Multiple organ dysfunction syndrome in patients with ... · PDF fileMULTIPLE ORGAN DYSFUNCTION SYNDROME IN PATIENTS WITH SEVERE SEPSIS Cellular effectors associated with the events

Multiple organ dysfunction syndrome in

patients with severe sepsis: more than just

inflammationROBERT A BALK1 AND RICHERT E GOYETTE2

1RUSH MEDICAL COLLEGE, RUSH-PRESBYTERIAN-ST LUKE’S MEDICAL CENTER, CHICAGO, ILLINOIS, USA2CONSULTANT IN HEMATOLOGY, KNOXVILLE, TENNESSEE, USA

Multiple organ system dysfunction syndrome in critically ill patients was first described in

1973 by Tilney et al(1). The authors reported that massive blood loss associated with the rup-

ture of abdominal aortic aneurysms led to progressive failure of previously intact organs.

Shortly thereafter, Eiseman et al described ‘multiple organ failure’ as a syndrome occurring in

patients kept alive solely by mechanical and pharmacologic support(2). In addition to empha-

sizing the economic significance of the disorder, this report stressed the association between

sepsis and dysfunction of one or more organ systems. The syndrome was more fully charac-

terized in 1980, when Fry et al stressed the role of infection in its pathogenesis and noted that

the temporal sequence of organ failure often progresses from the lung to the liver, gastric

mucosa and kidney(3).

Multiple organ dysfunction syndrome (MODS) was brought to the attention of the general med-

ical community through the American College of Chest Physicians (ACCP)/Society of

Critical Care Medicine (SCCM) Consensus Conference definitions and terminology(4). In

this model, MODS characterized an entity that produced progressive physiologic failure of

several organ systems in acutely ill patients, such that homeostasis could not be maintained

without intervention(4). In addition, MODS could be either primary or secondary. Primary

MODS resulted from direct organ-system injury (eg pulmonary contusion) or the accompa-

nying haemodynamic alterations (eg hypotension), whereas secondary MODS characterized

an exaggerated host response to the inciting insult, usually becoming manifest after a latent

period(4,5).

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EDITED BY RA BALK, 2001.

INTERNATIONAL CONGRESS AND SYMPOSIUM SERIES NO 249 PUBLISHED BY THE ROYAL SOCIETY OF MEDICINE PRESS LIMITED

INTERNATIONAL CONGRESS AND SYMPOSIUM SERIES 249

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R A BALK AND R E GOYETTE

As anticipated by the ACCP/SCCM committee, knowledge of the pathophysiology of sepsis

and MODS has evolved over the ensuing years. Within the past decade, it has become clear

that sepsis complicated by acute organ dysfunction and MODS is more than a set of isolated

inflammatory changes. The haemostatic system plays an integral role in the development of

and recovery from the septic process(6−11). This paper discusses advances in knowledge of the

tightly linked haemostatic and inflammatory mechanisms that are active in patients with

severe sepsis and MODS.

Multiple organ dysfunction occurs not only in patients with sepsis, but also may be associated

with other clinical conditions, including severe burns, acute necrotizing pancreatitis, severe

trauma or haemorrhagic shock(12). Although MODS may result from diverse mechanisms, the

host response is probably more important in the genesis of the process than is the specific bac-

terium, virus or traumatic insult. Despite improvements in fluid resuscitation, availability of

more potent antibiotics and greater sophistication in support and monitoring strategies, there

are no reliable or specific treatments for MODS. Unfortunately, MODS remains one of the

most common causes of death in noncoronary intensive care units (ICUs), with little change

in outcome over the past two decades(5,12).

Clinical markers of organ dysfunction

The prognosis of patients with severe sepsis is related to the severity of organ dysfunction at

the time of ICU admission (Figure 1). Mortality rate was lowest in patients with no organ

38

Figure 1

Relationship of number of organ failures on ICU admission, as defined by the Sequential Organ Failure

Assessment (SOFA) score, to the probability of ICU survival(13). Reproduced with permission from J-L Vincent(13)

100

80

60

40

20

0

Non

-sur

vivo

rs in

eac

h gr

oup

(%)

0(n=653)

1(n=506)

2(n=190)

3(n=72)

4(n=23)

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MULTIPLE ORGAN DYSFUNCTION SYNDROME IN PATIENTS WITH SEVERE SEPSIS

failure (9%) and increased progressively in patients with failure in one (22%), two (38%),

three (69%) and four or more (83%) organs (p<0.0001)(13). Other studies have shown that

mortality in severe sepsis is a function of the number of failing organ systems and the severity

of dysfunction within the system(14−16). The risk of mortality may also be influenced by the

duration of organ dysfunction(17,18).

In the past, it often was not important for clinicians to classify patients specifically with sepsis

and acute organ dysfunction (ie severe sepsis). This was because the treatment of septic

patients consisted of standard care, with additional interventions, such as institution of

mechanical ventilation or use of vasopressor therapy, employed as needed(4,19). However, as

specific interventions become available for the treatment of patients with sepsis and acute

organ dysfunction, searching for signs of acute organ dysfunction will become increasingly

important in order to facilitate timely administration of specific antisepsis therapies.

