Cardiopulmonary bypass and complement activation. Involvement of classical and alternative pathways

Complement is activated during cardiopulmonary bypass with consumption of the complement components C3, C4 and factor B. This takes place when either a bubble or membrane oxygenator is used and is not affected by steroid therapy. Complement activation is predominantly by the classical pathway and may be related to the aggregation of IgM found in bypass sera.     

A study on complement activation in cardiopulmonary bypass--experimental and clinical evaluations

Complement activation in patients undergoing cardiopulmonary bypass (CPB) was studied, with particular reference to anaphylatoxins. Complement levels were compared between a bubble oxygenator group (BOG) and a membrane oxygenator group (MOG). The influence of primed homologous blood on complement activation was also evaluated. C4a levels gradually increased during CPB in the BOG, whereas in the MOG they changed little. There was a marked initial rise of C4a levels in the BOG of high H/A (primed homologous vs. circulating autologous blood volume ratio). C3a levels increased more steeply in the BOG than in the MOG. In general C5a levels remained low in both groups, but were slightly higher in the BOG than in the MOG. Complement levels were determined in monkeys (Macaca fascicularis) undergoing continuous intraaortic infusion of 1) autologous blood extracorporeally bubbled with O2, 2) blood contacted with nylon, or 3) O2 microbubbles. The results indicated 1) elevation of C4a and C3a in the bubbled blood group, 2) elevation of C3a alone in the nylon group, and 3) no elevation of either anaphylatoxin. It was thus inferred that 1) during CPB, the complement might be rather dominantly activated via the classical pathway in the BOG, and via the alternative pathway in the MOG, 2) higher anaphylatoxin levels in the BOG than in the MOG might be related to mode and grade of blood trauma including plasma denaturation, and 3) the H/A ratio might be a factor able to modify complement activation.     

Reduction of complement activation during bypass by prime manipulation

Complement activation is believed to be of importance in the development of complications arising after cardiopulmonary bypass. The effect on complement activation of priming the extracorporeal circuit with crystalloid alone, crystalloid plus albumin, or crystalloid plus the plasma expander polygeline was assessed in 36 patients undergoing coronary artery operations with cardiopulmonary bypass using a bubble oxygenator. Activation of the alternative and common complement pathways was monitored before, during, and after the bypass period by measuring concentrations of factor B and its fragment Ba and C3 and its fragment C3d. Complement activation occurred in all three groups of patients, with no difference between the crystalloid and crystalloid-albumin groups. In contrast, Ba fragment concentrations were persistently and significantly lower during and after bypass in the polygeline group, denoting reduced complement activation. C3d levels also showed a tendency to be lower in this group. Our results indicate that addition of polygeline to the priming solution reduces complement activation. Because complement activation is associated with morbidity after cardiopulmonary bypass, addition of polygeline to the priming solution may offer an inexpensive method of reducing morbidity after cardiopulmonary bypass.     

Deleterious effects of cardiopulmonary bypass. A prospective study of bubble versus membrane oxygenation

A number of hematologic and immunologic parameters that reflect erythrocyte and platelet damage and host defense mechanisms against infection were studied in 20 patients undergoing cardiopulmonary bypass during coronary operations. The patients were randomly assigned to a group in which a bubble oxygenator or a hollow-fiber membrane oxygenator was used. Hemolysis, thrombocytopenia, and significant release of beta thromboglobulin occurred in patients from the bubble oxygenator group and, to much lesser extent, in patients from the membrane oxygenator group. Polymorphonuclear leukocytes and monocytes from bubble oxygenator patients demonstrated increased generation of reactive oxygen species in the resting state and in the presence of the stimulating agents N-formyl-methionyl-leucyl-phenylalanine, concanavalin A, and opsonized zymosan, as compared with cells from membrane oxygenator patients. No difference was found between bubble and membrane oxygenator patients in the time of occurrence or intensity of leukopenia during bypass, of leukocytosis at the end of bypass, nor in the rate of complement activation, as assessed by quantitation of plasma C3a antigen. Complement activation was dependent on the alternative pathway. Immunoglobulin M concentration significantly decreased during bypass in both groups of patients. The serum opsonizing capacity for endotoxin and serum bactericidal activity for Serratia marcescens were decreased in both groups, mainly because of hemodilution, although they were additionally affected by bubble oxygenation. Several deleterious hematologic consequences of cardiopulmonary bypass can be minimized by the use of a membrane oxygenator. However, complement activation remains a potential risk factor even in membrane oxygenator patients and requires further investigation to obtain better hemocompatible materials for cardiopulmonary bypass circuits.     

