Full text of DOI:10.1111/j.1553-2712.2001.tb01275.x

ACADEMIC EMERGENCY MEDICINE • February 2001, Volume 8, Number 2
117
Meta-analysis of the Risk of Torsades de Pointes in
Patients Treated with Intravenous Racemic Sotalol
KEITH A. MARILL, MD, TIM RUNGE, MD
Abstract. Objective: Intravenous (IV) racemic so- associated with IV sotalol treatment. Results: The
talol is useful for the treatment of multiple tachydys- search included 1,005 publications. There were 37 re-
rhythmias. The authors hypothesized that the risk of ports in which 962 patients received IV sotalol and
torsades de pointes (TdP) in patients treated with a met the inclusion criteria. There was one report of
single IV infusion of sotalol is lower than the 2–4% self-terminating TdP lasting 10 seconds among the
risk associated with chronic oral sotalol therapy. 962 patients included in the study. There was no re-
Methods: A MEDLINE search under the subject port of TdP associated with only IV racemic sotalol
heading ‘‘sotalol’’ was made of all publications involv- administration in any of the excluded studies. If it is
ing humans written in English or German from 1966 assumed that the risk of TdP is homogeneous in the
to October 1, 2000. A meta-analysis of all original re- population of patients treated with IV sotalol, then
ports including patients who were given a single in- based on the 962 included patients, the rate of TdP
fusion of at least 1.5 mg/kg or 100 mg of IV sotalol is 0.1% (95% CI = 0.003% to 0.6%). Conclusions: The
over 30 minutes or less was performed. Potential var- overall risk of TdP in patients treated with a single
iables predictive of TdP were assessed. The primary infusion of IV sotalol is low compared with that in
outcome was the observation of TdP associated with patients given chronic oral sotalol therapy. Key
IV sotalol infusion. Secondary measurements in- words: sotalol; torsades de pointes; tachycardia, ven-
cluded hypotension, bradycardia, and worsening of tricular; tachycardia, supraventricular; infusions, in-
congestive heart failure. All excluded studies and travenous; adverse effects. ACADEMIC EMER-
case reports were also examined for evidence of TdP GENCY MEDICINE 2001; 8:117–124
ACEMIC sotalol is a 1:1 mixture of the en-
Intravenous racemic sotalol terminates about
R
antiomers d and l sotalol. It has Vaughan- 70% of cases of atrioventricular nodal reentrant
Williams class II and class III antidysrhythmic and atrioventricular reciprocating tachycardias6–9
properties. Both isomers prolong the myocardial It is not as effective as adenosine or verapamil,10
action potential and the effective refractory period but it may be useful for patients with recurrent or
by blocking the slow potassium rectifier current. refractory supraventricular tachycardias (SVTs),
The l-isomer is also a nonselective beta-adrenergic particularly when calcium-channel blockers are
antagonist with no intrinsic sympathomimetic ac- contraindicated. The effective refractory period is
tivity.1
usually increased after sotalol administration in
A single infusion of intravenous (IV) racemic so- all myocardial tissue, including bypass tracts,
talol has multiple potential uses in the emergency which are present in patients with Wolff-Parkin-
setting. It has been shown to terminate sustained son-White (WPW) syndrome.11–14 It is for this rea-
ventricular tachycardia (VT) in 70% of cases, son that racemic sotalol may be particularly useful
which was significantly better than the results in slowing the rapid ventricular response to atrial
achieved with lidocaine.2 It may also prove to be fibrillation that may occur in patients with WPW
useful in the termination and suppression of re- syndrome.15,16
fractory VT3 and VT associated with acute myo-
Clinical enthusiasm for the use of IV sotalol has
cardial infarction (MI),3,4 and to facilitate defibril- at least partly been tempered by its potential to
lation of ventricular fibrillation.5
act as a prodysrhythmic agent as well as to induce
other adverse effects that may be related to its
beta-adrenergic antagonist properties such as bra-
dycardia, atrioventricular nodal (AV) block, hypo-
tension, and bronchospasm. Chronic oral admin-
istration of sotalol is associated with a 2–4% risk
of torsades de pointes (TdP).17–19 By definition, TdP
occurs in association with a prolonged corrected
QT (QTc) interval. Other factors that may contrib-
ute to its occurrence include an increase in inho-
mogeneity of repolarization, which may manifest
From New York University/Bellevue Medical Center, New
York, NY (KAM); and Texas Tech University Health Sciences
Center, El Paso, TX (TR).
Received June 26, 2000; revision received: October 10, 2000;
accepted October 16, 2000.
Address for correspondence: Keith A. Marill, MD, Emergency
Care Institute, Room 345A, Bellevue Hospital Center, 27th
Street and 1st Avenue, New York, NY 10016. Fax: 212-562-
3001; e-mail: marilk01@med.nyu.edu
Reprints are not available.

118
SOTALOL
Marill, Runge • IV SOTALOL AND TORSADES DE POINTES
as increased dispersion of the QTc interval,20–22 resented twice could be obtained, then both studies
and the presence of early afterdepolarizations were included but the duplicate patients were ex-
(EADs).23 We hypothesized that the risk of TdP is cluded from the second study.
lower in patients who receive a single IV infusion
of sotalol than in those who receive chronic oral Measurements. For the articles under study,
therapy. We performed an analysis of all studies in available data were collected with regard to pa-
the English and German literature in which pa- tient characteristics potentially associated with
tients received at least a 1.5-mg/kg or 100-mg IV the occurrence of TdP or other adverse events.
infusion of racemic sotalol over 30 minutes or less Characteristics such as female gender, history of
to determine the risk of occurrence of TdP, and ventricular dysrhythmias and left ventricular dys-
other adverse effects.
function, greater magnitude of QT-interval prolon-
gation, and hypokalemia increase the risk of TdP
in patients given oral sotalol.1,17–19 If subgroups of
included patients were described in sufficient de-
tail, the characteristics of each subgroup were de-
scribed.
