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Ann Thorac Surg 2001;71:745-754
© 2001 The Society of Thoracic Surgeons
a Alexion Pharmaceuticals, Inc, New Haven, Connecticut, USA
b Cardiothoracic Anesthesia and Critical Care Department, Emory University Hospital, Atlanta, Georgia, USA
Address reprint requests to Dr Mojcik, Department of Clinical Development, Alexion Pharmaceuticals, Inc, 25 Science Park, Suite 360, New Haven, CT 06511
e-mail: mojcikc{at}alxn.com
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Abstract |
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 TopFootnotes Abstract IntroductionContact activationCellular responseConclusionAcknowledgmentsReferences |
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Introduction |
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TopFootnotesAbstractIntroductionContact activationCellular responseConclusionAcknowledgmentsReferences |
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Ischemia-reperfusion, surgical trauma, endotoxemia, and blood contact with the artificial surfaces of the CPB apparatus all contribute to the systemic inflammatory response by activating humoral and cellular pathways [4, 5]. Soluble mediators of SIRS include plasma proteases, lipids, and cytokines. Cellular components, such as selectins and integrins, are also upregulated in immune and endothelial cells to facilitate the inflammatory response. Synergistic activity of these proinflammatory soluble and cellular mediators increases vasodilation and vascular permeability, promotes leukocyte activation, migration, and degranulation, and, ultimately, may lead to tissue damage and organ dysfunction [5, 6].
Aprotinin, a nonspecific serine protease inhibitor isolated from bovine lung tissue, reversibly complexes with the active sites of plasmin, kallikrein, and trypsin [7]. Initial reports of aprotinin usage during cardiac surgery demonstrated dramatic reductions in mean blood loss (two to fourfold) and transfusion requirements (eightfold) [8, 9]. Multiple randomized, placebo-controlled trials on aprotinin safety and efficacy have confirmed that high dose aprotinin therapy reduces mediastinal drainage by 31% to 81%, total transfusion amounts by 35% to 97%, and the proportion of patients requiring transfusion of blood or blood products by 40% to 88% [7, 10, 11]. Although the effects of aprotinin on clinical parameters of homeostasis are well-documented, the role of aprotinin in reducing the inflammatory response during CPB warrants further examination.
This review describes the molecular and cellular events that underlie the systemic inflammatory response to CPB. Furthermore, the role of aprotinin in limiting the activity of proinflammatory mediators during CPB, especially as they might relate to the manifestations of SIRS, is examined.
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Contact activation |
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TopFootnotesAbstractIntroductionContact activationCellular responseConclusionAcknowledgmentsReferences |
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Products of the kinin pathway also participate in the cellular inflammatory response by directly stimulating neutrophils. Neutrophil superoxide and hydrogen peroxide formation are reportedly upregulated in the presence of kallikrein [14]. In vitro experiments demonstrate that kallikrein and FXIIa promote neutrophil aggregation and elastase release [14, 15]. Damage caused by release of neutrophil proteolytic enzymes and superoxide-derived free radicals is not limited to invading organisms or foreign surfaces; endogenous tissues proximal to the released toxic substances may be deleteriously affected [12].
Estimations of plasma kallikrein levels, and therefore FXII activation, are derived by measuring kallikrein complexed with the C1-INH inhibitor. Sixty minutes following CPB, kallikrein-C1-INH levels are 1.75-fold higher than presurgery values [16]. At the onset of bypass, kallikrein inhibitor activity falls, indicating an imbalance of kallikrein systemically; even after adjustment for hemodilution, the imbalance remains until approximately 2 hours after CPB [17]. In simulated extracorporeal circulation (SECC), kallikrein-C1-INH complex levels peak, reaching 12.5 times baseline after only 20 minutes [16]. These observations suggest that FXII activation is increased and kallikrein production is upregulated following blood exposure to foreign materials. Indeed, kallikrein activation occurs almost instantaneously at the start of CPB, as evidenced by markedly reduced prekallikrein levels, increased kallikrein-like activity, and depleted kallikrein inhibitor [18].
In addition to responses to the bioincompatible surfaces of the CPB apparatus, heparin, an anticoagulant routinely used during cardiac surgery, slows FXIIa and kallikrein inactivation [13]. Plasma prekallikrein decreases with heparin administration [19]. Further, a transient but dramatic increase (nine to 10-fold) in spontaneous kallikrein activity has been observed during CPB, immediately after heparin infusion, with levels decreasing and normalizing by the end of CPB [17, 19]. Thus, heparin, along with the bypass circuit, appears to have profound effects on the contact activation system.
The onset of multisystem organ failure following CPB may be related to increased kallikrein activity. Seghaye and colleagues found that patients whose post-CPB kallikrein levels failed to return to baseline, presumably by consumption, tended to develop multisystem organ failure [20]. By the 3rd postoperative day, patients with multisystem organ failure were shown to exhibit significantly lower kallikrein levels than patients without the complication.
