CHAPTER 25
Supraventricular
Arrhythmias
James E. Tisdale
D
rugs may induce a variety of supraventricular
arrhythmias that may be associated with symptoms, hemodynamic instability, stroke, and, in some
cases, an increased risk of death. Supraventricular
arrhythmias that may be induced by drugs include
sinus bradycardia, atrioventricular (AV) nodal blockade, atrial fibrillation or flutter, atrial tachycardia,
and AV nodal reciprocating tachycardia.
SINUS BRADYCARDIA/
ATRIOVENTRICULAR (AV)
NODAL BLOCKADE
Sinus bradycardia is defined as a sinus rate <60
bpm.1 Drugs that inhibit sinus node function
resulting in sinus pauses or sinus arrest will also be
included in this section. Sinus pauses occur when
function of the sinus node is impaired transiently,
leading to “pauses” without p waves on the electrocardiogram (Figure 25–1).1,2 Sinus pauses are also
known as periods of sinus arrest.
AV nodal blockade occurs when conduction of
impulses from the atria to the ventricles through the
AV node is inhibited.3 AV nodal blockade is classified
as first, second, or third degree. First degree AV nodal
blockade is defined as prolongation of the PR interval to >0.2 seconds on an electrocardiogram (ECG).
Second degree AV block is a progression of AV nodal
dysfunction to the point at which some impulses are
not conducted from the atria to the ventricles. Third
degree AV nodal blockade, often referred to as “complete heart block” or “AV dissociation,” is defined by
the absence of a relationship between atrial and ventricular depolarization. During third degree AV nodal
blockade, atrial depolarization occurs independently
of ventricular depolarization, as a result of the complete inability of the AV node to conduct impulses.3
CAUSATIVE AGENTS
Sinus bradycardia with or without sinus pauses
may be associated with a wide variety of drugs
(Table 25–1).4-330 In addition to occurring as a result
22 minutes
23 minutes
FIGURE 25–1. Sinus pauses/sinus
28 minutes
arrest at several time points following ibutilide 1.0 mg/kg in a patient
subsequently determined to have
underlying sinus node dysfunction.
30 minutes
Reproduced with permission from Amin
et al.136
445
446
SECTION VI • Drug-Induced Cardiovascular Diseases
TABLE 25–1
Agents Implicated in Drug-Induced Sinus Bradycardia
Drug
Incidence
Level of Evidence
Adenosine4-6
Adrenergic b-receptor blockers7,8
Amiodarone9-11
Baclofen12-14,b
Bupivicaine15,16
Carbamazepine17,18
Cimetidine19-25
Cisplatin26-28
Citalopram29-31
Clonidine32-58
Clozapine59,60
Cocaine61
1–8%
0.6–3.8%
0–3%a
NK
NK
NK
NK
NK
0.1–1.0%
0–17.5%
NK
A
A
NK
4.4–55%
NK
0 –7%
5–16%
0.5–6.7%
0 –4%
0.6%
0.7–2.3%
NK
NK
2.0–13.2%
NK
NKd
B
A
C
B
A
B
B
B
A
C
C
B
B
B
11–24%
0 –4.5%
NK
0–5.5%e
NK
NK
NK
0–13%
OR 2.7 (95% CI, 1.4–5.4)
A
B
C
B
C
C
B
A
B
0–10%
0–0.7%
0.7%
3–29%
5%f
B
B
B
(see page xii for explanation)
Dexmedetomidine62-79
Diazepam21,b
Digoxin80-83
Diltiazem84-96
Dipyridamole97-103,c
Disopyramide104-107
Donepezil108-111
Dronedarone112,113
Escitalopram114
Etidocaine15
Flecainide115-121
Fluoxetine122-128
g-Hydroxybutyric acid129-131
Halothane132-135
Ibutilide136-139
Isradipine140,b
Ketamine141-145
Lidocaine146-151
Methadone152-154
Methylprednisolone155-161
Milrinone162
Neostigmine163-174
Nicardipine175,176
Nitroglycerin177-185
Olanzapine186-189
Paclitaxel190-198
199
Pentazocine
A
C
C
C
C
B
C
A
C
A
B
(Continued)
CHAPTER 25 • Supraventricular Arrhythmias
TABLE 25–1
Agents Implicated in Drug-Induced Sinus Bradycardia
Drug
Propafenone200-203
Propofol204-216
Physostigmine166,217,218
Pyridostigmine166
Ranitidine219-227
Remifentanil228-240
Risperidone241,242
Sevoflurane133,243-252
Sotalol253-274
Succinylcholine275-287
Tacrolimus288,289
Thalidomide290-301
Verapamil132,302-330
447
(Continued)
Incidence
0.7%g
10%h
0–50% (14.7% in analysis
of combined studies)
NK
NK
NK
0–39%
NK
0–53%
2.5–17.2%
0–50%
NK
3.2–53%
0–11%
Level of Evidence
B
B
B
B
C
C
A
C
A
A
A
C
A
A
CI = confidence interval; NK = not known; OR = odds ratio.
a
May be as high as 10% in patients receiving high doses (3 g over 24 hr) of intravenous amiodarone.
b
In overdose.
c
Reported with intravenous use
d
Incidence in g-hydroxybutyric acid intoxication: 38%.130
e
Incidence as high as 21.1% in infants.143
f
Intramuscular administration in children.
g
Oral propafenone.
h
Intravenous propafenone.
of drugs administered orally or intravenously, sinus
bradycardia and sinus pauses may be induced by
drugs administered as eye drops. Numerous cases
of sinus bradycardia associated with topical adrenergic b-receptor antagonists (b-blockers) have been
reported.331,332 The incidence of sinus bradycardia
associated with topical timolol is significantly
higher (18.4%) than that associated with topical
carteolol (4.5%).331 The lower incidence of sinus
bradycardia associated with carteolol may be a
result of the intrinsic sympathomimetic activity of
the drug.
Drugs that have been reported to cause AV
nodal blockade are listed in Table 25–2.4,5,17,83,86,
90,105,107,111,115,190-192,333-447
EPIDEMIOLOGY
The overall incidence of drug-induced sinus bradycardia or AV nodal blockade is unknown. The inci-
dence of sinus bradycardia and sinus pauses associated with specific agents, where known, is presented in Table 25–1, and the incidence of
drug-induced AV nodal blockade associated with
specific drugs, where known, is presented in Table
25–2.
Amiodarone has been reported to cause sinusnode and AV nodal bradyarrhythmias requiring
pacemaker insertion.11 In a study of 15,824
patients with atrial fibrillation and a history of
myocardial infarction who were receiving amiodarone, the incidence of pacemaker implantation
was 2.2% per person-year (mean duration [±SD] of
follow-up, 1.8±1.5 years), and was 5.2% per person-year during the first 90 days of therapy.11 The
odds ratio for pacemaker insertion to treat bradyarrhythmias associated with amiodarone use was
2.14 (95% confidence interval [CI] 1.30 to 3.54).448
Although the incidence of sinus bradycardia associated with conventional doses of intravenous
amiodarone (1 to 2 g/24 hr) is similar to that asso-
448
SECTION VI • Drug-Induced Cardiovascular Diseases
TABLE 25–2
Agents Implicated in Drug-Induced Atrioventricular Nodal Blockade
Drug
Incidence
Level of Evidence
(see page xii for explanation)
Aconite333,334
Adenosine4,5,335-351
Adrenergic b-receptor blockers352-361
Amiodarone357,362-366
Amitriptyline367,368
Bupivacaine369,370
Carbamazepine17,371-376
Chloroquine377-379
Cimetidine380
Citalopram381
Clonidine382-385
Cocaine386
Digoxin83,387-402
Diltiazem86,90,359,403-405
Dipyridamole406-408
Disopyramide105,107,409-411
Donepezil111,412
Etomidate413
Flecainide115,414
Guanabenz415
Hydroxychloroquine416
Imipramine417,418
Nicardipine419
Paclitaxel190-192,420
Pentamidine421
Phenylpropanolamine422,423
Propafenone424-426
Propofol427-429
Pyridostigmine430
Sotalol431
Thioridazine432,433
Verapamil359,385,405,434-447
C
A
NK
3–11%
NK
0–14.8%
NK
3.5%
NK
NK
NK
NK
NK
A
A
C
B
C
C
C
C
C
NK
NK
0–2%
NK
0–2%
NK
NK
NK
NK
NK
NK
NK
0 –4.4%
NK
C
B
A
C
B
C
C
C
C
C
C
C
B
C
NK
0.3%
NK
NK
0 –4.2%
NK
0–8%
C
A
C
C
B
C
A
NK = not known.