The descriptions of TdP or any other adverse
effects thought to be related to treatment with IV
sotalol were analyzed. If the adverse effects of IV
sotalol were inadequately or not specifically de-
scribed, the primary authors were contacted and
asked: ‘‘Were there are any adverse effects includ-
ing proarrhythmia such as torsades de pointes, hy-
M
ETHODS
Study Design. This study was a meta-analysis of
the risk of TdP associated with infusion of thera-
peutic doses of IV racemic sotalol. All available
original human research and case reports in the
English and German literature over a 34-year pe-
riod were eligible for inclusion. Included individual
studies were approved by respective local institu-
tional review processes.
Study Protocol. A National Library of Medicine potension, or bradycardia after administration of
MEDLINE search under the subject heading ‘‘so- IV sotalol?’’ All historical and diagnostic assess-
talol’’ was performed for all studies involving hu- ments were determined by the primary authors
mans occurring from 1966 to October 1, 2000. The and treating physicians according to their own
search was performed separately for English and criteria.
German language articles. All available abstracts
For each study included in the analysis, the
of the articles were reviewed. The articles whose number of different patients who met the inclusion
abstracts or titles described patients who might criteria and the dosages and durations of the so-
meet the enrollment criteria of our study were ob- talol infusions were documented. The sex, mean
tained and reviewed. Other studies in the bibliog- age, and past cardiac history of the patients were
raphy sections of these articles that were consid- recorded. This data set included any history of
ered relevant were also obtained and read.
coronary artery disease (CAD) or MI, which were
All original studies or case reports that de- classified separately, left ventricular aneurysm,
scribed the IV administration of a bolus of at least congestive heart failure (CHF) or congestive car-
1.5 mg/kg or 100 mg of racemic sotalol over 30 diomyopathy, hypertension, valvular heart disease,
minutes or less to one or more patients were in- or an explicit statement of the absence of known
cluded in the meta-analysis. Any patients in the cardiac disease. Frequently, the age and sex of the
included studies who received less than 1.5 mg/kg patients included in the analysis were presented
or 100 mg, or in whom the medicine was infused in addition to the data of excluded patients. For
over more than 30 minutes, were excluded. these studies the demographic data of the entire
Whether a subject’s single initial dose was followed group of patients are described. Any previous
by a prolonged IV infusion or ‘‘drip’’ of longer du- knowledge of the presence or absence of dysrhyth-
ration or recurrent infusions had no bearing on in- mias was recorded. Whether therapy with all other
clusion in this study. No study was excluded based antidysrhythmic medicines excluding digoxin was
on study design. Review articles that summarized stopped for at least four half-lives prior to sotalol
previously reported data were not included. Au- administration was noted. A stated history of the
thors who had published multiple studies were presence of asthma was documented.
contacted to confirm that the treatment of an in-
The cardiac rhythms at the time of sotalol in-
dividual patient had not been described multiple fusion were noted. If it was implied but not explic-
times, and that the same patient had not been itly stated by the authors that the patients had a
treated on multiple occasions. If either of these sinus rhythm, the rhythm was classified as ‘‘pre-
conditions was confirmed, then the study with the sumed sinus.’’ If, after review, the cardiac rhythm
largest number of patients was included, and the could not be determined it was defined as uncer-
other study or studies were excluded. However, if tain. It was noted whether a patient was experi-
a precise description of the patients who were rep- encing an MI at the time of sotalol infusion.

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119
T
ABLE 1. History of Cardiac Disease in the Study
The patients’ average weight, heart rate, and
systolic, diastolic, and mean blood pressures were
recorded, if available. The average QT and QTc in-
tervals of conducted supraventricular beats on the
electrocardiogram (ECG), the left ventricular ejec-
tion fraction, which may have been measured by a
Population
Number of
Patients
Cardiac Disease
Coronary artery disease
Myocardial infarction
239
57
variety of modalities, and the serum potassium Left ventricular aneurysm
12
Congestive heart failure or dilated cardio-
and magnesium were recorded.
myopathy
11
24
21
Adverse effects attributed to sotalol infusion,
including the occurrence of TdP, CHF or dyspnea,
presyncope, hypotension, either asymptomatic or
symptomatic, heart block or bradycardia, which
may or may not have occurred after cardioversion,
and other dysrhythmias such as premature ven-
tricular contractions (PVCs) or nonsustained VT,
Hypertension
Valvular heart disease
None
184
Total N = 536 patients where a history of cardiac disease was
described. Multiple diseases were described in some patients.
were recorded. The occurrence of TdP in patients been enrolled and described in another included
who received IV racemic sotalol but were excluded study.2 One study45 was excluded because the re-
from the study was also noted. If there was any sults had been previously described.44 The mean
uncertainty with regard to the interpretation of an and median number of patients included per arti-
adverse effect or another aspect of an individual cle were 26.7 and 17.0, respectively, and the min-
study, the primary study authors were contacted imum and maximum numbers of patients included
and questioned.
from an individual article were 2 and 109.
Age and sex were described precisely for 572
patients of interest. There were 423 men and 149
women, with a male:female ratio of 2.84:1, and the
average age was 56.1 years. There were 292 pa-
tients included in the study who were described,
in addition to 106 patients who were excluded. For
this group of 398 patients, the male:female ratio
was 2.06:1, and the average age was 52.1 years.
There were 98 included patients whose age and sex
were not stated.
