Comparison of Inflammatory Responses After Off-Pump and On-Pump Coronary Surgery Using Surface...

DOI: 10.1016/j.athoracsur.2005.11.059 2006;81:1683-1690 Ann Thorac Surg

Defraigne Janine M. Quaniers, Julie Leruth, Adelin Albert, Raymond R. Limet and Jean-Olivier

Surgery Using Surface Modifying Additives CircuitComparison of Inflammatory Responses After Off-Pump and On-Pump Coronary

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omparison of Inflammatory Responses After Off-ump and On-Pump Coronary Surgery Usingurface Modifying Additives Circuit

anine M. Quaniers, MD, Julie Leruth, MD, Adelin Albert, MD, PhD,aymond R. Limet, MD, PhD, and Jean-Olivier Defraigne, MD, PhD

Background. Cardiac surgery is followed by variousegrees of inflammation, which have harmful conse-uences. Because of the central role of extracorporealirculation (EC), off-pump coronary bypass surgery iseemed preferable. Do different modalities of EC chal-

enge this view?Methods. Four groups of similar patients underwent

oronary surgery: (group 1) on-pump, EC with closedurface modifying additives (SMA) circuit and no pumpuckers (n � 20); (group 2) on-pump, EC with open SMAircuit and pump suckers (n � 20); (group 3) off-pumpbeating heart) and heparin 3 mg/kg (n � 20); (group 4)ff-pump (beating heart) and heparin 1 mg/kg (n � 20).nterleukins (IL)-6, IL-8, IL-10, myeloperoxidase, elas-

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ddress correspondence to Dr Limet, Department of Cardiovascularurgery, CHU de Liège, 4000 Liège, Belgium; e-mail: rlimet@ulg.ac.be.

2006 by The Society of Thoracic Surgeonsublished by Elsevier Inc

ats.ctsnetjournDownloaded from

ere analyzed at various times: at induction (time I);fter heparin (time II); after complete revascularizationtime III); after protamine (time IV); and 24 hours latertime V).

Results. The TCC was significantly higher in groups 1nd 2 at time III. The pattern of IL-6 was the same for theour groups. No significant difference in myeloperoxy-ase content was noted; however, elastase was signifi-antly higher in the two EC (on-pump) groups.

Conclusions. Except for the complement system andlastase, on-pump surgery with SMA-coated circuits didot elicit any greater inflammatory response than off-ump surgery.

(Ann Thorac Surg 2006;81:1683–90)

systemic inflammatory reaction is observed aftercardiac surgery, and it is generally considered to be

aused by the use of extracorporeal circulation (EC).owever, both types of surgery, cardiac and noncardiac,

re associated with an inflammatory response due toissue trauma. Moreover, because cardiac surgery haseen exclusively carried out using EC for over fourecades, it has been difficult to define the relative rolelayed by EC and by surgery itself in the induction of the

nflammatory reaction.In order to reduce the harmful effects of EC, various

mprovements (mainly focused on physicochemical pa-ameters of EC) have been proposed. In the same way,ardiac stabilization systems have been developed allow-ng coronary artery bypass surgery without using EC. It isf major interest to know to what extent the latter moreecent technique can reduce the inflammatory reaction.ome studies have compared the off-pump techniqueith EC surgery performed with a classical circuit andave analyzed the evolution of different inflammatoryarkers. Some of these studies reported a lower inflam-atory response with off-pump surgery [1, 2], but others

id not see any differences [3]. However, when theff-pump technique was found to be superior in terms ofhe inflammatory response, it was not necessarily asso-

ccepted for publication Nov 3, 2005.

iated with marked benefits such as decreased morbidityr postoperative mortality [4, 5].For on-pump interventions, the surface modifying ad-

itives (SMA) circuit has been reported to be moreiocompatible than a classic EC circuit, notably in termsf platelet function preservation [6]. The primary goal ofhe present study was to compare coronary artery bypassurgery (CABG) performed with EC using SMA typeircuits with off-pump beating heart surgery, in terms ofnflammatory reaction. Since blood-air contact has beenhown to be a major factor contributing to postoperativenflammatory reaction, the use of a closed circuit and these of a blood recovery and washing device (cell-saver)inimize this inflammatory reaction. Thus, in our study,

he influence of a closed versus an open circuit and thenfluence of a cell-saver during EC were also examined.

aterial and Methods

atient Selectionatients in the age range of 40 to 80 years who underwentABG surgery between November 1999 and February002, and who were eligible for beating-heart revascular-zation were included in the study. Exclusion criteriaere emergency surgery, reintervention, chronic renal

nsufficiency, severe respiratory insufficiency, ejectionraction less than 0.30, previous history of neoplasia or of

