mm, but its effects are variable and

some patients suffer an extreme fall in BP. Cbonidine can cause

somnolence and confusion and should be avoided in patients

with encephabopathy.

Special SituationsAcute Renal Failure

Renal survival in malignant hypertension appears to be

related to the underlying renal disorder and the level of renal

function at presentation. Although the S-yr renal survival can

be as high as 60% in patients with essential hypertension,

patients with gbomerubonephnitis appear to fare much worse,

with only 4% renal survival over 18 months (24). Renal re-

covery is possible with adequate treatment of BP, particularly

if renal impairment at presentation is not severe. Progressive

deterioration is more likely in patients with a serum creatinine

above 3.4 mg/dl (6,9). Renal recovery may occasionally occur

in dialysis-dependent patients over a period ranging from I wk

to 2 yr (25). Because of the potential for recovery of renal

function, urgent antihypertensive treatment is necessary to

protect the kidney from further injury. At the same time,

caution is necessary to maintain euvobemia and to avoid com-

promising renal blood flow with the antihypertensive therapy.

Drugs of choice for this situation include oral and parenteral

labetabol, and oral agents such as short-acting nifedipine and

minoxidil combined with beta-blockers. ACEI can also be

extremely effective and are specifically indicated in sclero-

derma renal crisis. Antihypertensive treatment may reduce

glomenular filtration rate and temporarily worsen renal failure,

particularly if there is concomitant volume depletion. (26)

Under these conditions, volume replacement with intravenous

crystalboids may be indicated to improve renal perfusion. Con-

versely, in patients with nephrogenic edema or end-stage renal

failure, fluid removal with loop diuretics or by dialysis may

dramatically reduce BP. In the long term, strict BP control, the

use of biocompatible membranes for dialysis, and avoidance of

nephrotoxins and intradialysis hypotensive episodes may allow

the greatest chance for renal recovery. Finally, transplantation

should be postponed until at least 12 months because late

recovery of renal function can occur.

Hypertensive Encephalopathy

Hypertensive encephalopathy is an emergency that requires

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.

Cerebrovascular Accidents

The optimal treatment of severe hypertension in the presence

of cerebrovascular accidents, such as intracerebrab and sub-

arachnoid hemorrhage and cerebral infarction, remains to be

determined. The risks of elevated BP causing rebleeding and/or

cerebral edema need to be weighed against the risks of wors-

ening cerebral ischemia with too rapid BP reduction.

(I ,2,21 ,27,28). In patients with severely elevated BP (diastolic

BP > 130 mmHg), mean BP should be lowered cautiously by

20% or to a diastolic level of 100 to 1 10 mmHg during the

initial 24 h, with continuous infusion of labetabol under inten-

sive care unit settings. Nitroprusside can also be used, but it

may further increase intracranial pressure. Recently, the cere-

broselective calcium channel blocker nimodipine has been

used to reduce cerebral vasospasm in subarachnoid hemor-

rhage (27).

Left Ventricular Failure and Pulmonary Edema

Acute heart failure occurs as a result of an acute rise in

systemic vascular resistance and reduced left ventricular com-

pliance ( 1 ,2). Vasodilators such as nitroglycerin and nitroprus-

side are indicated, and their doses should be adjusted until

signs and symptoms of heart failure subside. Loop diuretics

can be used once the arterial resistance has been reduced.

ACEI and hydralazine may be considered subsequently. Labe-

tabol and beta-blockers may worsen cardiac function and

should be avoided.

Myocardial Infarction and Unstable Angina

Nitroglycerin is the agent of choice for severe hypertension

complicated by these conditions because it reduces myocardiab

oxygen consumption and may improve coronary blood flow

(1 ,2). Nitroprusside and labetalol may also be used. Beta-

blockade generally has little acute antihypertensive effect but is

useful in reducing myocardial oxygen consumption and heart

rate. Vasodilator drugs that stimulate reflex sympathetic activ-

ity. such as diazoxide, hydralazine, short-acting nifedipine, and

minoxidib, should be avoided.

Dissecting Aortic Aneurysm

The goal of therapy in this condition is to reduce the shear

forces on the aortic wall ( 1 ,2,29). Emergency reduction of BP

to the lowest tolerated level (systolic, 100 to I 10 mmHg) with

drugs that do not increase heart rate and contractility is re-

quired. Propranolol combined with nitroprusside is the treat-

Malignant Hypertension and Hypertensive Emergencies 141

ment of choice. It is imperative that beta-blockade is estab-

lished before the introduction of nitroprusside. Labetabol and

tnimethaphan are useful alternatives. If beta-blockers are con-

traindicated, verapamil can also be used. Drugs that can stim-

ulate reflex sympathetic activity are absolutely contraindicated.

