in the acute treatment of hypertensive crisis except in patients

with concomitant volume overload or HF. Many patients with

hypertensive emergencies are vasoconstricted and have normal or reduced plasma volumes; therefore, diuretics have little

effect and may actually aggravate renal impairment or cause

other adverse effects.22,64 Furthermore, when diuretics are given

acutely in combination with other antihypertensive agents, profound hypotension can occur.

The immediate value of diuretics in acute HF is related more

to their hemodynamic effects (venodilation) than to diuresis.

Venodilation after IV diuretic administration decreases rightsided cardiac filling pressures, decreases pulmonary artery and

wedge pressures, and increases cardiac output before diuresis

occurs.65 The presence of HF and severely elevated BP in M.R.

warrants the IV administration of a loop diuretic (e.g., furosemide 20 to 40 mg, torsemide [Demadex] 10 mg, or bumetanide

[Bumex] 1 mg).

DOSING AND ADMINISTRATION

CASE 21-2, QUESTION 4: How should nitroprusside be prepared and administered? What dose should be used initially?

Because of its extreme potency, sodium nitroprusside must be

prepared in exact concentrations and BP must be closely monitored. Sodium nitroprusside is supplied in units of 50 mg of

lyophilized powder. The powder is reconstituted with 2 to 3 mL

of 5% dextrose in water (D5W) or sterile water for injection,

shaking gently to dissolve.66 The contents of the vial are then

added to 250, 500, or 1,000 mL of D5W to produce a solution for

IV administration with a drug concentration containing 200, 100,

or 50 mcg/mL. This solution should have a slight brownish tint.

Nitroprusside decomposes on exposure to light, so the solution should be shielded with an opaque sleeve. It is not necessary

to protect the tubing from light. Reconstituted solutions are stable for 24 hours at room temperature. A change in the solution’s

color from light brown to dark brown, green, orange, or blue

indicates a loss in activity, and the solution should be discarded.

Effective infusion rates range from 0.25 to 10 mcg/kg/

minute.67 For M.R., an infusion of nitroprusside should be initiated at a rate of 0.25 mcg/kg/minute. The dose should be

increased slowly by 0.25 mcg/kg/minute every 5 minutes until

the desired pressure is achieved. A maximum infusion rate of 10

mcg/kg/minute has been recommended. If adequate BP reduction is not achieved within 10 minutes after maximal dose infusion, nitroprusside should be discontinued.4 The dosage must be

individualized according to patient response using continuous

intra-arterial BP recording and observing for signs or symptoms

of toxicity.

THERAPEUTIC END POINT

CASE 21-2, QUESTION 5: A nitroprusside infusion of 0.25

mcg/kg/minute is started. What is the goal of therapy?

For most patients BP should be reduced by no more than

25% within the first minutes to hour, then if stable, therapy

can be titrated to achieve a goal BP of 160/100 mm Hg during

the next 2 to 6 hours. Blood pressures can be reduced to nearnormal levels within 8 to 24 hours. However, because M.R. has

cerebral occlusive disease (carotid bruits), excessive reduction

of his BP should be avoided. Overly aggressive reduction of BP

in the presence of major cerebral vessel stenosis may decrease

cerebral blood flow and produce strokes or other neurologic

complications.

Normal cerebral blood flow remains relatively constant over

a wide range of systemic BP measurements through autoregulatory mechanisms.40,68 The autoregulatory effects can prevent

large alterations in cerebral blood flow from either slow or rapid

changes in systemic arterial pressures. In addition, the arterial BP

required to maintain cerebral perfusion is higher in hypertensive

patients than in normotensive individuals. If M.R.’s BP is reduced

excessively, cerebral blood flow may decrease sharply. Therefore,

a diastolic BP of 100 to 105 mm Hg would be a reasonable initial therapeutic goal for him in the first 6 hours. If hypotension

occurs, nitroprusside should be discontinued and M.R. should be

placed in the Trendelenburg position, in which the head is kept

lower than the trunk.

CYANIDE TOXICITY

CASE 21-2, QUESTION 6: M.R. is being treated with nitroprusside. However, during the last 36 hours, dose titration

to 7 mcg/kg/minute has been necessary to control his BP. Is

he at risk for developing cyanide toxicity? What indices of

toxicity should be monitored? Are there agents available to

prevent toxicity?

