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Ann Thorac Surg 2007;83:1760-1766
© 2007 The Society of Thoracic Surgeons
a Department of Cardiothoracic Surgery, Free University Medical Center, Amsterdam
b Department of Anesthesiology, Free University Medical Center, Amsterdam
c Department of Biomedical Engineering/Artificial Organs, University Medical Center, Groningen, the Netherlands
Accepted for publication February 7, 2007.
* Address correspondence to Dr van Oeveren, Department of Biomedical Engineering and Anesthesiology, University Medical Center Groningen, Antonius Deusinglaan 1, Groningen 9713 AV, the Netherlands (Email: w.van.oeveren{at}med.umcg.nl).
| Adult cardiac surgery:
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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Methods: A prospective, randomized trial was conducted in 49 patients undergoing elective coronary artery bypass graft surgery either with the use of a standard or mini-CPB system (Synergy). We determined early postoperative inflammatory response (leukocytosis, C-reactive protein, urine interleukin-6), platelet consumption and activation (urine thromboxane B2), proximal renal tubular injury (urine N-acetyl-glucosaminidase), and intestinal injury (intestinal fatty acid binding protein).
Results: In patients undergoing coronary artery bypass grafting with a mini-CPB system, we observed decreased priming volumes with subsequent attenuation of on-pump hemodilution, improved hemostatic status with reduced platelet consumption and platelet activation, decreased postoperative bleeding and minimized transfusion requirements. We also found reduced leukocytosis and decreased urinary interleukin-6. Levels of urine N-acetyl-glucosaminidase were on average threefold lower, and urinary intestinal fatty acid binding protein was 40% decreased in the patients on the mini-CPB system, as compared with standard CPB.
Conclusions: The use of the mini-CPB system during myocardial revascularization represents a viable nonpharmacologic strategy that can attenuate the alterations in the hemostatic system, reduce bleeding and transfusion requirements, decrease systemic inflammatory response, and reduce immediate postoperative renal and intestinal tissue injury.
Transient myocardial, renal, intestinal, and hepatic tissue hypoxia is demonstrated to occur even after uncomplicated cardiopulmonary bypass (CPB) in low-risk patients [1]. Ischemia/reperfusion injury has been documented in organs like kidneys and small intestine, possibly due to alterations in blood flow at the microcirculatory level [2]. In an attempt to reduce the deleterious effects of standard CPB and improve patient outcome, novel concepts based on minimal extracorporeal circulation with small biocompatible perfusion systems have been developed. However, the beneficial effects of the new mini-systems reported in some studies [3–5] were not confirmed by others [6].
This study was designed to assess the clinical relevance of a mini-CPB system. To correlate our clinical practice with previously reported results, we determined postoperative leukocytosis, and C-reactive protein (CRP) concentrations. The hemostatic status of the patients was assessed using systemic release of thromboxane as an indication of platelet activation, platelet consumption, coagulation variables, perioperative blood loss, and transfusion requirements. To enhance the relevance of our observations, and as a new contribution to this for and against mini-CPB discussion, we determined organ damage markers as direct subclinical indicators, whereas commonly used markers of blood activation only provide indirect evidence of perfusion quality. To assess ischemia/reperfusion injury in proximal renal tubules and small intestine, we used specific and sensitive biomarkers reported to be valuable indicators of tissue injury.
The enzyme N-acetyl-glucosaminidase (NAG) is a lysosomal enzyme of 130 kDa molecular mass, normally excreted in low amounts in urine as a consequence of the normal exocytosis process. This enzyme was proposed as a valuable marker of tubulointerstitial damage in various human glomerular diseases including primary and toxic glomerulonephritis [7, 8]. The inflammatory reaction in the kidneys was determined by urine interleukin-6 (IL-6) release. Intestinal fatty acid binding protein (IFABP) is a cytosolic protein readily released into the circulation after enterocytes damage; it is released into the blood stream and excreted by kidney early in the course of intestinal ischemia [9]. Elevated IFABP urine levels predict the development of gastrointestinal complications after CPB [10], and correlate with clinical development of the systemic inflammatory response syndrome in critical ill patients [11].
These organ damage markers were measured at baseline and at 2 hours after routine coronary artery bypass graft (CABG) procedures with two different systems.
