The impact of heparin-coated cardiopulmonary bypass circuits on pulmonary function and the release of inflammatory mediators.

UNLABELLED: Reduction of the inflammatory reaction with the use of heparin coating has been found during and after cardiopulmonary bypass (CPB). The question remains whether this reduced reaction also decreases the magnitude of CPB-induced pulmonary dysfunction. We therefore evaluated the effects of a heparin-coated circuit versus a similar uncoated circuit on pulmonary indices as well as on inflammatory markers of complement activation (C3b/c), elastase-alpha(1)-antitrypsin complex, and secretory phospholipase A(2) (sPLA(2)) during and after CPB. Fifty-one patients were randomly assigned into two groups undergoing coronary artery bypass grafting with either a heparin-coated (Group 1) or an uncoated (Group 2) circuit. During CPB, a continuous positive airway pressure of 5 cm H(2)O and a fraction of inspired oxygen (FIO(2)) of 0.21 were maintained. Differences in favor of the coated circuit were found in pulmonary shunt fraction (P < 0.05), pulmonary vascular resistance index (P < 0.05), and PaO(2)/FIO(2) ratio (P < 0.05) after CPB and in the intensive care unit. During and after CPB, the coated group demonstrated lower levels of sPLA(2). After CPB, C3b/c and the elastase-alpha(1)-antitrypsin complex were significantly less in the coated group (P < 0.001). The coated circuit was associated with a reduced inflammatory response, decreased pulmonary vascular resistance index and pulmonary shunt fraction, and increased PaO(2)/FIO(2) ratio, suggesting that the coated circuit may have beneficial effects on pulmonary function. The correlation with sPLA(2), leukocyte activation, and postoperative leukocyte count suggests reduced activation of pulmonary capillary endothelial cells. IMPLICATIONS: Heparin coating of the extracorporeal circuit reduces the inflammatory response during cardiopulmonary bypass. Analysis of indices of pulmonary function indicates that use of heparin coating may result in less impaired gas exchange.

Comparison of three commercially available hollow fiber oxygenators: gas transfer performance and biocompatibility.

The new generation of oxygenators have improved blood flow pathways that enable reduction in priming volume and, thus, hemodilution during cardiopulmonary bypass (CPB). We evaluated three oxygenators and two sizes of venous reservoirs in relation to priming volume, gas transfer, and blood activation. To compare priming volume, gas transfer, and biocompatibility of three hollow fiber oxygenators and two different size venous reservoirs, 60 patients were randomly allocated in groups to undergo cardiopulmonary bypass. In each group, an oxygenator with a different surface area and priming volume was used: 1.8 m2 and 220 ml (group 1, n = 23), 2.2 m2 and 290 ml (group 2, n = 20), and 2.5 m2 and 270 ml (group 3, n = 17). In groups 1 and 3, a large soft shell (1900 ml) venous reservoir was used, whereas in group 2, a smaller soft shell (600 ml) venous reservoir was used. Gas transfer was assessed by calculating the oxygen transfer rate for each group and per square meter for each oxygenator group. Partial arterial oxygen pressure (paO2) and partial arterial carbon dioxide pressure (paCO2) between the groups were assessed with forward stepwise regression analysis. Biocompatibility was evaluated through measurement of platelet numbers, complement activation products (C3b/c), coagulation (thrombin anti-thrombin III complex), and fibrinolysis (plasmin anti-plasmin complex). No differences were found in oxygen transfer rate per group. However, when correcting the oxygen transfer rate for surface area, group 1 demonstrated a higher oxygen transfer rate compared with group 2 (p < 0.05) at an FiO2 of 40 and 60% and compared with group 3 at an FiO2 of 60 and 70%. The regression analysis showed that the average arterial PO2 was the highest in group 3, i.e., 79.2 mm Hg higher than in group 1 (p < 0.001) and 73.5 mm Hg higher than in group 2 (p < 0.001). Group 3 also had the lowest average arterial pCO2, 0.57 mm Hg lower than in group 1 (p = 0.004) and 0.81 mm Hg lower than in group 2 (p < 0.001). During CPB, platelet numbers decreased significantly in all groups (p < 0.001), without differences between the groups. C3b/c levels increased in all groups during CPB. At cessation of CPB the C3b/c level in group 2 (398 nmol/L(-1)) was significantly higher compared to group 1(251 nmol/L(-1); p < 0.05) and group 3 (303 nmol/L(-1); p < 0.05). Thrombin anti-thrombin III complexes and plasmin anti-plasmin complex complexes increased during CPB to significantly high levels at cessation of CPB, but there were no differences between the groups. The oxygenator with the smallest surface area and lowest priming volume (group 1) had the highest oxygen transfer rate per square meter and showed the least blood damage, as depicted by complement activation. The oxygenator with the largest blood contact surface area and improved geometric configuration (group 3) showed the lowest oxygen transfer rate per square meter. However, this oxygenator elevated oxygen partial pressure the most and reduced carbon dioxide partial pressure the most. In group 2, where a smaller venous reservoir was used, the highest blood activation was observed.

