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Ann Thorac Surg 2005;79:655-665
© 2005 The Society of Thoracic Surgeons
a Division of Cardiac Surgery
b Division of Cardiac Anaesthesia
c Division of Surgery
d Division of Clinical Research
e Division of Rheumatology
f Division of Clinical Epidemiology, University of Ottawa, Ottawa, Ontario, Canada
Accepted for publication July 19, 2004.
O2 = mixed venous PO2; QS = right-to-left shunt blood flow; QT = total blood flow; RBC = red blood cell; RIA = radioimmunoassay; RITA = right internal thoracic artery; SMA = surface modifying additive; SMA-CPB = cardiopulmonary bypass with surface modifying additive; SVR = systemic vascular resistance; TCC = terminal complement complex; TNF = tumor necrosis factor; tPA = tissue plasminogen activator; UTI = urinary tract infection; 
O2 = oxygen cosumption index
* Address reprint requests to Dr Rubens, Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin St, Ottawa, Ontario K1Y 4W7, Canada (E-mail: frubens{at}ottawaheart.ca).
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Abstract |
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METHODS: In a factorial design, patients undergoing coronary artery bypass grafting were randomized (four groups; n = 17 per group) to CPB utilizing control circuits or a circuit prepared with a surface modifying active copolymer (SMA-CPB), with or without methylprednisolone (MPSS, 1 g intravenous). Leukocyte and complement activation, cytokine release, and bradykinin generation were measured. Clinical outcomes (blood loss, transfusion, arterial pressure response, and postoperative cardiac and pulmonary functions) were also examined.
RESULTS: The SMA-CPB was associated with a significant inhibition of elastase release (p = 0.026) and bradykinin generation (p = 0.027) during CPB. Terminal complement complex (TCC) generation was inhibited as an effect of SMA-CPB (p = 0.047). There was an interaction of SMA-CPB and MPSS to decrease both TCC (p = 0.042) and bradykinin generation (p = 0.028). There were strong effects of MPSS in inhibiting release of interleukin 6 (IL-6) (p = 0.007) and IL-8 (p < 0.001) and tissue plasminogen activator over time (p = 0.009) as well as decreasing peak day 1 creatine kinase (CK, p = 0.015) levels. Clinical effects of MPSS included decreased atrial fibrillation (p = 0.02), improved cardiac index over time, increased pulmonary compliance, and increased insulin need.
CONCLUSIONS: This trial suggests a potential beneficial effect for combined strategies to minimize inflammation after CPB. The specific effect of MPSS in decreasing postoperative atrial fibrillation and CK warrants further investigation of its role as a potential myocardial protective agent.
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Introduction |
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Previously, we completed a clinical trial which demonstrated that when CPB circuits prepared with polymers containing a surface modifying additive (SMA) are used for cardiac surgery, certain blood activation pathways are inhibited [1]. In particular, two phenomena occurred. First, derangements in coagulation and fibrinolysis occurring with uncoated CPB circuits were not seen with the modified circuit [1]. Second, acute vasodilation, suspected to be related to surface-mediated bradykinin generation, was not seen when the SMA surface was used [2].
In the current study, two specific questions were addressed: (1) Does the addition of steroid therapy (methylprednisolone, MPSS) inhibit the generation of inflammatory mediators and complement activation, independent of contact activation during and after CPB performed with control circuits versus circuits prepared with surface modifying additives (SMA-CPB)? Further, is this inhibition reflected by improved measures of pulmonary function and decreased cardiac injury? (2) Is CPB-induced bradykinin release inhibited by the use of SMA and steroids alone or in combination?
Due to the exploratory nature of this broad area and to support subsequent detailed larger clinical trials, a factorial design was utilized with measurement of a variety of biochemical and clinical markers reflective of the diverse effects of systemic inflammation.
