not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
COPYRIGHT© 2012 EDIZIONI MINERVA MEDICA
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other

REVIEW

The influence of anesthesia on cardiac repolarization

R. OWCZUK 1, M. A. WUJTEWICZ 1, A. ZIENCIUK-KRAJKA 2
M. ŁASIŃSKA-KOWARA 1, A. PIANKOWSKI 1, M. WUJTEWICZ 1

1Department of Anaesthesiology and Intensive Therapy, Medical University of Gdansk, Gdansk, Poland; 2Department
of Cardiology and Electrotherapy, Medical University of Gdansk, Gdansk, Poland

ABSTRACT
The drugs and techniques used in contemporary anaesthesia may provoke numerous side effects, including cardiac
rhythm disturbances. The prolongation of the repolarization time, reflected by the QT interval in a surface elec-
trocardiogram, is one of the mechanisms that lead to the occurrence of arrhythmias. In the paper, we present the
primary mechanism that is responsible for QT interval prolongation and subsequent torsade de pointes ventricular
tachycardia. The influence of anesthetics, regional anesthesia and perioperative supportive therapy on cardiac repo-
larization is described. (Minerva Anestesiol 2012;78:483-95)
Key words: Anesthesia - Anesthetics - Therapeutics.

S ince its inception, the primary goal of an-

esthesiology has remained the same: to guar-
antee a patient’s painlessness and safety during
a surgical procedure. The techniques and drugs
applied to achieve this aim have improved, and
these improvements have substantially increased
the safety of patients and limited mortality in the
perioperative period. Despite the introduction of
modern general and regional anesthetic agents,
the anesthesiologist must be aware that these ap-
proaches are not devoid of side effects. The as-
sociated side effects can involve the circulatory
system, and the observed clinical signs are hypo-
tension, instability of the heart rate, triggering of
the heart rate and conduction disturbances. The
arrhythmogenic properties of general anesthetics
or other proprietary information of the Publisher.
serious arrhythmias. The first death attributed to
this feature was noted eleven weeks after its first
use, and the victim was a fifteen years old girl.1
The drugs introduced to the anesthetic prac-
tice in the 20th century are characterised by a
better safety profile, but some of these drugs
still possess the ability to trigger life threatening,
intraoperative heart rhythm disturbances. Ha-
lothane is the most prominent example of such
a drug still in use in many, mostly less wealthy
countries, and this drug can cause ventricular ar-
rhythmias.
Among other factors, the prolongation of the
action potential duration of cardiomyocytes,
represented in the electrocardiogram (ECG) by
the QT interval, favours the appearance of seri-

have been known since the genesis of anesthe-
sia.1 Only a year after William Morton’s pres-
entation of a painless surgical procedure using
ether as an anesthesia in 1846, a new inhalation
agent was introduced – chlorophorm. This new
anesthesia seemed to be safer than the explosive
ether, but it showed a greater ability to provoke
ous ventricular arrhythmias. The QT interval is
defined as the time between the beginning of the
Q wave and the end of the T wave in the ECG.2
The duration of the QT interval is physiologi-
cally variable and is primarily influenced by the
heart rate. Faster heart rates produce shorter QT
intervals, and slower heart rates result in longer

Vol. 78 - No. 4 MINERVA ANESTESIOLOGICA 483

not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
COPYRIGHT© 2012 EDIZIONI MINERVA MEDICA
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is

OWCZUK The influence of anesthesia on cardiac repolarization

This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other

QT intervals. This variability has led to the in-
troduction of the term corrected QT-QTc, that
corresponds to a QT value calculated for a heart
rate of 60 beats per minute. The most common
correcting equations are presented below:3, 4
1.  Bazette’s formula (QTcb=QT RR-1/2)
2.  Fridericia’s formula (QTcf=QT RR-1/3)
3.  Framingham formula (QTcF=QT+0.154 x
[1-RR]).
Normal values of QTc interval related to age
and gender, according to Moss AJ et al.5 are pre-
sented in Table I.
Long QT syndrome (LQTS) occurs as an in-
herited or acquired disorder. It is speculated, that
the prevalence of inborn LQTS in USA amounts
to 1 in 5 000 people 6 but the Italian data suggest
more frequent occurrence (1 in 2000-3000 live
births).7
Ten phenotypes linked to the mutations in
various LQTS susceptibility genes have been
described. The most frequent are LQT1, LQT2
and LQT3 and their essential features are pre-
sented in Table II. Acquired LQTS is most often
caused by an electrolyte imbalance or provoked
by drugs that belong to particular therapeutic
groups. It is hardly possible to assess epidemi-
ology of this problem. The analysis performed
by Curtis et al. revealed that 22.8% of the pa-
tients received a prescription for at least one drug
responsible for QTc prolongation, and among
them, 9.4% received at least one QTc-prolong-
ing medication or at least one agent that inhib-
ited clearance of the drug.8
The prolongation of the QTc interval can
develop into a ventricular arrhythmia known as
torsade de pointes (TdP), which in some patients
degenerates towards ventricular fibrillation. Pro-
longation of the QTc interval can be a cause of
cardiac arrest, including its perioperative appear-
ance.9, 10 The significance of the problem is fur-
ther accentuated by the tendency towards QTc
prolongation, and the generation of TdP is the
commonest reason for the withdrawal of regis-
tered drugs from the United State (US) pharma-
ceutical market.11, 12 According to International
Conference on Harmonization (ICH) document
published in 2005 (E14 Clinical Evaluation of
QT/QTc Interval Prolongation and Proarrhyth-

Table I.—Normal QTc duration by age and gender.5

Children
QTc value (seconds) Male Female
(1-15 year old)
Normal <0.44 <0.43 <0.45
Borderline 0.44-0.46 0.43-0.45 0.45-0.46
Prolonged >0.46 >0.45 >0.46

Table II.—Characteristic of LQT1, LQT2 and LQT3 syndromes.

LQT1 LQT2 LQT3
Anomalous cardiac current IKs IKr INa
Gene encoding channel (location) KCNQ1 KCNH2 SCN5A
(11p15.5) (7q35-36) (3p21-24)
Prevalence among all LQTS ∼35% ∼30% ∼10%
ECG findings –– Prolonged T wave duration –– Low amplitudeT waves –– Long ST segment
–– Broad-based T wave pattern –– Bifid T waves in the inferior –– Narrow T wave
–– Short ST segment and lateral ECG leads
or other proprietary information of the Publisher.

TdP triggering factors –– Physical exertion (especially –– Auditori stimuli, noise –– Cardiac events occur mainly
swimming) –– Postpartum period during rest or sleep
–– Startle –– About 50% of cardiac
–– Anger events occur during rest
–– Fright or sleep
–– Running
–– Adrenergic stimulation
Effectiveness of beta-blocker TdP +++ ++ +/-
prevention

