The incidence, predictors and outcomes of QTc prolongation in critically ill patients

Journal Pre-proof The incidence, predictors and outcomes of QTc prolongation in critically ill patients

Hollie Russell, Leonid Churilov, Lisa Toh, Glenn M. Eastwood, Rinaldo Bellomo PII:

S0883-9441(19)30745-2

DOI:

https://doi.org/10.1016/j.jcrc.2019.09.014

Reference:

YJCRC 53381

To appear in:

Journal of Critical Care

Please cite this article as: H. Russell, L. Churilov, L. Toh, et al., The incidence, predictors and outcomes of QTc prolongation in critically ill patients, Journal of Critical Care(2018), https://doi.org/10.1016/j.jcrc.2019.09.014

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© 2018 Published by Elsevier.

Journal Pre-proof The incidence, predictors and outcomes of QTc prolongation in critically ill patients Hollie Russell1,3, Leonid Churilov2,3, Lisa Toh1,4, Glenn M Eastwood1, Rinaldo Bellomo1,2,* [email protected] 1

Department of Intensive Care, Austin Hospital, Heidelberg, Melbourne, Australia

2

Centre for Integrated Critical Care, The University of Melbourne, Victoria, Australia

3

Melbourne Medical School (Austin Clinical School), The University of Melbourne, Victoria,

Australia Faculty of Medicine, Nursing and Health Sciences, Monash University, Victoria, Australia

*

Corresponding author at: Department of Intensive Care, Austin Hospital, 145 Studley Rd,

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Heidelberg, Victoria, Australia

Funding

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This research did not receive any specific grant from funding agencies in the public,

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Declaration of interest

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commercial or non-for-profit sectors.

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The authors have no conflicts of interest to disclose.

Statement of prior publication and related content No parts of this manuscript, nor the data collected for this study have made available elsewhere, or are being considered for publication elsewhere in a manner that may be considered a duplicate publication of the same content.

Ethical adherence

Journal Pre-proof The following study was approved by the Austin Health Human Research Ethics Committee on October 27 2017 (Approval Number LNR/17/Austin/448).

Author contributions RB and HR developed the study design. RB and GE supervised data collection and project implementation by HR. Statistical analysis was performed by LC, LT and HR. The final manuscript was drafted by HR. All authors reviewed the manuscript version submitted for

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publication, and have committed to ensuring any questions related to the accuracy or integrity

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of the work are appropriately investigated and resolved.

Abstract

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Purpose: To study the incidence, predictors and outcomes of QTc prolongation (≥500 ms)

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during ICU admission.

Methods: Prospective observational study of patients admitted to a tertiary ICU during a two-

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month period. We obtained daily data on QTc intervals and arrhythmias from ICU monitors.

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We performed univariate and multivariable analyses to compare patients who did or did not experience QTc prolongation. Results: Of the 257 patients, 93 (36.2%) developed ≥1 episode of QTc ≥500 ms. Such patients had higher APACHE II scores (p<0.001), received more QT-prolonging medications (p=0.002), and more frequently developed non-sustained (<8 beats, p=0.007) and sustained ventricular tachycardia (≥8 beats; p<0.001). However, after adjustment for confounders, there was no independent association between QTc duration and odds of ventricular tachyarrhythmia (OR=0.921 [0.593-1.431], p=0.715). Moreover, 98% of ventricular tachyarrhythmias resolved spontaneously. Patients with QTc prolongation had longer ICU

Journal Pre-proof (p<0.001) and hospital length-of-stay (p=0.002), and greater ICU (p=0.030) and in-hospital mortality (p=0.015). No patient experienced sustained Torsades de Pointes or died from ventricular arrhythmia. Conclusions: A QTc ≥500 ms likely represents a marker of illness severity modulated by several risk factors, and carries no independent association with clinically-significant ventricular tachyarrhythmias. Thus, cessation of QT-prolonging medications to prevent arrhythmias may lack clinical benefit.

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Keywords: QT, QTc, Torsades de Pointes, critically ill, ICU, ventricular arrhythmia

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Abbreviations

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AICD automated implantable cardioverter-defibrillator

Acute Physiology and Chronic Health Evaluation II score

95% CI

95% confidence interval

CYP450

cytochrome P450

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ECG electrocardiogram

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APACHE II

intensive care unit

IRR

incidence rate ratio

OR

odds ratio

QT

interval from the beginning of the Q wave to the end of the T wave on the ECG, in

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ICU

milliseconds QTc

the QT interval duration corrected for heart rate according to Bazett’s formula (QTc =