The presence or absence of a history of cardiac
disease was defined for 536 patients, and is de-
scribed in Table 1. The history of dysrhythmias
was stated for 843 patients and the primary dys-
rhythmia of interest for each patient is presented
in Table 2. In 832 patients all antidysrhythmic
agents excluding digoxin were stopped for at least
Data Analysis. The SPSS software package
(SPSS, Version 9.0, SPSS Inc., Chicago, IL) was
used to tabulate data and Statxact software
(Statxact 3, Version 3.0.2, Cytel Software Corpora-
tion, Cambridge, MA) was used to calculate exact
95% confidence intervals (95% CIs). The estimated
rate and 95% CI of occurrence of TdP and other
adverse effects were calculated by pooling data from
the studies included in the analysis.24 The Free-
man-Halton extension of Fisher’s exact test was
used to determine whether there was an association
between the occurrence of hypotension and the car-
diac rhythm at the time of sotalol administration.
RESULTS
The English- and German-language MEDLINE four half-lives or 24 hours prior to administering
searches yielded 932 and 73 articles, respectively. sotalol. Fifteen patients were noted to have a his-
One hundred sixteen full articles were obtained tory of asthma.
and evaluated for inclusion. Both investigators in-
The cardiac rhythms of all the patients at the
itially reviewed abstracts and collected data on in- time of sotalol administration are shown in Table
cluded studies, although ultimately one investiga- 3. Ten patients in two studies were experiencing
tor (KAM) reviewed all abstracts, titles, and an acute MI at the time of sotalol infusion.2,4 The
collected data. There were 35 English- and two average heart rate before sotalol administration
German-language articles in which one or more was stated for 287 patients. Average heart rate as
patients were treated with IV racemic sotalol with a function of heart rhythm was as follows for the
a protocol that met the inclusion criteria. A total larger patient groups: presumed sinus rhythm (n
of 962 unique patients described in the 37 articles = 128) was 79 beats/min, atrial fibrillation (n =
were included in the analysis.2–4,6–9,11,15,16,25–52
A
120) was 137 beats/min, SVT (n = 10) was 173
subgroup of 25 patients in one article33 and all of beats/min, and VT (n = 18) was 176 beats/min. Av-
the patients in another article52 were excluded be- erage blood pressure prior to treatment was stated
cause some of them had also been enrolled in a for 105 patients. The systolic and diastolic values
larger included study performed by the same re- were 133 and 82 mm Hg. The average weight, cor-
search group.34 Two patients were excluded from rected QT interval, and ejection fraction were
an included study43 because the individuals had stated for 188, 130, and 184 patients, respectively.

120
SOTALOL
Marill, Runge • IV SOTALOL AND TORSADES DE POINTES
T
ABLE 2. History of Dysrhythmias in the Study Population
plasma potassium and magnesium, and the QT in-
terval was 360 msec. The patient was given 1.5
mg/kg (120 mg) sotalol over 15 minutes for chem-
ical cardioversion of atrial fibrillation. Sixteen
minutes after the infusion was begun, the patient
had a 10-second episode of TdP, which was asso-
ciated with mild dizziness. The TdP terminated
spontaneously, after which magnesium infusion
was administered to prevent recurrence. The QT
interval was 500 msec, with a mean heart rate of
85 beats/min before this event. The patient sub-
sequently converted from atrial fibrillation to sinus
rhythm 41 minutes after the start of the sotalol
infusion with no further TdP noted. There was no
other instance of TdP in the population under
study, and there was no report of TdP associated
with only IV racemic sotalol administration in any
of the excluded studies. If it is assumed that the
rate of TdP is homogeneous in the sample of 962
patients included in the study, then the rate of TdP
is 0.1% (95% CI = 0.003% to 0.6%).
Number of
Dysrhythmia
Patients
SVT (type unspecified)
AV nodal SVT
AV SVT with nonconcealed bypass tract
(WPW)
AV SVT with concealed bypass tract
WPW, dysrhythmia unspecified
Atrial fibrillation
124
14
48
11
6
208
38
17
Atrial flutter
Atrial fibrillation or flutter
Wide QRS complex tachycardia or tachy-
cardia of uncertain etiology
Premature ventricular contractions
Nonsustained VT
14
21
2
97
10
217
6
Sustained VT
VT (duration unspecified)
Sustained VT or ventricular fibrillation
Ventricular fibrillation
None
10
Total N = 843 patients where a history of dysrhythmia was
described, and each patient is represented only once by the
dysrhythmia of primary interest. SVT = supraventricular
tachycardia; AV = atrioventricular; WPW = Wolff-Parkinson-
White syndrome; VT = ventricular tachycardia.
Of the patients included in the analysis, asymp-
tomatic hypotension was reported in five,35 and 13
had hypotension with uncertain symptomatol-
ogy.7,32,43 Five patients experienced symptomatic
The average values were a weight of 77.6 kg, a hypotension or presyncope that did not necessitate
corrected QT interval of 411 milliseconds, and specific treatment.6,7 Two patients had hypotension
an ejection fraction of 40%. An average plasma that responded to fluid replacement,41 two required
potassium of 4.0 mmol/L and magnesium of 0.88 discontinuation of therapy,7 and two required both
mmol/L were noted in 92 and 52 patients, re- fluid replacement and discontinuation of therapy.51
spectively.35,51
In one study, 30 patients were given sotalol while
Fifty-seven patients received a fixed dose of so- in VT.2 One of 16 who received sotalol as a first
talol and 905 patients received a weight-based drug became hypotensive, lost consciousness, and
dose. Among the patients who received a fixed required electrical cardioversion. Two of 14 pa-
dose, 46 received 100 mg, ten received 120 mg, and tients who received sotalol after lidocaine lost con-
one received 150 mg. Among the patients who re- sciousness and required cardioversion. One pa-
ceived a weight-based dose, 887 received 1.5 tient, a 90-year-old man with CHF, renal failure,
mg/kg and 18 received 2.0 mg/kg. The minimum and a serum potassium level of 6.3 mEq/L, became
duration of infusion of sotalol was 1 minute and hypotensive, developed asystole, and died after re-
the maximum, defined as a study exclusion crite- ceiving lidocaine and sotalol. The rate of all forms
rion, was 30 minutes. The mean and median du- of hypotension or presyncope as a function of the
rations of infusion were 13.6 and 10 minutes, re- cardiac rhythm at the time of sotalol administra-
spectively.