ciated with oral amiodarone,449 the incidence may
be as high as 10% when doses of 3 g per 24 hours
are administered.450
Sinus bradycardia or arrest or AV nodal blockade
may be caused by digoxin, primarily in overdose or
other situations in which serum digoxin concentrations become elevated.83 The overall incidence of
sinus bradycardia or AV nodal blockade associated
with digoxin is unknown. In an analysis of patients
with a discharge diagnosis of digoxin intoxication,
“definite” sinus bradycardia and sinus pauses <2 seconds were documented in 26% and 19%, respectively, of those with digoxin intoxication.83 In addition,
“definite” second or third degree AV nodal blockade
was documented in 33% of patients with digoxin
intoxication.83 Sotalol has been reported to cause
CHAPTER 25 • Supraventricular Arrhythmias
clinically important sinus bradycardia and sinus
pauses in up to 17.2% of patients being treated for
atrial fibrillation, with 2.5% requiring permanent
pacemaker implantation.269
Zelster et al.359 reviewed a series of 169 consecutive patients admitted or discharged with the
diagnosis of second or third degree AV nodal blockade that was not caused by acute myocardial
infarction, vasovagal syncope, radiofrequency
ablation, or digitalis toxicity. Of these, 54% were
receiving therapy with b-blockers with or without
diltiazem, diltiazem alone, or verapamil. The investigators reported that drug discontinuation was followed by resolution of AV nodal blockade in 41%
of patients, but that 56% of these patients subsequently had recurrence of AV nodal blockade in
the absence of causative drugs. Based on their criteria for causation, the investigators concluded
that drugs were the specific cause of AV nodal
blockade in only 15% of the patients who were
receiving therapy with b-blockers with or without
diltiazem, diltiazem alone, or verapamil.359
MECHANISMS
Drug-induced sinus bradycardia may be caused by
inhibition of automaticity of the node, slowing of
sinus node conduction, or prolongation of sinus
node repolarization (Table 25–3). AV nodal blockade may be caused by agents that inhibit AV node
conduction or prolong AV node repolarization
(Table 25–4). Both the sinus node and the AV node
are heavily influenced by sympathetic and
parasympathetic nervous system activity. Drugs
that inhibit activity of the sympathetic nervous
TABLE 25–3
449
system (e.g., b-blockers) and drugs that stimulate
the parasympathetic nervous system (e.g., neostigmine, physostigmine, pyridostigmine) may cause
sinus bradycardia or AV nodal blockade. The action
potentials of both the sinus node and the AV node
depend primarily on calcium and sodium flux, and
calcium or sodium channel inhibitors may cause
sinus bradycardia, AV nodal blockade, or both.
Nitrates may cause a syndrome associated with
sinus bradycardia and hypotension.177-185 Sinus
bradycardia induced by nitrates is an idiosyncratic
reaction. This syndrome resembles neurocardiogenic syncope, but may occur when patients are in
the supine position. The mechanism of nitrateinduced sinus bradycardia remains unclear, but
evidence suggests that nitrates may stimulate
peripheral sensory receptors with vagal afferents to
the medulla, resulting in sympathetic nervous system inhibition via stimulation of central a2-receptors (Table 25–3).451
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
Normal heart rate is usually defined somewhat
arbitrarily as ranging between 60 and 100 bpm.
However, many individuals routinely have heart
rates <60 bpm and even <50 bpm without evidence
of symptoms. Patients with symptomatic sinus
bradycardia resulting in the need for medical attention typically have heart rates between 30 and 50
bpm, resulting in hemodynamic compromise.
Signs and symptoms associated with clinically
important sinus bradycardia and sinus pauses are
listed in Table 25–5.1
Mechanisms of Drug-Induced Sinus Bradycardia
Drug
All drugs that may cause sinus bradycardia (except nitrates)
Adrenergic b-receptor blockers
Mechanism
Inhibition of automaticity of the sinus node and/or slowing
of sinus node conduction and/or prolongation of
sinus node repolarization
Inhibit activity of sympathetic nervous system, leading to
inhibition of automaticity of sinus node
Clonidine
Stimulates central a2-receptors, reducing release of
norepinephrine
Neostigmine, physostigmine, pyridostigmine
Stimulate activity of the parasympathetic nervous system,
leading to inhibition of automaticity of sinus node
Stimulates peripheral sensory receptors with vagal afferents
to the medulla, resulting in sympathetic nervous system
inhibition via stimulation of central a2-receptors
Nitroglycerin
450
SECTION VI • Drug-Induced Cardiovascular Diseases
TABLE 25–4
Mechanisms of Drug-Induced Atrioventricular (AV) Nodal Blockade
Drug
All drugs that may cause AV nodal blockade
Adrenergic b-receptor blockers
Mechanism
Inhibition of conduction through the AV node
Inhibit activity of sympathetic nervous system, leading to
inhibition of conduction through the AV node
Clonidine
Stimulates central a2-receptors, reducing release of norepinephrine
Stimulate activity of the parasympathetic nervous system,
leading to inhibition of conduction through the AV node
Neostigmine, physostigmine, pyridostigmine
First degree AV nodal block is a common electrocardiographic phenomenon that is almost
always asymptomatic3, and is therefore not a druginduced disease as defined in this text. However,
second and third degree AV blockade can result in
bradycardia, leading to symptoms that result in the
need for medical attention or even requiring hospitalization.
Second degree AV block occurs most commonly in two distinct patterns. Mobitz type I seconddegree AV block (also known as Wenckebach) is
characterized by progressive prolongation of the
PR interval on ECG until a P wave is not followed
by a QRS complex (Figure 25–2).3 Mobitz type I is
usually caused by impulse conduction delay in the
AV node (as opposed to further down in the bundle of His).1 Mobitz type II second degree AV block
is typified by constant PR intervals with abrupt,
intermittent absence of QRS complexes (Figure
25–3). Mobitz type II second degree AV block often
occurs in specific patterns with P wave to QRS complex ratios such as 2:1, 3:1, or 4:1. This type of second degree AV block is likely caused by
impulse-conduction delay in the bundle of His.
During third degree AV nodal blockade, the AV
node is completely unable to conduct impulses,
and atrial depolarization occurs independently of
ventricular depolarization. Therefore, P waves and
QRS complexes are present on ECG but bear no
relationship to one another (Figure 25–4). Third
degree AV nodal blockade can occur either in the
AV node itself or further down in the bundle of
His.3
Second or third degree AV nodal blockade may
result in bradycardia, with heart rates in the range
of 40-60 bpm. Symptoms of second or third degree
AV nodal blockade are the same as those associated
with sinus bradycardia (Table 25–5).
Drug-induced sinus bradycardia or AV nodal
blockade must be distinguished from other causes
of sinus or AV node impairment. Dysfunction of
the sinus node unrelated to drug therapy is common, with a prevalence as high as 1 in 600 patients
over the age of 65 years.452 Intrinsic AV nodal
abnormalities also may occur during the aging
process. Transient sinus node dysfunction may
occur in the setting of acute myocardial ischemia
or infarction when the infarct/ischemia-related
vessel is the right coronary artery or the left circumflex artery, but permanent sinus-node damage
in this setting is uncommon. Myocardial infarction
may result in some degree of permanent AV nodal
dysfunction in some patients. Conditions to consider in the differential diagnosis of drug-induced
sinus bradycardia or AV nodal blockade are listed
in Table 25–6.1
TABLE 25–5 Signs and Symptoms Associated
with Drug-Induced Sinus Bradycardia and
Atrioventricular Nodal Blockade
•
•
•
•
•
•
•
Dizziness
Light-headedness
Fatigue
Weakness
Syncope
Chest pain
Symptoms of heart failure
FIGURE 25–2. Mobitz type I second degree AV nodal
blockade associated with phenylpropanolamine.
Reproduced with permission from Woo et al.423
CHAPTER 25 • Supraventricular Arrhythmias
1
2
3
451
ischemia or infarction. However, it may not be possible or desirable in every case to discontinue therapy with drugs suspected of causing sinus
bradycardia or AV nodal blockade. For example, bblocker therapy should not generally be discontinued in a patient being treated for heart failure or
after myocardial infarction. Rather, therapy with
the b-blocker should be continued and implantation of a permanent pacemaker considered as a
means to protect against possible drug-induced
sinus or AV node dysfunction.
RISK FACTORS
FIGURE 25–3. Mobitz type II second degree AV nodal
blockade associated with amiodarone.
Reproduced with permission from Mangiardi et al.363
Drug-induced sinus or AV node dysfunction
can often be distinguished from non–drug-related
sinus bradycardia or AV nodal blockade. When a
patient with symptoms that appear to be related to
sinus bradycardia/sinus pauses/sinus arrest or AV
nodal inhibition seeks medical attention, therapy
with drugs known to induce sinus or AV node dysfunction should typically be discontinued. If the
sinus or AV node dysfunction persists after five
half-lives of the respective drug(s) have passed, a
drug-induced cause may be ruled out. While awaiting drug washout, evaluation and diagnostic testing for nonpharmacologic causes can be
performed, including determination of serum
potassium and magnesium concentrations, thyroid
function tests, and assessment for myocardial
Risk factors for drug-induced sinus bradycardia are
listed in Table 25–7.41,136,453 Conditions that may
result in elevated plasma concentrations of drugs
known to cause sinus bradycardia increase the risk.
Patients with kidney disease who are receiving renally eliminated drugs that may cause sinus bradycardia (atenolol, clonidine, digoxin) are also at
increased risk. Kidney disease has been identified as
a risk factor for sinus bradycardia associated with
clonidine.41 Drugs that have been reported to cause
sinus bradycardia that require dose adjustment in
patients with kidney disease are listed in Table 25–8.
In addition, concomitant use of drugs that inhibit
the hepatic metabolism of drugs known to induce
sinus bradycardia should be avoided (Table 25–9).454
Other interactions may result in sinus bradycardia. Dipyridamole inhibits the cellular uptake of
adenosine455; therefore, patients receiving adenosine concomitantly with dipyridamole are at
increased risk of adenosine-associated sinus brady-
FIGURE 25–4. Third degree
AV nodal blockade associated
with carbamazepine.
