Increased anticoagulation during cardiopulmonary bypass by aprotinin.

In this prospective study, the effect of the antiproteinase aprotinin on anticoagulation during cardiopulmonary bypass was compared with placebo treatment in a randomized double-blind fashion. The kallikrein-inhibiting capacity was significantly increased in aprotinin-treated patients and decreased in the control patients. The intrinsic clotting system was also inhibited by aprotinin. We demonstrated during cardiopulmonary bypass and in vitro a significantly prolonged activated clotting time and a remarkable prolongation of the activated partial thromboplastin time by aprotinin at low heparin concentrations, whereas the antithrombin III consumption was significantly reduced. Aprotinin synergistically enhanced the anticoagulation by heparin, which allowed reduced heparinization. This is of clinical importance for use in both heparin-resistant and heparin-sensitive patients undergoing cardiopulmonary bypass and may also have advantages for routine use during bypass to reduce the adverse effects of heparin-protamine complexes.     

在体外及体外循环中抑肽酶对ACT的影响

选择健康献血员及心内直视手术病，观察抑肽酶对全血活化凝血时间的影响。结果：在体外肝素剂量与ＡＣＴ有显著线性相关。抑肽酶单狡应用并不使ＡＣＴ延，但与肝素合用可协同性延长ＡＣＴ值；在体外循环中抑肽酶延长ＡＣＴ的值更为显著，一般超过８００ｓ。结论：抑肽酶可与肝素协同性延长ＡＣＴ，体外循环中应用抑肽酶时应以ＡＣＴ大于８００ｓ作为肝素抗凝标准。     

The antithrombotic and antiinflammatory mechanisms of action of aprotinin

Aprotinin (Trasylol) is generally regarded to be an effective hemostatic agent that prevents blood loss and preserves platelet function during cardiac surgery procedures requiring cardiopulmonary bypass (CBP). However, its clinical use has been limited by the concern that such a potent hemostatic agent might be prothrombotic, particularly in relation to coronary vein graft occlusion. In this review we present a mechanism of action that challenges such a viewpoint and explains how aprotinin can be simultaneously hemostatic and antithrombotic. Aprotinin achieves these two apparently disparate properties by selectively blocking the proteolytically activated thrombin receptor on platelets, the protease-activated receptor 1 (PAR1), while leaving other mechanisms of platelet aggregation unaffected. We also review recent research leading to the discovery of novel antiinflammatory targets for aprotinin. A better understanding of its mechanisms of action has led to the conclusion that aprotinin is a remarkable drug with the capacity to correct many of the imbalances that develop in the coagulation system and the inflammatory system after CPB. Nonetheless, it has been clinically underused for fear of causing thrombotic complications, a fear that in light of recent evidence may be unfounded.     

体外循环中肝素、鱼精蛋白对血小板的激活及抑肽酶的抑制作用

目的研究在体外循环中肝素化及鱼精蛋白中和时血小板的激活以及应用抑肽酶对这种激活的抑制作用。方法２０例心脏瓣膜置换术患者随机等分为两组：对照组和抑肽酶组，分别于肝素化及应用鱼精蛋白前后检测血小板胞浆游离钙浓度，磷脂酶Ａ２活性及血浆血栓素水平。结果上述指标在肝素化及鱼精蛋白中和后均显著升高，其中鱼精蛋白中和时升高幅度更大，应用抑肽酶对肝素及鱼精蛋白所引起的上述改变均有显著抑制作用。结论抑肽酶对肝素和鱼精蛋白所致的血小板激活有显著抑制作用，这可能与抑肽酶在体外循环中的止血作用有关。     

Monitoring of heparin-induced anticoagulation with kaolin-activated clotting time in cardiac surgical patients treated with aprotinin.

