S. Rob Todd
Krista L. Turner
Frederick A. Moore
History
Despite significant technologic advances and the improved understanding of shock, it remains a diagnosis associated with significant morbidity and mortality. Hippocrates and Galen were the first to describe a “posttraumatic syndrome.” Then in 1737, LeDran, a French surgeon, used the term choc to characterize a severe impact or jolt (1). However, it was not until 1867 that Edwin Morris popularized the term (2). He defined shock as “a peculiar effect on the animal system, produced by violent injuries from any cause, or from violent mental emotions.”
In the late 1800s, Fischer and Maphoter further delineated the pathophysiology of shock (3,4). Fischer proposed a generalized “vasomotor paralysis” resulting in splanchnic blood pooling as the underlying mechanism of shock, while Maphoter suggested that the clinical manifestations appreciated in shock were the result of the extravascular leakage of fluids. A variation of Fischer's theory was supported by Crile in 1899 (5).
In the early 1900s, Walter B. Cannon proposed a toxin as the source of this altered capillary permeability and intravascular volume loss (6). Blalock challenged this theory in 1930 (7). He charged that significant hemorrhage alone could account for insufficient cardiac output in shock states and that it wasn't the result of circulating toxins. Then in the 1940s, Carl Wiggers demonstrated that following prolonged shock, irreversible circulatory failure could occur (8). At that time, hypotension was synonymous with shock, and blood pressure was the primary end point of resuscitation in shock. As such, volume resuscitation was the primary management strategy.
It wasn't until the turn of the 19th century that sources other than trauma were thought to cause shock. Sepsis was first depicted as causing shock during the Spanish American War (9). This was followed in 1906 with the description of anaphylactic shock. And subsequently in 1935, Tennant and Wiggers documented decreased myocardial contractility following coronary perfusion deprivation (10).
Definition of Shock
The definition of shock has historically been a moving target. Initially equated with hypotension, this is no longer the case (11,12). Shock is defined as an acute clinical syndrome resulting when cellular dysoxia occurs, ultimately leading to organ dysfunction and failure (13). Cellular dysoxia or inadequate tissue perfusion is critical in diagnosing shock, as there are many other causes of organ dysfunction and failure that are not resultant from shock.
Note the emphasis on shock as a syndrome, as this constellation of signs and symptoms predictably follows a well-described series of pathophysiologic events (14). Its clinical presentation varies widely based on the underlying etiology, the degree of organ perfusion, and prior organ dysfunction.
Classification of Shock
The incidence and prevalence of shock are poorly characterized for a multitude of reasons. First and foremost, the definition of shock continues to lack consensus. As such, the screening for shock tends to be inadequate, and thus it is underreported. Additionally, patients presumably die in the prehospital setting. Taking these facts into account, one can readily appreciate why the reported incidence and mortality of shock varies widely.
In 1937, Blalock classified shock (15). He defined four categories: hematogenic or oligemic (hypovolemic), cardiogenic, neurogenic, and vasogenic. Subsequently, Weil and Shubin characterized shock based on cardiovascular parameters (16). The categories included hypovolemic, cardiogenic, extracardiac obstructive, and distributive. Table 55.1 represents an adaptation of this system (17). It is important to appreciate that most shock states incorporate different components of each of the aforementioned shock categories.
Hypovolemic Shock
Hypovolemic shock represents a state of decreased intravascular volume. Inciting events include internal or external hemorrhage, significant fluid losses from the gastrointestinal tract (emesis, high-output fistulae, or diarrhea) or urinary tract (hyperosmolar states), and “third spacing” (“capillary leakage” into the interstitial tissues or the corporeal cavities) (Table 55.1). Additional etiologies include malnutrition and large open wounds (burns and the open abdomen) (16,18).
The pathophysiology of shock is dependent upon its classification. Hypovolemic shock is characterized by a decrease in intravascular volume with resultant decreases in pulmonary capillary wedge pressure and cardiac output (Table 55.2). There is a subsequent increased sympathetic drive in an attempt to increase peripheral vasculature tone, cardiac contractility, and heart rate. These initially beneficial measures ultimately turn detrimental, as their resultant hypermetabolic state predisposes tissues to localized hypoxia (14). Furthermore, the aforementioned increased peripheral vascular tone may result in tissue ischemia via an inconsistent microcirculatory flow. In cases of severe hypovolemic shock, a significant inflammatory component coexists.
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Table 55.1 Shock classifications |
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Cardiogenic Shock
Cardiogenic shock is defined as inadequate tissue perfusion due to primary ventricular failure. Its incidence has remained fairly stable, and ranges from 6% to 8% (19,20,21,22,23). In the United States, it is the most common cause of mortality from coronary artery disease (19). Despite medical advances, it remains the number one cause of in-hospital mortality in patients experiencing a transmural myocardial infarction, with rates ranging between 70% and 90% (21,24). Other causes include myocarditis, cardiomyopathies, valvular diseases, and arrhythmias (Table 55.1).
The most common inciting event in cardiogenic shock is an acute myocardial infarction. Historically, once 40% of the myocardium has been irreversibly damaged, cardiogenic shock may result. From a mechanical perspective, decreased cardiac contractility diminishes both stroke volume and cardiac output (Table 55.2). These lead to increased ventricular filling pressures, cardiac chamber dilatation, and ultimately univentricular or biventricular failure with resultant systemic hypotension. This further reduces myocardial perfusion and exacerbates ongoing ischemia. The end result is a vicious cycle with severe cardiovascular decompensation. Similar to hypovolemic shock, a significant systemic inflammatory response has been implicated in the pathophysiology of cardiogenic shock.
Obstructive Shock
In obstructive shock, external forces compress the thin-walled chambers of the heart, the great vessels, or any combination thereof. These forces impair either the diastolic filling or the systolic contraction of the heart (Table 55.1). Large obstructive intrathoracic tumors, tension pneumothoraces, pericardial tamponade, and constrictive pericarditis limit ventricular filling, while pulmonary emboli and aortic dissection impede cardiac contractility.
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Table 55.2 Shock hemodynamic parameters |
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The hemodynamic parameters witnessed in obstructive shock include increases in central venous pressure and systemic vascular resistance and decreases in cardiac output and mixed venous oxygen saturation (Table 55.2). The pulmonary capillary wedge pressure and other hemodynamic indices are dependent on the obstructive cause. In pericardial tamponade, there is equalization of the right and left ventricular diastolic pressures, the central venous pressure, and the pulmonary capillary wedge pressure (increased). However, following a massive pulmonary embolus, right ventricular failure leads to increased right heart pressures and a normal or decreased pulmonary capillary wedge pressure.
Distributive Shock
Distributive shock is characterized by a decrease in peripheral vascular tone. Septic shock is the most common form. Additionally, distributive shock includes the other oft-quoted classes of shock including anaphylactic, neurogenic, and adrenal shock (Table 55.1).
Physiologically, all forms of distributive shock exhibit a decreased systemic vascular resistance (Table 55.2). Subsequently, these patients experience a relative hypovolemia as evidenced by a decreased (or normal) central venous pressure and pulmonary capillary wedge pressure. The cardiac output is initially diminished; however, following appropriate volume loading, the cardiac output is increased.
Cellular Alterations
All forms of shock, especially hemorrhagic and septic, induce a host response that is characterized by local and systemic release of proinflammatory cytokines, arachidonic acid metabolites, and activation of complement factors, kinins, and coagulation as well as hormonal mediators. Clinically, this is the systemic inflammatory response syndrome. Paralleling the systemic inflammatory response syndrome is an anti-inflammatory response referred to as the compensatory anti-inflammatory response syndrome. An imbalance between these responses appears to be responsible for increased susceptibility to infection and organ dysfunction (25,26,27,28,29).
Systemic Inflammatory Response Syndrome
In 1991, a consensus conference of the American College of Chest Physicians and the American Society of Critical Care Medicine defined systemic inflammatory response syndrome (SIRS) as a generalized inflammatory response triggered by a variety of infectious and noninfectious events (30). They arbitrarily established clinical parameters through a process of consensus. Table 55.3 summarizes the diagnostic criteria for systemic inflammatory response syndrome. At least two of the four criteria must be present to fulfill the diagnosis of systemic inflammatory response syndrome. Note, this definition emphasizes the inflammatory process regardless of its etiology. Subsequent studies have validated these criteria as predictive of increased intensive care unit mortality, and indicated that this risk increases concurrent with the number of criteria present.
The systemic inflammatory response syndrome is characterized by the local and systemic production and release of multiple mediators, including proinflammatory cytokines, complement factors, proteins of the contact phase and coagulation system, acute phase proteins, neuroendocrine mediators, and an accumulation of immunocompetent cells at the local site of tissue damage (31).
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Table 55.3 Clinical parameters of the systemic inflammatory response syndrome |
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Compensatory Anti-inflammatory Response Syndrome
Shock stimulates not only the release of proinflammatory mediators, but also the parallel release of anti-inflammatory mediators (26). This compensatory anti-inflammatory response is present concurrently with systemic inflammatory response syndrome (Fig. 55.1) (32). When these two opposing responses are appropriately balanced, the patient is able to effectively recover without incurring secondary injury from the autoimmune inflammatory response (25). However, overwhelming compensatory anti-inflammatory response syndrome appears responsible for postshock immunosuppression, which leads to increased susceptibility to infections and sepsis (26,31,33). With time, the systemic inflammatory response syndrome ceases to exist and the compensatory anti-inflammatory response syndrome is the predominant force.
