Eur J Cardiothorac Surg 2005;28:127-132
© 2005 Elsevier Science NL
Comparison of minimally invasive closed circuit extracorporeal circulation with conventional cardiopulmonary bypass and with off-pump technique in CABG patients: selected parameters of coagulation and inflammatory system
Jens Wippermann
a
,
*
,
Johannes M. Albes
b
,
Martin Hartrumpf
b
,
Mirko Kaluza
a
,
Rü;diger Vollandt
c
,
Raimund Bruhin
a
,
Thorsten Wahlers
a
a Department of Cardiothoracic and Vascular Surgery, University Hospital Jena, Erlanger Allee 101, 07747 Jena-Lobeda, Germany
b Heart-Center Brandenburg, Bernau, Germany
c Department of Medical Statistics, Informatics and Documentation, University Hospital Jena, Jena, Germany
Received 15 September 2004;
received in revised form 4 March 2005;
accepted 31 March 2005.
* Corresponding author. Tel.: +49 3641 9322933; fax: +49 3641 934802. (Email: jens.wippermann{at}med.uni-jena.de).
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Abstract
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Objective: Closed circuit extracorporeal circulation (CCECC) has been developed to reduce deleterious effects of standard cardiopulmonary bypass (CPB). This study compares the effects of CCECC (CORx system), CPB, and off-pump coronary artery bypass grafting (OPCAB) on red blood cell damage, coagulation activation, fibrinolysis and cytokine expression. Methods: Thirty patients underwent coronary artery bypass grafting (CABG). Twenty of them were randomized into two groups: CCECC (n=10), CPB (n=10). While not randomized, OPCAB (n=10) served as a separate reference group. CCECC and CPB patients received cardioplegic arrest. Interleukin 6 (IL-6), free hemoglobin (fHb), von Willebrand factor activity (vWf), thrombin–antithrombin-III-complex (TATc), prothrombin fragment 1.2 (F 1+2) and plasmin–antiplasmin complex (PAPc) were assessed preoperatively, perioperatively and 24h postoperatively. Results: CCECC showed significantly lower red blood cell damage than CPB (fHb: CCECC, 7.1± 5.7µmol/l; CPB, 16.8±11.4µmol/l; P=0.025; OPCAB, 3.4±1.1µmol/l). Perioperatively, CCECC exhibited significantly lower activation of coagulation and fibrinolysis than CPB, but did not differ from OPCAB (vWf: CCECC, 133±52%; CPB, 241±128%; P=0.052; OPCAB, 153±58%; TATc: CCECC, 4.7±0.9ng/ml; CPB, 31.1±15.8ng/ml; P<0.001; OPCAB, 2.4±0.6ng/ml; PAPc: CCECC, 214±30ng/ml; CPB, 897±367ng/ml; P<0.001; OPCAB, 253±98ng/ml). In contrast, fibrinolysis markers and IL-6 were markedly increased in CCECC postoperatively (PAPc: CCECC, 458±98ng/ml; CPB, 159±128ng/ml; P<0.001; OPCAB, 262±174ng/ml; IL-6: CCECC, 123.4±49.8pg/dl; CPB, 18.8±13.1pg/dl; P<0.001; OPCAB, 31.6±26.2pg/dl). Conclusions: CCECC for CABG is associated with a significant reduction of red blood cell damage and activation of coagulation cascades similar to OPCAB when compared with conventional CPB while a delayed fibrinolytic and inflammatory activity was observed. These findings require further investigation to verify the promising concept of CCECC.
