Chapter 11C

Extracorporeal Circulation

The Inflammatory Response

Philippe Menasche/ L. Henry Edmunds, Jr.

PRIMARY BLOOD CONSTITUENTS
    Complement
    Neutrophils
    Monocytes
    Endothelial Cells
    Platelets
OTHER MEDIATORS OF INFLAMMATION
    Anaphylatoxins
    Cytokines
    Reactive Oxidants
    Endotoxins
    Metalloproteinases
    Angry Blood
CONTROL OF THE ACUTE INFLAMMATORY RESPONSE TO CARDIOPULMONARY BYPASS
    Off-Pump Cardiac Surgery
    Cardiopulmonary Bypass without an Oxygenator: The Drew-Anderson Technique
    Perfusion Temperature
    Perfusion Circuit Coatings
    Modified Ultrafiltration
    Leukocyte Filtration
    Complement Inhibitors
    Glucocorticoids
    Protease Inhibitors
    Other Inhibitors
    Comment
REFERENCES

   INTRODUCTION
 
The inflammatory response to cardiopulmonary bypass (CPB) is initiated by contact between heparinized blood and nonendothelial cell surfaces.484486 Blood contact with nonendothelial cell surfaces in the wound and in the perfusion circuit activates plasma zymogens and cellular blood elements that constitute part of the body's defense reaction to all noxious substances including infectious agents, toxins, foreign antigens, allergens, and also injuries. All surgery, like accidental trauma, triggers an acute inflammatory response, but the continuous exposure of heparinized blood to nonendothelial cell surfaces followed by reinfusion and circulation within the body greatly magnifies this response in operations in which CPB is used. Although far from fully described and understood, this primarily "blood injury" produces a unique response, which is different in detail from that caused by other threats to homeostasis.

The principal blood elements involved in this acute defense reaction are contact and complement plasma protein systems, neutrophils, monocytes, endothelial cells, and to a lesser extent platelets. Lymphocytes are also altered by CPB,487,488 but are more involved in the immune response to foreign proteins and acute rejection and do not materially contribute to the acute response to CPB. Likewise, eosinophils and basophil/mast cells are primarily activated by IL-5 and IgE antibodies, respectively, and have prominent roles in allergy, parasitic diseases, and histamine production. When activated during CPB, the principal blood elements release vasoactive and cytotoxic substances; produce cell signaling inflammatory and inhibitory cytokines; express complementary cellular receptors that interact with specific cell signaling substances and other cells; and generate a host of vasoactive and cytotoxic substances that circulate.489 Normally these reactive blood elements mediate and regulate the defense reaction,490492 but during CPB an orderly, targeted response is overwhelmed by the massive activation and circulation of these reactive blood elements.

Admittedly there is considerable overlap between the plasma and blood cellular responses involved in bleeding and thrombosis, ischemia/reperfusion,493 acute rejection, and acute and chronic inflammation, but these responses are separated in this book in the interests of simplification. This section offers a simplified overview of the acute inflammatory response to cardiopulmonary bypass; the detailed interactions of the body's defense system against hurtful stimuli are under active and intense investigation and are far beyond the authors' expertise.


   PRIMARY BLOOD CONSTITUENTS
 
Complement

The complement system constitutes a group of more than 30 plasma proteins that interact to produce powerful vasoactive anaphylatoxins, C3a, C4a, and C5a, and the terminal complement cytotoxic complex, C5b-9.494 Complement is activated by three pathways, but only the classical and alternative pathways are involved in cardiopulmonary bypass,495,496 although a role for the manose-lectin pathway has not been excluded. Direct contact between heparinized blood and the synthetic surfaces of the extracorporeal perfusion circuit activates the contact plasma proteins and the classical complement pathway.495 Activation of C1, possibly by activated factor XIIa, sequentially activates C2 and C4 to form C4b2a (classical C3 convertase) that cleaves C3 to form C3a and C3b (Fig. 11-15).494



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FIGURE 11-15 Steps in activation of the classical and alternative complement pathways and formation of the membrane attack complex, C5b-9. (Adapted with permission from Walport MJ: Complement. N Engl J Med 2001; 344:1058; and Plumb ME, Sadetz JM: Proteins of the membrane attack complex, in Volkankis JE, Frank ME (eds): The Human Complement System in Health and Disease. New York, Marcel Dekker, 1998; p 119.)

 
Generation of C3b activates the alternative pathway, which involves factors B and D in the formation of C3bBb, which is the alternative pathway C3 convertase that cleaves C3 to form C3a and C3b (see Fig. 11-15). Whereas the classical pathway proceeds in sequential steps, the alternative pathway contains a feedback loop that greatly amplifies cleavage of C3 by membrane-bound C3 convertase to membrane-bound C3b and C3a. During CPB complement is largely activated by the alternative pathway.496498

The complement system is activated at three different times during CPB and cardiac surgery: during blood contact with nonendothelial cell surfaces495,499; after protamine administration and formation of the protamine-heparin complex495,500; and after reperfusion of the ischemic, arrested heart.485 CPB and myocardial reperfusion activate complement by both the classical and alternative pathways; the heparin-protamine complex activates complement by the classical pathway.495 Other agonists that activate the classical pathway during CPB include endotoxin,496 apoptotic cells, and C-reactive protein.494

The two C3 convertases effectively merge the two complement pathways by producing C3b, which activates C5 to C5a and C5b (see Fig. 11-15). C3a and C5a are potent vasoactive anaphylatoxins. C5a, which avidly binds to neutrophils and therefore is difficult to detect in plasma, is the major agonist. C3b acts as an opsonin, which binds target cell hydroxyl groups and renders them susceptible to phagocytic cells expressing specific receptors for C3b.494,497 C5b is the first component of the terminal pathway that ultimately leads to formation of the membrane attack complex, C5b-9. In prokaryotic cells like erythrocytes, C5b-9 creates transmembrane pores, which cause death by intracellular swelling following loss of the intracellular/interstitial osmotic gradient. In eukaryotic cells, deposits of C5b-9 may not be immediately lethal but may eventually cause injury mediated by release of arachidonic acid metabolites (thromboxane A2, leukotrienes) and oxygen free radicals by macrophages and neutrophils, respectively.497

