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Ann Thorac Surg 2000;69:1084-1091
© 2000 The Society of Thoracic Surgeons
a Department of Cardiovascular Surgery and Centre de Recherche du Département de Chirurgie, University Hospital of Liège, Liège, Belgium
b Department of Anesthesiology, University Hospital of Liège, Liège, Belgium
Address reprint requests to Dr Defraigne, Department of Cardiovascular Surgery, C.H.U. Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, Belgium
e-mail: jo.defraigne{at}chu.ulg.ac.be
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Abstract |
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Methods. Two hundred patients undergoing cardiac surgery were randomized in four groups of 50 patients each: heparin-coated circuit with aprotinin (HCO-A) or without aprotinin (HCO) administration, and uncoated circuit with aprotinin (C-A) or without aprotinin administration (C). In groups receiving aprotinin, a high-dose regimen was given. In all groups, high initial doses of heparin were used (3 mg/kg intravenously). Tumor necrosis factor-
(TNF-), interleukin-6 (IL-6) and IL-8, and myeloperoxidase and elastase levels were measured in plasma samples taken before, during, and after CPB.
Results. In all groups, the TNF-, IL-6, and IL-8 levels reached a maximum after protamine administration. After 24 hours, they remained significantly elevated (IL-6 and IL-8) or returned to baseline values (TNF-). A similar pattern was observed with myeloperoxidase and elastase levels. No significant intergroup differences were observed.
Conclusions. CPB is associated with cytokine release and neutrophil activation, which are not attenuated by the use of heparin-coated circuits or by the administration of aprotinin. Aprotinin and heparin-coated circuits do not show additive effects.
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Introduction |
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(TNF-) [2, 3], interleukin-1 (IL-1) [4], IL-2 [3, 5], IL-6 [2, 3, 5], and IL-8 [6] have been reported during and after CPB, preceded by release of complement split products C3a and C5a. These data suggest that cytokines may serve as markers of the intense inflammatory processes associated with CPB. Some studies suggested that the use of heparin-coated circuits might attenuate the intensity of the inflammatory reaction with respect to cytokine release and neutrophil activation [7–10]. Unfortunately, these preliminary studies were performed on a small number of patients and other studies failed to confirm these results [11]. Thus, larger clinical studies appear to be required.
Aside from changes in design and structure of the bypass circuits, pharmacologic interventions have also been tested. Besides its well-known protective effects on platelets and its antifibrinolytic actions, some antiinflammatory properties have been recently attributed to aprotinin [12, 13]. This serine protease inhibitor could be able to blunt the release of TNF- occurring during CPB [14–17]. Other suggested actions of aprotinin include prevention of upregulation of neutrophil CD11b integrin necessary for neutrophil adherence and degranulation, suppression of the plasma increases of the proinflammatory cytokines IL-6 and IL-8, and enhancement of the release of the antiinflammatory cytokine IL-10 [12].
To our knowledge, the potential additive effects on cytokine release of heparin-coated circuits and of aprotinin therapy have never been examined. The present work was undertaken to document in a large cohort of patients submitted to CPB both the effect of heparin-coated circuits and of aprotinin on the release of cytokines and on granulocytes activation.
