Inflammation, coagulopathy, and the pathogenesis of multiple

organ dysfunction syndrome

John C. Marshall, MD, FRCSC

Objective: An improved understanding of the mechanisms
through which infecting pathogens harm the host is leading to
new formulations of the concept of sepsis. We review the roles of
inflammation and coagulation in the pathogenesis of the multiple
organ dysfunction syndrome, and explore the potential of new
therapies to restore the fine biological balance between proco-
agulant and anticoagulant mechanisms that are disrupted during
the life-threatening processes that lead to organ dysfunction.
Data Sources: Narrative review of published primary sources in
the basic and clinical literature.
Data Summary: Traditional models of host-pathogen interactions
ascribe the morbidity of infection to the direct cytotoxic effects of
micro-organisms on host tissues. However, abundant experimental
and clinical evidence has revealed that it is the response of the host,
rather than the trigger that elicited it, that is the more potent
determinant of outcome. The elucidation of a complex network of
host-derived inflammatory mediators raised the possibility that tar-
geting these individually could improve patient outcomes, and some
modest successes with this approach have been achieved. More
recently, it is becoming evident that the inflammatory response, in
turn, mediates its deleterious effects by inducing tissue hypoxia, and
cellular injury, either through tissue necrosis or through the induction
of programmed cell death or apoptosis. Thus, treatment strategies
that target the downstream consequences of the activation of in-
flammation, for example, microvascular coagulation or acute adrenal
insufficiency, represent the latest, and some of the most promising
approaches to attenuation of the septic response to improve survival,
and minimize organ dysfunction. The maladaptive sequelae of sys-
temic inflammation, embodied in the concept of the multiple organ
dysfunction syndrome, comprise the leading obstacle to survival for
patients admitted to a contemporary intensive care unit. Further
insights into this intimidatingly complex process will not only provide
potent new therapeutic options, but promise to transform critical
illness from a biological standoff, during which the clinician merely
supports failing organs, to a disease that can be successfully treated.
(Crit Care Med 2001; 29[Suppl.]:S99 S106)
KEY WORDS: sepsis; multiple organ dysfunction syndrome; in-
flammation; coagulopathy; apoptosis; complexity theory

A n evolving ability to support
vital organ system function
during a period of otherwise
lethal physiologic insufficiency
changed the process of hospital care over
the last half of the 20th century. Over a
relatively short period, the development
of techniques of positive pressure venti-
lation, hemodialysis, and invasive moni-
toring and cardiovascular support trans-
formed life-threatening illness from a
rapidly lethal event to a chronic state that
was, potentially, survivable. The impact
has been profound; for example, the mor-
tality of abdominal trauma on the battle-
From the Department of Surgery and the Pro-
gramme in Critical Care Medicine, University Health
Network, University of Toronto, Toronto, Ontario, Can-
ada.
Presented, in part, at the Margaux Conference on
Critical Illness, Margaux, France, November 8 12,
2000.
Address requests for reprints to: John C. Marshall,
MD, 9 Eaton North, Room 234, Toronto General Hos-
pital, 200 Elizabeth Street, Toronto, Ontario M5G 2C4,
Canada. E-mail: john.marshall@uhn.on.ca
Copyright 2001 by Lippincott Williams & Wilkins
field was virtually 100% before World
War I but had fallen to 2% to 3% during
the Arab-Israeli conflict in 1973 (1). Ne-
crotizing pancreatitis was uniformly le-
thal in the early 20th century (2); today,
the majority of patients survive. Advances
in the support of vital organ function
gave rise to intensive care units (ICUs) as
dedicated geographic venues for the ad-
ministration of these technologies (3)
and spawned an entirely new specialty
that of intensive care medicine.
The cost of this progress has been con-
siderable. The provision of critical care
services consumes more than 1% of the
gross national product of many countries
of the developed world (4). Moreover, the
very successes of this new discipline have
created an entirely unprecedented spec-
trum of clinical problems, arising in the
wake of the profound physiologic de-
rangements of critical illness and the he-
roic interventions applied to reverse
them. For example, the emergence of
Gram-negative organisms as significant
pathogens in hospitalized patients is a
phenomenon of the last half of the 20th
century (5), and their subsequent re-
placement by relatively avirulent organ-
isms such as coagulase-negative Staphy-
lococci, Candida, Pseudomonas, and the
Enterococcus, is an even more recent de-
velopment (6). The syndrome of acute
lung injury known as acute respiratory
distress syndrome was first described less
than four decades ago (7), and the role of
the mode of support in the syndromes
evolution has been appreciated only in
the last few years (8). Similarly, septic
shock became a describable entity (9)
only after resuscitation and organ system
support techniques were sufficiently ef-
fective that overwhelming infection
ceased to be a rapidly lethal event and was
transformed into a prolonged, but surviv-
able, process.
