trials have proved the superiority of ICD treatment over antiarrhythmic therapy for the secondary prevention of SCD. On the

basis of evidence from numerous clinical trials of primary and secondary prevention of SCD, the American College of Cardiology/

American Heart Association/Heart Rhythm Society 2008 guidelines for device-based therapy of cardiac rhythm abnormalities

assigned a class Ia-level evidence rating for ICD implantation in

three groups of patients. ICD therapy is indicated for (a) survivors of cardiac arrest caused by VF or hemodynamically unstable sustained VT, (b) patients with LVEF equal to or less than

35% caused by a prior MI who are at least 40 days after the

event and are in NYHA functional class II or III, and (c) patients

with LVEF equal to or less than 30% caused by prior MI who

are at least 40 days after the event and are in NYHA functional

class I.147

Although ICDs have been shown to improve survival in select

patient populations, the benefit may be offset by diminished quality of life associated with painful shocks, increased mortality compared with ICD patients who do not require shocks, and incomplete protection from the occurrence of SCD (5% of patients

fail to respond).148–150 In recent years, investigators have examined two different approaches to reducing the frequency of ICD

shocks. Antiarrhythmic medications and prophylactic catheter

ablation have been shown to reduce the incidence of ICD therapy.

The OPTIC (Optimal Pharmacological Therapy in Cardioverter

Defibrillator Patients) study enrolled 412 patients with St. Jude’s

Medical dual-chamber ICDs; LVEF of equal to or less than 40%

who had inducible VT or VF by programmed ventricular stimulation; LVEF of equal to or less than 40% with a prior history of

SuVT, VF, or cardiac arrest; or syncope of unknown cause with VF

or VT.148 The effect of amiodarone (mean dose range, 235–275

mg/day) plus β-blocker (metoprolol, carvedilol, or bisoprolol)

compared with sotalol (mean dose range, 183–190 mg/day) or

β-blocker alone (metoprolol, carvedilol, or bisoprolol) on the

primary end point, first occurrence of any shock delivered by the

ICD, was assessed for a median of 359 days (interquartile range,

236–367 days). One-year shock rates were 10.3%, 24.3%, and

38.5%, respectively, in amiodarone/β-blocker–treated patients,

in sotalol-treated patients, and in β-blocker–treated patients.

Patients receiving amiodarone combined with β-blocker had significantly lower risk of shock compared with patients receiving

β-blocker monotherapy (hazard ratio, 0.27; 95% CI, 0.14–0.52;

p <0.001) and sotalol monotherapy (hazard ratio, 0.43; 95%

CI, 0.22–0.85; p = 0.02). Of note, adverse effects such as pulmonary toxicity, thyroid effects, and symptomatic bradycardia

contributed to an 18.2% discontinuation rate for amiodarone at

1 year.

The SMASH-VT (Substrate Mapping and Ablation in Sinus

Rhythm to Halt Ventricular Tachycardia) study examined the

effect of radiofrequency catheter ablation of arrhythmogenic

ventricular tissue (ablation performed after ICD implantation in

87% of patients) on the incidence of ICD therapy (antitachycardia

pacing or shocks).149 This study investigated a population that

consisted of 128 patients who were mostly male (87%) and generally in NYHA functional class I or II (77%–84%). VF accounted

for 16% to 20% of index arrhythmias, and VT represented the

most common index arrhythmia (47%–52%). Approximately half

of the patients had an LEVF of equal to or less than 30%. Prophylactic catheter ablation resulted in a 65% reduction in ICD

therapy compared with ICD only during a mean follow-up time

of 22.5 ± 5.5 months (hazard ratio in ablation group, 0.35; 95%

CI, 0.15–0.78; p = 0.007).

A few years later, results from the VTACH (Ventricular Tachycardia Ablation in Coronary Heart Disease) study extended the

evidence that prophylactic catheter ablation may reduce the incidence of ICD therapy in patients with ICDs.150 One hundred

seven patients with stable VT, previous MI, and LVEF of 50% or

less were enrolled in this study. Sixty percent of the patients

had LVEF greater than 30%, and 2 in 3 patients had singlechamber ICDs. In this study, patients underwent ICD implantation a median of 3 days after ablation procedure or EP study.

The primary end point, time from defibrillator implantation to

recurrence of any SuVT or VF, occurred after a median of 5.9

months in the control group and 18.6 months in the ablation

group (p = 0.045, log-rank test). In addition, a difference in recurrence rates of VT or VF was observed only in patients with LVEF

exceeding 30%. The VTACH study investigators acknowledged

that because this study did not compare the relative efficacies

of ablation with antiarrhythmic drugs, the optimal approach for

reducing ICD therapy has yet to be established.

Clearly, S.L. should have the device placed: It is her best chance

for prolonging long-term survival. Depending on the number

of times the machine discharges per month and the patient’s

response, adjunctive antiarrhythmic drugs or prophylactic ablation may be needed.

Amiodarone

CASE 20-9, QUESTION 3: S.L.’s cardiologist would like to

start amiodarone as adjunctive therapy because S.L. has

expressed concern about the number of ICD discharges that

may occur after ICD placement. If S.L. is to be treated with

amiodarone, how should it be initiated and monitored?

Amiodarone exhibits properties of classes I, II, III, and IV

antiarrhythmic agents. Although it has class II effects on the heart,

amiodarone is virtually devoid of antiadrenergic effects outside

the heart and is not contraindicated in patients with asthma. The

antiadrenergic effects arise from inhibition of adenylate cyclase,

the enzyme that catalyzes production of the second-messenger

product cyclic adenosine monophosphate. Amiodarone can also

cause a reduction in β1-receptor density.151,152

Because of the extremely long half-life of amiodarone, loading

doses are used to accelerate the onset of drug effect. The OPTIC

trial used a loading dose of oral amiodarone 400 mg, given twice

daily for 2 weeks, followed by a daily dose of 400 mg for the next

4 weeks, and a daily maintenance dose of 200 mg thereafter.148

Although a concentration-effect relationship is hard to determine

for amiodarone, levels greater than 2.5 mg/L are associated with

an increased incidence of adverse effects.152

Amiodarone has many serious adverse effects involving a variety of organ systems, the most serious and life-threatening of

which is pulmonary toxicity. This historically occurred in 4%

to 6% of patients, and the mechanism may involve two distinct

pathways.153 Direct toxicity may arise from lung parenchymal cell

injury and a subsequent fibrotic response. The influx of inflammatory or immune effector cells to the lung could lead to indirect

pulmonary toxicity in amiodarone-treated patients. Pulmonary

toxicity consists of a variety of symptoms and conditions, such as

exertional dyspnea, weight loss, nonproductive cough, occasionally low-grade fever, pneumonitis that culminates in pulmonary