High-dose aprotinin appears to enhance the anticoagulant effects of heparin, as documented by increases in the activated clotting times (ACTs) during cardiopulmonary bypass; hence, some authorities have advocated reducing the dose of heparin in patients treated with aprotinin. An in vitro study by our group suggested that the increase of the ACT in the presence of aprotinin and heparin may be due to the use of celite as surface activator. We compared celite and kaolin as surface activators for the measurement of the ACT in cardiac surgical patients treated with aprotinin and in patients given no aprotinin. This double-blind, randomized, placebo-controlled study included 30 patients, of whom 14 received aprotinin and 16 received a placebo. Before, during, and after cardiopulmonary bypass, the ACT was measured with two Hemochron 400 systems with 12 mg of either celite (C-ACT) or kaolin (K-ACT) used as surface activator and with one Hepcon HMS system (HR-ACT), which uses kaolin as activator. The latter also was used for measurement of the blood heparin concentration. The ACTs of blood without heparin did not differ between aprotinin and control patients. During anticoagulation with heparin and cardiopulmonary bypass, the average C-ACTs were 784 +/- 301 s (aprotinin) and 496 +/- 120 s (control) (P < .001); the K-ACTs were 502 +/- 131 s (aprotinin) and 458 +/- 101 s (control) (P > .05); the HR-ACTs were 406 +/- 87 s (aprotinin) and 423 +/- 82 s (control) (P > .05), which was consistently less than C-ACT and K-ACT.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of nafamostat mesilate and minimal-dose aprotinin on blood-foreign surface interactions in cardiopulmonary bypass

BACKGROUND: The pharmacological inhibition of blood-foreign surface interactions is an attractive strategy for reducing the morbidity associated with cardiopulmonary bypass. We compared the inhibitory effects of nafamostat mesilate (a broad-spectrum synthetic protease inhibitor) and minimal-dose aprotinin on blood-surface interactions in clinical cardiopulmonary bypass. METHODS: Eighteen patients undergoing coronary surgery were divided into three groups: (1) the control group (heparin, 4 mg/kg; n = 6), (2) the nafamostat mesilate group (heparin plus nafamostat, 0.2 mg/kg bolus followed by 2.0 mg/kg/h during cardiopulmonary bypass; n = 6), and (3) the aprotinin group (heparin plus aprotinin, 2.0 x 10(4) KIU/kg; n = 6). Platelet count, platelet aggregation, beta-thromboglobulin, prothrombin fragment F1.2, thrombin-antithrombin complex, plasminogen activator inhibitor-1, alpha2-plasmin inhibitor-plasmin complex, D-dimer, neutrophil elastase, and interleukin-6 were measured before, during, and after bypass. Bleeding times and blood loss were recorded. RESULTS: There were no significant differences between groups in platelet count, beta-thromboglobulin, plasminogen activator inhibitor-1, interleukin-6, bleeding times, or blood loss. Platelet aggregation was better preserved at 12 hours after surgery in the nafamostat and aprotinin groups than in the control group. Prothrombin fragment F1.2, thrombin-antithrombin complex and neutrophil elastase levels were significantly reduced by aprotinin, but not by nafamostat as compared with the control group. The alpha2-plasmin inhibitor-plasmin complex and D-dimer were significantly lower with either of the drugs. Aprotinin showed better control of D-dimer than did nafamostat. CONCLUSIONS: Nafamostat mesilate fails to reduce thrombin formation and neutrophil elastase release, whereas minimal-dose aprotinin inhibits both. Neither nafamostat nor aprotinin inhibits platelet activation. Nafamostat reduces fibrinolysis during cardiopulmonary bypass, although its effect is not as potent as aprotinin.     

Aprotinin reduces intraoperative and postoperative blood loss in membrane oxygenator cardiopulmonary bypass.

To determine whether aprotinin can provide a significant improvement of hemostasis in cardiopulmonary bypass using a membrane oxygenator, we tested this drug in a prospective, randomized, double-blind, placebo-controlled clinical trial. The subjects were 80 male patients undergoing cardiopulmonary bypass for coronary artery bypass grafting. Forty patients received aprotinin and 40 patients served as placebo controls. Aprotinin (4 x 10(6) KIU) was given as a continuous infusion, starting before operation and continuing until after cardiopulmonary bypass; additionally, 2 x 10(6) KIU aprotinin was added to the pump prime. Intraoperative and postoperative bleeding, respectively two thirds and one third of the total perioperative blood loss, were both significantly reduced in the aprotinin-treated group (p less than 0.01). The total average perioperative blood loss, corrected to a hemoglobin concentration of 7 mmol/L, was 550 mL in the aprotinin-treated patients versus 900 mL in the control patients. This reduction in blood loss, furthermore, significantly decreased the amount of postoperative blood transfusions (p less than 0.05) and increased the percentage of patients who did not receive postoperative donor blood from 42% to 68%. Aprotinin increased the activated clotting time significantly during cardiopulmonary bypass, which led to a reduction in heparin usage. The improved hemostasis during operation, despite the prolonged activated clotting time, might even abolish the need for heparin conversion with protamine at the end of cardiopulmonary bypass, thus allowing retransfusion through cardiotomy suction to be continued, which saves the blood that is currently lost with vacuum suction.     