A major concern when using sodium nitroprusside is toxicity secondary to the accumulation of its metabolic byproducts, cyanide and thiocyanate. Sodium nitroprusside decomposes within a few minutes after IV infusion. Free cyanide, which

represents 44% of nitroprusside by weight, is released into the

bloodstream, producing prussic acid (hydrogen cyanide), which

is responsible for the acute toxicity.69 The amount of hydrogen

529Hypertensive Crises Chapter 21

cyanide released is directly proportional to the size of the dose.70

Endogenous detoxification of cyanide occurs through a mitochondrial rhodanese system, which, in the presence of a sulfur

donor such as thiosulfate, converts cyanide to thiocyanate.69 Theoretically, cyanide can be expected to accumulate in the body

when the rate of the sodium nitroprusside infusion exceeds 2

mcg/kg/minute for a prolonged period. The presence of hepatic

or renal impairment may also predispose the patient to cyanide

toxicity.71,72

It is generally stated that symptomatic cyanide toxicity occurs

infrequently, although several deaths have been reported after

the use of sodium nitroprusside.73 Cyanide toxicity occurs most

commonly when large doses (total dose 1.5 mg/kg) of nitroprusside are administered rapidly to patients undergoing a surgical procedure that requires induction of hypotension. However, cyanide toxicity and mortality associated with nitroprusside

exceed 3,000 and 1,000 cases per year, respectively, according to

two sources.73,74 The product label warns that sodium nitroprusside administration increases the body’s concentration of cyanide

ion to toxic and potentially fatal levels, even when given within

the range of recommended doses. The labeling further states that

infusions at the maximum recommended dose can overwhelm

the body’s ability to buffer the cyanide within 1 hour.

Although concurrent sodium thiosulfate administration has

been recommended in high-risk patients, no clinical data are available to indicate that it reduces overall mortality. Furthermore,

this intervention may result in the accumulation of thiocyanate,

particularly if sodium thiosulfate is given at high infusion rates or

to patients with renal insufficiency. A 1-year retrospective review

at a tertiary-care teaching hospital with a level 1 trauma center

found that none of the patients receiving nitroprusside at infusion

rates greater than 2 mcg/kg/minute were concurrently treated

with sodium thiosulfate.75 Hydroxocobalamin has also been used

to reduce the risk of cyanide toxicity secondary to nitroprusside

infusions, but its use is limited because of poor availability and

cost considerations.72 With the availability of safer alternatives

(e.g., fenoldopam, IV labetalol, IV nicardipine) for use in highrisk patients, the use of hydroxocobalamin or thiosulfate is rarely

required.

Cyanide toxicity can be detected early by monitoring M.R.’s

metabolic status. Lactic acidosis is an early indicator of toxicity because the progressive inactivation of cytochrome oxidase

by cyanide results in increased anaerobic glycolysis.76 A low

plasma bicarbonate concentration and low pH, accompanied by

an increase in the blood lactate or lactate-to-pyruvate ratio, and

an increase in the mixed venous blood oxygen tension could indicate cyanide toxicity.77 Additional signs of cyanide intoxication

include tachycardia, altered consciousness, coma, convulsions,

and the occasional smell of almonds on the breath.70,77 Hypoxemia resulting from pulmonary arterial shunting has also been

reported during nitroprusside therapy. Measuring serum thiocyanate levels is of no value in detecting the onset of cyanide

toxicity. If toxicity develops, the infusion should be stopped and

appropriate therapy for cyanide intoxication instituted. The need

for such a high-dose infusion of nitroprusside to maintain M.R.’s

pressure may increase his risk for cyanide toxicity, warranting

close monitoring of his acid–base balance.

THIOCYANATE TOXICITY

CASE 21-2, QUESTION 7: Explain the difference between

cyanide toxicity and thiocyanate toxicity. What is M.R.’s risk

for thiocyanate toxicity if he is continued on a dose of

7 mcg/kg/minute? Is monitoring of serum thiocyanate

concentrations necessary?

Sodium nitroprusside is more likely to produce thiocyanate

toxicity. Although this complication is also rare, patients with

renal impairment who receive infusions beyond 72 hours are

particularly susceptible. The cyanide released from nitroprusside is normally metabolized by thiosulfate in the liver to thiocyanate via sulfation. This conversion of cyanide to thiocyanate

proceeds relatively slowly, and thiocyanate levels rise gradually

in proportion to the dose and duration of sodium nitroprusside

administration. The half-life of thiocyanate is 2.7 days with normal renal function and up to 9 days in patients with renal failure.78

When sodium nitroprusside is infused for several days at moderate dosages (2–5 mcg/kg/minute), toxic levels of thiocyanate can

occur within 7 to 14 days in patients with normal renal function

and 3 to 6 days in patients with severe renal disease.69

Thiocyanate causes a neurotoxic syndrome manifested by

psychosis, hyperreflexia, confusion, weakness, tinnitus, seizures,

and coma.71,78 Prolonged exposure to thiocyanate can suppress

thyroid function through inhibition of iodine uptake and binding

by the thyroid gland.78 Routine measurement of blood levels of

thiocyanate is unnecessary and is recommended only in patients

with renal disease or when the duration of the nitroprusside

infusion exceeds 3 or 4 days. Nitroprusside should be discontinued if serum thiocyanate levels exceed 10 to 12 mg/dL.79,80

Life-threatening toxicity is of concern when blood thiocyanate

levels exceed 20 mg/dL. In emergency cases, thiocyanate can be

readily removed by hemodialysis.78

For M.R., the potential for thiocyanate toxicity is low because

his renal function is normal and the anticipated infusion duration

is relatively short. Therefore, measurement of thiocyanate levels

is not indicated at this time.