Perivenous support reduces early changes in human vein grafts: studies in whole blood perfused human vein segments.

BACKGROUND: Patency of vein grafts in coronary artery bypass grafting procedures is generally less favorable than those of selected arterial grafts. However, vein grafts still are needed in cardiac operations. It would be desirable to find measures to improve the patency of vein grafts next to antithrombotic regimens. Animal studies demonstrated that arterial pressure induces overdistention of the thin-walled vein grafts and that prevention of this overdistention with extravascular support ameliorates the arterialization process with, subsequently, more favorable patency. To evaluate whether perivenous stenting of the rather muscular human vein grafts is also beneficial, we designed an in vitro model to study the early effects of perivenous support in human vein grafts. METHODS: Seven paired segments of human vein graft obtained during coronary artery bypass grafting procedures were placed in a perfusion circuit and perfused simultaneously with autologous whole blood, with a pressure of 60 mm Hg (nonpulsatile flow). After 30 minutes of perfusion, one segment, and after 60 minutes of perfusion, the remaining segment were taken for histologic and immunohistochemical examination. In the next experiments 7 segments of human vein graft were placed in the circuit and supported with a polytetrafluoroethylene graft to prevent overdistention with 7 unstented segments as controls. RESULTS: In unsupported vein grafts perfused with autologous blood under a pressure of 60 mm Hg, a complete de-endothelialization was shown after 1 hour of perfusion. In the study vein grafts, with a perivenous polytetrafluoroethylene graft preventing overdistention (n = 7), the endothelium remained intact. Electron microscopic investigation of the media showed severe damage in the circular smooth muscle layer in the unstented group, whereas in the stented group almost no injury was found. CONCLUSION: In our in vitro closed-loop model, reproducible vessel wall changes were observed in all human vein graft specimens studied. The beneficial effect of perivenous support could also be established for the human greater saphenous vein, providing a basis for clinical application.

Inflammatory response to cardiopulmonary bypass using roller or centrifugal pumps.

BACKGROUND: The inflammatory response in 29 patients undergoing coronary artery bypass grafting using either roller or centrifugal (CFP) pumps was evaluated in a prospective study. METHODS: Patients were randomized in roller pump (n = 15) and CFP (n = 14) groups. Terminal complement complex activation (SC5b-9) and neutrophil activation (elastase) were assessed during the operation. Cytokine production (tumor necrosis factor-alpha, interleukin-6, interleukin-8) and circulating adhesion molecules (soluble endothelial-leukocyte adhesion molecule-1 and intercellular adhesion molecule-1) were assessed after the operation. RESULTS: Release of SC5b-9 after stopping cardiopulmonary bypass and after protamine administration was higher in the CFP group (p = 0.01 and p = 0.004). Elastase level was higher after stopping cardiopulmonary bypass using CFP (p = 0.006). Multivariate analysis confirmed differences between roller pump and CFP groups in complement and neutrophil activation. After the operation, a significant production of cytokines was detected similarly in both groups, with peak values observed within the range of 4 to 6 hours after starting cardiopulmonary bypass. However, interleukin-8 levels were higher using CFP 2 hours after starting cardiopulmonary bypass (p = 0.02). Plasma levels of adhesion molecules were similar in both groups within the investigation period. CONCLUSIONS: During the operation, CFP caused greater complement and neutrophil activation. After the operation, the inflammatory response was similar using either roller pump or CFP.

