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Ann Thorac Surg 2006;81:S2347-S2354
© 2006 The Society of Thoracic Surgeons

Supplement

Characterizing the Inflammatory Response to Cardiopulmonary Bypass in Children

Deborah J. Kozik, DO a , b , James S. Tweddell, MD a , b , *

a The Herma Heart Center, Children's Hospital of Wisconsin, Milwaukee, Wisconsin
b Division of Cardiothoracic Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin

Accepted for publication February 4, 2006.

* Address correspondence to Dr Tweddell, MS 715, Children's Hospital of Wisconsin, 9000 West Wisconsin Ave, Milwaukee, WI 53226. (Email: jtweddell{at}chw.org).

Presented at the Symposium on Harnessing the Effects of Neonatal Cardiopulmonary Bypass at the Fourth World Congress of Pediatric Cardiology and Cardiac Surgery, Buenos Aires, Argentina, Sept 21, 2005.


Doctor Tweddell discloses that he has a financial relationship with Bayer Corp.

 

   Abstract
Top
 Abstract
Introduction
 Components of the Systemic...
 Specific Organ System...
 References
 
Cardiopulmonary bypass is known to trigger a global inflammatory response. Age-dependent differences in the inflammatory response, the increased susceptibility to injury of immature organ systems, and the larger extracorporeal circuit to patient size ratio results in greater susceptibility of younger and smaller patients to the damaging effects of cardiopulmonary bypass. In this review the components of the inflammatory response to cardiopulmonary bypass are reviewed with special reference to the pediatric age group, including the age-specific impact on organ systems. In addition the current and evolving strategies to prevent, limit, and treat the inflammatory response to cardiopulmonary bypass in children are examined.

The damaging effects of cardiopulmonary bypass (CPB) and the subsequent inflammatory response are the result of the extreme conditions encountered during extracorporeal support, including (1) cell activation on contact with the foreign surfaces of the bypass circuit, (2) mechanical shear stress, (3) tissue ischemia and reperfusion, (4) hypotension, (5) nonpulsatile perfusion, (6) hemodilution with relative anemia, (7) blood product administration, (8) heparin and protamine administration, and (9) hypothermia. A global inflammatory response ensues with the activation of cellular and humoral cascades, including the activation of the complement, coagulation, and fibrinolytic pathways; endotoxin release; cytokine production; endothelial activation with expression of leukocyte adhesion molecules; activation of leukocytes and platelets; and production and release of oxygen-free radicals, nitric oxide, arachidonic acid derivatives, and proteolytic enzymes (Fig 1) [1, 2]. These inflammatory cascades result in a capillary leak syndrome and multiorgan dysfunction. Younger and smaller patients are more susceptible to the inflammatory response to CPB for several reasons including higher metabolic demands, reactive pulmonary vasculature, and immature organ systems with altered homeostasis. Smaller and younger patients, particularly infants and newborns, are also at increased risk because of the tremendous disparity between the CPB circuit size and the patient, with bypass circuit volumes often 200% to 300% greater than the patient's circulating blood volume. In addition, the greater metabolic demand of infants also requires higher pump flow rates, with neonates being perfused at rates up to 200 mL · kg–1 · min–1. The combination of a relatively larger CPB circuit and the increased flow rates necessary for younger and smaller patients results in greater exposure of the blood to the foreign surface of the bypass circuit.


Figure 1
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  		Fig 1. An overview of the inflammatory response to cardiopulmonary bypass. Cardiopulmonary bypass exposes the body to extreme, nonphysiologic conditions that initiates a global inflammatory response. Blood–artificial surface interaction results in activation of several amplifying protein cascade systems including those of the coagulation, fibrinolytic, kallikrein, and complement systems. Additional ischemia–reperfusion injury occurs as a result of the altered flow states and hypothermia. White blood cells, platelets, and endothelial cells are activated, leading to production of additional inflammatory mediators capable of further activation of humoral and cellular elements resulting in amplifying positive feedback loops. Ultimately capillary integrity is altered and multisystem organ dysfunction occurs. (IL = interleukin; TNF = tumor necrosis factor.)

