A review of anti-inflammatory strategies in cardiac surgery
Shared by: djd18436
Perfusion 2003; 18: 7 ¡/12 A review of anti-in ammatory strategies in cardiac surgery George Asimakopoulos1 and Terence Gourlay2 1 Cardiothoracic Surgery, West London Rotation, UK; 2 Cardiothoracic Surgery, NHLI Imperial College Faculty of Medicine, London, UK It is generally accepted that cardiac surgery is frequently published literature concerning the use of anti-inflam- associated with the development of systemic inflamma- matory techniques and pharmacological agents in car- tory response. This phenomenon is very variable clini- diac surgery. In particular, the anti-inflammatory effects cally, and can be detected by measuring plasma of off-pump surgery, leukocyte filtration, corticosteroids, concentrations of certain inflammatory markers. Com- aprotinin, phosphodiesterase inhibitors, dpoexamine, H2 plement component, cytokines and adhesion molecules antagonists and ACE inhibitors are reviewed. The overall are examples of these markers. Systemic inflammation conclusion is that although certain strategies reduce can be potentially damaging to major organs. Several plasma levels of inflammatory mediators, convincing anti-inflammatory strategies have been used in recent evidence of significant clinical benefits is yet to come. years, aiming to attenuate the development of systemic Perfusion (2003) 18, 7 ¡/12. inflammatory response. This article summarizes recently Systemic inflammatory response in cardiac The role of inflammatory markers in the study of surgery systemic inflammation in cardiac surgery was re- cognized over 20 years ago and has been reviewed extensively.1 ¡ 3 Briefly, plasma levels of several Cardiac surgery is associated with a complex net- ‘acute phase proteins’ increase during the systemic work of phenomena that can be summarized under inflammatory response. Well-investigated examples the term ‘systemic inflammatory response’. Non- include interleukin-(IL-)6, IL-1, C-reactive protein clinicians use the nearly synonymous term ‘acute and complement components C3 and C4. Contact phase response’. This condition can be detected by activation of Factor XII occurs once this is bound to measuring the concentration of certain molecules, negatively charged surfaces; in particular, within the ‘inflammatory mediators’, in plasma and tissues. CPB circuit. Activation of Factor XII leads to the The clinical relevance of the systemic inflammatory formation of bradykinin via conversion of prekallik- response can be assessed by measuring the perio- rein to kallikrein. Products of the bradykinin-form- perative dysfunction, which affects most major ing cascade bind to the surface of endothelial cells, organs. Systemic inflammatory response occurs in neutrophils and platelets and contribute to the relation to many different types of clinical injury, activation of these cells. Furthermore, cell activation such as major trauma, major noncardiac surgery, is also facilitated through the action of ‘cytokines’. infection, burns or pancreatitis. It is particularly This general term includes a large number of small frequent in cardiac surgery, however, possibly as a proteins with proinflammatory and anti-inflamma- result of the fact that more than one major inflam- tory properties. Cytokines such as IL-I, IL-6 and also matory insult takes place simultaneously. These tumour necrosis factor-a (TNF-a ), IL-8, transforming include the mechanical effects of intraoperative growth factor-b and many others are produced by tissue manipulation, ischaemia and subsequent cells and cause further cell activation. They mediate reperfusion of lungs and myocardium, and the their inflammatory actions by binding to specific potentially inflammatory effects of the cardiopul- cell-surface cytokine receptors. Inflammatory activa- monary bypass (CPB). tion of leukocytes and endothelial cells and inter- action between the two groups are critical steps in inflammation. Address for correspondence: Mr George Asimakopoulos, Cardiothoracic Department, St George’s Hospital, Blackshaw It has been shown, conclusively, that cardiac Road, London SW17 0QT, UK surgery is associated with increased plasma concen- E-mail: firstname.lastname@example.org trations of several inflammatory mediators.1 Activa- # Arnold 2003 10.1191/0267659103pf623oa Review of anti-inflammatory strategies in cardiac surgery G Asimakopoulos