T pulmonary bypass is highly variable. Although the

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1 Heparin Resistance After Preoperative Heparin Therapy or Intraaortic Balloon Pumping Mark H. Staples, MD, Robert F. Dunton, MD, Karl J. Karlson, MD, Howard K. Leonardi, MD, and Robert L. Berger, MD Overholt Division of Cardiothoracic Surgery, the New England Deaconess Hospital and Harvard Medical School, Boston, Massachusetts Heparin resistance, defined as failure of 500 IU per kilogram of body weight of heparin to prolong the activated clotting time (ACT) to 480 seconds or longer, was noted during 949 of 4,280 (22%) consecutive open heart surgical procedures performed on adults between 1986 and The total population was divided into the following four groups: group 1, preoperative intraaortic balloon support without concomitant heparin therapy (n = 138 patients); group 2, preoperative intravenous heparin therapy (n = 741 patients); group 3, intraaortic balloon support with concomitant intravenous heparin therapy (n = 137 patients); and group 4, controls, not receiving preoperatively the therapy given groups 1,2, or 3 (n = 3,264 patients). The ACT response to an initial dose of 500 IU/kg of heparin and the incidence of heparin resistance were 596 f 203 seconds and 30% in group 1; 506 f 149 seconds and 50% in group 2; 520 * 159 seconds and 53% in group 3; and 705 f 234 seconds and 14% in group 4, respectively. These results indicate that preoperative intravenous therapy and intraaortic balloon support are associated with a decreased ACT response to intraoperative heparin. Baseline ACT levels and preoperative platelet counts were not predictive of heparin resistance. A reduced ACT response to the initial dose of heparin was associated with increased requirements for supplementary anticoagulant therapy during the ensuing period on cardiopulmonary bypass, indicating that the decreased sensitivity to heparin extends beyond the initial episode of heparinization. These data reveal that preoperative intraaortic balloon support and intravenous heparin therapy are associated with a heightened resistance to heparin, necessitating modifications in the standard heparin dose schedule and mandating close surveillance of ACT for the duration of cardiopulmonary bypass. (Ann Thoruc Surg 2994;57:2222-6) he anticoagulant response to heparin during cardio- T pulmonary bypass is highly variable. Although the basic reason for the lack of a uniform effectiveness of this potent anticoagulant is poorly understood, preoperative intravenous heparin therapy and intraaortic balloon (IAB) pumping have been implicated as major etiologic factors in the resistance to heparin [14]. With the increased use of preoperative intravenous heparin therapy for the management of unstable angina pectoris in recent years, the incidence of resistance to heparin is rising and has assumed a clinical challenge of growing dimensions. Unfortunately, the available information on heparin resistance is based either on single case reports [5-71 or on small series [14], and the conclusions drawn from these accounts are inconclusive and inconsistent. To obtain more reliable data about heparin resistance during cardiopulmonary bypass, we examined our experience in 4,367 adult patients who had undergone heart operations. The present article describes the results of this analysis. Patients and Methods The available perfusion records of 4,367 consecutive adult patients who underwent open heart surgical procedures Accepted for publication Aug 23, Address reprint requests to Dr Berger, 135 Francis St, Boston, MA at New England Deaconess Hospital between January 1986 and November 1991 were reviewed and the relevant data about heparinization for cardiopulmonary bypass were collated. The entire population was then divided into four groups according to the following specific preoperative interventions that have been reported to influence the effectiveness of heparin administered during heart operations: group 1, IAB support without concomitant heparin therapy; group 2, preoperative intravenous heparin therapy; group 3, IAB combined with intravenous heparin therapy; and group 4, controls, receiving preoperatively none of the treatments given groups 1, 2, or 3. Only patients who received the preoperative heparin through the intravenous route were included in the heparin-pretreated populations (groups 2 and 3). Preoperative heparin therapy was usually initiated by the attending cardiologist, mostly to control myocardial ischemia or prevent infarction, and occasionally to protect against intracardiac clotting or peripheral embolization. The duration of the preoperative heparin therapy varied from hours in a small number of patients to several days in the majority. Accurate data about the duration of treatment were difficult to retrieve, but it has been shown that the dose and duration of preoperative heparin administration do not influence resistance to the anticoagulant [2], and, therefore, this aspect was not further pursued. Preoperative by The Society of Thoracic Surgeons /94/$7.00

