Chapter 12: Management of Shock

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

In the trauma patient presenting with multiple serious injuries and hemorrhagic shock, vascular access is necessary to restore intravascular volume rapidly. The most important factor in considering the procedure and route for vascular access is the anatomical location and magnitude of hemorrhagic injuries and the individual physician’s level of skill and expertise (see Chapter 10).

Venous access should never be initiated in an injured limb. In patients with injuries below the diaphragm, at least one IV line should be placed in a tributary of the superior vena cava, as there may be vascular disruption or obstruction of the inferior vena cava. In patients with severe multiple trauma in whom occult thoracoabdominal damage is suspected, it is ideal to have one IV access site above the diaphragm and one below the diaphragm, thus accessing both the superior vena cava and inferior vena cava, respectively. For rapid administration of large amounts of intravenous fluids, short large-bore catheters should be used. Doubling the internal diameter of the venous cannula increases the flow through the catheter 16-fold. When using 8.5 French pulmonary vascular catheter introducers, the side port should be removed, as this increases the resistance roughly four fold.

ATLS^TM guidelines recommend rapid placement of two large-bore (16-gauge or larger) IV catheters in the patient with serious injuries and hemorrhagic shock.⁸⁸ The first choice for IV insertion should be a peripheral extremity vein. The most suitable veins are at the wrist, the dorsum of the hand, the antecubital fossa in the arm, and the saphenous in the leg. The complication rate of properly placed intravenous catheters is low. Intravascular placement of a large-bore IV should be verified by checking for backflow. An IV site should infuse easily without added pressure. Intravenous fluids can leak into soft tissues when pumped under pressure through an infiltrated IV line, and may create a compartment syndrome.

Subclavian, internal jugular (IJ) and femoral catheterization should be used with caution in hypovolemic trauma patients as the venous collapse associated with their hypovolemia may increase the risk of inadvertent arterial puncture and cannulation. For this reason, the incidence of complications is higher and the rate of success is lower in these situations. Rapid peripheral percutaneous IV access may be difficult to achieve in patients with hypovolemia and venous collapse, edema, obesity, scar tissue, history of IV drug abuse, or burns. Subclavian or femoral vein catheterization usually provides rapid and safe venous access in experienced hands. The most frequent complication of subclavian venipuncture is pneumothorax. Pneumothorax is more likely to occur on the left side because the left pleural dome is anatomically higher.

Thrombophlebitis or line infection is more common with femoral catheters; however, this is most common with prolonged use. Subclavian and internal jugular (IJ) catheters should be inserted on the side of injury in patients with chest wounds, reducing the chances of collapse of the uninjured lung. A simple pneumothorax may result in respiratory compromise in individuals with pulmonary contusions or a pneumothorax in the contralateral hemithorax. Regardless of the site of insertion, it is extremely important not to force the wire or the introducer if resistance is encountered. Forcing the introducer could result in perforation of large central veins or arteries and bleeding. Venous air embolism is another complication of central line insertion. All central venous access lines should be placed with complete aseptic technique. Any lines placed during resuscitation of a trauma patient without strict aseptic technique should be removed as soon as the patient’s condition permits. Although percutaneous placement of IJ catheters is an excellent means of attaining rapid large-bore catheter access, this is a rather unusual site for intravenous insertion in trauma patients because of the possibility of cervical trauma and the need for cervical collar immobilization. In patients with hemodynamic shock and in situations where percutaneous peripheral or central venous access is either contraindicated or impossible to achieve, intraosseous (IO) placement is a feasible alternative for both volume replacement and infusion of therapeutic agents. Preferred locations are the proximal pretibial or lateral humeral approach.

Resuscitation Fluids

The type of fluid used for resuscitation is as important as the volume infused. Lactated Ringers (LR) solution remains the resuscitative crystalloid of choice in civilian trauma centers. Large volume resuscitation with normal saline produces or enhances the frequently present detrimental hyperchloremic metabolic acidosis. Similarly, the use of hypertonic saline as a first-line resuscitative fluid is not recommended. The Resuscitation Outcomes Consortium (ROC) trials for both shock and traumatic brain injury were halted after preliminary data showed no beneficial effect of hypertonic saline for either one of these groups studied in the clinical trials.^89,90 In addition, use of HTS appears to increase the coagulopathy seen in severe hemorrhagic shock.⁹¹

Interest in using 6% hetastarch in balanced salt solution (Hextend) arose based on encouraging military experience with this fluid. However, recent studies, including a porcine model of hemorrhagic shock, demonstrate Hextend results in a prolonged decrease in clotting capacity compared to LR. At this time, there is no evidence to endorse use of this fluid for resuscitation.⁹² There are other studies indicating that noncrystalloid fluids may be more effective as first line for resuscitation of shock. A promising alternative is the reintroduction of lyophilized plasma (LP). In a recent large animal model, the use of LP was found to be safe and effective as FFP for resuscitation after severe trauma.⁹³ Animals were subjected to a clinically comparable injury complex including multiple trauma characterized by extremity fracture, hemorrhage, severe liver injury, acidosis, and hypothermia. While submitting FFP to lyophilization decreased clotting factor activity by an average of 14%, animals treated with LP had similar coagulation profiles, plasma lactate levels, and post-injury blood loss compared with those treated with FFP. LP safety and efficacy in humans has yet to be confirmed.

Damage Control Resuscitation

There is significant evidence that the best resuscitative fluid for a person in persistent or severe hemorrhagic shock is not crystalloid nor colloid but in fact, a balanced infusion of blood components to mimic, as possible, replacement of fluid lost, that is, whole blood (see Chapter 13). This includes early administration of packed red blood cells (PRBCs), which have been shown alone to improve early outcomes when given in the prehospital setting.⁹⁴ A balanced transfusion strategy of PRBCs, FFP, and platelets has been suggested to enhance hemostasis and decrease death due to exsanguination (PROPPR Trial).⁹⁵ Additionally, aggressive resuscitation with blood products has also been shown to be associated with lower rates of multiple organ failure (MOF).⁹⁶

