The Insult of Cardiopulmonary Bypass?

In coronary artery bypass graft surgery (CABG), derangements in hemostasis and an integrated systemic inflammatory response (SIRs) contribute to bleeding, transfusion requirements, and adverse postoperative complications. The cardiopulmonary bypass (CPB) pump in coronary artery bypass of CABG has been identified as the culprit of the insult in CABG surgery. Therefore, off-pump CABG has recently gained popularity as an alternative operative technique to conventional CPB to reduce derangements in hemostasis and SIRs. Although CABG is more technically challenging without the use of CPB, advocates of off-pump surgery assert that the avoidance of CPB and subsequent myocardial ischemia-reperfusion will avoid derangements in hemostasis and SIRs, thus reducing perioperative bleeding, decreasing transfusion requirements, and translating into improved clinical outcomes for CABG patients.

A recent comprehensive review analyzed available evidence on differences between off-pump and on-pump procedures with respect to inflammation in patients undergoing CABG Ä1Å. The results, summarized in the table below, show that removal of the pump does not eliminate changes in inflammatory mediators and markers associated with CABG. Thus, the culprit of the insult of CABG surgery does not solely rest with CPB.

Derangements in hemostasis are observed on and off pump Ä2, 5Å. Blood loss and transfusion requirements were specifically evaluated in a recent review of 1235 patients undergoing CABG within a major university teaching hospital Ä38Å. The results show that 73% of patients on pump (all of whom were also administered a lysine analog antifibrinolytic agent) were transfused with packed red blood cells (RBCs), as compared with 46% of off-pump patients Ä38Å. Although the removal of the pump was associated with reduced transfusion requirements, patients in both groups were administered significant amounts of blood products. These data are in agreement with that of Nuttall, which showed an overall decrease —but not an elimination of— transfusion requirements in off-pump CABG Ä39Å. Interestingly, no difference in overall post-operative blood loss between the groups was observed, and significantly increased blood loss was seen in the off-pump group at 4 hours after surgery relative to the on-pump group Ä39Å. Thus, the derangements in hemostasis, blood loss, and transfusion requirements are not limited to CABG with CPB. Further, off-pump surgery patients are exposed to the risks associated with blood loss and transfusion of blood products. As blood products have been shown to contain cytokines and other pro-inflammatory substances, transfusion itself may further contribute to SIRs in the CABG patient.

Trasylol (aprotinin injection), a serine protease inhibitor, is indicated for prophylactic use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing CABG with CPB Ä40Å. The full Hammersmith dose of aprotinin (load, 2 million KIU (equivalent to one 200 ml vial); pump prime, 2 million KIU (equivalent to one 200 ml vial); continuous infusion 500,000 KIU/h (a total of one 200 ml vial, given a 4 hour pump run) provides inhibition of kallikrein, a major upstream protease in the promulgation of contact activation and the subsequent SIRs, as well as direct inhibition of plasmin. As aprotinin is a protein molecule and may generate hypersensitivity reactions, all patients should be administered a 1 ml (10,000 KIU) test dose prior to administration of the loading dose. The full Hammersmith dose of aprotinin relative to placebo significantly reduces blood loss (primary, 705 ml vs 1232 ml; repeat, 960 ml vs 1659 ml) and blood transfusion requirements (primary, 0.9 U vs 1.7 U; repeat, 1.6 U vs 3.7 U) in patients undergoing primary (n=1265) or repeat (n=299) CABG surgery Ä40Å. The numbers of patients exposed to donor blood is also reduced (primary, 37% vs 54%; repeat 47% vs 76%) relative to placebo. Data from the pivotal trials for licensure Ä40Å, as well as many other published studies Äreviewed in 6Å, show that aprotinin is a safe and effective tool for use in a blood management strategy.

Aprotinin inhibits pro-inflammatory cytokine release and maintains glycoprotein homeostasis on platelets Ä40Å. Effects on relevant hemostatic and inflammatory parameters in patients undergoing CABG with CPB with full dose aprotinin are summarized in the table above. Thus, the use of full dose aprotinin allows the surgical team to achieve a reduction in the inflammatory response generated by CABG. Many of these parameters are not eliminated by the removal of the pump from CABG, as evidenced by the table above.

As direct comparative on-pump and off-pump surgery data are now appearing in the literature, the data indicate that, removing the CPB from CABG, while impacting some inflammatory and transfusion parameters, does not eliminate the insult of CABG surgery. Additional investigation will be required to determine the role of sternotomy, surgical trauma, global ischemia, and other factors in the insult of CABG surgery. Currently, clinicians have aprotinin as an available and approved tool to reduce the insult of CABG surgery with CPB. This tool, with other approaches, can be integrated into a comprehensive strategy to manage blood transfusion and reduce the SIRs of CABG to impact patient care.