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Gabriel S. Aldea
Oz M. Shapira
Ashraf Osman
Harold L. Lazar
Richard J. Shemin
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Ann Thorac Surg 1998;65:425-433
© 1998 The Society of Thoracic Surgeons


Original Articles: Cardiovascular

Effect of Anticoagulation Protocol on Outcome in Patients Undergoing CABG With Heparin-Bonded Cardiopulmonary Bypass Circuits

Gabriel S. Aldea, MD, Paul O’Gara, CCP, Oz M. Shapira, MD, Patrick Treanor, CCP, Ashraf Osman, MD, Eva Patalis, MD, Charles Arkin, MD, Rhea Diamond, PhD, Viken Babikian, MD, Harold L. Lazar, MD, Richard J. Shemin, MD

Department of Cardiothoracic Surgery, Boston University Medical Center, Boston, Massachusetts, USA
Department of Pathology, Boston University Medical Center, Boston, Massachusetts, USA
Department of Neurology, Boston University Medical Center, Boston, Massachusetts, USA

Accepted for publication August 7, 1997.

Dr Aldea, Department of Cardiothoracic Surgery, Boston University Medical Center, 88 E Newton, Boston, MA 02118-2393.


    Abstract
 Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background. We have demonstrated that the use of heparin-bonded cardiopulmonary bypass circuits (HBCs) combined with a lower anticoagulation protocol as an adjunct to an integrated blood conservation strategy decreases the incidence and magnitude of homologous transfusion and improves clinical outcome in patients undergoing primary coronary artery bypass grafting. It is not known whether it is the lower anticoagulation protocol that influences outcome in patients treated with HBCs. Furthermore, the thrombogenic risk of using lower anticoagulation with HBCs still is debated.

Methods. To answer these questions, a prospective randomized study was conducted in which 244 patients undergoing primary coronary artery bypass grafting were treated with HBCs and randomized to undergo either a full (activated clotting time, >450 seconds) or a lower (activated clotting time, >250 seconds) anticoagulation protocol. In addition to clinical outcome, levels of thrombin generation markers during and after cardiopulmonary bypass were assessed in a consecutive subset of 58 patients (full anticoagulation profile = 28, lower anticoagulation profile = 30) by measuring thrombin-antithrombin complexes and prothrombin fragment 1.2. Levels of these markers also were correlated with the activated clotting time during cardiopulmonary bypass.

Results. Preoperative and intraoperative risk profiles and other characteristics were similar in both groups, with more than 60% of patients undergoing nonelective operation. Compared with the full anticoagulation protocol group, patients in the lower anticoagulation protocol group were less likely to require blood products (24.2% versus 35.8%, respectively; p = 0.047) and received substantially fewer homologous donor units (0.50 ± 0.92 versus 1.08 ± 2.10 U, respectively; p = 0.005). Clinical outcomes were uniformly outstanding (but similar) in both treatment groups, with a modest reduction in the length of the hospital stay in the lower anticoagulation protocol group (5.26 ± 1.23 versus 5.63 ± 1.73 days, respectively; p = 0.05). The use of HBCs with a lower anticoagulation protocol was not associated with any adverse clinical events. Thrombin generation increased during cardiopulmonary bypass in both treatment groups, but was unrelated to the anticoagulation protocol or the activated clotting time (r2 = 0.03). No differences between the full and lower anticoagulation protocol groups were noted in the number of microemboli detected by transcranial Doppler analyses during cardiopulmonary bypass (n = 40) or in the postoperative neurologic and neuropsychologic outcomes (n = 30).

Conclusions. This study definitively demonstrates that, when used appropriately, patients who are treated with HBCs and a lower anticoagulation protocol have a lower incidence and magnitude of homologous transfusion and are not at any added risk for clinical, hematologic (thrombin-antithrombin complex and fragment 1.2 measurements), or microscopic (transcranial Doppler analyses) thromboembolic complications or for neurologic or neuropsychologic deficits.


