Multiple Organ Dysfunction Syndrome in

Sepsis
Author: Ali H Al-Khafaji, MD, MPH; Chief Editor: Michael R Pinsky, MD, CM, Dr(HC), FCCP, MCCM more.
16 mei 2016
Background
Multiple organ dysfunction syndrome (MODS) is a continuum, with incremental degrees of physiologic
derangements in individual organs; it is a process rather than a single event. Alteration in organ function
can vary widely from a mild degree of organ dysfunction to completely irreversible organ failure. The
degree of organ dysfunction has a major clinical impact.

In a classic 1975 editorial by Baue, the concept of multiple, progressive or sequential systems failure
was formulated as the basis of a new clinical syndrome.[1] Several different terms were proposed
thereafter (eg, multiple organ failure, multiple system organ failure, and multiple organ system failure) to
describe this evolving clinical syndrome of otherwise unexplained progressive physiologic failure of
several interdependent organ systems.

Eventually, the term MODS was proposed as a more appropriate description. MODS is defined as a
clinical syndrome characterized by the development of progressive and potentially reversible physiologic
dysfunction in 2 or more organs or organ systems that is induced by a variety of acute insults, including
sepsis.

For patient education resources, see the Blood and Lymphatic System Center, as well as Sepsis (Blood
Infection).

Clinical continuum of sepsis

Sepsis is a clinical syndrome that complicates severe infection and is characterized by systemic
inflammation and widespread tissue injury. A continuum of severity from sepsis to septic shock and
MODS exists. The clinical process usually begins with infection, which potentially leads to sepsis and
organ dysfunction.[2] A consensus panel of the American College of Chest Physicians and the Society of
Critical Care Medicine developed definitions of the various stages of this process (see the image below).[3]

Stages of sepsis based on American College of

Chest Physicians/Society of Critical Care Medicine Consensus Panel guidelines.
Infection is usually a microbial phenomenon in which an inflammatory response to the presence of
microorganisms or the invasion of normally sterile host tissue by these organisms is characteristic.
However, viral infections can be indistinguishable from bacteria infections in their presentation.
 Bacteremia is the presence of viable bacteria in the blood.

Systemic inflammatory response syndrome (SIRS) may follow a variety of clinical insults, including
infection, pancreatitis, ischemia, multiple trauma, tissue injury, hemorrhagic shock, or immune-mediated
organ injury. SIRS is a nonspecific presentation of these insults and is defined by the presence of 2 or
more of the following:

Temperature greater than 38.0C or less than 36.0C

Heart rate higher than 90 beats/min
Respiratory rate higher than 20 breaths/min or arterial carbon dioxide tension below 32 mm Hg
White blood cell (WBC) count higher than 12,000/L, lower than 4000/L, or including more than 10%
bands
Sepsis is a systemic response to infection. It is identical to SIRS, except that it must result specifically
from infection rather than from any of the noninfectious insults that may also cause SIRS (see the image
below). That sepsis and SIRS are phenotypically similar underscores a common inflammatory pathway
causing both.

Venn diagram showing overlap of infection,

bacteremia, sepsis, systemic inflammatory response syndrome (SIRS), and multiorgan dysfunction.
In early 2016, the Society of Critical Care Medicine and the European Society of Intensive Care Medicine
convened a task force to address definitions and clinical criteria for sepsis. [4] The task force concluded that
sepsis should be defined as life-threatening organ dysfunction caused by a dysregulated host response to
infection. Organ dysfunction is represented by an increase in the Sequential [sepsis-related] Organ
Failure Assessment (SOFA) score[5] of 2 points or more, which is associated with an in-hospital mortality
greater than 10%.

Septic shock is defined as a subset of sepsis in which profound circulatory, cellular, and metabolic
abnormalities are associated with a greater risk of mortality than with sepsis alone.

Patients with septic shock can be clinically identified by a vasopressor requirement to maintain a mean
arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2 mmol/L (>18 mg/dL) in
the absence of hypovolemia. This combination is associated with hospital mortality rates greater than
40%.

