Multiple Organ Dysfunction

Syndrome
• The term multiple organ dysfunction syndrome
(MODS) was established by an expert consensus
conference in 1992 to describe a continuum of
physiologic derangements and subsequent dynamic
alterations in organ function that may occur during a
critical illness.
• MODS is associated with widespread endothelial and
parenchymal cell injury because of hypoxic hypoxia, direct
cytotoxicity, apoptosis, immunosuppression and
coagulopathy.
• Four clinical stages describe a patient with developing MODS:
• 1. increasing volume requirements and mild respiratory
alkalosis, accompanied by oliguria, hyperglycaemia and
increased insulin requirements
• 2. tachypnoea, hypocapnia and hypoxaemia, with moderate
liver dysfunction and possible haematological abnormalities
• 3. developing shock with azotaemia, acid–base disturbances
and significant coagulation abnormalities
• 4. vasopressor dependence with oliguria or anuria, ischaemic
colitis and lactic acidosis.
• Cellular damage in various organs in patients who develop
MODS begins with the onset of local injury that is then
compounded by activation of the innate immune system. This
includes a combination of pattern recognition, receptor
activation and release of mediators at the microcellular level,
leading to episodes of hypotension or hypoxaemia and
secondary infections.
• The primary therapeutic goal for nursing and medical staff is
prompt, definitive control of the source of infection or pro-
inflammation and early recognition of preexisting factors that
may lead to subsequent organ damage away from the initial
site of injury. This preemptive therapy is instituted to maintain
adequate tissue perfusion and prevent the onset of MODS.
Recognition and response to early signs of clinical
deterioration are therefore important to minimize further
organ dysfunction.
 PATHOPHYSIOLOGY
• MODS is a state characterised by aberrant cellular
responses involving multiple organ systems and
sequential processes. The pathogenesis of MODS is
complex, simultaneously involving every cell type,
neuro-hormonal axis and organ system
• In brief, hypoxic hypoxia results from altered metabolicregulation of tissue
oxygen delivery which contributes to further organ dysfunction. Microcirculatory
injury as aresult of lytic enzymes, and vasoactive substances (nitric oxide,
endothelial growth factor), is compounded by the inability of erythrocytes to
navigate the septic microcirculation.
• Mitochondrial electron transport is affected by endotoxins in sepsis, nitric oxide
and TNF-alpha, leading to disordered energy metabolism. This causes cytopathic
or histotoxic anoxia (the inability to use oxygen, even when available).
• This context of impaired oxygen utilisation rather than delivery results from
diminished mitochondrial production of cellular energy (ATP), despite normal or
even supranormal intracellular PO2 levels.Cytopathic hypoxia appears resistant
to resuscitation measures, and this may ultimately worsen already-existing organ
dysfunction. During sepsis or ischaemia mitochondria respond by facilitating cell
death rather than the restoration of homeostasis
• Apoptosis is normal physiological programmed cell death and
is the main mechanism to eliminate dysfunctional cells.
Apoptosis involves chromatin condensation, membrane
blebbing, cell shrinkage and subsequent breakdown of cellular
components into apoptic bodies.
• This normally orderly process is deranged in critical illness,
leading to tissue or organ bed injury and MODS.
Proinflammatory cytokines released in sepsis may delay
apoptosis in activated macrophages and neutrophils, but in
other tissues, such as gut endothelium, accelerated apoptosis
occurs.
• Necrosis is a form of cell death characterised by cellular swelling and loss
of membrane integrity as a result of hypoxia or trauma. Necrosis has been
termed ‘cellular energy crisis’, and is unregulated resulting in loss of
membrane sodium/potassium/ATP-ase pumps.
• This loss leads to cell swelling, rupture and spillage of intracellular contents
into surrounding regions creating collateral damage. Necrosis therefore can
involve significant amounts of tissue and organ bed damage.
• Apoptosis differs from necrosis in that it does not seem to involve the
recruitment of inflammatory cells or mediators to complete its task.
Activation of an enzyme cascade systematically cleaves proteins, including
the cell’s nuclear DNA, with the end-result being death of the cell. This
requires energy from mitrochondria and if not available necrosis of the cell
occurs.
• In ischemia/reperfusion, endoplasmic reticulum loses its
ability to process proteins which induces the expression of
heat shock proteins, affecting transcription of proteins
necessary for organ specific functions. For example, liver cell
metabolism, renal cell function or cardiac cell contractility
may be affected.