Key Words: Extracorporeal circulation • Inflammatory response • Coagulatory response • Low-prime volume circuit
Abbreviations: BMI = body mass index • CABG = coronary arteries bypass grafting • CCECC = closed circuit extracorporeal circulation • CORx = cardiovention CORx system • CPB = standard cardiopulmonary bypass • F 1+2 = prothrombin fragment 1.2 • FFP = fresh frozen plasma • fHb = free hemoglobin • ICU = intensive care unit • IL-6 = interleukin 6 • LITA = left internal thoracic artery • LVEF = left ventricular ejection fraction • OPCAB = off-pump coronary artery bypass grafting • PAPc = plasmin–antiplasmin complex • POD 1 = postoperative day 1 • TATc = thrombin–antithrombin complex • vWF = von Willebrand factor activation • WBC = white blood cell count
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1. Introduction
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Despite efforts to improve the biocompatibility of cardiopulmonary bypass (CPB), activation of inflammatory pathways including coagulation and fibrinolysis remains of major concern regarding potential pathologic consequences. The inflammatory response to extracorporeal circulation can result in clinically relevant organ dysfunction [1] while perioperative bleeding syndromes are not uncommon complications of CPB [2]. The consequence of an increased need for transfusion and for surgical re-exploration may negatively influence morbidity and mortality [3,4]. While off-pump coronary artery bypass grafting (OPCAB) has become a promising alternative to conventional bypass surgery some patients may still require extracorporeal support. Recently, additional concepts of extracorporeal circulation utilizing closed circuits with low-priming volume and centrifugal pumps were developed in order to meet the requirements of a truly minimal-invasive heart–lung machine for patients who do not qualify for conventional bypass surgery but who are also not ideal candidates for an off-pump approach [5,6]. The closed circuit extracorporeal circulation (CCECC) may affect hemostatic competence and inflammatory response to a lesser degree than CPB does. A direct comparison of hemostaseologic variables in patients undergoing coronary surgery with the three techniques, however, has not yet been undertaken. This study was performed to compare the changes in selected coagulation, fibrinolysis and inflammatory variables in patients undergoing coronary artery bypass grafting (CABG) with CCECC, standard CPB or OPCAB.
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2. Material and methods
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Patient selection and operation. After written informed consent 30 patients (59±11 years) underwent isolated elective coronary revascularization for single-, double-, or triple-vessel disease. All patients had a low risk profile (EuroScore<4) with sinus rhythm and a preoperative ejection fraction of more than 45%. Renal and hepatic function was normal (serum creatinine<100µmol/l; prothrombin time>70%). Conventional coronary revascularization with CPB and CCECC was performed for double- or triple-vessel disease. Patients with this morphology were randomly allocated to the CPB or CCECC group. Off-pump revascularization was performed in patients with double- and single-vessel disease. Finally, three groups (n=10) were defined: standard CPB, CCECC and OPCAB. In all patients, the left internal thoracic artery (LITA) and a respective number of vein grafts/anastomoses were used. All patients operated upon underwent median sternotomy, preparation and harvesting of the LITA after the pleura was opened, combined with conventional open venous harvesting.
Anesthesia protocol was standardized for all patients. This consisted of intravenous anesthesia with propofol infusion at 3mg/kg per h combined with remifentanylat 0.5–1.0µg/kg per min. Skeletal muscle relaxation was achieved by 0.1–0.15mg/kg pancuronium and the lungs were ventilated to normocapnia with air and oxygen. Standard monitoring was established. In addition to peripheral venous lines, all patients received a central venous line and a radial artery line. In the off-pump group, a pulmonary catheter was inserted routinely. All three groups received heparin at a dose of 400IU/kg to achieve a target activated clotting time (ACT) of 450s or above. ACT was measured (automatic coagulation timer ACT II; Medtronic HemoTec, Inc., Englewood, NJ, USA) directly after initial heparin administration and every 20min. Thereafter, additional 3000IU of heparin was given if required. Protamine was used at the end to reverse the effect of heparin and return the ACT to preoperative levels. After protamine administration, 1 million units of trasylol were additionally given in the CCECC and CPB group.
It is noteworthy that the investigated CCECC system (CardioVention, CORx-system, Santa Clara, CA, USA) was recently withdrawn from the market probably because of monetary reasons.
