A radical and effective way of counteracting the effects of SIRS may be the omission of CPB itself. This idea provided the impetus for reintroduction of off-pump coronary artery bypass (OPCAB) surgery—a technique that predates CPB but was rapidly off-staged by on-pump coronary artery bypass graft (CABG) soon after the invention of the heart-lung machine because of the attraction of operating on a still heart in a bloodless field [3].

Analysis of current best available evidence [4] from randomized controlled trials [6–28] indicates that OPCAB reduces the systemic inflammatory response but does not prevent it (grade A/level Ib). Use of OPCAB decreases concentrations of cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-8, IL-10, TNFsr1, and TNFsr2. It also attenuates the cellular inflammatory response, decreasing neutrophil and monocyte counts, neutrophil elastase, intracellular heat shock protein 70, and E-selectin concentrations. Indices of complement activation, such as C3a and C5a, are decreased. In addition, OPCAB attenuates other indices including platelet ß-thromboglobulin and ­procalcitonin. Finally, OPCAB decreases injury induced by reactive oxygen species (Table 27.3).

It would, however, be incorrect to expect that OPCAB will abolish the systemic inflammatory response completely. It is worth remembering that while performing OPCAB, the response to surgical trauma, manipulation of the heart, pericardial suction, heparin, protamine, other drugs, and anesthesia are still there, and all produce an increase in the markers of acute inflammation. Increasing acceptance to perform OPCAB in elderly patients and those with comorbid conditions is proof that this attenuated systemic inflammatory response reduces organ dysfunction [3].

Recently, a minimized extracorporeal circulation (MECC) system has been developed based on the concept of a short closed total CPB circuit [29]. The basic elements are a centrifugal pump, a membrane oxygenator, and an arterial filter. The priming volume can be reduced to 500 ml or less, thus limiting hemodilution. The complete circuit is coated with heparin to maximize biocompatibility. The blood-air interface is ­eliminated, and suction of shed blood is carried out only through a cell-saving device. Thus, blood is washed before retransfusion into the patient. In a randomized controlled trial, Fromes and colleagues [29] showed that the MECC ­system initiated a milder inflammatory reaction than standard CPB: IL-6, TNF-α, and elastase release was significantly less in patients who were operated on with the MECC system. However, currently there is a paucity of randomized controlled trials highlighting long-term survival, clinical outcomes, and delayed complications in this area. Despite this, MECC remains a promising alternative to conventional extracorporeal circulation, especially in terms of its inflammatory results.

Coating the artificial surfaces of the CPB circuit with heparin was initially suggested in the late 1960s [30], predominantly because of its known antithrombotic property [31]. Since then, however, it has been proven to have many other biocompatibile properties, including inhibition of contact, activation of complement and neutrophil, reduction in the release of proinflammatory cytokines, and improvement of platelet function [32]. Furthermore, it adsorbs lipoproteins to create a surface that may simulate cell membranes [32].

The method by which the circuit is coated and the type of heparin used may have implications for its effects on the coagulation and complement systems. The Duraflo II HCC (Baxter Healthcare Corp., Irvine, CA), which uses ionically bonded unfractionated heparin, reduces kallikrein and complement activation but is less effective in attenuating coagulation or fibrinolysis [33, 34]. The Carmeda Bioactive Surface system (Medtronic, Inc., Minneapolis, MN) uses end-attached, covalently bonded heparin that has been fragmented by treatment with nitric acid. The Carmeda circuit seems superior to the Duraflo II in reducing complement and neutrophil activation and endothelin-1 concentrations [35, 36].

A significant amount of work has been performed to evaluate any potential benefit in using heparin-bonded circuits (HBCs), but controversy remains. HBCs have been shown to reduce transfusion requirements, lung injury, neurocognitive dysfunction, and markers of occult myocardial damage in patients undergoing CPB [32]. A large multicenter randomized trial investigating HBCs for high-risk patients undergoing CPB showed reduced hospital length of stay (LOS) and intensive care unit (ICU) LOS and reduced renal and pulmonary postoperative dysfunction [33]. However, other studies have reported no difference between HBCs and standard circuits when investigating a range of differing outcomes [37, 38].

