S Raja, G Dreyfus
antioxidants, aprotinin, cardiopulmonary bypass, cytokine, systemic inflammatory response
S Raja, G Dreyfus. Pharmacologic Manipulation of Systemic Inflammatory Response after Cardiac Surgery. The Internet Journal of Thoracic and Cardiovascular Surgery. 2003 Volume 6 Number 2.
Cardiac surgery and cardiopulmonary bypass (CPB) activate a systemic inflammatory response characterized clinically by alterations in organ system function. Although significant morbidity is rare (approximately 1%-2% of cases) yet most patients undergoing CPB experience some degree of organ dysfunction as a result of activation of the inflammatory response. Various strategies have been developed aiming to reduce systemic inflammatory response and its deleterious effects on organ function after cardiac surgery. This article presents a review of pharmacologic manipulation of systemic inflammatory response after cardiac surgery.
Inflammation is a protective response of vascularized tissue that functions as part of normal host surveillance mechanisms to destroy or quarantine both harmful agents and damaged tissue.1,2,3 The hallmark of an inflammatory response is the complex humoral and cellular interaction with numerous pathways contributing to inflammation including activation, generation, or expression of thrombin, complement, cytokines, neutrophils, adhesion molecules, and multiple inflammatory mediators.4,5 Because of the redundancy of the inflammatory cascades, profound amplification occurs to produce multiorgan system dysfunction. Clinically we may see these inflammatory manifestations as coagulopathy, respiratory failure, myocardial dysfunction, renal insufficiency, and neurocognitive defects.6 Further, the inflammatory response that occurs during cardiopulmonary bypass (CPB) has been often referred to as a systemic inflammatory response syndrome (SIRS) similar to sepsis.7
Pharmacologic Strategies to Modulate the Inflammatory Response
The development of strategies to control the inflammatory response following cardiac surgery is currently the focus of considerable research efforts. Diverse techniques, including pharmacologic and immunomodulatory agents, maintainence of hemodynamic stability and minimization of exposure to CPB circuitry have been examined in clinical studies. This review discusses the role of pharmacologic agents in reducing or preventing inflammatory response after cardiac surgery.
Many effector proteins of the cytokine, complement, and hemostatic cascades are serine proteases,
Aprotinin, a complex polypeptide and nonspecific serine protease inhibitor, has clearly been demonstrated to prevent excessive blood loss during cardiac surgery.8 In addition, aprotinin has multiple actions that may suppress the inflammatory response, particularly at higher dosages. Antiinflammatory effects include attenuation of platelet activation, maintenance of platelet function,9 decreased complement activation,9 inhibition of kallikrein production,9 decreased release of TNFα,10 IL-6, and IL-8,11 inhibition of endogenous cytokine-induced iNOS induction,12 decreased CPB-induced leukocyte activation,9,13 and inhibition of up-regulation of monocyte and granulocyte adhesion molecules.14,15
In clinical studies, high-dose aprotinin reduces postbypass myocardial ischemia and myocyte damage16 and length of hospital stay in high-risk patients.17 However, a pump-prime-only dose of aprotinin may increase the risk of postoperative myocardial infarction.18 Levy et al found no such increase in the incidence of perioperative myocardial infarction in patients undergoing repeat CABG.19 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 grafts20 or for saphenous vein grafts after controlling for confounding factors.21
Aprotinin may reduce pulmonary and cerebral injury following CPB. Aprotinin decreases experimental CPB-induced and cytokine-induced bronchial inflammation22 and was demonstrated to attenuate lung reperfusion injury following CPB in one small clinical study.23 An early report of use of aprotinin in high-risk cardiac surgery patients indicated an incidence of fatal stroke of 0.5%, compared to rates of 2–3% in contemporary studies that did not use aprotinin.24,25 A multicenter trial of repeat CABG patients found that the incidence of stroke was reduced with high- or low-dose aprotinin.19 Lemmer et al failed to show a significant decrease in the incidence of stroke with three different dosage regimens in their large-scale multicenter study.18 However, a pooled analysis of six trials, including the aforementioned trials, found that high-dose aprotinin significantly reduced the incidence of stroke.26 Initial concerns over the potential for adverse effects of aprotinin on renal function appear unfounded.18 No single study of aprotinin has clearly demonstrated improved patient outcome to date.18,19 However, a recent metaanalysis reported that aprotinin reduces surgical blood loss, allogeneic blood transfusion, and the need for rethoracotomy, and decreases perioperative mortality almost twofold, with no increase in the risk of myocardial infarction.8 These data provides strong support for the use of aprotinin in patients undergoing cardiac surgery.