Although there are no universally accepted parameters for assessment of abnormal organ

function in patients with suspected MODS, a number of scoring systems have been developed

objectively to describe and quantify the level of organ dysfunction in critically ill patients.

Examples include the Multiple Organ Dysfunction Score, Sequential Organ Failure

Assessment (SOFA), Logistic Organ Dysfunction System (LODS) and Brussels score(13,16,20,21).

Most organ dysfunction scores have been designed for repeated assessment to describe evolv-

ing morbidity(22,23). These tools can help evaluate the need for and limitations of therapy and

they have been used primarily in evaluations of various investigational agents. With most of

these tools, evaluation of disease severity involves the use of clinical criteria and laboratory

markers to assess the major organ systems: respiratory, renal, hepatic, gastrointestinal,

haematologic and central nervous (Table 1)(5). The variation in specific criteria for organ

function assessment may reflect efforts to describe different populations, but it has con-

tributed to the confusion surrounding the terminology used to describe MODS and may have

hindered comparison of clinical study results.

Mediators and methods of organ dysfunction

MODS is a systemic process involving both coagulation and inflammatory pathways with

potential mediators including a complex variety of humoral substances, cellular effectors and

bacterial products(5,12,24−30). Important humoral mediators include the proinflammatory

cytokines tumour necrosis factor-(TNF)-a and interleukin (IL)-1, as well as IL-6, which has

both proinflammatory and anti-inflammatory properties(5,26). Other potential mediators

include soluble TNF-a receptors I and II (sTNFr-I, II), interferon (IFN)-g and various

growth factors, such as granulocyte colony-stimulating factor (G-CSF) and transforming

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growth factor (TGF)-β. This list also includes various adhesion molecules, products of

arachidonic acid metabolism (eg prostaglandins, prostacyclin [PGI2], thromboxane A2 and

leukotrienes), components of the complement system, bradykinin and other kinins, procoag-

ulants, coagulation factors and their degradation products, platelet activating factor (PAF),

nitric oxide (NO) and other reactive oxygen species, vasoactive polypeptides and amines,

endorphins, histamine and serotonin, neuroendocrine factors and myocardial depressant

factor.

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Table 1 Signs of acute organ dysfunction(5,6,16,23,127)

Respiratory dysfunction has been defined as an alteration in oxygenation status, reflected by a decrease inthe PaO2/FiO2 ratio or the need for supplemental oxygen; elevations in the level of PEEP; and/or the need forventilatory assistance. Gradations of these parameters indicate the severity of dysfunction, with failuresuggested by the need for FiO2 of ≥0.40, PEEP of ≥5–10 cmH2O and/or ventilatory assistance for ≥72 h

Renal dysfunction may be reflected by clinically significant alterations in the urine output or serum creatinine.Regardless of polyuria or oliguria, serum creatinine levels of ≥20 mg/l (>2 mg/dl) commonly indicate kidneyfailure, as may the need for dialysis or other replacement therapies to maintain fluid, acid-base and/orelectrolyte homeostasis

Cardiovascular dysfunction may be indicated by hypotension, atrial or ventricular arrhythmias, the need forinotropic or vasopressor support and elevated filling pressures (eg CVP, PCWP). In addition to gradations ofvarious parameters, the product of the heart rate and CVP:MAP ratio has been used to define dysfunctionseverity or cardiovascular failure

Hepatic dysfunction may be manifested as jaundice, hyperbilirubinaemia or elevated serum levels of hepaticenzymes, and less frequently as hypoalbuminaemia or a prolonged prothrombin time (PT). Liver failure may bedefined by parameter gradations, including a serum bilirubin of >20 mg/l (>2 mg/dl) for 48 h, with elevation ofglutamate dehydrogenase to twice normal level

Haematologic dysfunction may be characterized by thrombocytopenia, leukocytosis or leukopenia, andbiomarkers of coagulopathy, including abnormalities in the PT, activated partial thromboplastin time (APTT),fibrin split products, D-dimer or other evidence of DIC

Gastrointestinal dysfunction may be reflected by bleeding, intolerance of enteral nutritional support, intestinalischaemia or infarction, as well as less common manifestations, such as acalculous cholecystitis, pancreatitis,bowel perforation, ileus and necrotizing enterocolitis

Neurologic dysfunction is primarily reflected by alterations in level of consciousness and CNS function, andusually quantitated by the Glasgow coma Coma scoreScore. Encephalopathy also may be indicated by moresubjective criteria, such as psychosis, confusion, coma and obturation

Endocrine dysfunction is described less frequently and less readily evaluated than other organ systems. Itmay involve adrenal dysfunction/failure or be manifested by hyperglycaemia, hypertriglyceridaemia,hypoalbuminaemia, weight loss, cachexia and hypercatabolism

Immunologic dysfunction is less frequently evaluated, but may be indicated by the development ofnosocomial infections, increased leukocytosis, pyrexia and alterations in immune activity

PaO2/FiO2 = ratio of the arterial partial pressure of oxygen to inspired oxygen fraction; CVP = central venous pressure; PCWP = pul-

monary capillary wedge pressure; MAP = mean arterial pressure; EEG = electroencephalogram; DIC = disseminated intravascular

coagulation; PEEP = positive end-expiratory pressure

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Cellular effectors associated with the events characterizing MODS include: immune cells,

such as monocytes, macrophages, leukocytes, polymorphonuclear neutrophil leukocytes

(PMNs), mast cells and platelets; vascular and lymphatic endothelial cells; as well as lung

epithelial cells(12,27,28). Bacterial products implicated as mediators include endotoxin

(lipopolysaccharide [LPS]), other toxins and surface molecules from Gram-negative bacteria,

as well as exotoxins, enterotoxins, lipoteichoic acid and various cell-wall components of

Gram-positive organisms(29,30).

