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The effects of complement activation during cardiopulmonary bypass. Attenuation by hypothermia, heparin, and
F D Moore1, K G Warner, S Assousa
1Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts.
Insights
Cardiopulmonary bypass (CPB) activates complement, increasing C3a levels and neutrophil activation. Hypothermia, dilution, and heparin mitigate this response, protecting patients from complement-mediated injury during CPB.
Area of Science:
- Immunology
- Cardiovascular Surgery
Background:
- Complement activation is a significant concern during cardiopulmonary bypass (CPB).
- Elevated complement activation products like C3a desArg (C3a) have been linked to adverse outcomes in CPB patients.
- Neutrophil activation is a key cellular response to complement activation during CPB.
Purpose of the Study:
- To prospectively examine complement activation in patients undergoing CPB.
- To investigate the relationship between complement activation and neutrophil activation during CPB.
- To evaluate the impact of CPB-related variables (temperature, dilution, heparin) on complement activation.
Main Methods:
- Plasma C3a levels were measured in 100 CPB patients at various time points.
- Neutrophil activation markers (C3b receptors) were assessed in a subset of patients.
- In vitro experiments evaluated the effects of temperature, serum dilution, and heparin on complement activation and neutrophil response.
Main Results:
- Plasma C3a levels significantly increased during and after CPB.
- Higher C3a levels at 2 hours post-CPB were associated with prolonged mechanical ventilation.
- CPB induced neutrophil activation, evidenced by increased C3b receptor expression.
- Complement activation and neutrophil response were temperature-dependent and reduced by hypothermia, serum dilution, and heparin.
Conclusions:
- Complement activation is a prominent event during CPB, leading to increased C3a and neutrophil activation.
- Hypothermia, serum dilution, and heparin act as protective mechanisms by reducing complement generation and neutrophil response.
- These findings highlight the importance of managing CPB conditions to minimize complement-mediated inflammatory responses.
Abstract:
Complement activation was examined prospectively in 100 cardiopulmonary bypass (CPB) patients. Plasma C3a desArg (C3a) increased (cannulation: 234 +/- 33 ng/mL; 20 minutes on CPB: 622 +/- 51; 2 hours after CPB: 1143 +/- 109, p less than 0.0001). C3a at 2 hours was higher in the 13 patients requiring mechanical ventilation for longer than 1 day (1023 +/- 274) than in the 67 without respiratory complication (568 +/- 45, p less than 0.004). Five more patients were studied for neutrophil activation to confirm that a biologic effect of complement activation occurs during CPB; in these five patients C3a increased to 317% of baseline after 10 minutes on CPB with a corresponding rise in neutrophil cell surface receptors for the complement opsonin C3b (as measured by indirect immunofluorescence) to 168% (p less than 0.05). Both increases were sustained at 30 minutes. Temperature, dilution, and heparin were studied as variables relevant to CPB. Exposure of normal neutrophils to C5a in vitro caused an increase in C3b receptors which was dependent on temperature (0 specific fluorescence at 0 C, 30 at 25 C, 180 at 30 C, and 275 at 37 C). Generation of C3a and C5a in normal serum by zymosan was also temperature-dependent (ng/mL C5a generated: 0.7 at 25 C, 200 at 30 C, and 897 at 37 C; ng/mL C3a generated: 546 at 25 C, 10,872 at 30 C, and 65,667 at 37 C). Serum dilution to 33% decreased ng/mL C5a generated in the same system from 200 to 76 with no effect on C3a. Addition of heparin to 20 U/mL decreased ng/mL C3a generated from 10,872 to 913 and C5a from 200 to 8. Thus, hypothermia, dilution, and heparin protect CPB patients from complement activation by reducing both generation of C3a/C5a and the subsequent cellular response of neutrophil activation.