The ICU made possible a spectrum of
disorders that are characterized by their
strong association with inflammation and
described by their effects on the function
of individual organ systems: the acute
respiratory distress syndrome, acute re-
nal failure, disseminated intravascular
coagulation, septic shock, and stress gas-

Crit Care Med 2001 Vol. 29, No. 7 (Suppl.) S99

trointestinal bleeding, to name a few. Yet,
as emphasized so compellingly by Baue
(10) a quarter of a century ago, it is not
simply that any one of these organ system
derangements is the cause of all the oth-
ers. Rather, all share common features
that justify their consideration as mani-
festations of a common processinitially
described as multiple organ failure (11
14), and more recently termed multiple
organ dysfunction syndrome (MODS)
(15).
MODS is widely considered to be the
leading cause of morbidity and mortality
for patients admitted to an ICU (16 19).
However, despite its immediate and infi-
nitely recognizable manifestations in the
critically ill patient, its characterization
as a discrete syndrome with a common
and measurable pathologic basis has ben
problematic. First, patients admitted to
an ICU frequently have some degree of
preexisting physiologic impairment, so
that it may be difficult to differentiate
derangements that are acute and poten-
tially reversible from those that are
chronic and irreversible. Second, the
spectrum of disorders that lead to ICU
admission commonly includes diseases
that cause direct organ injury, for exam-
ple, pneumonia or trauma producing
acute lung injury, or mesenteric vascular
ischemia causing liver dysfunction. Fi-
nally, the challenge in characterizing or-
gan dysfunction in biochemical terms has
been not a lack of definable abnormali-
ties, but a surfeit (Table 1). Literally hun-
dreds of biochemical and cellular abnor-
malities have been described in patients
with MODS, and their very number has
made it difficult, if not impossible, to
define a single common underlying event
or process as the pathogenic basis of the
disorder. Indeed, it is not at all clear
whether MODS is a single pathologic pro-
cess with highly variable clinical expres-
sion or simply the limited phenotypic
expression of a large number of patholog-
ically divergent processes.
This paper will review the more prom-
inent theories about the pathogenesis of
MODS, recognizing that the mechanisms
that have been proposed are by no means
exclusive and are often best viewed as
differing perspectives on common patho-
logic processes.
Uncontrolled Infection
The first descriptions of the MODS
emphasized its common association with
occult or poorly controlled infection (9,
13, 20), frequently either peritonitis (14)
or pneumonia (21). However, more re-
cent reports indicate that infection, al-
though common in patients with MODS,
is not necessarily present (22) and fre-
quently follows, rather than precedes, the
development of the syndrome (6). Indeed,
nosocomial infection may be better con-
sidered a manifestation of MODS than a
cause of it. Characteristic infecting florae
include opportunistic organisms of low
intrinsic virulence (notably Candida, co-
agulase-negative Staphylococci, Pseudo-
monas, and Enterococci) (6), as well as
species whose emergence reflects local
environmental factors (notably Acineto-
bacter and Stenotrophomonas) or selec-
tive antimicrobial pressures (methicillin-
resistant Staphylococcus aureus,
vancomycin-resistant Enterococcus, and
extended-spectrum -lactamaseproduc-
ing Gram-negative organisms). Indeed,
the prevalence of infection with the
former group of organisms is strongly
associated with the severity of MODS
(Fig. 1) (23).
Microbial products such as endotoxin
may also be a cause of MODS. Endotox-
emia is much more common in the crit-
ically ill patient than is documented in-
fection (24) and correlates poorly with
culture-proven infection (25), suggesting
an important role for the absorption of
endotoxin from the gastrointestinal tract
(26) or lung (27).
