Shock is defined as the inadequate delivery of oxygen to tissues leading to cellular dysfunction and injury. In 1872 Gross described shock as a “rude unhinging of the machinery of life.”¹ Although this definition is less than precise, to this day it illustrates the physiologic derangements of decompensated shock. Significant hypoperfusion and cellular injury may occur despite normal systemic blood pressure, so equating shock with hypotension and cardiovascular collapse is a vast oversimplification and results in delayed recognition of early shock, when intervention is most effective at preventing end-organ dysfunction.

Shock is most precisely defined as inadequate delivery of oxygen and nutrients and removal of metabolites necessary for normal tissue and cellular function. The initial cellular injury that occurs is reversible. However, the injury will become irreversible if tissue hypoperfusion is prolonged or severe enough such that, at the cellular level, compensation is no longer possible. Rapid recognition of the patient in shock and the prompt institution of steps to correct shock is a critical skill for the trauma surgeon. Surgeons caring for injured patients must frequently initiate active treatment empirically, prior to a definitive diagnosis of the cause of shock.

The management of the patient in shock has been an integral component of the surgeon’s realm of expertise for centuries. Bernard suggested that an organism attempts to maintain constancy in the internal environment despite external forces that attempt to disrupt the milieu intérieur.² In the intact animal, the failure of physiologic systems to buffer the organism against these external forces results in the shock state. In addition, recent serial analysis of the genomic response to severe injury further identifies that the patients able to most rapidly restore homeostasis have the best outcomes.³ Cannon described the “fight or flight response” generated by elevated levels of catecholamines in the bloodstream and introduced the term homeostasis in 1926. He spent 2 years on the battlefields of Europe and published his classic monograph, Traumatic Shock, in 1923. Cannon’s observations led him to propose that shock was due to a disturbance of the nervous system that resulted in vasodilatation and hypotension. He proposed that secondary shock with its attendant capillary permeability leak was caused by a “toxic factor” released from the tissue.^4,5 Interestingly, Cannon is also credited with first proposing deliberate hypotension in patients with penetrating wounds of the torso to minimize internal bleeding since “if the pressure is raised before the surgeon is ready to check the bleeding that may take place, blood that is sorely needed may be lost.”⁶

Blalock documented that shock after hemorrhage was associated with reduced cardiac output and that hemorrhagic shock was due to volume loss, not a “toxic factor.”⁷ He also noted, however, that toxins could be important initiators of shock. In 1934, Blalock proposed the following four categories of shock that are still utilized today: hypovolemic, vasogenic, cardiogenic, and neurogenic (Table 12-1). Hypovolemic shock, the most common type, results from loss of circulating blood or its components. Thus, loss of circulating volume may be due to decreased whole blood (hemorrhagic shock), plasma, interstitial fluid, or a combination thereof. Vasogenic shock, as seen in sepsis, results from decreased resistance to blood flow within capacitance vessels of the circulatory system causing an effective functional decrease in circulating volume. Neurogenic shock is a form of vasogenic shock in which spinal cord injury (or spinal anesthesia) causes vasodilatation. Cardiogenic shock results from failure of the pump function as may occur with arrhythmias or acute heart failure. Two additional categories of shock have been added to those originally proposed by Blalock. Obstructive shock occurs when circulatory flow is mechanically impeded as with pulmonary embolism or a tension pneumothorax. Lastly, laboratory experiments and clinical experience have also confirmed the appropriateness of Cannon’s original proposal of traumatic shock as a unique entity. Injuries to soft tissue and fractures of long bones that occur in association with multisystem trauma and hypoperfusion do, in fact, cause the release of numerous “toxins” of normally excluded molecules, termed Damage Associated Molecular Patterns (DAMPs) or “danger signals” and secondary upregulation of proinflammatory mediators that can create a state of shock that is more complex than simple hemorrhagic shock.^8,9

In addition to seminal observations on the clinical syndrome of shock on the battlefield, the early and mid-20th century witnessed important laboratory contributions to our understanding of shock. In 1947, Wiggers developed a model of graded hemorrhagic shock based on the uptake of shed blood into a reservoir to maintain a prescribed level of hypotension.¹⁰ Shires and coworkers performed a series of classical laboratory studies in the 1960s and 1970s that demonstrated that a large extracellular fluid (ECF) deficit occurred in severe hemorrhagic shock that was greater than could be attributed to vascular refilling alone.¹¹ A triple isotope technique in dogs revealed that this ECF deficit persisted when shed blood or shed blood plus plasma was used in resuscitation. Only the infusion of both shed blood and lactated Ringer’s solution (an ECF mimic) repleted the red blood cell mass, plasma volume, and ECF.¹² Mortality after hemorrhage dramatically illustrated the importance of this observation: resuscitation with blood alone (80%), blood plus plasma (70%), and blood plus lactated Ringer’s solution (30%). The existence of this ECF deficit was subsequently confirmed in patients. Additional studies by this group demonstrated significant dysfunction of the cellular membrane in prolonged hemorrhagic shock.¹³ Depolarization of the cell membrane resulted in an uptake of water and sodium by the cell and loss of potassium in association with the loss of membrane integrity.¹³ The depolarization of the cell membrane was proportional to the degree and duration of hypotension. Studies in red blood cells, hepatocytes, and skeletal muscle suggested that an abnormality in membrane active transport (Na-K-ATPase pump) was the basis of the cellular membrane dysfunction.¹³ In addition, the uptake of fluid by the intracellular compartment was a major site of fluid sequestration following prolonged hemorrhagic shock. These changes were reversible with appropriate resuscitation. Thus, the importance of fluid resuscitation of severe hemorrhagic shock with isotonic saline or lactated Ringer’s solution in addition to red blood cells was confirmed. These studies also emphasized the important cellular effects underlying what had previously appeared to be a global circulatory phenomenon.