QT/(RR)1/2) TdP

Torsades de Pointes

VF

ventricular fibrillation

VT

ventricular tachycardia

Journal Pre-proof Introduction The QTc interval is a crucial component of the electrocardiogram (ECG). Significant prolongation beyond the typical QTc duration of 430-450 milliseconds (ms) is considered a marker of abnormal ventricular electrical activity.[1] Patients with a congenitally-prolonged QTc interval are at increased risk of life-threatening ventricular tachyarrhythmias, especially sustained Torsades de Pointes, a form of polymorphic ventricular tachycardia, as well as sudden cardiac death.[2, 3] However, patients with a ‘normal’ QTc can also acquire QTc

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prolongation because of illness or medications. Such patients may also be at risk of significant ventricular arrhythmias.[4, 5]

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Many extrinsic factors can precipitate an ‘acquired’ form of QTc prolongation. These

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include advanced age, electrolyte disturbances and many commonly-used medications,

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including antiarrhythmic, antiemetic, antimicrobial and antipsychotic drugs.[4] Medications may contribute to a prolonged QTc via two mechanisms: 1) direct inhibition of ventricular

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ion channels, in particular IKr, leading to a delay in ventricular repolarisation, and 2) CYP450

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inhibition, leading to increased serum levels of direct-acting drugs.[6]

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Critically ill patients are exposed to a large number of the above risk factors, and up to half may develop a prolonged QTc during their intensive care unit (ICU) admission.[7, 8] However, it is unclear whether this ‘acquired QTc prolongation of critical illness’ carries the same risk of ventricular tachyarrhythmias observed in the congenital form or in other acquired forms in non-critically ill patients.

Accordingly, we investigated the incidence of prolonged QTc, exposure to risk factors for QTc prolongation, incidence of clinically significant ventricular arrhythmias, and overall outcomes including mortality, among patients who developed a ‘prolonged’ QTc (500 ms) at any time during their ICU stay compared with those who maintained a ‘normal’ QTc (<500

Journal Pre-proof ms) throughout their ICU admission. In accordance with the findings of recent studies,[7-10] we hypothesised that >20% of ICU patients would develop a prolonged QTc, but that <1% would experience clinically important ventricular arrhythmias.

Methods

Study design We performed a prospective observational study in a tertiary medical-surgical ICU in

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Melbourne, Australia. All new consecutive ICU admissions of patients aged 18 years and older between February 5-March 27 2018 were screened for inclusion in the study and

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followed up to ICU discharge, unless they fulfilled exclusion criteria. The aim of such

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inclusions was to obtain an adequate sample size to estimate the true underlying incidence of QTc prolongation and its associations. We determined that recruiting 246 individual patients

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would provide a precision (half-width of the 95% confidence interval) of 0.1, to estimate

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whether the true underlying incidence of prolonged QTc approximates the predicted 20%.

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The only exclusion criteria were the presence of a permanent pacemaker or automated

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implantable cardioverter-defibrillator (AICD), and inadequate ECG recording data. All patients were followed until discharge from hospital or until the conclusion of data collection on May 7 2018. One admission episode per patient was analysed; readmissions were not included. The study protocol was approved by the Austin Health Human Research Ethics Committee on October 27 2017 (Approval Number LNR/17/Austin/448). Informed consent was waived, as the study was observational, and only involved analysis of information collected as part of routine care.

ECG data collection

Journal Pre-proof All patients received continuous 5-electrode ECG monitoring using the Philips IntelliVue MX800 bedside patient monitor (Philips, Boeblingen, Germany).[11] In addition, patients received a 12-lead capture ECG on admission and at least daily thereafter.

We obtained data on cardiac rhythm, heart rate, QT and QTc duration from the first 12-lead capture ECG of the day. If no 12-lead capture was performed, data was manually obtained from the continuous monitoring device, using the mean QT and QTc duration

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derived from three consecutive QRS complexes. This was measured from the section of recording with clearest T wave/isoelectric line differentiation, between 0300-0800 hours

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(when the majority of nurse-initiated 12-lead capture ECGs were performed). The mean from

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five consecutive QRS complexes was used if the rhythm was non-sinus. A prolonged QTc

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interval was defined as 500 ms.

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Arrhythmia information was obtained from the IntelliVue device’s cardiac monitoring function. Ventricular tachyarrhythmias included non-sustained or sustained ventricular

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tachycardia (VT), Torsades de Pointes (TdP) and ventricular fibrillation (VF). Non-sustained

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VT was defined as a run of <8 premature ventricular complexes (PVCs), while sustained VT was defined as a run of ≥8 PVCs, at heart rate >100 beats per minute.[11] The cardiac monitoring device used the Bazett formula (QTc=QT/RR1/2) to correct the QT interval for heart rate, where ‘RR’ refers to the interval between two consecutive R waves on the ECG.

