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Modulation of Systemic Inflammatory Response after Cardiac Surgery

Department of Cardiac Surgery, Royal Hospital for Sick Children, Glasgow, United Kingdom,
¹ Department of Cardiac Surgery, Harefield Hospital, London, United Kingdom

For reprint information contact: Shahzad G Raja, MRCS Tel: 44 141 201 0269 Fax: 44 141 201 9204 Email: drrajashahzad{at}hotmail.com, Department of Cardiac Surgery, Royal Hospital for Sick Children, Yorkhill NHS Trust, Dalnair Street, Glasgow G3 8SJ, Scotland, United Kingdom.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATHOGENESIS OF THE SYSTEMIC... NOVEL CARDIAC SURGICAL... STRATEGIES TO IMPROVE... FILTRATION TECHNIQUES PHARMACOLOGIC STRATEGIES STRATEGIES TO REDUCE ENDOTOXEMIA CONCLUSION REFERENCES

 
Cardiac surgery and cardiopulmonary bypass initiate a systemic inflammatory response largely determined by blood contact with foreign surfaces and the activation of complement. It is generally accepted that cardiopulmonary bypass initiates a whole-body inflammatory reaction. The magnitude of this inflammatory reaction varies, but the persistence of any degree of inflammation may be considered potentially harmful to the cardiac patient. The development of strategies to control the inflammatory response following cardiac surgery is currently the focus of considerable research efforts. Diverse techniques including maintenance of hemodynamic stability, minimization of exposure to cardiopulmonary bypass circuitry, and pharmacologic and immunomodulatory agents have been examined in clinical studies. This article briefly reviews the current concepts of the systemic inflammatory response following cardiac surgery, and the various therapeutic strategies being used to modulate this response.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATHOGENESIS OF THE SYSTEMIC... NOVEL CARDIAC SURGICAL... STRATEGIES TO IMPROVE... FILTRATION TECHNIQUES PHARMACOLOGIC STRATEGIES STRATEGIES TO REDUCE ENDOTOXEMIA CONCLUSION REFERENCES

 
Cardiac surgery and cardiopulmonary bypass (CPB) initiate a systemic inflammatory response largely determined by blood contact with foreign surfaces and the activation of complement. It is generally accepted that CPB initiates a whole-body inflammatory reaction.^1–2 Hemodynamic profiles, hematologic parameters, and several specific biological markers contribute to this systemic inflammatory reaction. The magnitude of the reaction varies, but the persistence of any degree of inflammation may be considered potentially harmful to the cardiac surgical patient. The systemic inflammation observed during and after cardiac surgery is related to the secretion of a large number of mediators, and to the activation of certain natural defense mechanisms. More accurately, during cardiac surgery using CPB, 5 plasma protein systems and 5 types of blood cells are activated to produce a massive acute defensive reaction that causes consumptive coagulopathy, circulates more than 70 hormones, cytokines, chemokines, vasoactive substances, cytotoxins, reactive oxygen species, and proteases of the coagulation and fibrinolytic systems, induces mild to huge interstitial fluid shifts, generates a host of microemboli < 500 microns, and results in temporary dysfunction of nearly every organ.^3–17

	PATHOGENESIS OF THE SYSTEMIC INFLAMMATORY RESPONSE AFTER CARDIAC SURGERY

TOP ABSTRACT INTRODUCTION PATHOGENESIS OF THE SYSTEMIC... NOVEL CARDIAC SURGICAL... STRATEGIES TO IMPROVE... FILTRATION TECHNIQUES PHARMACOLOGIC STRATEGIES STRATEGIES TO REDUCE ENDOTOXEMIA CONCLUSION REFERENCES

 
The inflammatory response after cardiac surgery is activated nonspecifically by surgical trauma, blood loss or transfusion, and hypothermia. Cardiopulmonary bypass is thought to specifically activate the inflammatory response via at least 3 distinct mechanisms.⁴ The first mechanism involves activation of the immune system following exposure of blood to the foreign surfaces of the CPB circuit.^4–22 The second mechanism involves ischemia-reperfusion injury to the end organs as a result of aortic crossclamping.^4,11–15 Restoration of perfusion on release of the aortic crossclamp is associated with activation of key indices of the inflammatory response.^4–5 Thirdly, endotoxemia may indirectly activate the inflammatory cascade.⁴ Splanchnic hypoperfusion, a common finding during and following CPB, may damage the mucosal barrier, allowing gut translocation of endotoxin. Systemic endotoxin concentrations correlate closely with the degree of cardiovascular dysfunction following CPB.^4,7

