Original Article

Pharmacologic Manipulation of Systemic Inflammatory Response after Cardiac Surgery

S Raja, G Dreyfus

Keywords

antioxidants, aprotinin, cardiopulmonary bypass, cytokine, systemic inflammatory response

Citation

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.

Abstract

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.

 

Introduction

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.

Aprotinin

Many effector proteins of the cytokine, complement, and hemostatic cascades are serine proteases, i.e., 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 studied of these inhibitors.

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

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 & vitamin E

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

N-acetylcysteine

High-dose N-acetylcysteine before or during bypass appears to act as a free radical scavenger53 and reduces the neutrophil oxidative burst response53 and elastase activity.54 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.55

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,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.

Mannitol

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

Cyclooxygenase Inhibitors

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.

Corticosteroids

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, e.g., immunosuppression, which may result from their use.

Complement-directed Therapies

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 in vivo heparin-protamine-induced complement activation without adverse effects.98

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

Conclusion

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.

Correspondence to

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: drrajashahzad@hotmail.com

References

1. Delves PJ, Roitt IM. Advances in immunology: the immune system. N Engl J Med 2000;343(Parts 1 and 2):37-49,108-17
2. Kay AB. Advances in immunology: allergy and allergic diseases. N Engl J Med 2001;344:30-37.
3. Marcus AJ. Thrombosis and inflammation as multicellular processes: significance of cell-cell interactions. Semin Hematol 1994;31:261-269.
4. Walport MJ. Advances in immunology: complement-first of two parts. N Engl J Med 2001;344:1058-1066.
5. Walport MJ. Advances in immunology: complement-second of two parts. N Engl J Med 2001;344:1140-1144.
6. Warltier DC, Laffey JG, Boylan JF, Cheng DC. The systemic inflammatory response to cardiac surgery: implications for the anesthesiologist. Anesthesiology 2002;97:215-252.
7. Levy JH, Tanaka KA. Inflammatory response to cardiopulmonary bypass. Ann Thorac Surg 2003;75:S715-20.
8. Levi M, Cromheecke ME, de Jonge E, Prins MH, de Mol BJ, Briet E, Buller HR. Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints. Lancet 1999;354:1940-7.
9. Wachtfogel YT, Kucich U, Hack CE, Gluszko P, Niewiarowski S, Colman RW, Edmunds LHJ. Aprotinin inhibits the contact, neutrophil, and platelet activation systems during simulated extracorporeal perfusion. J Thorac Cardiovasc Surg 1993;106:1-9.
10. Hill GE, Alonso A, Spurzem JR, Stammers AH, Robbins RA. Aprotinin and methylprednisolone equally blunt cardiopulmonary bypass induced inflammation in humans. J Thorac Cardiovasc Surg 1995;110:1658-62.