Reproduced with permission
from Ide and Kamijo.376
452
SECTION VI • Drug-Induced Cardiovascular Diseases
TABLE 25–6 Conditions to Consider in the
Differential Diagnosis of Drug-Induced Sinus
Bradycardia or Atrioventricular Nodal Blockade1
TABLE 25–7 Risk Factors for Drug-Induced Sinus
Bradycardia or Atrioventricular (AV) Nodal
Blockade
Intrinsic causes
• Idiopathic degeneration due to aging
• Myocardial ischemia/infarction (transient)
• Infiltrative diseases (sarcoidosis, amyloidosis,
hemochromatosis)
• Collagen vascular diseases (systemic lupus erythematosus, scleroderma, rheumatoid arthritis)
• Myotonic muscular dystrophy
• Surgical trauma (valve replacement, heart transplantation, correction of congenital heart disease)
• Infectious diseases (Chagas’ disease, endocarditis)
Extrinsic causes
• Autonomically mediated syndromes
• Neurocardiac syncope
• Carotid sinus hypersensitivity
• Situational disturbances (coughing, micturition,
defecation, vomiting)
• Hypothyroidism
• Hypothermia
• Electrolyte abnormalities
• Hyperkalemia
• Hypokalemia
• Hypermagnesemia
Sinus bradycardia41,136,453
• Pretreatment heart rate <60 bpm
• Underlying sinus-node dysfunction (may occur with
advancing age)
• Impaired baroreflex control (risk factor for nitroglycerin-induced sinus bradycardia)
• Concomitant use of >1 sinus-node inhibiting drug
• Elevated plasma drug concentrations due to organ
dysfunction or drug interactions
Atrioventricular nodal blockade
• Concomitant use of >1 AV nodal blocking drug
• Pretreatment PR interval >0.2 sec
• Underlying AV nodal disease (may occur with
advancing age)
• Elevated plasma drug concentrations due to organ
dysfunction or drug interactions
• Hypothyroidism (may be a risk factor for amiodarone-induced AV block)363
cardia/sinus pauses.6 A number of drugs inhibit the
elimination of digoxin, particularly amiodarone,456
verapamil,457 and quinidine,458 and concomitant
use of these drugs with digoxin increases the risk of
digoxin-induced sinus bradycardia, unless appropriate digoxin dose reduction is implemented. In
addition, patients receiving therapy with more
than one drug known to reduce heart rate are at
increased risk.41,459
Women are at greater risk for amiodaroneinduced bradycardia requiring implantation of a
permanent pacemaker.460 In a study of 1,005
patients with new-onset atrial fibrillation, the hazard ratio for amiodarone use requiring a permanent pacemaker was 4.69 (95% CI, 1.99 to 11.05)
in women, as compared with 1.05 (95% CI, 0.42 to
2.58) in men.460 Mechanisms for the increased risk
of bradycardia requiring pacemaker implantation
in women are unknown.
Specific risk factors for the majority of druginduced AV nodal blockade have not been identified. In the study by Zelster et al.359 of 169
consecutive cases of AV nodal blockade, there were
no significant differences in age, male sex, or presence of hypertension or ischemic heart disease
between patients receiving therapy with b-blockers
with or without diltiazem or verapamil and those
not receiving therapy with drugs that could induce
AV nodal blockade. Possible risk factors for druginduced AV nodal blockade are listed in Table 25–7.
Risk factors have been identified for AV nodal blockade induced by digoxin, and include the drug interactions listed above, inadequate dose reduction in
patients with kidney disease, hypokalemia, hypomagnesemia, hypoxia, and hypothyroidism.461
MORBIDITY AND MORTALITY
The incidence of morbidity, hospitalization, or
death associated with drug-induced sinus bradycardia or AV nodal blockade is unknown. Druginduced sinus bradycardia or AV nodal blockade
may result in the need for temporary or permanent
pacemaker implantation.11,30,448 In a population of
patients with new-onset atrial fibrillation, the
adjusted hazard ratio for amiodarone use leading
to a requirement for a permanent pacemaker was
2.01 (95% CI, 1.08 to 3.76).460 Death due to druginduced sinus bradycardia or AV block is likely very
uncommon.
PREVENTION
Drug-induced sinus or AV node dysfunction (or
both) is often preventable (Table 25–10). When
CHAPTER 25 • Supraventricular Arrhythmias
TABLE 25–8 Drugs Known to Cause Sinus
Bradycardia or Atrioventricular Nodal Blockade
That May Require Dose Adjustment in Patients
with Kidney Disease
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Acebutolol
Atenolol
Baclofen
Betaxolol
Bisoprolol
Carteolol
Cimetidine
Cisplatin (recommended to be avoided in cases of
preexisting renal dysfunction)
Clonidine
Dexmedetomidine
Digoxin
Disopyramide
Flecainide
Guanabenz
Isradipine
Nadolol
Nicardipine
Ranitidine
Sotalol
possible, drugs with the potential to inhibit sinus
or AV node function should be avoided in patients
with known sinus or AV node dysfunction in the
absence of a functioning pacemaker. Once a pacemaker has been implanted, however, patients with
sinus node dysfunction may receive sinus
node–inhibiting drugs, and patients with AV node
dysfunction may receive AV node–inhibiting
453
agents. Patients who are taking drugs with the
potential to cause sinus bradycardia, sinus pauses,
or AV nodal blockade should be taught to monitor
their heart rate daily, and to consult their pharmacist or physician if heart rate falls below 50 bpm or
if they experience symptoms of bradycardia (Table
25–5). Combinations of drugs that may inhibit
sinus or AV node function should be minimized,
but are not contraindicated if the benefits of such
therapy outweigh the risks.
Drug-induced sinus or AV node dysfunction
may be prevented by not exceeding maximum
daily doses of drugs known to cause these druginduced diseases and by appropriate dose adjustment of specific drugs to account for organ
dysfunction, drug interactions, or both.
Maintaining serum digoxin concentrations <2.0
ng/mL may prevent digoxin-associated sinus or AV
node dysfunction. In certain circumstances, substituting medications within a class may prevent
drug-induced sinus or AV node dysfunction. For
example, a patient with kidney disease who is
receiving atenolol is at higher risk for atenololinduced sinus bradycardia or AV nodal blockade as
a result of diminished atenolol clearance. In this
situation, replacing atenolol with a non–renally
cleared b-blocker such as metoprolol or propanolol
may reduce the likelihood of drug-induced sinus
bradycardia or AV nodal blockade.
Patients receiving drugs known to inhibit AV
nodal conduction should undergo a 12-lead ECG
periodically and at least every 6 months. First
degree AV block is not an absolute contraindication
to receiving AV nodal blocking drugs, but the PR
interval should be monitored every 3 to 6 months
TABLE 25–9 Drugs Known to Cause Sinus Bradycardia or Atrioventricular Nodal Blockade That Are
Substrates for Enzymes of the Cytochrome P-450 System454
1A2
Amitriptyline
Clozapine
Olanzapine
Propranolol
Verapamil
2B6
Methadone
2C8
Paclitaxel
2C19
Amitriptyline
Citalopram
Diazepam
Propranolol
2C9
Amitriptyline
Fluoxetine
2D6
Amitriptyline
Flecainide
Carvedilol
Fluoxetine
Imipramine
Lidocaine
Metoprolol
Nebivolol
Propafenone
Propranolol
Thioridazine
Timolol
3A4
Amiodarone
Cocaine
Carbamazepine
Diazepam
Diltiazem
Dronedarone
Lidocaine
Methadone
Nicardipine
Paclitaxel
Tacrolimus
Verapamil
454
SECTION VI • Drug-Induced Cardiovascular Diseases
TABLE 25–10 Approaches to Help Prevent DrugInduced Sinus Bradycardia and Atrioventricular
(AV) Nodal Blockade
TABLE 25–11 Management of Drug-Induced
Sinus Bradycardia or Atrioventricular (AV) Nodal
Blockade
For all drugs that may cause sinus bradycardia, AV
block, or both
• Patient should take pulse daily, report if <50 bpm.
• Do not exceed maximum daily doses.
• Use combinations of drugs that may cause sinus
bradycardia or AV block only when necessary and
when the benefits likely outweigh the risks.
• Avoid sinus or AV node–inhibiting drugs in patients
with underlying sinus node dysfunction, unless a
functioning pacemaker is present (in the case of AV
node inhibiting drugs, there must be a functioning
ventricular pacemaker).
For digoxin
• Measure serum digoxin concentrations:
• If kidney function is changing.
• If a drug that interacts with digoxin is added to
therapy.
• Every 6 mo if there is no organ dysfunction or concomitant use of interacting drugs.
• Discontinue the causative agent
• Temporary pacemaker
• If underlying sinus or AV node dysfunction—permanent pacemaker may be necessary (if AV node dysfunction, must be a ventricular pacemaker)
• In severe cases: atropine 0.5–1.0 mg every 3–5 minutes until heart rate increases or total dose of 0.04
mg/kg is administered
• If due to calcium-channel blocker or b-blocker overdose:
• Gastric lavage
• Activated charcoal 25–50 g in an aqueous slurry of
120–240 mL water
• Glucagon 2.0–5.0 mg intravenously
• Temporary pacemaker, if necessary
to ensure that AV nodal blockade is not progressing.