484 MINERVA ANESTESIOLOGICA April 2012

not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
COPYRIGHT© 2012 EDIZIONI MINERVA MEDICA
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
The influence of anesthesia on cardiac repolarization OWCZUK
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
Table III.—The factors that create favourable conditions for
TdP.
–– QTc prolongation
–– Female sex
–– Age above 65 years
–– Bradycardia (essential or drug induced)
–– Hypokaliemia
–– Hypomagnesemia
–– Hypocalcemia
–– Heart insufficiency
–– Ischemic heart disease
–– Cardiac muscle hypertrophy
–– Heart rhythm disturbances
–– Anorexia nervosa and malnutrition
–– Pituitary gland insufficiency
–– Certain combinations of drugs (ion channel blockers and
inhibitors of the cytochrome P-450)
–– Polymorphisms of the genes encoding the ion channels of the
heart or hepatic enzymes taking part in the drug metabolism.
mic Potential for Non-Antiarrhythmic Drugs)
assessment of all new pharmaceuticals agents
should include testing the effects on the QT/
QTc interval as well as the collection of cardio-
vascular adverse events.13
Although the list of drugs causing QTc pro-
longation is long, incidents of TdP associated
with their use are rare. This evidence supports
the view that the isolated prolongation of the
repolarization time is not sufficient to provoke
heart rhythm disorders. Currently, it is assumed
that the genesis of cardiac rhythm disturbances
is multifactorial and that the concomitant influ-
ence of triggering factors, which are infrequent
in general practice, prompts these disturbances.
The factors that create favourable conditions
for TdP are listed in Table III.2, 14-17
The repolarization phase of the acting poten-
tial in cardiomyocytes is primarily due to the
activation of both components of the late cor-
recting potassium current (IK), which has a rapid
component (IKr) and a slow component (IKs).
Medicines extend the duration of repolariza-
or other proprietary information of the Publisher.
tion primarily through blockade of the IKr. The
obstruction of this channel is responsible for
95% of drug-induced LQTS.18 The structure of
HERG channel is presented on http://syntheti-
corganic.blogspot.com/2008/07/killer-factor-
for-molecule-to-be-drug.html.
Structural changes in the channels that are as-
sociated with polymorphisms or mutations of
Vol. 78 - No. 4 MINERVA ANESTESIOLOGICA 485
the encoding genes contribute to the prolonga-
tion of QTc and the appearance of TdP.19 The
majority of the described mutations or polymor-
phic forms are found within the gene KCNH2,
which encodes the HERG channel. The genes
KCNQ1, KCNE1, KCNE2 and SCN5A encode
the α subunit of the IKs channel, the β subunit
of the KvLQT1 channel, the β subunit of the
HERG channel and the fast sodium channel,
respectively. Mutations in these genes have also
been detected.16, 20, 21
The blockade of ionic channels, the prolonga-
tion of repolarization and the intensification of
its dispersion can provoke activation of inward
cellular ionic currents through the opening of L-
type calcium channels. These calcium channels
and sodium-calcium exchangers can contribute
to the development of early after-depolariza-
tions, which can lead to ventricular extrasystoles.
Repeated ventricular extrasystoles, added to the
areas of slow conduction, can cause a reentry ef-
fect and the induction of TdP.22-24
The sequence of events illustrating the mecha-
nism of TdP development is presented in Figure
1. The most frequent clinical manifestations of
TdP are faints and convulsions (sometimes mis-
taken for epileptic fits) as well as the typical fea-
tures of sudden cardiac arrest if it progresses to
ventricular fibrillation. The majority of patients
with multi-shaped ventricular tachycardia re-
solves spontaneously into a sinus rhythm, and
some may degenerate into ventricular fibrilla-
tion.11, 25 The reasons for this remain unclear.
Isolated drug-induced prolongation of repo-
larization is not sufficient to initiate the chain
of events that lead to TdP. Prolongation of the
QTc interval in the ECG is not the only sign
of the torsadogenic property for a drug. For the
last two decades, studies on additional ECG pa-
rameters have been proposed to assess the risk
of TdP and the associated sudden cardiac death.
The most important parameters include QT dis-
persion (QTD) 26 and the transmural dispersion
of repolarization (TDR).27, 28
QT dispersion is defined as the difference be-
tween the longest and the shortest QT interval.
QT dispersion is measured in a 12-lead ECG
and reflects the surface differentiation of repo-
larization. The QT dispersion intensity (above
 This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
or other proprietary information of the Publisher.

486
OWCZUK

multi-shaped ventricular tachycardia.29

parameter to predict TdP induction.30, 31

100 ms) is thought to reflect an increased risk of

Another parameter of the electric function of

Clinical studies involving computerized
methods of analysis show low specificity of this
Figure 1.—Sequence of events illustrating the mechanism of TdP development.

MINERVA ANESTESIOLOGICA
COPYRIGHT© 2012 EDIZIONI MINERVA MEDICA

between the peak and the end of the T wave in a

the heart that can be affected by drugs and thus
The influence of anesthesia on cardiac repolarization

The (Tpeak – Tend) interval is defined as the time

reflect their torsadogenic potential is the TDR. Its

precordial lead. TDR results from differences in

ECG representation is the time (Tpeak – Tend).

April 2012
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
COPYRIGHT© 2012 EDIZIONI MINERVA MEDICA
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is

The influence of anesthesia on cardiac repolarization OWCZUK

This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other

Table IV.—Influence of anaesthetic drugs on QTc interval and transmural dispersion of repolarisation.
QTc TDR Additional information
Drugs for premedication and sedation
Midazolam ↔ ↔
Dexmedetomidine ↑­ No data Reported in children
Clonidine ↔ ↔ Administered orally
Pentobarbital ↑­ ↓ Reduces risk of TdP
Opioids
Fentanyl, remifentanil, Alfentanil ↔ No data
Sufentanil ­ No data
Volatile anaesthetics
N2O No data No data
Sevoflurane ­↑ ↔
Desflurane ­↑ No data
Isoflurane ­↑ No data
Halothane ↑ ­or ↓ ­ Conflicting data
Xenon No data No data
Intravenous anaesthetics
Thiopental, methohexital ­↑ No data
Propofol ­or ↓ or ↔ ↔ Conflicting data
Ketamine ­↑ No data Animal model
Etomidate ↔ ↔
Muscle relaxants
Succinylcholine ↑­ No data
Pancuronium ­↑ No data
Vecuronium, atracurium ↔ No data
­↑ prolongation, ↓ shortening, ↔ no influence

the duration of the action potential between the
layers of the myocardium (epicardium, M cells
and endocardium).32 The action potential has the
longest duration in the M cells due to the low
density of IKs channels in this layer along with
the high density of sodium channels and sodium-
calcium exchangers. Moreover, in comparison to
epi- and endocardial cells, M cells are more sensi-
tive to the blocking of IKr channels by the QTc-
extending drugs. Thus, the action potential is
further prolonged within the M layer, and it does
not significantly change in the other layers. This
prolongation results in the increased transmural
dispersion of the action potential.11, 28, 33
Depending on the simultaneous effects of
or other proprietary information of the Publisher.
a slight effect on TDR and little, if any, ability
to induce TdP (e.g., amiodarone and pentobar-
bital);
3.  drugs with biphasic effects. Below a cer-
tain concentration, these drugs simultaneously
prolong QTc and increase TDR. These changes
are promoted by the blockade of inward currents
(e.g., quinidine and cisapride). Once a critical
value of TDR is exceeded, TdP tachycardia can
emerge.
The list of drugs extending the QTc interval
and having potential torsadogenic effects is ex-
tensive and can be found on the web pages www.
qtdrugs.org or www.torsades.org. Interestingly,
no anesthetic agents are included, although stud-

drugs on changes in the QTc interval and the

TDR, Antzelevitch distinguishes the following
groups of drugs:27
1.  drugs inducing both QTc prolongation
and increased TDR, characterized by a high tor-
sadogenic potential (e.g., sotalol, dofetilid and
erythromycine);
2.  drugs causing QTc prolongation but with
ies on their influence on the electric function of
the heart have been conducted for a long time,
and there are numerous cases of intraoperative
TdP described in the literature.34-38
Table IV summarizes the effect of most drugs
commonly used in anesthesia on cardiac repo-
larization.

