clinical situation in which the elevated BP is immediately

520

521Hypertensive Crises Chapter 21

TABLE 21-1

Hypertensive Emergencies Versus Urgencies

Emergencies Urgencies

Severely elevated blood pressure

(diastolic >120 mm Hg)a

Severely elevated blood

pressure (diastolic

>120 mm Hg)a

Potentially life-threatening Not acutely life-threatening

End-organ damage acute or

progressing

Chronic end-organ damage

that is not progressing

CNS (dizziness, N/V,

encephalopathy, confusion,

weakness, intracranial or

subarachnoid hemorrhage,

stroke)

Optic disc edema

Eyes (ocular hemorrhage or

funduscopic changes, blurred

vision, loss of sight)

Heart (left ventricular failure,

pulmonary edema, MI, angina,

aortic dissection)

Renal failure or insufficiency

Requires immediate pressure

reduction

Treated for several hours to

days

Requires IV therapy (Table 21-2) Oral therapy (Table 21-3)

aDegree of blood pressure elevation less diagnostic than rate of pressure rise and

presence of concurrent diseases or end-organ damage. See Chapter 14, Essential

Hypertension, for staging of hypertension.

CNS, central nervous system; IV, intravenous; MI, myocardial infarction; N/V,

nausea and vomiting.

life-threatening and needs to be lowered to a safe level (not

necessarily to normal) within a matter of minutes to hours.1,3

Hypertensive emergencies are associated with acutely progressive secondary organ damage (e.g., stroke or myocardial infarction). A hypertensive urgency is not immediately life-threatening,

and a reduction of BP to a safe level can occur more slowly during

24 to 48 hours.1,6

Acute, potentially life-threatening elevations of BP can occur

in previously normotensive individuals with acute glomerulonephritis, head injury, or severe burns; during pregnancy

(eclampsia); and with use of recreational drugs such as cocaine.

Other causes include abrupt medication withdrawal or medication nonadherence, drug–drug interactions (including herbal

medications), erythropoietin administration, or drug–food interactions (i.e., patients receiving monoamine oxidase inhibitors

who ingest foods rich in tyramine).7–9 In addition, poor systolic

blood pressure control has been identified as an independent

risk factor for the development of hypertensive crisis.10 Effective

management of chronic hypertension has lowered the number

of patients who present with hypertensive crisis to approximately

1%.11

CLINICAL PRESENTATION OF

HYPERTENSIVE URGENCY

There are limited data describing the presentation and characteristics of those patients with a hypertensive urgency. In one study

evaluating characteristics of patients presenting to the emergency

room for hypertensive urgency, the most frequently reported

symptoms included headache (42%) and dizziness (30%). Other

symptoms include visual changes, chest discomfort, nausea, epistaxis, fatigue, and psychomotor agitation.12 It should be noted

that not all patients presenting with a hypertensive urgency will

have symptoms. In this same study, 90% of patients had a history of hypertension, 16% of the patients reported running out

of their medications, and 12% reported nonadherence to their

antihypertensive regimens.

CLINICAL PRESENTATION OF

HYPERTENSIVE EMERGENCY

Similar to hypertensive urgencies, hypertensive emergencies

rarely develop in patients without a previous history of

hypertension.13 Most commonly, they complicate the accelerated phase of poorly controlled, chronic hypertension.1 In several studies of patients with hypertensive emergency, a history

of hypertension was previously diagnosed in more than 90%

of the patients, suggesting that hypertensive emergencies are

almost entirely preventable.13,14 Hypertensive emergencies also

tend to occur in patients with catecholamine-producing adrenal

tumors (pheochromocytoma), or renal vascular disease. Additionally, hypertensive emergencies occur more often in African

Americans than in Caucasians, among patients who have no

primary-care physician, and among those who do not adhere

to their treatment regimens.13,15

Symptoms associated with hypertensive emergency are

highly variable and reflect the degree of damage to specific organ

systems. Rapid, severe BP elevation is not always the hallmark

of a hypertensive emergency. The primary sites of damage are

the central nervous system, heart, kidneys, and eyes. Although

hypertensive emergencies are much less common than hypertensive urgencies, without a thorough patient history it is often

difficult to know whether end-organ dysfunction is new or has

progressed.

In a study on the prevalence of end-organ complications in

hypertensive crisis, central nervous system abnormalities were

the most frequently reported. Cerebral infarctions were noted in

24%, encephalopathy in 16%, and intracranial or subarachnoid

hemorrhage in 4% of patients. Central nervous system abnormalities were followed in incidence by cardiovascular complications,

such as acute heart failure (HF) and pulmonary edema, which

were seen in 36% of patients, and acute myocardial infarction

(MI) and unstable angina, in 12% of patients. Acute dissection

was noted in 2%, and eclampsia, in 4.5% of patients.13

Central Nervous System

Central nervous system damage can present solely as a severe

headache or may be accompanied by dizziness, nausea, vomiting, and anorexia. Mental confusion with apprehension indicates

more severe disease, as does nystagmus, localized weakness, or a

positive Babinski sign (i.e., upward extension of the great toe and

spreading of the smaller toes when moderate pressure is applied

along a curve from the sole to the ball of the foot). Central nervous

system damage may be rapidly progressive, resulting in coma or

death. If a cerebrovascular accident has occurred, slurred speech

or motor paralysis may be present.