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Material and Methods |
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All blood-contacting surfaces, including the cannulas in the test CPB circuit, were prepared with the SMA copolymer (SMARxT, COBE Cardiovascular Inc, Arvada, CO) such that the surfaces were coated "tip-to-tip." The patients were randomly assigned to one of four groups: (1) Surgery with the modified CPB circuit (SMA-CPB) and MPSS (1 g intravenous [IV]) given before CPB; (2) surgery with SMA-CPB and placebo (saline bolus IV); (3) surgery with the standard circuit and MPSS (1 g IV); (4) surgery with standard circuit and placebo.
The perfusionist performed the treatment assignment immediately preoperatively by opening a sealed, numbered envelope. Randomization was in blocks of four, generated using SAS Version 8.2 (SAS, Cary, NC). The cannulas and tubing used in all of the CPB circuits were identical in appearance, so that all members of the surgical and anesthesia teams, except the perfusionist, were blinded to the circuit assignment. The steroid or placebo was given at the time of insertion of the central line and before the incision. All members of the surgical and anesthetic teams were blinded to the use of MPSS. Syringes containing the MPSS or the placebo (saline) were prepared in the hospital pharmacy and labeled with a code.
Primary Outcome Variables
A sample of blood for plasma ACE levels was taken at the time of insertion of the central line. Sampling for tissue plasminogen activator (tPA) and bradykinin were done at the following time points: at insertion of the central line, before heparin, after heparin administration but before initiation of CPB (poststernotomy), at 5, 10, 15, 20, 40, and 60 minutes after initiation of CPB, and 1 hour after separation from CPB. Sampling for cytokines, elastase, and terminal complement complex (TCC) was done at the following time points: at insertion of the central line before heparin, after heparin administration, just before initiation of CPB (poststernotomy), at placement of the aortic cross-clamp, at release of the aortic cross-clamp, and 1, 2, 4, 6, and 24 hours after protamine reversal. Blood specimens were obtained from the side-port of the right internal jugular vein catheter after removal of 6 dead space volumes of blood, into tubes with citrate (3.8%) or a combination of protease and peptidase inhibitors (bradykinin assay [3], then centrifuged to produce platelet-poor plasma. For bradykinin measurements, the plasma was immediately precipitated with ice-cold ethanol, with the supernatant stored at –80°C. Plasma ACE activity was measured utilizing the methods of Reneland and Lithell [4] with a modified enzyme linked immunosorbent assay (ELISA). The ELISAs were used for the measurement of elastase (Milenia elastase ELISA, Inter Medico, Markham, ON), interleukin 6 (IL-6, Medicorp, Montreal, PQ), interleukin 8 (IL-8, Peninsula Laboratories, Belmont, CA), TCC (Quidel Corp, San Diego, CA), and tissue plasminogen activator (tPA, American Diagnostica, Montreal, PQ) [1]. Bradykinin was measured according to the method of Nussberger and colleagues [3]. The ethanol extract was evaporated and the residue was dissolved in acetic acid. The sample was then subjected to isocratic high pressure liquid chromatography (Hewlett Packard 1090A) to separate bradykinin from precursors and metabolites. A commercial radioimmunoassay was then used to measure the bradykinin levels (RIK 7051, Peninsula Laboratories). This assay has a dynamic range of 1 to 128 pg/tube with a typical sensitivity of 9 pg/tube (IC50).
Secondary Outcome Variables
Hypotensive episodes during CPB (mean arterial pressure [MAP] is less than 50 mm Hg) were treated with 100 µg boluses of phenylephrine until the MAP exceeded 55 mm Hg. Intravenous inotropic agents were administered to patients coming off CPB if the cardiac index (CI) was less than 2.2 L · min–1 · m–2 in the presence of an adequate preload. The post-CPB, boluses of fluid (Ringers lactate) were administered for hypovolemia (pulmonary capillary wedge pressure [PCWP] < 12 mm Hg) in the presence of decreased cardiac index, low urine output (< 0.5 mL/ kg–1/h–1) or hypotension. Total fluid administered, inotrope use, and rationale for inotrope use, were documented in each case.