tion in the meta-analysis was as follows: sinus or
There were 12 trials involving 219 in- presumed sinus 3 of 545 (0.5%), SVT or atrial fi-
cluded patients in which the description of ad- brillation or flutter 26 of 379 (6.9%), and VT 4 of
verse effects due to IV sotalol was limited or ab- 31 (13.3%), p < 0.0001.
sent.9,26–28,36–38,42,43,47,49,50 One of the primary authors
Ten patients developed bradycardia and four
of each of these studies was contacted for clarifi- patients were thought most likely to have nonsus-
cation. Close clinical monitoring was described in tained monomorphic VT as opposed to SVT with
association with IV sotalol infusion in all of these aberrancy.32,35 Five patients developed transient
studies, and in 11 studies the infusion was per- asymptomatic bradycardia2 or new dysrhythmias6
formed in the electrophysiology lab.
after cardioversion with sotalol. One patient re-
Of the 962 patients included in the study, one ceived atropine and adrenaline for sinus bradycar-
patient was known to develop TdP after receiving dia associated with hypotension (Joseph AP, per-
IV sotalol35; a 62-year-old woman with a prior an- sonal communication, 2000).51 None of the other
terior MI presented with atrial fibrillation and a dysrhythmias were noted to require specific inter-
mean ventricular rate of 100 beats/min. The pa- vention.
tient had normal renal function with normal
Two patients developed ‘‘mild CHF’’44 and two

ACADEMIC EMERGENCY MEDICINE • February 2001, Volume 8, Number 2
121
developed ‘‘dyspnea.’’7 There was no report of bron-
chospasm. Three patients experienced AV block ne-
cessitating discontinuation of sotalol infusion.32
There was one death directly associated with so-
talol administration as noted above.
T
ABLE 3. Cardiac Rhythm at the Time of Initiation of
Sotalol Infusion
Number of
Patients
Rhythm
Sinus rhythm
62
475
8
247
28
17
87
31
7
Presumed sinus rhythm
Sinus with demand right ventricular pacemaker
Atrial fibrillation
DISCUSSION
Atrial flutter
The primary interest of this meta-analysis was to
determine the rate of TdP associated with the IV
administration of racemic sotalol. All studies with
therapeutic sotalol regimens of less than 1.5
mg/kg or 100 mg were excluded because these
doses have proven effective in the termination of
VT and SVT.2,6–9 Studies where the stated infusion
duration was more than 30 minutes were also ex-
cluded. Although it is uncertain whether longer in-
fusions would be as effective and associated with
the same risk of TdP, their application would be
less desirable in an emergency setting. The inclu-
sion of studies with lower total doses and longer
infusion durations might have lowered the per-
ceived risk of TdP while not representing the reg-
imen necessary for effective treatment.
This analysis used the pooling method for com-
bining data from divergent studies. In the homo-
geneous case, where the same value appears to be
measured in each study, it is most common to cal-
culate a weighted mean statistic where the
weights are the inverse of the variance of each in-
dividual value.53,54 In all but one study in this anal-
ysis there were 0 cases of TdP. Consequently, the
variances in these studies would be zero and the
inverse would be infinity. In this situation the sta-
tistic may be approximated by pooling the data.24
Other more complex models and techniques that
approximate the variance within and between
studies can be used.55 Ultimately, given the variety
of designs and sizes of studies and the incomplete
predictor data set in this meta-analysis that could
confound any model, the simplest and most trans-
parent appropriate combining methodology was
chosen.
Atrial fibrillation or flutter
Supraventricular tachycardia
Ventricular tachycardia
Uncertain
Total N = 962 patients.
mg/L were measured 5 minutes after rapid sotalol
infusions of 1 and 5 minutes, respectively, in one
study, but there was no corresponding peak in the
duration of the right ventricular effective refrac-
tory period (RVERP).41 When plasma concentra-
tions are comparable, there is conflicting evidence
of differential prolongation of the QT interval and
RVERP between oral and IV treatments.26,47,49
There may also be differential beta-adrenergic an-
tagonist effects, although the magnitudes of in-
duced bradycardia are similar.26,31,47,49 If there are
differential effects at similar plasma levels, it is
postulated this could be due to tissue accumulation
of the drug with chronic oral treatment or the pres-
ence of active metabolites. To date, no active me-
tabolites have been identified.1
Patients who received IV sotalol for termination
of tachydysrhythmias may have been protected
from developing TdP for multiple reasons. First,
tachycardic patients have a shortened QT interval
irrespective of medical therapy. Second, there is
conflicting evidence that sotalol has the property
of reverse use-dependence.7,28,42 The phenomenon
of reverse use-dependence refers to a relative de-
crease in the prolongation of the action potential
and refractory period as a function of increasing
heart rate. If sotalol does manifest reverse use-de-
pendence, then TdP may be relatively less likely to
occur after sotalol administration to tachycardic
patients. Studies in which sotalol was adminis-
tered IV often included invasive electrophysiologic
procedures. The increased adrenergic tone and sec-
ondary tachycardia that may be associated with
these investigations56 may have been protective,
regardless of the cardiac rhythm.
