Cardiac surgery using cardiopulmonary bypass (CPB) and cardioplegic arrest is associated with the activation of inflammatory pathways. Contact of blood with non-endothelial surfaces and air, surgical trauma, ischemia-reperfusion injury, changes in body temperature, and endotoxemia are thought to contribute to a CPB-related systemic inflammatory response (1). The inflammatory cascade can induce a variety of postoperative complications, including myocardial dysfunction, respiratory failure, renal failure, neurological disorders, or multiple organ failure responsible for significant postoperative morbidity and mortality (2). In addition, the use of CPB priming solutions and crystalloid cardioplegia can cause significant hemodilution that may be associated with adverse outcomes and increased requirements of blood transfusions (3,4).
To avoid adverse effects of CPB and cardioplegic arrest, beating heart surgery (BHS) without the use of CPB has gained increasing popularity (5). However, it remains controversial whether off-pump coronary artery bypass grafting (OPCAB) reduces perioperative morbidity (6,7). Miniaturized or simplified bypass systems (SBS) have been developed and introduced into clinical practice (8,9). SBS are closed-loop circuits consisting of the blood pump and the oxygenator, avoiding the venous reservoir, venting systems and the cardiotomy suction. Thus, foreign surface area, extracorporeal volume, hemodilution and blood-air contact are reduced. SBS can be used with or without cardioplegic arrest. Little information is available on the hemodynamic and immunologic effects of SBS in patients undergoing coronary artery bypass grafting (CABG). We therefore studied the hemodynamic and inflammatory consequences of BHS assisted by two different SBS in comparison with CABG surgery using conventional CPB (cCPB) circuits and hypothermic cardioplegic arrest.
We hypothesized that BHS and the use of SBS are associated with less hemodynamic instability and reduced inflammatory response after CPB when compared with cardiac surgery performed with a cCPB circuit. Our prospective, randomized, observational study focused primarily on intraoperative hemodynamics, which are often impaired after CPB, in part as a result of changes in the distribution of blood volume and a decrease in ventricular preload and thus in cardiac output (10). Therefore, intrathoracic blood volume index (ITBI) and cardiac output (CO) constituted primary outcome variables. Secondary variables were additional hemodynamic parameters, the need for catecholamine support, echocardiographic indices of ventricular function, laboratory markers of myocardial injury, and the levels of circulating proinflammatory and antiinflammatory cytokines. We determined the levels of interleukin (IL)-6 as a key mediator of the proinflammatory reaction and the levels of IL-10 as key mediator of the antiinflammatory reaction. Increases of proinflammatory cytokines have been strongly associated with adverse outcome after cardiac surgery (11). Serum concentrations of IL-6 have been shown to correlate with mortality in pediatric cardiac surgery (12). In addition, it has been demonstrated that IL-6 and IL 10 play key roles in hemodynamic status and myocardial damage after CPB (13–15).
After approval by the IRB committee and written informed patient consent, 45 patients suffering from 2- or 3-vessel coronary artery disease participated in the study. Patients with emergency operations, reoperations, occlusive peripheral arterial disease, intracardiac shunts, significant valvular heart disease, and severely decreased left ventricular function (ejection fraction ≤30%) were excluded.
The patients received 10 mg oxazepam orally in the evening before surgery and 1–2 mg flunitrazepam 1 h before arrival in the operating room. Preoperative medication was continued until the day of surgery. Anesthesia was induced with etomidate (0.1 mg/kg) and sufentanil (0.5–2 μg/kg). Muscle relaxation was obtained with rocuronium (1 mg/kg). Maintenance of anesthesia was performed with continuous infusion of sufentanil (2 μg · kg−1 · h−1) and isoflurane (0.5 MAC). During CPB, anesthesia was maintained with sufentanil and supplemental bolus doses of midazolam (0.05–0.1 mg/kg).
The patients were randomly assigned to 3 groups: 15 patients were operated with a conventional CPB-circuit (HL-20, Jostra, Hirrlingen, Germany) with a priming volume of 1900 mL (group A). CPB was performed in moderate hypothermia (28°C–32°C). Cardiac arrest was induced by a single and antegrade infusion of 2000 mL of crystalloid cardioplegic solution (Custodiol™; Köhler Chemie, Alsbach-Hähnlein, Germany) in the aortic root immediately after cross-clamping. Two groups of 15 patients each underwent BHS in normothermia with assistance of a SBS. Fifteen patients were randomized to the DeltaStream™ system (Medos, Stolberg, Germany), a system with a foreign surface area comparable to the conventional CPB circuit but with a reduced extracorporeal volume (group B) (Table 1). In the remaining 15 patients, the CORx™ system (CardioVention, Santa Clara, CA), a device with reduced foreign surface area and small extracorporeal volume (group C) was used. Both, the Deltastream™ and the CORx™ system were pre-filled with 600 mL of crystalloid priming solution (Table 1). No heparin coated surfaces were used. Cannulation for CPB was performed using a two-stage venous cannula via the right atrial appendage and an aortic cannula (both Medos, Stolberg, Germany). The different bypass circuits and the different techniques (BHS versus cardioplegic arrest) precluded blinding of physicians.