Complement activation in cardiopulmonary bypass, with special reference to anaphylatoxin production in membrane and bubble oxygenators

Complement activation by cardiopulmonary bypass (CPB) was studied in 82 patients divided into membrane (MOG) and bubble oxygenator groups (BOG). The influence of primed homologous to circulating autologous blood volume (H/A) ratio was also evaluated. C4a increased very slowly during CPB in both groups, maintaining slightly higher levels in the BOG than in the MOG, with the exception of a marked initial rise in the BOG with a high H/A ratio (greater than or equal to 20%). Anaphylatoxin C3a levels increased more steeply in the BOG than in the MOG. An obvious rise in anaphylatoxin C5a production was observed in the BOG alone. The influence of high H/A ratio perfusion on complement activation was milder in the MOG than in the BOG. In 20 monkeys (Macaca fascicularis), continuous intraaortic infusion with bubbled autologous blood increased C4a and C3a levels, while autologous blood extracorporeally contacted with nylon increased C3a levels alone. In vitro studies revealed that human immunoglobulin fractions denatured by oxygen bubbling produced C4a, C3a, and C5a in a dose-dependent manner, although human albumin treated identically as human immunoglobulin did not produce these complements. It was thus inferred that (1) during CPB, complement is predominantly activated via the classical pathway in the BOG and via the alternative pathway in the MOG; (2) higher anaphylatoxin levels in the BOG than in the MOG are related to mode and grade of blood trauma; (3) anaphylatoxin level differences in both groups tend to increase with high H/A perfusion; and (4) immunoglobulin-free sera may reduced classical pathway activation.     

Complement activation during cardiopulmonary bypass: mechanism and prevention

The mechanism of complement activation during cardiopulmonary bypass was studied for the prevention. In ten patients undergoing open-heart procedures, the serum levels of complement fractions (C3, C4, and C3 activator) were measured by a single radial immune diffusion method. In four of ten patients, the plasma levels of C3a, C4a, and C5a fractions were studied by the radioimmunoassay 2 antibodies method. The serum levels of C3, C4, and C3 activator decreased after cardiopulmonary bypass. The plasma levels of C3a, C4a, and C5a increased after bypass. The lower level of C3 activator shows that C3 activator was not excessively produced during cardiopulmonary bypass. Therefore it can be thought that much C4b2a from classical pathway as well as C3a over-production localizing extra-corporeal circuits and little inhibitors on alternative pathway resulted in increased complement activation. The prevention should be done from these etiologies.     

Complement activation before, during and after cardiopulmonary bypass

Plasma levels of the complement parent molecules C3, C4, and factor B and their split products, C3d, C4d, and Ba were measured in 12 patients undergoing cardiopulmonary bypass for coronary artery surgery. Alternative and common complement pathway activation, demonstrated by statistically significant rising levels of Ba (P less than 0.05), and C3d (P less than 0.05) and by elevated Ba:B (P less than 0.05) and C3d:C3 (P less than 0.05) ratios were found before the institution of cardiopulmonary bypass but following heparin administration suggesting that heparin may itself initiate alternative pathway activation. In addition, significant depletion of parent complement components and elevation of split product concentrations was seen during bypass suggesting classical and alternate pathway activation (P less than 0.01). This study clarifies the pathways of complement activation during bypass and presents evidence that heparin administration may initially activate the complement cascade.     