Activation of the protein C system during cardiopulmonary bypass with and without aprotinin.

BACKGROUND: The protein C system is important in the regulation of hemostasis. We studied its behavior during coronary artery bypass grafting procedures with and without aprotinin treatment using assays sensitive for activation of the protein C system. METHODS: In a prospective, double-blind, randomized study of 48 patients we investigated the levels of antigen to proteins C and S and of the complexes between activated protein C with its two major plasma inhibitors, protein C inhibitor and alpha1-antitrypsin in patients treated with placebo (n = 17), low-dose (n = 15), and high-dose (n = 16) aprotinin during elective coronary artery bypass grafting. RESULTS: The levels of proteins C and S showed a rapid decrease after heparinization, decreased greatly after start of cardiopulmonary bypass, and remained stable during cardiopulmonary bypass. Activated protein C inhibitor complexes were markedly elevated at the start of the procedure. Activated protein C-alpha1-antitrypsin decreased greatly after the start of cardiopulmonary bypass and remained stable during cardiopulmonary bypass. A significant peak was observed at the intensive care unit. Activated protein C-protein C inhibitor levels showed a peak after heparinization in accordance with the accelerating effect of heparin on the complex formation but decreased thereafter. Treatment with aprotinin did not notably alter any of the measured patterns. CONCLUSIONS: In this study no evidence was found for increased activation of the protein C system during coronary artery bypass grafting. Administration of aprotinin did not result in different patterns of activation of the protein C system.

Inflammatory response to cardiopulmonary bypass using two different types of heparin-coated extracorporeal circuits.

Previous reports have highlighted the disparity in biocompatibility of two differently engineered heparin coatings during the cardiopulmonary bypass (CPB) procedure. The aim of this prospective study was to evaluate the impact of the difference in haemocompatibility provided by either the Duraflo II equipment or the Carmeda equipment in the terminal inflammatory response observed after coronary artery surgery. Thirty patients were randomly allocated to two groups to be operated on using either Duraflo II equipment (group I) or Carmeda equipment (group 2) for extracorporeal circulation (ECC). Initial inflammatory response was assessed by terminal complement complex activation (SC5b-9). The late inflammatory response observed in the postoperative period was assessed by measuring cytokine production (tumour factor necrosis (TNF alpha), interleukin IL-6, interleukin IL-8) and circulating concentrations of adhesion molecules (ELAM-1, ICAM-1). The release of SC5b-9 after CPB and after protamine administration was lower in group 2 than in group 1 (p = 0.0002 and p = 0.006, respectively). A significant production of cytokines was detected in both groups with peak values observed within the time range of 4-6 h after the start of CPB.

Activation of the complement system during and after cardiopulmonary bypass surgery: postsurgery activation involves C-reactive protein and is associated with postoperative arrhythmia.

BACKGROUND: Complement activation during cardiopulmonary bypass (CPB) surgery is considered to result from interaction of blood with the extracorporeal circuit. We investigated whether additional mechanisms may contribute to complement activation during and after CPB and, in particular, focused on a possible role of the acute-phase protein C-reactive protein (CRP). METHODS AND RESULTS: In 19 patients enrolled for myocardial revascularization, perioperative and postoperative levels of complement activation products, interleukin-6 (IL-6), CRP, and complement-CRP complexes, reflecting CRP-mediated complement activation in vivo, were measured and related to clinical symptoms. A biphasic activation of complement was observed. The ratio between the areas under the curve of perioperative and postoperative C3b/c and C4b/c were 3:2 and 1:46, respectively. IL-6 levels reached a maximum at 6 hours post-surgery. CRP levels peaked on the second postoperative day. Each complement-CRP complex had peak levels on the second or third postoperative day. By multivariate analysis, maximum levels of CRP on the second postoperative day were mainly explained by C4b/c levels after protamine administration, leukocyte count on the second postoperative day, and preoperative levels of CRP. Peak levels of C4b/c after protamine administration (P=.0073) and on the second postoperative day correlated with the occurrence of arrhythmia on the same day (P=.0065). CONCLUSIONS: Cardiac surgery with CPB causes a biphasic complement activation. The first phase occurs during CPB and results from the interaction of blood with the extracorporeal circuit. The second phase, which occurs during the first 5 days after surgery, involves CRP, is related to baseline CRP levels, and is associated with clinical symptoms such as arrhythmia.