There was only one case of TdP after treatment
with IV racemic sotalol and the rate of TdP, 0.1%
(95% CI = 0.003% to 0.6%), was significantly
lower than the 2–4% risk associated with oral
sotalol treatment. Why is this so? Certainly the du-
ration of exposure is longer with chronic oral
therapy. MacNeil et al., however, found that the
majority of known TdP occurred within the first
three days of starting or adjusting the dose of oral
sotalol treatment.17 Average plasma sotalol levels
of 1.7 to 4.0 mg/L were comparable after IV infu-
sion7,25,26,30,31,40,44,46,48 and during oral therapy with
commonly used doses.26,31,44,47 However, plasma lev-
It is difficult to compare the rates of TdP asso-
ciated with the IV infusion of different class III
antidysrhythmics. The patient populations, infu-
sion protocols, and study designs are highly vari-
able. Despite these limitations, it is interesting to
note that prolonged IV infusions of amiodarone for
els may not directly reflect cardiac electrophysio- the treatment of refractory or recurrent VT have
logic activity. Peak plasma levels of 5.4 and 4.0 been described in multiple trials. In this popula-

122
SOTALOL
Marill, Runge • IV SOTALOL AND TORSADES DE POINTES
tion of severely ill patients, the rate of TdP was that was derived may be an approximation reflect-
about 1%.57,58 The rate of TdP was 1–3% in trials ing the characteristics of the sample populations
that have been investigated.
involving patients with a variety of dysrhythmias
treated with various doses of IV ibutilide.32,59–61
Torsades de pointes has not been associated with
infusion of bretylium62–64 or lidocaine,2,65,66 a class
IB antidysrhythmic.
The reporting of adverse events, including TdP,
may have suffered from multiple biases. There
may have been bias toward disproportionate re-
porting of adverse events because it allows the
publication of case reports. Conversely, the major-
ity of included studies were designed to test effi-
cacy and electrophysiologic effects, not toxicity.
Twelve reports inadequately addressed the ad-
verse effects of IV sotalol. Furthermore, authors
may have been less likely to monitor closely for or
to report adverse events that would diminish the
perceived utility of a novel therapeutic approach.
Post-infusion monitoring was not standardized in
the included studies. Some self-limited cases of
TdP may simply not have been observed. However,
most infusions were performed in the electrophys-
iology lab. It is likely that patient monitoring after
IV infusion was more intense than that experi-
enced by patients receiving oral sotalol on a
chronic basis, and if TdP were to have occurred
after sotalol infusion, it would likely have occurred
early during this intense monitoring period. Thus,
if this was a source of bias, it is unlikely to have
caused a qualitative change in the primary result.
The majority of patients in this meta-analysis
were treated with IV sotalol only after other anti-
dysrhythmics had been stopped for four half-lives
or 24 hours. The presence of other agents could
affect both the efficacy and, in particular, the tox-
icity of IV sotalol. This may limit the generaliza-
bility of our findings to ED patients who present
while taking chronic oral antidysrhythmic therapy.
The database regarding the efficacy and ad-
verse effects of IV sotalol is encouraging but
limited. Future prospective studies should be per-
formed to confirm sotalol’s utility in the manage-
ment of a variety of tachydysrhythmias and to clar-
ify further its adverse effect profile.
Hypotension was the most common adverse ef-
fect reported in the meta-analysis. It was most
common and severe in patients who received so-
talol alone or after lidocaine for termination of VT.
Considering only the initial treatment of VT, the
rates of hypotension were similar in the patients
randomized to sotalol (1 of 16, 6.3%) and lidocaine
(1 of 17, 5.9%).2 In the only other prospective trial
of medical treatment of spontaneous stable VT, hy-
potension was observed in two of 27 (7.4%) cases
treated with lidocaine and one of 28 (3.6%) treated
with procainamide.65 Despite the descriptive term
‘‘stable,’’ patients with this condition often have
profound underlying cardiac illness. In a retro-
spective study of spontaneous sustained stable VT,
the mortality associated with current treatment
regimens was two of 40 (5%).67
Because the l-isomer of sotalol is a nonspecific
beta-adrenergic antagonist, adverse effects associ-
ated with this class of drugs might be expected.
Two patients developed dyspnea, but there was no
case of bronchospasm despite the administration of
sotalol to some patients with known reactive air-
ways disease.41 Nevertheless, exacerbation of bron-
chospasm has been described in association with
oral racemic sotalol ingestion.68 Sinus bradycardia
and AV block necessitating discontinuation of ther-
apy were also rarely observed. These adverse
events may be related to both class II and class III
effects.69
LIMITATIONS AND FUTURE QUESTIONS
This meta-analysis had multiple limitations. The
literature search was limited to two languages
in the MEDLINE database, and associated bib-
liographies. There may be unincluded studies
that were referenced in other indexes but not in
MEDLINE, or were written in other languages.
However, it is unlikely exclusion of such studies
would have biased the results.
When analyzing the rate of TdP associated with
IV sotalol administration, it was assumed that the
rate is homogeneous. While there currently are in-
sufficient data to determine whether this assump-
tion is valid, consideration of the data regarding
oral sotalol therapy suggests that the rate is not
homogeneous. Risk factors for TdP in association
with oral sotalol treatment include female sex, his-
tory of VT or ventricular fibrillation, history of
CONCLUSIONS
Intravenous racemic sotalol is an effective medi-
cation for the termination or control of multiple
dysrhythmias. Torsades de pointes is an important
but rare complication of IV therapy. Torsades de
pointes occurred in association with the adminis-
tration of therapeutically proven doses in one of
962 (0.1%, 95% CI = 0.003% to 0.6%) cases, which
is substantially lower than the rate associated
with chronic oral sotalol therapy. Other reported
complications include hypotension, AV block, and
bradycardia. Further study of the utility of this
medicine in the emergency setting is warranted.