In addition, combinations of AV nodal blocking
drugs are best avoided in patients with pretreatment PR intervals >0.2 seconds. If the PR interval
progresses to >0.2 seconds while on AV nodal blocking therapy, it is not necessary to discontinue therapy, but more frequent ECG monitoring is
recommended and administration of additional AV
nodal blocking agents should be avoided.
MANAGEMENT
Management options for patients with druginduced sinus bradycardia or AV nodal blockade are
presented in Table 25–11. In some cases, a reduction
in dose of the offending medication may be sufficient, but in most cases in which drug-induced sinus
or AV node dysfunction has resulted in a hospitalization, discontinuation of therapy is necessary. In
the case of sinus bradycardia or AV block induced by
adenosine, treatment is not usually required because
the drug is metabolized very quickly (half–life 5 10
seconds) and the heart rate usually returns to pretreatment values within 20 to 30 seconds.
Percutaneous insertion of a temporary pacemaker may be necessary. If the patient is subsequently
diagnosed with underlying intrinsic sinus or AV node
dysfunction, therapy with the offending medication
may be reinitiated after the implantation of a permanent pacemaker. In severe cases, intravenous atropine
may be administered in doses of 0.5 to 1.0 mg every
3 to 5 minutes to a total dose of 0.04 mg/kg, the dose
at which full blockade of the parasympathetic nervous system occurs in humans.462
If the drug-induced bradycardia or AV block is
a result of an overdose of verapamil, diltiazem or a
b-blocker, gastric lavage may be performed if the
patient presents within 1 hour of ingestion.
Activated charcoal may be administered and may
be particularly useful if the drug was ingested in
the form of a sustained-release preparation.
Although administration of calcium salts has been
shown to be effective for reversing the hemodynamic effects of calcium-channel blockers, calcium
salts have not been particularly effective for reversing the electrophysiologic effects of these drugs.463
Glucagon 2 to 5 mg intravenously may be effective
for reversing the bradycardic effects of calciumchannel blockers or a b-blocker.463,464 Insertion of a
temporary pacemaker may be necessary.
For patients with a history of myocardial infarction or heart failure in whom sinus bradycardia or
AV nodal blockade induced by b-blockers develops,
implantation of a permanent pacemaker may be
necessary to allow the patient to continue therapy
with these agents,465 which have been shown to
prolong survival in these specific conditions.466,467
INFORMATION FOR PATIENTS
Patients should be instructed that specific drug(s)
may cause the heart rate (pulse) to become slower.
Patients should be taught to take their pulse and
to monitor their heart rate daily. Patients should
be instructed to consult their pharmacist or physi-
CHAPTER 25 • Supraventricular Arrhythmias
cian if their heart rate falls below 50 beats per
minute, or if they feel lightheaded, dizzy, tired,
weak, short of breath, or experience chest pain.
ATRIAL FIBRILLATION/
ATRIAL FLUTTER
Atrial fibrillation is a supraventricular arrhythmia that is characterized on ECG by an irregularly irregular pattern of narrow QRS complexes, an
absence of discernible P waves, and an undulating baseline (Figure 25–5). Atrial flutter is a
supraventricular arrhythmia that is characterized
on ECG by a regular pattern of narrow QRS complexes, with discernible P waves that exhibit a
“sawtooth” appearance (Figure 25–6). Atrial flutter is often associated with a ratio of P waves to
QRS complexes of 4:1, 3:1 or, in some cases, 2:1.
CAUSATIVE AGENTS
Drugs that have been associated with atrial fibrillation or atrial flutter are listed in Table
25–12.123,162,196,218,349,468-545 The majority of drugs
that have been associated with induction of atrial
fibrillation or flutter are cardiovascular agents, but
drugs from other classes have been implicated as
well, including the bisphosphonate drugs alendronate496,497 and zoledronic acid.545
EPIDEMIOLOGY
The overall incidence of drug-induced atrial fibrillation or flutter is not known, but it is likely very low.
Adenosine has been reported to cause a substantial
incidence of atrial fibrillation in patients undergoing treatment for AV nodal reentrant tachycardia.475
Although the incidence of alcohol-induced atrial
fibrillation (often referred to as the “holiday heart”
syndrome) is unknown, in a case–control study of
455
patients with acute idiopathic atrial fibrillation, 62%
of cases were associated with heavy alcohol use.489
In a prospective cohort study of the association
between self-reported alcohol use and incident atrial fibrillation, moderate alcohol intake was not associated with new-onset atrial fibrillation. However,
consumption of 35 or more drinks per week was
associated with a hazard ratio for atrial fibrillation of
1.45 (95% CI, 1.02 to 2.04) in men.546 About 5% of
cases of atrial fibrillation in men were estimated to
be attributable to heavy alcohol intake.
In a randomized study of the prevention of fractures in postmenopausal women, the bisphosphonate drug alendronate was found to increase the risk
of “serious” atrial fibrillation (1.5% vs. 1.0% in the
placebo group; relative hazard, 1.51; 95% CI, 0.97 to
2.40; P = 0.07).496 However, alendronate did not
increase the risk of “all atrial fibrillation adverse
events.” In addition, in a case–control study in
women, a higher proportion of patients with atrial
fibrillation had ever used alendronate as compared
with those who had never used any bisphosphonate
(odds ratio of atrial fibrillation, 1.86; 95% CI, 1.09 to
3.15).497 Furthermore, another bisphosphonate drug,
zoledronic acid, was reported to increase the risk of
“serious” atrial fibrillation as compared with placebo
(1.3% vs. 0.5%, P<0.001).545 However, zoledronic acid
did not increase the risk of all atrial fibrillation events.
In a cohort study of 15,795 patients with fractures
treated with oral bisphosphonates, the adjusted risk
of atrial fibrillation was higher than that in an ageand sex-matched group of patients with fractures
who did not receive the drugs (1.18; 95% CI, 1.08 to
1.29).547 A database analysis of over 40,000 women
conducted in the United Kingdom showed no evidence of an overall risk of bisphosphonate-associated
atrial fibrillation, but a potential increased risk of atrial fibrillation associated with alendronate during the
first few months of therapy.548 However, other studies
have not reported an increased risk of atrial fibrillation associated with bisphosphonates.549,550
Determining whether bisphosphonate drugs are associated with atrial fibrillation requires further study.
FIGURE 25–5. Atrial
fibrillation induced by
albuterol.
Reproduced with permission from Breeden and
Safirstein.485
456
SECTION VI • Drug-Induced Cardiovascular Diseases
FIGURE 25–6. Atrial flutter with 2:1 atrioventricular conduction induced by propafenone.
Reproduced with permission from Tai et al.498
New-onset atrial flutter associated with drugs is
also uncommon, but has been reported to occur in
patients with atrial fibrillation who are receiving
Vaughan Williams class IC antiarrhythmic agents (flecainide or propafenone) or amiodarone (Table 25–12).
MECHANISMS
Mechanisms by which some drugs induce atrial fibrillation or flutter are presented in Table 25–13. Atrial
fibrillation is believed to be induced by ectopic
impulses originating from pulmonary veins, atria, or
both, and it has been proposed that adenosine may
induce increased atrial ectopic activity, which may
then trigger the development of atrial fibrillation.475
In addition, atrial fibrillation is maintained by multiple reentrant wavelets, and evidence indicates that
the shorter the wavelength, the more likely that atrial fibrillation develops and is sustained.551,552
Wavelength is the product of the atrial conduction
velocity and the atrial effective refractory period.551,552 Adenosine has been shown to shorten the
atrial effective refractory period, and therefore may
promote reduction in atrial wavelength and the
development of multiple reentrant atrial
wavelets.553,554 The mechanism of alcohol-induced
atrial fibrillation is believed to be related to increased
sympathetic nervous system stimulation.494
Mechanisms by which the bisphosphonate
drugs alendronate and zoledronic acid may cause
atrial fibrillation are unclear. It has been suggested
that bisphosphonate drugs may cause atrial fibrillation through the release of inflammatory
cytokines,496,555 which have been associated with
the development of atrial fibrillation.556 Further
study is necessary to determine the mechanism of
bisphosphonate-induced atrial fibrillation and to
confirm that this is truly a disease that is induced
by drugs from this class.557
Many of the drugs that have been reported to
cause atrial fibrillation or atrial flutter have commonly been used for the management of these arrhythmias. Despite the fact that flecainide has been shown
to be effective for the prevention and management of
atrial fibrillation, data from studies in animals indicate that flecainide may shorten atrial conduction
velocity558 and wavelength,559 effects which may promote the development of atrial fibrillation.
Amiodarone-induced atrial fibrillation may, at least in
some cases, be due to amiodarone-induced thyrotoxicosis.560.561 Dobutamine has been shown to shorten
atrial effective refractory periods,562 while theophylline has been shown to increase atrial automaticity.563 Mechanisms by which other drugs may induce
atrial fibrillation or flutter require further study.
