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Ann Thorac Surg 2001;72:65-71
© 2001 The Society of Thoracic Surgeons
Accepted for publication March 4, 2001.
Address reprint requests to Dr Jidéus, Department of Thoracic and Cardiovascular Surgery, University Hospital, S-751 85 Uppsala, Sweden
e-mail: lena.jideus{at}kirurgi.uu.se
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Abstract |
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 Top Abstract IntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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Methods. Forty-one patients undergoing CABG were treated with TEA intraoperatively and postoperatively. Another 80 patients served as the control group. The sympathetic and parasympathetic activities were evaluated by analysis of neuropeptides, catecholamines and heart rate variability (HRV), preoperatively and postoperatively.
Results. Postoperative AF occurred in 31.7% of the TEA-treated patients and in 36.3% of the untreated patients (p = 0.77). TEA significantly suppressed sympathetic activity, as indicated by a less pronounced increase of norepinephrine and epinephrine (p = 0.03, p = 0.02) and a significant decrease of neuropeptide Y (p = 0.01) postoperatively in TEA-treated patients compared to untreated patients. The HRV variable expressing sympathetic activity was significantly lower and the postoperative increase in heart rate was significantly less in the TEA group than in the control group after surgery (p = 0.01, p < 0.001). Among patients developing AF, the maximal number of supraventricular premature beats per minute increased significantly in untreated patients postoperatively but remained unchanged in TEA-treated patients (p = 0.004 versus p = 0.86).
Conclusions. TEA has no effect on the incidence of postoperative sustained AF, despite a significant reduction in sympathetic activity.
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Introduction |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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Several studies have shown that thoracic epidural anesthesia (TEA) administered in addition to general anesthesia reduces sympathetic tone, as indicated by a reduction in heart rate, catecholamines and postoperative pain [5–10]. An attenuated sympathetic stress response to sternotomy has also been indicated by improved hemodynamic stability and reduced cardiac norepinephrine (NE) spillover in TEA-treated patients [11]. Moreover, epidural analgesia has been shown to reduce levels of ß-endorphin, serum cortisol and catecholamines after CABG, and further to decrease low-frequency fluctuations, of both heart rate and blood pressure in heart rate variability (HRV) consistent with a sympathetic blockade [12–15]. If TEA reduces sympathetic activity, it may theoretically decrease the incidence of AF. In none of these studies, however, was the effect of TEA on the incidence of AF studied.
The aim of this study was therefore, to evaluate the effect of TEA on the incidence of sustained AF after CABG, and to evaluate in more detail, its effects on the ANS by measuring HRV and certain neuropeptides.
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Material and methods |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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Thoracic epidural anesthesia
The day before surgery, a Portex 16 G epidural catheter was inserted through a Tuohy needle at the T2-T3, T3-T4, or T4-T5 interstitium. Epidural analgesia was induced with 8 to 14 mL of bupivacaine 5 mg/mL. The effect of the block was tested by the ability to discriminate cold bilaterally at the midclavicular line after 30 to 40 minutes. An extension from at least T1-T8 was accepted. The block was maintained with bupivacaine 5 mg/mL, with an infusion rate of 4 to 8 mL/h, until the patient arrived at the intensive care unit. Then on, analgesia was achieved by a continuous infusion of bupivacaine (2 mg/mL) and sufentanil (1 µg/mL) epidurally (3 to 7 mL/h) until the end of the study, ie, 96 hours after surgery, or until clinically sustained AF. Anesthesia was induced with intravenous fentanyl, thiopental, and pancuronium and was maintained with intermittent doses of fentanyl supplemented by isoflurane. In the TEA group, fentanyl was restricted to the dose given at the induction of the general anesthesia [19].
In the control group, postoperative pain was achieved with intermittent doses of ketobemidone as needed. In the TEA group, the patient was declared to have sufficient pain relief when TEA was used as the only analgesia postoperatively, which was achieved in all patients.