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Patients and Methods |
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= 1.0 and SD 
= 1.06584). With 
= 0.05 and 1-ß = 0.80, the appropriate sample size is 18. Therefore, at least 20 patients had to be included in each group. Included were patients scheduled for elective first time CABG, aged 45 to 75 years, with a left ventricular ejection fraction of more than 40%. All patients presented with acetylsalicylic acic medication until the day of operation. Patients with preoperative immunosuppressive therapy, preoperative use of nonsteroidal anti-inflammatory drug, requiring intra-aortic balloon support or aneurysmectomy, with insulin-dependent diabetes mellitus, or with a plasma creatinine level exceeding 150 µmol/L were excluded from the study.
Anesthesia
On the day of surgery, patients received their usual early morning dose of antianginal medication and 5 mg lorazepam; no diuretics were given. Anesthesia was induced using 3 to 7 µg · kg–1 intravenous sufentanil, combined with 0.1 mg · kg–1 pancuroniumbromide and skeletal muscle relaxant 0.1 mg · kg–1 midazolam. General anesthesia was maintained by a continuous infusion of propofol 5 to 15 mL · h–1 (20 mg · mL–1). Both groups had heparinization therapy dosages of 400 IU/kg and target activated clotting time time of 480 s, measured at initial dose and every 20 minutes thereafter. Protamine was used at the end of surgery to reverse the effect of heparinization therapy.
Cardiopulmonary Bypass
An S-III heart-lung machine with a centrifugal pump (Stöckert Instrumente GMBH, Munich, Germany) and heater-cooler device (Stöckert Instrumente GMBH) was used for the conventional CPB control group. The conventional extracorporeal circuit consisted of phosphorylcholine-coated circuit (Dideco SrL; Mirandola, Italy) including a coated centrifugal pump (Revolution; Cobe Cardiovascular, Arvada, Colorado), coated hollow fiber oxygenator (Apex M; Cobe), a coated soft shell collapsible venous reservoir (VRB 1800; Cobe), and a coated arterial line filter (D734, 40 µm; Dideco SrL). The total priming volume was 1,400 mL, consisting of 1,000 mL modified fluid gelatin (Braun Melsungen AG, Melsungen, Germany) and 400 mL lactated Ringer’s solution.
The Synergy mini-bypass system (Cobe) consisted of a totally closed phosphorylcholine coated system (Dideco SrL), a hollow fiber oxygenator with integrated arterial filter, centrifugal pump, and venous bubble trap for managing venous air. The Synergy system was used on the same S-III heart-lung machine. The mini-CPB was primed with the same prime fluids and volume as in the control group, with the exception that after priming, 600 mL was drained out of the system to come to 800 mL of prime volume.
In both groups, a retrograde autologous blood priming technique was performed after arterial cannulation and before initiation of CPB to further reduce prime by approximately 400 mL, as previously described [5]. In both groups, the standard additives to the priming, 200 mL aprotinin, 100 mL 20% mannitol, 50 mL 8.4% sodium bicarbonate containing 1,500 mg cefuroxim, and 5,000 IU bovine heparin, were kept in a separate infusion bag and administered after the priming procedure. Aprotinin was not administered systemically.
The same central arterial and venous cannulation technique was used in both groups, using an aortic 24-mm cannula (DLP; Medtronic, Minneapolis, Minnesota, or Terumo Cardiovascular Systems, Ann Arbor, Michigan) and right atrium venous cannulation (30/32F two-stage venous cannula; Edwards Lifesciences, Irving, California). In the mini-bypass group, the venous cannulation site was double pursestring sutured to minimize the risk of air aspiration into the venous line. In both groups, aortic root venting was performed with a 9F aortic root cannula (DLP). The nonpulsatile blood flow index was maintained between 2.2 and 3.0 L · min–1 · m–2 in both groups. All patients received an initial antegrade high-potassium cold crystalloid cardioplegia (1 L, 4°C) and an additional 100 to 200 mL every 20 minutes. The nasopharyngeal temperature was maintained at 34°C to 35°C during CPB.
Aspirated chest suction blood was stored in an autotransfusion reservoir (BT 894; Dideco SpA) and used to separate aspirated blood from the patient circulating volume. As the bleeding was low and not enough to warrant washing with a cell-saving system, this blood was discarded after the procedure. Peroperatively, the transfusion trigger for packed red cells was a hematocrit less than 25%. Postoperatively, packed red cells were transfused when hemoglobin was less than 6 mM, platelets were transfused when platelet count was less than 50 · 109/L, and fresh frozen plasma was transfused when the international normalized ratio greater than 1.7 and the activated partial thromboplastin time greater than 1.5 of the normal range. Ultrafiltration was not used in any of the patients of this study.