fibrosis, adult respiratory distress syndrome, respiratory failure,

and death. Physical examination usually reveals bibasilar rales,

with decreased breath sounds. Reticular infiltrates and patchy

acinar infiltrates are commonly observed in chest radiographs

of patients experiencing amiodarone-induced lung toxicity. Of

note, amiodarone-associated pulmonary toxicity has been well

documented in patients given chronic amiodarone doses of 375

to 685 mg/day, usually for a prolonged time.153 However, a lower

512 Section 2 Cardiac and Vascular Disorders

incidence of adverse pulmonary events was observed in patients

receiving amiodarone doses of 100 to 420 mg/day.154,155

Despite the lower incidence of adverse pulmonary events

observed in these studies, it is still necessary to monitor for the

development of pulmonary fibrosis. A baseline chest radiograph

and pulmonary function tests (diffusion capacity in particular)

are recommended by the manufacturer.156 The chest radiograph

should be repeated at 3- to 6-month intervals, and patients should

be specifically questioned about pulmonary symptoms because

early detection can decrease the extent of lung damage.156

Liver toxicity can range from an asymptomatic elevation of

transaminases (two to four times normal) to fulminant hepatitis. The mean latent period between the start of amiodarone

therapy and evidence of liver injury is 10 months, but with

rapid intravenous loading of amiodarone, a Reye’s-like fulminant hepatitis can occur within a few days, most likely caused by

the intravenous vehicle polysorbate-80. The precise mechanism

of amiodarone-induced hepatotoxicity has not been fully elucidated. However, higher doses and prolonged drug use appear

to place patients at higher risk of experiencing hepatotoxic

effects of amiodarone. Thus liver enzymes should be monitored at baseline, 1 month, 3 months, 6 months, and semiannually afterward.157 The most common gastrointestinal complaints

are nausea, anorexia, and constipation, which occur in 25% of

patients receiving amiodarone.156

Both hypothyroidism and hyperthyroidism have been

reported, although hypothyroidism is more common. The thyroid complications are a consequence of amiodarone’s large

iodine content and its ability to block the peripheral conversion of

thyroxine (T4) to triiodothyronine (T3). In addition, amiodarone

and its metabolite, desethylamiodarone, appear to be directly

cytotoxic to the thyroid gland.158

Other bothersome side effects are corneal deposits (usually asymptomatic), blue-gray skin discoloration in sun-exposed

areas, photosensitivity, exacerbation of heart failure, and central nervous system effects that include ataxia, tremor, dizziness, and peripheral neuropathy. Other than eye examination

and pulmonary function tests, which should be repeated when

the patient is symptomatic, other blood tests should be repeated

every 6 months for routine monitoring (after initial 6 months).156

Amiodarone also blocks multiple cytochrome P-450 enzyme systems and P-glycoprotein pumps, resulting in clinically significant

drug interactions.

Torsades de Pointes

PROARRHYTHMIC EFFECTS OF ANTIARRHYTHMIC

DRUGS AND CLINICAL PRESENTATION

CASE 20-10

QUESTION 1: L.G. is a 69-year-old woman who is taking

sotalol 80 mg twice daily for a previous episode of SuVT.

L.G. was admitted to the hospital 3 days ago for altered

mental status. She is also taking oral haloperidol 5 mg every

morning and 10 mg every evening, along with paliperidone

3 mg twice daily for schizophrenia. At baseline, her QTc

interval was 400 ms, and her CrCl was 50 mL/minute. Other

laboratory values are as follows:

Sodium, 139 mmol/L

Chloride, 108 mmol/L

Potassium, 4.0 mmol/L

CO2, 22 mmol/L

Blood urea nitrogen (BUN), 32 mg/dL

Serum creatinine, 1.5 mg/dL

Random glucose, 102 mg/dL

Calcium, 8.5 mg/dL

Albumin, 2.9 g/dL

Phosphorous, 3.3 mg/dL

Today, her ECG reveals a QTc interval of 502 ms and TdP,

with a ventricular rate of 110 beats/minute. What is QTc

interval prolongation? Why does QTc interval prolongation

indicate an increased risk of TdP? Could an antiarrhythmic

agent such as sotalol cause this arrhythmia? How does creatinine clearance factor into this?

The QT interval denotes ventricular depolarization (the QRS

complex in the cardiac cycle) and repolarization (from the end of

the QRS complex to the end of the T wave). Certain ion channels

in phases 2 and 3 of the action potential are vital in determining

the QT interval (Fig. 20-1). An abnormal increase in ventricular

repolarization increases the risk of TdP. TdP is defined as a rapid

polymorphic VT preceded by QTc interval prolongation. TdP

can degenerate into VF and as such can be life threatening (Fig.

20-15).159

Because there is tremendous variability in the QT interval

resulting from changes in heart rate, the QT is frequently corrected for heart rate (QTc interval). Several correction formulas

for the QT interval exist and give similar results at most heart

rates. The most common correction formula uses QT and R-R

intervals measured in seconds as follows: [QTc = QT/(R-R0.5)].

However, overcorrection of the QT interval may occur in persons with elevated heart rates (>85 beats/minute).160,161 The

Fridericia correction [QTc = QT/(R-R1/3)] represents an alternative correction method for patients with heart rates exceeding

85 beats/minute.

The ACC and AHA recently addressed the issue of the prevention of TdP in hospital settings. They stated that each 10-ms

increase in QTc confers an additional 5% to 7% TdP risk in

patients with congenital long-QT syndrome.161 The International Conference on Harmonization (ICH) stated that prolongation of QTc interval by more than 30 ms and in excess of

60 ms should be classified as a potential adverse effect and a

definite adverse effect, respectively.162

Class Ia and class III antiarrhythmic agents have been shown

to induce TdP in numerous literature reports.163 Of note, class

Ia antiarrhythmic agents do not exhibit dose-dependent association with TdP, whereas the incidence of TdP does appear to

be dose-related with class III antiarrhythmic agents. QT prolongation associated with the use of class Ia antiarrhythmic agents

is likely the result of blockade of outward potassium channels,

but it is offset by concomitant blockade of inward sodium channels at increased drug concentrations.163 TdP induced by class

III antiarrhythmic agents arises from prolonged repolarization

and cardiac refractoriness. With the exception of dronedarone,

all class III antiarrhythmic agents have been implicated in cases

of TdP. Amiodarone appears to have the lowest propensity for

inducing TdP; one literature review of 17 uncontrolled studies

(n = 2,878) showed an incidence of 0.7%.164 The reason for the

low propensity of amiodarone to cause TdP may be related to

the fact that it blocks both the rapid and slow component of

the delayed rectifier potassium channels. This provides less heterogeneity in ventricular repolarization and reduces the risk of

TdP compared with agents that prolong QTc interval solely by

blocking the rapid component of the delayed rectifier potassium

channel.

