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The Multiple Organ Dysfunction Syndrome

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 The Multiple Organ Dysfunction
Syndrome
Barry A. Mizock, MD, FACP, FCCM
Historical Perspective
The multiple organ dysfunction syndrome (MODS) arose paradoxically
as the result of advances in supportive therapy, and in this sense MODS
can be viewed as a “disease of medical progress.” The evolution of
MODS may be more easily understood from the perspective of advances
in resuscitation of combat injuries during the 20th century. In the First
World War, many injured soldiers died as the consequence of hemor-
rhagic (wound) shock. During the Second World War, administration of
whole blood by combat medics in the field reduced the incidence of
wound shock but enabled the emergence of posttraumatic renal failure as
a significant clinical sequelae of combat-related injury. During the Korean
War, the incidence of renal failure was reduced by more aggressive fluid
resuscitation, only to be followed in the Vietnam conflict by the
appearance of posttraumatic acute hypoxemic respiratory failure (eg, Da
Nang lung). The subsequent development of mechanical ventilation with
positive end-expiratory pressure and renal dialysis prolonged life in
critically ill patients and allowed the development of still other compli-
cations that had not been previously described. In 1969, Skillman and
colleagues reported a new clinical syndrome consisting of respiratory
failure, hypotension, sepsis, and jaundice that was associated with
hemorrhage from acute stress ulceration of the stomach.1 Tilney et al.
subsequently described a pattern of “sequential system failure” in 18
patients with ruptured abdominal aortic aneurysm who required hemodi-
alysis for postoperative renal failure.2 Virtually all their patients experi-
enced intraoperative hypotension, and the majority required a second
operative intervention. All patients developed failure of multiple organs
that followed a similar pattern of progression over time, with initial
involvement of the lungs and pancreas, followed by jaundice, coma,
gastrointestinal bleeding, and ultimately refractory hypotension. In 1975,
Baue described “multiple, progressive or sequential systems failure” in

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trauma patients.3 Predisposing factors included a period of shock result-
ing from injury or operation, sepsis, and cardiovascular instability.
Eiseman et al. first used the term “multiple organ failure.”4 Fry and
coworkers emphasized the association of infection and organ failure and
postulated that multiple organ failure (MOF) was the “fatal expression of
uncontrolled infection.”5 However, the central role of infection in the
evolution of organ failure was challenged by Goris and coworkers, who
noted that patients with MOF secondary to blunt trauma often lacked an
obvious focus of infection.6 They postulated that MOF resulted from an
excessive inflammatory response that could be triggered by either septic
or nonseptic injury. They used the term “generalized autodestructive
inflammation” to describe the inflammatory response in the bloodstream
that caused diffuse damage to the capillary endothelium resulting in tissue
hypoperfusion and organ failure. Meakins and Marchall felt that the
gastrointestinal tract was the “motor” that prolonged the duration of
systemic inflammation that in turn led to organ failure.7 Marshall and
Sweeney observed that the manifestations of sepsis were not uniform and
depended on the response of the host to the infectious process.8 In 1983,
Meakins described the “two-hit” model of postinjury MOF.9 He postu-
lated that traumatic injury or shock (the first hit) primes neutrophils and
macrophages for an enhanced inflammatory response following a subse-
quent insult such as a nosocomial infection (the second hit). In 1985,
Knaus and colleagues developed a scoring system for organ failure and
correlated the organ failure score with mortality.10 The term, “multiple
organ dysfunction syndrome” (MODS) was proposed in 1991 by a
Consensus Conference of the American College of Chest Physicians and
the Society of Critical Care Medicine.11 MODS was defined as “the
presence of altered organ function in an acutely ill patients such that
homeostasis cannot be maintained without intervention.” The “systemic
inflammatory response syndrome” (SIRS) was also introduced at this
conference to describe the clinical manifestations of systemic inflamma-
tion (eg, fever, tachypnea, tachycardia, leukocytosis). Although the
concept of SIRS has been criticized as lacking specificity, it is nonetheless
important because it emphasizes the fact that MODS can evolve from
either infectious or noninfectious causes (eg, trauma, burn, pancreatitis).
A more recent definition of MODS was provided by John Marshall, who
defined it as “the development of potentially reversible physiologic
derangement involving 2 or more organ systems not involved in the
disorder that resulted in ICU admission, and arising in the wake of a
potentially life-threatening physiologic insult.”12
DM, August 2009 477
Epidemiology
The reported incidence of MODS following trauma varies widely,
due in part to case-mix, as well as the use of different scoring systems
to define organ dysfunction. A recent study of adult intensive care unit
(ICU) trauma patients found that 47% had organ failure (defined as a
sequential organ failure score ⱖ3 in 2 or more organ systems) during
the ICU stay.13 They also noted that long-term functional status was
affected by organ failure; patients with MODS had 3.9 times greater
odds for requiring personal assistance in activities of daily living
compared to those without organ failure. A multiyear survey con-
ducted in SICU patients found that approximately 54% developed
some degree of MODS.14 The most common risk factors for the
development of MODS were hypoperfusion without shock, sepsis
without shock, and shock regardless of etiology. MODS is generally
recognized as the most common cause of death in the surgical
intensive care unit (SICU), and the severity of MODS correlates
significantly with mortality and length of hospitalization.15 A 12-year
prospective study of postinjury MODS found that the incidence and
severity of post-injury MODS decreased during the study period.16
The overall mortality rate did not change; however, the MODS-
specific mortality decreased. The observed improvement in outcome
was attributed to better supportive care and decreased use of blood
transfusion. A similar study performed over 17 years in SICU patients
found that mortality rate was unchanged despite significant increases
in admission APACHE III scores.17 In addition, the magnitude of
MODS (adjusted for illness severity) decreased during the period. The
authors attributed the unchanged risk-adjusted mortality over time to
the reduced magnitude of MODS consequent to improved supportive
management. A recently completed retrospective study of patients
with acute lung injury or acute respiratory distress syndrome (ARDS)
also demonstrated a decrease in mortality rate during the 12-year
period of observation, presumably reflecting improved supportive
care.18
In 2001, Angus et al. published an analysis of the epidemiology of
severe sepsis in the USA.19 The respiratory tract was found to be the
most common site of infection and had the strongest association with
mortality. The incidence of dysfunction of 1, 2, 3, and more than 4
organ systems was 73.6%, 20.7%, 4.7%, and 1%, respectively, and the
corresponding mortality was 21.2%, 44.3%, 64.5%, and 76.2%.
Mortality was also influenced by preexisting diseases (eg, chronic
478 DM, August 2009
TABLE 1. Risk factors for MODS
Infection
Peritonitis and intra-abdominal infections
Pneumonia
Necrotizing soft-tissue infections
Tropical infections (eg, falciparum malaria, typhoid fever, dengue fever)
Inflammation
Pancreatitis
Ischemia
Ruptured aortic aneurysm
Hypovolemic shock
Mesenteric ischemia
Immune reactions
Autoimmune disease
Reactive hemophagocytic syndrome
Antiphospholipid antibody syndrome
Transplant rejection
Graft vs host disease
Iatrogenic factors
Delayed or missed injury
Blood transfusion
Injurious mechanical ventilation
Treatment-associated increased intra-abdominal pressure
Intoxication
Drug reactions (anticonvulsants, carboplatin, antiretrovirals, colchicine, propofol,
amiodarone, monoclonal antibodies)
Arsenic intoxication
Drug intoxication (ecstasy, cocaine, salicylates, acetaminophen)
Endocrine
Adrenal crisis
Pheochromocytoma
Thyroid storm
Myxedema coma

lung, kidney, or liver disease, malignancy, complicated diabetes). A

recently completed European study, “Sepsis Occurrence in Acutely Ill
Patients” examined ICU admissions to 198 ICUs in 24 European
countries (3147 patients).20 The investigators found that 71% of ICU
patients had significant organ dysfunction and that sepsis was present
in 41% of the organ failures. In patients with sepsis, the lung was the
most common site of infection (68%) followed by the abdomen (22%).
There was a direct relationship between the number of organs failing
and the ICU mortality. MOF was more common in septic ICU patients
when compared to other ICU patients (75% vs 43%). The incidence of
2, 3, and ⱖ4 organ failures was also found to be greater in septic
patients. Those patients with 4 or more organ failures had mortality
rates of 65%. In addition, patients with severe sepsis had higher
DM, August 2009 479
FIG 1. Overview of cellular and molecular mechanisms leading to MODS. TLR, Toll-like
receptor; ACS, abdominal compartment syndrome.