Reduction in adverse effects of mechanical ventilation in rabbits with acute respiratory failure by treatment with extracorporeal CO2 removal and a large fluid volume of diluted surfactant.

The long-term outcome of infants with severe respiratory distress syndrome can be improved by optimizing surfactant therapy and minimizing the risk for pulmonary barovolutrauma and oxygen toxicity. The authors hypothesized that this may be achieved with low frequency ventilation and extracorporeal CO2 removal (LFV-ECCO2R), in combination with intratracheal instillation of a large fluid volume with diluted surfactant. Lung lavaged rabbits were initially ventilated with continuous positive pressure ventilation. The rabbits were randomized to treatment with LFV-ECCO2R and surfactant (experimental group), or surfactant only (control group). In the experimental group, the rabbits were treated with a large volume (16 ml/kg) of diluted surfactant (6.25 mg/ml) at a dose of 100 mg/kg body weight. After surfactant therapy, the FiO2 100% was gradually decreased. During 4 hours, the extracorporeal bloodflow was adjusted to maintain the PaCO2 between 4.0-6.0 kPa. Thereafter, the rabbits were allowed to breathe spontaneously with 2.5 cm H2O continuous positive airway pressure ventilation (CPAP) and 40% oxygen. In the control group, the rabbits received the same surfactant therapy. During the study period, the rabbits remained ventilated with an inspiratory oxygen concentration (FiO2) of 100% for 4 hours. The ventilator flow was adjusted to maintain the PaCO2 between 4.0 and 6.0 kPa. Thereafter, positive-end expiratory pressure was decreased to 2.5 cm H2O and FiO2 was gradually decreased to 40%. In the experimental group, FiO2 was decreased to 40% in a stepwise fashion whereby the PaO2 could be maintained easily within the normal range. Extracorporeal flow rates during perfusion ranged from 20-35 ml/kg/min and were sufficient to keep the PaCO2 and pH within normal limits. After 4 hours, the rabbits could breathe spontaneously with CPAP and 40% oxygen, while normal blood gas values were maintained. All rabbits survived the experiment. In the control group, all rabbits experienced severe hypoxemia, despite FiO2 of 100% oxygen and, during the course of weaning, all rabbits died because of hypoxia. In conclusion, the present study demonstrated that barovolutrauma due to mechanical ventilation, and oxygen toxicity due to high FiO2, can be minimized in an animal model of acute respiratory failure by the combination of LFV-ECCO2R and surfactant therapy.

Biocompatibility of three different membrane oxygenators: effects on complement, neutrophil and monocyte activation.

The inflammatory reaction of extracorporeal circuits can be assessed by measuring complement activation and the release of activation markers of leucocytes. The purpose of this study was to compare three commercially available membrane oxygenators with respect to complement (C3a), granulocyte (lactoferrin) and monocyte (interleukin-6, IL-6) activation. Thirty patients undergoing cardiac surgery were randomly assigned to undergo cardiopulmonary bypass (CPB) with one of the following oxygenators: a polypropylene hollow-fibre membrane (group 1; 2.2 m2), a polypropylene flat-sheet membrane (group 2; 3.1 m2) or a silicone envelope membrane (group 3, 3.5 m2). In all patients, a significant increase in C3a in plasma occurred during CPB with peak levels after the administration of protamine sulphate. In blood samples taken before aortic crossclamp release, at the end of CPB, and 20 min after protamine administration C3a was significantly lower in group 1 than in the other two groups. Lactoferrin increased significantly during CPB in all patients without a significant difference between the groups. IL-6 did not increase during CPB, but raised significantly after 4 h in the intensive care unit in all groups. Moreover, IL-6 was significant lower in group 1 than group 3. The data suggest that the polypropylene hollow-fibre membrane oxygenator, i.e. the oxygenator with the smallest surface area, is more biocompatible than the other types, probably because of a smaller contact surface area.