Together, C5a and C5b-9 play major roles in promoting neutrophil–endothelial cell interactions through upregulation of specific adhesion molecules (see below). Importantly, C5b-9 may also activate platelets and promote platelet-monocyte aggregates.501 As such, these complement proteins contribute to neutrophil loss from the circulation by adhesion to surface-bound platelets,501 but more importantly to endothelial cells. The interaction between complement proteins and neutrophils contributes to postoperative organ damage in both adults502 and in children.503

Normally, several regulatory proteins modulate the inflammatory actions of C5a and C5b-9 by inactivating convertases, which cleave C3 and C5,504 but these inhibitors are usually overwhelmed during CPB. Two proteins, factors H and I, are soluble; three others, complement receptor 1 (CD35), decay accelerating factor, and membrane cofactor protein (CD46), are membrane bound.494 Factor I cleaves C3 into inactive iC3b, which cannot form C3 convertase, but can be an opsonin.505 Factor H is the dominant complement regulatory protein and competes with factor B in binding to C3.494 CD59 and homologous restriction factor are direct inhibitors of the membrane attack complex.497,506

Neutrophils

Leukocyte counts decrease in response to hemodilution during CPB and increase moderately after operation.486,507 Only a few neutrophils attach to synthetic surfaces, to each other, or to platelets and monocytes.507,508 Nevertheless, neutrophils are strongly activated during cardiopulmonary bypass (Fig. 11-16).486,509 The principal agonists are kallikrein510 and C5a511,512 produced by the contact and complement systems, respectively.511,513,514 C5a, generated early during CPB and clinical cardiac surgery, is a particularly potent chemotactic protein that induces neutrophil chemotaxis, degranulation, and superoxide generation.515 Other agonists involved during CPB include IL1-ß,516 TNF-{alpha},492,517 IL-8,518 C5b-9,512 factor XIIa,519 heparin, histamine, hypochlorous acids, and products of arachidonate metabolism: B4 (LTB4),492 platelet activating factor (PAF), and thromboxane A2.515 Lastly, CPB, perhaps mediated by IL-6 and IL-8,520 partially inhibits neutrophil apoptosis and prolongs the period of neutrophil activity.521



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FIGURE 11-16 Scanning electron micrographs of resting neutrophils (left) and 5 seconds after exposure to a chemoattractant. (Reproduced with permission from Baggiolini M: Chemokines and leukocyte traffic. Nature 1998; 392:565.)

 
Neutrophils are recruited to localized areas of injury or inflammation by chemokines, complement proteins (C5a), IL-1ß, TNF-{alpha}, and adhesion molecules. Neutrophils respond to the CXC ({alpha}) family of chemokines that includes IL-8, platelet factor 4 (PF4), neutrophil activating factor-2 (NAF-2), and granulocyte chemotactic protein 2.522524 During CPB thrombin stimulates endothelial cell production of PAF (platelet activating factor).492 Thrombin and PAF cause rapid expression of P-selectin by endothelial cells490 and circulating IL-1ß and TNF-{alpha} stimulate endothelial cells to synthesize and express E-selectin.490,525 Regional vasoconstriction reduces blood flow rates within local vascular beds to allow neutrophils to marginate near endothelial cell surfaces. L-selectins are constitutively expressed by all types of activated leukocytes and lightly bind to endothelial cell mucin-like glycoproteins before being shed with the onset of transmigration.490 P-selectin weakly binds to PSGL-1 (P-selectin glycoprotein-1) on neutrophils526; E-selectin binds to a different sialyl Lewis antigen (CD62E). Selectin binding causes the slowly passing neutrophils to roll and eventually stop (Fig. 11-17).527 Stronger adherence is produced by intracellular adhesion molecule-1 (ICAM-1) expressed on endothelial cells, which binds ß2 neutrophil integrins, principally CD11b/CD18 (Mac-1) and to some extent CD11a/CD18.490,528 These adhesion molecules from the immunoglobulin superfamily completely stop neutrophils529 and the process of transmigration begins in response to chemoattractants and cytotoxins produced in the extravascular space.530,531 PECAM-1 expressed on leukocytes and endothelial cells mediates transmigration of leukocytes.532 This trafficking is strongly regulated by IL-8 produced by neutrophils, macrophages, and other cells. During CPB neutrophils express the Mac-1 (CD11b/CD18) receptor533,534 and CD11c/CD18, which binds to fibrinogen and a complement fragment,528 and VLA-4 ({alpha}1ß4) receptors that are involved in cellular adhesion.528 Neutrophil receptor CXCR1 is not affected by CPB, but CXCR2 is downregulated.535



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FIGURE 11-17 Mechanism of arrest and transmigration of neutrophils into the interstitial space. Neutrophils constitutively express L-selectin, which binds to endothelial cell glycoprotein ligands. Simultaneously, early response cytokines stimulate endothelial cells to rapidly express P-selectin and later E-selectin receptors, which weakly bind neutrophil PSGL-1 ligands. Marginated neutrophils, which are slowed by local vasoconstriction and reduced blood flow, lightly adhere to endothelial cells via selectin expression and begin to roll. Neutrophils activated by C5a, kallikrein, and early response cytokines express ß2 CD11b and c receptors, which bind firmly to cytokine-activated endothelial cell intergrins, ICAM-1 and VCAM-1. Once arrested, L-selectins are shed and PECAM receptors on endothelial cell surfaces mediate neutrophil transmigration through endothelial cell junctions, led by chemoattractants into the interstitial space.