Other Complications

Cardiac complications of hypertensive emergency include HF,

acute pulmonary edema, angina pectoris, and acute coronary

syndrome. Myocardial infarction can also be precipitated. Ocular symptoms of hypertensive emergency usually are related to

changes in visual acuity. Complaints of blurred vision or loss of

eyesight are often associated with funduscopic findings of hemorrhages, exudates (yellow deposits within the retina as a result

522 Section 2 Cardiac and Vascular Disorders

of leaks from capillaries and microaneurysms), and occasionally

papilledema (edema of the optic nerve). Acute kidney injury can

also develop. Markers of renal dysfunction include hematuria,

proteinuria, and elevated serum blood urea nitrogen (BUN) and

serum creatinine levels.

OVERVIEW OF TREATMENT

Oral Versus Parenteral Therapy

Hypertensive urgency is not an indication for parenteral treatment. Oral antihypertensive regimens are more appropriate for

the management of these urgent cases. Practitioners should exercise caution in the treatment of patients with elevated blood pressures in the absence of target organ damage. Aggressive dosing

with oral medications to rapidly lower BP is not without risk and

can lead to hypotension and subsequent morbidity. Some have

suggested that the termhypertensive urgency leads to overly aggressive treatment and should be discarded in favor of a less ominous

term such as uncontrolled blood pressure.6 In contrast, hypertensive emergencies require immediate hospitalization, generally in

an intensive care unit, and the administration of parenteral antihypertensive medications to reduce arterial pressure.16 Effective

therapy greatly improves the prognosis, reverses symptoms, and

arrests the progression of end-organ damage. Treatment reverses

the vascular changes in the eyes and slows or arrests the progressive deterioration in renal function. In those with acute kidney

injury, renal function may gradually improve, after 2 to 3 months

of adequate therapy, to the baseline renal insufficiency or to a new

level, slightly deteriorated from the original baseline renal function. The time required for recovery of renal function ranges from

2 weeks to 2 years. A low serum creatinine level, in the absence

of marked cardiomegaly or renal shrinkage, has been associated

with a good chance for recovery of renal function.17 In patients

with mild encephalopathy, neurologic symptoms resolve within

24 hours after treatment.18 Resolution of papilledema occurs

in 2 to 3 weeks, whereas funduscopic exudates can require up

to 12 weeks for complete resolution.19 Whether treatment can

completely reverse end-organ damage is related to two factors:

how soon treatment is initiated and the extent of damage at the

initiation of therapy.

There are two fundamental concepts in the management of

hypertensive emergencies. First, immediate and intensive therapy is required and takes precedence over time-consuming diagnostic procedures. Second, the choice of drugs will depend on

how their time course of action and hemodynamic and metabolic

effects meet the needs of the emergent situation. If encephalopathy, acute left ventricular failure, dissecting aortic aneurysm,

eclampsia, or other serious conditions are present, the BP should

be lowered promptly with rapid-acting, parenteral antihypertensive medications such as clevidipine, esmolol, enalaprilat,

fenoldopam, hydralazine, labetalol, nicardipine, nitroglycerin,

or nitroprusside (Table 21-2).1,3,4,20–24 If a slower BP reduction over the course of several hours or days is acceptable, as

in the case of a hypertensive urgency, rapid-acting oral therapy

using captopril, clonidine, labetalol, or minoxidil may be used

(Table 21-3).3,4,24–26 Figure 21-1 provides an overview of the

management of a hypertensive crisis. A summary of treatment

recommendations for acutely lowering BP for selected indications is listed in Table 21-4 on page 526.

Goals of Therapy

The rate of BP lowering must be individualized depending on

whether the patient presents with a hypertensive urgency or

emergency. Also, ischemic damage to the heart and brain can

be provoked by a precipitous fall in BP.26–30 As treatment is initiated, clinicians should recognize that the elderly and patients

with severely defective autoregulatory mechanisms are at high

risk for developing hypotensive complications. The latter group

includes those with autonomic dysfunction or fixed sclerotic

stenosis of cerebral or neck arteries.31 In addition, patients who

have chronically elevated BP are less likely to tolerate abrupt

reductions in their BP, and the amount of reduction appropriate

for those patients is somewhat less than for those whose BP is

acutely elevated.

For hypertensive emergencies, it is recommended that the

mean arterial pressure be reduced initially by no more than 25%

(within minutes to 1 hour); then if stable, this should be followed

by further reduction toward a goal of 160/100 mm Hg within

2 to 6 hours and gradual reduction to normal during the next

8 to 24 hours.4 A diastolic pressure of 100 to 110 mm Hg is an

appropriate initial therapeutic goal.1 Lower pressures may be

indicated for patients with aortic dissection. Another exception

to this rule applies in patients with acute cerebrovascular accidents. Cerebral autoregulation is disrupted in this setting, and

the use of antihypertensives may cause a reduction in cerebral

blood flow and increasing morbidity.32 Current guidelines recommend lowering BP after acute ischemic stroke if the systolic

blood pressure (SBP) is greater than 220 mm Hg or the diastolic

blood pressure (DBP) is greater than 120 mm Hg in patients

ineligible for thrombolytic therapy, or if the SBP is greater than

185 mm Hg or DBP is greater than 110 mm Hg in those who are

candidates for thrombolytics.33 A lower BP in patients undergoing thrombolytic therapy reduces the risk of intracerebral bleeding. In the setting of an ischemic stroke, it is recommended to

lower the BP by 15% to 25% within the first day.33 Additionally,

in those with hypertensive encephalopathy, cerebral hypoperfusion may occur if the mean BP is reduced by more than 40%.34