 
Immature and developing organ systems place the youngest patients at greatest risk. Brain development continues during infancy. Regions of brain development are associated with increased metabolic activity [3], specifically oxygen utilization, and these same areas of increased metabolic activity are at increased risk for bypass-related injury including ischemia, reperfusion, increased permeability, and edema formation. The lungs of newborns are also immature. There is a 10-fold increase in the number of alveoli in adults compared with infants, with most of this increase in number of alveoli completed by 8 years of age [4]. This relative pulmonary immaturity predisposes neonates to the development of pulmonary edema and pulmonary hypertension. Renal blood flow at birth is lower than later in infancy owing to higher renal vascular resistance. Renal blood flow increases during the first week of life, but does not reach adult values until 2 years of age [5]. Furthermore, neonates have less renal autoregulatory function than adults, which leads to limited sodium reabsorption and excretion, concentrating, and diluting mechanisms, and decreased ability to regulate acid–base homeostasis [5]. The immune system in neonates is also immature, with neutrophils showing functional deficits, including decreases in adhesiveness, deformability, and chemotaxis, as well as impaired complement generation [6].

In this article we will review the inflammatory response to CPB, focusing on the data in the pediatric age group. We will then review the impact of the CPB-induced inflammation on the major organ systems and conclude with a summary of the efforts to minimize the inflammatory response to CPB, focusing on the pediatric age group.


   Components of the Systemic Inflammatory Response
Top
 Abstract
 Introduction
 Components of the Systemic...
Specific Organ System...
 References
 
Complement Activation
Complement activation occurs through both the alternative (stimulated by foreign surface contact, endotoxin, and kallikrein) and classical (protamine) pathways [7–9]. The exposure of blood to extracorporeal circuits activates the alternative pathway, leading to the formation of C3a and C5a, whereas reversal of heparin with protamine activates the classical pathway with an associated rise in C4a levels and further rise in C3a levels [7–10]. The anaphylatoxins C3a and C5a cause activation, degranulation, and adhesion of neutrophils, and activation of basophils and mast cells with histamine release, as well as platelet aggregation [11–17]. Some studies have related elevated levels of complement with the occurrence of postoperative complications, specifically the need for prolonged mechanical ventilation, but these findings are not uniform, and other studies have shown no correlation between complement activation and acute lung injury or adverse hemodynamic responses [7, 10, 18]. Seghaye and associates [19] found that children who developed CPB-related complications had persistently higher C3 conversion than those without postoperative complications, but the same group failed to demonstrate a correlation between complement activation and adverse outcomes in neonates [20].

Neutrophil Activation
Neutrophils are activated by a wide variety of stimuli, including foreign surface contact, endotoxin, cytokines, complement, platelet-activating factor, and ischemia–reperfusion. Once activated, neutrophils begin the process of endothelial adherence and migration with subsequent release of proteases and oxygen-derived free radicals. Endothelial cell barrier dysfunction is impaired, with resultant fluid extravasation [21]. Studies in pediatric patients have shown a decrease in circulating leukocytes with initiation of CPB and a simultaneous rise in circulating neutrophil elastase and myeloperoxidase, indicating neutrophil adhesion, activation, and degranulation [22, 23]. Plasma levels of adhesion molecules have been shown to be higher in children undergoing open heart surgery compared with adults [24]. In children the expression of adhesion molecules is correlated with duration of CPB, suggesting that CPB results in ongoing neutrophil activation [25]. Furthermore, increased levels of adhesion molecules have been correlated with adverse outcomes in children undergoing open heart surgery, suggesting a central role of leukocyte activation in CPB-related injury [26].