Risk factors for QTc interval prolongation We collected data regarding risk factors for QTc prolongation daily from electronic medical records. The Acute Physiology and Chronic Health Evaluation II (APACHE II) score was used to represent illness severity at admission. Metabolic variables included sodium,

Journal Pre-proof potassium and magnesium, from the first-daily venous blood sample results, and ionised calcium from the first-daily arterial blood gas. QT-prolonging medications were selected from the Arizona Center for Education and Research on Therapeutics (AzCERT) database of medications known to prolong the QT interval,[12] and as those most commonly prescribed in our unit. Vasopressor or inotropic drug requirements at the time of the 12-lead capture ECG were also recorded.

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Outcomes of QTc interval prolongation

The management of ventricular tachyarrhythmias were categorised as follows:

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1) expectant management

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2) administration of magnesium sulphate (MgSO4; no target range) 3) replacement of potassium (as chloride; KCl) to within normal range (3.5-5 mmol/L)

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4) a combination of MgSO4 and KCl

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5) other management (amiodarone, ventricular pacing, cardiopulmonary resuscitation, defibrillation).

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The outcomes of these arrhythmias were then recorded as ‘resolved’, ‘fatal’, or

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‘incidental’ (detected in a patient receiving terminal care). Other patient outcomes included ICU and hospital length-of-stay, and ICU and in-hospital mortality.

Statistical analysis Statistical Analysis was performed using STATA ICv14 statistical software (StataCorp, College Station, TX, USA). The association between the QTc prolongation status (normal vs. prolonged), risk factor exposure and outcomes were investigated at both the ‘patient’ and ‘patient-day’ levels in two separate analyses.

Journal Pre-proof For patient-level analyses, patients were split into two groups: those who experienced QTc prolongation at any point during their ICU admission, and those with a normal QTc for their entire admission. Univariate analyses were performed to compare risk factor exposure and outcomes between the groups. Proportions were analysed using a Chi-squared test, or Fisher’s exact test if the expected frequency in any cell was 5. The Mann-Whitney U test was used for continuous non-parametric data. When patients were admitted for ≥1 day, the

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median value for each risk factor was used. Multivariable analysis was then performed to determine the association between total number of days with a prolonged QTc in a given patient, and the likelihood of developing a cardiac event, adjusted for length-of-stay, age, sex,

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APACHE II score and admission type (medical vs. surgical). This was investigated using

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zero-inflated negative binomial regression, and reported using Incidence Rate Ratios (IRRs)

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with corresponding 95% confidence intervals (CIs).

Further multivariable analyses were then conducted at the patient-day level due to the

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following were investigated:

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repetition of individual daily observations being clustered within individual patients. The

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1) the association between specific risk factors (serum electrolyte concentrations) and the presence or absence of QTc prolongation on a given day, and 2) the association between the presence or absence of a prolonged QTc and development of a cardiac event on a given day. These analyses were performed using random effect logistical regression modelling adjusted for the overall length-of-stay, age, sex, APACHE II score, and admission type (medical vs. surgical), with individual patients treated as random effects. For both analyses, the respective effects were reported using odds ratios (ORs) with corresponding 95% CIs.

Journal Pre-proof A two-tailed p value of <0.05 was considered to be indicative of statistical significance. No multiplicity correction was applied.

Results

Patient characteristics Overall, 271 patients were admitted to ICU during the study period. Of these, 14 were excluded; 6 due to the presence of a pacemaker/AICD and 8 due to inadequate ECG data.

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Thus, 257 patients were included in the final analysis (Figure 1), comprising 1191 patientdays of data. The clinical characteristics of study patients and their admission episodes are

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shown in Table 1. The majority (57.6%) of patients were male, and the overall median age

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was 62 years. 56.4% were surgical admissions; most commonly post-cardiac surgery

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(24.5%). The median APACHE II score was 14.

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Incidence and risk factors for prolonged QTc

In total, 93 patients (36.2%) experienced a QTc interval 500 ms at least once during

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their ICU admission. 56 (21.8%) had a prolonged QTc at the time of ICU admission; a

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further 37 (14.4%) developed QTc prolongation during their ICU stay. Table 2 shows a comparison of the clinical features and potential risk factor exposure between the prolonged and normal QTc groups on a ‘patient’ level. Patients with prolonged QTc were more likely to be aged ≥80 years, and to have lower ionised calcium and higher magnesium levels. They were also more likely to have received one or more QT-prolonging medications; specifically, amiodarone, ciprofloxacin, olanzapine and metoclopramide. Antiemetic drugs were the most commonly-prescribed QT-prolonging medications. Patients with prolonged QTc also displayed markers of increased illness severity such as higher APACHE II scores, and a

Journal Pre-proof greater requirement for mechanical ventilation and blood pressure support with vasopressor/inotropic medications.

Risk factors for prolonged QTc on a daily level On multivariable analysis at a patient-day level (Table 3), 39% of the variability in QTc measures was attributable to inter-patient differences after adjustment for age, sex and admission type (medical vs. surgical). On any given day, QTc prolongation was less likely as

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serum potassium and ionised calcium levels increased. No association was found between

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Outcomes in patients with prolonged QTc

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QTc duration and serum magnesium.

