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Acta Anaesthesiol Scand 2014; 58: 266–272 Printed in Singapore. All rights reserved © 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 bs_bs_banner 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. References 1. Zipes DP, Wellens HJJ. Sudden cardiac death. Circulation 1998; 98: 2334–51. 2. Myerburg RJ, Kessler KM, Castellanos A. Sudden cardiac death: epidemiology, transient risk and intervention assessment. Ann Intern Med 1993; 119: 1187–97. 3. Barsheshet A, Brenyo A, Moss AJ, Goldenberg I. Genetics of sudden cardiac death. Curr Cardiol Rep 2011; 13: 364– 76. 4. Abdon NJ, Herlitz J, Bergfeldt L. Drug-induced cardiac arrest maybe more common than believed. Lakartidningen 2010; 107: 521–5. Drug-induced long QT syndrome 5. Kenigsberg DN, Khanal S, Kowalski M, Krishnan SC. 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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