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J Thorac Cardiovasc Surg 1995;110:36-45
© 1995 Mosby, Inc.

CARDIOPULMONARY BYPASS, MYOCARDIAL MANAGEMENT, AND SUPPORT TECHNIQUES

Increased accuracy and precision of heparin and protamine dosing reduces blood loss and transfusion patients undergoing primary cardiac operations

Philadelphia, Pa.

Supported in part by International Technidyne Corporation, Edison, N.J.

Received for publication April 21, 1994. Accepted for publication Oct. 31, 1994. Address for reprints: David R. Jobes, MD, Department of Anesthesia, 4 North Dulles, The University of Pennsylvania Medical Center, 3400 Spruce St., Philadelphia, PA 19104-4283.

Abstract

Individual aspects of heparin or protamine dosing have been better controlled than previously as useful tests have become available. Although many variables including drug potency, drug source, and individual patient response have been separately identified, there has not been an attempt to integrate them into a single management strategy. This study was undertaken to learn whether more precise control of drug variables and patient response would affect blood loss and transfusion requirements. Adult patients having primary cardiac operations were prospectively randomized into two groups. A control group received heparin and protamine by conventional methods. The test group received heparin and protamine according to in vitro predictive tests integrating drugs, tests, and patient response. Supplemental protamine was given in this group only if heparin was specifically found by testing. Anticoagulation in all patients was maintained at an activated coagulation time greater than 400 seconds, and any other treatment for bleeding was at the discretion of the clinical team caring for the patients. Testing and treatment for both groups followed routine practice after patient arrival in the intensive care unit. Test patients received slightly more heparin and a markedly lower dose of protamine than the control patients. Testing identified patients with decreased heparin sensitivity (preoperative heparin therapy) and correctly predicted the effective heparin dose. Supplemental protamine was given twice as often to control patients and frequently when no heparin was detectable (retrospectively). Test patients exhibited less 24-hour chest tube drainage (671 ml versus 1298 ml) and fewer patients received transfusion (9/22 versus 18/24) with fewer donor exposures (22/22 versus 101/24). The management strategy used for heparin and protamine added accuracy and precision, which was associated with improved hemostasis. Although the observation is valid, the mechanism or mechanisms are not completely clear. Nevertheless, it is reasonable to apply basic pharmacologic principles and establishment of consistent, predictable protocols that are beneficial. It is against this background that the efficacy of additional drugs or equipment should be assessed. It is quite possible that only marginal if any improvement in hemostasis may be found in patients having primary, uncomplicated cardiac operation with the addition of more costly drugs or equipment. (J THORACCARDIOVASCSURG1995;110:36-45)

The dose of heparin required to inhibit coagulation for cardiopulmonary bypass (CPB) was initially chosen on an empiric basis with supplementation based on its half-life in the circulation. Protamine was given in proportion to heparin administered without knowledge of the actual heparin level at the time of protamine administration. Bull and associates ¹ in 1975 demonstrated significant patient-to-patient variability in dose response and duration of heparin effect. They recommended individualized heparin and protamine dosing with use of a dose-response plot based on the whole blood activated coagulation time (ACT). ² The goals were (1) to provide consistently adequate anticoagulation and (2) to administer a dose of protamine that would be more closely related to the heparin present at the termination of CPB. Since 1975 many investigators have used this and other methods to more precisely control heparin and protamine dosing. ^3-16

This management strategy reduced drug doses and was frequently associated with reduction of blood loss or transfusion requirements, or both. The lack of consistent findings of decreased bleeding or transfusion, or both, with lower drug doses may relate to differences in study design, patient populations, reporting terminology, doses, source and potency variability of drugs used, and test methods. However, the intuitive appeal of more precise treatment, the desire for improvements in hemostasis with associated reductions in transfusion, and the increasingly recognized undesirable effects of excess drugs prompted another investigation. A system for maintaining consistency of drugs and for individualizing patient dosing for both heparin and protamine that uses a matched injectable drug and in vitro dose-response assay has been introduced (RxDx System, International Technidyne Corporation, Edison, N.J.), thus amplifying the recommendations made by Bull and associates. ² It was the goal of this study to determine whether an attempt to control drug variables maximally would be associated with less bleeding and fewer transfusion requirements in adult patients undergoing primary cardiac operation with CPB.