mortality rates when compared to those with organ failure in the

absence of sepsis (32% vs 21%).
Although most cases of MODS occur secondary to shock, sepsis, and
severe trauma, many other conditions have also been reported to cause
MODS (Table 1).
480 DM, August 2009
Pathophysiology
Overview
Although great strides have been made in uncovering the pathophysi-
ology of MODS, many questions remain unanswered. Nevertheless,
recognition of several key concepts can facilitate our understanding of the
syndrome. First, a dysregulated immune response to critical illness plays
a central role in the pathogenesis of MODS. Second, following resusci-
tation from severe trauma or circulatory shock, an inflammatory response
in gut evolves that promotes dysfunction in distant organs. Third,
nosocomial or iatrogenic insults (“hits”) that occur in the post resuscita-
tion period promote an exaggerated immune response that leads to organ
dysfunction and MODS. Fourth, patients can recover completely from
MODS, which is consistent with a functional rather than structural
etiology. Finally, the mechanism(s) by which critical illness induces
dysfunction of individual organs is not uniform. These concepts will be
discussed in greater detail below.
Disordered Immune Response
Perhaps the most important pathogenic mechanism underlying MODS
is immune dysregulation.21 Although the traditional notion of MODS
ascribed organ failure to the toxic effect of an excessive systemic
inflammatory response, a more current view is that organ failure results
from loss of homeostasis between systemic inflammation and a counter-
balancing anti-inflammatory response.
The innate immune system is involved in the body’s initial response to
injury, microbial invasion, or toxic agents. The intensity of the inflam-
matory response is determined in part by various host factors (eg,
comorbid diseases, advanced age, nutritional status, genetics) as well as
inciting factors (eg, the severity of injury, the size of the infectious
inoculum, the portal of entry). The presence of microbial infection is
initially detected by mononuclear phagocytes (monocytes, tissue macro-
phages), and mast cells (Fig 1). These immune cells contain Toll-like
receptors (TLR) on their surface that allow the host to recognize
conserved molecular components of microorganisms known as pathogen-
associated molecular patterns.22 The TLR is the most important molecular
mechanism by which the host recognizes the presence of a pathogenic
organism and initiates the innate immune response. Recognition of
pathogen-associated molecular patterns by TLR may require the presence
of other molecules (eg, CD14, MD2) to facilitate binding to the receptor.
TLR receptors span the cell membrane; the intracellular domain interacts
DM, August 2009 481
with other molecules that result in the translocation of the proinflamma-
tory transcription factor nFKB into the nucleus. This in turn activates a
wide variety of genes responsible for the synthesis of pro- and anti-
inflammatory cytokines. There are at least 10 important TLRs in humans.
Components of gram-positive and gram-negative bacteria interact with
TLR2 and TLR4 receptors, respectively. Trauma activates the innate
immune system via damage-associated molecular patterns.23 Recent
research has clarified the mechanism by which damage-associated mo-
lecular patterns interact with mononuclear phagocytes to trigger the
systemic inflammatory response.24 Injured tissues release proteases that
degrade proteoglycans present in the extracellular matrix and basal
lamina of the vasculature. This process liberates soluble heparan sulfate
that acts as an endogenous agonist to release inhibition of the TLR4
receptor, thereby promoting the translocation of nFKB to the nucleus.
Once the innate response is triggered, extensive systemic activation of
the inflammation may ensue through a process of signal amplification by
cytokines and other mediators. The most important “early” or “proximal”
pro-inflammatory cytokines are tumor necrosis factor (TNF) and inter-
leukin-1 (IL-1). These cytokines have many local actions, including
stimulation of synthesis of other cytokines, upregulation of the expression
of tissue factor and adhesion molecules on nearby cells, induction of
certain enzymes (eg, phospholipase A2 [PLA2], nitric oxide synthase,
cycloxygenase-2). Inflammatory cytokines also augment the innate im-
mune response by “priming” neutrophils. Neutrophil priming causes a
marked increase in the response of these cells to an activating agent and
prolongs their lifespan by inhibiting apoptosis. Primed (activated) neu-
trophils have a marked increase in their capacity to release superoxides
and lipid mediators (eg, leukotrienes, prostaglandins) as well as an
upregulation in their expression of vascular adhesion molecules (eg,
selections, integrins).25 Following adhesion to the vascular endothelium,
activated neutrophils secrete enzymes (eg, elastase, matrix metallopro-
teinases) that facilitate their passage through the capillary wall (diapede-
sis). This process results in destruction of the endothelial cell basement
membrane and capillary leak. Once neutrophils enter tissues, they
produce large amounts of reactive oxygen species (ROS), resulting in
local oxidative injury. Following the initial phase, the inflammatory
response is prolonged by “late” or “distal” cytokines, such as IL-6, IL-8,
and high-mobility-group box 1 (HMGB1). HMGB1 is secreted actively
by inflammatory cells (macrophages, monocytes, dendritic cells) conse-
quent to stimulation by TNF or IL-1 and is also released passively by
necrotic (but not apoptotic) cells. HMGB1 is chemotactic for inflamma-
482 DM, August 2009
tory cells and promotes cellular damage by disrupting alveolar and
intestinal epithelial barriers.21
Excessive formation of C5a through the alternate complement pathway
is also thought to play an important role in the inflammatory response.21
C5a has multiple effects including (1) binding to mast cells that in turn
stimulates release of mediators that increase vascular permeability and
induce expression of p-selectin in endothelial cells; (2) activation of the
coagulation cascade by inducing expression of tissue factor; (3) stimu-
lating the production of proinflammatory cytokines. C5a also has an
immunosuppressive effect consequent to inducing apoptosis of T-lym-
phocytes.
Hemostasis has historically been viewed as a means to prevent excessive
blood loss following injury. However it has become apparent that, in the
setting of infection or injury, “cross-talk” between coagulation and inflam-
mation results in a synergistic enhancement of the innate immune
response.21,26 Inflammation serves to upregulate coagulation by increas-
ing the expression of tissue factor on the surface of endothelial cells,
tissue macrophages, and circulating monocytes.26 Activation of the
extrinsic clotting pathway by tissue factor and activated factor VII
produces thrombin that binds to protease-activated receptors on the
vascular endothelium. This in turn induces the synthesis of adhesion
molecules on endothelial cells as well as further stimulating the produc-
tion of inflammatory cytokines (eg, IL-6, IL-8). The procoagulant state
associated with sepsis results from (1) attenuation of natural anticoagulant
responses through a reduction in circulating levels of protein C and
antithrombin III; (2) decreased expression of thrombomodulin on endo-
thelial cells; (3) enhanced production of inhibitors of fibrinolysis (eg,
plasminogen-activator inhibitor).26 It can be seen, therefore, that inflam-
mation and coagulation interact during sepsis in an amplifying loop that
promotes widespread deposition of fibrin clots in the microcirculation.
The resultant impairment of tissue perfusion leads to organ dysfunction.
The severity of the local inflammatory response at the area of infection
or injury is modulated by an anti-inflammatory response. The “compen-
satory anti-inflammatory response syndrome” was proposed by Roger
Bone to describe the state of downregulated adaptive immunity that
occurs as the consequence of critical illness.27 The pathogenesis of
immune deactivation is multifactorial and includes increased production
of anti-inflammatory cytokines (eg, IL-4, IL-6, IL-10), soluble receptors
and receptor antagonists (eg, sTNFR, IL-1RA), prostaglandins (eg,
PGE2), and hormones (eg, glucocorticoids, catecholamines). In addition,
T-cell anergy and apoptosis, decreased expression of class II antigen-
DM, August 2009 483
FIG 2. Effects of pathways of the autonomic nervous system on inflammation during sepsis. (A)
In the adrenergic pro-inflammatory pathway high concentrations of circulating catecholamines
amplify the initial inflammatory response. (B) Activation of the cholinergic anti-inflammatory
pathway in sepsis attenuates the inflammatory response. (Reprinted with permission from
Rittirsch et al.21) (Color version of figure is available online.)

presenting molecules by circulating monocytes, and loss of dendritic cells

(an important link between innate and adaptive immunity) contribute to
suppressed immune responses and place the host at risk for subsequent
infection. The term “immunoparalysis” was proposed to describe a state
of severely comprised immunity secondary to injury or critical illness.28
Other have suggested that the term “leukocyte reprogramming” more
accurately describes this state.29
In addition to the interaction between coagulation and inflammation
described above, crosstalk also exists between the central nervous system
and the immune response.30 Activation of the sympathetic and enteric
nervous system consequent to critical illness results in an increase in
the level of circulating epinephrine and norepinephrine. These cat-
echolamines bind to adrenergic receptors on macrophages that in turn
stimulates release of proinflammatory cytokines31 (Fig 2). Tracey ob-
served that the proinflammatory effect of sympathetic activation was
484 DM, August 2009
modulated by the anti-inflammatory action of the cholinergic pathway.30
They described an inflammatory reflex of the vagus nerve in which
vagally mediated acetylcholine release and binding to nicotinic receptors
on macrophages inhibits the release of TNF and other proinflammatory
cytokines (eg, HBGB1). Autonomic dysfunction is common during
critical illness and is characterized by a relative excess in sympathetic
tone consequent to decreased vagal (parasympathetic) activity.32 This in
turn compromises the ability of the cholinergic anti-inflammatory path-
way to modulate systemic inflammation. Godin and Buchman speculated
that autonomic dysfunction may lead to MODS as the result of an
“uncoupling” of neurally mediated organ interactions.33 Under normal
conditions, healthy organs behave as “biological oscillators” in which
organs interact through autonomic signaling via sympathetic and para-
sympathetic pathways. Autonomic dysfunction disrupts interorgan com-
munication, and the resultant isolation of organs (“decomplexification”)
leads to systemic dysfunction and promotes transition into MODS.33
Uncoupling of biological oscillators is manifest clinically by loss of the
normal beat-to-beat variability of the heart rate.32 Monitoring of heart rate
variability can potentially be used as a means to diagnose transition into
MODS at an early stage (see below).
Munford and Pugin postulated the concept of “compartmentalization” of
the immune response to infection or injury.28 They proposed that the local
area of inflammation and the bloodstream can be viewed as separate immune
“compartments.” The inflammatory response is initially confined to the area
of infection or injury, while the immune response in circulating leukocytes is
concurrently downregulated as a mechanism to prevent immune-mediated
organ damage resulting from release of inflammatory mediators into the
circulation. Therefore, a proportional balance between the intensity of tissue
inflammation and the anti-inflammatory response in blood enables the body
to concentrate activated neutrophils and other effectors at the area of infection
or injury, while at the same time preventing damage in distant organs. Factors
that promote an imbalance between local inflammation and the anti-
inflammatory response lead to a loss of “immune compartmentalization” that
in turn results in organ injury and MODS (see below).
The Role of the Gut
Meakins and Marchall postulated that the gut served as the “motor” of
MODS in injured or critically ill patients.7 According to this view,
reperfusion-mediated oxidative damage to the intestinal epithelium trans-
forms the gut into a cytokine-generating organ that drives the systemic
inflammatory response and leads to downstream organ injury. Clark and
DM, August 2009 485
FIG 3. Crosstalk between the intestinal epithelium, immune system, and commensal bacteria is
central to initiating the systemic inflammatory response. (Reprinted with permission from Clark
and Coopersmith.34) (Color version of figure is available online.)

Coopersmith proposed that the gut can be viewed as comprising 3

components: the intestinal epithelium, the mucosal immune system, and
commensal intestinal bacteria34 (Fig 3). Significant crosstalk continually
occurs between these areas. Critical illness is associated with character-
istic abnormalities in each of the 3 components that in turn contribute to
adverse clinical sequelae. Intestinal epithelial hyperpermeability is com-
mon during critical illness.35 Previous studies have indicated that the
development of MODS is associated with a derangement in intestinal
permeability that is detectable before the onset of the syndrome.36 The
mechanism for increased permeability involves disruption of tight junc-
tions between epithelial cells consequent to decreased mucosal perfusion,
increased oxidant stress, inflammatory cytokines, or inhibition of mem-
brane pumps by peroxynitrite.35 The second component, gut-associated
lymphoid tissue (GALT), is responsible for maintaining mucosal immu-
nity.37 Immunoglobulin A (IgA) is produced by B-lymphocytes in GALT.
Secretory IgA is the oligomeric form of IgA present in mucus membranes
of gut epithelium. Secretory IgA acts to downregulate the release of
486 DM, August 2009
inflammatory cytokines (TNF, IL-6) in human macrophages, as well as
blunting gut-mediating priming of neutrophils.38 In addition, secretory
IgA binds to potential pathogens, trapping them in mucus, which allows
expulsion from the gut. Animal models of ischemia/reperfusion injury
demonstrated a reduction in lymphocytes in Peyer’s patches, the intra-
epithelial space, and the lamina propria.39 Maintenance of adequate
GALT function is dependent on enteral feeding. Therefore, nutritional
deprivation results in a fall in mucosal IgA levels that predispose to
infectious complications.37 In addition, because secretory IgA is impor-
tant for maintaining mucosal immunity of the pulmonary epithelium, a
decrease in its production predisposes to development of pneumonia.37
The third component of gut is enteric commensal bacteria. Alverdy and
colleagues were among the first to describe the interaction between the
host and intestinal bacteria during critical illness. They proposed the
concept of “gut-derived sepsis” to describe a stress-induced state of
systemic inflammation with organ dysfunction that is initiated and
perpetuated by intestinal bacteria.40 This concept dismisses the theory
that bacterial translocation is a major mechanism for SIRS, sepsis, and
MODS. Rather, it takes an anthropomorphic point of view that commen-
sal bacteria colonizing the intestines possess a certain “intelligence” that
enables them to sense a disruption in their microenvironment that in turn
alters their normal symbiotic interaction with the intestinal epithelium.41
Under conditions of severe stress (as would accompany critical illness),
commensal bacteria produce quorum sensing molecules that activate
virulence genes as a survival mechanism.41 Factors that trigger this
response are called “disordering agents” and include intestinal hypoper-
fusion, elevated levels of catecholamines, and lack of enteral nutrition.
Activation of virulence genes result in many deleterious effects such as
bacterial adherence to the intestinal epithelium that induces the release of
mucosally derived cytokines, increased permeability of epithelial tight
junctions, neutrophil activation, and apoptosis of epithelial cells.42 In
addition, the use of broad-spectrum antibiotics promotes “dysbiosis” in
which endogenous microbial flora are replaced by virulent nosocomial
pathogens.43 It can be seen, therefore, that the combined effect of
intestinal hyperpermeability, impaired gut mucosal immunity, and acti-
vation of virulence genes in commensal bacteria result in loss of immune
compartmentalization that leads to organ dysfunction.
Magnotti and colleagues proposed that the mechanism of pulmonary
injury following trauma, burn, or shock involved migration of gut-derived
inflammatory mediators to the lung via mesenteric lymph. They found
that acute lung injury could be prevented by prior interruption of
DM, August 2009 487
FIG 4. Inflammatory and organ dysfunction responses to injury. Normal response to an injury
or insult may decrease after 3-5 days or be reactivated by a complication. A continuous
inflammatory response is seen with systemic inflammatory response syndrome (SIRS) and can
eventually progress to organ failure. (Reprinted with permission from Cerra.120)

