Ann Thorac Surg 1997;63:482-488
© 1997 The Society of Thoracic Surgeons
Original Article: Cardiovascular
Effect of Heparin Loading During Congenital Heart Operation on Thrombin Generation and Blood Loss
Sophronia O. Turner-Gomes, MB, ChB,
Evan P. Nitschmann, BSc,
Geoffrey R. Norman, PhD,
Maureen E. Andrew, MD,
William G. Williams, MD
Departments of Pediatrics and Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, and University of Toronto, Toronto, Ontario, Canada
Accepted for publication September 14, 1996.
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Abstract
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Background. The heparin protocols used during cardiopulmonary bypass (CPB) in children undergoing surgical repair for congenital heart disease are extrapolated from adult data. Studies are needed that assess the optimal heparin dosing in these children, whose heparin clearance is increased compared with that in adults.
Methods. We assessed the effects of two commonly used doses of heparin in the prime solution at the start of CPB operation on plasma heparin levels, on thrombin production (thrombin–antithrombin III complexes, prothrombin fragment 1 + 2, D-dimer, and antithrombin III), and on the risk of hemorrhage. Before CPB, 48 children with congenital heart disease received heparin intravenously in a loading dose of 300 U/kg, followed by either 1 U/mL of heparin in the prime (low-dose group: 22 patients-acyanotic, 9; cyanotic, 13) or 3 U/mL of heparin in the prime (group: high-dose, 26 patients-acyanotic, 15; cyanotic, 11).
Results. In all patients, CPB resulted in the generation of thrombin. The duration of CPB was a significant covariate factor for heparin levels (p = 0.002), thrombin production (p < 0.001), and postoperative blood loss (p < 0.001). In the patients in the high-dose group, the total heparin dose and the plasma heparin levels were higher (p = 0.0005 and 0.005, respectively) and the D-dimer levels tended to be lower (p = 0.06). The postoperative blood loss was higher in the cyanotic patients (p = 0.02; both high-dose and low-dose groups), with 2 cyanotic patients (1 in low-dose group, 1 in high-dose group) requiring reoperation, one of whom subsequently died. The increased heparin dose had no significant effect on the rate or volume of postoperative blood loss.
Conclusions. Increasing the heparin dose in the prime solution from 1 to 3 U/mL increased the plasma heparin levels and showed a trend toward reducing the postoperative laboratory values indicative of fibrinolysis. Thrombin generation during CPB and the incidence of postoperative hemorrhage were not significantly altered. Larger randomized trials are needed to determine the optimal heparin-dosing regimen in patients with congenital heart disease.
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Introduction
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Children with congenital heart disease (CHD) are at increased risk for thromboembolism or hemorrhage after surgical repair involving cardiopulmonary bypass (CPB) [1–4]. Heparin is the mainstay of management during CPB operation, as an important anticoagulant and antithrombotic agent. Heparin protocols used in children undergoing CPB operations are extrapolated from adult data. However, we have observed that heparin clearance in children with CHD is increased compared with that in adults [5]. At our institution, CHD patients are given heparin in a loading dose of 300 U/kg, with 1 U/mL given in the prime solution at the start of CPB. Additional heparin is then given to keep the activated clotting time (ACT), measured using a Hemochron, above 400 seconds. Other institutions use similar loading doses of heparin, but they use higher doses (ie, 2–3 U/mL) in the prime solution (personal communications). We have found in our patients that thrombin is generated during CPB [6]. Thrombin is a key enzyme in hemostasis, because it cleaves fibrinogen so that a fibrin clot can form. Thrombin further induces its own production by means of the prothrombinase complex [7]. Heparin acts as a catalyst in the inhibition of thrombin and factor Xa by antithrombin III (ATIII) [8, 9]. We therefore hypothesized on the basis of this information that higher loading doses of heparin in the prime solution might increase the initial amount of thrombin that would be inhibited at the start of CPB. This would then decrease the risk of further thrombin generation during CPB without increasing the risk of hemorrhage.
