Stress, Inflammation, and Shock

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Chapter 2 Stress, Inflammation, and Shock

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.

The Clinical Manifestations of Severe Inflammation

The systemic inflammatory response syndrome (SIRS) is a clinical diagnosis defined by specific criteria (Table 2-1).⁸ Note that important hemodynamic instability is not a requirement for the diagnosis of SIRS. However, severe systemic inflammation often does result in profound circulatory disturbance. This disturbance is characterized by widespread vasodilation, myocardial depression (ejection fraction may be depressed but cardiac output may be dramatically increased), impaired peripheral perfusion due to microvascular failure, and relative hypovolemia due to intravascular fluid loss into the interstitium. Severe tissue hypoxemia may exist despite a very high cardiac output. Mixed venous oxygen saturation may be normal or increased and is not a good marker of tissue perfusion in this situation.

Table 2-1 Criteria for Diagnosis of the Systemic Inflammatory Response Syndrome

Rights were not granted to include this table in electronic media. Please refer to the printed book.

Bone RC, Balk RA, Cerra FB, et al: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee, American College of Chest Physicians/Society of Critical Care Medicine. Chest 101:1644-1655, 1992.

If this clinical state occurs in the context of infection it is classified as either severe sepsis or septic shock (Chapter 35). In cardiac surgical patients, the condition is variably known as low systemic vascular resistance syndrome, vasoplegic shock, or culture-negative septic shock. Low systemic resistance occurs in 20% to 45% of patients after cardiac surgery^9,¹⁰; severe shock occurs in 5% to 10% of patients.^10,¹¹

In addition to cardiovascular dysfunction, severe inflammation is associated with dysfunction of other organs, such as the lungs (acute lung injury, acute respiratory distress syndrome), kidneys, liver, gut, brain, and blood (coagulopathy, thrombocytopenia, and fibrinolysis). Involvement of multiple organs defines the condition of multiple organ dysfunction syndrome (MODS).⁸ MODS is a commonly described sequela of cardiac surgery; in one study MODS occurred in 11% of cardiac surgery patients and was associated with a mortality rate of 41%.¹² Although MODS can occur as a consequence of inflammation-mediated vasoplegic shock, it can also occur as a result of other forms of shock (see subsequent material). In the cardiothoracic intensive care unit, cardiogenic shock is an important cause of MODS.

It is important to emphasize that the adverse clinical effects of severe systemic inflammation are the consequence of the host’s response to a stimulus rather than being the consequence of the toxic effects of the stimulus itself. For this reason, identical clinical states (SIRS, vasoplegic shock, MODS) can arise from quite differing precipitating causes (cardiopulmonary bypass, sepsis, burns, and pancreatitis).

Prevention of SIRS and MODS

A wide range of strategies have been identified to attenuate the inflammatory response to cardiac surgery and cardiopulmonary bypass and potentially to reduce the incidence of MODS.² They include limiting allogenic blood transfusion, using biocompatible (heparin-coated) bypass circuits, using warm-blood cardioplegia, avoiding the reinfusion of blood obtained via cardiotomy suction, performing cardiac surgery “off-pump,” using aprotinin, and employing specific anesthesia techniques such as the use of inhaled anesthetic agents (sevoflurane or isoflurane) and regional anesthesia (epidural). However, with most of these strategies only a reduction in inflammatory-mediator production has been identified, not improved survival rates.

The treatment of post-cardiac-surgery vasoplegic shock in the intensive care unit is primarily supportive (Chapter 20). However, there is some very limited evidence supporting specific therapies, such as corticosteroids,¹³ methylene blue,¹¹ and vasopressin.¹⁴ Corticosteroids may also improve outcome after septic shock,^15,¹⁶ although this effect is controversial. Human recombinant activated protein C appears to improve outcome after severe sepsis.¹⁷

A number of interventions have been shown to reduce the development of MODS and, in some cases, improve survival rates. These interventions include early goal-directed fluid therapy,¹⁸ restrictive blood transfusion,¹⁹ lung-protective ventilation,²⁰ tight glycemic control,²¹ and enteral nutrition.²² The indications for and appropriateness of these therapies are discussed elsewhere in the book.

