Malignant Hypertension 

Updated: Jan 13, 2017
Author: John D Bisognano, MD, PhD, FACP, FACC; Chief Editor: Vecihi Batuman, MD, FASN 

Overview

Background

A hypertensive emergency is a condition in which elevated blood pressure (BP) results in target organ damage.[1]  The systems primarily involved include the central nervous system (CNS), the cardiovascular system, and the renal system. Malignant hypertension and accelerated hypertension are both hypertensive emergencies, with similar outcomes and therapies.

Accelerated hypertension is defined as a recent significant increase over baseline BP 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 BP (ie, systolic BP >220 mm Hg or diastolic BP >120 mm Hg) with no evidence of target organ damage.

In order to diagnose malignant hypertension, papilledema (see the image below) must be present.[2]  However, Cremer et al considered the presence of retinopathy as but one of various potential presentations for acute hypertension with multiorgan damage.[1]  Accordingly, they proposed a "more modern" definition for malignant hypertension, in which hypertensive emergencies, in the absence of retinopathy, would be based on the criteria of acute elevated BP accompanied by damage to a minimum of three different target organs.

Papilledema. Note the swelling of the optic disc, Papilledema. Note the swelling of the optic disc, with blurred margins.

Hypertensive emergencies necessitate immediate therapy to decrease BP within minutes to hours.[3]  In contrast, no evidence suggests a benefit from rapidly reducing BP 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.

Pathophysiology and Etiology

As many as 1% of patients with essential hypertension develop malignant hypertension, but the reason why 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 from 2000 to 2011, with a dramatic increase after 2007.[4]  However, no corresponding dramatic increase was 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 not for those with hypertensive encephalopathy.[4]

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 BP. 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 BP 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 by using computed tomography [CT] 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.[5, 6]

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 more likely to be present in malignant hypertension-induced thrombotic microangiopathy are (1) a previous history of hypertension, (2) high mean arterial pressure, (3) significant renal impairment but relatively modest thrombocytopenia, and (4) lack of severe ADAMTS-13 gene deficiency (activity < 10%) at diagnosis.[6]

For more information, see Hypertension.

Prognosis

In a retrospective analysis of 197 patients with malignant hypertension diagnosed between 1974 and 2007, Gonzalez et al found that at 5 and 10 years after presentation, the chances of renal survival were 84% and 72%, respectively.[7]  Reported predictors of renal outcome included whether the patient was diagnosed between 1974 and 1985, previous chronic renal impairment, the degree of proteinuria and the amount of renal function at baseline, the presence of microhematuria, systolic and diastolic BP, and proteinuria during follow-up. After multivariate analysis, the only significant risk factor was the mean proteinuria value during follow-up. The chances of renal survival in patients with a mean proteinuria value lower than 0.5 g/24 hr were 100% at 5 years and 95% at 10 years.

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 446 patients with malignant hypertension found an even higher 5-year survival rate.[8]  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 BP, along with the availability of additional classes of antihypertensive medications. The authors also found age, baseline creatinine level, and follow-up systolic BP to be independent predictors of survival.

A study by Amraoui et al found a higher all-cause mortality in patients with malignant hypertension (n=120) than in persons who were normotensive  (n=120) or hypertensive (n=120), even though the cardiovascular risk profile for the malignant hypertension patients was more favorable than that for the hypertensive control subjects.[9] 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 two control groups than in the malignant hypertension group. Annual all-cause mortality per 100 patient-years was 2.6 for the  malignant hypertension group, compared with 0.2 for the normotensive group and 0.5 for the hypertensive group.

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.

 

Presentation

History

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[10] ; agents that may cause a hypertensive emergency include cocaine, monoamine oxidase inhibitors (MAOIs), and oral contraceptives; the withdrawal of beta blockers, alpha stimulants (eg, clonidine), or alcohol also may cause a 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%).

Physical Examination

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 include occipital headache, cerebral infarction or hemorrhage, visual disturbance, and 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 acute kidney injury or chronic renal disease. 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).[11]

Hypertensive retinopathy. Note the flame-shaped he Hypertensive retinopathy. Note the flame-shaped hemorrhages, soft exudates, and early disc blurring.
 

DDx

 

Workup

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.[12]

Imaging Studies

Routine screening consists of chest radiography, 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 computed tomography (CT) of the head, transesophageal echocardiography (TEE), and renal angiography, are indicated only as directed by the initial workup.

Electrocardiography and Echocardiography

Electrocardiography (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, ECG and echocardiography reveal left atrial enlargement and left ventricular hypertrophy.

 

Treatment

Approach Considerations

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 (BP) autoregulation, and overzealous reduction of BP to reference range levels may result in organ hypoperfusion.

Hypertensive urgencies do not mandate admission to a hospital. The goal of therapy is with these cases is to reduce BP within 24 hours, which can be achieved on an outpatient basis.