Other side effects associated with nitroprusside therapy

include nausea, vomiting, diaphoresis, nasal stuffiness, muscular twitching, dizziness, and weakness. These effects are usually

acute and occur when nitroprusside is administered too rapidly.

They can be reversed by decreasing the infusion rate.

CASE 21-2, QUESTION 8: M.R.’s serum chemistries and

arterial blood gas values indicate a metabolic acidosis.

Should the nitroprusside infusion be continued at 7 mcg/kg/

minute? What alternative is available?

Although the duration of M.R.’s nitroprusside therapy has

been short, tolerance to the antihypertensive effect requires the

use of a high-dose infusion to maintain BP control. Thus, acidosis

may represent toxicity as a result of cyanide accumulation. The

nitroprusside infusion should be discontinued at this time, and

another rapidly acting, easily titratable parenteral antihypertensive such as fenoldopam or IV nicardipine should be initiated.

FENOLDOPAM

CASE 21-2, QUESTION 9: What are the advantages and

disadvantages of fenoldopam compared with sodium nitroprusside?

Fenoldopam is a parenteral, rapidly acting, peripheral

dopamine-1 agonist used to manage hypertensive crisis when

a rapid reduction of BP is required.81–84 Stimulation of the

dopamine-1 receptors vasodilates coronary, renal, mesenteric,

and peripheral arteries.85 Vasodilation of the renal vasculature

increases renal blood flow in hypertensive patients,60,61,63 a property that may be particularly advantageous in patients with

impaired renal function.62,86 However, no outcome data are available to document that this effect reduces morbidity and mortality in patients with hypertensive emergencies. Fenoldopam has

also been used to control perioperative hypertension in patients

530 Section 2 Cardiac and Vascular Disorders

undergoing cardiac bypass surgery because, relative to nitroprusside, it either maintains or increases urinary output.87,88

Fenoldopam is as effective as sodium nitroprusside for treatment

of hypertensive emergencies and does not cause either cyanide

or thiocyanate toxicity.57–59 Outcome studies will be required to

assess the impact of fenoldopam on increasing renal blood flow

and urine output in the management of patients with hypertensive emergencies. Until such time, it should be used only as an

alternative to nitroprusside in patients such as M.R., who are at

high risk for cyanide or thiocyanate toxicity.

CASE 21-2, QUESTION 10: If M.R. is converted to a

continuous infusion of fenoldopam, what is the dose of

this medication? What monitoring parameters should be

followed?

Fenoldopam is administered as a continuous infusion (without a bolus dose) beginning at a rate of 0.1 mcg/kg/minute. It

is then titrated upward, according to BP control, in increments

of 0.05 to 0.1 mcg/kg/minute at 15-minute intervals. The maximum dose is 1.6 mcg/kg/minute, and has been studied for up

to 48 hours of therapy. Clearance of fenoldopam is not altered

by renal or liver disease. Like nitroprusside, fenoldopam also

has a short duration of action, with an elimination half-life of

approximately 5 minutes, thus allowing for easy titration. Once

the target BP is achieved, fenoldopam can be gradually tapered

as oral therapy is initiated, if rebound hypertension has not

occurred.83,89

Fenoldopam is well tolerated and relatively free of side effects.

BP and heart rate should be followed closely to avoid hypotension and dose-related tachycardia. The vasodilating effect may

also cause flushing, dizziness, and headache. Serum electrolytes

should be monitored, and in some cases, potassium supplementation is required. Fenoldopam should be used cautiously in

patients with glaucoma or intraocular hypertension due to a

dose-dependent increase in intraocular pressure.90,91

CASE 21-2, QUESTION 11: Which antihypertensive agents

should be avoided in M.R.? Why?

Labetalol, a potent, rapidly acting antihypertensive with both

α- and β-blocking activity, is very effective in the treatment of

hypertensive emergencies,91–98 but it should not be used in M.R.

Hemodynamically, labetalol reduces peripheral vascular resistance (afterload), BP, and heart rate, with almost no change in

the resting cardiac output or stroke volume.99

M.R. is experiencing chest pain, and he is tachycardic; these

signs and symptoms are most likely caused by his severely elevated BP and the presence of acute left ventricular failure. Even

though labetalol might improve M.R.’s angina, the negative

inotropic action could acutely compromise his left ventricular

dysfunction, an effect that outweighs the potential benefit of

afterload reduction. In addition, even though labetalol is one of

the safest blocking drugs when used in patients with asthma,100

no β-blocker should be used as initial treatment in patients with

asthma. Labetalol should be used only if alternative methods of

reducing M.R.’s pressure fail.

