Multiple Organ Dysfunction Syndrome · Multiple Organ Dysfunction Syndrome Oya M. andacOglu and Stephen O. heard IMMeDIate COnCernS Major Problems Progressive dysfunction of multiple

528

CHAPTER

52Multiple Organ Dysfunction SyndromeOya M. andacOglu and Stephen O. heard

IMMeDIate COnCernS

Major Problems

Progressive dysfunction of multiple organ systems, culminat-ing in the syndrome of multiple organ dysfunction syndrome (MODS), has become a leading cause of death in critically ill and injured patients and is a disease of medical progress. Broader use of intensive care unit (ICU) resources, combined with improvements in single organ–directed therapy, such as mechanical ventilation and renal replacement therapy, has reduced early mortality after major physiologic insults. The result is a longer ICU stay for an increasing number of patients after severe sepsis and trauma, during which inflammation and tissue injury may result in MODS.

MODS represents a systemic disorder of immunoregula-tion, endothelial dysfunction, and hypermetabolism, with varying manifestations in individual organs. The mortality of MODS will increase as the number of failing organs increases, but organs differ in their host defense functions and sensi-tivity to host-derived inflammatory mediators or reductions in oxygen delivery (

.DO2). Therefore, diagnosis and therapy

focus on preventive measures. Changes in the cellular O2 sup-ply and metabolism may cause and complicate MODS. Conse-quences can include direct hypoxic organ damage, secondary ischemia/reperfusion (I/R) injury mediated by neutrophils and reactive O2 species (ROS), and enhanced injury by activation of cytokines. Initial and subsequent therapy follows a two-tiered approach, targeting systemic factors that contribute to ongoing inflammation and single organ–related problems. Efforts are first directed at stabilizing

.DO2 while addressing

life-threatening derangements in acid–base balance and gas exchange. Prompt correction of hemodynamic instability mini-mizes ischemia-related organ damage; time is a critical factor. Delays in completing initial resuscitation, eliminating foci of infection or devitalized tissue, or treating de novo organ-specific problems all worsen outcome. Late-phase (>72 hours) problems involve acquired immunosuppression, predisposition to second-ary infection, and hypermetabolism, which impairs wound healing and host defense.

epIDeMIOlOgy Of MultIple Organ DySfunCtIOn SynDrOMe

Significant advances have been made in critical care medicine over the past 35 years, particularly in the last decade. None-theless, many critically ill patients often suffer the progressive deterioration in the function of one or more organs, a phenom-enon that has been termed MODS (1), and is the leading cause of death for ICU patients. In MODS, the death rate remains

high even for patients who survive their ICU admission, and the financial costs are significant, with more than 60% of ICU resources consumed by these patients (2).

Individual organ dysfunction may result from a direct insult, such as pulmonary aspiration of gastric contents (pri-mary MODS), or it can be associated with a systemic process such as shock or pancreatitis (secondary MODS) (1). Altera-tions in organ function seen during MODS are a continuum rather than a discrete, dichotomous event indicating the failure of an organ. A number of organ dysfunction scores have been developed to predict the clinical outcome of these patients (Table 52.1). These scores establish the baseline degree of organ dysfunction and enable the clinician to evalu-ate the progression or resolution of organ dysfunction over time; in general, an increase in the number of dysfunctional organs increases the risk of death. Examples of early scores of organ failure include those published by Goris et al. (3) and Knaus et al. (4). Refinement of these scores led to the devel-opment of the MODS (5) and the sequential organ failure assessment (SOFA) scores (6). In principle, these are based on parameters for six organ systems: Cardiovascular, respira-tory, hematologic, renal, central nervous system (CNS), and hepatic (7); the difference in the scores lies in the descriptive parameter for cardiovascular dysfunction. The MOD score describes the degree of cardiovascular dysfunction as a com-posite of heart rate, central venous pressure, and mean arte-rial pressure (MAP) (pressure-adjusted heart rate), whereas the SOFA score describes cardiovascular dysfunction by the dose of vasoactive agents administered.

Several trials have evaluated the performance of these scores as descriptors of multiple organ dysfunction and fail-ure, and to assess the incidence of MODS in the intensive care unit. Moreno et al., in a prospective, international multicenter trial composed of 1,449 patients, were able to demonstrate that total maximum SOFA score and change in SOFA score over time (δ) can be used to quantify the degree of organ dys-function present on ICU admission, the degree of dysfunction or failure that appears during the ICU stay, and the cumu-lative insult suffered by the patient (7). These findings were subsequently confirmed by Ferreira et al. (10), demonstrating that changes in the SOFA score were a good indicator of prog-nosis. In their study of 352 consecutive patients, an increase in SOFA score during the first 48 hours of intensive care pre-dicted a mortality rate of at least 50% (10). In a group of patients with acute respiratory distress syndrome (ARDS), the Toronto ARDS Outcomes Group found a significant relation-ship between the change in MOD score over time of the ICU stay and the distance walked in 6 minutes up to 1 year follow-ing discharge from the ICU (11). The European Sepsis Occur-rence in Acutely Ill Patients (SOAP) multicenter trial analyzed data from 3,147 adult ICU admissions to determine the inci-dence of MODS and its associated mortality in mixed medical and surgical ICU populations (12). The overall rate of MODS,

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CHAPTER 52 Multiple Organ dysfunction Syndrome 529

TABLE 52.1 Comparison of the Physiologic and Biochemical Parameters Used by Four Scoring Systems for Organ Dysfunction and Failure

Organ SystemSequential Organ Failure Assessment (SOFA) (6)

Multiple Organ Dysfunction Score (MOD) (5)

Logistic Organ Dysfunction (LOD) (8) Brussels (9)

cardiovas-cular

Blood pressure and vasopressor use

Blood pressure and adjusted heart rate

Blood pressure and heart rate Blood pressure, fluid responsiveness, and acidosis

pulmonary paO2/FiO2 and mechanical ventilation

paO2/FiO2 paO2/FiO2 and mechanical ventilation

paO2/FiO2

hepatic Bilirubin Bilirubin Bilirubin and prothrombin time Bilirubin

hematologic platelets platelets platelets and white blood cell count

platelets

renal creatinine and urine output creatinine creatinine, blood urea nitrogen, or urine output

creatinine

central ner-vous system

glasgow coma score (gcS)

gcS gcS gcS

reprinted from Bernard gr. Quantification of organ dysfunction: seeking standardization. Crit Care Med. 1998;26:1767–1768, with permission.

defined as severe acquired dysfunction in two or more organ systems, was 43% for patients without a diagnosis of sepsis and 73% of those with a diagnosis of severe sepsis, a sub-stantially higher incidence than previously reported (4). Like other investigators, they found a direct relationship between the number of organs failing and the ICU mortality (Fig. 52.1). Single organ failure carried an ICU mortality rate of 6%, whereas patients with four or more failing organs had mortal-ity rates of 65%. Although earlier reports have suggested that the increase in mortality associated with an increased number of failed organs is independent of the identity of dysfunctional organ systems (13–15), the SOAP investigators found differ-ent results. Organ failure in patients with severe sepsis gener-ally carried a higher mortality than in those patients without a diagnosis of severe sepsis. In the group of patients with severe sepsis, failure of the coagulation system carried the highest mortality (52.9%), followed by the hepatic (45.1%), CNS (43.9%), cardiovascular (42.3%), and renal system (41.2%). Respiratory failure in this analysis was associated with a mor-tality risk of 34.5%. Certain subsets of patients admitted to the ICU appear to be at greater risk of MODS: patients older than 65 years (older than 55 years in trauma patients) (15), increased severity of illness as assessed by APACHE II scores (20 or more), and diagnosis of sepsis or ARDS on admission. Among the patients with severe sepsis, the SOAP investigators found as independent predictors of mortality the following: “medical” admissions, Pseudomonas species infection, SAPS II score on admission, SOFA score at the onset of sepsis, bloodstream infection, cirrhosis, and cumulative fluid balance within the first 72 hours of the onset of sepsis. The latter vari-able has been identified as an independent predictor of mortal-ity in other studies (16,17) but it remains uncertain whether a

positive fluid balance in the ICU is simply a marker of severity of illness or is harmful per se.

pathOphySIOlOgy

MODS usually occurs in patients who exhibit signs of a general-ized inflammatory response (systemic inflammatory response syn-drome [SIRS]; Table 52.2) (1). Although SIRS is often the result of infection (triggered by microbial products), other conditions such as necrotizing pancreatitis or trauma can release patient-derived factors called danger-associated molecular patterns (DAMPs) that lead to systemic manifestations of inflammation (18). Two or more SIRS criteria due to infection have been defined as sep-sis. However, the need for two SIRS criteria to define sepsis will exclude one out of eight patients with sepsis and organ failure (19). Updated guidelines have broadened the diagnostic criteria for sepsis that were originally proposed in 1992 (20). Analysis of these two definitions shows high sensitivity for diagnosing sepsis but with a low specificity (21). For those patients who present with SIRS only, a significant number will progress to sepsis, septic shock, and, ultimately, MODS (22). Although suspected or docu-mented infection is not required for the development of MODS, the syndromes of SIRS, sepsis, and MODS are closely related. Consequently, the review of the pathophysiology of MODS will also include discussions of SIRS and sepsis.