Thus, in the presence of hypertensive encephalopathy it is suggested that within the first hour of treatment the mean pressure

be lowered by no more than 20% or to a diastolic BP of 100 mm

Hg, whichever is greater.34,35

HYPERTENSIVE URGENCIES

Patient Assessment

CASE 21-1

QUESTION 1: M.M. is a 60-year-old African American man

with a long history of HF, poorly controlled hypertension

believed to be caused by nonadherence, and a history of

MI. He was referred from a community health center this

morning for a thorough evaluation of his elevated BP. He

has not taken his captopril, carvedilol, or hydrochlorothiazide for the past 7 days. M.M. is completely asymptomatic.

Physical examination reveals a BP of 180/120 mm Hg and a

pulse of 92 beats/minute. Funduscopic examination is pertinent for mild arteriolar narrowing, without hemorrhages

or exudates. The discs are flat. His lungs are clear, and

the cardiac examination is unremarkable. The electrocardiogram indicates normal sinus rhythm at a rate of 90 beats/

minute with first-degree atrioventricular block. The chest

radiograph is interpreted as mild cardiomegaly. Serum electrolytes, BUN, and serum creatinine are within normal limits. A urinalysis is significant for 2+ proteinuria. What is

the therapeutic objective in treating M.M.? How quickly

should his BP be lowered, and what therapeutic options are

available?

523Hypertensive Crises Chapter 21

TABLE 21-2

Parenteral Drugs Commonly Used in the Treatment of Hypertensive Emergencies

Drug (Brand Name) Class of Drug Dose/Route Onset of Action Duration of Action

Clevidipine (Cleviprex) 0.5 mg/mL Arterial vasodilator

(calcium-channel

blocker)

Initial: 1–2 mg/h; titrate dose to

desired BP or to a max of 16 mg/h

2–4 minutes 10–15 minutes after

D/C

Enalaprilata (Vasotec IV) 1.25 mg/mL,

2.5 mg/2 mL

ACE inhibitor 0.625–1.25 mg IV every 6 hours 15 minutes (max,

1–4 hours)

6–12 hours

Esmololb (Brevibloc) 100 mg/10 mL,

2,500 mg/10 mL concentrate

β-adrenergic blocker 250–500 mcg/kg for 1 minute, then

50–300 mcg/kg/min

1–2 minutes 10–20 minutes

Fenoldopam (Corlopam) 10 mg/mL,

20 mg/2 mL, 50 mg/5 mL

Dopamine-1 agonist 0.1–0.3 mcg/kg/min <5 minutes 30 minutes

Hydralazinec (generic) 20 mg/mL Arterial vasodilator 10–20 mg IV 5–20 minutes 2–6 hours

Labetalold (Normodyne) 20 mg/

4 mL, 40 mg/8 mL, 100 mg/

20 mL, 200 mg/20 mL

α- and β-adrenergic

blocker

2 mg/min IV or 20–80 mg every

10 minutes up to 300 mg total

dose

2–5 minutes 3–6 hours

Nicardipinee (Cardene IV) 25 mg/

10 mL

Arterial vasodilator

(calcium-channel

blocker)

IV loading dose 5 mg/h increased by

2.5 mg/h every 5 minutes to

desired BP or a max of 15 mg/h

every 15 minutes, followed by

maintenance infusion of 3 mg/h

2–10 minutes (max,

8–12 hours)

40–60 minutes after

D/C infusion

Nitroglycerinf (Tridil, Nitro-Bid IV,

Nitro-Stat IV) 5 mg/mL, 5 mg/

10 mL, 25 mg/5 mL, 50 mg/

10 mL, 100 mg/20 mL

Arterial and venous

vasodilator

IV infusion pump 5–100 mcg/min 2–5 minutes 5–10 minutes after

D/C infusion

Nitroprussideg (Nitropress), 50 mg/

2 mL (most commonly used)

Arterial and venous

vasodilator

IV infusion.a Start: 0.5 mcg/kg/min

Usual: 2–5 mcg/kg/min Max:

8 mcg/kg/min

Seconds 3–5 minutes after

D/C infusion

Phentolamine (Regitine) α-adrenergic blocker 1–5 mg IV initially, repeat as needed Immediate 10–15 minutes

Major Side Effects (All Can Cause Hypotension) Avoid or Use Cautiously in Patients With These Conditions

Atrial fibrillation, nausea, vomiting, headache, acute renal

failure, reflex tachycardia, MI

Allergy to soybeans, soy products, eggs or egg products, severe aortic stenosis,

defective lipid metabolism, heart failure

Hyperkalemia Hyperkalemia, renal failure in patients with dehydration or bilateral renal artery

stenosis, pregnancy (teratogenic)

Nausea, thrombophlebitis, painful extravasation Asthma, bradycardia, decompensated HF, advanced heart block