Cytokine Response
Proinflammatory cytokines, tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) are key to the resultant inflammation (34,35). Secondary proinflammatory cytokines are released in a subacute fashion and include IL-2, IL-6, IL-8, platelet-activating factor (PAF), interferon-γ, endothelin-1, leukotrienes, thromboxanes, prostaglandins, and the complement cascade (34,36).
Interleukin-6 also acts as an immunoregulatory cytokine by stimulating the release of anti-inflammatory mediators such as IL-1 receptor antagonists and TNF receptors, which bind circulating proinflammatory cytokines (35). IL-6 also triggers the release of prostaglandin E2 (PGE2) from macrophages (35). Prostaglandin E2 is potentially the most potent endogenous immunosuppressant (35). Not only does it suppress T-cell and macrophage responsiveness, but it also induces the release of IL-10, a potent anti-inflammatory cytokine that deactivates monocytes (35). A listing of pro- and anti-inflammatory mediators may be found in Tables 55.4 and 55.5.
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Figure 55.1. Postinjury multiple organ failure occurs as a result of a dysfunctional inflammatory response. SIRS, systemic inflammatory response syndrome; MOF, multiple organ failure; CARS, compensatory anti-inflammatory response syndrome. |
Cell-mediated Response
Shock alters the ability of splenic, peritoneal, and alveolar macrophages to release IL-1, IL-6, and TNF-α, leading to decreased levels of these proinflammatory cytokines (35). Kupffer cells, however, have an enhanced capacity for production of proinflammatory cytokines. Cell-mediated immunity requires not only functional macrophage and T cells, but also intact macrophage–T-cell interaction (35). Following injury, human leukocyte antigen (HLA-DR) receptor expression is decreased, leading to a loss of antigen-presenting capacity and decreased TNF-α production. Prostaglandin E2, IL-10, and TGF-β all contribute to this “immunoparalysis” (25,35).
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Table 55.4 Proinflammatory mediators |
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Table 55.5 Anti-inflammatory mediators |
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T helper cells differentiate into either TH1 or TH2 lymphocytes. TH1 cells promote the proinflammatory cascade through the release of IL-2, interferon-γ (IFN-γ), and TNF-β, while TH2 cells produce anti-inflammatory mediators (25,35). Monocytes/macrophages, through the release of IL-12, stimulate the differentiation of T-helper cells into TH1 cells (35). Because IL-12 production is depressed following trauma, there is a shift toward TH2, which has been associated with an adverse clinical outcome (25,35).
Adherence of the leukocyte to endothelial cells is mediated through the up-regulation of adhesion molecules. Selectins such as leukocyte adhesion molecule-1 (LAM-1), endothelial leukocyte adhesion molecule-1 (ELAM-1), and P-selectin are responsible for polymorphonuclear leukocytes (PMNLs) “rolling” (25,37). Up-regulation of integrins such as the CD11/18 complexes or intercellular adhesion molecule-1 (ICAM-1) is responsible for PMNL attachment to the endothelium (25). Migration, accumulation, and activation of the PMNLs are mediated by chemoattractants such as chemokines and complement anaphylotoxins (25). Colony-stimulating factors (CSFs) likewise stimulate monocyte- or granulocytopoiesis and reduce apoptosis of PMNLs during SIRS. Neutrophil apoptosis is further reduced by other proinflammatory mediators, thus resulting in PMNL accumulation at the site of local tissue destruction (25).
Leukocyte Recruitment
Proinflammatory cytokines enhance PMNL recruitment, phagocytic activity, and the release of proteases and oxygen-free radicals by PMNLs. This recruitment of leukocytes represents a key element for host defense following trauma, although it allows for the development of secondary tissue damage (38,39,40,41). It involves a complex cascade of events culminating in transmigration of the leukocyte, whereby the cell exerts its effects (42). The first step is capture and tethering, mediated via constitutively expressed leukocyte selectin denoted L selectin. L selectin functions by identifying glycoprotein ligands on leukocytes and those up-regulated on cytokine-activated endothelium (42).
Following capture and tethering, endothelial E selectin and P selectin assist in leukocyte rolling or slowing (37,43,44,45,46,47,48). P selectin is found in the membranes of endothelial storage granules (Weibel-Palade bodies) (45). Following granule secretion, P selectin binds to carbohydrates presented by P selectin glycoprotein ligand (PSGL-1) on the leukocytes (25). In contrast, E selectin is not stored, yet it is synthesized de novo in the presence of inflammatory cytokines (43,44). These selectins cause the leukocytes to roll along the activated endothelium, whereby secondary capturing of leukocytes occurs via homotypic interactions.
The third step in leukocyte recruitment is firm adhesion, which is mediated by membrane-expressed β1- and β2-integrins (49,50,51). The integrins bind to ICAM, resulting in cell–cell interactions and ultimately signal transduction. This step is critical to the formation of stable shear-resistant adhesion, which stabilizes the leukocyte for transmigration (49,50,51).
Transmigration is the final step in leukocyte recruitment following the formation of bonds between the aforementioned integrins and immunoglobulin (Ig)-superfamily members (42). The arrested leukocytes cross the endothelial layer via bicellular and tricellular endothelial junctions in a process coined diapedesis (52). This is mediated by platelet-endothelial cell adhesion molecules (PECAMs), proteins expressed on both the leukocytes and intercellular junctions of endothelial cells (42).
Proteases and Reactive Oxygen Species
Polymorphonuclear lymphocytes and macrophages are not only responsible for phagocytosis of micro-organisms and cellular debris, but can also cause secondary tissue and organ damage through degranulation and release of extracellular proteases and formation of reactive oxygen species or respiratory burst (25,39,40,41,53,54,55). Elastases and metalloproteinases, which degrade both structural and extracellular matrix proteins, are present in increased concentrations following trauma (25). Neutrophil elastases also induce the release of proinflammatory cytokines (25).
Reactive oxygen species are generated by membrane-associated nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase, which is activated by proinflammatory cytokines, arachidonic acid metabolites, complement factors, and bacterial products (56,57). Superoxide anions are reduced in the Haber-Weiss reaction to hydrogen peroxide by superoxide dismutase located in the cytosol, mitochondria, and cell membrane (25). Hydrochloric acid is formed from H2O2 by myeloperoxidase, while the Fenton reaction transforms H2O2 into hydroxyl ions (25). These free reactive oxygen species cause lipid peroxidation, cell membrane disintegration, and DNA damage of endothelial and parenchymal cells (58,59,60). Oxygen radicals also induce PMNLs to release proteases and collagenase as well as inactivating protease inhibitors (61).
Reactive nitrogen species cause additional tissue damage following trauma (62). Nitric oxide (NO) is generated from L-arginine by inducible nitric oxide synthase (iNOS) in PMNLs or vascular muscle cells and by endothelial nitric oxide synthase in endothelial cells (62). Nitric oxide induces vasodilatation (25). Inducible nitric oxide synthase is stimulated by cytokines and toxins, whereas endothelial nitric oxide synthase (eNOS) is stimulated by mechanical shearing forces (62,63). Damage by reactive oxygen and nitrogen species leads to generalized edema and the capillary leak syndrome (62).
Complement, Kinins, and Coagulation
The complement cascade, kallikrein-kinin system, and coagulation cascade are intimately involved in the immune response to shock. They are activated through proinflammatory mediators, endogenous endotoxins, and tissue damage. The classic pathway of complement is normally activated by antigen–antibody complexes (Ig M or G) or activated coagulation factor XII (FXII), while the alternative pathway is activated by bacterial products such as lipopolysaccharide (64,65,66). Complement activation following trauma is most likely from the release of proteolytic enzymes, disruption of the endothelial lining, and tissue ischemia. The degree of complement activation correlates with the severity of injury. The cleavage of C3 and C5 by their respective convertases results in the formation of opsonins, anaphylotoxins, and the membrane attack complex (MAC) (64,65,66). The opsonins C3b and C4b enhance phagocytosis of cell debris and bacteria by means of opsonization (64,65). The anaphylotoxins C3a and C5a support inflammation via the recruitment and activation of phagocytic cells (i.e., monocytes, polymorphonuclear cells, and macrophages), enhancement of the hepatic acute phase reaction, and release of vasoactive mediators (i.e., histamine) (52,65). They also enhance the adhesion of leukocytes to endothelial cells, which results in increased vascular permeability and edema. C5a induces apoptosis and cell lysis through the interaction of its receptor and the MAC (52,65,66). Additionally, C3a and C5a activate reparative mechanisms (65). C1 inhibitor inactivates C1s and C1r, thereby regulating the classic complement pathway. However, during inflammation, serum levels of C1 inhibitor are decreased via its degradation by PMNL elastases (65).
The plasma kallikrein-kinin system is a contact system of plasma proteases related to the complement and coagulation cascades. It consists of the plasma proteins FXII, prekallikrein, kininogen, and factor XI (FXI) (67). The activation of FXII and prekallikrein is via contact activation when endothelial damage occurs exposing the basement membrane (67). Factor XII activation forms factor XIIa (FXIIa), which initiates the complement cascade through the classic pathway, whereas prekallikrein activation forms kallikrein, which stimulates fibrinolysis through the conversion of plasminogen to plasmin or the activation of urokinaselike plasminogen activator (uPA) (67). Tissue plasminogen activator (tPA) functions as a cofactor. Additionally, kallikrein supports the conversion of kininogen to bradykinin (67). The formation of bradykinin also occurs through the activation of the tissue kallikrein-kinin system, most likely through organ damage as the tissue kallikrein-kinin system is found in many organs and tissues including the pancreas, kidney, intestine, and salivary glands. The kinins are potent vasodilators. They also increase vascular permeability and inhibit the function of platelets (67).