Unpublished details were kindly provided by Drs. Johann
CHF, and higher daily dose.17,19 Thus, the value Reisinger, Bramah Singh, Pramesh Kovoor, Elwyn Lloyd, P. J.

ACADEMIC EMERGENCY MEDICINE • February 2001, Volume 8, Number 2
123
19. Lehmann MH, Hardy S, Archibald D, Quart B, MacNeil
DJ. Sex difference in risk of torsades de pointes with d,l-so-
talol. Circulation. 1996; 94:2535–41.
20. Tan HL, Wilde AAM. T wave alternans after sotalol: evi-
dence for increased sensitivity to sotalol after conversion from
atrial fibrillation to sinus rhythm. Heart. 1998; 80:303–6.
21. Verduyn SC, Vos MA, Van der Zande J, Van der Hulst FF,
Wellens HJ. Role of interventricular dispersion of repolariza-
tion in acquired torsade-de-pointes arrhythmias: reversal by
Commerford, Rob Scott Millar, David Ho, Hung-Fat Tse, James
T. Vanderlugt, Claus Schmitt, Martin Karch, Tony Joseph, Ste-
phen Huang, Johannes Brachmann, Andre Waleffe, A. John
Camm, Matthias Antz, Klaus-Peter Kunze, Karl-Heinz Kuck,
Harry A. Kopelman, Thomas Meinertz, Ching-Tai Tai, Wen-
Chung Yu, Shih-Ann Chen, R. Stroobandt, and Peter Kowey.
The authors are grateful to Drs. Marc Vos, John Uther, and
Jochen Senges for their kind assistance in contacting authors,
to Drs. Sigrid Wolfram and Irwin Marill for assistance with magnesium. Cardiovasc Res. 1997; 34:453–63.
22. Hii JT, Wyse DG, Gillis AM, Duff HJ, Solylo MA, Mitchell
translation, to Dr. Lewis Goldfrank for editorial assistance,
and to Drs. Brian Nelson, Roger Lewis, and Sharon-Lise Nor-
mand for statistical advice and guidance.
LB. Precordial QT interval dispersion as a marker of torsade
de pointes. Disparate effects of class Ia antiarrhythmic drugs
and amiodarone. Circulation. 1992; 86:1376–82.
23. Vos MA, Verduyn SC, Gorgels APM, Lipcsei GC, Wellens
HJ. Reproducible induction of early afterdepolarizations and
torsades de pointes arrhythmias by D-sotalol and pacing in
dogs with chronic atrioventricular block. Circulation. 1995; 91:
864–72.
24. Ingelfinger JA, Mosteller F, Ware JH, Thibodeau LA. Us-
ing meta-analysis for research synthesis: pooling data from
several studies. In: Biostatistics in Clinical Medicine, 3rd Edi-
tion. New York: McGraw-Hill, 1994, p 340.
25. Rehm KD, Schnelle K, Dyde CJ, Blumner E, Arendts W.
Plasmaspiegel und Wirkung von Sotalol-HCl auf EKG-Zeitin-
tervalle nach parenteraler Applikation an gesunde Probanden.
Arzneimittelforschung. 1987; 37:1058–62.
26. Creamer JE, Nathan AW, Shennan A, Camm AJ. Acute
and chronic effects of sotalol and propanolol on ventricular re-
polarization using constant-rate pacing. Am J Cardiol. 1986;
57:1092–6.
27. Dickhuth HH, Bluemner E, Auchschwelk W, Zehnder M,
Irmer M, Meinertz T. The relationship between heart rate and
QT interval during atrial stimulation. Pacing Clin Electro-
physiol. 1991; 14:793–9.
28. Schmitt C, Brachmann J, Karch M, et al. Reverse use-
dependent effects of sotalol demonstrated by recording mono-
phasic action potentials of the right ventricle. Am J Cardiol.
1991; 68:1183–7.
29. Millar RN. Efficacy of sotalol in controlling reentrant su-
praventricular tachycardias. Cardiovasc Drugs Ther. 1990;
4(suppl 3):625–9.
30. Rizos I, Senges J, Jauernig R, et al. Differential effects of
sotalol and metoprolol on induction of paroxysmal supraven-
tricular tachycardia. Am J Cardiol. 1984; 53:1022–7.
31. Edvardsson N, Hirsch I, Emanuelsson H, Ponten J, Olsson
SB. Sotalol-induced delayed ventricular repolarization in man.
Eur Heart J. 1980; 1:335–43.
32. Vos MA, Golitsyn SR, Stangl K, et al. Superiority of ibu-
tilide (a new class III agent) over DL-sotalol in converting
atrial flutter and atrial fibrillation. Heart. 1998; 79:568–75.
33. Lau CP, Lok NS. A comparison of transvenous atrial defi-
brillation of acute and chronic atrial fibrillation and the effect
of intravenous sotalol on human atrial defibrillation threshold.
Pacing Clin Electrophysiol. 1997; 20:2442–52.
34. Tse HF, Lau CP, Ayers GM. Long-term outcome in patients
with chronic atrial fibrillation after successful internal car-
dioversion. Am J Cardiol. 1999; 83:607–9.
35. Reisinger J, Gatterer E, Heinze G, et al. Prospective com-
parison of flecainide versus sotalol for immediate cardioversion
of atrial fibrilllation. Am J Cardiol. 1998; 81:1450–4.
36. Tai CT, Chen SA, Chiang CE, et al. Characterization of
low right atrial isthmus as the slow conduction zone and phar-
macological target in typical atrial flutter. Circulation. 1997;
96:2601–11.
