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453

Chapter

47Hemorrhagic ShockEilEEn M. BulgEr and DaviD B. Hoyt

IntroductIon

The definition of shock describes the final common pathway of many disease states: ineffective tissue perfusion, resulting in severe dysfunction of organs vital to survival. The most commonly used classification system for shock includes four categories based on hemodynamic characteristics:

1. Hypovolemic shock resulting from a decreased circulat-ing blood volume in relation to the total vascular capac-ity and characterized by a reduction of diastolic filling pressures and volumes

2. Cardiogenic shock related to cardiac pump failure caused by loss of myocardial contractility/functional myocardium or structural/mechanical failure of the cardiac anatomy characterized by elevations of diastolic filling pressures and volumes

3. Extracardiac obstructive shock involving obstruction to flow in the cardiovascular circuit and characterized by either impairment of diastolic filling or excessive afterload

4. Distributive shock caused by loss of vasomotor control, resulting in arteriolar and venular dilations and character-ized by increased cardiac output and decreased systemic vascular resistance after fluid resuscitation

Although the hemodynamic characteristics of the vari-ous forms of shock may vary, the final common pathway—inadequate cellular perfusion—must be addressed early to prevent long-term sequelae and death (Fig. 47.1).

Hemorrhagic shock is a form of hypovolemic shock. It is a common, yet complicated, clinical condition that physicians are frequently called upon to evaluate and treat. Etiologies include trauma, postoperative bleeding, medical conditions, and iatrogenic causes. Diagnosis must be accurate and expe-dient. Therapy must be direct, efficient, and multifactorial in order to avoid the potential multisystem sequelae.

The purpose of this chapter is to review the pathophysiol-ogy of hemorrhagic shock, and to focus on the diagnostic and therapeutic approaches to early treatment. Current controver-sies and new and experimental therapies will also be discussed.

PatHoPHySIology

Circulatory Changes

Hemorrhage results in a predictable pattern of events that begins with acute changes in circulating blood volume and culminates in a final common pathway shared by all classifica-tions of shock (see Fig. 47.1). Hemodynamically, hypovolemic shock is characterized by a fall in ventricular preload, result-ing in decreased ventricular diastolic filling pressures and vol-umes. This in turn leads to a decrease in cardiac output and stroke volume (1–4). Following unloading of the cardiac baro-receptors and activation of the sympathetic nervous system,

tachycardia ensues in an attempt to compensate for the decrease in cardiac output and stroke volume (5). The sympathetic out-put also results in vasoconstriction, leading to a decrease in pulse pressure. Greater variations in blood pressure will occur with the respiratory cycle due to an increased sensitivity of the underfilled heart to changes in venous return with varying intrathoracic pressure (6–8). The increased sympathetic tone may prevent a severe drop in arterial blood pressure initially. However, continued blood loss will ultimately result in hypo-tension and shock. Due to compensatory vasoconstriction, systemic vascular resistance rises early after the development of hypovolemic shock, but may fall in later stages, potentially heralding irreversibility and death (1,9,10).

The response to blood loss is a dynamic process that involves competing adaptive (compensatory) and maladaptive responses at each stage of development. Although intravas-cular volume replacement is always a necessary component of resuscitation in hypovolemic shock, the complex biologic response to the insult may progress to a point at which such resuscitation is insufficient to reverse the progression of the shock syndrome. Severe hemorrhage leads to a series of inflammatory mediator, cardiovascular, and organ responses that may supersede the injury itself and ultimately drive recov-ery or death (9,11–14). Furthermore, ongoing blood loss con-tributes to a progressive coagulopathy and metabolic acidosis that further complicate the resuscitation of the patient.

Oxygen Balance

Shock is characterized by an oxygen deficit in tissues and cells. The significance of the deficit and the extent of cellular injury can be quantified as a function of both the severity and the duration of the deficit—the greater the severity, the longer the duration, the worse the outcome of shock.

Oxygen delivery to tissues is determined by cardiac output and the oxygen content in arterial blood. Oxygen content refers to the number of milliliters of oxygen contained in 100 mL of blood (mL/dL) and is a function of the hemoglobin concentra-tion, the oxygen saturation of hemoglobin, and the amount of oxygen dissolved in plasma (the calculation is [Hgb × 1.34 × O2 saturation] + [PaO2 × 0.0003]). During hemorrhage, as the cardiac output falls, oxygen delivery to the tissues also falls. Initially, the body will maintain sufficient uptake of oxygen by extracting more from the arterial blood. This will result in a fall in the mixed venous oxygen saturation (SvO2) with an increase in the arteriovenous oxygen content gradient (CaO2 − CvO2). Eventually, this compensatory mechanism also fails, and tissue hypoxia with lactic acidosis ensues. Cerebral and cardiac functions are maintained by diversion of blood flow from other organs (skin, muscle, and kidneys) (14). However, when these compensatory mechanisms are maximized, cardiac function and tissue oxygen delivery deteriorate further, and irreversible shock may develop (15).

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454 SeCtion 5 SHock anD MultiSyStEM FailurE

Critical oxygen delivery is a function of cellular needs for oxygen and the ability of cells to extract oxygen from the arterial blood. Many factors contribute to this equation. During hemorrhage, tissue oxygen needs may increase due to increased respiratory muscle activity and increased catechol-amine circulation (16). However, some evidence suggests that catecholamines downregulate the metabolic needs of cells during hypovolemic shock (2,3,17,18). Regional blood flow is modified during hypovolemic shock in an attempt to main-tain oxygen delivery to critical tissues (14,19). In addition, the individual needs of various tissues may vary during hemor-rhagic shock. For instance, the oxygen needs of the kidney may decline during hemorrhage because a fall in renal perfu-sion leads to a fall in glomerular filtration and a decrease in energy-consuming tubular absorption (14). In contrast, the gut may experience an increased oxygen debt early due to the high oxygen need of the mucosa, along with redistribution of blood away from the gut to more critical tissues. This is the physi-ologic basis for gastric tonometry as a means of measuring the adequacy of resuscitation early following hemorrhage (20).

Oxygen extraction in tissues is influenced by the position of the oxyhemoglobin dissociation curve (21–23). Factors that improve the ability of tissues to extract oxygen from

hemoglobin (i.e., shift the curve to the right) include acido-sis, hypercarbia, hyperthermia, and decreased blood viscosity. However, in any extreme, each of these factors can be over-come by inadequate oxygen delivery and cardiovascular col-lapse. Interestingly, the oxyhemoglobin curve has been shown to shift to the left in critically ill patients (24). The presence of 2,3-diphosphoglycerate (DPG) in transfused blood has also been associated with a left shift of the oxyhemoglobin dissocia-tion curve (25). Thus, although transfusions may increase the hemoglobin level, theoretically improving oxygen delivery, they may negatively affect the ability of tissues to extract oxygen from the hemoglobin.

The severity of oxygen debt during hypovolemic shock has been shown to be a major determinant of survival in animals and in patients following trauma, hemorrhage, and major sur-gery (10,15,26,27). A large oxygen debt has been associated with the development of acute respiratory distress syndrome (ARDS) and multiple-organ dysfunction syndrome (MODS) (26,28–30). Conversely, a high oxygen delivery and uptake dur-ing resuscitation has been associated with improved survival (15,27,31–33). Whether increasing oxygen delivery to supranor-mal levels ultimately improves survival during resuscitation in critical illness remains controversial, and the medical literature

Hypovolemicshock

Cardiogenicshock� Myocardial infarction

Distributiveshock� Sepsis

Extracardiacobstructive� Tension pnemothorax� Pericardial tamponade� Pulmonary embolism

↓preload

↓diastolic filling

↓cardiac output

↓SVR

Multiorgan dysfunction syndrome

Recovery Death

↓mean arterial pressure

SHOCK

CO

Maldistributionof flow

↑systemic vascular resistance (SVR)

↑ Oxygen deficit

Cellular injury

Cellular dysfunction

↑

FIgurE 47.1 Final common pathway of shock. Hemorrhagic shock results in acute changes in circulating blood volume that culminates in a final common pathway shared by all clas-sifications of shock.

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Chapter 47 Hemorrhagic Shock 455

has produced mixed results (28,34–37) with recent studies sug-gesting no clear benefit from this approach and concern that overly aggressive fluid resuscitation can lead to abdominal com-partment syndrome and other complications (37).

Cellular Response

During hypovolemic shock, the oxygen deficit in the tissues causes a fall in the mitochondrial production and concentra-tion of high-energy phosphates because of greater breakdown than production (38–43). This led many researchers to evalu-ate the utility of adenosine triphosphate (ATP) in the resuscita-tion of hemorrhagic shock (44,45). In the presence of sufficient oxygen, aerobic combustion of 1 mol of glucose yields 38 mol of energy-rich ATP. However, in the absence of sufficient oxygen, glucose taken up by the cells cannot be combusted because of insufficient uptake of pyruvate into the mitochon-drial tricarboxylic acid cycle. Pyruvate is then converted to lactate within the cytoplasm. Anaerobic glycolysis yields only 2 mol of ATP, which is then hydrolyzed into hydrogen ion, ultimately leading to intracellular and extracellular metabolic acidosis (Fig. 47.2) (38,39,46,47). This process is ultimately a function of the severity and duration of regional hypoper-fusion relative to oxygen demand and is more pronounced in some tissues (diaphragm, liver, kidney, gut) than in others (heart, skeletal muscle). Ultimately, a significant fall in the high-energy phosphates for a prolonged duration will lead to irreversible cellular injury and death.

