140

Liver toxicity can range from an asymptomatic elevation of transaminases (2–4

times normal) to fulminant hepatitis. The mean latent period between the start of

amiodarone therapy and evidence of liver injury is 10 months (onset can be as short

as 3–4 days), but with rapid IV loading of amiodarone, a Reye’s-like fulminant

hepatitis can occur as early as 1 day after starting therapy, most likely caused by the

IV 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, 3, 6 months, and

semiannually afterward.

140,141 The most common GI complaints are nausea, anorexia,

and constipation, which occur in 25% of patients receiving amiodarone.

140

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.

142

Recent reports have indicated that photosensitive eruptions occur in 7% of

amiodarone recipients.

143 Classical presentations of amiodarone photosensitivity

involve a burning and tingling sensation in sun-exposed skin with accompanying

erythema. Approximately 1% to 2% of patients receiving amiodarone for long-term

use develop blue-gray pigmentation on sun-exposed skin. Resolution of amiodaroneassociated photo-induced pigmentation may take up to 2 years, with gradual fading of

skin discoloration.

143

In recent years, amiodarone-associated optic neuropathy has

been highlighted in multiple case reports. A review of amiodarone-associated optic

neuropathy (January 1993–May 2011) revealed a total of 214 cases from the FDA’s

Adverse Event Reporting System, 59 published cases, and 23 cases from clinical

trials.

144 On average, patients received amiodarone for 9 months (range 1–84 months)

before experiencing vision loss. In 20% of cases, patients progressed to legal

blindness in at least one eye. Other bothersome side effects are corneal deposits

(usually asymptomatic), 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 tests should be repeated every 6 months (thyroid and

liver function) or annually (chest x-rays) for routine monitoring.

140,144 Amiodarone

also blocks multiple cytochrome P-450 enzyme systems and P-glycoprotein pumps,

resulting in clinically significant drug interactions.

p. 326

p. 327

Torsades de Pointes

PROARRHYTHMIC EFFECTS OF ANTIARRHYTHMIC DRUGS AND

CLINICAL PRESENTATION

CASE 15-8

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 citalopram

40 mg every morning for major depressive disorder. 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 CrCl affect 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. 15-1). 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. 15-13).

145

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-R

0.5

]). However, overcorrection of the QT

interval may occur in persons with elevated heart rates (>85 beats/minute).

146,147 The

Fridericia correction (QTc = QT/[R-R

1/3

]) 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 (LQTS).

147 The

International Conference on Harmonization 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.

148

Class Ia and class III antiarrhythmic agents have been shown to induce TdP in

numerous literature reports.

149 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.

150 TdP induced by class III antiarrhythmic

agents arises from prolonged repolarization and cardiac refractoriness. All class III

antiarrhythmic agents have been implicated in cases of TdP. A recent review of the

US FDA Adverse Event Reporting System (AERS) database showed the following

number of TdP cases that occurred during a 2-year time period: dronedarone (37),

amiodarone (29), dofetilide (12), and sotalol (4).

150

Incidence rates could not be

calculated because true denominators were not available and all events were selfreported. However, given the considerably larger prescriptive volume of

amiodarone, this agent appears to have a relatively low propensity for inducing TdP.

Class Ic antiarrhythmic agents do not exert significant effects on repolarization,

and therefore have rarely been shown to induce TdP. To date, eight cases of

flecainide-induced TdP have been published, along with one report of propafenoneassociated TdP.

151–153

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 467, 473, 483, and 512 milliseconds, and the incidence of TdP was 0.5%,

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

154

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 less than 40 to 60 mL/minute, the manufacturerrecommended dose should be 80 mg daily or 40 mg twice daily owing to sotalol’s

predominant renal clearance.

Figure 15-13 Torsades de pointes.

p. 327

p. 328

CASE 15-8, 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.

147 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 EAD.

Congenital 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.

147 Since 1995, approximately 1,000 individual LQTS-causing

mutations have been detected in 12 distinct LQTS-susceptibility genes. The LQTSsusceptibility genes KCNQ1 (encoded IKs α-subunit), KCNH2 (encoded IKr αsubunit), 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 LQTS 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.

CASE 15-8, QUESTION 3: Which nonantiarrhythmic agents cause TdP? What is the mechanism of TdP

initiation in this situation?

