Torsade de pointes is a rare but potentially fatal polymorphic ventricular tachycardia.1 This arrhythmia characterized by a typical twisting of the QRS complex morphology2 has several unique features among ventricular tachyarrhythmias.3 First, the ventricular rate in torsade de pointes is often <200 beats per minute, and it frequently terminates spontaneously, although it can degenerate into ventricular fibrillation and cardiac arrest. Second, torsade de pointes most frequently occurs when the heart rate–corrected QT (QTc) interval is prolonged >500 milliseconds and the electrocardiogram shows a characteristic QT-U wave deformity. Furthermore, torsade de pointes occurs nearly always in patients with an abnormal QT interval, which is commonly referred to as long QT syndrome, a condition of abnormal cardiac repolarization.2,4 The long QT syndrome can be congenital or acquired, or a combination thereof. Acquired long QT syndrome is commonly the result of QT interval–prolonging drugs.5,6 There is a strong correlation between QTc prolongation and the risk for torsade de pointes, but there is no absolute QTc threshold above which torsade de pointes routinely occurs. Several drugs that are routinely administered in the perioperative setting, such as antibiotics, sevoflurane,7–10 or ondansetron11–13 have been shown to cause QTc interval prolongation. Furthermore, in a recent study, we found that 80% of patients undergoing noncardiac surgery under general anesthesia developed postoperative QTc prolongation with a median increase of 23 milliseconds.14
Since the 1970s, >40 case reports of torsade de pointes occurring in the perioperative setting have been published. However, there has been no systematic review of this subject on the clinical features, precipitating events, and treatments of the potentially fatal arrhythmia occurring in the perioperative setting. The aim of this study was to perform a systematic review and analysis of all published case reports of perioperative torsade de pointes.
The Meta-analysis of Observational Studies in Epidemiology (MOOSE)15 and Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA)16 guidelines were followed in our systematic review. In December 2011, we performed a systematic search on MEDLINE for the following search terms: “Surgery AND Torsades de pointes,” “Surgery AND Torsade de pointes,” “Anesthesia AND Torsades de pointes,” “Anesthesia AND Torsade de pointes,” “Perioperative AND Torsades de pointes,” “Perioperative AND Torsade de pointes,” “Intraoperative AND Torsades de pointes,” “Intraoperative AND Torsade de pointes,” “Postoperative AND Torsades de pointes,” “Postoperative AND Torsade de pointes.” This search resulted in 289 hits (Fig. 1).
Case Report Selection
Case reports were eligible for inclusion when they reported episodes of torsade de pointes occurring in close temporal relationship to a surgical procedure either under general or regional anesthesia or sedation in human patients. The torsade de pointes event must have occurred between the immediate preoperative phase and the third postoperative day. We did not exclude any age group. Cases were considered from all languages, and a particular emphasis was put on including reports from non-English sources. If the publication could not be accessed electronically or in print, we attempted to contact authors by e-mail. The search and case report selection was primarily conducted by 1 author (JJ) with the help of a second (SP) under supervision by Peter Nagele. Selection of cases was typically straightforward and any initial disagreement resolved by consensus.
If available, the following variables were extracted from the case reports: patient characteristics (e.g., age, sex), timing of the torsade de pointes event, heart rates at baseline and at the event, electrolytes, administered drugs, preevent and postevent QT interval duration administered treatments such as defibrillation and magnesium, and outcome (fatal/nonfatal).
Correction for heart rate of the QT interval (QTc) is reported using the Bazett formula (QTcB = QT/√RR). Pooled categorical and nominal variables are summarized by frequencies and percentages in a fixed-effects meta-analysis. We compared QTc interval duration before the torsade de pointes event with QTc during or after the event using an unpaired 2-sided t test. The D’Agostino and Pearson omnibus normality test was used to determine whether QTc measurements were normally distributed before hypothesis testing (QTc values at baseline: P = 0.0606; QTc values at or after torsade de pointes: P = 0.5064). GraphPad 6.01 was used for graphing and statistical analysis (GraphPad Software Inc., La Jolla, CA).