Twenty-four hour Holter-electrocardiogram
Twenty-four hour Holter recordings immediately before the operation and from the morning of day 1 for four consecutive days, ie, 96 hours, or until clinically documented sustained AF (defined as AF lasting 30 seconds or longer) were obtained by a standard Del Mar Avionics three-channel tape recorder (Model 459, Del Mar Avionics, Irvine, CA). The tapes and batteries were exchanged every 24 hours. The ECG signal was digitized and stored using a commercially available PC-based system. All recordings were visually scanned and analyzed using a Del Mar Model 563 StrataScan Holter Analysis System.
Arrhythmia definitions and analysis
A supraventricular tachyarrhythmia (SVT) was defined as a narrow and regular or irregular QRS complex tachycardia with three or more consecutive beats with a heart rate above or equal to 100 beats per minute. AF was defined as the absence of consistent p waves before each QRS complex and with an irregular ventricular rate. A supraventricular premature beat (SPB) was defined as a narrow QRS complex occurring with 20% prematurity or more and differentiated from sinus arrhythmia on the basis of P-wave morphology, cyclic changes in preceding R-R intervals, or both. The following variables were analyzed for each 24-hour period recorded: maximal number of SPB per minute, mean number of SPB per hour, the number of episodes of SVT, and SVT with the maximal beats per minute (SVT maximum rate).
HRV definitions and analysis
The sympathetic and parasympathetic activity was evaluated by the analysis of HRV, which measures the variability in heart rate, reflecting the ability of the ANS to modulate the heart rate [17, 20]. The power spectrum of the frequency domain was divided into four different frequency bands: the total power (TP), 0.0033 to 0.40 Hz (ms2; the very low-frequency (VLF), 0.0033 to 0.04 Hz (ms2); the low-frequency (LF), 0.04 to 0.15 Hz (ms2) and the high-frequency (HF), 0.15 to 0.40 Hz (ms2) [21]. The HF component was used to reflect the vagally mediated tone and the LF component to reflect both sympathetic and parasympathetic influences. The LF/HF ratio was calculated in order to mirror sympathovagal balance [17].
Epochs with more than 4% of non-normal R-R intervals were excluded from further analysis. A total of 18 hours, with at least 60% of the daytime and 75% of the nighttime recordings had to be analyzable for a tape to be included [22]. The frequency variables were analyzed in 24-hour periods and also in day (7.30 to 21.30) and night (24.00 to 5.00).
Neuropeptides and catecholamines
The sympathetic and parasympathetic activity was further evaluated by measuring catecholamines and neuropeptides. Neuropeptide Y (NPY), chromogranin A (CgA) and chromogranin B (CgB), reflecting the sympathetic activity [23] and pancreatic polypeptide (PP) reflecting the parasympathetic activity [24].
Blood samples were taken during sinus rhythm preoperatively, in the morning at rest on day 1 and day 2, and collected from a cubital vessel in heparin-containing tubes and placed on ice until the analysis of CgA, CgB, NPY, and PP was done. The neuropeptides were measured by competitive radioimmunoassays [25–27] and the plasma levels of NE and epinephrine (E) at the routine clinical chemistry laboratory using HPLC techniques.
Statistical analysis
The associations of all preoperative and postoperative factors with or without TEA treatment, as well as the occurrence of postoperative AF, were analyzed using an unpaired t test or 
2 test, as required. Continuous variables are presented as means ± standard deviation (SD). Non-normal values were logarithmically transformed before analysis. Logistic regression was used when the dependent variable was dichotomous and represented an event or a presence/absence relation. Such an event or relation has a probability of occurrence which can also be stated as odds. The probability of the event, p, has the following relation to the concept of odds: odds (event) = p/(1-p). However, in order to obtain a linear relationship between the dependent variable, the event, and the predictors, we have to take the natural log of the odds. Our model then becomes: ln [p/(1-p)] = b0 + b1X1 + ... + bkXk. This can easily be rewritten as p = 1/(1 + e-Z), where Z is the linear combination of all the predictors: Z = b0 + b1X1 + ... + bkXk.
