Eur J Cardiothorac Surg 2006;29:699-702
© 2006 Elsevier Science NL
Comparison of the inflammatory response between miniaturized and standard CPB circuits in aortic valve surgery
Olivier M. Bical
a
,
*
,
Yves Fromes
a
,
Didier Gaillard
a
,
Marc Fischer
a
,
Olivier Ponzio
a
,
Philippe Deleuze
a
,
Marie-Françoise Gerhardt
b
,
François Trivin
b
a Department of Cardiac Surgery, Fondation Hôpital Saint-Joseph, 185 rue Raymond Losserand, 75674 Paris Cedex, France
b Department of Biochemistry, Fondation Hôpital Saint-Joseph, 185 rue Raymond Losserand, 75674 Paris Cedex, France
Received 21 July 2005;
received in revised form 26 December 2005;
accepted 31 January 2006.
* Corresponding author: Tel.: +33 144123376; fax: +33 144123383. (Email: ombical{at}hopital-saint-joseph.org).
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Abstract
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Objective: One of the complications of CPB is the systemic inflammatory response syndrome (SIRS). Recent developments tend to minimize the biological impact of CPB in using miniaturized closed circuit with reduced priming volume and less blood–air interface. The benefit of these miniaturized closed circuits in terms of inflammatory response has been proved in coronary surgery. However, in open heart surgery, the CPB circuit is no more closed and the benefit of the miniaturized set-up could disappear. The aim of the study is to compare the SIRS between standard and miniaturized circuits in aortic surgery. Methods: Forty patients who underwent singular aortic valve replacement were randomly assigned either to a standard CPB (group A, n
= 20) or to a miniaturized CPB (group B, n
= 20). Pertinent clinical and surgical data were collected. Hematological parameters (leukocyte and neutrophil counts) and biochemical parameters (C-reactive protein, cytokine tests) were determined pre-, on and post-CPB. Results: There were an increase in leukocyte and neutrophil counts and a decline in hematocrit in both groups. In both groups, there was a raise after CPB, in C-reactive protein, IL-6, TNF-
, neutrophil elastase, and IL-10. However, the raises of elastase and TNF- were significantly lower after the weaning of miniaturized CPB (116 ± 46 ng/ml and 10 ± 4 pg/ml, respectively) compared to standard CPB (265 ± 120 ng/ml, P
= 0.01 and 18 ± 7 pg/ml, P
= 0.03). The raise of IL-10 is also lower with miniaturized circuit (15 ± 6 pg/ml) compared to standard circuit (51 ± 26, P
= 0.004). Conclusions: This study demonstrates in aortic surgery, the lesser inflammatory response of a miniaturized CPB compared to a standard CPB. However, there is always some inflammation after CPB and a small bio-reactive free perfusion circuit is still to be found in open heart surgery.
Key Words: Cardio-pulmonary bypass • Inflammatory response • Aortic surgery • Cytokines
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1. Introduction
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Although the systemic inflammatory response syndrome (SIRS) is not an exclusive complication of cardio-pulmonary bypass (CPB), it is acknowledged that CPB is a major factor in SIRS apparition [1]. This inflammatory response may contribute to the development of postoperative complications, including respiratory failure, renal dysfunction, bleeding disorders, and multiple organ failure. Preventing these adverse inflammatory responses remains an important concern. The pathophysiology of SIRS is not completely known; it results in vascular injury and tissue damage by leukocyte–endothelial interactions mediated by cytokines and adhesion molecules [2]. The complex process of SIRS involves several protein families including pro-inflammatory cytokines (interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor- (TNF-)), adhesion molecules (i.e. sVCAM-1) and chemokines (i.e. PMN elastase) [2]. Other cytokine (IL-10) might have regulatory effects during the inflammatory process [3,4]. The assessment of the inflammatory state with CPB might be obtained by blood samples and measures in plasma of these inflammatory mediators.
