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Ann Thorac Surg 1999;67:689-696
© 1999 The Society of Thoracic Surgeons
a Cardiac Surgery University of Ottawa Heart Institute, Ottawa, Ontario, Canada
b Cardiac Anaesthesia, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
Accepted for publication August 21, 1998.
Address reprint requests to Dr Rubens, Ottawa Heart Institute, 40 Ruskin St, Ottawa, ON, K1Y 4W7 Canada
e-mail: frubens{at}heartinst.on.ca
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Abstract |
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 Top Abstract IntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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Methods. Thirty-four patients undergoing coronary artery bypass grafting were randomized to bypass using either a control circuit or a circuit prepared "tip-to-tip" with a triblock-copolymer (polycaprolactone-polydimethylsiloxane-polycaprolactone).
Results. There was a progressive increase in thrombin generation in the control group during bypass, which was not seen in the test group. The test surface decreased the release of tissue plasminogen activator and plasmin-
2-antiplasmin complex formation (p < 0.005). There was also an increased platelet count and a decreased platelet activation in the test group, as detected by GMP-140 expression and ß-thromboglobulin release (p = 0.017). There was also significantly more debris that accumulated on the arterial filter in the control group, as confirmed by scanning electron microscopy.
Conclusions. This clinical trial has demonstrated a significant difference in the hematologic effects of the test circuits, with evidence of platelet preservation, decreased fibrinolysis, and decreased thrombin generation. A larger trial would be necessary to establish the clinical relevance of these differences.
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Introduction |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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This clinical trial was designed to compare the hematologic biocompatibility of bypass circuits prepared with this block copolymer with that of standard circuits. Laboratory evaluation included platelet function and number, as well as thrombin generation and fibrinolysis. Blood loss and transfusion requirements in the two groups were also assessed.
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Material and methods |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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The patients were randomly assigned to operation with either the test circuit (SMARxT) or a standard circuit (COBE CML DUO, COBE Cardiovascular Inc, Arvada, CO). The perfusionist performed the assignment immediately preoperatively, by opening a sealed, numbered envelope before set-up of the extracorporeal circuit. The randomization was accomplished using a random number table (CRC Standard Mathematical Tables, 17 ed, The Chemical Rubber Co, Cleveland, OH, 1969, pp 625–9). The cannulae and tubing used in these two circuits were identical in appearance, therefore all members of the surgical and anesthesia teams, excluding the perfusionist, were blinded to the treatment assignment.
Anesthetic management
All cardiac medications, excluding aspirin, were continued up to the day of operation. The premedication included 0.1 mg/kg orally of diazepam 2 hours preoperatively and 0.1 mg/kg intramuscular morphine 1 hour preoperatively. The anesthetic induction included midazolam (0.04 mg/kg), sufentanil (0.5 µg/kg), and ketamine (1.5 mg/kg). Rocuronium (1 mg/kg) was used to facilitate endotracheal intubation. Anesthetic was maintained with midazolam 0.5 µg · kg-1 · min-1, sufentanil 0.5 µg · kg-1 · hr-1, rocuronium 10 µg · kg-1 · min-1, and isoflurane as required to maintain hemodynamic stability. No antifibrinolytics were given to the patients.
Heparin management
Before bypass all patients were anticoagulated with porcine heparin (Organon Teknika, Toronto, Ont, Canada) to achieve a kaolin-driven activated clotting time >480 seconds. Initial dosing was prescribed by a heparin dose-response with Hepcon instrumentation (Hemotec, Medtronic Inc, Parker, CO). Heparin (4,500 U) was also added to the 1.5-L pump prime to establish a 3.0 U/mL concentration. Upon initiation of bypass, the heparin serum concentration was monitored every 20 minutes by way of the Hepcon automated protamine assay and subsequent doses of heparin were administered as needed to sustain a heparin level of 3.0 U/mL [1]. After the termination of CPB, heparin reversal was accomplished with a 1:1 protamine-to-heparin ratio (milligram per milligram) dose of protamine sulfate (Fujisawa Canada, Inc, Markham, Ont, Canada) based on the final heparin serum concentration assayed. A low-dose heparin assay was performed to ensure zero residual heparin after reversal. Blood samples were drawn every 2 hours during the initial 8 hours in the recovery room for heparin levels. In only two instances (one control, one test group) was there any evidence of heparin rebound (heparin >0.2 IU/mL) and additional protamine was administered.