The postulated roles of the various endogenous and exogenous mediators have been reviewed

in a number of recent publications (24,26,28−30). Acting in concert, these humoral, cellular and

bacterial mediators produce the endothelial injury that leads to the clinical manifestations of

MODS (Table 2)(6,8,24,30-33).

Critical factors in the development of MODS

A number of factors appear to play a role in the development of MODS (Table 2)(5). However,

organ failure is a secondary event and it is probable that more than one hit is required before

the full manifestations of MODS develop. In patients with severe sepsis, MODS appears to

result from a cascade of bacterial factors, inflammatory mediators, endothelial injury, dis-

turbed haemostasis and microcirculatory failure.

Host factors

Organ dysfunction is a reflection of the host response and various patient-specific factors may

contribute to this process. Age, an important risk factor for MODS, may compound the

41

Table 2 Factors implicated in the development of multiple organ dysfunction syndrome(5)

● Host factors● Primary cellular injury● Inadequate tissue/organ perfusion: hypoperfusion● Microaggregation of microthrombi● Ischaemia/reperfusion● Diffuse endothelial cell injury● Circulating humoral factors● Circulating immune/inflammatory mediators● Protein calorie malnutrition● Bacterial toxin translocation● Defective red blood cells● Adverse effects of directed treatment/medication

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effects of pre-existing illness on organ dysfunction(23,34,35). Data suggest a strong genetic deter-

mination in the production of TNF-α and IL-10 and polymorphisms of these cytokines prob-

ably contribute to increased morbidity and mortality in severe sepsis(36−39). Also implicated are

genetic determinants for other cytokine mediators (eg IL-1 and IL-1ra) and toll-like receptor

4 (TLR4) that have an important role in the LPS response, as well as genetic variants for

superoxide dismutase (SOD), including manganese and extracellular SOD and alveolar sur-

factant proteins (SP-A and SP-B)(40). Gender, perhaps through differences in sex hormones

that influence immune and organ responses, has been implicated in the susceptibility to and

outcome of septic conditions(41,42). However, data are inconsistent in terms of outcome, which

may reflect other factors, such as differences in risk factor distribution or access to care(43,44).

Primary cellular injury and inadequate tissue/organ perfusion

Primary cellular injury may result directly from the underlying disease process (eg severe

tissue injury or a nidus of infection) or the toxic effects of various mediators(8,31,45,46). Excess

levels of proinflammatory cytokines and other systemic mediators can induce endothelial

damage and increase vascular permeability, shunt flow and vasospasm(8). Given these and

other sepsis-induced changes, maldistribution of blood flow can impair the delivery of oxy-

gen, nutrients and other substrates that are essential for organ function and preservation(5,47).

Low systemic perfusion pressure frequently accompanies severe sepsis and there also may be

selective alterations in the perfusion of an organ system. Sustained vasodilation of small arte-

rioles in skeletal muscle beds may be accompanied by hypoperfusion in the mesenteric circu-

lation, perhaps reflecting higher oxygen requirements of the gut(31,47).

Ischaemia/reperfusion

Microaggregates composed of neutrophils, platelets, red blood cells (RBCs) and fibrin can

impair microcirculatory flow, producing tissue ischaemia that may persist despite restoration

of blood flow (the no-reflow phenomenon)(48,49). RBC deformability is important to allow its

passage through a capillary with a smaller diameter and loss of this property may impair per-

fusion(5,47). Clinical and experimental data indicate that RBC deformability is decreased in

sepsis, producing stagnation or enhancing microaggregation with plugging of the microcir-

culation and arteriovenous shunting of blood(50,51). Distant septic foci may have an occluding

effect on microanastomosis and, in some cases, opening of arteriovenous shunts may deprive

capillary beds of blood flow(31,52,53). Reperfusion injury may involve toxic oxygen metabolites

(eg superoxide) that induce apoptosis through changes related to oxidative stress, C5b-9 mem-

brane attack complexes and disturbances in calcium homeostasis(27,48). Together, these factors

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may compound the endothelial damage and permeability abnormalities induced by bacterial

products, cytokines and other mediators.

Diffuse endothelial cell injury

Diffuse injury causes endothelial cell dysfunction and plays an important role in the develop-

ment of MODS. Vasomotor tone may be directly altered by local mediators, some of which

(eg endothelin, vasopressin) act as vasoconstrictors, whereas others (eg NO, bradykinin, hist-

amine, PGI2) produce vasodilatation, which may lead to low perfusion pressures or hypoten-

sion(25,27). Along with these changes, diffuse endothelial cell reperfusion injury can cause

oedema related to capillary leakage of protein-rich fluid and continued tissue damage.