Adrenergic Crises

In these conditions, which include pheochromocytoma, co-

caine and amphetamine overdose, clonidine withdrawal, and

monoamine oxidase inhibitors-tyramine reaction, plasma cat-

echolamines are grossly elevated (1 ,2). Nitroprusside is equably

as effective as phentolamine in controlling the hypertension.

Labetalol can also be used, but paradoxical hypertension may

occur. Beta-blockers should not be used alone until alpha-

blockade with phentolamine or phenoxybenzamine is

achieved. Hypertension due to cbonidine withdrawal should be

initially treated with the resumption of this drug.

Postoperative Hypertension

Postoperative hypertension due to increased sympathetic

tone and vascular resistance may occur in 30 to 50% of patients

after coronary artery bypass (I ,2,30). Prompt treatment is

required to prevent complications such as bleeding and coro-

nary ischemia. Nitroglycerin is the treatment of choice, but

nitroprusside can also be used in these patients. Analgesia and

cautious volume replacement may be helpful. Nicardipine and

labetabol may prove useful adjunctive therapy.

Eclampsia

In eclampsia, systolic BP needs to be controlled to a target

of 90 to I 10 mmHg before delivery. Intravenous hydralazine or

labetabol can be used as first-line drugs in combination with

magnesium sulfate (3 1 ). Calcium channel blockers may be

considered as second-line agents. Invasive monitoring is not

necessary in most cases. ACEI are contraindicated, and sodium

nitroprusside should be avoided.

SummaryHypertensive emergencies and urgencies are important

causes of morbidity and mortality. Malignant hypertension is a

hypertensive urgency characterized by grade III/IV retinopathy

and widespread endothelial damage. Control of BP is essential

in the treatment of these disorders. The effects of hypertension

on target organ function need to be balanced against the risks

of excessive BP lowering. In hypertensive emergencies, BP

should be lowered within minutes with parenteral agents to

prevent critical end-organ damage. In hypertensive urgencies,

BP can be lowered more slowly over several hours, often with

oral agents, to avoid a detrimental fall in BP. The absolute

indications for treatment and the optimal therapy depend on the

underlying condition.

ReferencesI . Nolan CR III, Linas SL: Malignant hypertension and other hy-

pertensive crises. In: Diseases of the Kidney, 5th Ed.. edited by

Schrier RW, Gottschalk CW, Boston, Little, Brown and Co.,1993, pp 1555-1643

2. Mann SI, Atlas SA: Hypertensive emergencies. In: Hvperten-

sion: Pathophvsio/ogv, Diagnosis and Management, 2nd Ed.,

edited by Laragh IH, Brenner BM, New York, Raven, 1995, pp3009-3022

3. Zampaglione B, Pascale C, Marchisio M. Cavallo-Perin P: Hy-

pertensive urgencies and emergencies: Prevalence and clinical

presentation. Hypertension 27: 144-147, 1996

4. Kincaid-Smith P. McMichael I, Murphy EA: The clinical course

and pathology of hypertension with papilboedema (malignant

hypertension). QJM 37: 117-153, 1958

5. Bechgaard P. Kopp H, Nielson I: One thousand hypertensivepatients followed from 16-22 years. Acta Med Scand

3l2[Suppll: 175-183, 1956

6. Gudbrandsson T, Hansson L, Herlitz H, Andr#{233}nL: Malignant

hypertension: Improving prognosis in a rare disease. Acta Med

Scand 206: 495-499, 1979

7. Stewart IH, Disney AP, Mathew TH: Trends in the incidence of

end-stage renal failure due to hypertension and vascular disease

in Australia, 1972-1991 . Aust N Z J Med 24: 696-700, 1994

8. Lip GY, Beevers M, Beevers G: The failure of malignant hyper-

tension to decline: A survey of 24 years’ experience in a multi-

racial population in England. J Hvpertens 12: 1297-1305, 1994

9. Yu SH. Whitworth IA. Kincaid-Smith PS: Malignant hyperten-

sion: Aetiology and outcome in 83 patients. C/in Exp Hvpertens

8: 1211-1230, 1986

10. Milne Fl, lames SH, Veriava Y: Malignant hypertension and its

renal complications in black South Africans. S Afr Med J 76:

