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J Thorac Cardiovasc Surg 2006;131:1352-1357
© 2006 The American Association for Thoracic Surgery
Cardiopulmonary Support and Physiology |
a Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden
c Department of Anesthesia and Intensive Care, Sahlgrenska University Hospital, Gothenburg, Sweden
b Departments of Anesthesia and Intensive Care, Eastern Hospital, Gothenburg, Sweden.
Received for publication August 2, 2005; revisions received November 23, 2005; accepted for publication December 12, 2005. * Address for reprints: Anders Jeppsson, MD, PhD, Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden (Email: anders.jeppsson{at}vgregion.se).
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Abstract |
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METHODS: Twenty-five patients undergoing coronary surgery (mean age, 68 ± 2 years; 80% men) were included in a prospective randomized study. The patients were randomized to retransfusion of cell-saver processed (n = 13) or cell-saver unprocessed (n = 12) suction blood during full cardiopulmonary bypass. Mean arterial blood pressure was continuously registered during retransfusion, and systemic vascular resistance was calculated. Plasma concentrations of tumor necrosis factor 
, interleukin 6, and complement factor C3a were measured in suction blood.
RESULTS: Retransfusion of cardiotomy suction blood induced a transient reduction in systemic vascular resistance in all patients. The peak reduction was significantly less pronounced in the group receiving cell-saver processed blood (–12% ± 2% vs –28% ± 3%, P = .001). There was a significant correlation between tumor necrosis factor concentration in retransfused cardiotomy suction blood and peak reduction of systemic vascular resistance (r = 0.60, P = .002).
CONCLUSIONS: The results suggest cardiotomy suction blood is vasoactive and might influence vascular resistance and blood pressure during cardiac surgery. The observed vasodilation is proportional to the inflammatory activation of suction blood and can be reduced by processing suction blood with a cell-saving device before retransfusion.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionLimitationsReferences |
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Cardiac surgery induces a systemic inflammatory response characterized by complement activation and release of proinflammatory and anti-inflammatory cytokines.
1,2
The inflammatory response might be subclinical but is, in its most severe forms, associated with peripheral vasodilation and hypotension.
3-6
Sustained hypotension can result in insufficient end-organ perfusion and ischemic complications.
Cardiotomy suction (CS) during cardiopulmonary bypass (CPB) is used to maintain an appropriate hemoglobin concentration and to reduce the need for homologous blood transfusions. However, there is a pronounced inflammatory activity in CS blood, and retransfusion of CS blood has therefore been suggested to contribute to the postoperative inflammatory response.
7-11
Inflammatory mediators, such as cytokines and complement split products, have vasoactive properties,
12-14
and CS blood might therefore influence vascular resistance. However, to our knowledge, no previous investigation has studied whether CS blood has hemodynamic effects when retransfused. Our first aim was thus to investigate potential hemodynamic effects of CS blood in vivo, and in addition, we sought to investigate whether potential effects could be related to concentrations of inflammatory mediators in CS blood. Finally, we wanted to study whether potential hemodynamic effects are reduced if the CS blood is processed with a cell-saver before retransfusion. For these purposes, a prospective randomized study was performed in patients undergoing coronary artery bypass grafting (CABG) with CPB.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionLimitationsReferences |
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The study group consisted of 25 patients with a mean age of 68 ± 2 years, 80% of whom were men. Patient characteristics are shown in Table 1. All patients were operated on with CPB. The Research Ethics Committee of the Medical Faculty, University of Gothenburg, approved the study protocol.
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The operations were performed with a standard nonpulsatile CPB technique with moderate hypothermia (nasopharyngeal temperature, 34°C) and hemodilution (hematocrit, 20% to 30%). A standard flow of 2.4 L · min–1 · m–2 was used. Cardioprotection was achieved with cold blood cardioplegia. No topical cooling was used. Weaning off CPB was performed after rewarming to a rectal temperature of at least 36°C.
Study Protocol and Analyses
The patients were randomly allocated into 2 groups. In the first group CS blood was evacuated from the reservoir and processed in a cell-saver device (autoLog; Medtronic, Minneapolis, Minn) before retransfusion (n = 13). In the second group CS blood was retransfused without further processing (n = 12). The cell-saver produced approximately 135 mL of washed, packed red blood cells. Ringer-acetate was added to the processed blood to maintain a retransfusion volume and hematocrit value comparable with those of the unprocessed group. All CS blood was retransfused during full CPB immediately before weaning by opening the hatch between the CS reservoir chamber and the venous return reservoir.