Derangements in Oxygen Delivery and Consumption

In most tissues, oxygen consumption ( .VO2) is determined by

metabolic demand and is independent of .DO2. When

.DO2 is

Mo

rtal

ity

70

60

50

40

30

20

10

00 1 2 3 4 or more

fIgure 52.1 relationship between the number of failed organs on admission and intensive care unit mortality. (From Vincent J-l, Sakr y, Sprung cl, et al. Sepsis in european intensive care units: results of the SOap study. Crit Care Med. 2006;34: 344–353, with permission.)

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530 SECTion 5 ShOck and MultiSySteM Failure

reduced, .VO2 is maintained by increased oxygen extraction by

the tissues. If .DO2 is reduced to the point where the meta-

bolic need cannot be met, .VO2 becomes “supply dependent”

(Fig. 52.2). The point at which .VO2 decreases is called the

critical .DO2. Although one study (23) suggested that the

critical .DO2 in anesthetized humans is 330 mL/min/m2, another

investigation in which life support was withdrawn in critically ill patients demonstrated that the value is substantially lower (24).

A number of studies from the 1970s, 1980s, and early 1990s seemed to suggest that systemic

.VO2 was supply depen-

dent over a wide range of .DO2 in patients with sepsis or ARDS,

a condition termed “pathologic supply dependency.” The validity of the concept of pathologic supply dependency was subsequently challenged as clinical investigations that utilized independent means to measure both

.DO2 and

.VO2 failed to

demonstrate pathologic supply dependency in patients with ARDS or sepsis.

More recently, there has been a recognition that non-global supply dependency may occur in patients. There is an increasing appreciation that the regional circulation and microcirculation—arterioles, capillary bed, and postcapil-lary venules—play a crucial role in the pathogenesis of organ

dysfunction in shock. Heterogeneous microcirculatory abnor-malities occur due to changes in the activation state and shape of endothelial cells, alterations in vascular smooth muscle tone, activation of the clotting system, and changes in red and white blood cell deformability. Alterations in microvascular circulation have been demonstrated in congestive heart fail-ure, cardiogenic shock, hemorrhage, and sepsis; in congestive heart failure these include reduced conjunctival microvascu-lar density and attenuated nailfold capillary recruitment dur-ing postocclusive reactive hyperemia (25). Animal models of hemorrhagic shock demonstrate attenuated functional capil-lary perfusion—a measure of the number of capillaries that are actively moving blood—of skeletal muscle and the intes-tinal villi (26,27). Renal and intestinal regional blood flow is reduced despite resuscitation and return of global hemody-namics back to baseline values (28). Tissue (skeletal muscle) oxygen saturation in septic patients is no different than that observed in healthy controls or postsurgical patients (29); however, microvascular compliance and skeletal muscle oxy-gen consumption is reduced, and postischemic reperfusion time is increased compared to controls. Sidestream dark field (SDF) imaging is a technique by which perfusion of small and large vessels in the microcirculation of mucosal surfaces can be seen and quantified. Clinical studies (30,31) where SDF imag-ing has been utilized have shown that the fraction of perfused small vessels in patients with severe heart failure, cardiogenic shock, or sepsis is significantly lower than in those critically ill patients without those conditions (Fig. 52.3). Furthermore, alter-ations in microvascular perfusion are a strong predictor of poor ICU outcome in patients with severe sepsis (32). Transfusion of packed red blood cells may improve microcirculatory perfusion in patients who are identified as having altered microcircula-tory perfusion by SDF imaging. Nonetheless, efforts to improve microcirculatory flow with a variety of agents—including nitro-glycerin, dobutamine (33), inhaled nitric oxide (NO) (34), enoxi- mone, dopamine, and corticosteroids—have had no effect on organ dysfunction (35).

Functional cellular hypoxia—“cytopathic hypoxia”—or metabolic failure is a condition where the cell is incapable of utilizing oxygen to produce ATP despite adequate oxygen delivery (36–38). The defect in oxygen utilization likely resides in the mitochondrion. Rapid autopsies of patients dying from

TABLE 52.2 American College of Chest Physicians/Society of Critical Care Medicine Definitions of Sepsis and Organ Failure

A. InfectionMicrobial phenomenon characterized by an inflammatory

response to the presence of the microorganism or the invasion of normally sterile host tissue by those organisms

B. Bacteremiathe presence of viable bacteria in the blood

C. Systemic inflammatory response syndrome (SIRS)the systemic inflammatory response to a variety of severe

clinical insults, manifested by any of the following conditions:1. temperature greater than 38°c or less than 36°c2. heart rate greater than 90 beats/min

3. respiratory rate more than 20 breaths/min or pacO2 less than 32 mmhg

4. WBc more than 12,000 cells/μl, less than 4,000 cells/μl, or more than 10% immature (band) forms

D. Sepsisthe systemic response to infection. the manifestations are the

same as those enumerated for SirS.E. Severe sepsis

Sepsis associated with organ dysfunction, hypoperfusion, or hypotension

F. Septic shockSepsis with hypotension, despite adequate fluid resuscitation,

and perfusion abnormalities, including but not limited to the following:1. lactic acidosis

2. Oliguria

3. acute alteration in mental status

G. Hypotensiona systolic Bp less than 90 mmhg or a reduction of more than

4 mmhg from baseline in the absence of other causes for hypotension

H. Multiple organ dysfunction syndromepresence of altered organ function in an acutely ill patient

such that homeostasis cannot be maintained without intervention

WBc, white blood cell; Bp, blood pressure.condensed from american college of chest physicians/Society of critical

care Medicine 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.

Critical DO2

Oxygen delivery

Oxy

gen

co

nsu

mp

tio

n

fIgure 52.2 the relationship between oxygen delivery and consump-tion. the solid line represents the normal relationship. the dashed line shows pathologic supply dependency. (From heard SO, Fink Mp. Multiple- organ dysfunction syndrome. in: Murray MJ, coursin dB, pearl rg, et al., eds. Critical Care Medicine. Perioperative Management. philadelphia, pa: lippincott Williams & Wilkins; 2002.)

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sepsis show normal gross histology but significant mitochon-drial injury on electron microscopic examination (39). Muscle biopsies from septic patients reveal that skeletal muscle ATP concentrations and respiratory chain activity are lower com-pared to samples obtained from control patients (40,41). The mechanism by which cytopathic hypoxia or metabolic failure occurs has not been fully elucidated. However, NO and its metabolite, peroxynitrite, are mediators released during sep-sis and are inhibitors of the mitochondrial electron transport chain (42). Single-strand breaks in nuclear DNA can occur in sepsis by a variety of endogenously formed oxidants, includ-ing peroxynitrite. Poly(ADP-ribose) polymerase (PARP) is a highly energy dependent enzyme that is activated by the for-mation of these DNA breaks and may cause cellular energy depletion (43,44). Porphyrin-based agents which increase the degradation of peroxynitrite improve cardiovascular func-tion and decrease the incidence of MODS in animal models of septic shock (45). If the reduction in ATP production is suf-ficient, cell death should occur; however, this does not appear to the overriding cause of MODS. More likely, a new steady state is reached where there is enough ATP production for cell survival but not for all metabolic functions (18).

rOle Of InflaMMatOry anD VaSOaCtIVe MeDIatOrS

Although early clinical series emphasized the implication of uncontrolled infection in the development of MODS, it is clear that MODS can occur with either extensive tissue injury such as that seen with trauma, pancreatitis, or sepsis. A large amount of evidence is available that implicates the release of inflam-matory mediators in the pathogenesis of MODS (Table 52.3).