2 1212 STAPLES ET AL Ann Thorac Surg 1994: heparin treatment was usually discontinued 4 hours before operation. Prothrombin, bleeding, and partial thromboplastin times as well as platelet counts were determined before the operation as part of the routine assessment of the coagulation state. The intraoperative heparinization protocol was uniform for all patients. The adequacy of anticoagulation was monitored by repeated determination of the activated clotting time (ACT). The more sophisticated coagulation tests were not routinely employed during the operations because ACT determination has been proved reliable and can be performed quickly and easily, so that the method has been accepted almost universally as the standard and practical guide for maintaining satisfactory anticoagulation during cardiopulmonary bypass. The baseline ACT was measured before cannulation for cardiopulmonary bypass. An initial dose of 500 IU per kilogram of body weight of porcine intestinal heparin was injected either into a central venous catheter or directly into the right atrium. A supplemental 10,000 IU of heparin was added to the pump oxygenator prime. All patients received the same form of porcine intestinal heparin. Five to 10 minutes after the administration of heparin, a second ACT was obtained. Satisfactory anticoagulation for cardiopulmonary bypass was defined as an ACT of 480 seconds or greater, and mechanical circulation was not instituted until this value was reached. If the initial postheparin ACT reading was less than 480 seconds, additional heparin, in amounts derived from Bull's dose-act response curve, was administered until the desired ACT was obtained [8, 91. The ACT was again determined 5 to 10 minutes after cardiopulmonary bypass was instituted, and this was repeated every 30 minutes thereafter for the duration of mechanical cardiopulmonary bypass support. Whenever the ACT fell to less than 480 seconds, new aliquots of the anticoagulant were administered. The presumed deficit was calculated from Bull's dose-act response curve [8, 91. After termination of cardiopulmonary bypass, the total circulating heparin level was estimated from Bull's heparin dose-act response curve and neutralized with 0.6 mg of protamine for each 1.0 mg of heparin. In some patients, an alternate plan of heparin reversal was employed. If a single dose of heparin sufficed for the whole procedure, a 0.6-mg to 1-mg protamine/heparin ratio was used for neutralization of the heparin. When the initial dose of heparin had to be supplemented with additional aliquots, the protamine/heparin ratio was reduced to 0.52, based on the total heparin administered during the procedure. The ACT was determined 5 minutes after completion of the protamine infusion. Measurements of ACT were made with the Hemochron 400 D system (International Technidyne, Edison, NJ) according to the manufacturer's instructions. The operations were performed with nonpulsatile roller pumps and a membrane oxygenator under moderate systemic hypothermia. The heart was arrested with warm blood cardioplegia and protected with cold blood cardioplegia and topical hypothermia. Toward the latter part of the study, retrograde warm blood cardioplegia was employed in a small number of operations. Patient age and sex, and the duration of cardiopulmonary bypass were analyzed separately for each of the four groups. The incidence of preoperative heparin therapy was determined for each of the years studied. Heparin resistance was defined as failure of the initial heparin dose of 500 IU/kg to prolong the ACT above 480 seconds. Additional heparin requirement refers to that heparin administered after an ACT of 480 seconds was reached, but does not include the supplemental aliquots used during the initial heparinization to