Controlled “Hypotensive” Resuscitation

Traditionally, the management of patients in shock has been focused on providing aggressive fluid resuscitation with crystalloid or colloid solutions to rapidly restore circulating blood volume and thus maintaining “optimal” vital organ perfusion. This approach can potentially increase bleeding by elevating the blood pressure and dislodging established blood clots.⁹⁷ Other unwanted effects of aggressive fluid resuscitation include worsening coagulopathy and increased tissue edema, which play a role in the occurrence of abdominal compartment syndrome and MODS/MOF. Hypotensive resuscitation is not a new concept; in 1918, Cannon et al described the deleterious effects of injecting fluids before the surgeon could achieve vascular control of the injury.⁶ Cannon suggested an end point of resuscitation prior to definitive hemorrhage control of a systolic pressure of 70–80 mm Hg, using a crystalloid/colloid mixture as his fluid of choice. In World War II, Cannon’s recommendations were followed by Beecher⁹⁸ who developed Cannon’s hypotensive resuscitation principals specifically for the care of combat casualties with truncal injuries. This approach was primarily an attempt to minimize transfusion volume and blood loss in the operating room. Bickell et al in 1994 published a prospective analysis comparing immediate and delayed fluid resuscitation in hypotensive adult trauma patients with penetrating torso injuries in the city of Houston.¹⁵ In the delayed group, fluid administration was withheld until the time of operative intervention. Improved survival was seen in this study population, with a trend toward fewer complications. These data corroborated the concept that delaying fluid resuscitation until hemorrhage is controlled improves outcome in this select group of penetrating trauma patients. In subsequent publications, other investigators have shown that increased prehospital time associated with attempts to place an intravascular access as well as the prehospital use of rapid infusion was correlated with increased mortality.^99,100,101 Importantly, the findings reported by Dutton were not significantly different when patients were randomized to either a blood pressure of 70 mm Hg or systolic blood pressures of 100 mm Hg.⁹⁹ Multiple recent papers have confirmed these findings.¹⁰² Such findings support a resuscitation approach that mimics the management of patients with another form of shock, those with a ruptured abdominal aortic aneurysm (AAA), in whom aggressive volume resuscitation during their preoperative management has been found to increase the perioperative risk of death regardless of their systolic blood pressure measurements.¹⁰³ Management protocols currently adapted from military experience recommend the use of a palpable radial pulse (approximately 80–90 SBP) and/or the presence of a normal mental status as the most appropriate indicators of adequate perfusion. Combat casualties found at the scene with a palpable radial pulse and normal mentation are given intravenous access but no intravenous fluids are infused until arriving to a far-forward facility where initial surgical management can be instituted. In civilian trauma, a goal directed approach in the prehospital setting demonstrated that while a 2 L bolus of crystalloid in the normotensive patient was associated with an increased mortality, the same bolus in the significantly hypotensive (SBP <90 mm Hg) patient led to an improvement in survival, supporting the need for a controlled volume in the severely hypotensive patient with a goal of SBP of 90 mm Hg.¹⁰⁴ Overall, preservation of native hemostatic mechanisms appears best achieved by allowing for a lower than normal blood pressure, therefore reducing the rate of bleeding, while still ensuring adequate tissue perfusion pressure for optimal survival. The characteristics of the local environment, the type of injury, and whether fast and adequate hemostasis can be promptly achieved are the current determinants for the use of limited resuscitation during prehospital care.

Exceptions to this resuscitative strategy include two main groups, elderly patients and those with traumatic brain injury (TBI). For an elderly patient, many of whom are on antihypertensive medications at baseline, even a systolic blood pressure of 110–120 mm Hg may be indicative of relative hypotension and therefore, resuscitation in these individuals must take their expected baseline perfusion pressures into account. Secondly, in civilian trauma centers, patients with multiple blunt injuries are the most common and the most critical injury is a traumatic brain injury. In the setting of potential TBI, hypotension remains the best-defined risk factor known to produce a secondary insult to the injured brain tissue at risk and a significant worsening of functional outcome. Hypotension in these individuals has been associated with an increased mortality. A controlled but less hypotensive (SBP 110 mm Hg) approach to resuscitation appears most appropriate in these settings.¹⁰⁴

Hypovolemic Shock

Hypovolemic shock occurs when rapid loss of fluids results in inadequate intravascular volume and subsequent inadequate perfusion. As previously noted, the most common cause of shock in the trauma patient is loss of circulating volume from hemorrhage. Acute blood loss causes decreased stimulation of baroreceptors (stretch receptors) in the large arteries resulting in decreased inhibition of vasoconstrictor centers in the brainstem, increased stimulation of chemoreceptors in vasomotor centers, and diminished output from atrial stretch receptors. These changes increase vasoconstriction and peripheral arterial resistance. Hypovolemia also induces sympathetic stimulation leading to the release of epinephrine and norepinephrine, activation of the renin–angiotensin cascade, and increased release of vasopressin. Peripheral and splanchnic vasoconstriction is prominent while lack of sympathetic effects on cerebral and coronary vessels and local autoregulation promote maintenance of blood flow to the heart and brain.¹⁹

Diagnosis

Shock in a trauma patient should be presumed to be due to hemorrhage until proven otherwise. Treatment is instituted as soon as shock is identified, typically before a source of hemorrhage is located.

The clinical and physiologic response to hemorrhage has been classified according to the magnitude of volume loss.⁸⁸ Loss of up to 15% of the circulating volume (700–750 mL for a 70-kg patient) may produce little in terms of obvious symptoms, while loss of up to 30% of the circulating volume (1.5 L) may result in mild tachycardia, tachypnea, and anxiety. Hypotension, marked tachycardia (pulse >110–120 beats/min), and confusion may not be evident until more than 30% of the blood volume has been lost, while loss of 40% of circulating volume (2 L) is immediately life-threatening. Symptoms of the degrees of hypovolemic shock are summarized in Table 12-2. Thus, there is a fine line between the development of mild symptoms of shock and the presence of life threatening blood loss. Young, healthy patients with vigorous compensatory mechanisms may tolerate larger volumes of blood loss while manifesting fewer clinical signs. These patients may maintain a near-normal blood pressure until a precipitous cardiovascular collapse occurs. Elderly patients may be taking medications that either promote bleeding (warfarin, aspirin) or mask the compensatory response to hypovolemia (β-blockers). In addition, atherosclerotic vascular disease, diminished cardiac compliance with age, inability to elevate heart rate or cardiac contractility in response to hemorrhage, and overall decline in physiologic reserve decrease the ability of the elderly patient to tolerate hemorrhage.^105,106

Understanding the mechanism of injury of the patient in shock will help direct the evaluation and management. Identifying the source of blood loss in patients with penetrating wounds is relatively simple since potential bleeding sources will be located along the known or suspected path of the wounding agent. Patients with penetrating injuries who are in shock usually require operative intervention. Occasionally, patients in shock from penetrating injuries may have problems that are readily treated by simple maneuvers outside the operating room. Treatment of a tension pneumothorax (obstructive shock) with insertion of a thoracostomy tube in the emergency department (ED) is one example. Generally speaking, though, shock from penetrating wounds is typically due to ongoing hemorrhage that mandates operative control.

