QTc dispersion is prolonged in patients with early postoperative adverse cardiovascular events and those with silent myocardial ischemia

QTc Dispersion Is Prolonged in Patients With Early Postoperative Adverse Cardiovascular Events and Those With Silent Myocardial Ischemia Keith J. Anderson, FRCA, and John W. Sear, PhD Objective: To determine if increased QT interval dispersion (corrected and not corrected for heart rate) is associated with perioperative silent myocardial ischemia or postoperative adverse cardiovascular events. Design: Blinded retrospective observational study. Setting: University hospital. Participants: One hundred eighty-one perioperative patients receiving general anesthesia for elective major vascular or orthopedic surgery. Interventions: None. Measurements and Main Results: QT dispersion, corrected and uncorrected for heart rate, was prolonged in patients suffering significant myocardial ischemia up to 48 hours assessed by Holter ECG monitoring, for early cardiac morbidity and all early cardiac events (including mortality) up to

1 month postoperatively. There were no significant changes in patients showing early cardiovascular mortality or late cardiac morbidity or mortality between 1 and 12 months postoperatively. Morbidity and mortality were determined from clinical notes, laboratory investigations, and autopsy when available. QT dispersion performed poorly as a screening test to identify those who subsequently developed early adverse cardiovascular outcomes. Conclusions: QT dispersion is prolonged in those at risk of early adverse cardiovascular events but is a poor screening tool. © 2004 Elsevier Inc. All rights reserved.

A

betes mellitus, and, interestingly, in peripheral vascular disease patients, to be associated with increased cardiac death.16,17 Darbar et al17 have suggested that a corrected dispersion of ⬎60 milliseconds is associated with high sensitivity (92%) and specificity (81%) for cardiac death in the community. Furthermore, they have shown this to correlate with diffuse coronary vascular disease at angiography. In a perioperative setting, other authors have failed to show any relationship between QTc dispersion (QTcD) and outcome (mortality) in a case-control study of patients after abdominal aortic aneurysm surgery.18 The object of this study was to determine if increased QTD or QTcD (corrected for heart rate) are associated with adverse cardiovascular events, cardiac death, and perioperative SMI in patients at risk for, or with proven, coronary artery disease.

NESTHESIA AND SURGERY in patients with peripheral vascular disease are known to be associated with significant morbidity and mortality.1,2 Orthopedic patients also have a high risk of coronary artery disease and perioperative ischemic complications. Perioperative silent myocardial ischemia (SMI) in orthopedic patients has a similar incidence (30%-40%) to that seen in vascular surgery (30%-40%)3,4; furthermore, a relatively high proportion (13%) of patients undergoing major orthopedic surgery have increased concentrations of CK-MB or troponin-I perioperatively.5 This group has therefore previously considered these patients together.6 The importance of preoperative assessment is not questioned, but controversy exists over the predictive utility of the tests available. The gold standard for preoperative cardiac evaluation is cardiac catheterization, although its role in noncardiac surgery is far from clear.7 In addition, this has a finite morbidity,8 is expensive, requires referral to a cardiologist, and is not available in all centers. Other tests have been suggested as markers for patients who are at risk of preoperative cardiac events. Stress electrocardiography9 and preoperative 24-hour Holter monitoring10 are relatively cheap and easily available but of debatable prognostic value. Dobutamine stress echocardiography,11 dipyridamole-thallium scintigraphy,12 and technetium-99 radionuclide angiography13 have all been advocated but are costly, not immediately available, and their relative merits are debatable.7,14 The resting 12-lead electrocardiogram (ECG), although widely available, is a poor indicator of perioperative (silent) myocardial ischemia, with only left ventricular hypertrophy and, to a lesser extent ST depression, indicating increased risk.15 Different leads on the same ECG often have a different QT interval duration (Fig 1). QT dispersion (QTD) is the difference between the maximum and minimum interval recorded in any of the 12 leads (ie, the range of the QT interval). Hence, QT dispersion is a relatively simple analysis of a routine 12-lead ECG. The QT interval is known to change with heart rate, so it is often corrected (QTc) using Bazett’s formula. It has become a topic of much research and debate in cardiology circles, despite the fact it is unclear what a “normal” dispersion is.16 An increase in QT dispersion has been shown in various disease states, such as cardiac failure, postmyocardial infarction, dia-

KEY WORDS: QT dispersion, cardiovascular outcome, vascular surgery, orthopedic surgery

METHODS The authors retrospectively studied the preoperative 12-lead ECGs from 181 patients (ages 43-90 years, 71 male) who had undergone elective vascular or major orthopedic surgery. These patients had previously been recruited, with institutional ethical approval, to studies reported elsewhere.19,20 Patients were only selected from the database of patients if they had a preoperative ECG available and had complete follow-up to 12 months postanesthesia and surgery. Because of these criteria, selected patients were random and nonconsecutive. These data were reanalyzed to assess whether there was any relationship between preoperative QT and QTc dispersion and cardiovascular outcome.