METHODS

Approval of the protocol was obtained from the University of Pennsylvania human studies committee. Consecutive patients undergoing primary elective cardiac operation were candidates when the planned procedures included either coronary artery bypass grafting, mitral valve replacement, aortic valve replacement, or any combination of the three. Patients who had previous cardiac operation, a history of bleeding disorder, or evidence of other organ dysfunction were excluded. Patients receiving preoperative heparin in whom the ACT exceeded 200 seconds (after sternotomy) were excluded. All three staff cardiac surgeons and six cardiac anesthesiologists agreed to the protocol before the study began, cared for patients in random combination, and were not directly informed of an individual patient's study status at the time of operation. Formal blinding was not attempted; however, none of the physicians who directed care of the study patients were members of the investigative team. The investigators who performed the tests did not participate in the decisions for treatment. Other than ACT findings, test results used for study purposes were not disclosed to the clinicians.

On arrival in the operating room, patients were screened for candidacy for the study. Once enrolled, patients were randomly assigned to the control group or test group by medical record number. The patient's preoperative hemoglobin and hematocrit values, platelet count, activated partial thromboplastin time, prothrombin time, and preoperative medications were recorded. The patient's weight and height were used to determine intravascular volume from a blood volume nomogram. ¹⁷

Whole blood ACT was determined in duplicate with use of a Hemochron 801 dual-chambered timer with a 300-second prewarming feature. A Hemochron CA510 tube (International Technidyne) (containing 12 mg of Celite diatomaceous earth, Johns Manville Corp., Denver, Colo.) was placed in the timer test well for 300 seconds to warm the glass tube and test well to 37º C. Ten milliliters of whole blood was aspirated from the arterial line before a 4 ml sample for testing was drawn. A 2 ml sample was added to the tube, the timer started, the tube shaken vigorously until the diatomaceous earth was completely dispersed throughout the blood sample (approximately 3 to 5 seconds), and then the tube was placed in the reaction well.

Anesthetic management
All current cardiovascular medications were maintained until patient transport to the operating room (including heparin) at which time they were discontinued. All patients were premedicated with morphine sulfate and scopolamine, and all received a 16-gauge peripheral intravenous catheter, 20-gauge radial artery catheter, and pulmonary artery catheter via the right internal jugular vein before induction of anesthesia. A combination of high-dose fentanyl, isoflurane or enflurane, and nondepolarizing muscle relaxant was used to produce anesthesia.

Test group
In the test group, heparin and protamine requirements were based on analysis of individual patient response in vitro to heparin and protamine with use of an integrated drug/test system. The components of the system include heparin and protamine for administration to the patient and test tubes containing the same drugs for determining the heparin and protamine response times.

The heparin response test (HRT) was performed simultaneously in duplicate with a preheparin, poststernotomy reference ACT. Two milliliters of whole blood was added to the heparin response test test tube containing 12 mg diatomaceous earth and 6 units of heparin from the same lot to be administered to the patient, (resulting in a concentration of 3 units per ml). The test was then done in the same way as the ACT. The prolongation of the ACT reflects individual patient response to heparin (heparin response test), which was used with the patients' estimated blood volume (EBV) to calculate a heparin dose to produce a target ACT. Product information suggested an expected standard deviation of ±82 seconds for a concentration of 3 units heparin per milliliter of blood. The projected ACT chosen was 482 seconds, thus we attempted to ensure a value greater than 400 seconds and avoid supplemental doses and delays in beginning CPB. Equation 1 was used to calculate the heparin dose in units:

The protamine response test (PRT) was used to determine the protamine dose. A 2 ml heparinized whole blood sample was added to the PRT test tube containing 12 mg diatomaceous earth and 0.04 mg protamine sulfate from the same lot of protamine to be administered to the patient. The test was then done in the same way as the ACT. The PRT was done within 10 minutes of the end of CPB simultaneously with an ACT (status ACT). The reduction of the ACT reflects individual patient response to protamine (0.02 mg/ml), which is used with the estimated blood volume (EBV) to calculate a protamine dose. The dose used in the study reflects the amount of protamine required to return the ACT to the poststernotomy ACT reference value. Equation 2 was used to calculate the protamine dose in milligrams:

The protamine was administered after the cessation of CPB over 5 to 10 minutes. Five minutes later, an ACT, thrombin time (TT), and heparin-neutralized thrombin time (HNTT) were obtained (International Technidyne). The TT test contains lyophilized thrombin and the HNTT test contains lyophilized thrombin plus 0.032 mg protamine sulfate. Heparin levels greater than 0.05 unit/ml will significantly prolong the TT but result in a normal HNTT. Thus the difference between them () when measured simultaneously can be used as a sensitive and specific indicator of residual heparin. One milliliter of distilled water was used to reconstitute the reagents at room temperature. Tubes were then prewarmed, 1 ml blood added, and the timer started. Thorough mixing of the liquid reagent and blood is accomplished readily by gently tilting the tube four times, and the tube is placed in the reaction well. Vigorous agitation must be avoided or foaming of the reagent before or after the blood is added will invalidate test results.