11. Harig F, Feyrer R, Mahmoud FO, Blum U, von der Emde J: Reducing the post pump syndrome by using heparin-coated circuits, steroids, or aprotinin. Thorac Cardiovasc Surg 1999; 47:111-8.
12. Hill GE, Robbins RA. Aprotinin but not tranexamic acid inhibits cytokine-induced inducible nitric oxide synthase expression. Anesth Analg 1997; 84: 1198-202.
13. Soeparwata R, Hartman AR, Frerichmann U, Stefano GB, Scheld HH, Bilfinger TV. Aprotinin diminishes inflammatory processes. Int J Cardiol 1996;26: S55-63.
14. Gilliland HE, Armstrong MA, Uprichard S, Clarke G, McMurray TJ. The effect of aprotinin on interleukin-8 concentration and leukocyte adhesion molecule expression in an isolated cardiopulmonary bypass system. Anaesthesia 1999;54:427-33.
15. Alonso A, Whitten CW, Hill GE. Pump prime only aprotinin inhibits cardiopulmonary bypass-induced neutrophil CD11b up-regulation. Ann Thorac Surg 1999; 67: 392-5.
16. Wendel HP, Heller W, Michel J, Mayer G, Ochsenfahrt C, Graeter U, Schulze J, Hoffmeister HM, Hoffmeister HE. Lower cardiac troponin T levels in patients undergoing cardiopulmonary bypass and receiving high-dose aprotinin therapy indicate reduction of perioperative myocardial damage. J Thorac Cardiovasc Surg 1995;109:1164-72.
17. Gott JP, Cooper WA, Schmidt FEJ, Brown WMr, Wright CE, Merlino JD, Fortenberry JD, Clark WS, Guyton RA. Modifying risk for extracorporeal circulation: trial of four antiinflammatory strategies. Ann Thorac Surg 1998;66:747-53.
18. Lemmer JHJ, Dilling EW, Morton JR, Rich JB, Robicsek F, Bricker DL, Hantler CB, Copeland JGR, Ochsner JL, Daily PO, Whitten CW, Noon GP, Maddi R. Aprotinin for primary coronary artery bypass grafting: A multicenter trial of three dose regimens. Ann Thorac Surg 1996;62:1659-67.
19. Levy JH, Pifarre R, Schaff HV, Horrow JC, Albus R, Spiess B, Rosengart TK, Murray J, Clark RE, Smith P. A multicenter, double-blind, placebo-controlled trial of aprotinin for reducing blood loss and the requirement for donor-blood transfusion in patients undergoing repeat coronary artery bypass grafting. Circulation 1995; 92: 2236-44.
20. Rich JB: The efficacy and safety of aprotinin use in cardiac surgery. Ann Thorac Surg 1998;66:S6-11.
21. Alderman EL, Levy JH, Rich JB, Nili M, Vidne B, Schaff H, Uretzky G, Pettersson G, Thiis JJ, Hantler CB, Chaitman B, Nadel A. Analyses of coronary graft patency after aprotinin use: results from the International Multicenter Aprotinin Graft Patency Experience (IMAGE) trial. J Thorac Cardiovasc Surg 1998;116:716-30.
22. Bruda NL, Hurlbert BJ, Hill GE. Aprotinin reduces nitric oxide production in vitro and in vivo in a dose dependent manner. Clin Sci (Colch) 1998;94:505-9.
23. Rahman A, Ustunda B, Burma O, Ozercan IH, Cekirdekci A, Bayar MK. Does aprotinin reduce lung reperfusion damage after cardiopulmonary bypass? Eur J Cardiothorac Surg 2000;18:583-8.
24. Bidstrup BP, Harrison J, Royston D, Taylor KM, Treasure T. Aprotinin therapy in cardiac operations: A report on use in 41 cardiac centers in the United Kingdom. Ann Thorac Surg 1993; 55: 971-6.
25. Royston D: Aprotinin versus lysine analogues. The debate continues. Ann Thorac Surg 1998; 65:S9-19.
26. Smith PK, Muhlbaier LH. Aprotinin: Safe and effective only with the full-dose regimen. Ann Thorac Surg 1996;62:1575-7.
27. Badger AM, DL O, Esser KM. Beneficial effects of the phosphodiesterase inhibitors BRL 61063, pentoxifylline, and rolipram in a murine model of endotoxin shock. Circ Shock 1994;44:188-95.