The intrinsic coagulation cascade is linked to the contact activation system via the formation of factor IXa (FIXa) from factor XIa (FXIa). Its formation leads to the consumption of FXII, prekallikrein, and FXI while plasma levels of enzyme–inhibitor complexes are increased (25). These include FXIIa-C1 inhibitor and kallikrein-C1 inhibitor. C1 inhibitor and α1-protease inhibitor are both inhibitors of the intrinsic coagulation pathway (68,69).
Although the intrinsic pathway provides a stimulus for activation of the coagulation cascade, the major activation following trauma is via the extrinsic pathway. Increased expression of tissue factor (TF) on endothelial cells and monocytes is induced by the proinflammatory cytokines TNF-α and IL-1β (69,70,71). The factor VII (FVII)–TF complex stimulates the formation of factor Xa (FXa) and ultimately thrombin (FIIa) (25). Thrombin-activated factor V (FV), factor VIII (FVIII), and FXI result in enhanced thrombin formation (25). Following cleavage of fibrinogen by thrombin, the fibrin monomers polymerize to form stable fibrin clots. The consumption of coagulation factors is controlled by the hepatocytic formation of antithrombin (AT) III (25). The thrombin–antithrombin complex inhibits thrombin, FIXa, FXa, FXIa, and FXIIa (72). Other inhibitors include TF pathway inhibitor (TFPI) and activated protein C in combination with free protein S (72). Free protein S is decreased during inflammation due to its binding with the C4b binding protein (68,72).
Disseminated intravascular coagulation (DIC) may occur following shock. After the initial phase, intra- and extravascular fibrin clots are observed. Hypoxia-induced cellular damage is the ultimate result of intravascular fibrin clots. Likewise, there is an increase in the interactions between endothelial cells and leukocytes (68,69,70,73). Clinically, coagulation factor consumption and platelet dysfunction are responsible for the diffuse hemorrhage (68,71). Consumption of coagulation factors is further enhanced via the proteolysis of fibrin clots to fibrin fragments (68,71). The consumption of coagulation factors is further enhanced through the proteolysis of fibrin clots to fibrin fragments by the protease plasmin (25,69,74).
Acute Phase Reaction
The acute phase reaction describes the early systemic response following shock and other insult states. During this phase, the biosynthetic profile of the liver is significantly altered. Under normal circumstances, the liver synthesizes a range of plasma proteins at steady-state concentrations. However, during the acute phase reaction, hepatocytes increase the synthesis of positive acute phase proteins (i.e., C-reactive protein [CRP], serum amyloid A [SAA], complement proteins, coagulation proteins, proteinase inhibitors, metal-binding proteins, and other proteins) essential to the inflammatory process at the expense of the negative acute phase proteins. The list of acute phase proteins is in Table 55.6 (75,76).
The acute phase response is initiated by hepatic Kupffer cells and the systemic release of proinflammatory cytokines (76). IL-1, IL-6, IL-8, and TNF-α act as inciting cytokines (77,78). The acute phase reaction typically lasts for 24 to 48 hours prior to its down-regulation (35). IL-4, IL-10, glucocorticoids, and various other hormonal stimuli function to down-regulate the proinflammatory mediators of the acute phase response (35). This modulation is critical. In instances of chronic or recurring inflammation, an aberrant acute phase response may result in exacerbated tissue damage (35).
The major acute phase proteins include CRP and SAA, the activities of which are both poorly understood (79,80). C-reactive protein was so named secondary to its ability to bind the C-polysaccharide of Pneumococcus. During inflammation, CRP levels may increase by up to 1,000-fold over several hours depending on the insult and its severity (35). It acts as an opsonin for bacteria, parasites, and immune complexes; activates complement via the classic pathway; and binds chromatin (35). Binding chromatin may minimize autoimmune responses by disposing of nuclear antigens from sites of tissue debris (35). Clinically, CRP levels are relatively nonspecific and not predictive of posttraumatic complications. Despite this fact, serial measurements are helpful in trending a patient's clinical course (35).
Serum amyloid A interacts with the third fraction of high-density lipoprotein (HDL3), thus becoming the dominant apolipoprotein during acute inflammation (81). This association enhances the binding of HDL3 to macrophages, which may engulf cholesterol and lipid debris. Excess cholesterol is then utilized in tissue repair or excreted (35). Additionally, SAA inhibits thrombin-induced platelet activation and the oxidative burst of neutrophils, potentially preventing oxidative tissue destruction (35).
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Table 55.6 Acute phase proteins |
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Diagnosis of Shock
Early diagnosis of shock affords the patient the best possible outcome. The patient in overt shock with hypotension and tachycardia is relatively easy to diagnose. However, more often than not, shock presents in more insidious forms, whereby underrecognition and delay in treatment can lead to a poor outcome. Moreover, the concurrent presence of mixed shock states can confuse the picture. Diagnosis of shock relies on both basic history and physical examination skills, as well as more advanced technology available to the clinician.
Numerous clues in a patient's history may help alert the physician to the possibility of impending shock. Large fluid losses via traumatic or gastrointestinal hemorrhage, third spacing from intra-abdominal surgery or pancreatitis, prolonged dehydration from vomiting or diarrhea, or insensible losses from burns may very easily tip the patient into hypovolemic shock. A history of infection, presence of indwelling catheters, or recent surgery may be implicated in septic shock. Neurogenic shock occurs almost exclusively after trauma, although limited forms are seen with spinal anesthesia. History of prolonged steroid use, particularly in the elderly, may indicate adrenal shock in the patient with hypotension postoperatively. Exposures to drugs, transfusions, or other allergens should be sought to rule out anaphylactic shock. Recent myocardial infarction or cardiac intervention can lead to pump failure and cardiogenic shock. A detailed history is especially important for obstructive forms of shock, in which any intervention involving the chest can lead to either immediate or delayed compromise via cardiac tamponade or tension pneumothorax. Likewise, a history of deep venous thrombosis (DVT) or risk factors for thrombosis should alert the physician to the possibility of acute massive pulmonary embolism in the hypotensive patient.
Physical examination can provide more clues than just basic blood pressure measurements. As noted previously, hypotension alone is neither exclusive to shock nor absolute for a diagnosis, and therefore is only a small component of the physical examination. Certain findings may vary based on the type and timing of shock. The end result of any form of shock, however, is diminished end-organ perfusion. Therefore, any signs or symptoms of organ dysfunction should be considered as possible indicators of shock (Table 55.7). Often, the first sign of shock manifests as mental status changes, whether excitatory or somnolent in nature. The patient may appear diaphoretic and clammy in cardiogenic shock or warm and dry in early distributive shock. Heart rate may also be variable, with tachycardia compensating for diminished cardiac output in the patient with intact sympathetic drive. Vasoplegic shock such as neurogenic or adrenal (or in the β-blocked patient) may not have the compensatory increase in heart rate normally seen, and may itself provide a clue as to the type of shock. Tachypnea is almost universally seen, as the body tries to buffer the lactate produced in a state of tissue hypoxia. The kidneys provide a sensitive measure of adequate end-organ perfusion, as manifested by low urinary output. Cardiogenic shock has its own specific physical findings including increased venous jugular distension, acute pulmonary edema, and new murmurs or arrhythmias.
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Table 55.7 Clinical recognition of shock |
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Various modalities for evaluating shock may be used either alone or in combination. Pooling data from multiple sources, however, is often required to get an adequate picture of shock resuscitation. Basic laboratory studies such as lactate level, base deficit, hemoglobin, creatinine, and cortisol may help provide evidence of or reason for shock. Likewise, a more advanced evaluation of shock may include echocardiogram, central venous pressure monitoring, tissue oxygenation and capnography, or advanced methods of determining cardiac output. Advantages and disadvantages of these more advanced modalities will be discussed later within the context of shock monitoring.
Management of Shock
Optimal management of shock depends first and foremost on early recognition of the syndrome and correct determination of its etiology. Ongoing assessment of interventions is likewise paramount, as adjustments can be made in type and degree of specific therapies. The underlying goal of shock management is to improve tissue oxygen perfusion. This may be accomplished by manipulating one or multiple physiologic parameters involved in oxygen delivery and extraction.
Forms of obstructive shock require the most prompt diagnosis, as continued mechanical impairment can be rapidly fatal. Conversely, adequate treatment of these etiologies can be just as rapid. Performing needle decompression for a tension pneumothorax or pericardiocentesis for cardiac tamponade can be all that is required for these forms of shock. Pharmacologic and fluid support can be used as an adjunct while relief of mechanical obstruction is ongoing.
Management of distributive and hypovolemic forms of shock likewise involves attempted source control early in the diagnosis. This may be in the form of hemorrhage control, removal of infected tissue, or avoidance of sources of anaphylaxis. Once the inflammatory cascade has set in, vasoactive medications are often used in addition to fluid provision to increase perfusion.