Different oxygenators for cardiopulmonary bypass lead to varying degrees of human complement activation in vitro

Complement activation was studied in vitro with six different membrane and bubble oxygenators for cardiopulmonary bypass. There was a similar increase in terminal (C5 to C9) activation with all oxygenators (p less than 0.001), ranging from 281% (117% to 444%) to 453% (225% to 680%) after 60 minutes (median and 95% confidence intervals). C3 activation was not observed with a hollow fiber membrane and a soft shell bubble oxygenator. On the other hand, a capillary membrane, a sheet membrane, a nonporous membrane, and a hard shell bubble oxygenator all induced a similar increase in C3 activation (p less than 0.01), ranging from 107% (23% to 346%) to 272% (88% to 395%) after 60 minutes. The differences in C3 activation could not be explained by the blood contact materials or any other single factor known to induce activation, which suggests that overall complement activation during cardiopulmonary bypass is a multifactorial effect. The tubing set per se induced only minor C3 activation but contributed to the overall formation of terminal complement complex. The study further indicates that an arterial line blood filter prevents activated neutrophils from being reinfused to the patient and should be used regardless of type of oxygenator.     

Complement (C3, C4) Consumption in Cardiopulmonary Bypass,Cardioplegia, and Protamine Administration

Anaphylatoxins produced by complement activation have been postulated to be responsible for postperfusion syndrome and protamine hypotension in patients undergoing cardiac surgical procedures. The consumption of serum complement components C3 and C4, which reflects the classic and alternate pathway activations of the complement system, was studied in 22 patients undergoing cardiac operations. Prior to the onset of cardiopulmonary bypass, the complement levels were within normal range. Rapid reduction in both C3 and C4 within minutes of cardiopulmonary bypass indicated rapid complement activation. Such a reduction in complement levels could not be accounted for by either hemodilution or transfusion of complement-poor blood. Aortic cross-clamping and cold potassium cardioplegia followed by myocardial reperfusion did not lead to further consumption of C3 and C4. Slow intravenous infusion of protamine sulfate after cardiopulmonary bypass did not change C3 and C4 levels significantly in our patients, although protamine and heparin-protamine complex have been shown to activate complement components in vitro.In another group of 9 similar cardiac surgical patients, C3 and C4 were found to return to normal levels within 24 hours after operation. This study thus confirms the rapid activation of the complement system by cardiopulmonary bypass but fails to demonstrate further activation of the complement system by cardioplegia or protamine administration.     