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1684 QUANIERS ET AL Ann Thorac SurgINFLAMMATION IN OPCAB AND ONCAB SURGERY 2006;81:1683–90

iabetes. Patients were randomized into four groups:roup 1, EC with closed SMA circuit without pumpuckers (n � 20); group 2, EC with open SMA circuit withump suckers (n � 20); group 3, beating heart (off-pump)eceiving heparin at 3 mg/kg (n � 20); group 4, beatingeart (off-pump) receiving heparin at 1 mg/kg (n � 20).hen complete beating-heart revascularization could

ot be carried out for a patient allocated to groups 3 or 4,hen he or she was withdrawn from the study. The Ethicsommittee of the University hospital approved the studynd each patient signed an informed consent prior to theperation.

nesthesiafter rachianesthesia (0.4 to 0.5 mg morphine), the in-uction was carried out by intravenous injection ofropofol (Diprivan; AstraZeneca SA, Brussel, Belgium)ontrolled by TCI (target control infusion), remifentanil0.25 to 0.5 �g/kg/min, Ultiva; GlaxoSmithKline Manu-acturing, Genval, Belgium), and rocuronium (1 mg/kg,smeron; Organon, Brussels, Belgium). The rectal andsophagus temperatures, the urine output, the electro-ardiogram, the central venous pressure, and the pulmo-ary (Swann-Ganz probe) and systemic (radial) arterialressure were monitored in the four groups. All patientseceived a high dose of aprotinine sulfate (Trasylol; BayerA, Brussel, Belgium) according to the protocol of Roy-ton [7]. Before starting the EC and before carrying outhe bypass operation in the off-pump groups, heparinas injected. In the two EC groups, the heparin was

njected in bolus to attain an activated coagulation timeACT) higher than 480 seconds (Hemochron 400; Inter-ational Technidyne Corp, Edison, NJ). The ACT waslso measured during the beating heart surgery, but onlyne dose of heparin was injected.

xtracorporeal Circulationhe extracorporeal circulation circuit was composed of aas polypropylene micropore plaque oxygenator (DuoMARxT; COBE Cardiovascular, Arvada, CO) and a heatxchanger. All components of the circuit in contact withlood were made from copolymeric additive modifiedaterial (SMARxT, COBE Cardiovascular), including the

rterial filter. Both the arterial and venous blood gases

Abbreviations and Acronyms

ACT � activated coagulation timeEC � extra-corporeal circulationLPS � lipopolysaccharidesMPO � myeloperoxidasePMN � polymorphonuclear neutrophilSE � standard errorSMA � surface modified additiveSIRS � systemic inflammatory reaction

syndromeTCC � terminal complement complexTCI � target control infusion

ere monitored continuously (CDI 400; Terumo Cardio- l

ascular Systems, Ann Arbor, MI and Sat-Crit COBE,espectively). The arterial injection pressure, the left ventuction pressure, and the injection of the cardioplegiaere systematically controlled.In group 1 a closed circuit was used; the venous

eservoir was composed by a closed soft reservoir withvariable capacity (COBE VRB 1200 SMARxT). The

lood from the left ventricle was collected in a secondoft reservoir (COBE VRB 1800 SMARxT) connected tohe venous reservoir. An open circuit was used forroup 2; the venous reservoir was composed of a rigideservoir (COBE HRV 4000 SMARxT) with integratedardiotomy reservoir (filter of 30 microns) and had aaximum storage capacity of 4,000 mL. Blood from left

ent suction and the shed blood from the pleuroperi-ardial cavities were aspirated into the reservoir. Inroup 1, the shed blood from the pleuropericardialavities was aspirated in a separate cardiotomy reser-oir. Then, the blood was treated with a cell-saverBRAT 2, COBE) before being, if necessary, reinfuseduring EC or after heparin neutralization. In the twoC groups, the priming volume of the circuit wasetween 1,700 and 1,800 mL of 2/3 of a crystalloidolution (Plasmalyte A; Baxter Healthcare, Deerfield,L) and 1/3 of synthesis gelatine (Haes-stéril 6%; Fre-enius, Lexington, MA). The hemodilution was ac-epted down to a minimum of 20% hematocrit.

After cannulation of the ascending aorta and the righttrium, EC was established with a pulsatile flow toaintain a minimal index of 2.4 L · m2 · minute. The flowas adjusted based on the hemodynamic parameters andn the venous saturation. Patients were operated onnder active normothermia (37°C). After aortic clamping,ntegrade cardioplegia was obtained by injection of arystalloid solution (St. Thomas solution) at 4°C in thescending aorta. During EC, an additional dose of hepa-in (Heparine Leo; Leo Pharmaceutical Products, Breda,he Netherlands) was administered if the ACT (Hemo-hron Junior; International Technidyne, Edison, NJ) wasess than 400 seconds. After completion of EC, the hep-rin was completely neutralized using protamine (Prota-ine 1000°; Leo Pharma, Wilrijk, Belgium) at a dose of 1g/100 IU of heparin. The residual volume of the circuitas reinfused into the patient and at the end of therocedure the EC circuit was rinsed and treated with theell-saver.

eating Hearthe surgical approach was a median sternotomy. Thetabilization material was the second model Octopusystem (Medronic Inc, Minneapolis, MN). One 4-0 Pro-ene (Ethicon, Somerville, NJ) suture was used to tempo-arily occlude the coronary artery above the anastomoticite. No coronary shunt was used. Suture for pericardialraction and Trendelenburg manipulation were used toacilitate the exposure with preservation of the hemody-amic stability. At the end of the intervention, the circu-

ating heparin was neutralized after ACT control.