Pentoxifylline is a nonspecific phosphodiesterase inhibitor with diverse antiinflammatory effects, many of which may be mediated by inhibition of phosphodiesterase IV.27 These include attenuation of TNFα release in sepsis,28,29 decreased endotoxin and cytokine activation of neutrophils,30 reduction of indices of endothelial injury and permeability,31 decreased pulmonary leukocyte sequestration, and attenuation of increases in pulmonary vascular resistance.32 Clinical studies to date have been limited. In one study, pentoxifylline decreased the duration of ventilation and hemofiltration and the incidence of MODS when administered postoperatively to selected high-risk cardiac surgical patients33 and may be of therapeutic benefit in human sepsis.34 However, pentoxifylline treatment did not improve postoperative renal35 or pulmonary36 function in other small clinical studies. Most 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.37 In a parallel study, the same investigators reported improved splanchnic perfusion and hepatic–renal function with pentoxifylline.38
Free Radical Scavengers and Antioxidants
Generation of reactive oxygen species (ROS) (hydrogen peroxide and the superoxide and hydroxyl radicals) occurs upon reperfusion following bypass,39 and these may be important contributors to tissue injury. Leukocytes activated during bypass may also release substantial amounts of cytotoxic ROS.40,41 When present in equimolar concentrations, superoxide and NO may combine form peroxynitrite, a more reactive and injurious free radical.42,43 Myocardial antioxidant enzymes, including glutathione reductase, superoxide dismutase, and catalase, are activated in proportion to the degree of myocardial ischemia and reperfusion injury.44 Host antioxidants become depleted after CPB,45,46 presumably as a result of consumption by free radicals. When ROS production exceeds host defense scavenging capacity, cellular injury results.39,47 There is an inverse correlation between preoperative total plasma antioxidant status and lipid peroxidation, the latter of which is directly correlated with indices of myocardial cellular injury.46 Furthermore, post-CPB coronary endothelial dysfunction appears to be partially mediated by ROS.48 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 (ascorbic acid) has been demonstrated to effectively scavenge free radicals, decreasing cell membrane lipid peroxidation39,49 and indices of myocardial injury, and improving hemodynamics with a shorter ICU and hospital stay.49 Vitamin E (α-tocopherol) reduces plasma concentrations of hydrogen peroxide, a marker of free radical concentrations,50 and decreases cell membrane lipid peroxidation39 following CPB. Preoperative supplementation with a combination of ascorbic acid, α-tocopherol, and allopurinol reduced cardiovascular dysfunction in both stable and unstable patients undergoing CABG. Unstable CABG patients sustained less myocardial injury and a decreased incidence of perioperative myocardial infarction.51 A more recent trial of combined α-tocopherol and ascorbic acid supplementation in CABG surgery revealed no detectable decrease in myocardial injury.52
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,47,56 lower markers of myocardial cellular injury,57 and improve recovery of myocardial function following CPB.58,59 However, other studies have demonstrated no improvement in either myocardial function60 or myocardial cellular injury with allopurinol use,56,61 casting doubt on its therapeutic potential.
Pretreatment of patients with mannitol reduces myocardial formation of cytotoxic free radicals after CPB in humans.47 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.48,62,63,64,65
Aspirin, the prototype nonsteroidal antiinflammatory 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 (ALI)66 and reverses pulmonary microvascular dysfunction in CPB models.67 One older clinical study of indomethacin demonstrated that it decreased the duration of postoperative fever, chest pain, malaise, and myalgias following CPB.68 However, inhibition of COX-1 appears to increase free radical-generated isoprostane formation, which aggravates postischemic myocardial dysfunction.69,70
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.71,72 COX-2 is up-regulated following CPB,71 in multiple tissues, including the brain,72 while COX-2 products, particularly thromboxanes73 and vasoconstrictor prostaglandins, are increased.67 COX-2 up-regulation following experimental CPB may contribute to postoperative coronary vasospasm71 and increased pulmonary vascular resistance.74 In addition, myocardial COX-2 is up-regulated during cardiac allograft rejection75 and myocardial infarction76 and contributes to endotoxin-induced myocardial depression.77 Inhibition of COX-2 attenuates the myocardial inflammatory response during cardiac allograft rejection,75 reduces endothelial dysfunction following myocardial ischemia and reperfusion,78 and improves cardiac function in experimental myocardial infarction.76 In addition, COX-2 inhibition decreases endotoxin-induced myocardial depression77 and lung ischemia and reperfusion injury.79 However, the clinical efficacy of specific COX-2 inhibitors in attenuating the inflammatory response to cardiac surgery remains to be determined.