A meta-analysis of 41 randomized trials including 3,434 patients found significant reductions in the duration of ventilation, the incidence of postoperative transfusion, resternotomy rates, ICU LOS, and hospital LOS [39]. This meta-analysis failed to show effect of HBCs on other adverse events evaluated. However, many of these positive effects were marginal and of moderate clinical significance.

Currently, the majority of trials performed in this area have been relatively underpowered to adequately explore key clinically relevant outcomes, have involved heterogeneous patient groups, and have studied a number of different HBCs [39]. Furthermore, the use of HBCs in clinical practice appears to vary among different centers and countries [40] with little up-to-date data available at present.

Hemofiltration is a process that uses ultrafiltration (convection or osmosis under a hydrostatic pressure gradient) to remove fluid and low-molecular-weight substances from plasma. Initially introduced to treat patients with renal failure and to correct accumulation of extravascular water following CPB, hemofiltration appears to exert beneficial antiinflammatory effects, particularly in pediatric patients (Table 27.4) [41–48].

The hemodilution associated with CPB is most marked in the pediatric population, and, as a result, modified ultra­filtration (MUF) has been studied more extensively and with more definitive outcomes within this population. Several pediatric studies have suggested that MUF may effectively remove some of the inflammatory mediators released during CPB, including complement, TNF-α, IL-6, IL-1, IL-8, and myeloperoxidase [41–48]. However, these findings have not always been replicated [49]. Clinical benefits also have been reported, including increased hematocrit, improved cardiovascular performance, and reduced postoperative chest tube drainage [41].

MUF is used less frequently in adult CPB patients, and any potential benefits remain controversial. There are a number of randomized controlled trials and case control studies that have reported positive clinical outcomes for adult patients [32]. It is noteworthy that there is a significant variation in the techniques used to perform UF and that the technique has been studied in a variety of patient subgroups, including CABG surgery patients, high-risk patients, and patients on chronic renal dialysis [32]. UF does appear to improve post-CPB hematocrit and in some instances postoperative transfusion requirements [32]. Luciani et al. [50] have performed the largest randomized controlled trial in adults and showed a significant reduction in hospital morbidity and a statistically nonsignificant fall in mortality. The reduction of proinflammatory cytokines and adhesion molecules by UF during or after CPB has been shown in adults, but has not always been associated with clinical advantage in terms of postoperative complications or LOS [51]. Finally, a recent meta-analysis of randomized trials investigated the effect of UF on perioperative coagulopathy in adult cardiac surgery and found that UF does appear to reduce postoperative hemorrhage and transfusion requirements, although the extent of these reductions was of arguable clinical benefit according to the authors [52].

In both patient groups, uncertainty does remain concerning both the type and combination of UF strategies [32]. Work is ongoing to clarify this and the overall risk/benefit to the patient because not only do some benefits appear ­transitory, but also UF is not without risk; increased plasma ­heparin concentrations, entrainment of air through the aortic cannula, an increase in the duration of exposure of the patient’s blood to nonendothelialized surfaces, hemodynamic instability, and human or equipment error all can occur [32, 53].

Leukocytes play a central role in the inflammatory response to cardiac surgery. Leukocyte depletion during cardiac surgery, by means of leukocyte-specific filters, decreases circulating leukocyte and platelet concentrations and attenuates indices of inflammation and oxidative stress [54–58]. There is increasing evidence that leukocyte depletion may limit pulmonary and myocardial injury following CPB. Benefits appear to be the most consistent in patients with risk factors such as left ventricular dysfunction, urgent surgery, or long CPB time. Leukocyte depletion has been shown to improve postoperative respiratory function in CPB patients, particularly in those with a low preoperative oxygenation capacity or long CPB time [56, 57]. In addition, leukocyte depletion of the residual heart-lung machine blood, which contains large quantities of activated leukocytes, prior to re-transfusion improved lung function in patients undergoing elective CABG [54]. Leukocyte depletion during CPB, combined with leukocyte depletion of transfused blood, decreased indices of myocardial cell injury in patients undergoing urgent CABG for unstable angina [58]. Conversely, in low-risk patients, depletion of activated neutrophils during CPB did not confer a clinical benefit [59]. Limiting leukocyte depletion to the reperfusion phase of CPB (following aortic declamping) did not appear to provide any clinical benefit to CABG patients [60]. Leukocyte depletion of blood cardioplegia alone attenuated myocardial cell injury and improved early myocardial function in patients with left ventricular dysfunction undergoing CABG with CPB [61, 62]. Leukocyte depletion of terminal blood cardioplegia (blood cardioplegia administered for 10 min immediately prior to aortic declamping as an adjunct to crystalloid cardioplegia) decreased myocardial injury and improved cardiac function in patients with left ventricular hypertrophy undergoing valve surgery [63].