As noted above, one product of the kinin-kallikrein cascade is the potent vasodilator bradykinin. During CPB, bradykinin levels progressively increase and return to near normal shortly after its end [21]. Accordingly, levels of kininogen, the precursor to bradykinin, significantly decrease during CPB [22]. Excessive production of bradykinin substantially augments vascular permeability, facilitating movement of plasma proteins and activated neutrophils into tissues, and possibly resulting in diffuse and specific organ edema [13, 23]. These actions exaggerate the inflammatory response and overall tissue injury.
Aprotinin inhibition of components of the contact activation protease pathways has been shown to be dose-dependent in a variety of in vitro systems and in the CPB setting. High-dose aprotinin administration includes an initial bolus of 2 x 106 kallikrein inhibitory units (KIU) (280 mg) of aprotinin following anesthesia induction and subsequent intravenous infusion of 70 mg/h (5 x 105 KIU) [24], resulting in plasma concentrations of approximately 35 µg/mL. This regimen also includes addition of 280 mg of aprotinin to the CPB unit pump prime fluid. The low-dose aprotinin regimen is similar, but with an initial bolus of 1 x 106 KIU (140 mg) and infusion of 35 mg/h (2.5 x 105 KIU) [24], resulting in plasma concentrations of about 17 µg/mL.
At concentrations approaching the high-dose regimen (30 µg/mL or greater), the 2.5-fold increase in kallikrein-C1-INH complex formation during SECC is completely inhibited compared with untreated groups [25]. Using radioimmunoassay, Wachtfogel and colleagues showed that 20 µg/mL aprotinin significantly, but incompletely compared with high dose, inhibited the increase in kallikrein-C1-INH complex levels observed under control CPB conditions [26]. Reduced complex formation in the presence of aprotinin suggests that aprotinin administration significantly blocks kallikrein activity [26]. Wendel and colleagues examined the effect of 28 µg/mL aprotinin on kallikrein-like activity [27]. In controls, kallikrein activity increased from 100% at SECC initiation to 140% at 60 minutes, whereas this increase was attenuated (120%) with aprotinin treatment [27].
During CPB, aprotinin preserves kallikrein inhibitor activity [11]. Fuhrer and associates found that the kallikrein inhibition capacity decreased during CPB for untreated patients, from 100% to 75%, whereas the aprotinin-treated group experienced an increase in kallikrein inhibition from 100% to 300% [18]. Further, the study reported that control prekallikrein levels decreased from 100% at baseline to 70% by the end of CPB, whereas aprotinin-treated patients exhibited a modest decrease to only 90% [18].
At clinically relevant plasma concentrations, aprotinin has been shown in vitro to decrease FXIIa activity by 20% [28], which may result from decreased kallikrein activity. As described above, kallikrein is a major activator of FXII, and without the amplifying effect of kallikrein, contact phase activation is slowed or inhibited [29]. During bypass, the decrease in FXIIa inhibitor levels, from 84% at baseline to 50% during CPB, was attenuated by aprotinin treatment (low, 75%) [18].
Aprotinin has a significant effect on reducing bypass-mediated changes in plasma bradykinin levels. Nagaoka and Katori tested aprotinin doses that are lower than the current standards (104 to 3 x 105 KIU/person) [22]. Nevertheless, a significant preservation of kininogen levels in the aprotinin group (9.5 µg/mg plasma protein) over the control group (6.5 µg/mg plasma protein) was observed, suggesting that bradykinin production was reduced. Because bradykinin formation results in hypotension, the authors also examined vascular tone; they found that control patients experienced a decrease in total peripheral resistance (TPR) whereas aprotinin prevented the decrease in TPR [22].
Fibrinolytic pathway
Fibrin clots are formed at the sites of surgical incision and function to maintain hemostasis during surgery. Activation of the fibrinolytic pathway coverts the zymogen plasminogen to the protease plasmin. Plasmin degrades fibrin plugs by proteolytically digesting fibrin. In addition to generating proinflammatory fibrin split products, plasmin amplifies the inflammatory response by directly activating FXII. Members of the kinin-kallikrein pathway augment activation of the fibrinolytic pathway by ultimately upregulating plasmin levels. Bradykinin promotes endothelial secretion of tissue plasminogen activator (t-PA) [30], a protease that targets plasminogen to liberate active plasmin. Kallikrein also cleaves plasminogen, although the kinetics of the reaction are slow. However, when associated with HMWK, kallikrein cleaves prourokinase to yield urokinase, an activator of u-PA [13], resulting in increased plasmin formation [31].
Throughout CPB, fibrinolysis is enhanced because of plasmin overexpression [32]. Maximal t-PA levels reportedly peak (four to sixfold) at onset or 1 hour into CPB [33], but also may exhibit a second peak following aortic cross-clamp release [34]. Concurrently, plasmin activity measured during CPB shows a rapid increase with heparin administration (10-fold) at the beginning of surgery, drops to moderately elevated levels during bypass (fourfold), and then returns to baseline by the end of surgery [19]. Similar to kallikrein, plasmin levels can be estimated by measuring plasmin inhibitor levels. During CPB, a 60% depletion of free plasmin inhibitor, 
2-antiplasmin, is observed, suggesting that plasmin (and therefore the fibrinolytic pathway) is active [35]. Further, formation of plasmin--antiplasmin complexes peaks in early CPB (four to fivefold increase over baseline), remains elevated 2 hours post-CPB (two to threefold), and returns to normal by 24 hours post-bypass [19].