Organ Injury Biomarkers
Kidney injury biomarker
The method of detection for urine N-acetyl-glucosaminidase (NAG) was a modified enzyme assay according to Lockwood and Bosmann [12] at pH 4.5 and corrected for nonspecific conversion (HaemoScan, Groningen, Netherlands).
Intestinal injury biomarkers
Intestinal fatty acid binding protein (IFABP) was measured by means of enzyme-linked immunosorbent assay (ELISA [HyCult Biotechnology BV, Uden, Netherlands]). Urine NAG and IFABP concentrations were measured preoperative (baseline) and postoperative, in the urine collected during the first 2 hours postoperative, as previous investigations showed peak postoperative values of both markers coming during the first 2 hours after the end of the surgical procedure [1].
Urinary thromboxane B2
Urinary thromboxane B2 (TxB2 [EIA kit; Biotrak Amersham, Buckinghamshire, United Kingdom]) was measured as marker for the arachidonic pathway activation of platelets. The antibody used in this EIA kit has a high affinity for TxB2 and 2,3-dinor-TxB2, the modified form of platelet-derived TxB2 in urine.
Interleukin-6
Interleukin-6 (IL-6 [ELISA kit; Biotrak Amersham]) was measured as a marker for renal inflammatory response [13], in addition to the leukocyte count and CRP in peripheral blood.
Urinary excretions of NAG, IFABP, IL-6, and TXB2 were calculated as ratio to urine ureum concentration to correct for urine dilution.
Statistical Analysis
Results are presented as mean ± SEM (unless stated otherwise). Before analysis, the data were tested for distribution according to the Kolmogorov-Smirnov goodness-of-fit test. Continuous variables where compared by means of parametric (Student t test) or nonparametric tests (Mann-Whitney). The Wilcoxon signed ranks test was used to compare variations in time within groups. Fisher’s exact test was used to compare discrete variables. Correlation between variables was tested using the Spearman correlation test.
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Platelet activation, as monitored by postoperative urine TxB2 (Table 3) increased significantly only in the standard CPB group (Wilcoxon signed ranks p < 0.001). At the end of operation, the values in the standard CPB group were 5 times higher than the values in the mini-CPB group (10.1 ± 2.4 versus 2.0 ± 0.31 ng/mmol ureum, Mann-Whitney p = 0.004).
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Inflammatory Response
Inflammatory response was quantified by measuring urine IL-6 and CRP concentrations and monitoring the leukocytosis. Postoperative CRP concentrations were similar in both groups (Table 1). Leukocytosis (Fig 2) was at all postoperative time points significantly higher in the standard CPB group as compared with the mini-CPB group.
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Intestinal Injury
Postoperative urine IFABP (Table 3) was significantly higher in the standard CPB group than in the mini-CPB group (346.8 ± 37.4 versus 231.4 ± 39.5 ng/mmol ureum, Mann-Whitney p = 0.009).
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Comment |
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In our study, the low hematocrit values registered at the beginning of extracorporeal procedure correlated significantly with high postoperative kidney proximal tubular damage and IL-6 response as well as intestinal tissue damage. A lower systemic IL-6 response was previously observed after use of a mini-CPB system [4]. Moreover, the higher perioperative hematocrits in the patients assisted with the mini-CPB system translated in lower transfusion requirements perioperatively. Lower prime volumes of the mini-CPB enabled a significantly reduced level of hemodilution during extracorporeal circulation. Clinical and experimental studies have shown that the currently recommended protocols for hemodilution during traditional CPB trigger hypoxia through a reduction of oxygen-carrying capacity uncompensated by autoregulatory or rheologic increase in organ blood flow, or both. In animal models, magnetic resonance and near-infrared spectroscopy suggested that brain injury might be caused by hypoxic-ischemic injury as a result of currently recommended protocols for hemodilution during CPB [14]. In clinical studies, a significant independent association was found between the lowest hematocrit during bypass and acute renal injury [15], with significant benefits on renal function after reduction of the bypass prime volume [16]. In addition, in-hospital morbidity and mortality and multiorgan failure correlated with the lowest hematocrit during standard CPB [17, 18].
It is important to note that, even with the active drainage and negative pressures associated with mini-bypass, we noticed a significant reduction in platelet activation and consumption in patients assisted by the mini-CPB as compared with the traditional system. The inhibition in platelet activation was probably mediated by the reduction in blood contact surface area and the elimination of the blood-air interface in the mini-CPB.