and T Gourlay 8 tion of the complement cascade takes place and has been examined in several clinical trials over the secretion of IL-6, IL-8 and TNF-a also occurs. last five years, whereby plasma levels of inflamma- Specific adhesion molecules increase their expres- tory mediators were measured in patients under- sion on the surface of leukocytes and endothelial going OPCAB (or MIDCAB) and compared with cells. Intensified interaction between these cell patients undergoing conventional CABG. A review groups leads to leukocyte sequestration in tissues, of the subject was published recently,4 and the migration into subendothelial areas and, often, to following conclusions were drawn: leukocyte-led tissue damage. The specific role of leukocytes and, in particular, neutrophils will be . CPB appears to be responsible for the activation of discussed in one of the following paragraphs. complement during cardiac surgery. . CPB specifically promotes secretion of the pro- inflammatory cytokines IL-8 and TNF-a and of the anti-inflammatory cytokine IL-10. Anti-inflammatory strategies . Plasma levels of the acute phase proteins C- reactive protein and IL-6 are raised equally in Dysfunction of lungs, kidneys, myocardium, intes- both patient groups. IL-6 levels, however, were tine and brain is common after cardiac surgery. reduced when MIDCAB patients were compared Although the dysfunction is usually temporary, it with OPCAB patients in one study. This suggests coincides strongly with activation of inflammatory that operative trauma, rather than CPB, initiates cascades. Pathological conditions, such as bacterial the release of IL-6. infections, acute ischaemia or embolic events are . CPB promotes activation of neutrophils. often at the forefront of organ dysfunction. It is likely, however, that systemic inflammatory re- OPCAB is being practised with various degrees of sponse also plays a significant role. Different anti- enthusiasm around the world. Although, admit- inflammatory strategies have been used over the tedly, there is still controversy with regards to its years with various degrees of success. In general, it clinical benefits, it appears to be less proinflamma- has been easier to demonstrate success in reducing tory than cardiac surgery with CPB. plasma concentrations of specific inflammatory mediators than to prove significant clinical benefit. This is probably due to the fact that most rando- leukocyte filtration mized trials were severely underpowered to show Activation of leukocytes and their mobilization reduction in morbidity and mortality. Some of the towards injured tissues are critical steps in inflam- anti-inflammatory strategies, such as leukocyte fil- mation. Neutrophils, in particular, play a major role tration and the perioperative administration of in conquering insults, such as bacterial invasion. corticosteroids, have been used extensively. Certain Activated neutrophils, however, may exert dama- others, such as the use of angiotensin-converting ging effects on tissues of the host organism, indir- enzyme (ACE) inhibitors, are relatively new con- ectly by releasing inflammatory mediators and cepts. The following paragraphs present an over- directly by damaging endothelial cells with proteo- view of commonly used anti-inflammatory methods lytic enzymes. and pharmacological agents in cardiac surgery. Specific receptors on the neutrophil surface can be activated by proinflammatory cytokines, inter- Off-pump CABG feron-g (IFN-g ), platelet activating factor (PAF) or Cardiac surgery without the use of CPB [off-pump complement components C3a and C5a. Neutrophils, coronary artery bypass grafting (CABG) or OPCAB] subsequently, secrete further inflammatory media- has been practised in many centres in recent years. tors (IL-1, TNF-a , IL-6, IL-8, IFN-g ), a process which OPCAB, on certain occasions, can be performed leads to amplification of leukocyte activation.5 The without the use of midline sternotomy, thus redu- damaging potential of the activated neutrophils cing operative trauma (minimally invasive direct depends on their ability to adhere to the endothe- coronary artery bypass or MIDCAB). The potential lium. Neutrophil-endothelial cell adhesion may be benefits are related to reduced manipulation of the followed by generation of oxidizing agents and by ascending aorta in high-risk cases, avoidance of release of several toxic