Class 1c antiarrhythmic agents do not exert significant effects

on repolarization, and therefore have rarely been shown to induce

TdP. To date, two cases of flecainide-induced TdP (with no associated triggering factor) have been published, along with one

report of propafenone-associated TdP.157,165,167

513Cardiac Arrhythmias Chapter 20

Sotalol is known to cause QTc interval prolongation in a

dose-dependent manner. Total daily doses of 160, 320, 480, and

>640 mg gave patients a steady-state QTc interval of 463, 467,

483, and 512 milliseconds, and the incidence of TdP was 0.5%,

1.6%, 4.4%, and 5.8%, respectively.167

It is likely that L.G.’s reduced renal function put her at high

risk for sotalol accumulation and accentuated QTc interval prolongation. In patients with a CrCl greater than 60 mL/minute,

the sotalol dose of 80 mg twice daily is appropriate, but in patients

like L.G. with a CrCl of less than 40 to 60 mL/minute, the starting

dose should be 80 mg daily owing to sotalol’s predominant renal

clearance.

CASE 20-10, QUESTION 2: What transient conditions or

other disorders can increase the risk of TdP in patients on

class Ia or III antiarrhythmic agents?

Hypokalemia, hypomagnesemia, hypocalcemia (rare cases of

TdP), concurrent use of more than one QT-prolonging drug,

advanced age, female sex, heart disease (heart failure or myocardial infarction), treatment with diuretics, impaired hepatic drug

metabolism, and bradycardia are important risk factors for TdP

in hospitalized patients.161 Hypokalemia may prolong QT interval by modifying the function of the inwardly rectifying potassium channel, resulting in heterogeneity and dispersion of repolarization. Prolonged ventricular cycle length can assume the

form of complete AV block, sinus bradycardia, or a rhythm in

which long cycles may progress to arrhythmogenic early afterdepolarizations.

Congenital long QT syndrome (LQTS) occurs in 1 in 2,500

individuals, and is a channelopathy associated with mutations identified in genes encoding voltage-gated sodium and

potassium channels.161 Since 1995, approximately 1,000 individual LQTS-causing mutations have been detected in 12 distinct LQTS-susceptibility genes. The LQTS-susceptibility genes

KCNQ1 (encoded IKs α-subunit), KCNH2 (encoded IKr α-subunit),

and SCN5A (encoded Nav1.5 α-subunit) account for nearly 75%

of all congenital LQTS cases.

Because L.G. did not have a family history of hereditary long

QT syndrome but was being treated with sotalol (an agent known

to be associated with TdP) in renal dysfunction, it can be assumed

that sotalol therapy was responsible for her arrhythmia.

PROARRHYTHMIC EFFECTS OF

NONANTIARRHYTHMIC AGENTS

CASE 20-10, QUESTION 3: Which nonantiarrhythmic agents

cause TdP? What is the mechanism of TdP initiation in this

situation?

Nonantiarrhythmic agents can also exhibit potassiumchannel inhibitory properties and can prolong the QTc interval.

Most of these drugs, including erythromycin, clarithromycin,

fluoroquinolones, azole antifungals, methadone, tricyclic antidepressants, and antipsychotics, cause QTc interval prolongation

by inhibiting the inwardly rectifying potassium ion channel, just

like quinidine and sotalol.161,162,169–173 Moreover, toxic concentrations of nonantiarrhythmic drugs can induce TdP as a result

of large doses, impaired kidney or liver function, or other drug

therapy that interferes with metabolism of nonantiarrhythmic

drugs.

Guidelines suggest that the risk of QTc prolongation is greater

with certain antipsychotic agents, such as thioridazine, ziprasidone, and risperidone. To date, the risk for QTc prolongation

with perphenazine, clozapine, olanzapine, quetiapine, aripiprazole, and haloperidol (except when given parenterally or in high

doses in the critically ill) appears to be minimal relative to that

with other antipsychotic agents.174 In recent years, considerable

controversy has been generated by the FDA recommendation of

continuous ECG monitoring of patients receiving intravenous

(off-label use in the United States) haloperidol. A review of 70

intravenous haloperidol-associated QT prolongation/TdP cases

that were identified by searching PubMed, EMBASE, and Scopus

databases, along with the FDA database, revealed 54 reports of

TdP. Cumulative doses of 5 mg to 645 mg were administered

to patients experiencing TdP, whereas cumulative doses ranging

from 2 mg to 1,540 mg were administered to patients (n = 16)

who experienced QTc prolongation (20–286 ms increase from

baseline) without TdP. Forty-two patients experienced QTc prolongation followed by TdP and received cumulative doses of 2 mg

to 1,700 mg. Ninety-seven percent of the 70 patients were determined to have additional risk factors for QTc prolongation or

TdP, including electrolyte imbalance, underlying cardiac disease,

concomitant proarrhythmic agents, and baseline QTc greater

than 450 ms. The authors of the review concluded that patients

with additional risk factors for developing QTc prolongation or

TdP who receive cumulative doses of intravenous haloperidol in

excess of 2 mg should have continuous ECG monitoring.171 Cases

of TdP associated with oral haloperidol have been reported to

a lesser degree in the PubMed database, relative to intravenous

haloperidol.172

During the past decade, multiple case reports of methadoneinduced TdP have been published. Pearson et al. conducted a

retrospective analysis of adverse events attributed to methadone

that were reported to the FDA during a period of 33 years.175

Forty-three patients (0.78%) experienced TdP, and 16 patients

(0.29%) experienced QT prolongation. The mean daily dose of

methadone was 410 mg (range, 29 mg to 1,680 mg), and 75% of

the patients had other risk factors for cardiac arrhythmia, such as

electrolyte imbalance, interacting medications, structural heart

disease, and female sex. The recent emergence of methadoneassociated TdP could be attributable to escalating doses used

in recent years, given the preponderance of published cases of

patients receiving very high doses of this agent.173

Currently, the utility of published cardiac risk data on antiinfective agents is limited, owing to underreporting, failure

to completely eliminate contributory confounding variables

(cardiac disease, electrolyte abnormalities, use of other QTprolonging drugs), and the retrospective nature of some postmarketing studies.162 However, the propensity of antimicrobial

agents to induce QT prolongation appears to be especially

marked with certain macrolide antibiotics (erythromycin, clarithromycin). All of the commercially available antifungal agents

(ketoconazole, itraconazole, fluconazole, voriconazole, posaconazole) have been shown to induce TdP and QT

prolongation.176 Among the quinolones, ciprofloxacin appears

to display the lowest potential for causing TdP.169,170

A list of nonantiarrhythmic agents implicated in causing QTc

interval prolongation and known pharmacokinetic drug interaction increasing the blood concentrations of these drugs is given

in Table 20-6.