Heparin coating of extracorporeal circuits inhibits contact activation during cardiac operations.

OBJECTIVE: Heparin coating reduces complement activation on the surface of extracorporeal circuits. In this study we investigated its effect on activation of the contact system in 30 patients undergoing coronary artery bypass grafting with the use of a heparin-coated (Duraflo II, Baxter Healthcare Corp., Edwards Division, Santa Ana, Calif.; n = 15) or an uncoated extracorporeal circuit (n = 15). METHODS: Plasma markers that reflect activation of contact (kallikrein-C1-inhibitor complexes), coagulation (prothrombin fragments F1 + 2), or fibrinolytic (plasmin-alpha 2-antiplasmin complexes) systems were determined before and during the operation. The generation of kallikrein-C1-inhibitor complexes was reduced by 62% (p = 0.06) after the onset of cardiopulmonary bypass and by 43% (p = 0.026) after the cessation of bypass in the group in which a heparin-coated circuit was used compared with the group in which the circuit was uncoated. Generation was reduced by 58% (p = 0.06) when the ratio of kallikrein-C1-inhibitor to prekallikrein after onset of bypass was considered. We detected significant increases in F1 + 2 levels in both groups and increases in plasmin-alpha 2-antiplasmin complexes in the heparin-coated group at cessation of bypass, but no intergroup differences were observed. Thus use of heparin-coated extracorporeal circuits during cardiac operations reduces formation of kallikrein-C1-inhibitor complexes when compared with use of uncoated circuits. The heparin coating is not accompanied by similar reductions in coagulation or fibrinolysis, suggesting that thrombin and plasmin formation during cardiopulmonary bypass occurs mainly independently of the contact system activation.

Clinical evaluation of Duraflo II heparin treated extracorporeal circulation circuits (2nd version). The European Working Group on heparin coated extracorporeal circulation circuits.

OBJECTIVES: To evaluate whether the application of heparin treated circuits for elective coronary artery surgery improves postoperative recovery, a European multicenter randomised clinical trial was carried out. METHODS: In 11 European heart centers, 805 low-risk patients underwent cardiopulmonary bypass (CPB) with either an untreated circuit (n = 407) or an identical but heparin treated circuit (n = 398, Duraflo II). RESULTS: Significant differences were found among participating centers with respect to patient characteristics, blood handling procedures and postoperative care. The use of heparin treated circuits revealed no overall changes in blood loss, blood use, time on ventilator, occurrence of adverse events, morbidity, mortality, and intensive care stay. These results did not change after adjustment for centers and (other) prognostic factors as analysed with logistic regression. In both groups no clinical or technical (patient or device related) side effects were reported. Because female gender and aortic cross clamp time appeared as prognostic factors in the logistic regression analysis, a subgroup analysis with these variables was performed. In a subpopulation of females (n = 99), those receiving heparin treated circuits needed less blood products, had a lower incidence of rhythm disturbances and were extubated earlier than controls. In another subgroup of patients with aortic cross clamp time exceeding 60 min (n = 197), the amount of patients requiring prolonged intensive care treatment (> 24 h) was significantly lower when they received heparin treated circuits versus controls. CONCLUSION: These findings suggest that improved recovery can be expected with heparin treated circuits in specific higher risk patient populations (e.g. females) and when prolonged aortic cross clamp time is anticipated. Further investigations are recommended to analyses the clinical benefit of heparin treated circuits in studies with patients in different well defined risk categories and under better standardised circumstances.

Heparin coating with aprotinin reduces blood activation during coronary artery operations.

