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Background: The past several years have seen remarkable interactions existing between different cells and organs affected
advances in understanding the basic cellular and physiologic by the septic process. The intricate cross-talk provided by tem-
mechanisms underlying organ dysfunction and recovery relating poral changes in mediators, hormones, metabolites, neural sig-
to sepsis. Although several new therapeutic approaches have naling, alterations in oxygen delivery and utilization, and by
improved outcome in septic patients, the far-reaching potential of modifications in cell phenotypes underlines the adaptive and even
these new insights into sepsis-associated mechanisms is only coordinated processes beyond the dysregulated chaos in which
beginning to be realized. sepsis was once perceived. Many pathologic processes previously
Aim: The Brussels Round Table Conference in 2006 convened considered to be detrimental are now viewed as potentially pro-
>30 experts in the field of inflammation and sepsis to review tective. Applying systems approaches to these complex processes
recent advances involving sepsis and to discuss directions that will permit better appreciation of the effectiveness or harm of
the field is likely to take in the near future. treatments, both present and future, and also will allow develop-
Findings: Current understanding of the pathophysiology under- ment not only of better directed, but also of more appropriately
lying sepsis-induced multiple organ dysfunction highlights the timed, strategies to improve outcomes from this still highly lethal
multiple cell populations and cell-signaling pathways involved in condition. (Crit Care Med 2007; 35:2408–2416)
this complex condition. There is an increasing appreciation of KEY WORDS: sepsis; multiple organ failure; pathogenesis
R ecent years have seen remark- sions are summarized in this article, pro- sepsis and acute lung injury. As nuclear
able advances in our under- vided an opportunity to review recent in- factor-B regulates many of the proin-
standing of the basic cellular sights into pathophysiologic mechanisms flammatory mediators associated with or-
and physiologic mechanisms and to discuss likely future directions, gan dysfunction, associations between
underlying organ dysfunction and recov- both in terms of investigation and treat- enhanced nuclear factor-B activation
ery relating to sepsis. The far-reaching ments. (A full listing of Round Table par- and poor outcome are not unexpected (6,
potential of these new insights are only ticipants is located in the Appendix.) 7). Engagement of TLR4 with lipopoly-
just beginning to be realized as new ther- saccharide, or TLR2 with Gram-positive
apeutic approaches. The Brussels Round Genetics bacterial products such as peptidoglycan,
Table Conference in 2006, whose discus- result in enhanced nuclear translocation
Various genetic polymorphisms are of nuclear factor-B after activation of
linked to outcome in sepsis (1, 2). Al-
upstream kinases. The interleukin-1 re-
though relevant studies are often flawed
ceptor–associated kinase has an amino
From the Department of Medicine, University of in terms of sample size, categorization of
Alabama at Birmingham School of Medicine, Birming- acid change at position 532 in approxi-
clinical problems (particularly microbiol-
ham, AL (EA); and Bloomsbury Institute of Intensive mately 25% of white people. Septic pa-
ogy and site of infection), and accuracy in
Care Medicine, Wolfson Institute for Biomedical Re- tients with this interleukin-1 receptor–
search, and Department of Medicine, University Col- determining nucleotide substitutions,
associated kinase variant haplotype had
lege London, UK (MS). several have been sufficiently large to
increased nuclear factor-B activation,
Dr. Singer has consulted for Ferring Pharmaceuti- provide convincing associations between
cals, San Diego, CA, and Eli Lilly, Indianapolis, IN, and more time on ventilatory support, greater
genetic alterations and outcome (e.g.,
has received grant funding from the Medical Research vasopressor requirements, and an in-
Council/Wellcome Trust. Dr. Abraham has not dis- substitution of G to A in the tumor ne-
creased mortality rate (8).
closed any potential conflicts of interest. crosis factor-␣ promoter at position 308)
Supported, in part, by unrestricted educational (2, 3).
grants provided by Apex Bioscience, Chapel Hill, NC; The Toll-like receptor (TLR) family in-
Eli Lilly, Indianapolis, IN; GlaxoSmithKline, Brentford,
Mediators of Cellular Activation
duces cellular activation after engage- in Sepsis
UK; and Hutchinson Technology, Hutchinson, MN. The
2006 Brussels Round Table Conference, whose pro- ment with microbial products such as
ceedings are reported in this article, was endorsed by lipopolysaccharide. Certain TLR4 recep- Cytokines. As multiple cell popula-
the European Society of Intensive Care Medicine, the tor polymorphisms are associated with tions are activated by microbial products,
Society of Critical Care Medicine, and the International decreased cellular activation and bron- it is not surprising that many proinflam-
Sepsis Forum.