Because L.G. was taking haloperidol in combination with

sotalol, it is likely that QTc-prolonging effects resulting from

concomitant use contributed to the development of TdP.

TREATMENT

CASE 20-10, QUESTION 4: How should TdP be treated?

What treatments should be considered for L.G.?

If the patient is significantly hemodynamically compromised

(frequently associated with a ventricular rate >150 beats/minute

514 Section 2 Cardiac and Vascular Disorders

TABLE 20-6

Nonantiarrhythmic Agents Implicated in QTc Interval Prolongation or Torsades de Pointesa

Drug Class Agent

Drugs That Increase Blood Concentrations

of These QTc Interval–Prolonging Drugs

Antianginal Ranolazine CYP3A4 inhibitors

Antibiotics: macrolides Erythromycin (lactobionate and base) CYP3A4 inhibitors

Antibiotics: fluoroquinolones Gatifloxacin, grepafloxacin, lomefloxacin, moxifloxacin,

sparfloxacin

Antibiotics: other Trimethoprim-sulfamethoxazole, pentamidine isethionate

Antidepressants Tricyclics, maprotiline CYP1A2, 2D6, or 2C9 inhibitors

Antiemetics Dolasetron

Antimalarials Mefloquine, quinine Sodium bicarbonate, acetazolamide, cimetidine

Antipsychotics Atypicals, butyrophenones, typicals CYP1A2, 2D6, 2C9, 3A4 inhibitors

Calcium-channel blockers Bepridil

Dopaminergics Amantadine Hydrochlorothiazide, quinidine, quinine,

trimethoprim-sulfamethoxazole

Narcotics Methadone CYP3A4 and 1A2 inhibitors

Sympathomimetics Albuterol, ephedra, epinephrine, metaproterenol,

terbutaline, salmeterol

Monoamine oxidase inhibitors

Other Arsenic, organophosphates

aAn up-to-date list can be found at http://www.azcert.org

and unconsciousness) while in TdP, electrical cardioversion is

the therapy of choice and should be given immediately. Stepwise

increasing shocks of 100 to 200, 300, and 360 J (monophasic

energy) can be tried if earlier shocks are unsuccessful.

MAGNESIUM

In a hemodynamically stable patient, magnesium is frequently

considered the drug of choice to restore normal sinus rhythm.

It benefits patients whether they have hypomagnesemia or normal serum magnesium levels. However, magnesium is not effective for patients with polymorphic VT without TdP and with

normal QT intervals. Before administering magnesium, potassium levels should be supplemented to the high normal range

of 4.5 to 5.0 mmol/L.177,178 A common magnesium regimen is

2 g given for 60 seconds through the intravenous route, with a

repeat dose administered 5 to 15 minutes later for refractory TdP.

Some experts have recommended repeat doses every 6 hours if

the QTc interval remains greater than 500 ms. Adult patients

experiencing persistently refractory dysrhythmias have received

continuous infusions of magnesium, with rates usually ranging

from 3 to 10 mg/minute. The exact mechanism of action for magnesium in TdP is not known, but it reduces the occurrence of

triggered activity such as early after-depolarizations. In addition,

magnesium blocks L-type calcium channels in the membrane,

and may stabilize the membrane gradient through activation of

the sodium-potassium ATPase.178

OTHER TREATMENT OPTIONS FOR TDP

The second class of drugs used to abolish TdP is the class Ib

antiarrhythmic agents (e.g., mexiletine, lidocaine). Unlike quinidine and the class III antiarrhythmic agents, the class Ib agents

do not inhibit potassium outflow during phases 2 and 3.178,179 In

addition, blockade of inward sodium channels causes a shortening of the QT interval in some patients. Preliminary data suggest

that class Ib antiarrhythmic agents have considerable benefit in

patients with sodium channel–activated QT prolongation, but

virtually no effect on patients with potassium channel blockade–

induced QT prolongation.180,181 In a landmark trial, mexiletine

was given to patients who had hereditary long QT syndrome,180

and the patients were analyzed by their genetic etiology of long

QT. The group with a deficient gene for the potassium channel

had no QT shortening, whereas those with a defective sodium

gene had significant shortening of the QT interval. These divergent responses were confirmed in an in vitro study using mexiletine with either clofilium, a potassium-channel blocker, or

almokalant, a pure sodium-channel activator.181

Cardioacceleration with isoproterenol (1–4 mcg/minute) or

cardiac pacing has also been shown to be beneficial.177,182,183

As previously described, sotalol, quinidine, and N-acetylprocainamide’s ability to prolong the action potential duration is

diminished at faster heart rates (reverse use dependence).184 The

more the inwardly rectifying potassium channels are activated,

the less susceptible the channels are to inhibition by potassiumchannel blocking drugs.

Transvenous pacing has been shown to be of some use in abolishing refractory TdP.177 Before adjusting the ventricular rate to

suppress ectopic ventricular beats, it is essential to ensure proper

catheter placement and cardiac capture. In general, ventricular

rates of 90 to 110 beats/minute can usually eliminate ventricular ectopy, but some patients may require rates as high as 140

beats/minute. Once control of TdP has been attained, the pacing

rate can be gradually decreased to the lowest paced rate that

suppresses further ectopy and dysrhythmia.

Because L.G. is hemodynamically stable, a bolus injection of

2 g of magnesium should be administered for 1 minute. In addition, she should receive potassium supplementation (infusion) to

achieve a potassium level of 4.5 to 5.0 mmol/L. If it is not successful within 5 to 15 minutes after the first bolus dose, a repeat dose

of magnesium 2 g should be administered to L.G. A continuous

infusion of magnesium at a rate of 3 to 10 mg/minute should be

given to L.G. if TdP persists after two bolus doses of magnesium.

If the arrhythmia recurs, cardiac pacing should be used.

Naturopathic Therapy for Arrhythmias

CASE 20-10, QUESTION 5: L.G. is interested in natural products to replace her antiarrhythmic therapy, which she says is

too expensive. Are there any herbal or natural agents that

can prevent or treat arrhythmias?