The incidence, severity, and clinical outcome of the systemic inflammatory response is influenced by a large number of factors that can be broadly classified as biomaterial-dependent and biomaterial-independent (Table 1).⁸ The precise role of each of these factors and the reasons why certain patients develop life-threatening perioperative complications are currently the focus of considerable research. Diverse therapeutic strategies to modulate the systemic inflammatory response after cardiac surgery are being examined in experimental and clinical studies.^8,12,14,17 We focus on these strategies and review the available literature to determine their impact in reducing the systemic inflammatory response.

	NOVEL CARDIAC SURGICAL TECHNIQUES AND TECHNOLOGY

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OFF-PUMP CORONARY ARTERY BYPASS
Concerns regarding the complications and cost of using CPB have led to renewed interest in off-pump coronary artery bypass (OPCAB) techniques. By avoidance of aortic crossclamping and CPB, OPCAB may decrease the inflammatory response and improve postoperative organ function and patient outcome, particularly in high-risk patients. Available evidence from a large number of prospective randomized controlled trials suggests that OPCAB reduces the elaboration of key mediators of the systemic inflammatory response (Table 2).²⁴ Use of OPCAB decreases concentrations of cytokines such as TNF-, IL-6, IL-8, IL-10, TNFsr1, and TNFsr2.^36–42 It also attenuates the cellular inflammatory response, decreasing neutrophil and monocyte counts, neutrophil elastase, and E-selectin concentrations.^29,37,38,41 Indices of complement activation, such as C3a and C5a, are decreased.^36,38 In addition, OPCAB attenuates other indices including platelet ß-thromboglobulin and procalcitonin. Finally, OPCAB decreases reactive oxygen-species-induced injury.^37–38,43

	STRATEGIES TO IMPROVE BIOCOMPATIBILITY OF THE EXTRACORPOREAL CIRCUIT

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Improving the biocompatibility of the CPB circuit in order to reduce contact activation of the immune system, particularly the complement cascade, may be a useful strategy to limit the inflammatory response. Potential approaches include the use of more biocompatible materials in the circuit and modifications to the surface of the circuit by coating with compounds that are less immunogenic.

HEPARIN-COATED CIRCUITS
A heparin-coated CPB circuit (HCC) enhances biocompatibility, reduces contact activation, and may decrease cardiovascular, respiratory, hemostatic, and neurologic dysfunction postoperatively.⁵⁰ 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, USA), which uses ionically bonded unfractionated heparin, reduces kallikrein and complement activation, but is less effective in attenuating coagulation or fibrinolysis.^51,52 The Carmeda Bioactive Surface system (Medtronic, Inc., Minneapolis, MN, USA) uses end-attached covalently bonded heparin that has been fragmented by treatment with nitric acid. The Carmeda circuit appears superior to the Duraflo II in reducing complement, neutrophil activation, and endothelin-1 concentrations.^53,54

Clinical studies suggest that the HCC decreases neutrophil activation, lessens myocardial injury, and reduces complement activation.^55–56 The largest study to date in low-risk patients revealed no overall clinical benefit, although subgroup analysis suggested that women, and patients with prolonged aortic crossclamp times may benefit from HCC.⁵⁷ The Duraflo II HCC decreased the duration of ventilatory support and intensive care unit (ICU) stay, and reduced the incidence of poor outcome (death or prolonged ICU stay) in a large study of high-risk patients.⁵¹ However, a similar but smaller study failed to confirm these benefits.⁵⁸ The benefits of HCC technology may be more apparent in patients with pre-existing organ dysfunction.⁵¹ Outcome may be improved when the Duraflo HCC is combined with silicone-coated oxygenators.⁵⁹ The HCC may attenuate the proinflammatory response more markedly and with greater myocardial protective effects when perfusion times are prolonged, especially in heart and heart-lung transplantation.⁶⁰ In a recently published randomized controlled trial comparing the Duraflo II totally heparin-coated CPB system with the Trillium Biopassive surface-coatedAffinity oxygenator (Medtronic, Inc., Minneapolis, MN, USA), only small differences in the inflammatory response between the two extracorporeal circulation devices were noticed.⁶¹

