A Chan

AA Fossa

AJ Moss

Amanda S. Y. Chan

Carl M. J. Kirkpatrick

Geoffrey K. Isbister

M Hodges

M Malik

RR Shah

S Luo

Stephen B. Duffull

VN Batchvarov

International Journal of Emergency Medicine

English

PubMed

Springer - Publisher Connector

ORIGINAL ARTICLE
Assessing risk of a prolonged QT interval–a survey
of emergency physicians
Amanda S. Y. Chan & Geoffrey K. Isbister &
Carl M. J. Kirkpatrick & Stephen B. Duffull
Received: 23 January 2008 /Accepted: 17 February 2008 /Published online: 18 March 2008
# Springer-Verlag London Ltd 2008
Abstract
Background Although QT prolongation is associated with
an increased risk of torsades de pointes (TdP), it is unclear
how clinicians determine risk in individual patients with
prolonged QT.
Aims To investigate physicians’ interpretation of electro-
cardiogram (ECG) values in patients with a prolonged QT
in reference to risk of TdP.
Methods A survey was sent to Australasian emergency
physicians (EPs) to investigate interpretation of ECG data
in risk assessment for TdP. The survey contained three
sections: demographic information, questions on heart rate
correction and six sets of ECG data which the clinician
ranked from low to high risk. Risk analysis for ECG values
was performed by producing histograms of the distribution
of responses for each of the six sets of ECG parameters.
These distributions were compared to predicted distribu-
tions based on Bazett’s corrected QT>500 ms and the QT
nomogram. The QT nomogram is a recently developed
method for assessing whether QT-HR pairs are associated
with increased risk of TdP by plotting them to determine if
they are above an at risk line—the nomogram.
Results Of 720 surveys sent out, 249 were returned (35%).
A heart rate correction was used by 90% of respondents and
the median “at risk” QTc judged by EPs was 450 ms
[interquartile range (IQR): 440–500 ms]. Respondents were
divided as to whether bradycardia increased the risk of TdP,
with equal numbers responding “no change” and “more
caution”. In four of the six sets of ECG parameters, EPs had
a similar risk distribution to that predicted by Bazett. For
one point predicted to be high risk by the QT nomogram,
there was a uniform (undecided) risk distribution by EPs.
Conclusions EPs mainly relied on Bazett’s correction as
their method of TdP risk assessment, which may be
problematic for bradycardic patients.
Keywords QT interval . Drug toxicity . Torsades de pointes .
Nomogram . Risk assessment
Introduction
Prolongation of the QT interval and risk of torsades de
pointes (TdP) are ongoing issues for both the pharmaceu-
tical industry in drug development and for clinicians
assessing patients following drug interactions or drug
overdose. During drug development the potential for a
drug to prolong the QT interval must be assessed on many
levels, including in vitro, animal and human studies [1].
Int J Emerg Med (2008) 1:35–41
DOI 10.1007/s12245-008-0014-6
DO00014; No of Pages
Author’s contributions: GKI, CK and SBDdesigned the survey and study;
AC undertook data collection; AC, CK and SBD undertook data
analysis; GKI and AC wrote the manuscript and all authors commented
on it.
Disclaimer: The views expressed in this paper are those of the author(s)
and not those of the editors, editorial board or publisher.
A. S. Y. Chan :G. K. Isbister :C. M. J. Kirkpatrick : S. B. Duffull
School of Pharmacy, University of Queensland,
Brisbane, Australia
G. K. Isbister
Menzies School of Health Research, Charles Darwin University,
Darwin, Australia
S. B. Duffull
School of Pharmacy, University of Otago,
Dunedin, New Zealand
G. K. Isbister (*)
Department of Clinical Toxicology, Newcastle Mater Hospital,
Edith St, Waratah, NSW 2298, Australia
e-mail: Geoffrey.isbister@menzies.edu.au
The current International Conference of Harmonisation
(ICH) guidelines stipulate that cautionary labelling should
be used on new drugs if QT prolongation occurs for more
than 5 ms, as this denotes some risk of TdP [2]. Drugs that
prolong the QT interval for more that 20 ms are considered
proarrhythmic and are generally not marketed [2]. These
are likely to be the upper bounds of proven safety rather
than the lower bound of proven risk.
Despite this increasing focus on QT prolongation by the
pharmaceutical industry and drug regulatory agencies, there
remains little information available to clinicians to guide
them in risk assessment of a drug-induced prolonged QT
[1]. Although small changes of 5 and 20 ms may be
relevant to the introduction of a new drug into the
population (i.e. 20 ms in a susceptible person with mild
undiagnosed congenital long QT syndrome), these criteria