BACKGROUND: This study was performed to evaluate whether the combination of heparin-coated extracorporeal circuits (ECC) and aprotinin treatment reduce blood activation during coronary artery operations. METHODS: Sixty patients were prospectively divided into two groups (heparin-coated ECC and uncoated ECC groups), which were comparable in terms of age, sex, left ventricular function, preoperative aspirin use and consequent intraoperative aprotinin use, number of grafts, duration of aortic cross-clamping, and duration of cardiopulmonary bypass. Blood activation was assessed at different times during cardiopulmonary bypass by determination of complement activation (C3 and C4 activation products C3b/c and C4b/c and terminal complement complex), leukocyte activation (elastase), coagulation (scission peptide fibrinopeptide 1 + 2), and fibrinolysis (D-dimers). RESULTS: Univariate analysis showed that heparin-coated ECC, under conditions of standard heparinization, did not reduce perioperative blood loss and need for transfusion. Heparin coating, however, reduced maximum values of C3b/c (446 +/- 212 nmol/L versus 632 +/- 264 nmol/L with uncoated ECC; p = 0.0037) and maximum C4b/c values (92 +/- 48 nmol/L versus 172 +/- 148 nmol/L with uncoated ECC; p = 0.0069). Levels of terminal complement complex, elastase, fibrinopeptide 1 + 2, and D-dimers were not significantly modified by the use of heparin-coated ECC. Multivariate analysis showed that the intergroup differences in maximum C3b/c and C4b/c values were more pronounced in women in part with high baseline values of C3b/c. We also found that aprotinin contributed to the reduction of maximum values of fibrinopeptide 1 + 2 and D-dimers, whereas heparin coating had no significant influence on these parameters. CONCLUSIONS: We found no evidence of combined properties of heparin-coated ECC and aprotinin in reducing complement activation, coagulation, and fibrinolysis. We therefore recommend use of both together to achieve maximal reduction of blood activation during cardiopulmonary bypass for coronary artery operations.

Clinical outcome after coronary surgery with heparin-coated extracorporeal circuits for cardiopulmonary bypass.

In this prospective randomized trial, we studied whether heparin-coated extracorporeal circuits (ECC), known to reduce complement activation, could improve the clinical outcome of 200 patients undergoing coronary artery surgery. Patients have been divided into two groups (heparin-coated ECC and uncoated ECC groups) which were similar in terms of age, gender, left ventricle function, preoperative aspirin use and consequent intraoperative aprotinin use, number of grafts, duration of aortic cross-clamping and cardiopulmonary bypass. Univariate analysis showed that heparin coating did not reduce significantly postoperative bleeding (640 +/- 311 versus 682 +/- 342 ml with uncoated ECC) nor the need for transfusion (19% of patients versus 25% with uncoated ECC). Adverse events, including all mortality and morbidity noticed during the five first postoperative days, occurred in 20 patients of the uncoated ECC group and in eight patients of the heparin-coated ECC group (p = 0.013). The most frequent complications were supraventricular arrhythmias that occurred in 13 patients of the uncoated ECC group and in four patients of the heparin-coated ECC group (p = 0.02). Multivariate analysis by stepwise logistic regression showed that only heparin coating of the ECC was shown as a significant predictive factor of adverse events reduction (p = 0.01; odds ratio = 0.34). These data suggest that heparin coating reduced postoperative complications in patients undergoing coronary artery surgery.

Endotoxaemia and postoperative hypermetabolism in coronary artery bypass surgery: the role of ketanserin.

In a randomized, double-blind clinical study in 29 patients undergoing elective coronary artery surgery, we assessed the role of ketanserin, an inhibitor of serotonin-induced vasoconstriction and weak alpha 1 sympathetic blocker, in reducing endotoxaemia and postoperative hypermetabolism. Male patients without major organ dysfunction were allocated randomly to receive either ketanserin or placebo. Hypermetabolism was defined as an increase in oxygen consumption in the early postoperative hours (delta Vo2). Circulating endotoxin (P = 0.04) and postoperative delta Vo2 (P = 0.03) were lower in the ketanserin patients. Endotoxaemia was associated also with low vascular filling. From these preliminary results we conclude that treatment with ketanserin during cardiac surgery may reduce but not abolish endotoxaemia and postoperative hypermetabolism.

Reduction of blood activation in patients receiving aprotinin during cardiopulmonary bypass for coronary artery surgery.

