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Original Articles: Adult Cardiac

Myocardial Revascularization by Left Ventricular Assisted Beating Heart Is Associated With Reduced Systemic Inflammatory Response

^a Cardiac Surgery Unit, School of Medicine, University Federico II, Naples, Italy
^b Cardiac Surgery Unit, Istituto Clinico Pineta Grande, Castel Volturno, Italy
^c ItalyCardiac Anaesthesia, Istituto Clinico Pineta Grande, Castel Volturno, Italy
^d ItalyLaboratory Medicine, Istituto Clinico Pineta Grande, Castel Volturno, Italy
^e Division of Cardiology, University of Perugia School of Medicine, Perugia, Italy
^f Cardiac Surgery Unit, S. Giovanni di Dio e Ruggi D'Aragona Hospital, Salerno, Italy

Accepted for publication July 29, 2008.

^_* Address correspondence to Dr Di Tommaso, Via V. Gemito, 33, Caserta, 81100, Italy (Email: lditommaso{at}tin.it).

	Abstract

Top Abstract Introduction Material and Methods Results Comment References

 
Background: The present study was designed to investigate whether use of left ventricular assisted technique (LVA) in beating-heart myocardial revascularization would exert less impact on patients' inflammatory response, as compared with minimal extracorporeal circulation (MECC).

Methods: Seventy-three consecutive high-risk patients undergoing myocardial revascularization were randomly assigned either to LVA (group A) or to MECC (group B). Monocyte count and plasma concentration of C-reactive protein, inflammatory cytokines interleukin-1β, interleukin-6, and tumor necrosis factor-, and polymorphonuclear elastase were measured at baseline and at various time points postoperatively.

Results: Preoperative clinical and demographic data did not differ between the two groups. The two groups also were similar with respect to mortality, number of grafts performed, duration of extracorporeal circulation, and need for inotropes. However, LVA was associated with significantly less inflammatory response postoperatively compared with MECC, as indicated by a significant difference in interleukin-6 (p = 0.002), C-reactive protein (p = 0.002), monocyte percentage (p = 0.006), tumor necrosis factor- (p = 0.002), and polymorphonuclear elastase (p = 0.001).

Conclusions: High-risk patients undergoing beating-heart myocardial revascularization with LVA show reduced inflammatory response compared with patients treated with the MECC.

	Introduction

Top Abstract Introduction Material and Methods Results Comment References

 
Off-pump myocardial revascularization has gained wide acceptance in cardiac surgery practice [1–3]. However, even with increased experience and the availability of technical aids, there remains a group of difficult patients with unstable clinical conditions or unfavorable anatomy for whom even a brief period of hemodynamic alteration may have negative consequences, leading to urgent conversion to cardiopulmonary bypass, to incomplete revascularization, and to less satisfactory results [4].

In these difficult patients, an alternative may be represented by the on-pump, beating-heart technique with the use of a complete cardiopulmonary bypass (CPB). Recently it has been demonstrated that the use of minimal extracorporeal circulation (MECC) in myocardial revascularization procedures elicits less inflammatory response than traditional CPB, while yielding good clinical results [5, 6]. But both these techniques, which give the hemodynamic benefit of the control of the cardiac output, imply the use of a complete—although reduced in MECC—cardiopulmonary circuit with the use of oxygenator and heat exchanger.

With the already reduced MECC circuit in mind, we hypothesized that the magnitude of the inflammatory response elicited by revascularization and its impact on patients could be further reduced by adopting a series of measures such as additional shortening of the circuit length, reducing the amount of hemodilution, eliminating the oxygenator with the heath exchanger, maintaining the lung ventilated and perfused throughout the procedure. Accordingly, in high-risk patients, we started a clinical experience in performing beating-heart myocardial revascularization during left ventricular assistance (LVA), with encouraging results [7].