Although often first observed as pulmonary oedema, such leakage and cellular infiltration

may also occur in the liver, kidneys, heart, skin, muscle and brain of patients with severe sep-

sis or trauma(27,47).

Humoral factors and immune/inflammatory mediators

Even if blood flow to various tissue beds is adequate, the ability of cells to extract or utilize

oxygen and substrate may be complicated by mitochondrial dysfunction or other factors

related to the metabolic disturbances in sepsis. Endotoxin has complex effects on cellular

energy metabolism and can reduce maximal oxygen consumption independent of any hypoxic

insult(54). Oxidants produced during endotoxin-induced shock can trigger the activation of the

nuclear enzyme poly (ADP-ribose) synthetase (PARS), leading to intracellular energetic fail-

ure. Experimentally, PARS activation mediates pulmonary microvascular and intestinal

mucosal dysfunction(55). Apart from the disease entity itself, sepsis induces a metabolic state

characterized by an increase in resting calorie consumption, extensive protein and fat catabo-

lism, negative nitrogen balance, hyperglycaemia and an increase in hepatic gluconeogene-

sis(56). This hypermetabolic state affects virtually all tissues, causing reduced gut function,

skeletal and respiratory muscle wasting, loss of body cell mass, impaired wound healing, alter-

ations in protein synthesis and impairment of the host response to infection. Along with

ischaemia/reperfusion injury and other causes of cellular damage, these metabolic distur-

bances suggest a mechanism for alterations in gut intestinal barrier function. At least in the-

ory, increased intestinal permeability permits the translocation of bacteria, bacterial products

and/or proinflammatory cytokines into the mesenteric lymph, the portal and/or systemic cir-

culation, representing a potential stimulus for the development of MODS(12,34,57,58). In animal

models of severe sepsis, reductions in mesenteric perfusion and oxygen delivery have been

associated with gut mucosal and microvascular injury, barrier dysfunction and bacterial

translocation, and these changes appeared to vary with the septic stage(58–60).

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In severe sepsis and other overwhelming insults, the systemic inflammatory response is char-

acterized by excess levels of proinflammatory cytokines and the concomitant activation of the

endothelium and circulating immune effector cells (eg PMNs). In this setting, IL-6 is an

important marker of systemic inflammation and sustained elevations of TNF-a and IL-6 are

associated with the development of MODS and death(24,45). Endothelial cell activation

involves the increased expression of potentially injurious molecules, including the inducible

form of nitric oxide synthase (iNOS) which generates excess NO, and intercellular adhesion

molecules (ICAM-1, ICAM-2) that promote neutrophil chemotaxis and endothelial cell

interactions(8). Simultaneously, PMN activation, characterized by loss of L-selectin and

increased ?2-integrin (CD11b/CD18) expression, further enhances endothelial-cell interac-

tions with the release of NO and lysosomal enzymes that induce microvascular injury(28,49,61).

In septic patients, upregulation of circulating PMN CD11b expression parallels the mean

serum IL-6 levels and predicts the severity of organ injury(62). Counterbalancing the systemic

inflammatory response, anti-inflammatory processes are reflected by increased levels of cir-

culating anti-inflammatory cytokines (eg IL-4, IL-13), increased expression of receptor

antagonists (eg IL-1ra) and shedding of soluble receptors such as TNF-a receptor I (sTNFr-

1)(27,28). In addition directly to blocking the binding of proinflammatory stimuli to their cell-

surface receptors, these mediators induce an anti-inflammatory state on TGF-a and IL-10,

thus further dampening the inflammatory response(26,63,64). At the cellular level, the anti-

inflammatory state involves a decrease in monocyte antigen processing ability related to

decreased HLA-DR expression, as well as impairment of PMN upregulation and eventual

apoptosis in response to proinflammatory stimuli(28). Persistence of this hyporesponsive state

has been associated with an increased risk of nosocomial infection and death(31,65).

The paradoxical coexistence of proinflammatory and anti-inflammatory substances and their

conflicting signals may cause immune dysregulation, which is primarily observed at the tran-

scriptional level(26−28). After early inflammatory changes induce its activation through oxida-

tive stress, nuclear factor kappa-β (NFκβ) migrates into the nucleus and promotes signal

translation for many proinflammatory cytokines, iNOS, adhesion molecules and acute-phase

proteins. Downregulation of the inflammatory response is related to inhibition of NFκβ acti-

vation by various factors, including IL-10, antioxidants, glucocorticoids and several feedback

mechanisms. The cellular stress response involves a transient downregulation of most cell

products but upregulation of heat shock proteins. At least in part by inhibiting NFκβ activa-

tion, these proteins protect against oxidative stress, attenuate the cellular response to proin-

flammatory stimuli and minimize subcellular injury(27).

Along with their previously highlighted effects, various inflammatory and humoral mediators

appear to play a role in sepsis-related myocardial dysfunction, which is characterized by

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decreased myocardial contractility, reduction in ejection fraction and consequent dilata-

tion(25). Bacterial products and both TNF-α and IL-1, perhaps by increasing NO formation

through iNOS, have been implicated as potential myocardial depressants(25,31,66). A number of

experimental and clinical studies have reported circulating humoral factors, termed myocar-

dial depressant factor(s), with negative inotropic effects on the heart in severe sepsis and sep-

tic shock(67,68). Other factors with negative inotropic properties include ?-atrial natriuretic

peptide, activated complement, arachidonic acid metabolites and neutrophil products, such as

oxygen free radicals(69).