Vol. 78 - No. 4 MINERVA ANESTESIOLOGICA 487

not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
COPYRIGHT© 2012 EDIZIONI MINERVA MEDICA
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
OWCZUK The influence of anesthesia on cardiac repolarization
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
Drugs used for premedication and sedation
The influence of the drugs used in premedica-
tion and sedation on the repolarization parame-
ters of the heart have been described. Midazolam
does not influence the QTc interval.39-41
According to our own studies, midazolam
does not change the TDR.42 No information is
available that considers the effect of other ben-
zodiazepines on the electric function of the ven-
tricles.9, 43
Recently, it has been shown that dexmedeto-
midine extends the QTc interval in children.44
Another α2–agonist, clonidine, does not affect
the repolarization parameters of the heart when
administered orally to healthy individuals.45
Pentobarbital was once used in premedication
and is still administered as a sedative for patients
after head trauma, especially in the US.46 Pento-
barbital possesses an interesting pharmacological
profile in relation to the repolarization param-
eters. It has been demonstrated in an experimen-
tal model that it causes QTc prolongation, but at
the same time decreases the TDR, thus prevent-
ing externally induced TdP incidents.47
General anesthesia
Volatile anesthetics
All of the halogenated vapours used in anes-
thetic practices cause prolongation of the repo-
larization time of the heart. Clinical studies have
demonstrated this effect for desflurane in adults
and in children,48-52 for sevoflurane in patients
of all age groups.43, 53-59 and for isoflurane.40,
41, 51, 60, 61 The data are unclear as to the effect
of halothane on the QTc interval because QTc
prolongation 61 and contraction have been re-
ported.40, 41, 62
The mechanisms of anesthetic action on car-
or other proprietary information of the Publisher.
diomyocyte repolarization are best known for
sevoflurane.63 Unfortunately, the presented re-
sults differ substantially. Studying the influence
of sevoflurane on Xenopus laevis oocytes, Ya-
mada found a dose-dependent restriction of the
ionic current flow through the HERG channels
(IKr).64 Other researchers observed an IKs current
blockade.65 In 2006, Kang et al. stated that the
488 MINERVA ANESTESIOLOGICA April 2012
sevoflurane-induced prolongation of the action
potential results from the blockade of the potas-
sium channels KvLQT1/minK (IKs current) and
Kv4.3. No effect on the HERG channels was de-
scribed.66
Isoflurane has been observed to restrict the
slow potassium current,67, 68 and halothane
blocks potassium channel HERG.69
The low arrhythmogenicity of modern vola-
tile anesthetics, despite the evident prolongation
of the action potential, results from not affect-
ing the TDR, which has been demonstrated for
sevoflurane.59, 70, 71 The ability of halothane to
induce ventricular arrhythmias can be explained
by the simultaneous intensification of TDR with
QTc prolongation, which has been observed in
dogs.72 Halothane sensitizes cardiomyocytes for
other IKr blocking drugs and substantially de-
creases the repolarization reserve.73, 74
Intravenous anesthetics
The effect of intravenous anesthetics on the
duration of the action potential varies. Thio-
pental causes QTc prolongation in humans,75, 76
and this has been confirmed in an experimental
model.77 In the same paper, it was shown that
another short-acting barbiturate, methohexi-
tal, shortens the action potential duration dur-
ing the potentialization of the flow through the
slow-correcting potassium channel.77 In hu-
mans, methohexital extends the QTc interval.76
The literature contains conflicting evidence
on the effect of propofol on the repolarization
parameters of the heart. Some researchers have
demonstrated the prolongation of the QTc in-
terval,78, 79 and other researchers have reported
the shortening of the QTc.80 Neither effect on
the repolarization duration has been observed in
subsequent studies.59, 81, 82
Propofol does not change the TDR.59, 82
The effect of ketamine on the QTc interval has
not been described, but its use for patients with
LQTS is not recommended because its sym-
pathomimetic properties can favour incidents of
TdP.9, 10, 83 This view is further supported by re-
ports that ketamine-induced QTc prolongation
has been observed in animal models.84
Etomidate does not affect the duration of re-
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
COPYRIGHT© 2012 EDIZIONI MINERVA MEDICA
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
The influence of anesthesia on cardiac repolarization OWCZUK
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
polarization,85 and the same conclusion has been
drawn from our own studies.86
Opioids
There are several studies concerning the influ-
ence of opioids used in anesthesia on QTc inter-
val. Cafiero and collaborates found that neither
fentanyl nor remifentanil prolonged QTc inter-
val.87 Similarly, alfentanil does not extend repo-
larization time. On the contrary, sufentanil was
found to prolong QTc interval.88 Opioids used
for postoperative pain relief (morphine, pethi-
dine) are believed not to affect QTc interval,83
although Song et al. have recently presented a
case report on patients with QTc prolongation
and ventricular tachycardia which followed in-
travenous pethidine (meperidine) administra-
tion.89
Muscle relaxants
Neuromuscular junction blockade with succi-
nylcholine causes QTc interval prolongation.41, 90
Vecuronium does not affect this ECG param-
eter,91 and its lack of autonomic nervous system
effects makes this drug suitable for patients with
LQTS. Atracurium and cis-atracurium do not
require reversal of the neuromuscular blockade,9
and atropine substantially extends QTc.92
Acetylcholinesterase blockers are not adminis-
tered without pretreatment with QTc-prolong-
ing atropine, and there is a lack of data on the
influence of acetylcholinesterase blockers on re-
polarization.
Regional anesthesia
Regional anesthesia can have variable effects
on the electric function of the heart. Changes in
the repolarization parameters can result directly
or other proprietary information of the Publisher.
from the blockade of preganglionic sympathet-
ic fibres and from indirect effects. The indirect
effects are caused firstly by the cardiac activity
induced by local anesthetics that are absorbed
from the depot into the central circulation and
secondly by reflexes that are induced in response
to the sympathetic blockade.
The influence of central blockades on the ac-
Vol. 78 - No. 4 MINERVA ANESTESIOLOGICA 489
tion potential duration depends on the type and
range of the blockade. According to our own
studies, spinal anesthesia to the level of T10
causes prolongation of the QTc, which can be
explained by the reflective and corrective in-
crease in the sympathetic tone of the unblocked
segments, including cardiac sympathetic fibres
(T1-T4).93
This phenomenon has been documented in
animal models in which the blockade of pregan-
glionic sympathetic fibres, caused by low epi-
dural anesthesia, led to an increased activity of
cardiac adrenergic fibres.94
Epidural blockade at the thoracic level, in-
cluding segments T1–T4, leads to QTc shorten-
ing and decreases the TDR.95
The drugs used for regional anesthesia (bupi-
vacaine, levobupivacaine and ropivacaine) do
not significantly affect the QTc interval or the
TDR.96, 97 Lidocaine, an amide local anesthetic
that belongs to class Ib of the antiarrhythmic
drugs (according to the Vaughan-Williams clas-
sification), slightly shortens the repolarization
time. When administered intravenously, it is
used for the treatment of TdP incidents in pa-
tients with secondary QTc prolongation.98, 99
The influence of the blockades of the periph-
eral neural structures on the QTc interval varies.
No changes have been observed after the brachial
plexus block from the interscalene approach.100
The QTc interval is prolonged after the right-
sided stellar ganglion blockade, but it is short-
ened when the block is carried out on the left
side.101 The latter is still being examined to di-
minish the risk of dangerous ventricular arrhyth-
mias in patients with LQTS.101
Anesthetic manoeuvres
Important changes in the parameters of heart
repolarization in anesthetic practices are trig-
gered not only by drugs. The manoeuvres per-
formed upon the patient during anesthetisation
through intensive fluctuations of the tone of the
autonomic nervous system can provoke prolon-
gation of the action potential and increase the
risk of rhythm disturbances. It is well known
that sympathetic stimulation increases the QTc
duration, and the autonomic system tone can in-
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
COPYRIGHT© 2012 EDIZIONI MINERVA MEDICA
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
OWCZUK The influence of anesthesia on cardiac repolarization
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
fluence the ability of drugs to prolong the QTc
duration.102
The most common anesthetic action associ-
ated with intense sympathetic stimulation is