are less helpful for the clinician making a risk assessment
for individual patients.
Unfortunately, there is no universally accepted criterion
to identify the level of QT duration that is associated with a
clinically significant increased TdP risk. Current methods
include QT intervals corrected for heart rate (HR). These
are termed QTc when corrected to a heart rate of 60 bpm.
Various formulae exist for the calculation of QTc and
Bazett’s formula (QTcB = QT/RR1/2) is the most commonly
used in clinical practice. However, this formula is known to
be less reliable for values of heart rate that differ
significantly from 60 bpm and poses a problem for
physicians in examining a patients’ risk of developing
TdP in cases of extreme bradycardia and more commonly
with tachycardia [3–6]. A recent study by our group has
evaluated a different approach based on pre-clinical study
data by Fossa et al. using a QT nomogram [7, 8].
The aim of this study was to assess physicians’
interpretation of electrocardiogram (ECG) values in refer-
ence to risk of TdP through the use of a survey.
Methods
A survey was developed to elucidate physicians’ perception
of risk of QT prolongation (Appendix). Institutional ethics
approval was obtained from the University of Queensland.
The survey was in three parts: part one recorded the
demographics, including specialty and experience (number
of years after receiving specialty qualification); part two
asked about use of HR correction formulae, what values of
QT/QTc physicians believed confer a significant risk and
whether this risk was modified by the presence of
bradycardia/tachycardia (more or less cautious); part three
asked the physician to rate the risk of developing TdP given
various ECG values (see Appendix). Risk was given on a 5-
point Likert scale where a value of 1 indicates “low risk”
and 5 “high risk”. Six different sets of ECG values were
provided. ECG values were provided in HR, absolute QT
interval and corrected QT interval according to Bazett’s
formula, the most commonly used in clinical practice.
Two sets of low risk and two sets of high risk values
according to the QT nomogram were chosen. Another two
sets of values were chosen which displayed “borderline”
risk as the QT-HR pair was on the border of the QT
nomogram line (see Fig. 1) [7]. When estimating the risk at
the defined points using Bazett’s correction factor, a
different risk assessment results. The prediction was used
whereby a QTc<440 ms denotes low risk and a QTc>
500 ms indicates high risk. Thus two of the survey points
are considered low risk, one point medium risk and three
points high risk. Differentiation between the predictive
qualities of the two methods, Bazett’s and the QT
nomogram, were identified using three survey points.
Survey points 2 and 6 are of borderline risk according to
the QT nomogram, but equate to high risk according to the
Bazett correction factor with QTc of 502 ms and 517 ms,
respectively. Survey point 4 was high risk according to the
4
6
1
5
2
3
200
300
400
500
600
700
800
20 40 60 80 100 120 140 160 180
HR (bpm)
Q
T
 I
n
te
r
v
a
l 
(m
s
)
QT Nomogram
Extrapolated QT Nomogram
Bazett's Correction Factor
(QTc=440ms)
Bazett's Correction Factor
(QTc=500ms)
Survey Points
Fig. 1 Plot of survey points
(QT versus HR) with Bazett’s
correction factor (440 ms and
500 ms) and the QT nomogram
line included [7]
36 Int J Emerg Med (2008) 1:35–41
QT nomogram, but only considered medium risk by
Bazett’s (QTc=476 ms). The differences in the risk
prediction by the two methods, identifiable using the
survey points, will allow for discrimination of physicians’
interpretation of risk.
A pilot survey was initially given to 10 clinical
toxicologists and 15 emergency physicians to determine
the appropriateness of the questions and survey layout.
Data were collated and analysed from the pilot survey and
modifications were made to improve the readability of the
survey, but no major changes were made to the content. The
surveys were then mailed to all emergency physicians via
the Australasian College for Emergency Medicine in mid-
January 2006 and included all Fellows of the Australasian
College for Emergency Medicine (FACEMs). Each survey
was sent with an accompanying cover letter and reply paid
envelope. A repeat mailing of the survey was sent in mid-
February 2006. In all cases the respondents were uniden-
tified. Data from returned surveys were entered into a
Microsoft Excel spreadsheet.
Data analysis
Parts one and two were summarized using descriptive
statistics. For part three, histograms of the distribution of