mesenteric lymph drainage.44,45 The identity of the causative mediator

released into the mesenteric lymph has not been determined. However,
there is some suggestion that it may be lipid in nature, possibly
arachidonic acid (AA) liberated from epithelial phospholipids by activa-
tion of PLA2.46 Acute lung injury could result from uptake and subse-
quent metabolism of AA by alveolar macrophages to pro-inflammatory
eicosanoids (eg, leukotriene B4).46
Gut dysfunction also mediates hepatic injury during sepsis. The
mechanism appears to involve an inflammatory-mediated increase in
sympathetic tone in the enteric nervous system. Gut-derived cat-
echolamines are carried downstream to the liver through the portal
488 DM, August 2009
circulation where they bind to receptors on hepatic macrophages. This in
turn stimulates production of ROS and other oxidants resulting in injury
to hepatocytes47 (see below).
Nosocomial and Iatrogenic Promoters of MODS
The “two-hit” hypothesis of posttraumatic MODS postulates that severe
trauma and associated tissue hypoperfusion primes leukocytes (first
“hit”), so that a subsequent, apparently minor insult (“second hit”)
generates an excessive inflammatory response that leads to MODS9 (Fig
4). A variety of nosocomial and iatrogenic factors can act as secondary
“hits” such as ventilator-associated pneumonia, blood transfusion, or the
abdominal compartment syndrome. Recent evidence suggests that the
mechanism for the excessive immune response following initial priming
involves enhanced TLR4 reactivity as the consequence of redistribution
of TLR4 to lipid rafts in the plasma membrane of mononuclear leuko-
cytes.48
Slutsky and Tremblay studied the association between acute lung injury
and organ dysfunction and proposed that mechanical ventilation could
serve as a “motor” of MODS.49 The term mechanotransduction is used to
describe intracellular signaling processes in response to external forces
such as stretch.50 Overstretching alveoli with excessive mechanical
ventilation induces the production of proinflammatory cytokines by
alveolar epithelial cells. In addition, excessive stretch causes damage to
epithelial and endothelial barriers resulting in the lung “leaking” inflam-
matory cytokines into the systemic circulation (eg, loss of immune
compartmentalization).28 This in turn can lead to organ dysfunction and
MODS. This process has been termed “biotrauma.”51 Alterations in
distant organs resulting from pulmonary biotrauma include increased
intestinal permeability, cellular (eg, renal and intestinal) apoptosis,
systemic capillary leak, and peripheral immunosuppression.52 Ciesla et al.
prospectively studied 1300 trauma patients and found that respiratory
dysfunction was an obligate event that preceded MOF.53 They observed
that lung dysfunction occurred in 99% of patients with 2 or more organ
dysfunctions, and that lung dysfunction preceded heart, liver, and kidney
dysfunction by an average of 0.6 days, 4.8 days, and 5.5 days, respec-
tively. The severity of lung dysfunction appeared to correlate with the
severity of heart, liver, and kidney dysfunction as well as the number
of other dysfunctional organ systems. Approximately 80% of their
patients were mechanically ventilated; this led the authors to speculate
that pulmonary biotrauma may have played an important role in the
pathogenesis of MOF.
DM, August 2009 489
 Blood transfusion has been shown to be an independent risk factor for
postinjury MODS and ARDS.54 A dose-response relationship exists
between number of units of blood transfused and organ dysfunction. In
addition, the age of the blood (eg, older than 14-21 days) transfused in the
first 6 hours following injury was also shown to an independent risk factor
for MODS.55 Several mechanisms have been postulated to explain
transfusion-associated organ dysfunction. Red cells stored for more than
15 days are poorly deformable and promote microcirculatory sludging
and obstruction, leading to tissue ischemia.56 In addition, stored red cells
are contaminated by leukocytes that release a variety of mediators that
can adversely affect immune function in the transfused patient.56 Recog-
nition of risks of blood transfusion led to more conservative transfusion
thresholds in ICU patients.57 In addition, routine leukopheresis of stored
red cells has been explored as a means to reduce morbidity and mortality
(see below).
The abdominal compartment syndrome (ACS) results from the adverse
effects of raised intra-abdominal pressure (IAP) on organ function. It has
been proposed that ACS is a modifiable link between traumatic shock and
MODS.58 Patients at greatest risk for ACS are those who have suffered
severe blunt or penetrating trauma, or ruptured abdominal aortic aneu-
rysm and who have received massive fluid resuscitation. Renal failure and
acute lung injury are the most common manifestations of ACS. The
pathophysiology of organ failure consequent to intra-abdominal hyper-
tension is unclear but is probably multifactorial. Potential mechanisms
include a direct mechanical effect of increased IAP on perfusion of
intra-abdominal organs, a reduction in pulmonary compliance, or a
cytokine-induced capillary leak syndrome.

Cellular Energetics, Mitochondria, and MODS

Ozawa et al. recognized the importance of the liver in biological
homeostasis and entertained the possibility that a deficit in the hepatic
bioenergetic state consequent to mitochondrial dysfunction plays an impor-
tant role in the pathogenesis of MODS.59 They studied patients with
postoperative MODS by measuring the ratio of ketone bodies (acetoacetate/
beta-hydroxybutyrate) in arterial blood (AKBR) as an indicator of the hepatic
redox state. They noted that the emergence of MODS was heralded by
alterations in hepatic mitochondrial redox as expressed by a decrease in the
AKBR. They observed that a persistent or progressive decrease in the AKBR
to less than 0.4 (normal ⱖ 0.7) was a significant sign of severe MODS, and
an AKBR of less than 0.25 was almost universally fatal. They concluded that
490 DM, August 2009
a hepatic energy deficit associated with decreasing AKBR may be the
metabolic basis of postoperative organ failure.
There are 2 “schools of thought” regarding the etiology of bioenergetic
failure accompanying critical illness. The first postulates that microvas-
cular injury secondary to diffuse endovascular inflammation promotes an
inhomogeneity of capillary flow resulting in tissue hypoxia and organ
dysfunction.60 De Backer and colleagues used orthogonal polarization
spectral imaging to document the presence of various microcirculatory
abnormalities in patients with sepsis.61 They observed that these alter-
ations were more severe in patients with a worse outcome. Sakr et al.
subsequently found that these abnormalities improved rapidly in survi-
vors of septic shock but persisted in patients who went on to die of
MODS, regardless of whether shock had resolved.62 However, perhaps
these findings represent an epiphenomenon because the results of other
studies indicated that bioenergetic failure could evolve even in the
presence of preserved microvascular flow.63,64 The second school of
thought proposes that bioenergetic failure results from decreased ATP
synthesis consequent to mitochondrial dysfunction (eg, “cytopathic hyp-
oxia”).65 Potential mechanisms underlying this process include (1)
oxidative damage to mitochondria; (2) depletion of mitochondrial popu-
lations due to autophagy (see below); and (3) the inability of the cell to
regenerate new mitochondria sufficient to match ongoing mitochondrial
loss.66 Oxidative damage to mitochondria is mediated by increased
production of ROS such as superoxides, hydrogen peroxide, and hydroxyl
radicals. Superoxides react with nitric oxide (NO) generated by mito-
chondrial NO synthase and induced NO synthase to form peroxyni-
trite.67,68 This molecule is a potent oxidant that directly impairs the
function of mitochondrial electron transport complex. In addition, per-
oxynitrite worsens cellular energetics by activating the enzyme poly-
(ADP-ribose) polymerase (PARP) that depletes cellular stores of NAD
and impairs mitochondrial synthesis of ATP.67 Mitochondria subjected to
oxidative damage undergo programmed apoptotic death, which is medi-
ated by membrane permeability transition pores. Damaged mitochondria
are subsequently removed through a process of autodigestion termed
“autophagy.”66 Mitochondrial loss is compensated by formation of new
organelles via binary fission in a process termed “biogenesis.”66 Severe
oxidative stress causes a disproportionate increase in autophagy; this in
turn reduces the number of functioning mitochondria resulting in a
decrease in the bioenergetic state. Clinical recovery from MODS is
marked by an increase in oxidative production of ATP as the consequence
of enhanced biogenesis. Singer et al. have proposed that a reduction in
DM, August 2009 491
FIG 5. Postulated progression of boenergetics and metabolism during sepsis and recovery. NO,
nitric oxide; ONOO⫺, peroxynitrite; ATP, adenosine 5=-triphosphage; MOF, multiple organ
failure. (Reprinted with permission from Singer.208)