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
The symptoms of drug-induced atrial fibrillation
and atrial flutter are related to the degree of tachycardia and the resultant effect on blood pressure
and cardiac output (Table 25–14). The symptoms of
atrial fibrillation may be indistinguishable from
those of atrial flutter, and therefore atrial fibrillation and atrial flutter must be distinguished from
CHAPTER 25 • Supraventricular Arrhythmias
TABLE 25–12
457
Agents Implicated in Drug-Induced Atrial Fibrillation or Atrial Flutter
Drug
Incidence
Level of Evidence
(see page xii for explanation)
Adenosine 349,468-482
Albuterol483-485
Alcohol486-495
Alendronate496,497
Amiodarone498, 499
Caffeine500
Diltiazem501
Dobutamine162,502-516
Enoximone513
Flecainide517,518
Fluoxetine123,519
Ipratropium bromide520
Levosimendan515
Loxapine519
Metaproterenol521
Methylprednisolone522-526
Milrinone162,527-530
Mitoxantrone531
Ondansetron532,533
Paclitaxel196,534
Physostigmine218,535
Propafenone498,518,536
Theophylline483,537-542
Verapamil543,544
Zoledronic acid545
1–12%a
NK
NK
0.5%
OR, 1.86 (95% CI, 1.09–3.15)
NK
NKb
NK
0–18%
8.3%
NK
B
C
B
A
B
B
C
A
A
C
NK
NK
0–9.1%
NK
2.5%
NK
2.9–5%
1.4%
NK
2% (atrial flutter)
1–1.7% (atrial fibrillation)
NK
9%c
NK
C
C
A
C
A
C
A
B
C
B
5%
0.8%
C
A
C
C
B
CI = confidence interval; NK = not known; OR = odds ratio.
a
Atrial fibrillation, 1–11%, atrial flutter, 1%.
b
Espresso only.
c
Percent of patients with atrial fibrillation who develop new atrial flutter during propafenone therapy.536
one another (and from other tachyarrhythmias) by
ECG (Figures 25–5 and 25–6).
The onset of drug-induced atrial fibrillation or
flutter is variable, depending on the inducing drug.
Adenosine-induced atrial fibrillation or flutter occurs
within 1 minute of administration of this extremely
short-acting agent.349 In a study of amiodarone- or
propafenone-induced atrial flutter, the mean (±SD)
time of onset was 5.0+5.5 months after the initiation
of treatment,498 whereas atrial flutter has been
reported in association with flecainide therapy of 2
months’ duration.517 The duration of episodes of
drug-induced atrial fibrillation or flutter is also somewhat variable; a case of albuterol-induced atrial fibrillation lasted several hours,484 whereas atrial flutter
associated with amiodarone or propafenone may
require intervention to terminate the arrhythmia.498
Sinus rhythm was the preceding rhythm in 88%
of patients in whom atrial fibrillation associated with
adenosine developed, whereas the remaining 12% of
patients had atrial ectopic activity prior to the development of atrial fibrillation.475 The mean ventricular
rate associated with adenosine-induced atrial fibrillation was 107+43 bpm.475 Adenosine-induced
458
SECTION VI • Drug-Induced Cardiovascular Diseases
TABLE 25–13
Mechanisms of Drug-Induced Atrial Fibrillation/Flutter
Drug
Adenosine, dobutamine, flecainide
Alcohol
Theophylline
Other drugs
TABLE 25–14 Signs and Symptoms Associated
with Drug-Induced Atrial Fibrillation/Flutter
•
•
•
•
•
Palpitations
Dizziness
Light-headedness
Shortness of breath
Chest pain (if underlying coronary artery disease is
present)
• Near-syncope
• Syncope
episodes of atrial fibrillation tend to be of short duration. The mean duration of episodes of atrial fibrillation associated with adenosine was 5.6+6.7 minutes
(range, 8 seconds to 20.7 minutes).475
Conditions to consider in the differential diagnosis of drug-induced atrial fibrillation/flutter are
presented in Table 25–15. Non–drug-induced atrial
fibrillation/flutter must be considered; drug-induced
atrial fibrillation/flutter is more likely in patients
who are receiving drugs that have been reported to
cause atrial fibrillation or flutter, particularly in
patients with no known risk factors or causes for
non–drug-induced atrial fibrillation/flutter, such as
hypertension, ischemic heart disease, heart failure,
valvular heart disease, rheumatic fever, or hyperthyroidism, or in those who have undergone thoracic
surgery within the previous 2 to 5 days.
Mechanism
Shorten atrial effective refractory period/atrial wavelength
Sympathetic nervous system stimulation
Increases atrial automaticity
Unknown
TABLE 25–15 Conditions to Consider in the
Differential Diagnosis of Drug-Induced Atrial
Fibrillation/Flutter
•
•
•
•
•
Atrial fibrillation or flutter not induced by drugs
Sinus tachycardia
Atrial tachycardia
Atrioventricular nodal reentrant tachycardia
Ventricular tachycardia
(58%), and therefore may be somewhat predictive
of impending drug-induced atrial fibrillation.475
Alcohol dose is a risk factor for alcohol-induced
atrial fibrillation. In one study, the mean dose of
alcohol consumed during the week prior to the
atrial fibrillation episode was 186g, as compared
with 86g in a control population in whom alcoholinduced atrial fibrillation did not develop.493
Another study found that the risk of alcoholinduced atrial fibrillation was increased in patients
who consumed more than an average of 30g alcohol daily.492 Alcohol withdrawal may increase the
risk of alcohol-induced atrial fibrillation.490
In patients receiving amiodarone for treatment
of atrial fibrillation, amiodarone-induced atrial flutter does not appear to be related to age, sex, presence
of structural heart disease, left ventricular function,
or duration of atrial fibrillation; however, left atrial
enlargement (>40 mm) may be a risk factor.498
Further study is needed to identify risk factors for
drug-induced atrial fibrillation or atrial flutter.
RISK FACTORS
Although all risk factors for drug-induced atrial fibrillation or flutter have not yet been fully characterized, known risk factors are presented in Table
25–16. Atrial fibrillation associated with adenosine
does not appear to be related to sex or age and may
occur in patients with no history of atrial fibrillation.475 Atrial fibrillation induced by adenosine is
not related to the type of arrhythmia being treated.475 Premature atrial contractions occur significantly more frequently in patients who have
experienced adenosine-induced atrial fibrillation
(100%) as compared with those who did not
MORBIDITY & MORTALITY
Symptoms associated with drug-induced atrial fibrillation or flutter could potentially result in hospitalization or prolonged duration of stay in a
hospital or critical care unit, although prolonged
duration of hospital stay as a result of druginduced atrial fibrillation or flutter has not been
reported. Hypothetically, drug-induced atrial fibrillation could result in stroke, but this has not yet
been described. Death due to drug-induced atrial
fibrillation or flutter has not been reported.
CHAPTER 25 • Supraventricular Arrhythmias
459
TABLE 25–16 Risk Factors for Drug-Induced
Atrial Fibrillation/Flutter
TABLE 25–17 Approaches to Help Prevent DrugInduced Atrial Fibrillation/Flutter
Adenosine
• Premature atrial contractions
Alcohol
• Dose > 30g daily
• Withdrawal
Amiodarone
• Left atrial hypertrophy
Other drugs
• Unknown
Alcohol492,493
• Avoid binge drinking/excessive doses
• Consume <30g daily
Methylprednisolone524
• Propafenone 300 mg three times daily
Other drugs
• Administer lowest effective dose
PREVENTION
For the most part, specific methods of prevention
have not been determined. However, the risk of
alcohol-induced atrial fibrillation can be minimized by avoiding binge drinking and excessive
doses of alcohol, and by consuming <30g alcohol
daily (Table 25–17).492,493 Moretti et al.524 reported
the case of a patient treated with intermittent
courses of high doses of intravenous methylprednisolone for multiple sclerosis in whom recurrent
atrial fibrillation attributed to the corticosteroid
developed. Pretreatment prophylaxis with sotalol
was ineffective, but pretreatment prophylaxis with
oral propafenone 300 mg three times daily was
effective at preventing methylprednisoloneinduced atrial fibrillation.
MANAGEMENT
The causative agent should be discontinued. In a
series of cases of adenosine-induced atrial fibrillation, 67% of patients converted to sinus rhythm
spontaneously, whereas 33% required cardioversion.475 Therefore, hemodynamically stable druginduced atrial fibrillation or atrial flutter is
associated with a high incidence of spontaneous
conversion, and treatment may not be necessary. In
patients who do not convert spontaneously to sinus
rhythm, intravenous drugs for ventricular rate control should be administered (Table 25–18).564 For
patients with normal left ventricular function, an
intravenous b-blocker or calcium-channel blocker
should be administered. Diltiazem may be preferred
over verapamil as a result of a lower risk of symptomatic hypotension.565 For patients with heart failure due to left ventricular dysfunction, intravenous
calcium-channel blockers and b-blockers should be
avoided because of the risk of exacerbation of heart
failure; intravenous digoxin or amiodarone should
be administered instead.564 In patients with rapid
heart rates that do not respond promptly to drug
therapy for ventricular rate control, or in patients
with atrial fibrillation/flutter in whom symptoms
are unacceptable, direct-current cardioversion
should be administered. However, if atrial fibrillation has been present for >48 hours, or if the duration of the episode of atrial fibrillation is unknown,
patients should undergo transesophageal echocardiography to rule out an atrial thrombus before
electrical or pharmacologic cardioversion is performed.