The sequelae of low ATP production are profound. About 60% of the energy produced by respiring cellular mitochon-dria is needed to fuel the sodium–potassium (Na+–K+) pump of the cell. This pump controls the gradient in electrolyte con-centrations and electric potential over the cell membrane. In the absence of sufficient ATP, the Na+–K+ pump is inhibited, resulting in an influx of sodium into the cell and efflux of potas-sium out of the cell. This in turn leads to cellular fluid uptake (38,40,48–51). Hyperkalemia may result due to potassium exchange between cells, the interstitial fluid, and vascular space.

Independent of the Na+–K+ pump, there may be a selec-tive increase in cell membrane permeability for ions during hemorrhagic shock. Hypovolemic shock has been shown to

lead to a rapid decrease in the transmembrane potential (with a less negative inner membrane potential), resulting in rapid electrolyte and fluid shifts across the membrane. Circulating heat shock proteins may also contribute to these changes inde-pendent of energy deficit (51–54).

Finally, calcium (Ca2+) influx into cells and their mitochon-dria inhibits cellular respiration and ultimately contributes to cellular damage and swelling. Plasma levels of free Ca2+ may also fall. This may have profound consequences on the func-tion of several organs during shock including the liver, kidney, heart, and vascular smooth muscle (49,50,55–61). Intracellu-lar lysosomes lose their integrity, and proteolytic enzymes are released and contribute to cellular dysfunction and cell death. The sum of the intracellular changes and alterations in signal-ing transduction pathways described above ultimately leads to the development of cellular dysfunction and MODS, which may be irreversible (61).

Neurohumoral Response

In response to hemorrhage and hypovolemia, a complex neu-rohumoral response is initiated in an attempt to maintain blood pressure and retain fluid. Decreased intravascular vol-ume stimulates baroreceptors in the carotid body and aor-tic arch, along with mechanoreceptors in the right atrium. This stimulation leads to several neurohumoral responses (Fig. 47.3). Circulating catecholamines are liberated by acti-vation of the sympathetic nervous system and the adrenal medulla. Direct sympathetic stimulation of the vessel wall leads to vasoconstriction. Angiotensin II is liberated via the renin–angiotensin–aldosterone system. Vasopressin (antidi-uretic hormone [ADH]) is released by the pituitary in hypovo-lemic shock and leads to vasoconstriction. Finally, decreased cardiac filling pressures reduce cardiac secretion of α-atrial natriuretic peptide (ANP), thereby reducing the vasodilatory and diuretic effects of ANP.

Macrocirculation

During loss of circulating blood volume, mechanisms are initi-ated to counteract the fall in cardiac output and oxygen delivery

CYTOPLASM MITOCHONDRIA

Anaerobic glycolysis Aerobic glycolysis

Glycogen Glucose Pyruvicacid

Citricacidcycle

2 ATP

O2

CO2

H2O

36 ATP

LactateH+ ion

FIgurE 47.2 cellular mechanisms during anaerobic and aerobic glycolysis. in anaerobic conditions, pyruvic acid cannot enter the citric acid cycle within the mitochondria and is instead shunted to the production of lactate. this process produces only two molecules of atP, as opposed to the 36 molecules of atP produced from glucose in the mitochondria during aerobic glycolysis. Hydrolysis of atP molecules in anaerobic conditions results in the production of hydrogen ions that cannot be cleared, leading to intra-cellular acidosis. (adapted from Mizock Ba, Falk Jl. lactic acidosis in critical illness. Crit Care Med. 1992;20:80–93.)

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by facilitating a redistribution of peripheral blood flow (14). Regional autoregulation takes place via a delicate balance of endogenous vasodilators and vasoconstrictors. Endothelial cells produce potent vasodilators such as endothelium-derived relaxing factor (nitric oxide [NO]), heme oxygenation–derived carbon monoxide (CO), and metabolic byproducts in tissues, including carbon dioxide (CO2), potassium, and adenos-ine (62–69). Some authors describe that inhibition of NO early following hemorrhage ameliorates early hypotension and improves mortality (70–74). Conversely, other authors describe endothelial dysfunction in organs with diminished NO production (75,76). Endothelin is a potent endothelial cell–derived vasoconstrictor that is released upon catechol-amine stimulation or hypoxia (77). The overall increase in sys-temic peripheral vascular resistance is distributed differently among various organs in the body (19). Vasoconstriction also occurs in the venous vasculature, increasing return of avail-able blood to the heart (4,78). The complex interplay of these mechanisms for vasodilation and vasoconstriction ultimately determines the regional redistribution of blood flow to organs following hemorrhagic shock. The redistribution of blood flow results in a greater share of oxygen delivery to organs with high obligatory metabolic demands (heart and brain), and a

lesser share to those with fewer demands including the skin, skeletal muscle, kidney, intestine, and pancreas (3,19,66,79).

Microcirculation

One of the most important determinants of tissue perfusion during shock is the response and function of the microvas-culature, which is defined as vessels less than 100 to 150 μm in diameter. Although arteries and medium-sized arterioles constrict in response to the extrinsic control mechanisms described above, terminal arterioles, venules, and capillaries remain unaffected and are more controlled by local metabolic factors.

Alterations in microvascular function and flow are affected through precapillary and postcapillary sphincters, which are sensitive to both extrinsic and intrinsic control mechanisms. Exchange of metabolites and compartmental regulation of flu-ids occur at the capillary level. Therefore, alteration of tone of the pre- and postcapillary sphincters can have significant effects on microcirculatory function (78,80,81). Failure to dilate sphincters supplying metabolically active tissues may result in ischemia and anaerobic metabolism with lactate pro-duction. Increased precapillary tone, as seen with sympathetic

Hemorrhage(decreased intravascular volume)

CNS Response

Sympatheticresponse

Pituitaryresponse

↑ Baroreceptor activity ↓ Renal Perfusion

↓ Flow by renal juxtaglomerularapparatus

↑ Mechanoreceptor activity

↑ Chemoreceptors

� Aorta, carotid, splanchic

� Right atrium, pulmonary artery

� Carotid, aorta, adrenal medulla

Hormonal� Epinephrine� Norepinephrine� Renin/angiotensin� Aldosterone

Neural� ↑ Cardiac contractility� ↑ Vasoconstriction� Flow redistribution

↑ Cardiac contractility↑ VasoconstrictionNa/H2O retentionFlow redistribution

Hormonal� ACTH release� ADH release

� Na/H2O retentionn� Maintain cardiovascular responsiveness

Cortisol releaseAldosterone secretion

FIgurE 47.3 neurohormonal response to hemorrhage. Hemorrhage results in a decrease in the circulating intravascular volume, which initiates a complex cas-cade of compensatory events. cnS, central nervous system; actH, adrenocorticotropic hormone; aDH, antidiuretic hormone.

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stimulation, results in increased blood pressure systemically and decreased hydrostatic pressure locally. In fact, the micro-vascular arterioles may even dilate in response to the above vasoconstriction due to release of metabolic byproducts of underperfusion (carbon dioxide, hydrogen ion, etc.). The decrease in hydrostatic pressure locally then leads to redistri-bution of fluid from the interstitium to the circulation. Con-versely, increased postcapillary tone (relative to precapillary tone) results in vascular pooling of blood and loss of fluid to the interstitium (as a result of increased hydrostatic pressure). This increased hydrostatic pressure may become accentuated in response to crystalloid resuscitation, leading to interstitial edema (81). Finally, hemorrhage and shock have also been shown to induce increased permeability of capillaries, leading to interstitial fluid leak during resuscitation (82,83).

Hypovolemic shock and hemorrhage also induce the expres-sion of endothelial adhesion molecules on neutrophils and endothelium (48,84). This results in neutrophil adherence and “rolling” of cells within the capillary bed (85–87). Capillary flow then diminishes and may also impair red blood cell flow. While this decrease in transit time may augment the ability of tissue to extract oxygen, it may also lead to microvascular thrombosis and further tissue ischemia (88,89).