Power calculation
In order to obtain a sample large enough for statistical analysis, a power analysis was made before the study. As there was no previous studies to refer to, the prior assumptions were an incidence ratio of 0.35 of postoperative AF without TEA treatment and an improvement of 50% (ie, to 0.175 with TEA treatment). The rather unrealistic number of 79 patients required in each group, when the power goal was set to 80%, led to the decision to lower the required power to 70%. In other words, 59 patients in each group were sufficient, or for example, 46 and 92 if groups were unequal. In our case, with a target of 45 and 96 patients, with and without TEA treatment, the power was about 71%.
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Results |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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The extension of the epidural anesthesia did not differ significantly between patients developing AF and those maintaining sinus rhythm (mean extension T1-T11 in both patient groups).
There were no early deaths, and no patient developed perioperative myocardial infarction but one patient in the TEA group suffered perioperative cerebral embolization, verified by computer tomography and the sequela resolved before discharge.
Effects on arrhythmia and HRV
The mean heart rate increased significantly in both patient groups after surgery (p < 0.001), but the increase was significantly less in the TEA group than in the control group (p < 0.001) (Table 2). Preoperatively, all patients developing AF had a significantly larger number of maximal SPB per minute compared to all patients remaining in sinus rhythm (8.6 ± 7.4 versus 4.7 ± 5.1, p < 0.001). After surgery, among patients developing AF, the maximal SPB per minute remained unchanged in the TEA-treated patients but increased significantly in the untreated group (11.5 ± 10.9 versus 10.6 ± 11.7, p = 0.86 and 7.3 + 4.7 versus 17.9 ± 18.5, p = 0.004). Furthermore, the maximal rate during postoperative SVT, among patients developing AF, was significantly lower in the TEA group than in the control group (137 + 26.0 versus 168 + 29.2, p = 0.02).
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Effects on neuropeptides and catecholamines
Treatment with TEA resulted in a significant decrease in NPY postoperatively, while control patients remained unaffected (p = 0.002 versus p = 0.60). However, the CgA and CgB levels remained unchanged postoperatively in both patient groups (Table 4). A significant decrease in PP was observed in both the TEA group and the control group on day 1 (p = 0.04 versus p = 0.0001). Furthermore, an increase of NE was suppressed by TEA postoperatively, so that NE remained unchanged in the TEA group but increased significantly in the control group on day 1 (p = 0.73 versus p = 0.002). The significant increase in E seen on day 1 in both patient groups was significantly lower in the TEA-treated patients, compared to the untreated patients (p = 0.002 versus p < 0.001).
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The spectral data were also treated in the same manner, a second set was used consisting of TP, HF, and LF/HF ratio, which were logarithmically transformed before analysis. The variables applied to day 1, except for the LF/HF ratio where values from both days 1 and 2 were included, and the regression was done in a stepwise manner. Two independent variables remained, namely HF on day 1 and the LF/HF ratio on day 2. A natural step would then be to merge the two data sets and study a model with the independent variables from the first set above and the spectral data. The best subset model again came up with two independent variables: mean heart rate on day 1 and the LF/HF ratio on day 2. The overall significance was even better than in the first set above, and the significance levels of the coefficients hovered around p = 0.01. Nevertheless, the misclassification ratio of the patients treated with TEA was quite high: 11 out of 28.
Discontinuation of ß-blockers after surgery was more frequent among TEA-treated patients (Table 1). Analysis of variance (ANOVA) could however not demonstrate that discontinuation of ß-blockers had any effect on the outcome. The lower heart rate in TEA-treated patients accounted much for the disparity in the use of ß-blockers. None of the variables in Table 1 had any effect on the outcome.
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Comment |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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In order to assess the degree of sympathetic suppression, we also analyzed NPY, which, besides its direct effects through its own receptors, has cumulative effects on the response of catecholamines to sympathetic stimulus and requires a certain level of sympathetic activity to respond [23]. The significantly reduced NPY levels observed on day 1 in our TEA-treated patients compared to the patients without TEA, further support an effective suppression of sympathetic activity by TEA. Both CGA and CGB, which are released together with catecholamines and NPY, can also be used as indices of a stronger sympathetic activity. However, since both of them remained unchanged after surgery in both patient groups, the increase in sympathetic activity postoperatively was probably moderate. We can therefore, conclude that our composite analysis of hormones showed that TEA efficiently suppressed the sympathetic outflow.
Sympathetic activity may also be evaluated by the analysis of HRV in the frequency domain [17]. In one of the few studies available on the effects of TEA on HRV, epidural analgesia was shown to decrease only low frequency fluctuations of both heart rate and blood pressure in the spectral analysis, consistent with a sympathetic blockade [15]. This is in accordance with our observation of significantly less increase in heart rate in TEA-treated patients compared to untreated patients postoperatively. One may therefore speculate why sympathetic blockade with ß-blockers and not TEA seem to be effective in reducing the incidence of postoperative AF [28]. Although this study was not designed to compare the efficacy of ß-blockers with TEA, the different responses may possibly be related to additional effects on the ANS. It has thus also been stated that TEA has a vagotonic effect on the cardiac ANS, since the TEA effect was shown to be attenuated by atropine [29]. In our study, the decrease in HRV variables on day 1 was significantly less pronounced in the TEA-treated patients compared to the patients without TEA. This applied especially to HF, which mirrors the vagotonic drive, and is consistent with concomitant vagal effect of TEA. This was not supported by the changes seen in PP levels, reflecting a parasympathetic drive [24], which significantly decreased in both patient groups on day 1. However, as we measured PP only in the morning at rest, the PP analysis does not reflect the circadian fluctuation in the parasympathetic activity.
Our study further showed that all of the HRV components were significantly higher in the daytime and the HF component remained significantly higher at nighttime in TEA-treated patients than in untreated patients. In long-term recordings, the VLF component accounts for approximately 95% of total power, while the physiologic correlate is still obscure, and the HF and LF component is thought to account for the remaining 5% of the total power [17]. Our study, in which TEA-treated patients showed a significant increase in both HF and LF in the daytime compared to control patients, therefore, supports other studies where LF is suggested to reflect both sympathetic activity and vagal activity [17]. The observation that only HF remained significantly higher at nighttime in the TEA-treated group compared to the control group is, however, in accordance with the circadian variation, where the sympathetic outflow is reduced at nighttime. The significant increase in VLF observed in the daytime in TEA patients compared to the control group therefore further raises the question as to whether HRV alone is such a useful tool in evaluating the ANS. HRV only measures fluctuations in autonomic inputs to the heart rather than the mean level of autonomic inputs [17].
Our finding that, among patients developing postoperative AF, TEA-treated patients had significantly fewer maximal SPB per minute and a significantly lower maximal rate during nonsustained SVT than in untreated patients, is consistent with a reduced sympathetic tone. This was also supported by the logistic regression analysis where the final variables, mean heart rate and SVT maximum rate remained independent on day 1, with the coefficients all significant at less than the 1% level. Such a response however, did not translate into a reduction in the risk of AF. In a previous study, TEA with bupivacaine and clonidine significantly reduced the frequency of arrhythmias requiring treatment after CABG from 32% to 18% [30]. In that study, however, both tachy- and bradyarrhythmias were included, and the effect on postoperative AF was not specifically addressed.
In summary, our results showed that the TEA treatment effectively suppressed the sympathetic activity, resulting in a relatively dominating vagotonic status in TEA-treated patients compared to untreated patients, but with no reduction in the incidence of postoperative AF. Neither the HRV nor the hormonal analysis could show that the ANS played a major role in the development of postoperative AF.
We previously showed that although the atrial areas increased after surgery, there was no significant difference between those patients developing AF and those who remained in sinus rhythm [3]. With the information gained from recent publications concerning triggering focus in the pulmonary veins, one may speculate whether the triggering mechanism of postoperative AF may be mechanical, such as distension of the pulmonary veins after surgery, in already vulnerable patients [31].
Further studies are mandatory to identify the mechanism, patients at risk, and to target these patients with more intensive prophylactic measures to reduce the incidence of postoperative AF.
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Acknowledgments |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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