Tachycardia, headache, nausea, flushing Glaucoma

Tachycardia, headache, angina Angina pectoris, MI, aortic dissection

Abdominal pain, nausea, vomiting, diarrhea Asthma, bradycardia, decompensated HF

Headache, flushing, nausea, vomiting, dizziness, tachycardia;

local thrombophlebitis change infusion site after 12 hours

Angina pectoris, decompensated HF, increased intracranial pressure

Methemoglobinemia, headache, tachycardia, nausea, vomiting,

flushing, tolerance with prolonged use

Pericardial tamponade, constrictive pericarditis, or increased intracranial pressure

Nausea, vomiting, diaphoresis, weakness, thiocyanate toxicity,h

cyanide toxicity (rare)i

Chest pain, nausea, vomiting, dizziness, headache, nasal

congestion, arrhythmia

Renal failure (thiocyanate accumulation), pregnancy, increased intracranial pressure

Angina pectoris, coronary insufficiency, MI or history of MI, hypersensitivity to

mannitol

aNot approved by the U.S. Food and Drug Administration for treatment of acute hypertension.

bApproved for intraoperative and postoperative treatment of hypertension.

c Parenteral hydralazine is an intermediate treatment between oral agents and more aggressive therapies such as nitroprusside. It can be given IV or intramuscularly, but

there is no appreciable difference in onset of action (20–40 minutes) between the two routes. This slow onset minimizes hypotension.

d Labetalol is contraindicated in acute decompensated heart failure because of its β-blocking properties. A solution for continuous infusion is prepared by adding two

100-mg ampules to 160 mL of IV fluid to give a final concentration of 1 mg/mL. Infusions start at 2 mg/min and are titrated until a satisfactory response or a cumulative dose

of 300 mg is achieved.

e Indicated for short-term treatment of hypertension when the oral route is not feasible or desirable.

f Requires special delivery system owing to drug binding to polyvinyl chloride tubing. Also see Chapters 17, Chronic Stable Angina, and 18, Acute Coronary Syndromes, for

further information regarding nitroglycerin.

g Nitroprusside is the drug of choice for acute hypertensive emergencies. It is supplied as 50 mg of lyophilized powder that is reconstituted with 2–3 mL of 5% dextrose in

water (D5W), yielding a red-brown solution. The contents of the vial are added to 250, 500, or 1,000 mL of D5W to produce a solution for IV administration at a

concentration of 200, 100, or 50 mcg/mL, respectively. The container should be wrapped with metal foil to prevent light-induced decompensation. Under these conditions,

the solution is stable for 4 to 24 hours. A rising BP may indicate loss of potency. A change in color to yellow does not indicate effectiveness. The appearance of a dark brown,

green, or blue color indicates loss in activity. The drug is more effective if the head of the bed is slightly raised. When changing to a new bag, the administration rate may

require adjustment.

hThiocyanate levels rise gradually in proportion to the dose and duration of administration. The half-life of thiocyanate is 2.7 days with normal renal function and 9 days in

patients with renal failure. Toxicity occurs after 7 to 14 days in patients with normal renal function and 3 to 6 days in renal failure patients. Thiocyanate serum levels should

be measured after 3 to 4 days of therapy, and the drug should be discontinued if levels exceed 10 to 12 mg/dL. Thiocyanate toxicity causes a neurotoxic syndrome of toxic

psychosis, hyperreflexia, confusion, weakness, tinnitus, seizures, and coma.

i

Signs of cyanide toxicity include lactic acidosis, hypoxemia, tachycardia, altered consciousness, seizures, and the smell of almonds on the breath. Concurrent administration

of sodium thiosulfate or hydroxocobalamin may reduce the risk of cyanide toxicity in high-risk patients.

ACE, angiotensin-converting enzyme; BP, blood pressure; D/C, discontinued; HF, heart failure; IV, intravenous; MI, myocardial infarction.

524 Section 2 Cardiac and Vascular Disorders

TABLE 21-3

Oral Drugs Commonly Used in the Treatment of Hypertensive Urgencies

Druga

(Brand Name) Dose/Route

Onset of

Action

Duration of

Action Major Side Effectsa

Mechanism of

Action

Avoid or Use

Cautiously in

Patients With

These Conditions

Captoprilb (Capoten)

12.5-, 25-, 50-, 100-mg

tablets

6.5–50 mg PO 15 minutes 4–6 hours Hyperkalemia,

angioedema,

increased BUN if

dehydrated, rash,

pruritus, proteinuria,

loss of taste

ACE inhibitor Renal artery

stenosis,

hyperkalemia,

dehydration,

renal failure,

pregnancy

Clonidine (Catapres)

0.1-, 0.2-, 0.3-mg

tablets

0.1–0.2 mg PO

initially, then

0.1 mg/h up to

0.8 mg total

0.5–2 hours 6–8 hours Sedation, dry mouth,

constipation

Central α2-agonist Altered mental

status, severe

carotid artery

stenosis

Labetalol (Normodyne,

Trandate) 100-, 200-,

300-mg tablets

200–400 mg PO

repeated every

2–3 hours

30 minutes–

2 hours

4 hours Orthostatic

hypotension, nausea,

vomiting

α- and β-adrenergic

blocker

Heart failure,

asthma,

bradycardia

Minoxidil (Loniten) 2.5-,

10-mg tablets

5–20 mg PO 30–60 minutes;

maximum

response in

2–4 hours

12–16 hours Tachycardia, fluid

retention

Arterial and venous

vasodilator

Angina, heart

failure

aAll may cause hypotension, dizziness, and flushing.

b Other oral ACE inhibitors too slow in onset to be useful but should be used for maintenance therapy to improve adherence as captopril requires multiple daily doses

ACE, angiotensin-converting enzyme; BUN, blood urea nitrogen; PO, orally.