Treatment of cardiogenic shock in particular warrants keen understanding of the physiologic process. Currently, initial therapy of cardiogenic shock consists of volume optimization, control of arrhythmias, use of the intra-aortic balloon pump, addition of vasopressors, and early revascularization in primary myocardial ischemia, with addition of inotropes only when these measures fail (82).
Classically, all forms of shock are treated in some capacity with a combination of fluids and vasoactive agents. Deliberation is ongoing regarding the dosing and selection of these modalities for resuscitation, and will be examined in greater detail.
Fluid Resuscitation
The initial treatment for all forms of shock is fluid administration. Provision of fluid helps restore perfusion and replace volume lost via hemorrhage, capillary leak, or redistribution. Historically, Blalock demonstrated reversal of shock state induced by tissue injury by using vigorous resuscitation of intravascular volume (83). As such, the use of fluids for shock management has become a cornerstone of therapy. Intravenous fluid is readily available, inexpensive, and easy to administer, and has low intrinsic morbidity. The etiology of shock and response to fluid will further dictate continued use of volume as primary therapy; however, all forms of shock potentially benefit from an initial fluid challenge (84). There are endless means of administering fluid given a particular clinical setting. General guidelines can be followed; however, considerable debate exists regarding the nuances of this most basic therapy. Deliberation should be given to the method of delivery, timing of administration, type of fluid, and volume of administration. Complications of fluid resuscitation, as well as emerging research in this area, should also be considered.
Route of Administration
The setting of shock dictates administration of fluid primarily via the intravenous route. Factors such as endotracheal intubation, mental status, adynamic or mechanical ileus, rapidity of response, and questionable absorption from the gastrointestinal tract preclude the enteric route as a primary vessel for fluid resuscitation in most cases. Intravenous access may be in the form of a peripheral or central venous catheter. Although the type of shock may guide the choice of catheter (i.e., an introducer catheter for a rapid infusion system or anticipated pulmonary artery catheter placement in cardiogenic shock, or a triple lumen for anticipated vasopressor therapy), the dictum of “two large-bore peripheral IVs” cannot be overstated (85). As per Poiseuille's Law, width and length of the catheter dictates flow; therefore, a long, narrow, peripherally inserted central catheter will be of little utility when infusing a large bolus of fluid quickly. In the severely volume depleted patient with collapsed veins, obtaining percutaneous venous access can prove difficult. Saphenous vein cut-downs or interosseus access, particularly in the trauma patient, can provide means of fluid administration until more permanent intravenous access can be obtained.
Timing of Administration
As stated previously, fluid is the initial therapy in all forms of shock. For forms of hypovolemic shock in particular, the concept of early restoration of intravascular volume to prevent circulatory collapse has long been recognized. In the hemorrhagic patient, aggressive volume resuscitation combined with source control may limit or prevent a state of irreversible shock, or the more currently described “lethal triad” of hypothermia, coagulopathy, and acidosis (86,87). The importance of the timing of volume loading is also being recognized in other forms of shock, particularly in sepsis (88). Amplification of the previously described immune response can potentially be avoided if perfusion is restored early in the pathophysiologic process (89). Often the resuscitation process begins in the prehospital phase, with ambulance personnel administering combinations of crystalloid and colloids en route. In this setting, timing of fluid resuscitation is given due attention. Delayed aggressive fluid resuscitation once the patient is already in the intensive care unit, and therefore later in the course of shock, as well as excessive doses of dobutamine (5–200 µg/kg/minute) can be detrimental (90).
Continued administration of fluid alone, however, should be based on the patient's underlying pathology. While vigorous fluid provision may be life sustaining in certain patients, an equal measure could prove counterproductive in others. Ongoing replacement of fluid should be based on both direct and insensible losses, keeping in mind the huge potential third-spacing loss into the interstitium. Again, the idea of pushing fluid beyond the initial phases of ischemia may propagate reperfusion injury, emphasizing early recognition and treatment of shock.
Volume of Resuscitation
Although there is general consensus regarding the timing of administration of fluids, there is little information to support the optimum volume to be given. Guidelines reference various quantities for crystalloid administration, including 500 mL, 1,000 mL, or the more universal 20 mL/kg bolus. The speed of the bolus likewise varies, although common sense dictates that rapid administration is preferred in the setting of hypotension.
Continued fluid administration beyond an initial bolus relies more on patient response than on arbitrary numbers. Physical examination characteristics such as jugular venous distension, skin turgor, and basic vital signs may give clues to volume state, but are notoriously subject to interpretation. The examiner is often misled by the appearance of gross edema, insomuch that it has no bearing on effective extracellular fluid volume in the patient with capillary leak. Efforts to measure intravascular volume status should be made, but these values should be interpreted in the context of cardiac output and ongoing therapy. Tools used to measure volume status include central venous pressure, pulmonary artery occlusion pressure, esophageal Doppler, and echocardiography, each with its own strengths and weaknesses (91,92,93,94). There is renewed interest in the actual measurement of blood volume rather than relying on surrogate markers (see Blood Volume chapter).
The amount of fluid required to achieve these goals will vary with patient size, cardiac status, type of fluid given, and timing and type of shock. Prominent guidelines direct the clinician to volume load to a central venous pressure of 8 to 10 mm Hg or a pulmonary capillary wedge pressure of >12 mm Hg prior to initiating vasopressor therapy for shock (95,96). Ideal volumes for shock resuscitation continue to be debated. In fact, restrictive fluid therapies for resuscitation have emerged in an effort to reduce the cardiac, wound healing, and pulmonary complications associated with large crystalloid infusions (97).
Fluid therapy in excess may lead to numerous complications. The coagulation profile may be altered secondary to dilution with excessive crystalloid infusion (98). Red blood cell mass is also diluted, and while this may not have a net effect on oxygen delivery, it may complicate interpretation of bleeding states. Tissue edema is also a consequence of volume resuscitation, and of these, the pulmonary component is most visible to the practitioner. Lung edema will manifest most readily with crystalloid therapy in the setting of hypoproteinemia—a common state in the shock patient (99). While some degree of pulmonary edema can be tolerated, critical hypoxia often threatens the recovery of patients who survive via massive volume resuscitation. The added mechanical impairment of ventilation induced by abdominal compartment syndrome, also seen with large volume resuscitation, further exacerbates the situation (100).
Types of Fluid
Considerable debate abounds regarding the types of fluid to be administered for shock resuscitation. The physiologic makeup of the human body allows for movement of fluids and solutes across compartments, specifically between the interstitium and intravascular space. Hydrostatic and oncotic forces dictate this movement at the capillary level, as explained by the Starling equation:
Jv = Kf{(Pc - Pi) - σ(πc - πi)}
where Jv is the net fluid flux (mL/minute). (Pc - Pi) is hydrostatic pressure difference between capillary (c) and interstitium (i), and (πc - πi) is the oncotic pressure difference between the capillary and interstitium, Kf is the filtration coefficient for that membrane (mL/minute per mm Hg), and is the product of capillary surface area and capillary hydraulic conductance. σ is the permeability factor (i.e. reflection coefficient) with one being impermeable, and zero being completely permeable. Imbalance in the forces—whether decreased oncotic pressure from hypoalbuminemia, increased hydrostatic pressure from heart failure, or decreased protein reflection coefficient with sepsis—occurs often with shock states. The choice of fluid type therefore requires appropriate knowledge of the characteristics of the fluid, as well as the pathophysiology of the shock state.
Crystalloids
Invariably, the workhorse of shock resuscitation is isotonic crystalloid. Composed of varying amounts of electrolytes and sugar, crystalloids are inexpensive, require no special tubing or preparation, and pose little to no allergy or transfusion risk. Almost every patient receives some form of intravenous crystalloid upon entering a hospital with little consequence as to the type given due to the low volumes given on average.
Crystalloids used in shock resuscitation are generally categorized as isotonic or hypertonic, describing the in vivo tonicity of the fluid. Typical isotonic crystalloids used are normal saline, lactated Ringer solution, or other commercially available combinations of electrolytes with sodium as the primary ion. Lacking protein components, the isotonic crystalloids readily distribute to the extracellular fluid compartment and will require larger volumes of infusion to maintain intravascular filling. Traditional philosophy dictates that a threefold volume of crystalloid to colloid is required for intravascular expansion. This ratio has recently been debated, however, and may actually be closer to a ratio of 1.5:1 when comparing crystalloid to 5% albumin (101).
Normal saline and lactated Ringer solution compromise the majority of isotonic crystalloid used for shock. Normal saline simply provides sodium with an equal amount of chloride for buffer. Hypernatremia and hyperchloremic metabolic acidosis are therefore potential consequences of continued normal saline administration (102). While the tonicity is essentially the same, the electrolyte composition of lactated Ringer is considered more physiologic, with inclusion of potassium and calcium, and reduction in chloride concentrations. Conversion of the lactate in lactated Ringer to bicarbonate in theory provides a buffer to metabolic acidosis in the patient with adequate liver function. Current compositions of lactated Ringer contain a racemic mixture of D- and L-lactate in solution. The presence of this D-isomer has been implicated as a potentiator of neutrophil activation in large volume infusions (103). Likewise, the presence of a large lactate load has been implicated in promoting respiratory acidosis in the spontaneously breathing patient (104).