Aprotinin reduces blood loss after cardiac surgery, particularly in patients taking aspirin. This study was performed to evaluate whether the reduction of contact phase activation by aprotinin is related to decreased complement activation during blood activation. Two hundred patients were prospectively operated on for coronary artery bypass. Aprotinin was used in the cardiopulmonary bypass (CPB) prime if aspirin was not discontinued 10 days before surgery and in patients undergoing second operation (n = 102). Blood loss was significantly reduced in patients receiving aprotinin (596 +/- 309 ml vs 754 +/- 329 ml without aprotinin; p = 0.0001), as was the need for transfusion (13% vs 34% without aprotinin; p = 0.0001) after surgery. Blood activation has been studied in 60 patients. Multivariate analysis showed that contact phase activation, as assessed by maximum values of C1 inhibitor/kallikrein complexes, was reduced by aprotinin treatment (p < 0.0001). Fibrinolytic activity decreased with aprotinin treatment, as reflected by lower values of D-dimers at the end of CPB (p < 0.0001). In addition, thrombin generation, as assessed by F1 + 2 scission peptide, was reduced by aprotinin (p = 0.01). However, the stepwise regression model emphasized that activation of the alternative and classic complement pathways, as reflected by C3b/c and C4b/c levels, was not affected by aprotinin; neither was leukocyte activation, as reflected by elastase release. These results suggest that aprotinin does not combine the reduction of complement activation with the reduced activation of the contact phase, fibrinolysis, or coagulation during CPB for coronary artery surgery.

Low-dose and high-dose aprotinin improve hemostasis in coronary operations.

Prophylactic aprotinin therapy has become a popular method to reduce bleeding associated with cardiac operations. Today essentially two dose regimens are used, a high-dose regimen with administration throughout the complete operative procedure and a low-dose regimen with administration only during bypass. In unblinded studies both regimens were found to be equally effective. This double-blind placebo-controlled study in 115 patients undergoing elective coronary artery bypass grafting was done to confirm these results without potential investigator bias. Intraoperative hemoglobin loss was significantly reduced (p < 0.01) by 42% in the high-dose group and by 17% in the low-dose group compared with loss in control subjects. Blood loss 6 hours after operation was 377 ml in the low-dose and 266 ml in the high-dose group compared with 630 ml in the placebo group (p < 0.05 and p < 0.001, respectively). The average number of transfusions with packed red blood cells was reduced 31% in the low-dose group and 45% in the high-dose group, but the reductions were not significant. In a subgroup of patients, markers for coagulation and fibrinolysis were studied to investigate whether a different extent of activation existed. Fibrinolysis as measured by D-dimer levels was completely inhibited by the high-dose regimen, but was only partly suppressed in the low-dose group as compared with findings in the placebo group. Thrombin generation during cardiopulmonary bypass as reflected by F1 + 2 levels was lower in patients treated with aprotinin, but the difference was not significant. Concentrations of thrombin inactivated by antithrombin III were not different between the groups. The observation that low-dose aprotinin significantly improved hemostasis but did not inhibit hyperfibrinolysis supports our previous finding that low-dose aprotinin mainly protects platelet adhesive function. The better result obtained with high-dose aprotinin may indicate the contribution of hyperfibrinolysis to bleeding after cardiopulmonary bypass. Because high-dose aprotinin is administered outside the period of full heparinization and might therefore increase the risk of thromboembolic complications, we propose a modification of the low-dose schedule to increase aprotinin levels sufficient for plasmin inhibition before release of the aortic crossclamp.

Heparin-coated circuits and aprotinin prime for coronary artery bypass grafting.