Metabolic and Hormonal Response

The early hyperglycemic response to trauma/hemorrhage is the combined result of enhanced glycogenolysis, caused by the hormonal response to stress including elevated epinephrine, cortisol, and glucagon levels; increased gluconeogenesis in the liver, partly mediated by glucagon; and peripheral resistance to the action of insulin (38,90). Increased gluconeogenesis in the liver, and to a lesser extent in the kidneys, follows increased efflux of amino acids, such as alanine and glutamine from the muscle to the liver, due to a breakdown of muscle protein. The latter is evidenced by increased urinary losses of nitrogen and a negative nitrogen balance. Lactate produced in muscle can also be converted to glucose in the liver (91). Increased epinephrine also results in skeletal muscle insulin resistance, sparing glucose for use by glucose-dependent organs such as the heart and brain. Later in shock, hypoglycemia may ensue, possibly because of glycogen depletion or hepatic ischemia (38,91,92). Fatty acids are increased early in shock, but later levels fall (90). Without energy for glycolysis, the cell depends on lipolysis and the autodigestion of intracellular protein for energy. Initially, ketone bodies and the branched-chain amino acids are used as alternative fuel sources. Without oxygen, these sources become inefficient, leading to hypertriglyceride-mia, increased β-hydroxybutyric acid and acetoacetate levels, and changes in the amino acid concentration pattern. As these metabolic changes occur, set in motion by cellular hypoxia and promoted by systemic hormonal changes, structural changes occur within individual cells (93).

Inflammatory and Immune Response

A detailed discussion of the inflammatory and immune response to trauma and hemorrhage is beyond the scope of this chapter. However, several general concepts can be intro-duced. Following hemorrhage and resuscitation, macrophages, including lung macrophages and Kupffer cells in the liver, may release pro-inflammatory cytokines such as tumor necrosis

factor (TNF)-α and interleukin (IL)-1, -6, and -8. During reperfusion, cytokines may induce and amplify the inflam-matory response to ischemia and may further induce local and remote organ damage (94–104). The reperfused gut, for example, may, together with the liver, be a source of systemi-cally circulating cytokines, and possibly endotoxin. Release of mediators into the mesenteric lymph, portal, or systemic circulations during reperfusion may have deleterious effects on remote organs, such as the lungs, due to neutrophil acti-vation and adherence, leading to pulmonary vascular injury with increased permeability (95,98,99). Antigen–antibody complexes activate the complement cascade, and comple-ment fragments thus generated can interact with other cyto-kines to promulgate the inflammatory response. Complement activation can yield potent vasodilating and leuko-attractant substances (105–108).

Oxygen radicals, such as hydrogen peroxide and superox-ide anion, are released by activated neutrophils in response to a variety of stimuli. They are also released when xanthine oxidase is activated after reperfusion in ischemia–reperfusion models. These highly reactive products lead to cell membrane dysfunction, increased vascular permeability, and release of eicosanoids (109–113).

This inflammatory process results in the local accumulation of activated inflammatory cells, which release various local toxins such as oxygen radicals, proteases, eicosanoids, platelet-activating factor, and other substances. When unregulated, such accumulations can cause tissue injury. The initial attachment of neutrophils to the vascular endothelium at an inflammatory site is facilitated by the interaction of adherence molecules on the neutrophil and endothelial cell surfaces (114–119).

Trauma-Induced Coagulopathy

Patients suffering from severe hemorrhagic shock will fre-quently develop a coagulopathy that can further complicate the control of hemorrhage. Previously, this coagulopathy was thought to be primarily due to loss of clotting factors during hemorrhage combined with dilution during the resuscitation phase. Recent evidence suggests that 25% to 40% of severely injured patients are already manifesting evidence of coagu-lopathy at the time of hospital admission (120,121). This has been termed trauma-induced coagulopathy. The etiology of trauma-induced coagulopathy is likely multifactorial and six key initiators of coagulopathy have been described (Fig. 47.4). These include tissue trauma, shock, hypothermia, academia, hemodilution, and inflammation (122). Tissue injury leads to exposure of subendothelial type III collagen and tissue fac-tor, which binds von Willebrand factor and platelets inducing coagulation. Hyperfibrinolysis also results from tissue injury due to release of endothelial tissue plasminogen activator and inhibition of plasminogen activator inhibitor-1 in the setting of shock (122). Hypothermia and academia can also directly impair coagulation protease activity. Recent data also suggest that depletion of coagulation factors early after injury may be driven by the protein C system (121). Over time, trauma patients who are initially coagulopathic with increased bleed-ing will transition to a hypercoagulable state, which increases the risk of thrombotic complications. Additional work is regarded to better understand the timing and mechanism of this transition. Evidence of trauma-induced coagulopathy upon hospital admission has been associated with a fourfold

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increase in mortality (123,124). Therefore, acute measurement of coagulation parameters during resuscitation from hemor-rhagic shock is indicated along with early efforts to address coagulation abnormalities.

dIagnoSIS

Early diagnosis of hemorrhagic shock is imperative to avoid delay in treatment. However, clinical signs are relatively insen-sitive for small amounts of blood loss. There is a progressive hemodynamic deterioration with ongoing blood loss. This classic progression is delineated in Table 47.1. Total blood volume is estimated at approximately 70 mL/kg in the aver-age adult, or nearly 5 L for a 70-kg person. The signs and symptoms of hemorrhagic shock vary based on the severity of blood loss. Traditionally, this progression has been defined as four classes of shock.

Class I hemorrhage is marked by a less than 750 mL esti-mated blood loss, or less than 15% of total circulating blood volume. There are minimal physical signs associated with this volume of blood loss. The patient may not have tachycardia, with a heart rate remaining less than 100 beats per minute; the systolic blood pressure and pulse pressure remain normal; the respiratory rate remains at 14 to 20 breaths per minute; and urine output remains adequate (>30 mL/hr). Only subtle phys-ical signs such as delayed capillary refill and slight anxiety may exist.

Class II hemorrhage is marked by an estimated blood loss of 750 to 1,500 mL (or 15% to 30% of the total circulating blood volume). Physical signs begin to manifest during this stage of hemorrhage. Although the systolic blood pressure may be maintained, the patient usually becomes tachycardic

(heart rate greater than 100 beats per minute), the pulse pres-sure begins to decrease, and capillary refill is delayed. The respiratory rate begins to increase (20 to 30 breaths per min-ute), urine output becomes diminished (20 to 30 mL/hr), and the patient becomes very anxious.

Class III hemorrhage is marked by an estimated blood loss of >1,500 to 2,000 mL (or >30% to 40% of total circulat-ing blood volume). During this phase, significant hemody-namic compromise becomes apparent. Heart rate increases to >120 beats per minute, systolic blood pressure decreases, pulse pressure decreases, capillary refill decreases, tachypnea worsens with a respiratory rate of 30 to 40 breaths per minute, urine output drops to 5 to 15 mL/hr, and the patient becomes confused, showing further evidence of decreased perfusion of the central nervous system.

Class IV hemorrhage is marked by an estimated blood loss of >2,000 mL (or >40% of total circulating blood volume). During this phase, most compensatory cardiovascular mecha-nisms have been maximized and total hemodynamic collapse is imminent. Signs of class IV hemorrhage include severe tachy-cardia with a heart rate >140 beats per minute, a decreased systolic blood pressure, a decreased pulse pressure, delayed capillary refill, significant tachypnea with a respiratory rate of >35 breaths per minute, minimal to no urine output, and severely altered mental status as marked by confusion and/or lethargy.

Another way to classify patients with hemorrhagic shock is based on their response to initial fluid resuscitation. Rapid responders will typically require a limited fluid resuscitation to normalize vital signs. Transient responders will improve fol-lowing fluid administration but then hypotension will recur. Nonresponders remain hypotensive despite fluid and blood product administration. Generally transient responders and

Resuscitation

COAGULOPATHY

Trauma Hemorrhage

Dilution

Hypothermia Hypothermia

AcidemiaFibrinolysis

Factorconsumption

Shock

Other diseases

Medications

Genetics

ACoTS

Inflammation

FIgurE 47.4 Mechanisms of trauma-induced coag-ulopathy. trauma results in hemorrhage, which leads to resuscitation, which in turn leads to dilution and hypothermia causing coagulopathy and further hemorrhage. this is the classic, “dilutional coagu-lopathy.” Hemorrhage also causes shock, which causes acidosis and hypothermia that also con-tribute to coagulopathy. Finally, trauma and shock can also cause acute coagulopathy of trauma–shock associated with factor consumption and fibrinolysis. coagulopathy is further associated with trauma-induced inflammation and modified by genetics, medications and acquired diseases. (With permission from Hess Jr, Brohi k, Dutton rP, et al. the coagulopathy of trauma: a review of mechanisms. J Trauma. 2008;65:748–754.)

TABLE 47.1 Clinical Classes of Hemorrhagic Shock

Class I Class II Class III Class IV

Blood loss <750 ml 750–1,500 ml >1,500–2,000 ml >2,000 ml

<15% 15–30% >30–40% >40%

Heart rate (bpm) <100 >100 >120 >140

Systolic blood pressure normal normal Decreased Decreased

Pulse pressure normal Decreased Decreased Decreased

capillary refill Delayed Delayed Delayed Delayed

respiratory rate (breaths/min) 14–20 20–30 30–40 >35

urine output (ml/hr) >30 20–30 5–15 Minimal

Mental status Slightly anxious anxious confused confused and lethargic

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nonresponders will require additional intervention to obtain hemorrhage control (Table 47.2).