Cardiac index (CI) and systemic vascular resistance (SVR) were measured following intubation, at the end of bypass, hourly to 6 hours after surgery, and then at 24 hours. Creatine kinase (CK) was measured at 4 hours and 12 hours after arrival in the intensive care unit (ICU) and if the level was greater than 800 IU/L, a troponin T level was determined. Pulmonary function was assessed using the following factors collected at intubation, 15 minutes after the end of bypass, and at 2 hours after arrival in the ICU: pressure of oxygen PO2 on fraction of inspired oxygen FIO2 1.0, pulmonary vascular resistance (PVR), pulmonary compliance, alveolar-arterial oxygen difference (AaDO2), oxygen delivery index (DO2I), arteriovenous oxygen content difference (avDO2), oxygen extraction rate (OER), and oxygen consumption index (O2) (see Appendix for equations).
Recorded blood volumes included the following; total readministered cardiotomy blood postcentrifugal washing, blood collected from protamine administration to skin closure, mediastinal shed blood in ICU (skin closure to 24 hours). Patients received transfusions during CPB if the hematocrit fell below 18%. In the postoperative period, patients received red blood cell (RBC) transfusions if the hematocrit fell below 21%. Surgical reexploration was indicated in any patient with suspected tamponade or if bleeding exceeded greater than 250 mL/h for four hours or 500 mL in any one hour. Non-RBC blood products were given. After heparin rebound has been ruled blood products were given as follows: platelets in aliquots of 5 U if the platelet count was less than 60,000/L or if there was suspicion of platelet dysfunction (long CPB run), fresh frozen plasma (15 mL/kg) if the international normalized ratio (INR) was greater than 1.8, and cryoprecipitate (1 U/4 kg body weight initial dose) if the fibrinogen level was less than 1.0 g/L.
Blood glucose was measured every 30 minutes. Measurements were repeated in the ICU hourly and insulin therapy was initiated following a standard protocol. Patients were monitored daily throughout their admission and at the follow-up clinic for the occurrence of infection (positive blood cultures, clinical sepsis, wound infection, pneumonia, urinary tract infection [UTI]). Wound infections were diagnosed according to Centers for Disease Control criteria for nosocomial infections [5].
Heparinization during CPB and intraoperative protamine reversal were identical for all groups. Plasma heparin concentration was measured by protamine titration and maintained at 3.0 U/mL (Hemotec, Medtronic Inc, Parker, CO). Cardiopulmonary bypass was conducted using a roller pump, a flat sheet polypropylene 1.3 m2 membrane oxygenator (COBE CML Duo, COBE Cardiovascular Inc, Arvada, CO), a 43 µm arterial filter (COBE Sentry with PrimeGard), a closed venous reservoir bag, ascending aortic cannula, and a two-stage single venous cannula return. All of the pumps were primed with 1,300 mL of Ringer’s lactate. Bypass flows were maintained at 2.4 to 3.2 L · m2 · min and the body temperature was reduced to 32°C during the period of cardiac anoxia. Cardiac arrest was achieved using topical pericardial saline irrigation as well as antegrade cold crystalloid cardioplegia through the aortic root and/or the bypass grafts at 20 minute intervals. At the completion of the procedure, the patient was rewarmed to a nasopharyngeal temperature of 37°C before separation from CPB. All scavenged blood from the mediastinum, collected intraoperatively and up to 4 hours postoperatively, was processed by filtration (30 µm) and centrifugal washing (BRAT, COBE Cardiovascular Inc.) Immediately upon arrival to the ICU, all patients were treated with an acetylsalicylic acid (ASA) suppository (650 mg).
Statistical Analyses
A 2 x 2 factorial design was used to evaluate the independent as well as the combined effects of MPSS and the SMA circuit. Baseline and outcomes variables were compared by using linear regression for continuous variables and logistic regression for categorical variables. To compare subgroups at specific time points, t tests were used. Regression models were developed by including the main effects of MPSS and the SMA circuit, and their interaction as an additional term. Variables recorded at multiple time points were examined by using mixed models repeated measures analysis. Log transformations were required for some variables as determined by examination of model fit and residuals. All analyses were performed using SAS version 8.2. A power analysis was done using PASS 6.0 (JL Hintze, Kaysville, UT, 1996) for a fixed effects analysis of variance. In an earlier study [1] we observed a large effect of circuit type on several key coagulation markers with a sample size of 17 per group. Assuming a moderately large effect size (f = 0.375) a power of 0.85 could be obtained for each factor and the interaction with 17 subjects per cell; ie, 68 patients.