Hypertonic Crystalloid
Combining the convenience of crystalloid with the tonicity of colloids, hypertonic saline has emerged as an important tool in shock resuscitation. Hypertonicity of the sodium concentration promotes influx of fluid from the interstitial space. As such, hypertonic saline is advantageous for rapid, low-volume resuscitation for hypovolemic shock, particularly in situations where resources may be scarce. Hypertonic solutions also favorably impact immune modulatory function. Studies particularly investigating hemorrhagic shock have found a decrease in neutrophil activation, and up-regulation of anti-inflammatory cytokine production with use of hypertonic saline (105,106).
While relatively safe compared to colloid infusion, the administration of high concentrations of sodium for volume resuscitation carries the concern for hypernatremia and hyperosmolarity. The neurologic consequences of rapid sodium flux are well known; however, these have not been described in the hypertonic saline resuscitation population. Compromise of renal function is likewise feared with high sodium and osmolar loads. While some patient populations exhibit increases in creatinine without clinical renal dysfunction, studies in the burn population support this trepidation regarding hypertonic saline (107,108). Reports of hypokalemia, metabolic acidosis, and impaired platelet aggregation have also been documented with hypertonic saline use (109).
Colloids
Pertaining to volume resuscitation, colloids generally consist of fluids that have a higher molecular weight based on composition consisting of protein, starches, or cells. These components increase the cost of colloids, make them susceptible to shortage, and mandate specialized tubing for delivery. Possibility for transfusion reaction is increased as some of these compounds are derived from blood products. Likewise, allergic reactions can be noted with some of the synthetic formulations.
Conceptually, colloids more rapidly expand intravascular volume owing to their higher oncotic pressure. This effect may not necessarily persist beyond a few hours, especially in the critically ill patient in which capillary permeability is altered (110). In addition to more rapid volume expansion with less fluid infusion, this same increase in intravascular oncotic pressure has prompted the employment of colloids with the intent to reduce or prevent secondary edema. This mechanism does not hold in critical illness, particularly for lung edema in which dysfunction is unrelated to capillary oncotic pressure in shock (111).
Despite these findings, colloids are an important component of shock resuscitation. Integration of colloids into most protocols usually follows initial infusion of crystalloids or while awaiting blood product transfusion (112).
Albumin
First used for fluid resuscitation during World War II, albumin is a colloid derived from pooled human plasma and diluted with sodium. Preparations consist of 5% or 25% solution in quantities of 250 to 500 mL or 50 mL, respectively. As a blood product derivative, albumin is subject to disadvantages faced by other donated products—namely periodic shortages, high acquisition costs, and refusal based on religious grounds. While transmission of viruses or other blood-borne diseases is theoretically a risk, only a few cases have been reported. Like any resuscitation fluid, patients are subject to sequelae of volume overload if infusion amounts are not monitored.
While indications for albumin use are broad, proven benefit to particular therapies is increasingly narrow. Numerous studies detailing poor prognosis with low serum albumin levels in critically ill patients prompted attempts to improve survival with intravenous supplementation (113,114,115). Compared with other colloid administration, albumin itself has no benefit in this patient population (116,117).
Albumin as a resuscitation fluid likewise has come under scrutiny. Previously, studies investigating albumin as a volume expander have been underpowered, prompting meta-analysis as the primary statistical measure of its worth. An initial Cochrane review comparing albumin to crystalloid examined 24 studies and found a 6% increase in absolute risk of death with albumin infusion (118). To confuse matters, subsequent meta-analysis of 55 studies bore out no difference in mortality between albumin and crystalloid for resuscitation (119). In 2004, the Saline versus Albumin Fluid Evaluation (SAFE) trial prospectively compared albumin to isotonic crystalloid for fluid resuscitation in a mixed intensive care unit population (101). Results showed no difference in morbidity or mortality overall with albumin use. Advocates for albumin hail this study as an indicator that its use poses no harm as previously indicated. Opponents likewise cite the study, but as an indicator that there is no advantage to using albumin for volume resuscitation. A revised Cochrane analysis following the SAFE study again reported no advantage to albumin infusion for hypovolemic patients (120). Results must be interpreted in light of the heavy weight thus given to the SAFE trial in this review.
Starches
In an attempt to retain the oncotic properties of albumin while decreasing cost and transfusion risk, synthetic colloid polymers have been developed for use in volume resuscitation. As one of the primary synthetic colloids, starches, of which hydroxyethyl starch is most popular, consist of polymers of amylopectin. Like other colloids, hydroxyethyl starch owes its main advantage to providing appropriate volume expansion with less infusion than that of crystalloids. Initial formulations of hydroxyl ethyl starch (HES) included high-molecular-weight moieties, accounting for an increased risk of coagulation and renal disturbances associated with their use (121,122,123). Lower-molecular-weight HES solutions have since been developed, with resultant fewer negative effects on bleeding (124).
Of particular interest in colloid resuscitation, hydroxyethyl starch has favorable effects both on vascular permeability and inflammatory properties in animal models. Reduced pulmonary capillary leakage has been described with hydroxyethyl starch use in comparison to crystalloid and gelatin resuscitation (125,126). While numerous studies have illustrated down-regulation of proinflammatory cytokines with hydroxyethyl starch use, some of these results may be an effect of the efficiency of volume resuscitation, and not necessarily the fluid itself (127,128,129). How this anti-inflammatory effect is translated into clinical outcomes is the subject of ongoing research.
Dextran
Among the lower-molecular-weight colloids, dextran consists of large glucose polymers of varying sizes. As a colloid, it does expand intravascular volume; however, the smaller-sized molecules redistribute quickly, giving it a short half-life. It improves microcirculation by decreasing blood viscosity and therefore primarily is used in situations where platelet adherence and red blood cell aggregation is discouraged, such as postcarotid endarterectomy. As such, the risk of bleeding limits their use as a primary resuscitation fluid. The combination of dextran with other fluids, most notably hypertonic saline, limits the adverse effects of dextran alone. Conceptually, the combination of the two would increase the amount and duration of oncotic pressure in the intravascular space compared with either alone. In animal models, the use of hypertonic saline plus dextran-70 is associated with improved hypovolemic resuscitation when compared to hypertonic saline alone. This effect has not translated well into human clinical studies, in which the combination shows no benefit over hypertonic saline alone in prehospital resuscitation (130,131). The administration of dextran plus hypertonic saline is considered safe, however, resulting in fewer complications than crystalloid in trauma resuscitation (132). Additional studies are needed to establish appropriate use of dextrans as they apply to shock resuscitation.
Gelatins
Gelatins consist of moderate-size molecular weight colloids derived from porcine sources. A perceived high level of antigenicity limits their use, particularly in the United States where they are not Food and Drug Administration (FDA) approved. The absolute incidence of anaphylaxis, however, is only 0.066% (133). Modified fluid gelatin is the most common colloid used worldwide, owing to its otherwise favorable side effect profile and inexpensive production costs. In comparison to crystalloids for shock resuscitation, gelatins provide superior volume expansion without additionally noted adverse effects of bleeding or pulmonary dysfunction (134,135,136). As gelatins gain approval throughout worldwide markets, further research is emerging to investigate their utility in shock resuscitation.
Blood Products
Provision of blood products as either a primary or adjunctive resuscitation fluid should be considered carefully. The risk of infection, immunosuppression, and transfusion reaction are well known (137,138). The cost of preparation, as well as short supply, also limits their use.
Blood products do provide an effective source of colloid for increasing oncotic pressure, but should only be used when secondary properties of the specific product are sought. Transfusing packed red blood cells, while increasing oxygen-carrying capacity, does not necessarily translate into improved survival in all situations. Targeting a specific hemoglobin concentration in critically ill patients may only benefit those with active coronary artery disease; otherwise, a restrictive transfusion policy to a hemoglobin level of 7.0 g/dL is safe (139). Specifically, in septic shock, the administration of red blood cells may benefit a subset of patients who have a low mixed venous oxygenation and low hemoglobin level after volume resuscitation with crystalloids (88). Measurement of red cell volume may be a better guide to blood transfusion rather than hemoglobin or hematocrit since the hemoglobin/hematocrit reflect red cell volume in relationship to plasma volume.
Fresh frozen plasma, cryoprecipitate, and platelets also have utility as colloids based on the coagulation profile. Each has the same adverse transfusion profile as administering red blood cells, however, and should only be used in combination with packed red blood cells for hemorrhagic shock, or in the setting of the coagulopathic patient requiring fluid resuscitation. Standard teaching of administering 1 unit of plasma for every 3 units of red blood cells has recently been challenged. More advanced hemorrhagic shock resuscitation requires a one-to-one ratio of plasma to red blood cell administration, with addition of platelets and cryoprecipitate based on laboratory evaluation (140).
Fluid Choices for Different Classifications of Shock
Debate abounds regarding appropriate use of crystalloids versus colloids in various shock states as illustrated by the numerous meta-analyses found in the literature. Differences in mortality are illustrated when subgroup analysis is performed; therefore, fluids for shock resuscitation can be examined based on underlying pathophysiology of the shock state. The two most studied categories are trauma-induced hemorrhagic shock and septic shock.
Hemorrhagic Shock Resuscitation
Current guidelines for hemorrhagic shock emphasize mixed crystalloid and colloid provision until blood products (either type specific or O negative) are available. Aggressive use of crystalloids during the Vietnam conflict resulted in improved mortality and reduction in renal failure, but also led to the emergence of acute lung injury and acute respiratory distress syndrome in the trauma population. Extensive use of crystalloids for trauma followed, with the popular concept of pushing fluids beyond supranormal resuscitation goals (141). Meta-analyses at the time provided further encouragement for this practice, with mortality favoring crystalloids over colloids in the trauma population (142). The advancement of damage control surgery led to improved outcomes while compensating for the accepted postoperative edema by leaving the abdomen open. Consequences of this large-volume approach are becoming more evident, with adverse cardiac, pulmonary, coagulation, and immunologic effects documented with massive crystalloid infusion (143).