Complement, Neutrophils, and Reactive Oxygen Metabolites

The complement cascade is activated via three pathways (Fig. 52.4). The classical pathway is triggered by antibody-coated targets or antigen–antibody complexes. The alternative path-way is activated by aggregated immunoglobulins, products of tissue trauma, lipopolysaccharide (LPS), and other complex polysaccharides. The lectin-ficolin pathway is initiated by the binding of organisms to mannose–binding lectin (MBL), a protein important in innate immunity (46). Once MBL is bound to a pathogen, an MBL-associated serine protease is produced, which forms a C3 convertase by cleavage of C4 and C2. Products of the complement pathway activate neutrophils, which can obstruct capillaries and release oxygen radicals and lysosomal enzymes—among other mediators, thereby damag-ing the endothelium. Furthermore, adhesion molecules, which

TABLE 52.3 Inflammatory Mediators Important in the Pathogenesis of Sepsis and the Multiple Organ Dysfunction Syndrome

complement (c3a, c5a)

neutrophil productsproteases

neutral proteaseselastasecathepsin gcollagenase

acid hydrolasecathepsins B and dβ-glucuronidaseglucosaminase

Oxygen radicalsSuperoxide anionhydroxyl radicalhydrogen peroxideperoxynitrite

Bradykinin

lipid mediatorsprostaglandinsthromboxane a2

prostaglandin i2prostaglandin e2

leukotrienes (ltB4, ltc4, ltd4, lte4)

platelet-activating factor (paF)

cytokinestumor necrosis factor α (tnF-α)interleukins (il-1, il-6, il-8)high-mobility group 1 (hMg-1)

Macrophage migration inhibition factor (MiF)

nitric oxide

reprinted from heard SO, Fink Mp. Multiple-organ dysfunction syndrome. in: Murray MJ, coursin dB, pearl rg, et al., eds. Critical Care Medicine. Perioperative Man-agement. philadelphia, pa: lippincott Williams & Wilkins; 2002, with permission.

A

B

fIgure 52.3 Sublingual microcirculation as assessed by orthogo-nal polarization spectral imaging in a healthy volunteer (a) and in a patient with early septic shock (B). normal capillary density is observed in panel a whereas low capillary density is observed in panel B. real-time images may be viewed at http://www.cooperhealthorg/content/gme_fellowship_shock.htm. (From de Backer d, creteur J, preiser J-c, et al. Microvascular blood flow is altered in patients with sepsis. Am J Respir Crit Care Med. 2002;166:98–104, with permission.)

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are expressed on both polymorphonuclear leukocytes (PMNs) and vascular endothelium in response to LPS and other inflam-matory mediators, facilitate the adherence and diapedesis of PMNs through the endothelium.

A significant amount of animal evidence exists suggesting that complement activation is important in the pathophysiology of MODS (47–50). Clinically, activation of both complement and neutrophils occurs in patients with ARDS or burns (51,52), and circulating plasma levels of C3a correlate with severity of injury and outcome in patients with multiple trauma (53). Evi-dence of complement and neutrophil activation has also been found in bronchoalveolar lavage (BAL) from patients with ARDS (54). Administration of a C1 inhibitor in patients with severe sepsis and septic shock reduces neutrophil activation (55) and improves renal function and SOFA scores compared to untreated control patients (56).

Reactive oxygen species—superoxide anion, hydrogen per-oxide, and the hydroxyl radical—are produced in the mito-chondria and released by activated PMNs. They can injure tissues by damaging DNA, cross-linking cellular proteins, and causing peroxidation of membrane lipids (57,58), diminished membrane fluidity and increased membrane permeability, resulting in cellular dysfunction. The conclusion that toxic oxygen radicals are important in the pathophysiology of respi-ratory dysfunction comes from clinical studies of patients with ARDS where plasma levels of lipid peroxides are elevated, levels of hydrogen peroxide are increased in the expiratory condensate (59), and oxidative damage to proteins in BAL fluid is found (60); ARDS patients have reduced levels of oxygen radi-cal scavengers (e.g., α-tocopherol, ubiquinone, and glutathione),

a sign of “oxidant stress” (61,62). Antioxidant therapies, how-ever, have not translated into improved outcome for patients with ARDS or MODS. The OMEGA trial which examined dietary supplementation with omega-3 fatty acids, gamma-linolenic acid, and a number of antioxidants on the outcome of patients with ARDS showed the antioxidant group had fewer ventilator-free days, ICU free days and nonpulmonary organ failure free days (63). Other studies suggest such inter-ventions may improve days “free” of acute lung injury (ALI) (64), mechanical ventilation (65), and incidence of new organ failures (65); decrease SOFA scores (66); and reduce oxidative stress during septic shock (67).

The Kallikrein–Kinin System

The kallikrein–kinin system is part of the contact system, and is composed of complement, coagulation, and kallikrein–kinins, with bradykinin, the end product of this cascade, resulting in vasodilation and increased vascular permeability. Some of these effects are mediated by the release of secondary mediators, such as NO and eicosanoids. A bradykinin recep-tor antagonist (CP-0127) for the adjuvant therapy of sepsis failed to alter the 28-day mortality (68).

The Coagulation System

LPS and many proinflammatory mediators will activate the coagulation system (Fig. 52.5), primarily by the extrinsic tis-sue factor–dependent pathway, as these mediators induce the expression of tissue factor (TF) on monocytes and endothelial

Classical pathway

Lectin pathway

Alternative pathway

MBL, MASPs

C3 (H2O) C3 (H2O)B

C3 (H2O)Bb

C3bB C3bBb C3b3bBb

C5b+C6+C7+C8+C9

Terminal membraneattack complex(MAC, C5b-9)

C1qC1r C1s

C4

C4

C4a

C4a

C3a C5

PMN

Exudation

CapillaryMastcell

C5a

C4bC2

C4b2a

C4b2a3b

C4bC2

Microbial surfaces(mannose) and

others (e.g., IgA)

Spontaneously occurringand after contact with

foreign surfaces (e.g., LPS)

Immune(IgG + IgM)

complexes andothers (e.g., CRP)

C1-INH

C2b

C3b

Activation

Anaphylatoxin

Macrophage Endothelialcell

CAM

Chemotoxicfactors

Vascular permeabilitymediators

C2b

Factor D Factor D

Factor IFactor H

MCPCR1

fIgure 52.4 the three complement activation pathways (classic, alternative, and lectin). igg, immunoglobulin g; igM, immunoglobulin M; iga, immuno-globulin a; crp, c-reactive protein; MBl, mannose-binding lectin protein; MaSp, MBl-associated proteases; c1-inh, c1-inhibitor; lpS, lipopolysaccharide; caM, cell adhesion molecules; Mac, membrane attack complex; pMn, polymorphonuclear leukocytes; Mcp, monocyte chemoattractant protein; cr1, complement component receptor 1. (From goldfarb rd, parrillo Je. complement. Crit Care Med. 2005;33:S482–S484, with permission.)

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cells (69). Although these same mediators activate the fibri-nolytic system, subsequent increases in plasminogen activa-tor inhibitor-1 (PAI-1) and thrombin-activatable fibrinolysis inhibitor (TAFI) effectively suppress fibrinolysis. Important coagulation inhibitors—antithrombin, tissue factor pathway inhibitor (TFPI), protein C, protein S, and the endothelial-bound modulators heparan sulfate and thrombomodulin—may be downregulated (69), resulting in a net procoagulant tendency with potential for the development of disseminated intravascular coagulation (DIC). DIC can cause microvascular

thrombosis and organ failure, and/or bleeding from consump-tion of platelets and clotting factors (70,71). Nonetheless, three clinical trials of anticoagulant therapy failed to showed benefit in patients with severe sepsis (72–74).

Prostaglandins, Leukotrienes, and Platelet-Activating Factor

Prostaglandins (PGs), leukotrienes (LTs), and platelet-activating factor (PAF) are potent lipid mediators formed by the stimula-tion of a membrane-bound enzyme, phospholipase A2 (PLA2), via a variety of mediators including norepinephrine, adenosine, bradykinin, PAF, tumor necrosis factor (TNF), and interleukin (IL)-1β (75). PLA2 catalyzes membrane phospholipids to lyso-PAF and arachidonic acid (Fig. 52.6). Both experimental and clinical studies support the notion that these mediators play a role in the pathophysiology of sepsis and MODS.

Elevated plasma levels of thromboxane B2 (TXB2), the metabolite of the prostaglandin thromboxane A2 (TXA2), are observed in animal models of sepsis and are correlated with organ injury and outcome. However, clinical trials of nonselec-tive inhibitors of cyclo-oxygenase (COX) (ibuprofen) showed no effect on survival in sepsis (76) and a trial evaluating the effectiveness of a selective inhibitor of a group IIA secretory phospholipase in patients with suspected sepsis and organ fail-ure showed no effect on organ function (77). Ketoconazole, an imidazole derivative that inhibits thromboxane synthase, prevents the development of ARDS in patients at risk (78,79); established ARDS is not reversed nor is survival improved (80).

Significant data exists supporting the role of PAF in the pathogenesis of sepsis and MODS. In vitro, incubation of macrophages with PAF will lead to an exaggerated release of TNF and TF by these cells after LPS exposure; LPS-induced release of TNF by macrophages is inhibited by PAF recep-tor antagonists. PAF expression on the surface of endothelial

IX IXaCross-talk

VII VIIaTF

X

Xa

Va

VIIIa

Feedback

Prothrombin Thrombin

FibrinFibrinogen

fIgure 52.5 revised coagulation scheme. Viia complex is capable of mediating the conversion of factor iX to iXa directly, thereby establish-ing a link between the two pathways. thus, tF appears to have a dual role with respect to coagulation: (i) tF initiates coagulation through activation of factor X, and (ii) through its action on factor iX, tF supports amplification. an additional mechanism that supports the importance of the intrinsic cascade is activation of factor Viii through feedback mechanisms involving thrombin. (From aird Wc. coagulation. Crit Care Med. 2005;33:S485–S487, with permission.)