Patients who suffer multisystem injuries from blunt trauma have multiple sources of potential hemorrhage. There are a limited number of sites, however, that can harbor sufficient extravascular blood volume to induce hypoperfusion or hypotension. Prehospital medical reports may confirm a significant blood loss at the scene of an accident, history of massive blood loss from wounds, visible brisk bleeding, or presence of an open wound in proximity to a major vessel. Injuries to major arteries or veins should be suspected when there is ongoing hemorrhage from an open pelvic fracture. While persistent bleeding from uncontrolled small vessels can, over time, precipitate shock if left untreated, attributing profound blood loss to these wounds (ie, scalp lacerations) should be done only after major intracavitary bleeding or other etiologies have been excluded. When major blood loss is not immediately visible, internal (intracavitary abdominal or thoracic) blood loss should be suspected. Intraperitoneal hemorrhage is probably the most common source of blood loss inducing shock. Its presence may be suspected based on physical examination (distended abdomen, abdominal tenderness, visible abdominal wounds), although the sensitivity of the physical examination for detecting substantial abdominal injuries after blunt trauma is notoriously unreliable. A large volume of intraperitoneal blood from abdominal injuries may be present before the physical examination is abnormal. Therefore, ultrasound Focused Assessment Sonography in Trauma (FAST) or diagnostic peritoneal aspiration is used frequently in the resuscitation area to rapidly identify potential intraperitoneal blood in the unstable patient. In selected patients, diagnostic laparotomy may be indicated. In addition, the chest can be a significant source of hemorrhage and each pleural cavity has the capacity to hold 2–3 L of blood. Diagnostic and therapeutic tube thoracostomy may be indicated in patients based on clinical findings, clinical suspicion, or evidence of a hemopneumothorax on a chest x-ray or pleural FAST. In addition, with the immediate removal of greater than 1000 mL of blood, a second CT should be considered to ensure patency and accurate monitoring of ongoing blood loss. Major retroperitoneal hemorrhage occurring in association with a pelvic fracture can be diagnosed by urgent pelvic radiography. The pattern of the pelvic fracture may provide clues as to the risk of massive blood loss, but none is adequately predictive in the individual patient to exclude further evaluation.¹⁰⁷

Treatment

Control of ongoing hemorrhage is a central component of resuscitation of the patient in shock, and is part of the primary survey. Treatment of hemorrhagic shock is instituted concurrently with diagnostic evaluation to identify a source. As mentioned earlier, all trauma patients in shock should be presumed to have hemorrhage until proven otherwise. The method of treatment will depend on the patient’s response to resuscitation, the specific injury or injuries responsible for the blood loss, and consideration of factors such as mechanism of injury, age of the patient, associated injuries, and institutional resources. Patients who fail to respond to initial resuscitative efforts should be assumed to have ongoing active hemorrhage from major vessels (external bleeding, pleural cavity, peritoneal cavity, retroperitoneum, or both thighs) and require prompt intervention. Identification of the body cavity harboring active hemorrhage will help focus operative efforts, but since time is of the essence, rapid treatment is essential and diagnostic laparotomy or thoracotomy may be indicated. Alternatively, dependent on most likely location of bleeding, endovascular control of difficult to achieve hemorrhage control can be attempted using emergent IR angiographic intervention with embolization or newly proposed retrograde endovascular balloon occlusion of the aorta (REBOA), where appropriate to rapidly control distal bleeding, with subsequent operative or angiographic control of bleeding source.¹⁰⁸ The actively bleeding patient cannot be resuscitated until control of ongoing hemorrhage is achieved.

Patients who respond to initial resuscitative efforts but then deteriorate hemodynamically frequently have injuries that require operative intervention. The duration of their response will dictate whether and which diagnostic maneuvers can be performed safely to identify the site of bleeding. Usually, however, hemodynamic deterioration denotes ongoing bleeding for which some form of intervention (operation or interventional radiology) is required. As noted earlier, with cessation of hemorrhage, even patients who have lost significant intravascular volume will often respond to resuscitative efforts if the depth and duration of shock have been limited.

A subset of patients fails to respond to resuscitative efforts despite adequate control of ongoing hemorrhage. These patients present in the following manner: have ongoing fluid requirements despite adequate control of hemorrhage; have persistent hypotension despite restoration of intravascular volume; often require vasopressor support to maintain their systemic blood pressure; and may exhibit a futile cycle of uncorrectable hypothermia, hypoperfusion, acidosis, and coagulopathy that cannot be interrupted despite maximum therapy. These patients have classically been described to be in decompensated or irreversible shock,⁶³ and mortality is inevitable once the patient manifests shock in its terminal stages; however, this is always a diagnosis made in retrospect. Hemodynamic decompensation or the paradoxical peripheral vasodilation that occurs with prolonged hemorrhage has been studied in animal models of shock,¹⁰⁹ but the mechanisms responsible for its development and the clinical factors that predict its onset in humans with shock have not been elucidated. In patients with hemorrhagic shock, survival is improved if the time between injury and control of bleeding is reduced. Clarke et al demonstrated that trauma patients with major abdominal injuries requiring emergency laparotomy had an increased probability of death with increasing length of time in the ED.¹¹⁰ This probability increased approximately 1% for every 3 minutes in the ED up to 90 minutes.

The priorities in patients with hemorrhagic shock are (a) secure the airway, (b) support breathing and ventilation, and (c) control the source of hemorrhage and volume resuscitation. In trauma, identifying the body cavity harboring active hemorrhage will help focus the operative effort. Because time is of the essence, simultaneous and rapid evaluation and treatment is essential. Diagnostic laparotomy or thoracotomy may be indicated. The actively bleeding patient cannot be resuscitated until control of ongoing hemorrhage has been achieved. There has been evolution in the management of these patients known as damage control resuscitation.¹¹¹ This strategy begins in the ED, continues into the operating room, and into the intensive care unit. Initial resuscitation is limited to keep systolic blood pressure around 90 mm Hg. Overly aggressive resuscitation during this phase has been shown to increase bleeding from recently clotted injured vessels. Intravascular volume resuscitation is accomplished with blood products and limited crystalloids. Too little volume infusion with resultant persistent hypotension and hypoperfusion is dangerous, yet overly vigorous resuscitation may be just as deleterious, and results in dilutional coagulopathy (see Chapter 13), compartment syndromes, acute lung injury, cerebral edema, acid–base and electrolyte disorders, and immune dysfunction. Control of hemorrhage is achieved in the operating room or angiography suite, and efforts to prevent hypothermia and coagulopathy are employed in emergency department (ED), operating room, and intensive care unit.

Cannon made the seminal observation that attempts to increase systolic blood pressure in soldiers with uncontrolled sources of hemorrhage are counterproductive, with increased bleeding and higher mortality.⁴ Several animal studies have confirmed the observation that attempts to restore normal blood pressure with fluids or vasopressors in the setting of active bleeding were rarely achievable and resulted in increased bleeding and higher mortality. A prospective, randomized clinical study compared delayed fluid resuscitation (on arrival in the operating room) with standard fluid resuscitation (with arrival of the paramedics) in hypotensive patients with penetrating torso trauma.¹⁵ The authors report that delayed fluid resuscitation resulted in a lower patient mortality. From these and other studies it is reasonable to conclude that in the setting of uncontrolled hemorrhage, any delay in surgical control of bleeding may increase mortality; with uncontrolled hemorrhage, attempting to achieve normal blood pressure may increase mortality, particularly with penetrating injuries and short transport times; a goal of systolic blood pressure of 80–90 mm Hg is adequate in the patient with penetrating injury; and profound hemodilution should be avoided by early transfusion of red blood cells. For the patient with blunt injury, where the major cause of death is traumatic brain injury, the increase of mortality with hypotension in the setting of brain injury must be avoided. In this setting, a systolic blood pressure of 110 mm Hg would seem to be more appropriate.