Extracorporeal circulation was performed with a nonpulsatile pump flow of 2.2 L · min−1 · m−2. Every patient received 500 mg methylprednisolone after induction of anesthesia. In addition, 1,000,000 KIU aprotinin was administered before CPB, 1,000,000 KIU during CPB (either as part of the pump prime in the cCPB group or IV in the other groups) and 1,000,000 KIU after CPB. Before CPB, 300 U/kg heparin was administered to achieve an activated clotting time >400 s. After weaning from CPB, heparin was antagonized with protamine in a ratio of 1:1.
All patients underwent median sternotomy. In the cCPB group, distal and proximal anastomoses were performed during ischemic arrest. In the Deltastream and Cor-X groups, the distal anastomoses were done with the use of a mechanical stabilizer (AXIUS™, Guidant, Diegem, Belgium). Proximal coronary anastomoses were performed during a period of tangential clamping of the ascending aorta. Mediastinal shed blood was collected using the cardiotomy suction (cCPB group) or collected and processed with a cell saver (CATS, Fresenius, Bad Homburg, Germany) and immediately retransfused (SBS groups). Blood left in the extracorporeal circuits at the end of CPB was retransfused immediately.
Intraoperative treatment was standardized according to clinical routine. Basic fluid substitution was performed with 1 mL · kg−1 · h−1 balanced crystalloid solutions. Hemodynamic stability was defined as a cardiac index >2.5 L · min · m−2 and mean arterial blood pressure >70 mm Hg. In case of hypovolemia (defined as an ITBI <850 mL/m−2), colloid solution (hydroxyethylstarch 130/0.4, Voluven®; Fresenius Kabi, Bad Homburg v.d.H., Germany) were infused. Packed red blood cells were transfused when the hemoglobin content was less than 7.0 g/dL. Arterial blood pressure during CPB was managed by fluid replacement (primarily with crystalloid solutions). After CPB, epinephrine was started when cardiac index was <2.5 L · min · m−2. Norepinephrine was administered when hemodynamic stabilization could not be achieved by adequate fluid replacement alone and systemic vascular resistance index (SVRI) was <1500 dyne·s · cm−5 · m−2.
Before induction of anesthesia, a 5F thermistor-tipped catheter (PV2015L20A; Pulsiocath, Pulsion Medical Systems, Munich, Germany) was inserted into the femoral artery. After induction of anesthesia, a 7.5F central venous catheter (AG-15854-E; Arrow International, Reading, PA) was placed in the right internal jugular vein.
Routine hemodynamic data were recorded continuously (S/5; Datex-Ohmeda, Duisburg, Germany). CO and ITBI were measured by transpulmonary thermodilution (PiCCOplus V 5.2.2; Pulsion Medical Systems) (16).
Indicator dilution measurements were performed by triple bolus injections of 20 mL of ice-cooled saline 0.9% into the right atrium. Hemodynamic measurements were performed after induction of anesthesia (T2), after pericardiotomy (T3), immediately after CPB (T4), and at the end of surgery (T5).
A multiplane transesophageal echocardiography (TEE) probe (Omniplane II T6210, Philips Medical Systems, Eindhoven, The Netherlands) connected to an ultrasonograph (Sonos 5500; Philips Medical Systems, Eindhoven, The Netherlands) was positioned to visualize either the transgastric short-axis view of the left ventricle at the level of the mid-papillary muscles or the midesophageal four-chamber view. For the assessment of cardiac contractility, left and right ventricular fractional area change were determined using standard formulas. The transmitral flow signal was evaluated using pulsed-wave Doppler for the analysis of mitral deceleration time and E/A wave flow velocity ratio. TEE measurements were performed after sternotomy (T3) and before chest closure (T4). Simultaneously acquired TEE images and electrocardiogram signals were obtained before and after CPB, recorded on a magneto-optical disk and analyzed off-line. For each measurement, an average of at least four consecutive cardiac beats was evaluated.