It is generally accepted that the mor-
bidity of bacterial infection arises indi-
rectly, through such downstream effects
as the activation of an inflammatory re-
sponse or the induction of intravascular
coagulation in the host. However, bacte-
rial products can be directly toxic to cells,
altering fundamental cellular processes,
as in the case of cholera toxin, or induc-
ing the apoptosis, or programmed cell
death, of neutrophils (28, 29) and epithe-
lial cells (30).
Although infection commonly triggers
MODS, the evidence that infection plays
an important role in the evolution of the
syndrome is not compelling. Meta-
analyses of the effects of infection pro-
phylaxis using the techniques of selective
digestive tract decontamination show a
striking reduction in rates of such infec-
tions as pneumonia, wound infection,
and bacteremia but a much more modest,
albeit statistically significant, reduction
in mortality (31, 32). Moreover, peritoni-
tis and pneumonia are frequent causes of
MODS, but the evidence that successful
treatment of either alters outcome is far
from compelling (3336). The pathogenic
role of endotoxin is equally uncertain:

Table 1. Conceptual models of multiple organ dysfunction syndrome

Pathologic Process Manifestations Therapeutic Implications

Uncontrolled infection
Systemic inflammation
Immune paralysis
Tissue hypoxia
Microvascular coagulopathy and
endothelial activation
Dysregulated apoptosis
Gut-liver axis
Persistent infection, nosocomial ICU-acquired infection, Aggressive use of antibiotics and source
endotoxemia control measures
Cytokinemia (particularly IL-6, IL-8, TNF), leukocytosis, Neutralization of specific cytokines (IL-1,
increased capillary permeability TNF, PAF) or of activational pathways
Nosocomial infection, increased anti-inflammatory cytokine G-CSF, interferon
levels (IL-10), decreased HLA-DR expression
Increased lactate Augmentation of DO2
Increased procoagulant activity, decreased anticoagulant Augmentation of anticoagulant mechanisms
activity, increased von Willebrand factor, soluble (APC, TFPI, antithrombin)
thrombomodulin; increased capillary permeability
Increased epithelial and lymphoid apoptosis, decreased Caspase inhibition
neutrophil apoptosis
Increased infection with gut organisms, endotoxemia, Kupffer Selective digestive tract decontamination,
cell activation enteral feeding

APC, activated protein C; G-CSF, granulocyte colony-stimulating factor; ICU, intensive care unit; IL, interleukin; PAF, platelet activating factor; TFPI,
tissue factor pathway inhibitor; TNF, tumor necrosis factor.

S100 Crit Care Med 2001 Vol. 29, No. 7 (Suppl.)


Figure 1. Association of nosocomial infection
caused endemic intensive care unit pathogens
with the severity of organ dysfunction, measured
using a numeric score. Nosocomial infection is
rare in patients without organ dysfunction; its
prevalence increases in direct relation to the se-
verity of multiple organ dysfunction syndrome
(MODS), and its evolution follows the develop-
ment of the syndrome, suggesting that nosoco-
mial infection is a reflection, rather than a cause,
of MODS. MOF, multiple organ failure. Figure is
reproduced with permission (23).
none of the dozen or more clinical trials
that have evaluated endotoxin neutraliza-
tion as a therapeutic strategy have shown
unequivocal evidence of benefit, and at
least one (37) raised the possibility that
such an approach might be harmful.
Uncontrolled Systemic
Inflammation
Clinical evidence of systemic inflam-
mation is evident in almost all patients
developing MODS (38 40); in fact, re-
mote organ dysfunction can be consid-
ered the functio laesa of systemic inflam-
mation. Although it is difficult to
differentiate the clinical manifestations of
inflammation from the infections that are
commonly their cause, it can be shown
that the severity of the clinical inflamma-
tory response, rather than the presence
or absence of infection, is the more im-
portant determinant of ICU survival (39)
(Fig. 2).
An extraordinary number of proin-
flammatory mediator molecules have
been implicated in the expression and
resultant morbidity of a systemic inflam-
matory response. The lethality of murine
endotoxemia, for example, can be pre-
vented by specific neutralization of more
than two dozen inflammatory mediators,
including interleukin (IL) 1, tumor ne-
crosis factor (TNF), high mobility group
1, interferon , leukemia inhibitory fac-
tor, macrophage migration inhibitory
factor, IL-12, and phospholipase A2 (41),
although their neutralization has variable
Crit Care Med 2001 Vol. 29, No. 7 (Suppl.)