With advances in our understanding of the pathophysiology and treatment of shock, new clinical problems soon became apparent. The Vietnam War provided a clinical laboratory for the rapidly expanding field of shock research. Aggressive fluid resuscitation with red blood cells, plasma, and crystalloid solutions allowed patients who previously would have succumbed to hemorrhagic shock to survive. Renal failure became a much less frequent clinical problem, but, in its place, fulminant pulmonary failure appeared as an early cause of death after severe hemorrhage. Initially labeled “shock lung” or “DaNang lung,” the clinical problem soon became recognized as the acute respiratory distress syndrome (ARDS). Flooding of the lung with excessive large volumes of crystalloid solution was initially proposed as the primary mechanism of ARDS. Currently, ARDS is seen as a component of the multiple organ dysfunction syndrome (MODS) or multiple organ failure syndrome (MOF), a result of the complex upregulation of proinflammatory mediators and mechanisms of the homeostatic response, in addition to excessive volume resuscitation. The concept of MODS/MOF will be discussed in a subsequent chapter (see Chapter 61).

Several decades of research utilizing modified Wiggers’ models of hemorrhagic shock emphasized the importance of early control of hemorrhage in conjunction with restoration of intravascular volume with red blood cells and crystalloid solutions. Studies have extended the observations initially made by Cannon in 1918 on the futility of vigorously resuscitating patients with ongoing bleeding and have challenged traditional thinking on the appropriate end points of resuscitation from uncontrolled hemorrhage.¹⁴ The concepts of delayed fluid resuscitation and limited or controlled resuscitation are now advocated, fueled by the clinical study by Bickell et al of patients with penetrating torso trauma.¹⁵ Additional observations in recent military conflicts, Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF), have confirmed the survival benefit of limited initial resuscitation until definitive surgical control of bleeding is feasible. Several essential concepts in the management of shock in the trauma patient, however, have withstood the test of time: (a) early definitive control of the airway must be achieved; (b) delays in control of active hemorrhage increase mortality; (c) poorly corrected hypoperfusion increases morbidity and mortality, that is, inadequate resuscitation results in avoidable early deaths; and (d) excessive fluid resuscitation exacerbates problems, that is, uncontrolled resuscitation is harmful.¹⁶

Pathophysiology of Shock

Shock exists when the delivery of oxygen and metabolic substrates to tissues and cells and removal of metabolites is insufficient to maintain normal aerobic metabolism. This concept implies an imbalance between substrate delivery (supply) and substrate requirements (demand) at the cellular level. Tissue hypoperfusion is associated with cardiovascular and neuroendocrine responses designed to compensate for and reverse inadequate tissue perfusion. The pathophysiologic sequelae of shock may be due to either the direct effects of inadequate tissue perfusion on cellular and tissue function or the body’s adaptive responses producing undesirable consequences. The magnitude of the shock insult and, therefore, the magnitude of the response varies depending on the depth and duration of shock.^17,18 The consequences of shock may also vary from minimal physiologic disturbance with complete recovery at one end of the spectrum to profound circulatory disturbance, end-organ dysfunction, and death at the other (Fig. 12-1). The accumulating evidence suggests that, while the quantitative nature of the host response to shock may differ between the various etiologies of shock, the qualitative nature of the body’s response to shock is similar regardless of the cause of the insult. This response consists, in part, of profound changes in cardiovascular, neuroendocrine, and immunologic function. Furthermore, the pathophysiologic responses vary with time and in response to resuscitation. For example, in hemorrhagic shock, the initial compensation for blood loss occurs primarily through the neuroendocrine responses to maintain hemodynamics. This represents the compensated phase of shock. With ongoing hypoperfusion, cellular death and injury are ongoing and the decompensated phase of shock ensues. Microcirculatory dysfunction, cellular injury, and activation of inflammatory cells can perpetuate the hypoperfusion and exacerbate tissue injury. The ischemia/reperfusion injury will often further exacerbate the initial insult. Persistent hypoperfusion results in further hemodynamic derangements and cardiovascular collapse, which has been termed the irreversible phase of shock. At this point, extensive parenchymal and microvascular injury has occurred, such that further volume resuscitation fails to reverse the process, leading to death of the patient.

Afferent impulses transmitted from the periphery are processed within the central nervous system (CNS) and activate the reflexive effector responses or efferent impulses designed to expand plasma volume, maintain peripheral perfusion and tissue oxygen delivery, and reestablish homeostasis. The afferent impulses that initiate the body’s intrinsic adaptive responses converge in the CNS and originate from a variety of sources. The initial inciting event is often loss of circulating blood volume; other stimuli that can produce the neuroendocrine response include tissue trauma, pain, hypoxemia, hypercarbia, acidosis, infection, change in temperature, emotional arousal, or hypoglycemia. The sensation of pain from injured tissue is transmitted via the spinothalamic tracts and activates the hypothalamic–pituitary–adrenal axis.¹⁹ The sensation of pain can also activate the autonomic nervous system (ANS) and increase direct sympathetic stimulation of the adrenal medulla to release catecholamines.