In the present study, we wanted to investigate whether this approach of LVA beating-heart myocardial revascularization is less injurious to the patient than revascularization performed during MECC in terms of activation of systemic inflammatory response. To this end, we have carried out a prospective, randomized study evaluating the changes in several inflammatory reaction markers brought about by LVA compared with those elicited with the MECC.

	Material and Methods

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Study Design
Seventy-three consecutive high-risk patients referred for elective myocardial revascularization surgery were prospectively enrolled either to LVA (group A, n = 38), or to MECC (group B, n = 35). High-risk patients were those with left ventricular ejection fraction less than 30%, unstable angina or ST-segment elevation, or both, left main stenosis plus occluded right coronary artery, intracoronary or calcified vessels, cardiogenic shock intraoperatively—these factors being present alone or in combination (Table 1). Indication for coronary artery surgery was established on the basis of current guidelines [8]. Randomization to the type of procedure was made after the patient was deemed eligible, and each patient was assigned to either group A or B by the last digit of his or her hospital admission number. Samples of inflammation markers were consecutively numbered and sent to the laboratory with the sole indication "inflammation study," without information on the type of surgical technique; therefore, intensive care unit (ICU) and laboratory personnel were not aware of the group of each patient. To minimize interferences with proinflammatory cytokines, we excluded from the study patients with renal insufficiency (preoperative creatinine level > 1.7 mg/dL), chronic obstructive pulmonary disease, recent infections, and chronic use of steroids or nonsteroid anti-inflammatory drugs. Patient's written consent was obtained, and the local Ethics Committee approved the protocol.

Anesthesia
Patients in both groups were premedicated with morphine sulphate (0.15 mg/kg^–1) and diazepam (0.15 mg/kg^–1) intramuscularly 1 hour before transfer to the operative theater. Anesthesia was then induced with fentanyl (3 µg/kg^–1) and propophol (2 mg/kg^–1) intravenously. Neuromuscular block was obtained by cisatracurium besylate (0.2 mg/kg^–1 intravenously). Anesthesia was maintained with remifentanil, propophol, and cisatracurium besylate. Patients were intubated and ventilated normally with oxygen in air (fraction of inspired oxygen 0.4 to 0.5).

Surgical Procedure
This study capitalizes on extensive experience previously achieved by our team with revascularization by means of LVA [7]. After anesthesia, in both groups the heart was exposed through median sternotomy, with the beating-heart technique, and in normothermia. The two systems, LVA and MECC, both use heparin-coated circuits, and they both lack an open reservoir. As major differences, in the LVA approach there is no oxygenator nor heat exchanger, circuit lines are shorter (and, hence, priming volume is reduced), and during the procedure, lungs continue to be ventilated and perfused.

In LVA patients (group A), a 20F to 22F arterial cannula (Maquet, Irrlingen, Germany) was introduced into the ascending aorta for arterial return, and a 24F two-stage cannula (Eurosets, Medolla, Italy) was introduced into the left atrium and advanced into the left ventricle. The two cannulas are directly connected through a short, heparin-coated circuit (Eurosets) to a centrifuge pump (Maquet) placed near the patient's head. The tubing length of the circuit is less than 150 cm, and the priming volume is small (200 mL lactated Ringer's solution). In this short circuit, there is no oxygenator with heat exchanger and no venous open reservoir. The system is started; blood is sucked from the left ventricle and pumped directly into the aorta. A flow of 1.5 to 2.0 L · min^–1 · m^–2 is obtained, affording normal cardiac output and hemodynamic stability throughout the operation [7]. During the procedure, lungs are normally ventilated and perfused.

In MECC patients (group B), a 22F to 24F arterial cannula (Maquet, Irrlingen, Germany) was introduced into the ascending aorta, and a single two-stage right atrial cannula (Maquet) was used for venous drainage. A totally heparin-coated closed circuit with a centrifuge pump (Maquet) was used. The circuit has a membrane oxygenator with integrated heat exchanger (Maquet). The circuit was primed with 800 mL Ringer's lactate, a flow of 1.5 to 2.0 L · min^–1 · m^–2 was obtained, and the aorta was not clamped.