28. Doherty GM, Jensen JC, Alexander HR, Buresh CM, Norton JA. Pentoxifylline suppression of tumour necrosis factor gene transcription. Surgery 1991; 110: 192-8.
29. Schade UF. Pentoxifilline increases survival in murine endotoxin shock and decreases formation of tumour necrosis factor. Circ Shock 1990;31:171-81.
30. Sullivan GW, Carper HT, Novick WJJ, Mandell GL. Inhibition of the inflammatory action of interleukin-1 and tumour necrosis factor (alpha) on neutrophil function by pentoxifylline. Infect Immun 1988; 56: 1722-9.
31. Tsang GM, Allen S, Pagano D, Wong C, Graham TR, Bonser RS. Pentoxifylline preloading reduces endothelial injury and permeability in cardiopulmonary bypass. ASAIO J 1996; 42: M429-34.
32. Turkoz R, Yorukoglu K, Akcay A, Yilik L, Baltalarli A, Karahan N, Adanir T, Sagban M. The effect of pentoxifylline on the lung during cardiopulmonary bypass. Eur J Cardiothorac Surg 1996; 10: 339-46.
33. Hoffmann H, Markewitz A, Kreuzer E, Reichert K, Jochum M, Faist E. Pentoxifylline decreases the incidence of multiple organ failure in patients after major cardio-thoracic surgery. Shock 1998;9:235-40.
34. Lauterbach R, Pawlik D, Kowalczyk D, Ksycinski W, Helwich E, Zembala M. Effect of the immunomodulating agent, pentoxifylline, in the treatment of sepsis in prematurely delivered infants: A placebo-controlled, double-blind trial. Crit Care Med 1999;27:807-14.
35. Kleinschmidt S, Bauer M, Grundmann U, Schneider A, Wagner B, Graeter T.Effect of gamma-hydroxybutyric acid and pentoxyfylline on kidney function parameters in coronary surgery interventions. Anaesthesiol Reanim 1997;22:102-7.
36. Butler J, Baigrie RJ, Parker D, Chong JL, Shale DJ, Pillai R, Westaby S, Rocker GM. Systemic inflammatory responses to cardiopulmonary bypass: A pilot study of the effects of pentoxifylline. Respir Med 1993;87:285-8.
37. Boldt J, Brosch C, Lehmann A, Haisch G, Lang J, Isgro F: Prophylactic use of pentoxifylline on inflammation in elderly cardiac surgery patients. Ann Thorac Surg 2001;71:1524-9.
38. Boldt J, Brosch C, Piper SN, Suttner S, Lehmann A, Werling C: Influence of prophylactic use of pentoxifylline on postoperative organ function in elderly cardiac surgery patients. Crit Care Med 2001;29: 952-8.
39. Barta E, Pechan I, Cornak V, Luknarova O, Rendekova V, Verchovodko P. Protective effect of alpha-tocopherol and L-ascorbic acid against the ischemic-reperfusion injury in patients during open-heart surgery. Bratisl Lek Listy 1991;92:174-83.
40. Tonz M, Mihaljevic T, von Segesser LK, Fehr J, Schmid ER, Turina MI. Acute lung injury during cardiopulmonary bypass: Are the neutrophils responsible? Chest 1995;108:1551-6 97.
41. Kharazmi A, Andersen LW, Baek L, Valerius NH, Laub M, Rasmussen JP. Endotoxemia and enhanced generation of oxygen radicals by neutrophils from patients undergoing cardiopulmonary bypass. J Thorac Cardiovasc Surg 1989; 98: 381-5.
42. Beckman JS, Koppenol WH: Nitric oxide, superoxide, and peroxynitrite. The good, the bad, and ugly. Am J Physiol 1996;271:C1424-37.
43. Salzman AL. Endotoxic notrosopenia. Intens Care Med 1998;24:1239-41.
44. Mezzetti A, Lapenna D, Pierdomenico SD, Di Giammarco G, Bosco G, Di Ilio C, Santarelli P, Calafiore AM, Cuccurullo F. Myocardial antioxidant defenses during cardiopulmonary bypass. J Card Surg 1993;8: 167-71.