responses (low to high risk) were produced for each set of
ECG values. These plots of response distributions were
compared to predicted distributions (see Fig. 2): the null
distribution (where every point was given uniform risk
weighting), a risk weighting according to Bazett’s formula
and a risk weighting according to the QT nomogram line
[7]. The null distribution assumed that the physician
response to the risk for each QT-HR combination was
uniform from low risk (1) to high risk (5). The distribution
according to Bazett’s correction formula was created by
using QTc=440 ms and QTc=500 ms as cut-off values.
QTc values of more than 500 ms were given a high risk
rating, those falling between 440 and 500 were medium risk
and those values less than 440 were considered low
risk. The QT nomogram line was used to predict the last
set of responses. Values of QT-HR falling above the line
were considered high risk, those on the line were given
medium risk and the values which fell below the line were
considered low risk. A visual analysis between the
distribution of the survey results and the predicted
distributions was then performed.
Results
Seven hundred and twenty surveys were sent in each
mailing and a total of 249 surveys were returned (34.6%).
Distribution 
of Responses 
1 
(HR=50bpm, QT=450ms, 
QTc=410ms)
2 
(HR=92bpm, QT==405ms, 
QTc=502ms)
3 
(HR=67bpm, QT=390ms, 
QTc=411ms)
4 
(HR=54bpm, QT=500ms, 
QTc=476ms)
5 
(HR=100bpm,QT=420ms, 
QTc=542ms)
6 
(HR=70bpm, QT=480ms, 
QTc=517ms)
Null 
Bazetts 
Correction 
Factor
QT
nomogram 
line 
Physician 
Responses
L ML M MH H L ML M MH H L ML M MH H L ML M MH H L ML M MH H L ML M MH H
L ML M MH H L ML M MH H L ML M MH H L ML M MH H L ML M MH H L ML M MH H
L ML M MH H L ML M MH H L ML M MH H L ML M MH H L ML M MH H L ML M MH H
L ML M MH H L ML M MH H L ML M MH H L ML M MH H L ML M MH H L ML M MH H
Fig. 2 Predicted responses for the null distribution, Bazett’s correction factor and the QT nomogram compared to the observed distribution of responses
Int J Emerg Med (2008) 1:35–41 37
In addition to emergency physicians, a few responses were
received from FACEM clinical toxicologists (2.8%) and
FACEM intensive care specialists (1.6%) (Table 1). The
majority of respondents had more than 5 years of
experience (75.5%) in their specialty.
In assessing risk of TdP, 89.9% of emergency physicians
answered that they use a correction factor and 87.5%
answered that they believed that a HR correction was a
better predictor than absolute QT. The median QTc at which
emergency physicians expressed concern about the devel-
opment of TdP was 450 ms [interquartile range (IQR):
440–500; range: 400–1,000 ms]. For those who chose to
use absolute QT interval, the median was 500 ms (IQR:
475–520; range: 440–1,000 ms). When asked whether
bradycardia (<50 bpm) would change their risk assessment
the respondents were divided with equal numbers of
responses for “no change” and “more caution”. With
tachycardia the majority responded “no change”.
In part three respondents were asked to rate the risk of
developing TdP given certain ECG values. The distribution
of responses where the emergency physicians’ responses
differed from the predicted response or when the QT
nomogram predicted response differed from the Bazett
prediction can be seen in Fig. 2 (columns 2, 4 and 6). For
survey points 1, 3 and 5, the distribution of responses were
found to be as per the predictions from the Bazett’s
correction factor and also the QT nomogram.
At survey point 2 (HR=92, QT=405, Fig. 2, column 2),
the physicians assessed a generally medium to high risk,
halfway between the medium risk predicted by the QT
nomogram and high risk predicted by Bazett’s HR
correction formula. At survey point 4 (HR=54 bpm, QT=
500 ms, Fig. 2, column 4), the responses form a relatively
uniform distribution with a risk assessment of between
medium-low to high, where the QT nomogram predicts a
high risk of developing TdP as opposed to Bazett’s formula
which predicts a medium risk. Only including respondents
who do not use HR correction formulae did not change this
(data not shown). At survey point 6 (HR=70, QT=480,
Fig. 2, column 6), the distribution of responses represented
high risk which was similar to that of Bazett’s correction
factor, but not the QT nomogram which predicted a
medium risk.
Discussion
Emergency physicians were found to mainly rely on
Bazett’s correction formula for their method of TdP risk
assessment with responses similar to those predicted for
Bazett’s for four of the six points. Of the other two points
one had tachycardia and the observed responses were less
