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564 P R I N C I P L E S A N D P R A C T I C E O F C R I T I C A L C A R E

Coagulation Activated protein C
Endothelium cascade Activated protein C

Tissue Factor
Factor VIlla
IL-6 PAI-1
IL-1 Inactivation
TNF-
Monocyte Factor Va Inactivation
Inhibition Protein C Inactivation Suppressed
Activated
fibrinolysis
THROMBIN TAFI
Neutrophil Fibrin
Inhibition IL-6 Reduction

Tissue factor of rolling Activated Fibrin clot
protein C
Inflammatory response Thrombotic response Fibrinolytic response
FIGURE 21.2 Tissue factor pathway (Courtesy Eli to Infection to Infection to Infection
Lilly and Company).

hospital non-survivors than in survivors. Using regression and fail, and the body is no longer able to maintain
analysis, maximum plasma DNA was an independent homeostasis (see Figure 21.2).
16
predictor of hospital mortality. 11
Initially, proinflammatory mediators are released locally
Other cellular organelles may also exhibit pathological to fight foreign antigens and promote wound healing.
reactions in MODS. In ischaemia/reperfusion, endoplas- Antiinflammatory mediators are also released to down-
14
mic reticulum loses its ability to process proteins which regulate the initial response to the insult. If the local
7
induces the expression of heat shock proteins, affecting defence system is overwhelmed, inflammatory mediators
transcription of proteins necessary for organ specific func- appear in the systemic circulation and recruit additional
tions. For example, liver cell metabolism, renal cell func- leucocytes to the area of damage. A whole-body stress
7
tion or cardiac cell contractility may be affected. This response ensues, further compounding the situation.
has led to the controversial concept of a mode of hiberna- If proinflammatory mediators and antiinflammatory
tion of cells at the expense of survival of the whole response is imbalanced, the patient may develop systemic
organism. 7 inflammatory response syndrome (SIRS) and subsequent
15
immunological dissonance of organ dysfunction. 2,15,16
Cellular communication is also altered in MODS. Cells
normally communicate through highly interactive bidi- Regardless of the trigger event, lymphocytes (T cells, B
rectional networks. The endothelium acts as a communi- cells, natural killer cells) and macrophages are activated
cation interface between cells, organs and systems and is by cytokines (cellular signalling agents) to commence the
involved in orchestration of systemic responses, includ- inflammatory or anti-inflammatory response. A number
ing haemodynamic regulation, inflammation and coagu- of Interleukins (IL) have been identified as key cytokines
lation; oxygen and nutrient delivery; oxidative stress and in proinflammatory (e.g. IL-1, IL-6; and similar to tumour
sensing of psychological stress and neuroendocrine alter- necrosis factor alpha [TNFα] actions) or antiinflamma-
ations. In critical illness, endothelia release molecules tory (e.g. IL-10, IL-6, IL-4) responses. The inflammatory
7
that trigger the immune and neuroendocrine systems to response results in clinical signs of hypoperfusion, culmi-
produce a generalised inflammatory response. The com- nating in shock.
7
bination of the pathophysiological processes involved Intracellular transcription factors, in particular nuclear
with the development of MODS, compensatory mecha- factor kappa B (NFκB), are important in innate and adap-
nisms and the effect on target organs and systems is now tive immunity, 17,18 as they regulate the transcription of
discussed. genes involved in the inflammatory and acute stress
SYSTEMIC RESPONSE response, leading to expression of TNFα, interleukins and
18,19
NFκB therefore plays an important role
tissue factor.
After an overwhelming incident such as trauma, sepsis or in response pathways in critical states including hypoxia,
18,20,21
non-infectious inflammation, a complex range of inter- ischaemia, haemorrhage, sepsis, shock and MODS.
related reactions occurs that result in a cascade of The inflammatory cascade activates a number of prosta-
responses. The complex host-response generated involves glandins and leucotrienes that also have pro- and anti-
the inflammatory immune systems, hormonal activation inflammatory effects. Thromboxane A2 plays a role in the
and metabolic derangements, resulting in multiple organ acute phase, in part due to stimulation of platelet aggre-
system involvement. 12,13 These host-responses are initially gation, leading to microvascular thrombosis and tissue
15
adaptive to maintain nutrient perfusion to the tissues, injury; it may also play a role in pulmonary broncho-
however eventually organ systems become dysfunctional constriction and myocardial depression.