45. Ballmer PE, Reinhart WH, Jordan P, Buhler E, Moser UK, Gey KF. Depletion of plasma vitamin C but not of vitamin E in response to cardiac operations. J Thorac Cardiovasc Surg 1994;108:311-20.
46. McColl AJ, Keeble T, Hadjinikolaou L, Cohen A, Aitkenhead H, Glenville B, Richmond W. Plasma antioxidants. Evidence for a protective role against reactive oxygen species following cardiac surgery. Ann Clin Biochem 1998;35:616-23.
47. England MD, Cavarocchi NC, O'Brien JF, Solis E, Pluth JR, Orszulak TA, Kaye MP, Schaff HV. Influence of antioxidants (mannitol and allopurinol) on oxygen free radical generation during and after cardiopulmonary bypass. Circulation 1986;74:III134-7.
48. Sellke FW, Shafique T, Ely DL, Weintraub RM. Coronary endothelial injury after cardiopulmonary bypass and ischemic cardioplegia is mediated by oxygen-derived free radicals. Circulation 1993;88:II395-400.
49. Dingchao H, Zhiduan Q, Liye H, Xiaodong F. The protective effects of high-dose ascorbic acid on myocardium against reperfusion injury during and after cardiopulmonary bypass. Thorac Cardiovasc Surg 1994;42:2768.
50. Cavarocchi NC, England MD, O'Brien JF, Solis E, Russo P, Schaff HV, Orszulak TA, Pluth JR, Kaye MP: Superoxide generation during cardiopulmonary bypass: Is there a role for vitamin E? J Surg Res 1986;40:519-27.
51. Sisto T, Paajanen H, Metsa-Ketela T, Harmoinen A, Nordback I, Tarkka M. Pretreatment with antioxidants and allopurinol diminishes cardiac onset events in coronary artery bypass grafting. Ann Thorac Surg 1995;59:1519-23.
52. Westhuyzen J, Cochrane AD, Tesar PJ, Mau T, Cross DB, Frenneaux MP, Khafagi FA, Fleming SJ. Effect of preoperative supplementation with alpha-tocopherol and ascorbic acid on myocardial injury in patients undergoing cardiac operations. J Thorac Cardiovasc Surg 1997;113:942-8.
53. Andersen LW, Thiis J, Kharazmi A, Rygg I. The role of N-acetylcystein administration on the oxidative response of neutrophils during cardiopulmonary bypass. Perfusion 1995;10:21-6.
54. De Backer WA, Amsel B, Jorens PG, Bossaert L, Hiemstra PS, van Noort P, van Overveld FJ. N-acetylcysteine pretreatment of cardiac surgery patients influences plasma neutrophil elastase and neutrophil influx in bronchoalveolar lavage fluid. Intens Care Med 1996;22:900-8.
55. Suter PM, Domenighetti G, Schaller MD, Laverriere MC, Ritz R, Perret C. N-acetylcysteine enhances recovery from acute lung injury in man: A randomized, double-blind, placebo-controlled clinical study. Chest 1994;105:190-4.
56. Zoran P, Juraj F, Ivana D, Reik H, Dusan N, Mihailo V. Effects of allopurinol on oxygen stress status during open heart surgery. Int J Cardiol 1994; 44:123-9
57. Tabayashi K, Suzuki Y, Nagamine S, Ito Y, Sekino Y, Mohri H. A clinical trial of allopurinol (Zyloric) for myocardial protection. J Thorac Cardiovasc Surg 1991;101:713-8.
58. Castelli P, Condemi AM, Brambillasca C, Fundaro P, Botta M, Lemma M, Vanelli P, Santoli C, Gatti S, Riva E: Improvement of cardiac function by allopurinol in patients undergoing cardiac surgery. J Cardiovasc Pharmacol 1995; 25: 119-25.
59. Bochenek A, Religa Z, Spyt TJ, Mistarz K, Bochenek A, Zembala M, Gryzbek H. Protective influence of pretreatment with allopurinol on myocardial function in patients undergoing coronary artery surgery. Eur J Cardiothorac Surg 1990; 4: 538-42.
