The predominant response to decreased cardiac output is to preserve perfusion to the heart and brain. This acute physiologic response is best characterized and understood in the context of hemorrhagic shock. Additionally, compensated shock is most easily understood in acute hemorrhagic shock, although inadequate organ perfusion with normal hemodynamics clearly exists in other forms of shock.

Acute hemorrhagic shock may be classified into four classes (Table 12.1). In class I shock, less than 15% of blood volume (approximately 750 mL in a 70 kg individual) has been lost. At this degree of blood loss, an increase in cardiac contractility and heart rate can maintain cardiac output and thus organ perfusion. In class II hemorrhagic shock, 15% to 30% of blood volume (approximately up to 1,500 mL in a 70-kg individual) has been lost. At this magnitude of blood loss, the acute compensatory mechanisms of increased heart rate and contractility can no longer maintain cardiac output. To maintain perfusion pressure, vasoconstriction of peripheral and mesenteric vascular beds increases resistance to blood flow, maintaining systolic blood pressure and increasing diastolic pressure (narrowed pulse pressure). While systolic blood pressure is preserved, cardiac output and delivery are decreased. This is the state of compensated shock. Class III hemorrhagic shock is defined as blood loss at 30% to 40% (approximately >1,500 mL in a 70-kg individual) of total body blood volume. At this degree of blood loss, cardiac output is severely altered and vasoconstriction can no longer maintain systolic pressure. Thus, perfusion pressure of the brain and heart are both now altered. Mental status changes and obvious signs of shock ensue. Class IV hemorrhagic shock is defined as greater than 40% of blood volume. At this degree of shock, profound hypotension, tachycardia, and severely depressed level of consciousness are manifested.

It is important to recognize that greater than roughly 1,500 mL of blood in a 70-kg individual must be lost before compensatory mechanisms are overwhelmed and hypotension develops. Significant blood loss with associated hypoperfusion of vital organs may exist prior to the development of hypotension. Inadequate organ perfusion induces cellular insult, as outlined below, regardless of blood pressure and must be recognized and treated.

Shock, or inadequate perfusion, creates hypoxia of the cells involved, which results in anaerobic rather than aerobic metabolism for cellular functions. This period of anaerobic metabolism produces “hypoxic priming” within the affected cells, characterized by a marked reduction in adenosine triphosphate (ATP) generation by the cell, an increase in oxidative stress, loss of antioxidant potential, and a buildup of acidic by-products, including lactic acid. The decrease in ATP production within hypoxic cells leads to a cascade of events including decreased ion exchange by the sodium-potassium adenosine triphosphatase pumps (Na⁺/K⁺-ATPase), calcium (Ca²⁺), cellular swelling, Ca²⁺ activation of phospholipases with activation of the arachidonic acid cascade, and generation of fatty acid reactive oxidant species. Additionally, cellular hypoxia leads to the ischemic generation of xanthine oxidase by irreversible proteolytic cleavage of xanthine dehydrogenase, the enzyme that normally catalyzes the metabolism of hypoxanthine (product of ATP utilization) to xanthine and subsequently uric acid via the generation of NADH from NAD+.

Reperfusion of cells following a period of hypoxic priming induces further oxidant injury and activation of the inflammatory cascade through several mechanisms. The xanthine oxidase enzyme, generated during hypoxia, catalyzes the conversion of hypoxanthine and oxygen to xanthine and subsequently uric acid and generating the oxidative species, superoxide (O₂^–). Additionally, hypoxia followed by reperfusion induces increased activity of nitric oxide synthetase and enhanced production of nitric oxide (NO), another oxidative species. NO and O₂^– interact to form yet another oxidative species, peroxynitrite (ONOO). These oxidative species generated by hypoxia and reperfusion directly injure mitochondria, proteins, chromosomes, and membrane structures. In severe shock states, oxidative stress can be greatly potentiated by cellular mitochondrial injury, a condition known as cytopathic hypoxia. Oxidative species, such as ONOO, can oxidize the components of the electron transport chain and open pores in the mitochondrial membrane, both contributing to mitochondrial dysfunction and loss of aerobic metabolism by the affected cells. The loss of mitochondrial function mandates anaerobic metabolic pathways by the affected cells, an ongoing reduction of ATP generation, thus further potentiating oxidative stress. The oxidative cellular injury introduced by shock potentiates oxidative injury produced by tissue trauma, infection, and sepsis as shown in Figure 12.1.