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Patients and Methods
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Using a protocol approved in April 1992 by the Human Subjects Committee at the Hospital for Sick Children, Toronto, Ontario, we obtained informed consent from parents of all patients before their inclusion in the study. Children under 1 year of age were excluded. Forty-eight consecutive patients with acyanotic or cyanotic CHD, aged 1.1 to 15.7 years (median, 3.6 years; mean, 5 years), were enrolled in the study. However, because of reservations on the part of the attending physicians regarding the potential for an increased risk of bleeding, we first conducted a pilot study that involved 15 patients (10 low-dose heparin, 5 high-dose heparin). No major episodes of bleeding were observed during this initial phase and we therefore continued the study, incorporating the patients from the pilot study into the formal study. Subsequent recruitment to the high-dose arm of the study was attempted in all patients. In the event that a child's parents refused his or her admittance into the high-dose arm (n = 4), a request was then made to include the patient as a control patient. At the end of the study, 8 more patients were recruited as controls. In all, 22 patients were recruited as controls and 26 as high-dose patients. The children's diagnoses and demographic data are summarized in Table 1
. Cardiopulmonary bypass was performed using a hollow-fiber membrane oxygenator (Dideco 0.8–3.5, Mirandola, Italy). The extracorporeal circuit was primed with Ringer's lactate, 5% albumin in normal saline solution, mannitol, and heparin in a dose of either 1 U/mL (22 patients: acyanotic, 9; cyanotic, 13) or 3 U/mL (26 patients: acyanotic, 15; cyanotic, 11). After the induction of anesthesia, a loading dose of heparin (300 U/kg) was administered. Additional heparin was given to maintain the ACT (Hemochron; International Technidyne Corp., Edison, NJ) above 400 seconds. After CPB, the effect of heparin was reversed with protamine in a 1.2:1 concentration. In accordance with our current practice, at the end of the surgical procedure, the tendency to hemorrhage was assessed by the surgeon and additional fresh frozen plasma and cryoprecipitate given if excessive small-vessel bleeding was detected. Once the sternotomy was closed, mediastinal blood drainage was recorded hourly throughout the patient's stay in the intensive care unit.
Collection of Samples
After the induction of anesthesia, preoperative blood samples were drawn from freshly inserted arterial lines. Blood samples were also obtained at five subsequent time points: immediately after heparin loading, 5 minutes after the start of CPB, at the end of hypothermia, after heparin reversal with protamine, and 2 hours after the patient's return from the operating room. The samples were collected into 3.8% trisodium citrate and centrifuged at 1,200 g at 4°C for 15 minutes. The supernatant was then removed and centrifuged again. Multiple aliquots of plasma were frozen at -70°C until assayed.
Hemodilution During Cardiopulmonary Bypass
To assess the degree to which plasma proteins were diluted by CPB, immunoglobulin G (IgG) levels were assessed in all samples by rate nephelometry (Kallestad Diagnostics, Chaskan, MN). As an additional measure of hemodilution, hematocrit values were measured in the preoperative and postoperative samples.
Thrombin Generation In Vivo
Thrombin–antithrombin III (TAT) complexes and levels of prothrombin fragment 1 + 2 were assayed using Behring enzyme-linked immunosorbent assay kits (Hoechst, Montreal, Que, Canada) [10, 11]. D-dimer levels were assayed using the enzyme-linked immunosorbent assay kit manufactured by Diagnostica Stago (Wellmark Diagnostics, Guelph, Ont, Canada) [12].
Additional Assays
The ATIII levels were measured functionally using a chromogenic substrate [13]. Heparin levels were analyzed using the antifactor Xa assay of Teien and associates [14].
Statistical Analysis
Analyses of variance and covariance with repeated measures were used to analyze the data. The design included two between-subject factors-cyanotic versus acyanotic and high-dose heparin versus low-dose heparin-and a within-subject factor-repeated factor of time. The factors of group and dose were adjusted for perioperative differences in the IgG levels and the perioperative levels of each assay. To correct for the effect of dilution, the preoperative IgG level was used as the second covariate. This analysis of covariance approach allowed for differences among patients before the administration of heparin to be adjusted. The data for the TAT and D-dimer assays were logged before analysis. Individual variations in analysis are discussed in the results section. A p value of less than 0.05 was considered significant.