LABETALOL

CASE 21-3

QUESTION 1: C.M., a 52-year-old Caucasian man, is admitted to the hospital with a 3-day history of increasing exertional substernal chest pain (without shortness of breath),

diaphoresis, nausea, and vomiting. His history is significant for poorly controlled hypertension, glaucoma, and

angina pectoris. Prior medications include dorzolamide

ophthalmic drops, atenolol, hydrochlorothiazide, and oral

nitrates. Physical examination reveals an anxious man who

is alert and oriented. He has a BP of 210/146 mm Hg without orthostasis and a regular pulse of 115 beats/minute.

Bilateral hemorrhages and exudates are present on funduscopic examination. The lungs are clear and the heart is

enlarged, but there are no murmurs or gallops. Examination

of the abdomen is unremarkable, and there is no peripheral

edema. The neurologic examination is normal.

Significant laboratory values include the following:

Sodium, 140 mEq/L

Chloride, 109 mEq/L

Bicarbonate, 18 mEq/L

BUN, 49 mg/dL

Serum creatinine, 2.8 mg/dL

Renal function was previously noted to be within normal

limits. Urinalysis shows proteinuria and hematuria. The electrocardiogram demonstrates sinus tachycardia with left-axis

deviation, left ventricular hypertrophy, and nonspecific ST-T

wave changes. The chest radiograph reveals mild cardiomegaly.

C.M. is given nitroglycerin sublingually and 1 inch of

nitroglycerin ointment is applied topically. He is started on

IV labetalol. Is this choice of treatment reasonable, considering C.M.’s angina and acute kidney injury?

The presence of chest pain, retinopathy, and new-onset renal

disease, as well as the magnitude of the BP elevation in C.M.,

classifies his presentation as a hypertensive emergency that warrants a prompt reduction in BP. The combination of sublingual

and topical nitroglycerin may help in acutely lowering his BP

and relieving his chest pain while waiting for more definitive

treatment to be implemented.

IV labetalol is a potent antihypertensive drug that has been

used successfully in hypertensive emergencies.92–98 Labetalol

blocks both β- and α-adrenergic receptors and also may exert a

direct vasodilator effect. Theβ-blockade is nonselective withβ to

α potency of 3:1 for oral and 7:1 for IV labetalol. Labetalol is particularly advantageous in C.M. because the immediate onset of

action will reduce peripheral vascular resistance without causing

reflex tachycardia. Myocardial oxygen demand will be reduced

and coronary hemodynamics will be improved, making this

agent an excellent choice for patients such as C.M., who have

anginal symptoms or MI. In addition, IV labetalol does not significantly reduce cerebral blood flow; therefore, it may be useful

in patients with cerebrovascular disease.1,23

Fenoldopam or nitroprusside could also be used to treat C.M.

Fenoldopam could potentially benefit renal function by increasing renal blood flow, but C.M.’s history of glaucoma would preclude its use. In addition, fenoldopam would not be beneficial

for C.M.’s anginal symptoms, and equally effective but less costly

alternatives are available. Treatment with nitroprusside would

expose C.M. to the potential risk of cyanide and thiocyanate toxicity with his new-onset renal failure. In contrast, labetalol has

been used successfully in patients with renal disease without deleterious side effects.101,102 Labetalol is eliminated by glucuronidation in the liver, with less than 5% of the dose being excreted

unchanged in the urine. Therefore, labetalol may be better tolerated than nitroprusside by patients with hepatic failure because

toxic nitroprusside metabolites also accumulate in this situation.

The presence of renal disease in C.M. will not necessitate an

alteration in the dose of labetalol.

531Hypertensive Crises Chapter 21

CONTRAINDICATIONS AND PRECAUTIONS

CASE 21-3, QUESTION 2: What cautions should be exercised when using labetalol in C.M.?

Labetalol’s disadvantages are primarily related to its

β-blocking effects. Therefore, it should not be used in patients

with asthma, heart block greater than first degree, or sinus bradycardia, and it should be used with caution in patients with decompensated HF93,97,103 (see Case 21-2, Question 10). None of these

are present in C.M. Like other β-blockers, labetalol may mask

the symptoms of hypoglycemia in insulin-dependent diabetic

patients; it should also be used with caution in patients with Raynaud’s syndrome.104 Labetalol has been effective in the treatment

of hypertension associated with pheochromocytoma and excess

catecholamine states as well as those with rebound hypertension from β-blocker withdrawal.105 However, because labetalol

is primarily a β-blocker, paradoxic hypertension may occur

in patients with pheochromocytoma. These individuals have

adrenal tumors that excrete high amounts of norepinephrine,

which results in relatively unopposed α-receptor stimulation.106

More clinical experience is required before labetalol can be recommended in patients with pheochromocytoma.6,92

There appears to be a positive correlation between age and

response to labetalol. Older patients achieve a greater reduction

in BP and, therefore, require smaller doses.104,107 Failure to lower

BP has also been observed.108–110 This phenomenon is believed

to be related to single-bolus administration or prior treatment

with α- and β-blocking drugs.103 However, subsequent studies

have confirmed the effectiveness of labetalol in the management

of hypertensive emergency in those pretreated with antihypertensives, including β-blockers.111

CASE 21-3, QUESTION 3: How should parenteral labetalol

be given to C.M.?