obtain the desired level of anticoagulation. Sensitivity to the initial dose of heparin, the total (2) intraoperative heparin requirement, and heparin consumption were calculated according to the following formulas: Postheparin ACT (s) - Baseline ACT (s) Heparin sensitivity = - Initial dose of heparin (IU) Total heparin requirement (IU/kg) = Z of heparin during operation (IU) Weight of patient (kg) Heparin consumption (IU/kg/min) = Total heparin requirement (IU) Duration of cardiopulmonary bypass (min) The mean values reported represent the average for the group * the standard deviation. One-way analysis of variance was used as appropriate, and group means were compared using Student's paired t test with Bonferroni's correction. The,$ test was used for comparison of categoric data. Values of p less than 0.05 were considered statistically significant. Results From a total surgical population of 4,367 consecutive patients, 138 were supported preoperatively with IAB without concomitant heparin (group l), 741 received a course of intravenous heparin therapy prior to the operation (group 2), 137 were treated preoperatively with heparin and IAB support (group 3), and 3,264 patients received neither heparin nor IAB assist preoperatively and served as controls (group 4). Eighty-seven patients were excluded from analysis because the initial heparin dose exceeded 500 IUkg. The mean ages for the four groups ranged from 64 8 to 66.8 years. The male-to-female ratio was approximately 2:l for the entire population and 2.8:l for the heparin--1ab cohort, and varied between 1.6 and 1.7:1 for the tlhree other groups. The mean duration of cardiopulmoi~ary bypass ranged from 138 to 159 minutes in the four groups (Table 1). The data also revealed that preoperative heparin therapy had been used with increasing frequency during the 6-year study period (Table 2). In 1986, 12% of 500 cardiac surgical patients were treated with preoperative heparin. By 1991, the incidence reached 32% in a surgical population of 722.

3 Ann Thorac Surg 1994; STAPLES ET AL 1213 The baseline ACT levels were not significantly different among the four groups (Table 3). Following the initial 500-IU/kg precannulation heparin dose, the ACT response was greatest in the controls (705 f 234 seconds), intermediate in the IAB group ( seconds), and smallest in the preoperative heparin therapy cohorts with or without concomitant IAB support (520 f 159 and 506 f 149 seconds, respectively) (see Table 3). The differences were statistically significant between the control (group 4) and each of the three intervention groups (groups 1, 2, and 3), as well as between the IAB group (group 1) and the two preoperative heparin therapy cohorts (groups 2 and 3). The addition of IAB to preoperative heparin therapy did not influence the ACTs, but the reverse, or adding heparin to IAB support, blunted the ACT response. As expected, the increments in ACT in the four groups showed a pattern similar to that of the absolute post-heparin administration ACT levels: the greatest rise occurred in the control group (569 f 213 seconds), an intermediate increase took place in the IAB group (452 f 210 seconds), and the least change was seen in the heparin-treated groups with or without simultaneous IAB assist ( and 369 f 123 seconds, respectively). The differences between the control and each of the three other groups and between the IAB and the two heparintreated groups were statistically significant (see Table 3). Heparin resistance was noted in 22% of the entire population of 4,280 patients. The incidence was lowest in the control patients (14%), intermediate in the IAB subset (30%), and highest in the preoperative heparin-treated groups with or without simultaneous IAB support (53% and 50%, respectively) (see Table 3). The addition of IAB to preoperative heparin therapy did not further increase the risk of heparin resistance developing (see Table 3). The differences between the control and each of the three intervention groups and between the IAB and the two preoperatively heparinized cohorts were statistically significant. Compared to controls, the relative risk (RR) of heparin resistance was approximately twice as great in the IAB-assisted cohort (RR = 2.12 [95% confidence intervals, 1.63, 2.771) and about three times higher in the preoperatively heparinized subsets (RR = 3.24 [95% confidence intervals, 3.09, 3.861). Heparin sensitivity was lower in the three