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Results
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Patient Population
The ages and diagnoses in the patients receiving high-dose and low-dose heparin were similar within the acyanotic and cyanotic group of patients with CHD (see Table 1
). However, the acyanotic children were older than the cyanotic children, which was a reflection of our current surgical practice (p < 0.05). The median total time on CPB was 45 minutes (14–129 minutes) for the acyanotic group and 132 minutes (95–264 minutes) for the cyanotic group. There was no appreciable difference between the total time on CPB between the high-dose and low-dose patients (Fig 1). The total dose of heparin received by the high-dose patients (median, 525 U/kg; range, 399–656 U/kg) was higher than that received by the low-dose patients (median, 403 U/kg; range, 325–636 U/kg) (p = 0.0005). No macroscopic thrombi were noted in the circuits during the CPB operation. All patients (except 2 acyanotic, 1 in the high-dose group) received blood products in the first 2 hours as replacement for mediastinal losses. There was no statistical difference between the low-dose and high-dose groups in the volume of albumin or other blood products received during the first 2 postoperative hours. Two patients with cyanotic CHD (patient 26 [high dose] and patient 44 [low dose]) required further surgical exploration for excessive small-vessel bleeding at 12 and 2 hours, respectively, after operation. Patient 26 subsequently died as the result of a low-output state at 20 hours after operation. The rate and volume of blood loss over the first 24 hours after operation were not significantly different between the high-dose and low-dose groups but was significantly less in the acyanotic than in the cyanotic children (p = 0.02) (see Fig 1). The duration of CPB was a significant covariate factor for blood loss up to 24 hours after operation (p < 0.001). The statistical interaction of time versus group (p = 0.003) indicated that the differences in blood loss between the acyanotic and cyanotic groups were due only in part to CPB duration.
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Fig 1. . Mediastinal blood loss up to 24 hours after operation was significantly less in the acyanotic than in the cyanotic children with congenital heart disease (p < 0.05) but was not significantly different between the high-dose and low-dose groups. Cardiopulmonary bypass (CPB) duration was a significant covariate factor for blood loss up to 24 hours after operation (p < 0.001).
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Hemodilution During Cardiopulmonary Bypass
Plasma concentrations of IgG decreased from preoperative values of 6.4 ± 0.5 g/L to postoperative values of 3.3 ± 0.2 g/L in the acyanotic patients and from 5.1 ± 0.4 g/L preoperatively to 2.1 ± 0.1 g/L postoperatively in the cyanotic patients (Fig 2). On the basis of these measurements, the degree of hemodilution occurring during CPB was 41% to 51%. To determine the contribution of hemodilution to changes in the plasma concentrations of coagulation factors, the preoperative IgG values were used as a second covariate for analysis of the coagulation variables.
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Fig 2. . Plasma immunoglobulin G (IgG) values over time. Cardiopulmonary bypass resulted in hemodilution of 41% to 51% in all groups. There was no significant difference in the degree of hemodilution in the groups. (CPB = cardiopulmonary bypass; hypoth = at end of hypothermia; NS = not significant; post CPB = after start of CPB; post-hep = after heparin loading; post-op = 2 hours after operation; post-prot = after protamine administration; Pre-op = post anesthesia.)
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Coagulation Assays
HEPARIN LEVELS.
The heparin concentrations in plasma determined by the antifactor Xa assay increased in all patients after heparin loading (Fig 3). Increasing the heparin dose in the prime solution raised the plasma heparin levels above 3 U/mL after the start of CPB (p = 0.005). This concentration was better maintained throughout operation in the acyanotic groups than in the cyanotic groups (p < 0.001). The duration of CPB was a statistically significant covariate factor for heparin levels over time (p = 0.002). When age was used as the second covariate in analysis of covariance designs for heparin levels, it was not found to have a statistically significant effect. However, this may be explained by the fact that no infants (ie, <1 year of age) were included in the study and the age ranges were 1.1 to 15.7 years (mean, 5.2 years) in the low-dose group and 1.1 to 13.9 years (mean, 4.8 years) in the high-dose group. Heparin was not detectable in any of the samples taken 2 hours after return of the patient to the intensive care unit from the operating room. Heparin levels were not found to be a statistically significant covariate factor for blood loss during the first 24 hours after operation.
THROMBIN GENERATION.
