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Ann Thorac Surg 2009;87:1119-1126. doi:10.1016/j.athoracsur.2008.12.047
© 2009 The Society of Thoracic Surgeons
Original Articles: Adult Cardiac
Myocardial, Inflammatory, and Stress Responses in Off-Pump Coronary Artery Bypass Graft Surgery With Thoracic Epidural Anesthesia
Massimo Caputo, MD*,
Hazaim Alwair, MRCS,
Chris A. Rogers, PhD,
Mark Ginty, MSc,
Christopher Monk, FRCA,
Sally Tomkins, FRCA,
Amir Mokhtari,
Gianni D. Angelini, FRCS
Bristol Heart Institute, Bristol Royal Infirmary, Bristol, United Kingdom
Accepted for publication December 15, 2008.
* Address correspondence to Dr Caputo, Bristol Heart Institute, Bristol Royal Infirmary, Bristol, BS2 8HW, United Kingdom (Email: m.caputo{at}bristol.ac.uk).
| CARDIOTHORACIC ANESTHESIOLOGY:
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Abstract
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Objectives: Epidural anesthesia has been suggested to exert a protective effect against the inflammatory and stress responses associated with surgery. The aim of this study was to evaluate the impact of thoracic epidural anesthesia on myocardial cell damage, inflammatory, and stress responses in patients undergoing off-pump coronary artery bypass graft (OPCABG) surgery.
Methods: Seventy-four patients (66 male [89%], mean age 65.2 years [SD 9.6]) undergoing OPCABG surgery were randomly assigned to receive either general anesthesia plus epidural (GAE [n = 36]) or general anesthesia only (GA [n = 38]). Troponin I, 8-isoprostane, cortisol, C3
, interleukin (IL)-6, IL-8, and IL-10 were measured preoperatively, at 30 minutes, and 4, 12, 24, and 48 hours postoperatively.
Results: Baseline characteristics were similar in the two groups. One patient died in the GAE group, but no other major postoperative complications were recorded in either group. The IL-6 and IL-8 levels were lower in the GAE group (ratio 0.83, 95% confidence interval: 0.68 to 1.02; p = 0.070) than in the GA group (ratio 0.90, 95% confidence interval: 0.78 to 1.02; p = 0.090). The difference in levels of IL-10 between the GAE and GA groups varied over time (p 
0.001). The C3, troponin I, 8-isoprostane, and cortisol release was similar in the two groups throughout (p 
0.12).
Conclusions: Thoracic epidural anesthesia does not provide any additional benefits in terms of reducing myocardial damage, inflammatory, and stress response compared with general anesthesia only in patients undergoing OPCABG surgery.
Adding regional anesthesia to general anesthesia in patients undergoing cardiac surgery is receiving increasing attention [1]. Two recent randomized trials [2, 3] have investigated the potential benefits of thoracic epidural anesthesia in patients undergoing coronary artery bypass graft (CABG) surgery. Scott and colleagues [2], studying patients receiving regional anesthesia using a combination of bupivacine and clonidine, demonstrated a reduction in the incidence of supraventricular arrhythmias, postoperative confusion, lower respiratory tract infection, and renal failure, as well as an earlier extubation in the intensive care unit, compared with control patients not given thoracic epidural anesthesia. Priestley and colleagues [3] found that thoracic epidural anesthesia was associated with better analgesia and earlier extubation compared with general anesthesia alone after CABG surgery, with no difference in the postoperative length of stay. A possible mechanistic explanation is that the inflammatory response induced by surgical trauma, cardiopulmonary, bypass, and ischemia reperfusion injury after cardioplegic arrest may be attenuated by the use of regional anesthesia [4]. Other studies, however, have shown no significant difference in extubation time in patients undergoing CABG with or without regional anesthesia [5].
In all these studies, the surgery was performed using cardiopulmonary bypass and cardioplegic arrest, which by triggering a substantial inflammatory response might have masked the benefits of regional anesthesia. The aim of this randomized controlled trial was, therefore to evaluate the impact of regional anesthesia on biochemical markers of myocardial cell damage, inflammatory, and stress responses in patients undergoing off-pump coronary artery bypass graft (OPCABG) surgery.
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Material and Methods
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Patients undergoing OPCABG surgery between August 2004 and August 2006 at Bristol Royal Infirmary were randomly assigned to receive either general anesthesia (GA) only or general anesthesia plus epidural (GAE). Patients requiring salvage CABG, who were in cardiogenic shock, or who had associated heart valve pathologies were excluded from the study. Patients on intravenous heparin, warfarin, or clopidogrel or who suffered from bleeding diathesis were also excluded.
