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Acta Anaesthesiol Scand 2014; 58: 266–272
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© 2014 The Acta Anaesthesiologica Scandinavica Foundation.
Published by John Wiley & Sons Ltd
ACTA ANAESTHESIOLOGICA SCANDINAVICA
doi: 10.1111/aas.12257
Review Article
Drug-induced long QT syndrome and fatal arrhythmias
in the intensive care unit
S. Beitland1,2, E. S. Platou3, K. Sunde1,2
1
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 2Department of Anaesthesiology, Division of Emergencies and Critical
Care, and 3Department of Cardiology, Division of Medicine, Oslo University Hospital, Oslo, Norway
Long QT syndrome (LQTS) is a genetic or acquired condition
characterised by a prolonged QT interval on the surface electrocardiogram (ECG) and is associated with a high risk of sudden
cardiac death because of polymorph ventricular tachyarrhythmia
called Torsade de Pointes arrhythmia. Drug-induced LQTS can
occur as a side effect of commonly used cardiac and non-cardiac
drugs in predisposed patients, often with baseline QT prolongation lengthened by medication and/or electrolyte disturbances.
Hospitalised patients often have several risk factors for
proarrhythmic response, such as advanced age and structural
heart disease. Patients in the intensive care unit (ICU) are particularly prone to develop drug induced LQTS because they receive
several different intravenous medications. Additionally, they
might have impaired drug elimination because of reduced kidney
and/or liver function, and also drug-drug-interactions. The clinical symptoms and signs of LQTS range from asymptomatic
patients to sudden death because of malignant arrhythmias, and
T
he sickest hospitalised patients in the intensive
care unit (ICU) are threatened by several fatal
complications, with severe arrhythmias and subsequent cardiac arrest as an example. Most of these
cases are caused by structural heart disease, but some
arrhythmic fatalities can occur due to prolongation of
the QT interval (QT) on the electrocardiogram (ECG)
causing Torsade de Pointes (TdP) tachycardia.1,2
Long QT syndrome (LQTS) can be inherited due to
genetic mutations known as Jervell, Lange–Nielsen
or Romano–Ward syndrome, often characterised by
a static QT prolongation and high risk of sudden
death in families.3 The acquired LQTS is more
common, typically with baseline QT prolongation
lengthened by precipitating medications and/or
electrolyte disturbances.4 Other factors such as myocardial ischaemia5 and hyperglycaemia6 can also
prolong the QT interval. Drug-induced LQTS has
been described for many types of cardiac and noncardiac medications frequently used in the ICU such
266
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it is therefore important to recognise the clinical characteristics
and typical ECG changes. Treatment of acquired LQTS is mainly
awareness, identification and discontinuation of QT prolonging
drugs, in addition to eventually supplement of magnesium and
potassium. Overdrive cardiac pacing is highly effective in preventing recurrences, and antiarrhythmic drugs should be
avoided. Recent data suggest that QT prolongation is quite
common in ICU patients and adversely affects patient mortality.
Thus, high-risk patients should be sufficiently monitored, and the
use of medications known to cause drug-induced LQTS might
have to be restricted.
Accepted for publication 9 December 2013
© 2014 The Acta Anaesthesiologica Scandinavica Foundation.
Published by John Wiley & Sons Ltd
as anaesthetics, sedatives, antibiotics, antimycotics,
antidepressives and antipsychotics. The mechanisms behind QT prolongation are that the medications act directly on ion channels of myocytes and/or
indirectly because of reduced drug elimination
caused either by reduced kidney and/or liver function or drug-drug-ineractions.7 It is imperative that
high-risk patients are identified and sufficiently
monitored both concerning QT prolongation and
drug accumulation.8–9 It is also debated whether the
use of medications known to cause drug-induced
LQTS might have to be restricted. Because druginduced LQTS is common in ICU patients and
adversely affects patient outcome, it is very important that clinicians are aware of risk factors, diagnosis, prevention and treatment in order to avoid
unnecessary hospital deaths. Thus, the aim of this
study was to review the current knowledge on druginduced LQTS in ICU patients, thereby giving clinicians an updated guide on how to deal with this
Records identified through
database searching
(n = 78)
Screening
Identification
Drug-induced long QT syndrome
Additional records identified
through other sources
(n = 16)
Records after duplicates removed
(n = 82)
Included
Eligibility
Records screened
(n = 82)
Records excluded (n = 49)
- Case reports (n =13)
- Subgroups (n = 19)
- Poisoning (n = 6)
- Detailed mechanism (n = 8)
- Detailed ECG (n = 3)
Full-text articles
assessed for eligibility
(n = 33)
Full-text articles excluded,
with reasons
(n = 0)
Fig. 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses
(PRISMA) flow diagram of search results
with an overview of included and excluded
studies. ECG, electrocardiogram.