Baroreceptors represent an important afferent pathway in initiating adaptive or corrective responses to shock. Volume receptors are present within the atria of the heart and are sensitive to changes in both chamber pressure and wall stretch.¹⁹ The receptors become activated with low-volume hemorrhage or mild reductions in right atrial pressure. Receptors in the aortic arch and carotid bodies respond to alterations in pressure or stretch of the arterial wall and respond to greater reductions in intravascular volume or changes in pressure. These receptors normally inhibit activation of the ANS. When these baroreceptors are activated, their output is diminished. Thus, there is increased ANS output principally via sympathetic activation at the vasomotor centers of the brainstem, and this produces centrally mediated constriction of peripheral vessels.

Chemoreceptors in the aorta and carotid bodies are sensitive to changes in oxygen tension, H⁺ ion concentration, and CO₂ level.²⁰ These receptors also provide afferent stimulation when the circulatory system is disturbed and activate effector response mechanisms. In addition, a variety of protein and nonprotein mediators produced at the site of injury and inflammation act as afferent impulses and induce a host response to shock and trauma. Some of these compounds are components of the host immunologic response to shock and include histamine, cytokines, eicosanoids, endothelins, and others that will be discussed in greater detail both in this chapter and in subsequent chapters.

Cardiovascular Response

The neuroendocrine and ANS responses to shock result in changes in cardiovascular physiology, which constitute a prominent feature in the body’s adaptive response and the clinical presentation of the patient in shock. Stimulation of sympathetic fibers innervating the heart leads to activation of β₁-adrenergic receptors that increase heart rate and contractility in an attempt to increase cardiac output.²⁰ Increased myocardial oxygen consumption occurs as a result of the increased workload. Adequate myocardial oxygen supply must be maintained or myocardial ischemia and dysfunction will develop.

Direct sympathetic stimulation of the peripheral circulation via the activation of α₁-adrenergic receptors on arterioles increases vasoconstriction and causes a compensatory increase in systemic vascular resistance and blood pressure. Selective perfusion of tissues due to regional variations in arteriolar resistance from these compensatory mechanisms occurs in shock. The majority of afterload increase to maintain mean arterial pressure (MAP), is provided by splanchnic vasoconstriction. Blood is shunted away from organs such as the intestine, kidney, and skin that are less essential to the body’s immediate needs to correct and respond to shock.²¹ Organs such as the brain and heart have autoregulatory mechanisms that attempt to preserve their blood flow despite a global decrease in cardiac output. Direct sympathetic stimulation also induces constriction of venous vessels, decreasing the capacitance of the circulatory system, and accelerating and augmenting blood return to the central circulation.

Increased sympathetic output increases catecholamine release from the adrenal medulla. Catecholamine levels increase and peak within 24–48 hours of injury before returning to baseline.²⁰ Persistence of elevation in catecholamine levels is consistent with ongoing hypoperfusion. Most of the epinephrine that circulates systemically is produced by the adrenal medulla, while norepinephrine is derived from synapses of the sympathetic nervous system.²¹ Catecholamines also have profound effects on peripheral tissues in ways that support the organism’s ability to respond to shock and hypovolemia. They stimulate hepatic glycogenolysis and gluconeogenesis to increase the availability of circulating glucose to peripheral tissues, increase glycogenolysis in skeletal muscle, suppress the release of insulin, and increase the release of glucagon.¹⁹ The genomic response is one of decreased intracellular signaling in response to insulin and decreased expression of cellular membrane proteins required for cellular uptake of glucose. These responses increase the availability of glucose to the tissues that require it for maintenance of essential metabolic activity. In addition, hyperglycemia functions as an endogenous osmotic load to further retain and increase intravascular volume.

Neuroendocrine Response

As discussed earlier, a variety of afferent stimuli lead to activation of the hypothalamic–pituitary–adrenal axis that function as an integral component of the adaptive response of the host following shock. Shock stimulates the hypothalamus to release corticotrophin-releasing hormone, which results in the release of adrenocorticotropin hormone (ACTH) by the pituitary. ACTH subsequently stimulates the adrenal cortex to release cortisol. Cortisol acts synergistically with epinephrine and glucagon to induce a catabolic state.²⁰ It stimulates gluconeogenesis and insulin resistance, resulting in hyperglycemia. It also induces protein breakdown in muscle cells and lipolysis, which provide substrates for hepatic gluconeogenesis. Cortisol causes retention of sodium and water by the kidney that aids in restoration of circulating volume. In the setting of severe hypovolemia, ACTH secretion occurs independently of negative feedback inhibition by cortisol. Absence of appropriate cortisol secretion during critical illness or after injury has been postulated as a contributor of ongoing circulatory instability in critically ill patients.^22,23,24 In addition, absence of immune cell glucocorticoid receptors prevents the normal downregulation of the immunoinflammatory response to stress and greatly increase mortality, particularly after sepsis.²⁵ The pituitary also releases vasopressin or antidiuretic hormone (ADH) in response to hypovolemia, changes in circulating blood volume sensed by baroreceptors and stretch receptors in the left atrium, and increased plasma osmolality detected by hypothalamic osmoreceptors.¹⁹ Epinephrine, angiotensin II, pain, and hyperglycemia enhance the production of ADH. ADH levels remain elevated for about 1 week after the initial insult, depending on the severity and persistence of the hemodynamic abnormalities. ADH acts on the distal tubule and collecting duct of the nephron to increase water permeability and sodium reabsorption, thus decreasing loss of water and preserving intravascular volume. Also known as arginine vasopressin, ADH acts as a potent mesenteric vasoconstrictor, shunting circulating blood away from the splanchnic organs during hypovolemia.²⁶ The intense mesenteric vasoconstriction produced by vasopressin may contribute to intestinal ischemia and predispose to dysfunction of the intestinal mucosal barrier in shock states. Vasopressin also regulates hepatocellular function by increasing hepatic gluconeogenesis and hepatic glycolysis.