Transient responders can be the most difficult to diag-nose. Retrospective studies have shown that patients with field hypotension who become normotensive on arrival to the emergency department have increased morbidity, mortality, need for operation, and admission rate to the intensive care unit (ICU) (125–127). Approximately 15% of these patients will need transfusion, with 37% requiring therapeutic surgery (127). Hence, even a brief episode of hypotension can be a marker for significant underlying injury. Tachycardia is one of the first signs of shock, although some patients may respond to traumatic hemorrhage with bradycardia as a result of a vagal nerve–mediated transient sympathoinhibition due to acute and sudden blood loss (1–3,128,129). Narrowing of the pulse pressure, low end-tidal CO2, and markers of acidosis (base deficit or lactate) are also useful predictors of compensated shock (130–134).

Special Populations

Geriatrics

Concurrent medication, such as β-blockers, may attenuate the physiologic response to hemorrhage. In the presence of β-blockade, tachycardia may be blunted or may not occur at all. Prior hydration status and use of diuretics can also alter the rate at which these signs present. Elderly patients may have atrial arrhythmias leading to a high ventricular response, making tachycardia less sensitive in this patient population Changes in blood pressure in geriatric patients may also be more difficult to assess. Those with a baseline hypertension may have what appears to be a normal adult blood pressure but may be in compensated shock and have significant organ hypoperfusion (130,135,136).

Pregnant Patients

Pregnant patients have a significantly increased total blood vol-ume, and thus can lose up to 1,000 mL of blood before pre-senting with any clinical signs of hemorrhage. Blood is diverted from the placenta via vasoconstriction; the mother’s total blood circulation is maintained at the expense of the fetus. Fetal distress may be the first sign of shock in the mother (137,138).

Pediatrics

Pediatric patients have extensive compensatory mechanisms, which can result in significant tachycardia before any

hypotension is manifested. Hypotension in a pediatric patient is an ominous sign and suggests advanced stages of hemorrhage.

Diagnostic Approach

The first priority in managing a patient with hemorrhagic shock is to identify and control the source of bleeding. If no obvi-ous source of external bleeding is identified, a rapid evaluation should be performed to identify likely occult sources of bleed-ing. In the trauma patient, significant internal hemorrhage can occur in four defined regions: the thoracic cavity, the perito-neal cavity, the retroperitoneum, and extremity fractures. These areas can be rapidly assessed via chest radiograph, a pelvic radiograph, focused assessment with sonography for trauma (FAST), and physical examination of extremities along with appropriate radiographs. In-depth coverage of the diagnosis of abdominal trauma is provided in a later chapter of this book. In nontrauma patients without clear evidence of bleeding, the gas-trointestinal tract should be rapidly evaluated via nasogastric tube, rectal examination, and endoscopy where appropriate. Additional diagnostic tests can be obtained based on clinical history, patient background, and condition. Abdominal aor-tic aneurysms can be identified on physical examination and bedside ultrasound. In selected instances, angiography may be used to identify and treat sources of hemorrhage not otherwise apparent (pelvic fractures, pancreatitis, lower gastrointestinal bleeding) (139–144). This should only be instituted when a spe-cific source of hemorrhage is highly likely and therapeutic inter-vention is sought. Computed tomography should be avoided in hemodynamically unstable patients with hemorrhage.

Laboratory Testing

Hematocrit and Hemoglobin

Hemoglobin and hematocrit measurements have long been part of the basic diagnostic workup of patients with hemor-rhage and/or trauma. However, in patients with rapid bleed-ing, a single hematocrit measurement on presentation to the emergency department may not reflect the degree of hemor-rhage. In a short transport or presentation time, prior to ini-tiation of resuscitation, the body’s compensatory mechanisms for fluid retention and resorption into the vascular space have not taken place, and initial hematocrit levels may remain stable despite significant blood loss. A retrospective study of 524 trauma patients (145) determined that the initial hemato-crit had a sensitivity of only 0.50 for detecting patients with an extent of traumatic hemorrhage requiring surgery. The

TABLE 47.2 Response to Initial Fluid Resuscitation and Patient Management

Rapid Response Transient Response No Response

vital signs return to normal transient response, recurrent hypotension, and/or tachycardia

remains abnormal

Estimated blood loss Minimal (10–20%) Moderate (20–40%) Severe (>40%)

additional crystalloid unlikely yes yes

need for blood transfusion unlikely Moderate to high immediate

Blood preparation type and cross-match (30–60 min)

type-specific (10–20 min) Emergency blood release (immediate type o rh-negative blood)

operative intervention Possible likely Highly likely

Early presence of surgeon yes yes yes

adapted from american college of Surgeons committee on trauma. Shock. in: Advanced Trauma Life Support. 7th ed. chicago, il: american college of Surgeons; 2004:79.

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diagnostic value is further confounded by the administration of intravenous fluids and red cell concentrates during resusci-tation (146–148).

Two prospective observational studies determined the sensitivity of serial hematocrit measurements for detecting patients with severe injury (148,149). In the first study (148), the authors compared values of hematocrit at admission and 15 and 30 minutes following arrival to the emergency depart-ment. A normal hematocrit on admission did not preclude sig-nificant injury. The mean change in hematocrit levels between arrival and 15 minutes, and 15 and 30 minutes was not sig-nificantly different in patients with or without serious injuries. However, a decrease of hematocrit by over 6.5% at 15 and 30 minutes had a high specificity for injury (0.93 to 1.0), but a low sensitivity (0.13 to 0.16).

Another prospective observational study examined the utility of serial hematocrit measurements during the initial 4 hours following admission (149). A significant limitation to this study is that they removed patients who required a blood transfusion in order to eliminate confounding variables. In the remaining 494 patients, a decrease in hematocrit of more than 10% between admission and 4 hours was highly specific for severe injury (0.92 to 0.96), but again, it was not sensitive (0.09 to 0.27).

Overall, decreasing hematocrit levels over time may reflect continued bleeding. However, patients with significant bleed-ing may maintain their hematocrit level, especially in the absence of resuscitation. Conversely, hematocrit levels may also be confounded by aggressive fluid resuscitation early dur-ing resuscitation (146,147). An initial hematocrit level will help to identify patients who present with pre-existing ane-mia who may have a lower threshold for hemorrhage. The hematocrit level should be used in conjunction with other measures of perfusion in order to determine the presence of occult hemorrhage.

Measurements of Perfusion

Lactate

Lactate was initially suggested as a diagnostic parameter and prognostic indicator of hemorrhagic shock in the 1960s. Substantial data exist that lactate levels as a marker of tissue oxygen debt can predict outcome in various forms of shock (46,150). Recent studies have suggested that early changes in lactate even in the prehospital environment may be predictive of the need for blood transfusion and hemorrhage control pro-cedures. A recent multicenter trial which enrolled 327 trauma patients with a systolic blood pressure ≤100 mmHg, trans-ported by ground advanced life-support services reported that prehospital lactate ≥2.5 mgmol/L was a better predictor than blood pressure or shock index for the need for resuscitative care (151).

During hemorrhage, not only is the initial lactate level important, but also the rate of clearance (152,153). Two prospective studies confirm this. In one prospective observa-tional study (152), 76 patients with multiple trauma were ana-lyzed with respect to clearance of lactate between survivors and nonsurvivors over 48 hours. If lactate normalized within 24 hours, survival was 100%. Survival decreased to 77.8% if normalization occurred within 48 hours, and to 13.6% in those in whom lactate levels remained elevated above 2 mEq/L

for more than 48 hours. This was confirmed in another pro-spective study of 129 trauma patients (153) in which initial lactate levels were higher in nonsurvivors. A prolonged time to normalization (>24 hours) was associated with the develop-ment of posttraumatic organ failure. Finally, venous lactate has been shown to be an excellent approximation for arte-rial lactate in acute trauma patients and is a useful marker for significant injury (154).

Taken together, these studies suggest that both the initial lactate level and the rate of clearance are reliable indica-tors of morbidity and mortality following trauma. However, whether lactate should be used as an end point of resuscitation or is merely a marker of tissue ischemia has not been clearly established.

Base Deficit

Base deficit values derived from arterial blood gas analysis have also been shown to provide an indirect estimation of tis-sue acidosis due to impaired perfusion (155–161). However, base deficit can be affected by resuscitation fluids (hyperchlo-remic metabolic acidosis) and exogenous administration of sodium bicarbonate. Despite these potential drawbacks, initial base deficit has been shown in several retrospective studies to correlate with transfusion requirements, organ dysfunction, morbidity, and mortality following trauma (26,162–167). The magnitude and severity of the base deficit also correlates to outcome, and is useful in both pediatric and elderly patients (165,166). Base deficit has been shown to be a better predictor of outcome than pH alone following traumatic injury (164).

Lactate versus Base Deficit

Although many studies have shown that both base deficit and serum lactate levels correlate with outcome following trauma and hemorrhage, these two parameters do not always correlate with each other (168,169). In fact, lactate has been found to be a superior predictor of mortality as compared to base deficit in a recent study of patients in the ICU following trauma (168). Both base deficit and lactate have been shown to correlate to outcome in nontraumatic etiologies of hem-orrhagic shock (170,171). Given that there are confounding variables following trauma that can affect measured levels of both lactate and base deficit, independent assessment of both parameters along with the patient’s clinical condition is recom-mended for the evaluation of shock in trauma patients.