During CPB, several attempts were made to reduce SIRS and endothelial cell activation as aprotinin use, heparin-coated circuit, suppression of pericardial aspiration, or modification of cardioplegia [5–7]. In coronary bypass surgery, we have previously shown that the use of a miniaturized closed CPB circuit (MECC® system, Jostra, France) can reduce systemic inflammation compared to standard CPB [8]. This advantage in the MECC® system could be explained by the reduced priming volume and by the limits of blood–air interfaces in a closed system. However, in open heart surgery like aortic valve replacement, a vent suction is needed and the advantage of the MECC® system could disappear with more blood–air interfaces in a circuit which is no more closed.
The aim of this study is to investigate in aortic valve surgery a modified set-up circuit of the MECC® system and to compare it to a standard circuit with regard to the systemic inflammatory process, in an attempt to obtain better postoperative biologic profile and clinical results.
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2. Materials and methods
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Between December 2002 and December 2003, this prospectively controlled randomized study enrolled 40 patients who were undergoing aortic valve replacement. Exclusion criteria were redo surgery and additional procedures to aortic valve replacement. They were randomly assigned to either standard CPB (group A, n
= 20) or to miniaturized CPB (group B, n
= 20). The protocol was accepted by the local ethical committee and all patients gave informed consent.
The standard CPB circuit (group A) consists of a membrane oxygenator (CML DUO®, Cobe, France), and a cardiotomy reservoir. Coating of the tubing was based on copolymer surface—modified (SMARTxT®, Cobe). The venous drainage was by gravity and the roller pump (Stoeckert, France) allows a non-pulsatile flow.
The miniaturized CPB circuit (group B) consists of the MECC® system (Jostra) with a membrane oxygenator and an arterial filter. The tubing was heparin coated (BIOLINE®, Jostra). The venous line is directly connected to a centrifugal pump without open venous reservoir which limitates the blood–air interfaces and allows reduced priming volume. At this set-up was added a small cardiotomy reservoir (Jostra) to collect only the blood return from the vent.
In both groups, the cannulas used were the same, non-coated, and the vent was implanted into the main pulmonary artery trunk. In both groups, the blood from pleuro-pericardial space was exclusively collected in a cell saving device. After the skin closure, this blood was centrifuged, washed in Ringer's lactate solution, recentrifugated and returned to the patient. All patients received 300 UI/kg bovine heparin infused intravenously before onset of CPB and anticoagulation was monitored by ACT measures with a Hemochron system. At the end of CPB, intravenous application of protamine sulfate in a 1/1 ratio of the initial dose of heparin served to antagonize heparin effects. No antifibrinolytic medications were used in both groups. Myocardial protection was accomplished using antegrade intermittent warm blood cardioplegia in both groups with an initial dose of 30 ml/kg repeated every 20 min. The operations were performed under tepid temperature (35 °C). The use of intra- and postoperative medications did not differ between the two groups.
2.1 Clinical and biological variables
Patient demographic data and medical history were collected prospectively, as well as the postoperative course including CPB time, aortic cross-clamp time, routine biochemical tests, and hematological test according to the usual practice of our department. Venous blood samples (10 ml) were obtained preoperatively and each day during 4 days to measure leukocytes, neutrophils, and C-reactive protein. Blood samples (10 ml) for measuring IL-1ß, IL-6, IL-10, soluble VCAM-1 (sVCAM-1), TNF-, and neutrophil elastase were obtained from the venous line of the patient at the following times: at induction of anesthesia (T1), after initiation of CPB (T2), at the end of CPB (T3), and after weaning of the CPB (T4); further samples were collected 6 h (T5) and 24 h (T6) after the end of the CPB.
The cytokine release (IL-1ß, IL-6, IL-10, TNF-) was evaluated by chemiluminescent immunometric assay (DPC) with the following minimum detectable dose: 5 pg/ml (IL-1ß), 2 pg/ml (IL-6), 5 pg/ml (IL-10), and 4 pg/ml (TNF-). The release of neutrophil elastase was investigated by an ELISA immunoassay kit with lower detection limit of 3 ng/ml (MedSystems Diagnostics Gmbh). Among the markers of endothelial activation, the soluble adhesion molecule, sVCAM was measured with a quantitative sandwich enzyme immunoassay with a sensitivity of 0.6 ng/ml (R&D Systems). C-reactive protein was measured using a nephelometric method (BN Prospec analyzer, Dade Behring).