intervention cohorts than in the control group. The reduction in sensitivity from the control level was most pronounced in Table 1. Clinical Characteristics of Study Patients No. of Sex Patients Duration of Group (%) Age (y) M F CPB (min) 1. IAB 138 (3) 64.8 f f PreHepRx 741 (17) PreHepRx 137 (3) 66.8? IAB 4. Control 3,264 (76) ,075 1, f 46 CPB = cardiopulmonary bypass; F = female; IAB = intraaortic balloon; M = male; PreHepRx = preoperative heparin therapy. Table 2. lncidence of Preoperative lntravenous Heparin Therapy Total PreHepRx No. of Year Cases No. Percentage PreHepRx = preoperative heparin therapy. the two preoperative heparin-treated groups but less pronounced in the heparinless IAB population. The differences were statistically significant between the control and the three intervention groups as well as between the IAB and the two heparin-pretreated cohorts (Table 4). The total heparin requirement during the operation was significantly higher in each of the three intervention groups than in the control group. The increase was largest following heparin pretreatment alone or heparin pretreatment combined with IAB pumping and less pronounced with IAB support alone (see Table 4). Heparin consumption was lowest in the control group, intermediate in the IAB-assisted groups with or without concomitant heparin therapy, and highest in the heparin alone cohort (see Table 4). The difference between the control and IABassisted groups was not statistically significant, however. Protamine neutralization of the intraoperatively administered heparin was not influenced by the preoperative interventions that altered heparin sensitivity. The protamine-heparin ratio required to restore the baseline ACTs was similar in all four groups, and independent of the ACT response to the initial heparin aliquot, the total amount of heparin administered during the procedure, and the duration of the intraoperative anticoagulation (see Table 4). After the desired 480-second ACT was reached, supplemental heparin was required in 51.2% of the heparinpretreated patients and 31% of the controls (p < 0.001) (Table 5). Similarly, the mean amount of additional heparin given was greater in the heparin-pretreated groups than in the controls (187 versus 158 IU/kg; p < 0.001). In the resistant population, the need for additional heparin was similar for both controls and the heparin-pretreated groups. In nonresistant patients, heparin pretreatment was associated with an increased additional heparin requirement and in a larger segment of the population. Heparin-resistant patients showed a greater requirement for additional heparin than did the nonresistant ones. The difference, however, was statistically significant only in the controls, and not in the heparin-pretreated groups. Comment Inadequate heparinization during cardiopulmonary bypass can result in complications that range from subtle

4 1214 STAPLES ET AL Ann Thorac Surg 1994;57:12114 Table 3. Intraoperative ACT Data and Incidence of Heparin Resistance Heparin No. of Resistance Patients Baseline ACT Post Heparin ACT Increase Group ("/.I (s) ACT is) (s) No. Percentage 1. IAB 138 (3) 145 f f 203" 452 f 210" 42 30"*' 2. PreHepRx 741 (17) 137 f f 149a,b 369 f 123a*b a.b.d 3. PreHepRx + IAB 137 (3) 143 f f 159a,b 377 f 16IaTb 72 53a.b.d 4. Control 3,264 (76) 136 -C f C a p < versus control. p < versus IAB. Relative risk = 2.12 (95% confidence intervals, 1.63, 2.77). Relative risk = 3.24 (95% confidence intervals, 3.09, 3.86). ACT = activated clotting time; IAB = intraaortic balloon; PreHepRx = preoperative heparin therapy disturbances in the coagulation cascade to severe coagulopathy. The clinical consequences include excessive postoperative bleeding, intravascular coagulation, and even thrombosis of the extracorporeal circuit. A predetermined fixed dose schedule of heparin cannot achieve safe levels of anticoagulation with regularity because of the wide variations in the response to heparin among different patients [8, 91. Familiarity with the factors that influence the effectiveness of intraoperative heparin therapy and a flexible approach to anticoagulation during cardiac operations are therefore mandatory. Previous reports on heparin resistance have been based on small patient populations. Esposito's group [l] identified 8 patients who exhibited heparin resistance during cardiopulmonary bypass, presumably because of the use of preoperative heparin