Antifibrinolytic therapy during cardiopulmonary bypass reduces proinflammatory cytokine levels: a randomized, double-blind, placebo-controlled study of epsilon-aminocaproic acid and aprotinin.
OBJECTIVE
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.
Greilich
Philip E
PE
Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center-Dallas Veterans Affairs Medical Center, 73590-9068, USA. philip.greilich@utsouthwestern.edu
Brouse
Chad F
CF
Whitten
Charles W
CW
Chi
Lei
L
Dimaio
J Michael
JM
Jessen
Michael E
ME
D000368:Aged; D015119:Aminocaproic Acid / Q000008:administration & dosage*; D000933:Antifibrinolytic Agents / Q000008:administration & dosage*; D007611:Aprotinin / Q000008:administration & dosage*; D002315:Cardiopulmonary Bypass / Q000009:adverse effects* / Q000379:methods; D001026:Coronary Artery Bypass / Q000009:adverse effects / Q000379:methods; D003327:Coronary Disease / Q000601:surgery; D016207:Cytokines / Q000097:blood* / Q000187:drug effects; D004311:Double-Blind Method; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D005500:Follow-Up Studies; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D007262:Infusions, Intravenous; D015850:Interleukin-6 / Q000032:analysis; D016209:Interleukin-8 / Q000032:analysis; D007431:Intraoperative Complications / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications / Q000517:prevention & control; D011336:Probability; D012016:Reference Values; D018570:Risk Assessment; D016896:Treatment Outcome
D000933:Antifibrinolytic Agents; D016207:Cytokines; D005338:Fibrin Fibrinogen Degradation Products; D018836:Inflammation Mediators; D015850:Interleukin-6; D016209:Interleukin-8; C036309:fibrin fragment D; D007611:Aprotinin; D015119:Aminocaproic Acid