Monitoring activated clotting time for combined heparin and aprotinin application: an in vitro evaluation of a new aprotinin-insensitive test using SONOCLOT

The kaolin-based activated clotting time (ACT) is commonly used for monitoring heparin-induced anticoagulation alone and combined with aprotinin during cardiopulmonary bypass. However, aprotinin prolongs ACT measurements. Recently, a new so-called 'aprotinin-insensitive' ACT test (SaiACT) has been developed for the SONOCLOT analyzer. In this study we evaluated and compared this new test for the SONOCLOT analyzer in vitro with an established kaolin-based ACT from HEMOCHRON (HkACT). Twenty-five patients undergoing elective valve surgery donated 80 mL of blood after induction of anesthesia. The blood was withdrawn in citrated tubes and processed to analyze effects of heparin (0, 1, 2, and 3 U x mL(-1)), aprotinin (0, 200 kIU x mL(-1)), and 25% hemodilution with calcium-free lactated Ringer's solution on ACT measurements. A total of 400 blood samples were analyzed and ACT was measured in a wide, clinically relevant range in duplicate with SaiACT and HkACT. Addition of aprotinin to heparinized blood samples induced no significant changes of SaiACT measurements. By contrast, HkACT readings increased significantly: aprotinin prolonged HkACT in heparinized blood samples by 20% +/- 37% (2 U x mL(-1)) and 24% +/- 18% (3 U x mL(-1)), respectively, and in vitro hemodilution increased this effect. IMPLICATIONS: Current standard techniques to measure heparin-induced anticoagulation during cardiopulmonary bypass are affected by aprotinin, a drug widely used in this setting. The aim of this study was to investigate in vitro a new, so-called 'aprotinin-insensitive' test from SONOCLOT to measure heparin-induced anticoagulation more reliably in combination with aprotinin.     

Use of aprotinin in patients undergoing deep hypothermic circulatory arrest: a review

Hemostatic derangements continue to be a major clinical challenge during thoracic aortic surgery using deep hypothermic circulatory arrest despite advances in surgical and pharmacologic therapy. Aprotinin, a broad-based, nonspecific serine protease inhibitor has been advocated for prophylactic use in cardiac surgery to decrease perioperative blood loss and blood transfusions. Its efficacy has been documented in several studies throughout the United States and Europe. Currently, aprotinin is advocated for use in patients undergoing cardiopulmonary bypass in the course of coronary artery bypass graft surgery. A review of current studies is provided that examines aprotinin usage under deep hypothermic circulatory arrest.     

The effects of aprotonin on platelets in vitro using whole blood flow cytometry

We sought to evaluate the effects of aprotinin on the number and function of the platelet glycoprotein (GP) IIb-IIIa receptor and on the expression of P-selectin in vitro in order to gain insight into the potential mechanisms involved in the platelet-protective action of aprotinin during cardiopulmonary bypass. Aprotinin at 50 to 200 kallikrein inhibiting units/mL decreased the expression of activated GP IIb-IIIa complex in response to adenosine diphosphate or thrombin receptor activator peptide 6 in a dose-dependent manner in both citrated and heparinized whole blood experiments. Aprotinin inhibited adenosine diphosphate-induced platelet aggregation, but it exhibited no effect on the expression of GP IIIa and P-selectin. These results indicate that aprotinin interferes with the platelet fibrinogen receptor function during pharmacological activation. Reduced aggregability and platelet adhesion to fibrinogen adsorbed to synthetic surfaces in the presence of aprotinin may prevent platelet consumption during clinical cardiopulmonary bypass. This in vitro study demonstrates that aprotinin decreases the agonist-induced expression of activated GP IIb-IIIa receptors that play a major role in platelet aggregation and adhesion to biomaterial surfaces. IMPLICATIONS: This in vitro study demonstrates that aprotinin decreases the agonist-induced expression of activated glycoprotein IIb-IIIa receptors that play a major role in platelet aggregation and adhesion to biomaterial surfaces.     