therapy. Cloyd and colleagues [2] reported on 42 patients who were treated with heparin before myocardial revascularization and showed diminished anticoagulant response during operation. In a more recent report, Dietrich and associates [3] made a similar observation in a subgroup of 12 patients who were heparinized before cardiac operations. The authors of these three articles concluded that a course of preoperative intravenous heparin therapy increases the risks of inadequate anticoagulation during cardiopulmonary bypass. The limited number of communications in the literature suggest that heparin resistance during cardiopulmonary bypass is a distinct clinical entity but the available documentation is inadequate and the data are inconsistent, so that the dimensions of the problem are poorly defined. The present study analyzed the factors in a large population that may be responsible for heparin resistance. The results confirm some of the existing beliefs, cast doubt on others, and permit new insights into the problem. The data from our study confirm the impression that preoperative intravenous heparin therapy has been used with increasing frequency in recent years, and thus heparin resistance during cardiac operations is posing a growing clinical challenge. In our institution, the use of preoperative heparin therapy has been gaining steadily, from a mere 12% of the cardiac surgical population in 1986 to 32% in Esposito and colleagues [l] maintained that a low baseline ACT can predict heparin resistance because they observed lower values in 8 resistant patients than in 38 controls. Cloyd and associates [Z] reported that, in their series of patients, baseline ACT levels did not predict the intraoperative response to heparin. Our study findings support Cloyd's, in that we found no significant differences in the baseline ACT values among the four groups that exhibited various degrees of resistance to intraoperative heparin. Furthermore, in the population we surveyed, the baseline ACTs were similar in both the resistant and nonresistant cohorts, regardless of whether the patients were controls or received preoperative heparin therapy. These observations lead us to believe that baseline ACTs cannot be used to forecast heparin resistance preoperatively. Our data also indicate that preoperative heparin therapy and IAB support are associated with decreased heparin sensitivity, an increased total heparin requirement, greater heparin consumption, and a higher incidence of heparin resistance during cardiopulmonary bypass. Table 4. Intraoperative Heparin Sensitivity, Requirement, Consumption, and Neutralization Group Heparin Sensitivity Heparin Heparin Protamine- Requirement Consumption Heparin (IUW (IU/kg/min) Ratio (mg) 1. IAB 0.9 f 0.3" 760? 131" 4.8? PreHepRx 0.73 f 0.2a,b 800 f 13F' 5.8 f 3.2a,b 3. PreHepRx + IAB 0.75 f 0.2a,b 790 f 116aTC 5.0 f 2.1d,' 4. Control 1.1 f f f a p < versus control. IAB = intraaortic balloon; p < versus IAB. IU = international unit; p < 0.05 versus IAB. p < 0.05 versus control. p < versus PreHepRw. PreHepRx = preoperative heparin therapy.

5 Ann Thorac Surg 1994; STAPLES ET AL 1215 Table 5. Additional Heparin Requirement Group Resistant Nonresistant Total Control Amount (IUkg) 191? f Incidence (%) PreHepRx Amount (IU/kg) 198 f * 131b 187 f 146b Incidence (%) b 51.2b a p < versus nonresistant. IU = international unit; p < versus control. PreHepRx = preoperative heparin therapy. Therefore, the history of preoperative heparin therapy alone should trigger concern about the possibility of heparin resistance and the prospect that greater-thanusual amounts of anticoagulant may be necessary for achieving safe intraoperative heparinization. The demonstrated need for more frequent and greater amounts of supplemental heparin in resistant patients compared to nonresistant ones indicates that the decreased influence of heparin extends beyond the phase of the initial heparinization, and therefore close monitoring of the ACT is essential for the entire duration of anticoagulation. Because the plasma concentration of heparin does not correlate with its anticoagulant activity [l, 31, the decreased sensitivity to heparin must be secondary either to reduced effectiveness or perhaps to impaired utilization of circulating heparin. As expected, the pattern of heparin resistance demonstrated by the four groups analyzed in this study parallels their ACT response to the initial dose