M.M. has stage 2 hypertension with a BP of 180/120 mm

Hg.4 However, the absolute magnitude of BP elevation does

not in itself constitute a medical emergency requiring an acute

reduction in BP. There is no evidence of encephalopathy, cardiac

decompensation, chest pain, or rapid change in renal function.

Therefore, no evidence exists to indicate a rapid deterioration in

the function of target organs. One would classify M.M.’s case as

a hypertensive urgency.

As is often the case, M.M.’s lack of BP control is related to

medication nonadherence. M.M.’s clinical presentation requires

that his BP be lowered during the next 12 to 24 to 48 hours while

being careful not to induce hypotension. Rapid-acting oral agents

can be used for this purpose; parenteral therapy is not warranted.

A number of different oral regimens using clonidine, captopril,

labetalol, or minoxidil are available. In M.M., restarting his medications in a controlled manner so as not to drop his BP too rapidly

may also be a reasonable option for treatment. Later, he can be

converted to a regimen designed to enhance adherence by selecting medications with once-daily dosing. For example, lisinopril

or another long-acting angiotensin-converting enzyme (ACE)

inhibitor would be preferred for maintenance instead of the captopril previously prescribed. Comprehensive patient counseling

will help M.M. better understand the severity of his disease and

the need to take his medications. One should also determine

and address barriers to medication adherence with the patient

including cost of therapy, lack of understanding of the benefits of

therapy, misconceptions of the side effect profiles, and so forth.

Timely follow-up within 1 week after treatment of hypertensive

urgency is of paramount importance for the appropriate management of these patients.

Oral Drug Therapy

RAPIDLY ACTING CALCIUM-CHANNEL BLOCKERS

CASE 21-1, QUESTION 2: M.M.’s physician has ordered

immediate-release nifedipine to be given 10 mg sublingually. Is this appropriate therapy to treat his hypertensive

urgency?

Clonidine, labetalol, minoxidil, and captopril have all been

used to lower BP acutely. These oral agents take several hours

to adequately lower pressure and are therefore useful in treating hypertensive urgencies but not emergencies. Oral ACE

inhibitors, other than captopril, are not useful for acutely lowering BP because their onset of action is too slow. The immediaterelease calcium-channel blockers, including diltiazem, verapamil, and nicardipine, can rapidly lower BP; however, the most

extensive experience is with nifedipine. Nifedipine, when given

orally or by the “bite and swallow” method, was previously recommended as a rapid-acting alternative to parenteral therapy

in the acute management of hypertension. However, its use has

been associated with life-threatening adverse events related to

ischemia, MI, and stroke.26–30 The prompt absorption of rapidly

acting dihydropyridine calcium-channel blockers is followed by

a sudden and precipitous decrease in BP as a result of peripheral

vasodilation. This reduces coronary perfusion, induces a reflex

tachycardia, and increases myocardial oxygen consumption.28,36

Decreased cerebral blood flow with sublingual nifedipine has

also been reported.37 Elderly patients with underlying coronary

or cerebrovascular disease, volume depletion, or concurrent use

of other antihypertensive drugs are at increased risk for significant adverse events. In addition, no outcome data are currently

available to critically assess the efficacy of this therapeutic intervention. Therefore, until more data become available, administration of immediate-release nifedipine capsules or other rapidly

acting calcium-channel blockers sublingually, by the “bite and

chew” method, or by swallowing intact is not recommended.

The cavalier use of immediate-release nifedipine to acutely

lower BP is potentially dangerous and should be discouraged in

M.M. M.M.’s BP can be managed safely using other oral medications. Captopril, labetalol, or clonidine can be used to lower

his BP, and he can be restarted on his oral maintenance regimen

with appropriate follow-up care.

525Hypertensive Crises Chapter 21

Diastolic BP >120 mm Hg? Follow treatment for

Hypertension in Chapter 14

Hypertensive Urgency

CV - MI Aortic Dissection Acute Kidney Injury

Goal BP reduction =

Gradual reduction to normal

over 24 to 48 hours;

avoid abrupt overcorrection

Restart any antihypertensive

medications that the patient

was previously receiving

If further reduction required

or if patient was not previously

receiving antihypertensive

medications, give PO captopril

OR PO clonidine OR PO

labetalol OR PO minoxidil

Evidence of

acutely progressive

end-organ damage?

Goal is

<185/110 mm Hg

Goal is

<220/120 mm Hg

CNS Stroke

Yes

Yes

Yes

Yes

No

No

No

Hypertensive

encephalopathy

Will patient receive

thrombolytic therapy?