Preoperatively, plasma concentrations of TAT, prothrombin fragment 1 + 2, D-dimer, and ATIII in CHD patients were within the normal range for children (Table 2). During operation, plasma concentrations of D-dimer, prothrombin fragment 1 + 2, and TAT increased significantly, and this could not be accounted for by hemodilution (p < 0.01) (Figs 4, 5). The duration of CPB was a statistically significant covariate factor for the increases in the concentrations of TAT, prothrombin fragment 1 + 2, and D-dimer (p < 0.001) and in the decrease in the concentration of ATIII (p = 0.03) occurring during CPB. When the effect of CPB duration on the coagulation variables was removed, there was no statistically significant difference in the TAT levels between the acyanotic and cyanotic patients. However, the increase in the prothrombin fragment 1 + 2 and D-dimer values and the expected decrease in the ATIII values were less in the acyanotic group than in the cyanotic group (p < 0.01, D-dimer and ATIII; p < 0.05, prothrombin fragment 1 + 2). Increasing the dose of standard heparin in the prime solution resulted in a trend toward lower D-dimer levels at the end of hypothermia (p = 0.06) (see Fig 5). However, the TAT and prothrombin fragment 1 + 2 values during operation and the D-dimer values at the end of operation did not differ significantly between the high-dose and low-dose groups (see Figs 4, 5). The ATIII levels also fell to a lesser degree in the high-dose heparin groups than in the low-dose groups, but this difference did not reach statistical significance (p = 0.1).
ASSOCIATION WITH PATIENT MORBIDITY.
The data in those patients who had excessive bleeding (n = 2) were compared with the data in the patients without bleeding (n = 46) (Table 3). Patient 26, aged 3.6 years, had a univentricular connection and was a candidate for a Fontan operation. He received high-dose heparin in the prime solution. There was no significant difference in any of his preoperative variables from those in other patients. The duration of CPB was 120 minutes (the mean CPB duration for cyanotic patients with CHD in the high-dose group was 134.7 minutes). At 12 hours after operation, his total mediastinal loss was 61 mL/kg (the mean total mediastinal loss at 12 hours for cyanotic CHD patients who did not undergo reoperation for bleeding was 20.1 ± 2.8 mL/kg [p < 0.001]). At reoperation, extensive oozing from suture sites as well as bleeding from a large mediastinal vessel were observed. The latter was occluded, the thoracic cavity was emptied of large thrombi, and blood loss was replaced with packed red blood cells, platelets and fresh frozen plasma. Despite these measures, he died at 20 hours of a low-output state. Patient 44, aged 2.2 years, has tetralogy of Fallot and was included in the low-dose heparin group. There were no significant differences in his preoperative coagulation variables or in the duration of CPB (136 minutes; mean CPB duration in the cyanotic CHD patients in the low-dose group, 162 minutes) from that of the other cyanotic patients. He was returned to the operating room 2 hours after operation because of excessive bleeding. His total mediastinal blood loss at that time was 71 mL/kg (the 2-hour mean total blood loss in cyanotic CHD patients without reoperation for bleeding was 8.9 ± 1.9 mL/kg [p < 0.001]). At reoperation, extensive oozing from suture sites and the sternotomy incision was noted. No large-vessel bleeding was identified. The hematoma was evacuated and mediastinal losses replaced with 5% albumin. His subsequent course was unremarkable.
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Comment
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This study assessed the effect of two doses of heparin in the CPB prime solution on plasma heparin levels, on indices of thrombin generation, and on the risk of hemorrhage. In our analyses of the data, we used the preoperative IgG level as a covariate factor. By doing so, we corrected for the influence of confounding factors, such as preoperative polycythemia and the degree of hemodilution during CPB. We identified that increasing the heparin concentration in the prime solution resulted in an increase in plasma heparin levels and tended to decrease the D-dimer levels during CPB operation. The increase in the plasma heparin levels was greater in the acyanotic patients than in the cyanotic patients. However, increasing the heparin dose in the prime solution did not significantly affect the rate or the volume of mediastinal blood loss up to 24 hours after operation. The duration of CPB was a significant covariate factor for postoperative blood loss.
In adults undergoing cardiac procedures using CPB, heparin levels of 2.5 to 4 U/mL in the prime solution are considered adequate for producing antithrombotic effects [15, 16], with anticoagulation monitored during CPB using the ACT. In our pediatric patients, however, a heparin concentration of 3 U/mL in the prime solution did not guarantee maintenance of the plasma heparin levels at that concentration throughout operation, despite ACT values above 400 seconds. Because ACT values vary with therapeutic manipulations such as hemodilution and hypothermia, they are a suboptimal tool to assess the effects of heparin during CPB [15, 16].