Table 4 compares electrocardiographic outcomes, length-of-stay, and mortality in

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patients with prolonged vs. normal QTc. On univariate analysis, patients in the prolonged

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QTc group were more likely to show non-sinus rhythms on their daily 12-lead ECG,

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including atrial fibrillation and atrial flutter.

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Ventricular tachyarrhythmias were also more common in the prolonged QTc group, specifically non-sustained and sustained VT. These arrhythmias, however, fully resolved in almost all cases with either expectant management, potassium replacement or magnesium supplementation. One episode was effectively managed with amiodarone and another required temporary transcutaneous ventricular pacing.

Ventricular tachyarrhythmias were observed in a further six patients during planned terminal care and thus were not actively managed. Overall, only two patients developed TdP. These episodes were transient and self-resolving, and actually occurred on days when the

Journal Pre-proof QTc interval was not prolonged. No patients died due to an unexpected arrhythmic event. However, QTc prolongation was associated with a longer median ICU and hospital length-ofstay, as well as greater ICU and in-hospital mortality.

Additionally, for the prolonged QTc group, we examined the cumulative effect of days spent with a QTc ≥500 ms on the likelihood of ventricular tachyarrhythmia. On multivariable analysis after adjustment for age, sex, length-of-stay, APACHE II score and

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admission diagnosis (medical vs. surgical), we found that each additional day spent with a QTc ≥500 ms had no significant influence on the likelihood of such events (OR=1.161

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[0.824–1.636], p=0.394).

Outcomes on patient-days with prolonged QTc

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Finally, we examined the association between QTc prolongation and the likelihood of

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ventricular tachyarrhythmias at a daily level. On any given day, having a QTc interval ≥500 ms did not significantly increase the odds of developing a ventricular tachyarrhythmia

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(OR=0.921 [0.593–1.431], p=0.715), after adjustment for age, sex, length-of-stay, admission

Discussion

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diagnosis, and APACHE II score, with individual patients treated as random effects.

Key findings We performed a study to explore the incidence, predictors, associations and outcomes of QTc prolongation in patients admitted to ICU in a tertiary Australian hospital. We found that more than a third of patients experienced a QTc ≥500 ms during their intensive care admission, the majority of which already a had prolonged QTc on arrival to ICU, and that increased illness severity, age ≥80, electrolyte disturbances and exposure to specific

Journal Pre-proof medications were risk factors for QTc prolongation. Moreover, we found that both atrial and ventricular tachyarrhythmias were also more common in the prolonged QTc group. However, we found that most of these arrhythmias were non-sustained and/or resolved spontaneously or with minimal intervention. Finally, after adjustment for confounders, a QTc interval ≥500 ms did not significantly increase the odds of developing a ventricular tachyarrhythmia, and each additional day spent with a QTc ≥500 ms also had no significant independent association with the likelihood of a ventricular arrhythmia. However, QTc prolongation was

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associated with a longer median ICU and hospital length-of-stay, as well as greater ICU and

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in-hospital mortality.

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Relationship with previous studies

The incidence of prolonged QTc in our patient population is consistent with previous

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literature.[7-9, 13] However, a large proportion of our patients were tachycardic at the time of

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their 12-lead ECG, meaning that QT correction using the Bazett formula–which may overestimate the QTc interval duration as heart rate increases[14-16]–may have led to some

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‘false-positive’ results. Previous studies reported that QTc duration increases with age in

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healthy subjects,[17] and that advanced age (≥60 years) is a risk factor for both QTc prolongation and TdP.[4, 18] Our findings are consistent with such studies.

Use of QT-prolonging medications was common, and was associated with prolonged QTc on univariate analysis in keeping with previous reports.[7, 9, 19] However, even when the QTc was prolonged and the patient was receiving one of such medications, there were no clinically relevant ventricular arrhythmias.

Journal Pre-proof Hypomagnesaemia is regarded as a common risk factor for QTc prolongation.[4, 20] Our prolonged-QTc group showed significantly higher serum magnesium levels. This is likely due to the confounding effect of intravenous MgSO4 administration, which is commonly used in ICU in patients with prolonged QTc,[21-23] and as safe management of frequent ventricular ectopy or atrial arrhythmias in our unit. On multivariable analysis, however, on any given day, serum magnesium levels were not associated with a prolonged QTc. Hypokalemia has also been linked with QTc prolongation.[18, 24, 25] Consistent with

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such studies, our multivariable analysis showed that on patient-days where serum potassium levels were higher, the odds of QTc prolongation were decreased, which highlights that even

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transient episodes of hypokalemia may significantly influence QTc duration. In this study,

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lower ionised calcium levels were associated with QTc prolongation in both univariate and

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multivariable analysis, also in keeping with the literature [4, 9, 18, 24]

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QTc prolongation at the time of ICU admission was common. The prolonged-QTc group showed greater mortality and required longer ICU and hospital admissions. These

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findings are aligned with other ICU studies which identified QTc prolongation as a marker

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for illness severity and poorer prognosis,[9] and demonstrated almost a three-fold increase in odds of non-arrhythmia-related mortality. This finding was reinforced by a recent study[26] reporting a 50% three-year mortality in patients who experienced a prolonged QTc while in hospital.