Figure 2. The differential impact of infection as a
microbial phenomenon and sepsis as the re-
sponse of the host was investigated in a study of
212 admissions to a surgical intensive care unit
(ICU). Infection was diagnosed using objective
microbiological and radiographic criteria, with-
out reference to clinical manifestations. The se-
verity of the septic response was graded using a
sepsis score that quantifies abnormalities in five
separate domains (temperature, white cell count,
change in level of consciousness, cardiac output
or systemic vascular resistance, and insulin re-
quirements) on a 3-point scale. Scores were cal-
culated daily; the maximum value was 15. Top,
when patients meeting criteria for infection were
evaluated, nonsurvivors had higher sepsis scores
than survivors, whether in response to commu-
nity-acquired or ICU-acquired infections. Bot-
tom, in contrast, when patients with an activated
septic response (a sepsis score of 7 or higher), no
infection-related variable could be identified that
discriminated survivors from nonsurvivors. Sep-
sis scores, however, remained higher in nonsur-
vivors. Figure is reproduced with permission
(39).
effects in other models. Cohort studies in
critically ill patients show that increased
circulating levels of cytokines such as
TNF and IL-6 (42 44), or markers of in-
creased release of TNF in response to
inflammatory stimuli (45, 46) are associ-
ated with organ dysfunction and an in-
creased risk of death.
Although the synthesis and release of
a panoply of biochemical mediators of
inflammation is characteristic of both ex-
perimental and clinical sepsis, the mech-
anisms through which these molecules
may induce organ injury are much less
clear. The cellular receptor for tumor ne-
crosis factor is a member of the Fas fam-
ily of death receptors that are capable of
initiating apoptosis or programmed cell
death in their cellular targets (47). How-
ever, the same receptor delivers an in-
flammatory and antiapoptotic signal to
cells such as neutrophils, and the extent
to which the effects of TNF reflect direct
cellular injury is uncertain. TNF and
other proinflammatory molecules can
also activate downstream effectors of
acute inflammation, for example, by up-
regulating the expression of inducible ni-
tric oxide synthase (48), which results in
increased release of nitric oxide and its
attendant effects on microvascular resis-
tance and capillary flow, or by augment-
ing neutrophil cytotoxic mechanisms by
inducing the release of oxygen radicals
and proteolytic enzymes (49, 50). More-
over, proinflammatory mediators can
also up-regulate endothelial cell adhesion
molecule expression (51) and activate en-
dothelial procoagulant activity (52),
while inhibiting the expression of throm-
bomodulin (53, 54), a critical factor in
the activation of the protein C anticoag-
ulant pathway.
An alternate model of the dysregulated
inflammatory response that accompanies
MODS suggests that the problem is not
so much excessive inflammation as an
acquired state of immunodeficiency or
immune paralysis (55). The potential
manifestations of this state of impaired
immunity are many and include anergy
to delayed hypersensitivity recall testing
with common antigens (56), impaired de
novo antibody synthesis to tetanus toxoid
(57), reduced monocyte expression of hu-
man leukocyte antigen-DR (HLA-DR)
(58), and increased circulating levels of
counterinflammatory cytokines such as
IL-10 (59) and transforming growth fac-
tor (60).
Clinical trials of a variety of strategies
designed to inhibit inflammation in crit-
ical illness have generally yielded disap-
pointing results, with pooled data from
studies of the neutralization of TNF or
IL-1 in sepsis showing a small but signif-
icant absolute mortality reduction of
3.5% to 5% (61). A recently completed,
unpublished North American study of
afelimomab, a monoclonal antibody to
TNF, suggested that this mortality bene-
fit can be increased if patients with an
exaggerated inflammatory response re-
flected in elevated circulating levels of
IL-6 are targeted and that neutralization
of TNF also reduces the severity of organ
dysfunction developing subsequent to the
onset of treatment. However, the rela-
S101
tively modest impact of such approaches
suggests either that multiple redundant
mediators must be targeted or that the
ultimate morbidity of sepsis results from
the downstream consequences of cyto-
kine activity. The lack of efficacy of early
high-dose corticosteroid therapy (62, 63)
or ibuprofen (64), strategies that would
be expected to reduce the levels of a num-
ber of inflammatory mediators, suggests
that the latter interpretation may be
more accurate.