Studies included in
qualitative synthesis
(n = 33)
problem that might lead to fatal consequences for our
patients.
Methods
A literature search for papers published up to and
including 15th May 2013 was performed in Ovid
Medline, Embase, Cochrane Library, UpToDate and
GIN (Guidelines International Network). An additional search was carried out in PubMed in order to
retrieve papers that have not yet been entered into
Ovid Medline. In Ovid Medline, the following
Medical Subject Headings were used: long QT syndrome AND (intensive care OR intensive care units
OR critical illness). A search for related terms in title
or abstracts was also performed. This search was then
adapted for use in the other databases. There were no
limitations regarding date of publication or study
design, but the population was limited to adult
humans above 18 years and the language limited to
English, German, Swedish, Danish or Norwegian.
The reference list of the retrieved papers was checked
for additional relevant studies. Studies presenting
case reports, subgroups of ICU patients and poisoning were excluded. Because the review is meant for
clinicians, also papers dealing with details on ECG
changes and/or QT prolonging mechanism were not
considered.
Results
After removing 12 duplicates, we were left with 82
papers, whereof 62 were clinical studies or case
reports and the remaining 20 were reviews or
guidelines. Forty-nine papers were excluded as
they presented only case reports (13), subgroups of
ICU patients (19, whereof 8 paediatric, 5 neurological, 2 cardiac, 1 pregnant, 1 burn, 1 psychiatric and 1
elderly) six poisoning, three details about ECG
changes and eight details about QT prolonging
mechanisms. One of the authors (SB) read the
abstracts and selected full-text papers for further
reading. A Preferred Reporting Items for Systematic
Reviews and Meta-Analyses (PRISMA) flow
diagram is presented in Fig. 1, and a complete list of
the included studies is given in Appendix 1. The
included papers were clinically heterogeneous; the
results are therefore presented in a narrative form
without sensitivity analysis. Additionally, information from the websites * and † were included, as they
were found highly relevant.
Discussion
QT prolongation is quite common in ICU patients
and might adversely affect patient outcome. In a
prospective study of ICU patients with continuous
QT monitoring, 24% of the patients had QT interval
prolongation (defined as QTc > 500 ms for ≥ 15 min)
during ICU stay, and 6 % of in-hospital cardiac
arrests were due to TdP arrhythmia.10 Furthermore,
ICU patients with QT prolongation had longer hos*http://www.qtdrugs.org (cited 28th December 2013)
†http://www.azcert.org (cited 28th December 2013)
267
S. Beitland et al.
Table 1
Table 2
Risk factors for drug-induced Torsade de Pointes arrhythmias.
Examples of drugs inducing Torsade de Pointes (TdP)
arrhythmias.
Female sex
Advanced age
Hypokalaemia
Hypomagenesaemia
Hyperglycaemia
Bradycardia
Recent conversion from atrial fibrillation
Structural cardiac disease
Myocardial ischaemia
Baseline QT prolongation
Subclinical long QT syndrome
Ion-channel polymorphism
Acute cerebral illness
Use of QT prolongation drugs
pital stay (276 h vs. 132 h, P < 0.0005) and higher
hospital mortality (8.7% vs. 2.6%, P < 0.0005) compared with ICU patients without QT prolongation,
respectively.11 In a more recent retrospective study,
37% of the patients experienced QT prolongation
(defined as QTc > 500 ms) during ICU stay.9 Clinicians should therefore be aware of acquired LQTS
and be able to identify patients at risk and avoid
specific drugs, hypokalaemia and hypomagnesaemia in such patients.
ECG criteria
Long QT is measured as a prolongation of the corrected QT interval (QTc) on ECG. On ECG, the QT
interval is measured from the beginning of the QRS
complex to T-wave termination, which represents
the ventricular depolarisation and repolarisation.7
The QT interval is influenced by heart rate and is
often corrected for the RR interval (i.e. the measured
distance between two subsequent R-waves), giving
QTc. A commonly used rate correcting formula is
the Bazett’s formula: QTc = QT/√RR.7 QT prolongation is considered when the QTc-interval is above
440 ms, arrhythmias often associated with QTcintervals above 500 ms.7,12,13 A study revealed that
the majority of physicians were unable to detect
LQTS during ECG interpretation,14 both the QT and
the QTc are therefore often automatically presented
by most modern ECG machines.