Heparin catalyzes the inhibition of thrombin by ATIII and thus prevents continued thrombin production [8, 9]. Therefore, increasing the heparin dose in the prime solution at the start of CPB and maintaining the level of heparin above 3 U/mL would protect against further thrombin production, because this would increase the amount of thrombin inhibited by ATIII. A reduction in the amount of thrombin generated would result in a reduction in D-dimer and TAT levels and in the amount of ATIII utilized to complex thrombin. We identified a trend toward lower D-dimer and higher ATIII values during operation, but the differences between the high-dose and low-dose heparin groups did not reach statistical significance. This failure to reach statistical significance might be due to a type II error, as our numbers of patients are small. Sample size calculation was also difficult, because the study was complex and there were many clinically interrelated variables. Selecting TAT, D-dimer, and ATIII as dependent variables of interest and, calculating as if for a t test, we concluded that our numbers would only have detected an effect size of 1. We would need to triple our numbers to conclusively prevent a type II error (power, 0.8). We also did not expect differences in the coagulation profiles between the high-dose and low-dose heparin groups after operation, because, once heparin has been neutralized, the small amounts of thrombin that might be present would induce further thrombin production by means of the prothrombinase complex [7]. This would continue until thrombin and clot lysis had been inhibited spontaneously [7–9].
The increased heparin loading did not affect the rate and volume of blood loss up to 24 hours after operation. Two patients experienced major postoperative bleeding, but as found in a previous study [6], there was no appreciable difference in the preoperative variables between those patients with bleeding leading to reoperation and those who did not require reoperation for bleeding. The postoperative bleeding in these 2 patients could be due to the relatively decreased capacity to generate thrombin after CPB operation, as opposed to the better preserved capacity to inhibit thrombin production described by us previously [6].
Significant differences in the responses to increased heparin levels in the prime solution were observed between the acyanotic and cyanotic groups. The acyanotic groups had higher heparin levels, and these were associated with lower TAT and D-dimer values and higher ATIII levels. We have identified that heparin clearance is faster in the younger cyanotic child [5]. The patients in the cyanotic group were younger than those in the acyanotic group as the result of differences in the diagnoses and in the ages at which the appropriate surgical procedures were performed. Data analysis did not identify age as a statistically significant covariate factor for the changes in heparin levels. However, this may have been due to the fact that the number of young children in this study was small (7 
2 years of age). Data analysis also identified that the presence of cyanotic CHD was a significant covariate factor for heparin levels over time. The presence of cyanosis might therefore help explain the differences that are seen in the heparin levels between the acyanotic and cyanotic groups.
The duration of CPB was a significant covariate factor for thrombin generation and postoperative blood loss. This is not surprising, because it is contact activation by the extracorporeal membrane that starts the coagulation process [17–19], followed by the further induction of thrombin production by means of the prothrombinase complex [7]. The difference in the CPB duration between the acyanotic and cyanotic groups is due to the different complexities of the surgical procedures performed and may explain the differences seen in thrombin generation and blood loss between the two groups.
In summary, during CPB operations in pediatric CHD patients, the use of 3 U/mL of heparin in the prime solution was found to lead to an increase in the plasma heparin levels without either an increase in the risk of hemorrhage or a decrease in the postoperative blood loss, as compared with the findings in patients receiving 1 U/mL in the prime solution. There was also a trend toward less generation of thrombin and less fibrinolysis during CPB. Further, younger cyanotic CHD patients have lower plasma heparin levels during CPB operation and are most at risk for subsequent thromboembolic or hemorrhagic complications. Although the ACT is of value in maintaining anticoagulation, recently developed high-dose heparin bedside assays may also be of value [20]. The heparin dosing during CPB in pediatric patients with CHD needs to be individualized, but increasing the heparin dose in the prime solution from 1 to 3 U/mL contributes to a reduction in the indices of subclinical consumptive coagulopathy without any change in morbidity. A larger randomized trial would be invaluable in determining the optimal regimen of heparinization during CPB in pediatric patients with CHD.
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Acknowledgments
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We gratefully acknowledge the assistance of Ms Mary Lou Schmuck, BA, Research Assistant, McMaster University, in the analysis of the data from this study. The assistance of the technologists at McMaster University Medical Centre is also greatly appreciated.
Supported by grant XG91-003 from the Hospital for Sick Children Foundation.
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Footnotes
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Address reprint requests to Dr Turner-Gomes, Department of Pediatrics, McMaster University Medical Centre, 1200 Main St W, Hamilton, ON, Canada L8N 3Z5.
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References
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Abstract
Introduction