ADDITIONAL TECHNICAL STRATEGIES
Other strategies with therapeutic potential to improve biocompatibility include coating of the circuitry with phosphatidylcholine, silicone, synthetic proteins and polymers, or surface-modifying additives.^62–67 The combination of NO gas infusion and a HCC is another useful and promising modification for enhancing the attenuation of bypass-induced blood activation, although the optimal dose of NO in terms of effectiveness and adverse effects to the whole body remains to be established.⁶⁸ Decreasing oxygenator surface area may also limit activation of the inflammatory response.⁶⁹

	FILTRATION TECHNIQUES

TOP ABSTRACT INTRODUCTION PATHOGENESIS OF THE SYSTEMIC... NOVEL CARDIAC SURGICAL... STRATEGIES TO IMPROVE... FILTRATION TECHNIQUES PHARMACOLOGIC STRATEGIES STRATEGIES TO REDUCE ENDOTOXEMIA CONCLUSION REFERENCES

 
HEMOFILTRATION
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 anti-inflammatory effects, particularly in pediatric patients.^70–75 Hemofiltration may remove proinflammatory mediators, with reductions in postoperative TNF-, IL-1, IL-6, IL-8, C3a, and myeloperoxidase concentrations.^70,76–78 This technique improves hemodynamic stability and early postoperative oxygenation, and reduces postoperative blood loss and duration of mechanical ventilation in pediatric cardiac surgery.^70,74,77 Hemofiltration may reduce pulmonary hypertension after congenital heart surgery, possibly by facilitating removal of endothelin-1.⁷⁸ Modified hemofiltration after CPB improves intrinsic left ventricular systolic function and diastolic compliance, increases blood pressure, and decreases inotropic drug use in the early postoperative period in infants.^79–80 Hemofiltration appears to be less effective in adults, although results of a prospective randomized controlled trial suggest that modified ultrafiltration after CPB is associated with reduced early morbidity and lower blood transfusion requirements.^81–83 Hemofiltration in adults undergoing CPB is less effective in removing proinflammatory cytokines than in pediatric patients, perhaps explaining its apparent lack of efficacy in this population.^82,84

LEUKOCYTE DEPLETION
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.^85–89 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.^87–88 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.⁸⁵ 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.⁸⁹ Conversely, in low-risk patients, depletion of activated neutrophils during CPB did not confer a clinical benefit.⁹⁰ Limiting leukocyte depletion to the reperfusion phase of CPB (following aortic declamping) did not appear to provide any clinical benefit to CABG patients.⁹¹ 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.^92–93 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.⁹⁴

The immunomodulatory effects of leukocytes in allogeneic blood have focused attention on the potential benefits of leukocyte depletion of stored blood.⁹⁵ A large-scale clinical trial conducted in CPB patients demonstrated that leukocyte depletion of transfused blood significantly reduced the overall 60-day mortality.⁹⁶ The difference in mortality was predominantly due to a marked reduction in noncardiac causes of death, particularly multi-organ failure.⁹⁶ In addition, leukocyte depletion reduced the postoperative infection rate in patients who received more than 3 units of blood.⁹⁶