The study was approved by the Hospital Research Ethics Committee, and informed consent was gained from all patients. Random treatment allocations were generated by computer in advance of starting the study, using block randomization with varying block sizes. Allocation details were concealed in sequentially numbered opaque sealed envelopes. The treatment allocation was revealed to the surgeon after the start of the operation.
Anesthetic and Surgical Technique
The anesthetic technique consisted of premedication with benzodiazepines, and induction with intravenous infusion of propofol at 3 mg · kg-1 · h-1 combined with fentanyl (10 to 20 µg/kg). Neuromuscular blockade was achieved with 0.1 to 0.15 mg/kg pancuronium bromide or vecuronium, and the lungs were ventilated to normocapnia with air and oxygen (45% to 50%). End-tidal CO2 was maintained between 35 and 40 mm Hg throughout. The surgical technique and the method of exposure and stabilization for performing anastomoses in patients undergoing OPCABG surgery have been described previously [6, 7]. Heparin (100 IU/kg) was administered before the start of the first anastomosis to achieve an activated clotting time of 250 s to 350 s. On completion of all anastomoses, protamine sulphate was given to reverse the effect of heparin and return the activated clotting time to less than 120 s. In addition, patients in the GAE group had a thoracic epidural catheter sited in the operating theater immediately before surgery at the T2-3 or T3-4 interspace. Bilateral neuraxial block was established from T1 to T10 with an initial bolus of 5 mL bupivacaine 0.5% followed by another 5-mL bolus after 10 minutes.
Determination of the spread of block was performed with ethyl chloride spray. If a "bloody tap" was to occur, the operation was postponed for 24 hours and commenced only if neurologic examination was completely normal the next morning. Any focal neurologic abnormality resulted in an urgent magnetic resonance imaging (MRI) scan to exclude epidural hematoma. After induction of GA and when central hemodynamic status was stable, a continuous infusion of 0.125% bupivacaine and 0.0003% clonidine (150 µg in 500 mL) was commenced at an initial rate of 10 mL/h. The epidural infusion protocol used was similar to the one used by Scott and colleagues [2].
In the GAE group, the epidural infusion continued for 72 hours. After surgery, the rate was titrated by the attending anesthesiologist according to clinical need; the goal was to maintain the neuraxial block between T1 and T10 throughout the infusion. "Top-up" bolus doses to a maximum of 4 mL 0.25% bupivacaine were administered when the patient complained of pain. If more than three increases to the infusion rate or more than three epidural top-up doses were required in any hour, analgesia was considered inadequate.
In the GA group, a patient-controlled analgesia intravenous morphine pump was started in the intensive care unit for 48 hours by using a 1-mg bolus dosing with a 5-minute lockout period. All patients in both groups received additional oral paracetamol (1 g) every 6 hours. Postoperative patient management was according to unit protocol as previously reported [7].
Outcome Variables and Sample Size
Primary end points for this study were the release of troponin I and 8-isoprostane as measurements of myocardial reperfusion injury and oxidative stress, and the release of markers of the whole body inflammatory response (complement activation C3 and interleukin [IL]-6, IL-8, IL-10, and cortisol). The sample size calculation was based on our previous experience in similar studies [8–11], in which standardized differences in the range 0.8 to 1.1 were observed for the total area under curves describing the levels of biochemical markers during the first 24 to 48 hours after surgery, for example, IL-6, IL-8, protein, and troponin I. Moreover, standardized differences for group comparisons tended either to be in this range and highly significant or very small and nonsignificant, suggesting that such markers are sensitive indicators of physiologically important differences. For this aspect of the trial, we recruited 37 patients to each of the two groups. This total sample size of 74 patients was sufficient to detect a standardized difference of 0.75 (in other words, about the minimum observed in our previous studies) or greater, with 90% power and 5% statistical significance (two-tailed).
Continuous monitoring for all the hemodynamic measurements was performed and recorded in the operating room, including mean arterial pressures, central venous pressure, and heart rates.