Pathophysiology of Cardiopulmonary Bypass: Current Issues

Much of the research related to cardiopulmonary bypass in recent years has been directed toward defining the changes in plasma and blood cells during bypass. In this review, recent information is reexamined for six areas of current interest. These areas are complement activation, immune response, anaphylactic reactions, coagulation, and cerebral dysfunction. Complement may be activated by either the classical or alternate pathway during cardiopulmonary bypass and protamine administration. Membrane oxygenators appear to diminish the degree of complement activation. Complement is a major factor in the whole body inflammatory response; which often accompanies cardiopulmonary bypass. A product of complement activation, C5a- desArg, causes activation and aggregation of granulocytes. Other products of complement activation lead to lysis of blood cells including granulocytes and red cells. Bubble oxygenators appear to have a distinct disadvantage compared to membrane oxygenators regarding infection. Airborne microorganisms are more likely to be entrained into circulating blood with bubble oxygenators than with membrane oxygenators. Bubble oxygenators cause a greater decrease in leukocyte number and function than membrane oxygenators. Anaphylactic reactions have been associated with use of antibiotics, blood products, protamine, and volume expanders during cardiopulmonary bypass. Protamine reactions may be on an immunological basis or due to direct toxicity of the drug. Free radicals including superoxide, hydrogen peroxide, and the hydroxyl radical may be generated during cardiopulmonary bypass and reperfusion. Free radical scavengers including; vitamin E, coenzyme Q, vitamin C, mannitol, and glutathione have been studied. The avoidance of blood transfusion because of risk of transmitted infection including AIDS has become a major goal in cardiac surgery. Factors that correlate with increased transfusion requirement include low hematocrit, female gender, increased age, small body size, low ejection fraction, reoperation, and emergency operation. Heparin resistance due to antithrombin III deficiency is being recognized more commonly. Antithrombin III deficiency may be corrected with fresh frozen plasma. Patients with heparin induced thrombocytopenia may be difficult to manage. Several management protocols are suggested. The most straightforward appears to be the use of aspirin preoperatively and platelet transfusions postoperatively. The incidence of cerebral dysfunction after cardiopulmonary bypass depends on the sensitivity of the test or indicator used. Perioperative stroke is associated with intrinsic cerebrovascular disease and atherosclerosis of the ascending aorta. Retinal angiograms during cardiopulmonary bypass show that microemboli are very common. Cerebroplegia has been shown to extend the period of safe circulatory arrest in animals. Much of the new knowledge concerning cardiopulmonary bypass is the result of close collaboration between cardiac surgeons and nonsurgical scientists.     

Complement activation during cardiopulmonary bypass. Comparison of bubble and membrane oxygenators

A prospective randomized trial involving 91 patients undergoing cardiopulmonary bypass compared the effects of bubble oxygenators (with and without methylprednisolone sodium succinate) and membrane oxygenators on complement activation and transpulmonary sequestration of leukocytes. Patients were divided as follows: Group I, 30 patients, bubble oxygenator; Group II, 31 patients, bubble oxygenator and methylprednisolone sodium succinate (30 mg/kg); Group III, 30 patients, membrane oxygenator. In Group I, C3a increased from 323 +/- 171 ng/ml during cardiopulmonary bypass to 1,564 +/- 785 ng/ml at 25 minutes after bypass (p less than 0.0001). A significant decrease in C3a was found in Groups II and III compared to Group I (p less than 0.0001). C5a did not change significantly during cardiopulmonary bypass in any group. Reestablishment of pulmonary circulation at the end of bypass produced significant transpulmonary leukocyte sequestration in Group I; the median cell difference was 1,700/microliter. Transpulmonary sequestration was significantly (p less than 0.0001) less in Group II (median cell difference = 200/microliter) and in Group III (median cell difference = 400/microliter) than in Group I. We conclude that cardiopulmonary bypass with a bubble oxygenator alone initiates significantly (p less than 0.0001) more C3a activation and leukocyte sequestration than when methylprednisolone sodium succinate (30 mg/kg) is given 20 minutes before the start of cardiopulmonary bypass with a bubble oxygenator or when a silicone membrane oxygenator is used.     

Reduced complement activation with heparin-coated oxygenator and tubings in coronary bypass operations.

Complement activation after cardiopulmonary bypass is correlated with postoperative organ dysfunction. Heparin coating of the entire blood-contact surface of the cardiopulmonary bypass circuit has proved to reduce complement activation in vitro. A membrane oxygenator and tubing setup coated with functionally active heparin was compared with an uncoated, otherwise identical setup in 20 patients undergoing routine coronary bypass operations. The concentrations of C3 activation products and the terminal complement complex were measured in sensitive and specific enzyme immunoassays. Peak concentrations of C3 activation products were 90.1 (74.7 to 107.4) AU/ml (medians and 95% confidence intervals) and 52.4 (35.7 to 76.4) AU/ml with the uncoated and coated setups, respectively (p = 0.02). The corresponding concentrations of the terminal complement complex were 26.2 (20.1 to 37.5) AU/ml and 13.7 (11.1 to 25.1) AU/ml (p = 0.03). Blood loss from the mediastinal drains during the first 12 postoperative hours was 533 (416 to 975) ml in patients treated with the uncoated setup and 388 (313 to 579) ml in the coated treatment group (p = 0.06) and was significantly correlated with peak concentrations of the terminal complement complex (p = 0.01). There were no differences in neutrophil counts nor platelet numbers between the treatment groups. The approximate 45% reduction in complement activation with the heparin-coated cardiopulmonary bypass device indicates a substantial improvement of biocompatibility.     