 
Using pseudopods and following the scent of complement proteins (C5a, C3b, and iC3b),536 IL-8,492,518,537,538 hypochlorous acids, leukotriene B4,539 and locally produced IL-1 and TNF-{alpha},492,537 neutrophils arrive at the scene of inflammation to begin the process of phagocytosis and release of cytotoxins. Organs and tissues experience periods of ischemia followed by reperfusion (lung, heart, brain) during CPB, and as a result express adhesion receptors540 and reactive oxidants,541 and are sources of neutrophil chemoattractants.520,542

Neutrophils vary considerably between individuals in expression of adhesive receptors543 and responsiveness to chemoattractants during CPB. There also is substantial variation in measurements of soluble and cellular adhesion receptors.534 The presence of diabetes,544 oxidative stress,545 and perhaps genetic factors (see below) influences expression of cellular and soluble adhesive receptors and cytokines, which affect neutrophil adhesion and release of granule contents. It is difficult to show a correlation between markers of neutrophil activation and measurements of organ dysfunction.546

Neutrophils contain a potent arsenal of proteolytic and cytotoxic substances. Azurophilic granules contain lysozyme, myeloperoxidase, cationic proteins, elastase, collagenases, proteinase 3, acid hydrolases, defensins, and phospholipase.547 Specific granules contain ß2 integrins, lactoferrin, lysozyme, type IV collagenase, histaminase, heparanase, complement activator, alkaline phosphatase, and membrane-associated NADPH (nicotinamide adenine dinucleotide) phosphate oxidase.515 Activated neutrophils, in a "respiratory burst," also produce cytotoxic reactive oxygen and nitrogen intermediates including superoxide anion, hydrogen peroxide, hydroxyl radicals, singlet oxygen molecules, N-chloramines, hypochlorous acids, and peroxynitrite.490,548 Finally, neutrophils produce arachidonate metabolites, prostaglandins, leukotrienes, and platelet-activating factor. During CPB these vasoactive and cytotoxic substances are produced and released into the extracellular environment and circulation.486,489 Circulation of these substances mediates many of the manifestations of the "whole body inflammatory response" or "systemic inflammatory response syndrome" (SIRS) associated with CPB and clinical cardiac surgery.549

Monocytes

Monocytes and macrophages (tissue monocytes) are relatively large, long-lived cells that are involved in both acute and chronic inflammation. Monocytes respond to chemical signals, are mobile, phagocytize microorganisms and cell fragments, produce and secrete chemical mediators, participate in the immune response, and generate cytotoxins.550 Monocytes are activated during CPB551 and have a major role in thrombin formation552 (see section 11B). Monocytes also produce and release many inflammatory mediators during acute inflammation including proinflammatory cytokines (principally TNF-{alpha}, IL-1ß, IL-6, IL-8, and MCP-1), reactive oxygen and nitrogen intermediates, and prostaglandins.524

The mechanism by which monocytes are initially activated during CPB is not known, but the most likely candidates are C5a,550 thrombin,553 platelet factor 4 (PF-4), and bradykinin,554 which are four potent agonists rapidly generated from blood contact with nonendothelial cell surfaces. Monocytes possess a huge list of surface receptors,550 but those apt to be involved in the inflammatory response to CPB are C5a and three other complement proteins; IL-1, CD11b/CD18, and CD 11c/CD18; LTB4; and the C-C family of chemokine receptors.550 Monocytes also possess C-reactive protein receptors, which, when activated, strongly upgrade proinflammatory cytokine production.491

C-C chemokines, MCP-1-4 (monocyte chemotactic protein), MIP-{alpha}, MIP-ß (monocyte inhibitor protein), and RANTES (regulated upon activation, normal T cell expressed and presumably secreted), are produced by a variety of cells including monocytes and are potent activators of monocytes.550 LTB4, cathepsin G, and azurodidin from neutrophils538; C5a; PF-4, platelet-derived growth factor, and platelet-activating factor (PAF); thrombin553; and the C-C family of chemokines are chemotactic for monocytes. Monocytes express ß1, ß2, and VLA-4 ({alpha}1ß4) integrins, which adhere to the immunoglobulin endothelial cell receptors ICAM-1, 2, and VCAM-1 to enable monocyte trafficking in response to chemotactic stimuli.490

Monocytes are the major source of the early response cytokines IL-1ß and TNF-{alpha},491,554 which play an important role in directing both neutrophils and monocytes to local sites of inflammation. Monocytes are also the major producer of IL-8,491 which also is produced by neutrophils492 and induces neutrophil chemotaxis.490 Other cytokines produced by monocytes include IL-1{alpha}, IL-6, and IL-10.491 Monocytes also produce important growth factors, matrix proteins, interferons, and a variety of enzymes, including elastase, collagenases, acid hydrolases, prostaglandins, and lipooxygenase products,524 and contain myeloperoxidase, which converts H2O2 into more powerful oxidants. Most of the cytotoxic substances—both oxygen-dependent (superoxide anion, hydroxyl radical, singlet oxygen, N-chloramines, and hypochlorous acids) and oxygen-independent (prostaglandins, leukotrienes, platelet activating factor, lysosomal proteases, lactoferrin, lysozyme, and defensins)—are released into phagosomes, and the amount of monocyte-derived cytotoxins that circulate is difficult to differentiate from cytotoxins produced by activated neutrophils. Lastly, monocytes generate nitric oxide (NO), which can react with reactive oxygen intermediates to produce reactive nitrogen compounds.