Fibrin degradation also increases during CPB [9], and fibrin degradation products have been implicated in impaired fibrin formation, platelet dysfunction, and endothelial disruption resulting in capillary injury [36]. Moreover, plasmin, a potent platelet inhibitor, reportedly degrades platelet adhesion receptors Gp Ib and Gp IIb in vitro [7], and by 50% in vivo during CPB [35], most notably at hypothermic temperatures [32]. When added to washed platelets, plasmin reduces platelet membrane Gp Ib content by approximately 75% [35]. Taken together, these observations suggest that stimulation of the fibrinolytic system in CPB may result in decreased platelet function.
During and after CPB, D-dimer levels, a measurement of the amount of fibrin degraded by plasmin, were lower in patients receiving aprotinin therapy compared with controls, indicating that plasmin activity was attenuated in aprotinin patients [37]. Reduced plasmin activity can be attributed to decreased plasmin production, direct inhibition of plasmin, or a combination of these two events. Interestingly, t-PA levels and plasminogen levels did not significantly differ between the groups, although less plasmin was bound to the endogenous inhibitor, 2-antiplasmin [37]. Taken together, these observations suggest that reduced fibrinolytic activity resulting from aprotinin administration most likely results from direct binding and inhibition of plasmin, rather than inhibition of t-PA-mediated plasmin generation.
Complement
The complement system, comprised of approximately 30 plasma and membrane proteins, functions in parallel with the immune system [38]. Activation proceeds through three independent pathways, each consisting of distinct molecular components and unique mechanisms of activation (Fig 2). All three pathways converge, generating two different C3 convertases (termed C3b,Bb and C4b,2a) that cleave the pivotal factor C3 into the small, diffusable C3a and the larger, membrane-delimited C3b (Fig 2) [38]. Following activation by C3b, membrane-bound C5b initiates assembly of the membrane attack complexes (MAC), an aggregation of proteins C5b through C9 [38]. In addition to forming pores in bacterial cell walls, MACs induce platelet prothrombinase activity and platelet-leukocyte binding via platelet expression of CD62P [39, 40]. The circulating anaphylatoxins C3a and C5a stimulate release of histamine and other inflammatory mediators from mast cells and basophils, leading to increased vascular permeability and smooth muscle contraction. C3a has also been implicated in tachycardia, coronary vasoconstriction, and reduced contractility [21]. C5a, a potent chemoattractant, stimulates neutrophil aggregation and adhesion to endothelial cells, and upregulation of the C3 receptor CD11b/CD18 or Mac-1 [38, 41]. In addition, C5a triggers neutrophil release of lysosomal enzymes, oxygen free radicals, and interleukins [42, 43].
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One prominent initial physiological response to CPB is massive complement activation, primarily by the alternative pathway (Fig 2) [46]. Plasma C3a levels increase within 2 minutes of CBP onset, remain elevated, and correlate with CPB duration. Removal of the cross-clamp and rewarming are characterized by an additional elevation of C3a levels, which peak at CPB termination five to 15-fold above baseline values. C3a levels return to normal 18 to 48 hours after surgery. Multiple organ dysfunction and overall morbidity have been strongly correlated with increased C3a levels following CPB [6, 47]. Interestingly, C3a levels do not change in non-CPB cardiac operations [47].
Other complement proteins also increase during CPB. C5b-9, elevated at the end of bypass, may continue to increase into the postoperative period. Subtle elevations in plasma C5 have been reported, but its rapid binding to leukocytes may mask these overall changes. Protamine administered to reverse heparin anticoagulation is associated with a two to 11-fold increase in plasma C4a over presurgery levels through direct activation of C1 [48, 49]. The terminal complement complex C5b-C9 is also observed following protamine administration [49].
Blocking components of the complement pathway reduces downstream effects of proinflammatory proteins. A single injection of anti-C5 mAb to patients undergoing CPB significantly decreases C5b-c9 expression in a dose-dependent manner. This reduction was associated with decreased CD11b expression, and clinically, decreased postoperative blood loss, a 40% reduction in creatine kinase-MB release, and an 80% reduction in the appearance of new cognitive deficits [50]. During stimulated extracorporeal circulation, C8 blockade preserves platelet counts and inhibits formation of monocyte-platelet aggregates compared with control while additional blockade of C5a reduced neutrophil activation [51]. In animal studies, protection against ischemia reperfusion injury was achieved by inhibition of the C5b-c9 complex with protease inhibitors [66] and with anti-C5 or anti-C8 [52].
Complement factors are also affected by aprotinin administration. During SECC, aprotinin doses at or above 30 µg/mL (ie, correlating to a high-dose aprotinin regimen) significantly reduced C1-C1-INH formation over control (1 U/mL versus 2.25 U/mL, respectively) [25], suggesting that aprotinin effectively reduced C1 plasma content. Interestingly, this effect was not observed with a low-dose aprotinin regimen of 20 µg/mL [26]. In an ex vivo hemodialysis model, aprotinin (0.8 x 106 KIU) provides a significant reduction (threefold) in the amount of C3a and C5a produced at 60 minutes [53]. However, levels of C3a and C4a are not significantly changed by aprotinin administration during CPB [9].