cautious than Bazett’s. The other (point 4) was more
concerning because this point is in a region of QT-HR
associated with TdP (Fig. 1) and the observed responses
were “undecided” with no trend in the distribution of
responses.
Survey point 4 gives the most insight into current
approaches to risk assessment in practicing clinicians. This
point is in a region where a number of cases of TdP have
been published and is above the QT nomogram line [7].
However, Bazett’s formula only predicts medium risk,
which has been shown to be the major problem with
Bazett’s formula [7]. Emergency physicians were generally
undecided for this point with the number of responses at
medium-low, medium, medium-high and high risk being
almost identical. Although physicians appear to follow
Bazett’s formula there is a mixed response for this point
with bradycardia, probably with some staying with Bazett’s
formula while others factor in the additional component of
bradycardia. This is supported by the divided response on
the influence of bradycardia and whether assessment should
be more cautious or not.
It is concerning that no previous studies have investi-
gated physician risk assessment of QT prolongation for
TdP. Possibly this is because there are no clearly defined
guidelines or methods for determining whether patients are
at risk. The commonest approaches use the QTc values, but
numerous cut-offs for “at risk” are defined in the literature
[1, 4, 9]. There appears to be a huge gap between research
being undertaken on the QT by drug regulatory agencies
and the pharmaceutical industry and clinicians who are
being increasingly faced with drug-induced prolonged QT
in individual patients. There also appears to be little
translation of the last few decades of research done on the
QT interval into clinical practice. For example, despite
Bazett’s formula being recognized as problematic outside
the HR range of 60–100 bpm [10], it is the most common
Table 1 Demographics of
survey respondents Emergency Intensive care Toxicology Other Totals
Registrar 1 – 2 1 4
<5 years 54 2 1 - 57
5–10 years 87 2 1 – 90
>10 years 93 1 3 1 98
Totals 235 5 7 2 249
38 Int J Emerg Med (2008) 1:35–41
formula used in clinical practice and is calculated routinely
by commercial electrocardiograph machines [3, 4]. This is
supported by our survey, which demonstrates that 90% of
emergency physicians use a HR correction formula, and the
risk assessment is similar to Bazett’s for most points and
there is confusion for a point clearly associated with TdP.
In summary, physicians in an emergency care setting
appeared to rely on corrected QT interval, typically using
Bazett’s formula, for TdP risk assessment. Interpretation of
risk was more varied in the presence of concurrent
bradycardia, but not tachycardia. There is a need for easily
accessible methods for determining risk assessment in
patients with a prolonged QT and guidelines to assist in
the implementation of such methods.
Limitations
A limitation of the study was that only emergency
physicians were surveyed. We did not include cardiologists,
intensive care physicians or general practitioners because of
difficulties with obtaining mailing lists. However, emer-
gency physicians are the group most likely and most
commonly to be making risk assessments about drug-
induced prolonged QT, because most patients with drug
overdoses or acute drug reactions present to an emergency
department and many with other causes of drug-induced
QT prolongation will get referred.
Responses were generally from physicians with more
than 5 years experience in the field, which may have also
affected the results because they may represent a more
traditional approach to the assessment of the QT interval.
However, there did not appear to be a difference between
respondents with less than and more than 5 years experience.
The response rate to the survey was only 35% despite it
being sent out on two occasions. This may introduce some
biases into the results if only emergency physicians who
felt comfortable with risk assessment of QT prolongation
responded.
Conflict of interest statement Nil
Funding Geoff Isbister is funded by an NHMRC Clinical Career
Development Award ID300785.
Int J Emerg Med (2008) 1:35–41 39
Appendix: Survey
40 Int J Emerg Med (2008) 1:35–41
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Int J Emerg Med (2008) 1:35–41 41


Assessing risk of a prolonged QT interval–a survey of emergency physicians

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Assessing risk of a prolonged QT interval–a survey of emergency physicians

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