substances from intracellular global ischaemia and reperfusion in the heart and granules of the neutrophils. Molecules such as lungs, avoidance of cardioplegic arrest and its oxygen-derived free radicals and proteolytic en- damaging effects on the endothelium, reduced cost zymes (e.g., elastase and metalloproteinases) cause and, last but not least, avoidance of the potentially extracellular damage in order to facilitate their inflammatory effects of the CPB. The latter concept migration into tissues.6 Review of anti-inflammatory strategies in cardiac surgery G Asimakopoulos and T Gourlay 9 In cardiac surgery, there is a positive correlation cocorticoids is exerted through their ability to between elastase plasma concentrations after CPB control the patterns of synthesis of proteins. and postoperative respiratory dysfunction, as shown The effects of corticosteroids on organ function by changes in the respiratory index and increase of and systemic inflammatory response in patients the intrapulmonary shunt.7 In CPB-associated lung undergoing cardiac surgery have been investigated injury, neutrophils appear to play a significant role. since the early 1960s. A recent article by Chatney After the administration of protamine, the neutro- presented an exhaustive review of published clin- phil count in the pulmonary artery exceeds the ical investigations using corticosteroids, mainly count in the systemic arterial blood, suggesting that methylprednisolone, in cardiac surgery.13 Chatney’s neutrophils are sequestrated in the lungs.8 Concen- review is comprehensive and renders repetition in trations of neutrophils in bronchial lavage fluid are this article unnecessary. The overall conclusion is higher after CPB in comparison with control pa- that, while the use of corticosteroids is associated tients.9 with a significant reduction in plasma levels of a In view of the role leukocytes play in inflamma- large variety of inflammatory mediators, there is no tion, removal of activated leukocytes by intraopera- proven clinical advantage. On the contrary, corti- tive filtration has been used as an anti-inflammatory costeroids may be detrimental to the operative out- strategy in cardiac surgery. Several trials using come. leukocyte filtration have been carried out since the mid-1990s. Results were reviewed in two recent Aprotinin articles.10,11 Filters have been mainly inserted in the Aprotinin (Trasylol® ) is a nonspecific serine pro- arterial, but also in the venous CPB line, the tease inhibitor that has been used extensively in cardioplegia line and the suction system. Filters in cardiac surgery since its efficacy in reducing post- the arterial line reduced postoperative leucocytosis operative bleeding was discovered in the mid- in some studies and were particularly efficient in 1980s.14 It possesses broad haemostatic properties reducing leukocyte counts when inserted in the that are mediated by blocking pathways of comple- venous part of the circuit. There appears to be no ment activation and fibrinolysis, as well as inhibit- difference with regards to plasma levels of inflam- ing the action of proteinases such as trypsin, matory mediators, but a minority of trials reported plasmin and kallikrein. 15 Although used mainly improved lung function when filters were used. for its haemostatic effects, aprotinin is also thought leukocyte-depleted cardioplegia is associated with to modify the inflammatory response to major reduced plasma levels of CK-MB. Despite some surgery through a general ability to inhibit neutro- promising results, the use of leukocyte filtration phil activation. Diminished activation of neutro- still remains limited to certain institutions. Further phils associated with aprotinin therapy has been optimization of timing, material and patient selec- demonstrated in previous clinical trials and in vitro tion might improve outcome further. studies, which studied markers of leukocyte activa- tion, such as expression of cell surface proteins and release of elastase, TNF-a and IL-8. 