laryngoscopy and intubation. QTc prolongation
is one of the symptoms of the increased tone of
the sympathetic part of the autonomic nervous
system, which is linked to the instrumentation
of the airway.81, 90, 103 Few authors have verified
the utility of various pharmacological agents to
prevent intubation associated with QTc prolon-
gation. Intravenous anesthetics used for induc-
tion, opioids and beta-blockers have been tested
for this purpose.78, 81, 104-107
Intravenous lidocaine before laryngoscopy
and intubation alleviates the changes in the re-
polarization parameters that are induced by the
aforementioned actions.86
Perioperative supportive drugs
Perioperative supportive therapy has im-
portant significance. In terms of their arrhyth-
mogenic potential, the drugs used for the proph-
ylaxis and treatment of postoperative nausea and
vomiting have the highest priority.
An effect of prolongation of repolarization has
been documented for setrones, which are block-
ers of the type 3 serotonin receptors: ondanset-
rone,108 granisetrone 109 and dolasetrone.110 The
electrophysiological changes result from the
HERG channel blockade.111
Dihydrobenzperidol (droperidol, DHBP),
still present in some markets, possesses a nega-
tive reputation as a TdP inciter. This derivative of
butyrophenone was once used for premedication,
neuroleptanalgesia, neuroleptanesthesia and, in
small doses, for postoperative nausea and vom-
iting (PONV) prevention. Dihydrobenzperidol
extends the QTc interval 108, 112 by the IKr current
blockade through the HERG channel.113
or other proprietary information of the Publisher.
The incidents of droperidol-induced polymor-
phous ventricular tachycardia resulted in a 2001
Federal Drug Administration (FDA) demand
for a black box warning against the potential side
effects of DHBP, namely TdP incidents.108, 114
Interestingly, DHBP as an antiemetic has been
replaced by the less-studied drug promethaz-
ine,115 which belongs to the phenotiazine group.
490 MINERVA ANESTESIOLOGICA April 2012
The effect of promethazine on the repolarization
parameters was not described until 2009.86
Pre- and perioperative comedication
A surgical patient, as well as any other, can
chronically receive drugs that are known to affect
repolarization time. Thus it seems necessary to
consider that anesthesia and anesthetic manoeu-
vres can potentiate their arrhythmogenic proper-
ties. The risk is highest in elderly patients treated
with antipsychotic and antidepressant drugs.
Among currently available  agents, thioridazine
and ziprasidone are associated with the most ex-
pressed QTc prolongation.116, 117 Haloperidol,
used for treatment of the postoperative delirium,
may provoke TdP and the risk of arrhythmia in-
creases with the intravenous administration.118
Some antibiotics included in prophylactic
regimens against perioperative infection induce
QTc prolongation and this feature has to be
considered during anesthesia for patients with
primary or secondary LQTS. These properties
are ascribed mainly to quinolones and mac-
rolides used as alternative antibiotics in some
prophylactic protocols.
Anesthetic management of
the patients with LQTS
For the patient with LQTS, perioperative pe-
riod carries an increased risk of malignant ven-
tricular arrhythmias. The problem is markedly
intensified in those with poor control of symp-
toms in spite of treatment with beta-blockers.83
Careful preparation and appropriate perioper-
ative management plays a key role in the preven-
tion of dysrhythmias. The preparation should be
based on strict cooperation with a cardiologist,
who is expected to help with the establishment
of proper pharmacological treatment before and
after anesthesia and to check and change ICD
settings if the latter had been implanted.
Routine preoperative 12-lead electrocardio-
gram can provide relevant information about
QTc duration and associated abnormalities (Ta-
ble II), but in 6% to 12% of patients with con-
genital LQTS, QTc interval is correct in routine
screening.119
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
COPYRIGHT© 2012 EDIZIONI MINERVA MEDICA
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
The influence of anesthesia on cardiac repolarization OWCZUK
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
When taking history it is necessary to pay at-
tention to symptoms indicative for an unrecog-
nized LQTS like syncope (especially after stress),
inborn deafness, unexplained sudden cardiac
death in family members.
Patients prophylactically treated with be-
ta-blockers have to continue their treatment
throughout the perioperative period. Measure-
ment and correction of plasma ions (potassium,
magnesium and calcium) to normal values is ob-
ligatory. It is reasonable to repeat the biochemis-
try during long lasting procedures.
As sympathetic activation can extend QTc
and precipitate TdP, the patients are encouraged
to receive premedication and midazolam seems
to be the most useful agent.
Continuous monitoring of ECG curve is
mandatory. It should begin before the induction
of anesthesia and last well into the postoperative
period. The monitoring should consist of at least
two leads, as short episodes of TdP are hardly
distinguished from monomorphic VT, when
traced in one lead only.9
Besides QT measurements and QTc interval
calculation, one should search for changes in T
wave morphology, because morphology of this
wave varies between different LQTS. A defibril-
lator and the equipment for transdermal/intra-
venous pacing must be available immediately.
External pads for defibrillation or temporary
pacing should be placed on the chest in patients
with known high risk of TdP or VF. A central
intravenous line should be introduced to allow
immediate administration of vasoactive drugs or
intravenous pacing if necessary.
The most effective way to prevent TdP/VF
is administration of short acting beta-blocker
(especially esmolol) in continuous infusion, re-
membering about possible bradycardia and di-
minished tolerance of hypovolemia.
Drugs safe for anesthesia in LQTS patients
or other proprietary information of the Publisher.
include propofol (for induction and mainte-
nance), isoflurane (for maintenance); vecuro-
nium, atracurium and rocuronium for muscle
relaxation. Analgesia is safely provided with
fentanyl, remifentanil or alfentanil. Reversion of
neuromuscular blockade with cholinesterase in-
hibitors should be avoided. The anesthesiologist
cannot forget about prevention of sympathetic
Vol. 78 - No. 4 MINERVA ANESTESIOLOGICA 491
hyperactivity in response to tracheal intuba-
tion. Adequate anesthesia depth, opioids, beta-
blockers or topical anesthesia to the mucous
membranes can prevent unfavourable reactions.
Regional anesthesia together with sedation can
be an effective method to reduce sympathetic
tone, but epinephrine should not be added as an
adjunct to the local anesthetics.43
As Valsalva-like manoeuvre can prolong QTc
interval, it is necessary to avoid high peak airway
pressures and long inspiratory to expiratory ra-
tios during positive-pressure lung ventilation. To
the contrary, increased intraabdominal pressure
due to pneumoperitoneum for laparoscopic sur-
gery does not change QTc duration.120
Hypothermia can also extend QTc interval, so
monitoring of the body temperature and warm-
ing patients should be implemented to maintain
body temperature at approximately 37 ºC.43
As TdP can occur during the recovery from
anesthesia, especially in children,121 extubation
should be performed during surgical anaesthe-
sia,9 and preceding esmolol administration may
prove beneficial.
After the operation a patient should be placed
in quiet environment, as sudden noise can in-
duce TdP, especially in patients with LQT2. It
seems that referral to ICU for direct postopera-
tive care can prove appropriate, due to better
monitoring and intensified surveillance. It can
be crucial in patients with a high risk of malig-
nant arrhythmia who are not protected by an
implemented cardioverter-defibrillator.
Adequate pain control must be ensured, as
pain increases sympathetic activation and subse-
quent QTc prolongation.9
Information about anesthetic management of
children with LQTS is sparse. Curry and asso-
ciates propose total intravenous anesthesia with
propofol as the safest method.10
General principles of anesthetic management
they recommend do not differ from those for
adults patient.
Pregnant women with LQTS create a special
group of patients and anesthesia for delivery can
pose a challenge. Regional anesthesia is advanta-
geous in LQTS parturients thanks to concomi-
tant pain relief and reduction of a stress response.
On the other hand, high epidural blockade can
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
COPYRIGHT© 2012 EDIZIONI MINERVA MEDICA
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
OWCZUK The influence of anesthesia on cardiac repolarization
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
result in unfavourable blood pressure fall and in-
creased parasympathetic activity.122  
It has been described that spinal anesthesia
reduces prolonged QTc interval in preeclamptic
patients.123
 