From the Nuffield Department of Anaesthetics, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom. Supported in part by a grant from the Wellcome Trust and a grant from LMA International. Presented in part at the American Society of Anesthesiologists meeting, New Orleans, LA, October 13-17, 2001. Address reprint requests to Keith J. Anderson, FRCA, University Department of Anaesthesia, Level 2 QEB, Glasgow Royal Infirmary, 10 Alexandra Parade, Glasgow G31 2ER, United Kingdom. E-mail: [email protected] © 2004 Elsevier Inc. All rights reserved. 1053-0770/04/1803-0006$30.00/0 doi:10.1053/j.jvca.2004.03.006

Journal of Cardiothoracic and Vascular Anesthesia, Vol 18, No 3 (June), 2004: pp 281-287

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Fig 1. Two reasonably healthy, representative electrocardiograms showing the measurement of QTc dispersion. (Reprinted from Darbar et al,17 with permission from BMJ Publishing Group.)

All surgery was conducted under general (⫾ regional) anesthesia, according to the type of surgery and the anesthesiologist’s choice. In most cases, a balanced volatile-opioid technique was used. All patients received postoperative analgesia and oxygen as deemed appropriate for the surgery. Patients were monitored with ambulatory ECG Holter monitoring (Medilog 6000FD, Medilog FD2; Oxford Instruments plc, Witney, United Kingdom) or Kontron 5100 (Kontron UK, Chichester, United Kingdom) for 48 hours postoperatively. Holter monitor traces were

examined by another investigator (JWS) who was blinded to the QT/QTc interval calculated. SMI was defined as ⬎1mm ST depression (horizontal or down-sloping) for greater than or equal to 60 seconds. Patients were followed for 12 months. This was done while in the hospital; at discharge; and at 1, 3, and 12 months postsurgery by a combination of personal contact, general/family practitioner questionnaire, outpatient visits, and note review if readmitted to the hospital. The incidence of major cardiovascular events and cardiac death was recorded at these visits.

Table 1. Cardiovascular Outcomes Displayed in Terms of Silent Myocardial Ischemia, Cardiovascular Morbidity, and Mortality Early

Late

Adverse Events

Positive n (%)

Negative n (%)

Positive n (%)

Negative n (%)

Total

Silent myocardial ischemia Cardiovascular morbidity Cardiovascular mortality All cardiovascular complications

59 (36) 21 (11) 7 (4) 28 (15)

105 (63) — — 153 (85)

— 7 (4) 8 (4) 15 (8)

— — — 166 (92)

164 28 (15) 15 (8) 181

NOTE. Early outcomes are those up to 1 month postoperatively, and late outcomes are those between 1 and 12 months postoperatively.

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Table 2. Comparison of Heart Rate, QT Dispersion, and QTc Dispersion for Patients With and Without Silent Myocardial Ischemia Parameter

Positive SMI

Negative SMI

n HR (bpm) QTD (ms) QTcD (ms)

59 73.1 (13.2) 101.7 (43.6) 110.9 (46.6)

105 70.6 (14.1) 84.2 (39.1) 90.3 (41.9)

Table 4. Comparison of Heart Rate, QT Dispersion, and QTc Dispersion for Patients With and Without Early Cardiac Death

p

Parameter

Cardiac Death

No Cardiac Death

p

0.25 0.01 0.006

n HR (bpm) QTD (ms) QTcD (ms)

7 77.1 (13.4) 120.0 (38.3) 136.7 (52.7)

174 71.7 (13.8) 89.7 (41.2) 97.0 (44.2)

0.36 0.09 0.10

NOTE. Results are mean (⫾ SD).

NOTE. Results are mean (⫾ SD).

this event, the authors therefore excluded this lead from the data analysis. Data calculations were performed by a spreadsheet (Microsoft Excel 2000; Microsoft Corp, Redmond, WA). Statistical analysis was performed using Minitab for windows (v12.2; Minitab Inc, State College, PA). HR, QTD, and QTcD were compared between groups suffering and not suffering from SMI and adverse cardiovascular outcome, respectively, using the student t test and Fisher’s exact test. Comparison of patients with early, late, and no cardiovascular outcome was performed by 1-way analysis of variance.