The CCECC system consisted of two primary components: (1) a single device which integrated the functions of oxygenation, blood pumping and air elimination into a single unit and (2) a low surface area closed-loop tubing circuit to accommodate more complex procedures. The integration of three functional modules into a single unit allowed the reduction of six separate connections of standard CPB (blood-in and blood-out connections for air-elimination, pump and oxygenator) to two connections only. Fig. 1
shows the three integrated modules and blood pathway. Blood entered the venous inlet via kinetic assistance from the centrifugal pump. The venous inlet directed blood into the air-elimination module. From there, blood flew down the inlet manifold into the centrifugal pump. The centrifugal pump propeled blood through the membrane oxygenation module and then back to the patient. The oxygenator was constructed of microporous polypropylene hollow fibers with an outer surface area of 1.2m2. Blood flew around the outside of the fibers and gas flew inside the lumen of the hollow fiber membrane. The priming volume of the oxygenator–centrifugal-pump unit contained 385ml. The tubing pack consisted of standard 3/8 polyvinylchloride. Tubes, which were not heparin-coated, are similar to a standard CPB perfusion circuit. The total surface area of the circuit was less than 1.4m2 compared to 4m2 of standard CPB.
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Fig. 1. Cutaway view of the CCECC (CORx-unit; provided by CardioVention). The device combines the primary functions of standard CPB, integrating air handling, gross filtration, and oxygenation and pumping into a single integrated unit.
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Surgical technique in CCECC patients. Arterial cannulation (Jostra 24 Fr., Jostra AG, Hirrlingen, Germany) was performed via the ascending aorta. A single tailored two-stage right atrial cannula (Stöckert 40/32 Instruments GmbH, Mü;nchen, Germany) was used for venous drainage. To avoid air drainage, the purse-string suture around the venous cannula was kept thoroughly airtight. The air-elimination module was capable of eliminating large boluses of air, but the removal of continuous air incorporation into the venous blood flow remained problematic. In the setup applied, the arterial arm of the tubing was shortened to 40cm length while the venous part had a length of 80cm. This additionally decreased the priming volume by 20% (approximately 160ml). The initial priming volume in our setting was 820ml, containing 500ml HAES-solution 6%, 300ml Ringer solution, 5000 IE heparin and 20ml albumin 20% vs. 1750ml priming volume used in standard CPB. In all patients operated upon with heart–lung machine, the aorta was cross-clamped and antegrade, warm blood cardioplegia (Calafiore) was administered for 3min initially and was repeated every 15min. Venting of the heart was performed via a combined cardioplegia-vent-cannula connected to the venous line. While the operations were performed under normothermic conditions, a systemic heat exchanger (Sorin CCS 14, Stöckert Instrument GmbH, Mü;nchen, Germany) was employed in all setups to prevent cooling at the end of CPB. Furthermore, a cell saver system was used for suction. At the end of operation, remaining blood in the circuit was re-transfused or processed by cell saver and substituted directly after arrival on the intensive care unit (ICU). Drainage loss was measured in all groups using the calibration of a closed evacuation system (Pleur-Evac Sahara: Genzyme GmbH, Neu-Isenburg, Germany).
Blood sampling and biochemical measurements. In each group blood samples were retrieved from the central venous line at the following three time points: preoperatively, perioperatively (30min after start of bypass in the CPB and CCECC group) and 24h postoperatively (POD 1). Free hemoglobin (fHb) was measured by spectrophotometry to determine hemolysis. Coagulation and fibrinolysis were analyzed by means of thrombin–antithrombin complex (TATc), prothrombin fragments 1.2 (F 1+2) and plasmin–antiplasmin complex (PAPc). Interleukin 6 (IL-6) was chosen to determine inflammation and platelets function was measured by von Willebrand factor activity (vWF). Enzyme-linked immunosorbant assays were applied to determine TATc, F 1+2, PAPc and IL-6 levels (ELISA Enzygost TATc micro, Enzygost F 1+2 micro, Enzygost PAPc micro, Dade Behring, Marburg, Germany and Quantikine, R&D Systems, Inc., Minneapolis, USA). vWF was tested against lyophilized donor platelets while ristocetin was added as an activator. The activity was analyzed with a commercially available agglutination test (Behring Coagulation Timer, Dade Behring, Marburg, Germany).