Kinin Production
Kinin peptides are potent vasodilators that also participate in inflammation, leading to increased vascular permeability and neutrophil chemotaxis [27]. The contact activation system is composed of kinin–kallikrein, fibrinolytic-coagulation, and complement systems. During CPB, factor XII is activated by contact with artificial surfaces, producing factor XIIa (Fig 2), which then converts prekallikrein to kallikrein in the presence of high-molecular-weight kininogen. Kallikrein then enters a positive feedback loop with factor XIIa to activate additional factor XII; it also cleaves surface-bound high-molecular-weight kininogen to produce bradykinin [28]. In addition to the response to the CPB circuit, plasma kallikrein levels have been found to significantly increase after the administration of heparin [29]. The biologic effects of kinins are mediated through B1 and B2 receptors. B2 receptors are expressed in many cell types and have a high specific affinity for bradykinin [27]. Activation of B2 receptors leads to the release of calcium, nitric oxide, eicosanoids, free radicals, and cytokines [30]. Bradykinin can also bind to receptors on endothelial cells, which then produce vasoactive prostaglandins and nitric oxide, leading to vasodilatation and increased capillary permeability. Bradykinin has also been found in the brain parenchyma, with increased levels seen in the brain interstitial space during cerebral ischemia [31]. Mediated by activation of the B2 receptor, bradykinin can increase the permeability of the blood–brain barrier after ischemia–reperfusion, resulting in plasma extravasation with edema formation and perturbation of the cerebral blood flow [31]. Studies in rats have shown ischemic cerebral injury is decreased by antagonism of bradykinin receptors [32]. Aprotinin, a strong inhibitor of bradykinin formation, has been shown to decrease the risk of neurologic injury in adults exposed to CPB [33].


Figure 2
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  		Fig 2. Contact of the blood with foreign surfaces results in production of kallikrein. Kallikrein enters into a positive feedback loop with factor XII, activating both the coagulation cascade and the fibrinolytic system. Kallikrein results in production of bradykinin. In addition kallikrein activates the renin–angiotensin system and complement cascades. (HMW = high-molecular-weight.) (Reprinted from Murkin JM. Cardiopulmonary bypass and the inflammatory response: a role for serine protease inhibitors? J Cardiothoracic Vasc Anesth 1997:11(Suppl 2):19–23, by permission of Elsevier Science, Inc.)

 
Arachidonic Acid Activation
The arachidonic acid cascade is activated by a number of inflammatory stimuli that result in activation of cyclooxygenase and phospholipase A2. Arachidonic acid pathway activation results in production of thromboxanes, leukotrienes, and prostaglandins [34]. The neutrophil cell membrane is the primary source of arachidonic acid, but the lung is also a major site of the synthesis, release, and degradation of the eicosanoids. Thromboxane A2, a strong vasoconstrictor and promoter of platelet aggregation, comes primarily from platelets and release occurs to a great extent in the lungs. Prostaglandin E1, prostaglandin E2, and prostacyclin are also released during CPB. These substances have vasodilating and platelet antiaggregant effects that counterbalance the effects of thromboxane A2. Leukotriene B4, a strong chemoattractant that promotes plasma leakage and leukocyte adhesion, is also increased during and for a short time after CPB [35]. The magnitude of eicosanoid production during CPB is greatest in the very young [36].

