Malignant Hypertension

Author: John D Bisognano, MD, PhD, FACP, FACC; Chief Editor: Vecihi Batuman, MD, FACP, FASN
Updated: Dec 03, 2015

Hypertensive Emergencies
A hypertensive emergency is a condition in which elevated blood pressure results in target organ
damage.[1] The systems primarily involved include the central nervous system, the cardiovascular
system, and the renal system. Malignant hypertension and accelerated hypertension are both
hypertensive emergencies, with similar outcomes and therapies. In order to diagnose malignant
hypertension, papilledema (as seen in the image below) must be present. [2] However, Cremer et al
consider the presence of retinopathy as but one of various potential presentations for acute
hypertension with multiorgan damage.[1] Therefore, they have proposed a "more modern" definition for
malignant hypertension, in which hypertensive emergencies, in the absence of retinopathy, be based
on the criteria of acute elevated blood pressure accompanied by damage to a minimum of three
different target organs.[1]

Papilledema. Note the swelling of the

optic disc, with blurred margins.

Up to 1% of patients with essential hypertension develop malignant hypertension, but the reason some
patients develop malignant hypertension whereas others do not is unknown. The characteristic
vascular lesion is fibrinoid necrosis of arterioles and small arteries, which causes the clinical
manifestations of end-organ damage. Red blood cells are damaged as they flow through vessels
obstructed by fibrin deposition, resulting in microangiopathic hemolytic anemia.
In a retrospective study that evaluated hospital admissions data from the Nationwide Inpatient Sample
for malignant hypertension, hypertensive encephalopathy, and essential hypertension, Polgreen et al
found an increasing trend for malignant hypertension and hypertensive encephalopathy between the
years 2000 and 2011, with a dramatic increase after 2007. [3] However, there was no corresponding
dramatic increase seen in morbidity for both conditions, which the investigators believed might have
resulted from coding changes in diagnostic-related groups in 2007. Mortality declined significantly for
patients with malignant hypertension, but there was no change for those with hypertensive
encephalopathy.[3]
Another pathologic process is the dilatation of cerebral arteries following a breakthrough of the normal
autoregulation of cerebral blood flow. Under normal conditions, cerebral blood flow is kept constant by
cerebral vasoconstriction in response to increases in blood pressure. In patients without hypertension,
flow is kept constant over a mean pressure of 60-120 mm Hg. In patients with hypertension, flow is
constant over a mean pressure of 110-180 mm Hg because of arteriolar thickening. When blood
pressure is raised above the upper limit of autoregulation, arterioles dilate. This results in

hyperperfusion and cerebral edema, which cause the clinical manifestations of hypertensive
encephalopathy.
Other causes of malignant hypertension include any form of secondary hypertension; complications of
pregnancy; use of cocaine, monoamine oxidase inhibitors (MAOIs), or oral contraceptives; and the
withdrawal of alcohol, beta-blockers, or alpha-stimulants. Renal artery stenosis, pheochromocytoma
(most pheochromocytomas can be localized using computed tomography (CT) scanning of the
adrenals), aortic coarctation, and hyperaldosteronism are also secondary causes of hypertension. In
addition, both hyperthyroidism and hypothyroidism can cause hypertension.
The following conditions should also be considered when making the diagnosis: stroke, intracranial
mass, head injury, epilepsy or postictal state, connective-tissue disease (especially lupus with cerebral
vasculitis), drug overdose or withdrawal, cocaine or amphetamine ingestion, acute anxiety,
and thrombotic thrombocytopenic purpura.[4, 5]
Because malignant hypertension-induced thrombotic microangiopathy may mimic thrombocytopenic
purpura, the possibility exists that plasma exchange rather than antihypertensive agents might initially
be administered to patients. In a literature review, Khanal et al reported that factors that are more likely
to be present in malignant hypertension-induced thrombotic microangiopathy are: a previous history of
hypertension, high mean arterial pressure, significant renal impairment but relatively modest
thrombocytopenia, and lack of severe ADAMTS-13 gene deficiency (activity <10%) at diagnosis. [5]
For more information, see Hypertension.