Transfusion of packed red blood cells and other blood products is essential in the treatment of the patient in hemorrhagic shock (see Chapter 13). FFP should also be transfused in patients with massive bleeding due to the frequently associated coagulopathy.^112,113 A number of retrospective studies in the military and civilian population support the concept of early transfusion of FFP, platelets, and packed red blood cells.^113,114,115 A recent multicenter trial (PROPPR) comparing FFP, platelets and pRBC in a 1:1:1 ratio versus a 1:1:2 ratio indicted no overall improvement in survival at 24 hours or 30 days⁹⁵, however, the interpretation of this study remains debated (see Chapter 13).

Neurogenic Shock

Neurogenic shock refers to diminished mean arterial pressure (MAP) and tissue perfusion as a result of loss of vasomotor tone to peripheral vascular beds. Loss of vasoconstrictor impulses results in increased vascular capacitance, decreased venous return, and decreased cardiac output. Neurogenic shock is typically due to injuries to the spinal cord from fractures of the cervical or high thoracic vertebrae that disrupt sympathetic regulation of peripheral vascular tone (see Chapter 23). Occasionally, an injury such as an epidural hematoma impinging on the spinal cord can produce neurogenic shock without an associated vertebral fracture. Penetrating wounds to the spinal cord can produce neurogenic shock, as well. Sympathetic input to the heart that normally increases heart rate and cardiac contractility and input to the adrenal medulla that increases the release of catecholamines can be disrupted by a high injury to the spinal cord, preventing the typical reflex tachycardia that occurs with the relative hypovolemia from increased venous capacitance and loss of vasomotor tone. Acute spinal cord injury results in activation of multiple secondary injury mechanisms: (a) vascular compromise to the spinal cord with loss of autoregulation, vasospasm, and thrombosis, (b) loss of cellular membrane integrity and impaired energy metabolism, and (c) neurotransmitter accumulation and release of free radicals. Importantly, hypotension contributes to the worsening of acute spinal cord injury as a result of further reduction in blood flow to the injured spinal cord.

Diagnosis

The classic description of neurogenic shock consists of decreased blood pressure associated with bradycardia or normal heart rate indicating the absence of reflexive tachycardia due to disrupted sympathetic discharge, warm extremities due to loss of peripheral vasoconstriction, motor and sensory deficits indicative of an injury to the spinal cord, and radiographic evidence of a fracture in the vertebral column (see Chapter 23). Determining the presence of neurogenic shock may be difficult, however, since patients with multisystem trauma that includes an injury to the spinal cord often have a traumatic brain injury that may make identification of motor and sensory deficits difficult. Furthermore, associated injuries may cause hypovolemia and complicate the clinical presentation. In a subset of patients with injuries to the spinal cord from penetrating wounds, most patients with hypotension had blood loss as the etiology (74%) and not a neurogenic cause, and few (7%) had all the classic findings of neurogenic shock.¹¹⁶ Hypovolemia from hemorrhage should be sought and excluded before the diagnosis of neurogenic shock is made. To assume that the cause of hypotension in a multiply injured patient is due to neurogenic shock without first evaluating and treating potential hemorrhage is often a costly mistake. In patients who have neurogenic shock, the severity of the spinal cord injury seems to correlate with the magnitude of the cardiovascular dysfunction. Patients with complete motor deficits from spinal cord injury are over five times more likely to require vasopressors for neurogenic shock compared to those with incomplete lesions.¹¹⁷ Similarly, patients with high cervical spine injuries (C1–C5) were more likely to require cardiovascular intervention compared to those with lower C- or high T-spine injuries.¹¹⁸

Treatment

After the airway is secured and ventilation is adequate, fluid resuscitation and restoration of functional intravascular volume will often improve systemic blood pressure and perfusion in neurogenic shock. Most patients with neurogenic shock will respond to volume resuscitation alone, with adequate improvement in perfusion and resolution of hypotension. Administration of vasoconstrictors can improve peripheral vascular tone, decrease vascular capacitance, and increase venous return, but should only be considered once hypovolemia is excluded and the diagnosis of neurogenic shock established. If the patient’s blood pressure has not responded to appropriate volume resuscitation, continuous infusion of dopamine or a pure α-agonist such as phenylephrine may be used. Specific treatment for the shock state per se is often brief and the need to administer vasoconstrictors typically lasts only 24–48 hours. The duration of the need for vasopressor support for neurogenic shock may correlate with the overall prognosis for improvement in neurologic function.¹¹⁷ Appropriate rapid restoration of blood pressure and circulatory perfusion may also improve perfusion to the spinal cord, prevent progressive ischemia of the spinal cord, and minimize secondary injury to the spinal cord.¹¹⁹ Restoration of normal hemodynamics should precede any operative attempts to stabilize the vertebral fracture. Patients who are hypotensive from spinal cord injury are best monitored in intensive care unit, and carefully followed for evidence of cardiac or respiratory dysfunction.

Cardiogenic Shock

Cardiogenic shock refers to a failure of the circulatory pump leading to diminished forward flow and subsequent tissue hypoxia, in the setting of adequate intravascular volume. Hemodynamic criteria for cardiogenic shock include sustained hypotension (ie, systolic blood pressure ≤90 mm Hg for at least 30 minutes), reduced cardiac index (<2.2 L/[min m²]), and elevated pulmonary artery occlusion pressure (>15 mm Hg).¹²⁰ Acute myocardial infarction is the most common cause of cardiogenic shock. In this population, mortality for cardiogenic shock ranges between 50 and 80%. In the trauma patient, inadequate cardiac function after blunt thoracic trauma can be due to blunt myocardial injury, cardiac arrhythmia, myocardial infarction, or direct injury to a cardiac valve. As the average age of the population increases, the prevalence of comorbid medical conditions in trauma patients will also increase. Elderly patients with preexisting intrinsic cardiac disease will be more susceptible to suffering an acute myocardial infarction or significant arrhythmia associated with the stress of injury that can also induce cardiac failure and cardiogenic shock (see Chapter 56). Diminished cardiac output or contractility in the face of adequate intravascular volume (preload) may lead to under perfused vascular beds and reflexive sympathetic discharge. Increased sympathetic stimulation of the heart, either through direct neural input or from circulating catecholamines, increases heart rate, myocardial contraction, and myocardial oxygen consumption. Patients with fixed, flow-limiting stenoses of the coronary arteries may not be able to increase coronary perfusion to meet the increased myocardial oxygen demands and these lesions, therefore, further increase the risk for myocardial damage.¹⁹ Diminished cardiac output decreases coronary artery blood flow, resulting in a scenario of increased myocardial oxygen demand at a time when myocardial oxygen supply may be limited. Acute heart failure can also result in fluid accumulation in the pulmonary microcirculatory bed, impairing the diffusion of oxygen from the alveolar space, and decreasing myocardial oxygen delivery even further.