The effect of temperature and aprotinin during cardiopulmonary bypass on three different methods of activated clotting time measurement

The activated clotting time (ACT) is used frequently for monitoring blood anticoagulant response with heparin before, during, and after cardiopulmonary bypass (CPB). Many cardiac procedures involving CPB require reduction of the patient's blood temperature and use of the serine protease inhibitor, aprotinin. Three different methods of ACT measurement were compared to show the effects of different CPB temperatures and the presence of aprotinin. A total of 42 patients were included in the study: 14 received CPB at 28 degrees C, 14 received CPB at 32 degrees C, and 14 normothermic (37 degrees C) CPB. Within each temperature group, seven received aprotinin. The ACT in each group of patients was measured by a celite activator (C-ACT), a kaolin activator (K-ACT), and a celite, kaolin and glass activator (MAX-ACT). All three methods of ACT measurement showed significant increases (p < .05) in clotting times at hypothermic CPB compared with normothermic groups. During heparinization the C-ACT was significantly increased (p < .05) in the presence of aprotinin. Comparability between the 3 ACT measurement methods showed a very high correlation between C-ACT and K-ACT clotting times (R2 = .8962), and slightly lower correlation between MAX-ACT and C-ACT (R2 = .7780), and MAX-ACT and K-ACT (R2 = .7827). All ACT measurements are affected by changes in blood temperature. The C-ACT measurement is prolonged with aprotinin, whereas the MAX-ACT and K-ACT method of measurement in the presence of aprotinin are not significantly altered. It appears that the MAX-ACT produces lower values and may necessitate additional heparin therapy for ACT target values considered safe during CPB. Further study is required from these additional findings.     

Anticoagulation for cardiac surgery in patients receiving preoperative heparin: use of the high-dose thrombin time

Patients receiving heparin infusions have an attenuated activated clotting time (ACT) response to heparin given for cardiopulmonary bypass (CPB). We compared patients receiving preoperative heparin (Group H) to those not receiving heparin (REF group) with respect to ACT, high-dose thrombin time (HiTT), and markers of thrombin generation during CPB. Sixty-five consecutive patients (33 Group H, 32 REF group) undergoing elective CPB were evaluated. ACT and HiTT were measured at multiple time points. Plasma levels of thrombin-antithrombin III complex and fibrin monomer were determined at baseline, during CPB, and after protamine administration. Transfusion requirements and postoperative blood loss were measured and compared. ACT values after heparinization increased less in Group H and were significantly lower than those in the REF group (P < 0.01). HiTT values did not differ significantly between the two groups. Blood loss and transfusion requirements were not significantly different between the two groups. Plasma levels of thrombin-antithrombin III complexes and fibrin monomer also did not differ between groups at any time, despite a lower ACT in Group H after heparinization and during CPB. Our data suggest that thrombin formation and activity are not enhanced in patients receiving heparin therapy, despite a diminished ACT response to heparin. The utility of ACT and the threshold values indicative of adequate anticoagulation for CPB are relatively undefined in patients receiving preoperative heparin. HiTT should be investigated as a safe and accurate monitor of anticoagulation for CPB in patients receiving preoperative heparin therapy. Implications: The diminished activated clotting time response to heparin, in patients receiving preoperative heparin therapy, poses difficulties when attempting to provide adequate anticoagulation for cardiopulmonary bypass. Current data suggest that heparin resistance is not observed when high-dose thrombin time is used to monitor anticoagulation and that a lower activated clotting time value in these patients may be safe.     

In vitro effects of aprotinin on activated clotting time measured with different activators.

