Con: Heparin-Bonded Cardiopulmonary Bypass Circuits Should Be Routine for All Cardiac Surgical Procedures

“The important thing in science is not so much to obtain new facts as to discover new ways of thinking about them.” —Sir William Bragg Despite advances in the care of cardiac surgical patients over the past 50 years, we are still confronted with challenges similar to those that preoccupied our pioneers. Surgeons, anesthesiologists, and perfusionists alike have been concerned with exposure of blood to the extracorporeal circuit, which is inherently not as physiologic as the endothelial cell layer. Exposure of blood to any artificial surface promotes thrombogenicity and is potentially fatal, requiring adequate intraoperative anticoagulation. Over the years, heparin has remained the sine qua non for the conduct of cardiopulmonary bypass (CPB), and adequacy of anticoagulation has mostly required achieving a minimal target activated clotting time (ACT) rather than acquiring an optimal therapeutic level during surgery. A number of reports have cited the successful use of various surface modifying agents on the extracorporeal circuits used in cardiac surgery (1–6). Of these, modifications of material surface through heparin immobilization (so-called “heparin-coated circuits”) have been most ubiquitously investigated (7). There have been mixed reports regarding their efficacy as well as inefficacy (8–22). Interpretation of these results is difficult and may cause confusion about whether to use heparin-coated circuits for CPB. Certainly, their routine use has remained infrequent, as a survey in the United States shows that only a small proportion (17%) of centers routinely use heparin-coated circuits in cardiac surgery (23). Historically, two principal mechanisms have been proposed for the beneficial effects of heparin-coated circuits (24,25): Improved biocompatibility of the circuit material leads to decreased activation of complement and leukocytes and, hence, a decreased systemic inflammatory response to CPB. Heparin immobilization also allows for its direct exposure to flowing blood, making the artificial surface more hydrophilic and biocompatible. This may help in augmenting the anticoagulation effect, inhibition of activation of thrombin and the fibrinolytic system, decreased coagulopathy, and, possibly, less perioperative bleeding. The first point raises the most fundamental issue—that of the “systemic inflammatory response.” The signs of a localized inflammatory response are well known (calor, rubor, dolor, tumor, and functio laesa), but what are the clinical features of a systemic inflammatory response and is it really harmful to the patient (26)? The systemic or generalized inflammatory response cannot as yet be characterized clinically in animal or human models. It only attracts a default diagnosis in critically ill patients who manifest high output syndromes and organ dysfunction in the presence of infection, shock, or trauma. Although the inflammatory response to CPB has been compared to systemic inflammatory response syndrome (SIRS) accompanying sepsis, there is no consensus on how to define it or evidence to suggest that its manifestation increases postoperative morbidity and mortality (27). Inflammation is crucial for wound healing and repair, and to imply that a generalized response is inappropriate highlights the gleam of only a single edge of this double-edged sword. Thus, to state that heparin-coated circuits decrease contact activation and systemic inflammatory response should attract little attention unless that translates into improved outcomes for our patients. Initial investigations indicated an improvement in biochemical markers (28–30); and a few trials suggest an association between the use of heparin-bonded CPB circuits and decreased morbidity (8,9). One report further demonstrates that patients exposed to heparin-coated circuits have a decreased inflammatory response, reduced pulmonary vascular resistance, and improved Pao2/Fio2 ratios after surgery; however, this was not associated with a decreased lung ventilation time or intensive care unit stay (12). Another investigation suggests the use of heparin-bonded circuits during surgery to decrease postoperative neurocognitive dysfunction, but the authors did not find an association of this clinical effect with complement or coagulation activation (11). Postoperative organ dysfunction may not, however, be related to activation of the terminal complement complex, granulocyte activation, or to the use of heparin-coated circuits (28,31). Certain research groups have shown benefits with heparin-bonded circuits only when these have been used with other perfusion modifications such as reduced systemic heparin and avoidance of cardiotomy suction blood (2,9,32,33). Obviously, post-CPB morbidity and mortality may be related to many mechanisms other than the use of biocompatible circuits making it difficult to show a benefit based purely on alteration of one component of inflammation. An early goal for heparin-bonded circuits was to increase thrombo-resistance because systemic heparin was believed to cause postoperative platelet dysfunction and fibrinolysis (34). Initial studies compared the effects of full (ACT > 480 s) versus reduced (ACT ∼250 s) heparinization in conjunction with heparin-coated circuits. The reduced systemic anticoagulation protocol seemed safe and was associated with decreased postoperative bleeding, although not consistently (9,15,16,21,32,33,35,36). Postoperative chest tube drainage continues to occur almost uniformly after cardiac surgery and although its etiology may be multifactorial, microvascular coagulopathy remains the most common cause (37,38). Microvascular coagulopathy also occurs in sepsis and multiple organ dysfunction syndrome. Initially thought to be a mere epiphenomenon, it is now believed to be a critical step in development of multiple organ dysfunction syndrome (39): central to this is thrombin and its regulatory anticoagulant protein C pathway (40). Thrombin has both procoagulant and proinflammatory effects, and its inappropriate regulation by activated protein C is associated with increased mortality (41,42). Thrombin levels also increase during cardiac surgery despite full anticoagulation with heparin (43–47). Patient-specific heparin dosing and its monitoring limit thrombin generation and consumption of coagulation factors associated with decreased transfusions in the postoperative period (48–51). Is it possible that the coagulopathy after cardiac surgery is a manifestation of the host inflammatory response? Could the risk of postoperative hemorrhage be further decreased with a more precise anticoagulation protocol in combination with heparin-bonded circuits? Future investigations may need to evaluate different thrombin inhibitors that are used in conjunction with biocompatible circuits with clinically relevant end-points. Heparin-coated circuits have cost implications as well. Currently, at the London Health Sciences Centre, London, Ontario, the use of heparin-coated circuits would offset the case costing by more than C$150 per CPB surgery. In a managed health care environment, the added expense could only be justified if it leads to a reduction in morbidity and mortality. In summary, heparin-coated circuits are proposed to improve biocompatibility by reducing coagulation and inflammatory activation, neither of which have been universally demonstrated. Organ dysfunction after cardiac surgery is likely multifactorial in etiology, and a direct benefit on patient outcome by attenuating inflammation to CPB is yet to be established. Many questions regarding the use of heparin-coated circuits need to be addressed before their use becomes routine, including the extent of systemic anticoagulation. There is no doubt that advances in technology will herald more physiological but complex biocompatible materials on CPB circuits. However, justifying the added expense of this technology will require data showing that patient outcomes are improved and not just that its use is associated with alteration of surrogate markers of organ injury.

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