(See Chapter 59 for

appropriate usage of

thrombolytic) Reduce MAP

by <20 to 30%

Preferred: IV nicardipine

Alternatives: IV fenoldapam;

IV labetalol

Goal of 25% MAP

reduction in 1st hour, then

to 160/100 mm Hg within 6

hours, then reduction to

normal over next 24 hours

Goal SBP 100–120 mm Hg

and MAP <80 mm Hg

Goal of 25% MAP reduction

in 1st hour, then to 160/100

mm Hg within 6 hours, then

reduction to normal over

next 24 hours

IV nitroglycerin plus IV

beta-blocker (metoprolol

OR esmolol OR labetalol

IV nitroprusside OR IV

nicardipine OR IV

fenoldapam PLUS IV

beta-blocker

(labetalol OR esmolol)

Preferred: IV nicardipine

Alternative: IV fenoldapam

FIGURE 21-1 Overview of management for a hypertensive crisis. BP, blood pressure; CNS, central nervous system;

IV, intravenous; MAP, mean arterial pressure; MI, myocardial infarction; SBP, systolic blood pressure.

For an audio walk-through of this algorithm, go to http://thepoint.lww.com/AT10e.

CLONIDINE

CASE 21-1, QUESTION 3: A decision is made not to use

nifedipine, but rather to give M.M. oral clonidine. What is

an appropriate starting and maintenance dose?

Clonidine is considered a safe, effective first-line therapy for

hypertensive urgency. It is a centrally acting, α2-adrenergic agonist that inhibits sympathetic outflow from the central nervous

system. After acute administration, clonidine reduces mean arterial pressure, cardiac output, stroke volume, and cardiac rate.

There is little change in the total peripheral resistance or renal

plasma flow. The initial reduction in cardiac output is caused by

decreased venous return to the right side of the heart secondary

to venodilation and bradycardia, not secondary to decreased

contractility. Guanabenz has a similar mechanism of action, but

documented efficacy in the treatment of hypertensive urgency is

lacking.

BP can be lowered gradually over the course of several hours

using oral clonidine. Traditional dosing regimens have included

an initial oral loading dose (0.1–0.2 mg) followed by repeated

doses of 0.1 mg/hour until the desired response is achieved or

until a cumulative dose of 0.5 to 0.8 mg is reached.38 A significant reduction in BP is first seen within 1 hour, and the mean

arterial pressure decreases by 25% in most patients after several

hours. Anderson et al. reported a 94% response rate to an oral

loading dose.38 Patients required a mean total dose of 0.45 mg,

and the maximum response occurred 5 to 6 hours after the start

526 Section 2 Cardiac and Vascular Disorders

TABLE 21-4

Treatment Recommendations for Hypertensive Emergency

Clinical Presentation Recommendation Rationale

Aortic dissection Nitroprusside, nicardipine, or fenoldopam plus

esmolol or IV metoprolol; labetalol;

trimethaphan. Avoid inotropic therapy.

Vasodilator will decrease pulsatile stress in aortic vessel to

prevent further dissection expansion. β-blockers will

prevent vasodilator-induced reflex tachycardia.

Angina, myocardial infarction Nitroglycerin plus esmolol or metoprolol;

labetalol. Avoid nitroprusside.

Coronary vasodilation, decreased cardiac output, myocardial

workload, and oxygen demand. Nitroprusside may cause

coronary steal.

Acute pulmonary edema, left

ventricular failure

Nitroprusside, nicardipine, or fenoldopam plus

nitroglycerin and a loop diuretic. Alternative:

enalaprilat. Avoid nondihydropyridines,

β-blockers.

Promotion of diuresis with venous dilatation to decrease

preload. Nitroprusside, enalaprilat decrease afterload.

Nicardipine may increase stroke volume.

Acute kidney injury Nicardipine or fenoldopam. Avoid nitroprusside,

enalaprilat.

Peripheral vasodilation without renal clearance.

Fenoldopam shown to increase renal blood flow.

Cocaine overdose Nicardipine, fenoldopam, verapamil, or

nitroglycerin. Alternative: labetalol. Avoid

β-selective blockers.

Vasodilation effects without potential unopposed

α-adrenergic receptor stimulation. CCBs control

overdose-induced vasospasm.

Pheochromocytoma Nicardipine, fenoldopam, or verapamil.

Alternatives: phentolamine, labetalol. Avoid

β-selective blockers.

Vasodilation effects without potential unopposed

α-adrenergic receptor stimulation.

Hypertensive encephalopathy,

intracranial hemorrhage,

subarachnoid hemorrhage,

thrombotic stroke

Nicardipine, fenoldopam, or labetalol. Avoid

nitroprusside, nitroglycerin, enalaprilat,

hydralazine.

Vasodilation effects without compromised CBF induced by

nitroprusside and nitroglycerin. Enalaprilat and

hydralazine may lead to unpredictable BP changes when

carefully controlled BP management is required.

BP, blood pressure; CBF, cerebral blood flow; CCB, calcium-channel blocker; IV, intravenous.

of therapy. Some authors, however, have cautioned against the

use of sequential loading doses, citing lack of benefit over placebo

and the potential for unpredictable adverse effects, particularly

abrupt occurrences of hypotension.39 If loading doses are to be

used, it is especially important to reduce doses in patients with

volume depletion, those who have recently used other antihypertensive drugs, and the elderly.1,23,40

The acute response to oral clonidine loading is not predictive

of the daily dose required to maintain BP control. Maintenance

oral therapy with clonidine is somewhat empiric; however, total

daily doses should be spread between twice and three times daily

dosing owing to the drug’s short half-life.