If general anesthesia is required, all of the rules
presented above should be adopted.
In the everyday practice anesthesiologists
 
meet the problem of secondary prolongation of
the cardiac repolarization relatively frequently,
 
because many drugs used for anesthesia extend
QTc interval. The prolongation rarely results in
serious consequences, but occasionally it can lead
to TdP and VF. As the disturbances seem to be  
related to a genetic predisposition, it is reasona-
ble to refer everybody who developed torsade de
 
pointes in the perioperative period to a cardiolo-
gist to diagnose potential chanellopathy as the
reason for cardiac arrhythmia. When a patient  
with established diagnosis of LQTS requires an-
esthesia, careful preparation, proper monitoring  
and appropriate anesthesia are essential to avoid
grave tachydysrhyhmias.
 
References
 
   1. Sykes K, Bunker J. Anesthesia and the practice of medi-
cine: historical perspective. London; Royal Society of
Medicine Press Ltd; 2007.
   2. Zaręba W. Drug induced QT prolongation. Cardiol J  
2007;14:523-33.
   3. Bazette HC. An analysis of the time-relations of electrocar-  
diograms. Heart 1920;7:353-70.
   4. Charbit B, Samain E, Merckx P, Funck-Brentano C. QT  
interval measurement: Evaluation of automatic QTc meas-
urement and new simple method to calculate and interpret
corrected QT interval. Anesthesiology 2006;104:255-60.
   5. Moss AJ, Robinson J. Clinical features of the idiopathic
long QT syndrome. Circulation 1992;85 (Suppl. 1):I140-  
4.
   6. Ackerman MJ. The long QT syndrome: ion channel dis-
ease of the heart. Mayo Clinic Proceedings 1998;73:250-  
69.
   7. Crotti L, Pedrazzini M, Ferrandi C, Ferrandi C, Insolia
R, Goulene K et al. Prevalence of the long QT syndrome.  
Circulation 2005;112(suppl. II):660.
   8. Curtis LH, Østbye T, Sendersky V, Hutchison S, Allen  
LaPointe NM, Al-Khatib SM et al. Prescription of QT-
or other proprietary information of the Publisher.
prolonging drugs in a cohort of about 5 million outpa-
tients. Am J Med 2003;114:135-41.  
   9. Booker PD, Whyte SD, Ladusans EJ. Long QT syndrome
and anesthesia. Br J Anaesth 2003;90:349-66.  
  10. Curry TB, Gaver R, White RD. Acquired long QT syn-
drome and elective anesthesia in children. Pediatric An-
esthesia 2006;16:471-8.
  11. Chiang CE. Drug-induced long QT syndrome. J Med Biol
Engineering 2006;26:107-13.  
  12. Lasser KE, Allen PD, Woolhandler SJ, Himmelstein DU,
Wolfe SM, Bor DH. Timing of new black box warnings
492 MINERVA ANESTESIOLOGICA April 2012
and withdrawals for prescription medications. J Am Med
Assoc 2002;287:2215-20.
13. International Conference on Harmonisation of Techni-
cal Requirements for Registration of Pharmaceuticals for
Human Use:E14:The clinical evaluation of QT ⁄ QTc in-
terval prolongation and proarrhytmhic potential for non-
antiarrhythmic drugs. (http://www.ich.org).
14. Abriel H, Schläpfer J, Keller DI, Gavillet B, Buclin T, Bi-
ollaz J et al. Molecular and clinical determinants of drug-
induced long QT syndrome: an iatrogenic channelopathy.
Swiss Medical Weekly 2004, 134:685-94.
15. Letsas KP, Efremidis M, Filippatos GS, Sideris AM.
Drug-induced long QT syndrome. Hellenic J Cardiol
2007;48:296-9.
16. Letsas KP, Efremidis M, Kounas SP, Pappas LK, Gavriela-
tos G, Alexanian IP et al. Clinical characteristics of patients
with drug-induced QT interval prolongation and torsade
de pointes: identification of risk factors. Clin Res Cardiol
2009;98:208-12.
17. Litwin JS, Kleiman RB, Gussak I. Acquired (drug-in-
duced) long QT syndrome. w:Gussak I., Antzelevitch C.
(ed.):Electrical diseases of the heart. London: Springer-
Verlag; 2008.
18. De Bruin ML, Pettersson M, Meyboom RH, Hoes AW,
Leufkens HG. Anti-HERG activity and the risk of drug-
induced arrhythmias and sudden death. Eur Heart J
2005;26:590-7.
19. Fitzgerald PT, Ackerman MJ. Drug-induced torsades de
pointes: the evolving role of pharmacogenetics. Heart
Rhythm 2005;2(Suppl. 2):S30-7.
20. Yang P, Kanki H, Drolet B, Yang T, Wei J, Viswanathan P
et al. Allelic variants in long-QT disease genes in patients
with drug-associated torsades de pointes. Circulation
2002;105:1943-8.
21. Senen JB, Vrints CJ. Molecular aspects of the congenital
and acquired long QT syndrome: clinical implications. J
Mol Cell Cardiol 2008;44:633-46.
22. Gupta A, Lawrence AT, Krishnan K, Kavinsky CJ, Tro-
hman RG. Current concepts in the mechanism and man-
agement of drug-induced QT prolongation and torsade de
pointes. Am Heart J 2007;153:891-9.
23. Roden DM, Viswanathan PC. Genetics of acquired long
QT syndrome. J Clin Invest 2005;115:2025-32.
24. Yap YG, Camm AJ. Drug induced QT prolongation and
torsades de pointes. Heart 2003;89:1363-72.
25. Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P,
Menon V et al. Prevention of torsade de pointes in hospital
settings: a scientific statement from the American Heart
Association and the American College of Cardiology
Foundation. J Am Coll Cardiol 2010;55:934-47.
26. Kautzner J, Malik M. QT interval dispersion and its clinical
utility. Pacing and Clinical Electrophysiol 1997;20:2625-
40.
27. Antzelevitch C. Role of transmural dispersion of repolari-
zation in the genesis of drug-induced torsades de pointes.
Heart Rhythm 2005;2(Suppl 2):S9-15.
28. Antzelevitch C. Drug-induced spatial dispersion of repo-
larization. Cardiol J 2008;15:100-21.
29. Malik M, Batchvarov VN. Measurement, interpretation
and clinical potential of QT dispersion. J Am Coll Cardiol
2000;36:1749-66.
30. Shah RR. Drug-induced QT dispersion: does it predict the
risk of torsade de pointes? J Electrocardiol 2005;38:10-8.
31. Yamaguchi M, Shimizu M, Ino H, Terai H, Uchiyama K,
Oe K et al. T wave peak-to-end interval and QT disper-
sion in acquitted long QT syndrome:a new index for ar-
rhythmogenicity. Clinical Science (Lond) 2003;105:671-
6.
32. Lubiński A, Lewicka-Nowak E, Kempa M, Baczyńska AM,
Romanowska I, Świątecka G. New insight into repolari-
zation abnormalities in patients with congenital long QT
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
COPYRIGHT© 2012 EDIZIONI MINERVA MEDICA
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
The influence of anesthesia on cardiac repolarization OWCZUK
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
syndrome: the increased transmural dispersion of repolari-
zation. Pacing Clin Electrophysiol 1998;21:172-5.
  33. Antzelevitch C. Arrhythmogenic mechanism of QT pro-
longing drugs: is QT prolongation really the problem? J  
Electrocardiol 2004;37(Suppl):15-24
  34. Abe K, Takada K, Yoshiya I. Intraoperative torsade de
pointes ventricular tachycardia and ventricular fibrilla-
tion during sevoflurane anesthesia. Anest Analg 1998;  
86:701-2.
  35. Dolenska S:Intraoperative cardiac arrest in acquired long
QT syndrome. Br J Anaes 2009;102:503-5.  
  36. Douglas RJ, Cadogan M. Cardiac arrhythmia during pro-
pofol sedation. Emerg Med Australasia 2008;20:437-40.
  37. Rodriguez-Borregan JC, Buron-Mediavilla FJ, Arnaiz-
Arnaiz V, Marco-Moreno JV. Torsades de pointes inducias  
por sevoflurano. Medicina Intensiva 2009, 33:55-6.
  38. Saussine M, Massad I, Raczka F, Davy JM, Frapier JM.