The effects in vitro of aprotinin on the activated clotting time measured with both celite- and kaolin-activated tubes were investigated in 21 consecutive patients requiring cardiopulmonary bypass. Four whole-blood samples (2 ml per sample) from each patient were tested simultaneously with Hemochron automated timing systems (International Technidyne Corp., Edison, N.J.) before, during, and after cardiopulmonary bypass. One tenth milliliter of either aprotinin (at a final concentration of 80, 120, or 180 KIU/ml) or saline solution was mixed in vitro with blood samples before determination of the activated clotting time. Aprotinin had no inhibitory effect on the activated clotting times of unheparinized blood. After heparin administration, aprotinin in the above concentrations prolonged the activated clotting times measured with celite-activated tubes by 47% to 71%, as compared with the measurements of the activated clotting time without the addition of aprotinin. The activated clotting times in kaolin-activated tubes were not increased, however, by the in vitro addition of aprotinin. Our in vitro results indicate that aprotinin in concentrations from 80 to 180 KIU/ml does not significantly enhance the inhibitory effects of heparin on the intrinsic coagulation system as evaluated by measurement of the activated clotting times in kaolin-activated tubes. The anticoagulation effect of heparin in patients receiving aprotinin infusion should be monitored with kaolin-activated instead of celite-activated tubes because the celite makes the measured activated clotting time unreliable in patients receiving aprotinin therapy. These in vitro results require confirmation in vivo in patients receiving aprotinin therapy.     

Antifibrinolytic therapy during cardiopulmonary bypass reduces proinflammatory cytokine levels: a randomized, double-blind, placebo-controlled study of epsilon-aminocaproic acid and aprotinin

OBJECTIVES: Aprotinin is a broad-spectrum serine protease inhibitor that has been shown to attenuate the systemic inflammatory response in patients undergoing cardiac surgery with cardiopulmonary bypass. Although epsilon-aminocaproic acid is similar to aprotinin in its ability to inhibit excessive fibrinolysis (ie, plasmin activity and D-dimer formation), its ability to influence proinflammatory cytokine production remains unclear. This study was designed to compare the effects of epsilon-aminocaproic acid and aprotinin on plasma levels of interleukin-6 and interleukin-8 during and after cardiopulmonary bypass. METHODS: Sixty patients were randomized in a double-blind fashion to receive epsilon-aminocaproic acid, aprotinin, or saline (placebo) in similar dosing regimens (loading dose, pump prime, and infusion). Arterial blood samples were collected before, during, and after cardiopulmonary bypass, and plasma levels of D-dimer, interleukin-6, and interleukin-8 were measured. Data were analyzed using repeated measures analysis of variance. RESULTS: Both epsilon-aminocaproic acid and aprotinin administration resulted in significant (P <.05) reductions in D-dimer and interleukin-8 levels compared with saline. These reductions in D-dimer and interleukin-8 levels did not differ between the 2 drug-treated groups. The effect of these two antifibrinolytic agents on interleukin-6 was qualitatively similar to that noted with interleukin-8 but did not reach statistical significance. CONCLUSIONS: When dosed in a similar manner, epsilon-aminocaproic acid seems to be as effective as aprotinin at reducing interleukin-6 and interleukin-8 levels in patients undergoing primary coronary artery bypass graft surgery. These data indicate that suppression of excessive plasmin activity or D-dimer formation or both may play an important role in the generation of proinflammatory cytokines during and after cardiopulmonary bypass.     

Aprotinin inhibits thrombin formation and monocyte tissue factor in simulated cardiopulmonary bypass.

BACKGROUND: Aprotinin reduces perioperative bleeding after open heart surgery, primarily by inhibiting fibrinolysis. In addition, the drug has both procoagulant and anticoagulant effects that involve complex reactions of coagulation proteins and cells that are incompletely understood. This study tests the hypothesis that aprotinin has an anticoagulant effect on the extrinsic coagulation pathway. METHODS: Human heparinized blood was recirculated through a membrane oxygenator with and without high concentrations of aprotinin (18.4 microM). Serial plasma samples were obtained at intervals up to 240 minutes. RESULTS: Aprotinin significantly reduced the progressive increase in prothrombin fragments (F1.2) and thrombin-antithrombin complex beginning immediately. Aprotinin also significantly reduced monocyte expression of tissue factor and Mac-1. Aprotinin did not significantly reduce factor VII or factor VIIa. CONCLUSIONS: During simulated cardiopulmonary bypass, aprotinin immediately inhibits kallikrein and thrombin formation via the intrinsic coagulation pathway. Later, aprotinin inhibits monocyte expression of tissue factor and the extrinsic coagulation pathway. The ability of aprotinin to inhibit monocyte tissue factor provides a means to reduce thrombin formation in blood aspirated from the wound during open heart surgery.     