Endothelial Cells

Endothelial cells are activated during CPB and OHS by a variety of agonists. The principal agonists for endothelial cell activation during CPB are thrombin, C5a,555 and the cytokines IL-1ß and TNF-{alpha}.537,556 Other agonists, such as endotoxin, histamine, and INF-{gamma} (from lymphocytes), are less important during CPB, and endothelial cells are largely unresponsive to chemokines.525

IL-1ß and TNF-{alpha} induce the early expression of P-selectin and the later synthesis and expression of E-selectin, which are involved in the initial stages of neutrophil and monocyte adhesion.490 The two cytokines also induce expression of ICAM-1 and VCAM-1, which firmly bind neutrophils and monocytes to the endothelium and initiate leukocyte trafficking to the extravascular space (see Fig. 11-17).492,525,537 Experimentally ICAM-1 is upregulated during CPB in pulmonary vessels557 and there is evidence that P- and E-selectins are upregulated during CPB and in myocardial ischemia-reperfusion sequences. IL-1ß and TNF-{alpha} induce endothelial cell production of the chemotactic proteins IL-8 and MCP-1, and induce production of PGI2 (prostacyclin) by the cyclooxygenase pathway532,558 and NO by NO synthase.532,559 These two vasodilators reduce shear stress and increase vascular permeability and therefore enhance leukocyte adhesion and transmigration. Lastly, IL-1ß and TNF-{alpha} stimulate endothelial cell production of proinflammatory cytokines, IL-1, IL-6, IL-8, MCP-1, and PAF.525

In addition to NO and PGI2, endothelial cells produce the vasoconstrictor endothelin-1489,560 and inactivate other vasoactive mediators, including histamine, norepinephrine, and bradykinin.561 Prostacyclin concentrations increase rapidly at the beginning of CPB and then begin to decrease.562 Endothelin-1 peaks several hours after CPB ends.563

Platelets

Platelets are probably initially activated during CPB by thrombin, which is the most potent platelet agonist, but plasma epinephrine, PAF, vasopressin,564 cathepsin G565 from other cells, serotonin and ADP secreted by platelets, and internally generated thromboxane A2566 contribute to activation as CPB continues.489 Platelets possess several protease-activated receptors564 to most of these agonists and to collagen, which has an important role in adhesion and thrombus formation. Collagen binding causes release of thromboxane A2 and ADP, which help recruit platelets.564 Platelets contribute to the inflammatory response by synthesis and release of eicosanoids566; serotonin from dense granules; IL-1ß567; CXC chemokines, PF4, NAP-2 (neutrophil activating protein), IL-8, and ENA-78 (endothelial cell neutrophil attractant); and C-C chemokines, MIP-1a, MCP-3, and RANTES568 from alpha granules. Platelets also produce and release acid hydrolases from membrane-bound lysozymes. Platelet-secreted cytokines, NAP-2, RANTES, PF4, IL-1ß, IL-8, and ENA-78 may be particularly involved in the inflammatory response to CPB because of strong activation of platelets in both the wound and perfusion circuit.

Circulating monocytes and neutrophils constitutively express PSGL-1, which interacts with aggregated platelets via P-selectin expressed on activated platelets.526 Platelets aggregrate using platelet GPIIb/IIIa ({alpha}2bß3) receptors attached to symmetrical fibrinogen molecules to form bridges between platelets. During CPB platelets aggregate with each other and also to monocytes and neutrophils.507,561


   OTHER MEDIATORS OF INFLAMMATION
 
Anaphylatoxins

The anaphylatoxins C3a, C4a, and C5a are bioactive protein fragments released by cleavage of complement proteins C3, C4, and C5. These fragments have potent proinflammatory and immunoregulatory functions and contract smooth muscle cells, increase vascular permaeability, serve as chemoattractants, and in the case of C5a, activate neutrophils and monocytes.514 Anaphylatoxins contribute to increased pulmonary vascular resistance, edema, and neutrophil sequestration and an increase in extravascular water during CPB. The duration of postoperative ventilation directly correlates with plasma C3a concentrations.502 C3a and C5a are important mediators in ischemia/reperfusion injuries. All three anaphylatoxins are produced during CPB, but the amount of C4a is small until protamine is given569,570 and nearly all C5a is bound to neutrophils.492 C3a is the principal circulating anaphylatoxin.485,569,570

Cytokines

Cytokines are small, cell-signaling peptides produced and released into blood or the extravascular environment by both blood and tissue cells. Cytokines stimulate specific receptors on other cells to initiate a response in that cell. All blood leukocytes and endothelium produce cytokines, but many tissue cells including fibroblasts, smooth muscle cells, cardiac myocytes, keratinocytes, chrondrocytes, hepatocytes, microglial cells, astrocytes, endometrial cells, and epithelial cells also produce cytokines.537,554,571 IL-1ß and TNF-{alpha} are early response cytokines that are promptly produced at the site of injury by resident macrophages.537 These cytokines stimulate surrounding stromal and parenchymal cells to produce more IL-1ß and TNF-{alpha} and chemokines, particularly IL-8 and MCP-1, which are powerful chemoattractants for neutrophils and macrophages, respectively. Together with IL-6, the cytokine that regulates production of acute-phase proteins (e.g., C-reactive protein, {alpha}2-macroglobulin) by the liver,572 these five cytokines are the major proinflammatory cytokines involved in the acute inflammatory response to CPB.

The major anti-inflammatory cytokine involved during CPB is IL-10.573 IL-10 inhibits synthesis of proinflammatory cytokines by monocytes and macrophages574 and induces production of IL-1 receptor antagonist IL-1ra, which downgrades the response to IL-1.554,575 IL-13 downregulates production of IL-1, IL-8, and Il-10 and reduces monocyte production of reactive oxidants576; its role during CPB is undetermined.