	PHARMACOLOGIC STRATEGIES

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APROTININ
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. Aprotinin, a complex polypeptide and nonspecific serine protease inhibitor, has been clearly demonstrated to prevent excessive blood loss during cardiac surgery.^97–99 In addition, aprotinin has multiple actions that may suppress the inflammatory response, particularly at higher dosages.¹⁰⁰ Anti-inflammatory effects include attenuation of platelet activation, maintenance of platelet function, reduced complement activation, inhibition of kallikrein production, decreased release of TNF-, IL-6, and IL-8, inhibition of endogenous cytokine-induced nitric oxide synthase induction, decreased CPB-induced leukocyte activation, and inhibition of upregulation of monocyte and granulocyte adhesion molecules.^100–108 In clinical studies, high-dose aprotinin reduced post-bypass myocardial ischemia, myocyte damage, and length of hospital stay in high-risk patients.^109–110 Concerns over graft patency following aprotinin therapy have been reduced by the IMAGE trial which found no difference in early (10 day) patency rates for internal mammary artery grafts or saphenous vein grafts after controlling for confounding factors.^111–112 Aprotinin may reduce pulmonary and cerebral injury following CPB.^113–117 Initial concerns over the potential for adverse effects of aprotinin on renal function appear unfounded.¹¹⁸ A meta-analysis of the available evidence reported that aprotinin reduced surgical blood loss, allogeneic blood transfusion, and the need for redo thoracotomy, and decreased perioperative mortality almost twofold, with no increase in the risk of myocardial infarction.⁹⁷ These data provide strong support for the use of aprotinin in patients undergoing cardiac surgery.

PENTOXIFYLLINE
Pentoxifylline is a nonspecific phosphodiesterase inhibitor with diverse anti-inflammatory effects, many of which may be mediated by inhibition of phosphodiesterase IV.¹¹⁹ These include attenuation of TNF- release in sepsis, decreased endotoxin and cytokine activation of neutrophils, reduction of indices of endothelial injury and permeability, decreased pulmonary leukocyte sequestration, and attenuation of increases in pulmonary vascular resistance.^120–124 Clinical studies to date have been limited. Recently, in elderly cardiac surgical patients, pentoxifylline attenuated the increase in neutrophil elastase, C-reactive protein, and proinflammatory cytokines (IL-6, IL-8, and IL-10). These patients also had reduced requirements for vasoactive medication and a shorter time to tracheal extubation.¹²⁵ In a parallel study, the same investigators reported improved splanchnic perfusion and hepatic-renal function with pentoxifylline.¹²⁶

FREE-RADICAL SCAVENGERS AND ANTIOXIDANTS
Generation of reactive oxygen species (ROS), such as hydrogen peroxide and the superoxide and hydroxyl radicals, occurs upon reperfusion following bypass, and these may be important contributors to tissue injury.¹²⁷ Leukocytes activated during bypass may also release substantial amounts of cytotoxic ROS.^128–129 When present in equimolar concentrations, superoxide and NO may combine to form peroxynitrite, a more reactive and injurious free radical.^130–131 Myocardial antioxidant enzymes, including glutathione reductase, superoxide dismutase, and catalase, are activated in proportion to the degree of myocardial ischemia and reperfusion injury.¹³² Host antioxidants become depleted after CPB, presumably as a result of consumption by free radicals.^133–134 When ROS production exceeds host defense scavenging capacity, cellular injury results.^127,135 There is an inverse correlation between preoperative total plasma antioxidant status and lipid peroxidation; the latter directly correlates with indices of myocardial cellular injury.¹³⁴ Furthermore, post-CPB coronary endothelial dysfunction appears to be partially mediated by ROS.¹³⁶ Free-radical scavengers, such as enzymatic scavengers, antioxidants, and iron chelators, may be potentially useful therapeutic adjuncts to control the deleterious effects of the inflammatory response.

HIGH-DOSE VITAMIN C AND VITAMIN E
High-dose vitamin C (ascorbic acid) has been demonstrated to effectively scavenge free radicals, decreasing cell membrane lipid peroxidation and indices of myocardial injury, and improving hemodynamics, with a shorter ICU and hospital stay.^127,137 Vitamin E (-tocopherol) reduced plasma concentrations of hydrogen peroxide, a marker of free-radical concentration, and decreased cell membrane lipid peroxidation following CPB.^127,138 Preoperative supplementation with a combination of ascorbic acid, -tocopherol, and allopurinol reduced cardiovascular dysfunction in both stable and unstable patients undergoing CABG. Unstable CABG patients sustained less myocardial injury and had a decreased incidence of perioperative myocardial infarction.¹³⁹ However, a more recent trial of combined -tocopherol and ascorbic acid supplementation in CABG surgery revealed no detectable decrease in myocardial injury.¹⁴⁰

N-ACETYLCYSTEINE
High-dose N-acetylcysteine before or during bypass appears to act as a free-radical scavenger and reduces the neutrophil oxidative burst response and elastase activity.^141–142 In an early interventional trial in patients with established acute lung injury, N-acetylcysteine was shown to improve oxygenation and lung mechanics, although no impact on progression to acute respiratory distress syndrome was noted.¹⁴³