Cytokines
Cytokines are produced by monocytes, macrophages, lymphocytes, and endothelial cells. Production is stimulated by ischemia–reperfusion, complement activation, and endotoxin release, and is further amplified by the effect of other cytokines. Cytokines can be either protective or damaging depending on their concentration, the cell they are acting on, and the presence of other cytokines [1, 2]. The most important cytokines produced during CPB are the proinflammatory cytokines tumor necrosis factor {alpha}, interleukin (IL) 1, IL-6, and IL-8, and the antiinflammatory cytokines IL-10 and IL-1 receptor antagonist (IL-1ra) [1, 2]. Tumor necrosis factor {alpha}, IL-1, IL-6, and IL-8 levels all increase after CPB, and all are participants in the acute inflammatory response. Tumor necrosis factor {alpha} and IL-1 are early inflammatory cytokines that initiate the inflammatory response and are also pyrogenic. Tumor necrosis factor {alpha} facilitates leukocyte–endothelial interaction, and elevation of tumor necrosis factor {alpha} in postoperative infants has been correlated with capillary leak syndrome [23]. Tumor necrosis factor {alpha} has also been shown to have a negative inotropic effect in animal studies looking specifically at cardiac function [37]. Interleukin 6 and IL-8 begin to rise near the end of CPB and continue to increase in the first few hours after surgery. Interleukin 6 acts on B cells to differentiate into plasma cells and stimulates hepatocytes to make acute-phase proteins. Increasing IL-6 levels correlate with adverse outcomes [38]. Interleukin 8 stimulates neutrophil chemotaxis, and levels appear to be related to the duration of CPB [39]. Interleukin 10 and IL-1ra are the major antiinflammatory cytokines, whose role is to limit the production of proinflammatory cytokines [1, 2]. They are produced as a response to inflammation and are stimulated in part by the proinflammatory cytokines, especially IL-6.

Cytokines are both participants in inflammation and markers of the ongoing response. The ratio of proinflammatory to antiinflammatory cytokines is predictive of outcome. In patients with the systemic inflammatory response as a result of sepsis, an increased ratio of IL-6 to IL-10 is correlated with poor outcome, and conversely, an elevated ratio of IL-10 to IL-6 in infants undergoing cardiac surgery was predictive of a better outcome [40, 41]. Although the antiinflammatory cytokines limit the extent of the inflammatory response and begin to restore homeostasis, an excessive antiinflammatory cytokine response may follow an excessive proinflammatory response and result in immunocompromise [42–44].

Platelet-Activating Factor and Endothelins
Platelet-activating factor is a phospholipid synthesized by platelets and vascular endothelial cells. Platelet-activating factor receptors are present on platelets as well as neutrophils, monocytes, and endothelial cells. It is a potent neutrophil chemoattractant, activator, and aggregant, and plays an important role in myocardial ischemia–reperfusion injury [45].

Endothelin-1 is the most potent endogenous vasoconstrictor involved in the regulation of arterial blood pressure and cardiac output [46]. The lung is an important site for both clearance and production of endothelin-1, and an increase in endothelin concentrations has been correlated with endotoxin levels during CPB [47]. The vasoconstrictor effects of endothelin may lead to intestinal hypoperfusion, resulting in translocation and endotoxin release into the circulation [47].

Thrombin
Cardiopulmonary bypass is a strong procoagulant stimulus. Heparin inhibits the formation of thrombus, but it does not prevent the expression of tissue factor on activated endothelial cells and monocytes, which is central to the extrinsic system of coagulation. Activated endothelial cells and monocytes express tissue factor; when factor VII comes in contact with tissue factor, the coagulation cascade is activated, leading to the conversion of prothrombin to thrombin. The production of thrombin by itself has significant inflammatory and thrombotic properties [48]. Once generated, thrombin leads to increased expression of P-selectin on endothelial cells, which causes neutrophil adherence and activation [49]. Increased activation of thrombin receptors on leukocytes can also lead to the release of chemotactic and inflammatory cytokines [49].

The individual elements of the inflammatory response to CPB ultimately combine through redundancy, positive feedback loops, and amplifying cascades to yield the characteristic, generalized post-CPB injury picture. The end result of this complex inflammatory response is endothelial damage, capillary leak, and end-organ dysfunction.


