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Department of Anaesthesiology and Intensive Care Medicine and Department of Cardiothoracic and Vascular Surgery University Hospital Schleswig-Holstein, Campus Kiel, Germany
Address correspondence and reprint requests to Berthold Bein, MD, Department of Anaesthesiology and Intensive Care Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Schwanenweg, 21, D-24105 Kiel, Germany. Address e-mail to bein{at}anaesthesie.uni-kiel.de.
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Abstract |
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Introduction |
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The principal advantage of this procedure for the questions raised concerning the effect of volatile anesthetics on the myocardium is the controlled ischemia applied to the tissue during the suture of the anastomosis between the graft (usually the left internal mammary artery) and the coronary vessel (left anterior descending coronary artery, LAD) (12). We hypothesized that if the reported preserved cardiac function during sevoflurane anesthesia was clinically relevant, the use of sevoflurane would have beneficial effects on intraoperative myocardial function as assessed with transesophageal echocardiography (TEE) both during ischemia and reperfusion.
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Methods |
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Patients received 0.1–0.2 mg/kg midazolam 30 min before induction of anesthesia; preoperative cardiac medication was continued until the morning of surgery except for angiotensin converting enzyme inhibitors. Because the sulfonylurea-class type of oral antidiabetics and theophylline antagonize activation of KATP-channels, thus interfering with preconditioning (3,6), none of the patients included had oral antidiabetic medication or was treated with theophylline. Patients were randomly assigned to receive either sevoflurane (group A, n = 26) or propofol (group B, n = 26) anesthesia by opening of sealed envelopes.
Anesthesia was induced with propofol (2 mg/kg) and remifentanil (0.5 µg/kg) in both groups. Tracheal intubation was facilitated with rocuronium (0.6 mg/kg) and ventilation was adjusted to a Petco2 of 35 mm Hg. After tracheal intubation, a multiplane TEE probe (5 MHz; Philips Medical Systems, Best, The Netherlands) was inserted. Standard monitoring included 5-lead electrocardiogram (ECG), arterial blood pressure, heart rate, central venous pressure, cardiac index (CI), nasopharyngeal temperature, and peripheral oxygen saturation; data were recorded minute by minute in all patients. The arterial catheter was connected to a monitor for pulse contour analysis (Pulsion Systems, Munich, Germany), and the resulting signal was processed for determination of hemodynamic variables. Additionally, extravascular lung water index and intrathoracic blood volume index were recorded after induction of anesthesia. Depth of anesthesia was determined with bispectral index (BIS XPTM; Aspect Medical Systems, Newton, MA) and aimed at a BIS between 40 and 50 during surgery.
After baseline ECG and hemodynamic measurements 5 min after induction of anesthesia, propofol administration was stopped in group A and sevoflurane was administered at 1 MAC end-tidal concentration. In group B, propofol infusion was continued at a rate of 3–4 mg · kg–1 · h–1. In both groups, remifentanil was administered at a rate of 0.3 µg · kg–1 · min–1. Immediately after LAD clamping and after restoration of blood flow hemodynamic and echocardiographic measurements were repeated. If mean arterial blood pressure was less than 60 mm Hg, vasoconstrictive therapy was started using norepinephrine.
At the end of the surgical procedure, patients were tracheally extubated when the nasopharyngeal temperature was 
35.5°C. Adverse events were recorded postoperatively in both groups and defined as myocardial infarction cardiac troponin T (cTNT) positive, unstable angina, new renal impairment (need for hemofiltration), and stroke.
The MIDCAB approach is an off-pump cardiac surgical procedure that has been described in detail elsewhere (12). Briefly, an anastomosis between the left internal mammary artery and the LAD coronary artery was performed on the beating heart via a left lateral thoracotomy. The heart was partially immobilized with a special stabilizer (AccessTM; Guidant, Santa Clara, CA) during the vessel suture. To facilitate surgical access, one-lung ventilation was established during the procedure with the Fio2 adjusted at 1.0. Apneic oxygenation (2 L/min O2) together with continuous positive airway pressure (CPAP, 5 cm H2O) was applied to the collapsed lung via an oxygenation device (Broncho-CathTM CPAP system, Mallinckrodt Medical, Athlone, Ireland).