In out-of-hospital, emergency department, or general hospital ward settings, adult patients with suspected
infection can be rapidly identified as being more likely to have poor outcomes typical of sepsis if they
have at least two of the following clinical criteria that together constitute a new bedside clinical score
termed quick SOFA (qSOFA)[6] : respiratory rate of 22/min or greater, altered mentation, or systolic blood
pressure of 100 mm Hg or less.
The task force recommended that these updated definitions and clinical criteria should replace previous
definitions

MODS is the presence of altered organ function in an acutely ill patient such that homeostasis cannot be
maintained without intervention. Primary MODS is the direct result of a well-defined insult in which organ
dysfunction occurs early and can be directly attributable to the insult itself. Secondary MODS develops as
a consequence of a host response and is identified within the context of SIRS. The inflammatory
response of the body to toxins and other components of microorganisms causes the clinical
manifestations of sepsis.

Malignant intravascular inflammation

Sepsis has been referred to as a process of malignant intravascular inflammation. Normally, a potent,
complex, immunologic cascade ensures a prompt protective response to microorganism invasion in
humans. A deficient immunologic defense may allow infection to become established; however, an
excessive or poorly regulated response may harm the host through maladaptive release of indigenously
generated inflammatory compounds (see the image below).

Pathogenesis of sepsis and multiorgan failure.

Lipid A and other bacterial products release cytokines and other immune modulators that mediate the
clinical manifestations of sepsis. Interleukins, tumor necrosis factor (TNF)-, interferon gamma (IFN-),
and other colony-stimulating factors are produced rapidly within minutes or hours after interactions of
monocytes and macrophages with lipid A.

Inflammatory mediator release becomes a self-stimulating process, and release of other such mediators,
including interleukin (IL)-1, platelet activating factor, IL-2, IL-6, IL-8, IL-10, and nitric oxide (NO), further
increases cytokine levels. This leads to continued activation of polymorphonuclear leukocytes (PMNs),
macrophages, and lymphocytes; proinflammatory mediators recruit more of these cells. All of these
processes create a state of destructive immunologic dissonance.

Sepsis is described as an autodestructive process that permits extension of the normal pathophysiologic
response to infection to involve otherwise normal tissues and results in MODS. Organ dysfunction or
organ failure may be the first clinical sign of sepsis, and no organ system is immune from the
consequences of the inflammatory excesses of sepsis. Mortality increases as organ failure increases.

Although uncontrolled, once MODS develops systemic evidence of both proinflammatory and anti-
inflammatory up-regulation are usually present, suggesting that failure of host defense homeostasis is the
final pathway from sepsis to MODS, rather than simple hypotension-induced end-organ injury, as may
occur with hemorrhagic shock. Survival from severe sepsis with MODS is usually associated with a
generalized reduction in both the proinflammatory and anti-inflammatory response.

A novel hypothesis has recently emerged that survival from severe sepsis requires a generalized down-
regulation of the bodys immune response, energetic functions, and associated organ performance. Thus,
MODS may by the hosts adaptive response to overwhelming inflammation, allowing inflammation to clear
without causing permanent end-organ harm. As discussed below, all organs reveal a generalized
hyporesponsiveness that is clearly abnormal in health but may mark a survival strategy in severe sepsis.

Dysfunction of organ systems

Circulatory derangement

Significant derangement in autoregulation of circulation is typical of sepsis. Vasoactive mediators cause

vasodilatation and increase microvascular permeability at the site of infection. NO plays a central role in
the vasodilatation of septic shock. Also, impaired secretion of vasopressin may occur, which may permit
persistence of vasodilatation.

Changes in both systolic and diastolic ventricular performance occur in sepsis. Through the use of the
Frank-Starling mechanism, cardiac output often is increased to maintain blood pressure in the presence
of systemic vasodilatation. Patients with preexisting cardiac disease are unable to increase their cardiac
output appropriately.

Regionally, sepsis interferes with the normal distribution of systemic blood flow to organ systems.
Consequently, core organs may not receive appropriate oxygen delivery, and the result is what is known
as regional hypoperfusion.