   Specific Organ System Dysfunction
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 Abstract
 Introduction
 Components of the Systemic...
 Specific Organ System...
References
 
Cardiopulmonary Dysfunction
Cardiopulmonary dysfunction is present to some degree in every patient having open heart surgery. The heart is affected both by aortic cross-clamping, which results in ischemia and reperfusion injury, and by direct surgical trauma, which is a consequence of the corrective procedure. With cross-clamp removal the heart is reperfused with activated leukocytes and platelets that then interact with the endothelium of the postischemic myocardium. As mentioned above, tumor necrosis factor {alpha} has been shown to have negative inotropic effects. Other inflammatory mediators have been implicated as well. Neonates with increased myocardial dysfunction after the arterial switch operation have higher levels of proinflammatory cytokines IL-6 and IL-8 [50]. Although it is not possible to separate out the individual contributions of the direct myocardial injury as a consequence of ischemia and the additional injury caused by inflammatory mediators, the inflammatory response is increasingly recognized as a major contributor to postoperative myocardial dysfunction [51].

Cardiopulmonary bypass also alters the pulmonary circulation such that only the bronchial circulation supplies the lungs. The lung is both a source and a target of the inflammatory response to CPB. The inflammatory injury related to CPB results in increased pulmonary vascular resistance, decreased compliance, decreased functional residual capacity, increased ventilation–perfusion mismatch with intrapulmonary shunting, leakage of fluid into the interstitial space, and reduced surfactant activity [4, 52]. Hemodilution promotes fluid extravasation by reducing oncotic pressure. Ischemia can also lead to the loss of endothelial pulmonary vascular tone control, which is amplified by reperfusion [53]. The sequestration of activated neutrophils in the pulmonary vasculature, along with activated complement, cytokines, and leukotrienes, can induce alveolar and capillary membrane damage, further increasing interstitial edema [52].

Renal Dysfunction
Preoperative renal dysfunction or injury and low cardiac output after CPB contribute to renal dysfunction after surgery. Glomerular filtration rate and renal diluting and concentrating abilities are immature in neonates and very young infants. The pathophysiology involves a broad pattern of mechanisms, including intraoperative hypoperfusion of the kidneys, nonpulsatile perfusion, and mediators of the systemic inflammatory response. The release of vasoconstrictor compounds during CPB, including catecholamines, vasopressin, and thromboxane, leads to activation of the renin–angiotensin system, which can further compromise renal perfusion [54]. Renal dysfunction can contribute to increased total body water, delayed fluid clearance after CPB, pulmonary interstitial edema, and prolonged ventilatory support.

Cerebral Dysfunction
The developing infant brain is particularly susceptible to injury by hypoxia, ischemia–reperfusion, and inflammatory mediators because of its fragile vasculature and its high metabolic activity [55]. Intraoperative causes of brain injury include abnormalities of cerebral autoregulation and cerebral perfusion, ischemia–reperfusion, inflammation, and emboli. In addition to surgery other causes of the cerebral sequelae of congenital heart disease include preexisting structural abnormalities, genetic syndromes, preoperative hypoxia, and hypoperfusion. Neurologic examinations performed in the postoperative period have identified a variety of abnormalities including seizures, hypotonia, pyramidal findings, asymmetry of tone, and feeding difficulties [56, 57].

Stress Response to Cardiopulmonary Bypass
The stress response to CPB is characterized by the release of a large number of neurohumoral substances, including catecholamines, vasopressin, prostaglandins, cortisol, and growth hormones [34]. This response is more extreme in the neonate than that seen in adult cardiac surgical patients [58]. Stimuli include prolonged foreign surface contact, hypothermia, low perfusion pressure, and nonpulsatile perfusion. Deleterious consequences include vasoconstriction and reduced organ perfusion, direct tissue injury, pulmonary hypertension, endothelial damage, and increased pulmonary vasoreactivity.