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Results |
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With regards to tPA release (Fig 4), when the non-MPSS groups were compared, the SMA circuit significantly decreased the total release of tPA at 15 minutes of CPB (t test, p = 0.038). There was a significant inhibitory effect of MPSS on tPA release (p = 0.009) that reduced the impact of the SMA circuit. The changes in bradykinin were not associated with any differences in intraoperative phenylephrine use (SMA circuit effect, p = 0.537; MPSS effect, p = 0.892) or total crystalloid administration (SMA circuit effect, p = 0.479; MPSS effect, p = 0.572). The circuit did not have an effect on the blood pressure response; however, MPSS was associated with a significant fall in the blood pressure over the entire 10 minutes examined (p = 0.046), with the largest difference occurring at seven minutes (with MPSS 62.5 mm Hg, 95% CI [57.4 to 68.1]; without MPSS 74.2 mm Hg, 95% CI [67.6 to 80.2]).
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Comment |
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There were three specific components related to systemic inflammation evaluated in this trial; white cell activation, complement activation, and bradykinin generation. White cell activation was inhibited by both SMA-CPB and MPSS. In particular, interleukin release was significantly inhibited by the MPSS, whereas there was a prominent inhibition of elastase release due to SMA-CPB. Complement activation was inhibited by both MPSS and SMA-CPB, and there was also an interactive effect of the combined strategy to inhibit complement. Finally, an interactive effect of MPSS and SMA-CPB to decrease bradykinin generation was demonstrated.
Although there were no specific clinical effects related to the test biomaterial, MPSS use was associated with specific changes. Markers of myocardial injury (CK) and the incidence of atrial fibrillation were decreased with MPSS and pulmonary compliance and CI were significantly improved. Finally, there were no detrimental safety effects seen with either the SMA-CPB or with the MPSS administration.
Previous Work on SMA and Steroids in CPB
The SMA circuit represents a new generation of biomaterial developed for CPB into which a triblock-copolymer of the general formula polycaprolactone-polydimethylsiloxane-polycaprolactone has been incorporated into the polymer used to prepare the circuit [7]. The SMA migrates to the surface of the base polymer during the manufacturing process, yielding a stable microdomain-like configuration. The conceptual advantage of this approach capitalizes upon the localization of alternating hydrophobic (polysiloxane) and hydrophilic (polycaprolactone) "domains" on the blood-contacting surface. The amount of protein that is adsorbed is minimized and they undergo little conformational change during this process [8]. As a consequence, cell interaction with the surface is also minimized [8].
In our previous randomized trial testing the SMA surface, two major effects were found [1, 2]. First, SMA-CPB demonstrated clear properties of thromboresistance. The test circuit was associated with marked platelet preservation in terms of activation and platelet count. Thrombin generation and tPA release were also significantly decreased with SMA-CPB [1]. Second, although this first trial was not powered to detect clinical differences, a marked disparity was identified in the blood pressure response of the control and SMA-CPB groups upon the initiation of CPB [2]. In particular, there was a rapid drop in blood pressure in the control patients, large enough to require an intervention (fluid, 
-agonist) in most cases. The inhibition of bradykinin generation as a systemic effect of the SMA surface stood out as a unifying hypothesis, which explained both the effect on tPA release and the prevention of systemic vasodilation related to the initiation of CPB [9].
Steroids have been utilized in numerous clinical conditions to minimize the effects of acute inflammation and it was intuitive to consider they may have a role in minimizing the whole body inflammation associated with CPB. These drugs function to reduce early inflammatory processes such as increased capillary permeability, edema formation, and leukocyte migration. The mechanisms behind their antiinflammatory effects are related to suppression of stimulus-dependent expression of many proinflammatory proteins through the inhibition of transcriptional pathways in target cells. This is likely due to a direct inhibitory interaction between activated glucocorticoid receptors and activated transcription factors, such as nuclear factor-kB and activator protein-1 [10].