The primary major outcome measures were cardiovascular morbidity and cardiac death, as well as the occurrence of perioperative SMI (which is itself a marker of postoperative cardiovascular adverse events). Cardiovascular morbidities noted (and definition) consisted of myocardial infarction (history, ECG changes, increased CK-MB or troponin); unstable angina (chest pain, ECG changes, no response to simple sublingual nitrate, requiring the introduction of additional therapies, eg, heparin, ␤-blockade, verapamil, angioplasty, or coronary artery bypass surgery); left ventricular failure (dyspnea, increased jugular, or central venous pressure, chest signs, and chest x-ray changes); arrhythmias, both atrial fibrillation and ventricular arrhythmias (confirmed on 12-lead ECG); and cerebrovascular accident (clinical signs and computed tomography scan of the brain). Cardiac mortality was supported by the combination of the clinical history, laboratory investigations, and autopsy when available. The baseline ECG was taken presurgery on admission to hospital (this was within 24 hours of surgery). HR, QT, and corrected QT (QTc) dispersion were measured from the hard copy of the preoperative ECG taken with standard paper speed of 25 mm/s by a single observer (KJA), who was blinded to perioperative Holter monitoring results and patient outcome. The QT intervals and RR interval were recorded, and 2 consecutive cardiac cycles were averaged for each lead. The RR interval was measured from the start of the R wave to the start of the subsequent R wave; heart rate was calculated from this and the speed of the ECG graph paper. The QT interval was measured for each lead from the beginning of the QRS complex to the end of the T wave (return to the T-P baseline); if U waves were present, the measurement was taken to the nadir of the curve between T and U. Its values were expressed in milliseconds. The QT interval is known to vary with duration of the cardiac cycle; hence, each QT interval was then corrected for heart rate with Bazett’s formula (QTc ⫽ QT/RR1⁄2). The units of QTc are milliseconds. The QT interval often differs between different leads of the same standard 12-lead ECG. The QT and QTc dispersion (QTD and QTcD, respectively) were defined as the difference between the maximum and minimum QT and QTc intervals, respectively (Fig 1). If the QT interval cannot be calculated for all leads (for instance, when the T wave is indiscernible), various data transformations have been suggested.17 However, this did not change the significance of results. Furthermore, the authors argue that if the interval in a particular lead cannot be measured, this lead cannot be assumed to be outside the maximum or minimum QT interval measured in other leads. In

Data were obtained for 181 patients. Sixteen patients underwent major joint arthroplasty surgery including revisions; the remaining 165 patients underwent vascular surgery (aortic aneurysmectomy, carotid endarterectomy, or infrainguinal arterial revascularization). There were no adverse intraoperative events. One hundred sixty-four patients had 48 hours of postoperative Holter monitoring; the remaining 17 patients were excluded because of the preexisting presence of left ventricular hypertrophy or strain, digitalis effects, or machine failure. All 181 patients were followed up for 12 months postoperatively. Cardiovascular outcomes were separated into early (complications before 1 month postoperatively) and late (complications between 1 month and 12 months postoperatively) and are summarized in Table 1. Cardiovascular events occurred between days 2 and 330 postoperatively. Early morbidity consisted of 7 cardiac arrhythmias, 5 episodes of acute cardiac failure, 4 episodes of unstable angina, 3 myocardial infarctions, and 2 cerebrovascular accidents. Late morbidity consisted of 3 episodes of unstable angina, 3 cerebrovascular accidents, and 1 episode of acute cardiac failure. Comparisons of heart rate, QT dispersion, and QTc dispersion between groups with and without adverse outcomes are made in Tables 2 through 6. The resting heart rates from the preoperative ECGs showed no difference between those patients with and without perioperative silent myocardial ischemia or between patients exhibiting postoperative morbidity and/or mortality. However, there

Table 3. Comparison of Heart Rate, QT Dispersion, and QTc Dispersion for Patients With and Without Early Morbidity

Table 5. Comparison of Heart Rate, QT Dispersion, and QTc Dispersion for Patients With and Without All Cardiac Deaths

Parameter

Positive Morbidity

Negative Morbidity

n HR (bpm) QTD (ms) QTcD (ms)

21 76.0 (19.0) 127.6 (36.3) 141.3 (63.3)

160 71.4 (12.9) 86.0 (36.3) 92.9 (39.0)

Results are mean (⫾ SD).

RESULTS

p

Parameter

Cardiac Death

No Cardiac Death

p

0.29 0.004 0.002

n HR (bpm) QTD (ms) QTcD (ms)

15 76.1 (14.5) 106.7 (39.0) 119.0 (46.2)

166 71.7 (13.7) 89.3 (41.5) 96.6 (44.5)

0.26 0.12 0.09

NOTE. Results are mean (⫾ SD).