Proinflammatory cytokines increase during and after clinical cardiac surgery using CPB, but peak concentrations usually occur 12–24 hours after CPB ends (Fig. 11-18).570,577581 Measured amounts differ greatly in timing and within and between studies, probably because of differences in the duration of CPB, perfusion temperatures,582 perfusion equipment, and aortic cross-clamp times; differences in methods of myocardial protection; possibly variable concentrations of inhibitory cytokines583,584; and perhaps exogenous factors such as priming solutions, anesthesia, and intravascular drugs.570,577581 Plasma concentrations of proinflammatory cytokines are significantly higher during normothermic (37°C) versus tepid (32°C-34°C) CPB.582 The ischemic/reperfused heart is a major source of inflammatory cytokines and reactive oxidants.541,542,585



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FIGURE 11-18 Changes in IL-1ß (A) and IL-6 (B) in 30 patients who had elective first-time myocardial revascularization. Letters on x-axis represent the following events: A, induction of anesthesia; B, 5 minutes after heparin; C, 10 minutes after starting CPB; D, end of CPB; E, 20 minutes after protamine; F, 3 hours after CPB; G, 24 hours after CPB. (Redrawn from Steinberg JB, Kapelanski DP, Olson JD, Weiler JM: Cytokine and complement levels in patients undergoing cardiopulmonary bypass. J Thorac Cardiovasc Surg 1993; 106:1008.)

 
Some of the variation in measurements between studies also may be due to patient factors such as age, left ventricular function, and genetic factors.586 The presence of the APOE4 allele (one of the common human polymorphisms of the gene encoding apolipoprotein E) is associated with increased TNF-{alpha} and IL-8.586 Patients who are homozygous for TNF-ß2 have elevated levels of TNF-{alpha} and IL-8 during both on- and off-pump cardiac surgery.587 Carriers of APOE4 have reduced concentrations of IL-1ra, the inhibitory peptide of IL-1.588 Additional hints of a genetic role in the acute inflammatory response are the association between postoperative serum creatinine and different APO{varepsilon} alleles589 and the association between length of stay after coronary artery surgery and 174GG polymorphism of the IL-6 gene.590

{alpha}2-Macroglobulin ({alpha}2-M) is a ubiquitous plasma protein that inhibits all four classes of proteases and has been shown to specifically bind to TNF-{alpha}, ILl-ß, IL-6, and IL-8.591 The precise role of {alpha}2-M in the regulation of cytokines is unknown, but the inhibitor may be involved in clearance of plasma and extravascular cytokines.591

Reactive Oxidants

Neutrophils, monocytes, and macrophages produce reactive oxidants, which are cytotoxic inside the phagosome, but act as cytotoxic mediators of acute inflammation outside. Four enzymes generate a large menu of reactive oxidants: NADPH (nicotinamide adenine dinucleotide phosphate) oxidase, superoxide dismutase, nitric oxide synthase, and myeloperoxidase.548 The enzyme NADPH oxidase adds a free electron to molecular oxygen to create superoxide (O2-) and two hydrogen ions, H+. Superoxide dismutase catalyzes the conversion of superoxide to hydrogen peroxide, H2O2, and molecular oxygen. Nitric oxide synthase produces nitric oxide (NO) from NADPH, arginine, and oxygen, and myeloperoxidase uses H2O2 to oxidize halide ions to hypochlorous acids.592 The four products produced by these enzymes, O2-, H2O2, NO, and HOCl, generate all reactive oxidants from nonenzymatic reactions with other molecules or ions.548

Free radicals have one or more unpaired electrons and are highly reactive in scavenging hydrogen ions from other molecules. OH. is produced from H2O2 by low-valence iron or copper ions, which are reduced to the original low valence after the reaction by various reducing agents, such as ascorbic acid. Secondary free radicals, containing carbon, oxygen, nitrogen, or sulfur, are formed when a free radical reacts with molecules that lack unpaired electrons548; this self-perpetuating sequence produces a chain reaction of highly cytotoxic substances.

HOCl reacts with amines and amino acids, which are widely distributed in biological systems, to form chloramines and aldehydes, respectively. The products of HOCl reactions are often more toxic than the parent molecule. To varying degrees, some chloramines are lipid soluble.548 Singlet oxygen (1O2) is a very reactive form of oxygen that is produced by neutrophils by an oxidized halogen and hydrogen peroxide. Peroxynitrite is formed by NO and superoxide (O2-, which produces an unknown nitrating agent that catalyzes nitration in neutrophils and macrophages.548

Endotoxins

Endotoxins, including lipopolysaccharides, are fragments of bacteria that are powerful agonists for complement,593 neutrophils, monocytes, and other leukocytes. Endotoxins have been detected during CPB593596 and after aortic cross-clamping using a very sensitive bioassay.597,598 Sources include contaminants within sterilized infusion solutions, the bypass circuit, and possibly the gastrointestinal tract due to changes in microvascular intestinal perfusion, which may translocate bacteria.599 Intestinal microvascular blood flow is sensitive to both flow rate and duration of CPB. In some instances leakage of endotoxin into the systemic circulation occurs if clearance by the hepatic Kupffer cells fails. The quantitative significance of the role of endotoxin in the acute inflammatory response to CPB is unknown.

Metalloproteinases

CPB induces the synthesis and release of matrix metalloproteinases,600 which are one of the four major classes of mammalian proteinases. These proteolytic enzymes have a major role in degradation of collagens and proteins in the extracellular matrix and vascular basement membrane and in the pathogenesis of atherosclerosis and postinfarction left ventricular remodeling. The interstitial collagenases, MMP-8 and MMP-13, increase approximately 4-fold, peak at the end of CPB and 30 minutes later, respectively, and soon return to normal plasma concentrations. The gelatinase pro-MMP-9 increases 3-fold with release of the aortic cross-clamp and remains elevated 24 hours after CPB ends. The increase in pro-MMP-2 is modest, but it remains elevated at 24 hours. The significance and possible injury produced by activation of these interstitial degradation enzymes over the long term remain to be determined.