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Anesthesia
Induction was performed with etomidate (0.2 mg/kg, Hypnomidate; Janssen Phamaceutica, Beerse, Belgium), sufentanyl (0.5 µg/kg, Sufenta; Janssen Phamaceutica), midazolam (0.1 mg/kg, Dormicum; Hoffmann-La Roche, Grenzach, Germany), and pancuronium (0.1 mg/kg, Pavulon; Organon, Oss, The Netherlands). Electrocardiogram, invasive arterial blood pressure, central venous and pulmonary arterial pressures, urinary output, and rectal and esophageal temperatures were monitored in each groups. Anesthesia was maintained with sufentanyl (3 to 4 µg/kg/h), midazolam (0.2 mg/kg), and pancuronium (if necessary). Cefuroxime (1.5 g, Cefacidal; Bristol-Myers-Squibb, Sermoneta, Italy) was given intravenously before sternotomy as prophylaxis against infection. After endotracheal intubation, patients were ventilated to normocapnia using a mixture of oxygen and air. In patients receiving aprotinin, high doses of aprotinin (Trasylol; Bayer, Leverkusen, Germany) were used (one bolus intravenously of 2 x 106 U before surgery and 2 x 106 U in the prime solution followed by intravenous administration of 500 x 103 U/h). Before connection of the extracorporeal circuit for CPB, heparin (300 IU/kg, Heparin Leo; Leo Pharmaceutical Products BV, Weesp, The Netherlands) was administered to achieve an activated coagulation time (ACT) (Hemochron 400; International Technidyne Corp, Edison, NJ) greater than 480 seconds in the groups not receiving aprotinin and greater than 800 seconds in the groups receiving aprotinin.
Cardiopulmonary bypass
The extracorporeal circuit (Baxter Healthcare Corp, Irvine, CA) consisted of a hard-shell venous reservoir (BMR-1500; Bentley/Baxter), a roller pump (Cobe Laboratoires, Gloucester, England), a hollow-fiber membrane oxygenator (Univox; Bentley/Baxter), a prebypass filter (Pall, Gloucester, England), an arterial filter (Sentry, Cobe), a cardiotomy reservoir (BCR-3500; Bentley/Baxter), and polyvinyl tubings (Bentley Bypass 65 tubing; Bentley/Baxter). In the heparin-coating groups, all parts of the extracorporeal circuits were passively coated with heparin (Duraflo II; Baxter Healthcare Corp). The standard priming of the extracorporeal circuit was 2,000 mL of gelatin (Gelofusin; Braun Medical, Emmenbrück, Switzerland) or blood depending on the expected hematocrit with addition of 5,000 IU of heparin sodium and 100 to 150 cc mannitol 20%. The standard perfusion protocol aimed at a hematocrit of 18% to 20% during CPB.
A standard cannulation technique was used with a cannula in the ascending aorta (ARL2211; Research Medical, Midvale, UT) and a cannula in the right atrium (two-stage venous cannula) (PWR3651; Research Medical), except for mitral valve surgery, where a double venous cannulation was used. The left ventricle was vented with a cannula introduced through the right upper pulmonary vein (TF020L; Research Medical), except in case of mitral valve surgery. Moderate systemic hypothermia (32°C) or normothermia in some cases were used. Nonpulsatile extracorporeal circulation was initiated at a target flow rate of 2.4 L/m2/min. Venous and arterial gas were monitored (SatCrit; Cobe, on the venous side, and CDI 400; 3M Health Care, Minneapolis, MN, on the arterial side). The flow was not corrected according to temperature but the index was sometimes increased to maintain the arterial pO2 at 160 to 180 mm Hg and the pCO2 at 40 mm Hg. Base excess was not corrected until pH 7.2. After aortic cross-clamping, a single dose of approximately 800 mL (600 to 1,000 mL) of cold (4°C) high-potassium crystalloid cardioplegia (St. Thomas Hospital No. 1 cardioplegic solution) was infused into the aortic root (and in some cases through retrograde sinus cannula) to provide myocardial preservation. Topic pericardial cooling was used during the infusion of the cardioplegic solution. During CPB, additional heparin was administered if the ACT was lower than 400 seconds in the groups without aprotinin administration and lower than 800 seconds in the groups receiving aprotinin. Extracorporeal circulation was terminated at an esophageal temperature of 37°C. After CPB was completed, heparin was neutralized with protamine sulfate (1 mg/100 IU heparin). During the operation, except during CPB where pump suction was used, all shed blood was retrieved with a blood recovery system (Cell Saver; Haemonetics Inc, Braintree, MA). After termination of the CPB, the residual volume in the perfusion circuit was collected and returned to the patient.