515Cardiac Arrhythmias Chapter 20

HERBAL THERAPIES

Many herbal remedies have been touted as beneficial in “normalizing heart rhythm,” but efficacy data from human studies

are lacking for most agents.185 Avoid using herbal products that

contain cardiac glycosides such as lily of the valley, oleander, Strophanthus hispidus seeds, squill, dogbane, Adonis vernalis, ouabain,

and Thevetia peruviana. Although the effects can mimic those of

digoxin, there is no way to monitor blood concentrations, so they

cannot be used safely.

FOOD SUPPLEMENTS AND MINERALS

Omega-3 polyunsaturated fatty acids (n-3 PUFAs), coenzyme

Q10, and l-carnitine are the best-studied alternative therapies for

arrhythmias.186–192

The largest prospective randomized controlled trial to test

the efficacy of n-3 PUFAs for secondary prevention of coronary

heart disease was the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI) prevention study.187 In

this trial, 11,324 patients with coronary heart disease were randomized to 300 mg of vitamin E, 850 mg of n-3 PUFAs (given

as eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]

ethyl esters), both, or neither. After 3.5 years, the group given

n-3 PUFAs had a 20% reduction in overall mortality and a 45%

reduction in sudden death. Vitamin E was ineffective. Limitations to this study were that it was not placebo-controlled, and

the dropout rate was 25%. Of note, the antiarrhythmic efficacy

trials of PUFAs in patients with automatic ICDs have yielded

inconsistent results, with one study suggesting a proarrhythmic

effect associated with n-3 PUFAs. A meta-analysis of three trials

of n-3 PUFA use in patients with automatic ICDs demonstrated

an absence of overall antiarrhythmic effect.188 To date, with the

exception of one epidemiological study suggesting benefit from

n-3 PUFA consumption in AF prevention, subsequent trials have

not been confirmatory. A recent canine model study conducted

by Sakabe et al. showed that consumption of oral n-3 PUFA

supplements resulted in suppression of congestive heart failure–

induced (triggered by ventricular tachypacing) atrial structural

remodeling.189

Kowey et al. assessed the safety and efficacy of prescription omega-3 fatty acids (Lovaza) in a prospective, randomized, double-blind, placebo-controlled, parallel group study that

included 542 patients with confirmed symptomatic PAF and 121

patients with persistent AF.193 The primary outcome was symptomatic, first recurrence of AF in PAF patients. During the first

week of the study, subjects received either placebo or a daily

dose of 8 g of prescription omega-3 fatty acid. During weeks 2

through 24, patients received a maintenance dose of 4 g/day of

prescription omega-3 fatty acid. After 24 weeks of treatment, the

primary outcome occurred in 52% of prescription drug–treated

patients and in 48% of placebo-treated patients (hazard ratio, 1.15;

95% CI, 0.90–1.46; p = 0.26). The investigators concluded that

treatment of PAF patients (with no structural heart disease) with

prescription omega-3 fatty acids did not lower the recurrence of

symptomatic AF.

How is it possible to reconcile the potential proarrhythmic

effect of n-3 PUFAs in patients with automatic ICDs with earlier

studies suggesting protection from life-threatening ventricular

arrhythmias? Differing mechanisms of arrhythmia generation

may account for the conflicting findings reported within these

study populations. n-3 PUFAs have been shown to exert a variety of cellular electrophysiological effects, such as slowing of

impulse conduction and shortening of action potential duration.

Patients who have experienced a recent MI are at heightened risk

for arrhythmias caused by triggered activity. Consequently, the

electrophysiological effects of n-3 PUFAs would have a beneficial

reduction in arrhythmias in this population. However, patients

with ischemic disease who have not experienced an MI may have

arrhythmias initiated by re-entry. This population may therefore

be at increased risk for arrhythmias associated with n-3 PUFAs.186

Coenzyme Q10, a vitaminlike entity that is present in cardiac

cells, serves as an electron carrier in oxidative phosphorylation.

This supplement has been shown to enhance cell membrane stabilization in vitro, and by acting as a free radical scavenger, it

exerts bioenergetic and antioxidant effects. Furthermore, coenzyme Q10 has demonstrated its ability to inhibit platelet aggregation and human vitronectin receptor expression.190 Singh et al.

performed a randomized, double-blind, placebo-controlled study

that included 154 patients who experienced acute MI. Patients

were randomly assigned to receive coenzyme Q10 (120 mg/day,

divided in two doses) or placebo for 28 days. At 28 days’ followup, 25.3% of placebo-treated patients experienced arrhythmias,

compared with 9.5% of coenzyme Q10–treated patients (relative

risk, 0.37; 95% CI, 0.22–0.66; p <0.05).190

Carnitine functions as a vital cofactor for the transport of fatty

acyl groups from the cytoplasm to the mitochondrial matrix,

where β-oxidation of the fatty acyl groups results in ATP production. Ventricular arrhythmias have been attributed to tissue

fatty acid accumulation during myocardial ischemia; l-carnitine

may be able to counteract the deleterious effect of high levels of

free fatty acids.191 Rizzon et al. conducted a double-blind, parallel group, placebo-controlled trial that included 56 patients who

experienced acute MI. Patients underwent random allocation to

receive placebo or carnitine dosed at 100 mg/kg every 12 hours for

36 hours. Carnitine treatment lowered the number of premature

ventricular beats evaluated by Holter recording for 2 days.192

CARDIOPULMONARY ARREST

Cardiopulmonary Resuscitation

Cardiac arrest from VF, pulseless VT, pulseless electrical activity (PEA), and asystole are life-threatening emergencies. Table

20-7137,194–200 reviews commonly used drugs for these indications, and Figure 20-16 highlights key features of the management

of pulseless arrest in the 2010 AHA Guidelines. This section will

review important aspects of therapy and will give clinical pearls,

but the reader should also review the national consensus source

document for these disorders, which includes more detail than

can be given here.194

Treatment

CASE 20-11

QUESTION 1: M.N., a 52-year-old man, is visiting his wife,

who is hospitalized for pneumonia. He goes into the bathroom and 2 minutes later his wife hears a dull thud. She

calls out for her husband, but he does not respond. After

an additional 2 minutes, health care workers open the bathroom door and find M.N. unresponsive and pulseless. CPR

is initiated and a code blue is called. The ECG shows VF (Fig.

20-13), and there is no BP. In addition to CPR, what initial

therapy is available?

Determining the underlying rhythm disturbance is important

because it directs health care workers to follow the Advanced

Cardiac Life Support (ACLS) algorithm for pulseless VT or VF

(Fig. 20-16). This algorithm calls for electrical defibrillation first,

516 Section 2 Cardiac and Vascular Disorders

TABLE 20-7

Commonly Used Drugs in Cardiac Arrest

Drug Formulation Dosage/Administration Rationale/Indications Comments

Amiodarone 50 mg/mL

Vials: 3, 9, 18 mL

300 mg diluted in 20–30 mL

D5W or NS; additional 150

mg (diluted solution) can

be given for recurrent or

refractory VT or VF.