Measurement of Coagulopathy

Standard Coagulation Studies

Traditional studies of coagulation include prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen level, and platelet count. Although no tightly controlled trials have been performed, current recommendations for therapeutic end points in hemorrhagic shock include maintaining PT and aPTT at less than 1.5 times the normal value, maintaining a platelet count of >100 in patients with active bleeding or trau-matic brain injury, and maintaining a fibrinogen level of >1 g/L.

While these laboratory studies are standard, they do pres-ent several drawbacks. To begin, in vivo coagulation depends on the interaction between platelets and coagulation factor enzymes. Laboratory values of PT and aPTT are performed on platelet-poor plasma and fail to evaluate the cellular

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interactions of clotting. PT and aPTT measurements also do not take into account hypothermia-induced coagulopathy because samples are warmed prior to measurement. Platelet and fibrinogen assays give numerical values, but fail to assess function. Finally, each of these tests takes time, in most centers up to 30 to 45 minutes. This lag time makes these studies clini-cally inefficient because when the results become available, they may not truly reflect the patient’s clinical condition. During resuscitation, actively bleeding patients are in a constant state of flux. One study has suggested that with efficient laboratory processing and emergency hemorrhage panel which includes PT/INR, platelet count, and fibrinogen can have results avail-able within 20 minutes (172). Alternative point-of-care testing such as the iSTAT handheld analyzer can provide rapid bedside results, but is currently limited to activated clotting time (ACT) and PT/international normalized ratio (INR) (173).

Thromboelastography

The thromboelastograph (TEG) analyzer is a bedside machine that provides a functional evaluation of overall coagulation on whole blood at the same temperature as the patient. The TEG has been shown to be a more sensitive measure of coagula-tion disorders than standard coagulation measures (174). The TEG assay provides a tracing that measures clotting (R value), clot formation (α angle), clot strength (maximum amplitude [MA]), and clot lysis (LY 30) (Fig. 47.5). Elongation of the R value represents a deficiency in coagulation factors. The α angle represents the rate of fibrin accumulation and cross-linking, which can be affected by fibrinogen function and, to a lesser degree, platelet function. The MA is a measure of clot strength and is affected primarily by platelets and, to a lesser degree, fibrinogen. A recent study investigating the util-ity of the admission TEG in trauma patients found that the TEG data were superior to conventional coagulation tests at predicting coagulopathy. The TEG data identified patients at increased risk for early transfusion and identified patients with fibrinolysis (175). Several authors have proposed TEG-guided resuscitation strategies for trauma patients with hemorrhagic shock (175,176).

trEatmEnt

Trauma is by far the most common etiology for hemorrhagic shock. While other causes do exist, management priorities are similar regardless of the source of bleeding. Diagnosis, evaluation, and management must often occur simultaneously. A methodical approach is necessary to optimize outcome (Table 47.3). Unique to hemorrhagic shock, as opposed to other forms of shock, is that definitive management frequently requires surgical or procedural intervention to cease bleeding. The diagnostic pathway and interventions pursued become part of the resuscitation pathway. What follows is a summary of the interventions, diagnostic studies, monitoring strategies, and resuscitation techniques for hemorrhagic shock.

Immediate Management

When approaching any patient in shock, the sequence of events should be to address the issues of airway, breathing, and circu-lation—also known as the “ABCs.” Most patients with fully developed shock require tracheal intubation and mechanical ventilation, even if acute respiratory failure has not yet devel-oped. Studies have shown that during shock, the respiratory muscles require a disproportionate percent of the cardiac out-put (16). Failure to mount a hyperventilatory response to a metabolic acidosis is a significant predictor of the need for subsequent intubation in trauma patients (177). Mechanical ventilation allows flow to be redistributed, lessens the work of breathing, may help reverse lactic acidosis, and supports the patient’s airway until other therapeutic measures can be

Coagulation Fibrinolysis

MAα

K

R

FIgurE 47.5 thromboelastogram. the thromboelastograph (tEg) ana-lyzer is a bedside machine that provides a functional evaluation of overall coagulation on whole blood at the same temperature as the patient. the thromboelastograph assay provides a tracing that mea-sures time to clot formation (r value), speed to a certain clot strength (k value), rate of clot formation (α angle), overall clot strength (maxi-mum amplitude [Ma]) and clot lysis (ly 30).

TABLE 47.3 Key Steps in the Approach to a Patient with Hemorrhagic Shock

1. Early recognitiona. Signs and symptoms may be subtle.b. astute clinical acumen is necessary to identify hemorrhage

prior to hemodynamic collapse.2. obtain an accurate patient history

a. traumab. recent surgical proceduresc. Medical history

(i) gastrointestinal disease (peptic ulcer disease, varices, etc.) (ii) atherosclerosis (aneurysmal disease)(iii) coagulation disorders

d. Medication use (i) antiplatelet therapy (ii) anticoagulants

3. initiate interventiona. “aBcs”—airway, breathing, circulationb. initiate resuscitation

(i) crystalloid (ii) Blood products

1. type o uncross-matched blood if in extremis2. cross-matched blood when available3. clotting factors: 1:1:1 ratio of plasma:platelets:red

blood cells for those meeting criteria for massive transfusion

4. Directed physical examinationa. External sources of bleeding (consider tourniquet)b. internal sources of bleeding

5. Expedite definitive treatmenta. Surgical controlb. Endoscopic controlc. angiographic control

6. correct coagulopathy (simultaneous with definitive treatment)

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effective. Tracheal intubation is also required if there is evi-dence of mental status changes, such that airway protection is questionable. Evidence of hypoxemia and/or hypoventilation is also an absolute requirement for early intubation.

Perhaps most complex is the patient with evidence of com-pensated hemorrhagic shock whose mental status is still intact. In this type of patient, clinical acumen is imperative. If the initial response to resuscitation is sustained (i.e., “a responder”), then close observation of the airway may be appropriate while additional workup and treatment are pursued. However, in a patient who is not responsive or has a transient response to fluid resuscitation, control of the airway early is necessary prior to respiratory collapse (177). In addition, if diagnostic and therapeutic interventions, such as angiography and embo-lization, are required during resuscitation to control hemor-rhage, early airway control should be obtained.

Once the airway is secured, it is important to closely moni-tor techniques of ventilation. Studies have shown that there is a tendency of rescue and medical personnel to hyperventi-late patients during resuscitation (178,179). Hyperventilated patients have been shown to have an increased mortality when compared to nonhyperventilated patients in the setting of severe traumatic brain injury (180–182). Animal studies have sup-ported this information, showing that cardiac output increases with hypoventilation and decreases with hyperventilation and positive end-expiratory pressure (PEEP) (183,184). Thus, ade-quate appropriate ventilator strategies are imperative early in hemorrhagic shock to optimize tissue perfusion and outcome.

The management steps to restore adequate circulation include identifying and controlling the source of hemorrhage and intravenous fluid and blood product resuscitation to restore tissue perfusion. The first step is to control obvious hemorrhage immediately.

Hemorrhage Control

Resuscitation of the bleeding patient requires early identifica-tion of potential bleeding sources followed by prompt action to minimize blood loss, restore tissue perfusion, and achieve hemodynamic stability. This is particularly important in the trauma patient where multiple sources may be involved. Wound compression is the initial maneuver to control an exsanguinat-ing wound. For massive soft tissue injuries or major vascular injury to an extremity, placing a tourniquet proximally may decrease hemorrhage and allow resuscitation prior to defini-tive control (185). Fractures should be splinted or placed in traction. Evidence of pelvic instability or hemorrhage may be temporized by a sheet or a pelvic binder (186,187). In the presence of massive trauma, patients may present with coagu-lopathy in the emergency department and this should be pre-emptively addressed. The same principles should be applied to nontraumatic hemorrhagic shock, such as gastrointestinal bleeding and ruptured aortic aneurysms: rapidly identify and attenuate the obvious sources of hemorrhage.

Multiple studies have confirmed that patients in need of emergency surgery for ongoing hemorrhage have a better survival if the elapsed time to definitive care is minimized (188–192). Those patients with unnecessary delays in diag-nosis and definitive treatment will have increased morbidity and mortality. A multicenter retrospective review of over 500 deaths in the operating room concluded that delayed trans-fer to the operating room was a cause of death that could be avoided by shortening the time to diagnosis and resuscitation

(193). The development of trauma systems has significantly contributed to improved trauma outcomes by triaging more severely injured patients to hospitals that have systems in place to rapidly diagnose, resuscitate, and definitively treat patients with hemorrhagic shock (188–190). The implementation of trauma systems has resulted in improved outcomes in severely injured patients, decreased time to operating room in hypo-tensive patients, decreased complications, decreased hospital length of stay, and decreased mortality, especially in patients with severe injury as measured by an ISS of >15 (190). Defini-tive prompt care is critical to optimize outcomes in patients with trauma and hemorrhage.