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1685Ann Thorac Surg QUANIERS ET AL2006;81:1683–90 INFLAMMATION IN OPCAB AND ONCAB SURGERY

iochemical Measurementshe arterial blood samples were collected from the radialrtery catheter into sterile vacuum tubes. After centrifu-ation, the plasma was collected and then stored at70°C until biochemical analysis. Results were corrected

or hemodilution at each time point. Interleukins (IL-6,L-8, and IL-10), myeloperoxydase (MPO), and the termi-al complex of the complement (TCC) were measureduring and after the operation. Specifically, measure-ents were made at induction (time I), after the injection

f heparin (time II), after myocardial revascularizationtime III), after neutralization of heparin by the prota-

ine (time IV), and 24 hours after the surgery (time V). Inddition, the leukocyte count, the neutrophil percentage,he hemoglobin, and the hematocrit were also measuredt each time point. Elastase was assayed at times I, IV,nd V. The IL-6, IL-8, and IL-10 in plasma were analyzedy “sandwich” solid-phase enzyme amplified sensitivity

mmunoassay (MEDGENIX-EASIA; Biosource EuropeA, Fleurus, Belgium) performed on a microtiter plate.olymorphonuclear neutrophil (PMN) elastase was de-

ermined by homogenous immunoassay (Ecoline, Merck,armstadt, Germany), MPO by double radioimmunoas-

ay (Pharmacia MPO RIA, Pharmacia and Upjohn JAB,ppsala, Sweden). The sC5b-9 (TCC) was measured by

nzyme-linked immunosorbent assay (Quidel, San Di-go, CA).

tatistical Analysisesults were expressed as means � standard deviations

or quantitative variables and as frequencies and propor-ions (%) for categoric variables. In figures, means were

able 1. Patient Characteristics in the Four Experimental Gro

VariableGroup 1(n � 20)

Gro(n �

ender M/F 18/2 1ge (years) 66 � 7.8 62 �

jection fraction 0.66 � 0.13 0.69 �

peration time (min) 199 � 43 211 �

PB time (min) 74 � 17 81 �

ross-clamp time (min) 39 � 9.4 41 �

raft/patient 3.3 � 0.7 3.1 �

irst 24 hour postoperativelood loss (mL)

708 � 342 765 �

ntubation time (hours) 11 � 2.0 12 �

CU length of stay (days) 2.8 � 1.9 2.4 �

ospital stay (days) 11 � 4.9 10 �

omplications (number)Myocardial infarction 0Documented infection 3Cerebral dysfunction 9Atrial fibrillation 9Wound complications 2

PB � coronary pulmonary bypass; ICU � intensive care unit.

lotted with their standard error (SE). E

Patients serial biochemical measurements were ana-yzed by the general linear mixed model (GLMM), whichllows to assess the time effect, the group effect (type ofurgery), and the interaction effect (time � group), whileccounting for repeated data within each subject. Fornterleukins, a log-transform was applied to the data toormalize their distributions. The GLMM was then car-ied out on the transformed data. Results were consid-red significant at the 5% critical level (p � 0.05). Calcu-ations were done using SAS and S-PLUS statisticalackages (SAS Institute Inc, Cary, NC).

esults

emographic and Preoperative Datahe four groups were similar in terms of age, sex, and leftentricular function (see Table 1). No statistically signif-cant differences were found for the two EC groups withespect to the clamping time and the total pump time.he average number of bypasses was similar in the fourroups as were the total operative time, the postoperativelood loss in the first 24 hours, and postoperative com-lications. Two deaths occurred in group III (beatingeart, heparin 3 mg/kg).

erminal Complement Complexhe evolution of TCC during the operation in each studyroup is depicted in Figure 1. The GLMM analysisevealed a highly significant time effect (p � 0.0001),roup effect (p � 0.0053), and interaction effect (p �.0001). At time III (after myocardial revascularization),CC concentrations rose to about 800 mg/mL in the two

Group 3(n � 20)