Central venous blood samples were obtained in endotoxin-free evacuated blood collection tubes containing sodium citrate (Monovettes; Sarstedt, Nümbrecht, Germany). Plasma was separated from blood cells by centrifugation at 2000g for 10 min and stored at –80°C until analysis. Plasma levels of tumor necrosis factor (TNF)-α, IL-1β, IL-6, IL-10, and interferon (IFN)-γ were analyzed using specific enzyme-linked immunosorbent assays (BD Biosciences, San Diego, CA). Cytokine samples were obtained at the following time points: at the morning of surgery (T0), before (T1) and after induction of anesthesia (T2), before CPB (T3), immediately after CPB (T4), at the end of surgery (T5), 6 h (T6), 12 h (T7), and 24 h (T8) after surgery. In addition, arterial and central venous blood samples were obtained for determination of hemoglobin content, lactate concentration, oxygen saturation, and blood-gas analysis (ABL 700; Radiometer Copenhagen, Brønshøj, Denmark).
Troponin T serum levels (cut-off value for myocardial damage: 0.1 μg/L), leukocyte and platelet counts were determined using routine laboratory techniques at the morning of surgery (T0), 6 h (T6), and 12 h (T7) after surgery.
As the present study primarily focused on hemodynamic variables, prestudy power analysis was based on changes in the primary outcome variables, i.e., CO and ITBI. Power analysis revealed a minimal sample size of 8 patients to detect a 25% effect in ITBI and CO, when a level of significance of 0.05 and a power of 80% were to be achieved. For fractional area change, a sample size of 12 patients was needed to reveal a 15% change with the same statistical power and level of significance. Data were statistically analyzed using a commercially available software package (Statistica© for Windows version 6.0; Statsoft, Tulsa, OK). Differences in and between groups were tested using multiple analysis of variance, one-way analysis of variance, or with Kruskal-Wallis analysis of variance, if appropriate. In case of significant differences in multiple or one-way analysis of variance, post hoc testing was performed using the Fisher least-significant difference test. Proportions were compared using the Fisher's exact test. A level of P < 0.05 was considered statistically significant.
Demographic and biometric data were similar among groups. The groups did not differ with regard to time of surgery, perfusion time and number of grafts (Table 2). Chronic preoperative cardiac medication was comparable among groups.
Hemodynamic variables throughout the perioperative time course (including the CPB period) did not differ statistically among the three groups (Tables 3 and 4; Figure 1A and 1B). In all groups, a significant increase in heart rate and cardiac index (Figure 1A) after CPB was observed, accompanied by a significant decrease in SVRI. Groups did not differ with respect to ITBI at all time points (Figure 1B). Mean arterial blood pressure, central venous pressure, and stroke volume index remained unchanged during the study period. In all groups, central venous oxygen saturation did not change throughout the study. Lactate concentrations were significantly increased in all groups after CPB but to a lesser degree in group B. The number of patients who received norepinephrine was similar among groups (Table 5). However, the dose of norepinephrine to increase SVRI to predefined values of hemodynamic stability was significantly increased in both SBS groups at the end of surgery. In contrast, the dosage of epinephrine to increase CO was similar in all groups after CPB and at the end of surgery. However, in both SBS groups, significantly fewer patients received epinephrine than in the cCPB group (Table 5).
Echocardiographically derived variables of systolic left and right ventricular function were similar before and after CPB (Table 4). In contrast, diastolic function was significantly impaired in all groups after CPB, as indicated by a significant decrease in E/A wave inflow velocity ratio and in mitral deceleration times. Patients of the cCPB group received a significantly larger amount of crystalloid fluids during CPB than patients of group B and group C (Table 5). This difference remained significant for the whole study period when comparing total crystalloid input. Total colloid input did not differ among groups throughout the study period. Urine output was similar in all groups. Intraoperative transfusion of 2 U of packed red blood cells was deemed necessary only in one patient (group C).
A significant decrease in hemoglobin content occurred after initiation of CPB and at end of surgery. As expected, the decrease in hemoglobin was most pronounced in the cCPB group (Figure 2).
A significant decrease in the platelet count (Figure 3A) and a significant increase in the leukocyte count (Figure 3B) occurred in all groups 6 and 12 h after surgery when compared with preoperative controls. No differences among groups were detected.
No release of TNF-α could be detected in this study. Low levels of IL-1β and IFN-γ were found in only two patients of each group. Six h after end of surgery (T6), plasma levels of IL-6 were significantly increased only in SBS patients (Figure 4A). Only patients of the cCPB group developed a significant increase in IL-10 (Figure 4B), whereas this did not occur in SBS patients. Immediately after cessation of CPB (T4) and at end of surgery (T5), the plasma concentrations of IL-10 were significantly larger in cCPB patients than in both SBS groups (Figure 4B).