Microcirculation is the key target organ for injury in sepsis since vascular endothelium is universally
affected by the circulating inflammatory mediators. Although it is unclear if microcirculatory abnormalities
are the cause or an innocent bystander of the end-organ injury, clear microvascular dysfunction is seen.
A decrease in the number of perfused capillaries is seen, although with application of vasodilator
therapies, full microvascular recruitment occurs. Mitochondrial dysfunction also occurs and is often
associated with reduced mitochondrial transmembrane potential gradients, which are necessary to drive
oxidative phosphorylation. The end result is an apparent inability of end-organs to extract oxygen
maximally.

Debate continues as to whether this failure of energy metabolism is an adaptive cytoprotective

mechanism similar to hibernation or reflects primary mitochondrial pathology. These are areas of active
research but do not presently translate into clear clinical practice guidelines. Increased capillary
endothelial permeability leads to widespread protein-rich tissue edema.

Septic shock and SIRS are characterized by reversible myocardial depression, which can prove resistant
to catecholamine and fluid administration. Circulating myocardial depressant factorprobably
representing the synergistic effects of TNF-, IL-1, other cytokines, and NOis implicated in
pathogenesis. The two characteristics of this acute stress myocardial depression are impaired adrenergic
responsiveness and diastolic dysfunction leading to relative catecholamine resistance and small rather
than dilated hearts. Macrovascular myocardial ischemia and hypoperfusion are unlikely contributors.

In severe sepsis and septic shock, microcirculatory dysfunction and mitochondrial depression cause
regional tissue distress, and regional dysoxia therefore persists. This condition is termed microcirculatory
and mitochondrial distress syndrome (MMDS).[7] Sepsis-induced inflammatory autoregulatory dysfunction
persists, and oxygen need is not matched by supply, leading to MODS.
Redistribution of intravascular fluid volume resulting from reduced arterial vascular tone, diminished
venous return from venous dilation, and release of myocardial depressant substances causes
hypotension.

Pulmonary dysfunction

Endothelial injury in the pulmonary vasculature leads to disturbed capillary blood flow and enhanced
microvascular permeability, resulting in interstitial and alveolar edema. Neutrophil entrapment within the
pulmonary microcirculation initiates and amplifies the injury to alveolar capillary membranes. Acute lung
injury and acute respiratory distress syndrome (ARDS) are frequent manifestations of these effects.
Indeed, sepsis and pneumonia are the most common causes of ARDS.

Gastrointestinal dysfunction

The gastrointestinal (GI) tract may help propagate the injury of sepsis. Overgrowth of bacteria in the
upper GI tract may be aspirated into the lungs, producing nosocomial or aspiration pneumonia. The
normal barrier function of the gut may be affected, allowing translocation of bacteria, endotoxins, and
normal digestive proteases into the systemic circulation and extending the septic response.

Septic shock can cause paralytic ileus that can lead to a delay in the institution of enteral feeding. Excess
NO production is thought to be the causative agent of sepsis-induced ileus. The optimal level of nutritional
intake is interfered with in the face of high protein and calorie requirements. Narcotics and muscle
relaxants can further worsen GI tract motility.

Liver dysfunction

As a consequence of the role the liver plays in host defense, the abnormal synthetic functions caused by
liver dysfunction can contribute to both the initiation and progression of sepsis. The reticuloendothelial
system of the liver acts as a first line of defense in clearing bacteria and their products; liver dysfunction
leads to a spillover of these products into systemic circulation.

Liver failure (shocked liver) can be manifested by elevations in liver enzymes and bilirubin, coagulation
defects, and failure to excrete toxins such as ammonia, which lead to worsening encephalopathy.