Exhibits antiadrenergic properties

and blocks sodium, potassium,

and calcium channels. First-line

antiarrhythmic for pulseless VT

and VF.

Excipients (polysorbate 80 and

benzyl alcohol) can induce

hypotension. Failing to dilute can

induce phlebitis.

Epinephrine 0.1 mg/mL (1:10,000)

or 1 mg/mL

(1:1,000)

10 mL of a 1:10,000 solution

of epinephrine (1 mg; dilute

1:1,000 solution in 0.9%

sodium chloride) every

3–5 minutes.

Increases coronary sinus perfusion

pressure through α1

stimulation.

Indicated in pulseless VT, VF,

asystole, and PEA.

If administered through peripheral

catheter, need to flush the line to

get drug into the central

compartment.

Vasopressin 20 units/mL

Vials: 0.5, 1 mL,

10 mL

40-unit dose can be used to

replace first or second dose

of epinephrine

Increases coronary sinus perfusion

pressure through vasopressin

receptor stimulation.

Indicated in pulseless VT, VF,

asystole, and PEA.

Vasopressin is an acceptable

alternative to epinephrine, may

work better if time from cardiac

arrest to ACLS is delayed.

ACLS, Advanced Cardiac Life Support; D5W, 5% dextrose in water; NS, normal saline; PEA, pulseless electrical activity; VF, ventricular fibrillation; VT, ventricular

tachycardia.

but other clinicians should work to establish IV access in case

defibrillation fails.194

EXTERNAL DEFIBRILLATION

Although commercially available manual defibrillators provide

monophasic or biphasic waveform shocks, the biphasic defibrillator has become the preferred device owing to its high first-shock

efficacy (>90% termination of VF at 5 seconds after shock).194

Biphasic defibrillators deliver one of two waveforms, a truncated

exponential waveform or a rectilinear waveform. Most commercially available biphasic defibrillators display the device-specific

energy dose range that should be used. Respective initial selected

energies of 150 J to 200 J and 120 J are reasonable choices for initial

shocks delivered by truncated exponential waveform and rectilinear waveform defibrillators, respectively. However, if a health care

provider operating a manual biphasic defibrillator is uncertain of

the effective energy dose to terminate VF, using the maximal

shock energy setting available is preferred. For second and subsequent shocks delivered by manual biphasic defibrillators, the

same or higher energies should be used. For first and subsequent

shocks, a shock of 360 J should be delivered if a monophasic

defibrillator is used to terminate VF.

CASE 20-11, QUESTION 2: The initial shock fails to cause

a return of spontaneous circulation in M.N. An IV catheter

is established in a peripheral arm vein. The algorithm now

calls for epinephrine or vasopressin, but which one should

be used?

EPINEPHRINE AND VASOPRESSIN

Although epinephrine stimulates β1-, β2-, and α1-adrenergic

receptors, it is the α1-adrenoceptor effects that are most closely

associated with efficacy in VF or pulseless VT.137,194 Applying

α1-adrenoceptor stimulation increases systemic vascular resistance (via vasoconstriction), which elevates coronary perfusion

Cardiac arrest,

patient not DNR

1. Check rhythm

3. Continuous CPR/monitor CPR quality

Unsuccessful ROSC

2. Shock VF/VT,

but do not shock

asystole/PEA

Postcardiac

arrest care

Start

CPR

Successful ROSC

Drugs:

Epinephrine IV/IO 1 mg every 3–5 minutes

Vasopressin 40 units IV can substitute for

1st or 2nd epinephrine dose

Amiodarone 300 mg for 1st and 150 mg

for 2nd dose in refractory VF/VT

Treat reversible causes

FIGURE 20-16 Cardiac arrest

treatment algorithm. CPR,

cardiopulmonary resuscitation; DNR,

do not resuscitate; IO, intraosseous;

IV, intravenous; PEA, pulseless

electrical activity; ROSC, restoration

of spontaneous circulation; VF,

ventricular fibrillation; VT, ventricular

tachycardia.

517Cardiac Arrhythmias Chapter 20

pressure. This increase in coronary perfusion pressure is most

likely the key to enhancing the return of spontaneous circulation

after subsequent electrical defibrillation. Epinephrine may convert fine VF to a coarse variety that may be more amenable to

defibrillation.

The recommended dose of epinephrine is 1 mg (10 mL of

a 1:10,000 dilution; refer to Table 20-7) given by IV push. The

dosage can be repeated at 3- to 5-minute intervals during resuscitation. If the drug is given IV through a peripheral catheter,

which in this case includes a peripherally inserted central catheter

(PICC), then a 20-mL flush with normal saline is recommended

to ensure delivery into the central compartment. Only chest

compressions cause blood circulation in VF or pulseless VT, so

movement of drugs from the periphery to the heart (where the

benefit will occur) is severely impaired.

If intravenous access is unavailable, health care providers may

attempt to establish intraosseous (IO) access in the patient. For

IO injection of drugs, a cannula should be placed in a noncollapsible venous plexus; the onset and systemic drug concentrations

achieved with IO administration are similar to that achieved by

central venous access. Typical sites of intraosseous needle insertion include the anterior tibial bone marrow, the distal femur,

medial malleolus, or the anterior superior iliac spine.197

Vasopressin is an exogenously administered antidiuretic hormone. In supraphysiologic doses, vasopressin stimulates V1

receptors and causes peripheral vasoconstriction. Vasopressin

use during CPR causes intense vasoconstriction to the skin, skeletal muscle, intestine, and fat, with much less constriction of coronary vascular beds. Cerebral and renal vasodilation occurs as well.

The results of a prospective, randomized, controlled, multicenter study (n = 1,186) that enrolled out-of-hospital cardiac

arrest patients who presented with VF, PEA, or asystole showed

that administration of vasopressin as adjunctive therapy resulted

in similar survival to hospital admission rates compared with

adjunctive epinephrine therapy.195 In this study, patients were randomly assigned to receive two ampules of 40 international units

of vasopressin or two ampules of 1 mg of epinephrine. The second dose of vasopressor was injected if spontaneous restoration

of circulation did not occur within 3 minutes after the first injection of the drug. If the absence of spontaneous circulation persisted, the physician administering CPR had the option of injecting epinephrine. The primary outcome measure of the study

was overall survival to hospital admission. The reported survival

rates were similar between the two treatment groups for both

patients with PEA and those with VF. Of note, a post hoc analysis showed that survival to hospital admission rates were 29%

and 20%, respectively, for vasopressin- and epinephrine-treated

patients who presented with asystole requiring CPR (p = 0.02).