Sample Collection and Analysis
Samples of blood (1 to 2 mL) were collected in bottles placed immediately under ice, preoperatively, at the end of the operation, and 4, 12, 24, and 48 hours postoperatively. Samples were immediately centrifuged at 4°C, at 4,000 rpm for 15 minutes. The resulting plasma was then frozen in liquid nitrogen, before storage at –80°C. Subsequently, the samples were thawed and analyzed for troponin I and cortisol (using an enzyme-linked immunosorbent assay [ELISA], Access, R&D System, Minneapolis, MN), 8-isoprostane (using an enzyme immunoassay [Caymen Chemicals, Ann Arbor, MI]), IL-6, IL-8, and IL-10 (ELISA [Amersham Biosciences, Little Chalford, Buckinghamshire, UK]), and complement activation C3 (ELISA [BD Biosciences Pharmingen, San Jose, CA]).
Statistical Analysis
Continuous measures are summarized using the mean and standard deviation or median and interquartile range if the distribution was skewed, and categorical data are presented as a number and percentage. After-surgery measurements of troponin I, cortisol, 8-isoprostane, c3, and IL-6, IL-8, and IL-10 were compared using a mixed regression model, with adjustment for preoperative readings. A variety of models describing the correlation between repeated measurements on the same patient were examined, and the structure leading to the lowest value for the Schwarz's Bayesian information criterion was chosen in each case. All six measures followed a skewed distribution. To induce normality, all measures were transformed to the logarithmic scale for analysis. After analysis, the results were transformed back to the original measurement scale. The results are presented as geometric means, and the difference between GA and GAE is expressed as a ratio of geometric means with 95% confidence intervals (CI). Changes in treatment effect over time were assessed using the F test, and if statistically significant at the 10% level, the treatment effect (ratio of geometric means) is reported separately at each time point, otherwise an overall effect of treatment is given (estimate of common ratio of geometric means).
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Results
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Seventy-four patients were recruited to the study, 36 randomly assigned to GAE and 34 to GA. All patients received the treatment allocated. Patient characteristics were similar between the two groups (Table 1). Clopidogrel was stopped at least 5 days before surgery in all patients, and 12 patients (3 in the GAE group, 9 in the GA group) continued to take aspirin until the day of surgery. Proportionally fewer operations were classified as urgent in the GAE group (22% versus 50%).
Operative details and hemodynamic data recorded before, during, and after surgery are given in Table 2. The mean number of grafts and duration of surgery was similar in the two groups (p = 0.62). All operations were carried out off pump, as planned. Complications relating to the use of the epidural occurred in 5 patients; in 2 patients, the epidural catheter slipped out, and in 3 patients, it failed to produce a regional block. The association of bupivacine and clonidine did not result in any complications for all patients.
Proportionally more patients in the GAE group required intraoperative vasoconstrictors compared with patients in the GA group (28% versus 13%, respectively; p = 0.15) owing to the vasodilating properties of the epidural treatment. Clinical outcomes are reported in Table 3. There was one death in intensive care unit after 13 days. This patient suffered a myocardial infarction postoperatively and died of multiorgan failure. There were no other major postoperative complications in either group. The incidence of atrial fibrillation (19% versus 47%, p = 0.01) and the median postoperative stay (5 days [4 to 6] versus 6 days [5 to 7], p = 0.07) were lower in the GAE group than in the GA group.
Biochemical markers levels are summarized in Table 4. For IL-6, IL-8, C3, troponin, isoprostane-8, and cortisol, the treatment effect (namely, the ratio of the mean response for GAE:GA group) remained constant over the time course studied (p 0.093). On average, the IL-6 response was 17% lower (95% CI: –32% to +2%, p = 0.070) and the IL-8 response 10% lower (95% CI: –22% to +2%, p = 0.094) in the GAE group (Figs 1 and 2).
The mean IL-10 response was similar between the two groups at the end of the surgery (p = 0.18), but after 4 hours was significantly reduced in the GAE group (–37%, 95% CI: –59% to –6%, p = 0.024). At 12 hours, the trend was reversed, with a 34% higher mean in the GAE group (95% CI: –5% to +87%, p = 0.089). Thereafter, the trend reversed again with lower, nonsignificant (p 0.087) mean responses in the GAE group (Table 4). The release of C3, isoprostane-8, and cortisol were similar in the two groups (+1%, +4%, –2% in the GAE group, respectively; p 0.64; Table 4). Troponin I was on average 39% higher for the patients given an epidural (95% CI: –9% to +113%, p = 0.12; Table 4).
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Fig 1. Postoperative interleukin (IL)-6 release (adjusted for baseline response) over time in the general anesthesia plus epidural group (circles) and the general anesthesia only group (squares).
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Fig 2. Postoperative interleukin (IL)-8 release (adjusted for baseline response) over time in the general anesthesia plus epidural group (circles) and the general anesthesia only group (squares).