Directed treatment/medication

Treatment itself may be associated with organ dysfunction. Blood transfusions have been

associated with immune suppression and increased risk for infection, and have been identified

as an independent risk factor for the development of MODS(34,70). Other commonly impli-

cated treatments include nephrotoxic antimicrobial agents (eg aminoglycosides, amphotericin

B) and invasive devices. Although it does not appear to rapidly disrupt the Protein C/Protein

S system, haemodialysis may involve systemic anticoagulation or activation of PMNs on pas-

sage over the membranes, with damage to microvasculature in the lungs or other organs(71,72).

In the host response, the systematic activation of the immune response invariably is accom-

panied by excessive intravascular activation of coagulation associated with a relative insuffi-

ciency of fibrinolysis(73,74). This imbalance may result in the generation and deposition of

fibrin, leading to the formation of microvascular thrombi that can compromise blood supply

to various organs(11,32,75,76). This condition, termed disseminated intravascular coagulation

(DIC), is most commonly found in patients with severe sepsis and serves as a strong predictor

of a poor prognosis(77,78). As discussed, recent studies in severe sepsis have underscored the

crucial role of the coagulation system and microvascular thrombosis, which may be a primary

factor driving organ dysfunction and death(6-9,32,77).

Haemostatic abnormalities in severe sepsis and MODS

Coagulation abnormalities

The close association between the coagulation system and the inflammatory response is a

phylogenetically ancient, adaptative response that has been preserved from the early stages of

eukaryotic evolution(79). Although lacking formed elements of blood, most invertebrate

species possess a common cellular and humoral pathway of inflammation and clotting that is

activated after trauma or infection. A similar linkage occurs in vertebrates, with proinflam-

matory stimuli activating both the coagulation cascade and immune effector cells.

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Haemostatic activation appears to be almost universal in patients with severe sepsis. Evidence

of this response has been reported by experimental studies in humans and primates, and con-

firmed by recent clinical studies in severe sepsis which have employed sensitive and specific

markers of coagulation activation(75,78,80−83). For example, elevated levels of D-dimer, indicat-

ing activation of both coagulation and fibrinolysis, and depressed concentrations of Protein

C, indicating a relative lack of physiologic anticoagulation, were identified in almost 100% of

patients in the Ibuprofen in Sepsis trial(83,84). In contrast, the combination of clinical and lab-

oratory abnormalities traditionally required for a diagnosis of DIC are uncommon. In a large

prospective survey, the incidence of DIC in patients with severe sepsis was only 18%(14). In the

Ibuprofen in Sepsis trial, fewer than 10% of the study population developed thrombocytope-

nia, prolongation of the PT and APTT, increased fibrin split products and decreased fibrino-

gen levels, the classical laboratory markers of DIC(84). Supporting the value of the newer

assays, recent investigations suggest a continuum of coagulopathy in sepsis, with coagulation

abnormalities developing before the onset of clinical parameters of severe sepsis or septic

shock(7,73−75,85).

During infection or after experimental stimulation with endotoxin or certain proinflamma-

tory cytokines (eg TNF-α, IL-1, IL-6), the expression of tissue factor (TF) is rapidly upreg-

ulated on monocytes and perhaps a subset of endothelial cells(6,86). This is immediately followed

by a decrease in levels of the extrinsic clotting system components, factor VII and factor VIIa.

Activation of the final common pathway is reflected by increases in markers for the genera-

tion of thrombin, such as prothrombin fragment F1.2 and thrombin−antithrombin (TAT) com-

plexes(73,81). As indicated by these haemostatic changes, TF expression in sepsis activates the

extrinsic system of coagulation, with the conversion of prothrombin to thrombin(11).

The intrinsic system may be less important in generating the initial haemostatic response to

sepsis or tissue injury, but appears to play a more critical role in amplifying the response via

activation of the fibrinolytic system(11,75,87). Activation of this system involves a combination of

cross-talk and feedback mechanisms. Factor VIIa of the extrinsic system activates factor IX of

the intrinsic system to factor IXa (cross-talk). Thrombin, generated by the actions of both the

extrinsic and intrinsic systems, amplifies the initial prothrombotic response by activating the

intrinsic system through conversion of factor XI to XIa and factor VIII to VIIIa (feedback).

Fibrinolysis abnormalities

Fibrinolysis is normally tightly linked to coagulation. By removing thrombi and preserving

the fluidity of the blood, fibrinolysis is an essential component of microcirculatory homeosta-

sis(9). Endothelial cells are the principal sources of tissue-type plasminogen activator (t-PA),

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the primary enzyme responsible for activation of fibrinolysis through the conversion of plas-

minogen to plasmin(8,88). In turn, plasminogen activator inhibitor type-1 (PAI-1), a product of

platelets and endothelium, is the primary inhibitor of both t-PA and urokinase-type plas-

minogen activator (u-PA)(8,9). Additional inhibition of fibrinolysis occurs through the actions

of α2-antiplasmin and thrombin-activatable-fibrinolytic inhibitor (TAFI).