An in-hospital study of 200 cardiac arrest patients (initial

rhythm: 16%–20% VF, 3% VT, 41%–54% PEA, 27%–34% asystole) showed no difference in 1-hour or hospital discharge survival

for vasopressin 40 units versus epinephrine 1 mg.196 Similarly, a

meta-analysis of five randomized trials showed no survival advantage of vasopressin treatment versus epinephrine treatment at the

times of hospital discharge or 24 hours after treatment.197

On the basis of these trials, it would be reasonable to use a

single dose of vasopressin 40 units as an alternative to either the

first or second dose of epinephrine 1 mg in the treatment of VF

(or pulseless VT).

CASE 20-11, QUESTION 3: Because M.N. has an IV site and

the time from cardiac arrest to ACLS was brief, epinephrine

was chosen and a 1-mg bolus was given, followed with a

20-mL normal saline flush. The arm was elevated for 20 seconds to ensure adequate delivery. Thirty seconds after

administration a 200-J shock is given (via biphasic manual

defibrillator), but it fails to convert VF. What can be done

now?

The most recently updated ACLS guideline calls for the use of

amiodarone in cases of VF or pulseless VT that do not respond

to CPR, shocks, and a vasopressor.194

IV AMIODARONE AND LIDOCAINE

Amiodarone’s effect in VF or pulseless VT was studied in the

ARREST (Amiodarone for Resuscitation of Refractory Sustained

Ventricular Tachyarrhythmias) trial.198 This study was conducted

in patients who experienced cardiac arrest in an out-of-hospital

situation with therapy given by paramedics in the field. Patients

who failed three stacked shocks and one dose of epinephrine

with an electrical countershock were randomly assigned to amiodarone 300 mg IV bolus or placebo. This was followed by other

antiarrhythmic agents historically used in ACLS (2000 guidelines:

lidocaine, procainamide, or bretylium) if the clinicians desired.

Amiodarone significantly increased the chance of survival to hospital admission (44% vs. 34% of placebo group; p = 0.03), but

survival to hospital discharge was not changed. Of note, 66% of

patients received antiarrhythmic drug treatment for pulseless VT

or VF after amiodarone administration. In addition, recipients of

amiodarone were more likely to experience hypotension (59%

vs. 48% of placebo; p = 0.04) or bradycardia (41% vs. 25% of

placebo group; p = 0.004).

The occurrence of hypotension among amiodarone recipients

has been attributed to the presence of two excipients, polysorbate

80 and benzyl alcohol. Of interest, a study conducted by Somberg

et al.199 showed that a new formulation of amiodarone (AmioAqueous) had a similar risk of hypotension as lidocaine after VT

termination (1% in both groups).

The ALIVE (Amiodarone Versus Lidocaine in Ventricular

Ectopy, n = 347) trial directly compared IV amiodarone 300 mg

to lidocaine 1 to 1.5 mg/kg bolus.199 In this trial, patients needed

to fail three stacked shocks and epinephrine plus an additional

shock to be eligible for randomization to either amiodarone or

lidocaine. Amiodarone was given as an initial dose of 5 mg/kg followed by a shock. If unsuccessful, a dose of 2.5 mg/kg was given

followed by a subsequent shock. Lidocaine was given as a 1.5

mg/kg bolus followed by a shock. If therapy failed, then a second

bolus of 1.5 mg/kg was used with a subsequent shock. If the first

antiarrhythmic drug failed, other routine antiarrhythmic drugs

for cardiac arrest (per 2000 ACLS guidelines: e.g., procainamide,

bretylium) could be tried. Patients given amiodarone were 90%

more likely to experience the primary outcome, survival to hospital admission, than those given lidocaine (p = 0.009). Unfortunately, no significant advantage to hospital discharge occurred

(5% vs. 3%).

On the basis of these findings, amiodarone is the only antiarrhythmic agent with proven ability to improve return of spontaneous circulation and short-term survival versus other antiarrhythmic therapy. However, it has not yet been shown to improve

survival to hospital discharge.

CASE 20-11, QUESTION 4: Amiodarone 300 mg followed

by electrical defibrillation fails to cause a return of spontaneous circulation in M.N. A subsequent 150-mg dose also

fails. However, M.N. did convert to normal sinus rhythm for

9 seconds before going back into VF. Should resuscitation

be discontinued?

518 Section 2 Cardiac and Vascular Disorders

M.N. is at serious risk of death as a result of VF. However, as

long as M.N. remains in VF it is appropriate to continue active

therapy. If M.N. degenerates into asystole after this long period of

VF, then the resuscitation efforts should be discontinued. However, if a patient only had a brief period of VF before having

asystole, it is prudent to apply active therapy.

Pulseless Electrical Activity

CASE 20-12

QUESTION 1: J.D. is an 80-year-old woman who experiences cardiac arrest in the hospital. A rhythm is noted on

the monitor, but no femoral pulse is felt. M.N. is in pulseless electrical activity. How should she be treated?

The clinical situation in which there is organized electrical

activity on the monitor without a palpable pulse is called PEA.

Although electrical activity is present, it fails to stimulate the contractile process. Virtually all patients in true PEA die. However,

not all patients who present with a rhythm and no pulse are in

true PEA. Therefore, it is important to rule out treatable causes

in patients who appear to be in PEA. The major treatable causes

are hypovolemia, hypoxia, acidosis, hyperkalemia, hypokalemia,

hypothermia, cardiac tamponade, pulmonary embolism, acute

coronary syndrome, trauma, and drug overdose. In the absence

of an identifiable cause, the focus of resuscitation is to administer high-quality CPR, and after the initial rhythm check, resume

CPR during the establishment of IV or IO access.194

Once IV or IO access becomes available, administer

epinephrine 1 mg every 3 to 5 minutes or give one dose of

vasopressin 40 units in place of the first or second dose of

epinephrine, as published studies have failed to demonstrate a

survival advantage of either vasopressor for patients experiencing

PEA.194,196,197

Asystole

CASE 20-13

QUESTION 1: K.K. is a 73-year-old man who experiences

cardiac arrest. The ECG shows a flat line, and the patient

is determined to be in asystole (Fig. 20-17). Is this rhythm

treatable?