Plasma samples
Venous blood samples for estimation of cytokine levels, myeloperoxydase, and elastase were drawn on four occasions: after the induction of anesthesia (T1), 5 minutes after aorta unclamping (T2), after protamine administration (T3), and 24 hours after protamine administration (T4). Blood was collected in sterile evacuation blood collection tubes containing ethylenediaminetetraacetic acid as anticoagulant. Plasma was separated from blood cells by centrifugation at 3,000 g for 10 minutes at 4°C and stored at -70°C until analysis.
Cytokines assay technique
TNF-, IL-6, and IL-8 in plasma were analyzed by "sandwich" solid-phase enzyme-amplified sensitivity immunoassay performed on a microtiter plate (MEDGENIX-EASIA; BioSource Europe S.A., Fleurus, Belgium). Antigen captured by an oligoclonal system (monoclonal antibodies [mAbs]) directed against distinct epitopes of TNF-, Il-6, or IL-8 was used. Briefly, standards or samples containing TNF-, IL-6, or IL-8 reacted with capture mAbs (mAbs1) coated on the microtiter plate and with a mAb (mAbs2) labeled with horseradish peroxidase (HRP). Bound enzyme-labeled antibodies were measured through a chromogenic reaction. The amount of substrate turnover was determined colorimetrically by measuring the absorbance that was proportional to the cytokine concentration. A standard curve for each cytokine was plotted, and the TNF-, IL-6, and IL-8 concentration in a sample was determined by interpolation from the respective standard curve. The use of the enzyme-amplified sensitivity immunoassay (EASIA) Reader (linearity up to 3 OD units) and a sophisticated data reduction method (polychromatic data reduction) resulted in high sensitivity in the low range and in an extended standard range.
The minimum detectable concentrations for TNF-, IL-6, and IL-8 were, respectively, 3, 2, and 0.7 pg/mL.
Myeloperoxidase (MPO)
MPO was measured by a commercially available "sandwich" enzyme-linked immunosorbent assay kit (Bioxitech MPO-EIA; Oxis International, Portland, OR). Antigen captured by a solid-phase mAb was detected with a biotin-labeled goat polyclonal anti-MPO. An avidine alkaline phosphatase conjugate then binds to the biotinylated antibody. The alkaline phospahatase substrate p-nitrophenyl-phosphate (pNPP) is added, and the yellow product (p-nitrophenol) was monitored at 405 nm and compared with a standard curve. The standard curve was obtained by plotting point-to-point the absorbance values at 405 nm as a function of the logarithm of standard MPO concentration. The detection limit of the assay was 1.5 ng/mL.
Elastase
Elastase was determined by a commercially available immunoassay (Ecoline PMN elastase; Merck, Darmstadt, Germany). In this method, latex particles were coated with antibody fragments F(ab')2 against human neutrophil elastase. If neutrophil elastase-1-proteinase inhibitor complex was present in the test sample, the latex particles agglutinated and the turbidity in the reaction vessel intensified. The change in turbidity was measured photometrically by a Merck MEGA photometer. The extent of the turbidity was proportional to the elastase concentration present in the sample. The detection limit of the assay was 4 ng/mL.
At each sampling point, values of cytokine levels, myeloperoxidase, and elastase were corrected for hemodilution on the basis of hematocrit changes (Technicon H2; Bayer, Leverkusen, Germany).
Clinical data
Postoperative chest drainage volume and amounts of transfused blood products were analyzed.
Data analysis and statistics
The results were expressed as mean ± standard error (SEM). The Student’s t test and the F test for paired sample and unpaired samples were used for statistical analysis of differences between prebypass values and different time points within one group or of differences between groups at the same time points. Data not normally distributed were analyzed using the Mann-Whitney or Wilcoxon tests. Categorical variables were analyzed using a 
2 test. A p value less than 0.05 was considered to indicate a statistically significant difference between measured values.