Study implications Our findings imply that QTc prolongation occurs commonly in critical illness, is associated with older age, specific medications, and electrolyte disturbances, and is likely to represent a marker of illness severity. Moreover, our findings imply that both atrial and

Journal Pre-proof ventricular arrhythmias are relatively common in such patients; however, these events do not appear to be related to the QTc interval itself, and typically resolve spontaneously. Consequently, our study suggests that given the overall low incidence of life-threatening QTc-related arrhythmias, QT-prolonging medications are likely ceased more often than is clinically beneficial with regard to arrhythmia prevention.

Strengths and Limitations

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Our study carries several strengths. It involved a sizable cohort of critically ill patients with daily QTc assessment over more than 1000 days of monitoring. It included daily

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comprehensive review of 24-hour monitoring data to identify even short-lived rhythm

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disorders. In addition, it was accompanied by collection of daily data on medications and key

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electrolytes that may be associated with such rhythm disturbances and a prolonged QTc.

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Our study also carries several limitations. It is single-centre in design. However, our ICU is typical of other tertiary ICUs in developed countries, and our findings are likely to be

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representative of such ICUs. The majority of data was obtained by a single researcher to

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maximise the quality and stability of data collection, yet may have introduced ascertainment bias. To minimise this, we collected numerical information, which was automatically classified and was, therefore, not open to interpretation. The QTc interval was measured once-daily for each patient, and was not recorded immediately prior to arrhythmic events. This restricts our ability to determine a precise temporal relationship between risk factor exposure, QTc duration, and episodes of arrhythmia. Also, some episodes of prolonged QTc were likely not detected. No adjustments were made for QTc duration in the setting of intraventricular conduction abnormalities. In these circumstances, QT-related arrhythmia risk may vary from that of patients in sinus rhythm.

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We included several of the most common QT-prolonging medications used in ICU. If other such drugs were prescribed, because of their uncommon use, their impact would not have materially affected our findings. We considered the QTc interval as ‘normal’ or ‘prolonged’ according to the literature cut-off value of 500 ms. Longer QTc intervals may confer higher risk. However, as episodes of QTc >550 ms were exceedingly rare, a much larger sample size would be required to accurately determine if a higher cut-off point exists.

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In future, we hope to perform such a study, with QTc analysed on a continuous scale.

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Conclusion

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QTc prolongation is common in the critically ill, and is more commonly seen with age ≥80 years, the use of QT-prolonging medications and electrolyte disturbances. Patients with a

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prolonged QTc demonstrated a higher incidence of atrial and ventricular tachyarrhythmias,

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but there was no independent association between a prolonged QTc and the odds of such arrhythmias on a patient or daily level. Furthermore, when arrhythmias occurred, they were

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transient and lacked clinical significance. These findings imply that in such patients,

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cessation of potentially useful drugs which prolong the QTc may not be highly clinically beneficial with regard to arrhythmia prevention. Finally, the characteristics of patients with a prolonged QTc and their greater mortality rates in the absence of arrhythmia-induced deaths suggest that QTc prolongation may represent an independent marker of illness severity.

Acknowledgements The authors would like to thank Helen Young, Leah Peck, Laurent Bitker, Luca Cioccari and Stephen Warrillow for their support during this project.

Appendix 1. Distribution of QTc interval duration

Journal Pre-proof Number of patients 4 6 28 85 138 151 104 65 36 15 6 4 3

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QTc interval duration Number of patient-days <350 ms 4 350 to <375 ms 7 375 to <400 ms 33 400 to <425 ms 164 425 to <450 ms 277 450 to <475 ms 329 475 to <500 ms 186 500 to <525 ms 100 525 to <550 ms 46 550 to <575 ms 18 575 to <600 ms 7 600 to <625 ms 4 ≥625 ms 5 Minimum QTc duration = 260 ms Maximum QTc duration = 661 ms Mean = 460 ms Median = 456 ms Mode = 440 ms

Goldenberg I, Moss AJ, Zareba W. QT interval: how to measure it and what is

lP

[1]

re

References

8167.2006.00408.x

Moss A, Schwartz P, Crampton R, Tzivoni D, Locati E, MacCluer J, et al. The long

ur

[2]

na

"normal". J Cardiovasc Electrophysiol 2006;17(3):333-6. https://doi.org/10.1111/j.1540-

44. [3]