The comprehensive search strategy identified 46 case reports of perioperative torsade de pointes.17–60 These reports were published between 1978 and 2011. Of the 46 cases, 29 occurred in female patients (67%), 14 in male patients (33%), and 2 were of unknown sex. Five patients had a diagnosis of congenital long QT syndrome. The median age among patients with congenital long QT syndrome who developed torsade de pointes was 11 years (range: 8–32 years); among patients without congenital long QT syndrome the median age was 56 years (range: 6 weeks–80 years).
The mean duration of the baseline QTc interval (available in 27/46 cases) was 457 ± 67 milliseconds (minimum 320 milliseconds; maximum 647 milliseconds). At the time of the event, or shortly thereafter, the mean QTc increased to 575 ± 77 milliseconds (minimum 413 milliseconds; maximum 766 milliseconds; data available for 33/46 patients) as shown in Figure 2. At the time of the event, the median heart rate was 62/min (minimum 40/min to maximum 105/min; data available for 15/46 patients). In 24 patients, the QTc interval duration was available before and after the event. These results showed that the QTc increased by +118 milliseconds (99% confidence interval [CI], 70–166 milliseconds; P < 0.001; Fig. 2). Two patients had only a minor change in their respective QTc (<±10 milliseconds); all others had a substantial prolongation of the QTc interval at the time of the event. Before the torsade de pointes episode, 14 of 27 patients (52%; 99% CI, 27%–77%) had a QTc >440 milliseconds and 6 of 27 had a QTc >500 milliseconds (22%); after the event, 32 of 33 (97%; 99% CI, 89%–100%) had a QTc >440 milliseconds and 26 of 33 (79%; 99% CI, 61%–97%) had a QTc >500 milliseconds.
The systematic review and meta-analysis identified several characteristics associated with perioperative torsade de pointes (summarized in tables): Table 1 reports the time point, and Table 2 lists all surgical procedures during which torsade de pointes events occurred. Preceding events identified by the authors of the individual case reports are shown in Table 3. In 9 cases (20%), the combination of several factors such as hypokalemia or congenital long QT syndrome and QT interval–prolonging drug was identified as the trigger for the torsade de pointes event. Table 4 lists all implicated drugs. Two episodes of perioperative torsade de pointes were fatal (case fatality rate: 4%); 40% were treated with magnesium and more than 1 in 4 patients required defibrillation. Table 5 lists all commonly used treatment strategies.
In what we believe is the first systematic analysis of perioperative torsade de pointes, we were able to identify 46 case reports. There are several pertinent findings resulting from the pooling of the available evidence from these case reports. First, nearly all episodes of perioperative torsade de pointes occurred when the QTc interval was substantially prolonged. Our data show an increase of >100 milliseconds at the time of the event compared with baseline in the majority of patients whereas only 2 patients had no significant increase in QTc. It therefore appears that QTc interval prolongation is nearly always required to develop perioperative torsade de pointes, but in itself is not sufficient to trigger actual episodes. As in other settings, perioperative torsade de pointes appears to be triggered by a simultaneous occurrence of several factors in the presence of QTc prolongation, such as hypokalemia, bradycardia, or drug–drug interactions. In a recent prospective study, we found that among 469 patients undergoing noncardiac surgery under general anesthesia, >80% developed postoperative QTc prolongation, and 1 patient developed torsade de pointes (incidence rate of 0.4%).14 As in this report, many of these patients received several drugs within a short period of time that likely contributed to QTc prolongation. Consistent with previous evidence, perioperative torsade de pointes appears to be more prevalent in women than in men.61,62 Patients with diagnosed congenital long QT syndrome had episodes of perioperative torsade de pointes at a much earlier age (median age, 11 years)63 compared with patients without this diagnosis (median age, 56 years).