Membrane phospholipids

Arachidonic acid Isoprostanes

PLA2 inhibitor PLA2

ROI

COX-1COX-2

TX synthaseTX syn inhibitors

5’ LO

15 HETELXA4

12 HETE LTA4 PGH2

TXA2

PGD

LXA4

LTC4LTD4LTE4

LTD4 receptorantagonists

TXA2 receptorantagonists

LTB4 receptor antagonists

LTB4 PGI2 PGE2

PGJ2

− H2O

5’ LO inhibitor

15’ LO12’ LO

COX inhibitors

fIgure 52.6 the eicosanoid pathway. pla2, phospholipase a2; rOi, reactive oxygen intermediates; cOX, cyclo-oxygenase; lO, lipo-oxygenase; hete, hydroxyeicosatetraenoic acid; lt, leu-kotriene; tX, thromboxane; lX, lipoxin; pg, prostaglandin. (From cook Ja. eicosanoids. Crit Care Med. 2005;33: S488–S491, with permission.)

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cells will result in PMN adherence and activation. In addi-tion, stimulation of PAF receptors on the endothelium results in changes in cell shape and cytoskeletal structure. Clinically, depressed plasma levels of PAF acetylhydrolase (PAF-AH), the enzyme responsible for metabolizing PAF, have been observed in critically ill patients and correlate inversely with organ dysfunction. However, a phase III trial of recombinant PAF-AH failed to improve outcome or prevent organ dysfunction (81). A subsequent study of critically ill patients revealed that plasma levels of PAF-AH were variable over time and with severity of illness (82,83), providing a partial explanation for the lack of efficacy of recombinant PAF-AH.

Cytokines

Cytokines are small proteins secreted by nearly all nucleated cells and exhibiting autocrine, paracrine, or endocrine activ-ity (84,85); they are generally classified as proinflammatory or anti-inflammatory. This classification, however, is somewhat arbitrary as an individual cytokine may act in either fashion, depending on the underlying biologic process. Proinflamma-tory cytokines such as TNF and IL-1 can stimulate the release of other mediators: PAF, NO, LTs, and PGs.

TNF assumes an important role in the pathogenesis of human sepsis, septic shock, and MODS; it is directly cyto-toxic to some cell types, will induce the expression of adhe-sion molecules on neutrophils and endothelial cells to promote the recruitment of these cells to the site of injury or infection and will increase endothelial permeability. Metabolic effects attributable to TNF include activation of the acute-phase response, fever (along with IL-1), skeletal muscle catabolism, and increased peripheral lipolysis and hepatic lipogenesis (85). When injected into normal volunteers, small doses of LPS or recombinant TNF will reproduce many of the metabolic and hemodynamic changes observed in sepsis (83,86). Similar findings are observed in animal studies, and treatment with anti-TNF antibodies will prevent many of the adverse con-sequences of endotoxic or live gram-negative bacterial shock (87). However, in studies of critically ill patients, the correla-tion of plasma TNF levels and outcome is variable (88,89), possibly related to timing and method of the TNF assay, acuity, etiology, or treatment of the patient’s illness, or patient genetic differences. The modulation of TNF as a therapy for sepsis and MODS remains murky as multiple studies failed to show significant benefit of either anti-TNF antibodies or soluble TNF receptors in severe sepsis (90). In one trial where patients were stratified according to initial plasma levels of IL-6 (as a marker of severity of illness), outcome was improved, and organ dysfunction was ameliorated with the administration of a monoclonal antibody to TNF (91).

Like TNF, IL-1 has a wide variety of biologic actions and has been implicated in the pathogenesis of sepsis and MODS (92); these molecules often act synergistically. IL-1 induces the expression of COX-2 and inducible nitric oxide syn-thase (iNOS) expression (93). Furthermore, IL-1 increases the expression of other cytokines—most notably TNF and IL-6—chemokines, adhesion molecules, and a number of tissue proteases and matrix metalloproteases (93). IL-1 also stimulates the release of myeloid progenitor cells, resulting in neutrophilia (93). However, use of IL-1 receptor antagonists in patients with sepsis does not reduce mortality nor reverse organ failure (94–96).

Interleukin 6 (IL-6) is another cytokine that has been iden-tified to be important in the response to infection and devel-opment of MODS. Small doses of endotoxin administered to normal volunteers will stimulate the release of IL-6 (97). IL-6 will persist for longer periods of time in the blood than other cytokines and may serve as an important marker for the out-come of patients with sepsis or septic shock. Both the IL-6 receptor and the signaling receptor gp130 are required for the biologic activity of IL-6 to be realized (97). Murine models of hemorrhagic shock indicate that IL-6 is important in the devel-opment of gut barrier dysfunction (97). In addition, IL-6 may be important in promoting thrombosis during sepsis. Passive immunization with an anti–IL-6 antibody reduces activation of the coagulation cascade in a primate model of endotoxico-sis but has no effect on the coagulation abnormalities associ-ated with low-dose LPS in humans (98).

IL-8 is a chemotactic cytokine (chemokine) expressed prin-cipally by monocytes and macrophages by stimulation with LPS, bacteria, TNF, and IL-1 (99). IL-8 induces chemotaxis of inflammatory cells, and its presence at sites of inflammation may persist for long periods of time (99). That IL-8 is impor-tant in the development of MODS is made by the observation of high IL-8 levels in BAL fluid from patients with ARDS or pneumonia (100). Although neutralizing IL-8 may reduce car-diac ischemia/reperfusion injury in dogs, a reduction in che-mokines increases mortality in animal models of pneumonia (99).

High-mobility group box 1 (HMGB1) is a cytokine that was been identified as an inflammatory mediator (Fig. 52.7) (101). HMGB1 is released in a delayed manner from a variety of cells in response to LPS or bacteria (102). Exposure of the lung to HMGB1 increases neutrophil accumulation, edema, and other proinflammatory cytokines, whereas gastrointestinal expo-sure results in increased gut permeability and translocation of bacteria to mesenteric lymph nodes (102). Administration of this cytokine to animals causes death as a result of epithelial barrier disruption. Treatment of experimental endotoxicosis or sepsis with antibodies to HMGB1 or HMGB1 antagonists improves survival (101–103). There have been no clinical studies to evaluate the efficacy of anti-HMGB1 therapies in sepsis or other inflammatory conditions.

Macrophage migration inhibitory factor (MIF) is a cytokine that is found in macrophages in preformed cytoplasmic pools (104). It is released rapidly in response to bacterial products and works to upregulate and sustain the activation of a variety of cell types to produce TNF, IL-1, IL-6, and IL-8 (104). The major action of MIF may be the regulation of p53-dependent apoptosis. Anti-MIF therapy in animal models of sepsis is protective (104). Although MIF appears to be an important mediator of sepsis and sepsis-induced MODS (105), it does not appear to play a prominent role in tissue injury resulting from trauma (106).

Nitric Oxide

NO is an inorganic free-radical gas, produced by catalysis of one of the terminal guanidine nitrogens of L-arginine by the NOS group of enzymes (107). Two general classes of NOS have been described: Constitutive (calcium-dependent) NOS (neuro-nal and endothelial) and inducible (calcium-independent) NOS (108). The production of the latter enzyme is induced by LPS, TNF, and a variety of other inflammatory mediators. A variety

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of cells and tissues release NO, including endothelium, vascu-lar smooth muscle, neutrophils, and mononuclear, glial, mast, hepatic, and adrenal medullary cells (108). Vasorelaxation, neurotransmission, and microbicidal activity are some of the important functions that NO possesses. The role that NO plays in the host is a function of the rate and timing of its produc-tion and the surrounding environment. Normally, NO acts as a

direct signaling molecule (e.g., vasorelaxation and neurotrans-mission), and low levels of NO (produced by constitutive NOS and at times by inducible NOS) have protective effects (Fig. 52.8) (108). Alternatively, it may function as an indirect cyto-toxic agent and induce intestinal barrier dysfunction.

Significant experimental and clinical evidence suggests that NO plays an important role in the pathophysiology of

FeverAnorexia / Weight lossTaste aversionPainNeurite outgrowth

Neutrophil infiltrationEndothelial activationInflammationEdemaInjury

ArthritisInflammationArthritisInflammation

HMGBI

Macrophage activationMonocyte activationNeutrophil activationEndothelial activation↑ tPA / PAI

↑ Nitric oxide synthaseLoss of epithelial barrier functionBacterial translocationRelease of liver enzyme

fIgure 52.7 inflammatory responses in vari-ous areas of the host that are medicated by high-mobility group box 1 (hMgB1). tpa, tissue plasminogen activator; pai, plasmino-gen activator inhibitor. (From Wang h, yang h, tracey kJ. extracellular role of hMgB1 in inflam-mation and sepsis. J Intern Med. 2004;255: 320–331, with permission.)

Vasomotor relaxation

Protectiveeffects

Protectiveeffects (lowlevels)

Deleteriouseffects(high levels)

Triggers: Inflammation,cell stress, tissue injury,hypoxia, bacterialproducts, cytokines

NO

NOeNOS

iNOS

Decreased platelet aggregation

Reduced leukocyte adhesion

Radical scavenger

Host defense

Gut mucosal integrity

Exaggerated vasodilation

Altered vascular permeability

Cytotoxicity (DNA damage,lipid peroxidation)

Intestinal barrier dysfunctionfIgure 52.8 the divergent effects of nitric oxide (nO) derived from the endothelium (enOS, endothelial nitric oxide synthase) or as a con-sequence of inflammation (inOS, inducible or inflammatory nOS.) (From levy rM, prince JM, Bil-liar tr. nitric oxide: a clinical primer. Crit Care Med. 2005;33:S492–495, with permission.)

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sepsis and MODS. iNOS and NO production increase in ani-mals during both endotoxic and hemorrhagic shock. iNOS-deficient mice are protected from LPS-induced hypotension, and have a higher survival following endotoxicosis (109). NO contributes to TNF-induced cardiac dysfunction in a concen-tration-dependent fashion (110). Increased urinary excretion of NO metabolites (nitrite and nitrate) has been reported in septic patients and correlates inversely with systemic vascular resistance (SVR) (111).

Excess NO in the presence of superoxide anion results in the formation of peroxynitrite (ONOO (–)), a reactive oxidant that causes lipid peroxidation, inhibits mitochondrial respira-tion, inactivates glyceraldehyde-3-phosphate dehydrogenase, inhibits membrane sodium/potassium ATP activity, and triggers DNA single-strand breakage. As mentioned previously, DNA damage activates the nuclear enzyme, PARP, which can lead to cellular energy depletion and death (109). Furthermore, exces-sive amounts of NO and peroxynitrite can activate the tran-scription factor, NFκB, and amplify the inflammatory response (112).

The efficacy of inhibitors of NOS in the treatment of sep-sis and MODS is unclear, and the use of some inhibitors may actually be detrimental. Although hypotension, vascular leak, and vasopressor requirements can be reduced with the use of nonspecific NOS inhibitors, microcirculatory blood flow can be altered, resulting in organ injury. Indeed, a large random-ized, prospective trial evaluating the efficacy of the nonspecific NOS inhibitor, L-N (G)-monomethylarginine, in patients with septic shock was stopped early because the death rate was higher in the intervention group (113).

the enDOthelIuM

The role of the vascular endothelium is to control the flow of nutrients, blood cells, and a broad array of biologically active molecules to the tissues; this is achieved via membrane-bound receptors for a plethora of molecules and through tight junc-tion proteins and receptors that regulate cell–cell and cell–matrix relationships (114). Endothelial cell injury may well impair the delivery of nutrients to tissues and allow the extrav-asation of proinflammatory mediators into the interstitial space.

Significant data supports the role of an impaired endothe-lium in the development of MODS. Endothelial cell exposure to LPS will cause anatomic changes including nuclear vacuol-ization, cytoplasmic swelling and fragmentation, and detach-ment from the internal elastic lamina (115). In humans with septic shock, elevated levels of circulating endothelial cells can be detected and correlate with outcome. High plasma levels of molecules that are expressed on the surface of endo-thelial cells (i.e., thrombomodulin [TM], intercellular adhe-sion molecule [ICAM]-1, and E-selectin) are observed during sepsis and ALI, and are an indirect indication of endothelial damage (116) and predict organ failure and death (117). This injury appears to be sustained, as injection of small doses of LPS into human volunteers will result in high plasma levels of TM that peak at 24 hours and of TF that are still increasing at 48 hours (114).

The uninjured endothelial cell has important anticoagulant properties. Several heparin-like molecules are expressed on the surface of the cells to accelerate the inactivation of serine

proteases of coagulation by antithrombin (114). Thrombo-modulin binds thrombin and forms a complex that activates protein C; exposure of the endothelial cells to inflammatory or septic mediators will shift the endothelial cells to a procoagu-lant state by increasing expression of TF and internalization of TM, and the endothelial cell will have impaired release of tissue plasminogen activator and an increased release of PAI-1. This procoagulant/antifibrinolytic state is associated with fibrin deposition, platelet consumption, microthrombi, tissue ischemia and necrosis, and an increased risk of death (118).

Before leukocytes and monocytes can migrate into tis-sues, they must adhere to the endothelium, accomplished by the local synthesis of PAF, IL-1, IL-8, and TNF, which stimulates the expression of surface molecules called selectins on leukocytes (L-selectin) and endothelial cells (E-selectin). The interplay between these selectins allows loose binding of the leukocyte to the endothelium. Leukocytes are bound more strongly to the endothelium by the interaction between the CD11/CD18 complex, which is expressed on the leukocyte, and the ICAM-1, which is expressed on the endothelial cell membrane. In animal models of sepsis, endotoxicosis, or isch-emia/reperfusion, monoclonal antibodies to the CD11/CD18 integrin or to L-selectin will improve organ dysfunction (119). Knockout animals lacking either ICAM-1 or E-selectin have improved survival during experimental sepsis (120). Clinically, plasma ICAM-1 levels are higher in patients with septic shock than in healthy controls or patients with SIRS (116), and the levels correlate with the severity of shock.

Endothelium-derived relaxation is also impaired in sep-sis, and such alteration may contribute to MODS. In normal volunteers, small doses of LPS will also impair endothelium-dependent relaxation for days (121). These data help explain the observations that reactive forearm hyperemia is attenuated in patients with sepsis. In addition, the importance of intact ecNOS in these patients is supported by the observation that treatment of patients with septic shock by nonselective NOS inhibitors is associated with no change or an increase in mor-tality compared to untreated patients (113).

epIthelIal BarrIer DySfunCtIOn

Epithelial cells help maintain normal organ function by the maintenance of distinct compartments. The tight junctions between adjacent epithelial cells serve several important functions: (a) differentiation (122) of the cell into apical and basolateral domains, (b) preservation of cellular polarity, (c) generation of distinct internal environments formed by the epithelial layer, and (d) providing a semipermeable barrier that regulates the passive diffusion of solutes between the paracel-lular pathway and prevents entry of microbes and toxins (e.g., intestine and lung) (122).

Data from studies using cultured epithelial monolayers show that NO and peroxynitrite, as well as other proinflam-matory mediators, increase the permeability of the monolayer. The mechanism for this increase in permeability is incom-pletely understood; however, some data suggest that there is a decrease in the expression and improper localization of some of the tight junction proteins. Other investigations have determined that inhibition of the epithelial cell membrane Na (+)-K (+)-ATPase pump by these mediators results in cellular swelling and an increase in intracellular sodium concentration,

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which ultimately impairs the expression and localization of the tight junction proteins. Data from murine models of endo-toxemia indicate that LPS will decrease the expression and alter the localization of tight junction proteins in the intestine compared to control animals (123). Furthermore, these ani-mals will have increased number of bacteria recovered from regional mesenteric lymph nodes. NO appears to be important in the disruption of gut barrier function, as neither intestinal permeability nor bacterial translocation is observed when knockout mice lacking iNOS are treated with LPS. Similar alterations in hepatic (124) and pulmonary (125) epithelial barrier function and tight junction protein expression and localization have been shown during murine endotoxicosis.

Derangements in Gut Barrier Function

Although epithelial barrier function in the intestine may be altered during sepsis and other inflammatory states, other com-ponents of the gut barrier will prevent the bacteria or bacterial products from gaining access to systemic organs (126). In addi-tion to alterations in the epithelial barrier described previously, other clinical conditions that can contribute to altered gut barrier function include antibiotics, stress ulcer prevention, hypoalbu-minemia, vasoactive agents, and use of hyperosmolar feeding preparations. The clinical importance of the disrupted gut barrier function in the pathogenesis of MODS remains ill defined.

apOptOSIS

Apoptosis (programmed cell death) is the term used to describe a specific method by which cells die; the event is a well-defined, active, and energy-dependent process. There are two primary pathways involved in apoptosis: The intrinsic (mitochondrial and endoplasmic reticulum) pathway and the extrinsic (“death receptor”) pathway (127). The latter pathway is activated by receptors such as Fas, with the subsequent activation of two enzymes, caspase-8 or -10. The intrinsic pathway stimulates caspase-9 by loss of the mitochondrial membrane potential and movement of cytochrome c into the cytosol. These initia-tor caspases cleave effector caspases (e.g., caspase-3 and -7), which result in the cleavage of cellular proteins and DNA and, ultimately, apoptosis (128).

