Page 821 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

552 PART 5: Infectious Disorders

Infections caused by diverse microorganisms and involving many factor, nuclear factor kappa B (NFκB), is liberated from its inhibitor
different body sites may present as SIRS, which is a clinical syn- (IκB) and is able to dislocate into the cell nucleus and bind to DNA and
drome defined by (a) hyperthermia >38.0°C or hypothermia <36.0°C, modulate gene function. 13-15
(b) tachycardia ( heart rate >90/min), (c) tachypnea (respiratory rate During sepsis high levels of circulating DAMPs from invading micro-
<32 mm Hg), (d) leucocyto- organisms and/or damaged host tissue activate host immune cells, leading
>20 per minute) or hyperventilation (Pa CO 2
sis (WBC count >12.000/mm ) or leukopenia (WBC count <4.000/mm to inflammation characterized by the so-called cytokine storm. The early
3
3
or the presence of >10% immature neutrophils (bands) as defined by the phase of sepsis creates a proinflammatory environment, which is caused
American College of Chest Physicians/Society of Critical Care Medicine by the excessive activation of the host immune system by tissue damage
(ACCP/SCCM) Consensus Conference. SIRS driven by infection and/or severe infection, leading to severe dysregulation of various body
12
progresses along a continuum, described as sepsis, severe sepsis, septic systems. Central hubs of the inflammatory response during sepsis include
16
shock, and multisystem organ failure. Along this continuum the host’s the complement anaphylatoxin C5a, macrophage migration-inhibitory
immune system is operating at varying levels of activation, driven by factor (MIF), Toll-like receptor 4 (TLR4), high-mobility group box 1
complex interactions between the host and infectious agent(s). Host protein (HMGB1), interleukin-17A (IL-17A) but also the coagulation, the
immune response includes innate immune response that incorporates endocrine, the innate and adaptive immune, and the autonomic nervous
humoral and cellular components. The humoral component includes systems (adrenergic and cholinergic pathways). 3
release of cytokines, chemical substances that are directly toxic to invad- One of the significant molecules produced during sepsis is TNF, which
ing microbes or that act as mediators for immune cell activation. The propagates inflammatory pathways in multiple organ systems and also
cellular component includes circulating monocytes, tissue macrophages, plays a very important role in the activation of programmed cell death or
neutrophils, and lymphocytes. apoptosis. Also, interleukin (IL)-6 induces the production of acute phase
As a result of the actions of the innate immune system tissue mac- proteins in the liver, for example, C-reactive protein and fibrinogen.
rophages engulf and digest pathogens, produce cytokines, and present Another enzyme activated during sepsis is inducible nitric oxide synthase
pathogen particles (antigens) to lymphocytes, providing linkage to the (iNOS) leading to nitric oxide (NO) production and finally cyclic guano-
adaptive immune system. Neutrophils are attracted by chemokines sine monophosphate (cGMP) that leads to local and systemic vasodila-
and migrate to infected tissues where they phagocytose pathogens and tion, which correlates clinically to hypotension and shock. 17
secrete toxic substances such as reactive oxygen species (ROS) that Vasodilation and intravascular volume depletion from increased capil-
destroy invading microorganisms. Eosinophil and basophil granulocytes lary leak and external losses observed in early sepsis lead to underfilling of
secrete mediators creating an inflammatory milieu locally in the infected the heart and a low cardiac output, which in conjunction with myocardial
tissues and systemically in the circulation. As a consequence peripheral depression potentially causes an oxygen supply-demand imbalance in var-
leukocytosis is observed due to bone marrow stimulation with left shift of ious organ beds. Further imbalance may occur due to decreased oxygen
neutrophils (immature forms), dilation and leakage of the adjacent vessels delivery to the tissues by alterations of the microcirculation observed in
due to the action of vasoactive inflammatory mediators (NO) to facilitate patients with sepsis. Following adequate volume resuscitation patients
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the migration of inflammatory cells into the infected tissue, which leads typically exhibits high cardiac output hypotension, although during the
to efflux of plasma into tissues. Taken all together these processes lead to early hours to days of sepsis a propensity for continued loss of intravascu-