    Introduction
 Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
The bonding of heparin to all the surfaces that come into contact with blood during cardiopulmonary bypass (CPB) was developed in an attempt to limit the blood-material reaction, enhance biocompatibility and thromboresistance, and limit the postperfusion syndrome [1] [2] [3] [4] [5] [6] [7] [8]. We have demonstrated that, compared with the use of conventional circuits and a full anticoagulation protocol (FAP), the use of "tip-to-tip" heparin-bonded CPB circuits (HBCs) with a lower anticoagulation protocol (LAP; activated clotting time [ACT], >280 seconds) results in a significant reduction in the incidence and magnitude of homologous transfusion and an improvement in clinical outcome, including the incidence of postoperative myocardial infarction (MI), respiratory complications, and atrial fibrillation; inotropic requirements; the time to extubation; and the length of the hospital stay (and therefore the cost) [9]. It is not known whether it is the LAP or the use of HBCs that most greatly influences outcome. The current study was designed to study the effect of the anticoagulation protocol used on clinical outcome in patients treated with HBCs and to answer definitively concerns regarding the thrombogenic risk of this novel technology in the presence of an LAP (target ACT, >250 seconds).


    Material and Methods
 Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
An integrated blood conservation strategy was developed and used on all patients undergoing primary coronary artery bypass grafting (CABG) at our institution. The strategy included maximum cell-saving and the use of large-bore directional arterial cannulas, centrifugal pumps, hollow-fiber membrane oxygenators, closed venous reservoirs, low priming solution volumes (<600 mL), near-normothermic bypass (no active cooling), precise heparin and protamine titration, {epsilon}-aminocaproic acid (Amicar; American Reagent, Shirley, NY) administration, and tip-to-tip HBCs. Strict transfusion threshold protocols were observed, meticulous attention was paid to technical details, and a concerted effort was made by the surgeons, perfusionists, anesthesiologist, and nurses to minimize homologous transfusion.

To eliminate variability between surgeons and perfusionists, we standardized all the components, configurations, and techniques of CPB. Standardized, uniform transfusion thresholds and protocols, extubation protocols, and surgical intensive care unit and hospital management pathways were applied uniformly to all patients [9]. The study was reviewed by and received approval from the Boston University Medical Center Institutional Review Board (IRB protocol number 3610, approved July 1995). All patients undergoing primary CABG were treated with HBCs and assigned randomly to one of two treatment groups: the LAP group (target ACT, >250 seconds) or the FAP group (target ACT, >450 seconds). Two hundred sixty consecutive patients undergoing CABG within a 6-month period were evaluated and 244 patients were randomized, representing an accrual of 93.8% of eligible patients. Six patients refused randomization and were treated with an FAP and 10 others were treated outside the protocol with an LAP and HBCs at their surgeons’ request (because of religious beliefs, a recent cerebrovascular accident, or an acute gastrointestinal bleed requiring transfusion within a month of CABG). Also excluded from randomization were patients who experienced catheterization laboratory emergencies or required reoperative CABG, all of whom were treated with HBCs and an LAP.

Cardiopulmonary Bypass Circuit
The entire CPB circuit (from tip to tip) was heparin-bonded. Heparin-bonded circuits consisted of a tip-to-tip circuit, cardiotomy, oxygenator, cardioplegia set (Duraflo II; Baxter, Irvine, CA), directional arterial cannula (20F or 22F), antegrade and retrograde cardioplegia administration set and catheters (DLP Inc, Grand Rapids, MI), and a centrifugal Biopump (Carmeda; Medtronic Inc, Minneapolis, MN). Centrifugal pumps were used exclusively.

Anticoagulation Protocol and Cardiopulmonary Bypass Technique
The heparin dose was measured by a dose-response assay using the Hepcon Heparin Management System (Medtronic Inc) titrated to achieve and maintain an ACT of greater than 250 seconds in the LAP group (n = 124) and greater than 450 seconds in the FAP group (n = 120). In both groups, the ACT was checked every 20 minutes throughout CPB. Cardiopulmonary bypass was initiated slowly with an empty (closed) venous reservoir and a low volume (<600 mL) of Plasmalyte priming solution (Travenol; Baxter) using a modified retroautologous priming technique. Once the venous reservoir was filled, flow was increased to maintain venous saturation of 60% to 75%. Core temperature was not allowed to drift below 34°C and active cooling was avoided. During the entire procedure, all field drainage was directed to a cell-saving device (Haemonetics Corp, Braintree, MA). In both treatment groups, no discard suckers were used and all sponges were soaked in saline solution, wrung into a sterile reservoir by the scrub nurse, and directed to the cell-saving device. Cardiotomy pump suckers were used sparingly and only in the event of significant and active bleeding.