Before clamping the LAD, 100 IU/kg of unfractioned heparin was administered to achieve an activated clotting time of approximately 200 s to facilitate anastomosis. After restoration of blood flow heparin was antagonized with protamine at a ratio of 1 mg protamine for 100 IU heparin. All patients were operated on and anesthetized by the same surgeon and anesthesiologist.
TEE examinations were performed with the ultrasound system SONOS 5500 (Philips) using a 5-MHz transducer. Mitral valve inflow velocity pattern was recorded from the midesophageal four-chamber view with the pulsed-wave Doppler sample volume positioned at the tips of the mitral leaflets during diastole. Fractional area change (FAC) was determined with the TEE probe positioned to obtain a transverse plane, transgastric short-axis view of the left ventricle (LV) at midpapillary level. By rotating the image to approximately 120°, the LV outflow tract (LVOT) and the ascending aorta were imaged and a pulsed wave (pw) Doppler was positioned at the LVOT with the sample volume just below the aortic valve for determination of ejection time and the velocity time integral. Beam position and gain settings were optimized to achieve the greatest amplitude and clarity of the Doppler spectrum. All measurements were performed according to the recommendations of the American Society of Echocardiography (13).
The index of myocardial performance (MPI) has been developed to reflect both systolic and diastolic functions of the myocardium (14,15). Figure 1 depicts a schematic representation of its elements and the derived calculations. The interval (a) was measured from mitral valve closing to opening, which is equal to the sum of isovolumetric contraction time, ejection time, and isovolumetric relaxation time. LV ejection time (b) was measured from the onset to the end of LV outflow. The sum of isovolumetric contraction time and isovolumetric relaxation time was obtained by subtracting (b) from (a). MPI was then calculated as (a – b)/b. As myocardial contractility and relaxation are energy-dependent, the isovolumetric intervals are lengthened by myocardial dysfunction, while, in contrast, ejection time shortens. Thus, MPI tends to increase with the degree of myocardial dysfunction. The unique feature of the MPI is rooted in the simultaneous acquisition of systolic and diastolic function variables, thus providing information on global heart performance. MPI was used as an early indicator of cardiac ischemia during stress echocardiography (16,17) and showed a direct correlation to invasive measurements both in animals and humans (18,19).
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The ratio of peak early (E) to atrial filling velocity (A) is a sensitive marker of myocardial ischemia (20). The impaired LV relaxation during ischemia provokes a larger fraction of end-diastolic volume being delivered by the atrial contraction, thus decreasing the E/A ratio. Mean values were obtained by averaging at least five sequential beats. Peak velocities of transmitral inflow were measured in early (E) and late (A) diastole. All TEE examinations were recorded on a SVHS videotape and, on completion of the study, analyzed off-line by an experienced investigator blinded as to the anesthetic used.
Blood was sampled in all patients for determination of cTNT, creatine kinase (CK), and creatine kinase MB (CK-MB). Samples were obtained before the start of surgery, 6 h after the end of surgery, after 24 h, and after 72 h. Sensitivity of cTNT determination by our laboratory was reported as 0.05 ng/mL. CK-MB was rated positive if the CK-MB value was >6% of an increased CK (reference range in our institution, CK <180 U/L in males and <160 U/L in females).
Patients were monitored with a 5-lead ECG throughout the study period. ECG evidence of myocardial ischemia was defined as a 0.1 mV horizontal or downsloping ST segment depression or horizontal ST segment elevation at 60 milliseconds after the J-point in one or more of the applied leads during LAD clamping compared with the baseline 5 min before disruption of blood flow.