ATP production during sepsis or other types of critical illness is an

adaptive response that can be viewed a form of hibernation.69 In this
view, metabolic downregulation serves as a protective mechanism in
which a reduction in ATP demands in vital organs decreases the
susceptibility to cell death and enables recovery through mitochondrial
biogenesis (Fig 5). However, a prolonged critical imbalance between
autophagy and biogenesis ultimately results in irreversible organ failure.
A study in septic patients found an association between NO overproduc-
tion, antioxidant depletion, mitochondrial dysfunction, and reduced ATP
concentrations that correlated with organ failure and adverse outcome.70
Organ-Specific Mechanisms of Dysfunction
Although the overall immunologic milieu of sepsis is inflammatory,
there may be significant variations in immune status between organs. This
492 DM, August 2009
phenomenon occurs as the result of activation of a diverse variety of
transcriptional programs in various organs during sepsis. A recent study
examined the temporal sequence of sepsis-induced gene expression
patterns in lung, liver, kidney, thymus, spleen, and brain.71 The investi-
gators found that sepsis-induced gene expression was either specific to a
particular organ, observed in multiple organs, or occasionally divergent in
certain organs. Brain appeared to be protected from sepsis-induced gene
activation relative to other organs, and genes that enhanced the inflam-
matory response were not uncommonly counterbalanced by genes with
anti-inflammatory effects. The significance of these observations is
2-fold: (1) the immune response to sepsis in individual organs may vary
widely; (2) the pathogenesis of organ dysfunction during MODS may not
be uniform. The following section summarizes current mechanistic
theories accounting for dysfunction of individual organs during MODS.
Lung. The lung is typically the first organ to be involved in MODS. The
initial insult that triggers acute lung injury may either be direct (eg,
pneumonia, aspiration, toxic inhalation) or indirect (mesenteric ischemia/
reperfusion injury, acute pancreatitis, peritonitis). A recent study sug-
gested that there is no difference in mortality between these 2 groups.72
The development of ALI/ARDS has been divided into 2 phases.73 The
initiator phase is characterized by release of pro-inflammatory mediators
(eg, cytokines, complement, prostaglandins, thromboxanes, leukotrienes)
by monocytes, alveolar macrophages, and vascular endothelial cells. The
resultant inflammatory response promotes the sequestration of primed
neutrophils in the pulmonary vasculature. During the effector phase,
activated leukocytes release proteolytic enzymes (eg, elastase, matrix
metalloproteinases) and ROS. These molecules mediate injury to lung by
degrading components of the basement membrane resulting in alveolar
flooding and surfactant deactivation. As discussed above, mechanical
ventilation may exacerbate lung injury by inducing apoptotic injury to
alveolar epithelial cells. Apoptotic death is mediated by mitochondrial
damage and release of soluble Fas ligand (sFasL) that triggers membrane
death receptors.74 Systemic release of sFasL may also serve as a mediator
of distant organ injury (see below). As previously described, the mech-
anism of ARDS following indirect injury to lung (eg, secondary to
trauma, hemorrhagic shock, or burn) appears to be mediated by the
release of lipid-based mediators from gut into mesenteric lymph.44,45 A
recent study in rats found that splanchnic ischemia/reperfusion activates
PLA2 in colonic mucosa, promoting release of AA into mesenteric
lymph.75 AA is then taken up by alveolar macrophages and neutrophils
and metabolized into inflammatory eicosanoids that cause acute lung
DM, August 2009 493
injury.46 A study of patients with ARDS found that elevated plasma
leukotriene B4 levels showed the best correlation with lung-injury
severity and outcome.76
Fibrin deposition in alveoli is also an important pathologic feature of
ALI/ARDS. This process has been termed “pulmonary coagulopathy.”77
The underlying pathophysiology involves a cytokine-mediated enhance-
ment of thrombin generation, as well as decreased fibrinolysis. Genera-
tion of thrombin in alveoli is triggered by the extrinsic clotting pathway
through an interaction between neutrophils and platelets. Pulmonary
coagulopathy appears to play an important role in mediating ventilator-
induced lung injury.77
Liver. Although decreased hepatic perfusion causes acute liver dysfunc-
tion in patients with circulatory shock, this process is short-lived and
usually resolves following adequate hemodynamic resuscitation. A latent
period generally ensues, followed by a subsequent phase of dysfunction
secondary to diffuse hepatic inflammation. A postoperative study of
patients who underwent high-risk surgery found that the subgroup that
developed hepatic failure had increased production of inflammatory
cytokines in the hepatosplanchnic area despite increased hepatic blood
flow.78 Septic animal models have provided evidence that gut-derived
catecholamines play an important role in the pathogenesis of hepatic
injury. Norepinephrine appears to induce hepatic injury by activating
adrenoreceptors on Kupffer cells; this in turn enhances TNF and NO
production, resulting in mitochondrial damage.79,80 A recent study found
that epinephrine and norepinephrine were able to mimic the deleterious
effects of lipopolysaccharide on human hepatocytes via a beta-adrener-
gically mediated induction of IL-6 production.81 In addition, spill-over of
inflammatory cytokines from the liver into the systemic circulation
promotes downstream pulmonary dysfunction.82 Elevated blood levels of
carbamoyl phosphate synthase-1 have been shown to be an early marker
of hepatic mitochondrial damage and depletion in animal models of
sepsis.83
Kidney. Although acute tubular necrosis following posttraumatic or
hemorrhagic shock results from renal hypoperfusion, this mechanism
plays a lesser role in acute renal failure accompanying sepsis.84 Recent
studies have indicated that during severe sepsis, renal failure evolves
despite the preservation of global renal blood flow.85 The mechanism
appears to involve a reduction in glomerular filtration consequent to
vasodilation of the efferent arteriole more than the afferent arteriole.
Septic acute kidney injury (AKI) therefore may represent a unique form
of hyperemic acute renal failure.86 Inflammatory mediators also play a
494 DM, August 2009
role in the pathogenesis of AKI. For example, TNF has been shown to be
directly toxic to the kidney by inducing apoptosis of renal cells.86 As
mentioned above, injurious mechanical ventilation may promote AKI by
generating increased local production of inflammatory and proapoptotic
mediators (eg, sFasL) in lung that spill over into the systemic circulation
causing downstream renal injury.87 A recent study of MODS in burn
demonstrated that SIRS and pulmonary dysfunction requiring mechanical
ventilation were present and preceded AKI in virtually all patients.88
Heart and Peripheral Circulation. In 1981, Calvin et al. reported that
septic patients who were adequately volume resuscitated had echocardio-
graphic evidence of a decreased left ventricular ejection fraction and
increased end-diastolic volume.89 Subsequent studies confirmed impaired
left ventricular systolic and diastolic dysfunction in sepsis and have
demonstrated the presence of similar alterations in right ventricular
function. Elevations in biomarkers of myocardial injury (eg, troponins)
commonly accompany sepsis and appear to be related to the degree of
ventricular dysfunction.90 A variety of mechanisms for “septic cardiomy-
opathy” have been postulated.90 Myocardial ischemia does not appear to
play a major role in the pathogenesis of septic cardiomyopathy except in
patients with underlying coronary artery disease. Inflammatory cytokines
(eg, TNF) have been proposed as potential mediators in early sepsis, but
cytokines are not felt to explain the prolonged duration of myocardial
dysfunction in sepsis. The most promising candidate is NO, which is
produced in excessive amounts during sepsis as the consequence of
induced expression of NOS in the myocardium.90,91 Peroxynitrite
(formed from NO and superoxide) causes oxidative mitochondrial injury
that is linked to decreased cardiac contractility.92 Peroxynitrate also
impairs oxidative metabolism by activating PARP.67 A recent study
confirmed the presence of significant PARP activation in patients with
septic cardiomyopathy.93 Elevated levels of NO also decrease cardiac
contractility by down-regulation of beta-adrenergic receptors in the
myocardium, and by reducing cytosolic calcium. It has been suggested
that a reversible decrease cardiac contractility during sepsis may reflect
myocardial hibernation.94
The peripheral circulation is also involved by the septic process. This is
manifest by peripheral vasodilation that steadily worsens as MODS
progresses into frank organ failure and ultimately becomes refractory to
exogenous vasoconstrictors. Results from septic animal models impli-
cated NO as the cause of septic vasodilation.95 However, this conclusion
was based on data obtained only a few hours after sepsis induction. The
involvement of NO in vasodilation in the later phases of sepsis has been
DM, August 2009 495
more difficult to confirm. There is some evidence supporting the role of
enhanced production of cyclic guanosine monophosphate as an important
mediator of vasodilation in the later stages of sepsis.96 Erythrocytes have
also been demonstrated to play an important role in septic vasodilation.97
Erythrocytes have been shown to possess the capacity to synthesize NO
that in turn reacts with hemoglobin to form S-nitroso hemoglobin.98
These “septic” erythrocytes stimulate vasodilation in a process dependent
on cyclic GMP. According to this view, erythrocytes mediate vasodilation
during sepsis by virtue of their ability to store and transport NO in the
form of S-nitrosothiols.99
Brain. The term “septic encephalopathy” (SE) describes the acute
alteration in level of consciousness accompanying severe sepsis. SE is the
most common encephalopathy in the ICU, with a prevalence varying
between 9% and 71% based on how it is defined (eg, clinical criteria,
EEG, evoked potentials).100 Most organ-failure scoring systems use the
Glasgow coma score to stage the severity of neurologic dysfunction
during MODS. However, the use of the Glasgow coma score to stage
neurologic dysfunction may be confounded by concomitant use of
sedatives during mechanical ventilation. The observation that SE is often
completely reversible suggests a functional rather than structural etiology,
although structural abnormalities on magnetic resonance imaging and
long-term cognitive impairment have been described.101,102 In addition,
patients with severe sepsis and SE were found to have elevated levels of
neuron-specific proteins indicating brain injury.103 It is therefore probable
that the etiology of SE is multifactorial. One theory ascribes the
pathogenesis of SE to sepsis-induced alterations in aromatic amino acid
metabolism.104,105 Increased permeability of the blood-brain barrier
enables entry of aromatic AA-derived neuroamines (“false neurotrans-
mitters”) into brain that cause altered mental status. Another theory
postulates that increased blood-brain barrier permeability promotes SE by
allowing entry of circulating inflammatory mediators (eg, cytokines) into
the central nervous system (CNS). A recent animal study also demon-
strated that endotoxemia stimulates local production of TNF by microglia
and astrocytes.106 The authors hypothesized that TNF could mediate
encephalopathy by inducing brain edema, neutrophil infiltration, astrocy-
tosis, and apoptotic cellular death.
Organ Failure Scoring Systems in MODS
Organ failure scores were developed mainly as a descriptive tool that
facilitated comparing the status of various ICU patients. Scoring systems
may be based on physiological derangement (eg, APACHE, SAPS), or on
496 DM, August 2009
TABLE 2. Comparison of scoring variables: SOFA, LODS, MODS*
Organ Variable SOFA108 LODS107 MODS109
Respiratory PaO2/FIO2 Yes Yes Yes
MV Yes Yes
Hematology Platelets Yes Yes Yes
WBC Yes
Liver Bilirubin Yes Yes Yes
Prothrombin time Yes
Cardiovascular Mean arterial pressure Yes
Systolic blood pressure Yes
Heart rate Yes
PAR Yes
Dopamine Yes
Dobutamine Yes
Epinephrine Yes
Norepinephrine Yes
CNS Glasgow coma score Yes Yes Yes
Renal Creatinine Yes Yes Yes
Blood urea nitrogen Yes
Urine output Yes Yes
CNS, central nervous system; LODS, Logistic Organ Dysfunction System; MODS, Multiple
Organ Dysfunction Score; MV, mechanical ventilation; PAR, pressure-adjusted heart rate;
SOFA, Sequential Organ Failure Assessment; WBC, white blood cells.
207
*Reprinted with permission from Afessa et al.