Jo

QT syndrome: prospective longitudinal study of 328 families. Circulation 1991;84(3):1136-

Steinberg C. Diagnosis and clinical management of long-QT syndrome. Curr Opin

Cardiol 2018;33(1):31-41. https://doi.org/10.1097/HCO.0000000000000465 [4]

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. Circulation 2010;121(8):1047-60. https://doi.org/10.1161/CIRCULATIONAHA.109.192704

Journal Pre-proof [5]

Thomas SH, Behr ER. Pharmacological treatment of acquired QT prolongation and

torsades de pointes. Br J Clin Pharmacol 2015;81(3):420-7. https://doi.org/10.1111/bcp.12726 [6]

Roden DM. Drug-Induced Prolongation of the QT Interval. N Engl J Med

2004;350:1013-22. https://doi.org/10.1056/NEJMra032426 [7]

Kozik TM, Wung SF. Acquired long QT syndrome: frequency, onset, and risk factors

in intensive care patients. Crit Care Nurse 2012;32(5):32-41.

[8]

ro of

https://doi.org/10.4037/ccn2012900

Hoogstraaten E, Rijkenberg S, van der Voort PH. Corrected QT-interval prolongation

-p

and variability in intensive care patients. J Crit Care 2014;29(5):835-9.

[9]

re

https://doi.org/10.1016/j.jcrc.2014.05.005

Pickham D, Helfenbein E, Shinn JA, Chan G, Funk M, Weinacker A, et al. High

lP

prevalence of corrected QT interval prolongation in acutely ill patients is associated with

na

mortality: results of the QT in Practice (QTIP) Study. Crit Care Med 2012;40(2):394-9. https://doi.org/10.1097/CCM.0b013e318232db4a Javanainen T, Ishihara S, Gayat E, Charbit B, Jurkko R, Cinotti R, et al. Prolonged

ur

[10]

Jo

corrected QT interval is associated with short-term and long-term mortality in critically ill patients: results from the FROG-ICU study. Intensive Care Med 2019;45(5):746-8. https://doi.org/10.1007/s00134-019-05555-8 [11]

Philips IntelliVue Patient Monitor MX600/MX700/MX800 Instructions for Use,

https://umanitoba.ca/faculties/health_sciences/medicine/units/anesthesia/media/Philips_MX8 00.pdf; 2012 [accessed 18 April.2018]. [12]

Risk Categories for Drugs that Prolong QT & Induce Torsades de Pointes (TdP),

https://www.crediblemeds.org/new-drug-list/.

Journal Pre-proof [13]

Armahizer MJ, Seybert AL, Smithburger PL, Kane-Gill SL. Drug-drug interactions

contributing to QT prolongation in cardiac intensive care units. J Crit Care 2013;28(3):243-9. https://doi.org/10.1016/j.jcrc.2012.10.014 [14]

Vandenberk B, Vandael E, Robyns T, Vandenberghe J, Garweg C, Foulon V, et al.

Which QT Correction Formulae to Use for QT Monitoring? J Am Heart Assoc 2016;5(6). https://doi.org/10.1161/JAHA.116.003264 [15]

Luo S, Michler K, Johnston P, Macfarlane PW. A comparison of commonly used QT

ro of

correction formulae: The effect of heart rate on the QTc of normal ECGs. Journal of Electrocardiology 2004;37:81-90. https://doi.org/10.1016/j.jelectrocard.2004.08.030 Karjalainen J, Viitasalo M, Manttari M, Manninen V. Relation between QT intervals

-p

[16]

re

and heart rates from 40 to 120 beats/min in rest electrocardiograms of men and a simple method to adjust QT interval values. J Am Coll Cardiol 1994;23(7):1547-3.

Reardon M, Malik M. QT Interval Change with Age in an Overtly Healthy Older

na

[17]

lP

https://doi.org/10.1016/0735-1097(94)90654-8

Population. Clin Cardiol 1996;19(12):949-52. Benoit S, Mendelsohn A, Nourjah P, Staffa J, Graham D. Risk factors for prolonged

ur

[18]

Jo

QTc among US adults: Third National Health and Nutrition Examination Survey. Eur J Cardiovasc Prev Rehabil 2005;12(4):363-8. [19]

Dube KM, DeGrado J, Hohlfelder B, Szumita PM. Evaluation of the Effects of

Quetiapine on QTc Prolongation in Critically Ill Patients. J Pharm Pract 2017:897190017711875. https://doi.org/10.1177/0897190017711875 [20]

Tong G, Rude R. Magnesium deficiency in critical illness. J Intensive Care Med

2005;20(1):3-17. https://doi.org/10.1177/0885066604271539 [21]

Zipes D, Camm A, Borggrefe M, Buxton A, Chaitman B, Fromer M, et al.

ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias

Journal Pre-proof and the Prevention of Sudden Cardiac Death - Executive Summary. Circulation 2006;114(10):1088-132. https://doi.org/10.1161/circulationaha.106.178104 [22]

Tzivoni D, Banai S, Schuger C, Benhorin J, Keren A, Gottlieb S, et al. Treatment of

torsade de pointes with magnesium sulfate. Circulation 1988;77(2):392-7. [23]

Baker WL. Treating arrhythmias with adjunctive magnesium: identifying future

research directions. Eur Heart J Cardiovasc Pharmacother 2017;3(2):108-17. https://doi.org/10.1093/ehjcvp/pvw028 Diercks DB, Shumaik GM, Harrigan RA, Brady WJ, Chan TC. Electrocardiographic

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[24]

manifestations: electrolyte abnormalities. J Emerg Med 2004;27(2):153-60.

Tan H, Hou C, Lauer M, Sung R. Eiectrophysiologic Mechanisms of the Long QT

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[25]

-p

https://doi.org/10.1016/j.jemermed.2004.04.006

Interval Syndromes and Torsade de Pointes. Ann Intern Med 1995;122(9):701-14. Gibbs C, Thalamus J, Heldal K, Holla OL, Haugaa KH, Hysing J. Predictors of

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mortality in high-risk patients with QT prolongation in a community hospital. Europace

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2018;20(FI1):f99-f107. https://doi.org/10.1093/europace/eux286

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Figure 1: Flow diagram of patient screening and selection

Table 1. Demographic and baseline clinical characteristics Total patients (n=257) Age Sex (% male) APACHE II Received mechanical ventilation during admission QTc ≥500 ms on day 1 of ICU admission QTc≥500 ms developed during ICU admission Admission type Surgical Medical Admission diagnosis - operative Cardiovascular Gastrointestinal

62 (50-72) 148 (57.6%) 14 (10-19) 141 (54.9%) 56 (21.8%) 37 (14.4%) 145 (56.4%) 112 (43.6%) 63 (24.5%) 34 (13.2%)

Journal Pre-proof Respiratory Neurological Renal/genitourinary Gynaecological Musculoskeletal/skin Admission diagnosis - non-operative Cardiovascular Respiratory Gastroenterology Neurology Sepsis Renal Metabolic Non-operative other

15 (5.8%) 8 (3.1%) 8 (3.1%) 4 (1.6%) 13 (5.1%)

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14 (5.4%) 22 (8.6%) 16 (6.2%) 19 (7.4%) 21 (8.2%) 3 (1.2%) 13 (5.1%) 4 (1.6%)

Data presented as number of patients/admissions (percentage of total), or median (interquartile range).

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Table 2. Characteristics and exposure to potential risk factors for QTc prolongation in patients with normal vs. prolonged QTc during ICU admission Univariate analysis Prolonged QTc Normal QTc p value (n=93) (n=164) Age 62 (51-74) 63 (49-71) 0.237 Age ≥ 80 years 15 (16.1%) 11 (6.2%) 0.028* Sex (% female) 42 (45.2%) 67 (40.9%) 0.589 APACHE II 14 (10-19) 12 (9-16) <0.001* Mechanical ventilation during admission 61 (65.6%) 81 (49.4%) 0.012* Admission diagnosis (% surgical) 50 (52.1%) 101 (58.1%) 0.414 Admission diagnosis (% cardiac surgery) 26 (27.1%) 37 (21.3%) 0.351 Admission diagnosis (% non-operative 7 (7.3%) 9 (5.2%) 0.662 cardiology) Heart rate 84 (76-89) 75 (71-91) 0.134 ≥1 episode of bradycardia (sinus or non2 (2.2%) 7 (4.3%) 0.593 sinus) ≥1 episode of sinus bradycardia 1 (1.1%) 7 (4.3%) 0.265 ≥1 episode of sinus tachycardia 31 (33.3%) 49 (29.9%) 0.565 + Na (normal 135-145 mmol/L) 140 (137-142) 139 (137-141) 0.166 K+ (normal 3.5-5.0 mmol/L) 4.2 (4.05-4.40) 4.3 (4.00-4.51) 0.137 2+ Ionised Ca (normal 1.10-1.30 mmol/L) 1.10 (1.07-1.15) 1.15 (1.11-1.17) 0.002* Mg2+ (normal 0.70-1.10) 1.03 (0.85-1.24) 0.92 (0.80-1.08) 0.027* Vasopressor/inotrope^ therapy for ≥1 day 49 (52.7%) 49 (29.9%) <0.001* ≥1 dose of QT-prolonging medication 66 (76.3%) 82 (57.9%) 0.002* Quetiapine 18 (19.4%) 20 (12.1%) 0.170 Haloperidol 7 (7.5%) 4 (2.4%) 0.106 Olanzapine 6 (6.5%) 1 (0.6%) 0.018* Amiodarone 18 (19.4%) 7 (4.3%) <0.001* Ciprofloxacin 5 (5.4%) 1 (0.6%) 0.045* Erythromycin 2 (2.2%) 3 (1.8%) 0.771 Azithromycin 9 (9.7%) 9 (5.5%) 0.312 Clarithromycin 2 (2.2%) 1 (0.6%) 0.617