16,17 Corticosteroids Aprotinin has been in clinical use for over 30 Corticosteroids can be divided into mineralocorti- years and, although several in vitro and in vivo coids and glucocorticoids. The latter have a variety studies have investigated its anti-inflammatory ef- of metabolic, immunosuppressing and anti-inflam- fects, the exact mechanism of action remains un- matory actions. Their anti-inflammatory effects in- known. Recognition of aprotinin’s antiplasmin clude decreased production of prostaglandins and effects led to its use as an antifibrinolytic agent. cytokines, decreased expression of surface adhesion Although Tice et al. 18 reported the use of aprotinin molecules, suppression of neutrophil adhesion and to reduce bleeding in cardiac surgery as early as phagocytosis, and also decreased proliferation of 1963, the drug’s potential role in postoperative lymphocytes. Glucocorticoids bind to specific cyto- haemostasis remained initially unrecognized. The plasmic receptors. The receptors have glucocorti- serendipitous discovery at the Hammersmith Hos- coid-binding domains and DNA-binding domains. pital that aprotinin, given at certain doses, signifi- The binding of the glucocorticoid to its receptor cantly reduces bleeding after cardiac surgery drew results in translocation of the receptor-glucocorti- wide attention to the drug and resulted in its coid complex into the nucleus. The subsequent extensive worldwide use.15,19 binding of the complex to the promoter region of Aprotinin is a basic polypeptide with a molecular specific genes results in altered gene activation and weight of 6512 Da. Its activity is often expressed as transcription.12 The physiological influence of glu- kallikrein inactivator units (KIU) or trypsin inacti- Review of anti-inflammatory strategies in cardiac surgery G Asimakopoulos and T Gourlay 10 vator units (TIU), based on aprotinin’s biological matory mediators in cardiac surgical patients. action properties. Clinically, aprotinin in used as a Enoximone reduced plasma levels of inflammatory continuous infusion following a loading dose. The cytokines and soluble adhesion molecules when full Hammersmith dose aims to suppress kallikrein used intraoperatively in patients aged over 80 years activity and consists of: 1) a loading dose of 2 ½/106 undergoing CABG.25 Milrinone was associated with KIU (280 mg); 2) a CPB pump prime dose of 2 ½/106 reduced secretion of the acute phase proteins KIU; and 3) a maintenance infusion of 0.5½/106 amyloid A and IL-6 after CPB.26 The use of the KIU/hour until the end of the operation. The newly developed olprinone was associated with concentration of aprotinin regarded as necessary to reduced IL-10 levels and moderate reduction in block kallikrein action under laboratory conditions gastric acidosis intraoperatively.27 is ~ /200 KIU/mL of plasma.15,19 Pentoxifylline, a methyl xanthine derivative, is A metaanalysis, however, of trials investigating known for its protective effects on endothelium. the influence of aprotinin on clinical outcome after When given to cardiac surgical patients in the cardiac surgery demonstrated decreased mortality in perioperative period, its use was associated with patients treated with aprotinin. 20 It is unclear, of reduced production of cytokines, reduced leukocyte course, whether this favourable result is primarily activation and sequestration in the lungs and im- attributable to the haemostatic or the anti-inflam- provement in indices of pulmonary injury.28 ¡ 30 matory effects of aprotinin. Previous studies in cardiac surgery showed that aprotinin is related to Dopexamine decreased proinflammatory cytokine production, Dopexamine is used as an intravenous infusion for increased IL-10 production21 and decreased NO its inotropic and vasodilatory properties. It acts on production.22 beta-2 receptors in cardiac muscle and on peripheral dopamine receptors. It produces vasodilatation in Phosphodiesterase inhibitors the renal and splachnic microcirculation and is, Phosphodiesterase inhibitors inhibit cyclic adeno- therefore, regarded as protective towards the gut sine 3?,5?-monophosphate phosphodiesterase mucosal barrier, causing subsequent reduction in (cAMP) and have been used over the last two ischaemia-induced endotoxaemia and inflammatory decades for their positive inotropic effects. Phos- response. phodiesterase converts cAMP into the physiologi- Two small randomized trials suggested that do- cally inactive 5?