Despite the aforementioned benefits, currently, there is not enough high-quality or consistent evidence to advocate the routine use of leukofiltration as an anti-inflammatory strategy within routine CPB.

Under physiologic conditions, blood flow occurs in a pulsatile manner, but during CPB this situation changes, a variation that may worsen the inflammatory response [1, 32]. A large number of studies have thus been conducted to investigate any possible benefits in using centrifugal pumps, originally developed for prolonged postoperative cardiac assist and for extracorporeal membrane oxygenation [32]. Centrifugal pumps have been reported to reduce platelet aggregation (and thus lower susceptibility to postoperative thrombotic phenomena) [64], decrease the incidence of neurologic and renal complications [65], decrease chest tube drainage, and reduce transfusion requirements [66]. However, other randomized controlled trials comparing the two pump types have failed to show improvements in blood transfusion rates, postoperative cardiac performance, duration of postoperative mechanical ventilation, ICU LOS, hospital LOS, and mortality [64]. More importantly, the impact of centrifugal pumps on inflammation is an underexplored area, and there is a paucity of evidence to validate their universal usage as a strategy to reduce SIRS.

The optimal temperature at which to conduct CPB remains a controversial area. The controversy is further compounded by the varying definitions of “normothermia” used by different investigators. Some groups refer to a temperature of 33–34 °C as normothermia, while others regard 36–37 °C as physiologic normothermia [32]. Significant reductions in the levels of inflammatory mediators (e.g., p-selectin, IL-1, IL-8, and elastase) have been shown when comparing hypothermic patients (28–30 °C) with patients at 34 °C [67]. However, although hypothermia appears to delay this reaction, it does not prevent it entirely, and other groups looking at similar molecular markers have found no difference among three differing temperatures [68]. The clinical outcome data are no more convincing. Some studies suggest that moderate hypothermia (32 °C) may reduce neuropsychologic injury, but benefits are best described as modest [69]. It can be said that although there is a significant level of evidence to suggest that hyperthermia must be avoided in patients on CPB [70], there is currently not enough evidence to clearly identify the optimal temperature at which CPB should be conducted.

Corticosteroid pretreatment may blunt the inflammatory response in humans by several distinct mechanisms. Administration of glucocorticoids prior to CPB may attenuate endotoxin release and complement activation [71, 72]. Methylprednisolone lowers post-CPB concentrations of the proinflammatory cytokines TNF-α, IL-6, and IL-8 and increases concentrations of the antiinflammatory cytokines IL-10 and IL-1ra, but not IL-4 [73]. Corticosteroids also attenuate post-CPB leukocyte activation, neutrophil adhesion molecule upregulation, and pulmonary neutrophil sequestration [2, 74]. Pre-bypass administration of methylprednisolone in aprotinin-treated patients improves early postoperative indices of pulmonary, cardiovascular, hemostatic, and renal function [75]. Glucocorticoid pretreatment may improve cardiac performance and reduce evidence of bronchial inflammation following CPB [76]. Low-dose methylprednisolone in the pump prime solution appears to attenuate myocardial cell damage [77]. However, the ability of corticosteroid pretreatment to attenuate post-CPB pulmonary inflammation, endotoxemia, and complement activation is disputed [2, 78]. The clinical implications of corticosteroid use are not yet fully elucidated, and clear benefit is not yet demonstrated. The dosage, formulation, and timing of administration of corticosteroids may be critical, and differences in dosage regimens may explain conflicting results. Preoperative combined with pre-bypass administration may be superior to pre-bypass administration alone [79]. It is premature to advocate the use of corticosteroids in the absence of proven outcome benefit, determination of optimal dosage regimens, and characterization of the harmful effects that may result from their use [2].