60. Coetzee A, Roussouw G, Macgregor L. Failure of allopurinol to improve left ventricular stroke work after cardiopulmonary bypass surgery. J Cardiothorac Vasc Anesth 1996;10:627-33.
61. Taggart DP, Young V, Hooper J, Kemp M, Walesby R, Magee P, Wright JE. Lack of cardioprotective efficacy of allopurinol in coronary artery surgery. Br Heart J 1994;71:177-81.
62. Chambers DJ, Astras G, Takahashi A, Manning AS, Braimbridge MV, Hearse DJ. Free radicals and cardioplegia: Organic anti-oxidants as additives to the St Thomas' Hospital cardioplegic solution. Cardiovasc Res 1989;23:351-8.
63. Morita K, Ihnken K, Buckberg GD, Ignarro LJ. Oxidative insult associated with hyperoxic cardiopulmonary bypass in the infantile heart and lung. Jpn Circ J 1996;60:355-63.
64. Dworkin GH, Abd-Elfattah AS, Yeh TJ, Wechsler AS. Efficacy of recombinant-derived human superoxide dismutase on porcine left ventricular contractility after normothermic global myocardial ischemia and hypothermic cardioplegic arrest. Circulation 1990; 82: IV359-66.
65. Prasad K, Chan WP, Bharadwaj B. Superoxide dismutase and catalase in protection of cardiopulmonary bypass-induced cardiac dysfunction and cellular injury. Can J Cardiol 1996;12:1083-91.
66. Cave AC, Manche A, Derias NW, Hearse DJ. Thromboxane A2 mediates pulmonary hypertension after cardiopulmonary bypass in the rabbit. J Thorac Cardiovasc Surg 1993; 106: 959-67.
67. Shafique T, Johnson RG, Dai HB, Weintraub RM, Sellke FW. Altered pulmonary microvascular reactivity after total cardiopulmonary bypass. J Thorac Cardiovasc Surg 1993;106:479-86.
68. Butler J, Pathi VL, Paton RD, Logan RW, MacArthur KJ, Jamieson MP, Pollock JC. Acute-phase responses to cardiopulmonary bypass in children weighing less than 10 kilograms. Ann Thorac Surg 1996;62:538-42.
69. Heindl B, Becker BF. Aspirin, but not the more selective cyclooxygenase (COX)-2 inhibitors meloxicam and SC 58125, aggravates postischaemic cardiac dysfunction, independent of COX function. Naunyn Schmiedebergs Arch Pharmacol 2001;363:233-40.
70. Mobert J, Becker BF. Cyclooxygenase inhibition aggravates ischemia-reperfusion injury in the perfused guinea pig heart: Involvement of isoprostanes. J Am Coll Cardiol 1998;31:1687-94.
71. Metais C, Li J, Simons M, Sellke FW. Serotonin-induced coronary contraction increases after blood cardioplegia-reperfusion: Role of COX-2 expression. Circulation 1999;100:II328-34.
72. Hindman BJ, Moore SA, Cutkomp J, Smith T, Ross-Barta SE, Dexter F, Brian JE Jr. Brain expression of inducible cyclooxygenase 2 messenger RNA in rats undergoing cardiopulmonary bypass. A nesthesiology 2001; 95: 1380-8.
73. Erez E, Erman A, Snir E, Raanani E, Abramov D, Sulkes J, Boner G, Vidne BA. Thromboxane production in human lung during cardiopulmonary bypass: Beneficial effect of aspirin? Ann Thorac Surg 1998;65:101-6
74. Sato K, Li J, Metais C, Bianchi C, Sellke F. Increased pulmonary vascular contraction to serotonin after cardiopulmonary bypass: Role of cyclooxygenase. J Surg Res 2000;90:138-43.
75. Yang X, Ma N, Szabolcs MJ, Zhong J, Athan E, Sciacca RR, Michler RE, Anderson GD, Wiese JF, Leahy KM, Gregory S, Cannon PJ. Upregulation of COX-2 during cardiac allograft rejection. Circulation 2000;101:430-8.
76. Saito T, Rodger IW, Hu F, Shennib H, Giaid A: Inhibition of cyclooxygenase-2 improves cardiac function in myocardial infarction. Biochem Biophys Res Commun 2000;273:772-5.