Journal Pre-proof Fluconazole Ketoconazole Ondansetron Metoclopramide

2 (2.2%) 0 36 (38.7%) 34 (36.6%)

2 (1.2%) 0 48 (29.3%) 32 (19.5%)

0.956 0.158 0.004

All heart rate variables refer to heart rate on the daily ECG from which the QT interval duration was measured. Episodes of both sinus and non-sinus bradycardia (<60 beats per minute) were considered as risk factors for early after-depolarisation. Only episodes of sinus tachycardia (>100 beats per minute) were recorded as a marker of illness severity. Data presented as number of patients/admissions (percentage), or medians with interquartile range. ^Adrenaline, noradrenaline or milrinone * represents significance at p <0.05.

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Table 3. Association between potential risk factors for QTc prolongation and development of a prolonged QTc on a daily level Multivariable analysis Rho p value Variability in QTc due to inter-patient 0.394 <0.001* differences OR 95% CI p value Risk factor for QTc prolongation Serum potassium (1 mmol/L increase) 0.629 0.416-0.952 0.028* Serum ionised calcium (0.1 mmol/L increase) 0.630 0.479-0.827 <0.001* Serum magnesium (0.1 mmol/L increase) 0.999 0.987-1.012 0.948

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OR refers to the odds of developing a QTc interval ≥500 ms, for every 1 mmol/L increase in serum potassium, or 0.1 mmol/L increase in serum ionised calcium or magnesium, on any given patient-day. Adjusted for age, sex, admission type (medical vs. surgical), APACHE II and length-of-stay. * represents significance at p <0.05.

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Table 4. Outcomes in patients with prolonged vs. normal QTc Univariate analysis Prolonged QTc (n=93) Cardiac rhythm ≥1 episode of atrial fibrillation 20 (21.5%) ≥1 episode of atrial flutter 9 (9.6%) ≥1 episode of other rhythm^ 15 (16.1%) ≥1 day of atrial pacing 13 (14.0%) ≥1 day of ventricular pacing 2 (2.2%) ≥1 day of atrioventricular pacing 3 (3.2%) Arrhythmias ≥1 episode of any ventricular tachyarrhythmia 57 61.3%) ≥1 episode of non-sustained VT 55 (59.1%) ≥1 episode of sustained VT 39 (41.9%) ≥1 episode of TdP 0 ≥1 episode of VF 7 (7.5%) Total number of cardiac-event days 200 Management of arrhythmias Expectant management/spontaneous resolution 129 (64.5%) Electrolyte administration 69 (34.5%) Other management (amiodarone, temporary 16 (8.0%)

Normal QTc (n=164)

p value

10 (6.1%) 2 (1.2%) 4 (2.4%) 8 (4.9%) 0 3 (1.8%)

<0.001* 0.004* <0.001* 0.020* 0.251 0.777

72 (43.9%) 67 (40.9%) 25 (15.2%) 2 (1.2%) 6 (3.7%) 134

0.011* 0.007* <0.001* 0.741 0.287 <0.001*

105 (77.6%) 29 (21.6%) 2 (1.5%)

0.010* 0.016* 0.020*

Journal Pre-proof pacing) Outcomes of arrhythmias Resolved with expectant management or electrolytes Resolved with other management Patient deceased due to arrhythmia Patient deceased due to other causes; arrhythmia detected incidentally Long-term outcomes ICU length of stay (days) Survived ICU (% admissions) Hospital length of stay (days) Survived hospital (% admissions)

195 (97.5%)

131 (97.8%)

0.832

2 (1.0%) 0 3 (1.5%)

0 0 3 (2.2%)

0.518

4 (3-6) 83 (86.5%) 16 (8-27) 73 (78.5%)

3 (2-4) 165 (94.8%) 9 (6-18) 148 (90.2%)

<0.001* 0.030* 0.002* 0.015*

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Cardiac rhythms refer to those observed at the time of the daily 12-lead ECG. Data presented as number of patients/admissions (%), or medians with interquartile range. ^‘Other’ rhythms include junctional and ectopic atrial rhythms, and atrioventricular conduction delay. * represents significance at p <0.05.

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acquired QTc prolongation ≥500 ms is common in ICU risk factors include hypokalemia, hypocalcaemia, and QT-prolonging medications no independent link was found between a QTc ≥500 ms and ventricular tachyarrhythmia a QTc ≥500 ms may, however, be a marker of increased illness severity no prolonged-QTc patients developed Torsades or died of ventricular arrhythmias

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Highlights