of intraoperative heparin. The ACT response was greatest and the incidence of heparin resistance the lowest (14%) in the control group. Heparin pretreatment, with or without concomitant IAB support, resulted in the smallest ACT change and the highest incidence of resistance to intraoperative heparin. The ACT response and heparin resistance were intermediate in those who received preoperative IAB support alone. The incidence of heparin resistance in our patients probably would have been even higher had we given the commonly employed lower initial dose of 300 IU/kg of heparin instead of our standard 500 IUkg. The available information about the role of IAB in heparin resistance is limited and inconsistent. Kamath and Fozard [4] reported that 11 patients who were assisted with IAB preoperatively exhibited a diminished ACT response to intraoperative heparin. These authors did not specify whether heparin was used concomitantly with IAB. Cloyd and associates [2] reported that 26 patients who were treated with a combination of IAB and preoperative heparin showed a diminished ACT response, similar to that in the 16 others who received preoperative heparin therapy alone. They concluded that IAB probably does not reduce the sensitivity to heparin. It should be noted, again, that Cloyd s group based their opinion on a comparison of heparin alone or heparin plus IAB with control results, but did not examine the independent influence of IAB. Our results in 138 patients, who were treated with a combination of IAB and heparin, support Cloyd s claim that IAB does not enhance the resistance associated with the preoperative heparin therapy. However, we observed a reduced anticoagulant response in another 137 patients, who were assisted with IAB alone and did not receive concomitant heparin therapy. The reduced sensitivity with IAB alone that we observed is not consistent with Cloyds conclusion that IAB is not an independent influence. The availability of separate preoperative heparin therapy and IAB support cohorts in our series allowed characterization of the independent contribution of each of these two forms of interventions to the development of heparin resistance. It is apparent that IAB by itself impairs the effectiveness of heparin but the influence is less pronounced than that exerted by preoperative heparin therapy. When the two modalities were combined, the effect of heparin predominated and the addition of IAB did not enhance heparin resistance. Three major theories have been advanced to explain heparin resistance: (1) heparin-induced thrombocytopenia; (2) a heparin-induced decrease in the circulating antithrombin I11 (AT-111) level; and (3) enhancement of factor VIII activity. Clinically significant heparin-induced thrombocytopenia does not become manifest until 7 to 10 days after the initiation of treatment. It has been postulated that the destroyed platelets release factor IV, which binds heparin and neutralizes its anticoagulant action. The platelet count was not abnormally low in the four heparinpretreated populations of Cloyd, Dietrich, Esposito, and our series [l-31. Actually, platelets were more abundant in the heparin-resistant than in the heparin-nonresistant cohort. Furthermore, the duration of the preoperative heparin therapy was shorter than 7 days in the overwhelming majority of our patients. Finally, heparin resistance was encountered even in the absence of preoperative heparin therapy. Thus, heparin-induced thrombocytopenia does not appear to play a role in the etiology of heparin resistance during cardiopulmonary bypass. Antithrombin-111, a plasma a2 globulin, binds and inactivates thrombin so that it is a potent inhibitor of blood clotting. Heparin exerts its influence by accelerating the inactivation of thrombin by AT-111. Marciniak and Gockerman [ 101 reported that continued intravenous heparin therapy depletes plasma AT-111 levels and the depletion reduces the effectiveness of subsequently administered heparin. In heparin-pretreated patients, Esposito and colleagues [l] found normal AT-I11 levels but Dietrich and associates [3] and others [5, 10, 111 noted a decrease. The present study did not address AT-I11 activity, and therefore we are not in a position to draw any conclusions about it. An increase in factor VIII activity has been implicated in the development of paradoxical hypercoagulability while on heparin therapy for deep venous thrombosis [9]. We cannot comment on the possible role of factor VIII in the production of heparin resistance because we did not measure its activity. Previous reports have raised the possibility that the