Thromboxane release was significantly reduced in patients belonging to the mini-CPB group. The measurement of (2,3 dinor-)TxB2 in urine is thought to be most reliable, as ex vivo activation of platelets in whole blood samples may increase TxB2 [19]. Urine IL-6 is a specific marker of the kidney inflammatory response, whereas NAG and IFABP measurements are usually performed in urine, as these markers are immediately excreted by their origin and low molecular weight. The serum half-life time of TxB2 and IFABP is very short and variable. Since plasma creatinine concentrations and urine output were similar in both groups, urine samples of these markers were considered more reliable than serum samples in our study.
Transient proximal tubules injury was significantly attenuated during use of the mini-CPB system, as shown by the threefold lower urine concentrations of NAG. Transient intestinal tissue injury, as quantified by the urinary excretion of IFABP, was also significantly decreased in patients with a mini-CPB system, which may reflect a better intestinal tissue protection against ischemia/reperfusion injury.
In a previously conducted study, Nollert and coworkers [20] reported only minimal gains in systemic inflammatory response syndrome reduction with a mini-CPB system, because issues relating to safety, as the effective air management, prematurely terminated their study. The Synergy mini-system used in this study included two levels of safety: an automatic air purge system that detects and removes microbubbles from the venous side, and a secondary sensor for managing massive air leaving the system through use of an electric clamp on the arterial line. We have reported previous clinical experience with this system and showed that it offers the same level of safety as a conventional system [5]. As a result, micro-air management was not of concern during the operative course of this study. It happened to be no issue in the routine use of the system, because it was never activated in this study.
Another report on the clinical benefits of the mini-bypass systems comes from a recently published large sample size study performed by Abdel-Rahman and colleagues [6]. This study used a CorX mini-bypass system (Cardiovention, Santa Clara, California), now defunct. In comparison, our study, although smaller in sample size, showed much better results with reduced platelet consumption and platelet activation, decreased postoperative bleeding and minimized transfusion requirements, attenuated proinflammatory cytokine release, and important decrease in renal and intestinal injury release biomarkers. First and foremost, the phosphorylcholine coating has been well documented to improve platelet function preservation and reduce complement activation [21], whereas the CorX system was not biocoated. Other studies of mini-bypass systems showing positive benefits have typically been biocoated. The management of the suction blood and vent blood in the study conducted by Abdel-Rahman was unclearly specified. Based on the reported level of blood loss, it seems that a cell-saving device was used to manage the vent blood as well. An overuse of the autotransfusion system could have had a significant impact on the results by unnecessarily removing valuable blood components. To overcome this negative effect, we send the vent blood to a reservoir bag in the Synergy mini-bypass circuit, thereby allowing it to be easily reintroduced into the circulating volume of the patient. We did not register the same excessive intraoperative fluid loss, and thus all the aspirated suction blood collected into a separate reservoir was discarded at the end of the operation.
Limitations of the Study
Additional to leukocyte count and CRP, we used solely urinary concentration of the cytokine IL-6 as an indicator for the renal inflammatory response. Although aprotinin dosage was similar in both groups, the final effective concentration in the circulating blood was approximately 8% higher in the less diluted mini-CPB group This study was intended to provide an initial indication toward potential clinical benefits, and a study on a much larger scale in terms of sample size and follow-up duration is warranted to provide a better assessment of long-term clinical benefits.
Conclusion
The data presented in this study support the idea of alternative revascularization procedures with minimized closed CPB systems. Decreased priming volumes with subsequent ameliorated on-pump hemodilution, improved hemostatic status of the patients with reduced platelet consumption and platelet activation, decreased postoperative bleeding, and minimized transfusion requirements—all these data bring extra confirmation of the growing evidence already existing in the scientific literature regarding the use of these novel mini-CPB concepts [3, 4, 22, 23]. By showing inhibition of the inflammatory response, as indicated by less important leukocytosis and decreased IL-6 release in the patients on mini-CPB, we corroborate as well the comparable evidence reported after use of similar minimized concepts of CPB [4, 24]. As a unique contribution to the efforts made in this investigation field, we bring evidence of effective protection against perioperative proximal tubular injury and intestinal tissue injury offered by the mini-CPB system. The protection might prove to be especially beneficial for the increasingly aging population undergoing these forms of major surgery. In these patients, multiple organ injury is known to develop with perioperative organ dysfunction, resulting not only in increased in-hospital mortality but also in adversely affected long-term outcome.
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in healthy subjects Biochim Biophys Acta Mol Cell Res 1992;1133:247-254.[Medline]Related Article
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