Monitoring activated clotting time for combined heparin and aprotinin application: in vivo evaluation of a new aprotinin-insensitive test using Sonoclot.

OBJECTIVE: Kaolin-based activated clotting time assessed by HEMOCHRON (HkACT) is a clinical standard for heparin monitoring alone and combined with aprotinin during cardiopulmonary bypass (CPB). However, aprotinin is known to prolong not only celite-based but also kaolin-based activated clotting time. Overestimation of activated clotting times implies a potential hazardous risk of subtherapeutic heparin anticoagulation. Recently, a novel 'aprotinin-insensitive' activated clotting time test has been developed for the SONOCLOT analyzer (SaiACT). The aim of our study was to evaluate SaiACT in patients undergoing CPB in presence of heparin and aprotinin. METHODS: Blood samples were taken from 44 elective cardiac surgery patients at the following measurement time points: baseline (T0); before CPB after heparinization (T1 and T2); on CPB, before administration of aprotinin (T3); 15, 30, and 60 min on CPB after administration of aprotinin (T4, T5, and T6); after protamine infusion (T7). On each measurement time point, activated clotting time was assessed with HkACT and SaiACT, both in duplicate. Furthermore, the rate of factor Xa inhibition and antithrombin concentration were measured. Statistical analysis was done using Bland and Altman analysis, Pearson's correlation, and ANOVA with post hoc Bonferroni-Dunn correction. RESULTS: Monitoring anticoagulation with SaiACT showed reliable readings. Compared to the established HkACT, SaiACT values were lower at all measurement time points. On CPB but before administration of aprotinin (T3), SaiACT values (mean+/-SD) were 44+/-118 s lower compared to HkACT. However, the difference between the two measurement techniques increased significantly on CPB after aprotinin administration (T4-T6; 89+/-152 s, P=0.032). Correlation of ACT measurements with anti-Xa activity was unchanged for SaiACT before and after aprotinin administration (r2=0.473 and 0.487, respectively; P=0.794), but was lower for HkACT after aprotinin administration (r2=0.481 and 0.361, respectively; P=0.041). On CPB after administration of aprotinin, 96% of all ACT values were classified as therapeutic by HkACT, but only 86% of all values were classified therapeutic if ACT was determined by SaiACT. Test variability was comparable for SaiACT and HkACT. CONCLUSIONS: The use of SaiACT may result in more consistent heparin management that is less affected by aprotinin and a corresponding increase in heparin administration for patients receiving aprotinin.     

Does aprotinin influence the inflammatory response to cardiopulmonary bypass in patients?

OBJECTIVES: Aprotinin has been shown to have anti-inflammatory properties, but its effects on the inflammatory reaction to cardiopulmonary bypass remain controversial. This prospective, randomized, double-blind study evaluated the influence of aprotinin on various blood markers of inflammation during and after cardiopulmonary bypass. METHODS: Sixty male patients underwent coronary artery bypass grafting. The patients were randomized into 3 groups: a placebo group, a second group receiving 2,000,000 KIU of aprotinin followed by an infusion of 500,000 KIU/h and 2,000,000 KIU in the pump prime, and a third group receiving half this dosage. Measurements of tumor necrosis factor, interleukin 6, interleukin 8, interleukin 10, endotoxin, histamine, complement factors, prekallikrein, and prostaglandin D(2) were obtained at baseline, 30 minutes after study drug loading, 10 minutes after the beginning of cardiopulmonary bypass, before the end of bypass, 4 hours after bypass, and on the first and second postoperative days. RESULTS: Aprotinin had no significant effect on any of these parameters. As expected, aprotinin reduced early blood loss in both treated groups. CONCLUSIONS: These results indicate that aprotinin at doses currently used to reduce blood loss has no significant influence on the systemic inflammatory response during moderate hypothermic cardiopulmonary bypass in human subjects, as assessed by the mediators measured in this study.     

Heparinase in the activated clotting time assay: monitoring heparin-independent alterations in coagulation function.