Myocardial Protection
The myocardial protection techniques used were identical in the LAP and FAP groups. In both groups, priming of the blood cardioplegia line was performed on CPB with blood rather than with crystalloid solution. Cold (4°C) blood cardioplegia was administered in an antegrade fashion in all patients and was supplemented with retrograde cardioplegia in most patients. In all patients, cardioplegia also was administered down the saphenous vein grafts. Cardioplegia was readministered every 20 minutes while the cross-clamp was applied. Before each dose, 50 mL of cardioplegia, presumed to be stagnant in the tubing, was discarded to the surgical field and directed to the cell-saving device. Topical cooling with cold saline was used to supplement myocardial protection.

Weaning From Cardiopulmonary Bypass and Reversal of Anticoagulation
Patients were warmed actively to a core temperature of 37°C before weaning from CPB. Once they were weaned from CPB, a test dose of protamine (Elkins-Sunn, Cherry Hill, NJ) was administered and the cannulas were removed promptly. To prevent blood stagnation after line clamping, the circuit was recirculated continuously in both the LAP and FAP groups. After hemodynamic stability was confirmed (after the protamine test dose), the arterial, venous, pump sucker, and cardioplegia lines were drained quickly of blood by retrograde siphoning, allowing the lines to be refilled (and deaired) with crystalloid solution. All blood was directed to the cell-saving device. Thus, a crystalloid-primed circuit was available in the event of hemodynamic deterioration. In both groups, the protamine reversal dose was verified and titrated by the Hepcon Heparin Management System (Medtronic Inc). In the both the LAP and FAP groups, 10 g of {epsilon}-aminocaproic acid (Amicar; American Reagent) was administered intravenously over 30 minutes after heparin administration and before the initiation of CPB. An additional 10 g was administered intravenously by continuous infusion over 5 hours. Aprotinin was not used in either treatment group.

Transfusion Practices
All surgically correctable bleeding was addressed carefully. Patients received a transfusion of red blood cells when the intraoperative hematocrit fell below 20% during CPB or the postoperative (ie, surgical intensive care until to hospital discharge) hematocrit fell below 25%. Persistent postoperative bleeding in excess of 300 mL in the first hour or 500 mL in the first 2 hours was considered to be an indication for the transfusion of platelets (5 to 10 U) and fresh frozen plasma (2 U) in the presence of confirmatory laboratory test results.

Transcranial Doppler Analysis
A subset of 40 consecutive patients (LAP = 20, FAP = 20) was selected by block randomization to undergo perioperative transcranial Doppler (TCD) monitoring to assess the risk of particulate microemboli. A TC-2020 instrument (Nicolet/EME "Pioneer"; Eden Medical Electronics, Madison, WI) equipped with a 2-MHz probe was used for TCD monitoring during this study. The probe was positioned carefully by an experienced technician over the left temporal bone window and immobilized with a specially designed headband. In 10 patients, the right side was insonated because of an inadequate left temporal bone window. The proximal middle cerebral artery M1 segment or the supraclinoid internal carotid artery was insonated at a depth of 55 to 65 mm. Signals over the middle cerebral artery were recorded continuously and all significant events and potential artifacts were noted and their relation to the different, specifically predefined, surgical maneuvers and steps of the operation (ie, sternotomy, aortic cannulation, antegrade and retrograde cardioplegia catheter cannulation, initiation of CPB, application of the aortic cross-clamp, removal of the aortic cross-clamp, application of the partial aortic occlusion clamp, removal of the partial aortic occlusion clamp, weaning from CPB, aortic decannulation, and reversal of anticoagulation was recorded).

An experienced technologist was present in the operating room throughout the course of the operation, monitoring both the patient and the instrument screen. A written and electronic log of the course of surgical events and any potential sources of artifact was maintained. The disc was reviewed at the end of the study and microemboli counts as well as signal amplitude and duration measurements were performed. The data were evaluated by an experienced neurologist [10] [11]. Microembolic signals or high-intensity transient signals occurred randomly throughout the cardiac cycle (while the heart was beating), were associated with a characteristic "chirping" sound on the audio output, had an intensity greater than 3 dB higher than that of surrounding blood, and lasted at least 25 ms. Most lasted less than 100 ms. These criteria were similar to those used routinely in our laboratories and those of other investigators [12] [13] [14].