Angry Blood

Blood circulating during clinical cardiac surgery with cardiopulmonary bypass is a stew of vasoactive and cytotoxic substances, activated blood cells, and microemboli. Shear stress, turbulence, cavitation, and other rheologic forces and C5b-9 cause hemolysis of some red cells. Complement anaphylatoxins,514 bradykinin formed by activation of the contact proteins,490,513 and proinflammatory cytokines stimulate endothelial cells to contract, allowing extravasation of intravascular fluid into the extravascular space.601 Numerous circulating vasoactive substances cause vasoconstriction or vasodilatation of heterogeneous regional vascular networks.489 As neutrophils and monocytes migrate across the endothelial cell barrier, stromal and parenchymal cells are exposed to a cytotoxic environment mediated by neutral proteases, collagenases, and gelatinases, reactive oxidants, lipid peroxides, C5b-9, and other cytotoxins.486,545,602,603 This injury is magnified by microemboli produced from platelet-leukocyte aggregates, lipids, and other blood elements and emboli from other sources (see sections 11B and 11D). The manifestations of the inflammatory response include systemic symptoms such as malaise, fever, increased heart rate, mild hypotension,582 interstitial fluid accumulation,604 and temporary organ dysfunction, particularly of the brain, heart, lungs, and kidneys.

The magnitude of this defense reaction during and after CPB is influenced by many exogenous factors that include the surface area of the perfusion circuit, the duration of blood contact with extravascular surfaces, general health and preoperative organ function of the patient, blood loss and replacement, organ ischemia and reperfusion injury, sepsis, different degrees of hypothermia, periods of circulatory arrest, genetic profiles, corticosteroids, and other pharmacologic agents.


   CONTROL OF THE ACUTE INFLAMMATORY RESPONSE TO CARDIOPULMONARY BYPASS
 
Off-Pump Cardiac Surgery

Myocardial revascularization without either CPB or cardioplegia reduces the acute inflammatory response but does not prevent it.605607 The response to surgical trauma, manipulation of the heart, pericardial suction, heparin, protamine, other drugs, and anesthesia produces an increase in the markers of acute inflammation, C3a, C5b-9, proinflammatory cytokines (TNF-{alpha}, IL-6, IL-8), neutrophil elastase, and reactive oxidants,545 but the magnitude of the response is significantly less than that observed with CPB.606608 Although it has not been shown that the attenuated acute inflammatory response directly reduces organ dysfunction,605,608 elderly patients and those with reduced renal and pulmonary function tolerate off-pump surgery with less morbidity and mortality than patients treated with CPB.608611

Cardiopulmonary Bypass without an Oxygenator: The Drew-Anderson Technique

In 1959 Drew and Anderson introduced deep hypothermia and the use of the patient's own lungs for gas exchange during open cardiac surgery using separate right and left perfusion systems.612 Richter et al reintroduced this method for coronary revascularization at 30°C to 32°C and demonstrated that absence of an oxygenator significantly reduced peak concentrations of IL-6 and IL-8 without changing the anti-inflammatory cytokines IL-1ra and IL-10.613 These cytokine changes correlated with better postoperative blood gases and pulmonary function, smaller blood losses, and shorter times to extubation. A later study confirmed attenuation of the pulmonary inflammatory response by demonstrating lower levels of cytokines and fewer platelet-monocyte microaggregates in blood exiting from the lung, as compared with conventional bypass.614 This method is not likely to achieve wide acceptance because of the need for multiple cannulations and a cluttered operative field. Miniaturization of perfusion circuits, however, may be feasible and preliminary data suggest that this approach attenuates the inflammatory response.615

Perfusion Temperature

Release of mediators of inflammation is temperature sensitive. Normothermic CPB increases the release of cytokines and other cellular and soluble mediators of inflammation,582 whereas hypothermia reduces production and release of these mediators until rewarming begins.616 Perfusion at tepid temperatures between 32°C and 34°C is a reasonable compromise for many operations requiring 1 to 2 hours of CPB.580,602

Perfusion Circuit Coatings

Ionic- or covalent-bonded heparin perfusion circuits are the most widely used surface coatings and are often combined with reduced doses of systemic heparin in first-time myocardial revascularization patients.617 It is well established that heparin is an agonist for platelets, complement, factor XII, and leukocytes (see section 11B), but there is no reproducible evidence that heparin coating either produces a nonthrombogenic surface or reduces activation of the clotting cascade.618622 A review of a large portion of this literature concluded that heparin-bonded circuits reduced concentrations of the terminal complement complex, C5b-9 (Fig. 11-19), 623 but for nearly every study showing a beneficial anti-inflammatory or anti-thrombotic effect another study shows no effect.621 Clinical trials that have combined heparin-coated circuits with reduced systemic heparin and exclusion of field-aspirated blood from the perfusion circuit have demonstrated modest clinical benefits.624 However, most trials, including a large European trial of 805 patients, have not observed clinical benefits except in certain subsets of patients that are not the same between studies617,625629 and which report sporadic differences that barely reach statistical significance.628,629 Excluding unwashed field blood from the perfusion circuit reduces admixture of high concentrations of thrombin,552 fibrinolysins,630 cytokines, and activated complement (authors' unpublished data) and leukocytes to the perfusate. Exclusion of these inflammatory mediators may be more important in reducing the amounts of vasoactive and cytotoxic substances circulating within the body than the heparin surface coating.



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FIGURE 11-19 Changes in C5b-9 (TCC) terminal complement complex in heparin coated (n = 15) and uncoated (n = 14) perfusion circuits during myocardial revascularization. The two curves are significantly different by ANOVA (p = .004). (Reproduced with permission from Videm V, Mollnes TE, Fosse E, et al: Heparin-coated cardiopulmonary bypass equipment, I: biocompatibility markers and development of complications in a high-risk population. J Thorac Cardiovasc Surg 1999; 117:794.)