77. Grandel U, Fink L, Blum A, Heep M, Buerke M, Kraemer HJ, Mayer K, Bohle RM, Seeger W, Grimminger F, Sibelius U. Endotoxin-induced myocardial tumor necrosis factor-alpha synthesis depresses contractility of isolated rat hearts: Evidence for a role of sphingosine and cyclooxygenase-2-derived thromboxane production. Circulation 2000; 102:2758-64.
78. Bouchard JF, Lamontagne D. Mechanisms of protection afforded by cyclooxygenase inhibitors to endothelial function against ischemic injury in rat isolated hearts. J Cardiovasc Pharmacol 1999;34:755-63.
79. Sunose Y, Takeyoshi I, Tsutsumi H, Kawata K, Tokumine M, Iwazaki S, Tomizawa N, Ohwada S, Matsumoto K, Morishita Y. Effects of FK3311 on pulmonary ischemia-reperfusion injury in a canine model. J Surg Res 2001;95:167-73.
80. Sprung CL, Caralais PV, Marcial EH, Pierce M, Gelbard MA, Long WM, Duncan RC, Tendler MD, Karpf M. The effects of high dose corticosteroids in patients with septic shock. N Engl J Med 1984;311:1137-43.
81. Wan S, LeClerc JL, Huynh CH, Schmartz D, DeSmet JM, Yim AP, Vincent JL. Does steroid pretreatment increase endotoxin release during clinical cardiopulmonary bypass. J Thorac Cardiovasc Surg 1999;117:1004-8.
82. Andersen LW, Baek L, Thompsen BS, Rasmussen JP. The effect of methylprednisolone on endotoxemia and complement activation during cardiac surgery. J Cardiothorac Anesth 1989;3:544-9.
83. Dernek S, Tunerir B, Sevin B, Aslan R, Uyguc O, Kural T. The effects of methylprednisolone on complement, immunoglobulins and pulmonary neutrophil sequestration during cardiopulmonary bypass. Cardiovasc Surg 1999;7:414-8.
84. Kawamura T, Inada K, Nara N, Wakusawa R, Endo S. Influence of methylprednisolone on cytokine balance during cardiac surgery. Crit Care Med 1999;27:545-8.
85. Wan S, LeClerc JL, Schmartz D, Barvais L, Huynh CH, Deviere J, DeSmet JM, Vincent JL. Hepatic release of interleukin-10 during cardiopulmonmary bypass in steroid treated patients. Am Heart J 1997;133: 335-9.
86. Jansen NJ, van Oeveren W, van Vliet M, Stoutenbeek CP, Eysman L, Wildevuur CR: The role of different types of corticosteroids on the inflammatory mediators in cardiopulmonary bypass. Eur J Cardiothorac Surg 1991;5:211-7.
87. Tassani P, Richter JA, Barankay A, Braun SL, Haehnel C, Spaeth P, Schad H, Meisner H. Does high-dose methylprednisolone in aprotinin-treated patients attenuate the systemic inflammatory response during coronary artery bypass grafting procedures? J Cardiothorac Vasc Anesth 1999;13:165-72.
88. Kawamura T, Inada K, Okada H, Okada K, Wakusawa R. Methylprednisolone inhibits increase of interleukin 8 and 6 during open heart surgery. Can J Anaesth 1995;42:399-403.
89. Hill GE, Snider S, Galbraith TA, Forst S, Robbins RA. Glucocorticoid reduction of bronchial epithelial inflammation during cardiopulmonary bypass. Am J Resp Crit Care Med 1995;152: 1791-5.
90. Yilmaz M, Ener S, Akalin H, Sagdic K, Serdar OA, Cengiz M. Effect of low-dose methyl prednisolone on serum cytokine levels following extracorporeal circulation. Perfusion 1999; 14: 201-6.
91. Yared JP, Starr NJ, Hoffmann-Hogg L, Bashour CA, Insler SR, O'Connor M, Piedmonte M, Cosgrove DM. Dexamethasone decreases the incidence of shivering after cardiac surgery: A randomized, double-blind, placebo-controlled study. Anesth Analg 1998;87:95-9.