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Cellular response |
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TopFootnotesAbstractIntroductionContact activationCellular responseConclusionAcknowledgmentsReferences |
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Neutrophils
Neutrophils respond to soluble inflammatory mediators by first rolling, tightly adhering, and then transmigrating across the microvascular endothelial barrier to invade the interstitium [12]. In addition to phagocytosing foreign pathogens and damaged tissue particles, activated neutrophils degranulate, releasing toxic substances, proteolytic enzymes, and proinflammatory mediators, which recruit more leukocytes [12].
Neutrophil adherence to the vascular endothelium is a two-step process. First, circulating leukocytes slow and roll along the endothelial surface. Three classes of lectins (L-selectins [leukocytes]; E-selectins [activated endothelial cells]; and P-selectins, [endothelial cells and platelets]) mediate this process by binding to carbohydrate moieties [12]. Integrins, heterodimers consisting of a distinct chain and a common ß polypeptide chain, tightly adhere rolling neutrophils to the microvasculature, a prerequisite for neutrophil extravasation [12]. Six leukocyte integrins have been identified, including LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18), and these bind to the immunoglobulin superfamily molecules (intracellular adhesion molecule [ICAM]-1 and 2 or ICAM-1, respectively) upregulated on activated endothelial cells. Mac-1 also contributes to several other inflammatory responses, including chemotaxis and production of oxygen free radicals.
Activated neutrophils release intracellular stores of effector proteins from primary and secondary granules to facilitate the inflammatory process. Elastase, a serine protease found in primary granules, appears to mediate neutrophil extravasation, tissue infiltration, and endothelial cell injury [12, 54]. Membrane components of the nicotine adenine dinucleotide phosphate (NADPH) oxidase complex are stored in secondary granules, and, once assembled, the complex catalyzes the production of superoxide anion. This toxic substance is the precursor to other oxygen free radicals such as hydrogen peroxide, hydroxyl anion, and oxygen halides, and acts with myeloperoxidase to catalyzes the production of the cytolytic hypochlorous acid [55]. Importantly, superoxide anion readily diffuses across membranes and produces metabolites outside the cell.
Recent reports suggest that neutrophil extravasation and tissue damage are linked. In the dog model, neutrophil adherence to myocytes via CD11b/CD18 is associated with a neutrophil respiratory burst and myocyte injury in vitro [56]. In addition, blocking neutrophil adherence to canine myocytes or cultured endothelial cells with mAb to CD18, CD11b, and ICAM-1 inhibits neutrophil superoxide production [56, 57]. Thus, substantial neutrophil activation can result in widespread oxidative tissue damage.
Cardiopulmonary bypass has dramatic effects on leukocyte function. An immediate drop in leukocyte number is observed at CPB onset because of hemodilution and leukocyte adsorption to the extracorporeal circuit [36]. A significant increase in circulating neutrophils follows [58, 59], and up to 50% of circulating neutrophils are sequestered into lung capillaries after removal of the aortic cross-clamp, depending on CPB duration and time to cross-clamp removal [60]. Neutrophil sequestration into the lung capillaries is associated with endothelial cell and type II pneumocyte damage [60]. Neutrophil aggregates have also been detected in the brains of patients undergoing CPB [61]. At the molecular level, proteins that govern neutrophil activity are upregulated during CPB. Neutrophil L-selectin levels increase just after CPB is initiated and fall by the end of CPB [62, 63]. Endothelial E-selectin protein levels and atrial E-selectin and ICAM-1 mRNA levels increase during CPB [64]. Integrin expression is also affected, as production of neutrophil Mac-1 (CD11b/CD18) increases and peaks at the end of CPB to time of cross-clamp removal [64, 65].
During CPB, neutrophils release elastase, lactoferrin, and myeloperoxidase (MPO) [21, 36]. Lactoferrin and MPO increase during bypass, peak at the end of CPB, and decline rapidly after surgery to preoperative levels [65]. Similarly, plasma elastase levels rise during CPB, peak at the end of surgery but remain elevated at least 24 hours postoperatively [4, 46]. Coincidentally levels of elastase-1-proteinase inhibitor complex rise and peak during CPB [58]. Interestingly, patients with multiorgan system failure exhibit significantly higher elastase levels at the end of CPB than those without this complication [20].
Rather than influencing the absolute number of plasma neutrophils during CPB, evidence indicates that aprotinin modulates components of neutrophil activation and extravasation. In vitro leukocyte hyperactivation, stimulated by exposure to plasma from CPB patients, was reduced by aprotinin in a dose-dependent manner [66]. Using fluorescence microscopy; low-dose and pump-prime only aprotinin treatments were shown to blunt CPB-induced CD11b upregulation [67, 68]. Further, Asimakopoulus and colleagues recently reported that, compared with placebo, high-dose aprotinin significantly decreases CD11b/CD18 upregulation 15 minutes following CPB onset [69].