Tissue Hypoxia
Reduced oxygen delivery or utilization
would be expected to inhibit the normal
physiologic functions of the cell; there-
fore, the assumption that cellular hypoxia
is the final common pathway to organ
dysfunction is attractive (65, 66). Al-
though adequate initial resuscitation
usually restores oxygen delivery at the
level of the whole organism, regional
hypoxia in tissues such as the gastroin-
testinal tract (67, 68) or brain (69) is a
well-documented phenomenon. In-
creased circulating concentrations of lac-
tate are also suggestive of tissue hypoxia,
either global or regional, and are associ-
ated with an adverse outcome (70, 71).
Unfortunately, the initial enthusiasm
for resuscitation to supranormal values
to correct occult tissue hypoxia (72) has
not been supported by more recent ran-
domized trials (73); indeed, the use of
transfusion (74) or large doses of dobut-
amine (75) to increase oxygen delivery
actually worsens outcome and increases
the severity of organ dysfunction. In the
case of transfusion, at least, it appears
that the deleterious effects arise from the
failure of transfused red cells to reach the
tissues, because of microvascular plug-
ging by aged and poorly deformable red
cells (76). Alternatively, tissue hypoxia
may result from derangements in the in-
tracellular utilization of oxygen, in the
face of adequate delivery, a pathologic
state that has been termed cytopathic
hypoxia (77).
Dysregulated Apoptosis
Apoptosis describes a physiologic pro-
cess through which cells activate an en-
dogenous program that leads to the con-
trolled death of the cell and its
transformation to membrane-bound ves-
icles that are cleared by macrophages
without evoking an inflammatory re-
sponse (78). The normal expression of
S102
apoptosis is fundamental to such pro-
cesses as embryologic development, im-
mune maturation, aging, cell turnover at
epithelial surfaces, and the resolution of
inflammation. The expression of apopto-
sis is altered in critical illness. Apoptosis
of lymphocytes and gut epithelial cells is
increased (79, 80), whereas that of neu-
trophils is delayed (81 83). Excessive ap-
optosis has been implicated as a mecha-
nism of liver (84), kidney (85), and
cardiac (86) disease, and interventions
that modulate the expression of apoptosis
can improve outcome in a variety of ex-
perimental models of inflammation (87).
Intriguingly, the induction of apoptosis
by Pseudomonas in tracheal epithelial
cells (88) or by Escherichia coli in lung
neutrophils (89) results in improved sur-
vival in experimental pneumonia and in-
testinal ischemia/reperfusion injury, re-
spectively.
Therapies targeting the expression of
apoptosis are not yet clinically available;
therefore, their ability to prevent organ
dysfunction in the critically ill patient
remains unproven.
Microvascular Coagulopathy
The mechanisms that regulate the ex-
pression of inflammation are intimately
linked to those that control the expres-
sion of coagulation, and multiple lines of
evidence point to a pivotal role for inap-
propriate intravascular coagulation as a
final common pathway to organ dysfunc-
tion. Cohort studies demonstrate a strik-
ing association between dysregulated co-
agulation and the development of organ
dysfunction. In a longitudinal study of
136 patients who had sustained multiple
trauma, Gando and colleagues (90)
showed that early evidence of dissemi-
nated intravascular coagulation was a
powerful predictor of subsequent organ
dysfunction and that a platelet count of
less than 80,000/ml had a sensitivity of
83.3% and a specificity of 100% for the
prediction of MODS (90).
The coagulopathy of critical illness is
biologically complex and intertwined at
multiple levels with the biological pro-
cesses described earlier. Coagulation is
initiated through tissue factor expressed
on the surface of endothelial cells and
monocytes, a process that can be induced
by microbial products such as endotoxin
(91) or cell surface components of Bacte-
roides fragilis (92), by inflammatory cy-
tokines (52, 93), or by integrin cross-
linking (94). Tissue factor on the cell
surface activates factor VII, and the re-
sulting complex of factor VIIa and tissue
factor converts factor X to factor Xa. In
concert with factor Va, factor Xa converts
prothrombin to thrombin, which in turn
results in the cleavage of fibrinogen to
fibrin. Although fibrin deposition plays a
critical role in hemostasis and in the lo-
calization of microorganisms within an
abscess cavity, intravascular coagulation
impedes oxygen delivery to tissues and
can induce further inflammatory injury,
indirectly through the response to hy-
poxia and directly through signals deliv-
ered to the thrombin receptor. Engage-
ment of the thrombin receptor activates
the nuclear transcription factor NFB
(95), causing the transcription of a broad
array of proinflammatory gene products
and resulting in the release of nitric oxide
(96). Nor is the thrombin receptor
unique as a mechanism through which
an inflammatory response is amplified.