Sample size was calculated based on a 0.14 difference in MPI between baseline and the ischemic period, as this is the difference reported between normal subjects and patients with multivessel coronary artery disease, thus indicating clinical relevance (14,21). A sample size of 22 patients for each group was calculated using an 
= 0.01 and a power of 90%. Hemodynamic, laboratory, and TEE data between groups were tested by two-way analysis of variance factoring by group and time. One-way analysis of variance for repeated measures followed by Dunnett’s posttest correction and the Friedman test with Dunn’s posttest correction were performed to detect changes over time within the same group. Values between groups were compared using unpaired Student’s t-test or with Mann-Whitney U-Test. Proportions were compared with Fisher’s exact test or 
2 test, as appropriate. Parametric data are presented as mean ± sd, and nonparametric data are presented as median and range. A P value of < 0.05 was considered statistically significant.
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Results |
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The incidence of ST segment changes during anastomosis and the number of patients with increased cTNT and CK-MB postoperatively was comparable and small in both groups. In each group, one patient had an increased cTNT; 3 and 4 patients presented with an increased CK-MB in the propofol and sevoflurane groups, respectively. Thirty-one percent of the propofol-treated patients showed significant ST segment changes during LAD occlusion compared with 21% of patients in the sevoflurane group (Table 2). There were no postoperative adverse events in either group. Duration of intensive care unit and hospital stay were similar between groups.
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Discussion |
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Avoiding, or at least attenuating, ischemic stress imposed on the myocardium is an issue of paramount importance in anesthesia. Volatile anesthetics have cardioprotective properties by preconditioning myocardial tissue against ischemia. For example, it was demonstrated in two recent clinical studies that cardiac function after CPB is preserved with sevoflurane whereas there was no protection in propofol-treated patients (8,9). Moreover, myocardial cell damage (as assessed with cardiac troponin I) was significantly less in the sevoflurane group. In a small study in patients undergoing off-pump cardiac surgery, troponin I was significantly higher in the propofol group compared with the sevoflurane-treated patients (peak difference, 0.88 ng/L) (10). However, these results were only supported in part by a larger, randomized, double-blind trial (72 patients) performed in coronary artery bypass graft surgery patients undergoing CPB, where no difference in myocardial cell damage was detected (11).
They found, however, a difference in brain natriuretic peptide (BNP, not investigated in our study). BNP is thought to reflect global myocardial function and is increased in patients with diastolic dysfunction and LV hypertrophy (22). Moreover, there is a strong correlation between increased BNP values and a deteriorated MPI (23). Accordingly, we would suggest that the Doppler-derived values obtained in our study reflect a more favorable response during regional myocardial ischemia.
The MIDCAB procedure is a clinical model for a controlled, short lasting (<25 minutes in our study), and completely reversible cardiac ischemia in humans. As the ischemic period is limited, a sublethal ischemic stress is applied to the myocardial cells at risk, which is usually not sufficient to provoke sustained cell damage (24). Therefore, a marked increase in biochemical markers of myocardial cell damage cannot be expected in most cases and, consistently, was not found in our study. In daily anesthetic practice, cardiac ischemia is routinely monitored by changes in ST segment trending. Apart from limited sensitivity and specificity for ischemic events, the preconditioning effect itself is not reflected by a difference of ECG changes during ischemia between preconditioned and non-preconditioned groups (25). However, it was demonstrated that the ischemic stress applied provokes the development of hypokinetic segments within the LV (26). In the present study this was clearly reflected in the significantly increased MPI, shortened ejection time, and decreased E/A ratio in the propofol group, whereas no differences were observed in the sevoflurane group. Moreover, the myocardium does not recover to full contractility immediately after restoration of blood flow but remains in a decreased contractility state for several hours. This was confirmed by our study, as MPI remained increased in the propofol group 5 minutes after restoration of blood flow (Fig. 2). In comparison, the E/A ratio and ejection time appeared to be less sensitive.
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It has been demonstrated that 
-1 opioid agonists also can exert preconditioning effects on myocardium (27). As we used remifentanil in our anesthetic regimen, which is not a -1 agonist, it should therefore not have affected the preconditioning phenomenon. Moreover, there was no difference in remifentanil dosage between groups.