After the administration of agents to control
the ventricular rate, drug-induced atrial fibrillation
or flutter should be converted to sinus rhythm,
using either elective direct-current cardioversion or
pharmacologic cardioversion. Acceptable agents
for pharmacologic cardioversion include amiodarone, dofetilide, flecainide, ibutilide, or
propafenone (Table 25–18). If the atrial fibrillation
was induced by a sodium channel blocking agent,
conversion to sinus rhythm should be achieved
using direct-current cardioversion or ibutilide. It
should be noted, however, that the effectiveness of
antiarrhythmic drug therapy for drug-induced atrial fibrillation or atrial flutter has not been studied.
In patients with atrial fibrillation in whom new
atrial flutter induced by amiodarone or
propafenone develops, radiofrequency catheter
ablation of the isthmus between the tricuspid
annulus and the inferior vena cava has been used
to terminate the atrial flutter while allowing
patients to remain on antiarrhythmic drug therapy
for the management of the atrial fibrillation.498,499
Radiofrequency catheter ablation of drug-induced
atrial flutter is successful in 90% to 100% of
patients, and drug-induced atrial flutter did not
recur in 14 of 15 patients during a 1-year follow-up
period.498
If the drug-induced atrial fibrillation is a result
of a theophylline overdose, activated charcoal may
460
SECTION VI • Drug-Induced Cardiovascular Diseases
TABLE 25–18
Treatment Options for Drug-Induced Atrial Fibrillation564
Discontinue the offending agent.
Drug/Treatment
Recommended Doses
Ventricular rate control in patients with normal left ventricular function
Esmolol
Loading dose: 500 mcg/kg IV over 1 min
Maintenance infusion: 60–200 mcg/kg/min IV
Metoprolol
Propranolol
2.5–5 mg IV bolus over 2 min; up to 3 doses
0.15 mg/kg IV
Diltiazem
Loading dose: 0.25 mg/kg IV over 2 min
Maintenance infusion: 5–15 mg/hour IV
Verapamil
0.075–0.15 mg/kg IV over 2 min
Ventricular rate control in patients with heart failure due to left ventricular systolic dysfunction
Digoxin
0.25 mg IV every 2 hr, up to total dose of 1.5 mg
Amiodarone
Conversion to sinus rhythm
Direct-current cardioversion
Amiodaroneb
Dofetilide
Flecainideb
Ibutilide
Propafenoneb
Loading dose: 150 mg IV over 10 min
Maintenance infusion: 0.5–1 mg/min IV
200 J initially, followed by 360 J, if necessarya
Loading dose: 5–7 mg/kg IV over 30–60 min
Maintenance dose: 1.2–1.8 g daily by continuous IV infusion
CrCL >60 mL/min: 500 mcg orally twice daily
CrCL 40–60 mL/min: 250 mcg orally twice daily
CrCL 20–40 mL/min: 125 mcg orally twice daily
CrCL <20 mL/min: contraindicated
200–300 mg single oral dose
1 mg IV over 10 min. Repeat with a second 1 mg dose 10 min after the first dose if
atrial fibrillation persists.
600 mg single oral dose
CrCL = creatinine clearance; IV = intravenously.
a
Applies to both monophasic and biphasic shocks.
b
If the cause of the atrial fibrillation is a sodium channel blocking drug (amiodarone, flecainide, propafenone), avoid the use of additional sodium channel blocking agents and administer direct-current cardioversion or ibutilide. If the atrial fibrillation is caused by
theophylline toxicity: administer activated charcoal 50–100 g, followed by 50 g every 4 hr. Alternatively, continuous hemodialysis with
filtration may be performed.
be administered.566 Alternatively, continuous hemodialysis with filtration may be performed.542
INFORMATION FOR PATIENTS
Patients who are taking drugs known to cause atrial fibrillation or flutter should be instructed that
the medication, in rare instances, may cause the
heart rate (pulse) to become faster. Patients should
take their pulse daily, and should be instructed to
consult their pharmacist or physician if the heart
rate increases to above 100-120 bpm, or if they feel
palpitations, light-headed, dizzy, tired, weak, or
short of breath or experience chest pain.
ATRIAL TACHYCARDIA
Atrial tachycardia is a supraventricular arrhythmia
that is characterized on ECG by narrow QRS complexes, at a rate usually between 100 and 250
bpm.567 There are two primary types of atrial tachycardia: focal atrial tachycardia (which will be
referred to simply as “atrial tachycardia”), in which
the arrhythmia is initiated at a single atrial focus,
and multifocal atrial tachycardia, in which there
are multiple atrial foci. Focal atrial tachycardia is
characterized by regular intervals between QRS
complexes on ECG, while multifocal atrial tachycardia is associated with irregular QRS intervals and
three or more P wave morphologies.567 Atrial
CHAPTER 25 • Supraventricular Arrhythmias
TABLE 25–19
461
Agents Implicated in Drug-Induced Atrial Tachycardia
Drug
Incidence
Level of Evidence
(see page xii for explanation)
Albuterol483
Caffeine568,569
Digoxin83,388,570-580
Phenylpropanolamine569
Terbutaline581
Theophylline537,581-586
a
NK
NK
0 –4%
NK
NK
0–16%a
C
C
B
C
C
B
Incidence increases with increasing serum theophylline concentration
tachycardia may occur intermittently, which is
commonly referred to as “paroxysmal atrial tachycardia.”
CAUSATIVE AGENTS
Drugs that have been reported to cause atrial
tachycardia are listed in Table 25–19.83,388,483,537,568586
EPIDEMIOLOGY
Paroxysmal atrial tachycardia is often described as
a characteristic arrhythmia associated with digoxin
toxicity.578 However, at one large urban medical
center, “definite” paroxysmal atrial tachycardia
was documented in only 2% of 219 patients with a
discharge diagnosis of digoxin intoxication.83 In
this analysis, paroxysmal atrial tachycardia
occurred less frequently than any other arrhythmia
associated with digoxin intoxication. Therefore,
TABLE 25–20
despite the commonly held belief that paroxysmal
atrial tachycardia is commonly associated with
digoxin toxicity, it appears to occur relatively
rarely.
The incidence of multifocal atrial tachycardia
associated with theophylline is dependent on
serum theophylline concentrations.586 In an analysis of 100 patients receiving theophylline, atrial
tachycardia did not occur in the patients with
serum theophylline concentrations <10 mcg/mL.
However, in patients with serum theophylline concentrations between 10 and 20 mcg/mL, the incidence of atrial tachycardia was 8%, and the
incidence rose to 16% in patients with serum theophylline concentrations >20 mcg/mL.586
MECHANISMS
Mechanisms of drug-induced atrial tachycardia are
not entirely clear, but are likely related to increasing the automaticity of atrial tissue (Table
25–20).567 This may occur because of b-receptor
Mechanisms of Drug-Induced Atrial Tachycardia
Drug
Albuterol, terbutaline
Caffeine, theophylline
Digitalis glycoside toxicity
Mechanism
Stimulation of b-receptors, leading to enhanced atrial
automaticity
Phosphodiesterase inhibition, leading to increased plasma
concentrations of cyclic adenosine monophosphate, resulting in enhanced atrial automaticity
Extreme inhibition of the sodium–potassium–adenosine
triphosphatase pump, leading to markedly increased
myocyte concentrations of sodium, which is exchanged
with calcium, ultimately resulting in markedly increased
myocyte calcium concentrations, promoting enhanced
atrial automaticity
462
SECTION VI • Drug-Induced Cardiovascular Diseases
stimulation associated with drugs such as albuterol
or terbutaline or through phosphodiesterase inhibition and the resulting elevated concentrations of
cyclic adenosine monophosphate associated with
caffeine or theophylline.
The mechanism of paroxysmal atrial tachycardia with AV nodal blockade associated with
digitalis glycoside toxicity is likely related to
extreme inhibition of the sodium–potassium–
adenosine triphosphatase pump. This leads to
markedly increased myocyte sodium concentrations, which in turn is exchanged with calcium,
ultimately resulting in markedly increased
myocyte concentrations of calcium. This promotes enhanced atrial automaticity due to
delayed phase-4 repolarization in the atrial action
potential.587
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
The symptoms of drug-induced atrial tachycardia
are related to heart rate and the resultant effect on
blood pressure and cardiac output (Table 25–21).
The diagnosis of drug-induced atrial tachycardia
must be made primarily on the basis of the appearance on ECG (Figure 25–7). Conditions to consider
in the differential diagnosis of drug-induced atrial
tachycardia are presented in Table 25–22.
RISK FACTORS
Risk factors for drug-induced atrial tachycardia are
presented in Table 25–23. Paroxysmal atrial tachycardia with AV nodal blockade is extremely rare at
therapeutic serum digoxin concentrations, but
occurs primarily when serum digoxin concentrations increase to >2.0 ng/mL. Therefore, risk factors
for digoxin-induced paroxysmal atrial tachycardia
TABLE 25–21 Signs and Symptoms Associated
with Drug-Induced Atrial Tachycardia
Palpitations
Dizziness
Light-headedness
Shortness of breath
Chest pain (if underlying coronary artery disease is
present)
• Near-syncope
• Syncope
•
•
•
•
•
V1
V2
V3
FIGURE 25–7. Paroxysmal atrial tachycardia with varying
AV nodal blockade induced by digitalis toxicity. Arrows are
pointing to p waves, which are occurring at regular intervals.