Lack of electrical activity or asystole, like PEA, carries a grave

prognosis. Its development usually indicates a prolonged arrest,

which may explain its poor response to treatment. However, a

few patients will go directly from a sinus rhythm into asystole and

may be resuscitated. Enhanced parasympathetic tone, possibly

attributable to a vagal reaction, manipulation of the airway from

intubation, suctioning or insertion of an oral airway, or chest

compression, may play a role in inhibiting supraventricular and

ventricular pacemakers.137,194

As described in K.K. a post hoc analysis performed by Wenzel

et al.194 demonstrated superior survival rates at the time of hospital admission in vasopressin-treated patients, compared with

epinephrine-treated patients. However, no difference in intact

FIGURE 20-17 Asystole.

neurologic survival was noted between the two vasopressor

treatment groups. Consequently providers may choose to administer vasopressin 40 units IV (in place of the first or second dose

of epinephrine) or epinephrine 1 mg IV every 3 to 5 minutes.

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT10e. Below are the key references

and website for this chapter, with the corresponding reference

number in this chapter found in parentheses after the reference.

Key References

Connolly SJ et al. Comparison of β-blockers, amiodarone plus

β-blockers, or sotalol for prevention of shocks from implantable

cardioverter defibrillators: the OPTIC study: a randomized trial.

JAMA. 2006;295:165. (148)

Drew BJ et al. Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation

[published correction appears in Circulation. 2010;122:e440]. Circulation. 2010;121:1047. (161)

Epstein AE et al. ACC/AHA/HRS 2008 Guidelines for DeviceBased Therapy of Cardiac Rhythm Abnormalities: a report of the

American College of Cardiology/American Heart Association

Task Force on Practice Guidelines (Writing Committee to Revise

the ACC/AHA/NASPE 2002 Guideline Update for Implantation

of Cardiac Pacemakers and Antiarrhythmia Devices): developed

in collaboration with the American Association for Thoracic

Surgery and Society of Thoracic Surgeons [published correction

appears in Circulation. 2009;120:e34]. Circulation. 2008;117:e350.

(147)

Fuster V et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American

College of Cardiology/American Heart Association Task Force

on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to

Revise the 2001 Guidelines for the Management of Patients With

Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society

[published correction appears in Circulation. 2007;116:e138]. Circulation. 2006;114:e257. (11)

Hazinski MF, ed. Highlights of the 2010 American Heart Association

Guidelines for CPR and ECC. Dallas, TX: American Heart Association; 2010. (194)

Hohnloser SH et al. Effect of dronedarone on cardiovascular

events in atrial fibrillation. N Engl J Med. 2009;360:668. (82)

Opolski G et al. Rate control vs. rhythm control in patients with

nonvavular persistent atrial fibrillation. The results of the Polish

How to Treat Chronic Atrial Fibrillation (HOT CAFE) Study. ´

Chest. 2004;126:476. (36)

Roy D et al. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med. 2008;358:2667. (38)

Singer DE et al. Antithrombotic therapy in atrial fibrillation:

American College of Chest Physicians Evidence-Based Clinical

Practice Guidelines (8th Edition). Chest. 2008;133(6 Suppl):546S.

(42)

Wann LS et al. 2011 ACCF/AHA/HRS focused update on the

management of patients with atrial fibrillation (updating the

519Cardiac Arrhythmias Chapter 20

2006 guideline): a report of the American College of Cardiology

Foundation/American Heart Association Task Force on Practice

Guidelines. Heart Rhythm. 2011;8:157. (32)

Zipes DP et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of

Cardiology/American Heart Association Task Force and the

European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death). Circulation. 2006;114:e385. (118)

Key Websites

Blaufuss Medical Multimedia Laboratories ECG Tutorial.

http://www.blaufuss.org.

21 Hypertensive Crises

Kristin Watson, Brian Watson, Kelly Summers, and Robert Michocki

CORE PRINCIPLES

CHAPTER CASES

1 Hypertensive crisis is defined as a diastolic blood pressure greater than 120 mm Hg.

This disorder can be further classified as hypertensive urgency or hypertensive

emergency when there is evidence of acutely progressive end-organ damage.

Case 21-1 (Question 1),

Table 21-1

2 Risk factors for the development of a hypertensive crisis include, but are not limited

to, medication nonadherence, cocaine use, and drug–drug and drug–food

interactions.

Case 21-1 (Question 1),

Case 21-7 (Question 1)

3 Hypertensive urgency can be treated with oral antihypertensive agents including

clonidine, labetalol, or captopril. Caution must be taken to prevent rapid reductions

in blood pressure. The use of short-acting calcium-channel blockers are not

recommended because of the risk of cardiovascular and cerebrovascular events seen

with the use of immediate-release nifedipine.

Case 21-1 (Question 2)

4 The organs primarily affected as a result of a hypertensive emergency are the central

nervous system, eyes, heart, and kidneys.

Case 21-2 (Question 1)

5 Parenteral therapy should be used to manage hypertensive emergencies, and

therapeutic options are dictated by the affected organ(s) and other patient

comorbidities. Mean arterial pressure should be reduced by no more than 25%

initially, then subsequently reduced toward a goal of 160/100 mm Hg, for most

patients, during the next 2 to 6 hours. Gradually reduce blood pressure to normal,

for most patients, during the next 8 to 24 hours.

Case 21-2 (Questions 2, 3,

5, 9–11), Case 21-3

(Questions 1, 2, 6),

Case 21-4 (Questions 1, 2),

Table 21-4

6 Nitroprusside, a therapeutic option for hypertensive emergencies, has been

associated with cyanide and thiocyanate toxicity, and monitoring is required to

minimize the risk of these toxicities, especially in patients with renal impairment.

Case 21-2 (Questions 6–8)

7 The most commonly used agents for the management of postoperative hypertension

are nicardipine, nitroglycerin, nitroprusside, and labetalol.

Case 21-5 (Questions 1–2)

8 Management of aortic dissection requires prompt control of blood pressure without

increasing the force of cardiac contraction or heart rate.

Case 21-6 (Question 1)

9 The preferred treatment options for cocaine-induced hypertensive crisis are

nicardipine, verapamil, or nitroglycerin in combination with a benzodiazepine. The

use of β-blockers may lead to α-adrenergic vasoconstriction.

Case 21-7 (Question 1)

The term hypertensive crisis is arbitrarily defined as a severe elevation in blood pressure (BP), generally considered to be a diastolic

blood pressure greater than 120 mm Hg.1 If these disorders are

not treated promptly, a high rate of morbidity and mortality will

ensue.2 However, even with effective therapy, the 5-year mortality for patients with a history of hypertensive crisis is 26%.3

These disorders are divided into two general categories: hypertensive emergencies and hypertensive urgencies (Table 21-1).4,5

The distinction between emergency and urgency usually

depends on the clinical assessment of the life-threatening nature

of each episode. The term hypertensive emergency describes a