Experimentally, the infusion of TNF or IL-1 can activate fibrinolysis, reflected by the appear-

ance of plasmin–α2-antiplasmin (PAP) complexes that have no proteolytic activity but serve as

a sensitive indicator of plasmin generation(7,9). Approximately 1−2 hours after infusion of

proinflammatory cytokines or endotoxin, inhibition of the early burst of fibrinolytic activity

is shown by a progressive increase in the synthesis of PAI-1, a decrease in PAP complex lev-

els and the appearance of t-PA–PAI-1 complexes. This appears to be secondary to a cytokine-

induced increase in PAI-1 synthesis in several organs, which may contribute to the imbalance

between coagulation and fibrinolysis and result in disruption of the microcircula-

tion(7,75,76,81,89,90). Levels of PAI-1 may remain within the normal range in patients with uncom-

plicated sepsis, but are usually markedly elevated in patients with septic shock and correlate

with an unfavourable outcome(8,85,91,92).

Microcirculatory thrombosis

Although a number of interactive factors appear to promote the development of MODS,

cytokine-induced prothrombotic abnormalities within the microcirculation play a major role

in the process. The thrombotic diathesis results when proinflammatory cytokines upregulate

TF, downregulate the Protein C/Protein S system and impair the body’s natural ability to dis-

solve clots by stimulating the production and release of PAI-1(9). Within hours of the onset of

sepsis, these haemostatic alterations produce a dramatic imbalance favouring thrombosis in

the microvasculature and sometimes the macrovasculature.

Microvascular thrombosis can be observed in both experimental models of sepsis and in sep-

tic patients. Experimentally, rats with Pseudomonas aeruginosa septic abscesses develop sterile

microthrombi in distant, surgically-created microvascular anastomoses(52). Skin biopsies from

patients with infectious purpura fulminans show dermal vascular thromboses and haemor-

rhagic necrosis(93,94). Microcirculatory abnormalities also play a role in the genesis of the acute

respiratory distress syndrome (ARDS), a frequent organ system dysfunction in patients with

severe sepsis and other disorders. As previously mentioned, MODS probably results as a

consequence of a number of insults rather than a single event, with a majority of the action

occurring in the microvasculature. For the purpose of this discussion, the following section

concentrates on haemostatic and microvascular issues.

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Acute respiratory distress syndrome as a model of MODS

Although a number of infectious and inflammatory disorders are associated with the develop-

ment of ARDS, the highest incidence occurs in patients with severe sepsis(70). The respiratory

system is often the first organ system to fail clinically and the pathophysiology of the process

illustrates many important elements of MODS, including endothelial activation, inflamma-

tory and haemostatic changes and vascular alterations.

Endothelial activation

Endothelial cell activation and injury are considered by many to be the principal mechanisms

underlying the pathophysiologic manifestations of ARDS(8,95). Activation of pulmonary vascu-

lar endothelial cells, defined by a change in phenotype or function, can be induced by various

stimuli including thrombin, systemic cytokines (eg TNF-α, IL1) and bacterial products (eg

LPS)(95,96). The endothelial cells can then shift to a prothrombotic state, with increased

expression of surface receptors for thrombin, von Willebrand factor (vWF) and adhesion

molecules (eg ICAM-1)(11). Suggesting an activation-dependent mechanism, the sepsis-

induced upregulation of selectins and integrins can lead to sequestration of inflammatory cells

within the pulmonary vasculature, which is one of the earliest changes in ARDS(95,97,98). The

complexity of endothelial cell activation, including gene clustering and the expression of

adhesion and signaling molecules that mediate neutrophil interactions, has been demon-

strated by in vitro systems(95). Alternatively, concentrations of soluble forms of these molecules

may serve as surrogate markers of endothelial cell activation and injury(99). Recent studies have

detected elevated plasma levels of these markers in patients with ARDS and acute lung injury

(ALI), with degrees of elevation suggesting differences in endothelial cell activity among

high-risk subgroups(100,101).

Thrombin regulates endothelial cell function by binding to either the thrombin receptor

(TR) or thrombomodulin (TM). Binding to the TR shifts the balance of the endothelial

cell to a prothrombotic phenotype, characterized by the release of PAI-1, downreglation of

TM expression and other changes involving NFκβ transcription(8). In tissue culture, throm-

bin produces endothelial cell injury, manifested by increased microvascular permeability,

altered endothelial cell shape and disassembly of actin myofilaments(102). Microscopically,

thrombin increases endothelial cell permeability and produces gaps between adjacent

endothelial cells. Deposition of fibrin in the microvasculature is histologically associated

with endothelial cell injury and may contribute to the development of ARDS in septic

patients(96).

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Inflammatory and haemostatic activation

Of the proinflammatory cytokines associated with increased activity within the lungs of

ARDS patients, TNF-α appears to play a pivotal role in initiating the coagulation

response(64,96). Increased levels of TNF have been found in the pulmonary microcirculation or

bronchopulmonary secretions of ARDS patients compared with patients with sepsis alone,

failure of other organ systems or other types of lung disease(46,103,104). Studies comparing bron-

choalveolar lavage and plasma levels of TNF in patients with ARDS indicate that the cytokine

is lung derived, probably of alveolar macrophage origin and suppressed by IL-10(64,105). A

functionally active membrane-associated TNF on these cells may contribute to lung injury

through the increased expression of its surface receptor.