The use of corticosteroids in the context of CPB continues to be controversial because of their potential risks. Past negative experience, particularly with the use of corticosteroids in septic shock,80 has served to emphasize the need for caution when considering corticosteroid use, even in noninfective inflammatory conditions, where their potent antiinflammatory actions might be expected to be beneficial. However, there have been significant advances in the understanding of the molecular mechanisms by which corticosteroids might blunt the inflammatory response to cardiac surgery.
Corticosteroid pretreatment may blunt the inflammatory response in humans by several distinct mechanisms. Administration of glucocorticoids prior to CPB may attenuate endotoxin release81 and complement activation.82,83 Methylprednisolone lowers post-CPB concentrations of the proinflammatory cytokines TNFα,10 IL-6, and IL-8,84 and increases concentrations of the antiinflammatory cytokines IL-10 and IL-1ra,84 but not IL-4.85 Corticosteroids also attenuate post-CPB leukocyte activation,86 neutrophil adhesion molecule up-regulation,10 and pulmonary neutrophil sequestration.83 Prebypass administration of methylprednisolone in aprotinin-treated patients improves early postoperative indices of pulmonary, cardiovascular, hemostatic, and renal function.87 Glucocorticoid pretreatment may improve cardiac performance88 and reduce evidence of bronchial inflammation following CPB.89 Low-dose methylprednisolone in the pump prime solution appears to attenuate myocardial cell damage.90 Dexamethasone91,92and methylprednisolone68,93decrease the incidence of postoperative fever. In animal studies, corticosteroid pretreatment improved several indices of lung injury, including pulmonary compliance, alveolar– arterial gradient, pulmonary vascular resistance, and extracellular fluid accumulation.94 However, the ability of corticosteroid pretreatment to attenuate post-CPB pulmonary inflammation,95 endotoxemia,83 and complement activation is disputed.86,96
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 prebypass administration may be superior to prebypass administration alone.94 It is premature to advocate the use of corticosteroids in the absence of proven outcome benefit, determination of optimal dosage regimens, and characterization of harmful effects,
Therapies that utilize endogenous soluble complement inhibitors may be a suitable approach to reduce 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.97 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.97 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
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.99
Endotoxin-blocking & antimediator Therapies
Direct antimediator therapies that focus upon the endotoxin molecule itself and the proinflammatory cytokine cascade following CPB offer new approaches. However, the complex pathway observed in patients with SIRS does not appear to readily respond to antimediator therapy. Multicenter clinical trials blocking endotoxin and proinflammatory mediators such as IL-1 or TNF-α conducted in SIRS patients have shown no benefit in reducing mortality secondary to sepsis. 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 antiinflammatory 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.100
The experience with antimediator therapy in sepsis suggests a need for caution in considering the application of these therapies to control the inflammatory response to CPB. Nevertheless, antimediator therapies may be worthy of investigation for two reasons. These therapies may enhance our understanding of the inflammatory process following CPB. Their administration prior to bypass, in order to modulate the inflammatory pathways at their earliest stages, might constitute a more successful approach than that used in other clinical scenarios, such as in sepsis, where the inflammatory response may be already well developed before antimediator therapy is possible.
Selective Inhibitors of Endothelial Cell Activation
Current evidence suggests that therapeutic efforts in patients with SIRS should include modulation of endothelial cell function. Better 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 h after CPB, thereby preventing the neutrophils from mediating widespread organ damage. In this regard, blockade of endothelial and neutrophil selectin adhesion molecules results in marked attenuation of cerebral injury in an animal model of CPB and deep hypothermic circulatory arrest.101 Inhibition of neutrophil adhesion markedly reduced pulmonary injury in a porcine model of CPB.102 However, there may be limits to this approach because adhesion molecule blockade increases susceptibility to infection.103 Finally, methods to prevent nuclear localization of the transcriptional activator NF-κB in order to prevent endothelial cell activation are also being studied in animal models.104
Although our understanding of the basic pathophysiology of systemic inflammatory response to CPB has significantly advanced in the last 2 decades, these experimentally derived ideas have yet to be fully integrated into clinical practice. Treatment of the systemic inflammatory response to CPB is also confounded by the fact that inhibition of inflammation might disrupt protective physiologic responses or result in immunosuppression. It is unlikely that a single therapeutic strategy will ever be sufficient in itself to totally prevent CPB-associated morbidity. However, the combination of multiple pharmacologic and mechanical therapeutic strategies, each selectively targeted at different components of the inflammatory response, may eventually result in significantly improved clinical outcomes following cardiac surgery.
Dr. Shahzad G. Raja, MRCS Department of Paediatric Cardiac Surgery Alder Hey Children's Hospital Liverpool L12 2AP United Kingdom Fax: +44(0)151 252 5643 Tel: +44(0)151 252 5635 Email: firstname.lastname@example.org