The renin–angiotensin system is activated in shock, as well. Decreased perfusion of the renal artery, β-adrenergic stimulation, and increased sodium concentration in the renal tubules cause the release of renin from the juxtaglomerular cells.²⁰ Renin catalyzes the conversion of angiotensinogen (produced by the liver) to angiotensin I, which is then converted to angiotensin II by angiotensin-converting enzyme (ACE) produced in the lung. While angiotensin I has no significant functional activity, angiotensin II is a potent vasoconstrictor of both splanchnic and peripheral vascular beds and also stimulates the secretion of aldosterone, ACTH, and ADH. Aldosterone, a mineralocorticoid, acts on the nephron to promote reabsorption of sodium and, as a consequence, water in exchange for potassium and hydrogen ions that are lost in the urine.

Immunologic and Inflammatory Response

The inflammatory and innate immune responses are a complex set of interactions between circulating soluble factors and cells that arise in response to trauma, infection, ischemia, toxic, or autoimmune stimuli.²⁷ The function of the host’s immune system after shock is intimately related to alterations in the production of mediators generally considered part of the body’s innate response to localized inflammation and infection. However, when these mediators gain access to the systemic circulation, they induce changes in a number of tissues and organs. Therefore, activation of proinflammatory pathways is an integral component of the host response to shock. While proinflammatory activation is a central feature of septic shock, proinflammatory cytokine production and mediator release also occurs in other forms of shock such as hypovolemic shock-induced ischemia and tissue injury and, in particular, traumatic shock, which releases DAMPs and other endogenous stimulatory molecules from the damaged tissue.^9,28,29,30 In fact, severe trauma and shock have been shown to alter the normal gene response in up to 80% of the entire human genome, leading to a total body “genomic storm.”³ Thus, as initially proposed by Cannon in the early part of the 20th century, inflammatory “toxic” mediators can be a cause of shock as well as a by-product of the body’s response to shock. Most mediators have a variety of effects due to the redundant and overlapping nature of the host response to injury. Therefore, in addition to regulating immune function in the host, many of these mediators have effects on the cardiovascular system, coagulation system, cellular metabolism, and cellular gene expression. It deserves to be mentioned, however, that many compounds already discussed that have substantial effects on the cardiovascular or neuroendocrine response to shock, such as catecholamines, can also have effects on immune function and the activation of proinflammatory cytokines.³¹ Cytokines are small polypeptides and glycoproteins that exert most of their actions in a paracrine fashion and are responsible for fever, leukocytosis, tachycardia, tachypnea, and the upregulation of other cytokines. Their levels are elevated in hemorrhagic, septic, and traumatic shock.²⁷ The overexpression of certain cytokines is associated with the metabolic and hemodynamic derangements often seen in septic shock or decompensated hypovolemic shock, and cytokine production after shock correlates with the development of MODS.^28,29,30,32 The immune response to injury and infection is discussed in greater detail in Chapter 61. A brief review of several of the key components of the immune response is provided below.

Tumor necrosis factor-α (TNF-α) is one of the earliest proinflammatory cytokines released by monocytes, macrophages, and T cells in response to injurious stimuli.³³ The classic model of TNF-α production is the injection of bacterial endotoxin in an animal or human subject. Under these controlled conditions, TNF-α levels peak within 90 minutes of the insult and return to baseline within 4 hours. Endotoxin stimulates TNF-α release and may be a primary inducer of cytokines, as in the case of septic shock. TNF-α release may also be a secondary event following the release of DAMPs and other mediators from injured tissue.⁸ TNF-α levels are increased after hemorrhagic shock,³⁴ and TNF-α levels correlate with mortality in animal models of hemorrhage.³⁵ In humans, TNF-α, interleukin-6 (IL-6), and IL-8 levels increase during hemorrhagic shock, although the magnitude of the increase is less than that seen in septic patients.³⁶ Once released, TNF-α can cause peripheral vasodilation, activate the release of other cytokines such as IL-1β and IL-6, induce procoagulant activity and increased consumption of coagulation factors, and stimulate a wide array of cellular metabolic changes.³³ TNF-α enhances mechanisms of host defense against infection by promoting activation of macrophages and neutrophil intracellular killing of pathogens.³⁷ During the stress response, TNF-α contributes to breakdown of muscle protein and cachexia, as well.³³ Despite being linked to tissue injury and dysfunction, TNF-α appears to be essential in combating bacterial infection since neutralizing TNF-α in infection models using live bacteria (peritonitis, pneumonia) increases mortality.^38,39,40