Thrombin-Antithrombin and Prothrombin Fragment 1.2 Measurements
A subset of 58 consecutive patients (LAP = 30, FAP = 28) was selected by block randomization to undergo detailed evaluation of thrombin generation products. Thrombin generation during CPB was determined by quantitative measurements of thrombin-antithrombin (TAT), which expresses the inactivation of thrombin by antithrombin III, and of prothrombin fragment 1.2, which expresses the conversion of prothrombin to thrombin. Individual measurements of TAT and fragment 1.2 were performed using specific Enzygnost enzyme immunoassay systems (Behring Diagnostic Inc, Westwood, MA). Analyses were performed in duplicate for each sample and compared with standards according to the required protocol. Measurements were made in each patient before the initiation of CPB (after heparin administration), 10 minutes after the initiation of CPB (initial CPB), after cross-clamp release as the patient was being weaned from CPB but before protamine administration (end of CPB), and 2 hours and 5 hours after the operation. In an additional 11 consecutive patients treated with HBCs and an LAP, the effects of protamine reversal and the potential reinfusion of blood from the cell-saving device and mediastinal blood on thrombin generation were assessed by measuring TAT levels before CPB, at the end of CPB, 15 minutes after protamine administration, from reinfused blood in the cell-saving device at the end of the operation, and from shed chest tube blood collected within 1 hour of chest closure.

Neurologic and Neuropsychologic Evaluation
A subset of 30 consecutive patients was selected to undergo neurologic and neuropsychologic evaluation. These patients were evaluated before CABG (session 1), just before hospital discharge (session 2), and approximately 3 weeks after hospital discharge (session 3). At each session, the patients were given a neurologic evaluation using the National Institutes of Health stroke scale and a broad spectrum of neuropsychologic tests. These tests included subtests of the computer-assisted Neurobehavioral Evaluation System (Neurobehavioral Evaluation Inc, Winchester, MA) assessing sustained attention, finger-tapping speed, memory for patterns, verbal learning and recall, simple and complex sequencing, and mood, along with a traditional neuropsychologic test of visual-motor skill (Santa Ana Formboard Test). All neurologic and neuropsychologic tests were administered by experienced members of the neurology service who were blinded to the treatment group status (FAP versus LAP) of the patients.

The data from these behavioral tests were analyzed to follow the progress of each individual patient rather than just to examine changes in group means. This choice recognizes the likelihood that individual patients might be impaired on different measures (so that averaging data across measures might obscure patterns of change). Consideration also was given to possible practice effects resulting from repeated testing with the same instruments. There is no agreed-on standard for changes in individual performance that are considered meaningful. The value chosen here as an index of a meaningful effect was a change of 20% from baseline.

Statistics
All data and figures are presented as the mean plus or minus the standard deviation. Continuous variables were evaluated by Student’s t test or analysis of variance, and categoric variables were tested by {chi}2 test, where appropriate. The effect of individual independent categoric variables (dichotomous, present or absent) on a categoric outcome were analyzed using univariate analyses and presented as odds ratios with 95% confidence limits. Multiple linear regression analyses with a least-squares model were used to determine the effect of independent variables on a continuous dependent outcome variable. Logistic regression models were used when the dependent variable (outcome) was dichotomous (ie, the presence of homologous transfusion or the occurrence of postoperative complications). Independent variables were both continuous (ie, age, ejection fraction, total pump time) and dichotomous, with several dummy variables (ie, gender, elective versus urgent operation, preoperative renal failure or cerebrovascular accident/transient ischemic attack [CVA/TIA], use of HBCs, postoperative MI, need for inotropic support or intraaortic balloon counterpulsation, CVA/TIA, pulmonary complications, atrial fibrillation). Absolute p values were reported. Differences were considered statistically significant at p less than 0.05.