Changes in inflammatory cytokines in patients with early ARDS are associated with histologic

alterations that can be divided into exudative, proliferative and fibrotic stages(97). In the early

phases of sepsis-induced ARDS, intracapillary neutrophil aggregates are focally prominent

and associated with widening of the alveolar septa by interstitial oedema, fibrin deposits and

extravasated erythrocytes(97). Platelet sequestration also occurs(106). This phase is marked by a

prothrombotic diathesis, which primarily results from activation of the extrinsic system and

may be local or become generalized(96). Levels of TF, which have a critical role in initiating

the extrinsic pathway, are increased in the bronchoalveolar fluid of ARDS patients(107).

Fibrinolytic activity is depressed as shown by increased concentrations of PAI-1 on bron-

cholveolar lavage in the acute stage of lung injury(108). The combination of endothelial cell

damage, sequestration of inflammatory cells, increased coagulation and depressed fibrinolysis

promote the deposition of fibrin and the development of hyaline membranes with subsequent

alveolar fibrosis.

Vascular alterations

Pulmonary vascular lesions correlate with the duration of respiratory failure. In postmortem

lung specimens, thrombotic and thromboembolic lesions are detected in 95% of patients with

ARDS(97). In the microcirculation, these lesions consist of hyaline platelet−fibrin thrombi in

capillaries and arterioles, and laminated fibrin clots in small arteries and arterioles. Larger

thrombi are found in arteries with a diameter >1 mm. Although it is difficult to determine if

these thrombi are formed in situ or are of embolic origin, the combination of histologic and

haemostatic changes suggests that local microvascular thrombosis plays a major role. Over

time, fibrocellular intimal proliferation develops and contributes significantly to elevations in

pulmonary vascular pressure. In the later stages, pulmonary vascular remodelling produces

dramatic changes evident on angiography, as arterioles become more tortuous and blunted,

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and pulmonary capillaries undergo progressive dilatation. Increased arterial muscularization

in ARDS may result from hypoxia, pulmonary hypertension or oxygen toxicity. Experimental

data suggest that such structural remodelling is irreversible.

Vascular bed-specific determinants in MODS

With the preponderance of evidence supporting microvascular thrombosis, it might seem

surprising that extrapulmonary thrombi are difficult to demonstrate in the septic population.

However, coagulation abnormalities are clearly related to the development of organ dysfunc-

tion and death, and changes in sensitive laboratory tests support the direct relation-

ship(30,73,78,83,92,109). The thrombotic diathesis of sepsis is reflected by an elevation in the

TAT/PAP ratio, which is significantly higher in patients with severe sepsis than in postsurgi-

cal controls(7). This prothrombotic state appears to contribute directly to mortality as

TAT/PAP ratios are higher in nonsurvivors of sepsis than in survivors(7,9).

Failure to demonstrate widespread thrombosis appears to be secondary to several factors. For

example, the effects of cytokines appear to be vascular-bed specific(11,46,110). Levels of TNF in

bronchopulmonary secretions are elevated in ARDS patients compared with those having

serious infections or other types of lung disease(103,104). Studies comparing bronchoalveolar

lavage and plasma levels of TNF in ARDS patients indicate that the cytokine is lung derived

and probably of alveolar macrophage origin(105). Moreover, sepsis is a dynamic process that

evolves through stages marked by differential levels of proinflammatory and anti-inflamma-

tory cytokines(65,111). The cytokine mix can vary enormously over the course of the disease;

thus, the inappropriate timing of administration of investigational anti-inflammatory thera-

pies has been postulated as one possible mechanism for clinical trial failures(79).

Concentrations of cytokines may be lower in areas that are remote from the primary process

and may vary with regional blood flow and tissue perfusion(11,46,110). Finally, reperfusion may

fragment and sweep microthrombi from tissue beds, with subsequent clearance by the reticu-

loendothelial system.

Natural inhibitors of coagulation

The body has a number of natural inhibitors of the haemostatic system that localize coagula-

tion and maintain homeostasis. These endogenous inhibitors include antithrombin (AT III),

tissue factor pathway inhibitor (TFPI) and Protein C (PC). Because almost all patients with

severe sepsis have a coagulopathy, the potential role of natural antithrombotic proteins in this

disorder is discussed.

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Antithrombin

Antithrombin (AT III) is a single-chain glycoprotein that inactivates not only thrombin (fac-

tor II), but also inhibits the clotting-related serine proteases, factors XIIa, XIa, Xa and Ixa(8,73).