6 1216 STAPLES ET AI, Ann Thorac Surg 1994; intravenous nitroglycerin therapy frequently employed in patients with unstable angina pectoris may contribute to the development of heparin resistance [ The results reported to date are conflicting and inconclusive. We did not address the issue in our analysis and more studies are necessary to clarify the influence of intravenous nitroglycerin on heparin resistance. Because the individual responses to heparin are variable, a predetermined fixed dose schedule for use in cardiopulmonary bypass, without close monitoring of the anticoagulant state, exposes the patient to a significant risk of inadequate anticoagulation with serious and even lethal consequences. At the present time, there is no reliable clinical predictor for identifying heparin resistance during cardiopulmonary bypass. The data presented in this article provide convincing documentation that preoperative intravenous heparin therapy and IAB support predispose to heparin resistance. The use of these two therapeutic modalities should flag the enhanced possibility that a higher-than-ordinary heparin requirement may be necessary for achieving safe anticoagulation and should emphasize the need for close attention to the management of anticoagulation. Monitoring of ACT can identify an abnormal response to heparin and facilitate administration of the appropriate dosage to ensure adequate anticoagulation. Furthermore, the documented need for larger additional heparin requirements in an appreciable segment of the resistant population mandates surveillance of ACT levels during the entire period of heparinization. Finally, it appears from our study that doses of heparin higher than the widely used initial anticoagulating dose of 300 IUkg may have to be used in patients on preoperative heparin therapy or on IAB support. Supported in part by the Thoracic Foundation. We thank members of the Deaconess Perfusion Team for helping to take care of our patients, maintaining excellent records, and sharing the data; Walter H. Dzik, MD, Director of Blood Bank, for reviewing the manuscript, and 8. J. Bloom and Ilana L. Berger for assisting in the collection of the data. References 1. Esposito RA, Culliford AT, Colvin SB, Thomas SJ, Lackner H, Spencer FC. Heparin resistance during cardiopulmonary bypass: the role of heparin pretreatment. J Thorac Cardiovasc Surg 1983;85:34& Cloyd GM, DAmbra MN, Akins CW. Diminished anticoagulant response to heparin in patients undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg 1987;94: Dietrich W, Spannagl M, Schramm W, Vogt W, Barankay A, Richter JA. The influence of preoperative anticoagulation on heparin response during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1991;102: Kamath BSK, Fozard JR. Control of heparinization during cardiopulmonary bypass. Anesthesia 1980;35: Chung F, David TE, Watt J. Excessive requirement for heparin during cardiac surgery. Can Anaesth SOC J 1981;28: 28C Soloway HB, Christiansen TW. Heparin anticoagulation during cardiopulmonary bypass in an AT-I11 deficient patient. Am J Clin Pathol 1980;73: Anderson EF. Heparin resistance prior to cardiopulmonary bypass. Anesthesiology 1986;64: Bull BS, Huse WM, Brauer FS, Korpman RA. Heparin therapy during extracorporeal circulation. 11. The use of a dose-response curve to individualize heparin and protamine dosage. J Thorac Cardiovasc Surg 1975;69: Bull BS, Korpman RA, Huse WM, Briggs BD. Heparin therapy during extracorporeal circulation. I. Problems inherent in existing heparin protocols. J Thorac Cardiovasc Surg 1975;69: Marciniak E, Gockerman JP. Heparin-induced decrease in circulating antithrombin-111. Lancet 1977;2: Denson KE. The ratio of factor VIII-related antigen and factor VIII biological activity as an index of hypercoagulability and intravascular clotting. Thromb Res 1977;10: Habbab MA, Haft JI. Heparin resistance induced by intravenous nitroglycerine. A word of caution when both drugs are used concomitantly. Arch Intern Med 1987; Lepor NE, Amin DK, Berberian L, Shah PK. Does nitroglycerine induce heparin resistance? Clin Cardiol 1989;12: Schoenenberger RA, Menat L, Weiss P, Marbet GA, Ritz R. Absence of nitroglycerine-induced heparin resistance in healthy volunteers. Eur Heart J 1992;13: