s. rob todd, krista l. turner, and frederick a. moore · aforementioned increased peripheral...

380

Chapter

44Shock: GeneralS. Rob Todd, KRiSTa L. TuRneR, and FRedeRicK a. MooRe

IntroductIon

Despite significant technologic advances and improved under-standing of shock, it remains a diagnosis associated with signif-icant 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), defining shock as “a peculiar effect on the animal system, produced by violent inju-ries from any cause, or from violent mental emotions.”

In the late 1800s, Fischer and Maphoter further delineated the pathophysiology of shock (3,4), with Fischer proposing a generalized “vasomotor paralysis” resulting in splanchnic blood pooling as the underlying mechanism, while Maphoter suggested that the clinical manifestations appreciated in shock were the result of the extravascular leakage of fluids. A varia-tion of Fischer’s theory was supported by Crile in 1899 (5).

In the early 1900s, Walter B. Cannon (6) proposed a toxin as the source of this altered capillary permeability and intravas-cular volume loss. Blalock (7) challenged this theory in 1930, charging that significant hemorrhage alone could account for insufficient cardiac output (CO) in shock states and that a circulating toxin was not needed. In the 1940s, Carl Wiggers (8) demonstrated that, following prolonged shock, irreversible circulatory failure could occur. At that time, hypotension was synonymous with shock, as blood pressure was the primary end point of resuscitation in shock. As such, volume resuscita-tion was the primary management strategy.

It was not until the turn of the 19th century that etiologies 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. Subsequently, Tennant and Wiggers docu-mented, in 1935, decreased myocardial contractility following coronary perfusion deprivation (10).

defInItIon of Shock

The definition of shock has historically been a moving tar-get. Initially equated with hypotension (11,12), shock is now defined as an acute clinical syndrome resulting from cellular dysoxia, 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 con-stellation 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 charac-terized for a multitude of reasons. First and foremost—even today—the definition of shock continues to lack consensus. As such, screening for shock tends to be inadequate, and thus it is underreported. Additionally, patients presumably die from shock in the prehospital setting. Taking these facts into account, one can readily appreciate why the reported inci-dence and mortality of shock varies widely.

Blalock’s 1937 classification of shock (15) defined four cat-egories: hematogenic or oligemic (hypovolemic), cardiogenic, neurogenic, and vasogenic. Subsequently, Weil and Shubin (16) characterized shock based on cardiovascular parameters. The categories included hypovolemic, cardiogenic, extracar-diac obstructive, and distributive; Table 44.1 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 intra-vascular 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 leak-age” into the interstitial tissues or the corporeal cavities) (see Table 44.1). Additional etiologies include malnutrition and large open wounds (burns and the open abdomen) (16,18).

The pathophysiology of shock is dependent upon its clas-sification. Hypovolemic shock is characterized by a decrease in intravascular volume with resultant decreases in pulmonary capillary wedge pressure (PCWP) and CO (Table 44.2). 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 pre-disposes tissues to localized hypoxia (14). Furthermore, the aforementioned increased peripheral vascular tone (systemic vascular resistance; SVR) may result in tissue ischemia via an inconsistent microcirculatory flow. In cases of severe hypovo-lemic shock, a significant inflammatory component coexists.

Cardiogenic Shock

Cardiogenic shock is defined as inadequate tissue perfusion due to primary ventricular failure. Its incidence has remained fairly stable, ranging from 6% to 8% (19–23). In the United States, it is the most common cause of mortality from coro-nary artery disease (CAD) (19). Despite medical advances, car-diogenic shock remains the number one cause of in-hospital

LWBK1580_C44_p380-395.indd 380 29/07/17 11:08 AM

Chapter 44 Shock: General 381

mortality in patients experiencing a transmural myocardial infarction (MI), with rates ranging between 70% and 90% (21,24). Other causes include myocarditis, cardiomyopathies, valvular heart diseases, and dysrhythmias (Table 44.1).

The most common inciting event in cardiogenic shock is an acute MI. Historically, once 40% of the myocardium has been irreversibly damaged, cardiogenic shock may result. From a mechanical perspective, decreased cardiac contractility dimin-ishes both stroke volume (SV) and CO (see Table 44.2). These lead to increased ventricular filling pressures, cardiac chamber dilatation, and ultimately univentricular or biventricular fail-ure 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 (see Table 44.1). Large obstruc-tive intrathoracic tumors, tension pneumothoraces, pericardial tamponade, and constrictive pericarditis limit ventricular fill-ing, while pulmonary emboli (PE) and aortic dissection impede cardiac contractility.

The hemodynamic parameters witnessed in obstructive shock include increases in central venous pressure (CVP) and SVR, and decreases in CO and mixed venous oxygen satu-ration (SvO2) (see Table 44.2). The PCWP and other hemo-dynamic indices are dependent on the obstructive cause. In pericardial tamponade, there is equalization of the right and left ventricular diastolic pressures, the CVP, and the PCWP (increased). However, following a massive PE, right ventricular failure leads to increased right heart pressures and a normal or decreased PCWP.

Distributive Shock

Distributive shock is characterized by a decrease in SVR. Sep-tic shock is the most common form although, additionally, dis-tributive shock includes the other oft-quoted classes of shock including anaphylactic, neurogenic, and adrenal shock (see Table 44.1). Physiologically, all forms of distributive shock exhibit a decreased SVR (see Table 44.2). Subsequently, these patients experience relative hypovolemia as evidenced by a decreased (or normal) CVP and PCWP. The CO is initially diminished; however, following appropriate volume loading, the CO increases.

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

TABLE 44.1 Shock Classification

HypovolemicHemorrhagic

•Trauma, gastrointestinal, retroperitoneal

nonhemorrhagic

•dehydration, emesis, diarrhea, fistulae, burns, polyuria, “third spacing,” malnutrition, large open wounds

CardiogenicMyocardial

• infarction, contusion, myocarditis, cardiomyopathies, pharmacologic

Mechanical

•Valvular failure, ventricular septal defect, ventricular wall defects

dysrhythmias

Obstructiveimpairment of diastolic filling

• intrathoracic obstructive tumors, tension pneumothorax, positive-pressure mechanical ventilation, constrictive pericarditis, pericardial tamponade

impairment of systolic contraction

•Pulmonary embolism, acute pulmonary hypertension, air embolism, tumors, aortic dissection, aortic coarctation

DistributiveSeptic, anaphylactic, neurogenic, pharmacologic,

endocrinologic

TABLE 44.2 Shock Hemodynamic Parameters

CVP PCWP CO SVR Sv−o2

Hypovolemic ↓↓ ↓↓ ↓↓ ↑ ↓Cardiogenic Left ventricular myocardial infarction nl or ↑ ↑ ↓↓ ↑ ↓ Right ventricular myocardial infarction ↑↑ nl or ↑ ↓↓ ↑ ↓

Obstructive Pericardial tamponade ↑↑ ↑↑ ↓ or ↓↓ ↑ ↓ Massive pulmonary embolism ↑↑ nl or ↓ ↓↓ ↑ ↓

Distributive early nl or ↑ nl ↓ or nl or ↑ ↑ or nl or ↓ nl or ↓ early after fluid administration nl or ↑ nl or ↑ ↑ ↓ ↑ or nl or ↓ Late nl nl ↓ ↑ ↑ or ↓

cVP, central venous pressure; PcWP, pulmonary capillary wedge pressure; co, cardiac output; SVR, systemic vascular resistance; Sv−o2, mixed venous oxygen saturation; nl, normal.

LWBK1580_C44_p380-395.indd 381 29/07/17 11:08 AM

382 SeCtion 5 SHocK and MuLTiSySTeM FaiLuRe

coagulation as well as hormonal mediators. Clinically, this is the systemic inflammatory response syndrome (SIRS). Paral-leling this response is an anti-inflammatory response referred to as the compensatory anti-inflammatory response syndrome (sometimes abbreviated CARS). An imbalance between these responses appears to be responsible for increased susceptibility to infection and organ dysfunction (25–29).

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 SIRS as a generalized inflammatory response triggered by a variety of infectious and noninfectious events (30). They arbitrarily established clinical parameters through a consensus process; Table 44.3 summarizes the SIRS diagnos-tic criteria. At least two of the four criteria must be present to fulfill the diagnosis of SIRS. Note, this definition emphasizes the inflammatory process regardless of its etiology. Subsequent studies have validated these criteria as predictive of increased ICU mortality, and indicated that this risk increases concur-rent with the number of criteria present. SIRS 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 accu-mulation of immunocompetent cells at the local site of tissue damage (31).

Compensatory Anti-Inflammatory Response Syndrome

Shock stimulates not only the release of proinflammatory medi-ators, but also the parallel release of anti-inflammatory media-tors (26). This compensatory anti-inflammatory response is present concurrently with SIRS (Fig. 44.1) (32). When these

two opposing responses are appropriately balanced, the patient is able to effectively recover without incurring second-ary injury from the autoimmune inflammatory response (25). However, overwhelming CARS appears responsible for post-shock immunosuppression, which leads to increased suscep-tibility to infections and sepsis (26,31,33). With time, SIRS ceases to exist and CARS 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-acti-vating factor (PAF), interferon-γ (IFN-γ), endothelin-1, leukot-rienes, thromboxanes, prostaglandins, and the complement cascade (34,36).

IL-6 also acts as an immunoregulatory cytokine by stimu-lating the release of anti-inflammatory mediators such as IL-1 receptor antagonists and TNF receptors, which bind circu-lating proinflammatory cytokines (35). IL-6 also triggers the release of prostaglandin E2 (PGE2) from macrophages (35); PGE2 is potentially the most potent endogenous immunosup-pressant (35). Not only does it suppress T-cell and macro-phage 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 44.4 and 44.5.

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 produc-tion 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. PGE2, IL-10, and TGF-β all contribute to this “immunoparalysis” (25,35).

T-helper cells differentiate into either TH1 or TH2 lym-phocytes; TH1 cells promote the proinflammatory cascade through the release of IL-2, IFN-γ, and TNF-β, while TH2 cells

TABLE 44.3 Clinical Parameters of the Systemic Inflammatory Response Syndrome

1. Heart rate >90 beats/min2. Respiratory rate >20 breaths/min, or Paco2 <32 mmHg3. Temperature >38°c or <36°c4. Leukocytes >12,000 cells/mm3 or <4,000 cells/mm3 or ≥10%

juvenile neutrophil granulocytes

Paco2, arterial partial pressure of co2.

Infections

Late MOF

Early MOFFirst Hits

(Injury,Hypotension,

Hypoxia)

Second Hits(Ischemia/Reperfusion,

Compartment syndromes,Operative interventions)

Moderate SIRS

Severe SIRS

Moderate CARS

Severe CARS

Recovery/Repair

SepsisfIGure 44.1 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.

LWBK1580_C44_p380-395.indd 382 29/07/17 11:08 AM


produce anti-inflammatory mediators (25,35). Monocytes/macrophages, through the release of IL-12, stimulate the dif-ferentiation of T-helper cells into TH1 cells. Because IL-12 pro-duction is depressed following trauma, there is a shift toward TH2, which has been associated with an adverse clinical out-come (25,35).

Adherence of the leukocyte to endothelial cells is mediated through the upregulation 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) “roll-ing” (25,37). Upregulation 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 com-plement anaphylotoxins (25). Colony-stimulating factors (CSFs) likewise stimulate monocyte- or granulocyto-poiesis and reduce apoptosis of PMNLs during SIRS. Neutrophil apoptosis is further reduced by other proinflammatory media-tors, 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 oxy-gen-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 (38–41). Recruitment involves a complex cascade of events culminating in transmigration of the leukocyte, whereby the cell exerts its effects (42). The first step is cap-ture and tethering, mediated via constitutively expressed leukocyte selectin denoted L selectin; L selectin functions by identifying glycoprotein ligands on leukocytes and those upregulated on cytokine-activated endothelium (42). Fol-lowing capture and tethering, endothelial E selectin and P selectin assist in leukocyte rolling or slowing (37,43–48). P selectin is found in the membranes of endothelial storage granules, termed Weibel–Palade bodies (45). Following gran-ule 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 acti-vated endothelium, whereby secondary capturing of leuko-cytes occurs via homotypic interactions. The third step in leukocyte recruitment is firm adhesion, which is mediated by membrane-expressed β1- and β2-integrins (49–51). 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 (49–51).

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 bicel-lular 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).

TABLE 44.4 Proinflammatory Mediators

Mediator Action

iL-1 iL-1 is pleiotropic. Locally, it stimulates cytokine and cytokine receptor production by T cells as well as stimulating b-cell proliferation. Systemically, iL-1 modulates endocrine responses and induces the acute phase response.

iL-6 iL-6 induces acute phase reactants in hepatocytes and plays an essential role in the final differentia-tion of b cells into ig-secreting cells. additionally, iL-6 has anti-inflammatory properties.

iL-8 iL-8 is one of the major mediators of the inflamma-tory response. it functions as a chemoattractant and is also a potent angiogenic factor.

iL-12 iL-12 regulates the differentiation of naive T cells into TH1 cells. it stimulates the growth and func-tion of T cells and alters the normal cycle of apoptotic cell death.

TnF-α TnF-α is pleiotropic. TnF-α and iL-1 act alone or together to induce systemic inflammation as above. TnF-α is also chemotactic for neutrophils and monocytes, as well as increasing neutrophil activity.

MiF MiF forms a crucial link between the immune and neuroendocrine systems. it acts systemically to enhance the secretion of iL-1 and TnF-α.

iL, interleukin; ig, immunoglobulin; TnF, tumor necrosis factor; MiF, migration inhibitory factor.

TABLE 44.5 Anti-Inflammatory Mediators

Mediator Action

iL-4 iL-4, iL-3, iL-5, iL-13, and cSF2 form a cytokine gene cluster on chromosome 5q, with this gene par-ticularly close to iL-13.

iL-10 iL-10 has pleiotropic effects in immunoregulation and inflammation. it downregulates the expres-sion of TH1 cytokines, MHc class ii antigens, and costimulatory molecules on macrophages. it also enhances b-cell survival, proliferation, and antibody production. in addition, it can block nF-κb activity, and is involved in the regulation of the JaK-STaT signaling pathway.

iL-11 iL-11 stimulates the T cell–dependent develop-ment of immunoglobulin-producing b cells. it is also found to support the proliferation of hematopoietic stem cells and megakaryocyte progenitor cells.

iL-13 iL-13 is involved in several stages of b-cell matura-tion and differentiation. it upregulates cd23 and MHc class ii expression, and promotes ige isotype switching of b cells. it downregulates macrophage activity, thereby inhibiting the production of proinflammatory cytokines and chemokines.

iFn-α iFn-α enhances and modifies the immune response.

TGF-β TGF-β regulates the proliferation and differentia-tion of cells, wound healing, and angiogenesis.

α-MSH α-MSH modulates inflammation by way of three mechanisms: direct action on peripheral inflam-matory cells; actions on brain inflammatory cells to modulate local reactions; and indirect activation of descending neural anti-inflam-matory pathways that control peripheral tissue inflammation.

iL, interleukin; cSF, colony-stimulating factor; TH, T helper; MHc, major histocompat-ibility complex; ig, immunoglobulin; iFn, interferon; TGF, transforming growth factor; MSH, melanocyte stimulating hormone.

LWBK1580_C44_p380-395.indd 383 29/07/17 11:08 AM


Proteases and Reactive Oxygen Species

Polymorphonuclear lymphocytes and macrophages are not only responsible for phagocytosis of microorganisms and cel-lular debris, but can also cause secondary tissue and organ damage through degranulation and release of extracellular proteases and formation of reactive oxygen species (ROS) or respiratory burst (25,39,40,41,53–55). Elastases and metal-loproteinases, which degrade both structural and extracellu-lar matrix proteins, are present in increased concentrations following trauma (25). Neutrophil elastases also induce the release of proinflammatory cytokines (25).

ROS 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 cyto-sol, mitochondria, and cell membrane (25). Hydrochloric acid is formed from H2O2 by myeloperoxidase, while the Fenton reac-tion transforms H2O2 into hydroxyl ions (25). These free ROS cause lipid peroxidation, cell membrane disintegration, and DNA damage of endothelial and parenchymal cells (58–60). 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), which induces vasodilation, is generated from L-arginine by inducible nitric oxide synthase (iNOS) in PMNLs or vascular muscle cells and by endothelial NOS (eNOS) in endothelial cells (62). iNOS is stimulated by cytokines and toxins, whereas eNOS is stimu-lated by mechanical shearing forces (62,63). Damage by reac-tive 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 coagu-lation cascade are intimately involved in the immune response to shock. They are activated through proinflammatory media-tors, endogenous endotoxins, and tissue damage. The classic pathway of complement is normally activated by antigen–antibody complexes (Ig M or G) or activated coagulation fac-tor XII (FXIIa), while the alternative pathway is activated by bacterial products such as lipopolysaccharide (64–66). Com-plement activation following trauma is most likely from the release of proteolytic enzymes, disruption of the endothelial lining, and tissue ischemia; the degree of complement activa-tion correlates with the severity of injury. The cleavage of C3 and C5 by their respective convertases results in the forma-tion of opsonins, anaphylotoxins, and the membrane attack complex (MAC) (64–66). The opsonins C3b and C4b enhance phagocytosis of cell debris and bacteria by means of opsoniza-tion (64,65). The anaphylotoxins C3a and C5a support inflam-mation 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 path-way. However, during inflammation, serum levels of C1 inhibi-tor 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). Activation of FXII and prekallikrein is via contact, when endothelial damage occurs and exposes the basement membrane (67). Factor XII activa-tion 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 acti-vation of urokinase-like 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, 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 coag-ulation pathway (68,69).

Although the intrinsic pathway provides a stimulus for activation of the coagulation cascade, the major activation fol-lowing trauma is via the extrinsic pathway. Increased expres-sion of tissue factor (TF) on endothelial cells and monocytes is induced by the proinflammatory cytokines TNF-α and IL-1β (69–71). 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). Follow-ing 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 acti-vated 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 extravascu-lar 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 (68–70,73). Clinically, coagulation factor consumption and platelet dysfunction are responsible for the diffuse hemorrhage (68,71). Consumption of coagulation fac-tors is further enhanced via the proteolysis of fibrin clots to fibrin fragments (68,71). The consumption of coagulation fac-tors is further enhanced through the proteolysis of fibrin clots to fibrin fragments by the protease plasmin (25,69,74).

LWBK1580_C44_p380-395.indd 384 29/07/17 11:08 AM


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, both positive and negative, is shown in Table 44.6 (75,76).

The acute phase response is initiated by hepatic Kupffer cells and the systemic release of proinflammatory cytokines IL-1, IL-6, IL-8, and TNF-α (77,78). The acute phase reaction typically lasts for 24 to 48 hours prior to its downregulation (35). IL-4, IL-10, glucocorticoids, and various other hor-monal stimuli function to downregulate 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). CRP was so named secondary to its ability to bind the C-polysac-charide 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 bac-teria, 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 measure-ments are helpful in trending a patient’s clinical course (35).

SAA interacts with the third fraction of high-density lipo-protein (HDL3), thus becoming the dominant apolipoprotein during acute inflammation (81). This association enhances the binding of HDL3 to macrophages, which may engulf cho-lesterol 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 destruc-tion (35).

dIaGnoSIS of Shock

Early diagnosis of shock affords the patient the best pos-sible 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 spac-ing 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. Neuro-genic shock occurs almost exclusively after trauma, although limited forms are seen with spinal anesthesia. History of pro-longed 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 MI 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 tam-ponade 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 PE in the hypotensive patient.

Physical examination can provide more clues than just basic blood pressure measurements. As noted previously, hypoten-sion alone is neither exclusive to shock nor absolute for a diag-nosis, 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, how-ever, is diminished end-organ perfusion. Therefore, any signs or symptoms of organ dysfunction should be considered as possible indicators of shock (Table 44.7). Often, the first sign of shock manifests as mental status changes, whether excit-atory or somnolent in nature. The patient may appear dia-phoretic and clammy in cardiogenic shock or warm and dry in early distributive shock. Heart rate may also be variable with

TABLE 44.6 Acute Phase Proteins

Group Individual Proteins

Positive acute phase proteins

Major acute phase proteins

c-reactive protein, serum amyloid a

complement proteins c2, c3, c4, c5, c9, b, c1 inhibitor, c4-binding protein

coagulation proteins Fibrinogen, prothrombin, von Willebrand factor

Proteinase proteins α1-antitrypsin, α1-antichymotrypsin, α2-antiplasmin, heparin cofactor ii, plasminogen activator inhibitor i

Metal-binding proteins

Haptoglobin, hemopexin, cerulo-plasmin, manganese superoxide dismutase

other proteins α1-acid glycoprotein, heme oxygen-ase, mannose-binding protein, leukocyte protein i, lipoprotein (a), lipopolysaccharide-binding protein

Negative acute phase proteins

albumin, prealbumin, transferrin, apo-lipoprotein ai, apolipoprotein aii, α2-Heremans–Schmid glycoprotein, inter-α-trypsin inhibitor, histidine-rich glycoprotein, protein c, protein S, antithrombin iii, high-density lipoprotein

Positive acute phase proteins increase production during an acute phase response. negative acute phase proteins are those that have decreased production during an acute phase response.

LWBK1580_C44_p380-395.indd 385 29/07/17 11:08 AM


tachycardia compensating for diminished CO in the patient with intact sympathetic drive. Vasoplegic shock, such as neu-rogenic 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 mani-fested by low urinary output. Cardiogenic shock has its own specific physical findings including increased venous jugular distension, acute pulmonary edema, and new murmurs or dysrhythmias.

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 (Hgb), creatinine, and cortisol may help provide evidence of or reason for shock. Likewise, a more advanced evaluation of shock may include echocardiogram, CVP monitoring, tissue oxygenation and capnography, or advanced methods of determining CO. Advantages and disad-vantages 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, determination of its etiol-ogy, and correction of the underlying source while supporting

the patient hemodynamically. Rapidity and adequacy of shock resolution will help prevent secondary reperfusion injury and prolonged morbidity. Variables of shock resuscitation must be frequently reassessed and therapy adjusted accordingly.

The underlying goal of shock management is to improve tissue oxygen perfusion. This may be accomplished by manip-ulating one or multiple physiologic parameters involved in oxygen delivery (DO2) and extraction. Forms of obstruc-tive shock require the most prompt diagnosis, as continued mechanical impairment can be rapidly fatal. Adequate treat-ment of these etiologies can be just as rapid in the form of needle decompression for a tension pneumothorax or pericar-diocentesis for cardiac tamponade. Management of distribu-tive and hypovolemic forms of shock likewise involves source control early in the diagnosis. This may be in the form of hem-orrhage control, removal of infected tissue (source control), or removal of an anaphylactic source. Once the inflammatory cascade has initiated, vasoactive medications are often used in addition to fluid provision to increase perfusion. Treatment of cardiogenic shock employs multimodality treatment including volume optimization, vasopressors, control of dysrhythmias, use of inotropes and the mechanical-assist devices, and early revascularization in primary myocardial ischemia (82).

Classically, all forms of shock are primarily treated 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 here in greater detail.

Fluid Resuscitation

The initial treatment for all forms of shock is fluid adminis-tration. Provision of fluid helps restore perfusion and replace intravascular volume lost via hemorrhage, capillary leak, or redistribution. Intravenous fluid is readily available, inexpen-sive, easy to administer, and has low intrinsic morbidity. The etiology of shock and response to fluid will further dictate con-tinued use of volume as primary therapy; however, all forms of shock potentially benefit from an initial fluid challenge (83). Deliberation should be given to the method of delivery, timing of administration, type of fluid, and volume of administration.

Route of Administration

The setting of shock dictates administration of fluid primar-ily via the intravenous route, which 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 a triple lumen cath-eter for anticipated vasopressor therapy), the dictum of “two large-bore peripheral IVs” cannot be overstated (84). As per Poiseuille’s Law, width and length of the catheter dictates flow; therefore, a long, narrow, peripherally inserted central cath-eter 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 diffi-cult; saphenous vein cut-downs or interosseous access, par-ticularly in the trauma or pediatric patient, can provide means of fluid administration in these extreme situations.

Timing and Volume of Administration

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,

TABLE 44.7 Clinical Recognition of Shock

Organ System

Symptoms or Signs Causes

cnS Mental status changes

↓ cerebral perfusion

circulatory

Cardiac Tachycardia adrenergic stimulation, depressed contractility

other dysrhythmias

coronary ischemia

Hypotension depressed contractility sec-ondary to ischemia or MdFs, right ventricular failure

new murmurs Valvular dysfunction, VSd

Systemic Hypotension ↓ SVR, ↓ venous return

↓ JVPs Hypovolemia, ↓ venous return

↑ JVPs Right heart failure

disparate periph-eral pulses

aortic dissection

Respiratory Tachypnea Pulmonary edema, respira-tory muscle fatigue, sepsis, acidosis

cyanosis Hypoxemia

Renal oliguria ↓ Perfusion, afferent arteriolar vasoconstriction

Skin cool, clammy Vasoconstriction, sympa-thetic stimulation

other Lactic acidosis anaerobic metabolism, hepatic dysfunction

Fever infection

cnS, central nervous system; MdFs, myocardial depressant factors; VSd, ventricular septal defect; SVR, systemic vascular resistance; JVPs, jugular venous pulsations.

LWBK1580_C44_p380-395.indd 386 29/07/17 11:08 AM


volume resuscitation combined with source control may limit or prevent a state of irreversible shock, or the “lethal triad” of hypothermia, coagulopathy, and acidosis (85,86). The impor-tance of the timing of volume loading is also paramount in all forms of shock, particularly in sepsis (87). Amplification of the previously described immune response can potentially be avoided if perfusion is restored early in the pathophysiologic process (88). Often the resuscitation process begins in the prehospital phase, with ambulance personnel administering crystalloid en route. Standard fluid boluses in the patient with shock typically amounts to 20 to 30 mL/kg at a time.

Overly aggressive fluid resuscitation both early and late in the course can be harmful in some circumstances. The concept of hypotensive resuscitation in the patient in whom mechani-cal control of bleeding has not been achieved—whether in traumatic injury, aortic aneurysm rupture, or gastrointestinal bleed—advocates for limited early aggressive fluid administra-tion. Measures to raise blood pressure, particularly with fluid administration, may be counterproductive in this setting. In the penetrating thoracic trauma patient, early administration of large volumes of crystalloid has been shown to increase bleed-ing and subsequent mortality. Pushing fluid and intravascular volume beyond the initial phases of ischemia may propagate reperfusion injury and can be detrimental to further recovery. Restrictive fluid therapies for resuscitation have emerged in an effort to reduce the cardiac, wound healing, and pulmo-nary complications associated with large crystalloid infusions. Once patients have been stabilized, a more restrictive strategy of fluid administration can prevent subsequent morbidity.

Continued fluid administration beyond an initial bolus relies more on the patient’s pathology and response to treat-ment rather than on arbitrary numbers. Physical examination characteristics such as jugular venous distension, skin turgor, urine output, and basic vital signs may give clues to volume state, but are notoriously subject to interpretation. The exam-iner is often misled by the appearance of gross edema, insomuch as it has no bearing on effective extracellular fluid volume in the patient with capillary leak. New tools for approximating intravascular volume status are emerging to provide dynamic variables for the clinician to use when estimating appropriate-ness for further volume resuscitation. Measures such as stroke volume variation (SVV) and pulse pressure variation (PPV) can provide more accurate assessment of volume status and are replacing CVP and pulmonary artery pressures as primary tools in the ICU (89–92); these will be discussed further below.

Types of Fluid

Considerable debate abounds regarding the types of fluid to be administered for shock resuscitation. Often the determination to use crystalloid versus colloid depends on fluid availability, clinical scenario, and regional practice differences. The fact that there is so much debate over the preferred fluid type indi-cates the lack of conclusive evidence for the superiority of one fluid over another.

crystalloids. Composed of varying amounts of electrolytes and sugar, crystalloids are inexpensive, require no special tubing or preparation, and pose little to no risk of adverse reaction. Crystalloids used in shock resuscitation are gener-ally 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 pri-mary ion. Lacking protein components, the isotonic crystal-loids readily distribute to the extracellular fluid compartment and will require larger volumes of infusion to maintain intra-vascular 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 (93).

Normal saline (0.9% saline solution) and lactated Ringer solution compromise the majority of isotonic crystalloid used for shock. Normal saline provides sodium with an equal amount of chloride for buffer; hypernatremia and hyperchlo-remic metabolic acidosis are therefore potential consequences of continued normal saline administration (94). Because of this, normal saline should be used for resuscitation typically only for head trauma patients, as hyponatremia can increase morbidity in this patient population.

While the tonicity is essentially the same, the electrolyte composition of lactated Ringer solution is physiologically closer to plasma, with inclusion of potassium and calcium, and reduction in chloride concentrations. Lactated Ringer is considered one of the “balanced” crystalloids as a different anion is used besides chloride to balance the cations in solu-tion (95). A chloride restrictive strategy is associated with less acute kidney injury in the critical care setting, and therefore these types of balanced solutions are favorable.

hypertonic crystalloid. Combining the convenience of crystalloid with the tonicity of colloids, hypertonic saline (HTS) has emerged as an important tool in shock resuscitation. Hypertonicity of the sodium concentration promotes influx of fluid from the interstitial space. As such, HTS is advan-tageous for rapid, low-volume resuscitation for hypovolemic shock, particularly in situations where resources and space are limited, such as a combat setting. Hypertonic solutions also favorably impact immune modulatory function. Stud-ies investigating hemorrhagic shock have found a decrease in neutrophil activation, and upregulation of anti-inflammatory cytokine production with use of HTS. Additional data suggest that HTS positively affects cardiac function in addition to vol-ume expansion in septic shock (96,97).

While relatively safe compared to colloid infusion, the administration of high concentrations of sodium for volume resuscitation carries the concern for hypernatremia and hyper-osmolarity. Compromise of renal function is likewise feared with high sodium and osmolar loads (98,99). Reports of hypo-kalemia, metabolic acidosis, and impaired platelet aggregation have also been documented with HTS use (100). Primary use of HTS is in the traumatic brain injury patient; small volumes should be used and electrolytes, creatinine, and serum osmo-larity should be checked frequently to avoid the abovemen-tioned complications.

colloids. In reference to volume resuscitation, colloids gen-erally consist of fluids that have a higher molecular weight based on composition consisting of protein or starches. These components increase the cost of colloids, make them suscep-tible to shortage, and mandate specialized tubing for delivery. The possibility of transfusion reaction is increased, as some of these compounds are derived from blood products. Like-wise, allergic reactions can be noted with some of the synthetic formulations.

LWBK1580_C44_p380-395.indd 387 29/07/17 11:08 AM


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 (101). In addition to more rapid volume expansion with less fluid infusion, this same increase in intravascular oncotic pres-sure has prompted the employment of colloids with the intent to reduce or prevent secondary edema; this effect has not been appreciated clinically, however. Studies reveal that edema for-mation is more dependent on fluid volume than on fluid type per se (102).

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 disad-vantages faced by other donated products—namely, periodic shortages, high acquisition costs, and refusal based on reli-gious 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 stud-ies detailing poor prognosis with low serum albumin levels in critically ill patients prompted attempts to improve survival with intravenous supplementation (103–105). Compared with other colloid administration, albumin itself has no benefit in this patient population (106,107).

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 (108). To confuse matters, subsequent meta-analysis of 55 studies showed no difference in mortality between albumin and crystalloid for resuscitation (109, 110). In 2004, the Saline versus Albumin Fluid Evaluation (SAFE) trial prospectively compared albumin to isotonic crystalloid for fluid resuscitation in a mixed ICU population (93); results showed no difference in morbidity or mortality overall with either fluid choice, although traumatic brain injury patients did show increased morbidity with albumin use. Subsequent multicenter studies demonstrated no difference in morbidity or mortality for albumin versus crys-talloid in septic shock resuscitation.

Starches. Synthetic colloid polymers were developed for use in volume resuscitation in an attempt to retain the oncotic properties of albumin while decreasing cost and transfu-sion risk. Initial formulations of hydroxyethyl starch (HES) included high–molecular-weight moieties, accounting for an increased risk of coagulation and renal disturbances associ-ated with their use (111–113). Lower–molecular-weight HES solutions were subsequently developed, with resultant fewer negative effects on bleeding, but concern for dose-dependent impaired renal function persisted (114).

While numerous studies have illustrated downregulation of proinflammatory cytokines with HES use, some of these results may be an effect of the efficiency of volume resuscitation, and not necessarily the fluid itself (115–117). Ongoing concerns

about increase in renal failure and mortality in septic and mixed ICU populations prompted the U.S. Food and Drug Administration to add a warning regarding use of HES prod-ucts in 2013. As such, HES use is not supported at this time.

Despite the theoretical advantage of colloids over crystalloids for shock resuscitation, there is no evidence from randomized controlled trials to demonstrate mortality difference. Studies demonstrating improved short-term gains with colloids use a heterogeneous population and/or fluid composition, making interpretation and application difficult. In larger studies, short-term physiologic gains made from colloid use do not translate in to longer-term improvement. As colloids are not associated with improvement in survival, and are considerably more expensive, it is hard to justify their use (118).

Special Fluid Considerations

Hemorrhagic Shock Resuscitation

Aggressive use of crystalloids during the Vietnam conflict resulted in improved mortality and reduction in renal fail-ure, but also led to the emergence of acute lung injury and acute respiratory distress syndrome in the trauma popula-tion. Extensive use of crystalloids for trauma followed, with the popular concept of pushing fluids beyond supranormal resuscitation goals (119). Consequences of this large-volume approach are becoming more evident, with adverse cardiac, pulmonary, coagulation, and immunologic effects documented with massive crystalloid infusion (120).

With the recognition of the “blood lethal triad” of coagu-lopathy, acidosis, and hypothermia in the bleeding trauma patient, methods to physiologically break this cycle have come into play. Pushing crystalloids for shock resuscitation merely aggravates this pathway. Appropriate resuscitation in hemorrhagic shock includes measures such as damage control surgery and hemostatic resuscitation. The goals of damage control surgery are to stop ongoing hemorrhage and provide control of any visceral injury in a truncated manner such that the patient can return to the ICU for warming and resuscita-tion. Key to this approach is a massive transfusion strategy in which blood is provided in a balanced manner and in prefer-ence to crystalloid or other colloid during this time period. Since the patient bleeds whole blood, it makes physiologic sense to provide blood products in a manner that resembles that of whole blood. Major studies including PROMMTT and PROPPR have demonstrated survival benefits for hemor-rhagic shock when providing platelets:FFP:RBC in as close to a 1:1:1 ratio as possible (121,122). The combination of early mechanical bleeding control with this hemostatic resuscitation is the current standard for hemorrhagic shock resuscitation.

Pharmacotherapy in Shock

Primary therapy for shock involves treating the cause and supplementation with fluids. When these modalities fail, vaso-pressors are typically employed as supplementation. 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.

LWBK1580_C44_p380-395.indd 388 29/07/17 11:08 AM


Vasopressors

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, vasopres-sors may help limit volumes of fluid given; however, peripheral and end-organ vasoconstriction have their own adverse effects. Striking the balance between volume and vasopressors in the context of timing and type of shock is therefore a key compo-nent to resuscitation. With early recognition of shock, vaso-pressors can often be avoided by restoration of volume (123).

End-organ arterial autoregulation generally compensates for decreased MAP within a certain range; however, local vasoconstriction and vasodilatation may be unable to over-come extremes of perfusion. Administering catecholamine vasopressors may help improve MAP and therefore improve tissue perfusion by redistributing CO. The venous compart-ment also benefits from vasopressor therapy by decreasing compliance and therefore improving effective volume. Clas-sifications of vasopressors consist of natural and synthetic ver-sions of catecholamines (Table 44.8).

norepinephrine. A naturally occurring vasopressor, norepi-nephrine 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 blood pressure, with the addition of increased venous return via decreasing venous capacitance; this subsequently leads to increased cardiac fill-ing pressure. Effect on the coronary arterial flow is enhanced via the increase in diastolic blood pressure. The β-adrenergic

TABLE 44.8 Sympathomimetic Drugs

Adrenergic Effects

Arrhythmogenic Potential

Drug Usual IV dose ` a Dopa Setting

dopamine 1–2 μg/kg/mina 1+ 1+ 3+ 1+ oliguria despite “normal” blood pressure

2–10 μg/kg/min10–30 μg/kg/min

2+3+

2+2+

3+3+

2+3+

initial emergency treatment of hypotension (any cause)

alternative treatment for bradycardia

dobutamine 2–30 μg/kg/min 1+ 3+ 0 2+ cardiac shockPulmonary edema with marginal

blood pressure

norepinephrine 0.01–0.1 μg/kg/min(0.5–80 μg/min)

3+ 2+ 0 2+ initial emergency treatment of hypotension (any cause, especially sepsis)

epinephrine 0.5–1 mgb (1:10,000) 1+ 2+ 0 3+ cardiac arrest0.01–0.3 μg/kg/min(1–200 μg/min)

Severe hypotension and bradycardia

0.3–0.5 mg SQ (1:1,000)c 2+ 3+ 0 3+ anaphylaxis

Phenylephrine 0.1–1 μg/kg/min(20–200 μg/min)

3+ 0 0 0 distributive shock when no cardiac effect is desired

isoproterenol 0.03–0.3 μg/kg/min(2–20 μg/min)

0 3+ 0 3+ Refractory bradycardia

denervated hearts

Milrinoned Load: 50 μg/kg over 10 min

0 0 0 2+ cardiogenic shock

Then: 0.375–0.75 μg/kg/min

dopa, dopamine.aincreases renal and splanchnic blood flow. no impact on aKi.bMilligram doses are in bold to differentiate from micrograms.cSQ: Subcutaneous dosing, may be repeated every 15–20 min.dPhosphodiesterase inhibitors; require loading dose.

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 CO.

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 (124). The drug is safe and easily titratable, and lacks the tachydysrhythmic properties of other frequently used agents for shock. 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 shock (125).

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 vaso-constriction. 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 inot-ropism. Due to counter effects of β2-vasodilation, the diastolic blood pressure is only slightly affected, with a lesser degree of increase in MAP than seen with 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 primar-ily β-receptors. This property makes epinephrine attractive as a primary inotrope; however, the range of that particular low dose

LWBK1580_C44_p380-395.indd 389 29/07/17 11:08 AM


varies with each patient and titration may prove dangerous. Epi-nephrine is advocated as a secondary pressor for septic shock, and as the primary pressor for cardiac arrest resuscitation.

dopamine. As the hormone precursor of norepinephrine and epinephrine, dopamine stimulates α-, β-, and dopami-nergic receptors in a dose-dependent fashion. This results in mixed vasoconstrictive, inotropic, chronotropic, and vasodila-tory effects.

Classically, “renal-dose” dopamine ranges from 0 to 5 μg/kg/min and results in vasodilation of renal and mesenteric vas-cular 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 (126). Conversely, at high doses of 10 to 20 μg/kg/min, α-effects predominate, resulting in almost pure vaso-constriction. β-Receptor stimulation at middle doses of 5 to 10 μg/kg/min 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.

In the past, dopamine has been postulated as the first ino-trope of choice in cardiogenic failure with hypotension (127). More recent recommendations, however, identify sympathetic inotropes such as dopamine as increasing mortality when used for primary left heart failure (128). Likewise, in septic shock, norepinephrine has a more reliable dosing profile and has demonstrated more beneficial outcomes compared to dopa-mine (129). Tachydysrhythmias are the predominant concern with dopamine, conversely making it potentially useful in shock with associated bradycardia.

Phenylephrine. Phenylephrine is a rapidly acting vasopres-sor with a short duration of action and pure α1-receptor stimu-lation. As such, it increases MAP primarily by increasing SVR. Reflex bradycardia may develop; therefore, it is occasionally used for distributive shock in the face of tachydysrhythmias. This same unopposed increase in SVR also impairs CO in the patient with impaired pump function. The use of phenyleph-rine has since fallen out of favor, and is generally reserved for the pregnant patient with shock for whom other vasopressors may be detrimental or as rescue therapy in patients with a high CO and low SVR. Its rapid onset and short duration of action also makes it useful in the context of low intraoperative blood pressure due to vasodilatory inhaled anesthetics.

Inotropes

As a group, inotropic agents augment CO by increasing con-tractility. Sources of left ventricular failure are many, including exacerbation of congestive heart failure (CHF), acute infarc-tion, or sepsis-related cardiomyopathy. The inflammatory state that accompanies some forms of cardiogenic shock may result in vasodilation instead of vasoconstriction, making particular inotropes less useful for restoration of tissue perfusion (130). 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 myo-cardial work and exacerbate ischemia.

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 β2-receptors. This combined stimulation results in a net increase in inotropic and chrono-tropic parameters. In theory, vasodilatory (β2) effects are lim-ited, making dobutamine useful in increasing pump function without lowering blood pressure. In practice, some degree of vasodilation is encountered, resulting in decreased blood pres-sure and tachycardia acutely. With increase in CO, however, the BP generally corrects to normal. For this reason, adequate volume loading prior to initiation of dobutamine is empha-sized. Likewise, the lack of increase in BP makes dobutamine a poor selection as monotherapy in primary cardiogenic shock. At higher doses, vasoconstriction may dominate leading to increased myocardial O2 consumption (VO2), so it should be used with caution in states where ischemia is present. Cur-rently, dobutamine is the standard inotrope used in noncar-diogenic shock (such as sepsis) when cardiac contractility is compromised (131).

Isoproterenol. With practically no α-adrenergic stimulation, isoproterenol functions as a pure β-agonist. β1-Stimulation results in increased SV and heart rate, while β2-stimulation induces vasodilatation. The net result is that of enhanced CO without the benefit of redistribution of blood flow. Increased myocardial VO2 exacerbated by lack of coronary perfusion due to decreased diastolic pressures may lead to cardiac isch-emia. Use of isoproterenol is generally limited to β-blocker overdose or in the atropine-resistant transplanted heart.

Phosphodiesterase Inhibitors. A novel agent in vasoactive treatment, milrinone is the most common synthetic phospho-diesterase III inhibitor. Reduction in this enzyme results in an increase in cyclic adenosine monophosphate (cAMP), a modu-lator of myocardial contractility. Additional increase in cAMP results in vasodilation, with the net effect of increasing CO and, at higher doses, tachycardia. This vasodilatory effect may decrease effective left ventricular preload, but may also benefit afterload reduction, reducing cardiac work. In the hypotensive patient, acute vasodilation may not be tolerated, thus, while not recommended in vasodilatory shock for this reason, milri-none may be used in specific situations for cardiogenic shock. These include advanced heart failure in patients awaiting heart transplant, in acute decompensation of CHF on standard med-ications, and in patients in cardiogenic shock with long-term β-blocker use (132). Amrinone is an additional agent in this class, but its use is limited by its side effect profile.

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. It also opens ATP-dependent potassium channels, leading to enhanced ventricular contractil-ity without compromising diastolic function. This vasodilatory effect makes it particularly useful for myocardial protection. The drug is primarily used for acute and chronic heart failure; dosing is 0.05 to 0.2 μg/kg/min. It performs similarly to dobutamine for acute heart failure.

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 NO-induced vaso-dilatation. Likewise, studies of hemorrhagic and vasodilatory

LWBK1580_C44_p380-395.indd 390 29/07/17 11:08 AM


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 to reduce catecholamine administration (133). Although evidence from meta-analysis demonstrates decreased mortality with vasopressin adminis-tration versus norepinephrine in septic shock, a recent ran-domized control trial demonstrates no difference (134).

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 find-ings, many patients remain in a state of occult hypoperfusion and ongoing tissue acidosis with resultant multiple organ fail-ure and death (12,135). Consequently, better end points of resuscitation are needed to guide resuscitation efforts.

The holy grail of shock resuscitation in recent years has been that of achieving adequate end-organ DO2. DO2 is a function of cardiac index (CI), Hgb, and oxygen saturation (SaO2), as seen in the Fick’s equation. The use of DO2 as a resuscitation end point has had varying results. In the 1970s, Shoemaker et al. (136) reviewed the physiologic patterns in surviving and nonsurviving shock patients, observing that sur-vivors had significantly increased DO2, VO2, and CO values (DO2 ≥600 mL/min/m2, VO2 ≥170 mL/min/m2, and CI ≥4.5 L/min/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. Further work by Shoemaker’s group and others have shown that utilization of this “supra-normal resuscitation” strategy decreases morbidity and mor-tality in critically ill patients (137).

More recently, however, supranormal resuscitation has been associated with significant morbidity—ongoing tissue ischemia, abdominal compartment syndrome, coagulopathy, and CHF—and mortality. Velmahos et al. (138) documented improved survival in patients who achieved supranormal DO2; however, they concluded that “this was not a function of the supranor-mal resuscitation, but rather the patient’s own ability to achieve these parameters”. As demonstrated here, the utilization of DO2 and, more specifically, “supranormal resuscitation” in the man-agement of shock has had varying degrees of success. Different strategies to monitor end-organ perfusion, as well as methods to assess volume responsiveness, are more commonly used.

Basic Hemodynamic Monitoring

Basic monitoring in patients with shock includes noninvasive vital sign measurements, cardiac rhythm, and urinary output and other clinical variables of end-organ perfusion. The hemo-dynamic profiles of shock are depicted in Table 44.2. It is these parameters that often guide the management of shock and, in that context, meticulous equipment calibration and documen-tation are essential (139,140). These measurements are subject

to many potential artifacts as seen in Table 44.9 (14). There-fore, it is critical for the clinician to evaluate these variables in concert with the patient’s clinical picture.

Invasive Hemodynamic Monitoring

Central venous catheters are commonly used in this patient population. As such, CVP measurements are readily available and were, in the past, often used as a rough guideline in the resuscitation of shock. It is increasingly recognized that there is actually very little correlation between intravascular volume sta-tus and CVP. As a consequence, utilization of CVP during shock resuscitation has fallen out of favor. Similarly, PACs can provide numerous additional hemodynamic parameters; 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 (141–144). Observational studies and meta-analysis have suggested that PACs may actually increase mortality, ICU length of stay, hospital costs, and resource utilization (145).

Blood and Serum Markers

Numerous laboratory values can provide some clues to degree and correction of shock. SvO2 can be obtained from a PAC and provides an indication of the end result of DO2 and VO2; an approximation of this can also be obtained from a central venous catheter (ScvO2), although the value will be higher. While both SvO2 and ScvO2 can be obtained continu-ously, and while initially considered essential to goal-directed resuscitation, both methods have fallen out of favor, both due to need for invasive monitoring, and due to equivalency of lactate clearance as a surrogate.

Base deficit is defined as the amount of base, in millimoles, required to increase 1 L of whole blood to the predicted pH based on the PaCO2 (146). In shock states, the base deficit may serve as a surrogate marker for anaerobic metabolism and subsequent lactic acidosis if metabolic acidosis is the pri-mary disorder and not a compensatory response (147). In this sense, it is superior to pH secondary to the many compensa-tory mechanisms in place to normalize pH (148). Base deficit has numerous confounders, so it should be used as a method to trend resuscitation and not as a stand-alone measure.

Serum lactate levels are used extensively in monitoring shock resuscitation. In patients suffering from noncardiogenic shock, Vincent et al. documented a correlation between ini-tial serum lactate levels and patient outcomes (149). However, in shock resuscitation it is the lactate trend that is most pre-dictive of mortality. Patients whose lactate levels normalized (serum levels <2 mmol/L) within 24 hours had less than 10% mortality, those who normalized between 24 and 48 hours had a 25% mortality, while those who did not normalize by 48 hours had over 80% mortality. Lactate measurement is now an integral part of the Surviving Sepsis Guidelines for monitoring resuscitation (125).

Esophageal Doppler

Esophageal Doppler measurement uses estimation of aortic velocity as a surrogate for CO. It also provides a reasonably accurate measure of SVV. Despite variable degrees of artifact with this method, it is well studied and provides the most accu-rate estimation of CO when compared to PAC measurements.

LWBK1580_C44_p380-395.indd 391 29/07/17 11:08 AM


SVV is also extremely valuable from this method, with data supporting its use during perioperative resuscitation. Use is limited by discomfort to the patient and possible complications from insertion.

Near-Infrared Spectroscopy

Near-infrared spectroscopy (NIRS) 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 Hgb to do so and allows for the measurement of tissue oxygenation, PO2, PCO2, and pH (150). Taylor et al. (151) documented a close correlation between tissue oxygenation

TABLE 44.9 Common Artifacts in Hemodynamic Measurements

Variable Artifact Causes Comments/Corrective Action

Vascular pressures (including PCWP)

Preload overestimation

Technical:improper leveling of transducer avoid with rigid nursing protocolsimproper calibrationimproper system frequency responseRespiratory:not recording pressures at end-expiration

during mechanical ventilationactive expiratory effort

avoid digital readoutsuse analog tracingsSuspect with respiratory distress; consider

neuromuscular blockadePositive end-expiratory pressure usually not significant with <10 cm H2o

PeePimproper positioning of catheter tip Suspect if tip in upper lobes on chest

radiograph or Pad < PcWPCardiac:Mitral regurgitation Read PcWP as post–a waveMitral stenosis interpret with caution as preload estimateacute changes in left ventricle

complianceSuspect in presence of myocardial

ischemia

Preload underestimation

Technical: as for overestimationRespiratory:not recording pressures at end-expiration

during spontaneous breathing

Cardiac output inaccuracies Technical:incorrect injectable volume; thermistor

contact with vessel wall; incorrect computational constant

inspect temperature curves; suspect if pulmonary artery waveform is damp-ened; follow rigid nursing protocol

Cardiac:Tricuspid regurgitation do not use in presence of significant

tricuspid regurgitationWide variation Technical: as for inaccuracies delete measurements with >20% variation

from the meanRespiratory:Variable respiratory rate during

mechanical ventilationaverage measurements throughout

respiratory cycle

Mixed venous oxygen saturation

inaccuracies Technical:Light reflecting against vessel wall,

catheter kinkingnote computer error messages

Presence of significant Hgbco Measure Hgbco directly at least once

Misinterpretation Shifts in oxygen dissociation curve correlate with Pvo2 measurementsdependence on oxygen delivery correlate with oxygen delivery

measurements

extravascular lung water

inaccuracies inaccurate measurement of cardiac output (as above)

correlate cardiac output with regular thermodilution measurements

underestimation Presence of significant areas of nonperfused lung

Measurements suspect in presence of significant regional disease (i.e., lobar pneumonia) or known vascular obstruction

Systemic vascular resistance

inaccuracies inaccurate measurement of cardiac output (as above)

inaccurate measurement of blood pressure

Measure directly (see above)

PcWP, pulmonary capillary wedge pressure; PeeP, positive end-expiratory pressure; Pad, pulmonary artery diastolic; Hgbco, carboxyhemoglobin; Pvo2, mixed venous oxygen partial pressure.

measurements and hemodynamic parameters in a model of hemorrhagic shock. In this study, NIRS was also better able to differentiate “responder” from “nonresponder” animals in comparison to lactate levels or global DO2. This technology is limited by cost and waveform interference.

Photoplethysmography

Similar to NIRS, photoplethysmography (PPG) uses measure-ment of intensity of light as it relates to a waveform produced peripherally. Essentially, PPG technology uses pulse oximeter data to calculate a variability index similar to PPV which is then used to predict fluid responsiveness. Although it does not correlate as

LWBK1580_C44_p380-395.indd 392 29/07/17 11:08 AM


well to intravascular measurements of PPV, it has the advantage of being noninvasive, less expensive, and easy to use.

Bioimpedance

Bioimpedance and bioreactance devices assess thoracic volume status based on noninvasive measurement of electrical current via Ohm’s law. In theory, they can be used to roughly assess SV and, therefore, when multiplied times the heart rate, yield CO. Typically, they are most useful for measuring volume respon-siveness. Although these are noninvasive and easy to use, they are limited by a large amount of artifact.

Arterial Waveform Analysis

Increasingly popular for assessing fluid responsiveness, arterial waveform analyzers estimate SV and CO. This can be done either with an arterial catheter or with both an arterial and venous catheter to improve accuracy in some devices. Measur-ing the variation in stroke volume during the respiratory cycle can estimate the SVV, which is a rough estimate of where the heart is on the Starling curve. These devices can be extremely useful when determining need for further fluid administration in patients who are mechanically ventilated. Use of SVV, instead of CVP, has favorable outcomes on perioperative patients in particular, as these individuals receive, in general, less fluid.

10. Tennant R, Wiggers CJ. The effect of coronary occlusion on myocardial contraction. Am J Physiol. 1935;211:351–361.

11. Wo CJ, Shoemaker WC, Appel PL, et al. Unreliability of blood pressure and heart rate to evaluate cardiac output in emergency resuscitation and critical illness. Crit Care Med. 1993;21:218–223.

12. Scalea TM, Maltz S, Yelon J, et al. Resuscitation of multiple trauma and head injury: role of crystalloid fluids and inotropes. Crit Care Med. 1994;22:1610–1615.

13. Mello PM, Sharma VK, Dellinger RP. Shock overview. Semin Respir Crit Care Med. 2004;25:619–628.

14. Jimenez EJ. Shock. In: Civetta JM, Taylor RW, Kirby RR, eds. Critical Care. 3rd ed. Philadelphia, PA: Lippincott–Raven Publishers; 1997:359.

15. Blalock A. Shock: further studies with particular reference to the effects of hemorrhage. Arch Surg. 1937;29:837–857.

16. Weil MH, Shubin H. Proposed reclassification of shock states with special reference to distributive effects. In: Hinshaw LB, Cox BG, eds. The Funda-mental Mechanisms of Shock. New York: Plenum Press; 1972:13.

17. Kumar A, Parrillo JE. Shock: classification, pathophysiology, and approach to management. In: Parrillo JE, Dellinger RP, eds. Critical Care Medicine. 2nd ed. St. Louis, MO: Mosby, Inc.; 2002:371.

18. Warden GD. Burn shock resuscitation. World J Surg. 1992;16:16–23. 19. National Center for Health Statistics: Health, United States, 1986, DHHS

Pub No (PHS) 87–1232, Washington, DC: US Government Printing Office; 1986.

20. Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myo-cardial infarction. Lancet. 1986;1:397–402.

21. Goldberg RJ, Gore JM, Alpert JS, et al. Cardiogenic shock after acute myocardial infarction: incidence and mortality from a community-wide perspective, 1975 to 1988. N Engl J Med. 1991;325:1117–1122.

22. Collaborative Group. Third International Study of Infarct Survival. ISIS-3 a randomised comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41,299 cases of suspected acute myocardial infarction. Lancet. 1992;339:753–770.

23. The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med. 1993;329:673–682.

24. Hochman JS, Boland J, Sleeper LA, et al. Current spectrum of cardio-genic shock and effect of early revascularization on mortality: results of an international registry. SHOCK Registry Investigators. Circulation. 1995; 91:873–881.

25. Keel M, Trentz O. Pathophysiology of trauma. Injury. 2005;36:691–709. 26. Bone RC. Sir Isaac Newton, sepsis, SIRS, and CARS. Crit Care Med. 1996;

24:1125–1128. 27. Lyons A, Kelly JL, Rodrick ML, et al. Major injury induces increased pro-

duction of interleukin-10 by cells of the immune system with a negative impact on resistance to infection. Ann Surg. 1997;226:450–458.

28. Malone DL, Kuhls D, Napolitano LM, et al. Back to basics: validation of the admission systemic inflammatory response syndrome score in predict-ing outcome in trauma. J Trauma. 2001;51:458–463.

29. Rangel-Frausto MS, Pittet D, Costigan M, et al. The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. JAMA. 1995;273:117–123.

30. American College of Chest Physicians/Society of Critical Care Medi-cine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med. 1992;20:864–874.

31. Van Griensen M, Krettek C, Pape HC. Immune reactions after trauma. Eur J Trauma. 2003;29:181–192.

32. Neidhardt R, Keel M, Steckholzer U, et al. Relationship of interleukin-10 plasma levels to severity of injury and clinical outcome in injured patients. J Trauma. 1997;42:863–870.

33. Schroder O, Laun RA, Held B, et al. Association of interleukin-10 promoter polymorphism with the incidence of multiple organ dysfunction following major trauma: results of a prospective pilot study. Shock. 2004;21:306–310.

34. Dinarello CA. Proinflammatory cytokines. Chest. 2000;118:503–508. 35. Cook MC. Immunology of trauma. Trauma. 2001;3:79–88. 36. Giannoudis PV, Hildebrand F, Pape HC. Inflammatory serum markers in

patients with multiple trauma. Can they predict outcome. J Bone Joint Surg Br. 2004;86:313–323.

37. Seekamp A, Jochum M, Ziegler M, et al. Cytokines and adhesion mol-ecules in elective and accidental trauma-related ischemia/reperfusion. J Trauma. 1998;44:874–882.

38. Botha AJ, Moore FA, Moore EE, et al. Postinjury neutrophil priming and activation: an early vulnerable window. Surgery. 1995;118:358–364.

• Shock is likely the most common life-threatening diag-nosis made in the ICU.

• Despite technologic advances, it remains a significant source of morbidity and mortality.

• As the etiologies of shock are vast, the diagnosis of shock and its inciting source can be difficult to iden-tify. 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, pharmaco-logic agents, and resuscitation strategies.

• Past and current research efforts continue in hopes of optimizing the diagnosis and management of shock with the ultimate goal of improving patient outcomes.

key Points

References 1. LeDran HF. A Treatise, or Reflections Drawn from Practice on Gun-Shot

Wounds. London: England; 1737. 2. Morris EA. A Practical Treatise on Shock after Operations and Injuries.

London: Hardwicke; 1867. 3. Fischer H. Ueber den Shock. Samml Klin Vortr. 1870:10. 4. Maphoter ED. Shock, its nature, duration, and mode of treatment. BMJ.

1879;2:1023. 5. Crile GW. An Experimental Research into Surgical Shock. Philadelphia,

PA: JB Lippincott; 1899. 6. Cannon WB. Traumatic Shock. New York: D. Appleton and Company;

1923. 7. Blalock A. Experimental shock: the cause of the low blood pressure pro-

duced by muscle injury. Arch Surg. 1930;20:959–996. 8. Wiggers CJ. The Physiology of Shock. Cambridge, MA: Harvard Univer-

sity Press; 1950. 9. Report of the Surgeon General of the Army. 1900:318.

LWBK1580_C44_p380-395.indd 393 29/07/17 11:08 AM


39. Cochrane CG. Immunologic tissue injury mediated by neutrophilic leuko-cytes. Adv Immunol. 1968;9:97–162.

40. Fujishima S, Aikawa N. Neutrophil-mediated tissue injury and its modula-tion. Intensive Care Med. 1995;21:277–285.

41. Smith JA. Neutrophils, host defense, and inflammation: a double-edged sword. J Leuk Biol. 1994;56:672–686.

42. Kubes P, Ward PA. Leukocyte recruitment and the acute inflammatory response. Brain Pathol. 2000;10:127–135.

43. Abbassi O, Kishimoto TK, McIntire LV, et al. E-selectin supports neu-trophil rolling in vitro under conditions of flow. J Clin Invest. 1993; 92:2719–2730.

44. Bevilacqua MP, Pober JS, Mendrick DL, et al. Identification of an induc-ible endothelial-leukocyte adhesion molecule. Proc Natl Acad Sci. 1987; 84:9238–9242.

45. Geng J-G, Bevilacqua MP, Moore KL, et al. Rapid neutrophil adhesion to activated endothelium mediated by GMP-140. Nature. 1990;343:757–760.

46. Jones DA, Abbassi O, McIntire LV, et al. P-selectin mediates neutro-phil rolling on histamine-stimulated endothelial cells. Biophys J. 1993; 65:1560–1569.

47. Kanwar S, Steeber DA, Tedder TF, et al. Overlapping roles for L-selectin and P-selectin in antigen-induced immune responses in the microvascula-ture. J Immunol. 1999;162:2709–2716.

48. Robinson SD, Frenette PS, Rayburn H, et al. Multiple, targeted deficien-cies in selectins reveal a predominant role for P-selectin in leukocyte recruitment. Proc Natl Acad Sci. 1999;96:11452–11457.

49. Diamond MS, Springer TA. The dynamic regulation of integrin adhesive-ness. Curr Biol. 1994;4:506–517.

50. Berlin C, Bargatze RF, Campbell JJ, et al. Alpha 4 integrins mediate lymphocyte attachment and rolling under physiologic flow. Cell. 1995; 80:413–422.

51. Hemler ME. VLA proteins in the integrin family: structures, functions, and their role on leukocytes. Annu Rev Immunol. 1990;8:365–400.

52. Schmidt OI, Infanger M, Heyde CE, et al. The role of neuroinflammation in traumatic brain injury. Eur J Trauma. 2004;30:135–149.

53. Goris RJ, te Boekhorst TP, Neytinck JK, et al. Multiple organ failure— generalized autodestructive inflammation? Arch Surg. 1985;120:1109–1115.

54. Martins PS, Kallas EG, Neto MC, et al. Upregulation of reactive oxygen species generation and phagocytosis, and increased apoptosis in human neutrophils during severe sepsis and septic shock. Shock. 2003;20:208–212.

55. Powell WC, Fingleton B, Wilson CL, et al. The metalloproteinase matri-lysin proteolytically generates active soluble Fas ligand and potentiates epithelial cell apoptosis. Curr Biol. 1999;9:1441–1447.

56. Grote K, Flach I, Luchtefeld M, et al. Mechanical stretch enhances mRNA expression and proenzyme release of matrix metalloproteinase-2 (MMP-2) via NAD(P)H oxidase-derived reactive oxygen species. Circ Res. 2003;92: e80–e86.

57. Winterbourn CC, Buss IH, Chan TP, et al. Protein carbonyl measurements show evidence of early oxidative stress in critically ill patients. Crit Care Med. 2000;28:143–149.

58. Kazzaz JA, Xu J, Palaia TA, et al. Cellular oxygen toxicity. Oxidant injury without apoptosis. J Biol Chem. 1996;271:15182–15186.

59. Kretzschmar M, Pfeiffer L, Schmidt C, et al. Plasma levels of glutathione, alpha-tocopherol and lipid peroxides in polytraumatized patients; evi-dence for a stimulating effect of TNF alpha on glutathione synthesis. Exp Toxicol Pathol. 1998;50:477–483.

60. Shohami E, Beit-Yannai E, Horowitz M, et al. Oxidative stress in closed-head injury: brain antioxidant capacity as an indicator of functional out-come. J Cereb Blood Flow Metab. 1997;17:1007–1019.

61. Lewen A, Matz P, Chan PH. Free radical pathways in CNS injury. J Neu-rotrauma. 2000;17:871–890.

62. Laroux FS, Pavlick KP, Hines IN, et al. Role of nitric oxide in inflamma-tion. Acta Physiol Scand. 2001;173:113–118.

63. Skidgel RA, Gao XP, Brovkovych V, et al. Nitric oxide stimulates macro-phage inflammatory protein-2 expression in sepsis. J Immunol. 2002;169: 2093–2101.

64. Fosse E, Pillgram-Larsen J, Svennevig JL, et al. Complement activation in injured patients occurs immediately and is dependent on the severity of the trauma. Injury. 1998;29:509–514.

65. Mollnes TE, Fosse E. The complement system in trauma-related and isch-emic tissue damage: a brief review. Shock. 1994;2:301–310.

66. Stahel PF, Morganti-Kossmann MC, Kossmann T. The role of the comple-ment system in traumatic brain injury. Brain Res Brain Res Rev. 1998; 27:243–256.

67. Sugimoto K, Hirata M, Majima M, et al. Evidence for a role of kallikrein–kinin system in patients with shock after blunt trauma. Am J Physiol. 1998; 274:1556–1560.

68. Abraham E. Coagulation abnormalities in acute lung injury and sepsis. Am J Respir Cell Mol Biol. 2000;22:401–404.

69. Idell S. Coagulation, fibrinolysis, and fibrin deposition in acute lung injury. Crit Care Med. 2003;31:s213–s220.

70. Fan J, Kapus A, Li YH, et al. Priming for enhanced alveolar fibrin deposi-tion after haemorrhagic shock: role of tumor necrosis factor. Am J Respir Cell Mol Biol. 2000;22:412–421.

71. Gando S, Kameue T, Matsuda N, et al. Combined activation of coagulation and inflammation has an important role in multiple organ dysfunction and poor outcome after severe trauma. Thromb Haemost. 2002;88:943–949.

72. Rigby AC, Grant MA. Protein S: a conduit between anticoagulation and inflammation. Crit Care Med. 2004;32:S336–S341.

73. Levi M, de Jonge E, van der Poll T. New treatment strategies for dissemi-nated intravascular coagulation based on current understanding of the pathophysiology. Ann Med. 2004;36:41–49.

74. Lo EH, Wang X, Cuzner ML. Extracellular proteolysis in brain injury and inflammation: role for plasminogen activators and matrix metalloprotein-ases. J Neurosci Res. 2002;69:1–9.

75. Du Clos TW. Function of C-reactive protein. Ann Med. 2000;32:274–278. 76. Whicher JT, Evans SW. Acute phase proteins. Hosp Update. 1990:899. 77. Lennard AC. Interleukin-1 receptor antagonist. Crit Rev Immunol. 1995;

15:77–105. 78. Chikanza IC, Grossman AB. Neuroendocrine immune responses to inflam-

mation: the concept of the neuroendocrine immune loop. Bailliere’s Clin Rheumatol. 1996;10:199–225.

79. Emsley J, White HE, O’Hara BP, et al. Structure of pentameric human serum amyloid P component. Nature. 1994;367:338–345.

80. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med. 1999;340:448–454.

81. Urieli-Shoval S, Linke RP, Matzner Y. Expression and function of serum amyloid A, a major acute-phase protein, in normal and disease states. Curr Opin Hematol. 2000;7:64–69.

82. Babaev A, Frederick PD, Pasta DJ, et al. Trends in management and out-comes of patients with acute myocardial infarction complicated by cardio-genic shock. JAMA. 2005;294:448–454.

83. Moore FA, McKinley BA, Moore EE, et al. Inflammation and the host response to injury, a large-scale collaborative project: patient-oriented research core—standard operating procedures for clinical care III. Guide-lines for shock resuscitation. J Trauma. 2006;61:82–89.

84. American College of Surgeons. Advanced Trauma Life Support for Doc-tors. 7th ed. Chicago: American College of Surgeons; 2004.

85. Wiggers CJ. Experimental Hemorrhagic Shock. New York: Common-wealth Fund; 1950.

86. Bergstein JM, Slakey DP, Wallace JR, et al. Traumatic hypothermia is related to hypotension, not resuscitation. Ann Emerg Med. 1996;27:39–42.

87. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treat-ment of severe sepsis and septic shock. N Engl J Med. 2001;345:1368–1377.

88. O’Neill PJ, Cobb LM, Ayala A, et al. Aggressive fluid resuscitation following intestinal ischemia-reperfusion in immature rats prevents metabolic derange-ments and down regulates interleukin-6 release. Shock. 1994;1:381–387.

89. Smith T, Grounds RM, Rhodes A. Central venous pressure: uses and limi-tations. In: Pinsky MR, Payen D, eds. Functional Hemodynamic Moni-toring. Update in Intensive Care and Emergency Medicine. No. 42. New York: Springer-Verlag; 2005:99.

90. Marini JJ, Leatherman JW. Pulmonary artery occlusion pressure: mea-surement, significance, and clinical uses. In: Pinsky MR, Payen D, eds. Functional Hemodynamic Monitoring. Update in Intensive Care and Emergency Medicine. No. 42. New York: Springer-Verlag; 2005:111.

91. Singer M. Esophageal Doppler monitoring. In: Pinsky MR, Payen D, eds. Functional Hemodynamic Monitoring. Update in Intensive Care and Emergency Medicine. No. 42. New York: Springer-Verlag; 2005:193.

92. Vignon P. Hemodynamic assessment of critically ill patients using echocar-diography Doppler. Curr Opin Crit Care. 2005;11:227–234.

93. Finfer S, Bellomo R, Boyce N. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004;350: 2247–2256.

94. Williams EL, Hildebrand KL, McCormick SA, et al. The effect of intrave-nous lactated Ringer’s solution versus 0.9% sodium chloride solution on serum osmolality in human volunteers. Anesth Analg. 1999;88:999–1003.

95. Koustova E, Stanton K, Gushchin V, et al. Effects of lactated Ringer’s solu-tions on human leukocytes. J Trauma. 2002;52:872–878.

96. Rhee P, Wang D, Ruff P, et al. Human neutrophil activation and increased adhesion by various resuscitation fluids. Crit Care Med. 2000;28:74–78.

97. Gushchin V, Stegalkina S, Alam HB, et al. Cytokine expression profiling in human leukocytes after exposure to hypertonic and isotonic fluids. J Trauma. 2002;52:867–871.

LWBK1580_C44_p380-395.indd 394 29/07/17 11:08 AM


98. Khanna S, Davis D, Peterson B, et al. Use of hypertonic saline in the treat-ment of severe refractory posttraumatic intracranial hypertension in pedi-atric traumatic brain injury. Crit Care Med. 2000;28:1144–1151.