Subsequent protamine in the test group was administered only if the TT/HNTT indicated residual heparin (TT/HNTT >12 seconds). When heparin was detected, 10 mg of protamine was given and the tests repeated. This process continued until no heparin was detectable. When no heparin was detected, treatment for microvascular bleeding in the operating room was at the discretion of the surgeon or anesthesiologist, who could use any modality except protamine. Protocol restriction ended after arrival in the surgical intensive care unit and any treatment (including protamine) or routine testing was at the discretion of the surgical staff who were not involved in the study.

Control group
The control group represented institutional practice. The initial dose of porcine-derived heparin was 300 units/kg and ACT was determined 5 minutes after the bolus dose. If the ACT exceeded 400 seconds, the patient was placed on CPB. If the ACT was less than 400 seconds, 5000 units supplemental heparin was administered and the ACT repeated until the result exceeded 400 seconds.

The initial protamine dose was 10 mg protamine per 100 units heparin infused. This was based on the total number of units of heparin given to the patient throughout operation, excluding the 5000 units of heparin in the pump prime. The protamine was administered after the cessation of CPB over 5 to 10 minutes. Five minutes later an ACT was obtained. Additional protamine or any other treatment for bleeding was given at the discretion of the cardiac surgeon or the anesthesiologist, using independent judgment with or without regarding the ACT results. A heparin response test was obtained before heparin administration, a PRT before protamine administration, and TT/HNTT after protamine administration. These values were not available to the clinicians but were saved for later comparison.

Conditions common to all patients
All patients received 5000 units of porcine-derived heparin in a pump prime of 2.2 L of balanced electrolyte solution. Throughout the study all patients in both groups received heparin and protamine that were from the same lot and concentration. In both groups, 5 minutes after the beginning of CPB and every 30 minutes thereafter the ACT was measured. Additional heparin was administered only if the ACT dropped below 400 seconds. All tests were done in duplicate and the average values used for data analysis. Blood scavenged before and after CPB and residual pump contents were filtered and washed. The resultant packed red blood cells suspended in normal saline solution were returned to the patient intravenously. No attempt was made to measure blood loss in the operating room. Blood collected from the chest tubes during wound closure was included as part of the total postoperative blood loss and measured by volume. Transfusions, additional drugs, or any other measures to treat bleeding in the operating room and surgical intensive care unit were chosen at the discretion of the anesthesia and surgery staff by routine means of assessment and transfusion guidelines.

Data collected
All drug doses and test results were recorded along with the time administered. Any intraoperative blood product transfusions were noted, as well as any medications to treat bleeding. Hematologic profile (hemoglobin and hematocrit values, platelet count, prothrombin time, and activated partial thromboplastin time), volume of mediastinal blood drainage, transfusions, and medications were recorded during the first 24-hour postoperative period and were obtained from the intensive care unit nursing records. Any patient with incomplete data resulting from return to the operating room after operation, death in the first 24 hours, or deviations from protocol was removed from the study.

Data were analyzed by Student's t test, analysis of variance (with Sheffe's test), Fisher's exact test, ² test, and F test where appropriate.

RESULTS

Demographics
Fifty-two patients were entered into the study and six were excluded from data analysis. Three patients were excluded from the test group because of dose calculation errors and use of an incorrect lot of heparin. Three patients were excluded from the control group: one patient was returned to the operating room because of excessive bleeding for which a specific site was found and ligated, and a second patient was returned to the operating room after operation for treatment of an acute ischemic episode and subsequently died. The third patient was excluded because of a drug dose error. Drug dose errors were clinically unimportant but were deviations from protocol and were considered grounds for exclusion.

No patient previously receiving heparin had an ACT greater than 200 seconds. The results of the randomization process and the patient characteristics are illustrated in Table I. There were no differences between control and test groups for the features listed. Both groups were also similar with regard to laboratory results for standard coagulation tests and hemoglobin concentration (Table II). There was a slightly higher hemoglobin value in the test group 12 hours after admission to the surgical intensive care unit but there were no differences at the time of discharge from the hospital. All patients for whom data were collected were discharged from the hospital to their homes. Postoperative complications were arrhythmias (heart block necessitating pacemaker insertion: two in the test group; one in the control group), transient acute renal failure (one in the test group), and wound infection (one in each group).