Before cannulation, in both groups, 2 mg/kg heparin was administered intravenously and supplemented throughout the procedure to achieve an activated clotting time between 250 and 300 s. The Hepcon HMS (Medtronic, Minneapolis, Minnesota) automatic dose mode was used to monitor anticoagulation and to calculate heparin and protamine during and after the procedure.

The left internal thoracic artery was harvested as a pedicle and always used to graft the left anterior descending coronary artery only, or left anterior descending artery and diagonal branch (sequential grafting). Radial artery or saphenous vein connected to the left internal thoracic artery proximally in a T-graft configuration was used to revascularize non–left anterior descending coronary artery vessels.

Owing to the possible activation of inflammatory cells in cardiotomy suction blood and in retransfused mediastinal shed blood, in this study, all mediastinal shed blood was discarded.

At the end of the procedure, patients (intubated and sedated) were transferred to the ICU. Clinical criteria dictated extubation and discharge from the ICU. Hematocrit less than 25% was set as a standardized value for allogenic transfusion in both groups.

Biochemical Determinations
Laboratory investigations included routine clinical and biochemical evaluations. Specific evaluations of high-sensitivity C-reactive protein (CRP), cytokine release of interleukin (IL)-1β, IL-6, tumor necrosis factor- (TNF-), and polymorphonuclear (PMN) elastase, were also performed.

Blood samples for inflammatory markers (IL-1β, IL-6, TNF-) were collected into sterile Vacutainer tubes with separation gel and centrifuged at 4,000 rpm for 10 minutes. The resultant serum was stored at –70°C until analyses were performed with enzyme-linked immunoassorbant assay (ELISA [DRG Instruments GmbH, Marburg, Germany]). Normal ranges for inflammatory markers were as follows: IL-1β, 0 to 15 pg/mL; IL-6, 0 to 8 pg/mL; TNF-, less than 8 pg/mL. Release of neutrophil elastase was determined using an ELISA immunoassay kit, with lower detection limit of 2.0 ng/mL. Plasma CRP was measured by CRP HS ELISA test (normal range, 0.068 to 8.2 mg/L). Monocytes counts were expressed as percentage (normal value, 3% to 7%) of the leucocytes (>12,000 upper limits of the normal value for our laboratory; ADVIA 120 Siemens, Milan, Italy). Because prime volume and hemodilution during surgery were different between the groups, all measured inflammatory variables were normalized for hematocrit values. Serial blood samples were drawn at five different time points: time 1, at the induction of anesthesia; time 2, at the beginning of the extracorporeal circulation; time 3, at sternal closure; time 4, 6 hours later in the ICU; and time 5, on the first postoperative morning.

Statistical Analysis
Continuous data are presented as mean ± SD. The nonparametric Mann-Whitney U test (continuous variables) or ² test (categorical variables) were used to compare clinical variables between the two groups. Two-way analysis of variance (ANOVA) with correction for repeated measures was used to evaluate differences over time in concentrations of inflammatory markers between the groups. A p value of less than 0.05 was considered statistically significant. Data were analyzed by SPSS 12.01 for Windows (SPSS, Chicago, Illinois).

	Results

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Baseline Data
Preoperative demographic and clinical data did not differ significantly between the two groups (Table 1).

Clinical Course
No in-hospital death occurred. In no case was interruption of the procedure necessary, and all procedures were completed as planned. All patients underwent the planned, complete myocardial revascularization, no device-related complications occurred during the procedure, and all patients left the operative theater in sinus rhythm with minimal (dobutamine, 3 to 5 /kg/min), or no inotropic support.