Accelerated hypertension and hypertensive urgency

Accelerated hypertension is defined as a recent significant increase over baseline blood pressure that
is associated with target organ damage. This is usually seen as vascular damage on funduscopic
examination, such as flame-shaped hemorrhages or soft exudates, but without papilledema.
Hypertensive urgency must be distinguished from hypertensive emergency. Urgency is defined as
severely elevated blood pressure (ie, systolic >220 mm Hg or diastolic >120 mm Hg) with no evidence
of target organ damage.
Hypertensive emergencies require immediate therapy to decrease blood pressure within minutes to
hours.[6] In contrast, no evidence suggests a benefit from rapidly reducing blood pressure in patients
with hypertensive urgency. In fact, such aggressive therapy may harm the patient, resulting in cardiac,
renal, or cerebral hypoperfusion. This article discusses hypertensive emergency, but therapy for
hypertensive urgency is discussed briefly.

Patient education
Patients must be taught an appropriate diet for long-term management, and upon discharge, patients
should not only know the signs and symptoms that should prompt immediate notification of a physician
but also know the proper dosing and adverse effects of their medications.
For patient education resources, see the Diabetes Center as well as High Blood Pressure.

Evaluation
The history should include screening for symptoms of malignant hypertension, focusing on the cardiac,
renal, and central nervous systems. Underlying medical disorders should be reviewed, including the
possibility of eclampsia. The patient's medications and other drugs should be thoroughly reviewed [7] ;
agents that may cause a hypertensive emergency include cocaine, MAOIs, and oral contraceptives;
the withdrawal of beta-blockers, alpha-stimulants (eg, clonidine), or alcohol also may cause
hypertensive emergency.
In one review, the most common presentations of hypertensive emergencies at an emergency
department were chest pain (27%), dyspnea (22%), and neurologic deficit (21%).
A thorough physical examination should be conducted, with the focus on the cardiovascular and
central nervous systems and on the retinal examination.

Cardiovascular system
The cardiac presentation of malignant hypertension is angina and/or myocardial infarction, congestive
heart failure, or pulmonary edema. Orthostatic symptoms may be prominent.
The heart's initial response to systemic hypertension is to develop concentric left ventricular
hypertrophy. Eventually, the left ventricle becomes dilatated. This is reflected on physical examination
by a fourth heart sound initially, followed by the typical changes of dilated cardiomyopathy.
Blood pressure must be checked in both arms to screen for aortic dissection or coarctation. If
coarctation is suspected, blood pressure also should be measured in the legs. Furthermore, screen for
carotid or renal bruits; palpate the precordium, looking for sustained left ventricular lift; and auscultate
for a third or fourth heart sound or murmurs.
The patient's volume status must also be assessed with orthostatic vital signs, examination of the
jugular veins, assessment of the liver size, and investigation for peripheral edema and pulmonary
rales.

Central nervous system

Neurologic presentations are occipital headache, cerebral infarction or hemorrhage, visual
disturbance, or hypertensive encephalopathy (a symptom complex of severe hypertension, headache,
vomiting, visual disturbance, mental status changes, seizure, and retinopathy with papilledema). Focal
signs and symptoms are uncommon and may indicate another process, such as cerebral infarct or
hemorrhage.
A complete neurologic examination is needed to screen for localizing signs. Note that focal neurologic
signs might not be attributable to encephalopathy; focal signs mandate screening for cerebral
hemorrhage, infarct, or the presence of a mass.

Renal, gastrointestinal, and ophthalmologic systems

Renal disease may present as oliguria or any of the typical features of renal failure. Gastrointestinal
symptoms are nausea and vomiting; in addition, diffuse arteriolar damage can result in
microangiopathic hemolytic anemia.
Patients may complain of blurred vision. A funduscopic examination may reveal flame-shaped retinal
hemorrhages, soft exudates, or papilledema (see the following images). [8]

Hypertensive retinopathy. Note the

flame-shaped hemorrhages, soft exudates, and early disc blurring.