Diagnosis

Rapid identification of the patient with pump failure and institution of treatment are essential in preventing further decreases in cardiac output after such an injury. If increased myocardial oxygen needs cannot be met, there will be progressive and unremitting cardiac dysfunction. Blunt injury to the heart is rarely severe enough to induce pump failure,¹²¹ but manifestations of shock in the setting of a patient at risk should raise one’s index of suspicion (see Chapter 26). Elderly patients with known preexisting cardiac disease are at increased risk of suffering injury-related cardiac complications including cardiac failure. Furthermore, elderly patients with intrinsic cardiac disease are at risk to suffer a primary cardiac event that induces syncope, a fall, or loss of control of one’s vehicle that then leads to presentation to a trauma center.

Making the diagnosis of cardiogenic shock involves the identification of cardiac dysfunction or acute heart failure in a susceptible patient. Since patients with blunt cardiac injury typically have multisystem trauma,^122,123 hemorrhagic shock from intra-abdominal bleeding, intrathoracic bleeding, and bleeding from fractures must be excluded. In most instances of blunt cardiac injury the symptoms are self-limited with no long-term cardiac sequelae. Relatively few patients with blunt cardiac injury will develop dysfunction of the cardiac pump and those who do generally exhibit cardiogenic shock early in their evaluation.¹²¹ Therefore, establishing the diagnosis of blunt cardiac injury is secondary to excluding other etiologies for shock and establishing that significant cardiac dysfunction is present. Invasive cardiac hemodynamic monitoring, which generally is not necessary, may be useful in the complex patient with the combination of hemorrhagic shock and cardiogenic shock, when it is necessary to exclude right ventricular infarction or mechanical cardiac complications, or in the patient with known preexisting myocardial disease (see Chapter 55). This typically involves continuous monitoring of cardiac output and other hemodynamic variables using the pulmonary artery catheter (PAC).^{124,125,126,127} Transesophageal echocardiography (TEE) provides excellent views of the myocardium that are not hindered by subcutaneous air, bandages covering chest wounds, chest tubes, or unfavorable body habitus that may limit evaluation of cardiac function by transthoracic echocardiography. The rapid evaluation of cardiac function by TEE may be problematic, in the presence of severe maxillofacial trauma, or unstable injuries to the cervical spine that can interfere with placement of the probe. Trauma surgeons are becoming increasingly more experienced in the use of ultrasound as part of the initial resuscitation and to diagnose penetrating cardiac wounds.^128,129 There is growing evidence that evaluation of cardiac function using bedside ultrasound by surgeons, emergency medicine, and intensivists demonstrates adequate accuracy to direct treatment.^130,131

Treatment

Patients with blunt cardiac injury will often have associated injuries that produce hypovolemia, and expansion of intravascular volume as an initial maneuver can improve perfusion significantly. However, hypervolemia can magnify the physiologic derangements produced by cardiac dysfunction and should be avoided. In addition, under conditions of limited flow, anemia becomes a potential limiting factor and requires transfusion to higher levels as a buffer to help ensure adequate oxygen delivery. In the face of acute MI or acute myocardial ischemia, maintaining a hematocrit of 30 appears to be indicated.¹³² When profound cardiac dysfunction exists, ionotropic support may be indicated to improve cardiac contractility and cardiac performance.¹³³ Several agents are available and selection is dependent on the overall cardiovascular pathophysiology (see Chapter 55).

Patients whose cardiac dysfunction is refractory to cardiotonics may require mechanical circulatory support with an intra-aortic balloon pump.¹³³ This can be inserted at the bedside in the intensive care unit via the femoral artery through either a cutdown or percutaneous approach. In addition, recent data support use of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) for acute cardiac failure due to trauma.¹³⁴ Aggressive circulatory support of patients with cardiac dysfunction from intrinsic cardiac disease has led to more widespread application of these devices and more familiarity with their operation by both physicians and critical care nurses (see Chapter 56). Patients who have suffered an acute myocardial infarction following injury should have preservation of existing myocardium and cardiac function as priorities of therapy. The use of anticoagulation or thrombolytic therapy for the management of acute coronary syndromes will depend on associated injuries and the risk of secondary bleeding. Patients in cardiac failure from an acute myocardial infarction may benefit from pharmacologic or mechanical circulatory support, similar to that of patients with cardiac failure related to blunt cardiac injury. Additional pharmacologic tools include the use of β-blockers to control heart rate and myocardial oxygen consumption, nitrates to promote coronary blood flow through vasodilation, and ACE inhibitors to reduce ACE-mediated vasoconstriction that increases myocardial workload and oxygen consumption.¹³⁵ Selected patients who do not have significant associated injuries may be candidates for coronary angiography and subsequent procedures to improve coronary blood flow such as transluminal angioplasty, coronary artery stents, or urgent coronary artery bypass grafting.

Septic Shock (Vasodilatory or Distributive Shock)

The multidisciplinary consensus consortium, Surviving Sepsis Campaign, has established useful standardized definitions for the patient with an inflammatory response +/– sepsis.¹³⁶ First, the systemic inflammatory response syndrome (SIRS) defines the clinical innate immune clinical manifestation that occurs in response to a wide variety of physiologic insults, and is defined as the presence of two or more of the following conditions: temperature greater than 38°C or, less than 36°C, pulse rate greater than 90 beats/min, respiratory rate greater than 20 breaths/min or PaCO₂ less than 32 mm Hg, white blood cell count greater than 12,000/mm³ or less than 4000/mm³, or greater than 10% immature (band) forms. Sepsis is defined as the systemic inflammatory response in association with proven infection. Severe sepsis occurs when sepsis is associated with hypoperfusion and organ dysfunction. Perfusion abnormalities may be manifested by lactic acidosis, oliguria, or an acute alteration in mental status. Septic shock is a subset of severe sepsis and is defined as sepsis-induced hypotension despite adequate fluid resuscitation along with the presence of perfusion abnormalities that may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status. Patients who require inotropic or vasopressor agents may no longer be hypotensive by the time they manifest hypoperfusion abnormalities or organ dysfunction, yet they would still be considered to have septic shock.¹³⁷

Septic shock is a clinical syndrome that occurs as part of the body’s immune and inflammatory response to invasive or severe localized infection, typically from bacterial or fungal pathogens. In its attempt to eradicate the pathogens, the innate immune system elaborates a wide array of proinflammatory mediators (cytokines and chemokines). These mediators enhance effector mechanisms for macrophage and neutrophil killing, increase procoagulant-induced microcirculatory thrombosis and fibroblast activity to localize the invaders, and increase surrounding microvascular blood flow to enhance delivery of bactericidal mediators to the area of invasion. When this response is overly exuberant or becomes systemic rather than localized, manifestations of sepsis become evident. These findings include peripheral vasodilation, fever, leukocytosis, and tachycardia.^138,139 Sepsis is an uncommon etiology for shock in the acute presentation of a trauma patient unless there has been a substantial delay between injury and presentation to the ED. Typically, invasive infection in the injured patient occurs days to weeks after injury and is prevalent in the severely injured patient who develops a nosocomial infection in the intensive care unit.