    Results
 Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
The preoperative and intraoperative risk profiles were comparable in the LAP and FAP groups, with the exception of a higher incidence of low ejection fraction in the LAP group (Table 1). No statistically significant differences between preoperative and discharge hematologic parameters were noted between the treatment groups (Table 2). By design, both the initial heparin dose (54% reduction) and the total heparin dose (57% reduction) were significantly lower in the LAP group (Table 3). The ACTs at the initiation and completion of CPB were significantly lower in the LAP group. Consequently, protamine reversal also was significantly lower in the LAP group (54% reduction). The total amount of shed pleural and mediastinal blood measured from the time of sternal closure was similar in the LAP and FAP groups at 12 hours (381 ± 204 versus 415 ± 222 mL, respectively; p = 0.22) and at 24 hours (561 ± 290 versus 580 ± 281 mL, respectively; p = 0.60). Compared with patients treated with an FAP, patients treated with an LAP were less likely to require transfusion (24.2% versus 35.8%, respectively; p = 0.047; 32% reduction; odds ratio 0.57 with a 95% confidence interval of 0.33 to 0.99). The magnitude of homologous donor exposure was reduced significantly in the LAP group compared with the FAP group (0.50 ± 0.92 versus 1.08 ± 2.10 U, respectively; p = 0.005; 54% reduction) (Table 4). Most transfusions (92%) were administered during the first 24 hours after operation. To ensure that subtle differences in patient profiles did not account for these differences, multivariate analyses were performed to identify independent predictors of homologous transfusion. These independent predictors were total pump time, gender, anticoagulation protocol (LAP versus FAP), and preoperative hematocrit. Age, preoperative diabetes, hypertension, renal dysfunction (creatinine >2.5), chronic obstructive pulmonary disease, prior CVA/TIA, prior MI, ejection fraction, body surface area, operative circumstance (urgent versus elective), left main disease, prior aspirin therapy, intravenous nitroglycerin or heparin, preoperative platelet count, fibrinogen level, and aortic cross-clamp time were not independent predictors of homologous transfusion (Table 5).


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Preoperative and Intraoperative Patient Profiles and Risk Characteristics

 

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Hematologic Profiles of the Treatment Groups Before Operation and at the Time of Hospital Discharge

 

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Anticoagulation, Activated Clotting Time, and Protamine Reversal Profiles of the Treatment Groups

 

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Transfusion Requirements of the Treatment Groups

 

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Multivariate Analyses of Independent Predictors of Homologous Transfusion

 
The clinical results were outstanding and were similar in both the LAP and FAP groups (Table 6). Patients treated with an LAP had a lower total incidence of thromboembolic complications, defined as perioperative MI, CVA/TIA, and vascular complications (0.8% versus 5.0%, respectively; p = 0.049), and they had a modest reduction in hospital stay (5.26 ± 1.123 versus 5.63 ± 1.73 days, respectively; p = 0.05).


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Clinical Outcomes of the Treatment Groups

 
To quantify further thrombin generation during CPB, TAT and fragment 1.2, markers of thrombin generation, were measured in 58 consecutive patients (LAP = 30, FAP = 28) (Table 7). The concentrations of TAT and fragment 1.2 increased progressively and significantly during CPB (p = 0.0007 by analysis of variance) and decreased during the postoperative period (Fig 1). There were no statistically significant differences in these measurements between the LAP and FAP groups.


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Thrombin Generation in the Treatment Groups

 


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Comparison of thrombin generation during and after cardiopulmonary bypass (CPB) with a lower anticoagulation profile (LAP) and a full anticoagulation profile (FAP). (A) Thrombin-antithrombin (TAT). (B) Prothrombin fragment 1.2 (F1.2). (PO = postoperative; *p < 0.001 by analysis of variance.)

 
The relation between the highest thrombin level generated during CPB (after CPB but before protamine administration) and the simultaneous ACT was evaluated in these 58 patients. Using regression analysis, we observed that the maximum levels of thrombin generated correlated poorly with the ACT during CPB (r2 = 0.029) (Fig 2). Similar results were obtained from an analysis of fragment 1.2. The contribution of protamine reversal and the potential effect of the administration of blood from the cell-saving device and shed chest tube blood on measurements of serum TAT levels were defined in an additional subset of 11 consecutive patients. These results demonstrated large variability in the amount of TAT formed during CPB. Thrombin-antithrombin levels did not change between the end of CPB and 15 minutes after protamine administration (Fig 3). Blood from the cell-saving device contained higher levels of TAT. This increase was statistically significant compared with pre-CPB levels (p = 0.01) and approached, but did not reach, statistical significance compared with levels after protamine administration (p = 0.06). Shed chest tube blood (collected within 1 hour of chest closure) showed a nearly 10-fold increase in TAT levels compared with pre-CPB levels (p = 1.24 x 10-14), as well as a 4-fold increase over levels measured after protamine administration (p = 8.76 x 10-9).