Conduct of bypass
In the control group, CPB was conducted using a roller pump, a flat sheet polypropylene 1.3 m2 membrane oxygenator (COBE Cardiovascular Inc). The remainder of the circuit included a 43-µm arterial filter (COBE Sentry with PrimeGard, COBE Cardiovascular Inc), a closed venous reservoir bag, circuit tubing, an ascending aortic cannula, and a two-stage single venous cannula return. The base resin for all of these components was polyvinylchloride. In the test group, the base resin for all of the surfaces was identical to the control group, although all were prepared during manufacture with the test biomaterial (SMARxT, COBE Cardiovascular Inc). Bypass flows were maintained at 2.4 to 3.2 L · m-2 · min-1. If necessary, volume was given at the perfusionist’s discretion to maintain flows. No restrictions were placed prospectively on the use of either crystalloid (Ringer’s lactate) or colloid (pentastarch) solutions. The body temperature was reduced to a systemic temperature of 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 the bypass grafts at 20-minute intervals. All CPB solutions were filtered by a 40-µm transfusion filter (SQ40S Pall Biomedical Products Co, East Hills, NY). At the completion of the procedure, the patient was rewarmed to a nasopharyngeal temperature of 37°C and then weaned from CPB after mechanical ventilation had been restarted.
Management of mediastinal shed blood
To exclude the effects of the activation of shed blood from the mediastinum, a cardiotomy suction system was not used in these patients. Cardiac venting was accomplished through the aortic root by gravity drainage directly into the venous CPB line. All scavenged blood from the mediastinum, collected intraoperatively and up to 4 hours postoperatively, was processed by filtration (30 µm), and centrifugation and washing (BRAT, COBE Cardiovascular Inc) before reinfusion. After 4 hours, all subsequent blood was discarded unless clinical situations (eg, excessive bleeding/no operating room available for taking the patient back) warranted otherwise.
Perioperative and postoperative management
Red blood cells (allogeneic or autologous) were administered to maintain a hematocrit of 21 during bypass and 24 postoperatively, in the absence of hemodynamic instability. Strict guidelines were used in both groups for the administration of platelets, cryoprecipitate, and fresh frozen plasma after bypass. Immediately upon arrival to the intensive care unit, all patients were treated with an acetylsalicylic acid suppository (650 mg). Oral administration of enteric-coated acetylsalicylic acid (325 mg) was commenced the following day. All patients were started on subcutaneous heparin (5,000 U every 12 hours) on the first postoperative day.
Collection of blood specimens
Blood specimens were obtained from the side-port of the right internal jugular vein sheath after removal of six dead space volumes of blood. The sampling was carried out at the time points indicated in Table 1.
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2-antiplasmin complex (Dade Behring Canada Inc, Mississauga, ON, Canada). Platelet ß-thromboglobulin was assessed with radioimmunoassay (Wellmark Diagnostics, Guelph, ON, Canada). Fibrinogen was assessed with a fibrometer with a standard clotting assay [4] (Blood Coagulation Analyser, Fibrometer Lab Equipment, Markham, ON, Canada) and D-dimer was measured with an enzyme-linked immunosorbent assay (Murex Diagnostics, Guelph, ON). Routine hematology variables were then determined including red blood cell mass, white blood cell count, and platelet count (Serono, model 9000, Baker Diagnostic, Allentown, PA). For the preparation of whole blood for flow cytometry, blood was slowly aspirated into collection syringes from the side port of the introducer of the jugular vein cordis sheath (ArrowFlex, Arrow International Inc, Reading, PA) after discarding the initial 10 mL. All of the blood samples were immediately transferred to Diatube-H vacutainer tubes (Becton Dickenson, Braintree, MA) from the collection syringes. The cap to the vacutainer tube was removed before adding the blood to the anticoagulant to prevent blood activation from the vacuum.