ADVERSE EFFECTS AND PRECAUTIONS

CASE 21-1, QUESTION 4: What are the adverse effects and

precautions that should be considered before recommending the use of clonidine?

Oral clonidine is generally well tolerated. Adverse effects

include orthostatic hypotension, bradycardia, sedation, dry

mouth, and dizziness. Clonidine can decrease cerebral blood

flow by up to 28%; it should not be used in patients with severe

cerebrovascular disease.41 Clonidine also should be avoided in

patients with HF, bradycardia, sick sinus syndrome, or cardiac

conduction defects,23 as well as patients at risk for medication

nonadherence because of the rebound hypertension.42,43

OTHER ORAL DRUGS

CAPTOPRIL

CASE 21-1, QUESTION 5: M.M. has a history of HF and normal renal function. Based on these findings, would captopril

be a reasonable choice for initial treatment? How should it

be given? What if his BUN or serum creatinine were elevated?

Captopril has been used both orally and sublingually to

acutely lower BP.44,45 Captopril decreases both afterload and

preload, and lowers total peripheral vascular resistance.23 For

this reason, captopril and other ACE inhibitors are often considered the drugs of choice in patients with HF as they have been

shown to reduce mortality in this patient population. (See Chapter 19, Heart Failure, for a discussion of the use of ACE inhibitors

in HF.) Given that M.M. appeared to be well controlled on his

ACE inhibitor before abruptly stopping his medications, it is reasonable to restart an ACE inhibitor and reinforce medication

adherence issues.

After oral administration, the onset of action of captopril occurs within minutes and peaks 30 to 90 minutes after

ingestion.46 Clinically, it reduces BP within 10 to 15 minutes,

with effects persisting for 2 to 6 hours. Sublingual captopril is as

effective as nifedipine but without reflex tachycardia in acutely

reducing mean arterial pressure in both urgent and emergent

conditions.45–48

Despite these beneficial effects, captopril, as well as all other

ACE inhibitors, must be used with caution in patients with renal

insufficiency or volume depletion. In most cases, an elevated

BUN or serum creatinine will provide a clue to the existence

of these conditions; however, captopril can also induce severe

renal failure in patients with bilateral renal artery stenosis or

renal artery stenosis in a solitary kidney. Such conditions may

not be easy to detect in the context of an acute hypertensive

emergency. Therefore, in patients in whom these conditions can

be excluded, captopril can be considered for therapy. First-dose

hypotension is a common limiting factor with captopril use. This

complication is most likely to occur in the elderly and in patients

with high renin levels such as those who are volume depleted or

those receiving diuretics. Under these circumstances, initial doses

should not exceed 12.5 mg, with repeat doses an hour or more

later if necessary. Although he was not taking his diuretic, M.M.

is still likely to have high renin levels as a result of his history of

HF. Therefore, captopril would be a reasonable choice as initial

therapy in M.M., which can later be replaced by a longer-acting

ACE inhibitor.

527Hypertensive Crises Chapter 21

MINOXIDIL AND LABETALOL

CASE 21-1, QUESTION 6: What other oral agents are used

in the treatment of hypertensive urgency?

Minoxidil, a potent oral vasodilator, has been used successfully

in the treatment of hypertensive urgencies.49,50 An oral loading

dose of 10 to 20 mg produces a maximal BP response in 2 to

4 hours and can be followed by a dose of 5 to 20 mg every

4 hours if necessary. Unfortunately, its onset of action is slower

than that of clonidine or captopril. Another complicating factor is that β-blockers and loop diuretics generally must be used

concomitantly to counteract minoxidil-induced reflex tachycardia and fluid retention.50 Because of this, minoxidil should only

be prescribed by those who have experience with prescribing this

agent and managing these adverse effects. These adverse effects

make this agent a less than ideal choice in M.M. because of his

history of HF. Minoxidil should be used only in patients presenting with hypertensive urgency who are not responding to other

antihypertensive therapies or who have previously been taking

this agent.

Oral labetalol, a combined α- and β-receptor antagonist, is

an alternative to oral clonidine or captopril for the treatment

of severe hypertension, but the most appropriate dosing regimen remains to be determined.51–54 Initial doses of 100 to

300 mg may provide a sustained response for up to 4 hours.52

Labetalol (200 mg given at hourly intervals to a maximum dose of

1,200 mg) was comparable to oral clonidine in reducing mean

arterial pressure.54 An alternative regimen using 300 mg initially

followed by 100 mg at 2-hour intervals to a maximum of 500 mg

was also successful in acutely lowering BP.53 However, Wright

et al.55 were unable to achieve an adequate BP response in a

small series of patients using a single loading dose of 200 to

400 mg. Because labetalol can cause profound orthostatic

hypotension, patients should remain in the supine position and

should be checked for orthostasis before ambulation. In addition,

labetalol should be avoided in patients with asthma, bradycardia,

or advanced heart block.

HYPERTENSIVE EMERGENCIES

Patient Assessment

CASE 21-2

QUESTION 1: M.R., a 55-year-old African American man,

presents to the emergency department with a 3-day history

of progressively increasing shortness of breath. During the

past 2 days, he experienced a severe headache unrelieved

by ibuprofen, as well as substernal chest pain, anorexia, and

nausea. His medical history includes asthma and a 5-year history of angina, which resulted in hospitalization for an acute

inferior MI 2 months before admission. He has been taking

albuterol via metered-dose inhaler, furosemide, isosorbide

dinitrate, felodipine, and lisinopril, but discontinued these

medications on his own 3 weeks ago.

