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Ann Thorac Surg 1998;65:480-484
© 1998 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Inflammatory Mediators in Adults Undergoing Cardiopulmonary Bypass: Comparison of Centrifugal and Roller Pumps

Cardiothoracic Department, Killingbeck Hospital, Leeds, United Kingdom

Accepted for publication August 20, 1997.

Dr Ashraf, Cardiothoracic Surgery, Leeds General Infirmary, Great George St, Leeds, UK, LS1 3UQ.

	Abstract

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. The nonocclusive centrifugal pump is used for cardiopulmonary bypass (CPB) and mechanical cardiac assistance. This study examined its impact on proinflammatory cytokine release.

Methods. Forty-one patients undergoing elective coronary artery bypass grafting were randomized prospectively to either a standard roller pump group (n = 21) or a centrifugal vortex pump group (n = 20) for CPB. The two groups were well matched in age, sex, severity of disease, and duration of CPB and aortic cross-clamping. Plasma levels of the cytokines tumor necrosis factor-, interleukin-1ß, interleukin-6, and interleukin-8, as well as terminal complement, neutrophil counts, and leukocyte elastase, were analyzed before, during, and after CPB.

Results. In both groups, traces of tumor necrosis factor- were observed infrequently and interleukin-1ß was not detected. Plasma levels of interleukin-6 and interleukin-8 increased during and after CPB, reaching a peak at 2 hours after protamine administration in both groups before returning toward baseline at 24 hours. The release of interleukin-6 was significantly greater in the centrifugal group (p < 0.05), whereas the interleukin-8 concentration did not differ between the groups throughout the study period. Levels of terminal complement increased in both groups perioperatively, reaching a peak 30 minutes after protamine administration, whereas neutrophil counts and elastase peaked 2 hours after protamine administration. Plasma terminal complement, neutrophil counts, and elastase release were significantly higher in the centrifugal group (p < 0.05). Peak terminal complement correlated (r = 0.64, p < 0.01) with peak elastase in the centrifugal group only.

Conclusions. This study confirms the proinflammatory nature of CPB in adults and demonstrates that use of the centrifugal pump induces a greater systemic inflammatory response than use of the standard roller pump.

	Introduction

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
The systemic inflammatory response that occurs to a varying extent in all patients after cardiopulmonary bypass (CPB) continues to be a significant cause of morbidity and occasional mortality. Postoperative bleeding, infection, systemic organ dysfunction, and acute respiratory distress syndrome are complications characteristic of CPB with the occurrence of a "whole-body inflammatory reaction" [1] [2]. Several studies have shown that this involves complement activation, neutrophil degranulation, and free radical production, together with cytokine release, leading to an increase in capillary permeability, the accumulation of interstitial fluid, and organ dysfunction [3] [4] [5].

Proinflammatory cytokines are potent intercellular signaling molecules and, particularly when produced in excess, potential mediators of vascular injury and organ dysfunction [2] [3] [4] [5]. Reports on the release of tumor necrosis factor- (TNF-) and interleukin-1ß (IL-1ß) in response to CPB have been inconsistent [3] [6] [7] [8] [9] [10]. Plasma levels of the cytokines interleukin-6 (IL-6) and interleukin-8 (IL-8) are elevated after CPB and may be associated with post-CPB cardiac dysfunction [5]. It has been proposed that if cytokine release could be reduced during CPB, some of the hazardous clinical effects of CPB might be avoided.

Both roller and centrifugal pumps are used in extracorporeal circuits. The intrinsic safety features of centrifugal pumps contribute to their widespread use for long-term extracorporeal support as well as for routine cardiac operations [11] [12]. Studies have shown beneficial effects of the centrifugal pump over the roller pump in terms of reduced hemolysis, reduced neutrophil and complement activation, and improved platelet preservation [11] [12] [13] [14]. The aim of this prospective, randomized study was to evaluate the systemic inflammatory profiles associated with the use of the standard roller pump and the centrifugal vortex pump in adult patients undergoing elective coronary artery bypass grafting.

	Material and Methods

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
After ethical committee approval and informed consent were obtained, 41 patients undergoing coronary artery bypass grafting were randomized to either a standard roller pump group (n = 21) or a nonocclusive centrifugal pump group (n = 20) for CPB. All patients had effort-induced angina pectoris refractory to maximal antianginal therapy, multivessel coronary artery disease (>70% vessel occlusion), and an ejection fraction of greater than 0.40. Exclusion criteria were unstable angina, myocardial infarction within the previous 3 months, reoperation, diabetes mellitus, liver or kidney failure, chronic obstructive airways disease, and oral anticoagulant or immunosuppressant therapy.

