Numerous advances in perioperative care have allowed increasingly high-risk patients to safely undergo cardiac surgery. Although mortality rates of 1% are quoted for “low-risk” cardiac surgery, results from large series of patients older than 65 years suggest that mortality rates are actually more substantial.¹ Postoperative morbidity is common and complications include atrial fibrillation, poor ventricular function requiring inotropic agents, and non–cardiac-related causes such as infection, gastrointestinal dysfunction, acute lung injury, stroke, and renal dysfunction.²

Many postoperative complications appear to be caused by an exaggerated systemic proinflammatory response to surgical trauma.³ The most severe form of this inflammatory response leads to multiple organ dysfunction syndrome and death. Milder forms of a proinflammatory response cause less severe organ dysfunction, which does not lead to admission to an intensive care unit but nevertheless causes suffering, increased hospital length of stay, and increased cost. The etiology and the clinical relevance of systemic inflammation after cardiac surgery are poorly understood. Systemic inflammation is a multifactorial process and has profound secondary effects on both injured and normal tissues. Proinflammatory mediators can have beneficial as well as deleterious effects on multiple organ systems. According to most theories, tissue injury, endotoxemia, and contact of blood with the foreign surface of the cardiopulmonary bypass (CPB) circuit are some of the major factors postulated to initiate a systemic inflammatory response. Nevertheless, there is controversy surrounding the etiology as well as pathogenesis of inflammation in the perioperative period.

SYSTEMIC INFLAMMATION AND CARDIAC SURGERY

The systemic inflammatory response after cardiac surgery is multifactorial. A schematic of the inflammatory process is depicted in Figure 6-1. There does not appear to be much disagreement with the statement that all of these processes may happen and may be responsible for causing complications in cardiac surgical patients. Tissue injury, endotoxemia, and contact of blood with the foreign surface of the CPB circuit are thought to initiate a systemic inflammatory response after cardiac surgery. What is least understood and most controversial is the issue of which of these many processes is the most clinically relevant. It appears as if major surgery is an important cause of systemic inflammation and that CPB further exacerbates the elaboration of proinflammatory mediators.

Figure 6-1 Overview of inflammation. TNF = tumor necrosis factor; IL = interleukin; PAF = platelet-activating factor; DIC = disseminated intravascular coagulation.

Mechanisms of Inflammation-Mediated Injury

Activation of neutrophils and other leukocytes is central to most theories regarding inflammation-induced injury.⁴ Neutrophil activation leads to the release of oxygen radicals, intracellular proteases, and fatty acid (e.g., arachidonic acid) metabolites. These products, as well as those from activated macrophages and platelets, can cause or exacerbate tissue injury.

In localized areas of infection, oxygen free radicals liberated by activated neutrophils aid in the destruction of pathogens.⁵ Complement, in particular C5a, results in activation of leukocytes and oxygen free radical formation. These activatedneutrophils liberate toxic amounts of oxygen free radicals such as hydrogen peroxide, hydroxyl radicals, and superoxide anion. Oxygen free radicals are thought to cause cellular injury ultimately through damage to the lipid membrane.

A related mechanism of injury results from the degranulation of neutrophils. Activated neutrophils release granules containing myeloperoxidase, as well as other toxic digestive enzymes such as neutrophil elastase, lactoferrin, β-glucuronidase, and N-acetyl-β-glucosaminidase.⁶ Release of these intracellular enzymes not only causes tissue damage but also reduces the number of cells that can participate in bacterial destruction.

Another mechanism of inflammation-mediated injury involves microvascular occlusion. Activation of neutrophils leads to adhesion of leukocytes to endothelium and formation of clumps of inflammatory cells as microaggregates.

Finally, activated leukocytes release leukotrienes such as leukotriene B₄. Leukotrienes are arachidonic acid metabolites generated by the lipoxygenase pathway. They markedly increase vascular permeability and are potent arteriolar vasoconstrictors. These leukotriene-mediated effects account for some of the clinical signs of systemic inflammation, in particular generalized edema as well as “third-space losses.” Prostaglandins, generated from arachidonic acid via the cyclooxygenase pathway, also act as mediators of the inflammatory process.

Physiologic Mediators of Inflammation

Cytokines

Cytokines are believed to play a pivotal role in the pathophysiology of acute inflammation associated with cardiac surgery.⁷ Cytokines are proteins released from activated macrophages, monocytes, fibroblasts, and endothelial cells that have far-reaching regulatory effects on cells. They are small proteins that exert their effects by binding to specific cell surface receptors. Many of these proteins are called interleukins because they aid in the communication between white blood cells (leukocytes).

Cytokines are an important component of the acute-phase response to injury or infection. The acute-phase response is the host’s physiologic response to tissue injury or infection and is intended to fight infection as well as contain areas of diseased or injured tissue. Cytokines mediate this attraction of immune system cells to local areas of injury or infection. They also help the host through activation of the immune system, thus providing for an improved defense against pathogens. Most cytokines are proinflammatory, whereas others appear to exert an anti-inflammatory effect, suggesting a complex feedback system designed to limit the amount of inflammation. Excessive levels of cytokines, however, may result in an exaggerated degree of systemic inflammation, which may lead to greater secondary injury. Numerous cytokines (e.g., tumor necrosis factor [TNF], interleukin [IL]-1 to IL-16) and other protein mediators have been described and may play an important role in the pathogenesis of postoperative systemic inflammation (Box 6-1).^8,9

BOX 6-1 Most Commonly Measured Biochemical Markers of Inflammation

• Tumor necrosis factor-α

• Interleukin-8

• Interleukin-6

• C-reactive protein

Complement System

The complement system describes at least 20 plasma proteins and is involved in the chemoattraction, activation, opsonization, and lysis of cells. Complement is also involved in blood clotting, fibrinolysis, and kinin formation. These proteins are found in the plasma as well as in the interstitial spaces, mostly in the form of enzymatic precursors.

The complement cascade is illustrated in Figure 6-2. The complement cascade can be triggered by either the classical pathway or the alternate pathway. In the alternate pathway, C3 is activated by contact of complement factors B and D with complex polysaccharides, endotoxin, or exposure of blood to foreign substances such as the CPB circuit. Contact activation (Fig. 6-3) describes contact of blood with a foreign surface with resulting adherence of platelets and activation of factor XII (Hageman factor). Activated factor XII has numerous effects, including initiation of the coagulation cascade through factor XI and conversion of prekallikrein to kallikrein. Kallikrein leads to generation of plasmin, which is known to activate the complement as well as the fibrinolytic systems. Kallikrein generation also activates the kinin-bradykinin system.

Figure 6-2 Simplified components of the complement system.

(Paul WE: Introduction to the immune system IN Paul WE: Fundamental Immunology. New York, Roven, 1989.)

Figure 6-3 Contact activation of the complement cascade during cardiopulmonary bypass. Activation of complement occurs primarily through the alternate pathway.

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