 
New surface coatings are being developed or undergoing clinical trials.631 Surface-modifiying additives (SMA) are chemicals used in low concentrations to reduce interfacial energy and modify the mosaic of adsorbed surface plasma proteins. One commercially available SMA uses a triblock copolymer containing polar and nonpolar chains of polycaprolactone-polydimethylsiloxane-polycaprolactone.632 In clinical trials this surface significantly reduced platelet loss and granule release, and reduced markers of thrombin generation.632,633 PMEA (poly-2-methylethylacrylate) is another manufactured surface coating designed to reduce surface adsorption of plasma proteins. Laboratory studies show reduced surface adsorption of fibrinogen and reduced bradykinin and thrombin generation in pigs.634 Early clinical studies show significant reductions in C3a, C4D, and neutrophil elastase, but ambivalent effects on IL-6 and platelets.635,636

Modified Ultrafiltration

Although effective in pediatric cardiac surgery,637,638 ultrafiltration to remove intravascular (and extravascular) water and inflammatory substances has produced mixed results in adults.639,640 Dialysis during CPB in adults may be beneficial in removing water, potassium, and protein wastes in patients with renal insufficiency.

Leukocyte Filtration

The role of neutrophils in the acute inflammatory response has led to development of leukocyte-depleting filters for the CPB circuit. Multiple groups have investigated these filters in clinical trials, but consistent efficacy in reducing markers of neutrophil activation and improvement in respiratory or renal function are lacking. Most clinical studies fail to document significant leukocyte depletion or clinical benefits.641643 Active sequestration of leukocytes and platelets using a separate cell separator during CPB may have beneficial clinical effects,644,645 but requires a separate inflow cannula and separator system.

Complement Inhibitors

The central role of complement in the acute inflammatory response to CPB provides ample rationale for inhibition. The anaphylatoxins and C5b-9 are direct mediators of the inflammatory response, and C5a is the principal agonist for activating neutrophils and is a potent chemoattractant for neutrophils, monocytes, macrophages, eosinophils, basophils, and microglial cells.514 C1-inhibitor (C1-Inh) is a natural inhibitor of complement C1 components C1s and C1r, factor XIIa, kallikrein, and factor XIa.504 Factor H and C4BP inhibit C3 and C5 convertase subunits, but are poor inhibitors of induced activation of the complement system.504 None of these inhibitors are attractive candidates for inhibiting complement activation during CPB.

The sequential activation cascade with convergence of the classical and alternative pathways at C3 offers many opportunities for inhibition by recombinant proteins. Using a humanized, recombinant antibody to C5 (h5G1.1-scFv), Fitch et al demonstrated that generation of C5b-9 was completely blocked in a dose-response manner (Fig. 11-20) and that neutrophil and monocyte CD11b/CD18 expression was attenuated in patients during and for several hours after clinical cardiac surgery using CPB.646 In addition they observed reduction in markers of myocardial and cognitive functional injury.646



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FIGURE 11-20 Inhibition of C5b-9, complement terminal attack complex, with placebo (solid circles) and 2 µg/kg of h5G1.1-scFv (open circles) during clinical cardiac surgery with CPB. Letters on x-axis represent the following events: A, before heparin; B, 5 minutes after drug; C, 5 minutes after cooling to 28°C; D, after beginning rewarming; E, 5 minutes after reaching 32°C; F, 5 minutes after reaching 37°C; G, 5 minutes after CPB; H, 2 hours after CPB; I, 12 hours after CPB; J, 24 hours after CPB. HcG1.1-scFv completely inhibited formation of the C5b-9 terminal attack complex. (Data redrawn from Fitch JCK, Rollins S, Matis L, et al: 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.)

 
Fung et al496 used an anti-factor D monoclonal antibody to inhibit production of complement proteins, Bb, C3a, sC5b-9, and C5a, via the alternate pathway and attenuate upregulation of neutrophil and platelet adhesive receptors during CPB in vitro.496 Undar confirmed these results during CPB in baboons and additionally found inhibition of complement C4d, attenuation of IL-6 concentrations, and reduced markers of cardiac injury.647 Compstatin, a very small (1593-Da) synthetic peptide, binds C3 and therefore inhibits both the classical and alternative pathways.494 This peptide inhibits generation of C3a and sC5b-9 and neutrophil binding during in vitro CPB.648 In baboons, after activation of complement by the heparin-protamine complex, compstatin completely inhibits C3 cleavage without causing any change in hemodynamic measurements or side effects.649

Other complement recombinant protein inhibitors have been developed and are under active investigation and in clinical trials because of the importance of this plasma protein system in CPB, ischemia/reperfusion, and injuries that summon the acute inflammatory response.504,650652 Experimentally, recombinant soluble complement inhibitor 1 (sCR1) improves cardiac and pulmonary function after CPB in pigs.653 Recombinant soluble complement receptor I and CAB-2, a chimeric protein constructed from the genes encoding the complement regulatory proteins, human membrane cofactor protein, and human decay-accelerating factor target C3/C5 convertases, have been developed and are under investigation.501,504,651,654 Although any effective and safe inhibitor is welcome, C3 may be a better target for inhibition because both activation pathways are blocked at the point of convergence and because C3 concentrations in plasma are 15 times greater than C5.504,649,655

Glucocorticoids

Many investigators have used glucocorticoids to suppress the acute inflammatory response to CPB and clinical cardiac surgery, but beneficial effects in adult patients have been inconsistent.656658 Steroids reduce release of rapid-response cytokines, TNF-{alpha}, and IL-1ß from macrophages,659 enhance release of IL-10,660,661 and suppress expression of endothelial cell selectins and neutrophil integrins.662 Clinically, glucocorticoids decrease endotoxin release,663 shift the cytokine balance towards the anti-inflammatory side,659,663666 and decrease expression of neutrophil integrins.656 Clinical results from a few randomized trials are conflicting: one study observed earlier extubation and reduced shivering,667 but another found increased blood glucose levels and delayed extubation.668 Differences in specific steroids, dosing, and timing may explain some of these discrepancies.