37. Yu WC, Chen SA, Tai CT, et al. Effects of procainamide
and DL-sotalol on the changes of atrial electrophysiology in-
duced by high current stimulation. Pacing Clin Electrophysiol.
1998; 21:2064–9.
References
1. Fitton A, Sorkin EM. Sotalol: an updated review of its phar-
macological properties and therapeutic use in cardiac arrhyth-
mias. Drugs. 1993; 46:678–719.
2. Ho DSW, Zecchin RP, Richards DAB, Uther JB, Ross DL.
Double-blind trial of lignocaine versus sotalol for acute termi-
nation of spontaneous sustained ventricular tachycardia. Lan-
cet. 1994; 344:18–23.
3. Llewellyn MJ, Ramsdale DR. Termination of refractory
ventricular tachycardia by a combination of intravenous so-
talol and overdrive ventricular pacing. Clin Cardiol. 1987; 10:
416–8.
4. Lloyd EA, Charles RG, Gordon GD. Beta-blockade by sotalol
in early myocardial infarction decreases ventricular arrhyth-
mias without increasing left ventricular volume. S Afr Med J.
1988; 74: 5–10.
5. Dorian P, Newman D. Effect of sotalol on ventricular fibril-
lation and defibrillation in humans. Am J Cardiol. 1993; 72:
72A-79A.
6. Jordaens L, Gorgels A, Stroobandt R, Temmerman J. Effi-
cacy and safety of intravenous sotalol for termination of par-
oxysmal supraventricular tachycardia. Am J Cardiol. 1991; 68:
35–40.
7. Sung RJ, Tan HL, Karagounis L, et al. Intravenous sotalol
for the termination of supraventricular tachycardia and atrial
fibrillation and flutter: a multicenter, randomized, double-
blind, placebo-controlled study. Am Heart J. 1995; 129:739–48.
8. Borggrefe M, Breithardt G. Elektophysiologische Wirkung
von Sotalol bei Supraventrikularen Tachykardien. Z Kardiol.
1985; 74:506–11.
9. Waleffe A, Nzayinambaho K, Rodriguez LM, Dehareng A,
Kulbertus HE. Mechanisms of termination of supraventricular
tachycardias by intravenous class III antiarrhythmic agents. A
comparison of amiodarone and sotalol. Eur Heart J. 1989; 10:
1084–9.
10. DiMarco JP, Miles W, Akhtar M, et al. Adenosine for par-
oxysmal supraventricular tachycardia: dose ranging and com-
parison with verapamil. Ann Intern Med. 1990; 113:104–10.
11. Kunze KP, Schluter M, Kuck KH. Sotalol in patients
with Wolff-Parkinson-White syndrome. Circulation. 1987; 75:
1050–7.
12. Mitchell LB, Wyse DG, Duff HJ. Electropharmacology of
sotalol in patients with Wolff-Parkinson-White syndrome. Cir-
culation. 1987; 76:810–8.
13. Touboul P, Atallah G, Kirkorian G. Effects of intravenous
sotalol in patients with atrioventricular accessory pathways.
Am Heart J. 1987; 114:545–50.
14. Nathan AW, Hellestrand KJ, Bexton RS. Electrophysio-
logical effects of sotalol—just another beta blocker? Br Heart
J. 1982; 47:515–20.
15. Madrid AH, Moro C, Marin Huerta EM. Atrial fibrillation
in Wolff-Parkinson-White syndrome: reversal of isoproterenol
effects by sotalol. Pacing Clin Electrophysiol. 1992; 15:2111–5.
16. Bennett DH. Acute prolongation of myocardial refractori-
ness by sotalol. Br Heart J. 1982; 47:521–6.
38. Yu WC, Chen SA, Lee SH, et al. Tachycardia-induced
change of atrial refractory period in humans: rate dependency
and effects of antiarrhythmic drugs. Circulation. 1998; 97:
2331–7.
39. Stroobandt R, Kesteloot H. Efficacy of intravenous sotalol
on ventricular arrhythmias occurring during maximal exercise
17. MacNeil DJ, Davies RO, Deitchman D. Clinical safety pro-
file of sotalol in the treatment of arrhythmias. Am J Cardiol.
1993; 72:44A-50A.
18. Soyka LF, Wirtz C, Spangenberg RB. Clinical safety profile
of sotalol in patients with arrhythmias. Am J Cardiol. 1990; stress testing. Arch Int Pharmacodyn Ther. 1983; 264:290–7.
65:74A-81A.
40. Stroobandt R, Holvoet G, Verbeke N, Kesteloot H. Effects

124
SOTALOL
Marill, Runge • IV SOTALOL AND TORSADES DE POINTES
of intravenous sotalol, aprindine and the combination of sotalol 54. Berlin JA, Laird NM, Sacks HS, Chalmers TC. A compar-
and aprindine on chronic high frequency ventricular arrhyth- ison of statistical methods for combining event rates from clin-
mias in man. Eur Heart J. 1987; 8:372–7.
ical trials. Stat Med. 1989; 8:141–51.
41. Ho DSW, Zecchin RP, Cooper MJ, Richards DAB, Uther 55. Normand SLT. Meta-analysis; formulating, evaluating,
JB, Ross DL. Rapid intravenous infusion of D-L sotalol: time combining, and reporting. Stat Med. 1999; 18:321–59.
to onset of effects on ventricular refractoriness, and safety. Eur 56. Turton MB, Deegan T, Coulshed N. Plasma catecholamine
Heart J. 1995; 16:81–6.
levels and cardiac rhythm before and after cardiac catheteris-
42. Kovoor P, Byth K, Uther JB, Ross DL. Does sotalol have ation. Br Heart J. 1977; 39:1307–11.
reverse-use dependence during tachyarrhythmias? Am J Car-
diol. 1996; 78:247–50.