Torsade de pointes during sevoflurane anesthesia in a child
with congenital long QT syndrome. Pediatric Anesthesia  
2006;16:63-5.
  39. Michaloudis D, Fraidakis O, Lefaki T, Kanakoudis F,
Askitopoulou H. Anesthesia and the QT interval in hu-
mans. The effects of isoflurane and halothane. Anaesthesia  
1996;51:219-24
  40. Michaloudis D, Fraidakis O, Petrou A, Gigourtsi C, Parth-
enakis F. Anesthesia and the QT interval. Effects of isoflu-  
rane and halothane in unpremedicated children. Anesthe-
sia 1998;53:435-9.
  41. Michaloudis DG, Kanakoudis FS, Petrou AM, Konstan-
tinidou AS, Pollard BJ. The effects of midazolam or pro-  
pofol followed by suxamethonium on the QT interval in
humans. Eur J Anaesthesia 1996;13:364-8.
  42. Owczuk R, Twardowski P, Dylczyk-Sommer A, Wujtewicz
MA, Sawicka W, Drogoszewska B et al. Influence of pro-  
methazine on cardiac repolarization:a double-blind, mida-
zolam-controlled study. Anesthesia 2009;64:609-14.
  43. Kies SJ, Pabelick CM, Hurley HA, White RD, Ackerman
MJ. Anesthesia for patients with congenital long QT syn-
drome. Anaesthesiology 2005;102:204-10.  
  44. Hammer GB, Drover DR, Cao H, Jackson E, Williams
GD, Ramamoorthy C et al. The effects of dexmedetomi-
dine on cardiac electrophysiology in children. Anesth An-  
alg 2008;106:79-83.
  45. Yeragani VK, Tancer M, Uhde T. Heart rate and QT
interval variability: abnormal alpha-2 adrenergic func-  
tion in patients with panic disorder. Psychiatry Research
2003;121:185-96.
  46. Pérez-Bárcena J, Llompart-Pou JA, Homar J, Abadal JM,
Raurich JM, Frontera G et al. Pentobarbital versus thio-
pental in the treatment of refractory intracranial hyperten-  
sion in patients with traumatic brain injury: a randomized
controlled trial. Critical Care 2008;12:R112.
  47. Shimizu W, McMahon B, Antzelevitch C. Sodium pento-  
barbital reduces transmural dispersion of repolarization
and prevents torsades de pointes in models of acquired and
congenital long QT syndrome. J Cardiovasc Electrophysiol
1999;10:154-64.  
  48. Aypar E, Karagoz AH, Ozer S, Celiker A, Ocal T. The ef-
fects of sevoflurane and desflurane anesthesia on QTc in-
terval and cardiac rhythm in children. Pediatric Anesthesia
or other proprietary information of the Publisher.
2007;17:563-7.  
  49. Karagöz AH, Basgul E, Celiker V, Aypar U. The effect of
inhalational anesthetics on QTc interval. European Jour-
nal of Anaesthesiology 2005;22:171-4.
  50. Owczuk R, Wujtewicz MA, Sawicka W, Lasek J, Wujte-  
wicz M. The influence of desflurane on QTc interval. An-
est Analg 2005;101:419-22.
  51. Yildirim H, Adanir T, Atay A, Katircioğlu K, Savaci S. The  
effects of sevoflurane, isoflurane and desflurane on QT in-
terval of the ECG. Eur J Anaesthesiol 2004;21:566-70.
  52. Kim SH, Park SY, Che WS, Jin HC, Lee JS, Kim YI. Ef-
Vol. 78 - No. 4 MINERVA ANESTESIOLOGICA 493
fect of desflurane at less than 1 MAC on QT interval pro-
longation induced by tracheal intubation. Br J Anaesthesia
2010;104:150-7.
53. Nakao S, Hatano K, Sumi C, Masuzawa M, Sakamoto
S, Ikeda S et al. Sevoflurane causes greater QTc interval
prolongation in elderly patients than in younger patients.
Anest and Analg 2010;110:775-9.
54. Gürkan Y, Canatay H, Agacdiken A, Ural E, Toker K. Ef-
fects of halothane and sevoflurane on QT dispersion in
pediatric patients. Pediatric Anesthesia 2003;13:223-7.
55. Kim HS, Kim JT, Kim CS, Kim SD, Kim K, Yum MK.
Effects of sevoflurane on QT parameters in children
with congenital sensorineural hearing loss. Anaesthesia
2009;64:3-8.
56. Kleinsasser A, Kuenszberg E, Loeckinger A, Keller C,
Hoermann C, Lindner KH et al. Sevoflurane, but not pro-
pofol, significantly prolongs the Q-T interval. Anest and
Analg 2000;90:25-7.
57. Loeckinger A, Kleinsasser A, Maier S, Furtner B, Keller C,
Kuehbacher G et al. Sustained prolongation of the QTc
interval after anesthesia with sevoflurane in infants during
the first 6 months of life. Anesthesiology 2003;98:639-42.
58. Paventi S, Santevecchi A, Ranieri R. Effects of sevoflu-
rane versus propofol on QT interval. Minerva Anestesiol
2001;67:637-40.
59. Whyte SD, Booker PD, Buckley DG. The effects of pro-
pofol and sevoflurane on the QT interval and transmu-
ral dispersion of repolarization in children. Anesth Analg
2005;100:71-7.
60. Schmeling WT, Warltier DC, McDonald DJ, Madsen KE,
Atlee JL, Kampine JP. Prolongation of the QT interval by
enflurane, isoflurane, and halothane in humans. Anesth
Analg 1991;72:137-44.
61. Owczuk R, Wujtewicz MA, Sawicka W, Wujtewicz M,
Świerblewski M. Is prolongation of the QTc interval dur-
ing isoflurane anesthesia more prominent in women pre-
treated with anthracyclines for breast cancer? Br J Anaesth
2004;92:658-61.
62. Güler N, Kati I, Demirel CB, Bilge M, Eryonucu B, Topal
C. The effects of volatile anesthetics on the Q-Tc interval.
J Cardiovasc Thorac Anesth 2001;15:188-91.
63. Hüneke R, Faβl J, Rossaint R, Lückhoff A. Effects of
volatile anesthetics on cardiac ion channels. Acta Anaesth
Scand 2004;48:547-61.
64. Yamada M, Hatakeyama N, Malykhina AP, Yamazaki M,
Momose Y, Akbarali HI. The effects of sevoflurane and
propofol on QT interval and heterologously expressed
human ether-a-go-go related gene currents in Xenopus
oocytes. Anesth Analg 2006;102:98-103.
65. Shibata S, Ono K, Iijima T. Sevoflurane inhibition of the
slowly activating delayed rectifier K+ current in guinea pig
ventricular cells. J Pharmacol Sci 2004;95:363-73.
66. Kang J, Reynolds WP, Chen X-L, Ji J, Wang H, Rampe
DE. Mechanisms underlying the QT interval-prolonging
effects of sevoflurane and its interactions with other QT-
prolonging drugs. Anesthesiology 2006;104:1015-22.
67. Chen X, Yamakage M, Yamada Y, Tohse N, Namiki A.
Inhibitory effects of volatile anesthetics on currents pro-
duced on heterologous expression of KvLQT1 and minK
in Xenopus oocytes. Vasc Pharmacol 2002;39:33-8.
68. Suzuki A, Bosnjak ZJ, Kwok WM. The effects of isoflurane
on the cardiac slowly activating delayed-rectifier potassium
channel in Guinea pig ventricular myocytes. Anesth Analg
2003;96:1308-15.
69. Li J, Correa AM. Kinetic modulation of HERG potassium
channels by the volatile anesthetic halothane. Anesthesiol-
ogy 2002;97:921-30.
70. Whyte SD, Sanatani S, Lim J, Booker PD. A comparison
of the effect on dispersion of repolarization of age-adjust-
ed MAC values of sevoflurane in children. Anesth Analg
2007;104:277-82.
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
COPYRIGHT© 2012 EDIZIONI MINERVA MEDICA
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
OWCZUK The influence of anesthesia on cardiac repolarization
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
  71. Kang J, Chen XL, Reynolds WP, Rampe D. Functional in-
teraction between DPI 201-106, a drug that mimics con-
genital long QT syndrome, and sevoflurane on the guinea-
pig cardiac action potential. Clin Experiment Pharmacol
Physiol 2007;34:1313-6.
  72. Weissenburger J, Nesterenko VV, Antzelevitch C. Trans-
mural heterogeneity of ventricular repolarization under
baseline and long QT conditions in the canine heart in
vivo; torsades de pointes develops with halothane but