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plasma concentration are represented in Figure 2. In all groups, circulating levels of TNF- were significantly increased 5 minutes after aorta unclamping (T2) when compared with prebypass levels (fourfold increase, p < 0.001). A more marked increase was observed after protamine administration (sixfold increase, p < 0.001). Twenty-four hours after CPB, the TNF- levels returned to control value but remained significantly elevated when compared with the prebypass values (p < 0.05). No significant intergroup differences were observed at any sampling time, and the pattern of the increase was similar in all groups.
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Comment |
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, and stimulates neutrophil adhesion and degranulation [1].
In the present study, cytokine production and neutrophil activation were observed. The plasma levels of TNF-, IL-6, IL-8, MPO, and elastase increased dramatically during the CPB and remained significantly elevated 24 hours later. Our results with IL-6 and IL-8 are fully in agreement with previous literature reports, where a time-dependent increase in IL-6 and/or IL-8 levels was consistently found during and after CPB [7, 9, 10], with persistent levels after 24 hours correlating with the durations of CPB or cross-clamping [5]. IL-6 is produced by a variety of cell types and is considered as the main inducer of the acute phase injury, preceding release of acute phase proteins, and serves as a promoter of CPB-associated inflammation. IL-8 is a powerful chemoattractant protein for neutrophils, and its serum levels of IL-8 are considered as a marker for the severity of tissue damage, with prognostic value, as in the septic shock [16]. IL-8 regulates the degree of neutrophil-mediated injury, thus giving it a potentially major role in the tissue damage experienced during CPB [6] and in lung injury during acute respiratory distress syndrome (ARDS) [16].
Reports concerning levels of TNF- during CPB are inconsistent. Our observation agrees with some previous reports [2, 7], but contrasts with other reports showing no or a very modest increase in TNF- levels [5] or only detecting trace amounts of TNF- [9, 19]. These differences may perhaps be explained by several factors such as the magnitude of surgical stress, the length of CPB, the variable levels of TNF--soluble receptors scavenging TNF-, a downregulation by prostaglandins E2, or by differences in the assay method. In our study, a sandwich method was used for TNF- measurement, with a low threshold of detection (3 pg/mL). In addition, because a rise in IL-8 is generally preceded by a TNF- release, it remains elusive why in studies where the levels of TNF- did not change, increased levels of IL-6 and IL-8 were reported [5, 20].
Because of suggested positive correlations between cytokine levels and the incidence of post-CPB complications [5], a variety of technical and pharmacological approaches has been attempted to attenuate this response. The present study was designed to evaluate both the effects of heparin-coated extracorporeal bypass circuits and of aprotinin administration on the CPB-associated inflammatory parameters. Compared with uncoated circuits, reduction of complement split products levels has been reported with heparin-coated circuits, which might reduce the inflammatory process during CPB through an inhibitory effect on the complement system [20].
As shown in Figures 2, 3, and 4, we were not able to demonstrate a beneficial effect of heparin-coated circuits on cytokines release, because at each sampling time, no significant differences with the standard uncoated circuit were observed in the TNF-, IL-6, and IL-8 plasma levels. Because each group had similar intraoperative characteristics, eventual differences in duration of bypass, central core temperature, cross-clamp times, or procedure done did not affect the results. Several reports, however, mentioned that heparin-coated circuits blunted the increases in TNF-, IL-6, or IL-8 levels (although significant increases were noted) [7, 9, 21], or simply delayed them without complete prevention [20]. Such differences may perhaps partly result from the number of patients investigated. These previous studies were performed in small samples sizes (varying from 6 to 15 patients), exhibiting borderline significance levels and high standard errors. Additionally, in one study [20], the maximum levels of IL-6 and IL-8 reported in the control group were considerably higher than those in our patients (1,500 pg/mL for IL-6 and 600 ng/mL for IL-8 vs for 450 pg/mL for IL-6 and 90 pg/mL for IL-8 in the present report). Due to marked patient response to CPB, larger clinical studies are needed to clarify the situation, as stated by some authors [11, 22]. Our work on 50 patients in each group attempted to fill this gap and to obtain more accurate data.