There was a comparable extent of myocardial necrosis after CPB, as indicated by the postoperative troponin T serum levels (Figure 5).
The present study demonstrated for the intraoperative time period no hemodynamic benefit of normothermic BHS with SBS compared with the use of cCPB and hypothermic cardioplegic arrest. We observed comparable changes in diastolic function of the left ventricle after surgery in all three groups. Patients undergoing BHS with assistance of SBS needed increased amounts of norepinephrine to achieve predefined hemodynamic goals. Furthermore, the use of miniaturized bypass systems and avoidance of cardioplegic arrest did not result in a decreased release of IL-6 in response to CPB. Only hypothermic cCPB and cardioplegic arrest were associated with a significant increase in the release of the antiinflammatory cytokine IL-10.
Cardiac surgery with CPB usually elicits a systemic inflammatory response syndrome. Surface-dependent (contact of blood with non-endothelial surfaces and air) and surface-independent factors (hypothermia, ischemia-reperfusion, endotoxemia, and the surgical trauma itself) are thought to induce a complex inflammatory response by activation of different cellular and humoral components of the immune system (1). Various attempts have been made to modulate the inflammatory response, including pharmacological strategies and modification of surgical techniques and equipment (1,17). One attempt to decrease the CPB-induced inflammatory response is the use of miniaturized or SBS with reduced foreign surface area and blood-air interface (8,18). The results of the present study do not support this theoretical benefit of SBS, as no difference in proinflammatory cytokine release was found. Moreover, in all groups, a similar increase of leukocyte count combined with a decreased number of platelets were observed (Figure 3), a finding that is typical for the interaction of the immune system and platelets in response to CPB (19). The perioperative IL-6-release was not decreased in both SBS groups and even showed a significant increase when compared with baseline values (Figure 4A). This is in contrast to the results of Fromes et al. (18), who found significantly less IL-6-release in patients operated with SBS compared with those undergoing cCPB. However, in their study, minimal extracorporeal circulation (MECC©, Jostra, Germany) was used and cardiac arrest was induced with warm blood cardioplegia in the cCPB and in the SBS group. Moreover, Fromes et al. used heparin-coated tube systems and methylprednisolone or aprotinin was not administered. In our patients, neither reduction of extracorporeal volume and/or foreign surface area nor normothermia and avoidance of cardioplegic arrest in the SBS groups resulted in decreased IL-6-levels. The CPB circuit itself might elicit an inflammatory response, independent of the size of the extracorporeal volume and/or the foreign surface area. In addition, the release of IL-6 may have been induced by the surgical procedure and thus might have been independent from different types of CPB circuits, temperature, and cardioplegic arrest. Although in some studies an attenuation of the inflammatory activation was observed in off-pump versus on-pump surgery (11), our latter hypothesis is supported by several other studies in which the proinflammatory IL-6 release was similar in patients undergoing on-pump versus off-pump surgery (20) and normothermic versus hypothermic CPB (21). Moreover, the routine use of corticosteroids and aprotinin in our patients may have led to a reduced proinflammatory response regardless of the type of extracorporeal circuit.
Only the use of cCPB and cardioplegic arrest along with moderate hypothermia induced a significant antiinflammatory response as indicated by the increase in IL-10 in the cCPB group (Figure 4B). The underlying mechanisms for the increase of IL-10 only in the cCPB group are not obvious. Diegeler et al. (20) demonstrated a significantly larger IL-10 release in patients submitted to normothermic cCPB and cardioplegic arrest when compared with patients undergoing OPCAB procedures. In another study, perioperative IL-10 release was principally reduced in hypothermia but increased after prolonged duration of hypothermia (22). Therefore, it cannot be clarified whether the increased IL-10 release in this study was induced by hypothermia, cardioplegic arrest, or the use of cCPB. Although the underlying mechanisms remain to be elucidated, the increase in IL-10-synthesis along with the use of cCPB might have influenced systemic hemodynamics. Vasodilation was less pronounced in the cCPB group at the end of surgery, as indicated by a reduced need for norepinephrine to achieve hemodynamic target values (Table 5). This finding may have been caused by the differences in perioperative cytokine release (13). IL-10 plays a protective role by suppressing the production of proinflammatory cytokines (23). Disturbances in the ratio of proinflammatory and antiinflammatory cytokines leading to a net proinflammatory response were shown to be associated with myocardial damage after CPB (15,24).