The exact role of apoptosis in the development of MODS is unclear. Data from clinical studies show that upregulation of apoptotic pathways occurs in patients with ARDS (129). Furthermore, widespread apoptosis occurs in splenic and colonic lymphoid populations in patients who die from sep-sis and MODS (130,131). The effect of apoptosis on immune function includes loss of various immune cells and impairment of immunity by apoptosis-induced immunosuppression of the remaining immune cells (132). Therapies directed against these programmed pathways are under intense investigation and include inhibition of cytochrome c release, use of RNA interference for gene silencing, and caspase inhibitors (132).

COMplex nOnlInear SySteMS

The body may be considered a biologic network that is com-plex, highly coupled, and nonlinear (133). The host response to trauma, shock, or sepsis—involving metabolic, neural,

endocrine, inflammatory, and immune components is such an example (134). The behavior of such a system cannot be pre-dicted with great reliability; however, the system is “attracted” to specific states or stable configurations: “organized variabil-ity” (134,135). A large enough perturbation to an organ or mediator network may have unexpected and significant results elsewhere in the host and ultimately lead to MODS (136). In the healthy individual, there is a high degree of heart rate (beat-to-beat) variability; this may be lost and mortality increased in critically ill patients (137). In fact, normal volunteers injected with small doses of LPS exhibit loss of heart rate variability (138). Decreased heart and respiratory rate variability during spontaneous breathing trials predict extubation failure (139). Other examples of increased regularity of rhythms associated with disease include Cheyne–Stokes respiration, parkinsonian gait, neutrophil count in chronic myelogenous leukemia, and fever in Hodgkin disease (135). However, several diseases— acromegaly and Cushing disease—are associated with increased complexity (135). These data suggest that health is determined by “distance” from thermodynamic equilibrium: too much or too little variation (low or high entropy) represents pathologic conditions (135).

genetIC SuSCeptIBIlIty

Single base variations in DNA—single nucleotide polymor-phisms (SNPs)—are commonly used to discern genetic differ-ences among patient populations (140). Approximately 1 in every 1,000 bases in the human genome is different between two unrelated individuals (140). By comparing healthy indi-viduals to patients, SNPs involved in disease can be identified. Indeed, some—but not—all clinical studies have documented an increased risk of death and organ dysfunction in patients suffering from sepsis or ARDS and who are homozygotes for SNPs (141–145); this may have future clinical implications.

preVentIOn anD treatMent Of MultIple Organ DySfunCtIOn SynDrOMe

Prevention and treatment of MODS are nonspecific and include the goals of maintaining adequate tissue oxygenation, finding and treating infection, providing adequate nutrition support, minimizing iatrogenic complications, and when nec-essary, providing artificial support (e.g., dialysis or mechanical ventilation) for individual dysfunctional organs.

Resuscitation

An episode of circulatory shock is probably the most com-mon event that occurs before the development of MODS. As a result, timely restoration of intravascular volume and oxygen delivery is important in preventing or abrogating MODS in high-risk patients (146).

In the ICU, the use of colloids as resuscitation fluid has been the subject of a number of important recent publications, which culminated in the Food and Drug Administration (FDA) issuing a black box warning on the use of hydroxyethyl starch (HES). The efficacy of volume substitution and insulin therapy

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in severe sepsis (VISEP) study (147), the Scandinavian starch for severe sepsis/septic shock (6S) trial (148), and the crys-talloid versus hydroxyethyl starch (CHEST) trial (149) com-pared the use of starches with modified Ringer lactate, Ringer acetate, and sodium chloride 0.9%, respectively, for resuscita-tion. All trials failed to show a survival benefit with the use of starch, but demonstrated an increased risk of AKI. An updated systematic review and meta-analysis on the use of colloid ver-sus crystalloids for fluid resuscitation in critically ill patients concluded that the use of colloids was not associated with an improvement in survival (150). Resuscitation with albumin compared to crystalloid in patients with severe sepsis does not alter 28- or 90-day mortality (151). However, there may be a benefit to the administration of albumin in septic shock as 90-day survival was higher and duration of vasopressor support was shorter in this subgroup (152).

The role of chloride in influencing the adverse effects of colloids or crystalloids on renal function has been recently questioned (153). A prospective, open-label, sequential period pilot study suggested that the use of balanced crystalloid or colloids solutions compared to chloride-rich solutions was associated with a significant decrease in the incidence of AKI and need for renal replacement therapy (154).

Assessing the adequacy of tissue oxygenation can often be difficult. The clinical parameters used most often, including arterial blood pressure, skin color, temperature, urine flow, mixed venous oxygen saturation, and blood lactate concen-trations, may be unreliable. Although observational studies found that “supranormal” levels of

.DO2,

.VO2, and cardiac

index were associated with higher survival rates, the majority of work over the past 15 years clearly show that resuscitation to these end points in critically ill patients is of no benefit, or actually worsens outcome. Likewise, the use of the pulmonary artery catheter to guide therapy has not been shown to be of benefit in a large number of studies (155–157) and pulmonary capillary wedge pressure does not accurately reflect ventricular volume, even in normal volunteers (158). Less invasive, and probably safer, monitors have been developed for monitor-ing cardiac output that compare favorably with the accuracy of the thermodilution method. Use of systolic blood pressure variation (SPV), pulse pressure variation (PPV), stroke vol-ume variation (SVV), left ventricular end-diastolic area (as assessed by transesophageal echocardiography) and respira-tory variability of the inferior vena cava diameter may be of greater benefit to guide volume resuscitation (159). Whatever monitor is used, resuscitation for severe sepsis or septic shock needs to happen early while avoiding fluid overload (16,17). Protocol-based algorithms do not appear to improve mortal-ity (160–162); initial fluid therapy is 30 mL/kg of crystalloid (146). A higher transfusion threshold in established septic shock does not alter outcome (163). If vasopressor support is needed, norepinephrine is the vasopressor of choice and is titrated to achieve a MAP of 65 mmHg (164). Vasopressin (0.03 units/min) may be added to achieve the MAP goal or to reduce the dose of norepinephrine (146). Dobutamine may be added if signs of hypoperfusion persist and transthoracic or transesophageal echocardiography suggests cardiac dys-function. Corticosteroids may be administrated if fluids and vasopressors have not restored hemodynamic stability (146). The abdominal compartment syndrome can be the cause of persistent hypotension and should be ruled out by measuring bladder pressure (165).

Mechanical Ventilation

The method by which patients are mechanically ventilated can contribute to organ dysfunction. A plethora of experimental and clinical data indicate that overdistension of the lung through the use of large tidal volumes will cause lung injury, stimulate the release of inflammatory mediators, and effect derangements in organs other than the lung (166–168). Use of small tidal volumes (6 mL/kg) in the care of patients with ALI and ARDS decreases mortality and increase ventilator-free and organ failure–free days (169). Nonetheless, an analysis of data from nine randomized ARDS trials demonstrated a direct correlation between driv-ing pressure and survival (170). In addition, short-term use of cisatracurium (171) (48 hours) and the prone position (172) in patients with severe ARDS will improve outcome.

Cyclic “opening” and “closing” of collapsed airways during tidal ventilation is also thought to cause lung injury (173). A small study of patients with ARDS suggests that the use of posi-tive end-expiratory pressure (PEEP) above the lower inflection point of the respiratory system compliance curve reduces mortal-ity and the number of failed organs compared to control patients (174). Although this concept has been called into question by data demonstrating that efforts to improve recruitment of col-lapsed lung units with high levels of PEEP do not reduce mortality or duration of mechanical ventilation (175), the experimental protocol in this study was altered in mid-study, making question-able any conclusions drawn from this particular investigation. A systematic review and meta-analysis revealed that higher PEEP compared to lower PEEP in patients with moderate-to-severe ARDS was associated with improved survival (176). A computed tomography (CT) scan investigation of patients with ARDS showed that ventilator-induced hyperinflation rather than cyclic recruitment/derecruitment is associated with a greater release of pulmonary inflammatory mediators (177).

Fluid management is also an important component in the care of the patient with ARDS or ALI. Data show that a restrictive fluid strategy where cumulative fluid balance is kept close to zero in these patients improves the oxygenation index and increases the number of ventilator-free days without increasing the number of other organ failures (178).