-AMP by hydrolysis. cAMP acts as a pexamine is associated with reduced secretion of hormonal and, also, inflammatory messenger by acute phase proteins in patients undergoing CPB. activating protein kinase A, which alters the activity There was increased creatinine clearance but no of proteins. An increase in intracellular cAMP measurable effect on splachnic blood flow. 31,32 enhances Ca2 » influx, resulting in a positive ino- tropic effect. Similarly, increase in intracellular H2 antagonists cyclic guanosine monophosphate (cGMP) also pro- Histamine is a biogenic amine, synthesized in hu- duces physiological effects. Nitric oxide, an impor- man mast cells, which plays a significant role as tant vasodilator and anti-inflammatory molecule, mediator in the immediate hypersensitivity reaction increases intracellular cGMP concentrations. and the acute inflammatory response. Histamine is Drugs such as enoximone, milrinone and olpri- stored in secretory granules and exerts its actions none inhibit selectively a subgroup of phosphodies- after degranulation and release into extracellular terases, the phosphodiesterase III. This leads to an space. Its biological effects are mediated through its increase in the tissue concentration of cAMP only. interaction with cellular H receptors. H2 receptors On the other hand, the earlier ‘classic’ phosphodies- mediate gastric acid secretion, but also activation of terase inhibitors, such as pentoxiphyllin, are less lymphocytes, neutrophils and endothelial cells. selective and also cause an increase in cGMP within These effects may stem from an increase in intra- the cardiac myocyte. Phosphodiesterase inhibitors cellular cAMP concentrations.33,34 The most impor- have a peripheral vasodilatory effect in addition to tant role of peripheral H2 receptors in humans their potential anti-inflammatory properties. appears to be the regulation of gastric acid secretion Although the exact mechanism of their anti-inflam- and H2 antagonists, such as cimetidine, were devel- matory effect is not entirely clear, they inhibit oped primarily for the treatment of peptic ulcers. leukocyte, macrophage and endothelial activa- Protamine is a small positively charged protein tion. 23,24 that constitutes the only known effective antidote to Published trials demonstrated that phosphodies- heparin. The formation of protamine/heparin com- terase III inhibitors reduce plasma levels of inflam- plexes after administration of heparin in cardiac Review of anti-inflammatory strategies in cardiac surgery G Asimakopoulos and T Gourlay 11 surgical procedures can lead to a form of anaphy- sure lowering effect and is possibly due to direct lactic reaction, involving release of histamine.35 tissue action.41 Furthermore, results from the Heart This is the theoretical basis for the use of H2 Outcomes Prevention Evaluation (HOPE) trial de- antagonists as potential anti-inflammatory agents monstrated that ACE inhibition, using ramipril, in cardiac surgery. Two early publications reported reduces the risk of cardiovascular death and myo- that the use of cimetidine during CPB reduces cardial infarction in patients at risk.42 Consequently, haemodynamic instability after administration of ACE inhibitors are regarded as potential anti-inflam- protamine.36,37 In a recent trial, cimetidine infusion matory agents in acute inflammatory conditions was associated with reduced plasma levels of IL-8 such as cardiac surgery. A recently published non- and neutrophil elastase levels.38 randomized study showed that IL-6 plasma levels after cardiac surgery were lower in patients who ACE inhibitors received ACE inhibitors preoperatively.43 ACE splits off histidyl-leucine from the physiologi- In conclusion, there is wide recognition of the fact cally inactive angiotensin I, forming the octapeptide that systemic inflammatory response takes place in angiotensin II. This is an extremely potent vasocon- association with cardiac surgery. Postoperative mor- strictor, which also promotes release of aldosterone bidity is often related to inflammatory phenomena, and norepinephrine.39 ACE is widely distributed in prompting basic scientists and clinicians to develop the body, but it is particularly active in the pulmon- anti-inflammatory strategies that aim to attenuate ary endothelium. ACE inhibitors reduce blood the damaging effects of systemic inflammation. pressure by lowering angiotensin II plasma concen- Several methods and drugs are currently used in trations and also through a diuretic effect. It has also trials with various degrees of success. While been recognized that angiotensin II affects cell reduction in plasma levels of inflammatory media- growth, inflammation, fibrosis and coagulation.40 tors has been achieved on many occasions, no single Numerous recent trials provide evidence that ACE anti-inflammatory method has been shown to re- inhibition reduces cardiovascular events via a me- duce convincingly postoperative morbidity and chanism that is independent from the blood pres- mortality. References 1 Asimakopoulos G. Mechanisms of the systemic in am- 10 Matheis G, Scholz M, Simon A, Dzemali G, Moritz A. matory response. Perfusion 1999; 14: 269 ¡/77. Leukocyte ltration in cardiac surgery: a review. 