As in other studies on SIRS during CPB, the biologic values were not corrected for hemodilution [8,9].
2.2 Statistical analysis
Data were processed with Statview software (Abacus Concepts Inc., Berkeley, CA, USA). All data were expressed as mean with one standard deviation. Intergroup comparison was performed with the Mann–Whitney test for unpaired data. Intragroup comparison was done using the Wilcoxon test for paired data. Normally distributed values between groups were compared by the Student's t-test or in case of repeated measurements over the time by analysis of variance (ANOVA) for repeated measures. Non-normally distributed data were compared either with the Fisher's exact test or the Mann–Whitney U-test with Bonferroni correction.
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3. Results
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Clinical characteristics and operative details are summarized in Table 1
. All patients tolerated the surgical procedure in particular with regard to the CPB techniques and survived without significant complications related to the study. In both groups, there were no rethoracotomy for any reasons, no infectious complications and the patients received neither homologous nor red blood cell products. Significant differences appear only in relation to the types of CPB as the priming volume is reduced in the group B compared to the group A (Table 1). Leukocyte and neutrophil counts were similar in all patients prior to surgery and postoperative course and displayed a parallel rise peaking at day 2 (data not shown). C-reactive protein levels were identical in both groups preoperatively (5 ± 3 mg/l). After CPB, C-reactive protein levels were significantly elevated in group A and in group B, at day 1 (81 ± 30 mg/l and 97 ± 45 mg/l), at day 2 (181 ± 65 mg/l and 184 ± 46 mg/l), at day 3 (196 ± 78 mg/l and 170 ± 55 mg/l) and at day 4 (154 ± 83 mg/l and 151 ± 46 mg/l). However, at these different time points no significant differences appeared between the two groups. The levels of IL-1ß did not change at the different times in the two groups (data not shown). The levels of IL-6 followed a raise peaking 6 h after CPB without any significant differences between the two groups (Fig. 1
). Elastase levels increased and reached its peak after weaning of CPB with significant differences between the two groups (Fig. 2
). At this time, the levels are lower in the group B (116 ± 46 ng/ml) compared to group A (265 ± 120 ng/ml, P
= 0.01). The levels of TNF- were also significantly lower after weaning of CPB in group B (10 ± 4 pg/ml) compared to group A (18 ± 7 pg/ml, P
= 0.03) (Fig. 3
). The levels of IL-10 were lower at any time in group B compared to group A with a statistical difference after weaning of CPB (15 ± 6 pg/ml vs 51 ± 26 pg/ml, P
= 0.004) (Fig. 4
). No significant differences in plasma levels of sVCAM-1 could be measured in either group at any time point (data not shown).
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Table 1. Clinical characteristics of patients and operative details comparing standard CPB (group A) and miniaturized CPB (group B)
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Fig. 1. IL-6 levels (pg/ml) at different times with a standard CPB (group A) and with a miniaturized CPB by MECC® system (group B). T1 at induction of anesthesia, T2 after initiation of CPB, T3 at the end of CPB, T4 after weaning of CPB, T5 6 h after CPB, T6 24 h after the CPB.
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Fig. 2. Elastase levels (ng/ml) at different times with a standard CPB (group A) and with a miniaturized CPB by MECC® system (group B). T1 at induction of anesthesia, T2 after initiation of CPB, T3 at the end of CPB, T4 after weaning of CPB, T5 6 h after CPB, T6 24 h after the CPB; *
P
= 0.01.
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Fig. 3. TNF- levels (pg/ml) at different times with a standard CPB (group A) and with a miniaturized CPB by MECC® system (group B). T1 at induction of anesthesia, T2 after initiation of CPB, T3 at the end of CPB, T4 after weaning of CPB, T5 6 h after CPB, T6 24 h after the CPB;
*
P
= 0.03.
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Fig. 4. IL-10 levels (pg/ml) at different times with a standard CPB (group A) and with a miniaturized CPB by MECC® system (group B). T1 at induction of anesthesia, T2 after initiation of CPB, T3 at the end of CPB, T4 after weaning of CPB, T5 6 h after CPB, T6 24 h after the CPB; *
P
= 0.004.