Acute Renal Failure

Acute tubular necrosis (ATN) accounts for over 75% of the cases of acute renal failure (ARF) in the ICU (179), with a mor-tality rate ranging from 40% to 80%. The most common insult that predisposes ICU patients to ATN is persistent prerenal azotemia (179). Furthermore, in the critically ill patient, there is often more than one insult to the kidney: sepsis; exposure to aminoglycosides, amphotericin B, or radiocontrast agents; and the administration of nonsteroidal anti-inflammatory agents. Efforts to minimize these insults to the kidneys should be maximized. Timely resuscitation is important to prevent renal ischemia but targeting oliguria reversal as part of goal-directed management does not reduce renal dysfunction (180). If ami-noglycosides must be used to treat infection, once-daily dos-ing (181) or the use of drug levels to discern pharmacokinetics (182) appears to reduce the risk of nephrotoxicity. Use of lipo-somal preparations of amphotericin B reduces the risk of renal damage (181). If patients are to receive contrast agents, hydra-tion with sodium bicarbonate solutions have been shown to reduce the risk of subsequent renal dysfunction (183). Although

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N-acetylcysteine has been purported to reduce the risk of con-trast-induced ARF (184), the observed results may be a reflec-tion of the activation of creatinine kinase or an increase in the tubular secretion of creatinine (181). Medications such as “low-dose” dopamine or fenoldopam, which increase renal blood flow or loop diuretics, have no impact on preserving renal func-tion in high-risk patients and should be avoided (181).

Debridement of Necrotic Tissue and Fracture Stabilization

The presence of dead or devitalized tissue appears to predispose patients to the development of MODS, hence timely debridement of dead tissue is an important component in prevention. Early surgical fixation of major lower extremity fractures will result in a lower incidence of ARDS and pneumonia. However, “dam-age control” orthopedics has recently gained popularity and is a concept whereby fractures are initially treated with external fixation; definitive therapy occurs later when the patient is more stable. The inflammatory response appears to be attenuated in these patients, and the incidence of organ dysfunction is no higher compared to patients undergoing definitive therapy (185).

Infection

Sepsis is an important cause (or correlate) of MODS, making it imperative to rule out an active source of infection in the critically ill population. Prompt hemodynamic resuscitation and timely administration of antibiotics are crucial, as well as source control (146).

Intra-abdominal Sepsis

There are many diseases presenting with intra-abdominal sepsis treated primarily by surgery (i.e., perforated viscus); these will not be discussed herein. Rather, we will review disease processes those have both medical and surgical aspects requiring ICU care, close monitoring, resuscitation, and possible intervention.

pancreatitis. Pancreatitis is a common disease among both medical and surgical ICU patients. There have been impor-tant changes over the past several decades in the management of pancreatitis: overall there is consensus regarding nonop-erative management in the setting of acute severe pancreatitis that mainly includes liberal fluid resuscitation, early enteric nutrition, and avoidance of empiric antibiotics without objec-tive evidence of infection (186). There is less endocrine and exocrine insufficiency in patients managed nonoperatively in severe acute pancreatitis compared to operative management (187). Necrosis of pancreatic parenchyma or extrapancreatic tissue is present in 10% to 20% of patients with acute severe pancreatitis and is associated with high morbidity and mortal-ity rates. Nonoperative management should still be the same as recommended for severe acute pancreatitis.

Urgent endoscopic retrograde cholangiopancreatography (ERCP) is indicated when cholangitis is suspected. A recent Cochrane review showed no benefit of antibiotics in prevent-ing infection of necrotic pancreatic material except when imi-penem was considered; in this case a significant decrease in pancreatic infection was found. None of the studies included in the review were adequately powered for mortality (188).

As a result of a shift from early surgical debridement to a staged, minimally invasive, multidisciplinary, step-up approach, outcome following necrotizing pancreatitis has improved

substantially (189). Diagnosing infected necrosis is important, as it typically requires invasive intervention. Gas in a necrotic collec-tion demonstrated on imaging investigations is considered proof of infection, occurring in around 40% of patients with infected necrosis. Utilization of fine-needle aspiration (FNA) may be help-ful in patients without radiologic evidence of infection. However, there is a clear lack of consensus on the use of FNA to diagnose infected necrotizing pancreatitis (190). Common practice is that FNA must be considered for patients who fail to recover from organ dysfunction and without signs of findings of infection on radiologic studies. Positive FNA result hence documented infec-tion would warrant staged multidisciplinary “step-up” approach (189). Once infection is documented, there is good evidence—and consensus—about the approach to treatment.

The initial step in the “step-up” approach is drainage, either percutaneous or transluminal, by means of cystgastrostomy, or cystduodenostomy, followed by surgical or endoscopic transluminal debridement if needed. The response rate to ini-tial drainage is up to 30%; debridement is delayed until the acute necrotic collection has become encapsulated, typically no earlier than 6 to 8 weeks.

acute Mesenteric Ischemia. This is another major source of intra-abdominal sepsis, and may occur due to mesenteric arterial thrombus, embolus, or venous thrombus; these are dealt with elsewhere. On the other hand, acute mesenteric isch-emia may occur as a secondary problem due to ongoing sepsis, in the setting of underlying mesenteric atherosclerosis. This scenario is the least common type of mesenteric ischemia, also known as “low flow state” ischemia or “nonocclusive mesen-teric ischemia”; however, it has higher morbidity and mortal-ity compared to thromboembolic ischemia (191). Essentially, patients become septic from a source other than the abdomen and, if this progresses, the untreated hypotension and hypovo-lemia can cause ischemia in the gastrointestinal system.

Treatment of nonocclusive mesenteric ischemia relates to optimization of hemodynamics, elimination of vasopressor treatment, and correction of any systemic factors contribut-ing to shock. Patients with peritoneal signs on examination or evidence of bowel necrosis or perforation on CT scan require surgical exploration to remove any source of sepsis; a second-look laparotomy should be performed routinely.

antibiotic Duration for Intra-abdominal Infections. This has been investigated after successful treatment of intra-abdom-inal infection. In patients with intra-abdominal infections who have undergone an adequate source-control procedure—via surgical or percutaneous drainage—the outcomes after fixed-duration antibiotic therapy (approximately 4 days) are similar to those after a longer course of antibiotics (approximately 8 days); the latter extending until after resolution of physiologic abnormalities (192).

Pulmonary Sepsis

Ventilator-associated pneumonia (VAP) can play a role in the development and course of MODS. Proven preventive measures include noninvasive positive pressure ventilation, elevation of the head of the bed (193), continuous subglottic suctioning, in-line suctioning systems, weaning protocols, optimization of sedation with daily “wake-ups” or protocolized sedation for the patient (194,195), and chlorhexidine oral rinse.

VAP can be difficult to diagnose because radiographic findings are commonly used to secure the diagnosis and the

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findings are inaccurate. Recently, a ventilator-associated event (VAE) algorithm has been developed that utilizes duration of mechanical ventilation and new alterations in FiO2 and PEEP as well as new administration of antibiotics to define compli-cations of mechanical ventilation. At this point it is intended as a surveillance tool but, because most VAEs are associated with pneumonia, ARDS, atelectasis, or congestive heart fail-ure, the tool can provide insight into quality of care at an institution (196).

Selective digestive decontamination (SDD) is a technique by which topical nonabsorbable antibacterial and antifungal agents (usually with a concomitant 3- to 5-day course of sys-temic antibiotic therapy) are applied to the oropharynx and proximal bowel in mechanically ventilated patients to reduce the incidence of nosocomial infections, organ dysfunction, and mortality. A meta-analysis of 57 randomized controlled tri-als demonstrated a favorable effect on bloodstream infections and mortality (197,198). Fears concerning the emergence of resistance organisms do not appear to be well founded in ICUs where there is a low level of antibiotics resistance (199) although in one trial, there was a gradual increase in amino-glycoside-resistant gram-negative bacteria (200). SDD may very well reduce the incidence and prevalence of colonization with resistant gram-negative aerobic bacteria (201). However, the use of SDD in the United States does not enjoy widespread popularity for reasons that remain unclear.

Catheter-Related Sepsis

Catheter-related bloodstream infections (CRBSIs) may con-tribute to the development and propagation of MODS. Proven strategies to reduce the risk of CRBSIs include hand-washing prior to catheter insertion, use of maximum barrier precautions (cap, mask, sterile gloves and gown, and a large sterile drape that covers the patient), use of an alcohol-based chlorhexidine skin preparation solution, avoiding the femo-ral site for catheter insertion, and removing catheters when no longer needed (202,203). If these measures are ineffec-tive in reducing the risk of infection, catheters with antiseptic surfaces (204,205) or impregnated with antibiotics (206) or the use of chlorhexidine dressing sponges can reduce the risk of infection.