Clustering of tissue factor has also been
shown to initiate gene expression for
proinflammatory cytokines, including
TNF (97).
Activation of coagulation is tonically
inhibited by three major endogenous an-
ticoagulant pathways. Antithrombin III is
an inhibitor of serine proteases that in-
activates a number of coagulation factors.
It complexes with thrombin to form
thrombin-antithrombin complexes and,
through its binding to endothelium, ini-
tiates the release of prostacyclin, an in-
hibitor of platelet aggregation (98). Tis-
sue factor pathway inhibitor synthesized
by endothelial cells inhibits factor Xa and
the factor VIIatissue factor complex
(99). Finally, protein C is synthesized pri-
marily in the liver, although extrahepatic
synthesis occurs, particularly in the kid-
ney and testis (100), and circulates as an
inactive precursor. The protein C path-
way is activated through the binding of
thrombin to thrombomodulin on the en-
dothelial surface, generating activated
protein C, a serine protease that com-
plexes with protein S to inhibit factors Va
and VIIIa (101).
The biology of protein C exemplifies
the complex interactions between coagu-
lation and inflammation that can amplify
both and hence increase the resultant
tissue injury. Protein C binds to a specific
receptor on endothelial cells, the endo-
thelial cell protein C receptor (EPCR), a
process that amplifies the generation of
activated protein C by thrombin-throm-
bomodulin complexes (102). Inhibition of
this interaction with a blocking antibody
Crit Care Med 2001 Vol. 29, No. 7 (Suppl.)
Table 2. Coagulation abnormalities in trauma and sepsis
Coagulation Markers
Increased
Procoagulant activity/tissue factor
Fibrinogen
Thrombin-antithrombin
Fibrinopeptide A
Prothrombin fragment 1 2
Plasmin 2-antiplasmin complexes
D-dimers
Thrombomodulin
tPA activity
tPA antigen
Plasminogen activator inhibitor-1
von Willebrand factor
von Willebrand factor propeptide
Platelet thrombospondin
tPA, tissue plasminogen activator.
results in increased mortality, in associ-
ation with an inflammatory cell infiltrate
in the liver, kidneys, and adrenal glands,
as well as elevated circulating levels of
IL-6 and IL-8 (103). Proinflammatory cy-
tokines such as TNF inhibit EPCR expres-
sion by augmenting EPCRs shedding
from the endothelial cell surface and
down-regulating its transcription (93).
Moreover 1-antitrypsin, an acute-phase
reactant, shortens the half-life of acti-
vated protein C (APC). Thus, APC inter-
actions in vivo are predominantly anti-
inflammatory, whereas inflammation
reduces APC levels and activity. As de-
scribed earlier, the binding of thrombin
to its receptor initiates NFB-dependent
inflammatory gene transcription; in addi-
tion, thrombin up-regulates endothelial
P selectin expression and induces synthe-
sis of platelet-activating factor (104). In
addition to its role in the activation of
protein C, thrombomodulin exhibits anti-
inflammatory properties; its administra-
tion to rats challenged with endotoxin
prevented pulmonary leukosequestration
and pulmonary vascular injury (105).
Yet another example of the complex
interactions between these physiologic
processes is seen in the interactions be-
tween coagulation and programmed cell
death. Phosphatidylserine is normally ex-
pressed asymmetrically on the inner as-
pect of the cell membrane. As part of the
expression of apoptosis, phosphatidylser-
ine becomes exteriorized and serves as
one of the markers by which macro-
phages recognize and engulf apoptotic
cells. However, exteriorized phosphati-
dylserine is also a potent stimulus for
activation of the alternate pathway of
complement and for induction of proco-
Crit Care Med 2001 Vol. 29, No. 7 (Suppl.)
Decreased
Platelets
Antithrombin III
Protein C antigen
Protein C inhibitor
Protein S
Factor VII
Factor XII
agulant activity leading to thrombin gen-
eration (106).