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used for early cardiac morbidity alone: sensitivity 86%, specificity 18%, and positive and negative predictive values 4% and 97%, respectively.

Table 6. Comparison of Heart Rate, QT Dispersion, and QTc Dispersion for Patients With All Early and Late Cardiovascular Complications (Including Death) All Cardiovascular Complications Parameter

Early

Late

None

p

n HR (bpm) QTD (ms) QTcD (ms)

28 76.3 (17.6) 125.7 (53.3) 140.1 (60.0)

15 72.5 (14.0) 92.0 (35.0) 97.1 (33.2)

138 71.1 (12.9) 83.9 (35.0) 90.1 (37.6)

0.20 ⬍0.001 ⬍0.001

DISCUSSION

NOTE. Individual differences between groups are based on 1-way analysis of variance. Results are mean (⫾ SD).

was significantly greater QT dispersion and QTc dispersion in patients showing perioperative silent ischemia (Table 2), as well as those developing early postoperative morbidity (Table 3). There were no significant differences between the QT dispersion or QTc dispersion in patients who died in the early or late study periods and their surviving controls (Tables 4-5). When both morbidity and mortality were grouped together (Table 6), there were significant differences in QT dispersion and QTc dispersion for both early and late complications when compared with controls (patients exhibiting no complications). Between-group comparisons of patients exhibiting early and late complications showed significant differences at the 2% and 1% levels, respectively, (using an unpaired t test). Post hoc power analysis, assuming a significance level of 0.05, revealed adequate power (⬎0.95) for detecting differences in QT dispersion between those patients with and without early cardiovascular morbidity, silent myocardial ischemia, and all early cardiovascular events (versus none) but not early cardiovascular death (power ⬍0.80). Tables of the sensitivity and specificity of QTc dispersion for predicting either perioperative silent myocardial ischemia or all early cardiac morbidity and mortality at various abnormal cutoff levels are shown in Table 7. Receiver-operated characteristic curves were constructed from this table (Figs 2 and 3), together with the inflexion points at given levels of QTc dispersion. Although the receiver-operated curve for perioperative SMI was not different from the line of identity, for all early adverse cardiovascular complications, a cutoff of 60 milliseconds was associated with 96% sensitivity but a low specificity of 21%. The associated positive and negative predictive values were 18% and 97%, respectively. The following similar values were found when a cutoff of 60 ms for QTc dispersion was

Risk factors for development of perioperative (silent) myocardial ischemia, cardiac morbidity, and mortality have previously been described for this cohort of patients.2,3,6,19,20 The data show that QT dispersion was significantly prolonged in patients who developed silent myocardial ischemia in the first 48 hours postoperatively and in those who suffered adverse cardiovascular events in the first postoperative month. This difference persisted when QT dispersion was corrected for heart rate (QTcD), indicating that the change in QT dispersion between the groups was not merely as a result of a different heart rate. Indeed, there was no difference between the resting heart rate in the 2 groups of patients. QT dispersion was clearly not a marker for either early or late cardiac death in the authors’ patients; it did, however, identify a cohort of patients at risk of early cardiac morbidity. There was a significant prolongation of both QT and QTc dispersion in those patients showing morbidity. It is possible, however, that this lack of utility of QT dispersion as a marker for early cardiac death was limited by the low incidence of that event, and hence the study may not be large enough to detect a difference with a power of 80% or more. However, the combination of early morbidity and mortality resulted in an increased event rate, which may explain the observed difference in significance. The QT dispersion measured for the patients without cardiovascular morbidity and mortality was greater than that previously suggested to be normal (up to 70 milliseconds).16-18 However, there is no current standard method for measuring QT dispersion, and it remains unclear what “normal” dispersion is.16 Darbar et al17 also measured QT and QTc dispersion manually. However, they used 3 observers and averaged their measurement. It is unclear what their interobserver and intraobserver variation was. It has been shown that there is a significant lack of agreement between automated and manual measurement of QT dispersion.21-23 Indeed, even for automated measurement, there is a much larger variability in reproducibility of QT dispersion measurement than for conventional ECG indices (R-R, S-T, Q-T intervals).24 The coefficient of variance for QT measurement in the same patient can be as high as 44%.24 The authors used only 1 observer who could

Table 7. Calculation of Sensitivity and Specificity at Various Cut-off Levels for QTc Dispersion Used to Predict Silent Myocardial Ischemia and All Early Adverse Cardiovascular Events, Respectively Silent Myocardial Ischemia