Statistical analysis. Data were compiled with a Microsoft Excel database. Results were expressed as mean values±standard deviation (SD). Statistical analysis was performed using SPSS statistical package for Windows (Version 9.0, SPSS, Inc., Chicago, IL). Numeric variables with normal distribution were analyzed by means of analysis of variance (ANOVA) and post hoc comparisons with Tukey honestly significant difference adjustment. 
2-test was used for analysis of categorical variables. A P value of less than 0.05 was indicated statistical significance. The OPCAB group was not included in the comparative statistical analysis because it was not randomized. Descriptive statistics, however, were used in all groups.
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3. Results
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Demographic data did not differ significantly between the groups concerning age, body surface area, and left ventricular function. The majority of the patients were male (n=25). As also illustrated in Table 1
there was no difference between CCECC and CPB group with regard to duration of extracorporeal circulation time and aortic cross-clamp time. OPCAB patients received fewer bypass grafts per patient compared with the CCECC and CPB group (OPCAB, 1.5±0.4; CCECC, 3.5±0.8; CPB, 3.7±0.8; P<0.05). In-hospital stay was significantly shorter in the OPCAB group than in all other groups. Chest tube drainage was lower in OPCAB patients, but without showing significance compared with the CCECC and CPB group. The least cumulative amounts of blood and fresh-frozen plasma units were substituted in the OPCAB group, although statistical differences between the three groups were not detected (Table 1). All patients of all groups tolerated the surgical procedure and survived without significant complications related to the study. None of the patients developed postoperative myocardial infarction. Rethoracotomy for bleeding was necessary in two patients (one in OPCAB, one in CPB). CCECC allowed a reduced hemodilution, but significance was not reached (Table 2
).
3.1. Hemolysis
Free hemoglobin showed a sharp increase during operation with conventional CPB (16.8±11.4µmol/l) with a peak twice as high as the corresponding level of CCECC patients (P=0.025) and more than fivefold higher than the OPCAB group (P=0.0013). On POD 1, levels gradually dropped in the CCECC and in the CPB group (Table 2).
3.2. Coagulation and fibrinolysis
Prothrombin fragments 1.2 (F 1+2) levels remained rather stable in the OPCAB and in the CPB group, while a steep and significant increase during operation was noted in the CCECC group (Fig. 2 ). Similar findings were observed in the analysis of thrombin–antithrombin complex (TATc). A marked increase was found again in the CPB group while both other groups remained unaltered (Table 2). In both analyses the observed differences disappeared at the first postoperative day. In contrast, plasmin–antiplasmin complex exhibited corresponding values only intraoperatively. Whereas in the postoperative course a marked elevation was detected in the CCECC group while both other groups showed values in the vicinity of the preoperative values (Fig. 3
).
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Fig. 2. Changes of prothrombin fragments 1.2 levels. Preoperatively (1), perioperatively (2) and 24h postoperatively (3). *P<0.0001 vs. CCECC.
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Fig. 3. Changes of plasmin–antiplasmin-complex levels. Preoperatively (1), perioperatively (2) and 24h postoperatively (3). *P<0.0001 vs. CCECC,
P<0.0001 vs. CPB.
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3.3. Inflammation
The time course of IL-6 release in peripheral blood exhibited marked alterations. In the CCECC as well as in the CPB group, a slight increase was noted during surgery. Postoperatively CCECC showed a further and dramatic increase until the first postoperative day, while in the CPB group as well as in the OPCAB group the values remained nearly stable. (Fig. 4
).
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Fig. 4. Changes of interleukin 6 release. Preoperatively (1), perioperatively (2) and 24h postoperatively (3). *P<0.0001 vs. CPB.
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3.4. Platelet count and activation
In all groups, the total number of platelets dropped intraoperatively and remained low at POD 1. Statistical differences between the three groups were not observed. Platelets activity remained stable in the OPCAB patients, while an increase was noted at POD 1 in both the CPB and the CCECC group. In the CPB group, levels were already increasing during operation in contrast to CCECC patients. This difference almost reached statistical significance (Table 2).