View larger version (21K): [in this window] [in a new window]   Fig. 1. Sensitivity to heparin in vitro (3 units per milliliter blood in ACT test tube) compared with in vivo (postbolus intravenous heparin ACT calculated as ACT seconds per unit per milliliter using nomogram for estimated blood volume). Two groups of patients were identified from the 46 study patients: 21 who were receiving heparin intravenously (Preop. Heparin) before coming to operating room and 25 who were not (No Preop. Heparin).

Blood loss and transfusion (Table IV)
Operating room blood loss is partly reflected in the quantity of washed cells from intraoperative scavenging and residual pump blood, which was the same in both groups. Allogeneic packed blood cells were administered with equal frequency in the operating room to patients in both groups (control, 5; test, 4). Chest tube drainage was greatest in the first 4 hours in both groups and greater in the control group during the first 12 hours (Fig. 2). Total loss was also greater for the entire 24-hour period in the control group. Autotransfusion of chest tube drainage was practiced similarly in both groups with more patients receiving a greater volume in the control group. Twelve patients in the control group and five in the test group received packed red blood cells in the surgical intensive care unit. Five patients were given platelets and five patients were given fresh frozen plasma in the control group whereas no patient in the test group received either of these products. Forty percent of the patients in the test group received allogeneic transfusion in contrast to 75% in the control group. The total number of donor exposures was notably greater in the control group.

View larger version (27K): [in this window] [in a new window]   Fig. 2. Chest tube drainage as measured in 4-hour intervals in the surgical intensive care unit for first 24 hours after operation. Time 0 represents accumulation begun in operating room during closure of chest incision until arrival in surgical intensive care unit. No patient exhibited active bleeding after recording period. ANOVA, Analysis of variance.

Patient selection and study design
The patients in this study underwent typical primary cardiac surgical procedures and those receiving aspirin and heparin were included. The average volume of postoperative blood loss in the control group (1298 ± 747 ml) is quite similar to 1016 ± 25 ml, the estimated average of total blood lost by 540 patients undergoing primary coronary artery bypass grafting from 18 institutions in the United States. ¹⁸ Formal blinding was not done but given that the maintenance minimum heparin effect was the same in both groups the heparin management was unlikely to be biased. Bias affecting therapy of microvascular bleeding is more likely, because the clinicians could use any modality except protamine for the test patients in the operating room and were thus aware of the grouping. However, the existing clinical prejudice was for more aggressive treatment of observed microvascular bleeding, yet no patient in the test group received platelets or fresh frozen plasma. Similarly, such treatment (including protamine), if efficacious, should have favored less bleeding in the control group. In addition, treatment of the test group in the surgical intensive care unit after the end of the protocol was decided by surgical staff who were not involved in the study and often not present during the intraoperative phase.

In vitro predictability of in vivo drug effect: heparin
All patients received adequate anticoagulation (ACT >400 seconds) with the initial dose in the test group. The postbolus heparin effect was consistently more than predicted by in vitro results in patients not previously receiving heparin. We do not have an explanation for this observation, which suggests that patients not previously receiving heparin generate more anticoagulant effect after a bolus of heparin than takes place in circulating blood alone as measured by the ACT in vitro.

Conversely, patients previously receiving heparin are less sensitive to doses administered before CPB, an observation in patients undergoing cardiac operation that has been made by others. ^19-21 An explanation may lie in previous reports of decreased levels of antithrombin III associated with prolonged heparin therapy. ^{22, 23} Besides diminished heparin sensitivity, it is interesting to note that there was an extremely high correlation between in vitro and in vivo heparin effect as measured by the ACT in patients previously receiving heparin. This observation suggests that the response to heparin in these patients is limited to an effect in circulating blood only. The in vitro response to heparin (heparin response test) was sufficiently reliable in predicting the in vivo response and resulted in all patients receiving adequate anticoagulation with the initial dose of heparin. Patients with diminishing heparin effect caused by discontinuation of preoperative heparin therapy should have a heparin response test done after sternotomy and immediately before heparin for administration CPB. This group demonstrated the highest accuracy of the in vitro test.