164-167, 1989

I I . Saunders E: Hypertension in African-Americans. Circu/ation 83:

1465-1467, 1991

12. Shea 5, Misra D, Ehrlich MH, Field L, Francis CK: Predisposing

factors for severe, uncontrolled hypertension in an inner-city

minority population. N EngI J Med 327: 776-778. 1992

13. Webster I, Petrie IC, leffers TA, Lovell HG: Accelerated hyper-

tension: Patterns of mortality and clinical factors affecting out-come in treated patients. QJM 86: 485-493. 1993

14. Davis BA, Crook IE, Vestal RE, Oates IA: Prevalence of reno-

vascular hypertension in patients with grade 11 or IV hyperten-

sive retinopathy. N Engi J Med 301: 1273-1276. 1979

15. Helmchen U, Wenzeb UO: Benign and malignant nephrosclerosis

and renovascular disease. In: Rena/ Pathology: Wit/i C/inica/ and

Functional Correlations, 2nd Ed., edited by Tisher CC, Brenner

BM, Philadelphia. I. B. Lippincott. 1994, pp 1201-123616. Ruggenenti P. Remuzzi G: Malignant vascular disease of the

kidney: Nature of the lesions, mediators of disease progression,

and the case for bilateral nephrectomy. Am J Kidney Dis 27:

459-475, 1996

17. Keith NM, Wagener HP. Barker NW: Some different types of

essential hypertension: Their course and prognosis. Aiti J Med Sci

197: 332-343. 1939

I 8. Dodson PM, Lip GY. Eames SM. Gibson IM, Beevers DG:

Hypertensive retinopathy: A review of existing classification

systems and a suggestion for a simplified grading system. J Hum

Hypertens 10: 93-98. 1996

19. McGregor E, Isles CG. lay JL. Lever AF. Murray GD: Retinalchanges in malignant hypertension. Br Med J Cliii Res 292:

233-234. 1986

20. Lip GY, Beevers M, Beevers DG: Complications and survival of

3 15 patients with malignant-phase hypertension. J Hvpertens I 3:

915-924, 1995

21. Phillips SI, Whisnant IP: Hypertension and the brain. Arc/i

Intern Med 152: 938-945. 1992

142 Journal of the American Society of Nephrology

22. Grossman E, Messerli FH, Grodzicki T, Kowey P: Should a

moratorium be placed on sublingual nifedipine capsules given

for hypertensive emergencies and pseudoemergencies? JAMA

276: 1328-1331, 1996

23. Opie LH: Calcium channel blockers for hypertension: Dis-

secting evidence for adverse effects. Am J Hvpertens 10:

565-577, 1997

24. Kawazoe N, Eto T, Abe I, Takeshita 5, Ueno M, Kobayashi K,

Uezono K, Muratani H, Kimura Y, Tomita Y, Tsuchihashi T,

Onoyama K, Kawasaki T, Fukiyama K, Omae T, Fujishima M:

Long-term prognosis of malignant hypertension: Difference be-

tween underlying diseases such as essential hypertension and

chronic glomerulonephritis. C/in Nephrol 29: 53-57, 1988

25. James SH, Meyers AM, Milne Fl, Reinach SG: Partial recovery

of renal function in black patients with apparent end-stage renal

failure due to primary malignant hypertension. Nephron 71:

29-34, 1995

26. Woods 1W, Blythe W, Huffines WD: Management of malignant

hypertension complicated by renal insufficiency: A follow-up

study. N Eng/ J Med 291 : 10-14, 1974

27. Vermeulen M: Subarachnoid haemorrhage: Diagnosis and treat-

ment. J Neuro/ 243: 496-501 , 1996

28. Strandgaard 5: Hypertension and stroke. J Hypertens l4[Suppl]:

523-527, 1996

29. Crawford ES: The diagnosis and management of aortic dissec-

tion. JAMA 264: 2537-2541, 1990

30. Marty L: Role of isradipine and other antihypertensive agents in

the treatment of peri- and postoperative hypertension. Acta An-

aesthesiol Scand Supp/ 99: 53-55, 19933 1 . Sibai BH: Treatment of hypertension in pregnant women. N Eng/

J Med 335: 257-265, 1996