Preparation of platelets
Aliquots of whole blood (5 µL), which had been taken in Diatube-H tubes, were added to several Eppendorff tubes containing Tyrode’s albumin (TA, Tyrode’s buffer with 3.5 g/L bovine serum albumin) and glycyl-L-prolyl-L-arginyl-L-proline (Sigma Chemicals, St. Louis, MO) (2.5 µL of 1.25 mmol/L). The glycyl-L-prolyl-L-arginyl-L-proline was added to inhibit fibrin polymerization. All samples were then incubated for 30 minutes (37°C) before addition of the antibodies as described below. The optimal concentrations of the added antibodies used in these experiments were determined in previous experiments with blood from normal controls in which the platelets were maximally stimulated with thrombin as described below. The minimum amount of antibody required to detect activation was determined, and in subsequent experiments, the antibody concentration was doubled.
Addition of antibodies
Activated glycoproteins IIb/IIIa
Undiluted fluorescein isothiocyanate (FITC)-conjugated mouse immunoglobulin (Ig) M (2.5 µL; Caltag Laboratories, San Francisco, CA) was added to the negative control sample and 5 µL of FITC-conjugated PAC-1 (Dr. Sanford Shattil, Hospital of the University of Pennsylvania, Philadelphia, PA) was added to the test samples. The samples were then incubated at 22°C for 30 minutes and read immediately in the flow cytometer.
Platelet thrombospondin
Undiluted rat IgG2a (5G11; 10 µL) directed against human thrombospondin (Caltag Laboratories) was added to the test samples. No antibody was added at this point to the negative control sample. All samples were incubated for 30 minutes (22°C) after which they were washed twice with 500 µL of plain Tyrode’s solution, and resuspended in TA (50 µL). After this, 10 µL of undiluted FITC-conjugated anti-rat IgG2a mouse IgG1 (Caltag Laboratories) was added to each sample. The samples were incubated at 22°C for another 30 minutes in the dark then washed twice with 500 µL of plain Tyrode’s solution. They were then resuspended in 50 µL of TA and read on the flow cytometer.
CD62P(GMP-140)
Unlike the above activation assays, GMP-140 was measured on fixed platelets as described by Kuhne and colleagues [5] as follows. Samples of whole blood were mixed with equal volumes of 1% paraformaldehyde for 20 minutes (22°C). Samples of 5 µL were then added to 25 µL of FACsFlow buffer (Becton Dickenson, Braintree, MA) in an Eppendorff tube. In the test samples, 2.5 µL of undiluted FITC-conjugated CD 62P (BioCan Scientific, Mississauga, ON, Canada) was added, whereas in the negative control samples, 2.5 µL of undiluted FITC-conjugated rabbit IgG (BioCan Scientific) was added. The tubes were incubated at 4°C for 30 minutes, and then read immediately on the flow cytometer.
Glycoprotein Ib
Unfixed whole blood (5 µL) was added to 50 µL of TA, followed by 2.5 µL of undiluted FITC-conjugated CD42 (Pharmingen, San Diego, CA) or 6D1, an antibody to a different epitope of the glycoprotein Ib receptor (Dr. Barry Coller, Mount Sinai Hospital, New York, NY). In the negative control samples, 2.5 µL of undiluted FITC-conjugated rabbit IgG was added. The tubes were incubated at 4°C for 30 minutes, and then read immediately on the flow cytometer.
Monocyte-tissue factor
To 50 µL of unfixed whole blood, 10 µL of phycoerythrin-labeled CD14 (Becton Dickenson, Braintree, MA) as well as 10 µL of mouse FITC-labeled anti-human tissue factor (American Diagnostica) was added. In the negative control tube, 10 µL of phycoerythrin-labeled CD14 as well as 10 µL of mouse polyclonal FITC-labeled IgG (Becton Dickenson) were added. All tubes were incubated on ice for 30 minutes in the dark, then fixed with 250 µL of a solution containing formaldehyde (9.25%) and methanol (3.25%) for 60 seconds. At the end of the incubation, 4 mL of TA was added and the mixture was incubated at 22°C for 30 minutes in the dark. The mixture was then washed with TA, centrifuged, and the final pellet was resuspended in 400 µL of TA before the reading of the flow cytometer.