Risk factors
Multiple clinical risk factors for LQTS has been identified, outlined in Tables 1 and 2.6,14 Risk factors
related to the patients, like gender, genetic polymorphism and presence of congestive heart failure are
unavoidable but have to be kept in mind by the
clinician. However, risk factors occurring during the
ICU stay can be modified by patient treatment such
268
Antiarrhythmics (Amiodarone, Sotalol)
Antibiotics (Erythromycin, Clindamycin)
Antimycotics (Fluconazole, Voriconazole)
Antiviral drugs (Atazanavir)
Anti-emetics (Ondansetron, Domperidon)
Antihistamines (Clemastine, Astemizole)
Anticonvulsives (Fosfenytoin, Felbamat)
Antidepressives (Amitryptiline, Sertraline)
Antipsychotics (Haloperidol, Clozapine)
Promotility medications (Cisapride)
Sedatives (Midazolam, Droperidol)
Anaesthetics (Sevoflurane)
Other (Methadon)
Updated and complete lists of drugs is found on the web sites
http://www.qtdrugs.org and http://www.azcert.org (both cited
28th December 2013)
as hypokalaemia, hypomagnesaemia and druginduced LQTS. Awareness on the many medications
known to cause drug-induced LQTS is imperative,
especially when the drugs are combined in the same
patient.15–26 Previous medical reports have revealed
that development of drug-induced LQTS is often
associated with one or several risk factors in addition to drug exposure,27 but TdP from amiodarone
alone is very rare.7,18
Illustrating case report
A 75-year-old male was admitted to our ICU because
of complications following elective coronary artery
bypass grafting surgery. He developed multiple
organ failure and several episodes of polymorph
ventricular arrhythmias with TdP configuration.
Most of them were self-limiting (Fig. 2A), while
others were sustained with cardiac arrest (Fig. 2B)
requiring immediate cardiopulmonary resuscitation
(CPR) and defibrillation. He had both chronic and
acute risk factors for drug-induced TdP arrhythmias
and received three drugs that might cause QT
prolongation, i.e., haloperidol, erythromycin and
amiodarone. The patient was treated with discontinuation of drugs known to cause QT prolongation
and with overdrive atrial pacing with frequency of 90
heartbeats/min. The treatment was very effective in
preventing new ventricular arrhythmias, and after 3
days, the arrhythmias vanished and pacemaker treatment could be discontinued. The patient stayed for a
total of 43 days in the ICU and was discharged to the
ward and subsequently to his home. He gave us
permission to publish this case report in addition to
the ECG and arterial pressure documentation presented in Fig. 2.
Drug-induced long QT syndrome
A. Self-limiting ventricular arrhythmia
II
V5
Art1
150
0
B. Sustained TdP arrhythmia
II
V5
Art1
150
0
Documentation of the presented patients arrhythmias, firs line is ECG lead II, second line
ECG lead V5 and third line is arterial pressure curve from a radial artery catheter
Clinical symptoms and signs
The clinical symptoms and signs of LQTS range from
asymptomatic patients to sudden death because of
malignant arrhythmias.7,28 Most patients have a baseline QT prolongation often lengthened by known
precipitating factors, and the risk of malignant
arrhythmias in a given individual is difficult to
predict.25 The occurrence of TdP is often self-limiting
but may degenerate into life-threatening ventricular
fibrillation requiring immediate CPR and defibrillation as in our patient.7,28
Diagnosis
Patients at risk should be identified from the medical
history, and the clinician should be alerted if factors
known to cause QT prolongation are present. Especially elderly women with cardiovascular disease are
at risk (Fig. 2). As already described, the clinical
symptoms and signs can vary a lot. The diagnosis is
made from ECG, with measurement of a prolonged
QTc interval. One should also pay attention to variability of QT duration during arrhythmic activity
such as atrial fibrillation, as such variability is associated with high risk of malignant arrythmias.7,29
Documentation of arrhythmias using telemetry often
reveals polymorph ventricular arrhythmias with
typical TdP configuration with variable duration and
Fig. 2. Electrocardiogram (ECG) and
arterial pressure documentation of the
presented patient’s arrhythmias showing
typical Torsade de Pointes (TdP)
configuration.
