Stress, Inflammation, and Shock

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Chapter 2 Stress, Inflammation, and Shock

Ravi Taneja, Davy C.H. Cheng

The systemic inflammatory changes that accompany cardiac surgery and cardiopulmonary bypass can sometimes result in a clinical state that resembles septic shock. It is now recognized that severe systemic inflammation is a nonspecific host response to a range of physiologic stressors, of which infection and cardiopulmonary bypass are but two examples. Additionally, there is evidence that inflammation plays an important role in other forms of shock (e.g., hemorrhagic and cardiogenic shock).

In this chapter the physiologic basis and interrelationships among stress, inflammation, and shock are reviewed, with particular emphasis on cardiac surgery patients.

NEUROENDOCRINE AND METABOLIC EFFECTS

Tissue injury results in the activation of nociceptors, which transduce a signal of actual or threatened tissue damage, via the sensory neurones, to the medulla of the brain. This signal is then integrated within the brain stem and results in activation of the sympathetic nervous system, the renin-angiotensin-aldosterone system, and the hypothalamic-pituitary axis. Hypothalamic corticotropin releasing hormone stimulates the release of adrenocorticotropic hormone from the anterior pituitary, which in turn stimulates the release of cortisol and other glucocorticoids from the adrenal cortex. In addition, growth hormone is released from the anterior pituitary, vasopressin from the posterior pituitary, and glucagon from the pancreas. The secretion of thyroid hormones and insulin are suppressed.¹

This neuroendocrine response results in a multitude of changes throughout the body.

Heart rate and blood pressure are immediately increased. Blood flow is directed away from organs such as the gut and the skin. The kidneys retain sodium and water, and urine output is reduced. The metabolic consequences consist of increased catabolism of carbohydrates, proteins, and lipids. Hepatic glycogenolysis is facilitated by cortisol and catecholamines and, later, gluconeogenesis occurs from precursors such as lactate and amino acids. Despite increased glucose production, glucose uptake into most cells is decreased because of reduced insulin release and tissue insulin resistance, resulting in hyperglycemia. Protein catabolism is promoted primarily through the action of cortisol. An adult may lose as much as 0.5 kg of protein mass per day following major surgery. The amino acids that are released by protein catabolism, in particular alanine and glutamine, are used for hepatic gluconeogenesis and the synthesis of acute phase proteins (fibrinogen, C-reactive protein, α₂-macroglobulin). Catecholamines, growth hormone, and reduced levels of insulin promote lipolysis and the breakdown of triglycerides into glycerol and free fatty acids. Thus, under conditions of metabolic stress, the myocardium continues to utilize free fatty acids as its predominant energy substrate while, despite hyperglycemia, glucose uptake is inhibited due to reduced levels of insulin. Because fatty acids are a less oxygen-efficient fuel than glucose, these effects can provoke or exacerbate myocardial ischemia.

THE INFLAMMATORY RESPONSE TO SURGERY AND CARDIOPULMONARY BYPASS

Inflammation is primarily a protective response to tissue injury that helps destroy or quarantine harmful agents or damaged tissue. Inflammation may be localized (e.g., the region of redness, swelling, and warmth surrounding an insect bite) or systemic. Systemic inflammation occurs in a variety of clinical situations, including major surgery, cardiopulmonary bypass, burns, pancreatitis, myocardial infarction, and sepsis. The systemic inflammatory response is a continuum. At one end of the spectrum is a barely detectable, self-limited state manifested by a mild fever, leukocytosis, and an increase in inflammatory markers (e.g., C-reactive protein). This is the situation that typically occurs following major surgery or a myocardial infarction. At the other end of the spectrum is a profoundly harmful, self-reinforcing syndrome manifested by circulatory shock and multiple organ failure.^2,³

The Mechanisms of the Inflammatory Response

During cardiac surgery, systemic inflammation develops in response to a number of pathophysiologic processes, including surgical trauma, hypothermia, exposure of blood to the cardiopulmonary bypass circuit, blood loss or transfusion, translocation of endotoxin from the gut to the circulation, and ischemia-reperfusion injury.

The mechanisms of inflammation and the interactions among the various components are extremely complex and only a brief description is provided here. The process is summarized in Fig. 2-1.

Figure 2.1 A schematic representation of the inflammatory response and its effects.

Cytokines

Cytokines, which include the interleukins and interferons, are simple polypeptides and glycoproteins that are released from leukocytes, fibroblasts, and endothelial cells in response to tissue injury. Cytokines, particularly interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), act primarily to amplify the inflammatory response, mainly by activating leukocytes. Cytokines also cause direct myocardial depression.

Contact Activation: Platelets, Coagulation, Complement

The exposure of blood to the cardiopulmonary bypass circuit causes the activation of platelets and the coagulation and complement cascades:

• Platelets. Activated platelets release a variety of vasoactive substances, such as platelet factor 4 and thromboxane B, and can bind to leukocytes forming aggregates within the microcirculation.

• Coagulation. Under normal circumstances, thrombin formation is maintained at low levels and is restricted to wound sites by three principal anticoagulant systems: (1) antithrombin III, which inhibits the activity of factors IIa (thrombin) Xa, XIIa, XIa, and IXa; (2) tissue factor pathway inhibitor, which blocks the activity of factor X and the factor VII/tissue factor complex; (3) activated protein C. Activated protein C is formed from circulating protein C by the binding of thrombin to the endothelial surface protein thrombomodulin. Activated protein C inhibits factors V and VIII and promotes fibrinolysis. Thrombin levels increase during and after cardiopulmonary bypass despite full anticoagulation with heparin.⁴ This is partly due to contact activation but is also due to heparin-mediated inhibition of activated protein C by protein C inhibitor. Thrombin has a number of proinflammatory effects, including endothelial activation, platelet activation, and leukocyte chemotaxis. Thrombin generation also contributes to microvascular thrombosis and obstruction.

• Complement. The complement cascade consists of more than 30 plasma and cell membrane proteins. In addition to contact activation through exposure to the bypass circuit, complement is also activated during cardiac surgery by ischemia-reperfusion, by heparin-protamine complexes, and by endotoxin. The products of the complement cascade have a wide variety of proinflammatory effects including activation of leukocytes and platelets.

Endotoxin

Endotoxin is a lipopolysaccharide released from gram-negative bacteria during their growth and replication. Endotoxin can result in the production of large quantities of TNF-α and IL-6 by macrophages and endothelial cells. Endotoxemia is a critical component in the pathogenesis of gram-negative septic shock. Endotoxin is also present in the blood after cardiopulmonary bypass; its presence may be related to impaired gut barrier function due to splanchnic ischemia.⁵

Nitric Oxide

Tissue trauma and various inflammatory mediators (e.g., IL-1, TNF-α) result in the synthesis of large quantities of the inducible form of nitric oxide synthetase (iNOS). This can lead to the production of very high levels of nitric oxide and the formation of the cytotoxic compound peroxynitrite, which is formed by a reaction between nitric oxide and the oxygen-derived free radical superoxide. The effects of peroxynitrite and high levels of nitric oxide include pathologic vasodilation, myocardial depression, and the suppression of aerobic metabolism within the mitochondria.

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