The advent of synthetic colloids, as well as further research regarding hypertonic saline use, renewed interest in the concept of small-volume resuscitation, particularly on the battlefield. Hypertonic saline, dextran, and hydroxyethyl starch have the advantages of long shelf life, convenient preparation, and small aliquot volumes for equal resuscitation. This is particularly important in combat situations, where low-bolus 7.5% hypertonic saline is now the standard for initial resuscitation (144). Current battlefield practice has translated to civilian trauma, with the use of these compounds in the prehospital setting (132).
Hypotensive resuscitation in the hemorrhagic patient is an additional emerging concept. This strategy may be applied to the patient in whom mechanical control of bleeding has not been achieved—whether in traumatic injury, aortic aneurysm rupture, or gastrointestinal bleed (145,146,147). Measures to raise blood pressure, particularly with fluid administration, may be counterproductive. In the penetrating thoracic trauma patient, early administration of large volumes of crystalloid has been shown to increase bleeding and subsequent mortality (148). This is a very specific patient population, however, and further examination of fluid administration by a recent Cochrane review provided insufficient evidence for or against the use of early, large-volume resuscitation in hemorrhagic shock (149).
Septic Shock Resuscitation
Resuscitation for septic shock is currently a highly investigated topic, with numerous guidelines and protocols taking the forefront in hospital initiatives. While a large number of investigations seek the optimal pharmacologic therapy, fluid management is still a source of debate. The inflammatory process and resulting capillary leak inherent to sepsis creates an additional variable when considering which fluids to administer. The logical choice would therefore be a colloid with the idea of maintaining higher intravascular oncotic pressure. When comparing filling pressures and oxygen delivery, however, there is no appreciable difference between colloids and crystalloids, except in amount of fluid required. Despite delivering two to three times more fluid with crystalloid, patient outcomes are the same (150). With the exception of small subgroup analyses indicating a trend toward improved outcome with albumin resuscitation (SAFE), there are insufficient data to definitively support colloids over crystalloids for septic shock resuscitation. As such, large practice guidelines such as the Surviving Sepsis Campaign either incorporate a combination of fluids or simply leave this choice to the practitioner (95).
Pharmacotherapy in Shock
When incorporating pharmacotherapy for treatment of shock, catecholamines classically come to mind. Sympathomimetics are still the standard for raising the mean arterial pressure (MAP) in the hypotensive patient who is not responding to fluids. Shock is not hypotension alone, however, and other agents can be used to compensate for the diminished tissue perfusion defined by this syndrome. Drugs used for shock will be examined here by the classifications of vasopressor, inotrope, and miscellaneous, although these categories may overlap to a degree. An overview of the more common sympathomimetics is listed in Table 55.8.
Vasopressors
End-organ arterial autoregulation generally compensates for decreased MAP within a certain range. Local vasoconstriction and vasodilatation may be unable to overcome extremes of perfusion. Administering vasopressors may help improve MAP and therefore improve tissue perfusion by redistributing cardiac output. The venous compartment also benefits from vasopressor therapy by decreasing compliance and therefore improving effective volume.
Vasopressors are generally given after an initial fluid bolus has failed or had marginal effect. Within the context of avoiding the consequences of excessive fluid administration, vasopressors may help limit volumes of fluid given; however, peripheral and end-organ vasoconstriction have their own adverse effects. Striking the balance between volume and pressors in the context of timing and type of shock is therefore a key component to resuscitation. With early recognition of shock, vasopressors can often be avoided by restoration of volume.
Classifications of vasopressors consist of natural and synthetic versions of catecholamines (Table 55.8). Each pressor has its own advantage and disadvantage, although practitioners generally use only a few common agents in their armamentarium. The limited number of randomized controlled trials for in vivo use of pressors makes selection often one of familiarity, availability, and current trends (151). Often, surrogate end points serve as the basis for judging responsiveness to a drug agent, a strategy that may or may not manifest in improved patient outcome. There are some general recommendations, however, for certain drug regimens in particular types of shock.
Norepinephrine
A naturally occurring vasopressor, norepinephrine is released by the postganglionic adrenergic nerves in response to stress. It has potent α-adrenergic effects, with less potent β1 stimulation. The α-adrenergic effects lead to increased systolic and diastolic pressure, with the addition of increased venous return via decreasing venous capacitance. This subsequently leads to increased cardiac filling pressure. Effect on the coronary arterial flow is enhanced via the increase in diastolic blood pressure. The β-adrenergic effects lead to increased chronotropic function, although this is limited by the baroreflex of vasoconstriction, resulting in zero net change in heart rate. Enhanced inotrope stimulation and stroke volume are likewise negated by an increase in left ventricular afterload, leading to a limited increase in cardiac output.
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Table 55.8 Sympathomimetic drugs |
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Historically, the exaggerated peripheral vasoconstrictive properties of the drug have promoted a level of distrust leading to the often quoted “Leave 'em Dead.” These fears are largely unfounded at indicated dosing ranges, and use of the drug may actually enhance renal function (152). The drug is safe and easily titratable, and lacks the tachyarrhythmic properties of other frequently used agents for shock. A resurgence in the use of norepinephrine has occurred with the recognition of its beneficial properties, and is now recommended as the first-line vasopressor in the treatment of septic shock (95). Norepinephrine is also useful for other forms of distributive shock and as a temporizing agent in cardiogenic shock.
Epinephrine
Epinephrine is the major physiologic adrenergic hormone of the adrenal medulla and represents the maximum in catecholamine stimulation. The agent potently stimulates α1 receptors with resultant marked venous and arterial vasoconstriction. These changes may lead to detrimental effects on regional blood flow, particularly on mesenteric and renal vascular beds. β effects lead to increased heart rate and inotropism. Due to counter effects of β2 vasodilation, the diastolic blood pressure is only slightly affected, with a lesser degree of increase in MAP than norepinephrine. Stimulation of β2 receptors and blunting of mast cell response also makes epinephrine highly effective for anaphylaxis. Epinephrine has dose-dependent effects, with very low doses stimulating primarily β receptors. This property makes epinephrine attractive as a primary inotrope; however, the range of that particular low dose varies with each patient and titration may prove dangerous. In general, the use of epinephrine is considered a drug of last choice or in extreme situations such as cardiac arrest.
Dopamine
Dopamine has long been the workhorse in shock resuscitation, although the preponderance of its use has slowed with increasing evidence of deleterious effects (153). As the hormone precursor of norepinephrine and epinephrine, dopamine stimulates α, β, and dopaminergic receptors in a dose-dependent fashion. This results in mixed vasoconstrictive, inotropic, chronotropic, and vasodilatory effects.
Classically, “renal-dose” dopamine ranges from 0 to 5 µg/kg/minute and results in vasodilation of renal and mesenteric vascular beds via dopamine receptors. Although this stimulation results in diuresis, the overall effect on renal function and need for renal replacement therapy is unchanged and may actually be worsened (154). Conversely, at high doses of 10 to 20 µg/kg/minute, α effects predominate, resulting in almost pure vasoconstriction. β-Receptor stimulation at middle doses of 5 to 10 µg/kg/minute results in increased inotropic and chronotropic function leading to increased MAP similar to norepinephrine. However, without simultaneous activation of α receptors at this dose, vasodilatation by dopamine receptors is unopposed and reflex tachycardia may predominate. These dose-related effects are simply a guideline, as responsiveness to titration varies patient to patient, particularly in critical illness.
In the past, dopamine has been postulated as the first inotrope of choice in cardiogenic failure with hypotension (155). More recent recommendations, however, identify sympathetic inotropes such as dopamine as increasing mortality when used for primary left heart failure (156). Likewise, in septic shock, norepinephrine has a more reliable dosing profile and has demonstrated more beneficial outcomes compared to dopamine (157).
Phenylephrine
Phenylephrine is a rapidly acting vasopressor with a short duration of action and pure α1 stimulation. As such, it increases MAP primarily by increasing systemic vascular resistance. Reflex bradycardia may develop; therefore, it is occasionally used for distributive shock in the face of tachyarrhythmias. This same unopposed increase in vascular resistance also impairs cardiac output in the patient with impaired pump function. The use of phenylephrine has since fallen out of favor, and is generally reserved for the pregnant patient with shock for whom other vasopressors may be detrimental.
Inotropes
As a group, inotropic agents augment cardiac output by increasing contractility. Sources of left ventricular failure are many, including exacerbation of congestive heart failure, acute infarction, or sepsis-related cardiomyopathy. Although improvement of pump function in these situations seems logical as a primary therapy, no literature supports any positive benefit on mortality when inotropes are used. This may be particularly true when the agents are used in a long-term fashion. As with other forms of pharmacotherapy for shock, inotropes should be used only in a short-term situation until underlying pathology can be corrected. Prolonged use can increase myocardial work and exacerbate ischemia.