Shock

Shock may be defined as the failure of the circulatory system to maintain adequate perfusion to vital organs. It is usually classified on the basis of the cause:

• Hypovolemic shock occurs as the result of reduced intravascular volume; it may be hemorrhagic or nonhemorrhagic.

• Cardiogenic shock occurs due to pump failure, most commonly secondary to a large anterior myocardial infarction or as a consequence of severe postoperative myocardial stunning.

• Obstructive shock refers to the presence of a mechanical obstruction to cardiac function; the term includes tension pneumothorax, cardiac tamponade, and severe valvular obstruction.

• Vasodilatory shock includes a range of conditions characterized by pathologic vasodilation; the term includes “inflammatory shock,” neurogenic shock, and anaphylaxis.

It is usual to think of the various types of shock as being distinct entities and, indeed, each type of shock has its own characteristic clinical features. For instance, warm, dilated peripheries are a feature of vasodilatory shock, and pulmonary edema is a trait of cardiogenic shock. However, the similarities among the various forms of shock are far more striking than the differences. All forms of shock result in the activation of identical neuroendocrine pathways and provoke a systemic inflammatory response. Myocardial dysfunction is the defining characteristic of cardiogenic shock, but it is also an important feature of septic shock.^23,²⁴ In fact, in some forms of septic shock, notably meningococcemia, myocardial dysfunction may be the primary hemodynamic manifestation.²⁵ Hypovolemia is a feature not only of hypovolemic shock but also of vasodilatory shock. Indeed, prior to fluid resuscitation, septic shock may be clinically indistinguishable from hypovolemic shock. Also, there is evidence that hypovolemia and inappropriate vasodilation occur in cardiogenic shock.^26,²⁷

As already stated, systemic inflammation is strongly associated with certain forms of vasodilatory shock. However, shock itself, irrespective of the cause, precipitates a potent inflammatory response. Thus, following the initial period of resuscitation, cardiogenic shock ²⁸ and hemorrhagic shock²⁹ resemble a sepsislike syndrome, with increased levels of inflammatory markers and pathologic vasodilation. One of the primary mechanisms of the postresuscitation systemic inflammatory response is ischemia-reperfusion,³⁰ which is defined as tissue injury that is directly related to revascularization. Ischemia-reperfusion is also an important mechanism underlying myocardial stunning, as discussed in Chapter 1. All forms of shock can ultimately lead to MODS.

REFERENCES

1 Desborough JP. The stress response to trauma and surgery. Br J Anaesth. 2000;85:109-117.

2 Laffey JG, Boylan JF, Cheng DC. The systemic inflammatory response to cardiac surgery: implications for the anesthesiologist. Anesthesiology. 2002;97:215-252.

3 Levy JH, Tanaka KA. Inflammatory response to cardiopulmonary bypass. Ann Thorac Surg. 2003;75:S715-S720.

4 Despotis GJ, Avidan MS, Hogue CWJr. Mechanisms and attenuation of hemostatic activation during extracorporeal circulation. Ann Thorac Surg. 2001;72:S1821-S1831.

5 Andersen LW, Landow L, Baek L, et al. Association between gastric intramucosal pH and splanchnic endotoxin, antibody to endotoxin, and tumor necrosis factor-alpha concentrations in patients undergoing cardiopulmonary bypass. Crit Care Med. 1993;21:210-217.

6 Beghetti M, Silkoff PE, Caramori M, et al. Decreased exhaled nitric oxide may be a marker of cardiopulmonary bypass-induced injury. Ann Thorac Surg. 1998;66:532-534.

7 Crouser ED, Julian MW, Blaho DV, et al. Endotoxin-induced mitochondrial damage correlates with impaired respiratory activity. Crit Care Med. 2002;30:276-284.

8 Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee, American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992;101:1644-1655.

9 Kristof AS, Magder S. Low systemic vascular resistance state in patients undergoing cardiopulmonary bypass. Crit Care Med. 1999;27:1121-1127.

10 Carrel T, Englberger L, Mohacsi P, et al. Low systemic vascular resistance after cardiopulmonary bypass: incidence, etiology, and clinical importance. J Card Surg. 2000;15:347-353.

11 Levin RL, Degrange MA, Bruno GF, et al. Methylene blue reduces mortality and morbidity in vasoplegic patients after cardiac surgery. Ann Thorac Surg. 2004;77:496-499.