clinical implications. It is imperative that the clinician
recognises the precipitating factors and characteristically ECG changes, as knowledge deficiency might
adversely affect patient safety.30
Treatment
Management of acquired LQTS is mainly identification and discontinuation of precipitating drugs
in addition to correction of hypokalaemia and
hypomagnesaemia.7,28 Acute treatment consists of
intravenous magnesium sulphate administration
irrespective of the serum magnesium concentration
and supplement of potassium in order to keep the
serum levels in the high normal range. Overdrive
cardiac pacing is highly effective in preventing recurrences, and the recommended heart rate is 90–110
beats/min.7,31 The effects of diverse antiarrhythmica
in the treatment of LQTS are controversial, and these
drugs should therefore be avoided.7,28
Drug-induced LQTS
Several drugs have been proven or suspected to
cause QT prolongation, a complete and maintained
list of these drugs are available at the web sites ‡ and
‡http://www.qtdrugs.org (cited 28th December 2013)
269
S. Beitland et al.
§. Many of these medications are frequently used
in the ICU, such as different types of anaesthetics,
sedatives, antibiotics, antimycotics, antidepressives
and antipsychotics. The mechanism behind druginduced QT prolongation is primarily blockade of
potassium ion channels (Ikr) in myocytes causing
prolonged cardiac repolarisation.7 A secondary
mechanism is blockade of hepatic degradation of
drugs because of inhibition of the cytochrome P450
enzyme CYP3A4.7 Co-administration of drugs that
are substrates for CYP3A4 and/or IKr blockers
has an additive toxic effect, and intravenous administration in high doses leading to high-serum
concentrations seems to be harmful.7,28 In a study
of the prescription of QT prolonging medications in
the ICU, 2.9 % of the patients received such
drugs, and the most frequently administered agents
among these were amiodarone, haloperidol and
levofloxacine.32 In another study of drug interactions
contributing to QT prolongation in ICU patients,
43% had pharmacodynamic and 47% pharmacokinetic interactions.9 The most commonly used
drugs related to such interactions were ondansetron,
amiodarone, metronidazole and haloperidol.9
Restrictions on the use of QT prolonging drugs
Some drugs have been withdrawn from market
because of unexpected sudden death associated with
QT prolongation.33 Based on reports of adverse
events, the Food and Drug Administration strengthened the label warning for intravenous haloperidol
in 2007.34 In clinical studies, intravenous haloperidol
have both given QT prolongation35 and been associated with arrhythmias.24 In ICU patients, intravenous
haloperidol has been shown to give QT prolongation, with the highest odds for developing TdP
arrhythmia in patients with long QTc intervals.25
Recently, the Scandinavian pharmaceutical company
Janssen Pharma has proscribed intravenous administration of haloperidol because of this side effect,
even though the antipsychotic drug has been widely
used for many years. Haloperidol has been the drug
of choice in the treatment of acute delirium in ICU
patients, and clinicians are therefore now uncertain
how to handle this situation.34
Preventive guidelines
According to the American Heart Association practice standards for ECG monitoring, there are four
§http://www.azcert.org (cited 28th December 2013)
270
indications for QT interval monitoring in hospital
settings: initiation of a drug known to cause TdP,
overdose from potentially proarrhythmic agents,
new-onset bradyarrhythmias, and severe hypokalaemia or hypomagnesaemia.8 In the presence of
such risk factors, the QT interval should therefore be
monitored, and each hospital ought to have a protocol for such observations.28 Automatic QT monitoring systems has been developed and can be used in
high-risk patients when available.28 In a study of
LQTS in the ICU, only half of the patients with
acquired LQTS received known QT prolonging
medications;36 some therefore recommend that QT
interval monitoring should be applied to all ICU
patients. Further, some argue that computerised
clinical decision systems that may help clinicians to
detect and avoid important drug interactions should
be applied in the ICU.9
Summary
QT prolongation is quite common in ICU patients
and might adversely affect patient outcome; clinicians should identify patients at risk and avoid specific drugs, hypokalaemia and hypomagnesaemia
in such patients. It is important to recognise
the polymorph ventricular tachycardia and TdP
configuration, and its association to QT interval prolongation. The risk of QT prolongation must be balanced against clinical benefits of the precipitating
drug in each individual patient. Risk patients should
be identified and monitored sufficiently, especially
those receiving several medications combined with
impaired kidney and/or liver function. With a good
clinical indication, it seems like drugs causing QT
prolongation can be safely used in patients under
continuous ECG monitoring, as long as they are not
combined with other QT prolonging drugs. In situations without telemetry surveillance, alternative
drugs should be preferred.
Conflict of interest: None
Funding: Departmental funding only.
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Address:
Sigrid Beitland
Department of Anaesthesiology
Division of Emergencies and Critical Care
Oslo University Hospital
Postboks 4956 Nydalen
N-0424 Oslo
Norway
e-mail: [email protected]
272
Supporting information
Additional Supporting Information may be found in
the online version of this article at the publisher’s
web-site:
Appendix 1. List of included studies