Intravenous Access

Access to the bloodstream should be obtained expediently. Two peripheral large-bore intravenous catheters (18 gauge or larger) are necessary. If cannulation of a peripheral vein is dif-ficult due to collapse, then central venous access should be secured. In the presence of trauma to the torso, venous access above and below the diaphragm is preferable. When obtain-ing intravenous access, it is important to note that the maxi-mal rate of infusion via a catheter is directly proportional to the diameter of the catheter and indirectly proportional to the length. Therefore, a 9 French percutaneous introducer sheath will infuse fluids more rapidly than a 7 French triple-lumen catheter. A large-bore peripheral intravenous catheter will also infuse fluids more rapidly than a 7 French triple lumen catheter due to a shorter length and less resistance. Intraos-seus access is an option for both adults and children when i.v. access is difficult. Fluids and blood products can be delivered via this route. However, this should be considered temporary access until better intravenous access can be obtained.

Adjunctive Measures

Historical teachings have been that tilting a patient into head-down position (i.e., Trendelenburg) diverts blood volume into the central circulation and improves venous return, thereby improving stroke volume and cardiac output in hypovolemic shock. However, studies do not show any significant redis-tribution of blood volume centrally (194). In fact, the head-down position can worsen gas exchange and cardiac function. Therefore, the Trendelenburg position is no longer recom-mended as a resuscitative technique. If this type of measure is deemed desirable, raising the legs above the level of the heart should be adequate (195).

The use of pneumatic antishock garments (PASGs, previously military antishock trousers [MAST]) currently has a limited role in the management of hypotensive trauma patients. Although their use was almost universal for hemorrhage control in the late 1970s and 1980s, recent studies have demonstrated that they have no effect on patients with thoracic injury. In fact, some evidence suggests that mortality is higher when PASGs are applied (196,197). No survival advantage has been dem-onstrated in the pediatric population, although there may be a small survival benefit in children with a systolic blood pressure of less than 50 mmHg (198). The main utility of PASGs cur-rently is as a temporizing agent to stabilize pelvic fractures.

Fluid Resuscitation

Careful attention to fluid resuscitation is necessary during management of hemorrhagic shock to optimize outcome. It

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is still unclear which type of fluid should be employed in the initial treatment of the bleeding patient.

Several meta-analyses have shown an increased risk of death in patients resuscitated with colloids as compared with crystalloids (199–202) during hemorrhagic shock. While three of these studies suggested that the effect was particularly significant in the trauma population, the results of a recent meta-analysis showed no significant difference (203). A trial evaluating 4% albumin versus 0.9% normal saline in nearly 7,000 ICU patients showed that albumin administration was not associated with worse outcome. There was a trend, how-ever, toward higher mortality in the trauma subgroup that received albumin (p = 0.06) (204). The difficulty with inter-preting these meta-analyses and the individual studies is that they are very heterogeneous. Each evaluates different patient populations and resuscitation strategies, and mortality may not always be a primary end point. However, given these results, crystalloid resuscitation is currently the accepted stan-dard as initial therapy for hemorrhagic shock.

Many synthetic colloid solutions such as hetastarch and dextran have also been associated with coagulopathy. Recent research suggests that hetastarch solutions with a high mean molecular weight and a high C2/C6 ratio suppress coagu-lation more than solutions with rapidly degradable low–molecular-weight colloids (205–207). This coagulopathy may be produced by one of several potential mechanisms includ-ing a reduction in von Willebrand factor, platelet dysfunction, reduced factor VII levels, and an interaction with fibrinogen (173,208).

Crystalloid solutions are not without side effects. Resus-citation with fluids that contain supraphysiologic concentra-tions of chloride can lead to hyperchloremic acidosis. This can be significant in patients where lactic acidosis may already be present. Lactated Ringer solution contains a more physiologic concentration of chloride (109 mEq/L) than normal saline (NS 154 mEq/L), and therefore may be the preferred choice. Ani-mal studies have also shown that resuscitation with normal saline can lead to more coagulopathy and increased blood loss than resuscitation with lactated Ringer solution (209).

Massive resuscitation with crystalloid fluids alone can lead to several significant complications including cardiac and pul-monary complications, gastrointestinal dysmotility, coagu-lation abnormalities, and immunologic dysfunction (210). Reports of lactated Ringer solution and normal saline increas-ing reperfusion injury and leukocyte adhesion suggest that crystalloid resuscitation may worsen acidosis and coagulopa-thy in severely injured patients and possibly increases the risk of ARDS, systemic inflammatory response syndrome (SIRS), and multi-organ failure (MOF) (210–213). Abdominal com-partment syndrome has been clearly associated with exces-sive use of crystalloid resuscitation (214–218). Recently, there has been increased focus on early use of blood products in order to minimize crystalloid use in the resuscitation of hem-orrhagic shock. Finally, resuscitation strategies that focus on early aggressive fluid resuscitation to normalize blood pressure before bleeding is controlled may result in increased hemor-rhage and increased mortality. This has led some authors to suggest that “hypotensive resuscitation” should be the goal until the source of hemorrhage is controlled (219–222). How-ever, the exact goals for mean arterial pressure and trigger points for bleeding have not been established. The potential adverse sequelae when used in patients with associated injuries

or comorbidities (i.e., severe closed head injury) have not been clearly established.

Damage Control Resuscitation

Damage control resuscitation (DCR) is a term that has recently been coined to describe a specific strategy during the resuscita-tion phase of trauma care (173,223–225). It should be initiated within minutes of presentation and is meant to pre-emptively address issues associated with resuscitating critically injured patients: prevention of hypothermia, acidosis, and coagulopa-thy. DCR involves two components: hypotensive resuscitation and hemostatic resuscitation (Table 47.4).

Hypotensive Resuscitation

Hypotensive resuscitation refers to the concept that fluid should be administered at a rate that returns the systolic blood pres-sure to a safe but lower than normal pressure until operative control of bleeding can be established. The traditional treat-ment of hemorrhaging patients has used early and aggressive fluid administration to restore blood volume. However, this approach may increase hydrostatic pressure on the wound or injured vessel, leading to dislodgement of blood clots, a dilution of coagulation factors, and undesirable cooling of the patient. Low-volume fluid resuscitation, or “permissive hypotension,” may avoid the adverse effects of early aggressive resuscitation while maintaining a level of tissue perfusion adequate for short periods. This strategy has been suggested historically for the management of ruptured abdominal aortic aneurysm patients (226), and has recently regained attention in the trauma pop-ulation (220–222,227–230). It has shown promise in animal studies and human trials of penetrating trauma (220,227), but has yet to be confirmed in large-scale prospective random-ized human clinical trials in the broader trauma population. A Cochrane database review in 2003 found that there was not conclusive evidence from randomized controlled trials (RCTs) for or against early or larger volumes of intravenous fluid resuscitation in uncontrolled hemorrhage (231). A recent pilot study in the prehospital environment suggested that a con-trolled resuscitation strategy was safe in blunt trauma patients, but patients with evidence of severe TBI were excluded (221).

TABLE 47.4 Damage Control Laparotomy and Damage Control Resuscitation

DAMAGE CONTROL LAPAROTOMY1. Abbreviated laparotomy (initial procedure)

• control of bleeding• control of contamination• restitution of blood flow

2. Resuscitation in the intensive care unit (24–48 hr)• core rewarming• correction of acidosis• reversal of coagulopathy• optimization of ventilation and hemodynamics

3. Definitive surgical repair (days to weeks)• restoration of continuity• completion of resection• removal of packs• closure of abdomen

DAMAGE CONTROL RESUSCITATION•Hypotensive resuscitationa

•Hemostatic resuscitation

aHypotensive resuscitation requires experienced physician oversight and careful patient selection.

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Although the concept of permissive hypotension seems prom-ising in some circumstances, further work needs to be done. In addition, it requires extraordinarily tight control by an expe-rienced physician who is guiding fluid resuscitation moment to moment. Hypotensive resuscitation should not be consid-ered in patients with traumatic brain injury and spinal cord injury where adequate cerebral perfusion pressure is crucial to ensure tissue oxygenation (143,232). It should also be carefully considered in elderly patients and may be contraindicated in patients with a history of chronic hypertension (143).

Hemostatic Resuscitation

Conventional resuscitation practice for damage control has focused on rapid reversal of acidosis and prevention of hypothermia. Surgical techniques are aimed at control-ling hemorrhage and contamination rapidly, with definitive repair occurring following hemodynamic stabilization. How-ever, early, direct treatment of coagulopathy was previously neglected, and viewed as a byproduct of resuscitation, hemo-dilution, and hypothermia. Delay in the availability of blood products has also hindered the ability to employ immediate resuscitation with clotting factors.

It has now been demonstrated that acute traumatic coagu-lopathy is present in 25% to 40% of critically injured patients on arrival to the emergency department (120,123,233). The presence of coagulopathy may be even higher in patients with severe closed head injury, with an incidence of 21% to 79% when stratified by ISS (234). It has also been shown that the presence of early coagulopathy is an independent predictor of mortality following trauma (123).