In vitro predictability of in vivo drug effect: protamine
The calculation for initial protamine dose in the test group used the preheparin ACT value when it was below the upper limit of the normal range (122 ± 10 second), and if the dose was exact it would leave no residual heparin nor an excess of protamine. There was therefore no attempt to provide excess protamine for prevention of heparin rebound to assess the accuracy of the method. Four of 22 patients had measurable heparin effect (by TT/HNTT) after the initial dose of protamine. The incremental administration of small doses of protamine to these four patients averaged 30 mg (range 20 to 50 mg) to reach complete neutralization. Considering the inherent variations in estimating blood volume and the measurements of ACT, the calculations were surprisingly accurate.

Doses of heparin and protamine
Close matching of heparin dose to variable individual patient response is readily evident from the wide range of initial doses in the test versus control groups (14,500 to 50,000 versus 19,000 to 29,000 units) but with a shorter range of response (postbolus ACT 447 to 894 seconds versus 325 to >1000 seconds). There are several explanations for the slightly increased total dosage of heparin seen in the test group. More initial heparin was given in the test group partly because the target time was set 1 standard deviation higher than 400 seconds to avoid values less than the minimum needed to begin CPB. Lower total heparin dosage would have been likely in more sensitive patients if the heparin in the pump prime had been eliminated. Also the in vitro prediction was unexpectedly in excess of the in vivo result. If a projected ACT of 400 seconds was consistently achieved and maintained, a lower total heparin dosage (and therefore protamine dose) would be likely because the average ACT at the end of CPB was 521 seconds. It would be expected that with longer CPB, the average heparin used would be the same for empiric and test-guided dosing because of maintenance of the same minimum effect (in this study an ACT of 400 seconds). However, a test-guided approach would clearly favor reduced heparin for CPB of shorter duration in more sensitive patients. The result would be a lower dose of heparin and also of protamine while the desired heparin effect was achieved and maintained.* It is unlikely that the higher dosage of heparin in the test group accounts for the difference in blood loss. The dosages and ACT values for both groups are well within the range reported to be adequate. Both groups showed the same average ACT and PRT at the end of CPB, and the same number of patients in both groups required supplemental heparin for maintenance effect. The contribution of the method of heparin dosing in this study to the outcome is not clear.

The initial and total dosages of protamine administered were markedly different between the groups. Previous reports have attributed reduced blood loss or transfusion to lower protamine dosages but have not identified a mechanism. A number of studies demonstrate that heparin and protamine adversely affect platelet number and function. Ellison, Edmunds, and Coleman ²⁴ found that these drugs in combination inhibited adenosine diphosphate and epinephrine-induced platelet aggregation in normal volunteer subjects. The inhibition was observed only when protamine was present with heparin in neutralizing and excess amounts. No inhibition was seen with heparin alone, protamine alone, or when heparin was underneutralized. One of the lowest doses of protamine associated with significantly less bleeding was accompanied by a higher platelet count after protamine administration than that in a control group. ²⁵ The administration of protamine in the presence of heparin is associated with an inflammatory type of response with a wide range of effects associated with complement and neutrophil activation. ^{26, 27} An acute decrease in the number of circulating platelets is observed after protamine administration, which is associated with an acute rise in complement levels. ²⁶ A similar course is followed by neutrophils. Neutrophil activation is thought to result from action by complement resulting in neutrophil-endothelial adhesion and sequestration. ²⁷ A similar mechanism may be affecting platelets and the possibility of a dose-related effect (protamine or heparin-protamine complex) on both platelets and neutrophils should be considered for additional investigation.

Concern for inadequate heparin neutralization and heparin rebound prompts most clinicians to administer a large initial dose of protamine in the belief that they are preventing bleeding without causing harm. In addition, they frequently judge heparin effect by visual assessment of coagulation at the surgical site or by the ACT, or by both methods. More protamine is given on the basis of these two nonspecific and insensitive criteria. The control group in this study received a commonly used dose of protamine that was intended to provide complete neutralization and some degree of excess to prevent heparin rebound. When this dose was judged inadequate by the aforementioned criteria in the control group, additional protamine was given. Despite this liberal approach, evidence (TT/HNTT) of heparin effect was found in two patients in the operating room and one additional patient on arrival in the surgical intensive care unit. Fourteen supplemental doses of protamine were given to patients in the control group, 13 of these when there was no heparin detectable by TT/HNTT. The method used in the control group does not guarantee neutralization or protection against the reappearance of heparin but contributes to the larger doses of protamine likely to be responsible for more bleeding, not less. The lowest effective dose of protamine is associated with improved hemostasis, decreased blood loss, and decreased transfusion requirements and is a worthwhile goal. The only way to achieve that goal is to individualize the dose by test specific methods (see following section).