Anti-inflammatory Effects of SMA-CPB and MPSS
The SMA circuit-mediated inhibition of elastase was a robust finding in the current trial. Elastase, which is released from activated polymorphonuclear leukocytes during extracorporeal circulation, is one of the most powerful cytotoxic enzymes because of its biological effects and it may have a role in producing postoperative pulmonary dysfunction [11]. This neutrophil product is also a known promoter of chemotaxis of neutrophils and expression of neutrophil adhesion molecules [12]. Although it has been suggested that one of the key mechanisms stimulating elastase release is kallikrein release [13], blockade of this pathway with the nonspecific protease inhibitor nafamostat mesilate did not prevent rise in elastase after CPB [14]. On the other hand, surface-mediated inhibition of elastase release was also seen after CPB with a similar copolymer surface (poly[2-methoxyethylacrylate], PMEA, Terumo Corp, Tokyo, Japan) in which comparable minimized protein adsorption is effected [15]. The fact that our results with regards to the elastase effect of SMA-CPB have differed from other investigators [6] may be related to methodologic approaches in these trials such as a different ELISA [6]. Interestingly, heparin-coated circuits (HCC) have not been shown to have an effect on elastase of this magnitude [16]. The inability of steroids to suppress CPB-related increases in elastase levels in the current trial has been demonstrated by other investigators [17].
There was a convincing MPSS-mediated inhibition of cytokine release as measured by IL-6 and IL-8. Steroids have been previously shown to blunt the release of tumor necrosis factor (TNF) [18], IL-6 [18, 19], and IL-8 [18, 19] during cardiac surgery. These cytokines are recognized as critical early mediators of organ injury and thus they may play a role in initiating the cascade that leads to the postpump perfusion that is observed clinically. The clinical contribution of these latter changes is difficult to infer in this small trial, but some of the outcomes that have been most evident in other clinical studies with steroids include improved SVR response after normothermic bypass [18]; improved postoperative cardiac performance after standard CPB [20], and a reduced incidence of hemodynamic instability [21]. Cytokines may also play a role in pulmonary sequestration of neutrophils [21] and recent in vitro work has shown that IL-8 can produce neutrophil sequestration in the lungs [22] and thus it may be one of the stimuli for the acute injury identified after CPB. Thus this may be the mechanism in the current trial related to the improved pulmonary compliance in the groups receiving MPSS. Finally, the fact that the surface (SMA) had no effect on these cytokines supports the argument that the stimulus of cytokine rise is not related to the biomaterial, but rather to changes such as intestinal submucosal flow and bacterial translocation [23]. Therefore, changes in cytokine levels would not be impacted by the choice of the surface and indeed this has been born out in studies with PMEA [15] and HCC [24].
The current trial demonstrated a convincing suppression of complement activation during CPB as an effect of the SMA surface, MPSS, and as an interactive effect of the two agents together. Although steroids have previously been shown to block complement activation with CPB [25] the effect of the SMA surface on this component of inflammation has not been consistently shown [6]. On the other hand, surface-mediated complement inhibition has certainly been a reproducible antiinflammatory property of HCC [26]. The mechanism proposed for the latter effect with HCC may involve selective adsorption of high molecular weight kininogen whose inhibition by antithrombin III may be facilitated by the surface heparin [27]. In our trial, we elected to focus on the downstream product of the complement pathway (TCC) and it is possible that we missed changes in earlier steps in complement such as the anaphylatoxins C3a and C5a that may have shed more light on this property and its mechanisms.
The effect of MPSS on CK levels (though not fractionated) was a significant change that was unexpected a priori. These data were collected prospectively as the trial was designed as an exploratory descriptive study, and as such was not powered for clinically relevant events. Regardless, there is a possibility that the changes in CK represent a potential cardiac-preserving effect of MPSS that may have contributed to the significant decrease in the rate of atrial fibrillation as well as the improvement in the CI that was seen. Other investigators have shown a similar decrease in atrial fibrillation with steroids [28] and the relative paucity of data on detrimental effects related to steroid use in cardiac surgery leads us and others [29] to question why it is not more widely used perioperatively. For example, the safety profile in our current trial was unremarkable, perhaps related to the aggressive treatment of hyperglycemia with a standardized insulin protocol. A larger trial would be necessary to confirm this effect, but we believe that these data should not be summarily discounted and they should be used to support the potential consideration of this drug in further trials as a myocardial protective agent.