All Early Adverse Cardiovascular Events

QTcD Cutoff (ms)

Sensitivity

Specificity

Sensitivity

Specificity

ⱖ60 ⱖ70 ⱖ80 ⱖ90 ⱖ100 ⱖ110

0.95 (0.92-0.98) 0.88 (0.83-0.93) 0.73 (0.66-0.80) 0.59 (0.42-0.67) 0.49 (0.42-0.57) 0.41 (0.33-0.48)

0.25 (0.18-0.31) 0.36 (0.29-0.44) 0.44 (0.36-0.51) 0.57 (0.50-0.65) 0.67 (0.59-0.74) 0.70 (0.63-0.77)

0.96 (0.94-0.99) 0.96 (0.94-0.99) 0.89 (0.85-0.94) 0.82 (0.77-0.88) 0.71 (0.65-0.78) 0.61 (0.54-0.68)

0.21 (0.15-0.27) 0.31 (0.25-0.38) 0.42 (0.35-0.49) 0.57 (0.50-0.64) 0.65 (0.58-0.72) 0.69 (0.63-0.76)

NOTE. Results are shown as proportion (and 95% confidence interval).

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Fig 2. ROC curve for ability of QTc dispersion to predict postoperative SMI. Cut-off level for QTc dispersion (ms): , 60; , 70; , 80; , 90; , 100; , 110.

Fig 3. ROC curve for ability of QTc to predict early adverse cardiovascular events (including death). Cut-off level for QTc dispersion (ms): , 60; , 70; , 80; , 90; , 100; , 110.

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have introduced a methodologic measurement error, causing measurement bias (either positive or negative). However, such error would be consistent within 1 observer and would be the same for patients subsequently developing positive outcome measures as those who did not. Such systematic errors could be reduced, but not eliminated, by automatic measurement from a suitably programmed ECG microprocessor. QT and QTc dispersion have been shown to be prolonged in patients at cardiovascular risk in various disease states such as acute myocardial infarction, diabetes, and peripheral vascular disease.14,16 This is an association and does not imply causation. In fact, it has been suggested that an increase in QT dispersion reflects nonhomogenous ventricular repolarization23 and, as such, may be expected to be found in patients with areas of abnormal, damaged, or ischemic myocardium. The observation that the mean QT and QTc dispersion was greater for those patients subsequently suffering SMI and/or adverse cardiovascular events is an intriguing one. It prompted the authors to determine whether raised QTc dispersion may be used as a noninvasive marker of patients at particularly high risk for perioperative cardiac morbidity or mortality. To use a continuous variable such as QTc dispersion as a screening test, there must be a cutoff value above which the screening test (QTc dispersion) is said to be positive. An ROC curve is useful to decide the best cutoff value to use. To do this, sensitivity and 1-specificity were calculated at QTc dispersion cutoff levels of 60, 70, 80, 90, 100, and 110 milliseconds. The constructed ROC curves for SMI and early cardiovascular morbidity are shown in Figures 2 and 3. Neither ROC curve has sufficient area under the curve to suggest that QTc dispersion would perform well as a predictive test for either SMI or all

early cardiovascular events. Nevertheless, if the best cutoff value to be that farthest from the line of no difference (thick solid) is taken, statistics can be calculated to describe the performance of QTc dispersion as a screening test for adverse events at these points. For SMI, the best cutoff value appears to be 70 milliseconds. At this point, the sensitivity is 88%, specificity 36, positive predictive value 44% (95% confidence interval 36-51), and positive likelihood ratio 1.38 (1.05-1.81). For all early adverse cardiac events, the best cutoff value appears to be 90 milliseconds. At this point, the sensitivity is 82%, specificity 57%, positive predictive value 26%, (19%-32%), and likelihood ratio 1.90 (1.53-2.38). In short, neither test would perform particularly well as a screening test to identify patients who are at high cardiac risk and require further cardiac investigations. SMI patients with a QTcD of greater than 70 milliseconds would have a false-positive rate of 74% and a falsenegative rate of 16%. For all early adverse cardiovascular events, patients with a QTcD greater than 90 milliseconds would have a false-positive rate of 76% and a false-negative rate of 5%. In summary, preoperative QTc dispersion was prolonged in patients who subsequently went on to develop postoperative silent myocardial ischemia, early cardiac morbidity, and allcause early adverse cardiovascular events. Despite this, it performs poorly as a predictive test and cannot be currently recommended as a screening tool for identifying those patients at risk for cardiovascular morbidity and mortality who would warrant more thorough cardiac investigation. Furthermore, in view of the difficulties with the reproducibility of QT dispersion measurements, the observed association should be considered cautiously.25

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