The beneficial properties of AT III also may reflect its anti-inflammatory effects. When

bound to the endothelial cell via glycosaminoglcans (GAG), AT may release prostaglandin I2

(prostacyclin, PGI2), a vasodilator and inhibitor of platelet aggregation. Antithrombin is also

implicated in endotoxin resistance and the reduced release of oxygen radicals and TNF-?

from monocytes stimulated by LPS(73). In severe sepsis, the dramatic decline of AT results

from its acute consumption by thrombin, with the formation of TAT complexes, its extrava-

sation due to increased permeability and its degradation by neutrophil elastase and other pro-

teases(8,30). In animal studies, high levels of AT III (>150%) produced favourable results in

DIC and MODS. Similarly, high doses of AT III generally were required to overcome the

problem of antithrombin consumption in clinical studies. In a randomized, placebo-con-

trolled study of 35 patients with septic shock, high-dose AT III significantly shortened the

duration of DIC and reduced mortality, although the difference was not statistically signifi-

cant(112). Subsequently, a 14-day, prospective study of 29 surgical patients reported that AT III

attenuated the SIRS response, improved lung function and prevented both liver and kidney

dysfunction(113). In a double-blind, randomized, placebo-controlled trial of 120 patients, AT

III reduced mortality only in a subset of septic shock patients(114). Despite these promising

preclinical and clinical findings, a meta-analysis of separate, large multicentre, double-blind,

placebo-controlled trials failed to demonstrate a significant reduction in 28-day mortality in

patients with severe sepsis treated with AT III(115). There was evidence of a significant

decrease in organ system dysfunction. A subsequent large, multicentre, prospective, random-

ized, double-blind, placebo-controlled trial also failed to demonstrate improved survival asso-

ciated with AT replacement therapy in severe sepsis and septic shock(116).

Tissue factor pathway inhibitor

Tissue factor pathway inhibitor (TFPI) is found in plasma, associated with apolipoprotein II,

and on the endothelium of small capillaries. TFPI is a potent but slow inhibitor of the TF-

factor VIIa complex. During sepsis, TFPI levels remain stable or increase, presumably due to

release from endothelial cells. A preclinical trial of TFPI in a porcine model of septic shock

demonstrated improved cardiac output and attenuation of cytokine responses to sepsis,

reducing peak TNF-α and IL-8 levels (p <0.05 vs control)(117). The study concluded that TFPI

treatment attenuated important mediator components within the inflammatory response, but

did not provide significant survival benefit(117). A phase III clinical trial of recombinant TFPI

in patients with severe sepsis is ongoing.

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Activated Protein C

In its natural state, Protein C is an inactive serine protease. Activated Protein C, in the pres-

ence of its cofactor Protein S, has antithrombotic, anti-inflammatory and profibrinolytic

properties. The conversion of Protein C to activated Protein C requires the action of throm-

bin complexed with the endothelial cell glycoprotein, thrombomodulin (TM)(10). This results

from a TM-induced alteration in the substrate specificity of thrombin from fibrinogen to

Protein C. Thus, generation of activated Protein C occurs in rough proportion to thrombin

formation. The binding of activated Protein C to Protein S facilitates cleavage of factors

VIIIa and Va, thereby modulating coagulation through suppression of further thrombin pro-

duction(9,118). Levels of Protein C decline early in sepsis, predominantly due to consumption

and depletion(78,85,118). Activated Protein C activity also decreases in this setting as a result of

consumption and endothelial cell injury, with the loss of Protein C receptors and TM expres-

sion on endothelial cells(86). Concomitantly, levels of both free Protein S and the inactive

Protein S–C4b-binding protein complex remain within normal limits, which supports the

role of Protein C as the determinant of sepsis severity. Consistent with its pharmacologic

effects, reduced levels of Protein C correlate with morbidity and mortality in sepsis.

In addition to its anticoagulant effect, activated Protein C enhances fibrinolysis by neutraliz-

ing PAI-1 and accelerating t-PA-dependent clot lysis in a TAFI-dependent manner(9,119,120). In

addition to its indirect effect on inflammation through inhibition of thrombin formation,

activated Protein C has direct anti-inflammatory effects. In preclinical models, activated

Protein C inhibited LPS-induced TNF-α production and translocation of NFκβ in mono-

cytes; suppressed proinflammatory cytokine release from monocytes; inhibited selectin-

mediated cell adhesion; and protected baboons from lethal doses of Escherichia coli endo-

toxin(80,121-124). As indicated by transcriptional profiling, activated Protein C may directly affect

endothelial cell function through suppression of NFκβ binding and functional activity,

including inhibition of TNF-α-induced upregulation of surface adhesion molecules (eg

ICAM-1, E-selectin), and through modulation of gene expression to prevent apoptosis and a

switch to cell survival mechanisms(125). In patients with severe meningococcaemia, activated

Protein C appeared to improve the host response and reduce cytokine-mediated organ dys-

function(126,127). The effects of recombinant human activated Protein C [drotrecogin alfa (acti-

vated)] have been recently published(82) and are discussed by Bernard later in this monograph.

Conclusion

Severe sepsis is sepsis with acute organ dysfunction and is frequently accompanied by a sepsis-

induced coagulopathy. Organ dysfunction in this population may be an early manifestation of

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MODS, a progressive physiologic dysfunction of several organ systems such that homeostasis

cannot be maintained without intervention. The presence of MODS marks a population at

high risk for mortality. The pathophysiology of MODS is a complex relationships between

inflammation, thrombosis and impaired fibrinolysis. Only by recognizing and addressing all

of these components can there be hope of decreasing the mortality of patients with sepsis and

acute organ dysfunction.

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