The changes in lung compliance that were demonstrated related to MPSS use were consistent with those demonstrated in the surgical literature [30]. We measured compliance as tidal volume over peak inspiratory pressure. Although this is affected by airway resistance, it was measured in the same manner in both groups and therefore we believe the differences illustrated reflect a true effect of the treatment.
Effects of Strategies on Hemodynamics and Bradykinin
There was no circuit-related difference seen in the MAP at the time of institution of CPB, the fluid requirements or the amount of alpha agonist administered between the groups. The stabilization of the blood pressure in the control group may be related to the mandatory discontinuation of ACEI, a strategy that was not used in the first trial [2]. It has previously been shown that the effect of bradykinin is intensified in the presence of ACEI; this phenomenon is believed be a major contributor to dialysis hypotension [31]. Although not proven, it does raise the question as to whether routine conversion of ACEI to angiotensin II receptor antagonists may facilitate perioperative management during CPB. The effect of these interventions on tPA release was also measured in parallel to the bradykinin measurements due to the relationship of tPA to the initial hypothesis of endothelial stimulation. Inhibition of tPA release due to SMA-CPB was demonstrated as in our earlier work [1]. The inhibitory effect of MPSS on tPA release was more evident and similar to that demonstrated by Jansen and colleagues [17]. In fact, some investigators have suggested that steroids may have a role in minimizing blood loss due to this action [30]. A decrease in the 24 hour chest tube drainage was seen in the current trial related to MPSS, but the effect was not statistically significant.
Limitations
In the current study, we addressed whether the study interventions influenced (1) the generation of inflammatory mediators, vasodilators, and complement, and (2) the clinical outcomes potentially related to these markers, during and after CPB. By necessity, to fully describe these effects and outcomes, several variables from each system were analyzed and therefore the interpretation of statistically significant results must be made with caution.
Future Studies
The findings of this study stimulate several new questions regarding the clinical application of these strategies in cardiac surgery. First, what is the clinical relevance of using steroids during cardiac surgery in light of the concerns of the potential side effects of wound complications and post-CPB pulmonary dysfunction [32]? With regards to wound infections, steroids have never been conclusively demonstrated to be associated with this problem in a prospective clinical trial [33, 18] despite the fact that T-cell function may be inhibited and the incidence of hyperglycemia may be increased [34]. We also demonstrated a definite increase in insulin requirements in patients receiving steroids, but the infection rate in all groups was low. Considering the issue of the pulmonary effects of steroids, we demonstrated a significant MPSS-mediated improvement in pulmonary compliance. Other investigators have confirmed improved compliance [30] but at a cost of worsening oxygenation and delayed extubation [35]; however, the mechanism for this is unclear and further trials are suggested [32].
Second, SMA-CPB was associated with definite reproducible changes in surrogate markers related to blood activation (tPA, elastase, thrombin generation), but in this small sample size their clinical relevance was not evident. Perhaps benefits related to SMA-CPB may only be demonstrated in larger clinical trials with higher risk populations.
Conclusion
This clinical trial was designed as an exploratory study to help provide insight into the potential mechanisms by which combined strategies involving a biocompatible CPB circuit and MPSS may improve outcomes after cardiac surgery. Independent effects were seen on leukocyte function whereas a synergistic effect was seen on both bradykinin release and complement activation. Clinical benefits were more pronounced as an effect of the MPSS administration with particular evidence of decreased CK levels and a decreased incidence of atrial fibrillation. This evidence, in the context of the relative safety demonstrated with MPSS, supports the need for larger clinical trials in high risk patients to determine the clinical relevance and potential economic advantage of this strategy.
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– = SMA-CPB; · · • · · = MPSS; –•– = SMA-CPB and MPSS; · · 