IL-1β has actions that are similar to TNF-α and can cause hemodynamic instability and vasodilation.³³ It has a very short half-life (6 minutes) and primarily acts locally in a paracrine fashion. IL-1β produces a febrile response by activating prostaglandins in the posterior hypothalamus and causes anorexia by activating the satiety center. This cytokine also augments the secretion of ACTH, glucocorticoids, and β-endorphins.³³ In conjunction with TNF-α, IL-1β can induce the release of other cytokines such as IL-2, IL-4, IL-6, IL-8, granulocyte/macrophage colony-stimulating factor (GM-CSF), and interferon-γ (IFN-γ). IL-2 expression is important for the cell-mediated immune response, and its attenuated expression has been associated with transient immunosuppression of injured patients. IL-6 has consistently been shown to be elevated in animals subjected to hemorrhagic shock or trauma and in patients with major surgery or trauma. Elevated IL-6 levels correlate with mortality in some forms of shock.⁴¹ IL-6 contributes to neutrophil-mediated injury to the lung after hemorrhagic shock⁴² and may play a role in the development of diffuse alveolar damage and ARDS. IL-6 and IL-1β are mediators of the hepatic acute phase response to injury and enhance the expression and/or activity of complement, C-reactive protein, fibrinogen, haptoglobin, amyloid A, and α₁-antitrypsin. Activation of neutrophils is promoted by IL-6, IL-8, and GM-CSF, and IL-8 also serves as a potent chemoattractant to neutrophils.

The complement cascade is activated by injury and shock and contributes to proinflammatory activation in both animal models and human patients. Complement consumption can occur after hemorrhagic shock and may contribute to the hypotension, coagulopathy and metabolic acidosis observed following resuscitation.⁴³ The degree of complement activation is proportional to the magnitude of the traumatic injury and may serve as a marker for severity of injury in trauma patients.⁴⁴ Patients in septic shock also demonstrate activation of the complement pathway with elevation of the activated complement proteins C3a and C5a.⁴⁵ Activation of the complement cascade can contribute to the development of organ dysfunction.^46,47 The development of ARDS and MODS/MOF in trauma patients correlates with the intensity of complement activation.^28,30

Activation of neutrophils is one of the early changes induced by the inflammatory response, and neutrophils are the first cells to be recruited to sites of injury and inflammation. These cells are important in the clearance of infectious agents, foreign substances that have penetrated host barrier defenses, and toxic-generating nonviable tissue. On the other hand, activated neutrophils and their products may also produce bystander cell injury and organ dysfunction. Activated neutrophils generate and release a number of substances such as reactive oxygen species, lipid peroxidation compounds, proteolytic enzymes (elastase, cathepsin G), and vasoactive mediators (leukotrienes, eicosanoids, and platelet-activating factor [PAF]). Oxygen radicals such as superoxide anion, hydrogen peroxide, and the hydroxyl radical are potent inflammatory molecules that activate peroxidation of lipids, inactivate cellular enzymes, and consume cellular antioxidants (such as glutathione and tocopherol). Intestinal ischemia and reperfusion cause activation of neutrophils and induce neutrophil-mediated organ injury in experimental animal models.⁴⁸ In animal models of hemorrhagic shock, activation of neutrophils correlates with irreversibility of shock and mortality,⁴⁹ and neutrophil depletion prevents many of the pathophysiologic sequelae of hemorrhagic and septic shock.^50,51 Human data corroborate the activation of neutrophils in trauma and shock and suggest that neutrophil activation may play a role in the development of MODS/MOF after injury.⁵² Plasma markers of neutrophil activation such as elastase and other enzymes correspond to phagocytic activity or correlate with severity of injury.²⁹ In this context, markers of neutrophil activation may predict the development of ARDS and MODS/MOF after shock (see Chapter 61).

Interactions between endothelial cells and leukocytes are important in host defense and the initiation and perpetuation of the inflammatory response in the host. The vascular endothelium regulates blood flow, adherence of leukocytes, and activation of the coagulation cascade. Adhesion molecules such as intercellular adhesion molecules (ICAMs), vascular cell adhesion molecules (VCAMs), and the selectins (E-selectin, P-selectin) are expressed on the surface of endothelial cells and are responsible for the adhesion of leukocytes to the endothelium. The interaction of surface proteins on leukocytes and vascular endothelial cells allows activated neutrophils to marginate into the tissues in order to engulf invading organisms. Unfortunately, the migration of activated neutrophils into tissues can also lead to neutrophil-mediated cytotoxicity, microvascular damage, and tissue injury.⁵³ This tissue damage contributes to microvascular thrombosis, simultaneous coagulopathy and organ dysfunction after shock.

Cellular Effects

Depending on the magnitude of the insult and the intrinsic compensatory mechanisms present in different cells, the response at the cellular level may be one of adaptation, dysfunction and injury, or death. The aerobic respiration of the cell, that is, oxidative phosphorylation by mitochondria, is the pathway most susceptible to inadequate oxygen delivery and toxic oxygen radicals. As oxygen tension within cells decreases, oxidative phosphorylation decrease and the generation of adenosine triphosphate (ATP) slows or stops. The loss of ATP, the cellular “energy currency,” has widespread effects on cellular function, physiology, and morphology.⁵⁴ As oxidative phosphorylation slows, the cells shift to anaerobic glycolysis that generates ATP from the rapid breakdown of cellular glycogen.⁵⁵ However, anaerobic glycolysis is much less efficient than oxygen-dependent mitochondrial pathways. Under aerobic conditions, pyruvate, the end product of glycolysis, is fed into the Krebs cycle for further oxidative metabolism. Under hypoxic conditions, the mitochondrial pathways of oxidative catabolism are impaired and pyruvate is instead converted to lactate. The accumulation of lactic acid and inorganic phosphates is accompanied by a reduction in pH resulting in intracellular metabolic acidosis. As cells become hypoxic and ATP depleted, other ATP-dependent cell processes are affected: synthesis of enzymes and structural proteins, repair of deoxyribonucleic acid (DNA) damage, and intracellular signal transduction. Tissue hypoperfusion also results in decreased availability of metabolic substrates and the accumulation of metabolic by-products such as oxygen radicals and organic ions that may be toxic to cells.