Hemostatic resuscitation employs blood components early in the resuscitation process to restore both perfusion and nor-mal coagulation function while minimizing crystalloid use. Several retrospective studies from both the military and civil-ian communities have suggested that trauma patients who are resuscitated with higher ratios of fresh frozen plasma to packed red blood cells have a higher survival (225,235–239). These studies have all suffered from survival bias in that patients in the high-ratio groups survived long enough to reach the higher ratios. This has led to controversy in the field with some authors suggesting that high-ratio resuscitation leads to greater exposure of patients to blood products and thus increased risk of ARDS and MOFS (240). To address this issue, a recently multicenter clinical trial randomized 680 trauma patients at risk for massive transfusion to received either a 1:1:1 ratio of plasma:platelets:PRBCs versus a 1:1:2 ratio. While there was no significant difference in 24-hour (1:1:1 at 12.7% vs. 1:1:2 at 17%, p = 0.12) and 30-day (1:1:1 at 22.4% vs. 1:1:2 at 26.1%, p = 0.26) mortality, exsanguination which was the pri-mary cause of death in the first 24 hours was reduced in the 1:1:1 group (9.2% vs. 14.6%, p = 0.03). In addition, more patients in the 1:1:1 group achieved hemostasis. There was no difference in subsequent complication in the hospital including the rates of nosocomial infection or organ failure (241).

Massive Transfusion Protocols

Massive transfusion has been traditionally defined as the need for 10 or more units of red cells in the first 24 hours. However, most patients who die from exsanguination die within the first 6 hours and many die before high-volume transfusions can be

initiated. This has led to the proposal that massive transfu-sion be viewed as a rate of bleeding over time rather than an absolute number of blood products administered. In order to employ DCR, it is vital to recognize the patient who is likely to need a massive transfusion early to that blood products can be initiated and crystalloid resuscitation minimized. There have been several scoring systems developed to help identify patients at risk for a massive transfusion (242–246). Many of these scores rely on laboratory data such as PT/INR, base deficit, or hemoglobin, which may not be immediately avail-able. The ABC score has been validated as a simple approach which uses data that are rapidly available upon patient arrival (Table 47.5). The ABC score relies on systolic blood pressure, heart rate, penetrating mechanism, and a positive FAST exam-ination for intraperitoneal fluid (243).

Once you have identified a patient in need of a massive transfusion, several studies have shown the benefit of having a structured protocol to ensure good communication with the blood bank so that blood products can be rapidly available at the bedside (247,248). The logistics of rapid access to blood products can be challenging especially in smaller centers with limited blood supply. Prethawed plasma or liquid plasma has been advocated in larger centers to improve rapid access to a bal-anced resuscitation strategy (249). The results of the PROPPR study discussed above provide compelling evidence to consider a 1:1:1 strategy in the MTP protocol (Table 47.6) (241).

Most authors recommend an empiric resuscitation strategy during the period of active hemorrhage with a fixed ratio of bleed products administered without focusing on the results of traditional coagulation test results due to the inherent delay in receiving these results (250,251). This is an area of controversy with other arguing for a focused factor replacement strategy or a TEG-guided resuscitation utilizing the results of bedside testing (252). Additional study is needed to define the opti-mal approach. Most authors agree that once hemorrhage con-trol has been achieved, a more targeted correction of residual coagulation abnormalities is a reasonable approach. Once the patient has stabilized and is no longer at risk for ongoing hem-orrhage, a restrictive transfusion approach in the ICU is recom-mended with a target transfusion threshold of hemoglobin of 7 mg/L (253).

TABLE 47.5 ABC Score to Predict Need for Massive Transfusion

Component Yes No

Penetrating mechanism 1 0

SBP ≤90 mmHg 1 0

Hr ≥120 beats/min 1 0

Positive FaSt examination 1 0

total score of 2 or greater is predictive of need for massive transfusion in trauma patients in the emergency department (243).

SBP, systolic blood pressure; Hr, heart rate; FaSt, focused abdominal sonogram for trauma.

TABLE 47.6 Recommended Empiric Massive Transfusion Protocol for Acute Ongoing Hemorrhage

Current Suggested Protocol for Traumatic Hemorrhage

•6 units of packed red blood cells•6 units of fresh frozen plasma•1 platelet pheresis (or 6–10 units of platelets)•cryoprecipitate as indicated (fibrinogen <100 g/dl)

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Despite acceptable survival rates, there are several known complications to massive transfusion (Tables 47.7 and 47.8) (254–259). Physicians caring for patients who require massive transfusion must anticipate, identify, and rapidly treat these potential complications in order to optimize outcome.

Adjuncts for Management of Coagulopathy

Several recent studies have explored the use of additional adjuncts for the management of trauma-induced coagulopa-thy and for the management of patients with coagulopathy secondary to pre-injury treatment with anticoagulant medi-cations such as Coumadin. These adjuncts include activated factor VIIa, tranexamic acid (TXA), prothrombin concentrate complex (PCC), and cryoprecipitate or fibrinogen concen-trates. The summary of the current data for each is presented below.

Activated Factor VIIa

Recombinant factor VIIa is a synthesized analog of human factor VII that has been used effectively in the treatment of patients with hemophilia as well as other congenital and acquired coagulopathies. There were subsequently several case series reporting on the off-label use of factor VIIa for manage-ment of severely bleeding trauma patients (260,261). Adminis-tration of factor VIIa resulted in rapid correction of PT, but its efficacy was unclear. A recent meta-analysis of 29 RCTs of fac-tor VIIa in nonhemophilia patients concluded that there was no evidence of a mortality benefit and while there was a trend

toward reduction in the need for blood transfusions, there was also evidence of a increased thrombotic complications (262). It has also been recognized that factor VIIa is not effective in patients who are hypothermic or have severe metabolic aci-dosis which limits its applicability in the setting of massive transfusion following injury (263).

Tranexamic Acid

TXA is an antifibrinolytic agent that acts by inhibiting the binding of plasmin to plasminogen. It remains unclear the optimal assessment for fibrinolysis in trauma patients. Sev-eral authors have used TEG analysis and have reported that 2% to 34% of trauma patients have evidence of fibrinolysis on admission (175,264–268). This wide range is due to the heterogeneity of the populations studied. The use of TXA in trauma patients has increased dramatically in response to the CRASH 2 study (28-day mortality 14.5% TXA group vs. 16.0% placebo, RR 0.91, 95% CI 0.85 to 0.97) (269,270). This study demonstrated a survival benefit for patients receiv-ing the drug within 3 hours of injury, but interestingly out-come was worse if the drug was given beyond 3 hours. The greatest benefit also appeared to be in the patients with the greatest risk of hemorrhage (SBP <75 mmHg). Two additional retrospective studies suggest a survival advantage in military casualties receiving TXA in US and UK support hospitals in Afghanistan (271,272). These data have led to a recommen-dation that TXA be considered for injured soldiers in need of blood transfusion as early as possible but ideally within 3 hours after injury and strongly advocated in patients judged to need a massive transfusion (273).

There remain many questions about the optimal dos-ing, patient selection, and safety related to the use of TXA in injured patients (273). There are several studies ongoing to address the use of TXA in the prehospital setting and to help clarify the dosing and appropriate patient selection (274). Studies are also underway to evaluate the use of TXA for patients with severe TBI to determine its impact on the pro-gression of intracranial hemorrhage.

Prothrombin Concentrate Complex

Prothrombin complex concentrate (PCC) is a concentrated for of clotting factors used for reversal of vitamin K antagonists such as warfarin in patients with active hemorrhage. It has been particularly advantageous for patients on warfarin with intracranial hemorrhage (275,276). There are three factor (II, IX, X) and four-factor preparations (II, VII, IX, X). The PCC concentration of these factors is approximately 25 times that of plasma (277). Due to the lack of factor VII in the three-factor preparations, some additional plasma may be required. PCC has the advantage of a long shelf life as it is reconstituted for use and can be given in a small volume which results in less risk of fluid overload in elderly patients. It also results more rapid correction of coagulopathy compared to the time delay of thawing frozen plasma. PCC is not advocated for general use in the bleeding patient who is not on warfarin as there is concern for potential prothrombotic complications (277).

Cryoprecipitate/Fibrinogen Concentrates

There is limited clinical data to guide the use of cryoprecipitate or fibrinogen concentrates in trauma patients (278). Cryopre-cipitate is a rich source of fibrinogen and has been variably uti-lized in massive transfusion protocols in the United States. One

TABLE 47.7 Noninfectious Transfusion-Associated Complications

Acute (within 24 hr of transfusion)Hemolytic reactionsFebrile nonhemolytic reactionsallergic reactionstransfusion-related acute lung injury (trali)HypothermiaHypocalcemiaHypo- or hyperkalemiaacid-base derangements

Delayed (more than 24 hr after transfusion)alloimmunizationimmunosuppressionPosttransfusion purpuragraft vs. host diseaseMultiple organ dysfunction syndrome

TABLE 47.8 Infectious Transfusion-Associated Complications (254–257)

Type of Infectious ComplicationIncidence Per All Transfused Components

Bacterial contamination (PrBcs + platelets)

1 per 2,000

Hepatitis B transmission 1 per 205,000PrBc-related bacterial sepsis 1 per 500,000–786,000Hepatitis a transmission 1 per 1,000,000Hepatitis c transmission 1 per 1,600,000Hiv transmission 1 per 2,135,000

PrBc, packed red blood cell; Hiv, human immunodeficiency virus.