Some methodological issues of our study should be noted. As during vessel suture the surgical field is, in part, fixed by a epicardial stabilizer attached to the myocardial wall, TEE measurements may be influenced. The reduced cardiac output in both groups during LAD clamping and reperfusion may be attributed to stabilizer placement. The impact of myocardial stabilization is particularly important if regional myocardial function is judged according to the 16-segment model recommended by the American Society of Echocardiography.
However, one study investigating TEE during MIDCAB found only a small decrease in LV end-systolic and end-diastolic dimensions after stabilizer placement; global cardiac function remained unchanged (28). Thus, the myocardial performance was thought to be the "second best" alternative in this patient population. Furthermore, MPI is thought to be largely a load-independent index of cardiac function, which limits the influence of changes in wall stress, probably by epicardial stabilization (29). Because systemic hemodynamics and indices of preload and afterload were comparable between groups and remained unchanged during the study period, an influence of differing loading conditions on TEE-derived variables, especially the load-dependent E/A ratio, is unlikely. Most importantly, such an influence would have occurred in both treatment groups in a similar fashion. The MPI was not yet tested for its reaction in response to acute myocardial ischemia. A relevant change, however, is well derived mathematically because ischemia shortens ejection time (b becomes smaller) while at the same time isovolumetric relaxation is impaired (a becomes larger).
As patients with a preoperative ejection fraction of 
40% were excluded from our study, our results are not applicable to this subgroup of patients. Further studies will have to evaluate the impact of sevoflurane-mediated preconditioning in patients with lower preoperative ejection fractions.
Although we sought to achieve an end-tidal concentration of 1 MAC sevoflurane during surgery, depth of anesthesia was controlled with BIS to allow for a comparable depth of anesthesia in both groups. There was, however, a significant difference between groups both during LAD clamping and the remaining study period. Because the mean difference found was small (8 and 5, respectively) compared with the recommended BIS range [40–60], this appears to be of no clinical relevance. This is emphasized by more patients in the sevoflurane group requiring norepinephrine despite a slightly deeper level of anesthesia in the propofol group. Even more important regarding the assessment of TEE-derived variables, however, is a comparable level of preload and afterload during data acquisition, and that was well accomplished in our study.
The sevoflurane concentration ranged between 0.5 and 1 MAC in individual patients during the study period. Because the preconditioning effects of sevoflurane may depend on MAC (4), our results cannot be extrapolated to different sevoflurane concentrations.
The magnitude of coronary blood flow reduction during LAD clamping may depend on the extent of preexisting coronary artery disease. Thus, the ischemic stress imposed on the myocardium should be large if the occluded vessel contributes a substantial part of total blood supply before clamping. Effects after clamping, however, should be minimal if the vessel was completely occluded preoperatively. It is noteworthy that there was no difference between both groups with respect to the number of patients with a severe (>80%) LAD stenosis.
The deteriorated cardiac function in the patients with preexisting severe stenosis in the propofol group, however, suggests an additional mechanism of ischemic stress during the MIDCAB procedure. At our institution the LAD is clamped as proximally as possible so that the disruption of collateral blood flow originating from the LAD just in front of the morbidly occluded section cannot be excluded. It is difficult to quantify the exact degree of collateral circulation in a patient suffering from coronary artery disease. This holds true, however, for each study performed in this patient population. Significant differences with respect to myocardial cell damage, a very important issue, have been reported in groups as small as 10 patients (8–10). Therefore we believe that the effect of an uneven collateral circulation was even better controlled for in our sample size of 25 patients in each group.
Clinical outcome and hospital stay did not differ between groups. Therefore, the influence of the anesthetic used on long-term patient outcome remains speculative.
In conclusion, cardiac function as assessed with TEE was preserved during ischemia in patients anesthetized with sevoflurane in contrast to the patients who were treated with propofol. This suggests that sevoflurane may have protective properties against ischemia in patients with coronary artery disease not only during cardiac surgery with CPB but also in patients undergoing noncardiac surgery. The cardioprotective effects of sevoflurane reported in experimental conditions may therefore have important clinical ramifications.
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