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Comment
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This randomized controlled trial has examined the effects of regional anesthesia on myocardial cell damage inflammatory and stress response in patients undergoing OPCABG surgery. The choice of adding clonidine in combination with bupivacine in the epidural protocol was based on several factors: it allows a lower infusion rate of bupivacine, reducing the likelihood of bupivacine dose-related complications; using clonidine also allows minimizing the postoperative use of opioids; furthermore, clonidine provides stable analgesia in its own right. The dose of clonidine in our epidural infusion (0.6 µg/mL running at a maximum of 15 mL/h, or approximately 200 µg/day) was nevertheless extremely small.
Our data show that regional anesthesia does not provide any significant reduction in the release of markers of myocardial cell damage, inflammatory, and stress response when compared with GA only. These findings differ with those reported in recent studies, which suggested that regional anesthesia exerts protective effects against the perioperative stress and inflammatory responses [12], and attenuates the endocrine and metabolic response to major abdominal surgery [13]. Furthermore, regional anesthesia did not alter the postoperative cortisol production. Our data are consistent with the findings of Helbo-Hansen and colleagues [14], who described no attenuation of the postbypass increase in plasma adrenocorticotrophic hormone, cortisol, and renin concentrations, but are contrary to those of Liem and colleagues [15], who showed lower postoperative cortisol levels when thoracic epidural anesthesia was induced. One reason for this discrepancy may be that the levels of these hormones fluctuate with the timing of plasma sampling, which may have been different in two studies [16].
The incidence of perioperative myocardial infarction in patients undergoing on-pump CABG with regional anesthesia varies from 5.1% [3] to 14.8% [17]. The most recent meta-analysis including 15 clinical studies and 1,178 patients undergoing CABG [18] showed that regional anesthesia did not affect myocardial infarction and mortality rates. We did not find any significant difference in troponin I release between the two groups, suggesting that regional anesthesia does not impact on myocardial cell injury during OPCABG surgery. However, we have previously shown that troponin I release after OPCABG surgery is minimal and much reduced compared with on-pump CABG, thereby possibly masking the anti-ischemic properties of regional anesthesia, which have been described in other series [16].
In the GAE group, we observed remarkably stable heart rates throughout the procedure, beta-adrenergic blockers were not needed, even during periods of intense surgical stimulation such as sternotomy, and during dislocation of the heart to the perform coronary anastomosis. The major determinant of heart rate is the balance of the sympathetic and parasympathetic systems. High regional anesthesia, including the upper five thoracic segments, blocks the cardiac afferent and efferent sympathetic fibers, resulting in a loss of the chronotropic and inotropic drive to the myocardium.
The strengths of this study are that the data come from a randomized trial; the biochemical analyses were carried out without knowledge of the treatment group, and there were few missing data—for five of the seven markers, the data were complete. Furthermore, all available data were included in the analysis; cases with missing data were not excluded, nor were the missing data imputed.
The main limitation of the study is that it was not blinded. While it is recognized that lack of masking can inadvertently affect the assessment of clinical variables, all patients are managed according to strict Unit protocols, and data were collected in a consistent manner throughout. A further weakness is the small sample size; a larger study may have identified more clinically and statistically significant differences in myocardial and stress response between the two groups. The power calculation was based on findings from previous trials in similar patients but comparing different interventions. In hindsight, smaller differences might have been anticipated. Clinical endpoints are reported for completeness, although these were not the focus of the study, which was not powered to investigate differences in clinical outcome between the two groups. Only two statistically significant differences in clinical outcome were found: proportionally more patients in the GAE group required inotropes, and proportionally fewer experienced atrial fibrillation compared with the GA group. A larger trial, powered to evaluate important clinical endpoints, is being carried out at our institution and will be reported separately.
The main argument against the use of thoracic epidural anesthesia for conventional CABG surgery is the fear of an increased risk of thoracic epidural hematoma caused by the need to administrate a large dose of heparin immediately before cardiopulmonary bypass. This perceived increased risk cannot be quantified, but the incidence of epidural hematoma after catheter insertion without heparinization is approximately 1 in 10,000 [12]. Given the overall incidence rates of 4% for stroke and 2% for mortality after CABG and the 10-year survival rates for these patients [2], the risk may be offset by the potential benefits, but more data need to be gathered before this can be established.
In conclusion, thoracic epidural anesthesia does not offer any additional benefits in terms of reduced myocardial cell damage, inflammatory, and stress response compared with general anesthesia only in patients undergoing OPCABG surgery.
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References
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Abstract
Introduction