Diagnosis

Attempts to standardize terminology have led to the establishment of criteria for the diagnosis of sepsis in the hospitalized adult. These criteria include manifestations of the host response to infection (fever, leukocytosis, mental contusion, tachypnea, tachycardia, hypotension, oliguria), as well as identification of an offending organism.¹³⁶ Septic shock requires the presence of these conditions associated with hypotension resistant to volume resuscitation and evidence of organ dysfunction due to tissue hypoperfusion. Recognizing septic shock in the trauma patient begins with defining high-risk groups as follows: critically ill patients in the intensive care unit with organ dysfunction requiring invasive support and who are immunosuppressed from their injuries where nosocomial infection rates are high, patients who have suffered injuries associated with significant contamination (colorectal wounds with fecal spillage, soft tissue wounds embedded with soil or dirt), patients with injuries that may be associated with persistent devitalized tissue (crush injuries), patients whose wounds put them at risk for complications (anastomotic disruption, pancreatic leak), or patients with missed injuries. The clinical manifestations of septic shock should prompt the empiric initiation of treatment after obtaining appropriate cultures and before bacteriologic confirmation of an organism or source of active infection is identified. An aggressive search for the source of the infection includes a thorough physical examination, inspection of all wounds, evaluation of intravascular catheters or other foreign bodies, sampling of appropriate body fluids for culture, and adjunctive imaging studies as needed.

The hemodynamic parameters characteristic of septic shock include peripheral vasodilatation with resultant decrease in systemic vascular resistance. Initially, there is a hyperdynamic cardiac state; and, after volume resuscitation, the cardiac output is significantly elevated. Changes in cardiac preload and filling pressures reflect the volume status of the patient. Diagnosis and treatment does not usually require placement of a pulmonary arterial catheter to guide therapy in patients with septic shock. Most of these patients can be resuscitated using central venous pressure, ScvO₂, and serum lactate.

Treatment

Obtunded patients may require intubation to protect their airway while patients whose work of breathing is excessive may require intubation and mechanical ventilation to prevent respiratory collapse. Since vasodilation and a decrease in total peripheral resistance combine to produce hypotension, restoration of circulatory volume is essential. Empiric antibiotics that cover the most likely pathogens should be chosen while culture results are pending (see Chapter 18). Antibiotics should be tailored to cover the responsible organisms once culture data are available and, if appropriate, the spectrum of coverage narrowed. Long-term empiric use of broad-spectrum antibiotics should be minimized to reduce the development of resistant organisms and avoid the potential complications of fungal overgrowth and antibiotic-associated colitis from Clostridium difficile.¹⁴⁰

In the trauma patient, intravenous antibiotics alone will frequently be insufficient to adequately treat a severe surgical infection. Source control, that is, drainage of infected fluid collections, removal of infected foreign bodies, and debridement of devitalized tissue are essential to eradicate the infection. This process may require multiple operations. For patients who manifest symptoms of septic shock early in their hospitalization, consideration of the possibility of a missed injury to a hollow viscus should be entertained. Missed abdominal injuries represent a significant source of sepsis and the septic response leading to MODS/MOF.^141,142 Vasopressor therapy may be required as a supportive measure when hypotension is refractory to volume infusion in patients in septic shock. α-Adrenergic agents promote peripheral vasoconstriction, improve systemic blood pressure, and can be titrated by continuous infusion to target an adequate mean arterial pressure to maintain core organ perfusion (see Chapter 55).

In 2008 the multidisciplinary Surviving Sepsis Campaign published international guidelines for the management of severe sepsis and septic shock.¹³⁷ These recommendations include the early goal-directed resuscitation of the septic patient during the first 6 hours after recognition, obtaining blood cultures before initiation of antibiotic therapy, prompt performance of imaging to identify the source of infection, the administration of broad-spectrum antibiotic therapy within 1 hour of diagnosis of septic shock, subsequent narrowing antibiotic coverage after microbiologic data are obtained, source control, and administration of crystalloid or colloids for fluid resuscitation.

While prior clinical studies demonstrated improvements in outcome using these recommendations, recent clinical trials to evaluate the effect of these guidelines using protocol-based resuscitation for patients who present in septic shock have not demonstrated an improvement in outcomes compared to current standard therapy.^143,144,145 The Surviving Sepsis Campaign last updated their guidelines in 2012, and the management in the first 6 hours after identification of septic shock continues to focus on goal-directed resuscitation.¹⁴⁶

Other issues to address in the care of the patient with sepsis include: 1. Stress-dose glucocorticoid therapy should be given primarily to patients with septic shock based on clinical parameters and only if hypotension is poorly responsive to fluid and vasopressor therapy, so-called “refractory shock.” 2. In the absence of active coronary artery disease with evidence of acute ischemia or acute ongoing hemorrhage, a target hemoglobin of 7 g/dL is appropriate to trigger transfusion. 3. All patients with acute lung injury or ARDS requiring mechanical ventilation should receive low pressure ventilation (LPV) support with low tidal volumes (6 mL/kg) and maintaining plateau airway pressures less than or equal to 30 cm H₂O. 4. Controversy has existed regarding how tight glycemic control should be in the critically ill patient. Large randomized control trials suggest that complications of excessively tight glycemic control may outweigh the benefits,^147,148,149 and therefore liberalizing maintaining blood glucose to 140–150 mg/dL appears to be a reasonable target.

Multiple strategies for immune modulation have been developed and tested for the treatment of sepsis and septic shock. In the past, use of antiendotoxin antibodies, anticytokine antibodies, cytokine receptor antagonists, immune enhancers, antinitric oxide compounds, and oxygen radical scavengers have been tried.^{150,151,152,153,154,155,156} Each of these compounds is designed to alter a specific aspect of the host immune response to shock. However, to date each of these strategies has failed to demonstrate efficacy in improving patient outcome despite utility in well-controlled animal experiments. For example, previous trials demonstrated efficacy of activated protein C in improving mortality from sepsis,¹⁵⁷ but subgroup analysis of patients with sepsis at low risk of death, documented an increased risk of bleeding complications associated with therapy without a substantial improvement in survival.¹⁵⁸ It is unclear whether the failure of these interventions is due to poorly designed clinical trials, inadequate understanding of the interactions of the complex immune response to injury and infection, or use of animal models of shock that poorly represent human disease.¹⁵⁹ Sepsis and nosocomial infections in critically ill patients continue to represent significant sources of morbidity and consume substantial health care resources. Despite advances in critical care, the mortality rate for severe sepsis and shock remains at 30–50%. In the United States, 750,000 cases of sepsis occur annually, one-third of which are fatal.¹⁶⁰

Obstructive Shock

Hypoperfusion can be due to mechanical or anatomical obstruction impeding venous return to the heart or preventing cardiac filling. The end result of either of these two events is decreased cardiac output leading to decreased peripheral perfusion. Most commonly, obstruction is due to the presence of a tension pneumothorax, massive pulmonary embolism, or cardiac tamponade (see Chapter 26). Obstructive shock has also been described in adult patients with tense ascites and pediatric patients with extremely distended stomachs. With any of these conditions, there is decreased cardiac output associated with increased central venous pressure.