The second main finding of our study is that no differences in left and right ventricular function after CPB were found. Systolic myocardial function was comparable in all groups (Table 6). In addition, the impairment of left ventricular diastolic function after CPB was independent from the type of CPB (Table 6). The echocardiographic Doppler findings (i.e., a decrease in E/A wave mitral inflow velocity ratio and mitral deceleration time) are consistent with an increase in left ventricular stiffness after surgery and support previous data in patients operated with cCPB (25). The decrease in left ventricular compliance observed after cCPB is often attributed to global ischemia during and postischemic reperfusion injury after cardiac arrest (25). Moreover, diastolic stiffness can be caused by myocardial edema after CPB, as myocardial lymph flow has been shown to almost cease during cardiac arrest (26). As patients in the SBS groups did not undergo cardiac arrest, alternative mechanisms must be involved in the impairment of diastolic function after BHS. Intraoperative displacement of the heart and the pressure exerted on the myocardial surface with stabilization devices may interrupt myocardial lymph flow during BHS. Moreover, BHS is not associated with global but with regional myocardial ischemia from temporary occlusion of coronary arteries during the surgical procedure (17,27). In our study, both techniques (cCPB and SBS) resulted in a comparable extent of myocardial necrosis in all groups (Figure 5). Finally, the administration of vasoactive and positive inotropic drugs in the post-bypass period may have further contributed to the observed changes in diastolic function variables (28).
Our study has a number of limitations. The cCPB group differed from the SBS groups not only with respect to the bypass circuit but also in terms of temperature regimens and handling of shed blood. In addition, all patients received corticosteroids and aprotinin according to clinical routine in our department. Both drugs modulate the inflammatory response by inhibiting the production of proinflammatory cytokines and enhancing the release of IL-10 (13,29). The absence of detectable levels of TNF-α, IL-1β, and IFN-γ in our patients is in accordance with other studies in which the use of corticosteroids and aprotinin led to undetectable or low levels of cytokines (13,20,21). Moreover, a cell-saver device was used in both SBS groups to avoid uncontrolled blood loss. Blood processed by the cell-saver is additionally exposed to foreign surfaces and air, theoretically resulting in immunologic activation. However, there is evidence that red cell salvaging attenuates the proinflammatory response associated with CPB (30) or at least does not cause an additional inflammatory response (31) when compared with the cardiotomy suction. Patients of the cCPB group received significantly more crystalloids than patients of the SBS groups, mainly because of the use of crystalloid cardioplegic solution and the increased extracorporeal volume of the CPB circuit (Table 7). This led to a more pronounced hemodilution during CPB (Figure 2) and probably also to a dilution of cytokines and cell counts. However, the degree of hemodilution was similar at the end of surgery, suggesting that the observed differences in cytokine release are most likely not related to fluid balance.
Another limitation is the use of load-dependent and heart rate-dependent echocardiographic measures of left and right ventricular function. However, echocardiographic measurements are still considered the clinical standard for the estimation of ventricular function, at least in the perioperative setting. The variables of diastolic function used in the present study (i.e., E/A ratio and deceleration time) are affected by changes in cardiac preload and heart rate. However, intrathoracic blood volume, which is a sensitive variable of preload, was kept constant and heart rate was similar among groups. Our data therefore strongly support the hypothesis that hypothermic CPB and normothermic BHS are similar with respect to effects on diastolic function. In addition, blinding in the intraoperative time period was not possible for technical reasons. However, echocardiographic and laboratory analysis were performed by investigators unaware of the patients' study affiliation. Because of the considerable standard deviations of cytokine levels and troponin values, the number of included patients is too small to detect significant differences in myocardial necrosis and cytokine release with acceptable statistical power. Therefore, these variables were not considered to be primary target variables. In contrast, the failure of our study to detect between group differences in the main outcome variables should not be attributed to inadequate statistical power, as illustrated by acceptably narrow confidence intervals for the different variables. Last, our observations focused on the intraoperative time period. Some of the sequelae of the inflammatory response associated with cardiac surgery and the use of CPB (e.g., respiratory failure or renal insufficiency) may not become fully apparent until the postoperative period. However, intraoperative hemodynamics and ventricular function have been shown to be affected by the inflammatory response directly after CPB (14,32).
In summary, the results of this randomized, prospective study show that neither the decrease in extracorporeal volume alone by the Deltastream™ device nor the additional reduction of foreign surface area by the CORx™ system were effective in improving hemodynamic and myocardial performance after CPB in our patients. In addition, miniaturized bypass systems and avoidance of cardioplegic arrest were not able to attenuate the proinflammatory immune response after CPB. In contrast, only the use of hypothermic CPB and ischemia arrest led to a significant release of the antiinflammatory cytokine IL-10 after CPB, which may have contributed to reduced need for vasopressor support.
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