ALLOPURINOL
Allopurinol is an inhibitor of the enzyme xanthine oxidase, a pivotal generator of free radicals during reperfusion injury. Allopurinol may decrease myocardial formation of cytotoxic free radicals, lower markers of myocardial cellular injury, and improve recovery of myocardial function following CPB.^{135,144–147} However, other studies have demonstrated no improvement in either myocardial function or myocardial cellular injury with allopurinol use, casting doubt on its therapeutic potential.^{144,148–149}

PHOSPHODIESTERASE INHIBITORS
Pharmacologic interventions to maximize splanchnic perfusion may attenuate the inflammatory response. Immune cells contain type IV and type III phosphodiesterase, and phosphodiesterase inhibitors appear to directly limit inflammatory activation and organ dysfunction in sepsis models.^150–151 Milrinone attenuates the reduction in gastric intramucosal pH, reduces both venous and hepatic endotoxin concentrations, and may decrease postoperative IL-6 concentrations in healthy patients undergoing cardiac surgery, although this has been disputed.^152–153 Dopexamine attenuates the postoperative increase in IL-6 concentrations and reduces gastrointestinal permeability, but does not improve splanchnic perfusion (as measured by intramucosal pH) or decrease plasma endotoxin concentrations, following CPB.^154–155

MANNITOL
Pretreatment of patients with mannitol reduces myocardial formation of cytotoxic free radicals after CPB.¹³⁵ Other free-radical scavengers, antioxidants that appear from animal studies to possess therapeutic potential, include methionine, reduced glutathione, dimethylthiourea, mercaptopropionyl glycine, superoxide dismutase, catalase, and desferrioxamine.^{136,156–159}

CORTICOSTEROIDS
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.^160–162 Methylprednisolone lowers post-CPB concentrations of the proinflammatory cytokines TNF-, IL-6, and IL-8, and increases concentrations of the anti-inflammatory cytokines IL-10 and IL-1ra, but not IL-4.^{103,163–164} Corticosteroids also attenuate post-CPB leukocyte activation, neutrophil adhesion molecule up-regulation, and pulmonary neutrophil sequestration.^103,162,165 Pre-bypass administration of methylprednisolone in aprotinin-treated patients improves early postoperative indices of pulmonary, cardiovascular, hemostatic, and renal function.¹⁶⁶ Glucocorticoid pretreatment may improve cardiac performance and reduce evidence of bronchial inflammation following CPB.^167–168 Low-dose methylprednisolone in the pump prime solution appears to attenuate myocardial cell damage.¹⁶⁹ However, the ability of corticosteroid pretreatment to attenuate post-CPB pulmonary inflammation, endotoxemia, and complement activation is disputed.^{161,165,170–171} 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.¹⁷² 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.

COMPLEMENT-DIRECTED THERAPIES
Therapies that utilize endogenous soluble complement inhibitors may be a suitable approach to reducing contact activation and thereby control the inflammatory response. A recent two-stage randomized clinical trial of a monoclonal antibody specific for human C5 demonstrated its efficacy and safety in patients undergoing CPB.¹⁷³ The generation of activated complement mediators and leukocyte adhesion molecule formation was inhibited in a dose-dependent manner. Furthermore, C5 inhibition resulted in a dose-dependent reduction in myocardial injury, postoperative cognitive deficits, and coagulation dysfunction. These data suggest that C5 inhibition may represent a promising therapeutic modality for preventing complement-mediated inflammation and tissue injury in patients undergoing CPB.¹⁷³ Compstatin, a recently discovered peptide inhibitor of complement, may have the potential to prevent complement activation during and after cardiac surgery. In preliminary primate studies, compstatin completely inhibited in vivo heparin-protamine-induced complement activation, without adverse effects.¹⁷⁴ Other promising strategies include the C1 inhibitor, recombinant soluble inhibitor-1, monoclonal antibodies to C3 and C5a, and strategies that attenuate complement receptor 3-mediated adhesion of inflammatory cells to the vascular endothelium. Utilization of membrane-bound complement regulators may also be feasible by means of transfection techniques.¹⁷⁵