Global hypoxia and reperfusion directly activates the proinflammatory nuclear transcription factor NF-κB with increased production of cytokines (TNF, IL-1, IL-6, IL-8), chemokines, coagulation factors, adhesion molecules, and activation of tissue macrophages and neutrophils. The shock state also directly activates the innate immune system through the release of a variety of substances (referred to as “damage-associated molecular patterns” or DAMPs) that are recognized by tolllike receptors (particularly TLR4) expressed on endothelial cells, neutrophils, and tissue macrophages. Systemic activation of macrophages and neutrophils results in direct tissue damage and still further cellular oxidant injury. As in the case oxidant generation, activation of the proinflammatory state and the innate immune system by shock potentiates the activation of the inflammatory cascade caused by other insults such as tissue trauma, infection, and sepsis.

The persistence of the shock state creates a nonlinear increase in oxidative injury and activation of the inflammatory cascade and innate immune system. Increasing severity and persistence of shock will produce systemic inflammatory response syndrome (SIRS) and organ dysfunction, culminating in MODS.

Additionally, shock also creates and enhances vasodilation resulting in distributive shock. SIRS can result from or be exacerbated by shock. Activation of the inflammatory cascade and the subsequent proinflammatory state outlined above produces physiologic changes in temperature (hyperthermia, temperature > 38°C or less commonly hypothermia, temperature < 36°C), heart rate (tachycardia HR > 90), minute ventilation (respiratory rate > 20), and changes in white blood cell count (leukocytosis WBC > 12,000, bandemia > 10% bands, or less commonly leukopenia WBC < 4,000), with two or more of these changes defining SIRS. As the severity of this process progresses, organ dysfunction will be manifest, thus defining severe SIRS. The presence of SIRS and severe SIRS in which the etiology is infectious defines sepsis and severe sepsis, respectively. In critically ill patients, SIRS and sepsis are very common, occurring in roughly 75% to 80% of this population. However, SIRS is significantly more common than is sepsis, a fact that should be considered when making decisions regarding empiric antibiotics in response to fever and leukocytosis.

During shock, vascular smooth muscle function is altered leading to vasodilation. Vascular smooth muscle function is directly altered by a loss of ATP production, decreased cytoplasmic calcium and decreased phosphorylation of myosin, decreasing smooth muscle contraction. The resulting vasodilation is propagated by the up-regulation of nitric oxide synthetase and subsequently increased nitric oxide production, resulting in even greater vascular smooth muscle relaxation. As a result, systemic vascular resistance falls and distributive (or vasodilatory) shock develops. Thus, a distributive shock state may develop secondary to other forms of shock. The vasodilated state may persist for days and may require prolonged vasoconstrictive agents to ensure adequate mean arterial pressure (MAP) to ensure tissue perfusion. Increasing severity and length of hypoperfusion increases the magnitude of this series of events. Thus, hypovolemic, obstructive, and cardiogenic shock may all initiate a state of distributive or vasodilatory shock following resuscitation. After correction of the original underlying physiologic defect (e.g., hemorrhagic shock), subsequent therapy may be required to correct the vasodilatory component rather than continuing pure volume replacement.

Additionally, tissue hypoxia and sepsis both may lead to defects in the production of vasopressin by the hypothalamus and cortisol by the adrenal glands. Additionally, the use of etomidate as an induction agent for endotracheal intubation is commonly associated with a period of adrenal insufficiency. Deficiencies of either vasopressin or cortisol will produce vasodilation and distributive shock that is refractory to inotropic support. These deficiencies will coexist with the distributive shock resulting from nitric oxide-induced vasodilation and may complicate management of other forms of shock.

While large volumes of blood loss may be sustained without the development of coagulopathy if normotension is maintained, coagulopathy develops at much a much smaller volume of blood loss if shock is present. Tissue hypoxia directly potentiates coagulopathy, and on-going shock will worsen derangements that are introduced by blood loss, hypothermia, and infection. Significant overlap of the coagulation system, the anticoagulant and fibrinolytic pathways, and the inflammatory system exists, and hypoperfusion and tissue hypoxia will potentiate alteration in both pro- and

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