Diagnosis and Treatment

The manifestations of a tension pneumothorax are the presence of shock in the context of diminished breath sounds over one hemithorax, hyperresonance to percussion, jugular venous distension, and shift of mediastinal structures to the unaffected side. Unfortunately, not all of the clinical manifestations of tension pneumothorax may be evident on physical examination. Hyperresonance may be difficult to appreciate in a noisy resuscitation area. Jugular venous distension or tracheal deviation may be obscured by a cervical collar in the multiply injured patient and not seen unless specifically sought. Furthermore, hypovolemia from concurrent bleeding may diminish central venous pressure and prevent jugular venous distension even when increased pleural, pulmonary artery or pericardial pressure restricts outflow. For the multiply injured patient with life-threatening hypotension, the placement of bilateral chest tubes may be both diagnostic and therapeutic. In these circumstances, a chest x-ray is both unnecessary and potentially a dangerous waste of time. Due to the immediate threat to life, the diagnosis of tension pneumothorax should be a clinical one. If a chest x-ray is obtained, due to missing the diagnosis on clinical examination, the typical findings include deviation of mediastinal structures, depression of the hemidiaphragm (deep sulcus sign), and hypo-opacification with absent lung markings.

Cardiac tamponade results from the accumulation of blood within the pericardial sac and most commonly occurs from penetrating trauma. While precordial wounds are most likely to injure the heart and produce tamponade, any projectile or wounding agent that passes in proximity to the mediastinum can potentially produce tamponade. Blunt rupture of the heart is fortunately rare, but the diagnosis is aided by the FAST examination that is performed immediately on all patients at risk. The manifestations of cardiac tamponade may be as catastrophic as total circulatory collapse and cardiac arrest or they may be extremely subtle. A high index of suspicion is warranted to make a rapid diagnosis. Patients who present with circulatory arrest due to cardiac tamponade from a precordial penetrating wound require emergency pericardial decompression through a left anterolateral thoracotomy, and the indications for this maneuver are reviewed in Chapter 14. Cardiac tamponade may also be associated with hypotension, muffled heart tones, jugular venous distension (Beck Triad), and elevated central venous pressure with tachycardia. Absence of these clinical findings, however, may not be sufficient to exclude cardiac injury and cardiac tamponade. Muffled heart tones may be difficult to appreciate in a busy trauma center, jugular venous distension and central venous pressure may be diminished by coexistent bleeding and hypovolemia. Therefore, patients at risk for cardiac tamponade whose hemodynamic status permits should undergo additional diagnostic tests.

Invasive hemodynamic monitoring may support the diagnosis of cardiac tamponade if elevated central venous pressure, pulsus paradoxus (decreased systemic arterial pressure with inspiration), or elevated right atrial and right ventricular pressure by pulmonary artery catheter is present. These hemodynamic profiles suffer from lack of specificity, the time required to obtain them, and their inability to exclude cardiac injury in the absence of tamponade. Chest radiographs may provide information on the possible trajectory of a projectile, but are rarely diagnostic since the acutely filled pericardium distends poorly. Pericardial ultrasound as part of a surgeon-performed FAST examination, through either the subxiphoid or transthoracic approach, provides excellent results in detecting pericardial fluid.^128,129 The yield in identifying pericardial fluid obviously depends on the skill and experience of the ultrasonographer, body habitus of the patient, and absence of wounds that preclude visualization of the pericardium. Standard two-dimensional transthoracic echocardiograpy (TTE) or transesophageal echocardiography (TEE) to evaluate the pericardium for fluid are typically performed by cardiologists or anesthesiologists skilled at evaluating ventricular function, valvular abnormalities, and integrity of the proximal thoracic aorta. These skilled examiners are not immediately available at all hours and waiting for this test may result in inappropriate delays. In addition, while both ultrasound techniques may demonstrate the presence of fluid or characteristic findings of tamponade (large volume of pericardial fluid, right atrial collapse, poor distensibility of the right ventricle), negative tests do not exclude cardiac injury per se.^161,162 Pericardiocentesis to diagnose pericardial blood and potentially relieve tamponade has a long history in the evaluation of the trauma patient. Its inability to evacuate clotted blood and potential to produce cardiac injury make it a poor alternative. Diagnostic pericardial window represents the most direct method to determine the presence of blood within the pericardium (see Chapter 26). It can be performed through either the subxiphoid or transdiaphragmatic approach.^163,164 Some authors report performing this technique using local infiltrative anesthesia. However, the ability to achieve satisfactory safety and visualization in the trauma victim who may be intoxicated, in pain, or anxious from hypoperfusion usually mandates the use of general anesthesia. Once the pericardium is opened and tamponade relieved, hemodynamics will usually improve dramatically and formal pericardial exploration can be performed. Exposure of the heart can be achieved by extending the incision to a formal sternotomy, performing a left anterolateral thoracotomy, or performing bilateral anterior thoracotomies (“clamshell”) as reviewed in Chapters 14 and 24.

Traumatic Shock

Some authors consider traumatic shock a separate clinical entity.⁶³ Traumatic shock is used to define a combination of several insults after injury that, alone, may be insufficient to induce shock, but produce profound hypoperfusion when combined. Hypoperfusion from relatively modest loss of volume can be magnified by the proinflammatory activation that occurs following direct-injury or shock-induced tissue damage. The systemic response after trauma, combining the effects of soft tissue injury, long bone fractures, and blood loss, is clearly a different physiologic insult than simple hemorrhagic shock alone. In addition to ischemia or ischemia/reperfusion, simple hemorrhage alone can induce qualitatively proinflammatory activation and cause many of the cellular changes typically attributed previously only to septic shock.^9,28,32 Examples of traumatic shock include small-volume hemorrhage accompanied by significant injury to tissue (femur fracture, crush injury) or combination of hypovolemic with neurogenic, cardiogenic, or obstructive shock that induces rapidly progressive activation of proinflammatory innate immunity and potential diffuse tissue and organ bystander injury. As a consequence, MODS/MOF, including ARDS, develops relatively often in the blunt trauma patient, but rarely after pure hemorrhagic shock alone. The hypoperfusion deficit in traumatic shock is magnified by the proinflammatory activation that occurs following the induction of shock and the release of “danger” stimuli following tissue damage.

At a cellular level, the pathophysiology of traumatic shock may be attributable to the release of cellular products termed damage-associated molecular patterns (DAMPs, eg, mitochondrial DNA, ribonucleic acid, uric acid, and high mobility group box 1, HMGB1) that activate the same set of cell surface receptors as bacterial products, initiating similar cell signaling.^8,9 The receptors are termed pattern recognition receptors (PRPs) and include the toll-like receptor (TLR) family of proteins. In laboratory models of traumatic shock, the addition of a soft tissue or long bone injury to the hemorrhage produces lethality with significantly less blood loss than when the animals are stressed by hemorrhage alone.