Evidence suggests that aprotinin reduces elastase release from neutrophils. In simulated extracorporeal circuits, aprotinin was shown to inhibit elastase release, most likely through kallikrein inhibition [25, 26]. Increased elastase:1-protein inhibitor (PI) complexes have been shown to be significantly inhibited by aprotinin in SECC; control levels increased from 100% to 1,000% (60 minutes) and to 1,400% (90 minutes), whereas with aprotinin, the change was to 700% at 60 minutes and 900% at 90 minutes [27]. Similar results have been reported during CPB. Following cross-clamp release, elastase:1-proteinase INH complexes decrease by nearly 50% in aprotinin-treated patients compared with controls [9].
Recent reports support a role for elastase during neutrophil transmigration through the endothelial barrier. In vitro and in vivo studies demonstrate that elastase inhibitors prevent neutrophil extravasation across an endothelial barrier and attenuate leukocyte infiltration in the affected tissue [54, 70]. Intravenous aprotinin treatment has recently been shown to inhibit leukocyte extravasation across rate venule endothelium, whereas leukocyte rolling and tight adhesion remained intact [71]. In parallel experiments, dose-dependent aprotinin inhibition of leukocyte transmigration was observed in vitro using a monolayer of human umbilical vein endothelial cells (HUVEC) [71]. These findings provide a potential mechanism for the observation that aprotinin significantly limits leukocyte accumulation in the lung during CPB [72].
Platelets
Although the hemostatic properties of platelets are well documented, recent evidence suggests their additional role in inflammation [73]. Platelets contribute to the inflammatory response by releasing mediators such as plasminogen and fibrinogen [12]. Activated platelets bound to microvascular endothelium participate in recruitment of neutrophils and monocytes by secreting IL-8, a neutrophil chemoattractant, and MCP-1, a monocyte chemoattractant. The association of neutrophils to thrombin-activated platelets is similar to that of neutrophils and endothelium. Neutrophil rolling on surface-adherent platelets requires P-selectin [74]. Neutrophil arrest results from the neutrophil integrin Mac-1 interacting with platelet surface glycoprotein (GP) IIb/IIIa (CD41a/CD61a), which presents the Mac-1 ligand fibrinogen [75].
CPB has multiple effects on platelets. Hemostasis defects result from decreased platelet number and function post-CPB [76, 77]. As platelets make a first pass through the oxygenator, GP IIb receptor fragments lost from the platelet coat the foreign surface, causing the absolute platelet count to fall [75]. Further, platelets activated by this interaction, as well as contact system factors, aggregate and release the potent vasoconstrictor and potentiator of platelet aggregation, thromboxane A2 [78]. Platelets activated during CPB exhibit increased surface P-selectin levels (1.4-fold), which peak about 120 minutes into bypass and return to presurgery values on postoperative day 1 [79]. This may even be an underestimation, as approximately 25% to 30% of platelets are sequestered in the lung and spleen during CPB [73]. Rinder and Fitch corroborated these findings by showing an increase in the number of P-selectin-positive platelets and leukocyte-platelet conjugates as a result of bypass [42]. Following CPB, antibody binding to platelet receptors, including GP Ib, GP IIb, GP IIa, and GP IIb/IIIa [75], is reduced, indicating that these surface proteins are diminished during CPB. This is mediated in part by plasmin, which directly releases GP Ib from the platelet surface [80].
Aprotinin prevents platelet dysfunction and improves hemostasis during CPB indirectly by inhibiting plasma proteases such as plasmin and kallikrein and directly by preserving the platelet surface adhesive receptor GP Ib [75]. The 50% decrease in GP Ib glycoproteins observed within 5 minutes of CPB in untreated patients was not observed for those treated with aprotinin [81]. Aprotinin pretreatment of washed platelets reduced loss of platelet GP Ib by 60% following addition of plasmin [35]. Further, aprotinin treatment is also associated with reduced P-selectin surface expression on platelets and decreased leukocyte-platelet conjugates during CPB [82]. Therefore, aprotinin may limit leukocyte recruitment and infiltration during CPB by inhibiting platelet-leukocyte interactions.
One mechanism that may explain direct effects of aprotinin on platelets may result from its actions on protease-activated receptors (PARs). PARs on the surface of platelets are activated by the serine protease thrombin [83]; thrombin, the most potent known activator of platelets, is generated by contact activation [84]. Thrombin acts by cleaving the unique seven-transmembrane spanning, G-protein coupled PAR-1 in the extracellular N-terminal domain, thus liberating a portion of the N-terminus and allowing it to interact with the second extracellular loop [83]. On platelets, thrombin-mediated activation of PAR1, and to a lesser extent PAR4, signals platelet aggregation and secretion [85]. Aprotinin appears to inhibit thrombin-mediated platelet aggregation in vitro by preventing proteolytic activation of PAR1 [86]. Thus, aprotinin may reduce amplification of CPB-induced cellular mediated inflammatory response on platelets indirectly through effects on plasma proteases, and directly, possibly via action on protease-activated receptors.