clinical signs of local inflammation, including redness (rubor), swelling lar volume persists often resulting in recurrent hypovolemia and requiring
(tumor), increased temperature (calor), and pain (dolor). the clinician managing the patient with septic shock to repeatedly return
Thus, infection may present with signs and symptoms of SIRS and to the question of whether additional intravascular volume is needed.
may resolve with the use of antibiotic and/or other supportive measures. Also, the inflammatory insult of sepsis appears capable of causing
Normally, the immune system controls local inflammation and structural and functional damage to the mitochondria. 19,20 Mitochondrial
eradicates invading pathogens. When local control mechanisms fail, dysfunction may be due to direct inhibition of the respiratory enzyme
however, systemic inflammation and then sepsis occurs. complexes from increased concentrations of nitric oxide and its metabo-
Cells of the innate immune system recognize molecular patterns of lite, peroxynitrite, and by direct damage from increased production of
most microbes including viruses, bacteria, fungi, and protozoa to pro- reactive oxygen species. Also, recent studies report a genetic down-
duce inflammation at the local level or systemically. Thus inflammation regulation of new mitochondrial protein formation, which is associated
starts when damage-associated molecular patterns (DAMPs) bind to with intramitochondrial defense mechanisms (glutathione, superoxide
immune cell pattern recognition receptors (PRRs), which rapidly initiate dismutase) being depleted or overwhelmed. 21,22
host defense responses. DAMPs are both pathogen-associated molecular The therapeutic window during this initial hyperinflammatory response
patterns (PAMPs) that are expressed by both invading and innocuous for initiating treatment with anti-inflammatory drugs is likely narrow
microorganisms and intracellular proteins or mediators that are released (<24 hours), after which a treatment to increase immune function may be
from damaged tissues and dying cells, which are known as alarmins such more beneficial. This may in part explain a number of negative therapeu-
as high mobility group box 1 and S100a proteins. PAMPs include lipopoly- tic trials directed at reducing inflammatory mediators in septic patients.
saccharides (LPS, endotoxin) contained in the cell wall of gram-negative Evidence from several studies has shown that certain anti-inflammatory
bacteria, lipoteichoic acid and peptidoglycan from gram-positive bacteria, pathways seem activated very early in septic patients. 23-25 The systemic anti-
bacterial DNA, or viral RNA. PRRs include Toll-like receptors (TLRs), inflammatory response may be useful for the attenuation of deleterious
intracellular NOD proteins, and peptidoglycan recognition proteins. systemic proinflammatory effects and the concentration and compartmen-
The recognition, binding, and interaction of DAMPs (eg, LPS) by talization of the inflammation at the site of infection. 26
PRRs (eg, TLRs) located on the immune cell surface result in signal However, when anti-inflammatory mechanisms dominate, the immune
transduction and in turn to a complex intracellular cascade of enzymes system is depressed, a condition termed immunoparesis or immunoparal-
(kinases), which activate proteins. These proteins activate additional ysis, and the body’s susceptibility to nosocomial infections and the reacti-
intracellular pathways leading to activation of transcription factors vation of dormant pathogens such as cytomegalovirus is increased. 27,28 The
within the cell nucleus binding to DNA, thus activating hundreds of state of immunoparesis is associated with declining levels of numerous
specific genes coding for proteins, which are increased during the hormones, a reduced metabolic rate, and in some tissues frank bioener-
inflammatory process in a time-dependent fashion. For example, in getic failure. The observation of these responses to infection has raised the
gram-negative sepsis LPS binds to TLR4 and CD 14 activating myeloid hypothesis that immune system stimulation during this phase of sepsis
differentiation protein (MyD)-88, which then activates interleukin-1 could be beneficial. 29,30 Similar to the notion of SIRS, this phase of the
receptor–associated kinase (IRAK), which, in turn, stimulates the tumor course of sepsis has been termed the compensatory anti-inflammatory
necrosis factor receptor–associated factor (TRAF) and, consequently, response syndrome (CARS). Interestingly, it seems most deaths related to
the TRAF-associated kinase (TAK). As a result, the nuclear transcription sepsis occur during this phase.

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