BACKGROUND: The biocompatibility of an extracorporeal circuit is improved by heparin bonding onto its inner surface. To determine the effect of heparin-coated circuits for cardiopulmonary bypass with aprotinin prime on postoperative recovery and resource utilization, a prospective study was done in 102 patients undergoing coronary artery bypass grafting with full systemic heparinization. METHODS: Patients were randomly allocated to be treated with either a heparin-coated circuit (n = 51) or an uncoated circuit (n = 51). Differences in blood loss, need for blood transfusion, morbidity, and intensive care stay were analyzed. RESULTS: No differences in blood loss and need for blood transfusion were found between the groups. The relative risk for adverse events in the heparin-coated group was 0.29 (95% confidence interval ranging from 0.10 to 0.80). Adverse events included myocardial infarction (2 patients in the uncoated group versus 0 in the heparin-coated group), rethoracotomy for excessive bleeding (1 versus 2), rhythm disturbance (7 versus 2), respiratory insufficiency (4 versus 0), and neurologic dysfunction (2 versus 0). The lower incidence of adverse events in the heparin-coated group was associated with a shorter intensive care stay (median, 2 days; range, 2 to 5 days) compared with the uncoated group (median, 3 days; range, 2 to 19 days, p = 0.03). The cost savings of 1 day of intensive care stay counterbalanced the additional costs of heparin-coated circuits. CONCLUSIONS: The use of heparin-coated circuits for cardiopulmonary bypass with aprotinin prime resulted in a significant reduction in mobidity in the early postoperative phase and a concomitant decrease in intensive care stay, resulting in important cost savings.

Specific complement inhibition with heparin-coated extracorporeal circuits.

BACKGROUND: Although it is well established that heparin-coated extracorporeal circuits reduce complement activation during cardiac operations, little in vivo information is available on the reduction in alternative and classic pathway activation. METHODS: In a prospective, randomized study involving patients undergoing coronary artery bypass grafting with standard full heparinization, we compared heparin-coated circuits (Duraflo II) (10 patients) with uncoated circuits (10 patients) and assessed the extent of initiation of complement activation by detecting iC3 (C3b-like C3) concentrations, classic pathway activation by C4b/c (C4b, iC4b, C4c) concentrations, terminal pathway activation by soluble C5b-9 concentrations, and C3 activation by C3a (C3a desArg) and C3b/c (C3b, iC3b, C3c) concentrations. RESULTS: Heparin-coated extracorporeal circuits significantly reduced circulating complement activation product C3b/c and soluble C5b-9 concentrations at the end of cardiopulmonary bypass and after protamine sulfate administration compared with the uncoated circuits, but not iC3, C4b/c, or C3a concentrations. CONCLUSIONS: Heparin-coated extracorporeal circuits reduce complement activation through the alternative complement pathway, probably at the C3 convertase level, and, consequently, the terminal pathway. C3b/c seems to be a more sensitive marker than C3a to assess complement activation during cardiac operations.

Increased oxygen consumption after cardiac surgery is associated with the inflammatory response to endotoxemia.

OBJECTIVE: The aim of this study was to determine whether the increase in post-operative oxygen consumption (delta VO2) in cardiac surgery patients is related to endotoxemia and subsequent cytokine release and whether delta VO2 can be used as a parameter of post-perfusion syndrome. DESIGN: Prospective study. SETTING: Operating room and intensive care unit of a university hospital. PATIENTS: Twenty-one consecutive male patients undergoing elective coronary artery bypass surgery without major organ dysfunction and not receiving corticosteroids. MEASUREMENTS AND RESULTS: Plasma levels of endotoxin, tumor necrosis factor (TNF) and interleukin-6 (IL-6) were measured before, during and for 18 h after cardiac surgery. Oxygen consumption, haemodynamics, the use of IV fluids and dopamine, body temperature and the time of extubation were also measured. Measurements from patients with high delta VO2 (> or = median value of the entire group) were compared with measurements from patients with low delta VO2 (< median). Patients with high delta VO2 had higher levels of circulating endotoxin (P = 0.004), TNF (P = 0.04) and IL-6 (P = 0.009) received more IV fluids and dopamine while in the ICU, and were extubated later than patients with low delta VO2. Several hours after delta VO2 the patient's body temperature rose. Forward stepwise regression analysis showed that circulating endotoxin and TNF explained 50% of the variability of delta VO2. CONCLUSIONS: This study demonstrates that patients with high post operative oxygen consumption after elective cardiac surgery have higher circulating levels of endotoxin, TNF and IL-6 and also have more symptoms of post-perfusion syndrome. Early detection of high VO2 might be used as a clinical signal to improve circulation in order to meet the high oxygen demand of inflammation. In addition, continuous measurement of VO2 provides us with a clinical parameter of inflammation in interventional studies aiming at a reduction of endotoxemia or circulating cytokines.