Therapy for this form of shock is focused on correction of the individual elements to diminish the cascade of proinflammatory activation contributing to its progression. Therapeutic maneuvers include prompt control of hemorrhage, adequate volume resuscitation to correct oxygen debt, early debridement of nonviable tissue (including amputation as necessary), stabilization of bony injuries, and appropriate treatment of soft tissue wounds.

A major ongoing controversy is what should be the end points to measure adequate resuscitation (see Chapter 55). Porter and Ivatury performed an extensive review of the data regarding end points for the resuscitation of trauma patients.¹⁶⁵ Most clinicians would agree that heart rate, systemic arterial blood pressure, skin temperature, and urine flow provide relatively little information about the adequacy of oxygen delivery to tissues. Physiologically, shock begins when oxygen delivery (DO₂) falls below the tissue oxygen consumption (VO₂) requirements. A persistent mismatch between the DO₂ and VO₂ has been associated with progressive multiple organ dysfunction. Unfortunately, there are major limitations in our ability to assess perfusion status. Due to these limitations, it is necessary to use surrogates of tissue hypoxia. During anaerobic metabolism, large quantities of pyruvate are converted to lactate rather than being recycled by entering the tricarboxylic acid cycle. Meanwhile, because of the stoichiometry of substrate-level (as contrasted with oxidative) phosphorylation of ADP to ATP, there is a net accumulation of protons.¹⁶⁶ Accordingly, both increases in arterial base deficit (BD) or blood lactate concentration are evidence of an increase in the rate of anaerobic metabolism. Numerous studies have documented that high blood lactate levels portend an unfavorable outcome in patients with shock,¹⁶⁷ but it has not been proven that survival is improved when therapy is titrated using blood lactate concentration as an end point.

BD is the amount of base (in millimoles) required to titrate 1 L of whole blood back to a pH of 7.40 with the sample maintained at 37°C and fully saturated with oxygen and equilibrated with an atmosphere containing carbon dioxide at a PCO₂ of 40 mm Hg. In practice, BD is calculated by arterial blood gas analyzers using the nomogram developed by Astrup et al¹⁶⁸ BD has been shown to have prognostic value in patients with shock.¹⁶⁹ However, it remains to be proven that titrating therapy to a BD end point improves survival. In fact, few published data have demonstrated that using a monitoring tool to guide resuscitation improves outcome in critically ill patients.¹⁷⁰

There are numerous parameters that have been used as surrogates to measure intravascular volume as a surrogate for adequate resuscitation, including central venous pressure (CVP), pulse pressure variation (PPV), and inferior vena cava (IVC) diameter. PPV has been found to be a reliable predictor of hypovolemia and fluid responsiveness in the critically ill in numerous studies.¹⁷¹ Similarly, the IVC diameter has been shown to correlate with the central venous pressure and to predict fluid responsiveness in critically ill patients.¹⁷² One study found that patients with an IVC diameter of less than 2 cm were almost uniformly volume responsive compared to those with IVC diameters of greater than or equal to 2 cm.¹⁷³ However, while at greatly reduced risk for complication, similar to CVP, use of IVC diameter to guide resuscitation has not been shown to improve survival.

Pulse pressure (PP) is the difference between the systolic and diastolic blood pressure at any given point in time as measured in mm Hg. Pulse pressure variation (PPV) is the difference in pulse pressure that occurs over a respiratory cycle. The formulaic description of this would be PP_max–PP_min/PP_mean. PPV increases in states of hypovolemia where decreased intrathoracic blood volume and therefore, ventricular filling pressures are more sensitive to changes in intrathoracic pressure that occur during a respiratory cycle with positive pressure ventilation.¹⁷⁴ A PPV of 13% has been shown to discriminate between patients in whom additional volume will increase their cardiac index (responders) and those that will not (nonresponders) with a sensitivity and specificity of 94% and 96% respectively.¹⁷⁵ In order to accurately measure PPV, a patient must have an arterial line and be passively adapted (usually sedated) to mechanical ventilation with a closed thoracic cavity. Once again, however, resuscitation using an end point of a PPV of less than 13% has not been shown to improve outcomes in critical illness.

Near-infrared spectroscopy (NIRS) offers a technique for continuous, noninvasive, bedside monitoring of tissue oxygenation. It measures oxygenation in the tissue’s microvasculature and, thus, not only examines the adequacy of tissue perfusion but also provides a potential window to noninvasively study tissue metabolism. In the clinical setting, NIRS has been used for continuous monitoring of metabolic variables including tissue O₂ availability, tissue O₂ consumption, tissue O₂ saturation (StO₂),¹⁷⁶ and changes and rate of StO₂ decrease due to vascular occlusion,^177,178 in diverse populations of patients (trauma,^{170,171,172,173,174,175,176,177,178,179} sepsis,¹⁸⁰ and heart failure). However, due to the exquisite sensitivity of the technique and the rapid and labile nature of peripheral perfusion in critically ill patients with rapidly changing blood volumes, the reproducibility and ability to utilize the technology for therapeutic decisions has been difficult and the technology has not gained wide acceptance.

Arterial waveform analysis is a noninvasive way to measure cardiac output in critically ill patients. The LiDCO (LiDCO, London, UK) is a monitoring device that utilizes a pulse contour cardiac output algorithm (PulseCO¹⁸¹) based on an enormous dataset of empiric observations and datapoints, to estimate cardiac output and systemic vascular resistance in the absence of invasive techniques. This particular device is calibrated using a lithium dilution CO method. There is some evidence that the information garnered from this device is most useful at a single point in time, and, when used for continuous assessment, the serial values show limited agreement or reproducibility.¹⁸² In small clinical trials, use of devices that utilize arterial waveform analysis have shown some promise but large, multicenter trials looking at patient outcomes have yet to be described.¹⁸³ Again, the marked cardiovascular variability of the critically ill hypovolemic patient and confounded in the setting of multiple underlying comorbidities affecting CV responses have significantly limited the effectiveness of the approach.

Recent reviews suggest that our lack of understanding of the effects of shock and resuscitation stem from a discrepancy between the need to identify effective strategies aimed at restoring normal oxygen delivery and the fact that most resuscitation research is aimed at controlling inflammation and coagulopathy. While the degree of activation of the inflammatory mechanisms and coagulation derangements are directly related to the magnitude of the hypoxia-induced tissue injury, it is naïve to believe that by simply correcting oxygen delivery or modulating a specific pathway would prevent the already established detrimental processes and ensuing multiple organ injury.¹⁸⁴

Until more practical logistical and quantitative methods are introduced to measure the accumulative effect of the oxygen deficit and subsequent host response, it is likely that we will continue to use a combination of surrogates of tissue perfusion. We can estimate the magnitude of the systemic insult by assessing the BD or lactic acid at the time of initiating resuscitation and follow how these parameters respond to our interventions. In addition to these parameters, we can also use noninvasive methods to quantitatively assess the potential adequacy of resuscitation, and, hopefully, build a more complete picture of the patient’s magnitude of injury and ongoing response to resuscitation.