Group 4(n � 20) p Value

18/2 17/3 0.9663 � 11 61 � 10 0.39

0.66 � 0.13 0.64 � 0.12 0.71198 � 48 196 � 33 0.69

N.A. N.A. 0.64N.A. N.A. 0.69

2.9 � 0.7 3.1 � 1 0.23759 � 383 686 � 188 0.89

12 � 4.0 11 � 1.9 0.973.7 � 6.7 2.5 � 0.8 0.6513 � 10 11 � 2.7 0.39

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ical patients. Concentrations remained high at time IVprotamine injection) in the EC groups, and then re-urned to values similar to initial ones 24 hours after theperation. Overall, no difference was observed betweenhe time evolution of TCC in the two EC groups (p �.31). In the “beating heart” groups, TCC concentrationsid not change during the operation and were compara-le in both groups (p � 0.72).

nterleukin-6igure 2 displays the time evolution of IL-6 concentra-ions in the four patient groups. Overall, no significantifferences could be discerned between the IL-6 evolu-

ion in the study groups (p � 0.13). By contrast, GLMM

ig 1. Plasma concentrations of the terminal complement complexTCC) at: time I, induction of anesthesia; time II, after the injectionf heparin; time III, after myocardial revascularization; time IV, af-er neutralization of heparin by protamine; time V, at 24 hours afterurgery. Data are expressed as the mean � the standard deviation.—— � group 1; . . . . . . � group 2; - - - - - � group 3; – – – – –

group 4.)

ig 2. Plasma interleukin-6 (IL6) concentrations at: time I, inductionf anesthesia; time II. after the injection of heparin; time III, afteryocardial revascularization; time IV, after neutralization of heparin

y protamine; time V, at 24 hours after surgery. Data are expresseds the mean � the standard deviation. (—— � group 1; . . . . . . �

nroup 2; - - - - - � group 3; – – – – – � group 4.)

nalysis confirmed a highly significant time effect (p �.0001); IL-6 increasing stepwise during the surgical op-ration. Twenty-four hours after surgery, concentrationsmounted to 167 � 70 pg/mL in group 1, 323 � 311 pg/mLn group 2, 264 � 121 pg/mL in group 3, and 257 � 163g/mL in group 4. The GLMM analysis revealed no

nteraction effect (p � 0.077).

nterleukin-8ean serial levels of IL-8 in each patient group are

lotted on a log-scale in Figure 3. Group comparison justeached the 5% critical level (p � 0.051) being essentiallyue to group 2, which differed from group 1 (p � 0.042)nd from group 4 (p � 0.015), while being similar toroup 3 (p � 0.50). The statistical analysis also revealed aighly significant time effect (p � 0.0001) and a moderateut significant time-group interaction effect (p � 0.019).Despite an overall increase of IL-8 levels from time I

induction) to time IV (after protamine) in each groupexcept for group 3, p � 0.15), the time evolution wasot similar in all groups. A significant drop in IL-8

evels were observed at time II (after heparin) inroups 1 (p � 0.014) and 3 (p � 0.0065), while a highlyignificant increase was found between times III (re-ascularization) and IV (protamine injection) in group(p � 0.0001). It should be observed that, 24 hours afterperation, IL-8 levels were still significantly increasedith respect to baseline: 13 � 15 vs 3.2 � 5.3 pg/mL inroup 1 (p � 0.0009), 17 � 15 vs 5.8 � 9.2 pg/mL inroup 2 (p � 0.0008), 14 � 11 vs 7.9 � 9.3 pg/mL inroup 3 (p � 0.066), and 11 � 14 vs 4.3 � 10.9 pg/mL (p

0.0006) in group 4.

nterleukin-10or the different groups, the minimal detection limit was

ig 3. Plasma interleukin-8 (IL8) concentrations at: time I, at induc-ion of anesthesia; time II, after the injection of heparin; time III,fter myocardial revascularization; time IV, after neutralization ofeparin by protamine; time V, at 24 hours after surgery. Data arexpressed as the mean � the standard deviation. (—— � group 1;. . . . . � group 2; - - - - - � group 3; – – – – – � group 4.)

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yeloperoxydasehe evolution of MPO in the four groups is displayed inigure 4. Overall, no significant difference between theroups could be highlighted by GLMM analysis (p �.061). There was a clear time effect (p � 0.0001) but nonteraction effect (p � 0.072), indicating that the time-elated evolution of MPO was parallel in each group. The

PO concentrations increased after the injection of hep-rin, reached a peak in concentration after myocardialevascularization, and then decreased until 24 hours afterhe surgery, reaching levels observed at baseline. Peakevels observed after complete revascularization (timeII) were 136 � 67 ng/mL in group 1, 191 � 127 ng/mL inroup 2, 115 � 76 ng/mL in group 3, and 106 � 39 ng/mL

n group 4, respectively.