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Relation between thrombin generation as measured by thrombin-antithrombin (TAT) and activated clotting time (ACT).

 


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Comparison of thrombin-antithrombin (TAT) generation during cardiopulmonary bypass (CPB) and from reinfused blood from the cell-saving device and chest tube drainage. (CS = cell-saving device; *p < 0.01 compared with before CPB; **p < 0.00001 compared with after protamine administration and before CPB.)

 
The risk of particulate thromboembolism was assessed further by measuring particulate microemboli in the middle cerebral artery using TCD monitoring in 42 consecutive patients. Data obtained by TCD monitoring were deemed adequate in 40 patients (LAP = 20, FAP = 20). For all 40 patients, most of the particulate emboli (71%) occurred during aortic manipulation (aortic cannulation and decannulation, and partial or complete clamping and unclamping) compared with all other periods during CPB (20.65 ± 29.83 versus 8.42 ± 12.68 embolic events per patient, respectively; p = 0.03). There were no differences in the number of emboli related to CPB, aortic manipulation, or the total number of embolic events between the LAP and FAP groups (Table 8).


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Number of Particulate Microemboli Detected by Transcranial Doppler Monitoring in the Treatment Groups

 
Detailed neurologic and neuropsychologic evaluations were performed in a subset of 30 consecutive patients (LAP = 19, FAP = 11) to determine whether there were differences in sensory, motor, cognitive, or affective function between the LAP and FAP groups. Patients were evaluated before CABG (preoperative day 1.93 ± 3.06; session 1), just before hospital discharge (postoperative day 3.77 ± 0.73; session 2), and approximately 3 weeks after hospital discharge (postoperative day 23.25 ± 7.34; session 3). The National Institutes of Health neurologic stroke scale detected no statistically significant changes in neurologic function between test sessions in either group and no differences between the LAP and FAP groups on this measure. For the entire group of 30 patients, the mean neurologic stroke score was 0.50 ± 1.01 for session 1, 0.63 ± 1.69 for session 2, and 0.39 ± 0.78 for session 3.

Because the same neuropsychologic tests were used in all three sessions, practice effects were expected. It can be assumed that most such effects on these novel tasks will occur between the first and second attempts at performance (ie, between sessions 1 and 2). Thus, any observed change between these two sessions is likely to underestimate a possible decline. This can be remedied by considering performance in session 3, 3 weeks after CABG. Performance at that time presumably reflects recovery from any negative effects of operation, unavoidably confounded by the emerging effects of practice, as well as by possible real improvement attributable to the beneficial effects of CABG. However, for the purpose of deriving the most sensitive estimate of any immediate postsurgical decline, gains between session 1 and session 3 can be considered to result entirely from practice. Accordingly, an appropriate measure of the decline in session 2 was taken to be the difference in score between that session and session 3, expressed as a percentage of the patient’s baseline score (session 1). Using the 20% of 20% of measures criterion [15], 86.6% of all patients demonstrated post-CABG deficits in neuropsychologic function in session 2 (a mean decline in 37.0% ± 19.6% of measures). In contrast, comparing performance in session 3 directly with performance at baseline, 10.7% of patients showed decrements of 20% in 20% of measures (a mean decline in 6.96% ± 8.97% of measures). The difference in the number of patients that showed deficits in session 2 compared with session 3 is statistically significant (correlated t test, p < 0.001). Moreover, in session 3, 85.7% of patients showed a gain over baseline of 20% in at least 20% of measures (a mean gain in 28.93% ± 17.27% of measures). Thus, for the group as a whole, neuropsychologic test results showed a substantial decrement in performance in the immediate post-CABG period, followed by evidence of a return to baseline levels or higher as early as 3 weeks after operation.