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recent study demonstrated that cryoprecipitate use in trauma patients requiring massive transfusion varied from 7% to 81% among the trauma centers involved (279). One retrospective study from the US military suggested that administration of cryoprecipitate was independently associated with improved survival in critically injured soldiers (271). More studies are needed to clearly define the appropriate use of this product in the setting of a massive transfusion.

Preventing Hypothermia

All fluids during resuscitation from hemorrhagic shock should be warmed to prevent hypothermia. Equipment is now avail-able that allows the rapid infusion of blood and/or crystalloids at warmed temperatures (i.e., up to 750 mL fluid per minute warmed to over 37°C). Other techniques during resuscitation that can be used to prevent hypothermia in the acutely hemor-rhaging patient include warming the circuit on the ventilator in ventilated patients, ensuring the patient is covered with warm blankets at all times following exposure and thorough exami-nation, warming the resuscitation and operating rooms, using forced air external warming blankets during resuscitation and in the operating room, and using warm water blankets on the operating room table. Hypothermia is clearly associated with increased mortality following resuscitation from hemorrhagic shock, and every attempt to prevent or minimize its occurrence and severity should be employed (280,281).

currEnt controvErSIES and ExPErImEntal tHEraPIES

Red Cell Substitutes

Although the blood supply in the United States is safe and currently has sufficient capacity to meet most patient needs, there is room for considerable improvement. The current sys-tem is dependent on blood donors on a regular basis, and the blood supply is subject to seasonal shortages due to holidays and convenience. The gap between the donor pool and the increasing transfusion requirements of an aging population is narrowing, and shortages are becoming more frequent. The risk of transmission of known infectious diseases still exists (Table 47.8), while the threat of new and emerging infections such as West Nile virus and Creutzfeldt–Jakob disease under-scores the risk of a tainted blood supply (282).

The ideal red cell substitute has several characteristics including an ability to deliver (and potentially enhance) oxygen delivery, no risk of disease transmission, no immuno-suppressive effects, available in abundant supply, universally compatible, prolonged shelf life, similar in vivo half-life to the red blood cell, available at a reasonable cost, easy to admin-ister, able to access all areas of the human body (including ischemic tissues), and effective at room air or ambient condi-tions (282–284).

The two main types of oxygen carriers that are used as red blood cell substitutes are hemoglobin-based oxygen carri-ers (HBOCs) and perfluorocarbons (PFCs). Based on previous clinical trials, many obstacles still need to be overcome. Adverse effects associated with HBOCs include severe vasoconstriction due to binding of nitric oxide and dysregulation of endothelin; nephrotoxicity; interference of macrophage function; antige-

nicity; oxidation on storage; activation of complement, kinin, and coagulation; iron deposition with concerns of hemochro-matosis and iron overload; gastrointestinal distress; neurotox-icity free radical generation; and interference with diagnosis of transfusion reaction. Adverse effects of PFCs include limited shelf life, flulike symptoms during infusion, complement and phagocytic activation, and short circulation time (283). The most promising product known as polyheme progressed to a phase III clinical trial for trauma patients in the United States; however, this trial failed to demonstrate benefit and the prod-uct is no longer available (285).

Freeze-dried or Lyophylized Plasma

Given the increased use of plasma as a critical component of massive transfusion protocols with the adoption of higher ratios of plasma to red blood cells, there is considerable interest in the development of a plasma product with a prolonged shelf life that could be reconstituted for rapid administration perhaps even in the prehospital environment. There are several promis-ing animal studies of these products in hemorrhagic shock and injury models but clinical trials are still needed (286,287).

Hypertonic Saline

Hypertonic saline (7.5% saline ± 6% dextan-70) has been investigated as an alternative resuscitation strategy in critically injured patients (288). Hypertonic resuscitation evokes an increase in serum osmolarity, which results in the redistribu-tion of fluid from the interstitial and intracellular space to the intravascular space. This leads to a rapid restoration of circu-lating intravascular volume with a small amount of resuscita-tion fluid. Hypertonic saline has also been shown to decrease intracranial pressure via its osmotic effects (289,290). This is particularly beneficial in patients with hypovolemic shock and closed head injury due to the ability of hypertonic saline resuscitation to concurrently restore circulating blood volume, improve tissue (including cerebral) perfusion, and lower intra-cranial pressure (290).

Hypertonic saline resuscitation has also been shown to have significant immunomodulatory effects that could miti-gate the dysfunctional inflammatory response seen after trau-matic injury (291–298). The hypertonicity associated with hypertonic saline resuscitation is associated with significant effects on the innate and adaptive immune systems.

The most commonly studied dose for resuscitation of shock in trauma patients has been 7.5% saline with or without 6% dextran given as a 250 cc bolus in the prehospital setting. Sev-eral early clinical trials and meta-analyses suggested improved outcome in patients resuscitated with hypertonic saline (299–301). However, the largest RCT conducted in the prehospi-tal setting failed to show improved survival in patient with hemorrhagic shock and enrollment was closed early due to a potential safety concern with a higher number of early deaths in the hypertonic saline groups (302). A subsequent meta-analysis concluded that this was due to collider bias in the enrollment and no safety issue was identified (303). Hyper-tonic fluids have also been studied in patients with severe traumatic brain injury due to their ability to treat intracranial hypertension. Another large prehospital study failed to dem-onstrate improvement in 6-month neurologic outcome with this approach (304). Various concentrations of hypertonic saline continue to be used in the hospital for ICP management but further study is needed to assess this approach.

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Resuscitative Endovascular Balloon Occlusion of the Aorta

A final emerging therapy that warrants discussion is the use of resuscitative endovascular occlusion balloons of the aorta (REBOA) as a temporizing measure for resuscitation of patients in extreme hemorrhagic shock from bleeding in the abdomen or pelvis. Early reports suggest that an intra-aortic balloon can be placed at the bedside via a femoral percutaneous approach to reduce hemorrhage until surgical or angiographic control can be achieved (305–307). For pelvic hemorrhage, the bal-loon is placed in Zone 3 of the aorta below the renal vessels. For abdominal hemorrhage, the balloon is placed in the distal thoracic aorta (Zone 1). This approach has been suggested as a potential alternative to the traditional cross-clamp on the aorta applied during emergency department thoracotomy. This approach will result in significant tissue ischemia and so must be performed in a setting where rapid hemorrhage con-trol can be achieved to minimize the time of balloon inflation. Current data to support this approach are confined to case series from a limited number of institutions. Further study is warranted to further define the utility of this approach.

Summary

Hemorrhagic shock is a common, yet complicated, clinical condition that physicians are frequently called upon to eval-uate and treat. Diagnosis must be accurate and expedient. Therapy must be direct, efficient, and multifactorial in order to avoid the potential multisystem sequelae. Metabolism and function of all organs are altered during hemorrhagic shock. A better understanding of the pathophysiology of hemor-rhagic shock has led to improved resuscitation techniques and improved survival over recent years. Damage control lapa-rotomy and DCR have changed the approach to management in patients with multisystem trauma and hemorrhagic shock. Staged resuscitation and operative intervention to avoid irre-versible shock are now the mainstays of care. Recognition of acute traumatic coagulopathy has improved the composition of massive transfusion protocols to include the increased use of clotting factors early during resuscitation. New experimen-tal therapies for resuscitation are being evaluated and appear promising. Overall, survival following hemorrhagic shock has improved. Early diagnosis, definitive cessation of bleed-ing, and comprehensive hemostatic resuscitation are the key elements to successful outcome.

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• Hemorrhagic shock is a common disorder that requires a high index of suspicion for early recognition and treatment.

• Young patients will compensate for moderate blood loss without major changes in blood pressure, so the clinician must consider other markers of impaired per-fusion including the development of metabolic acidosis and coagulopathy.

• Trauma-induced coagulopathy is common in severely injured patients and requires early treatment with blood products.

Key Points

• Treatment for hemorrhagic shock focuses on rapid con-trol of the source of hemorrhage coupled with fluid and blood product resuscitation.

• For patients requiring a massive transfusion, a bal-anced resuscitation including plasma, platelets, and red cells is warranted.

• There is no advantage to colloid resuscitation in this setting and excessive crystalloid resuscitation should be avoided.

• Efforts should be made to prevent and treat hypother-mia which may exacerbate ongoing bleeding.

• Damage control surgery is preferred in the setting of ongoing coagulopathy, acidosis, and hypothermia.

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