ig 5. Plasma elastase concentrations at: time I, induction of anes-hesia; time IV, after neutralization of heparin by protamine; time V,t 24 hours after surgery. Data are expressed as the mean � thetandard deviation. (—— � group 1; . . . . . . � group 2; - - - - - �

ig 4. Plasma myeloperoxidase (MPO) concentrations at: time I,nduction of anesthesia; time II, after the injection of heparin; timeII, after myocardial revascularization; time IV, after neutralizationf heparin by protamine; time V, at 24 hours after surgery. Data arexpressed as the mean � the standard deviation. (—— � group 1;. . . . . � group 2; - - - - - � group 3; – – – – – � group 4.)

aroup 3; – – – – – � group 4.)

lastases seen in Figure 5, the evolution of elastase activityiffered markedly according to the type of operation. Thisas confirmed by GLMM analysis, which yielded signif-

cant group (p � 0.0001), time (p � 0.0001), and time �roup interaction (p � 0.0001) effects. Group 2 differedignificantly from group 1 (p � 0.0021), group 3 (p �.0001), and group 4 (p � 0.0001), while the two off-pumproups were similar (p � 0.79). At time IV (after prota-ine), elastase levels reached 107 � 59 �g/mL in group 1,

20 � 145 �g/mL in group 2, 43 � 50 �g/mL in group 3,nd 33 � 15 �g/mL in group 4. One day after surgery, asompared with baseline (induction), elastase levels weretill increased; in group 1 (84 � 44 vs 36 � 42 �g/mL, p �.0001), in group 2 (84 � 36 vs 38 � 31 �g/mL, p � 0.0001),n group 3 (77 � 36 vs 25 � 10 �g/mL, p � 0.0001), and inroup 4 (92 � 36 vs 30 � 19 �g/mL, p � 0.0001). Thuslastase levels dropped in the EC groups after completeevascularization (ie, between times IV and V) whilencreasing in the two off-pump groups.

olymorphonuclear Neutrophil Counthe evolution of PMN count as seen in Figure 6 waslobally the same in each surgical group (p � 0.93).owever, a highly significant time effect (p � 0.0001) was

ound, mainly explained by a marked increase of theMN count 24 hours after the operation (time V). TheLMM analysis also revealed a significant time-group

nteraction effect (p � 0.0001), indicating that groupifferences exist at various time points. In particular, asompared with time III (after complete revasculariza-ion), the mean PMN count decreased in the two off-ump groups at time IV (after protamine); 3.2 � 1.6 vs 2.9

2.0 in group 3 (p � 0.014), and 3.9 � 1.5 vs 3.0 � 1.6 inroup 4 (p � 0.0025). By contrast, an increase was seen inhe EC groups; 3.5 � 1.0 vs 4.0 � 1.5 in group 1 (p � 0.040)

ig 6. Variations of the polymorphonuclear neutrophil (PMN) count at:ime I, induction of anesthesia; time II, after the injection of heparin;ime III, after myocardial revascularization; time IV, after neutralizationf heparin by protamine; time V, at 24 hours after surgery. Data arexpressed as the mean � the standard deviation. (—— � group 1;. . . . . � group 2; - - - - - � group 3; – – – – – � group 4.)

nd 3.9 � 1.4 vs 4.6 � 1.5 in group 2 (p � 0.014).

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hrough the dosage of its numerous markers, the activa-ion of the complement is probably the most documentedn cardiac surgery under EC as well as in renal dialysisboth involving biomaterial). The contact of blood withrtificial material induces a series of reactions leading to,mong others, the activation of the complement, essen-ially attributed to the activation of the alternative path-ays [8–10]. In our study, the TCC concentrations were

ignificantly higher in the two EC groups, confirmingxisting scientific evidence. However, the biomaterial isot the only cause of activation, since the classic pathwayan also be notably activated by the heparin-protamineomplex [11, 12], as well as the lectin pathway, activatedy the lipopolysaccharide [13], among others. The isch-mia-reperfusion activates the classic and the alternativeathways [14, 15] as well as other factors (blood transfu-ions, air-blood contact, surgical trauma) which alsoctivate the complement. This complement activationeads, in theory, to the inflammatory activation cascade.

In fact, some studies have demonstrated a relationshipetween activation of the complement and some inter-

eukins, such as IL-6, IL-8, IL-10, and tumor necrosisactor alpha (TNF�) [4, 16, 17]. However, in our study theoncentrations of IL-6 evolved similarly in the fourroups, while the complement activation was different.ur results are in agreement with other studies that doot show a direct relationship between IL-6 and IL-10nd the complement [13]. The IL-6 concentration is anmportant parameter reflecting the importance of theurgical trauma [18–20] because it is closely associatedith the development of complications, an unfavorable

volution for the patient, and the initiation of a systemicnflammatory reaction syndrome [20]. The IL-6 is a cen-ral mediator in the cytokines network and it plays aivotal role in modulating the inflammatory response