The consequences of intracellular acidosis on cell function can be quite profound. Decreased intracellular pH can alter the activity of cellular enzymes, lead to changes in cellular gene expression, impair cellular metabolic pathways, and interfere with ion exchange in the cell membrane.^56,57,58 Acidosis can also lead to changes in cellular calcium (Ca²¹) metabolism and Ca²⁺-mediated cellular signaling that can, by itself, interfere with the activity of specific enzymes and alter cell function.^56,59 These changes in normal cell function can produce cellular injury or cell death.⁶⁰ Changes in both cardiovascular function and immune function in the host can be induced by acidosis,^61,62 although translating these in vitro effects to the physiologic sequelae of shock produced in the intact organism are difficult.

As cellular ATP is depleted under hypoxic conditions, the activity of the membrane Na⁺, K⁺-ATPase slows and thus the regulation of cellular membrane potential and volume is impaired.¹³ Na⁺ accumulates intracellularly while K⁺ leaks into the extracellular space. The net gain of intracellular sodium is accompanied by an increase in intracellular water and the development of cellular swelling and tissue edema. This cellular influx of water is associated with a corresponding reduction in ECF volume.⁶³ Swelling of the endoplasmic reticulum is the first ultrastructural change seen in hypoxic cell injury. Eventually, swelling of the mitochondria and cells is observed. The changes in cellular membrane potential impair a number of cellular physiologic processes such as myocyte contractility, cell signaling, and the regulation of intracellular Ca²⁺ concentrations. Once intracellular organelles such as mitochondria, lysosomes or cell membranes rupture, the cell will undergo death by either apoptosis or necrosis.^64,65,66 Hypoperfusion and hypoxia cause widespread cell death by apoptosis. Animal models of shock and ischemia/reperfusion have demonstrated apoptotic cell death in lymphocytes, intestinal epithelial cells, and hepatocytes.⁶⁵ Apoptosis has also been detected in trauma patients with ischemia and reperfusion injury. Apoptosis of lymphocytes and intestinal epithelial cells occurs within the first 3 hours of injury.⁶⁶ Apoptosis in intestinal mucosal cells may compromise barrier function of the intestine and lead to proinflammatory activation of submucosal immune cells with release of mediators into the portal circulation during shock. Also, lymphocyte apoptosis has been hypothesized to contribute to the immune suppression that is observed in trauma patients and increased risk of nosocomial infections.

Tissue hypoperfusion and cellular hypoxia result not only in intracellular acidosis but also in systemic metabolic acidosis as metabolic by-products of anaerobic glycolysis exit the cells and gain access to the circulation. In the setting of acidosis, oxygen delivery to the tissues is improved as the oxyhemoglobin dissociation curve is shifted toward the right.¹⁹ The decreased affinity of hemoglobin for oxygen in erythrocytes results in increased tissue O₂ release and increased tissue extraction of oxygen. In addition, hypoxia stimulates the production of erythrocyte 2,3-diphosphoglycerate (2,3-DPG), which also contributes to the shift to the right of the oxyhemoglobin dissociation curve and increases O₂ availability to the tissues during shock.

Epinephrine and norepinephrine released after shock have a profound impact on cellular metabolism in addition to their effects on vascular tone. Hepatic glycogenolysis, gluconeogenesis, ketogenesis, breakdown of skeletal muscle protein, and lipolysis of adipose tissue are all increased by these catecholamines.²⁶ Cortisol, glucagon, and ADH also participate in the regulation of catabolism during shock. Epinephrine induces the release of glucagon while inhibiting the release of insulin by pancreatic β-cells. In addition, shock blocks genomic and cellular responses necessary for insulin recognition and uptake and utilization of glucose. The result is a catabolic state with glucose mobilization, hyperglycemia, protein breakdown, negative nitrogen balance, lipolysis, and insulin resistance during shock and injury.^26,63 The relative underutilization of glucose by peripheral tissues preserves it for the glucose-dependent organs such as the heart and brain. In addition to inducing changes in cellular metabolic pathways, shock also induces changes in cellular gene expression. The DNA-binding activity of a number of nuclear transcription factors is altered by the production of oxygen radicals, nitrogen radicals, or hypoxia that occurs at the cellular level in shock.⁶⁷ The expression of other gene products including heat shock proteins,⁶⁸ vascular endothelial growth factor (VEGF), inducible nitric oxide synthase (iNOS), and cytokines is also increased in shock.^69,70,71 Many of these shock-induced gene products, such as cytokines, have the ability to subsequently alter gene expression in specific target cells and tissues.³³ These pathways will be discussed in greater detail elsewhere but they emphasize the complex, integrated, and overlapping nature of the response to shock.