Measurement of platelet and leukocyte markers by flow cytometry and data analysis
The samples were read on a FacScan Analyzer (Becton Dickenson) with an argon laser, reading 50,000 events. The primary gate was selected using a dot plot of forward and side scatter. The background fluorescence was usually less than 2% for all of the experiments.
Morphologic analysis
Arterial filters from test and control circuits were fixed by filling the filters with 2% glutaraldehyde in saline solution. The filters were drained and dried with filtered compressed air. Samples were harvested after cutting the filters apart with a band saw. The samples were dehydrated for 20 minutes in a graded ethanol and hexamethyldisilazane (Ted Pella, Inc, Redding, CA) series (90% ethanol in reverse osmosis distilled water, 95% ethanol in reverse osmosis distilled water, pure ethanol, and 50% ethanol/50% hexamethyldisilazane solutions, and finally pure hexamethyldisilazane). After dehydration, samples were sputter-coated with 200 
of gold particles and examined on JEOL JSM-6400 scanning electron microscopy (Rocky Mountain Laboratories, Golden, CO) at 10 KV accelerating voltage.
Data analysis and statistics
Sample size was based on detecting a minimally clinically important difference of 25% between the control and test groups in the level of TAT at 40 and 60 minutes on CPB. Seventeen patients per group were sufficient to detect this difference with = 0.05 and ß = 0.20. Continuous variables were analyzed using t tests and categorical variables were analyzed using a 
2 test or Fisher’s exact test as appropriate. Repeated measures were analyzed using repeated measures of analysis of variance (ANOVA). If the ANOVA was significant (p < 0.05), then t tests were done at individual time points using the Bonferroni correction for multiple testing.
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Results |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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Laboratory results
Platelet number and activation
There was no significant difference in the expression of glycoprotein Ib detected on the platelet surface by either of the antibodies 6D1 or CD42 (results not shown). In both groups, there was an expected decrease in the platelet count after going on CPB, associated with hemodilution. However, the platelet count was better preserved in the test group, both during and after bypass (p < 0.05 sample points 5, 6, 8, 9; Fig 1A ).
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-granule after activation) were significantly decreased in the test group during bypass and for 1 hour after administration of the protamine (ANOVA p = 0.017; Fig 1B). To confirm these changes in the platelets, a variety of markers of activation were measured by flow cytometry. GMP-140 or P-selectin was significantly decreased during bypass (ANOVA p = 0.0132; Fig 1C). Neither platelet thrombospondin nor activated glycoprotein IIb/IIIa demonstrated significant differences (results not shown).
Thrombin generation
The generation of thrombin was assessed using measurements of both TAT (Fig 2A ) and F1.2 (Fig 2B). With both markers, there was a progressive increase in the generation of thrombin during the later stages of CPB in the control group, not seen in the test group. During CPB, only TAT showed an overall difference (ANOVA; TAT, p = 0.011; F1.2, p = 0.158). However, both markers have the same pattern of change. Monocyte tissue factor, which is a known source for thrombin generation, showed a progressive increase in expression in the control group with longer periods on CPB, but these changes were not significant as a result of a large amount of variability (Fig 2C). There was no difference in the generation of fibrinopeptide A during and after CPB (results not shown).
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2-antiplasmin (Fig 3B) increased quickly after the initiation of CPB in the control group, this increase was not seen in the test group. D-Dimer did not show a significant difference between the test and control groups. Similarly, there was no difference in the levels of fibrinogen in the two groups (results not shown).
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Comment |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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In this trial, significant changes were found in the effect of this surface on a variety of aspects related to coagulation, fibrinolysis, platelet function, and number. Although there was a decrease in the platelet count with initiation of CPB and hemodilution, the platelet count continued to decrease in the control group and this change was not seen in the test group. This difference persisted into the postoperative period. There was also evidence for decreased platelet activation with CPB in the test group as demonstrated by decreased expression of the platelet surface marker GMP-140 and decreased release of ß-thromboglobulin.