For treatment of his hypertensive emergency, C.M. should be

placed in the supine position. IV labetalol can be given by pulse

administration or continuous infusion.92–97 Small incremental

bolus injections are administered, beginning with 20 mg given

over 2 minutes, followed by 40 to 80 mg every 10 to 15 minutes

until the desired response is achieved or a cumulative dose of

300 mg is reached. The desired response is usually achieved with

a mean dose of 200 mg in 90% of patients.93 After IV injection,

the maximal effect occurs within 5 to 10 minutes,95 and the

antihypertensive response may persist for more than 6 hours.111

Because the rate of BP reduction is accelerated with an increase

in infusion rate,95 a controlled continuous infusion may provide

a more gradual reduction in arterial pressure with less frequent

adverse effects.97,112 A solution for continuous infusion (0.5–2.0

mg/minute) is prepared by adding two ampules (200 mg total) to

160 mL of IV fluid to give a final concentration of 1 mg/mL. The

infusion can then be started at a rate of 2 mg/minute and titrated

until a satisfactory response is achieved or until a cumulative dose

of 300 mg is reached.

PARENTERAL TO ORAL CONVERSION

CASE 21-3, QUESTION 4: C.M. was treated with a labetalol

infusion and required a cumulative dose of 180 mg to

achieve a diastolic pressure of 100 mm Hg. His anginal

symptoms resolved almost immediately, but 3 hours after

the infusion, C.M. became faint and dizzy while ambulating.

Should oral labetalol be withheld in C.M.?

Postural hypotension and dizziness are dose related and more

commonly associated with the IV route of administration.99,103

C.M. should remain in a supine position after the IV administration of labetalol, and his ability to tolerate an upright position should be established before permitting ambulation. Oral

labetalol can be given to C.M. when his symptoms resolve. There

is no correlation between the oral maintenance dose and the total

initial IV dose. C.M. should be started on an empiric dose of

100 to 200 mg of oral labetalol twice daily, and this should be

titrated as necessary.

CASE 21-3, QUESTION 5: What other side effects can occur

with labetalol therapy?

Other side effects commonly associated with labetalol include

nausea, vomiting, abdominal pain, and diarrhea in up to 15% of

the patients.103 Scalp tingling is an unusual side effect that has

been reported in a few patients after IV administration; it tends

to disappear with continued treatment. Other side effects include

tiredness, weakness, muscle cramps, headache, ejaculation failure, and skin rashes.

NITROGLYCERIN

CASE 21-3, QUESTION 6: Would parenteral nitroglycerin

be an acceptable alternative to labetalol for C.M.?

Hypertensive emergencies in the setting of unstable angina or

MI requires an immediate reduction in BP. Nitroprusside has been

used successfully, but IV nitroglycerin can have more favorable

effects on collateral coronary flow in patients with ischemic heart

disease.113 By diminishing preload, nitroglycerin decreases left

ventricular diastolic volume, diastolic pressure, and myocardial

wall tension, thus reducing myocardial oxygen consumption.114

These changes favor redistribution of coronary blood flow to the

subendocardium, which is more vulnerable to ischemia. At high

dosages, nitroglycerin dilates arteriolar smooth muscles, and this

reduction in afterload also decreases myocardial wall tension and

oxygen consumption.115

IV nitroglycerin has a rapid onset of action and a short duration, and is easily titratable. It is generally appropriate to begin

IV nitroglycerin at dosages in the range of 5 to 10 mcg/minute,

increased as needed to control pressure and symptoms. The usual

dose is in the range of 40 to 100 mcg/minute. The major limiting

side effects are headache and the development of tolerance. In

general, IV nitroglycerin is well suited for use in patients such

as C.M. who have angina or in patients who have hypertensive

emergency associated with MI or coronary artery bypass surgery.

HYDRALAZINE

CASE 21-4

QUESTION 1: T.M., a 30-year-old Caucasian man with

a history of chronic glomerulonephritis and poorly controlled hypertension, came to the emergency department

complaining of early morning occipital headaches during

the past week. He has no other complaints. He has not

taken any BP medication in a month. Physical examination

revealed an afebrile man in no acute distress with a BP of

160/120 mm Hg without orthostasis and a regular pulse of

90 beats/minute. Funduscopic examination revealed bilateral exudates without hemorrhages or papilledema. The

lungs were clear. Cardiac examination was pertinent for

cardiomegaly and an S4 gallop. The remainder of the physical workup was normal.