2 Asimakopoulos G, Taylor KM. The effects of cardio- Perfusion 2001; 16: 361 ¡/70. pulmonary bypass on leukocyte and endothelial adhe- 11 Asimakopoulos G. The in ammatory response to CPB: sion molecules. Ann Thorac Surg 1998; 66: 2135 ¡/ the role of leukocyte ltration. Perfusion 2002; 17: 7¡/ 44. 10. 3 Boyle EM Jr, Pohlman TH, Johnson MC, Verrier ED. 12 Shupnik MA, Chrousos GP, Siragy HM. Glucocorti- The systemic in ammatory response. Ann Thorac coids and mineralocorticoids. In Brody TM, Larner J, Surg 1997; 64: S31 ¡/S37. Minneman KP eds. Human pharmacology. Molecular 4 Asimakopoulos G. Systemic in ammation and cardiac to clinical , third edition. St Louis, MO: Mosby, 1998: surgery: an update. Perfusion 2001; 16: 353 ¡/60. 488 ¡/92. 5 Fujishima S, Aikawa N. Neutrophil-mediated tissue 13 Chaney MA. Corticosteroids and cardiopulmonary injury and its modulation. Intensive Care Med 1995; bypass. A review of clinical investigations. Chest 21: 277 ¡/85. 2002; 121: 921 ¡/31. 6 Weiss SJ. Tissue destruction by neutropils. N Eng J 14 Royston D, Bidstrup BP, Taylor KM, Sapford RN. Effect Med 1989; 320: 365 ¡/76. of aprotinin on need for blood transfusions after repeat 7 Tonz M, Mihaljevic T, von Segesser LK, Fehr J, Schmid open heart surgery. Lancet 1987; ii: 1289 ¡/91. ER, Turina M. Acute lung injury during cardiopul- 15 Taylor KM. Effect of aprotinin on blood loss and blood monary bypass. Are the neutrophils responsible? use after cardiopulmonary bypass. In Pifarre R ed. Chest 1995; 108: 1551 ¡/56. Anticoagulation, hemostasis, and blood preservation 8 Braude S, Nolop KB, Fleming JS, Krausz T, Taylor KM, in cardiovascular surgery. Philadelphia, PA: Hanley & Royston D. Increased pulmonary transvascular protein Belfus Inc, 1993: 132. ux after canine cardiopulmonary bypass. Am Rev 16 Wachtfogel YT, Kucich U, Hack CE, Gluszko P, Nie- Respir Dis 1986; 134: 867 ¡/72. wiarowski S, Colman RW, Edmunds LH. Aprotinin 9 Jorens PG, Van Damme J, De Backer W, Bossaert L, de inhibits the contact, neutrophil, and platelet activation Jongh RF, Herman AG, Rampart M. Interleukin-8 in the systems during simulated extracorporeal perfusion. J bronchoalveolar lavage uid from patients with the Thorac Cardiovasc Surg 1993; 106: 1 ¡/10. adult respiratory distress syndrome (ARDS) and pa- 17 Hill GE, Pohorecki R, Alonso A, Rennard SI, Robbins tients at risk for ARDS. Cytokine 1992; 4: 592 ¡/97. RA. Aprotinin reduces interleukin-8 production and Review of anti-inflammatory strategies in cardiac surgery G Asimakopoulos and T Gourlay 12 lung neutrophil accumulation after cardiopulmonary 31 Berendes E, Mollhoff T, Van Aken H, Schmidt C, Erren bypass. Anesth Analg 1996; 83: 696 ¡/700. C, Deng MC, Weyand M, Loick HM. Effects of dopex- 18 Tice DA, Reed GE, Clauss RH, Worth MH. Hemorrhage amine on creatinine clearance, systemic in ammation, due to brinolysis occurring with open-heart opera- and splachnic oxygenation in patients undergoing tions. J Thorac Cardiovasc Surg 1963; 46: 673 ¡/76. coronary artery bypass grafting. Anesth Analg 1997; 19 Royston D. Controversies in the practical use of 84: 950 ¡/57. aprotinin. In Pifarre R ed. Anticoagulation, hemosta- 32 Bach F, Grundmann U, Bauer M, Buchinger H, Soltesz sis, and blood preservation in cardiovascular surgery. S, Graeter T, Larsen R, Silomon M. Modulation of the Philadelphia, PA: Hanley & Belfus Inc, 1993: 150. in ammatory response to cardiopulmonary bypass by 20 Levi M, Cromheecke ME, de Jonge E, Prins MH, de Mol dopexamine and epidural anesthesia. Acta Anaesthe- BJ, Briet E, Buller HR. Pharmacological strategies to siol Scand 2002; 46: 1227 ¡/35. decrease excessive blood loss in cardiac surgery: a 33 Nilsson G, Costa JJ, Metcalf DD. Mast cells and meta-analysis of clinically relevant endpoints. Lancet basophils. In Gallin JI, Snyderman R eds. In amma- 1999; 354: 1940 ¡/47. tion. Basic principles and clinical