Jessen and colleagues [2] have previously demonstrated in a porcine model of CPB that the mechanism of preservation of the platelet count by the SMA relates to decreased platelet deposition on the oxygenator. Neutrophil deposition was also decreased in the test group. Gu and colleagues [10] found similar platelet preservation in a clinical trial in which patients were randomized to standard circuits or SMA circuits. Platelet activation, as measured by ß-thromboglobulin release, was decreased in the test group during CPB. There was also significantly decreased deposition of platelets on the arterial and venous tubing of the circuit, as measured by labeled monoclonal antibody to the platelet glycoprotein IIIa. The platelet preservation and the decreased expression of GMP-140 in the present trial may be related to decreased platelet–neutrophil aggregate formation and the level of heparinization may be insufficient to prevent this in the control group [11, 12].
Thrombin generation did occur with CPB in the control group but not in the test group in this study, despite carefully controlled heparin levels (3 U/mL on CPB) [13]. The role of tissue factor from the pericardial well as a source for thrombin generation was excluded by the washing of all shed blood. Therefore, the mechanism for thrombin generation may be related to contact activation of the blood related to the circuit. In vitro experiments with human blood have demonstrated that SMA blended polymers delay contact activation and reduce coagulation activity, as measured by TAT generation [3]. Another potential mechanism for thrombin generation may be related to the expression of tissue factor on circulating monocytes as there was a trend to an increase in its expression in the control group toward later stages of CPB in a pattern similar to the generation of thrombin.
It has been advocated that heparin-coated circuits could be used with lower levels of heparin during CPB [14]. However, some investigators have failed to confirm a decrease in thrombin generation with this approach [15, 16]. There are also some reports that this approach may be dangerous as thrombosis has been described on CPB [17]. The SMA-modified surface shows particular promise that it may fulfill this need safely, potentially with lower heparin levels (activated clotting time > 280 seconds). Decreased heparin administration has many advantages. Heparin itself has been clearly demonstrated to be a potent activator of platelets, and it may contribute to platelet dysfunction after operation [18]. Heparin has also been demonstrated to be a major stimulant of fibrinolysis [19]. In a carefully controlled trial, Aldea and colleagues [20] demonstrated that the use of a lower activated clotting time, combined with a heparin-coated surface, markedly decreases shed blood postoperatively, and this was associated with significantly decreased transfusion requirements.
tPA release during CPB has been demonstrated in previous trials [21] and this release can be inhibited by the administration of aprotinin [22], possibly secondary to direct inhibition of heparin-mediated release of tPA [22]. The inhibition of tPA antigen release during and after CPB in the test group in this trial was not anticipated as antifibrinolytics were not used. This suggests that heparin is not the culprit for tPA release and that the block copolymer prevents the release from the blood of an alternative product that would otherwise stimulate endothelial cell release of tPA. The potential known agonists for tPA release include histamine, bradykinin, adrenaline, endothelin-1 or –3, prostacyclin and its stable biotransformed metabolite 6-keto-prostaglandin E1, and thrombin [23–26]. Because thrombin generation only appears to be occurring during the later stages of CPB, this latter agonist is unlikely to be causative in this trial.
There were parallel decreases in plasmin-2-antiplasmin in the test group that were likely related to the increased tPA, but the difference in D-dimer was not significant. Furthermore, although this was a small trial, the overall blood loss in the two groups was not statistically different. This suggests that in this trial, the induced fibrinolysis that may result from tPA release in the control group, is likely controlled by inhibitory mechanisms. These may include not only plasmin complexing with -2 antiplasmin, but also direct inhibition of tPA by plasminogen activator inhibitors [22]. However, these regulatory mechanisms may be overwhelmed in cardiac operations that require longer CPB or in cases in which the intraoperative blood loss is much greater, such as reoperations, resulting in increased bleeding and transfusion requirements in these patients. Further trials should be completed to evaluate the role of this CPB circuit in these patient groups.
In summary, this trial has demonstrated a significant difference in the hematologic effect of circuits prepared with SMAs, with evidence of platelet preservation, decreased tPA release, and decreased thrombin generation on CPB. These changes were not associated with differences in postoperative blood loss or transfusion requirements; however, a larger clinical trial would be necessary to definitively demonstrate this. Further work should be done to evaluate the clinical relevance of these changes. Circuits prepared with this surface should also be evaluated for their potential application and safety for CPB with low levels of systemic heparin, as this approach may be a mechanism to decrease the need for homologous blood products in patients undergoing cardiac operation.
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Acknowledgments |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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