532 Section 2 Cardiac and Vascular Disorders

Laboratory results include the following values:

Hematocrit, 32%

BUN, 40 mg/dL

Serum creatinine, 2.5 mg/dL (baseline serum creatinine

1.9 mg/dL)

Bicarbonate, 18 mEq/L

Urinalysis reveals 2+ protein, 2+ hemoglobin with 4 to

10 red blood cells per high-power field. The electrocardiogram demonstrates normal sinus rhythm with left ventricular hypertrophy. The chest radiograph is unremarkable.

T.M.’s presentation meets criteria for a hypertensive

emergency (i.e., diastolic BP >120 mm Hg and presence

of worsening renal function). Intravenous antihypertensive therapy is required for T.M. T.M. was given 20 mg

hydralazine IV, and a repeat BP after 1 hour was 150/100

mm Hg. What are the advantages and disadvantages of parenteral hydralazine, and when should it be used to acutely

lower BP?

Hydralazine is a direct vasodilator that reduces total peripheral resistance through relaxation of arterial smooth muscle. It

is rarely used to treat hypertensive emergencies because its antihypertensive response is less predictable than that of other parenteral agents. Additionally, hydralazine has a prolonged half-life,

which can be problematic if too fast correction or hypotension

occurs.22 It is not consistently effective in controlling crises associated with essential hypertension.

CONTRAINDICATIONS

Hydralazine should not be used in patients with coronary heart

disease because the reflex tachycardia causes an increase in

myocardial oxygen demand, which may result in the development or worsening of ischemic symptoms. In addition,

hydralazine should be avoided in patients with aortic dissection because of its reflex cardiostimulating effect. In contrast,

hydralazine can be useful in patients such as T.M., who have

chronic renal failure because the reflex increase in cardiac output is accompanied by an increase in organ perfusion.21

DOSING AND ADMINISTRATION

Parenteral hydralazine should be considered an intermediate

treatment between oral agents and more aggressive therapy with

such agents as fenoldopam or nitroprusside. It can be given IV

or intramuscularly. The onset of action develops slowly over 20

to 40 minutes, thus minimizing the risk of acute hypotension.

Parenteral doses are considerably lower than oral doses because

of increased bioavailability.

OTHER PARENTERAL DRUGS

CASE 21-4, QUESTION 2: Are there alternatives to

hydralazine for parenteral treatment of hypertensive crisis?

INTRAVENOUS ENALAPRILAT

Enalaprilat, the active metabolite of the oral prodrug enalapril

(Vasotec), is approved by the U.S. Food and Drug Administration for the treatment of hypertension when oral therapy is

not feasible. However, enalaprilat has been used to treat severe

hypertension.116–121 The initial dose is 0.625 to 1.25 mg IV and

can be repeated every 6 hours, if necessary. To minimize the risk

of hypotension, the initial doses should not exceed 0.625 mg in

patients receiving diuretics or in patients with clinical evidence

of hypovolemia. The onset of action is within 15 minutes, but

the maximal effect may take several hours. Because only 60%

of the patients respond to BP reduction within 30 minutes, it

cannot be reliably used to acutely lower pressure in hypertensive

emergencies.119 Although higher initial doses have been successfully used to achieve BP control,120 some evidence indicates that

doses greater than 0.625 mg do not significantly alter the magnitude of enalaprilat’s antihypertensive effect.118 Enalaprilat also is

beneficial in patients with HF. Precautions for the use of enalaprilat are similar to those of captopril (see Case 21-1, Question 5).

Because of the prolonged time required to achieve an adequate

response, limited clinical experience, and variable response rates

(especially in African Americans), enalaprilat cannot be recommended for the routine treatment of patients with hypertensive

emergencies.119,121

INTRAVENOUS CALCIUM-CHANNEL BLOCKERS

CASE 21-5

QUESTION 1: H.C. is a 71-year-old Caucasian man undergoing urgent coronary artery bypass graft surgery after an MI.

H.C. has a history of a cerebrovascular accident and chronic

kidney disease (serum creatinine is stable at 1.6 mg/dL). Two

hours after surgery H.C.’s systolic BP began to increase to

162 to 171 mm Hg with a diastolic BP of 121 to 133 mm Hg.

H.C. was administered IV nicardipine postoperatively for BP

control. Is nicardipine an appropriate choice for H.C.?

Nicardipine

Postoperative hypertension is typically short lived and is most

commonly seen after neurosurgical, head and neck, vascular, and

cardiothoracic procedures (as is the case with H.C.). Treatment

is typically only required for 6 hours postoperatively, and up to

24 to 48 hours for some. Adequate control of BP postoperatively is

necessary to minimize the risk of cardiovascular, neurological, or

surgical-site complications such as bleeding.122 When selecting

an agent, one should consider therapies with a quick onset and

short duration of action as well as established efficacy and safety

in the postoperative setting.