Shock induces profound changes in tissue microcirculation that may contribute to organ dysfunction, and the systemic sequelae of severe hypoperfusion. These changes have been studied most extensively in the microcirculation of skeletal muscle in models of sepsis and hemorrhage. Whether microcirculatory changes are primarily a result of the development of shock or a pathophysiologic response that promotes tissue injury and organ dysfunction has been difficult to determine. Intuitively, it would seem that both are likely to be true. After hemorrhage, larger arterioles vasoconstrict, most likely due to sympathetic stimulation, while smaller distal arterioles dilate, presumably due to local metabolic mechanisms.⁷² Flow at the capillary level, however, is heterogeneous with swelling of endothelial cells and the aggregation of leukocytes producing microvascular thrombosis and diminished capillary perfusion in some vessels both during shock and following resuscitation.^73,74 Damaged endothelial cells express procoagulant mediators and diffuse consumption of coagulation factors. Hemorrhage-induced microcirculatory dysfunction also occurs in diverse vascular beds besides skeletal muscle and contribute to tissue injury and organ dysfunction.^75,76 In sepsis, similar changes in microcirculatory function occur. Regional differences in blood flow can be demonstrated after proinflammatory stimuli, and the microcirculation in many organs is heterogeneous.^{77,78,79,80,81} Aggregation and sludging of neutrophils in the microcirculation with thrombosis can aggravate shock-induced hypoperfusion, induce direct cellular injury via toxic neutrophil-dependent processes such as production of oxygen radicals or release of proteolytic enzymes, and impair cellular metabolism.⁸²

The decreases in microcirculatory blood flow and capillary perfusion result in decreased capillary hydrostatic pressure. The changes in hydrostatic pressure promote an influx of fluid from the extravascular or extracellular space into the capillaries in an attempt to increase circulating volume. These changes are associated, however, with additional decrements in the volume of ECF due to simultaneous increased cellular swelling. These basic cellular and microcirculatory changes have significant physiologic importance in the ability of the organism to recover from circulatory shock. Resuscitation with volumes of fluid sufficient to restore the ECF deficit is associated with improved outcome after shock as described earlier.¹²

Quantifying Cellular Hypoperfusion

Hypoperfused tissues and cells experience what has been called oxygen debt, a concept first proposed by Crowell.⁸³ The oxygen debt is the deficit in tissue oxygenation over time that occurs during shock. When oxygen delivery (DO₂) is limited, oxygen consumption (VO₂) may be inadequate to match the metabolic needs of cellular respiration due to a deficit in oxygen at the cellular level. The measurement of oxygen deficit is calculated by taking the difference between the estimated oxygen demand and the actual value obtained for oxygen consumption (VO₂). Under normal circumstances, cells can “repay” or negate the oxygen debt during reperfusion. The magnitude of the oxygen debt correlates with the severity and duration of hypoperfusion. In a canine model of hemorrhagic shock, Crowell and Smith demonstrated a direct relation between survival and degree of shock.⁸⁴ They determined that a marker of mortality was the inability to recover from the oxygen debt. The median lethal dose (LD₅₀) occurred at 120 mL/kg of oxygen debt. Dunham et al showed via regression analysis that the probability of death could be directly correlated to the calculated oxygen debt in a canine model of hemorrhagic shock.⁸⁵ Their study demonstrated that the LD₅₀ for oxygen debt was similar (113.5 mL/kg) to that found by Crowell in their earlier studies. Dunham et al were also able to confirm a relation between the rate of accumulation of the oxygen debt and survival. In human patients a relation between oxygen debt and survival has also been shown. In over 250 high-risk surgical patients, the calculated oxygen debt correlated directly with organ failure and mortality.⁸⁶ The maximum oxygen debt in nonsurvivors (33.2 L/m²) was greater than that of survivors with organ failure (21.6 L/m²) and survivors without organ failure (9.2 L/m²). In addition, the total duration of oxygen debt and the time required to restore perfusion correlated with outcome in this study. Survivors were able to reverse the oxygen debt while the hallmark of nonsurvivors was the inability to repay the oxygen debt. Thus, the magnitude of the oxygen debt, its rate of accumulation, and the time required to correct it, that is, severity and duration of hypoperfusion, all correlate with survival.

Unfortunately, it is difficult to directly measure the oxygen debt in the resuscitation of trauma patients. The easily obtainable clinical parameters of arterial blood pressure, heart rate, urine output, central venous pressure, and pulmonary artery occlusion pressure are poor indicators of the adequacy of tissue perfusion. Therefore, surrogate parameters have been sought to estimate the oxygen debt. Experimental animal studies show that serum lactate and base deficit (BD) correlate with oxygen debt.⁸⁵ Cardiac output, blood pressure, and shed blood volume were all inferior to the BD and lactate in estimating the oxygen debt and in predicting mortality in hemorrhaged animals.⁸⁵ Dunham et al showed a direct correlation between arterial lactate and probability of survival in a model of canine hemorrhage (Fig. 12-2).⁸⁵ The LD₅₀ for lactate was 12.9 mmol/L in hemorrhaged dogs.