clinical or laboratory parameters that enable staging of the severity of

organ dysfunction. In 1985, Knaus et al. published a description of an
“Organ Failure Score” that viewed organ dysfunction as an “all-or-
nothing” phenomenon.10 Recognition that organ injury represents a
spectrum prompted the development of systems in which the total score
was determined based on varying degrees of dysfunction in individual
organs. The most commonly used scoring systems are the “Multiple
Organ Dysfunction Score” (MODS), “Sequential Organ Failure As-
sessment Score” (SOFA), and “Logistic Organ Dysfunction System”
(LODS).107-109 All 3 systems use clinical and laboratory variables in 6
organs (respiratory, hematologic, liver, cardiovascular, CNS, renal) to
calculate a total score. The variables differ slightly between the 3 systems
(Table 2). Trending of the composite score during the patient’s hospital
course enables prognostication of the mortality risk. Recently, Oda et al.
developed the “Cellular Injury Score” as a means to quantify the degree of
cellular dysfunction in ICU patients.110 The total Cellular Injury Score is
determined using the arterial ketone body ratio, osmolality gap, and blood
lactate. Studies comparing the performance of the various scoring systems
have failed to demonstrate clear superiority of 1 over another.111-113
DM, August 2009 497
Clinical Manifestations and Course of MODS
The clinical manifestations and temporal evolution of organ failure
during MODS is influenced by host factors (eg, advanced age, comorbid
diseases, immunosuppressive drugs) and genetic factors. For example,
patients with liver cirrhosis who become septic manifest an accelerated
evolution of MODS due to impaired hepatic clearance of circulating
inflammatory mediators.114 Genetic factors are also important in deter-
mining the severity and progression of organ failure. Individuals who
possess certain genetic polymorphisms in genes controlling the synthesis
of cytokines (eg, TNF, IL-10) or TLR receptors manifest an excessive
inflammatory response to acute injury or sepsis to that places them at
higher risk for the development of MODS.115
In 1980, Fry and colleagues described a characteristic temporal se-
quence of organ involvement in patients who developed MOF following
emergency surgery.5 They observed that lung was involved earliest,
followed by liver, gastric mucosa, and kidney. Twenty-five years later,
Ciesla et al. reconfirmed acute lung injury as the initial manifestation of
post-trauma MODS.53 Moore and colleagues observed that postinjury
MOF was a bimodal phenomenon in which some patients developed early
evidence of organ failure (eg, by day 3 of hospitalization), while in others
organ failure developed later.116 When compared to the late MOF group,
patients with early organ failure died sooner, had more cardiac dysfunc-
tion (shock was an important risk factor), and had greater evidence of
hyperinflammation. In contrast, patients with late MOF were older, had
greater evidence of hepatic failure, and were more likely to have an
infection as a “second hit.” Ciesla and colleagues found that early
dysfunction of multiple organs during resuscitation is a reversible
phenomenon that often resolves during the resuscitation period and
should therefore not be considered as synonymous with postinjury
MOF.117
Frank Cerra described the typical clinical course of MODS in the
surgical patient.118 He divided the evolution of MODS into 4 stages.
Stage 1 is characterized by an acute event that is associated by a variable
period of hypotension. Stage 2 is the period of active resuscitation that
lasts up to 24 hours. Stage 3 is the phase of stable hypermetabolism (eg,
increased oxygen consumption) that may persist for 7-10 days. During
this time the patient appears to be stable and doing well by the usual
clinical criteria. The clinical onset of MODS is typically heralded by the
appearance of low-grade fever, accompanied by tachycardia and dyspnea.
Signs of mental confusion may also be present. The chest X-ray
498 DM, August 2009
demonstrates patchy infiltrates. Laboratory evidence of a low-grade
disseminated intravascular coagulation (DIC) and thrombocytopenia may
be seen. At this point, the pulmonary status worsens, necessitating
intubation and mechanical ventilation. The hemodynamic profile is
hyperdynamic (eg, increased cardiac contractity) with cardiac index in
the range of 4.5 LPM and systemic vascular resistance of ⬍600
dyne-s/cm/5m2. Urine urea nitrogen output is substantial (eg, ⬎15 g/d),
reflecting catabolism of skeletal muscle. Glucose intolerance and moder-
ate hyperlactatemia (eg, blood lactate of 2-5 mM/L) are often seen. After
7-10 days, hyperbilirubinemia appears, followed by an increase in serum
creatinine. Hyperglycemia with insulin resistance and hyperlactatemia
become more pronounced. Bacteremia may occur at this point, usually
with enteric organisms. The need for inotropic support increases and is
accompanied by progressive deterioration in renal function, worsening
encephalopathy and gastrointestinal bleeding. Stage 4 usually occurs
between day 14 and 21. Renal failure worsens to the point that dialysis is
required. Death usually occurs 21-28 days after the initial event. Two
variants of this syndrome were also described:
1. Primary pulmonary injury. This is typically associated with acute lung
injury such as aspiration pneumonia. In this variant the patient
deteriorates more rapidly than in the classical pattern, with failure of
kidneys and sometimes liver becoming manifest a few days before
death.
2. Major organ failure without pulmonary involvement. This is the least
common pattern. It typically manifests as progressive liver and renal
failure in the absence of obvious pulmonary dysfunction or injury.
Russell et al. studied the evolving pattern of organ dysfunction in early
sepsis and its relation to outcome.119 They assessed the function of 6
systems in ICU patients (cardiovascular, pulmonary, neurologic, coagu-
lation, renal, hepatic) at the onset of sepsis syndrome and on day 3 of the
syndrome and determined how this change affected 30 day mortality.
Pulmonary dysfunction was the most common organ failure at the onset
of sepsis syndrome but was not related to mortality. However, progressive
worsening of neurologic, coagulation, and renal function over the first 3
days was associated with significantly higher 30-day mortality rate.
Metabolic Alterations
Severe trauma, burn, or infection induces a syndrome of characteristic
metabolic alterations that has been termed the hypermetabolic stress
response.120 These changes include increased oxygen consumption,
DM, August 2009 499
TABLE 3. Stress stratification by metabolic criteria
Stress Urine Plasma Plasma Insulin VO2
Level Nitrogen, g/d Lactate, mM/L Glucose,a mg/dL Resistance mL/min/m2
Low ⬍10 ⬍1.5 ⬍150 None ⬍140
Mid 10-20 1.5-3.0 150-250 Some 140-180
High ⬎20 ⬎3 ⬎250 Yes ⬎180
a
In the absence of diabetes mellitus, pancreatitis, and steroid therapy.

hyperglycemia, hyperlactatemia, and protein catabolism. Sixty to 65% of

stressed patients demonstrate a hypermetabolic response, but 15%-20%
have a seemingly inappropriate hypometabolic response.121 Metabolic
criteria such as oxygen consumption, urine urea nitrogen excretion, blood
glucose level, and insulin resistance may be useful in stratifying the
severity of stress and identifying clinically significant hypermetabolism
(Table 3). A discussion of stress-induced alterations in carbohydrate,
lipid, and protein metabolism follows.
Carbohydrate Metabolism
Modest degrees of hyperglycemia (eg, blood glucose of 200-300
mg/dL) are common during SIRS and MODS as the consequence of
increased hepatic glucose production, as well as peripheral insulin
resistance in skeletal muscle.122 The degree of insulin resistance parallels
the severity of hypermetabolism (as quantified by systemic oxygen
consumption). Uncontrolled hyperglycemia is associated with increased
morbidity and mortality, and aggressive control of hyperglycemia in
hospitalized patients is associated with improved outcome (see below). A
minority of patients with severe sepsis or MODS (especially with
underlying chronic liver disease) may become hypoglycemic because of
depressed glucose production. Hyperlactatemia is common during evolv-
ing MODS and increases in parallel with the severity of the stress
response. The pathogenesis of stress-induced hyperlactatemia as well as
its diagnostic and prognostic utility will be discussed in greater detail
below.
Lipid Metabolism
The major alterations in lipid metabolism during SIRS and MODS
include increased lipolysis and fatty acid recycling, hypertriglyceridemia,
and hepatic steatosis.123 Serum triglycerides may be elevated as the
consequence of increased production and/or decreased clearance. Hyper-
triglyceridemia may become clinically manifest as lipemic serum, partic-
ularly in patients who are receiving intravenous lipids (eg, total parenteral
500 DM, August 2009
nutrition, propofol). Hypocholesterolemia is common in patients with
critical illness and may have prognostic value. In a study of patients with
trauma, the mean value of cholesterol was consistently lower than
predicted based on age and sex-specific data from the general population.
Patients who went on to recover demonstrated an increase in serum
cholesterol, whereas those who developed MODS had a decreased or
fixed cholesterol.124
Protein Metabolism
The main alterations in protein metabolism during SIRS or MODS
include skeletal muscle catabolism and negative nitrogen balance.123
Patients with severe trauma, burns, or sepsis often develop rapid and
profound depletion of lean body mass that has been termed “auto
cannibalism.”125 Glucocorticoids and cytokines (eg, TNF, IL-1) are
probably the most important mediators of protein catabolism during
critical illness. The degree of protein catabolism increases in direct
proportion to the severity of stress and is reflected by the amount of
urinary urea nitrogen excretion. Glutamine released from muscle is used
as a preferred energy source by enterocytes and immune cells. Glutamine
is also used to synthesize heat-shock proteins and the antioxidant
glutathione. Glutamine becomes conditional during catabolic stress, and
depletion of free glutamine stores may have deleterious effects on gut and
immune function.126 Hepatic protein synthesis becomes “reprioritized”
during hypermetabolic stress, resulting in an increase in synthesis of acute
phase proteins, while albumin synthesis is down-regulated. Late MODS is
characterized by a decrease in hepatic protein synthesis that is refractory
to nutritional stimulation.120

Laboratory Examinations
There is no specific laboratory test for MODS. However, abnormalities
in the following tests are commonly seen.
Acid-base
Patients with MODS commonly have complicating metabolic acidosis
that is usually multifactorial.127 Although the anion gap is often elevated
as the result of acute renal failure or hyperlactatemia, in many patients the
increase in the anion gap cannot be completely explained. The presence
of “unidentified anions” has been documented in critically ill patients, and
can account for a substantial proportion of the increase in the anion
gap.128 Recent evidence suggests that these anions may be intermediates
of the Krebs cycle.129 An increase in unmeasured anions during critical
DM, August 2009 501
illness appears to be associated with increased mortality.129 Patients with
circulatory shock who are resuscitated with large amounts of normal
saline may develop hyperchloremic metabolic acidosis as the conse-
quence of a decrease in the strong-ion difference.127

Complete Blood Count

MODS is usually accompanied by a normocytic anemia that is multi-
factorial in etiology. Underlying causes include gastrointestinal bleeding,
frequent phlebotomies, and impaired hematopoiesis. The white blood cell
count is generally elevated but may be inappropriately low. Thrombocy-
topenia is common in critically ill patients, with some studies reporting
prevalence as high as 50%. In patients with trauma or sepsis, the presence
of thrombocytopenia accompanied by clinical or laboratory evidence of
DIC has a high sensitivity and specificity for predicting MODS.130 A
syndrome of thrombocytopenia-associated multiple organ failure has
been described that includes a spectrum of pathology including DIC,
thrombotic thrombocytopenic purpura, and secondary thrombotic mi-
croangiopathy.131

Liver Function Tests

Liver dysfunction during critical illness is associated with a poor outcome
that is independent of other organ dysfunctions; critical risk factors include
shock, sepsis, mechanical ventilation with positive end-expiratory pressure,
and major surgery.132 Diagnosis of hepatic dysfunction in its early stages
may be difficult due to insensitivity of standard liver function tests. Most
organ failure scoring systems grade the severity of hepatic dysfunction based
on serum bilirubin and/or transaminases. Significant direct hyperbiliru-
binemia is usually secondary to cholestasis.132 However, correctable causes
of hyperbilirubinemia such as biliary tract calculus, acalculus cholecystitis, or
a hemolytic reaction should also be considered.