Alterations in levels of factors that
regulate the balance between coagulation
and fibrinolysis are common in critically
ill patients and cause a shift toward a
procoagulant state (Table 2). Changes in
these parameters precede the develop-
ment of organ dysfunction (107) and per-
sist in those patients who develop organ
dysfunction or die (108). Moreover, pro-
tein C levels are decreased in acute renal
failure, a discrete manifestation of MODS
(109), and in patients with neutropenia
(110).
A variety of strategies that target the
coagulation cascade improve survival in
experimental models (111). In human
volunteers, infusion of TNF activates co-
agulation and reproduces the coagulo-
pathic profile of critical illness (112); par-
adoxically, neutralization of TNF may
augment coagulation (113). Early studies
suggesting benefit for administration of
antithrombin III (114, 115) were not rep-
licated in a recent large phase III multi-
center trial (S. Opal, unpublished obser-
vations). Recombinant tissue factor
pathway inhibitor has shown promise in
early-phase clinical studies, and a large
multicenter phase III study is in progress.
The administration of protein C has been
shown to improve outcome in purpura
fulminans (116), and a phase II study of
APC in sepsis showed a striking trend
toward improved survival in a small co-
hort of patients (117). The as yet unpub-
lished results of a large phase III study of
APC, terminated at an interim analysis
because of impressive evidence of clinical
efficacy (118), should provide the most
compelling evidence thus far that dys-
T
he disparate bio-
logical processes
that comprise in-
flammation are intimately
interrelated, and strategies
directed at one manifesta-
tion may have significant
and unexpected conse-
quences for others.
regulated coagulation is fundamental to
the pathogenesis of MODS.
CONCLUSIONS
MODS is a prototypical exemplar of
the application of complexity theory to an
understanding of the pathophysiology of
critical illness (119, 120). It arises
through the interactions of a network of
physiologic insults including infection,
the host inflammatory response, tissue
ischemia, injury, and the interventions
used to sustain organ function during a
time of otherwise lethal insufficiency. Its
mediators are many and interdependent,
with the activity of one inducing the ex-
pression of others that amplify, inhibit, or
otherwise modify the expression of the
process. The clinical syndrome that
emerges reflects the state of dynamic bal-
ance that exists between each of the com-
ponent mediators and can be considered
an emergent system.
The implications of an understanding
of the complex nature of organ dysfunc-
tion are critical to the development of
rational strategies to prevent or treat the
process. Strategies directed against
events early in the process may be effec-
tive as prophylaxis but are unlikely to
have a significant effect on a process
whose expression, at least from the per-
spective of the element targeted, has be-
come autonomous. For example, al-
though the prevention of infection in
critical illness may reduce morbidity and
mortality (121), once such downstream
events as proinflammatory mediator re-
lease have been activated, their persis-
tence is not necessarily dependent on
continuing infection. Similar consider-
S103
ations may help to explain the relatively
modest impact of neutralization of early
proinflammatory mediator release in pa-
tients with sepsis (122), although the po-
tential merits of targeting later circulat-
ing mediators such as high mobility
group 1 (123) remain to be determined.
In contrast, activation of coagulation is a
relatively late consequence of the inflam-
matory response and, therefore, concep-
tually a more attractive therapeutic tar-
get.
In reality, the disparate biological pro-
cesses that comprise inflammation are
intimately interrelated, and strategies di-
rected at one manifestation may have sig-
nificant and unexpected consequences for
others. Unfortunately, these processes are
not demonstrated particularly well in
small-animal models, and the elucidation
of the richness of these interactions
emerges only slowly, as data from trials of
a variety of interventional strategies ac-
cumulate.
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Question and Answer Session After
Scientific Review
Benoit Vallet. You have indicated
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S106
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John Marshall. Absolutely. But I
would disagree with the term failure
to describe these trials. In many cases,
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but inconclusive or suggestive of only
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and end-all of the story. In fact, it may
be that the final common pathway is
related more to endocrine insufficiency
rather than intravascular coagulopathy.
At this stage, I think it is difficult to
speculate on the extent to which coag-
ulation is clinically important, nor am I
sure that we can define a direct cyto-
toxic role for inflammation.
Crit Care Med 2001 Vol. 29, No. 7 (Suppl.)