PROARRHYTHMIC EFFECTS OF NONANTIARRHYTHMIC AGENTS

Nonantiarrhythmic agents can also exhibit potassium-channel inhibitory properties

and can prolong the QTc interval. Most of these drugs, including arsenic trioxide,

macrolide antibiotics, fluoroquinolones, azole antifungals, methadone,

antidepressants, organophosphorus compounds, and antipsychotics, cause QTc

interval prolongation by inhibiting the inwardly rectifying potassium ion channel, just

like quinidine and sotalol.

155 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.

On August 24, 2011, the US FDA sent out an alert to health care providers and

patients on new dosing recommendations for citalopram due to concerns of QTc

interval prolongation and TdP when using this agent at higher doses.

156 Key

recommendations included: (1) prescribing citalopram at a dose of ≤20 mg/day for

patients older than 60 years of age (also, in patients <60 years with hepatic

impairment or taking cimetidine); and (2) prescribing citalopram at a dose of ≤40

mg/day for younger patients. Hasnain and associates recently conducted a

comprehensive review of published literature on QTc

interval prolongation and/or

TdP risk associated with antidepressants and second-generation antipsychotics

(SGAPs).

157 The authors identified the highest number (16) of case reports

implicating citalopram, relative to other antidepressants, including fluoxetine (9),

escitalopram (6), venlafaxine (5), and sertraline (2). Case report material revealed

quetiapine as the SGAP with the largest number of QTc

interval prolongation and/or

TdP cases (16), followed by ziprasidone (13), risperidone (13), amisulpride,

olanzapine (6), and clozapine (5). The authors of the review noted that patients had at

least one additional risk factor for QTc

interval prolongation in 92% of the reports.

In addition, they acknowledged that the information yielded by case reports did not

allow for comparison between drugs and generalization to clinical practice.

During the past two decades, multiple case reports of methadone-induced TdP

have been published. Guidelines recommend QT interval monitoring, but some

experts have questioned the necessity of screening patients.

158 Kao et al.

158

reviewed

the FDA Adverse Event Reporting System (FAERS) database for QTc

interval

prolongation or TdP events linked with methadone compared to other agents,

including antiarrhythmic drugs and other opioids. Between 2000 and 2011, the three

most commonly implicated drugs included dofetilide (359 cases), methadone (211),

and sotalol (119). The authors acknowledged limitations of their analysis (voluntary

and selective reporting to FAERS, along with the inability to determine incidence

rates), but suggested that a REMS specific to methadone may be warranted, in order

to lower the risk of TdP. The recent emergence of methadone-associated 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.

159

Currently, the utility of published cardiac risk data on anti-infective 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.

148

However, the propensity of antimicrobial agents to induce QT prolongation appears

to be especially marked with macrolide antibiotics.

160 All of the commercially

available antifungal agents have been shown to induce TdP and QTc prolongation,

with a larger number of cases attributed to fluconazole, followed by voriconazole.

160

Among the marketed quinolones in the United States, ciprofloxacin appears to

display the lowest potential for causing TdP.

161

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 15-6.

Because L.G. was taking citalopram in combination with sotalol, it is likely that

QTc-prolonging effects resulting from concomitant use contributed to the

development of TdP.

TREATMENT

CASE 15-8, 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 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.

155 A common magnesium regimen is 2

g given for 60 seconds through the IV route, followed by an infusion of 2 to 4

mg/minute.

155 The exact mechanism of action for magnesium in TdP is not known, but

it reduces the occurrence of triggered activity such as EAD. In addition, magnesium

blocks L-type calcium channels in the membrane, and may stabilize the membrane

gradient through activation of the sodium-potassium ATPase.