not pentobarbital anesthesia. J Cardiovasc Electrophysiol
2000;11:290-304.
  73. Sakaguchi Y, Sugiyama A, Takao S, Akie Y, Takahara A,
Hashimoto K. Halothane sensitizes the guinea-pig heart to
pharmacological IKr blockade: comparison with urethane-
anesthesia. J Pharmacol Sci 2005;99:185-90.
  74. Takahara A, Sugiyama A, Hashimoto K. Reduction of re-
polarization reserve by halothane anesthesia sensitizes the
guinea-pig heart for drug-induced QT interval prolonga-
tion. Br J Pharmacol 2005;146:561-7.
  75. McConachie I, Keaveny JP, Healy TE, Vohra S, Million L.
Effect of anesthesia on the QT interval. Br J Anaesthesia
1989;63:558-60.
  76. Saarnivaara L, Klemola UM, Lindgren L. QT interval of
the ECG, heart rate and arterial pressure using five non-
depolarizing muscle relaxants for intubation. Acta Anaes-
thesiol Scand 1988;32:623-8.
  77. Martynyuk E, Morey TE, Raatikainen MJ, Seubert CN,
Dennis DM. Ionic mechanisms mediating the differential
effects of methohexital and thiopental on action potential
duration in guinea pig and rabbit isolated ventricular myo-
cytes. Anaesthesiology 1999;90:156-64.
  78. Kim DH, Kweon TD, Nam SB, Han DW, Cho WY, Lee
JS. Effects of target concentration infusion of propofol
and tracheal intubation on QTc interval. Anaesthesia
2008;63:1061-4.
  79. Saarnivaara L, Lindgren L. Prolongation of QT interval
during induction of anesthesia. Acta Anesthesiologica
Scandinavica 1983;27:126-30.
  80. Michaloudis D, Kanoupakis E. Propofol reduces idi-
opathic prolonged QT interval and QT dispersion during
implantation of cardioverter defibrillator. Anesth Analg
2003;97:301-2.
  81. Chang DJ, Kweon TD, Nam SB, Lee JS, Shin CS, Park CH
et al. Effects of fentanyl pretreatment on the QTc interval
during propofol induction. Anaesthesia 2008;63:1056-60.
  82. Hume-Smith HV, Santani S, Lim J, Chau A, Whyte
SD. The effect of propofol concentration on dispersion
of myocardial repolarization in children. Anesth Analg
2008;107:806-10.
  83. Wisely NA, Shipton EA. Long QT syndrome and anesthe-
sia. Eur J Anaesthesiol 2001;19:853-9.
  84. Hamlin RL, Kijtawornrat A, Keene BW, Hamlin DM. QT
and RR intervals in conscious and anesthetized guinea pigs
with highly varying RR intervals and given QTc-lengthen-
ing test articles. Toxicological Sciences 2003;76:437-42
  85. Lischke V, Wilke HJ, Probst S, Behne M, Kessler P. Pro-
longation of the QT-interval during induction of anesthe-
sia in patients with coronary artery disease. Acta Anaesthe-
siologica Scandinavica 1994;38:144-8.
  86. Owczuk R, Wujtewicz MA, Sawicka W, Piankowski A,
or other proprietary information of the Publisher.
Polak-Krzeminska A, Morzuch E et al. The effect of in-
travenous lidocaine on QT changes during endotracheal
intubation. Anaesthesia 2008, 63:924-31.
  87. Cafiero T, Di Minno RM, Di Iorio C. QT interval and QT
dispersion during the induction of anesthesia and tracheal
intubation:a comparison of remifentanil and fentanyl.
Minerva Anestesiol 2011;77:160-5.
  88. Blair JR, Pruett JK, Crumrine RS, Balser JJ. Prolongation
of QT interval in association with the administration of
large doses of opiates. Anesthesiology 1987;67:442-3.
  89. Song MK, Be EJ, Bek JS, Kwon BS, Kim GB, Noh CI
494 MINERVA ANESTESIOLOGICA April 2012
et al. QT  Prolongation and Life Threatening Ventricular
Tachycardia in a Patient Injected With Intravenous Mepe-
ridine (Demerol®). Circ J 2011;41:342-5.
  90. Saarnivaara L, Klemola UM, Lindgren L, Rautiainen P,
Suvanto A. QT interval of the ECG, heart rate and arte-
rial pressure using propofol, methohexital or midazolam
for induction of anesthesia. Acta Anaesthesiol Scand 1990,
34:276-81.
  91. Michaloudis DG, Kanakoudis FS, Xatzikraniotis A, Bis-
chiniotis TS. The effects of midazolam followed by admin-
istration of either vecuronium or atracurium on the QT
interval in humans. Eur J Anaesthesiol 1995;12:577-83.
  92. Annila P, Yli-Hankala A, Lindgren L. Effect of atropine on
the QT interval and T-wave amplitude in healthy volun-
teers. Br J Anaesthesia 1993;71:736-7.
  93. Owczuk R, Sawicka W, Wujtewicz MA, Lasek J, Kawecka
A, Wujtewicz M. Influence of spinal anesthesia on correct-
ed QT interval. Reg Anesth Pain Med 2005;30:348-52.
  94. Taniguchi M, Kasaba T, Takasaki M. Epidural anesthesia
enhances sympathetic nerve activity in the unanesthetized
segments in cats. Anesth Analg 1997;84:391-7.
  95. Owczuk R, Steffek M, Wujtewicz MA, Szymanowicz W,
Twardowski P, Marjanski T et al. Effects of thoracic epi-
dural anesthesia on cardiac repolarization. Clin Experi-
ment Pharmacol Physiol 2009;36:880-3.
  96. Knudsen K, Beckman Suurkula M, Blomberg S, Sjovall J,
Edvardsson N. Central nervous and cardiovascular effects
of i.v. infusions of ropivacaine, bupivacaine and placebo in
volunteers. Br J Anaesthesia 1997;78:507-14.
  97. Stewart J, Kellett N, Castro D. The central nervous system
and cardiovascular effects of levobupivacaine and ropi-
vacaine in healthy volunteers. Anesth Analg 2003;97:412-6.
  98. Katz RI, Quijano I, Barcelon N, Biancaniello T. Ventricular
tachycardia during general anesthesia in a patient with con-
genital long QT syndrome. Can J Anesth 2003;50:398-403.
  99. Khan IA, Gowda RM. Novel therapeutics for treatment of
long-QT syndrome and torsade de pointes. Int J Cardiol
2004;95:1-6.
100. Borgeat A, Ekatodramis G, Blumenthal S. Intrascalene
brachial plexus anesthesia with ropivacaine 5 mg/mL and
bupivacaine 5 mg/mL:effects on electrocardiogram. Reg
Anesth Pain Med 2004;29:557-63.
101. Fujii K, Yamaguchi S, Egawa H, Hamaguchi S, Kitajima
T, Minami J. Effects of head-up tilt after stellate ganglion
block on QT interval and QT dispersion. Reg Anesth Pain
Med 2004;29:317-22.
102. Smith AH, Norris KJ, Roden DM, Kannankeril PJ. Auto-
nomic tone attenuates drug-induced QT prolongation. J
Cardiovasc Electrophysiol 2007;18:960-4.
103. Ay B, Fak AS, Toprak A, Göğüş YF, Oktay A. QT disper-
sion increases during intubation in patients with coronary
artery disease. J Electrocardiol 2003;36:99-104.
104. Erdil F, Demirbilek S, Begec Z, Ozturk E, But A, Ozcan
Ersoy M. The effect of esmolol on the QTc interval dur-
ing induction of anesthesia in patients with coronary artery
disease. Anesthesia 2009;64:246-50.
105. Korpinen R, Klemola UM, Simola M, Toivonen H. The
electrocardiographic and hemodynamic effect of metohex-
ital and propofol with and without esmolol. Acta Anesthe-
siol Scand 2006;50:188-92
106. Korpinen R, Saarnivaara L, Siren K. QT interval of the
ECG, heart rate and arterial pressure during anesthetic
induction: comparative effects of alfentanil and esmolol.
Acta Anaesthesiol Scand 1995;39:809-13.
107. Korpinen R, Saarnivaara L, Siren K, Sarna S. Modification
of the hemodynamic responses to induction of anesthesia
and tracheal intubation with alfentanil, esmolol and their
combination. Can J Anesth 1995;42:298-304.
108. Charbit B, Funck-Brentano C. Droperidol-induced proar-
rhythmia. Anesthesiology 2007;107:524-6.
109. Pinarli FG, Elli M, Dagdemir A, Baysal K, Acar S. Elec-
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
COPYRIGHT© 2012 EDIZIONI MINERVA MEDICA
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is