THERAPIES TO INHIBIT ENDOTHELIAL CELL ACTIVATION
Current evidence suggests that therapeutic efforts in patients with SIRS should include modulation of endothelial cell function. Improved definition of the molecular mechanisms of endothelial cell activation may facilitate development of therapies that allow selective inhibition of vascular endothelial activation. Adhesion molecule blockade may prevent neutrophil adherence during the first 24 hours after CPB, thereby preventing the neutrophils from mediating widespread organ damage. In this regard, blockade of endothelial and neutrophil selectin adhesion molecules resulted in marked attenuation of cerebral injury in an animal model of CPB and deep-hypothermic circulatory arrest.¹⁷⁶ Inhibition of neutrophil adhesion markedly reduced pulmonary injury in a porcine model of CPB.¹⁷⁷ However, there may be limits to this approach because adhesion molecule blockade increases susceptibility to infection.¹⁷⁸ Finally, methods to prevent nuclear localization of the transcriptional activator nuclear factor-kappa B, in order to prevent endothelial cell activation, are also being studied in animal models.¹⁷⁹

CYCLOOXYGENASE INHIBITORS
Aspirin, the prototype nonsteroidal anti-inflammatory drug (NSAID), is widely used in cardiac surgical patients for the purposes of pain relief and antiplatelet activity. However, the potential for NSAIDs to attenuate the inflammatory response to cardiac surgery has not been widely evaluated in clinical trials. Traditional NSAIDs, such as indomethacin, inhibit both the constitutive cyclooxygenase 1 (COX-1) as well as COX-2, the inducible isoform activated by inflammatory stimuli. Nonspecific COX inhibition attenuates the increase in pulmonary vascular resistance and acute lung injury and reverses pulmonary microvascular dysfunction in CPB models.^180–181 The only published clinical study of indomethacin demonstrated that it decreased the duration of postoperative fever, chest pain, malaise, and myalgias following CPB.¹⁸² However, inhibition of COX-1 appears to increase free-radical-generated isoprostane formation, which aggravates post-ischemic myocardial dysfunction.^183–184

Specific COX-2 inhibitors exhibit considerable potential to attenuate the inflammatory response following cardiac surgery. COX-2 has been implicated in the pathogenesis of adverse events after cardiac surgery.^185–186 COX-2 is up-regulated in multiple tissues following CPB, including the brain, while COX-2 products, particularly thromboxanes and vasoconstrictor prostaglandins, are increased.^{182,185–187} COX-2 up-regulation following experimental CPB may contribute to postoperative coronary vasospasm and increased pulmonary vascular resistance.^185,188 In addition, myocardial COX-2 is up-regulated during cardiac allograft rejection and myocardial infarction and contributes to endotoxin-induced myocardial depression.^189–191 Inhibition of COX-2 attenuates the myocardial inflammatory response during cardiac allograft rejection, reduces endothelial dysfunction following myocardial ischemia and reperfusion, and improves cardiac function in experimental myocardial infarction.^{189–190,192} In addition, COX-2 inhibition decreases endotoxin-induced myocardial depression and lung ischemia and reperfusion injury.^191,193 However, the clinical efficacy of specific COX-2 inhibitors in attenuating the inflammatory response to cardiac surgery remains to be determined.

	STRATEGIES TO REDUCE ENDOTOXEMIA

TOP ABSTRACT INTRODUCTION PATHOGENESIS OF THE SYSTEMIC... NOVEL CARDIAC SURGICAL... STRATEGIES TO IMPROVE... FILTRATION TECHNIQUES PHARMACOLOGIC STRATEGIES STRATEGIES TO REDUCE ENDOTOXEMIA CONCLUSION REFERENCES