• Cellular communication is also altered in MODS. Cells normally
communicate through highly interactive bidirectional networks. The
endothelium acts as a communication interface between cells, organs
and systems and is involved in orchestration of systemic responses,
including haemodynamic regulation, inflammation and coagulation;
oxygen and nutrient delivery; oxidative stress and sensing of
psychological stress and neuroendocrine alterations.
• In critical illness, endothelia release molecules that trigger the
immune and neuroendocrine systems to produce a generalised
inflammatory response. The combination of the pathophysiological
processes involved with the development of MODS, compensatory
mechanisms and the effect on target organs and systems is now
discussed.
 SYSTEMIC RESPONSE
• The complex host-response generated involves the
inflammatory immune systems, hormonal activation
and metabolic derangements, resulting in multiple
organ system involvement.
• These host-responses are initially adaptive to
maintain nutrient perfusion to the tissues, however
eventually organ systems become dysfunctional and
fail, and the body is no longer able to maintain
homeostasis.
• Initially, proinflammatory mediators are released locally to fight
foreign antigens and promote wound healing. Antiinflammatory
mediators are also released to downregulate the initial
response to the insult. If the local defence system is
overwhelmed, inflammatory mediators appear in the systemic
circulation and recruit additional leucocytes to the area of
damage. A whole-body stress response ensues, further
compounding the situation.
• If proinflammatory mediators and antiinflammatory response is
imbalanced, the patient may develop systemic inflammatory
response syndrome (SIRS) and subsequent immunological
dissonance of organ dysfunction.
• Regardless of the trigger event, lymphocytes (T cells, B cells,
natural killer cells) and macrophages are activated by
cytokines (cellular signalling agents) to commence the
inflammatory or anti-inflammatory response. A number of
Interleukins (IL) have been identified as key cytokines in
proinflammatory (e.g. IL-1, IL-6; and similar to tumour
necrosis factor alpha [TNFα] actions) or antiinflammatory (e.g.
IL-10, IL-6, IL-4) responses. The inflammatory response results
in clinical signs of hypoperfusion, culminating in shock
• Intracellular transcription factors, in particular nuclear factor kappa B
(NFκB), are important in innate and adaptive immunity,as they
regulate the transcription of genes involved in the inflammatory and
acute stress response, leading to expression of TNFα, interleukins and
tissue factor.NFκB therefore plays an important role in response
pathways in critical states including hypoxia, ischaemia,
haemorrhage, sepsis, shock and MODS.
• The inflammatory cascade activates a number of prostaglandins and
leucotrienes that also have pro- and antiinflammatory effects.
Thromboxane A2 plays a role in the acute phase, in part due to
stimulation of platelet aggregation, leading to microvascular
thrombosis and tissue injury;it may also play a role in pulmonary
bronchoconstriction and myocardial depression.
• INFLAMMATION
• Inflammation is part of innate immunity, a generic
response to injury, and is normally an excellent
mechanism to localize injury and promote
• Neutrophils,macrophages, natural killer cells,
dendrites, coagulation and complement are the
principal active components of the innate host
response.
• The classic signs of inflammation are:
• l pain
• l edema
• l erythema and heat (from vasodilation)
• l leucocyte accumulation and capillary leak
• EDEMA
• Edema occurs as a consequence of alterations to
tissue endothelium, with increased microvascular
permeability (‘capillary leak’).
• INFECTION AND IMMUNE RESPONSES
• Infection exists when there is one of the following: positive
culture, serology, presence of polymorphonuclear leucocytes
in a normally sterile body fluid except blood, and clinical
focus of infection such as perforated viscus or pneumonia.
• In sepsis, the most common sites of infection are the lungs
(34–54%), intra-abdominal organs (15–28%) and urinary
tract (5–10%).30,31 The incidence of bloodstream infections
is 30–40%, although one third of cases with septic shock
have negative blood cultures; one reason suggested for this
is antibiotic administration prior to sample collection
• The type of infecting organism has also changed over
time, with Gram-positive bacteria predominant,
accounting for at least one-third of pathogens in
septic shock; Gramnegative, fungal, viruses and
parasitic organisms are also involved.
• The increasing incidence of resistant organisms
partially as a result of the indiscriminate use of
antibiotics, is an ongoing concern.
• Tissue injury and the production of inflammatory
mediators lead to:
• l coagulation via the expression of tissue factor and
factor VIIa complex (tissue factor pathway; the
primary cascade for initiation of coagulation;
previously termed the ‘extrinsic’ pathway)
• l coagulation amplification via factors Xa and Va,
leading to massive thrombin formation and fibrin
clots (common coagulation pathway).