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4. Discussion
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The SIRS is not an exclusive complication of CPB but CPB remains a major factor in SIRS apparition [1,2]. Several attempts were made to reduce SIRS during CPB and miniaturized closed circuits are one of these attempts because they minimize the most hazardous CPB drawbacks, e.g. hemodilution, and blood–air contact. These efforts have led to the development of the MECC® which is a miniaturized closed system. The first clinical development was introduced for CABG procedures in University Hospital of Regensburg in Germany. Later, we have shown that in coronary bypass surgery, the MECC® system, used as a total CPB, reduces SIRS compared to standard circuit [8]. However, in open heart surgery like aortic valve surgery, a vent is needed and the advantage of the MECC® system could disappeared as the closed system is modified in a semi-closed one with more blood–air contacts. Our data indicated that in aortic valve surgery, the miniaturized CPB with the MECC® system is still associated with lesser inflammation response than the standard CPB circuit.
The biological values were not corrected for hemodilution as organ function and postoperative complications appear to depend first on actual effective concentrations [9]. The IL-1 levels did not display variations at any time of observation, which confirms that the secretion of this cytokine is not stimulated by CPB [8]. C-reactive protein and IL-6 are known to be sensitive indicators of inflammation in the acute phase reaction [10,11]. In our study, C-reactive protein concentrations and IL-6 levels increased in all patients during CPB with no differences between the two groups. This is in correlation with the nondifferent C-reactive protein and IL-6 elevations in patients who underwent CABG with CPB or without the use of CPB [9,12]. These markers seem mainly activated by the surgical procedure and not by the CPB and they do not seem valid markers to analyze the SIRS after CPB procedures.
The TNF- and elastase seem more sensitive markers for systemic inflammation secondary to CPB [13,14]. In our previous study, the TNF- release and elastase release were lower with the MECC® system compared to the standard circuit [8]. In aortic surgery, we confirm these results in spite of more blood–air interfaces in the set-up used than in the set-up for coronary surgery.
The IL-10 is a potent anti-inflammatory molecule, which acts by inhibiting the synthesis of pro-inflammatory cytokines. The IL-10 synthesis like others down-regulation molecules of inflammatory response is activated in different stress conditions [15]. In our study, the IL-10 release shows a significant decrease when the miniaturized MECC® system is used compared to the standard circuit. This could be explained by the lower level of systemic inflammatory response with the MECC system and by a need of less anti-inflammatory action.
Soluble forms of adhesion molecules may serve as markers of endothelial activation or damage [16]. We did not observe significant differences between the standard and the MECC® circuits. This could confirm the fact that active venous drainage used in the MECC® set-up does not induce greater endothelial damage than passive drainage as used in the standard CPB.
In as much as the pathophysiology of SIRS after CPB appears to be multifactorial, it is unlikely that a single intervention could achieve the desired goal of reducing it. Miniaturized CPB system appears to be a possible solution towards this aim. It is observed with a closed system in coronary surgery and in our study, with a semi-closed system in aortic surgery.
The limitations of our study on inflammation after CPB are due to the relatively small number of patients in each group. With more patients, the statistical analysis of results might be easier. However, the clinical studies are difficult to organize and are expensive. The limitations of these studies seem more due to the sensibility and specificity of the markers used to quantify SIRS after CPB. Probably other products of complement activation have to be chosen as markers in next studies on CPB, for example, IL-8 which seems more specific of cardiac surgery stress [11].
In conclusion, efforts to minimize deleterious CPB effects during the perioperative period are more attractive and achievable target that could produce more immediate clinical benefits. In cardiac surgery, patients are vulnerable to many forms of injury during and immediately after operation, and the limitation of inflammatory response is an important step in healing. Miniaturized CPB systems in open heart surgery appear to limit inflammatory response but a small bio-reactive free perfusion circuit is still to be found.
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Acknowledgments
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This work was partially supported by a grant of the association "La Renaissance". The authors thank Mrs Danièle Paumier for her assistance in proofreading biochemical data and all the discussions.
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Abstract
1. Introduction