92. Miranda DR, Stoutenbeek C, Karliczek G, Rating W. Effects of dexamethason on the early postoperative course after coronary artery bypass surgery. Thorac Cardiovasc Surg 1982;30:21-7.
93. Toft P, Christiansen K, Tonnesen E, Nielsen CH, Lillevang S. Effect of methylprednisolone on the oxidative burst activity, adhesion molecules and clinical outcome following open heart surgery. Scand Cardiovasc J 1997;31:283-8.
94. Lodge AJ, Chai PJ, Daggett CW, Ungerleider RM, Jaggers J. Methylprednisolone reduces the inflammatory response to cardiopulmonary bypass in neonatal piglets: Timing of dose is important. J Thorac Cardiovasc Surg 1999;117:515-22.
95. Jorens PG, De Jongh R, De Backer W, Van Damme J, Van Overveld F, Bossaert L, Walter P, Herman AG, Rampart M. Interleukin-8 production in patients undergoing cardiopulmonary bypass: The influence of pretreatment with methylprednisolone. Am Rev Respir Dis 1993;148:890-5.
96. van Overveld FJ, De Jongh R, Jorens PG, Walter P, Bossaert L, De Backer WA. Pretreatment with methylprednisolone in coronary artery bypass grafting influences the levels of histamine and tryptase in serum but not in bronchoalveolar lavage fluid. Clin Sci (Colch) 1994;86:49-53.
97. Fitch JC, Rollins S, Matis L, Alford B, Aranki S, Collard CD, Dewar M, Elefteriades J, Hines R, Kopf G, Kraker P, Li L, O'Hara R, Rinder C, Rinder H, Shaw R, Smith B, Stahl G, Shernan SK. Pharmacology and biological efficacy of a recombinant, humanized, single-chain antibody C5 complement inhibitor in patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass. Circulation 1999;100:2499-506.
98. Soulika AM, Khan MM, Hattori T, Bowen FW, Richardson BA, Hack CE, Sahu A, Edmunds LH, Lambris JD. Inhibition of heparin/protamine complex-induced complement activation by Compstatin in baboons. Clin Immunol 2000;96:212-21.
99. Kirschfink M. Controlling the complement system in inflammation. Immunopharmacology 1997;38:51-62.
100. Goldie AS, Fearon KC, Ross JA, Barclay GR, Jackson RE, Grant IS, Ramsay G, Blyth AS, Howie JC. Natural cytokine antagonists and endogenous antiendotoxin core antibodies in sepsis syndrome. The Sepsis Intervention Group. JAMA 1995;274:172-7.
101. Shin'oka T, Nagashima M, Nollert G, Shum-Tim D, Laussen PC, Lidov HG, du Plessis A, Jonas RA. A novel sialyl Lewis X analog attenuates cerebral injury after deep hypothermic circulatory arrest. J Thorac Cardiovasc Surg 1999;117:1204-11.
102. Gillinov AM, Redmond JM, Zehr KJ, Wilson IC, Curtis WE, Bator JM, Burch RM, Reitz BA, Baumgartner WA, Herskowitz A, Cameron DE. Inhibition of neutrophil adhesion during cardiopulmonary bypass. Ann Thorac Surg 1994;57:126-33.
103. Sharar SR, Winn RK, Murry CE, Harlan JM, Rice CL. A CD18 monoclonal antibody increases the incidence and severity of subcutaneous abscess formation after high-dose Staphylococcus aureus injection in rabbits. Surgery 1991;110:213-9.
104. Boyle EMJ, Morgan EN, Kovacich JC, Canty TGJ, Verrier ED. Microvascular responses to cardiopulmonary bypass. J Cardiothorac Vasc Anesth 1999;13:30-5.

Author Information

Shahzad G. Raja, MRCS
Specialist Registrar, Department of Paediatric Cardiac Surgery, Alder Hey Hospital

Gilles D. Dreyfus, MD,PhD
Professor of Cardiac Surgery, Department of Cardiac Surgery, Harefield Hospital

Your free access to ISPUB is funded by the following advertisements:

Advertisement