correlates. Lippin- 21 Tassani P, Richter, JA, Barankay A, Braun SL, Haehnel cott Williams & Wilkins, 1999: 102. C, Spaeth P, Schad H, Meisner H. Does high-dose 34 Ganong WF. Synaptic and junctional transmission. In methylprednisolone in aprotinin-treated patients at- Ganong WF ed. Review of medical physiology . Con- tenuate the systemic in ammatory response during necticut: Appleton & Lange, 1993: 93. coronary artery bypass grafting procedures? J Cardi- 35 Weiss ME, Nyhan D, Peng Z, Horrow JC, Lowenstein E, othorac Vasc Anesth 1999; 13: 165 ¡/72. Hirshman C, Adkinson NF Jr. Association of protamine 22 Hill GE, Robbins RA. Aprotinin but not tranexamic IgE and IgG antibodies with life-threatening reactions acid inhibits cytokine-induced inducible nitric oxide to intravenous protamine. N Engl J Med 1989; 320: synthase expression. Anesth Analg 1997; 84: 1198 ¡/ 886 ¡/92. 202. 36 Casthely PA, Yoganathan D, Karyanis B, Salem J, 23 Ganong WF. The general and cellular basis of medical Yoganathan T, Komer C, Uribe M, Sclafani S, Hudac physiology. In Ganong WF ed. Review of medical A. Histamine blockade and cardiovascular changes physiology. Connecticut: Appleton & Lange, 1993: following heparin administration during cardiac sur- 36 ¡/39. gery. J Cardiothorac Anesth 1990; 4: 711 ¡/14. 24 Akera T, Brody TM. Drugs to treat heart failure: cardiac 37 Kambam J, Meszaros R, Merrill W, Stewart J, Smith BE, glycosides. In Brody TM, Larner J, Minneman KP eds. Bender H. Prophylactic administration of histamine1 Human pharmacology. St Louis, MO: Mosby, 1998: and histamine2 receptor blockers in the prevention of 218 ¡/19. protamine-related haemodynamic effects. Can J 25 Boldt J, Brosch C, Suttner S, Piper SN, Lehmann A, Anaesth 1990; 37: 420 ¡/22. Werling C. Prophylactic use of the phosphodiesterase 38 Tayama E, Hayashida N, Fukunaga S, Tayama K, III inhibitor enoximone in elderly cardiac surgery Takaseya T, Hiratsuka R, Aoyagi S. High-dose cimeti- patients: effects on hemodynamics, in ammation, dine reduces proin ammatory reaction after cardiac and markers of organ function. Intensive Care Med surgery with cardiopulmonary bypass. Ann Thorac 2002; 28: 1462 ¡/69. Surg 2001; 72: 1945 ¡/49. 26 Mollhoff T, Loick HM, Van Aken H, Schmidt C, Rolf N, 39 Ganong WF. Other endocrine organs. In Ganong WF Tjan TD, Asfour B, Berendes E. Milrinone modulates ed. Review of medical physiology. Connecticut: Ap- endotoxemia, systemic in ammation, and subsequent pleton & Lange, 1993: 415. acute phase response after cardiopulmonary bypass 40 Schiffrin EL. Vascular and cardiac bene ts of angio- (CPB). Anesthesiology 1999; 90: 72 ¡/80. tensin receptor blockers. Am J Med 2002; 113: 409 ¡/18. 27 Yamaura K, Akiyoshi K, Irita K, Taniyama T, Takahashi 41 Dzau VJ, Bernstein K, Calermajer D, Cohen J, Dahlof B, S. Effects of olprinone, a new phosphodiesterase Dean eld J, Diez J, Drexler H, Ferrari R, Van Gilst W, inhibitor, on gastric intramucosal acidosis and sys- Hansson L, Hornig L, Husain A, Johnston C, Lazar H, temic in ammatory responses following hypothermic Lonn E, Luscher T, Mancini J, Mimran A, Pepine C, cardiopulmonary bypass. Acta Anaesthesiol Scand Rabelink T, Remme W, Ruilope L, Ruzicka M, Schun- 2001; 45: 427 ¡/34. kert H, Swedberg K, Unger T, Vaughan D, Weber M. 28 Boldt J, Brosch C, Lehmann A, Haisch G, Lang J, Isgro Pathophysiologic and therapeutic importance of tissue F. Prophylactic use of pentoxifylline on in ammation ACE: a consensus report. Cardiovasc Drugs Ther 2002; in elderly cardiac surgery patients. Ann Thorac Surg 16: 149 ¡/60. 2001; 71: 1524 ¡/29. 42 Dagenais GR, Yusuf S, Bourassa MG, Yi Q, Bosch J, 29 Tsang GM, Allen S, Pagano D, Wong C, Graham TR, Lonn EM, Kouz S, Grover J. Effects of ramipril on Bonser RS. Pentoxifylline preloading reduces endothe- coronary events in high-risk persons: results of the lial injury and permeability in cardiopulmonary by- Heart Outcomes Prevention Evaluation Study. Circula- pass. ASAIO J 1996; 42: M429 ¡/34. tion 2001; 104: 522 ¡/26. 30 Turkoz R, Yorukoglu K, Akcay A, Yilik L, Baltalarli A, 43 Brull DJ, Sanders J, Rumley A, Lowe GD, Humphries Karahan N, Adanir T, Sagban M. The effect of pentox- SE, Montgomery HE. Impact of angiotensin converting ifylline on the lung during cardiopulmonary bypass. enzyme inhibition on post-coronary artery bypass Eur J Cardiothorac Surg 1996; 10: 339 ¡/46. interleukin 6 release. Heart 2002; 87: 252 ¡/55.