Cytokines
Cytokines are secreted proteins that act on local target cells to induce growth, differentiation, apoptosis, or chemotaxis [87]. Synergistic interactions among cytokines and their target cells amplify the inflammatory response by attracting leukocytes to the site of injury and stimulating additional cytokine release. Altered levels of some pro- and antiinflammatory cytokines during CPB have been documented. In general, the magnitude of cytokine response correlates with the length of CPB and aortic cross-clamp time [43]. Individual studies, however, vary greatly in the degree of change measured during and after CPB.
Interleukin-6 (IL-6), produced by T-cells, endothelial cells, and monocytes [12], mediates the acute-phase response to injury. Although IL-6 tends to increase during CPB, IL-6 elevation is not specific to CPB, as this occurs with major noncardiac operations [88]. Plasma IL-6 levels increase consistently within 2 to 4 hours of incision, peak 4 to 6 hours postoperatively, and secondarily peak 12 to 18 hours after CPB [89, 90]. IL-6 levels correlate with the cardiac index (r = 0.76) and systemic vascular resistance (r = 0.49) [91]. With respect to outcomes, the magnitude of early IL-6 peak is positively associated with abnormal myocardial wall motion on transesophageal echocardiography; the secondary peak is correlated with ischemic episodes on electrocardiogram [90]. Patients with increased postoperative oxygen consumption, a measure of decreased lung function, which positively correlates to development of post-perfusion syndrome, also exhibit relatively higher levels of IL-6 [92]. However, whether IL-6 functions as a mediator or merely a marker of inflammation is unclear [93].
IL-8, a potent neutrophil chemoattractant, stimulates neutrophil adhesion molecule expression [12]. Indeed, IL-8 is considered the primary mediator of lung neutrophilia following CPB. CPB patients exhibit IL-8 in bronchoalveolar lavage (BAL) fluid and culture supernatants from lipopolysaccharide-stimulated alveolar macrophages [94]. IL-8 has been associated with myocardial wall motion abnormalities, with peak concentrations positively correlated with the degree of abnormality observed in the transesophageal echocardiographic left ventricular wall [92].
Tumor necrosis factor (TNF) levels typically peak toward the end of CPB to 2 hours post-CPB [4, 92]. Levels increase threefold and may exhibit a biphasic pattern, with a secondary peak at 18 hours post-CPB [4]. The TNF peak at 2 hours post-bypass is also correlated with the degree of wall motion abnormality [92]. Further, patients with increased postoperative oxygen consumption, a measure of decreased lung function that positively correlates to development of post-perfusion syndrome, have been shown to exhibit elevated TNF levels [92].
Aprotinin has been shown in vitro to inhibit TNF secretion from activated macrophages by 51% [95]. In vivo, aprotinin may have similar effect, as CPB patients receiving low-dose aprotinin were reported to exhibit an average TNF level of 17 pg/mL versus 32 pg/mL in control patients [68]. IL-6 and IL-8 levels in aprotinin-treated CPB patients have also been investigated, and a preliminary study reports significantly lower IL-6 levels in aprotinin-treated patients (175 pg/mL; control, 375 pg/mL) just after the discontinuation of CPB [96]. Diego and colleagues demonstrated that both methylprednisolone and high-dose aprotinin significantly reduces IL-6 levels 24 hours post-CPB [97]. Interestingly, this group recently reported that at 1 and 24 hours post-CPB, the high-dose aprotinin regimen significantly increases levels of interleukin-10 [98], an antiinflammatory mediator that inhibits production of proinflammatory cytokines [12]. IL-8 measured in BAL fluid from aprotinin-treated CPB patients (12 pg/mL) is significantly lower than in control patients (48 pg/mL) [73]. BAL fluid from aprotinin-treated CPB patients is less chemoattractive to untreated neutrophils as compared with controls, a finding attributed to reduced IL-8 production by the aprotinin-treated group [73]. Moreover, aprotinin-treatment reduces the presence of neutrophils in BAL from CPB patients (control, 32.1%; aprotinin, 7.0%) [73, 99].
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Conclusion |
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TopFootnotesAbstractIntroductionContact activationCellular responseConclusionAcknowledgmentsReferences |
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Serine proteases play a central role in kinin-kallikrein, fibrinolytic-coagulation, and complement systems to bring about SIRs. Indeed, only three components of the coagulation cascade, calcium, factor V, and factor VIII, are not serine proteases. Moreover, serine proteases may modulate responses though activation of PARs, which have been identified in tissues throughout the body. Because the plasma protease pathways are interrelated, and also sometimes redundant, pharmacological attenuation of SIRs is a challenge.
Aprotinin, a nonspecific serine protease inhibitor, has been recognized for many years as a hemostatic agent. The protein inhibits activity of a variety of proteases, including trypsin, plasmin, kallikrein, and elastase in a dose-dependent manner. In review of the literature, an abundance of evidence from CPB and model systems, based upon relevant cellular and functional markers and outcomes, shows that aprotinin attenuates numerous aspects of the inflammatory response evoked by bypass surgery. Use of high-dose aprotinin, which targets inhibition of kallikrein production and function, appears to be a rational approach for suppressing activation and amplification of the systemic inflammatory response. Contrary to the trend toward increased target selectivity of pharmaceuticals, aprotinin, a promiscuous pharmacological agent, appears to be especially suited to reduce activation and amplification of the plasma protease pathways that lead to SIRS.