99. Huang PP, Stucky FS, Dimick AR, et al. Hypertonic sodium resuscitation is associated with renal failure and death. Ann Surg. 1995;221:543–554.

100. Kreimeier U, Messmer K. Small-volume resuscitation: from experimental evidence to clinical routine: advantages and disadvantages of hypertonic solutions. Acta Anaesthesiol Scand. 2002;46:625–638.

101. Fleck A, Hawker F, Wallace PI, et al. Increased vascular permeability: a major cause of hypoalbuminaemia in disease and injury. Lancet. 1985;1: 781–784.

102. Kohler JP, Rice CL, Zarins CK, et al. Does reduced colloid oncotic pressure increase pulmonary dysfunction in sepsis? Crit Care Med. 1981;9:90–93.

103. Blunt MC, Nicholson JP, Park GR. Serum albumin and colloid osmotic pressure in survivors and non-survivors of prolonged critical illness. Anaesthesia. 1998;53:755–761.

104. Golub R, Sorrento JJ Jr, Cantu RJ, et al. Efficacy of albumin supplementa-tion in the surgical intensive care unit: a prospective, randomized study. Crit Care Med. 1994;22:613–619.

105. McCluskey A, Thomas AN, Bowles BJ, et al. The prognostic value of serial measurements of serum albumin in patients admitted to an intensive care unit. Anaesthesia. 1996;51:724–727.

106. Stockwell MA, Soni N, Riley B. Colloid solutions in the critically ill. A randomized comparison of albumin and polygeline. I. Outcome and dura-tion of stay in the intensive care unit. Anaesthesia. 1992;47:3–6.

107. Boldt J, Hessen M, Mueller M, et al. The effects of albumin versus hydroxyethyl starch solution on cardiorespiratory and circulatory vari-ables in critically ill patients. Anesth Analg. 1996;83:254–261.

108. Cochrane Injuries Group Albumin Reviewers. Human albumin adminis-tration in critically ill patients: systematic review of randomised controlled trials. BMJ. 1998;317:235–240.

109. Wilkes MM, Navickis RJ. Patient survival after human albumin adminis-tration: a meta-analysis of randomized, controlled trials. Ann Intern Med. 2001;135:149–164.

110. Alderson P, Bunn F, Li Wan Po A, et al. Human albumin solution for resus-citation and volume expansion in critically ill patients. Cochrane Library. 2006;3.

111. Treib J, Haass A, Pindur G. Coagulation disorders caused by hydroxyethyl starch. Thromb Haemost. 1997;78:974–983.

112. Cittanova ML, Leblanc I, Legendre C, et al. Effect of hydroxyethyl starch in brain-dead kidney donors on renal function in kidney-transplant recipi-ents. Lancet. 1996;348:1620–1622.

113. Schortgen F, Lacherade JC, Bruneel F, et al. Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study. Lancet. 2001;357:911–916.

114. Treib J, Haass A, Pindur G, et al. All medium starches are not the same: influence of the degree of hydroxyethyl substitution of hydroxyethyl starch on plasma volume, hemorrheologic conditions, and coagulation. Transfu-sion. 1996;36:450–455.

115. Schmand JF, Ayala A, Morrison MH, et al. Effects of hydroxyethyl starch after trauma-hemorrhagic shock: restoration of macrophage integ-rity and prevention of increased circulating IL-6 levels. Crit Care Med. 1995;23:806–814.

116. Handrigan MT, Burns AR, Donnachie EM, et al. Hydroxyethyl starch inhibits neutrophil adhesion and transendothelial migration. Shock. 2005; 24:434–439.

117. Dieterich HJ, Weissmuller T, Rosenberger P, et al. Effect of hydroxyethyl starch on vascular leak syndrome and neutrophil accumulation during hypoxia. Crit Care Med. 2006;34:1775–1782.

118. Perel P, Roberts I, Ker K. Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database Syst Rev. 2013:2:CD000567.

119. Shippy CR, Shoemaker WC. Hemodynamic and colloid osmotic pressure alterations in the surgical patient. Crit Care Med. 1983;11:191–195.

120. Cotton BA, Guy JS, Morris JA Jr, et al. The cellular, metabolic, and systemic consequences of aggressive fluid resuscitation strategies. Shock. 2006; 26:115–121.

121. Mouncey PR, Osborn TM, Power GS; ProMISe Trial Investigators. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med. 2015; 372(14):1301–1311.

122. Holcomb JB, Tilley BC, Baraniuk S; PROPPR Study Group. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortal-ity in patients with severe trauma: the PROPPR randomized clinical trial. JAMA. 2015;313(5):471–482.

123. Mullner M, Urbanek B, Havel C, et al. Vasopressors for shock. Cochrane Database Syst Rev. 2004;3:CD003709.

124. Albanese J, Leone M, Garnier F, et al. Renal effects of norepinephrine in septic and nonseptic patients. Chest. 2004;126:534–539.

125. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580–637.

126. Bellomo R, Chapman M, Finfer S, et al. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Aus-tralian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet. 2000;356:2139–2143.

127. Hollenberg SM, Kavinsky CJ, Parrillo JE. Cardiogenic shock. Ann Intern Med. 1999;131:47–59.

128. Sakr Y, Reinhart K, Vincent JL, et al. Does dopamine administration in shock influence outcome? Results of the Sepsis Occurrence in Acutely Ill Patients (SOAP) Study. Crit Care Med. 2006;34:589–597.

129. Martin C, Viviand X, Leone M, et al. Effect of norepinephrine on the outcome of septic shock. Crit Care Med. 2000;28:2758–2765.

130. Kohsaka S, Menon V, Lowe AM, et al. Systemic inflammatory response syndrome after acute myocardial infarction complicated by cardiogenic shock. Arch Intern Med. 2005;165:1643–1650.

131. Vallet B, Chopin C, Curtis SE, et al. Prognostic value of the dobutamine test in patients with sepsis syndrome and normal lactate values: a prospec-tive, multicenter study. Crit Care Med. 1993;21:1868–1875.

132. Cuffe MS, Califf RM, Adams KF Jr, et al. Short-term intravenous milri-none for acute exacerbation of chronic heart failure: a randomized con-trolled trial. JAMA. 2002;287:1541–1547.

133. Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Engl J Med. 2001;345:588–595.

134. Cooper DJ, Russell JA, Walley KR, et al. Vasopressin and septic shock trial (VASST): innovative features and performance. Am J Respir Crit Care Med. 2003;167:A838.

135. Abou-Khalil B, Scalea TM, Trooskin SZ, et al. Hemodynamic responses to shock in young trauma patients: need for invasive monitoring. Crit Care Med. 1994;22:633–639.

136. Shoemaker WC, Montgomery ES, Kaplan E, et al. Physiologic patterns in surviving and nonsurviving shock patients: use of sequential cardiorespira-tory variables in defining criteria for therapeutic goals and early warning of death. Arch Surg. 1973;106:630–636.

137. Shoemaker WC, Appel PL, Kram HB, et al. Prospective trial of supranor-mal values of survivors as therapeutic goals in high risk surgical patients. Chest. 1988;94:1176–1186.

138. Velmahos GC, Demetriades D, Shoemaker WC, et al. Endpoints of resusci-tation of critically injured patients: normal or supranormal? A prospective randomized trial. Ann Surg. 2000;232:409–418.

139. Eisenberg PR, Jaffe AS, Schuster DP. Clinical evaluation compared to pul-monary artery catheterization in the hemodynamic assessment of critically ill patients. Crit Care Med. 1984;12:549–553.

140. Connors AF Jr, McCafree DR, Gray BA. Evaluation of right heart cath-eterization in the critically ill patient without acute myocardial infarction. N Engl J Med. 1983;308:263–267.

141. Shoemaker WC, Bland RD, Appel PL. Therapy of critically ill postopera-tive patients based on outcome prediction and prospective clinical trials. Surg Clin North Am. 1985;65:811–833.

142. Bishop MH, Shoemaker WC, Appel PL, et al. Prospective, randomized trial of survivor values of cardiac index, oxygen delivery, and oxygen consumption as resuscitation endpoints in severe trauma. J Trauma. 1995;38:780–787.

143. Pinsky MR. Beyond global oxygen supply-demand relations: in search of measures of dysoxia. Intensive Care Med. 1994;20:1–3.

144. Shoemaker WC, Appel PL, Kram HB. Hemodynamic and oxygen trans-port responses in survivors and nonsurvivors of high-risk surgery. Crit Care Med. 1993;21:977–990.

145. Connors AF Jr, Speroff T, Dawson NV, et al. The effectiveness of right heart catheterization in the initial care of critically ill patients. SUPPORT Investigators. JAMA. 1996;276:889–897.

146. Thoren A, Elam M, Ricksten SE. Differential effects of dopamine, dopex-amine, and dobutamine on jejunal mucosal perfusion early after cardiac surgery. Crit Care Med. 2000;28:2338–2343.

147. Balasubramanyan N, Havens PL, Hoffman GM. Unmeasured anions identified by the Fencl-Stewart method predict mortality better than base excess, anion gap, and lactate in patients in the pediatric intensive care unit. Crit Care Med. 1999;27:1577–1581.

148. Davis JW, Kaups KL, Parks SN. Base deficit is superior to pH in evaluating clearance of acidosis after traumatic shock. J Trauma. 1998;44:114–118.

149. Vincent J-L, Dufaye P, Berre J, et al. Serial lactate determinations during circulatory shock. Crit Care Med. 1983;11:449–451.

150. Horecker BL. The absorption spectra of hemoglobin and its derivatives in the visible and near infra-red regions. J Biol Chem. 1943;148:173–183.

151. Taylor JH, Mulier KE, Myers DE, et al. Use of near-infrared spectros-copy in early determination of irreversible hemorrhagic shock. J Trauma. 2005;58:1119–1125.

LWBK1580_C44_p380-395.indd 395 29/07/17 11:08 AM

s. rob todd, krista l. turner, and frederick a. moore · aforementioned increased peripheral...

Documents