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4. Discussion
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Although extracorporeal circulation has lost its dangers during the evolutionary steps of the past decades, the inflammatory response of the patient still exist but may vary in clinical significance [7]. Surgical manoeuvers, contact of blood components with artificial surface of the bypass circuit, aortic cross-clamping and reperfusion injury are considered to be the main causative factors, determined by activation of macrophages, complement, cytokines and the coagulation–fibrinolytic system [1]. Preventing or attenuating activation of these components during heart surgery may therefore be a worthwhile goal. Different strategies to reduce or inhibit inflammation during CABG have been investigated. OPCAB procedures were revisited in this context [8]. Other investigators have focused on new developments of CPB comprising minimized extracorporeal bypass systems in order to reduce foreign surfaces [9]. The newly developed CCECC system, which was used in this study, is based on a concept of a compactly built closed total CPB circuit. The systems key technology was the integrated single unit comprising a centrifugal pump, oxygenation and air-removal. A blood–air interface was eliminated and suction of shed blood was operated only through a cell saving device. Thus, blood was washed prior to re-transfusion into the patient. The present study demonstrated a satisfactory clinical applicability of the new technique. The main focus, however, was to analyze the blood activation compared to standard CPB and OPCAB procedures. Previous studies have shown that the early period after CPB procedures bears the highest risk for thrombotic complications which may also be at least in part responsible for the high early rate of graft occlusions occurring within the first month [10]. In addition to this problem other sequelae of thrombus formation can frequently occur. The incidence of perioperative stroke usually ranges from 2 to 3% even reaching 5% in some reports [11]. Our results indicate that the use of the CCECC resulted in a reduced alteration of the coagulation-cascade during the operation when compared with patients operated upon standard CPB, quite similar to OPCAB. Information concerning potential advantages of OPCAB with respect to CPB in terms of activation of the coagulatory system is still limited. During OPCAB, reduced platelets consumption as well as less activation of the fibrinolytic system than during CPB has been reported [12]. Interestingly, no differences in terms of endothelial or platelets activation markers were observed during the surgical procedure under different extracorporeal bypass conditions. In contrast, our study showed a significant elevation of TATc, F 1+2 and PAPc levels in the CPB group, which were confirmed by previous studies by Mannucci [13] and Ovrum [12]. During and early after cardiac surgery performed with CPB the authors demonstrated marked activation of coagulation by means of elevated levels of prothrombin fragment 1.2, and of thrombin–antithrombin complex followed by a marked activation of the fibrinolytic system. Indeed, increased levels of PAPc have been reported as a consequence of the activation of the coagulation system [12]. It is common knowledge that extensive interaction of blood with non-endothelial surfaces of the bypass circuits causes activation of these pathways. On the other side, other mechanisms like re-transfusion of pericardial blood collected during operation may also contribute significantly to activation of the coagulation–fibrinolytic systems. During bypass surgery continuous oozing and bleeding from the cut edges and particularly from the sternum into the surgical field, even after meticulous hemostasis, may activate monocytes following contact with the pericardium [14–16]. Indeed, high levels of markers for thrombin, fibrin and cytokine generation in mediastinal and pleural shed blood have been found [15]. In routine procedures with conventional extracorporeal circulation activated shed blood usually returns into the circulation by suction from the surgical field. In our study, a cardiotomy sucker was only used in the conventional CPB group. Therefore, the marked increase of TATc, F 1+2, PAPc and vWF levels during the operation which was solely found in the conventional CPB group finds adequate explanation. However, in contrast to the conventional CPB group a prolonged fibrinolytic activity was observed in the CCECC group. A twofold increase in PAPc level and a 100-fold increase in IL-6 level were detected 24h after surgery utilizing CCECC, whereas in patients undergoing CABG with CPB and OPCAB the fibrinolysis parameter had returned to almost normal, preoperative values. At present, we do not have a sound explanation for this particular finding. In the CCECC group, a blood saving device was used for suction. One may speculate that precursors for fibrinolytic activation may have been mediated during this process. Re-transfusion of these red blood cells, which was performed in the first hours after the surgical procedure, may then have triggered a delayed fibrinolytic activity. It is well known that washing of blood by cell savers reduces but does not eliminate proinflammatory cytokines and thus the pro-coagulatory properties of blood returned to the patient [17,18]. Aside from this hypothesis, the question arises as to whether an altered trasylol regime should be considered in this particular setup. However, this question requires clarification in further investigations. Cardiopulmonary bypass is responsible for a wide variety of changes in circulating platelets. Among the most common features is a rapid, early decrease in platelet numbers due to hemodilution. In the present setup, hematocrit (Hct) values of all groups dropped during the observation period. Although the lowest level was recorded in the CPB group, no significant differences in hemodilution could be detected between the groups. Although platelet count as well as von Willebrand factor activity did not reveal statistical differences between the investigated groups our findings provided at least some hints that CCECC did alter platelet function less than conventional CPB. Our observations were confirmed by Fromes and co-workers, who investigated a novel, albeit heparin-coated CCECC (MECC) system. They showed slightly lower platelet activation in the MECC group during extracorporeal circulation measured by ß-thromboglobulin levels than in a conventional CPB group [19].