 
ANTIENDOTOXIN AND ANTIMEDIATOR THERAPIES
Direct antimediator therapies that focus on the endotoxin molecule itself and the proinflammatory cytokine cascade following CPB offer new approaches. A recently published small randomized controlled trial of IgM-enriched intravenous immunoglobulin preparation showed it to be effective when used prophylactically in patients undergoing procedures with CPB.¹⁹⁴ However, the complex pathway observed in patients with SIRS does not appear to respond readily to antimediator therapy. Multicenter clinical trials blocking endotoxin and proinflammatory mediators such as IL-1 or TNF- conducted in SIRS patients have shown no benefit in reducing mortality secondary to sepsis.¹⁹⁵ Reasons for the relative failure of immunomodulatory therapies to date may include the timing of intervention, the heterogeneous nature of the inflammatory response, and the reciprocating and redundant nature of the proinflammatory cascades. High circulating concentrations of anti-inflammatory mediators, such as the cytokine antagonists IL-1ra, TNFsr1, and TNFsr2, may also limit the efficacy of therapies that aim to augment natural defenses against endotoxin or the proinflammatory cytokines.¹⁹⁶

SELECTIVE DIGESTIVE DECONTAMINATION
Selective digestive decontamination (SDD) is a technique to reduce the gut content of enterobacteria. This is achieved by preoperative administration of oral nonabsorbable antibiotics such as polymyxin E, tobramycin, and amphotericin B, and has been demonstrated to reduce plasma concentrations of endotoxin, TNF-, and IL-6 in patients undergoing CPB.¹⁹⁷ A recent meta-analysis of SDD suggests that it reduces rates of postoperative infection, but not mortality, in patients undergoing cardiac surgery.¹⁹⁸ Since mortality reduction with SDD in critically ill patients appears to be related to baseline mortality risk, trials of SDD in cardiac surgery thus far contain too many low-risk patients, resulting in inadequate study power. In high-risk cardiac surgical patients, SDD may prove worthwhile, but since its use raises both practical issues (notably the logistics of performing it) and theoretical concerns (changes in bacterial flora, emergence of resistance), its adoption is unlikely pending further studies.^198–199

ENTERAL NUTRITION AND IMMUNONUTRITION
Hypoalbuminemia and low body mass index independently predict increased morbidity and mortality after cardiac operations.²⁰⁰ In an early study, well-nourished patients undergoing valve surgery had a much shorter hospital stay compared to those with preoperative malnutrition.²⁰¹ Laboratory evidence in animals suggests that protein-calorie malnutrition decreases left ventricular function, and that myocardial glycogen concentration correlates with left ventricular function following CPB.^202–203 The beneficial role of early institution of enteral nutrition, particularly immunonutrition that contains supplements such as arginine, purine nucleotides, and omega-3 fatty acids, which are considered to enhance immune function, has been established in other groups of postoperative and critically ill patients. In critically ill patients, immunonutrition reduced the duration of ICU and hospital stay, infectious complications, duration of SIRS, and mechanical ventilation, compared to patients receiving conventional nutrition.²⁰⁴ In patients scheduled for elective gastrointestinal surgery, preoperative and postoperative immunonutrition had beneficial effects on immune function, complication rate, and duration of hospital stay.^205–206 The use of glutamine supplementation may improve the survival of patients with organ failure who require parenteral nutrition.²⁰⁷ There is no information available concerning the effect of nutritional support in patients undergoing cardiac surgery who have a complicated postoperative course.

	CONCLUSION

TOP ABSTRACT INTRODUCTION PATHOGENESIS OF THE SYSTEMIC... NOVEL CARDIAC SURGICAL... STRATEGIES TO IMPROVE... FILTRATION TECHNIQUES PHARMACOLOGIC STRATEGIES STRATEGIES TO REDUCE ENDOTOXEMIA CONCLUSION REFERENCES

 
The therapeutic potential of strategies to control the systemic inflammatory response after cardiac surgery is clear. However, the optimal therapeutic strategy (or strategies), and the optimal target subgroup of cardiac surgical patients, remains to be fully elucidated. Our goal must be to attenuate the deleterious effects of the systemic inflammatory response while preserving the ability of the patient to mount an appropriate defense to the physiologic trespasses of the perioperative period. Modulation of the stress response, rather than simple inhibition, is likely to confer substantial benefit. Furthermore, therapeutic strategies should be focused on the subset of cardiac surgical patients most likely to suffer deleterious consequences, and hence most likely to experience benefit. This subgroup of high-risk patients is increasingly well characterized. Large-scale clinical trials of the more promising therapeutic strategies, restricted to the patient group at significant risk of perioperative morbidity, are urgently needed.

	REFERENCES

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