Differential Diagnosis
Acute Renal Failure
Aortic Coarctation
Aortic Dissection
Chronic Renal Failure
Eclampsia
Hypercalcemia
Hyperthyroidism
Pheochromocytoma
Renal Artery Stenosis
Subarachnoid Hemorrhage
Thrombotic Thrombocytopenic Purpura

Workup for Malignant Hypertension

Laboratory studies
Initial laboratory studies include a complete blood cell (CBC) count and electrolytes (including
calcium), blood urea nitrogen (BUN), creatinine, glucose, coagulation profile, and urinalysis. Other
laboratory studies are indicated only as directed by the initial workup. These may include
measurements for cardiac enzymes, urinary catecholamines, and thyroid-stimulating hormone (TSH),
and 24-hour urine collection for vanillylmandelic acid (VMA) and catecholamines.
Renal function should be evaluated through urinalysis, complete chemistry profile, and CBC count.
Expected findings include elevated BUN and creatinine, hyperphosphatemia, hyperkalemia or
hypokalemia, glucose abnormalities, acidosis, hypernatremia, and evidence of microangiopathic
hemolytic anemia and azotemic oliguric renal failure. Urinalysis may reveal proteinuria, microscopic
hematuria, and red blood cell or hyaline casts.

Diffuse intrarenal ischemia results in increased levels of plasma renin, angiotensin II, and aldosterone,
with resulting hypovolemia and hypokalemia. Sodium depletion is common and may be severe. [9]

Radiologic studies
Routine screening consists of a chest radiograph, which is useful for assessment of cardiac
enlargement, pulmonary edema, or involvement of other thoracic structures, such as rib notching with
aortic coarctation or a widened mediastinum with aortic dissection. Other studies, such as head CT
scanning, transesophageal echocardiogram (TEE), and renal angiography, are indicated only as
directed by the initial workup.

Electrocardiography
An ECG is an essential part of the evaluation to screen for ischemia, infarct, or evidence of electrolyte
abnormalities or drug overdose. In the earliest stages of malignant hypertension, electrocardiogram
and echocardiogram reveal left atrial enlargement and left ventricular hypertrophy.

Medical Management
Patients with malignant hypertension are usually admitted to an intensive care unit for continuous
cardiac monitoring, frequent assessment of neurologic status and urine output, and administration of
intravenous antihypertensive medications and fluids. Patients typically have altered blood pressure
autoregulation, and overzealous reduction of blood pressure to reference range levels may result in
organ hypoperfusion.
In patients with stroke, cardiac compromise, or renal failure, appropriate consultation should be
considered. In institutions with specialists in hypertension, prompt consultation may improve the overall
control of blood pressure.
Hypertensive urgencies do not mandate admission to a hospital. The goal of therapy is with these
cases is to reduce blood pressure within 24 hours, which can be achieved as an outpatient.
For more information, see Hypertension.

Pharmacotherapy
The initial goal of therapy is to reduce the mean arterial pressure by approximately 25% over the first
24-48 hours. An intra-arterial line is helpful for continuous monitoring of blood pressure. Sodium and
volume depletion may be severe, and volume expansion with isotonic sodium chloride solution must
be considered.[6]Secondary causes of hypertension should be investigated.
No trials exist comparing the efficacy of various agents in the treatment of malignant hypertension.
Drugs are chosen based on their rapidity of action, ease of use, special situations, and convention.
The most commonly used intravenous drug is nitroprusside. An alternative for patients with renal
insufficiency is intravenous fenoldopam. Labetalol is another common alternative, providing easy
transition from intravenous to oral dosing. However, a trial by Peacock et al demonstrated that
intravenous calcium blockers (eg, nicardipine) could be useful in quickly and safely reducing blood
pressure to target levels and seemed more effective than intravenous labetalol. [10]
Beta-blockade can be accomplished intravenously with esmolol or metoprolol. Also available
parenterally are diltiazem, verapamil, and enalapril. Hydralazine is reserved for use in pregnant
patients, whereas phentolamine is the drug of choice for a pheochromocytoma crisis. Oral medications
should be initiated as soon as possible in order to ease transition to an outpatient setting.

Diet and Activity

In patients with stroke, cardiac compromise, or renal failure, appropriate consultation should be
considered. In institutions with specialists in hypertension, prompt consultation may improve the overall
control of blood pressure.
Activity is limited to bedrest until the patient is stable. Patients should be able to resume normal activity
as outpatients once their blood pressure has been controlled.