Physical examination reveals an anxious-appearing man

who is alert, oriented, and in moderate respiratory distress. His vital signs include a pulse of 125 beats/minute,

respiratory rate of 36 breaths/minute, BP of 220/145 mm

Hg without orthostasis, and a normal body temperature.

Funduscopic examination shows arteriolar narrowing and

arteriovenous nicking without hemorrhages, exudates, or

papilledema. There is no jugular venous distention, but

bilateral carotid bruits are present. Chest examination

reveals decreased breath sounds with bilateral rales extending to the tip of the scapula. M.R.’s heart is displaced 2 cm to

the left of the midclavicular line with no thrills or heaves. The

rhythm is regular with an S3 and an S4 gallop; no murmurs

are noted. The remainder of M.R.’s examination is within

normal limits.

Significant laboratory values include the following:

Sodium, 142 mEq/L

Potassium, 4.9 mEq/L

Chloride, 101 mEq/L

Bicarbonate, 23 mEq/L

BUN, 30 mg/dL

Serum creatinine, 1.2 mg/dL

Hematocrit, 38%

Hemoglobin, 13 g/dL

White blood cell count and differential, within normal

limits

Urinalysis shows 1+ hemoglobin and 1+ protein. Microscopic examination of the urine reveals 5 to 10 red blood

cells per high-power field and no casts. Pulse oximetry

reveals an oxygen saturation of 88%. An electrocardiogram

demonstrates sinus tachycardia and left ventricular hypertrophy. The chest radiograph shows moderate cardiomegaly

and bilateral fluffy infiltrates.

What aspects of M.R.’s history and physical examination

are characteristic of an emergent need to immediately lower

his BP?

As discussed previously, hypertensive crisis occurs most often

in African American men and individuals between the ages of

40 and 60. Furthermore, many patients who present with hypertensive crisis have a recent history of discontinuing the use of

their antihypertensives,13,15 as is the case with M.R. and M.M. in

Case 21-1.

Recent-onset severe headache, nausea, and vomiting are consistent with central nervous system signs of severe hypertension, as are the acute onset of angina (substernal pain) and acute

HF (shortness of breath, increased pulse and respiratory rate,

cardiomegaly, S3, and chest radiographic findings of pulmonary

edema). The absence of signs of right-sided HF such as jugular

venous distention or hepatomegaly suggests an acute onset of

HF caused by hypertension as opposed to a gradual worsening

of chronic HF. M.R.’s urinary sediment is relatively unimpressive at this time, especially in light of his history, and his ocular complications are minimal. M.R.’s presentation is considered

hypertensive emergency because of the presence of HF symptoms; M.R. should be admitted to the hospital as intravenous

(IV) antihypertensive therapy is warranted.

Parenteral Drug Therapy

NITROPRUSSIDE

CASE 21-2, QUESTION 2: M.R. is to be started on nitroprusside. Is this an appropriate choice of drug? What alternatives to nitroprusside are available?

M.R.’s arterial pressure should be lowered with parenteral

medications, which have a rapid onset of action. Nitroprusside, fenoldopam, and IV nitroglycerin all decrease total peripheral resistance rapidly with minimal effect on myocardial oxygen consumption and heart rate. Of these agents, either nitroprusside or fenoldopam would be preferred in patients with

528 Section 2 Cardiac and Vascular Disorders

hypertension accompanied by decompensated HF in the absence

of MI. Parenteral nitroglycerin is similar to nitroprusside except

that it has a relatively greater effect on the venous circulation and

less effect on arterioles. It is most useful in patients with coronary insufficiency, ischemic heart disease, MI, or hypertension

after coronary bypass surgery (also see Case 21-3, Question 6). In

addition, nitroprusside and IV nitroglycerin may both decrease

elevated left ventricular diastolic pressures in patients presenting

with hypertensive emergency. Fenoldopam and nitroprusside are

equally efficacious in acutely lowering BP.56–59 Both drugs have

an immediate onset, are easily titratable, have a short duration

of action, and are relatively well tolerated. Fenoldopam may also

increase renal blood flow, thereby reducing the risk for worsening renal function.60–63 Unlike nitroprusside, fenoldopam does

not cause cyanide or thiocyanate toxicity, but it is considerably

more expensive than nitroprusside.

Therefore, in the absence of any significant renal or liver disease, nitroprusside is the preferred treatment for M.R.

HEMODYNAMIC EFFECTS

Nitroprusside has many pharmacologic effects that should

improve M.R.’s condition. It dilates both venous and arterial vessels, thereby increasing venous capacitance and decreasing the

venous return or preload on the heart (see Chapter 19, Heart

Failure). A decrease in the pulmonary capillary wedge pressure

and ventricular filling pressure will ultimately improve M.R.’s

pulmonary edema. Afterload is also decreased as a result of arterial dilation. This action increases cardiac output, reduces arterial

pressure, and increases tissue perfusion.

CONCURRENT USE OF DIURETICS

CASE 21-2, QUESTION 3: Should M.R. be given a diuretic

before nitroprusside therapy is begun?

Administration of potent IV diuretics is relatively ineffective