Serum Albumin
Although hypoalbuminemia is often interpreted as indicating protein-
calorie malnutrition, the etiology of hypoalbuminemia during critical
illness usually is due to other factors including cytokine-induced suppres-
sion of albumin synthesis (eg, reprioritization of protein synthesis),
albumin catabolism, dilutional hypoalbuminemia, and third-space losses.
Hypoalbuminemia carries an adverse prognosis during critical illness but
has a low sensitivity and specificity for predicting hospital mortality.133
502 DM, August 2009
Plasma Markers of Sepsis—Procalcitonin
Differentiating septic vs nonseptic causes of MODS has therapeutic
implications because misdiagnosis of infection may result in unnecessary
administration of antibiotics. Measurement of plasma markers of infec-
tion such as procalcitonin (PCT) may be useful in this regard. Although
PCT has value as a marker of severe systemic inflammation, infection,
and sepsis, its clinical utility is limited by a lack of specificity. PCT levels
may also be elevated in various noninfectious conditions, such as
inhalational injury, pulmonary aspiration, pancreatitis, trauma, and burn,
and postoperatively.134 The lack of specificity is due in large part to the
limited sensitivity of currently used assays (eg, LUMItest). Newer assays
(eg, Kryptor) have improved sensitivity and may enhance the diagnostic
utility of PCT as an indicator of infection.134
Monitoring Patients with MODS
The word monitor is derived from the Latin word monere which means
“to warn.” In addition to identifying acute physiological alterations,
current techniques of monitoring are useful in directing therapeutic
interventions, as well as providing a measure of prognosis. Techniques
that monitor indexes of global or regional perfusion can be used to guide
hemodynamic resuscitation of circulatory shock and prevent progression
to MODS. A review of the more commonly used modalities follows.
Hemodynamic Monitors of Tissue Perfusion
During the 1970s extensive experience was gained using the pulmonary
artery catheter to assess global hemodynamics and guide resuscitation of
shocked patients. In addition to measuring filling pressures and cardiac
output, right heart catheterization also enables measurement of mixed
venous oxygen saturation (SvO2). This parameter gives an indication of
the relationship between systemic oxygen delivery and oxygen demand.
In this regard, a SvO2 less than 70% is suggestive of inadequate systemic
oxygen delivery and should prompt appropriate therapy with fluid
loading, inotropic agents, or blood transfusion.135
The use of the pulmonary artery catheter has decreased markedly over
the past 15 years due to complexity of insertion, related complications,
and failure to demonstrate improved outcome. Rivers et al. demonstrated
the utility of monitoring oxygen saturation in the superior vena cava
(ScvO2) with a central venous catheter as a surrogate for SvO2 in patients
with severe sepsis or septic shock.136 They found that an early goal-
directed approach of hemodynamic resuscitation targeted at attaining a
ScvO2 ⬎ 70% conferred a 32% relative reduction in the 28-day all-cause
DM, August 2009 503
mortality. There are several limitations of SvO2 or ScvO2-based moni-
toring. These parameters reflect the global (whole-body) relationship
between oxygen supply and demand; a normal value therefore does not
rule out regional hypoperfusion. In addition, in some patients with sepsis,
the expected fall in SvO2 or ScvO2 consequent to inadequate oxygen
delivery may be masked by a defect in oxygen extraction secondary to
microvascular shunting or mitochondrial dysfunction. Measurement of
cardiac output using an esophageal Doppler probe is a minimally invasive
technique that can be used to direct hemodynamic resuscitation without
the associated risks of pulmonary artery catheterization. A recent study
used a Doppler-guided fluid-management protocol for resuscitating
trauma patients and found a lower incidence of infectious complications,
and a reduced duration of ICU and hospital stays.137
Indexes of Regional Perfusion
Although cardiac output is typically increased in MODS, it is not evenly
distributed due to regional differences in autoregulation of blood flow.
Consequently, certain organs may be hypoperfused despite adequate
indexes of global perfusion. In this regard, the hepatosplanchnic circula-
tion is highly vulnerable to a reduction in tissue perfusion because it has
limited ability to autoregulate. Fiddian-Green speculated that occult
splanchnic hypoperfusion served as a “motor” of MOF.138 Recognition of
this phenomenon stimulated the development of a gastric tonometer that
could be used to monitor splanchnic perfusion in critically ill patients.
Gastric tonometry enables determination of parameters that reflect gastric
perfusion (eg, gastric intramucosal pH [pHi] and pCO2). A study of septic
ICU patients found that a low gastric pHi more accurately predicted
development of MODS and a fatal outcome than hemodynamic and
oxygen-derived variables obtained by invasive monitoring.139 Initial
studies suggested that ICU patients in whom therapy was guided by
gastric pHi measurements had improved survival compared to patients
who were treated with standard practices.140 However, results of subse-
quent studies were disappointing, and the use of gastric tonometry as a
clinical monitoring tool has been largely abandoned.141 Nakagawa and
colleagues discovered that perfusion of the upper esophagus and tongue
reflects that of the splanchnic circulation. They developed a tonometric
device that measured the PCO2 of sublingual tissues (PslCO2), and
observed that during circulatory shock, significant linear correlations
were noted between PslCO2, gastric PCO2, cardiac index, and arterial
lactate.142 Creteur et al. found that sublingual capnometry could be used
to monitor microcirculatory changes in septic patients.143 Unfortunately,
504 DM, August 2009
a sublingual capnometer is no longer commercially available, because the
manufacturer initiated a voluntary recall of the device in 2004.
Near-infrared spectroscopy (NIRS) is a technique that uses a sensor that
is applied to the skin (typically over the thenar eminence); infrared light
is transmitted through the subcutaneous tissues, and the resulting change
in intensity during transmission enables measurement of tissue oxygen
saturation (StO2). Normal values of StO2 obtained from the thenar
eminence approximate 87% ⫾ 6%. NIRS is reliable and easy to use. The
major limitation is limited sensitivity in detecting milder degrees of tissue
hypoxia. Animal models of hemorrhagic shock indicated that peripheral
muscle StO2 obtained by NIRS was a more sensitive indicator of shock
and adequate resuscitation. Subsequent human studies in trauma indicated
that NIRS was an accurate means to identify the severity of shock (in
severe shock StO2 typically falls to ⫾ 45%).144 In addition, NIRS may be
useful in directing hemodynamic resuscitation because StO2 changes
rapidly in response to variations in perfusion pressure. NIRS has also
been shown to predict the development of MODS during resuscitation of
traumatic shock.145 Cerebral NIRS was recently introduced as a means to
monitor cerebral oxygenation and hemodynamics in critically ill patients
with brain injury.
Orthogonal polarization spectral imaging is a technique that enables
monitoring of the microcirculation by imaging capillary flow in the
sublingual area. Unfortunately, technologic problems with the orthogonal
polarization spectral imager (eg, blurring due to internal scatter of light)
limited a more extensive usage of this device in the clinical setting. A new
technique, sidestream dark-field imaging, has improved visualization and
may prove more useful in accurately assessing microcirculatory flow.146
These data could potentially be used to guide microcirculatory-targeted
resuscitation (see below).
Biochemical Markers of Impaired Tissue Perfusion
Measurement of blood lactate is commonly performed in critically ill
patients as a means to assess tissue perfusion. Hyperlactatemia (eg, blood
lactate ⬎ 2 mM/L) is commonly interpreted as reflecting tissue dysoxia
resulting from an imbalance between oxygen delivery and oxygen
demand. Unfortunately, hyperlactatemia has been shown to lack speci-
ficity as an indicator of tissue dysoxia. Other factors that can produce
hyperlactatemia during critical illness include the stimulatory effect of
epinephrine on muscle lactate production, cytokine-mediated increase in
lactate production by inflammatory cells, thiamine deficiency, malig-
nancy, and drug-induced hyperlactatemia.147 Furthermore, measurement
DM, August 2009 505
of blood lactate has limited sensitivity in detecting regional hypoperfu-
sion because increased local production of lactate may be masked by
efficient metabolism in liver and other organs. Measurement of blood
lactate has also been used as a means to assess prognosis. Weil and Afifi
found that a single time-point measurement of lactate at presentation was
useful in predicting mortality in patients with circulatory shock.148 As the
lactate concentration increased from 2.1 mM/L to 8 mM/L, the estimated
probability of survival decreased from 90% to 10%. However, subsequent
studies indicated that sequential measurements of lactate during resusci-
tation from circulatory shock provide more useful prognostic information.
Bakker et al. found that in patients with septic shock, the initial blood
lactate did not differentiate survivors from nonsurvivors.149 However,
only the survivors had a significant decrease in lactate during the first 24
hours of septic shock. They also observed that the duration of lactic
acidosis was the only significant predictor of organ failure. Manikis et al.
found a correlation between lactate clearance and mortality following
trauma.150 They also noted that the duration of hyperlactatemia (eg,
“lac-time”) correlated with the development of organ failure. Abramson
et al. also studied lactate clearance and survival following injury.151 All
patients in whom lactate normalized (lactate ⱕ 2 mM/L) within 24 hours
survived. In contrast, the survival rate was 75% when lactate levels
normalized between 24 and 48 hours, and only 14% of when lactate did
not return to normal by 48 hours.
Monitoring of the arterial base deficit (BD) has been used as a means to
predict the development of postinjury MODS.152 This approach is based
on the correlation between metabolic acidosis and tissue hypoperfusion.
However, the increase in the BD following trauma does not appear to
correlate with lactate.153 This suggests the presence of other causes of
metabolic acidosis (eg, unmeasured anions) in trauma.128 Attaining a
normal BD has been recommended as a therapeutic endpoint in resusci-
tation of patients with trauma. In this regard, BD would be expected to
share the same limitations as lactate (eg, lack of sensitivity, slow response
to resuscitation).
Other Monitoring Modalities
The observed association between elevated IAP and subsequent organ
dysfunction (the ACS) led to the recommendation that patients at risk
undergo monitoring of IAP.58,154 Patients at highest risk are trauma
patients who have undergone “damage control” laparotomy with intra-
abdominal packing, ruptured abdominal aortic aneurysms, retroperitoneal
hemorrhage, circumferential abdominal wall burn with eschar, severe
506 DM, August 2009
pancreatitis, massive ascites, and liver transplantation. Common factors in
these patients include massive fluid resuscitation, bowel edema, and
forced closure of a noncompliant abdomen. In 2007, an international
consensus group of multidisciplinary critical care specialists provided
practice guidelines for the diagnosis, management, and prevention of
intra-abdominal hypertension and ACS.154
As mentioned above, autonomic dysfunction is common during
critical illness, and it has been proposed that monitoring of autono-
mic function in patients at risk might facilitate early diagnosis of
MODS.33,155 Recent studies have shown that loss of heart rate
variability is a marker of increased risk of progression into MODS as
well as an indicator of adverse prognosis.155 The most common
approach to monitoring of autonomic function at the bedside involves
obtaining a 24-hour Holter ECG recording. Heart rate variability can
then be calculated using commercial software programs.