Significance of the concentrated red cell and albumin priming method with particular reference to anaphylatoxin generation.

Anaphylatoxins generated by cardiopulmonary bypass were observed in basic and clinical studies (n = 120 in the latter). In vitro immunoglobulin fractions denatured by oxygen bubbling produced C4a, C3a, and C5a, but albumin identically treated did not. Therefore concentrated red cells with albumin were used to prime homologous blood for clinical application during cardiopulmonary bypass. Complement levels were compared with type of oxygenator (bubble or membrane) and the ratio of primed homologous blood to circulating autologous blood volume. With the bubble oxygenator at a low ratio of homologous to autologous blood (arbitrarily defined as less than 20%), C3a levels during cardiopulmonary bypass tended to be lower in the concentrated red cells plus albumin priming group than in the ordinary priming group (p less than 0.1, at 60 and 90 minutes of cardiopulmonary bypass). C4a and C3a levels increased less after protamine administration with concentrated red cells plus albumin priming (p less than 0.05, p less than 0.01, respectively, 90 minutes after protamine) than with ordinary priming. Such changes in the membrane oxygenator group were less remarkable. Thus C3a levels were approximately the same in both oxygenator groups primed with concentrated red cells plus albumin. The higher the homologous to autologous ratio, the steeper the C4a and C3a increase from the beginning of cardiopulmonary bypass with the bubble oxygenator. This tendency was less remarkable in the membrane oxygenator group. Early postoperative pulmonary function was improved by concentrated red cells plus albumin priming, especially in the bubble oxygenator group. In conclusion, (1) oxygenator systems primed with concentrated red cells plus albumin produced less anaphylatoxin than those with homologous blood, especially with the bubble oxygenator, and (2) our clinical results support the importance of immunoglobulin denatured by oxygen bubbling in anaphylatoxin generation (by means of the classical pathway), as shown by our in vitro study.     

Neutrophil lysosomal enzyme release and complement activation during cardiopulmonary bypass

Complement activation and neutrophil degranulation were concomitantly studied during uncomplicated cardiopulmonary bypass (CPB). Plasma concentrations of complement factor C4, complement split product C3d, the neutrophil lysosomal enzyme elastase complexed with alpha 1-proteinase inhibitor (PI) and fibronectin were measured in 12 patients, C3d and elastase/PI increased significantly during CPB (volume-corrected results). The C3d rise was almost linear, whereas elastase/PI showed exponential increase. Mean elastase/PI and mean C3d concentrations at different times during CPB covaried closely. The study showed that during CPB neutrophil lysosomal enzyme release is intimately related to complement activation, although activation of the two systems may be caused by a common third activator within the extracorporeal circuit.     

Time for new concepts about measurement of complement activation by cardiopulmonary bypass?