The Cochrane review regarding the use of prophylactic steroids in pediatric patients undergoing CPB reported that the existing evidence did not support this practice in this patient group [80]. Similarly, the Cochrane review for this practice in adults showed no beneficial effect of corticosteroid use on mortality or cardiac and pulmonary complications in cardiac surgery patients [81].

Finally, recent expert guidelines on CABG surgery from the American Heart Association and the American College of Cardiology state “corticosteroid administration is inexpensive and appears to reduce the risk of the systemic inflammatory response associated with CPB with little downside risk. Current understanding supports liberal prophylactic use in patients undergoing extracorporeal circulation” [82]. Hence, at present, evidence for the efficacy and safety of corticosteroids is controversial.

Many effector proteins of the cytokine, complement, and hemostatic cascades are serine proteases; when activated, they catalyze the next step in the cascade by hydrolyzing and activating further proteins, a process termed “cascade amplification”. Control processes that limit inflammation to the sites of injury and reduce systemic inflammation include serine protease inhibitors. Aprotinin is the best known and most studied of these inhibitors [2]. Aprotinin, a nonspecific serine protease inhibitor isolated from bovine lung tissue, was first used clinically in the 1960s to treat acute pancreatitis [83]. Knowing that it inhibited kallikrein, one of the key components of the contact system, led in the 1980s to it being tested as a potential antiinflammatory agent in CPB. However, the key findings of initial studies were that it significantly decreased the perioperative hemorrhage associated with cardiac surgery [84]. These findings led to the widespread adoption of aprotinin to reduce postoperative bleeding in cardiac surgery.

Subsequent studies confirmed that aprotinin possesses important antiinflammatory properties. It inhibits trypsin, chymotrypsin, plasmin, kallikrein, elastase, and thrombin [85]. By inhibiting kallikrein and plasmin, it reduces the levels of contact activation and limits fibrinolysis. It prevents proteolysis of the major thrombin receptor on platelets (protease activated receptor 1) [86], inhibiting platelet activation and suggesting simultaneous pro- and antithrombotic effects. Aprotinin reduces complement activation; the levels of circulating proinflammatory cytokines such as Il-6, IL-8, and TNF-α; and expression of leukocyte adhesion molecules (MAC-1) [87]. Aprotinin has been shown to reduce markers of myocardial injury (troponin T, CK-MB, and lactate dehydrogenase) in patients undergoing CABG surgery [88], and a meta-analysis suggested a decrease in all-cause mortality of almost twofold [89].

Despite the aforementioned benefits, aprotinin is no longer available for routine use. This restriction came into force following publication of the results of the studies by Mangano et al. [90], Karkouti et al. [91], and more importantly the Canadian BART (Blood Conservation using Antifibrinolytics) trial, which compared aprotinin to two lysine analogs (tranexamic acid and aminocaproic acid) in high-risk patients undergoing cardiac surgery [92]. The high-quality BART trial reported in late May 2008 and provided modest evidence that aprotinin was the more effective hemostatic agent because patients who received it had a reduced risk of massive postoperative bleeding and need for postsurgical administration of blood products [92]. Despite this, patients who received aprotinin had an increased risk of 30-day mortality of more than 50 % (relative risk, 1.53; 95 % confidence interval, 1.06–2.22), an outcome that led trial investigators to conclude that aprotinin should no longer be used in patients undergoing high-risk cardiac surgery [92]. Whether aprotinin now has a role in cardiac surgery appears doubtful; the conventional wisdom had always been that it was for patients at a high risk of bleeding who had the most to gain from aprotinin, but it was precisely this cohort whom BART was set up to investigate, and the study subsequently provided convincing evidence of the superiority of lysine analogs in this role. What is clear is that many lessons can be learned from the “aprotinin story” regarding the assessment of new pharmaceuticals as they enter clinical practice [32, 93].