Reproduced with permission from Storstein and Rasmussen.571
with AV block are the same as those for digoxin
toxicity. Since digoxin is cleared primarily by the
kidneys, renal dysfunction is a primary risk factor
for digoxin toxicity and digoxin-induced atrial
tachycardia with AV nodal blockade. In addition,
drug interactions that result in increased serum
digoxin concentrations enhance the risk of digoxin-related arrhythmias. Amiodarone,456 verapamil,457 and quinidine458 are known to
significantly increase serum digoxin concentrations.
Paroxysmal atrial tachycardia with AV block associated with digitalis toxicity may occur in patients
across a wide range of ages. In one series, in which 31
cases of paroxysmal atrial tachycardia with AV block
were reported in association with digitoxin, the age
range of patients varied from 20 to 73 years (average,
52).571 There were 15 women and 16 men, with a variety of underlying cardiovascular disorders, including
valvular heart disease (n = 14), congenital heart diseases (n = 6), and ischemic heart disease (n = 1).571 As
mentioned previously, elevated serum theophylline
concentration is a risk factor for theophylline-
TABLE 25–22 Conditions to Consider in the
Differential Diagnosis of Drug-Induced Atrial
Tachycardia
•
•
•
•
•
•
Atrial fibrillation
Atrial flutter
Atrial tachycardia not induced by drugs
Sinus tachycardia
AV nodal reentrant tachycardia
Ventricular tachycardia
CHAPTER 25 • Supraventricular Arrhythmias
463
TABLE 25–23 Risk Factors for Drug-Induced
Atrial Tachycardia
TABLE 25–24 Approaches to Help Prevent DrugInduced Atrial Tachycardia
Digoxin
• Serum digoxin concentrations >2.0 ng /mL
• Kidney disease
• Drug interactions leading to elevated serum digoxin
concentrations
Theophylline
• Serum theophylline concentrations >20 mcg /mL
Digoxin
• Maintain serum digoxin concentrations <2.0 ng /mL
• Appropriate dose adjustment for kidney disease
• Appropriate dose adjustment in the presence of interacting drugs, particularly amiodarone, verapamil, or
quinidine
Theophylline
• Maintain serum theophylline concentrations <20
mcg /mL
induced atrial tachycardia. New supraventricular
arrhythmias including multifocal atrial tachycardia
were reported in 7 patients with serum theophylline
concentrations between 21 and 40 mcg/mL.585
MORBIDITY AND MORTALITY
Patients with paroxysmal atrial tachycardia with AV
nodal blockade may present to the emergency
department and require hospitalization for management of digoxin toxicity. The incidence of mortality
associated with digitalis-induced paroxysmal atrial
fibrillation and AV nodal blockade has not been
reported, but is likely extremely low. In the series of
31 patients with digitoxin-induced paroxysmal atrial tachycardia, two patients died, but neither death
appears to have been related to the arrhythmia or
the digitoxin toxicity.571 Patients with atrial tachycardia associated with other drugs may also present
to the emergency department for treatment, particularly in the event of theophylline toxicity.
PREVENTION
Digoxin-associated paroxysmal atrial tachycardia
with AV nodal blockade is usually preventable by
maintaining serum digoxin concentrations <2.0
ng/mL (Table 25–24). Measurement of serum digoxin
concentrations is therefore recommended in patients
who may be at risk for elevated concentrations,
including patients with kidney disease or changing
kidney function and those receiving concomitant
therapy with drugs known to increase serum digoxin
concentrations (particularly amiodarone, verapamil,
or quinidine). In patients with kidney disease, appropriate dose adjustment should be made. In general,
patients with calculated creatinine clearance588 ≤20
mL/min should received an initial reduced digoxin
dose of 0.125 mg daily.589 In patients with calculated
creatinine clearance <20 mL/min who are receiving
concomitant therapy with drugs known to inhibit
the elimination of digoxin, the initial digoxin dose
should be 0.125 mg every other day.
Atrial tachycardia associated with theophylline
may be prevented by maintaining serum theophylline concentrations <20 mcg/mL.
MANAGEMENT
Treatment options for drug-induced atrial tachycardia are presented in Table 25–25. Digoxin-associated paroxysmal atrial tachycardia with AV nodal
blockade should be managed by withholding
digoxin therapy until serum digoxin concentrations decline to <2.0 ng/mL. Because paroxysmal
atrial tachycardia with AV block is rarely lifethreatening, it is usually not necessary to administer digoxin immune antibody fragments. In the
very rare event that the arrhythmia is hemodynamically unstable, synchronized direct current
cardioversion should be used to terminate the
arrhythmia. Attempts to sedate the patient should
be made, unless the urgency of the situation does
not permit them. Initial cardioversion energy
should be 50 J. Subsequent cardioversion attempts
should be performed with 100, 200, 300, and 360
J. Following the conversion of hemodynamically
unstable paroxysmal atrial tachycardia with AV
block, digoxin immune antibody fragments should
be administered to prevent recurrence of the
hemodynamically unstable arrhythmia.
Drug-induced atrial tachycardia may be
responsive to treatment with adenosine.590 In addition, drug-induced atrial tachycardia may be treated with verapamil583 or metoprolol.591 In one
study, intravenous metoprolol was more effective
than verapamil for termination of atrial tachycardia.592 Intravenous magnesium has also been effective for managing multifocal atrial tachycardia,593,594 although in one study it was not more
effective than placebo.595 If the drug-induced atrial
464
SECTION VI • Drug-Induced Cardiovascular Diseases
TABLE 25–25
Management of Drug-Induced Atrial Tachycardia
Discontinue the offending agent.
Drug
Recommended Doses
Hemodynamically unstable
Synchronized DC cardioversion (initial energy 50 J, followed by 100 J, 200 J, 300 J,
360 J, if necessary)
If due to digoxin toxicity:
Administer digoxin immune antibody fragments. The dose is based on the serum
digoxin concentration:
Number of 38-mg vials = serum digoxin concentration x weight (kg) 4 100.
If the arrhythmia is a result of an acute digoxin overdose and the amount of digoxin
ingested is known, the dose of digoxin immune antibody fragments should be calculated as follows:
Number of 38-mg vials = mg digoxin ingested acutely x 0.8 4 0.5.
If due to theophylline toxicity:
Administer activated charcoal: 50–100 g, followed by 50 g every 4 hr
Hemodynamically stable
Metoprolol 25–50 mg single oral dose
or
5 mg IV x two doses, each administered over 5 min, doses separated by 20 min
Verapamil 5 mg IV administered over 2–5 min; second 5-mg IV dose may be administered 20 min later
Magnesium 2 g IV administered over 10 min
DC = direct current; IV = intravenously; J = Joules.
tachycardia is a result of a theophylline overdose,
activated charcoal may administered.566
ECG by regular, narrow QRS complexes, often with
an absence of discernible p waves (Figure 25–8).
INFORMATION FOR PATIENTS
CAUSATIVE AGENTS
Patients who are taking drugs that are known to
cause atrial tachycardia should be instructed that
the drug may in rare cases cause the heart rate
(pulse) to become faster. Patients should be taught
to take their pulse and to monitor their heart rate
daily. Patients should be instructed to consult their
pharmacist or physician if the heart rate increases
above 100 to 120 bpm, or if they feel light-headed,
dizzy, tired, weak, or short of breath or experience
chest pain.
Drugs that have been associated with AVNRT are
listed in Table 25–26.483,506,509,539,585,596-632
AV NODAL RECIPROCATING
TACHYCARDIA
AV nodal reciprocating tachycardia (AVNRT) is the
most common form of the group of arrhythmias
commonly referred to as “paroxysmal supraventricular tachycardia.” AVNRT is characterized on
EPIDEMIOLOGY
The incidence of drug-induced AVNRT is largely
unknown. The incidence of AVNRT associated with
albuterol and dobutamine is presented in Table
25–26.
MECHANISMS
Mechanisms of drug-induced AVNRT are somewhat unclear. Non–drug-related AVNRT was previously thought to be caused by a reentrant circuit
involving the AV node, in which there is antegrade conduction over the slow-conducting por-
CHAPTER 25 • Supraventricular Arrhythmias
FIGURE 25–8. AV nodal reciprocating tachycardia at a
rate of 200 bpm associated with fluoxetine.
465
provoke AV nodal reentry. In cases of AVNRT that
occurred in association with continuous
furosemide infusions in infants or children after
cardiac surgery, the authors speculated that a
rapid change in intravascular volume may have
contributed to the development of the arrhythmias, possibly as a result of intercompartmental
electrolyte shifts.626 Overall, the mechanisms by
which drug-induced AVNRT occurs have not been
determined, but are likely related to stimulation
of premature atrial depolarizations, alterations in
AV nodal conduction velocity or repolarization,
or both.