The influence of anesthesia on cardiac repolarization OWCZUK

This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other

trocardiographic findings after 5-HT3 receptor antagonists
and chemotherapy in children with cancer. Pediatric Blood
Cancer 2006;47:567-71.
110. Benedict CR, Arbogast R, Martin L, Patton L, Morrill B,
Hahne W. Single-blind study of the effects of intravenous
dolasetron mesylate versus ondansetron on electrocar-
diographic parameters in normal volunteers. J Cardiovasc
Pharmacol 1996;28:53-9.
111. Kuryshev YA, Brown AM, Wang L, Benedict CR, Rampe
D. Interactions of the 5-hydroxytryptamine 3 antagonist
class of antiemetic drugs with human cardiac ion channels.
J Pharmacol Experiment Ther 2000;295:614-20.
112. Shipton EA. Anesthetics and the rate corrected inter-
val: learning from droperidol. Curr Opin Anaesthesiol
2005;18:419-23.
113. Drolet B, Zhang S, Deschênes D, Rail J, Nadeau S, Zhou Z
et al. Droperidol lengthens cardiac repolarization due to block
of the rapid component of the delayed rectifier potassium cur-
rent. J Cardiovasc Electrophysiol 1999;10:1597-604.
114. Nuttall GA, Eckerman KM, Jacob KA, Pawlaski EM,
Wigersma SK, Marienau ME et al. Does low-dose droperi-
dol administration increase the risk of drug-induced QT
prolongation and torsade de pointes in the general surgical
population? Anesthesiology 2007;107:531-6.
115. Habib AS, Gan TJ. The use of droperidol before and after
the Food and Drug Administration black box warning: a
survey of the members of the Society of Ambulatory An-
esthesia. J Clin Anesth 2008;20:35-9.
116. Haddad  PM, Anderson IM. Antipsychotic-related QTc
prolongation, torsade de pointes and sudden death. CNS
Drugs 2007;21:911-36.
117. Nielsen J, Graff C, Kanters JK, Toft E, Taylor D, Meyer
JM. Assessing QT interval prolongation and its associat-
ed risks with antipsychotics. CNS Drugs 2011;25:473-
90.
118. Tisdale JE, Rasty S, Padhi ID, Sharma ND, Rosman H.
The effect of intravenous haloperidol on QT interval dis-
persion in critically ill patients: comparison with QT in-
terval prolongation for assessment of risk of torsades de
pointes. J Clin Pharmacol 2001;41:1310-8.
119. Khan IA. Clinical and therapeutic aspects of congenital and
acquired long QT syndrome. Am J Med 2002;112:58-66.
120. Di Iorio  C, Cafiero T, Di Minno RM. The effects of
pneumoperitoneum and head-up position on heart rate
variability and QT interval dispersion during laparoscopic
cholecystectomy. Minerva Anestesiol 2010;76:882-9.
121. Nathan AT, Berkowitz DH, Montenegro LM, Nicol-
son SC, Vetter VL, Jobes DR. Implications  of  anesthe-
sia  in  children  with  long QT syndrome. Anesth Analg
2011;112:1163-8.
122. Drake E, Preston R. Douglas Brief review: anesthetic im-
plications of long QT syndrome in pregnancy. Can J An-
esth 2007;54:561-72.
123. Sen S, Ozmert G, Turan H, Caliskan E, Onbasili A, Kaya
D. The effects of spinal anesthesia on QT interval in preec-
lamptic patients. Anesth Analg 2006;103:1250-5.

Received on May 16, 2011. - Accepted for publication on November 15, 2011.
Corresponding author: Dr Radoslaw Owczuk, Department of Anesthesiology and Intensive Therapy, Medical University of Gdansk, 80-
211 Gdansk, ul. Debinki 7, Gdansk, Poland. E-mail: r.owczuk@gumed.edu.pl
This article is freely available at www.minervamedica.it
or other proprietary information of the Publisher.

Vol. 78 - No. 4 MINERVA ANESTESIOLOGICA 495