21, 22]. An overexpression of IL-6 is associated withorbidity and mortality of the trauma or infected pa-

ients [23, 24]. Of particular interest is the absence, in ourtudy, of a relationship between IL-6 and the activation ofhe complement suggesting that it is no longer the only or

ain factor stimulating the inflammatory reaction. More-ver, in beating heart surgery as compared with ECurgery, the IL-6 concentrations are lower only if theurgical approach is different or if the average number ofypasses and myocardial ischemia are also lower.In the same way, IL-8 could not be related to the

ctivation of the complement, which contradicts othertudies [16, 25]. There is no relation between the evolu-ion of IL-8 and IL-6, MPO, or elastase. This chemokine,nown to play a role in migration, activation, and che-otactism of the PMNs and T lymphocytes, is not only

roduced by the PMNs, but also by the monocytes,astocytes, endothelial cells, fibroblasts, and smoothuscle cells. The myocardium is a major source of IL-8

uring consecutive reperfusion after a long period ofschemia [26, 27], and in rabbits an injection of antibodynti-IL8 prevented the development of myocardial isch-

ave advanced the hypothesis that the type of procedurewith or without EC) influences the production of IL-8notably by means of the activation of the complement)nd thus myocardial complication is observed postoper-tively [4]. However, in this study the average number ofypasses in the beating heart group was significantly less

han in the EC group. Therefore, it is likely that theperative myocardial ischemia was less intense in theeating heart group. An inverse relationship hypothesisay be suggested: the production of IL8 depends, among

ther things, on the degree of operative myocardialschemia, which could explain the absence of a relation-hip between TCC and IL-8 in our study because theverage number of bypasses was similar in each of theour groups studied. This hypothesis is reinforced by thetudy of Struber and colleagues [29], who showed thatL-8 concentrations were lower in surgery where onlyne bypass was carried out by anterior thoracotomy asompared with an average of three bypasses for the ECroups in this study.In the present study, the MPO and the elastase con-

entration profiles, both demonstrating the activation ofMNs, were different. The evolution of the MPO concen-

ration was similar in the four groups while the elastaseas significantly higher in the two EC groups. A close

elationship between activation of the complement andlastase concentration has been previously described [30,1]. The activation of PMNs by C5a [29, 32] could explainhe direct relationship between TCC and elastase. Lastly,n addition to the PMNs, the production of elastase by the

astocytes and the monocytes, and of MPO by theacrophages, could also explain a difference in the

oncentrations of these two molecules.The PMN counts were not significantly different be-

ween the groups. However, a decrease in the count atime IV (injection of protamine) was observed for the twoeating heart groups, while they increased in the ECroups. Although this fall is often associated with he-odilution during EC, a relationship between the acti-

ation of the complement and the decrease of circulatingMNs has also been described. Even if the hemodilutionnd the activation of the complement are significantlyore important in the two EC groups, it is not associatedith a decrease in the PMN count. This suggests aossible role played by the treatment of SMA surface,erhaps through preservation of the platelet function asreviously described [6], and the interactions between

he platelets and the leukocytes or endothelial cells.Some surface treatments, like heparin-coated circuits,

re potentially able to reduce the activation of the com-lement [33]. In contrast, the SMA circuits used in ECeduce platelet activation and diminish the postoperativelood loss, but they do not affect the complement activa-

ion [17]. In our study, difference between complementctivation and the other inflammatory markers suggestshat if the activation of the complement’s alternativeathway by EC occurs, then other factors related toardiac surgery can also be involved. First, the comple-ent activation can also occur in beating heart surgery.

n cardiac surgery performed with EC, EC could maintain

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r even amplify the activation induced by surgery by themplification loop of the alternative pathway, throughxation of the complement on the protein layer adsorbedt the circuit luminal surface. In beating heart surgeryhis amplification could not happened, but the first stepsf this activation could induce a significant activation ofhe inflammatory cascade, notably by C3a and its effectn the PMNs, causing their degranulation. In a studyomparing pediatric cardiac surgery with and withoutC, Tarnok and colleagues [16] demonstrated a signifi-ant activation of the complement in the two groups withspecific activation of the alternative pathway by EC, butlso a significant production of C3d and C5a in the groupithout EC. In addition, the consumption of C3, C4, C5,

nd C1 inhibitor factors, already observed after thenduction of anesthesia, was similar for the two groups.n contrast, if some studies comparing heart bypassurgery with and without EC observe different comple-ent marker concentrations, some parameters are often

ifferent (shorter operating times, smaller number ofypasses, or minimal invasive access during off-pumpurgery) [34]. This could explain the differences regard-ess of whether or not EC was used. Finally, the globalnflammatory cascade is initiated, beside the comple-

ent activation, by several phenomena such as ischemia-eperfusion, tissue trauma, and others.