43. Kovoor P, Eipper V, Byth K, Cooper MJ, Uther JB, Ross
DL. Comparison of sotalol with amiodarone for long-term
treatment of spontaneous sustained ventricular tachyarrhyth-
mia based on coronary artery disease. Eur Heart J. 1999; 20:
364–74.
44. Senges J, Lengfelder W, Jauernig R, et al. Electrophysio-
logic testing in assessment of therapy with sotalol for sus-
tained ventricular tachycardia. Circulation. 1984; 69:577–84.
45. Brachmann J, Senges J, Lengfelder W, et al. Contribution
of delayed ventricular repolarization to the anti-arrhythmic ef-
ficacy of sotalol. Eur Heart J. 1985; 6(suppl D):171–4.
46. Nademanee K, Feld G, Hendrickson J, Singh PN, Singh
BN. Electrophysiologic and antiarrhythmic effects of sotalol in
patients with life-threatening ventricular tachyarrhythmias.
Circulation. 1985; 72:555–64.
47. Kopelman HA, Woosley RL, Lee JT, Roden DM, Echt DS.
Electrophysiologic effects of intravenous and oral sotalol for
sustained ventricular tachycardia secondary to coronary artery
disease. Am J Cardiol. 1988; 61:1006–11.
48. Singh BN, Kehoe R, Woosley RL, Scheinman M, Quart B,
and the Sotalol Multicenter Study Group. Multicenter trial of
sotalol compared with procainamide in the suppression of in-
ducible ventricular tachycardia: a double-blind, randomized
parallel evaluation. Am Heart J. 1995; 129:87–97.
49. Antz M, Cappato R, Kuck KH. Metoprolol versus sotalol
in the treatment of sustained ventricular tachycardia. J Car-
diovasc Pharmacol. 1995; 26:627–35.
50. Lai L-P, Lin J-L, Lien W-P, Tseng Y-Z, Huang SKS. Intra-
venous sotalol decreases transthoracic cardioversion energy re-
quirement for chronic atrial fibrillation in humans: assessment
of the electrophysiological effects by biatrial basket electrodes.
J Am Coll Cardiol. 2000; 35:1434–41.
51. Joseph AP, Ward MR. A prospective, randomized controlled
trial comparing the efficacy and safety of sotalol, amiodarone,
and digoxin for the reversion of new-onset atrial fibrillation.
Ann Emerg Med. 2000; 36:1–9.
57. Kowey PR, Levine JH, Herre JM, et al. Randomized dou-
ble-blind comparison of intravenous amiodarone and bretylium
in the treatment of patients with recurrent, hemodynamically
destabilizing ventricular tachycardia and fibrillation. Circula-
tion. 1995; 92:3255–63.
58. Levine JH, Massumi A, Scheinman MM, et al. Intravenous
amiodarone for recurrent sustained hypotensive ventricular
tachyarrhythmias. J Am Coll Cardiol. 1996; 27:67–75.
59. Wood MA, Stambler BS, Ellenbogen KA, et al. Suppression
of inducible ventricular tachycardia by ibutilide in patients
with coronary artery disease. Am Heart J. 1998; 135:1048–54.
60. Volgman AS, Carberry PA, Stambler B, et al. Conversion
efficacy and safety of intravenous ibutilide compared with in-
travenous procainamide in patients with atrial flutter or fi-
brillation. J Am Coll Cardiol. 1998; 31:1414–9.
61. Oral H, Souza JJ, Michaud GF, et al. Facilitating trans-
thoracic cardioversion of atrial fibrillation with ibutilide pre-
treatment. N Engl J Med. 1999; 340:1849–54.
62. Nowak RM, Bodnar TJ, Dronen S. Bretylium tosylate as
initial treatment for cardiopulmonary arrest: randomized com-
parison with placebo. Ann Emerg Med. 1981; 10:404–7.
63. Olson DW, Thompson BM, Darin JC, Milbrath MH. A ran-
domized comparison study of bretylium tosylate and lidocaine
in resuscitation of patients from out-of-hospital ventricular fi-
brillation in a paramedic system. Ann Emerg Med. 1984; 13:
807–10.
64. Chandrasekaran S, Steinberg JS. Efficacy of bretylium
tosylate for ventricular tachycardia. Am J Cardiol. 1999; 83:
115–7.
65. Gorgels APM, Van Den Dool A, Hofs A. Comparison of pro-
cainamide and lidocaine in terminating sustained monomor-
phic ventricular tachycardia. Am J Cardiol. 1996; 78:43–6.
66. Anderson JL. Current understanding of lidocaine as an an-
tiarrhythmic agent: a review. Clin Ther. 1984; 6:125–41.
67. Marill KA, Greenberg GM, Kay D, Nelson BK. Analysis of
the treatment of spontaneous sustained stable ventricular
tachycardia. Acad Emerg Med. 1997; 4:1122–8.
68. Kuntz RE, Ruskin JN, Weinberger S, Lorell BH. The ad-
vantage of d-sotalol over dl-sotalol in a patient with ventricular
arrhythmias and comorbid bronchospasm. Chest. 1992; 102:
1627–9.
52. Tse HF, Lau CP, Ayers GM. Incidence and modes of onset
of early reinitiation of atrial fibrillation after successful inter-
nal cardioversion, and its prevention by intravenous sotalol.
Heart. 1999; 82:319–24.
69. McComb JM, McGovern B, McGowan JB, Ruskin JN,
Garan H. Electrophysiologic effects of d-sotalol in humans. J
Am Coll Cardiol. 1987; 10:211–7.
53. Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta block-
ade during and after myocardial infarction: an overview of the
randomized trials. Prog Cardiovasc Dis. 1985; 27:335–71.