Concentrations of the proinflammatory cytokines tumor necrosis factor (TNF) and interleukin (IL) 6 and complement factor C3a were measured in the separate CS reservoir before and after cell-saver processing. Samples for cytokine and complement analyses were collected into tubes with ethylenediamine tetraacetic acid and placed immediately on ice. The aliquots were centrifuged immediately, and the resultant plasma was stored at –70°C until analysis. TNF-, IL-6, and C3a levels were determined with commercially available enzyme-linked immunosorbent assay kits by using double-antibody enzyme-linked immunosorbent assays, according to the manufacturer's instructions. The following assays were used: TNF- and IL-6, R&D systems; C3a, Quidel (San Diego, Calif). Hemoglobin content and hematocrit value were also analyzed in CS blood before retransfusion.
Mean arterial blood pressure was continuously registered from the arterial line and stored with 200 samples per second by using a computer technique (Acknowledge; BioPac Systems, Santa Barbara, Calif). An investigator blinded to group affiliation analyzed the files.
Calculations
Systemic vascular resistance (SVR) was calculated according to the formula 
, where cardiac output equals the CPB flow rate. Plasma concentrations of TNF-, IL-6, and C3a in suction blood were corrected for hematocrit by relating measurements to a standard hematocrit value of 40% according to the following formula:
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Statistics
The nonparametric Mann-Whitney U test (continuous variables) and the Fisher exact test (categoric variables) were used to compare the groups. Differences within a group were compared with the paired nonparametric Wilcoxon test. Comparisons were made both with percentage change from baseline and with absolute values. Correlation was analyzed with the Spearman rank sum test. All the results are expressed as the mean ± standard error of the mean.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionLimitationsReferences |
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Baseline Variables
There were no statistically significant differences between the cell-saver group and the unprocessed group with respect to age, sex, ejection fraction, aortic clamp time, or number of grafts (Table 1).
CS Blood and SVR
The mean volume of collected CS blood during the operation was 477 ± 36 mL. The mean volume of retransfused CS blood was 403 ± 17 mL, and the mean hematocrit value was 15% ± 2%. The mean arterial pressure before retransfusion was 67 ± 3 mm Hg. Rapid retransfusion of CS blood induced a transient reduction in SVR immediately after retransfusion in all patients (Figures 1 and 2).
The mean time to minimum SVR was 42 ± 2 seconds.
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, IL-6, and C3a were significantly increased in unprocessed CS blood compared with systemic plasma concentrations at the same time point (TNF-: +280% ± 154%, P < .001; IL-6: +1268% ± 445%, P < .001; C3a: +473% ± 136%, P < .001). The absolute values were 10.1 ± 2.4 versus 4.5 ± 1.1 pg/mL (P = .010) for TNF-, 600 ± 174 versus 100 ± 46 pg/mL (P < .001) for IL-6, and 5294 ± 953 versus 1107 ± 107 ng/mL (P < .001) for C3a.
There were statistically significant correlations between TNF- concentrations in retransfused CS blood and 
% SVR (r = 0.60, P = .002, y = –0.15 to 0.02x; Figure 3) and between C3a and % SVR (r = 0.43, P = .043, y = –0.14 to 6 x 10–5x). No correlation between IL-6 and % SVR was detected (r = 0.22, P = .31).
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Inflammatory activation in CS blood
Cell-saver processing significantly reduced concentrations of TNF- (–38% ± 11%, P = .012) and C3a (–70% ± 14%, P = .016) in CS blood. In absolute values TNF- levels decreased from 7.5 ± 2.5 to 3.5 ± 1.6 pg/mL (P = .012) and C3a levels decreased from 4337 ± 1087 to 1757 ± 913 ng/mL (P = .021). IL-6 levels tended to decrease (–19% ± 34%, P = .27), from 633 ± 315 to 229 ± 81 pg/mL (P = .13).
Hemodynamic effects
Baseline SVR (immediately before retransfusion of CS blood) was comparable between the cell-saver group and the unprocessed group (1086 ± 82 vs 1115 ± 77 dynes · s1 · cm–5, P = .58).
During retransfusion of CS blood, the vasodilation was less pronounced in the group receiving cell-saver processed blood compared with that seen in the group receiving unprocessed blood (SVR = –140 ± 34 vs –326 ± 50 dynes · s1 · cm–5, P = .006). The relative reduction in SVR is depicted in Figure 2.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionLimitationsReferences |
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Inflammation and Hemodynamics
Cardiac surgery induces an inflammatory response. The inflammatory response can result in postoperative complications, such as prolonged ventilation and renal failure,
6,15-17
and has also been associated with myocardial injury.
18
In its most severe forms, the systemic inflammatory response is associated with peripheral vasodilation and hypotension,
1-6,13,19
and the inflammatory activation has also been connected with a vasoplegic syndrome after cardiac surgery.
3-5
Systemic levels of cytokines and complement factors are reduced during and early after CABG when CS is discarded,
7
which demonstrates that CS contributes to the inflammatory activation during and after cardiac surgery. CS blood contains high levels of cytokines (IL-1, IL-6, and TNF-) and complement split factors (C3a and sC5b-9),
7,10,11,20-23
which all have vasoactive properties.