In conclusion, it is well-recognized in cardiac surgeryhat EC is associated with the activation of the comple-

ent, mainly by the alternative pathway. However, EC isrobably not the only factor involved. Even if the activa-

ion of the complement remains higher than in theff-pump groups, some markers reflecting inflammatoryeaction reach similar values to those observed in off-ump surgery. The protection of the platelet functionay explain this phenomenon if consideration is given to

he well-known interactions between leukocytes, endo-helial cells, and platelets in all inflammatory processes.

oreover, this study shows that the closed circuit with-ut pump suckers results in an additional advantage.herefore, additional studies, combining the markerssed in this study with others, are needed to determine

he real contribution of surgery and EC to the genesis ofhe inflammatory response and to the clinical outcomes.ne study could concern the comparison between off-ump surgery and a heparin-coated circuit, which havehown an impact on complement activation [33].

his study was supported by a grant from the “Fonds deecherche Clinique du CHU de Liège” and by COBE Cardio-ascular, a division of the Sorin Group.

eferences

1. Ascione R, Lloyd CT, Underwood MJ, Lotto AA, Pitsis AA,Angelini GD. Inflammatory response after coronary revas-cularization with or without cardiopulmonary bypass. AnnThorac Surg 2000;69:1198–204.

2. Matata BM, Sosnowski AW, Galinanes M. Off-pump bypass

3. Johansson-Synnergren M, Nilsson F, Bengtsson A, JeppssonA, Wiklund L. Off-pump CABG reduces complement acti-vation but does not significantly affect peripheral endothelialfunction: a prospective randomized study. Scand CardiovascJ 2004;38:53–8.

4. Wan S, Izzat MB, Lee TW, Wan IY, Tang NL, Yim AP.Avoiding cardiopulmonary bypass in multivessel CABGreduces cytokine response and myocardial injury. Ann Tho-rac Surg 1999;68:52–6.

5. Wan IY, Arifi AA, Wan S, et al. Beating heart revasculariza-tion with or without cardiopulmonary bypass: evaluation ofinflammatory response in a prospective randomized study.J Thorac Cardiovasc Surg 2004;127:1624–31.

6. Defraigne JO, Pincemail J, Dekoster G, et al. SMA circuitsreduce platelet consumption and platelet factor release dur-ing cardiac surgery. Ann Thorac Surg 2000;70:2075–81.

7. Royston D. High-dose aprotinin therapy: a review of the firstfive years’ experience. J Cardiothoracic Vasc Anesth 1992;6:76–100.

8. Chenoweth DE, Cooper SW, Hugli TE, Stewart RW, Black-stone EH, Kirklin JW. Complement activation during cardio-pulmonary bypass: evidence for generation of C3a and C5aanaphylatoxins. N Engl J Med 1981;304:497–503.

9. Seghaye MC, Duchateau J, Grabitz RG, et al. Complementactivation during cardiopulmonary bypass in infants andchildren. Relation to postoperative multiple system organfailure. J Thorac Cardiovasc Surg 1993;106:978–87.

0. Gupta-Bansal R, Parent JB, Brunden KR. Inhibition of com-plement alternative pathway function with anti-properdinmonoclonal antibodies. Mol Immunol 2000;37:191–201.

1. Kirklin JK, Chenoweth DE, Naftel DC, et al. Effects ofprotamine administration after cardiopulmonary bypass oncomplement, blood elements, and the hemodynamic state.Ann Thorac Surg 1986;41:193–9.

2. Cavarocchi NC, Schaff HV, Orszulak TA, Homburger HA,Schnell WA Jr, Pluth JR. Evidence for complement activationby protamine-heparin interaction after cardiopulmonary by-pass. Surgery 1985;98:525–31.

3. Fiane AE, Videm V, Lingaas PS, et al. Mechanism of com-plement activation and its role in the inflammatory responseafter thoracoabdominal aortic aneurysm repair. Circulation2003;108:849–56. Epub 2003 Aug 04. Available at http://circ.ahajournals.org/cgi/content/full/108/7/849.

4. Collard CD, Vakeva A, Morrissey MA, et al. Complementactivation after oxidative stress: role of the lectin comple-ment pathway. Am J Pathol 2000;156:1549–56.

5. Jordan JE, Montalto MC, Stahl G. Inhibition of mannose-binding lectin reduces postischemic myocardial reperfusioninjury. Circulation 2001;104:1413–8.

6. Tarnok A, Hambsch J, Emmrich F, et al. Complement acti-vation, cytokines, and adhesion molecules in children un-dergoing cardiac surgery with or without cardiopulmonarybypass. Pediatr Cardiol 1999;20:113–25.

7. Fransen E, Maessen J, Dentener M, Senden N, Geskes G,Buurman W. Systemic inflammation present in patientsundergoing CABG without extracorporeal circulation.Chest. 1998;113:1290–5.

8. Froon AH, Greve JW, Van der Linden CJ, Buurman WA.Increased concentrations of cytokines and adhesion mole-cules in patients after repair of abdominal aortic aneurysm.Eur J Surg 1996;162:287–96.