Antiinflammatory Strategies
Strategies to limit the inflammatory response to CPB may limit morbidity and mortality, and improve early neurologic function and neurodevelopmental outcomes. The administration of corticosteroids before CPB suppresses the production of proinflammatory cytokines and augments production of antiinflammatory cytokines. Animal studies by Lodge and colleagues [59] using a piglet model showed a decrease in post-CPB fluid gain and improvement in pulmonary compliance and pulmonary vascular resistance in animals given methylprednisolone at a dose of 30 mg/kg 8 hours and again 1.5 hours before surgery [59]. Subsequent human studies using both Solu-Medrol and dexamethasone given before surgery have been shown to limit production of proinflammatory cytokines [60, 61]. Solu-Medrol 30 mg/kg given 4 hours before surgery resulted in improved pulmonary function with an associated reduction in proinflammatory mediators [62]. Administration of dexamethasone 1 mg/kg was associated with a reduction in troponin I levels, suggesting that steroid administration can ameliorate CPB-associated cardiac injury [63]. Timing of steroid administration seems critical as other studies indicate that steroids in pump prime alone or given immediately before surgery have little impact on outcome [64, 65]. It should be noted that thus far studies looking at preoperative administration of steroids include relatively small numbers of patients and that studies in adult patients have identified impaired oxygenation and prolonged endotracheal intubation among patients receiving preoperative steroids [66, 67]. Whether the apparent differences in the impact of preoperative steroid administration on adult and pediatric patients are related to real age-dependent changes in response to steroids, the impact of preexisting lung disease in adults versus the more common high-flow lesions seen in pediatric patients or simply an inadequate sample size remains unknown. Nevertheless the existing studies in children suggest a beneficial impact of steroids on postoperative pulmonary function.

Aprotinin (a nonspecific serine protease inhibitor) is another agent that can limit the systemic inflammatory response to CPB in both infants and adults. Aprotinin reversibly complexes with the active sites of plasmin, kallikrein, and trypsin, functioning to inhibit the activity of these proteases, as well as elastase and thrombin. Aprotinin has been shown to limit the CPB-induced activation of leukocytes and platelets [17]. In addition to reducing bleeding and helping maintain platelet function, the inhibition of fibrinolytic proteases decreases generation of fibrin degradation products, which are themselves proinflammatory [28].

Despite efforts to minimize the priming volume of CPB circuits and optimize CPB strategies, neonates and infants still exhibit excessive fluid accumulation during their exposure to CPB. Using ultrafiltration immediately after the cessation of CPB (modified ultrafiltration) reverses hemodilution, leads to a reduction in total body water content, improves systolic function, improves pulmonary function with decreased duration of postoperative ventilation, and decreases postoperative bleeding [68]. Modified ultrafiltration has been shown to remove proinflammatory cytokines IL-6, IL-8, and tumor necrosis factor {alpha} [69, 70].

Several strategies have been used to modify the surface of the CPB circuit and thereby ameliorate the inflammatory response. Heparin-bonded circuits have been shown to eliminate polyvinylchloride-induced complement activation, synthesis of chemokines, leukocyte CD11b expression, and neutrophil and platelet degranulation. One study has shown that heparin coating also eliminates the synthesis of leukotriene B4, prostaglandin E2, and thromboxane B2 [71]. Poly-2-methoxyethylacrylate is another surface-modifying agent using an amphiphilic strategy in which the surface of the CPB circuits exposes alternating hydrophilic and hydrophobic microdomains. The use of poly-2-methoxyethylacrylate-coated bypass circuits in adults has resulted in a reduction in complement activation and IL-6 production as well as improved pulmonary function compared with untreated circuits [72, 73]. Compared with heparin-bonded circuits, poly-2-methoxyethylacrylate was associated with superior preservation of platelets and lower levels of IL-6 and IL-8 production but not complement activation [74].

Ongoing research into pharmacologic strategies to reduce the inflammatory response has also been promising. A study by Fitch and colleagues [75] showed that the use of a single-chain antibody specific for human C5 was a safe and effective inhibitor of pathologic complement activation in patients undergoing CPB. They showed that C5 inhibition significantly attenuated postoperative myocardial injury, cognitive deficits, and blood loss. Complement receptor-1 (CR1) inhibits both C3 and C5 convertases of the classical and alternative complement cascade. Recombinant soluble CR1 (TP-10) has been shown to effectively block complement activation in vitro and in vivo. It has also been shown to protect the myocardium and lungs from some of the deleterious effects of CPB [76].