    Comment
 Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Although improved biocompatibility and thromboresistance of HBCs have been inferred from studies demonstrating attenuation of neutrophil, complement, and platelet activation during CPB, the safety and clinical relevance of these findings still are debated [1] [2] [3] [4] [5] [6] [7] [8] [9]. We have demonstrated that, compared with conventional CPB (ie, non–heparin-bonded circuits) with an FAP, the use of HBCs with an LAP as an adjunct to an integrated blood conservation strategy decreases both the incidence and the magnitude of homologous transfusion, improves clinical outcome (ie, time to extubation, pulmonary complications, incidence of postoperative MI, inotropic requirements), and results in shorter surgical intensive care unit and hospital stays (and therefore costs) [9]. This study was designed to answer the question whether an LAP affects clinical outcome in patients treated with HBCs and to define the clinical and subclinical thrombogenic risk in patients treated with this protocol. Because the circuit configurations, perfusion techniques, and clinical pathways of all aspects of patient management (ie, protocols for transfusion, use of inotropes, extubation, hospital discharge) were identical and standardized, only the variation in anticoagulation protocol can explain the differences in clinical outcome observed between the treatment groups.

Compared with patients treated with an FAP, patients treated with an LAP had a lower incidence (24.2% versus 35.8%, respectively; p = 0.047) and magnitude (0.50 ± 0.92 versus 1.08 ± 2.10 U, respectively; p = 0.005) of homologous transfusion. The preoperative and discharge hematologic profiles of the FAP and LAP groups were similar (Table 2), confirming that transfusion protocols were observed strictly and that no treatment group was overtransfused or undertransfused. The significant decrease in homologous transfusion (Table 4) cannot be explained by differences in postoperative chest tube drainage (which were similar in the LAP and FAP groups). We do not have a clear explanation of why patients treated with an LAP required fewer transfusions. These differences in the treatment groups may be related to unmeasured intraoperative (rather than postoperative) blood loss or to subtle differences in fluid requirements and dilution during or shortly after CPB.

We previously demonstrated that, compared with conventional circuits and an FAP, the use of HBCs with an LAP was associated with a significant reduction in thromboembolic risk, defined as the incidence of postoperative MI, CVA/TIA, and vascular thromboembolic complications (0.8% versus 6.8%, respectively; p < 0.01; odds ratio 0.12 with a 95% confidence interval of 0.01 to 0.95) [9]. Although several studies have demonstrated that the use of HBCs with an LAP is safe [1] [2] [15], wider clinical application of HBCs has been limited by concerns about potential thromboembolic risks with this protocol [17] [18] [19]. This study was designed to address definitively these concerns. The thromboembolic risk of the LAP and the FAP in patients treated with HBCs was assessed in four different ways: (1) by comparing the incidence of clinical thromboembolic complications; (2) by quantifying thrombin generation during CPB through measurement of the thrombin generation products TAT and fragment 1.2; (3) by quantifying the microembolic load using TCD monitoring over the middle cerebral artery during the operation; and (4) by evaluating any differences in neurologic and neuropsychologic outcomes. The overall incidence of postoperative thromboembolic complications (defined as MI, CVA/TIA, and vascular thromboembolic complications) was lower in patients treated with an LAP (0.8% versus 5.0%, respectively; p < 0.05). This reduction is attributable primarily to a reduction in the incidence of MI and CVA/TIA (Table 6). Thrombin generation (TAT and fragment 1.2) was measured during CPB at temporally and clinically defined intervals. The thrombin levels increased with the duration of CPB with HBCs, underscoring the need for anticoagulation during artificial perfusion with nonendothelialized surfaces. However, there was no difference between the amount of thrombin generated with the LAP and the FAP (Table 7).