The classic paradigm of cardiogenic shock with resulting reflexive increase in afterload has been recently challenged, with recognition of an inflammatory component to acute infarction. This inflammatory state results in vasodilation, making particular inotropes less useful for restoration of tissue perfusion (158). Likewise, the concept of pushing oxygen delivery to supranormal levels with excessive amounts of dobutamine (5–200 µg/kg/minute) to enhanced cardiac output has been largely abandoned, as it may worsen outcome (90).
Dobutamine
Dobutamine is a synthetic adrenergic agent derived from dopamine. Current formulation of the drug is as a racemic mixture, with the L-isomer stimulating α1 and the D-isomer stimulating β1 and β2receptors. This combined stimulation results in a net increase in inotropic and chronotropic parameters. In theory, vasodilatory (β2) effects are limited, making dobutamine useful in increasing pump function without lowering blood pressure. In practice, some degree of vasodilation is encountered, resulting in decreased blood pressure and tachycardia acutely. With increase in cardiac output, however, the blood pressure generally corrects to normal. For this reason, adequate volume loading prior to initiation of dobutamine is emphasized. Likewise, the lack of increase in blood pressure makes dobutamine a poor selection as monotherapy in primary cardiogenic shock. Currently, dobutamine is the standard inotrope used in noncardiogenic shock (such as sepsis) when cardiac contractility is compromised (159).
Dopexamine
Another of the synthetic catecholamines, dopexamine uniquely stimulates β2 and dopaminergic receptors with no α-adrenergic effects and minimal β1 stimulation. Resultant effects therefore include vasodilation and positive inotropy via increased stroke volume. The agent may also exert indirect vasoactive changes via inhibition of norepinephrine reuptake at the postganglionic synapse (160). Dopexamine is often compared to dobutamine in trials, with the possible benefit of improved splanchnic perfusion (161).
Isoproterenol
With practically no α-adrenergic stimulation, isoproterenol functions as a pure β agonist. β1 stimulation results in increased stroke volume and heart rate, while β2 stimulation induces vasodilatation. The net result is that of enhanced cardiac output without the benefit of distribution of blood flow. Increased myocardial oxygen consumption exacerbated by lack of coronary perfusion due to decreased diastolic pressures may lead to cardiac ischemia. Use of isoproterenol is generally limited to β-blocker overdose or in the atropine-resistant transplanted heart.
Milrinone
A novel agent in vasoactive treatment, milrinone is a synthetic phosphodiesterase III inhibitor. Reduction in this enzyme results in an increase in cyclic adenosine monophosphate (cAMP), a modulator of myocardial contractility. Additional increase in cAMP results in vasodilation, with the net effect of increasing cardiac output and tachycardia at higher doses. This vasodilatory effect may decrease effective left ventricular preload, but may also benefit afterload reduction, reducing cardiac work. In the hypotensive patient, this vasodilation may not be tolerated acutely. While not recommended in vasodilatory shock for this reason, milrinone may be used in specific situations for cardiogenic shock. These include advanced heart failure in patients awaiting heart transplant, in acute decompensation of congestive heart failure (CHF) on standard medications, and in patients in cardiogenic shock with long-term β-blocker use (162).
Levosimendan
Levosimendan is the singular drug in a new class of inotropic agents. Primary mechanism of action is by increasing the sensitivity of troponin C for calcium without enhancing influx of calcium itself. The advantage of this physiology would be increased contractility without risk of arrhythmias. The drug shows promise as a new agent and is currently undergoing further investigation (163).
Miscellaneous Pharmacologic Therapy
Numerous other noncatecholamine agents have been used for various shock states. These may work by treating the symptoms, such as increasing vascular tone, or by treating the source depending on the type of shock. Examples of drug therapy for source treatment include antibiotics for septic shock, histamine blockers for anaphylactic shock, or somatostatin analogues for gastrointestinal hemorrhagic shock (164,165,166). Septic shock, in particular, is a syndrome for which the “magic bullet” is constantly sought. Numerous drugs under investigation seek to manipulate the inflammatory cascade at multiple levels. The agents reviewed here are more commonly incorporated into shock management.
Vasopressin
Vasopressin is an attractive hormone for use in shock states not only for its vasoconstrictive properties, but also for its antidiuretic effects. As a noncatecholamine vasopressor, it acts via V1 receptors to restore vascular tone. Catecholamine responsiveness may decrease over time during severe sepsis, possibly due to an increase in nitric oxide–induced vasodilatation. This alternate mode of action makes vasopressin a logical treatment for catecholamine-resistant shock. Studies of hemorrhagic and vasodilatory shock have demonstrated a relative deficiency of vasopressin. For this reason, vasopressin is often used at a low dose without titration, in the manner of hormone replacement. Potentiation of adrenergic agents makes vasopressin particularly useful in combination with norepinephrine, and has been recommended for the treatment of septic shock (167). Addition of vasopressin allows for reduced dosing of more harmful catecholamines in this situation. The ongoing Vasopressin and Septic Shock Trial (VASST) will help to define the role of vasopressin compared to norepinephrine in sepsis (168).
Terlipressin
Terlipressin is an analogue of vasopressin that is used in countries in which vasopressin is not available. It is employed in a similar fashion, usually for the treatment of catecholamine-resistant shock. Early studies are favorable, showing an increase in MAP and a decrease in the need for catecholamine vasopressors (169). Splanchnic circulation is spared excessive vasoconstrictive effects, as demonstrated by an increase in gastric mucosal perfusion (170). Terlipressin is used as a single bolus in these studies due to its long half-life (6 hours). This long duration of action may be disadvantageous as the effects are not easily discontinued if necessary, as with a vasopressin drip.
Steroids
The use of steroids in critical care has long been the topic of debate and refinement. For the purposes of shock, however, more definitive literature is emerging to help clarify their role. The role of “stress-dose steroids” perioperatively to prevent hypotension in the adrenal-insufficient patient has been supported for many years. The concept of relative adrenal insufficiency complicating shock states is now established as a recognizable and treatable entity. A recent meta-analysis reviewed the use of 200 to 300 mg of hydrocortisone daily for patients with septic shock. Administration for 5 days or more reduced duration of shock and mortality without increasing associated side effects of infection (171). Use of steroids should be limited to patients with shock refractory to fluids and vasopressors, and with a chemical diagnosis of adrenal insufficiency. Fludrocortisone at a dose of 50 mg/day orally may be added to the hydrocortisone regimen (172).
Drotrecogin Alfa
Among the newer immunomodulatory agents, drotrecogin alfa has received the most attention. The agent is a recombinant form of activated protein C, which acts to down-regulate the proinflammatory state, anticoagulate, and enhance fibrinolysis to enhance reopening of the microcirculation. As such, it is used for severe sepsis rather than shock per se. Due to its effect on the coagulation profile, the drug has limitations in patients with a risk of bleeding. When used as a drip (24 g/kg/hour for 96 hours), the drug provided a 6% reduction in 28-day mortality for patients with severe sepsis. The drug is expensive, and treatment should be limited to the patient with septic shock requiring renal or respiratory support, as outlined in the PROWESS trial (173).
End Points of Resuscitation
The primary goal in the management of shock is a return to normal tissue perfusion. If shock is recognized promptly and timely appropriate treatment strategies are implemented, reversal of its clinical signs may be appreciated. These include improvement in mental status, normalization of vital signs, and restoration of urine output. However, despite these findings, many patients remain in a state of occult hypoperfusion and ongoing tissue acidosis with resultant multiple organ failure and death (12,174). This has been termed “compensated shock.” Consequently, better end points of resuscitation are needed to guide resuscitation efforts.
The ideal end point should be operator independent, noninvasive, readily available, safe, and inexpensive. Unfortunately, no single parameter has proven superior in its ability to drive resuscitation efforts. This being said, numerous parameters have been proposed and/or utilized including basic hemodynamic monitoring, invasive hemodynamic monitoring, oxygen delivery, oxygen consumption, mixed venous oxygen saturation, lung water, arterial base deficit, arterial lactate, capnometry, tissue oxygen and carbon dioxide electrodes, and near infrared spectroscopy. We will discuss several of these in more depth in the following paragraphs.
Basic Hemodynamic Monitoring
Basic monitoring in patients with shock includes noninvasive vital sign measurements, cardiac rhythm, and urinary output. During this timeframe, an accurate blood pressure reading is essential. There are several states that underestimate blood pressure measurements including tachycardia in instances of a narrow pulse pressure, arrhythmias, and peripheral vascular disease, all of which are not uncommon in this population (175). The utilization of Doppler is helpful in such instances; however, it does not always rectify the problem (176). When more detailed information is desired, invasive hemodynamic monitoring is indicated.
Invasive Hemodynamic Monitoring
The hemodynamic profiles of shock are depicted in Table 55.2. It is these parameters that often guide the management of shock. As such, meticulous equipment calibration and documentation are essential (177,178). These measurements are subject to many potential artifacts as seen in Table 55.9 (14).
Therefore, it is critical for the clinician to evaluate these variables in concert with the patient's clinical picture.
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Table 55.9 Common artifacts in hemodynamic measurements |
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Central venous catheters are commonly used in this patient population. As such, central venous pressure measurements are readily available, and often serve as a rough guideline in the resuscitation of shock. The problem is the lack of a well-defined goal for central venous pressure. Similarly, with pulmonary artery catheters, numerous additional hemodynamic parameters become available; however, it is not clear that the appropriate end point is the normalization of these values, nor is it clear how these end points should be achieved (179,180,181,182).