It is often proposed that the entire avoidance of CPB profoundly reduces hemostaseologic alterations [20,21]. This expectation could be confirmed when looking at our OPCAB group, in which all hemostatic markers exhibited an almost unaltered course throughout the entire observation period. In contrast, it should be noted that anesthesia alone [22] as well as surgical trauma can eventually result in an activation of the coagulation cascade. Indeed, despite total heparinization of the patient coagulatory activation as indicated by prothrombin fragment 1.2 and thrombin–antithrombin complex have been reported [23]. These data from the literature may serve as an explanation for the slight increase of F 1+2 markers already prior to the surgical procedure in the CPB as well as the OPCAB group. We therefore assume that this elevation is due to anesthesia alone. In addition, surgical chest wounds have been considered to be a major source of tissue factor and cytokines liberation, which activates the extrinsic pathway of the coagulation cascade and contributes to the onset of a postoperative hypercoagulatory state [15]. Therefore, even the most ideal extracorporeal circulation cannot guarantee to maintain entirely physiologic coagulation, but we speculate that CCECC will further help to reduce activation of coagulatory and inflammatory cascades to minimize the differences between CPB and OPCAB.
4.1. Limitations of the study
A number of cytokines are involved in the inflammatory response. IL-6, however, is a potent though not highly specific marker. It does not sufficiently represent the complex field of inflammation but may serve as a first indicator. A comparative statistical analysis was only performed between CPB and CCECC groups. The OPCAB group was used only as a separate reference group because it was neither randomized nor was the perioperative trasylol regime identical. The observation period was limited in our study to the first 24h after operation for budgetary reasons. Therefore, information regarding the further behavior of the investigated parameters was not available. Significant clinical effects of the observed differences in our study such as prolonged bleeding, necessity of rethoracotomy, length of intensive care unit stay, and hospitalization were not present. However, as the study was intended to analyze acute effects in the blood we did not expect significant clinical findings. Only studies on a much larger scale will provide adequate statistical power to assess the assumed benefits of a minimized extracorporeal system in terms of morbidity, clinical outcome and perhaps even mortality.
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5. Conclusion
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A low-prime volume, closed circuit CPB with centrifugal pump such as the CORx-system does have benefits in terms of reduction of humoral and cellular coagulatory derangement while a delayed fibrinolytic activity was observed. Furthermore, a marked IL-6 response cannot be readily explained and may indicate potentially adverse effects. Consecutive studies are necessary to further elucidate benefits and adverse effects of the presented system. These further insights may then be helpful to improve the concept of minimally invasive CPB.
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M. Ranucci, A. Balduini, A. Ditta, A. Boncilli, and S. Brozzi
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B. R. Untch, W. P. Jeske, J. Schwartz, S. Botkin, M. Prechel, J. M. Walenga, and M. Bakhos
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A. L. Lagan, D. D. Melley, T. W. Evans, and G. J. Quinlan
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G. J. Spalding, M. Hartrumpf, T. Sierig, N. Oesberg, C. G. Kirschke, and J. M. Albes
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M. Perthel, L. El-Ayoubi, A. Bendisch, J. Laas, and M. Gerigk
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Top
Abstract
1. Introduction