Fifty-one patients admitted for routine coronary bypass operations were randomized to cardiopulmonary bypass with a membrane oxygenator (Capiox) or a bubbler (Polystan or William Harvey). Complement activation was measured using enzyme immunoassays for concentrations of C3 activation products and the terminal complement complex. From 5.8 to 8.1 arbitrary units (AU)/mL (medians), the plasma concentrations of C3 activation products increased by 119.9 AU/mL (Capiox), 124.6 AU/mL (Polystan), and 79.5 AU/mL (William Harvey) to a peak at closure of the sternum (not significant when related to baseline concentrations). The increase in C3 activation products and baseline C3 activation were linearly correlated (R2 = 0.30; p less than 0.0001). From 5.5 to 6.1 AU/mL, the plasma terminal complement complex concentrations increased by 45.2 AU/mL (Capiox), 15.4 AU/mL (Polystan), and 17.4 AU/mL (William Harvey) to a peak before termination of cardiopulmonary bypass. Maximal terminal (C5-C9) activation was significantly higher in the membrane oxygenator group (p less than 0.0001) and showed no relationship to C3 activation. Measurement of C3 activation only gives no information about C5-C9 activation. At present, terminal complement complex quantitation is probably the best index of C5-C9 activation during cardiopulmonary bypass.     

Complement activation during prolonged extracorporeal membrane oxygenation

Short-term cardiopulmonary bypass activates the complement system, possibly resulting in pulmonary dysfunction from granulocyte aggregation and pulmonary endothelial damage. These effects may be inhibited by steroids. Prolonged extracorporeal membrane oxygenation (ECMO) is used for newborn respiratory failure, but the effects of ECMO on complement activation are unknown. Twenty-one newborn infants with respiratory failure treated with ECMO were randomly assigned to group I (control, no steroids) or group II (30 mg/kg intravenous methylprednisolone before ECMO). Depletion assays of C3 and C5 were performed in each group at intervals before and during ECMO (declining values indicate complement activation). The groups were compared for complement levels, survival, time on ECMO and on the ventilator, and total hospitalization time. Steroids significantly shortened the time on ECMO and time on the ventilator after ECMO but did not affect survival or total hospitalization time. Steroids also enhanced activation of C3 and C5. Complement activation occurs during ECMO. Steroid administration paradoxically causes earlier complement activation but shortens ECMO and ventilator times. Complement activation during ECMO is of questionable significance. The benefits of steroids during ECMO may be mediated through other mechanisms.     

Heparin-coated cardiopulmonary bypass equipment. II. Mechanisms for reduced complement activation in vivo

OBJECTIVE: Our objective was to study mechanisms for reduced complement activation by heparin coating of cardiopulmonary bypass equipment in clinical heart surgery. METHODS: Adults undergoing elective coronary artery bypass grafting were randomized to cardiopulmonary bypass with Duraflo II heparin-coated (n = 15) or uncoated (n = 14) sets (Duraflo coating surface; Baxter International, Inc, Deerfield, Ill). Blood samples were analyzed with the use of enzyme immunoassays for C1rs-C1 inhibitor complexes and the activation products Bb, C4bc, C3bc, C5a-desArg, and the terminal complement complex. Data were compared by repeated-measures analysis of variance. RESULTS: C1 was activated during bypass, and increases in C1rs-C1 inhibitor complexes were larger with heparin coating (P =.03). C4bc increased after administration of protamine, without intergroup differences (P =.69). Bb (P =.22) and C5a-desArg (P =.13) tended to increase less with heparin coating. Formation of C3bc (P =.03) and the terminal complement complex (P <.01) was significantly reduced with heparin coating. C5a-desArg increased 2-fold during bypass, whereas the terminal complement complex increased 10- to 20-fold. Maximal terminal complement complex concentrations were significantly correlated to maximal Bb and C3bc (R = 0.6, P <.001), but not to C1rs-C1 inhibitor complexes or C4bc (R < 0.05, P >.8). CONCLUSIONS: C1 activation during bypass was increased by heparin coating, but further classical pathway activation was held in check until administration of protamine. Heparin coating significantly inhibited C3bc and terminal complement complex formation. Terminal complement complex concentrations were related to alternative pathway activation and may be useful for evaluation of differences in bypass circuitry. Increases and intergroup differences in terminal complement complex concentrations were much larger than those in C5a-desArg.     