Recent observations regarding the inhibitory effect of glucocorticoids on transcription factor nuclear factor {kappa}B (NF kappa B) may provide a rationale for using glucocorticoids to suppress the acute inflammatory response to CPB.669 This inducible transcription factor controls the expression of genes encoding a wide array of proinflammatory mediators, including cytokines, inducible NO synthase (iNOS), and adhesion molecules, and is activated by IL-1ß, TNF-{alpha}, reactive oxidants, and other noxious stimuli.658,670 Given the multiplicity and redundancy of pathways involved in the inflammatory response to bypass, inhibition of a common "upstream" control point in transcriptional regulation of inflammatory genes is an attractive strategy. Kovacich et al showed that inhibiting NF-kappa B prevents IL-1-mediated hypotension.671 Thus the use of glucocorticoids for controlling the inflammatory response to CPB is conceptually attractive.672

Protease Inhibitors

Aprotinin is a natural serine protease inhibitor in the kunin superfamily that strongly inhibits plasmin and weakly inhibits kallikrein.673 Plasma concentrations of 4–10 KIU (kallikrein inhibitory units) of aprotinin completely inhibit plasmin, but 250 to 400 KIU are required to fully inhibit kallikrein.673 Clinical doses of aprotinin totally inhibit plasmin, but are not sufficient to completely inhibit kallikrein.674 The antifibrinolytic and platelet-sparing effects of the drug are well known and significantly reduce blood losses during and after complex cardiac surgery.675677 The anti-inflammatory effects of aprotinin are more difficult to quantitate and may reflect multiple mechanisms including partial kallikrein inhibition, direct effects, and inhibition of NF-kappa B.

In vitro aprotinin inhibits kallikrein formation, and attenuates complement activation and release of platelet beta thromboglobulin and neutrophil elastase.678 Aprotinin also reduces neutrophil transmigration and expression of ICAM-1 and VCAM-1 by endothelial cells.679,680 Clinically, aprotinin reduces circulating TNF-{alpha}, IL-6, IL-8, and neutrophil CD11b expression,657,681,682 and synergistically increases IL-10 synthesis.661,682 The drug may also attenuate neutrophil activation and myocardial damage during aortic cross-clamping683 and reduce overall mortality.676 Nevertheless, low- or high-dose aprotinin used in large, randomized controlled clinical trials fails to show a reduction in proinflammatory cytokines, activated complement, neutrophil elastase, and myeloperoxidase.633,684 Thus the efficacy of aprotinin as an anti-inflammatory agent remains unresolved.

Nafamostat mesilate is a trypsin-like protease inhibitor that inhibits platelet aggregation and release, formation of kallikrein, and factor XIIa and neutrophil elastase release during in vitro extracorporeal recirculation.685 Early clinical trials show that nafamostat mesilate inhibits fibrinolysis, preserves platelet numbers and function, reduces blood loss, and attenuates the acute inflammatory response by suppressing IL-6, IL-8, and malondialdehyde formation and neutrophil integrin expression.686,687

Other Inhibitors

Sodium nitroprusside is a vasodilator and potent activator of nitric oxide synthase (NOS), which catalyzes the production of nitric oxide (NO) from arginine, oxygen, and NADPH.548 During clinical cardiac surgery sodium nitroprusside attenuates complement activation in children688 and production of proinflammatory cytokines and retention of platelet-leukocyte coaggregates in reperfused hearts of adults.689 NO, however, reacts with superoxide (O2- to form reactive nitrogen molecules, which are cytotoxic548; thus, its clinical benefit is unclear.

Generation of reactive oxidants, initially from C5a activation of neutrophils,690 oxidizes membrane phospholipids to form lipid peroxidases, conjugated dienes, and malondialdehyde and other reactive species during cardiopulmonary bypass.690,691 Ischemia/reperfusion injuries produce the greatest concentrations of reactive oxidants and lipid peroxidases691,692 and have stimulated studies using antioxidants to counteract these cytotoxins.692695 Although exogenous vitamin E prevents depletion of circulating {alpha}-tocopherol during clinical cardiac surgery,693 beneficial effects in terms of reduced myocardial or pulmonary injury are inconclusive.692,693,695

Platelets, endothelial cells, neutrophils, and monocytes are regulated by two cyclic nucleotides: cyclic adenine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP). Increased cAMP inhibits NF-{kappa}B transcription in monocytes and endothelial cells.696 A multitude of phosphodiesterases (9 families) control intracellular concentrations of the two cyclic nucleotides and provide a mechanism for controlling regional groups of cells.697 A variety of drugs have been developed to inhibit specific PDE families; some have been studied for their effects on the acute inflammatory response to CPB. One study in patients who had clinical cardiac surgery with CPB shows no change in hemodynamics or oxygen transport and metabolism but does show improved splanchnic circulation and reduced absorbtion of endotoxin and production of IL-6.698

Comment

As summarized above, CPB and clinical cardiac surgery unleash a broad and intense acute inflammatory response that varies in degree between patients. The cause is the continuous recirculation of blood that is sequentially in contact with the wound, perfusion circuit, and intravascular compartment to which is added the washout of reperfused ischemic organs and tissues. The acute inflammatory response together with microembolization is responsible for most of the morbidity of CPB and clinical cardiac surgery. Given the magnitude and diversity of the acute inflammatory response, it appears unlikely that drug cocktails or indirect measures directed against specific mediators of this response will prove more than mildly effective. Efforts to temporarily inhibit the more important mediators, specifically complement699 and neutrophils, during the perioperative period are more attractive and achievable targets that could produce more immediate clinical benefits. Because our patients are vulnerable to infection and other forms of injury during and immediately after operation and because the acute inflammatory response is an important first step in healing, the clinician must remember that temporary, reversible inhibitors are probably safer than permanent inhibitors.


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