Likewise, we did not observe a reduction in granulocyte activation with heparin-coated circuits, although previous reports have reported less neutrophil enzyme release with heparin coating [7, 8, 10]. Once again, differences in patient population size may have influenced the results, because these studies were also performed on small patient populations. As an illustration, in their first study, Fosse and colleagues [8] reported less neutrophil activation with heparin coating whereas in their multicentric study, which included a more significant number of patients (75 in each group), as in the present study, the same authors did not observe a beneficial effect of heparin coating on myeloperoxidase and lactoferrin release [22]. Our results are close to those of Muehrcke and associates [11], who did not shown any benefit of heparin-coated circuits on neutrophil activation in patients undergoing reoperations for coronary or valvular surgery. In our study, the same high heparin levels used in all groups may also have contributed to the lack of effect of heparin-coated circuits. In fact, Ovrum and associates [23] showed that granulocytes activation in patients receiving heparin-coated circuits was attenuated only when a low systemic heparin dose was given. Finally, biomaterial-independent stimulation of the biological cascades still does exist, which may overwhelm any biomaterial-dependent mitigating properties of heparin coating. For example, cardiotomy suction of the pericardial shed blood with return to the patient [11], noncoated arterial filters (as in the present study), consequences of cardiac and lung reperfusions after unclamping, and length of CPB are multifactorial factors that may stimulate the various humoral and cell activations. As an example, IL-6 production is not specific to CPB and has been shown to be present after other major operations.
Aprotinin is a serine protease inhibitor, with well-known antifibrinolytic and platelet-protective actions that are demonstrated by our results concerning blood loss. Many of the various inflammatory cascades activated during CPB are enzyme mediated involving serine protease, like the complement and the kinin-kallikrein cascades. In vitro, aprotinin inhibits not only plasmin, but also kallikrein, neutral lysosomal proteins, elastase, and cathepsin G, the degranulation by-products of neutrophils [19]. Additionnally, TNF- synthesized initially as a membrane-bound precursor is then cleaved to yield soluble TNF-. This cleavage activity and secretion is partially inhibited by serine protease inhibitors, which makes possible their role in the regulation of TNF- production, thus suppressing a stimulus for the cytokine cascade [13]. In this perspective, Sawa and associates [24] showed a reduction in plasma levels of IL-6 and IL-8 in patients receiving nafasmostat mesilate, a serin protease inhibitor inhibiting the complement.
In our study, a high-dose regimen of aprotinin failed to inhibit cytokine production and neutrophil activation. In contrast, in clinical CPB, some studies suggested that aprotinin could have effects similar to those of glucocorticoids, such as reduction of the TNF- [14] or IL-6 plasma levels [15, 25] and increased production of IL-10, an antiinflammatory cytokine that suppresses the production of virtually all proinflammatory cytokines as well as its own production. Only high-dose regimens of aprotinin were effective, whereas low-doses were inefficient [25, 26]. Once again, this difference between our results and those of previous reports may be partly explained by differences in the patient population sizes. In addition, results with aprotinin do not appear always consistent and concordant. For example, in the study of Soepawarta and associates [27], in vitro activation of granulocytes isolated from the patients undergoing CPB, was reduced when aprotinin was added to the cell medium. However, these patients received aprotinin from the start of the procedure, and the plasma levels of IL-8 increased continuously during the procedure and were of the same magnitude as in our study.
In conclusion, our study confirms that CPB procedure is associated with a strong inflammatory response, as evidenced by significant increases in cytokine levels and neutrophil enzyme release. Neither the use of heparin-coated circuits nor the administration of a high-dose regimen of aprotinin prevented or attenuated cytokine production and neutrophil activation. Because multiple avenues are present to elicit the post-CPB inflammatory response, further research seems necessary to determine the best strategy for its prevention.
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during cardiopulmonary bypass. Acta Anesthesiol Scand 1996;40:311-317.[Medline]
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