The activated clotting time (ACT) is routinely used to monitor heparin during cardiopulmonary bypass surgery. Activated clotting times may be influenced by a number of factors other than heparin. The presence of heparin in blood samples disguises the occurrence of non-heparin-related changes in coagulation function. During cardiopulmonary bypass, it is difficult to ascertain baseline clotting time fluctuations with ACT alone. Previous attempts to establish accurate baseline data were imprecise and involved extensive sample handling. In this study, we present data obtained using a modified (ACT) assay that incorporates heparinase. The heparinase test cartridge (HTC) instantaneously, specifically, and completely removes heparin in the blood sample at the initiation of the test. In conjunction with standard ACT techniques, the clinician is provided with heparin-independent (baseline) and functional clotting data. The HTC/ACT assay was used in a case study involving 19 patients undergoing cardiopulmonary bypass surgery. The data gathered indicate the usefulness of this assay in monitoring incidents of baseline drift, hemodilution, and hypercoagulation and the efficacy of protamine reversal.     

Effects of Duraflo II heparin-coated cardiopulmonary bypass circuits on the coagulation system, endothelial damage, and cytokine release in patients with cardiac operation employing aprotinin and steroids

The effects of Duraflo II heparin coated cardiopulmonary bypass circuits, low-dose aprotinin, and steroids on the coagulation system, endothelial damage, and cytokine release were evaluated by comparing those treated with low-dose aprotinin and steroids. Twenty-four adult patients undergoing coronary artery bypass grafting, aortic valve replacement, or valve repair surgery were randomly assigned to 2 groups: either heparin-coated (Duraflo group, n = 12) or noncoated equipment (noncoated group, n = 12) groups. In the Duraflo group, the cardiopulmonary reservoir was also coated with heparin. There were no significant differences in age at the time of operation, aortic cross-clamp time, cardiopulmonary bypass time, and rectal temperature during cardiopulmonary bypass. Standard systemic heparinization was performed. Methylpredonisolone and low-dose aprotinin were given in both groups of patients. Serum XIIa factor, TAT, and IL-6 were significantly higher in the control group than in the Duraflo group during cardiopulmonary bypass (p < 0.01). Serum IL-8 was significantly higher in the control group than in the Duraflo group at 24 h after cardiopulmonary bypass (p < 0.05). No significant difference was found in serum thrombomodulin and TNF-alpha; both were within normal during the study period. These results indicate that the use of Duraflo II heparin coated equipment and a heparin-coated cardiopulmonary reservoir suppressed excess coagulation and inflammatory reaction induced by cardiopulmonary bypass.     

Variability of plasma aprotinin concentrations in pediatric patients undergoing cardiac surgery

OBJECTIVES: Infants and children undergoing cardiopulmonary bypass for repair of congenital heart defects are at substantial risk for excessive bleeding, contributing greatly to morbidity and mortality. Aprotinin significantly reduces bleeding and transfusion requirements in adults but is of indeterminate value for pediatric patients. The aim of this study was to determine plasma aprotinin concentrations in these patients with a functional aprotinin assay. METHODS: Thirty patients less than 16 years of age scheduled for cardiac surgery with aprotinin were enrolled. Aprotinin was administered as a 25,000 KIU/kg bolus, 35,000 KIU/kg cardiopulmonary bypass prime, and 12,500 KIU.kg(-1).h(-1) continuous infusion. Blood samples for aprotinin concentrations (kallikrein-inhibiting units/milliliter) were obtained before aprotinin; 5 minutes post-bolus; 5 minutes after cardiopulmonary bypass initiation; 30 and 60 minutes on cardiopulmonary bypass; on discontinuation of aprotinin; 1 hour after aprotinin discontinuation; and 4 hours after permanent separation from cardiopulmonary bypass. For analysis, patients were grouped according to weight (<10 kg, 10-20 kg, >20 kg). Differences between weight groups were assessed using an exact test for categoric variables and 1-way analysis of variance for continuous variables. RESULTS: Aprotinin concentrations differed significantly across weight groups. Five minutes after aprotinin bolus and initiation of cardiopulmonary bypass, there was significant correlation between weight and aprotinin concentration (r =.57, P =.003; r =.69, P =.001, respectively). CONCLUSION: A functional assay reveals significant variability in aprotinin concentration for pediatric patients using current weight-based aprotinin dosing. Additional investigation is necessary to determine target aprotinin concentration dosing regimens to provide better efficacy.