Other Sources of Sepsis

Many other inapparent sources of infection in critically ill patients may contribute to the development of MODS. Some of these sources of infection include purulent sinusitis, sup-purative thrombophlebitis, otitis media, perirectal abscess, epididymitis, prostatitis, calculous or acalculous cholecystitis, meningitis or brain abscess (particularly after instrumentation of the CNS), prosthetic intravascular graft infection, lower or upper urinary tract infection, and endocarditis. Physical exam-ination and appropriate laboratory and radiographic studies should exclude these conditions.

Nutrition Support

Malnutrition can contribute to the morbidity and mortality of sepsis and MODS. Proteolysis is a prominent finding in sep-sis and, although it cannot be suppressed by infusing amino acids, anabolism may be achieved by appropriate nutritional support. Furthermore, catabolism is mediated by endogenous catecholamines, and administration of β-adrenergic blocking

agents can reverse the hypermetabolic response and protein catabolism (207). Early nutritional support may be beneficial in patients at risk for developing MODS (208). Data exist to support enteral nutrition (EN) over parenteral nutrition (PN); therefore this should be the choice of feeding unless there is con-traindication to use of the GI system. Nutritional support should be initiated within the first 24 to 48 hours following admission (209), although the degree of caloric intake that is required is controversial (see below) (210).

Although current practice supports giving 20 to 25 kcal/kg/day (2 to 5 g/kg/day glucose, 0.5 to 1.0 g/kg/day of fat, and 1.2 to 1.5 g/kg/day of protein) in critically ill patients, a recent prospective randomized demonstrated that permis-sive “underfed” (moderate nonprotein calories but similar amount of protein compared to standard feeding) resulted in similar 90-day mortality rates and hospital and ICU lengths of stay despite the fact that caloric intake was reduced by 36% in the underfeeding group (211). Protein intake was similar between the two groups. It is to be determined whether cur-rent practice will change regarding nonprotein caloric intake in critically ill patients.

Insulin therapy of hyperglycemia has evolved in the criti-cally ill patients. A meta-analysis evaluated 26 trials involving 13,567 patients. Among the 26 trials that reported mortality, the pooled relative risk (RR) of death with intensive insulin therapy (titration of insulin to keep blood glucose between 80 and 110 mg/dL) compared to less “tight” glucose control was not significant. Among the 14 trials that reported hypoglyce-mia, the pooled RR associated with intensive insulin therapy was significantly higher. The ICU setting was a contributing factor, with patients in surgical ICUs appearing to benefit from intensive insulin therapy whereas patients in the other ICU set-tings did not. Intensive insulin therapy significantly increased the risk of hypoglycemia and conferred no overall mortality benefit among critically ill patients (212).

Specialty Formulas

A number of enteral nutritional formulas are available that pro-vide specific nutrients: glutamine, peptides, arginine, omega-3 fatty acids, nucleic acids, and antioxidants (e.g., vitamins E and C, β-carotene). Arginine is the substrate for NO synthase and is important in lymphocyte proliferation and wound heal-ing (213). Omega-3 fatty acids change membrane lipid compo-sition and can alter the inflammatory response (214). Nucleic acids assist in the proliferation of lymphocytes and intestinal crypt cells, as well as DNA and RNA synthesis (213). Several enteral nutrition formulas are available that include combina-tions of these additives. The Canadian Critical Care Clinical Practice Guideline Committee (215) recommends that arginine and other “select” nutrients not be routinely used for enteral nutrition. In patients with ARDS, a formula supplemented with fish oil, borage oil, and antioxidants should be consid-ered (215). Although glutamine should not be used in patients with shock or MODS, enteral glutamine should be considered in trauma and burn patients (215).

SuMMary

Standard therapy for patients with MODS includes adequate cardiovascular resuscitation, identification and timely treat-ment of infection, early enteral nutrition, glucose control,

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individualized support for dysfunctional organs, and mini-mizing iatrogenic complications by following clinical practice guidelines based on evidence-based medicine for mechanical ventilation and prevention of VAP and CRBSIs (Table 52.4). Development of well-functioning ICU teams helps facilitate these paradigms of care. Improved outcome may be realized if patients at high risk for developing the syndrome can be identified earlier so that preventive measures can be insti-tuted when appropriate. Because the pathogenesis of MODS involves numerous mediators, it is doubtful that all patients can be treated with a single agent or mode of therapy.

TABLE 52.4 Suggested Strategies for the Prevention of Multiple Organ Dysfunction Syndrome

Prevention of hospital-acquired infectionprevention of catheter-related bloodstream infections– implementation of educational initiatives– use of chlorhexidine solution for skin preparation– use of maximum barrier precautions– avoidance of the femoral insertion site; preference for

subclavian site– removing catheter as soon as possible when no longer neededStrict infection control measures and hand hygiene

Metabolic control and supportStrict glucose controlearly enteral nutrition

Early and appropriate treatment of infection and traumaearly hemodynamic resuscitation for severe sepsisearly resuscitation of trauma victims with blood productsprompt eradication of documented sources/foci of infectionearly fracture stabilization in multiple traumaappropriate empiric antibiotic therapy according to consensus

guidelines where available with earliest possible de-escalation of therapy according to culture results

Prevention of acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and ventilator-associated and aspiration pneumonia

elevation of the head of bed to 30 degrees in all patients without spine precautions

Stress gastritis prophylaxis according to consensus guidelineslung protective ventilation strategies in patients with ali/ardSimplementation of weaning protocolsdaily sedation holidayschlorhexidine oral rinse twice daily, oral care every 4 hrsSelective decontamination of the digestive tractuse of a subglottic suction endotracheal tube

Prevention of acute renal failurenormal saline administration to prevent contrast-induced

nephropathy with the addition of sodium bicarbonate or N-acetylcysteine as indicated

discontinuation of nephrotoxic drugs whenever possible; consider once-daily dosing regimens for aminoglycoside antibiotics

• MODS develops in up to 40% of critically ill patients without a diagnosis of sepsis and up to 70% of those with a diagnosis of severe sepsis. Mortality attributable to MODS rises as the number of failing organ systems increases; mortality rates in patients with one, two, or three failing organs average 30%, 50%, and over 70%, respectively, depending on the etiology of MODS and the organ systems involved.

Key points

• Population-based, but not individual, risks of mortal-ity can be predicted with high degrees of precision by several severity-of-illness scoring systems and models.

• MODS may result from “single-hit” insults such as severe infection or trauma, or may evolve through sev-eral stages, each having characteristic clinical features.

• An uncontrolled focus of infection, ongoing perfusion deficits resulting in diminished tissue

.DO2, injured or

devitalized tissue, and persistent inflammation com-monly initiate MODS.

• Fever or hypothermia and leukocytosis are not always the manifestations of sepsis but may represent systemic inflammation.

• TNF-α, IL-1, IL-6, IL-8, platelet-activating factor, ROS, and NO are pivotal early mediators in the host response to infection and have multiple pathophysi-ologic effects relevant to MODS.

• Inappropriate regulation of the production of cytokines, eicosanoids, ROS, and NO is thought to be of causal significance in MODS, as are pathologic neutrophil–endothelial interactions and cross-talk among elements of the coagulation, complement, and kinin cascades.

• Alterations in microvascular blood flow and mitochon-drial dysfunction likely play an important role in the pathogenesis of organ dysfunction in shock. The surface receptors and mediators associated with these alterations include oxidants, lectins, proteases, vasoactive products of iNOS, and altered adrenergic receptor sensitivity.

• Clinically occult dysfunction of the gastrointestinal (GI) mucosal barrier in the ICU is common because of splanchnic ischemia from shock, and may result in endogenous endotoxemia and bacterial translocation.

• Neutrophil- and ROS-mediated intestinal I/R injury in the postresuscitation period is a potential mechanism of remote organ damage. This may lead to a domino-like sequence of organ failures.

• The liver plays a pivotal but clinically inapparent role in systemic host defense through four mechanisms. First, mononuclear phagocytic (Kupffer) cell uptake processes control the magnitude and circulating half-life of endo-toxin, bacteria, and vasoactive by-products. Second, production and export of TNF-α with other mediators directly modulate lung function and cardiovascular sta-bility. Third, hepatobiliary clearance is important in the metabolic inactivation and detoxification of such media-tors. Fourth, the synthesis of acute-phase reactants regu-lates several key aspects of metabolism and inflammation.

• Reductions in total hepatic blood flow ( .QL) and

.DO2,

or its partitioning between portal venous and hepatic arterial flows, may alter the aforementioned mecha-nisms, thereby influencing systemic immunoregulation.

• Signs of established MODS are manifested differently in each organ (e.g., ARDS, ARF), yet such changes often reflect generalized endothelial injury and inflammation.

• Diverse medical conditions may mimic sepsis-related MODS and should be excluded when appropriate. These include connective tissue diseases, intoxications, and neoplasms.

• Early rapid resuscitation from shock, irrespective of its etiology, attenuates injury to regional organs and may decrease the incidence of MODS.

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