Operative data were also similar for both groups; in particular, there were no differences between the two groups regarding the duration of extracorporeal circulation, number of grafts performed, blood losses (Tables 1, 2). One patient in group A (2.6%, p = 0.5) developed ventricular fibrillation during the procedure, which was easily cardioverted and the heart did not distend. Weaning from both types of extracorporeal circulation was uncomplicated, two patients (one in group A and one in group B, 2.6% and 2.8%, respectively, p = 0.7) required temporary intra-aortic ballon pump assistance for low cardiac output after surgery. The intra-aortic ballon pump was removed successfully within 6 hours. Postoperative transthoracic or transesophageal echocardiogram were also similar in both groups, showing the same as preoperative or slightly better left ventricular function (Table 1). Creatine kinase–MB, troponin, 12-lead electrocardiography, and echocardiography excluded perioperative myocardial infarction, and the evolution of troponin I did not differ between the two groups. Few clinical outcomes were different between group A and B: patients in group A spent significantly less time on ventilator and had shorter ICU and hospital stays (Table 2).

Analyzing in detail the response of inflammatory cytokines between LVA and MECC groups, no significant differences were observed in the IL-1β trend. In contrast, patients operated on while on LVA showed significant less release of IL-6, CRP, TNF-, and PMN elastase trends compared with the MECC group (Table 3); monocyte percentage value was also significantly lower in this group (Table 3). The value of IL-1β grew in both groups and peaked at time 4, but without differences between the two groups studied (ANOVA repeated measures, p value between groups = 0.8). The value of IL-6 also peaked at time 4 (93.9 ± 56.4 versus 151.1 ± 61.4, in LVA versus MECC, respectively; p = 0.0001), with marked differences between groups A and B (ANOVA p = 0.002). Then both values, IL-1β and IL-6, decreased at 24 hours postoperatively. The TNF- response was significantly higher in group B compared with group A (ANOVA p = 0.002), reaching a peak value by time 3 (11.2 ± 6.5 versus 16.7 ± 8.6, in LVA versus MECC, respectively; p = 0.003), then it dropped in the early postoperative period.

View larger version (13K): [in this window] [in a new window]   Fig 1. Time course of changes in (A) plasma concentration of interleukin-6, (B) tumor necrosis factor, and (C) polymorphonuclear elastase at five different time points. (Diamonds = left ventricular assistance; boxes = minimal extracorporeal circulation.)

	Comment

Top Abstract Introduction Material and Methods Results Comment References

It has previously been documented that CPB circulation can elicit systemic increase of IL-6 [13]. Interleukin-6 is a proinflammatory cytokine with direct negative inotropic effects. In our study, plasma concentration of IL-6 increased more rapidly and to a larger extent in the MECC group as compared with the LVA group. The source of IL-6 in our study is not immediately evident, but it is interesting to underline that, among other cell types, activated monocytes can release it; in this respect, although blood monocyte count decreased in both groups, the decrease was greater in the MECC group. It is conceivable that the case of the LVA shorter circuit line and lack of oxygenator affords less intracircuit activation of monocytes; this, in turn, would explain higher monocyte count in this group (because of less peripheral margination outside blood stream), as well as reduced release of IL-6.

Tumor necrosis factor- is another cytokine released during the inflammatory response and, like IL-6, has negative inotropic effects. It is held responsible not only for deteriorating cardiac function but also for endothelial dysfunction, secondary to oxidative stress [14, 15]. In vitro, TNF- is a strong inducer of both apoptosis and necrosis, and through these mechanisms it could further deteriorate ventricular function [16]. In our study, we observed an increased production of TNF- in patients treated with MECC, starting at the end of the procedure and lasting until the early postoperative phase. In this respect, Lindholm and coworkers [17] have recently reported less increase in TNF- concentrations in patients who underwent cardiac surgery with use of a biocompatible CPB system, as compared with patients put on classic CPB circuit; our findings confirm the importance of using a less invasive and more physiologic circuit, and extend it to beating-heart surgery.