Management
Marshall emphasized that one of the keys to managing MODS is to
recognize patients at greatest risk.12 The optimal therapeutic approach
should be individualized but the overall goal is to minimize risk of
progression to MODS by (1) optimization of supportive management of
circulatory and respiratory dysfunction; (2) reducing the rate of protein
catabolism by prompt surgical debridement, burn wound excision and
grafting, fixation of long bone fractures; (3) providing early nutrition
support by the enteral route; (4) selective, targeted use of antibiotics; (5)
minimizing blood transfusions when possible.12 In 2004, a consensus
document, “Surviving Sepsis Campaign,” was published that provided
evidence-based guidelines for the management of severe sepsis and septic
shock. These guidelines provide a useful means to facilitate the manage-
ment of MODS and have led to substantial improvements in clinical
outcome. A revised version of the Surviving Septic Guidelines was
published in 2008.156
Timely Goal-Directed Hemodynamic Resuscitation
One of the most common events preceding MODS is circulatory shock,
and the risk for developing organ failure can often be predicted by events
that occur within the first 24 hours of admission.157 In this regard,
inadequate initial resuscitation has been shown to be one of the most
important factors increasing the risk of MODS, and optimizing hemody-
namic resuscitation is therefore a major therapeutic focus. Shoemaker and
colleagues first proposed using the pulmonary artery catheter in high-risk
DM, August 2009 507
surgical patients to direct interventions targeted toward attaining “su-
pranormal” values of systemic oxygen delivery.158 This approach was
based on observations that attaining a targeted hyperdynamic threshold
was associated with improved survival from acute surgical stress.159
Although targeting supranormal endpoints appeared to be beneficial in
certain groups of patients (eg, preoperative major surgery), it was not
found to be effective (and even potentially harmful) in others.160 Rivers
et al. in a study of patients with severe sepsis and septic shock found that
early goal-directed therapy (initiated within 6 hours of arrival to the
emergency room) directed toward attaining a ScvO2 ⱖ 70% conferred a
substantial reduction in mortality.136 The Rivers study also demonstrated
the importance of the timeliness of resuscitation (which was initiated on
arrival to the Emergency Department), since studies in which aggressive
resuscitation was delayed until after transfer to the ICU failed to show
improved outcome or a reduction in MODS.160 The beneficial effect of
timely hemodynamic resuscitation (eg, during the “golden window”) may
relate to amelioration of bioenergetic failure by providing oxygen and
substrate to mitochondria that are still functional.161 The resuscitative
guidelines provided by the Surviving Sepsis Campaign therefore empha-
size prompt initiation of therapy (ideally within 6 hours of Emergency
Department presentation), that includes fluid loading directed at reaching
a central venous pressure of 8-12 mm Hg, mean arterial pressure ⱖ 65
mm Hg, urine output ⱖ 0.5 mL/kg/h, and a ScvO2 ⱖ 70% (using blood
transfusion ⫾ dobutamine if necessary).156 Although vasopressors are
valuable in the initial treatment of circulatory shock refractory to fluid
loading or inotropes, the use of high-dose catecholamines in patients with
established, advanced MODS may be futile and possibly harmful.
Potential adverse effects of catecholamine infusion include stimulation of
bacterial growth, increasing factors relating to bacterial virulence and
biofilm formation, and an immunosuppressive effect on monocytes and
macrophages.162,163 In this regard, the use of noncatecholamine vasopres-
sors such as vasopressin may be of greater value; however, this theory
remains unproven. As mentioned above, sequential measurement of
lactate during resuscitation of circulatory shock has been used as a tool to
direct hemodynamic resuscitation.149-151 This approach targets normal-
ization of blood lactate as the resuscitative endpoint. A study in
postoperative cardiac surgery patients demonstrated that resuscitation
directed at attaining blood lactate ⬍ 2 mM/L (and SvO2 ⬎ 70), was
associated with shorter hospital stay and lower morbidity.164 A study of
trauma patients who were resuscitated with a protocol directed at
normalizing lactate found that patients in whom blood lactate returned to
508 DM, August 2009
normal within 24 hours had improved survival, and a decreased incidence
of MODS.165 Larger studies are required to confirm a beneficial effect of
this approach. The major limitation of lactate-guided therapy is a slow
response of blood lactate to hemodynamic resuscitation. In addition, it
may be impossible to normalize lactate in some patients because
increased lactate production may be stimulated by factors not related to
tissue perfusion.147
Source Control
All patients presenting with severe sepsis should be evaluated for the
presence of an infectious focus that would be amenable to drainage,
debridement of necrotic debris, removal of a potentially infected device,
or definitive surgical control (eg, amputation, bowel resection, etc).156
Antibiotic Therapy
Parenteral antibiotics should be started as soon as possible in patients
with severe sepsis; ideally within the first few hours of diagnosis and after
appropriate cultures have been obtained. The choice of empiric antibiotics
should be directed against the most likely pathogens. The initial regimen
should be reassessed after 48-72 hours based on cultures and clinical data
with the aim of narrowing the antibiotic spectrum if possible.156 Many
studies have explored the efficacy of selective decontamination of the
digestive tract and oropharynx in ICU patients as a means to reduce
nosocomial infections. A recent European study in intubated ICU patients
found that decontamination of the oropharynx and digestive tract using
parenteral plus topical antibiotics reduced the mortality rate.166
Limitation of Packed Red Cell Transfusion
Several studies have shown that blood transfusion is an independent risk
factor for postinjury MODS.54-56,167 An appreciation of the risks of blood
transfusion led to more conservative transfusion thresholds in ICU
patients.57 In addition, recognition that leukocyte-derived cytokines
contaminating the stored blood were responsible for many adverse effects
led to the routine use of leukodepleted blood in Europe and Canada.
Meta-analyses of studies that have explored this approach have not
clearly documented a beneficial effect.57 However, a recent Canadian trial
observed a reduction in hospital mortality after institution of a policy of
routinely administering leukodepleted blood.168 Administration of eryth-
ropoietin (EPO) has been shown to decrease transfusion requirements in
critically ill patients requiring prolonged ICU care.169 However, EPO
therapy has not been shown to have a significant effect in improving
DM, August 2009 509
clinical outcome, and administration of EPO is recommended only for
patients with coexisting conditions that warrant its use (eg, renal fail-
ure).156
Mechanical Ventilation of Acute Lung Injury and ARDS
As previously discussed, injurious mechanical ventilation has been
implicated as causing dysfunction of distant organs in patients with acute
lung injury and ARDS.49,51,52 An appreciation of this phenomenon led to
a “lung protective strategy” of mechanical ventilation that is directed
toward mitigating the adverse effects of excessive airway pressure (eg,
mechanotransduction).50 The ARDSnet study compared the outcome of
patients ventilated with a “lung-protective strategy” (tidal volumes of 6
mL/kg predicted body weight with plateau pressures maintained ⱕ 30 cm
H2O) to patients ventilated using “conventional” parameters (12 mL/kg
predicted body weight with plateau pressures ⱕ 50 cm H2O).170 When
compared to conventionally ventilated patients, those who were ventilated
with the lung-protective strategy had a 9% reduction in all-cause
mortality. A recent European study of septic ICU patients with ARDS
found that the use of tidal volumes greater than used by the ARDSnet
study was an independent risk factor for mortality.171
The use of prone positioning in mechanically ventilated patients with
ARDS has been demonstrated to improve oxygenation by enhancing
ventilation-perfusion matching.172 However, this technique is associated
with increased morbidity, and beneficial effects on mortality have not
been demonstrated.
Glucose Control
In the past, modest degrees of hyperglycemia (eg, 180-200 mg/dL) were
routinely tolerated by ICU physicians. In 2001, van den Berghe and
colleagues published a study in postoperative ICU patients that indicated
benefit from using continuous insulin infusion titrated to maintain
euglycemia (blood glucose, 80-110 mg/dL) when compared to traditional
targets for glucose control (blood glucose of 180-200 mg/dL).173 They
found that patients who were treated with intensive insulin therapy (IIT)
and who required ICU care for more than 5 days had significant
reductions in ICU and hospital mortality. The survival benefit was largely
related to a reduction in deaths due to MOF with a proven septic focus.
The beneficial effects appeared to be related to a reduction in glucose
levels rather than administration of insulin per se. The mechanisms by
which tight glucose control reduces MOF are not entirely clear but could
include (1) a reduction in ROS production; (2) an anti-inflammatory
510 DM, August 2009
effect consequent to decreased activation of receptors for advanced
glycation end-products; (3) reduced endothelial dysfunction; (4) a pro-
tective effect on mitochondria.174 A subsequent study of IIT by Van den
Berge et al. in the medical ICU setting demonstrated decreased in-hospital
mortality in patients who stayed in the ICU more than 5 days.175 In
addition, they found that IIT prevented acute renal injury. However, they
determined that the rate of hypoglycemia in medical ICU patients was
3-fold greater than seen in their 2001 study. A recently completed
investigation performed in a level 1 trauma center found that IIT (target
glucose, 80-130 mg/dL) was associated with excess hospital mortality
that was mainly seen in patients who had an ICU length of stay of 3 days
or less.176 They also noted that the incidence of hypoglycemia increased
with IIT. Although previous studies indicated that hypoglycemia was not
clearly linked with increased mortality, a recent retrospective database
review found that even a single episode of severe hypoglycemia was
independently associated with increased risk of mortality.177 Therefore, a
beneficial effect of IIT could be negated by an excessively high rate of
attendant hypoglycemia.178 These concerns led to a more liberal recom-
mendation for a target blood glucose by the Surviving Sepsis Campaign
(ie, maintaining blood glucose ⱕ 150 mg/dL).156
Steroids
A state of “relative adrenal insufficiency” (RAI) has been described in
critically ill patients in which serum cortisol levels are inadequate for the
ongoing stress response.179 Although the precise pathophysiology for
RAI is unclear, current evidence suggests that the adrenal axis is
suppressed as the consequence of a cytokine-mediated decrease in
synthesis and/or release of corticotropin-releasing hormone, adrenocorti-
cotrophic hormone (ACTH), or cortisol. The existence of RAI is
commonly identified by a blunted response to exogenous ACTH. A
randomized double-blinded study of low-dose hydrocortisone replace-
ment (ⱕ300 mg/d) plus fludrocortisone in patients with septic shock and
RAI demonstrated improved survival and shortened time on vasopressors
relative to placebo.180 However, this study was confounded by the fact
that 24% of the patients received etomidate, which can inhibit adrenal
corticoid synthesis. The recently completed CORTICUS Trial found that
hydrocortisone did not improve survival or reversal of shock in patients
with septic shock, either overall or in patients who did not have a response
to ACTH.181 However, hydrocortisone hastened reversal of shock in
patients in whom shock was reversed. In 2008, an international task force
of the American College of Critical Care Medicine provided recommen-
DM, August 2009 511
dations of the diagnosis and management of corticosteroid insufficiency
in critically ill adult patients.182 They concluded that adrenal insufficiency
is best diagnosed by an increase in serum cortisol (after 250 ␮g ACTH)
of ⬍9 ␮g/dL, or a random total cortisol of ⬍10 ␮g/dL. However, they
also felt that the ACTH stimulation test should not be used to identify
which patients should receive glucocorticoids. Hydrocortisone therapy
(200 mg/d for ⱖ7 d) should be considered in patients with septic shock,
particularly those who have had a poor response to fluid resuscitation and
vasopressors. The use of moderate-dose methylprednisolone, 1 mg/kg/d
for ⱖ14 days, was also recommended for patients with severe early
ARDS.182
Activated Protein C
Crosstalk between the innate immune system and the coagulation
pathway occurs during sepsis.21,26 These processes interact in an ampli-
fying loop that leads to organ dysfunction and MODS.183 Activated
protein C (APC) deactivates the coagulation system by inhibiting clotting
factors Va and VIIIa and restores the fibrinolytic system by blocking
plasminogen activator inhibitor. APC also has anti-inflammatory effects
that include limiting leukocyte chemotaxis and reducing thrombin pro-
duction. However, the levels of endogenous APC are depleted during
sepsis. In this regard, the PROWESS study was undertaken in 2001 to
investigate the beneficial effects of administration of recombinant human
activated protein C (rhAPC) to patients with severe sepsis.184 This study
found that 28-day mortality was reduced in patients receiving rhAPC
compared to placebo. This effect was most pronounced in patients with an
APACHE II score ⬎25. A beneficial effect was also observed in patients
with MODS (absolute risk reduction of 7.4%). However, subsequent
studies (VHA/UHC Survey, Canadian Survey) failed to confirm a
beneficial effect of rhAPC, and increased bleeding has been a consistent
finding in all sepsis trials conducted to date.185 Based on these data, the
Surviving Sepsis guidelines recommended that rhAPC should be consid-
ered only in adult patients with sepsis-induced organ dysfunction with
clinical assessment of high risk of death (eg, APACHE II ⱖ 25 or MOF).
Early Enteral Nutrition/Immunonutrition
Early enteral nutrition (eg, initiation of enteral nutrition within 24-48
hours of hospital admission) may be of benefit in patients at risk for
MODS. The mechanisms underlying the beneficial effect include preser-
vation of mucosal immunity by beneficial action on GALT, maintaining
antioxidant pools, and decreasing starvation-associated inflammatory
512 DM, August 2009
interactions between enteric bacteria and the intestinal epithelium. A
study of early enteral feeding in patients with shock indicated that patients
in whom enteral nutrition was begun more than 24 hours after admission
had evidence of increased intestinal permeability and more severe MODS
than those receiving early enteral nutrition.186 A recent retrospective
analysis of a large group of ICU patients who were mechanically
ventilated revealed that early enteral feeding (begun with 48 hours of
initiation of mechanical ventilation) reduced ICU and hospital morta-
lity.187 The European Society of Parenteral and Enteral Nutrition (ES-
PEN) guidelines supported the use of early enteral nutrition (⬍24 hours
after admission) in critically ill patients who are hemodynamically stable
and have a functioning gastrointestinal tract (level C evidence).188
In the late 1970s, it was noted that arginine supplementation in surgical
patients prevented apoptosis of lymphocytes and improved wound heal-
ing. In the 1980s, “immune-enhancing” enteral formulas became avail-
able for clinical use. These formulas contained varying mixtures of
arginine, omega-3 fatty acids, nucleotides, and antioxidants. Over the past
25 years, a large number of randomized controlled trials have been
conducted investigating the efficacy of immune-enhancing diets in
patients with trauma, major surgery, and critical illness. Although positive
results were seen in postoperative and trauma patients with regard to
decreased infections and length-of-stay, a meta-analysis of enteral immu-
nonutrition (containing a combination of arginine, glutamine, nucleotides,
and omega-3 fatty acids) in critically ill patients with sepsis indicated
possible harm.189 The exact reason(s) is not clear but may relate to
adverse effects of administration of supplemental arginine during sep-
sis.190 Concerns over the potential toxicity of arginine were reflected in
the Canadian Clinical Practice Guidelines that arginine-containing enteral
products not be used in mechanically ventilated critically ill adult
patients.191 ESPEN guidelines recommend against the use of arginine-
supplemented immune-enhancing diets in patients with severe sepsis but
support their use in elective surgical and trauma patients.188
Omega-3 fats derived from fish-oil (eg, eicosapentaenoic acid, docosa-
hexaenoic acid), as well as certain omega-6 fatty acids derived from
borage oil (gamma-linolenic acid), have been shown to be beneficial in
patients with ALI/ARDS. The mechanism(s) involves modulation of
pro-inflammatory eicosanoid and cytokine production, reducing oxidative
injury by stimulating glutathione production, and enhancing the produc-
tion of anti-inflammatory mediators (eg, resolvins).192 It is has also been
shown that omega-3 fatty acids have an anti-inflammatory effect on gut
that decreases the efflux of inflammatory mediators from gut to the
DM, August 2009 513
mesenteric lymph.193 Pontes-Arruda and colleagues recently completed a
prospective, randomized controlled trial in 165 mechanically ventilated
ARDS patients with sepsis, severe sepsis, or septic shock in which they
investigated the effect of an “immune” formula supplemented in eicosa-
pentaenoic acid, gamma-linolenic acid, and antioxidants on 28-day
all-cause mortality.194 When compared to control patients fed an isoca-
loric, isonitrogenous formula, patients who received the immune formula
had better oxygenation, more ventilator-free days, and more ICU-free
days. In addition, the group that received the immune formula had a
significant decrease in 28-day all-cause mortality with an absolute
reduction of 19.4%. A recent meta-analysis combined the results of this
study with 2 previous studies of similar design (411 patients in total) and
found that 28-day intention to treat, all-cause mortality was reduced by
49% (OR, 0.514; 95% CI).195 Both the Canadian Practice Guidelines and
the ESPEN Guidelines support the use of formulas enriched with
omega-3 fatty acids and antioxidants in patients with ARDS.188,191
Glutamine supplementation has been shown to be beneficial in patients
with organ dysfunction. Two single-center studies of MOF patients who
were receiving total parenteral nutrition showed survival benefit when
parenteral glutamine was supplemented at the level of 20-25 g/d.196,197
ESPEN Guidelines support supplementation of glutamine in patients with
burn or trauma.188
A reduction in plasma levels of the antioxidant selenium has been
documented in critically ill surgical patients, while an even greater
decrease is seen in patients with organ failure.198 A recent multicenter
randomized trial of high-dose parenteral selenium supplementation dem-
onstrated reduced mortality in patients with severe SIRS, sepsis, and
septic shock.199
Continuous Renal Replacement Therapy
Ronco et al. proposed the “peak concentration hypothesis” of MODS.
This theory posits that organ failure results from loss of “immuno-
homeostasis” secondary to excessive peaks in pro-inflammatory and
anti-inflammatory cytokines.200 They found that continuous renal re-
placement therapy could be combined with plasma filtration absorption
techniques to “clean” the plasma of excessive quantities of circulating
inflammatory mediators. This in turn would help restore immuno-
homeostasis by lowering elevated levels of cytokines into a more
physiological range. Anecdotal reports have indicated that certain patients
with MODS may dramatically improve with this therapeutic modality.201
However, at this point the Surviving Sepsis Guidelines do not support the
514 DM, August 2009
routine use of continuous renal replacement outside the setting of acute
renal failure.