The techniques of anesthesia and CPB were standardized. After premedication, anesthesia was induced with fentanyl (30 µg/kg, given intravenously) and muscle relaxation was achieved with pancuronium bromide (0.1 to 0.2 mg/kg, given intravenously). Anesthesia was supported by the inhalation of 1% isoflurane. The extracorporeal circuit consisted of either a Stockert roller pump (Stockert Instrumente, Munich, Germany) or a centrifugal vortex pump (Medtronic Biomedicus Inc, Eden Prairie, MN), a hollow-fiber membrane oxygenator (D703A; Dideco), polyvinylchloride tubing, a two-stage venous cannula, and a venous reservoir. The only difference in the entire perfusion circuit was the arterial pump. In both groups, the cardiotomy reservoir was integral to the venous reservoir and the cardiotomy suction was provided by three roller pumps.

Patients were heparinized just before the institution of CPB with 300 IU/kg, with additional doses given as necessary to maintain the activated clotting time at greater than 480 seconds. Nonpulsatile extracorporeal circulation was initiated at flows of 2.4 to 2.6 L · m^-2 · min^-1. Moderate systemic hypothermia 28° to 30°C by nasopharyngeal probe) was used uniformly. After aortic cross-clamping, cardiac arrest was achieved by the antegrade infusion of 1 L of cold-blood cardioplegic solution supplemented by topical saline slush. All distal anastomoses were performed, the cross-clamp was removed, and the proximal anastomoses to the aorta were completed during the rewarming period. Extracorporeal circulation was terminated at a nasopharyngeal temperature of 37°C. Heparin was neutralized after CPB with protamine sulfate (1 mg/100 IU of heparin). The operations were performed by two surgeons using a similar operative technique and the same perfusion protocol.

Biochemical Measurements
Venous blood samples (20 mL) were drawn and taken into sodium citrate (0.32% wt/vol, 1:9 parts blood) immediately after the induction of anesthesia, 5 minutes after the onset of CPB, at the end of CPB, and 30 minutes, 2 hours, and 24 hours after the administration of protamine sulfate. Specimens were centrifuged (10 minutes, 3,000 rpm, 4°C) immediately to obtain plasma, which was stored at -80°C before batch analysis. Enzyme-linked immunosorbent assay techniques were used to measure each of the cytokines (R & D Systems, Minneapolis, MN) and terminal complement (C5b-9; Quidel, San Diego, CA). Plasma neutrophil elastase concentrations were determined using an autoanalyzer technique (E Merck Diagnostica, Darmstadt, Germany). The limit of sensitivity of each assay undertaken was as follows: TNF- = 5 pg/mL, IL-1ß and IL-6 = 3 pg/mL, IL-8 = 20 pg/mL, C5b-9 = 16 ng/mL, and elastase = 20 ng/mL.

Neutrophil counts were measured at each sampling point. Results were not adjusted for hemodilution. Blood loss and blood transfusion were recorded until 24 hours after the operation. Packed red blood cells were infused when the hematocrit level was less than 30%. Cardiac output was measured by the thermodilution technique through a Swan-Ganz catheter (Baxter Edwards, Irvine, CA) from the mean of three readings. Cardiac index was calculated and reported in liters per square meter. Systemic and pulmonary vascular resistance were calculated by conventional formulas and were not indexed.

Statistical Analysis
Results are expressed as the median, with the range given in parentheses. Area under the curve analysis [15] assessed the overall difference between the groups over the course of the study. Nonparametric tests were used to assess at which time points differences between the groups were most marked. Spearman’s rank correlation coefficient was used to assess association (Statistica software). In all cases, p less than 0.05 was considered statistically significant.

	Results

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
The clinical characteristics of the 41 patients are summarized in Table 1. There were no statistically significant demographic differences observed between the centrifugal and roller pump groups in terms of age, CPB and cross-clamp times, or number of grafts. No patient required exploration for postoperative bleeding and there were no operative deaths or adverse complications. All patients were discharged from the intensive care unit on the first postoperative day.

Tumor Necrosis Factor- and Interleukin-1ß
Plasma levels of TNF- did not alter significantly with CPB in either group. Low levels of TNF- were detected in only 3 patients in the centrifugal group and 5 patients in the roller group at variable time points. Interleukin-1ß was not detectable at all in either group.

Interleukin-6
The initial baseline level of IL-6 was below the sensitivity threshold of the assay in both groups but rose progressively during CPB (Fig 1). The level peaked 2 hours after protamine administration at 341 pg/mL (range, 109 to 509 pg/mL) in the centrifugal group and 260 pg/mL (range, 103 to 522 pg/mL) in the roller group, then returned toward baseline in most of the patients after 24 hours. Interleukin-6 release was significantly higher in the centrifugal group than in the roller group (p < 0.05). Moreover, at the end of CPB, IL-6 levels were significantly higher (p = 0.02) in the centrifugal group compared with the roller group.

View larger version (13K): [in this window] [in a new window]   Changes in the circulating median concentration of interleukin-6 (IL-6) with time in patients who underwent cardiopulmonary bypass (CPB) with a roller (squares) or a centrifugal (triangles) pump. Error bars relate to the 25th to 75th interquartile range. (post-p = after protamine administration.)