9. Kragsbjerg P, Holmberg H, Vikerfors T. Serum concentra-tions of interleukin-6, tumour necrosis factor-alpha, andC-reactive protein in patients undergoing major operations.Eur J Surg 1995;161:17–22.

0. Cruickshank AM, Fraser WD, Burns HJ, Van Damme J,Shenkin A. Response of serum interleukin-6 in patientsundergoing elective surgery of varying severity. Clin Sci(Lond) 1990;79:161–5.

1. Kopf M, Baumann H, Freer G, et al. Impaired immune andacute-phase responses in interleukin-6-deficient mice. Na-

TMiUdbw

2. Fattori E, Cappelletti M, Costa P, et al. Defective inflamma-tory response in interleukin 6-deficient mice. J Exp Med1994;180:1243–50.

3. Oldenburg HS, Rogy MA, Lazarus DD, et al. Cachexia andthe acute-phase protein response in inflammation are regu-lated by interleukin-6. Eur J Immunol 1993 ;23:1889–94.

4. Damas P, Ledoux D, Nys M, et al. Cytokine serum levelduring severe sepsis in human IL-6 as a marker of severity.Ann Surg 1992;215:356–62.

5. Brasil LA, Gomes WJ, Salomao R, Buffolo E. Inflammatoryresponse after myocardial revascularization with or withoutcardiopulmonary bypass. Ann Thorac Surg 1998l;66:56–9.

6. Oz MC, Liao H, Naka Y, et al. Ischemia-induced interleu-kin-8 release after human heart transplantation. A potentialrole for endothelial cells. Circulation 1995;92(suppl):II428–32.

7. Neumann FJ, Ott I, Gawaz M, et al. Cardiac release ofcytokines and inflammatory responses in acute myocardialinfarction. Circulation 1995;92:748–55.

8. Lefer AM, Johnson G III, Ma XL, Tsao PS, Thomas GR.Cardioprotective and endothelial protective effects of [Ala-IL8]77 in a rabbit model of myocardial ischaemia and reper-fusion. Br J Pharmacol 1991;103:1153–9.

9. Struber M, Cremer JT, Gohrbandt B, et al. Human cytokine

otice From the American Boa

written) examination.

2006 by The Society of Thoracic Surgeonsublished by Elsevier Inc

out cardiopulmonary bypass. Ann Thorac Surg 1999;68:1330–5.

0. Aldea GS, Soltow LO, Chandler WL, et al. Limitation ofthrombin generation, platelet activation, and inflammationby elimination of cardiotomy suction in patients undergoingcoronary artery bypass grafting treated with heparin-bonded circuits. J Thorac Cardiovasc Surg 2002;123:742–55.

1. Rinder CS, Rinder HM, Smith BR, et al. Blockade of C5a andC5b-9 generation inhibits leukocyte and platelet activationduring extracorporeal circulation. J Clin Invest 1995;96:1564–72.

2. Rinder CS, Rinder HM, Johnson K, et al. Role of C3 cleavagein monocyte activation during extracorporeal circulation.Circulation 1999;100:553–8.

3. Fosse E, Thelin S, Svennevig JL, et al. Duraflo II coating ofcardiopulmonary bypass circuits reduces complement acti-vation, but does not affect the release of granulocyte en-zymes: a European multicentre study. Eur J CardiothoracSurg 1997;11:320–7.

4. Gu YJ, Mariani MA, Boonstra PW, Grandjean JG, vanOeveren W. Complement activation in coronary artery by-pass grafting patients without cardiopulmonary bypass: therole of tissue injury by surgical incision. Chest 1999;116:

responses to coronary artery bypass grafting with and with- 892–8.

rd of Thoracic Surgery

he 2006 Part I (written) examination will be held ononday, December 4, 2006. It is planned that the exam-

nation will be given at multiple sites throughout thenited States using an electronic format. The closingate for registration is August 1, 2006. Those wishing toe considered for examination must apply online atww.abts.org.To be admissible to the Part II (oral) examination, a

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A candidate applying for admission to the certifyingxamination must fulfill all the requirements of the Boardn force at the time the application is received.

Please address all communications to the Americanoard of Thoracic Surgery, 6333 N St. Clair St, Suite 2320,hicago, IL 60611; telephone: (312) 202-5900; fax: (312)02-5960; e-mail: info@abts.org.

Ann Thorac Surg 2006;81:1690 • 0003-4975/06/$32.00

DOI: 10.1016/j.athoracsur.2005.11.059 2006;81:1683-1690 Ann Thorac Surg

Defraigne Janine M. Quaniers, Julie Leruth, Adelin Albert, Raymond R. Limet and Jean-Olivier

Surgery Using Surface Modifying Additives CircuitComparison of Inflammatory Responses After Off-Pump and On-Pump Coronary

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