In fact, observational studies have suggested that pulmonary artery catheters may actually increase mortality, intensive care unit length of stay, hospital costs, and resource utilization (183). In 2005, Shah et al. performed a meta-analysis of 13 randomized clinical trials evaluating the use of pulmonary artery catheters (184). They documented no improvement in overall mortality or hospital length of stay. An even more recent randomized controlled trial by the National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network found no survival benefit and increased catheter-associated complications when comparing pulmonary artery catheters to central venous catheters in the management of patients with acute lung injury when utilized relatively late (within 48 hours), which is the time when resuscitation should already be completed (185). The only positive trial involving pulmonary artery catheters was in older trauma patients who were in severe shock (186). In this subset, Friese et al. documented a survival benefit when patients were managed with a pulmonary artery catheter. This was, however, a retrospective review of the National Trauma Data Bank.
Oxygen Delivery
Oxygen delivery (DO2) is a function of cardiac index (CI), hemoglobin (Hb), and oxygen saturation (SaO2) as seen in the Fick equation:
DO2 (mL/minute/m2) = (CI)
× (1.34 mL O2 carried by 1 g of Hb if 100% saturated)
× (Hb)(SaO2)
The use of oxygen delivery as a resuscitation end point has had varying results. In the 1970s, Shoemaker et al. reviewed the physiologic patterns in surviving and nonsurviving shock patients (187,188). They observed that survivors had significantly increased oxygen delivery, oxygen consumption, and cardiac index values (oxygen delivery ≥600 mL/minute/m2, oxygen consumption ≥170 mL/minute/m2, and cardiac index ≥4.5 L/minute/m2). In a subsequent prospective study, they documented decreased complications, lengths of stay, and hospital costs when employing these parameters as goals of resuscitation in high-risk surgical patients (189). Further work by Shoemaker's group and others have shown that utilization of this “supranormal resuscitation” strategy decreases morbidity and mortality in critically ill patients (180,190,191,192).
Others have been unable to demonstrate any benefit to supranormal oxygen delivery (193,194,195). Moreover, supranormal resuscitation has been associated with significant morbidity (i.e., ongoing tissue ischemia, abdominal compartment syndrome, coagulopathy, and congestive heart failure) and mortality (196). In 2000, Velmahos et al. documented improved survival in patients who achieved supranormal oxygen delivery; however, they concluded that “this was not a function of the supranormal resuscitation, but rather the patient's own ability to achieve these parameters” (197,198). More recently, Kern and Shoemaker reviewed all randomized clinical trials of hemodynamic optimization (199). They determined that a survival benefit was only appreciable in those studies with interventions prior to the onset of organ failure and mortality of >20% in the control group (200). As demonstrated here, the utilization of oxygen delivery and more specifically “supranormal resuscitation” in the management of shock has had varying degrees of success.
Mixed Venous Oxygen Saturation
Another end point previously examined was mixed venous oxygen saturation. In critically ill patients, Gattinoni resuscitated patients to one of three hemodynamic goals (193). These included a cardiac index between 2.5 and 3.5 L/minute/m2, cardiac index >4.5 L/minute/m2, and SvO2 ≥70%. There were no differences in multiple organ failure or mortality between the groups. This is in contrast to Rivers' study of severe sepsis/septic shock patients where reaching SvO2 ≥70% within 6 hours of resuscitation improved survival (88).
Base Deficit
Base deficit is defined as the amount of base in millimoles required to increase 1 liter of whole blood to the predicted pH based on the PaCO2 (161). It may be calculated using the arterial blood gas as follows (201):
Base Deficit = -[(HCO3) - 24.8 + (16.2)(pH - 7.4)]
In shock states, the base deficit may serve as a surrogate marker for anaerobic metabolism and subsequent lactic acidosis if metabolic acidosis is the primary disorder and not a compensatory response (202). In this sense, it is superior to pH secondary to the many compensatory mechanisms in place to normalize pH (203).
Secondary to its availability and rapidity, base deficit has been extensively studied as an end point of resuscitation. In a retrospective review, Davis et al. demonstrated that an increasing base deficit correlated directly with admission hypotension and increasing fluid requirements within the first 24 hours of admission (204). Furthermore, they determined that failure to normalize the base deficit was associated with increased mortality. Others have documented correlations between base deficit and blood product requirements, lengths of stay, acute lung injury, acute respiratory distress syndrome, renal failure, coagulopathy, multiple organ failure, and mortality (205,206,207,208,209,210,211,212,213,214,215,216,217,218,219).
In the clinical arena, base deficit levels have numerous confounders. These include alcohol intoxication, hyperchloremic metabolic acidosis secondary to aggressive normal saline or lactated Ringer resuscitation, and sodium bicarbonate administration (220,221). Base deficit may also be a normal compensatory response to respiratory alkalosis. As such, base deficit may be useful in trending resuscitation efforts; however, it is not a definitive stand-alone end point.
Lactate
Serum lactate levels are used extensively in monitoring shock resuscitation. In patients suffering from noncardiogenic shock, Vincent et al. documented a correlation between initial serum lactate levels and patient outcomes (222). However, in shock resuscitation it is the lactate trend that is most predictive of mortality. In trauma patients managed with “supranormal resuscitation,” Abramson et al. determined that the time to lactate normalization was an important predictor of mortality (223). Patients whose lactate levels normalized (serum levels below 2 mmol/L) within 24 hours had a <10% mortality, those who normalized between 24 and 48 hours had a 25% mortality, while those who did not normalize by 48 hours had a >80% mortality. This trend was corroborated by McNelis et al. in postoperative surgical patients (224). In the trauma population, Manikas et al. further demonstrated that initial and peak lactate levels correlated with multiple organ failure (225). Although the serum lactate level signifies shock and ongoing tissue ischemia, its utilization as an end point in the resuscitation of shock has yet to be validated.
Bicarbonate
During anaerobic metabolism, bicarbonate serves as a buffer for released hydrogen ions. Serum bicarbonate levels decrease as the acidosis worsens, and in essence act as a surrogate for metabolic acidosis. In recent studies, serum bicarbonate levels have been determined to better predict metabolic acidosis and mortality than pH, anion gap, or lactate (226,227). Unfortunately, bicarbonate suffers from the same limitations as base deficit; therefore, its use as an end point of resuscitation is unclear at this time.
Capnometry
During periods of shock and ongoing tissue hypoperfusion, blood flow to the most vulnerable organs (brain and heart) is preserved at the expense of other organs (kidneys, intestinal tract, and musculoskeletal system) (200). In theory, the expended organs will manifest this state with an increase in tissue PCO2 and a subsequent decrease in tissue pH. The splanchnic and oral mucosa are especially sensitive to such hypoxemic states; therefore, buccal, sublingual, and gastric capnometry would seem invaluable in monitoring shock resuscitation. Gastric capnometry is limited by gastric enteral nutrition, endogenous gastric acid secretion, and H2 blockers (228,229).
Buccal and sublingual capnography have been shown to directly correspond with blood pressure, cardiac output, and tissue perfusion in animal models (230,231). Furthermore, they are more accurate in predicting mortality than blood pressure is. Povoas et al. documented a correlation between sublingual and duodenal PCO2 and mesenteric blood flow during hemorrhagic shock in swine (232). In acutely ill humans, Weil et al. demonstrated a correlation between sublingual PCO2 and lactate levels, the presence of shock, and survival (233,234). Additional studies have shown a correlation between sublingual PCO2 and changes in regional microcirculatory blood flow and ongoing bleeding (235,236). Unfortunately, PCO2 levels vary widely in the population, making standardization quite difficult (198). Monitoring device for sublingual capnography was recalled in 2004 for infectious complications and may be reinstated in the future.
Near-infrared Spectroscopy
Near-infrared spectroscopy is the measurement of the wavelength and intensity of the absorption of near-infrared light by a sample. In medicine, it uses chromophores such as hemoglobin to do so and allows for the measurement of tissue oxygenation, PO2, PCO2, and pH (237). Taylor et al. documented a close correlation between tissue oxygenation measurements and hemodynamic parameters in a hemorrhagic shock model (238). In this study, near-infrared spectroscopy was also better able to differentiate “responder” from “nonresponder” animals in comparison to lactate levels or global oxygen delivery. McKinley et al. studied near-infrared spectroscopy in critically injured trauma patients (239). They determined that the oxygen saturation of hemoglobin in tissue (StO2) correlated well with systemic oxygen delivery, base deficit, and lactate. This modality is increasing in popularity with trials currently ongoing.
In shock resuscitation, the treatment strategy is to return normal tissue perfusion. Resuscitation end points are critical in this management. The ideal end point should be operator independent, noninvasive, readily available, safe, and inexpensive. Currently, no single parameter has proven superior in its ability to drive resuscitation efforts.
Summary
Shock is likely the most common life-threatening diagnosis made in the intensive care unit. Despite technologic advances, it remains a significant source of morbidity and mortality. Its etiology is vast. As such, the diagnosis of shock and its inciting source can be difficult to identify if not elusive. Aggressive diagnostic testing is required to avoid irreversible cellular injury, multiple organ failure, and potentially death. The primary goal in the management of shock is a return to normal tissue perfusion. This is attained via various volume resuscitation modalities, pharmacologic agents, and resuscitation end points. Past and current research efforts continue in hopes of optimizing the diagnosis and management of shock with the ultimate goal of improving patient outcomes.
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