161

p. 328

p. 329

Table 15-6

Nonantiarrhythmic Agents with Known Torsades de Pointes Risk

a

Drug Class Agent

Drugs That Increase Blood Concentrations of These

QTc Interval–Prolonging Drugs

Anesthetic, general Propofol, sevoflurane

Antibiotics:

macrolides

Azithromycin,

clarithromycin,

erythromycin (lactobionate

and base)

Antibiotics:

fluoroquinolones

Ciprofloxacin,

levofloxacin, moxifloxacin

Antibiotics: other Pentamidine isethionate

Anti-cancer Arsenic trioxide,

vandetanib

Antidepressants Citalopram, Escitalopram CYP3A4 or 2C19 inhibitors

Antiemetics Chlorpromazine,

droperidol, ondansetron

CYP3A4 (primary for ondansetron), 1A2 (primary for

chlorpromazine), or 2D6 inhibitors

Antifungals Fluconazole

Antimalarials Chloroquine, halofantrine Cimetidine (chloroquine), CYP3A4 inhibitors (halofantrine)

Antipsychotics Haloperidol, pimozide,

thioridazine

CYP2D6 (thioridazine) or 3A4 (pimozide) inhibitors

Cholinesterase

inhibitors

Donepezil CYP3A4 or 2D6 inhibitors

Narcotics Methadone CYP3A4, 2B6, and 2C19 inhibitors

Phosphodiesterase 3

inhibitor

Anagrelide, cilostazol CYP1A2 (anagrelide), 3A4 (primary for cilostazol), or 2C19

inhibitors

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

Other Treatment Options for TdP

Numerous other strategies have been utilized for patients who fail to respond

adequately to standard therapeutic approaches, including calcium-channel blockers,

αblockers, potassium-channel openers, lidocaine, and mexiletine.

162 However, the

evidence supporting these alternative agents is not compelling enough to classify

them as first-line options for abolishing TdP.

Cardio acceleration with isoproterenol (1–4 mcg/minute) or cardiac pacing has

also been shown to be beneficial.

163–165 As described previously, the ability of

sotalol, quinidine, and N-acetylprocainamide to prolong the APD is diminished at

faster heart rates (reverse use dependence).

166 The more the inwardly rectifying

potassium channels are activated, the less susceptible the channels are to inhibition

by potassium-channel blocking drugs.

Transvenous pacing has been shown to be of some use in abolishing refractory

TdP.

163 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 over 1 minute, followed by an infusion administered at a rate

of 2 to 4 mg/minute. In addition, she should receive potassium supplementation

(infusion) to achieve a potassium level of 4.5 to 5.0 mmol/L. If the arrhythmia recurs,

cardiac pacing should be used.

CARDIOPULMONARY ARREST

Cardiopulmonary Resuscitation

Cardiac arrest from VF, pulseless VT, pulseless electrical activity (PEA), and

asystole are life-threatening emergencies. Table 15-7

167–173

reviews commonly used

drugs for these indications, and Figure 15-14 highlights key features of the

management of pulseless arrest in the 2010 AHA Guidelines (2015 update to be

released in October 2015). 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.

167

Treatment

CASE 15-9

QUESTION 1: M.N., a 52-year-old man, is visiting his wife, who is hospitalized for pneumonia. His past

medical history is significant for hypertension and type 2 diabetes mellitus. 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. 15-12), 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. 15-14). This algorithm calls for electrical defibrillation

first, but other clinicians should work to establish IV access in case defibrillation

fails.

167

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.

167 Most commercially available

biphasic defibrillators display the device-specific energy dose range that should be

used. 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.

p. 329

p. 330

Table 15-7

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. Firstline 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, 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.

Vasopressin is an

acceptable

alternative to

epinephrine, may

work better if time

Indicated in pulseless

VT, VF, asystole, and

PEA.

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.

CASE 15-9, 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.

167 Applying α1

-adrenoceptor stimulation increases systemic vascular resistance

(via vasoconstriction), which elevates coronary perfusion 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 15-7) 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, 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.

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.

Figure 15-14 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.

p. 330

p. 331

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 (primary outcome measure) compared

with adjunctive epinephrine therapy.

168

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 reported survival rates were

similar between the two treatment groups for both patients with PEA and those with

VF.

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.

169

Similarly, a meta-analysis of five randomized trials showed no survival advantage of

vasopressin treatment versus epinephrine treatment at the time of hospital discharge

or 24 hours after treatment.

170

Since the publication of the 2010 ACLS guideline, some study investigators have

focused on assessing long-term outcomes in out-of-hospital cardiac arrest

patients.

174,175 Hagihara and associates

174 showed that out-of-hospital cardiac arrest

patients who received epinephrine prior to hospital arrival had lower rates of 1-

month survival and 1-month survival with favorable neurologic function, compared

to patients who did not receive epinephrine (p < 0.001). Similarly, Goto et al.