Innovative Therapies
Patients with circulatory shock who have been resuscitated to targeted
endpoints of global perfusion may have persisting abnormalities in
microcirculatory flow that can lead to MODS.60-62 Recent research has
indicated that disturbances in microcirculatory flow secondary to sepsis
may improve with administration of certain vasoactive agents such as
nitroglycerin or selective inhibitors of inducible nitric oxide synthase.202
A therapeutic approach that directly targets the microcirculation has been
proposed but has not been clinically validated.203
As discussed above, impaired oxidative metabolism secondary to
mitochondrial dysfunction plays an important role in the pathophysiology
of MODS. In this regard, administration of electron donors (eg, succinate)
that are able to bypass defective components of the respiratory chain have
been explored as therapeutic agents.204
The use of pharmacologic blockade of PARP to improve bioenergetics
by reducing oxidative damage to mitochondria has shown promise in
animals and could potentially be of benefit in patients.205
Electrical pacing of the vagus nerve has been explored as a means to
suppress inflammation by stimulating the cholinergic anti-inflammatory
system.30 This technique could potentially be useful as an anti-inflam-
matory modality in patients with SIRS or MODS.
Conclusions
Technologic advances have facilitated the support of failing organs in
critically ill patients. However, it has also become increasingly clear that
supportive therapies also have adverse effects that can lead to organ
failure. To quote John Marshall: “Critical illness can be conceptualized as
a process of repetitive acute insults, starting for example, with a
life-threatening insult such as multiple trauma and hemorrhagic shock. It
then evolves in response to a series of sequential and poorly understood
insults including massive fluid resuscitation, mechanical ventilation,
vasoactive therapy and nosocomial infection, and the ecological derange-
ments induced by broad-spectrum antibiotics.”206 The reduction in the
incidence of MODS observed over the past decade reflects improvements
in supportive management. However, an emphasis on supportive tech-
nology in the absence of interventions directed toward the primary
pathophysiology is unlikely to improve outcome in a meaningful way.
This represents our therapeutic goal for the future.
DM, August 2009 515
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