Nuclear factor kappa B (NF-{kappa}B) is the principal transcription factor controlling expression of inflammatory genes; in the inactive state, NF-{kappa}B is found in the cytoplasm of a variety of somatic cells including endothelium. Nuclear factor kappa B is a heterodimer composed of two subunits: p50 and p65, and in the quiescent state it is bound to an inhibitory subunit, I{kappa}B. With stimulation by a variety of agents including proinflammatory cytokines and other mediators of inflammation, the I{kappa}B subunit is phosphorylated and separates from the heterodimer. Nuclear factor kappa B, a DNA-binding protein, then translocates to the nucleus, where it upregulates transcription of inflammatory genes including proinflammatory cytokines, adhesion molecules, and inducible nitric oxide synthase [77]. Many of these protein products are themselves activators of NF-{kappa}B, and a positive feedback loop is initiated, which can result in an excessive inflammatory response. The mechanism of NF-{kappa}B function is illustrated in Figure 3. Inhibition of NF-{kappa}B limits pathologic inflammatory responses that are central to a number of disease processes, including that resulting from CPB, and is an area of active investigation. Studies in piglets suggest that steroids can inhibit NF-{kappa}B and decrease adhesion molecule production and white cell activation, presumably by stabilizing I{kappa}B [78].


Figure 3
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  		Fig 3. Function of transcription factor nuclear factor kappa B (NF-{kappa}B). In the inactive state NF-{kappa}B is found in the cytoplasm of endothelial cells. With stimulation by a variety of agents, including proinflammatory cytokines and other mediators of inflammation, the inhibitory I{kappa}B subunit is phosphorylated and separates from the heterodimer. Nuclear factor kappa B then translocates to the nucleus, where it upregulates transcription of inflammatory genes including proinflammatory cytokines, adhesion molecules, and inducible nitric oxide synthase. These protein products are themselves activators of NF-{kappa}B, and this action results in a positive feedback loop. (Reprinted from [2] by permission of Cambridge University Press.)

 
The inflammatory response to CPB sets in play a series of reactions resulting in global activation of what are typically locally acting mediators of inflammation. Important to the normal, local, nonpathologic function of the inflammatory system is redundancy, positive feedback loops, and amplifying cascades—the very factors that render its global activation pathologic. With the exception of steroids, which have broad antiinflammatory effects, these properties of amplification, redundancy, and positive feedback loops may account for the failure of single-agent strategies to produce a significant reduction in the inflammatory response to CPB. Given the deleterious impact of the inflammatory response to CPB on the most vulnerable patients—neonates, infants, and children—who require the most complex procedures, a strategy that uses multiple agents to limit activation would appear to be logical. At the Children's Hospital of Wisconsin our routine antiinflammatory strategy includes the use of preoperative steroids (in neonates only, 10 to 30 mg/kg of Solu-Medrol) given 12 and 6 hours preoperatively, a surface- modified CPB circuit, the routine use of high-dose aprotinin (1.7 x 106 kallikrein inactivator units (KIU)/m2 as an intravenous loading dose, 1.7 x 106 KIU/m2 in the extracorporeal circuit prime, and a continuous infusion during the operation at 4.0 x 105 KIU · m–2 · h–1) and modified ultrafiltration. This kind of broad approach may, however, impact the coagulation cascade and immune system, and the value of this antiinflammatory strategy must be balanced against the individual patient's risk. The inflammatory response is not intrinsically pathologic and initiates the healing process. Amelioration of the excessive inflammatory response must be balanced and not subject the patient to increased risk of infection and wound complications. Ultimately we need to gain a better understanding of the inflammatory response including the preexisting triggers and the genes that are upregulated. This may provide for therapy not only directed at the specifics of the inflammatory response as it relates to CPB but also targeted to individual genetic vulnerabilities.


   References
Top
 Abstract
 Introduction
 Components of the Systemic...
 Specific Organ System...
 References
 

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