For more information, see Hypertension.

Pharmacologic Therapy

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 BP. Sodium and volume depletion may be severe, and volume expansion with isotonic sodium chloride solution must be considered.[3]  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 on the basis of 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 BP to target levels and seemed more effective than intravenous labetalol.[13]

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.

Surgical Care

An approach that is being clinically investigated 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 appeared promising in patients with heart failure.[14]  A phase III trial with the second-generation device for resistant hypertension has been registered.[14]

For more information, see Hypertension.

Complications

Properly diagnosing hypertensive emergency and urgency is essential to proper triage and treatment; however, reducing BP too rapidly can result in patient harm. Specifically, overzealous reduction of BP 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 BP.

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.

Diet

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.

Activity

Activity is limited to bedrest until the patient is stable. Patients should be able to resume normal activity as outpatients once their BP has been controlled.

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.

Consultations

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 BP.

 

Guidelines

Guidelines Summary

The 2003 Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) characterized hypertensive emergencies as severe blood pressure (BP) elevations (>180/120 mm Hg) associated with acute end-organ damage and characterized hypertensive urgency as severely elevated BP with no evidence of target organ damage.

Overly aggressive treatment of severe uncomplicated hypertensive urgency can lead to cumulative effects causing hypotension. According to the JNC-7 guidelines, early triage is required to determine which patients with acute hypertension are exhibiting symptoms of end-organ damage and require immediate intravenous parenteral antihypertensive therapy.[15]

JNC-7 further recommended that initial treatment goals should be to reduce the mean arterial  pressure by no more than 25% within minutes to 1 hour. If the patient is stable, BP should be reduced to 160/100-110 mm Hg within the next 2-6 hours.[4]

Several parenteral and oral agents are recommended to treat hypertensive emergencies, such as nitroprusside sodium, hydralazine, nicardipine, fenoldopam, nitroglycerin, and enalaprilat. Other agents that may be used include labetalol, esmolol, and phentolamine. Short-acting nifedipine should not be considered for the initial treatment of this condition, because of the risk of rapid, unpredictable hypotension and the possibility of precipitating ischemic events. Once the patient’s condition is stabilized, BP may be gradually reduced over the next 24-48 hours.[15]

The 2013 European Society of Hypertension (ESH)/European Society of Cardiology (ESC) guidelines provided similar recommendations.[16]

In 2013, the American College of Emergency Physicians (ACEP) released an update of its 2006 guidelines for hypertension in the emergency department (ED), which are focused on treating hypertensive urgency. The recommendations included the following[17] :

  • In ED patients with asymptomatic markedly elevated BP, routine screening for acute target-organ injury (eg, serum creatinine, urinalysis, electrocardiography [ECG]) is not required.
  • In select patient populations (eg, those with poor follow-up), screening for an elevated serum creatinine level may identify kidney injury that affects disposition (eg, hospital admission)
  • In patients with asymptomatic markedly elevated BP, routine ED medical intervention is not required
  • In select patient populations (eg, those with poor follow-up), emergency physicians may treat markedly elevated BP in the ED and/or initiate therapy for long-term control (consensus recommendation)
  • Patients with asymptomatic markedly elevated BP should be referred for outpatient follow-up (consensus recommendation)
 

Questions & Answers

Overview

What is malignant hypertension?

What are the pathophysiology and etiology of malignant hypertension?

Which conditions should be considered in apparent malignant hypertension?

What is the prognosis of malignant hypertension?

What education should be provided to patients with malignant hypertension?

Presentation

What information should be collected in the patient history in suspected malignant hypertension?

What is the focus of the physical exam for suspected malignant hypertension?

How is the cardiovascular system evaluated in the physical exam of a patient with suspected malignant hypertension?

How is the central nervous system evaluated in the physical exam of a patient with suspected malignant hypertension?

Which renal, GI, and ophthalmologic symptoms are associated with malignant hypertension?

DDX

What are the differential diagnoses for Malignant Hypertension?

Workup

Which lab studies are indicated in the workup of malignant hypertension?

Which imaging studies are indicated in the workup of malignant hypertension?

What is the role of ECG and echocardiography in the workup of malignant hypertension?

Treatment

What are the approach considerations in the treatment of malignant hypertension?

Which medications are used in the treatment of malignant hypertension?

What is the role of surgical care in the management of malignant hypertension?

What are the complications of malignant hypertension?

What are the dietary recommendations for patients with malignant hypertension?

What are the activity recommendations for patients with malignant hypertension?

What are further episodes of malignant hypertension prevented?

Which specialist consultations are indicated in the treatment of malignant hypertension?

Guidelines

What are the JNC-7 treatment guidelines for malignant hypertension?

What are the ACEP treatment guidelines for malignant hypertension?