Monitoring adequacy of heparin neutralization
The ability to confidently choose an accurate dose of protamine is only possible by assessment of the amount of neutralizable heparin in the circulation. Similarly, the ability to limit subsequent doses of protamine requires a sensitive and specific test for the presence of heparin. The partial thromboplastin time may be sensitive to heparin in other settings but is frequently abnormal after CPB for reasons other than heparin, is not specific for heparin, and is not useful. An ACT modified with serial protamine can be specific and quantitative for heparin and can be done by a manual or automated protamine titration. However, the ACT itself is relatively insensitive to heparin in quantities thought to contribute to postoperative bleeding and is similarly not useful. Alternatively, the whole blood TT is sensitive to heparin and its modification by the addition of protamine (HNTT) renders it specific for heparin. It is nearly as simple to use as the ACT and in addition can detect significant fibrinogen abnormalities while maintaining the ability to detect heparin.

Blood loss and transfusion requirements
Blood loss and transfusion in cardiac operations have received increasing emphasis, and methods to reduce both have been the subject of numerous reports. The goal is the least blood loss and therefore presumably the least transfusion consistent with preserving the benefits of operation at the lowest cost. Drugs (aprotinin, 1-deamino-8-D-arginine vasopressin [DDAVP], -aminocaproic acid, tranexamic acid), techniques (autologous fresh blood, platelet pheresis, allogeneic fresh blood, dilutional anemia, lower transfusion trigger), equipment (heparin-bonded circuits, membrane oxygenators, hemofiltration), tests (ACT, protamine titration, thromboelastography, Sonoclot [Sienco, Inc., Morrison, Colo.]), and perhaps other manipulations have been tried. Differences in the indices measured and reporting formats make comparisons of efficacy between reports difficult. However, one of the most accurately measurable and consistently reported assessments is the 24-hour chest tube blood loss. Admittedly it ignores intraoperative losses, which are seldom directly measured or reported and are more under direct technical control. However, chest tube collections probably more accurately reflect physiologic effects of CPB management. The lowest reported measured losses for adult patients having primary cardiac operation are approximately 400 to 600 ml. The lowest values reported have been generally achieved with the use of aprotinin but other measures have been as effective. For example, Øvrum and associates ²⁸ were able to avoid allogeneic transfusion in 98.6% of 500 patients having primary coronary artery bypass grafting whose average chest tube blood loss was 643 ± 354 ml. The only apparent difference between the study of Øvrum and associates ²⁸ and other reports was cessation of aspirin before operation and reinfusion of autologous blood drawn just before CPB, that is, no additional drugs or new technique was used to intentionally improve hemostasis. Boldt and colleagues ²⁹ found no difference in chest tube loss (approximately 400 ml) or transfusion requirement with or without aprotinin if normothermic bypass was used. A more appropriate comparison of our current study can be made with a recent report by Lemmer and associates ³⁰ of patients who received aprotinin or placebo (Table V). Patients reported by Lemmer and associates differed slightly from the current study by having coronary artery bypass grafting only (100% versus 80%), a higher incidence of aspirin therapy (62% versus 46%), and slightly longer hypothermic bypass time (98 minutes versus 80 minutes). These differences probably account for the slightly higher blood loss in the study of Lemmer and associates. ³⁰ However, the efficacy of treatments (more accurate and precise heparin and protamine dosing versus aprotinin) in the face of hypothermic CPB, aspirin therapy, and lack of fresh autologous transfusion is remarkably similar in reducing blood loss and transfusion requirements. The refinement of a basic element of CPB, anticoagulation and reversal, with patient-specific dosing strategy, should be established first as the background for the evaluation of drugs and techniques intended to improve hemostasis.

Acknowledgments

We thank Drs. Susan Nicolson and Norig Ellison for editorial advice and Joan Aster and Jeff Gilfor for assistance in preparing the manuscript.

Footnotes

*Experience after the study with RxDx System management and no heparin in the pump prime showed an average reduction of approximately 7000 units of heparin and 20 mg of protamine. Fifteen patients matched to the test patients for procedure and CPB time had an average total heparin dose of 21,967 ± 8698 units and total protamine dose of 125 ± 39 mg.

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