It is noteworthy that several drugs were implicated in the case reports of perioperative torsade de pointes, but not droperidol for which the Food and Drug Administration issued a “black box” warning regarding the QTc prolongation risk.12,13,64 Many other perioperatively administered drugs such as ondansetron65 and metoclopramide66 also prolong the QTc interval.
Among the 46 identified cases of perioperative torsade de pointes, procedures and conditions, such as cerebral aneurysm rupture, cardiac surgery, and pheochromocytoma, appear to be overrepresented. We do not have a clear explanation for this observation, and it may represent random chance, but perhaps it is related to elevated catecholamine levels. Catecholamine release and stress have been previously shown to trigger episodes of torsade de pointes,67,68 so these surgical procedures and conditions may be associated with a higher risk for perioperative torsade de pointes. It is noteworthy that only 4% of perioperative torsade de pointes cases were fatal. However, 1 in 4 patients required defibrillation, but the majority of events responded to magnesium, lidocaine, or were self-terminated.5
Evidence regarding even the most basic facts about perioperative torsade de pointes is largely missing. Because most episodes are unreported, there is little evidence regarding the precise incidence or prevalence of this condition. Nonsurgical hospitalized patients are at higher risk for torsade de pointes,3 and the perioperative period may also be a period of increased risk due to the potential exposure to multiple drugs that can affect myocardial repolarization.14 Forty-six case reports over 40 years may indicate a very low, negligible prevalence of perioperative torsade de pointes. Reporting bias, the tendency to underreport less desirable findings, was clearly a major limitation of our study. Neither numerator nor denominator is known to accurately estimate the prevalence of torsade de pointes in surgical patients, and only large-scale epidemiologic studies will be able to provide this evidence. Recently, the American Heart Association and the American College of Cardiology Foundation published guidelines on the “Prevention of Torsade de Pointes in Hospital Settings” with the goal to raise awareness about this potentially fatal arrhythmia and its prevention.3 The authors of this statement argue that hospitalized patients are often at higher risk for torsade de pointes as they have other risk factors for proarrhythmic response and are often exposed to multiple QT-prolonging drugs.
This study had several limitations. First, the quality of any systematic review is dependent on the available studies and published case reports. Case reports of perioperative torsade de pointes did not follow a uniform reporting standard, so missing data were a substantial limitation. Important variables such as medical risk factors, drugs, and level of electrolytes were not uniformly captured. Furthermore, it is to be expected that there are many more cases of perioperative torsade de pointes than represented by the 46 reports we identified. Second, cases that occurred in the 1970s and 1980s may have become less relevant for modern medical practice as several of the drugs implicated in perioperative torsade de pointes are no longer widely used (e.g., halothane, droperidol, flecainide, or sotalol). As mentioned earlier, reporting bias is without a doubt the most significant limitation of this study. Nevertheless, we believe that even given these severe limitations, our study provides novel and potentially important insights into perioperative torsade de pointes.
In conclusion, this systematic review identified several common characteristics among 46 case reports of perioperative torsade de pointes. Nearly all episodes were preceded by a substantial QTc prolongation that was commonly the result of several QTc-prolonging factors. Given the common exposure to drugs and physiologic stressors with potential effects on myocardial repolarization, increased vigilance for perioperative QTc interval prolongation and the potential for torsade de pointes may be warranted.
Name: Joshua Johnston, MD.
Contribution: This author helped conduct the study, analyze the data, and write the manuscript.
Attestation: Joshua Johnston has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Conflicts of Interest: The author has no conflicts of interest to declare.
Name: Swatilika Pal, MBBS, MS.
Contribution: This author helped conduct the study, analyze the data, and write the manuscript.
Attestation: Swatilika Pal has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Conflicts of Interest: The author has no conflicts of interest to declare.
Name: Peter Nagele, MD, MSc.
Contribution: This author helped design and conduct the study, analyze the data, and write the manuscript.
Attestation: Peter Nagele has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Conflicts of Interest: Peter Nagele received research funding from Roche Diagnostics.
This manuscript was handled by: Charles W. Hogue, Jr., MD.
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