Renal dysfunction

Acute kidney injury (AKI) often accompanies sepsis. Different etiologies for AKI have been reported, and
the cause is typically thought to be multifactorial.[8] The mechanism of AKI is complex but likely involves a
decrease in effective intravascular volume resulting from systemic hypotension, direct renal
vasoconstriction, release of cytokines, and activation of neutrophils by endotoxins and other peptides,
which contribute to renal injury. Still, most animal studies show that renal blood flow is increased, not
decreased, in sepsis, though associated with impaired tubular function and a lack of significant histologic
evidence of tubular injury.

Central nervous system dysfunction

Involvement of the central nervous system (CNS) in sepsis produces encephalopathy and peripheral
neuropathy. The pathogenesis is poorly defined but is probably related to systemic hypotension, which
can lead to brain hypoperfusion.

Coagulopathy
Subclinical coagulopathy, signaled by a mild elevation of the thrombin time (TT) or activated partial
thromboplastin time (aPTT) or a moderate reduction in the platelet count, is extremely common; however,
overt disseminated intravascular coagulation (DIC) may also develop. Protease-activated receptors
(PARs), especially PAR 1, form the molecular link between coagulation and inflammation; PAR1 exerts
cytoprotective effects when stimulated by activated protein C or low-dose thrombin but exerts disruptive
effects on endothelial-cell barrier function when activated by high-dose thrombin.[9]
Mechanisms of organ dysfunction and injury
The precise mechanisms of cell injury and resulting organ dysfunction in sepsis are not fully understood.
MODS is associated with widespread endothelial and parenchymal cell injury, some of which can be
explained by the following 4 proposed mechanisms.

Hypoxic hypoxia

The septic circulatory lesion disrupts tissue oxygenation, alters the metabolic regulation of tissue oxygen
delivery, and contributes to organ dysfunction. Microvascular and endothelial abnormalities contribute to
the septic microcirculatory defect in sepsis. The reactive oxygen species, lytic enzymes, and vasoactive
substances (eg, NO and endothelial growth factors) lead to microcirculatory injury, which is compounded
by the inability of the erythrocytes to navigate the septic microcirculation.

Direct cytotoxicity

Endotoxin, TNF-, and NO may cause damage to mitochondrial electron transport, leading to disordered
energy metabolism. This is called cytopathic or histotoxic anoxia, an inability to utilize oxygen even when
it is present.

Apoptosis

Apoptosis (programmed cell death) is the principal mechanism by which dysfunctional cells are normally
eliminated. The proinflammatory cytokines may delay apoptosis in activated macrophages and
neutrophils, but other tissues (eg, gut epithelium), may undergo accelerated apoptosis. Therefore,
derangement of apoptosis plays a critical role in the tissue injury of sepsis.

Immunosuppression

The interaction between proinflammatory and anti-inflammatory mediators may lead to an imbalance
between them. An inflammatory reaction or an immunodeficiency may predominate, or both may be
present.

Host response and other factors influencing outcome

Clinical characteristics that relate to the severity of sepsis include the host response to infection, the site
and type of infection, the timing and type of antimicrobial therapy, the offending organism, the
development of shock, the underlying disease, the patients long-term health condition, and the number of
failed organs. Factors that lead to sepsis and septic shock may not be essential in determining the
ultimate outcome.

The host response to sepsis is characterized by both proinflammatory responses and anti-inflammatory
immunosuppressive responses. The direction, extent, and duration of these reactions are determined by
both host factors (eg, genetic characteristics, age, coexisting illnesses, medications) and pathogen
factors (eg, microbial load, virulence).[10]

Inflammatory responses are initiated by interaction between pathogen-associated molecular patterns

expressed by pathogens and pattern recognition receptors expressed by host cells at the cell surface
(toll-like receptors [TLRs] and C-type lectin receptors [CLRs]), in the endosome (TLRs), or in the
cytoplasm (retinoic acid inducible gene 1like receptors [RLRs] and nucleotide-binding oligomerization
domainlike receptors [NLRs]).[10]

The consequence of exaggerated inflammation is collateral tissue damage and necrotic cell death, which
results in the release of damage-associated molecular patterns, so-called danger molecules that
perpetuate inflammation at least in part by acting on the same pattern-recognition receptors triggered by
pathogens.[10]