These data agree with some published results [16], but conflict with others [17] [18] [19]. These differences may reflect variations in different circuits (HBCs versus non–heparin-bonded circuits), perfusion techniques and practices, open versus closed systems, comparison of heterogeneous populations of patients undergoing both open cardiac and CABG procedures versus more homogeneous populations of patients undergoing primary CABG, degree of cooling and rewarming during CPB, use of different pumps (centrifugal versus roller pumps), use of cardiotomy suction, and, in particular, different practices of reinfusion of chest tube drainage (Fig 3). The current study minimized these confounding factors. There was exclusive use of HBCs, closed systems, centrifugal pumps, and no active cooling. Cardiotomy suckers were not used to prevent the reinfusion of shed mediastinal blood into the pump circuit. Further, chest tube drainage was not reinfused. With the use of these techniques, our data suggest that compared with an FAP, the use of HBCs and an LAP does not result in more thrombin generation during or after CPB. The higher levels of TAT noted in previous studies may be related to the reinfusion of shed mediastinal or chest tube blood, which may lead either to a true increase in thrombogenicity or to an elevation in measured levels of thrombin generation products.

The incidence of particulate microembolic events measured by continuous TCD monitoring demonstrated that patients treated with HBCs and an LAP are not at any increased risk for microembolization. Most microemboli detected during CPB (>70%) were related to aortic manipulation (cannulation and decannulation, clamping and unclamping) and not to CPB and artificial perfusion (Table 8), supporting the findings of previously published studies [20] [21] [22]. The overall incidence of detected emboli was substantially lower than that associated with routine carotid endarterectomy at our institution [11] and was lower than that reported by other investigators in patients undergoing open heart procedures [12] [13] [14]. Adverse neurologic events also were substantially less frequent in our series than in other published studies (1.6% versus 6.1%, respectively) [23]. The low incidence of TCD microemboli detection in our series correlates with this finding and suggests that these differences may be related to our technique of using HBCs and "soft" surgical aortic clamp inserts (Applied Medical, Laguna Hills, CA).

To examine post-CABG changes in sensory, motor, cognitive, and affective function, the National Institutes of Health neurologic stroke scale and an extensive battery of neuropsychologic tests were administered. None of these measures differentiated patients treated with an LAP and an FAP. In the immediate postoperative period (about postoperative day 4), the National Institutes of Health neurologic stroke scale revealed no statistically significant changes from preoperative baseline scores. At that time, however, 86.6% of the entire patient sample showed substantial decrements from baseline on neuropsychologic measures. By about 3 weeks after CABG, only 10.7% of patients continued to show substantial neuropsychologic deficits and 85.7% showed substantial gains over their baseline scores. Evidence that post-CABG performance decrements may be transient conflicts with some prior reports that documented deficits lasting as long as 6 months [15] [21]. This discrepancy may reflect differences in study techniques, such as the specific neuropsychologic tests used, but it also may represent a more rapid and complete recovery of cognitive function in patients treated with HBCs using the perfusion techniques described in this study. These findings have profound implications. A larger study with longer follow-up is being planned.

The use of HBCs with an LAP resulted in a lower incidence and magnitude of homologous transfusion and a shorter overall hospital stay compared with the use of HBCs with an FAP, but it did not result in some of the other dramatic improvements in clinical outcome observed when the use of HBCs with an LAP was compared with the use of conventional circuits with an FAP [9]. These findings suggest that both the HBC and the degree of anticoagulation affect clinical outcome, and that the addition of an LAP to HBCs further improves this outcome. These data support those of other studies that demonstrated that, in addition to the hemostatic benefits of lower anticoagulation, an LAP also is associated with a blunting of the inflammatory response to CPB, an effect that may contribute to further improvement in clinical outcome. Although complement activation is reduced by the use of HBCs with both an LAP and an FAP, granulocyte activation is reduced only in the presence of HBCs with an LAP [24]. These data suggest that differences in clinical outcome (eg, the incidence of pulmonary and thromboembolic complications) may be mediated in part by the attenuation of neutrophil activation with an LAP.

In summary, this study conclusively demonstrates that the use of HBCs with an LAP results in a lower incidence and magnitude of homologous transfusion but does not increase the clinical, microscopic, or hematologic thromboembolic risks in patients undergoing primary CABG. Thrombin generation levels, the incidence of microemboli detected by TCD monitoring during CPB, and neurologic and neuropsychologic test results after CPB were similar in the LAP and FAP groups and did not correlate with the degree of anticoagulation in the range evaluated. We suggest that the use of HBCs with an LAP should be considered for wider clinical application.


    Acknowledgments
 Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Supported in part by research grants from Baxter, Irvine, California, and Medtronic Inc, Minneapolis, Minnesota.


    References
 Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

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