Complications
Overzealous reduction of blood pressure can result in organ hypoperfusion, and target organ damage
can be missed without a thorough evaluation. Note that enalapril has an unpredictable response in
hypovolemic patients, with a possible uncontrolled drop in blood pressure.

Special Concerns
Properly diagnosing hypertensive emergency and urgency is essential to proper triage and treatment;
however, reducing blood pressure too rapidly can result in patient harm. In addition, all patients should
be carefully assessed for secondary causes of hypertension, and upon discharge, patients should
have close follow-up care. They should know the signs and symptoms that necessitate immediate
notification of a physician.

Surgical Therapy
A therapy under clinical trial involves implantation of a carotid baroreflex stimulator. Early phase III
results from the Rheos Pivotal Trial on continuous carotid baroreceptor pacing for resistant hypertesion
with a first-generation device were equivocal on safety and efficacy, but initial results with a
miniaturized second-generation device appear promising in patients with heart failure. [11] A phase III trial
with the second-generation device for resistant hypertension has been registered. [11]
Initially, patients treated for malignant hypertension are instructed to fast until stable. Once stable, all
patients should obtain good long-term care of their hypertension, including a diet that is low in salt. If
indicated, the patient should follow a diet that can induce weight loss.
For more information, see Hypertension.

Prognosis and Prevention

In a retrospective analysis of 197 patients with malignant hypertension, Gonzalez et al found that 5
and 10 years after presentation, the chances of renal survival were 84% and 72%, respectively. [12] The
investigators examined data from patients diagnosed between 1974 and 2007 and reported predictors
of renal outcome included whether or not the patient was diagnosed between 1974 and 1985, the
existence of previous chronic renal impairment, the degree of proteinuria and the amount of renal
function at baseline, the presence of microhematuria, systolic and diastolic blood pressure values, and
the proteinuria value during follow-up.[12] However, after multivariate analysis, the only significant risk
factor was found to be the mean proteinuria value during follow-up. [12] At 5 and 10 years after
presentation, the chances of renal survival in patients with a mean proteinuria value less than 0.5 g/24
h were 100% and 95%, respectively.[12]
Before the advent of effective therapy, the life expectancy of those affected by malignant hypertension
was less than 2 years, with most deaths resulting from stroke, renal failure, or heart failure. The
survival rate at 1 year was less than 25%, and at 5 years, it was less than 1%. However, with current
therapy, including dialysis, the survival rate at 1 year is greater than 90%, and at 5 years, it is 80%.
The most common cause of death is cardiovascular, with stroke and renal failure also common.
A British study that examined survival statistics over the course of 40 years in patients with malignant
hypertension found an even higher 5-year survival rate. [13]Reviewing information from 446 patients with
malignant hypertension, the authors determined that before 1977, the 5-year survival rate was 32%,
whereas for patients who were diagnosed between 1997 and 2006, the 5-year rate was 91%. The
investigators suggested that the change was associated with lower targets for and tighter control of
patients' blood pressure, along with the availability of additional classes of antihypertensive
medications.[13] The authors also found age, baseline creatinine level, and follow-up systolic blood
pressure to be independent predictors of survival.
A study by Amraoui et al found a higher all-cause mortality rate in patients with malignant hypertension
than in persons who were normotensive or hypertensive, even though the cardiovascular risk profile
for the malignant hypertension patients was more favorable than that for the hypertensive controls.
The study, which compared 120 patients with a history of malignant hypertension with 120
normotensive and 120 hypertensive persons, found that the malignant hypertension patients had lower
total cholesterol, low-density lipoprotein cholesterol, and body mass index values than did the

hypertensive controls. However, the median estimated glomerular filtration rate was higher in the
normotensive and hypertensive controls than in the malignant hypertension group. Annual all-cause
mortality per 100 patient-years was 2.6 for the patients with malignant hypertension, compared with
0.2 and 0.5 for the normotensive and hypertensive controls, respectively.[14]

Prevention
The best way to prevent further episodes of hypertensive emergencies is to ensure that the patient has
close outpatient follow-up for hypertension treatment. This can usually be accomplished by a general
medicine or family practice physician, but referral to a hypertension specialist should also be
considered for patients who require complex drug therapy or additional secondary workup.