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Acknowledgments |
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TopFootnotesAbstractIntroductionContact activationCellular responseConclusionAcknowledgmentsReferences |
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TopFootnotesAbstractIntroductionContact activationCellular responseConclusionAcknowledgmentsReferences |
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TopFootnotesAbstractIntroductionContact activationCellular responseConclusionAcknowledgmentsReferences |
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D. Royston, J. H. Levy, J. Fitch, W. Dietrich, S. C. Body, J. M. Murkin, B. D. Spiess, and A. Nadel Full-Dose Aprotinin Use in Coronary Artery Bypass Graft Surgery: An Analysis of Perioperative Pharmacotherapy and Patient Outcomes Anesth. Analg., November 1, 2006; 103(5): 1082 - 1088. [Abstract] [Full Text] [PDF]
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 D. Rosborough Cardiac Surgery in Elderly Patients: Strategies to Optimize Outcomes Crit. Care Nurse, October 1, 2006; 26(5): 24 - 31. [Full Text] [PDF]
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 A. Sedrakyan, A. Wu, G. Sedrakyan, M. Diener-West, M. Tranquilli, and J. Elefteriades Aprotinin use in thoracic aortic surgery: Safety and outcomes J. Thorac. Cardiovasc. Surg., October 1, 2006; 132(4): 909 - 917. [Abstract] [Full Text] [PDF]
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D. J. Kozik and J. S. Tweddell Characterizing the Inflammatory Response to Cardiopulmonary Bypass in Children Ann. Thorac. Surg., June 1, 2006; 81(6): S2347 - S2354. [Abstract] [Full Text] [PDF]
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 J. H. Fischer and M. Steinhoff Effects of aprotinin on endothelium-dependent relaxation of large coronary arteries Eur. J. Cardiothorac. Surg., December 1, 2005; 28(6): 801 - 804. [Abstract] [Full Text] [PDF]
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 S. G Raja and G. D Dreyfus Modulation of Systemic Inflammatory Response after Cardiac Surgery Asian Cardiovasc Thorac Ann, December 1, 2005; 13(4): 382 - 395. [Abstract] [Full Text] [PDF]
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 P. J. Hess Jr. Systemic inflammatory response to coronary artery bypass graft surgery Am. J. Health Syst. Pharm., September 15, 2005; 62(18_Supplement_4): S6 - S9. [Abstract] [Full Text] [PDF]
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J. H. Levy Overview of clinical efficacy and safety of pharmacologic strategies for blood conservation Am. J. Health Syst. Pharm., September 15, 2005; 62(18_Supplement_4): S15 - S19. [Abstract] [Full Text] [PDF]
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 G. J Murphy, R. Ascione, and G. D Angelini Coronary artery bypass grafting on the beating heart: surgical revascularization for the next decade? Eur. Heart J., December 1, 2004; 25(23): 2077 - 2085. [Abstract] [Full Text] [PDF]
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T. A. Khan, C. Bianchi, P. Voisine, J. Feng, J. Baker, M. Hart, M. Takahashi, G. Stahl, and F. W. Sellke Reduction of myocardial reperfusion injury by aprotinin after regional ischemia and cardioplegic arrest J. Thorac. Cardiovasc. Surg., October 1, 2004; 128(4): 602 - 608. [Abstract] [Full Text] [PDF]
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P. K. Smith, S. K. Datta, L. H. Muhlbaier, G. Samsa, A. Nadel, and J. Lipscomb Cost analysis of aprotinin for coronary artery bypass patients: analysis of the randomized trials Ann. Thorac. Surg., February 1, 2004; 77(2): 635 - 642. [Abstract] [Full Text] [PDF]
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 L. Tan, X. Sun, X. Zhu, Z. Zhang, J. Li, and Q. Shu Epidemiology of Nosocomial Pneumonia in Infants After Cardiac Surgery Chest, February 1, 2004; 125(2): 410 - 417. [Abstract] [Full Text] [PDF]
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A. Koster, S. Huebler, F. Merkle, T. Hentschel, M. Grundel, T. Krabatsch, L. Tambeur, M. Praus, H. Habazettl, W. M. Kuebler, et al. Heparin-Level-Based Anticoagulation Management During Cardiopulmonary Bypass: A Pilot Investigation on the Effects of a Half-Dose Aprotinin Protocol on Postoperative Blood Loss and Hemostatic Activation and Inflammatory Response Anesth. Analg., February 1, 2004; 98(2): 285 - 290. [Abstract] [Full Text] [PDF]
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A. H Olivencia-Yurvati, N. Wallace, S. Ford, and R. T Mallet Leukocyte filtration and aprotinin: synergistic anti-inflammatory protection Perfusion, January 1, 2004; 19(1_suppl): S13 - S19. [Abstract] [PDF]