A new case of bronchospasm under extracorporeal circulation

A case of bronchospasm occurring after the termination of cardiopulmonary bypass is reported. The complement fractions C3a, C4a and C5a were measured before and right after CPB. Complement activation is not specific to CPB but may occur in any thoracotomy. The statistically significant increase in complement C3a without any pulmonary symptomatology has been reported by several authors. Complement activation cannot therefore be considered as the explanation of this bronchospasm.     

Inhibition of complement, neutrophil, and platelet activation by an anti-factor D monoclonal antibody in simulated cardiopulmonary bypass circuits.

OBJECTIVES: Patients undergoing cardiopulmonary bypass frequently manifest generalized systemic inflammation and occasionally manifest serious multiorgan failure. Inflammatory responses of bypass are triggered by contact of blood with artificial surfaces of the bypass circuits, surgical trauma, and ischemia-reperfusion injury. We studied the effects of specific inhibition of the alternative complement cascade by using an anti-factor D monoclonal antibody (166-32) in extracorporeal circulation of human whole blood used as a simulated model of cardiopulmonary bypass. METHODS: Five healthy blood donors were used in the study. Monoclonal antibody 166-32 was added to freshly collected, heparinized human blood recirculated in a pediatric cardiopulmonary bypass circuit at a final concentration of 18 microg/mL. An irrelevant monoclonal antibody was used as a negative control with the same donor blood in a parallel bypass circuit on the same day. Blood samples were collected at different time points during recirculation for measurement of activation of complement, neutrophils, and platelets by immunofluorocytometric methods and enzyme-linked immunosorbent assays. RESULTS: Monoclonal antibody 166-32 inhibited the alternative complement activation and the production of Bb, C3a, sC5b-9, and C5a. Upregulation of CD11b on neutrophils and CD62P on platelets was also significantly inhibited by monoclonal antibody 166-32. This is consistent with the inhibition of the release of neutrophil-specific myeloperoxidase and elastase and platelet thrombospondin. The production of proinflammatory cytokine interleukin 8 was also suppressed by the antibody. CONCLUSIONS: The alternative complement cascade is predominantly activated during extracorporeal circulation. Anti-factor D monoclonal antibody 166-32 is effective in inhibiting the activation of complement, neutrophils, and platelets. Inhibition of the alternative complement pathway by targeting factor D could be useful in reducing systemic inflammation in patients undergoing cardiopulmonary bypass.     

Heparin-coated circuits reduce occult myocardial damage during CPB: a randomized, single blind clinical trial.

OBJECTIVES: Cardiopulmonary bypass is associated with a diffuse systemic inflammatory response that can cause considerable morbidity, including organ dysfunction and bleeding. Heparin-coated circuits have been shown to give a reduced inflammatory response with clinical benefits during open-heart surgery. However, the effects on lipid peroxidation, neutrophil activation and myocardial ischemic damage in the human have remained unknown. METHODS: In a randomized single blind trial, complement activation, neutrophil counts, malondialdehyde, and cardiac enzymes were studied in 39 patients undergoing open-heart surgery. Two groups were perfused with cardiopulmonary bypass circuits with (n=20) or without heparin-coating (n=19). RESULTS: The different complement factors (C3, C4, C3d, C3d/C3 and the C-function), neutrophil levels, MDA and the cardiac enzyme levels were comparable before CPB was started and significantly increased in both groups during bypass. There were significant intergroup differences in the neutrophil levels and MDA after reperfusion (P<0.0001). Furthermore, significant positive correlations between the lipid peroxidation, expressed as MDA levels, and the levels of neutrofils and the cardiac enzyme, CK-MB were seen within the groups. CONCLUSIONS: Heparin coated circuits did lead to a decreased neutrophil response and MDA level. The correlations between CK-MB and neutrophil and MDA levels suggest neutrophil activation leading to lipid peroxidation that may influence myocardial damage. Heparin coating improved biocompatibility and was associated with less occult myocardial ischemic damage in patients undergoing open heart surgery.