The proinflammatory cytokine IL-1β increases with progression of congestive heart failure and, in conjunction with TNF-, depresses myocardial function through a mechanism mediated by sphingosine. Previous studies reported conflicting results on IL-1 response after extracorporeal circulation, showing significant increase of IL-1 concentration in some [5], but not in other studies [18]. In the present study, no significant difference in the release of IL-1 were found between the two groups.

Plasma concentrations of elastase are a sensitive and reliable index of neutrophil activation; activation of neutrophils has been shown to occur in patients during CPB, as neutophils roll and stick to the surface of tubing and other components of the circuit [19, 20]. This situation triggers a rapid activation, manifested by an increase of neutrophil adhesiveness to the endothelium, which is mediated by their adhesions molecules CD11b and L-selectin, and is rapidly followed by the release of proteolytic enzymes (such as elastase) and oxidants [10, 21–23]. In adult as well in pediatric CPB, a marked stimulation of cellular expression of neutrophil adhesion molecules CD11b and L-selectin has been demonstrated [21]. In the LVA group, we observed that elastase release was significantly less pronounced. We speculate that in this group there was less granulocyte activation, and hence less elastase release. A similar decrease of PMN elastase value has been observed by others when a more physiologic circuit was employed compared with classic CPB circuit, further stressing the importance of a lighter CPB support [24].

In our LVA circulation, the lungs continue to be ventilated and perfused; in addition to reduced blood contact with the external circuit component, it is conceivable that preserved pulmonary perfusion and function might have exerted a significant contribution in reducing the inflammatory response. In fact, after reestablishing lung circulation, lung reperfusion injury is generally regarded as a main causative factor of postperfusion syndrome, as activated neutrophils accumulate on the lung and release elastase and oxidants [25–27]. Among the proteases produced by neutrophils, PMN elastase, besides playing a major role in ischemia-reperfusion lung injury, is the most injurious because it hydrolyzes most connective tissue components on various substrates [28, 29]. In fact, use of the specific PMN elastase inhibitor ONO-5046·Na has been shown to preserve pulmonary function [30].

Clinical Implications
The aim of our study was to investigate the differences in inflammatory markers, and it was not designed for comparison of clinical outcomes. Nevertheless, some findings may be worth mentioning. Patients operated on while on LVA required reduced ventilation time, and had shorter ICU and hospital stays. If confirmed in larger trials, these results may indicate a possible clinical benefit of the use of LVA.

Another interesting aspect of the use of LVA is its reduced costs. Compared with the MECC, avoiding use of an oxygenator with heat exchanger, reduced tubing length, and reduced priming solution may afford substantial savings.

Limitations
It should be stressed that the conclusions of our study are limited to the patient population studied and to the inflammatory markers analyzed. Different results may be obtained with another study design and with other inflammatory markers. Also, it is known that cytokines induce the production of other mediators of the cytokines family; therefore, blunting production of a single cytokine may fail to have major consequences. Furthermore, this study was designed to detect differences in the inflammatory response between LVA and MECC, not clinical outcomes. Subsequent, larger trials are necessary to document benefits and adverse effects of the presented system on clinical endpoints.

In conclusion, use of a closed, miniaturized system of LVA to perform beating-heart revascularization in high-risk patients may reduce the extent of inflammatory response to revascularization surgery. In addition, this approach may exert positive effects on lung function and on length of ICU and hospital stays. These findings may warrant further studies with clinical endpoints.

	References

Top Abstract Introduction Material and Methods Results Comment References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Paolo Stassano Luigi Di Tommaso Mario Monaco Severino Iesu Giuseppe Di Benedetto Paolo Pepino Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Stassano, P. Articles by Pepino, P. Search for Related Content PubMed PubMed Citation Articles by Stassano, P. Articles by Pepino, P. Related Collections Coronary disease Extracorporeal circulation Related Article