Reproduced with permission from Gardner et al.624
tion of the circuit and retrograde conduction over
the faster-conducting portion.633,634 However, it is
now recognized that the reentrant circuit often is
not confined to the AV node, but involves perinodal tissue.567 AV nodal or perinodal reentry is
usually initiated by a premature atrial impulse
that “uncovers” the latent reentrant circuit by
creating the circumstances required for reentry,
namely creating unidirectional block in the fast
pathway and further slowing of impulse conduction down the slow pathway. Therefore, it is possible that drugs that cause AVNRT do so by
stimulating premature atrial depolarizations that
TABLE 25–26
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
The symptoms of drug-induced AVNRT are similar
to those of other tachyarrhythmias (Table 25–27),
and are related to heart rate and the resultant effect
on blood pressure and cardiac output. Ventricular
rates associated with drug-induced AVNRT can be
quite fast, ranging from 150 to 300 bpm.625,626,631
Conditions to consider in the differential diagnosis
of drug-induced AVNRT are presented in Table
25–28. The diagnosis of AVNRT must be made primarily on the basis of the appearance on ECG
(Figure 25–8).
Agents Implicated in Drug-Induced Atrioventricular Nodal Reciprocating Tachycardia
Drug
Incidence
Level of Evidence
(see page xii for explanation)
Albuterol483,596-604
Caffeine605-607,b
Carbamazepine608
Clozapine609
Dobutamine506,509,610-623
Enoximone610
Fluoxetine624, 625
Furosemide626
Ipratropium627,628
Methylprednisolone629,630
631
Phenylpropanolamine
Theophylline483,539,583,585,596,632
0–21%a
NK
NK
NK
0–12%
NK
NK
NK
0.5%
NK
NK
NKa
NK = not known.
a
Incidence reported to be up to 76% in patients receiving concomitant therapy with albuterol and theophylline.
b
Suicide attempt or overdose, 2.7–35 g caffeine ingested; 1 case with intravenous caffeine administration.
A
C
C
C
A
A
C
C
A
C
C
C
466
SECTION VI • Drug-Induced Cardiovascular Diseases
TABLE 25–27 Signs and Symptoms Associated
with Drug-Induced Atrioventricular Nodal
Reciprocating Tachycardia
•
•
•
•
•
Palpitations
Dizziness
Light-headedness
Shortness of breath
Chest pain (if underlying coronary artery disease is
present)
• Near-syncope
• Syncope
TABLE 25–28 Conditions to Consider in the
Differential Diagnosis of Drug-Induced
Atrioventricular (AV) Nodal Reciprocating
Tachycardia
•
•
•
•
•
•
Atrial fibrillation
Atrial flutter
Atrial tachycardia
Sinus tachycardia
AV nodal reentrant tachycardia not induced by drugs
Ventricular tachycardia
RISK FACTORS
Known or potential risk factors for drug-induced
AVNRT are presented in Table 25–29. Albuterolinduced AVNRT appears to be more likely in
patients receiving the drug intravenously, particularly at infusion rates >60 mcg/min.597,603 AVNRT
associated with dobutamine occurs more commonly in men than in women,615 and in elderly
patients.509,616 In addition, severity of myocardial
ischemia has been shown to be an independent
predictor of dobutamine-induced AVNRT; in a
study of 1,076 patients undergoing dobutamine
stress myocardial perfusion imaging, the mean
myocardial infarction score (calculated based on
assessment of fixed perfusion defects during
myocardial perfusion scintigraphy) was 4.4±4.1 in
patients with AVNRT, as compared with 2.8±3.5 in
those without it, and the infarction score was an
independent predictor of AVNRT.616
All of the reported cases of AVNRT associated
with continuous furosemide infusions (n = 3
patients) have occurred in infants or children
after cardiac surgery. In these patients, the
arrhythmia occurred within 3 to 7 hours after the
initiation of a furosemide infusion of 1.0
TABLE 25–29 Risk Factors for Drug-Induced
Atrioventricular Nodal Reciprocating Tachycardia
Albuterol
• Continuous intravenous infusion
• Intravenous infusion rate >60 mcg/min
• Concomitant therapy with theophylline
Dobutamine
• Male sex
• Elderly
• Myocardial infarction score on dobutamine stress test
Furosemide
• Reported only in infants or children following cardiac
surgery
• Continuous infusion resulting in profound diuresis
(8–10 mL/kg /hr)
Theophylline
• Serum theophylline concentrations >20 mcg /mL
• Concomitant therapy with albuterol
mg/kg/hr. A common factor in these three
patients was substantial diuresis resulting from
the furosemide, in the range of 8 to 10 mL/kg/hr,
as compared with an average fluid elimination of
2.5 mL/kg/hr in 22 other patients who had
received a similar furosemide infusion.626 Serum
potassium concentration was below normal limits in one of the three patients in whom the
arrhythmia developed, but remained normal in
the other two cases. Therefore, it is possible that
a large amount of fluid loss may be a risk factor
or predictor of drug-induced AVNRT in infants or
children receiving a continuous infusion of
furosemide after cardiac surgery. Serum theophylline concentration is a risk factor for theophylline-induced supraventricular arrhythmias;
new supraventricular arrhythmias were reported
in 7 patients with serum theophylline concentrations between 21 and 40 mcg/mL.585 Risk factors
for AVNRT associated with other drugs have not
been identified.
MORBIDITY AND MORTALITY
Drug-induced AVNRT may result in symptoms sufficient to result in presentation to the emergency
department and hospitalization.605,606,624,628 In
addition, drug-induced AVNRT may result in prolongation of stays in the intensive care unit and
the hospital.625,626 Mortality associated with druginduced AVNRT is likely quite rare.
CHAPTER 25 • Supraventricular Arrhythmias
TABLE 25–30 Approaches to Help Prevent DrugInduced Atrioventricular Nodal Reciprocating
Tachycardia
Albuterol
• Avoid continuous intravenous infusions at rate >60
mcg/min
• Avoid concomitant therapy with theophylline
Furosemide
• Avoid diuresis of volumes >2.5 mL /kg /hr over periods
of 3–7 hr in infants/children after cardiac surgery
Theophylline
• Maintain serum theophylline concentrations <20
mcg /mL
• Avoid concomitant therapy with albuterol
PREVENTION
The likelihood of albuterol-induced AVNRT may be
reduced by avoiding continuous intravenous infusions at doses >60 mcg/min (Table 25–30).
Combinations of drugs that may induce AVNRT
should be avoided, particularly the concomitant
administration of albuterol and theophylline. In
the cases of furosemide-induced AVNRT in infants
and children after cardiac surgery, substantial fluid
elimination appears to have been a risk factor, and
in that population, avoidance of diuresis of vol-
TABLE 25–31
467
umes >2.5 mL/kg/hr over periods of 3 to 7 hours
may minimize the risk.626 Maintaining serum theophylline concentrations <20 mcg/mL reduces the
risk of theophylline-induced supraventricular
arrhythmias.
MANAGEMENT
Management options for drug-induced AVNRT are
presented in Table 25–31. As with other druginduced arrhythmias, initial management of druginduced AVNRT is discontinuation of therapy with
the offending agent. If the patient is hemodynamically unstable, synchronized direct-current cardioversion should be administered, using an initial
energy of 50 J.567 Sedation of the patient is always
preferred unless hemodynamic instability is so
severe that there is no time for sedation. If the initial conversion attempt is unsuccessful, subsequent
attempts at conversion should be made with
increasing amounts of energy (100 J, 200 J, 300 J,
360 J).567
In patients who are hemodynamically stable,
drug-induced AVNRT may respond to agents typically used to treat non–drug-induced AVNRT.
Adenosine has been found to be effective for
AVNRT associated with albuterol600,604 and may be
used as a drug of first choice for hemodynamically
Management Options for Drug-Induced AV Nodal Reciprocating Tachycardia
In hemodynamically unstable patients:
Discontinue the offending agent
Synchronized DC cardioversion (initial energy 50 J,
followed by 100 J, 200 J, 300 J, 360 J if necessary).
In hemodynamically stable patients:
Discontinue the offending agent
Vagal maneuvers (cough, carotid sinus massage, Valsalva)
Adenosine 6 mg IV rapid bolus, followed by saline flush
If no response within 2 minutes, adenosine 12 mg IV rapid
bolus, followed by saline flush
If no response within 2 minutes, adenosine 12 mg IV rapid
bolus, followed by saline flush
If no response to adenosine, and patient has LVEF > 40%
and/or no history of heart failure: Diltiazem 0.25 mg/kg IV
bolus, followed if necessary by 0.35 mg/kg IV bolus, followed by continuous infusion of 5-15 mg/hr; or verapamil
0.075-0.15 mg/kg IV over 2 minutes
If no response to adenosine, and patient has LVEF < 40%
and/or a documented history of heart failure: Digoxin 0.25
mg IV every 2 hours, up to total dose of 1.5 mg
DC = Direct current; IV = intravenously; J = Joules; LVEF = Left ventricular ejection fraction
468
SECTION VI • Drug-Induced Cardiovascular Diseases
stable AVNRT.567 Intravenous verapamil 2.5 mg has
been effective for terminating AVNRT associated
with fluoxetine.625 Intravenous verapamil should
be avoided in patients with left ventricular dysfunction567; in this population, intravenous digoxin should be administered.
INFORMATION FOR PATIENTS
Patients who are taking drugs that may cause
AVNRT should be instructed that the medication
may, in rare instances, cause the heart rate (pulse)
to become faster. Patients should be instructed to
take their pulse daily and to consult their pharmacist or physician if the heart rate increases to above
100 to 120 bpm, or if they feel palpitations, lightheaded, dizzy, tired, weak, or short of breath or
experience chest pain.
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