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P. E. Greilich, C. F. Brouse, C. W. Whitten, L. Chi, J. M. DiMaio, and M. E. Jessen Antifibrinolytic therapy during cardiopulmonary bypass reduces proinflammatory cytokine levels: a randomized, double-blind, placebo-controlled study of {epsilon}-aminocaproic acid and aprotinin J. Thorac. Cardiovasc. Surg., November 1, 2003; 126(5): 1498 - 1503. [Abstract] [Full Text] [PDF]
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D. L. Ngaage Off-pump coronary artery bypass grafting: the myth, the logic and the science Eur. J. Cardiothorac. Surg., October 1, 2003; 24(4): 557 - 570. [Abstract] [Full Text] [PDF]
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J. H. Levy and K. A. Tanaka Inflammatory response to cardiopulmonary bypass Ann. Thorac. Surg., February 1, 2003; 75(2): S715 - 720. [Abstract] [Full Text] [PDF]
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D. A. Bull and J. Maurer Aprotinin and preservation of myocardial function after ischemia-reperfusion injury Ann. Thorac. Surg., February 1, 2003; 75(2): S735 - 739. [Abstract] [Full Text] [PDF]
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D. Royston, T. Kovesi, and N. Marczin The unwanted response to cardiac surgery: Time for a reappraisal? J. Thorac. Cardiovasc. Surg., January 1, 2003; 125(1): 32 - 35. [Full Text] [PDF]
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D. Schmartz, Y. Tabardel, J.-C. Preiser, L. Barvais, A. d'Hollander, J. Duchateau, and J.-L. Vincent Does aprotinin influence the inflammatory response to cardiopulmonary bypass in patients? J. Thorac. Cardiovasc. Surg., January 1, 2003; 125(1): 184 - 190. [Abstract] [Full Text] [PDF]
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J. M. Bailey, K. A. Tanaka, and J. H. Levy Cardiac Surgical Pharmacology Card. Surg. Adult, January 1, 2003; 2(2003): 85 - 118. [Full Text]
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A H Olivencia-Yurvati, C A Ferrara, N Tierney, N Wallace, and R T Mallet Strategic leukocyte depletion reduces pulmonary microvascular pressure and improves pulmonary status post-cardiopulmonary bypass Perfusion, January 1, 2003; 18(1_suppl): 23 - 31. [Abstract] [PDF]
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L. Englberger, P. Markart, F.S. Eckstein, F.F. Immer, P.A. Berdat, and T.P. Carrel Aprotinin reduces blood loss in off-pump coronary artery bypass (OPCAB) surgery Eur. J. Cardiothorac. Surg., October 1, 2002; 22(4): 545 - 551. [Abstract] [Full Text] [PDF]
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J. S. Tweddell, G. M. Hoffman, K. A. Mussatto, R. T. Fedderly, S. Berger, R. D. B. Jaquiss, N. S. Ghanayem, S. J. Frisbee, and S. B. Litwin Improved Survival of Patients Undergoing Palliation of Hypoplastic Left Heart Syndrome: Lessons Learned From 115 Consecutive Patients Circulation, September 24, 2002; 106(12_suppl_1): I-82 - I-89. [Abstract] [Full Text] [PDF]
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R. D. B. Jaquiss, N. S. Ghanayem, M. C. Zacharisen, K. A. Mussatto, J. S. Tweddell, and S. B. Litwin Safety of Aprotinin Use and Re-Use in Pediatric Cardiothoracic Surgery Circulation, September 24, 2002; 106(12_suppl_1): I-90 - I-94. [Abstract] [Full Text] [PDF]
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L. Englberger, B. Kipfer, P. A. Berdat, U. E. Nydegger, and T. P. Carrel Aprotinin in coronary operation with cardiopulmonary bypass: does "low-dose" aprotinin inhibit the inflammatory response? Ann. Thorac. Surg., June 1, 2002; 73(6): 1897 - 1904. [Abstract] [Full Text] [PDF]
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M. A. Chaney Corticosteroids and Cardiopulmonary Bypass : A Review of Clinical Investigations Chest, March 1, 2002; 121(3): 921 - 931. [Abstract] [Full Text] [PDF]
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V. R. Conti and C. McQuitty Vasodilation and Cardiopulmonary Bypass : The Role of Bradykinin and the Pulmonary Vascular Endothelium Chest, December 1, 2001; 120(6): 1759 - 1761. [Full Text] [PDF]
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J. H. Levy Pharmacologic preservation of the hemostatic system during cardiac surgery Ann. Thorac. Surg., November 1, 2001; 72(5): S1814 - 1820. [Abstract] [Full Text] [PDF]
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P. E. Greilich, K. Okada, P. Latham, R. R. Kumar, and M. E. Jessen Aprotinin But Not {epsilon}-Aminocaproic Acid Decreases Interleukin-10 After Cardiac Surgery With Extracorporeal Circulation: Randomized, Double-Blind, Placebo-Controlled Study in Patients Receiving Aprotinin and {epsilon}-Aminocaproic Acid Circulation, September 18, 2001; 104 (2009): I-265 - I-269. [Abstract] [Full Text] [PDF]
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