BD is the amount of base in millimoles that is required to titrate 1 L of whole blood to a pH of 7.40 with the blood fully saturated with O₂ at 37°C (98.6°F) and a PaCO₂ of 40 mm Hg. It is usually measured by arterial blood gas analysis using automated devices and has a rapid turnaround time. Good correlation between the BD and survival has been shown in patients with shock.⁸⁷ At a BD of 0 mmol/L there was 8% mortality, while there was 95% mortality at a BD of 26 mmol/L. The LD₅₀ occurred at a BD of 11.8 mmol/L (Fig. 12-3).⁸⁷ Other clinical parameters such as blood pressure, heart rate, hemoglobin, plasma lactate, and oxygen transport variables were not nearly as accurate as the BD in determining the probability of death in these trauma patients. Neither BD nor serum lactate, however, is as precise at measuring physiologic stress as the oxygen debt. When compared in a model of hemorrhage and resuscitation, the lactate level decreased too slowly and tended to estimate higher residual oxygen debt while the BD decreased more rapidly and tended to estimate lower values of oxygen debt.⁸⁴ However, the BD appeared to reflect the measured oxygen debt more accurately. As will be discussed more fully later in the chapter (see Section “End Points in Resuscitation of the Trauma Patient”), both lactate and BD are useful in the assessment of trauma patients and in the evaluation of the patient’s response to resuscitation.

General Overview

Shock represents a condition of abnormal tissue perfusion. The manifestations of shock may be dramatic, as in the patient with profound hypotension or obvious external sources of blood loss, or findings may be subtle. As with other trauma-induced injuries, the evaluation, diagnosis, and treatment of the trauma patient in shock begin with the ABCs of the primary survey.⁸⁸ Advanced shock may produce coma with loss of the ability to maintain and protect the airway, so that endotracheal intubation is necessary. Marked tachypnea may be present as a symptom of a primarily respiratory homeostatic response, as the respiratory system attempts to compensate for metabolic acidosis, or in response to generalized anxiety from hypoperfusion of the CNS. In the primary survey, the circulation can be rapidly assessed by evaluation of the presence and location of the pulse (central vs peripheral), its rate, and its character. Absent peripheral pulses (radial, pedal) associated with weak, rapid central pulses (femoral, carotid) denote a profound circulatory disturbance that requires prompt intervention. Associated findings that may be manifestations of abnormal tissue perfusion include cool clammy skin, altered sensorium (confusion, lethargy, coma), and tachycardia. Low urine output, often used as an indicator of hypovolemia, is unlikely to be a useful tool in the initial assessment of the patient in shock in the trauma resuscitation area. Measurement of blood pressure may be misleading as systolic blood pressure may not be diminished in the early stages of shock. Compensatory mechanisms to maintain cerebral and coronary perfusion may maintain relatively normal systemic arterial pressure despite hypovolemia and significant underperfusion of splanchnic and peripheral tissues. Up to 30% of the blood volume may be lost before significant changes in blood pressure occur.⁸⁸ When present, however, hypotension represents a profound circulatory derangement and failure of compensatory mechanisms that portends imminent collapse, and requires immediate attention.

The correction of shock should begin immediately once it is recognized. Treatment generally begins before an etiology for shock is identified. The forms of shock are listed in Table 12-1, but the most common etiology for shock in the trauma patient is hypovolemia from loss of circulating volume (see algorithm, Fig. 12-4). Two large-bore intravenous lines (at least 14- or 16-gauge peripheral or number 7.5–8.5 French resuscitation lines) should be inserted and volume resuscitation instituted. The availability of rapid infusion systems facilitates rapid volume expansion with the delivery rate limited predominantly by the size and length, that is, resistance, of the intravenous cannula. Fluid warmers to heat the infusate are essential to prevent hypothermia. For patients in profound shock, immediate blood replacement is necessary. As soon as possible, fresh frozen plasma (FFP) and platelets should be infused as well, to prevent worsening of the frequently coexistent coagulopathy. Every institution should have a massive transfusion (MT) protocol in place to ensure immediate access to the critical blood components necessary. As correction of the shock state is underway, the etiology for shock is rapidly sought. Physical examination may indicate potential etiologies (ie, obvious external hemorrhage, flaccid warm extremities from spinal cord injury, or penetrating precordial wounds). Rapidly performed radiologic examinations (x-rays of chest and pelvis, and diagnostic ultrasound) can provide additional information while the initial resuscitation is being conducted and the response to resuscitation is evaluated. Diagnostic maneuvers that do not directly contribute to the identification and treatment of shock should be deferred until shock has been corrected. Trauma patients can be categorized into three general groups with respect to their response to resuscitative maneuvers (see treatment algorithm, Fig. 12-5). Responders are those patients who rapidly correct their shock state with minimal replacement of intravascular volume. These patients often have an intravascular volume loss but not ongoing, bleeding that has stopped or been tamponaded (multiple extremity fractures), or an etiology for hypoperfusion other than hypovolemia such as neurogenic shock or obstructive shock. Aggressive resuscitation should cease with return of normal clinical parameters to avoid excessive fluid overload. Transient responders represent patients who initially improve with resuscitative efforts, but subsequently deteriorate. This group of patients frequently has intracavitary bleeding that will require surgical control or IR intervention, for example, a liver or splenic laceration. Nonresponders represent those patients who have persistent manifestations of shock despite vigorous resuscitative efforts. These patients are gravely ill and often present in extremis. These patients typically have high-volume bleeding from injuries to major vessels or severe injuries to solid organs that require immediate operative control. They will rapidly expire from circulatory collapse or develop the progressive lethal triad of hypothermia, coagulopathy, and irreversible shock unless bleeding is rapidly controlled. Patients who have active, ongoing hemorrhage cannot be successfully resuscitated until hemorrhage has been controlled, and, thus, rapid identification of patients who require operative intervention is essential.

Vascular Access for Patients with Severe Hemorrhage