Nicardipine is a potent cerebral and systemic vasodilator and a

useful therapeutic option in the management of severe hypertension. Its onset of action is within 1 to 2 minutes, and its elimination half-life is 40 minutes.123 Hemodynamic evaluations demonstrated that IV nicardipine significantly decreased mean arterial

pressure and systemic vascular resistance and significantly

increased cardiac index with little or no change in heart rate.124

Titratable IV nicardipine has been studied extensively for use in

controlling postoperative hypertension 124–127 and hypertensive

emergencies 128–131

In the treatment of postoperative hypertension,124 IV

nicardipine was administered as an infusion titrated in the following manner: 10 mg/hour for 5 minutes, 12.5 mg/hour for

5 minutes, and 15 mg/hour for 15 minutes, followed by a maintenance infusion of 3 mg/hour thereafter. The mean response

time and infusion rate were 11.5 minutes and 12.8 mg/hour,

respectively. Ninety-four percent of the patients responded, and

adverse effects included hypotension (4.5%), tachycardia (2.7%),

and nausea and vomiting (4.5%).

The efficacy and safety of IV nicardipine for the treatment of

hypertensive crisis were documented in a double-blind, placebocontrolled multicenter trial of 123 patients.128 Therapy of IV

nicardipine was begun with dosages of 5 mg/hour and titrated

up to 15 mg/hour as indicated until the therapeutic end point

was achieved. The mean dosage of IV nicardipine at the end

of maintenance therapy was 8.7 mg/hour. Ninety-one percent

of patients on nicardipine achieved the prespecified BP target

533Hypertensive Crises Chapter 21

within a mean administration time of 77 minutes. In an openlabel trial,129 patients receiving nicardipine required significantly fewer dose adjustments per hour than patients receiving

nitroprusside (1.7 vs. 3.3, respectively). Serious adverse effects

reported in these trials were uncommon. The most commonly

reported adverse effects included headache, hypotension, tachycardia, dizziness, and nausea.

When compared with sodium nitroprusside for patients with

severe hypertension, IV nicardipine was as effective with fewer

adverse effects.129 In studies of patients receiving nicardipine

versus nitroprusside for postoperative hypertension after cardiac endarterectomy and coronary artery bypass grafting, breakthrough BP was controlled more rapidly with nicardipine and

required fewer overall dose titrations. In addition, nicardipine

was well tolerated and did not lead to an increased risk of

complications.132,133

Nicardipine is an appropriate choice of therapy for H.C.

because this agent has a rapid onset of action, and provides sustained BP control during the infusion period. It is easily titratable, with a predictable response, and is relatively free of severe

adverse effects, which is ideal in the postoperative setting. Therapy should be titrated to achieve a BP approximately 10% higher

than the patient’s baseline. In addition to nicardipine, nitroprusside, nitroglycerin, and labetalol are most commonly used to

manage postoperative hypertension.122 Finally, nicardipine may

be useful in patients with cerebral insufficiency or peripheral vascular disease. Because of the potential for reflex tachycardia, it

should be used with caution in patients with ongoing coronary

ischemia.

CASE 21-5, QUESTION 2: What other IV forms of calciumchannel blockers are available? Would any of these agents

be an appropriate choice of therapy for H.C.?

Nicardipine has been proven effective in multiple studies

of populations with hypertensive emergencies, and, as a dihydropyridine, has less negative inotropic activity compared with

nondihydropyridines. In contrast, the nondihydropyridines parenteral verapamil and diltiazem, although clinically effective for

prompt lowering of BP, have not been extensively studied in

patients with hypertensive emergencies. Clevidipine, a thirdgeneration dihydropyridine, has been shown to be useful in controlling BP in hypertensive emergencies and in the perioperative

setting.

Nondihydropyridines

IV verapamil (5–10 mg) produces a significant reduction in BP,

which occurs within 15 minutes and persists for 6 to 8 hours. As

a cardiovascular drug, it is primarily used as a rate-controlling

agent in the treatment of supraventricular tachycardias.