View larger version (14K): [in this window] [in a new window]   Changes in the circulating median concentration of interleukin-8 (IL-8) with time in patients who underwent cardiopulmonary bypass (CPB) with a roller (squares) or a centrifugal (triangles) pump. Error bars relate to the 25th to 75th interquartile range. (NS = not significant; post-p = after protamine administration.)

View larger version (15K): [in this window] [in a new window]   Changes in the circulating median concentration of terminal complement (C5b-9) with time in patients who underwent cardiopulmonary bypass (CPB) with a roller (squares) or a centrifugal (triangles) pump. Error bars relate to the 25th to 75th interquartile range. (post-p = after protamine administration.)

Plasma Leukocyte Elastase
In both groups, elastase levels increased during and after CPB, peaking 2 hours after protamine administration at 202 ng/mL (range, 96 to 560 ng/mL) in the centrifugal group and 183 ng/mL (range, 67 to 532 ng/mL) in the roller group (Fig 4). Plasma leukocyte elastase release during and after CPB was significantly higher in the centrifugal group than in the roller group (p < 0.05). Moreover, in the centrifugal group, the elastase level was significantly higher than in the roller group both at the end of CPB (p = 0.03) and 30 minutes after protamine administration (p = 0.02).

View larger version (15K): [in this window] [in a new window]   Changes in the circulating concentration of elastase with time in patients who underwent cardiopulmonary bypass (CPB) with a roller (squares) or a centrifugal (triangles) pump. Error bars relate to the 25th to 75th interquartile range. (post-p = after protamine administration.)

View larger version (11K): [in this window] [in a new window]   Correlation of circulating peak levels of terminal complement (C5b-9) and elastase in the centrifugal group.

	Comment

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

Interleukin-6 is a key mediator in the acute-phase response to injury or infection, inducing the synthesis of hepatic acute-phase proteins [2] [16] [17]. It is thought to be a useful marker of the degree of tissue injury. Elevation of plasma IL-6 levels occurs both after cardiac operations with CPB [16] and after major noncardiac operations [17] [18] [19]. In the present study, IL-6 release was significantly higher in the centrifugal group compared with the roller group. This implies the induction of a greater acute-phase response and suggests a greater degree of tissue trauma with the centrifugal pump.

The role of neutrophil activation in lung and myocardial injury after CPB has been well documented. This led us to measure IL-8, a potent neutrophil chemotactic and activating factor [3] [5] [20]. Unlike IL-6, there was no significant difference in IL-8 release between the centrifugal and roller groups. A possible explanation for this disparity in the release of these two cytokines is that IL-8 release occurs mainly in situations of ischemia-reperfusion injury [4] [20] [21], whereas IL-6 release reflects the body’s response to any kind of acute insult. Given comparable CPB durations, the production of IL-8 after reperfusion would be expected to be similar in the two groups.

Activation of the complement cascade, predominantly through the alternative pathway, occurs during CPB [1] [2] and results in the formation of the terminal complement complex C5b-9. Additional activation of the complement cascade by heparin-protamine complexes is reflected by further increments in C5b-9 levels after protamine infusion. In the present study, concentrations of C5b-9 were higher at the end of CPB and 30 minutes after protamine administration in patients perfused with centrifugal rather than standard roller pumps.

Complement fractions activate neutrophils with release of their proteolytic enzymes, which can contribute to the adverse effects of extracorporeal circulation. To monitor neutrophil activation, leukocyte elastase was measured in plasma, where it is present in an inactive form complexed with ₁-antiprotease [2] [4] [22]. The release of elastase was significantly higher in the centrifugal group compared with the roller group, and elastase levels were more pronounced immediately after CPB. Further, peak levels of elastase correlated with peak levels of C5b-9 in the centrifugal group. This is consistent with complement stimulation of neutrophils leading to elastase release. If this occurs at the endothelium (ie, that of the reperfused lung) as a result of IL-8 chemotaxis, it could contribute to endothelial injury and capillary leak after CPB [3] [4] [5]. Although we observed no statistically significant correlation between elastase levels and IL-8 levels, an association has been found by others [3] [4]. Clearly, the complex interactions of these molecules and cells at the endothelial level cannot be reflected accurately in statistical correlations of plasma levels.

In contrast to our results, another clinical study [12] with a similar duration of CPB demonstrated less complement activation with the centrifugal pump, although in a much smaller number of patients. An in vitro study [13] showed less C5b-9 release with the centrifugal pump during extracorporeal circulation that exceeded 8 hours. It is possible that a roller pump induces less of an inflammatory response over a short duration of extracorporeal circulation, whereas a centrifugal pump is less traumatic over a longer duration.

There were no differences in clinical outcomes between the two study groups. This finding does not preclude the potential clinical relevance of our biochemical findings. The magnitude of complement activation and cytokine release during and after CPB has been reported to be correlated significantly with the postoperative clinical outcome [5] [23] [24]. In summary, the greater production of IL-6, C5b-9, and elastase with centrifugal pumps suggests that these pumps are less "biocompatible" for short-term extracorporeal circulation.

	Acknowledgments

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
We thank Mr Martin Ward for excellent technical assistance.

	References

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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