12-14
Theoretically, CS blood can thus contribute to perioperative vasodilation, but to our knowledge, this issue has not previously been investigated.
We hypothesized that CS blood is vasoactive and established an in vivo method to investigate the effect in patients undergoing CABG with CPB. CS blood was collected in a separate reservoir during the operation and retransfused immediately before weaning of CPB during continuous blood pressure registration. The heart was completely unloaded, and thus a potential reduction in mean arterial pressure can be regarded as an effect caused by vasodilation. From the measured arterial pressure, the change in SVR was calculated. Retransfusion of unprocessed CS blood in this model caused a prompt reduction in systemic resistance (–28%), which thus demonstrates the vasoactive properties of CS blood. It is conceivable that this is an effect of the inflammatory activity in CS blood because the magnitude of the reduction in SVR correlated to the concentrations of TNF- in CS blood (Figure 3) and, to a lesser degree, to C3a. TNF-, IL-6, and C3a are not only markers of inflammation but also have their own important pathophysiologic effects.
24,25
TNF- increases stress hormone release and neutrophil adhesion, causes myocardial depression, and stimulates production of other cytokines, such as IL-6 and IL-8. TNF- has also vasoactive properties and has been demonstrated to stimulate production of inducible nitric oxide synthase.
2,26
One might thus speculate that the marked immediate effect of CS blood on SVR is mediated by nitric oxide.
The hemodynamic effects of CS blood might be attenuated or even absent if the suction blood is retransfused over a more extensive period. However, when we designed the present study, it was not known whether CS blood had any hemodynamic effects at all. The study was therefore intentionally designed to investigate the potential hemodynamic effects of CS blood in an artificial experimental set up with sudden retransfusion. If this design demonstrates hemodynamic effects, it would motivate further studies with different protocols and hypotheses to study the clinical importance.
Cell-saver Processing
Cell-saver processing reduces the amount of inflammatory mediators in CS blood significantly.
8,27,28
However, depending on the device, 5% to 20% of cytokines remain after processing.
27,28
In the present investigation cell-saver processing decreased TNF- and C3a concentrations in CS blood and reduced the systemic vasodilation by approximately 60% compared with unwashed blood (12% vs 28%). The subtotal reduction of inflammatory substances might explain why the reduction in SVR in the present study was not entirely abolished in the cell-saver group. Alternatively, other properties of the retransfused blood volume (viscosity and temperature) that are not influenced by cell-saver processing might have an effect on vascular resistance.
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Limitations |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionLimitationsReferences |
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Considering this, there are some limitations in the study design that need to be discussed. The hematocrit value of the retransfused blood was lower than that in the patient, indicating a lower viscosity. This might partly explain the reduction in SVR in both groups. However, because neither the hematocrit value nor the retransfused volume (constant pump flow) differed significantly between the processed and the unprocessed groups, this does not explain the marked intergroup difference caused by cell-saver processing. The temperature of the retransfused blood was not measured specifically but is probably somewhat lower than in the systemic circulation and similar between the 2 groups.
The dilution of the CS blood in the cell-saver group after processing can be debated. The rationale was as mentioned above, that it has been shown that blood viscosity can influence SVR.
29
To avoid differences in viscosity, we chose to replace the plasma with Ringer-acetate in the cell-saver group. One might argue that this was artificial and might have influenced the results. However, a pilot study was performed with the same experimental set up as in the present study, and in this model infusion of a comparable amount of Ringer-acetate did not influence vascular resistance.
Another issue is whether stasis of the CS blood in the reservoir might affect the levels of inflammatory mediators. This cannot be ruled out with the present study design, but it should be emphasized that the blood was continuously collected during CPB, and therefore the final content in the reservoir is a mix of suction blood collected over approximately 45 minutes. Again, the handling was identical in both groups, and this cannot explain intergroup differences.
Clinical Implications
CS blood is often suctioned directly into the venous reservoir and retransfused continuously, diluted in the circulating blood volume. Vascular effects of CS blood might thus be insignificant or even undetectable in routine cardiac surgery. However, in high-risk patients or in patients undergoing long or complicated operations with extensive intraoperative bleeding, the observed effect of CS blood on SVR might be of greater importance. Accordingly, the results of the present study do not indicate that the present handling of CS blood should be revised but propose that the importance of retransfusion of CS blood is investigated in studies with clinical end points.
The observation that processing CS blood with a cell-saving device significantly reduced the effect on SVR supports, at first sight, the use of cell-saving devices perioperatively, at least when considerable intraoperative bleeding can be expected. However, cell-saver processing might also have potential harmful effects on the blood, such as bleeding diathesis related to loss of platelets and coagulation proteins, which might counteract beneficial effects. Again, clinical studies are warranted.
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Acknowledgments |
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Footnotes |
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References |
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