IV diltiazem is approved for temporary control of the ventricular rate in atrial fibrillation or atrial flutter and for rapid

conversion of paroxysmal supraventricular tachycardia.134–136

Parenteral diltiazem has also been used to control hypertension that occurs intraoperatively and postoperatively137,138 and

in patients with acute coronary artery disease.139,140 However,

published experience with the use of IV diltiazem for the treatment of severe hypertension is limited. Onoyama et al.141 administered a continuous infusion of diltiazem at a dosage of 5 to

40 mcg/kg/minute to a small group of patients with hypertensive

crisis. A normotensive level was achieved within 6 hours without

any signs of organ ischemia. In a follow-up study,142 a continuous infusion of diltiazem averaging 11 mcg/kg/minute resulted

in a 25% reduction in both systolic and diastolic BP measurements within 30 minutes. The magnitude of the decrease was

directly correlated with the pretreatment BP level. Atrioventricular nodal conduction abnormalities were noted in both studies during drug infusion. Patients receiving IV diltiazem require

continuous monitoring by electrocardiogram and frequent BP

checks. This form of therapy should be avoided in patients with

sick sinus syndrome or advanced degrees of heart block. Until

additional information is available, caution should be exercised

in using parenteral diltiazem to lower BP acutely. In addition, use

of nondihydropyridines should be avoided when acutely treating

any hypertensive patient with concomitant systolic HF owing to

their negative inotropic effects.

Clevidipine

Clevidipine is another intravenous dihydropyridine calciumchannel blocker with arterial-selective vasodilation properties.143

Clevidipine is quickly metabolized in extravascular tissue and

blood by esterases, leading to a short elimination half-life of

1 minute144 and complete resolution of hemodynamic effects

within 10 minutes after the end of a 24-hour continuous

infusion.145 Clevidipine demonstrates a quick onset of action of 1

to 2 minutes.146 These pharmacokinetic and pharmacodynamic

properties make it an attractive agent for managing hypertensive emergencies. Clevidipine demonstrated efficacy in treatment

of hypertension in both preoperative and postoperative cardiac

surgery patients.147,148 In this setting, therapy was initiated at a

rate of 0.4 mcg/kg/minute. Target BP was a reduction of at least

15% from baseline. The dose was titrated every 90 seconds by

doubling the dose up to an infusion rate of 3.2 mcg/kg/minute,

then increasing the dose by 1.5 mcg/kg/minute to a maximum

rate of 8 mcg/kg/minute. Clevidipine demonstrated a median

time of effectiveness within 6 minutes in greater than 90% of the

patients who received the study medication.

Clevidipine has been compared individually with nitroglycerin, nitroprusside, and nicardipine in management of perioperative hypertension in cardiac surgery patients.143 This was a

compilation of three parallel protocols that randomly assigned

patients to clevidipine or the comparison agent. Outcomes were

assessed by the occurrence of death, stroke, MI, or renal dysfunction from time of drug administration until postoperative day 30.

There were no differences between clevidipine and the pooled

comparison groups with regard to 30-day outcomes. Clevidipine

was more effective in maintaining patients within a predefined

BP target range when compared individually with nitroglycerin

and nitroprusside, but this did not translate to differences in clinical outcomes. The incidence and severity of adverse events were

similar among patients who received clevidipine and comparison

agents.

A prospective, open-label study was conducted evaluating

patients who presented in the emergency department or intensive care unit with systolic BP of greater than 180 mm Hg or

diastolic BP greater than 115 mm Hg.149 Patients were titrated

on clevidipine to a patient-specific systolic BP range that was

determined by the treating physician using criteria such as the

patient’s presenting condition, comorbidities, and baseline blood

pressure. The initial infusion rate was 2 mg/hour for at least

3 minutes, then titrated every 3 minutes until the target BP was

achieved or to a maximum rate of 32 mg/hour. If the target BP

was achieved, the medication was continued for 18 to 96 hours.

Overall, clevidipine demonstrated effectiveness in reaching the

target BP in 88.9% of patients within a median time of 10.9 minutes. Only 7.7% of patients required concomitant intravenous

antihypertensives during the entire study infusion. The majority (91.3%) of patients were able to effectively transition to oral

antihypertensive therapy.

Based on the limited data, nondihydropyridines would not

be an appropriate choice of therapy for H.C. Additionally, IV

verapamil has a long duration of action, which is not an ideal

534 Section 2 Cardiac and Vascular Disorders

characteristic in the setting of postoperative hypertension. Clevidipine, however, has a rapid onset of action and short duration

of action. This agent has also been shown to be efficacious in

controlling BP in the perioperative setting.

CASE 21-5, QUESTION 3: What factors should clinicians

consider before recommending the use of clevidipine?

There are two attributes to the medication that should also

be noted before initiation: reflexive tachycardia and formulation.

It has been demonstrated that clevidipine infusions can increase

heart rate by up to approximately 20 beats/minute.145 Clevidipine is nearly water-insoluble; the medication is formulated in a

20% lipid emulsion. Because of this feature, patients with serum

triglycerides greater than 400 mg/dL should not receive clevidipine, and any remaining drug should be discarded after 4 hours

of use. Clevidipine is contraindicated in patients with allergies to

soybeans, soy products, eggs, or egg products. This agent is also

contraindicated in those with defective lipid metabolism or acute

pancreatitis (if accompanied by hyperlipidemia), and in patients