For information regarding this article, E-mail: chial reactivity post–lipopolysaccharide matory and anti-inflammatory cytokines
m.singer@ucl.ac.uk exposure (4) and a predisposition to are involved in the host response to in-
Copyright © 2007 by the Society of Critical Care shock with Gram-negative organisms (5). fection. Several cytokines, including tu-
Medicine and Lippincott Williams & Wilkins Increased activation of the transcrip- mor necrosis factor-␣ and interleukin-1,
DOI: 10.1097/01.CCM.0000282072.56245.91 tion factor nuclear factor-B occurs in have been targeted by specific pharmaco-
crovasculature is compromised in sepsis, esis of renal failure, although most of the stimulates cell death pathways. However,
both before and after seemingly adequate evidence is derived from studies using as cell death is an uncommon phenome-
volume resuscitation. In humans, this under-resuscitated animal models (57). non in sepsis (41), this implies a meta-
has been directly shown in the sublingual Indirect evidence for changes in afferent bolic shutdown akin to hibernation that
circulation (47), although how these and efferent arteriolar tone within the could explain the functional yet minimal
changes relate to other organ beds re- kidney is drawn from the improved urine morphologic derangements seen in mul-
mains to be determined. output seen with vasopressin (acting on tiple organ failure. The increased venous
The severity of shock and a require- the efferent arteriole) as compared with oxygen saturations seen in resuscitated
ment for high-dose catecholamines are norepinephrine (acting primarily on the sepsis could be explained by a combina-
both important prognostic indicators. afferent arteriole) (58). tion of shunting and decreased mito-
Because early correction of hypotension There is an ongoing debate regarding chondrial utilization, whereas the main-
and tissue hypoperfusion has a major im- the contributions of microvascular dys- tained or elevated tissue oxygen tensions
pact on survival (53), the role of the cir- function and bioenergetic derangements recorded in various organ beds (60, 61)
culation in causing organ dysfunction is toward the development of multiple or- may represent a reduction in metabolic
vital, at least in the initial phases of the gan failure. Both can be combined within activity to match, or even exceed, the
disease. a paradigm that supports both findings. reduction in energy supply related to de-
Regional changes in blood flow are Microvascular shunting can lead to re- creased oxygen delivery or mitochondrial
well described in sepsis. There is a dis- gional areas of tissue hypoxia and re- dysfunction.
proportionate increase in metabolic re- duced generation of adenosine triphos- Metabolic Alterations. Considerable
quirements of the hepatosplanchnic area phate (59). In addition, decreased mito- attention has been paid to the role of
that often exceeds the increase in chondrial respiration can be related to hyperglycemia in the pathogenesis of or-
splanchnic blood flow (54). Variable ef- decreased expression of mitochondrial gan failure since the finding that inten-
fects have been reported on gut blood protein, hormonal influences, and direct sive insulin therapy with tight glycemic
flow, and studies suggest redistribution inhibition/damage from reactive nitrogen control resulted in survival benefit and
of blood away from the mucosa and mi- and oxygen species, despite adequate ox- prevention of further organ failure (62).
crovilli (55). Coronary perfusion does not ygenation (cellular dysoxia) (48). If met- Was the gain achieved mainly through
seem to be affected, despite coexisting abolic activity continues in excess of en- prevention of hyperglycemia or from pro-
myocardial depression (56). Renal hypo- ergy provision, adenosine triphosphate vision of additional insulin? The acute
perfusion is implicated in the pathogen- levels will fall below the threshold that toxicity of high glucose levels may be