Sepsis Clinical Trial
Official title:
Application of Stimulated Immune Response Change to Predict Outcome of Patient With Severe Sepsis
Persistence of a marked compensatory anti-inflammatory innate immune response after an insult
is termed immunoparalysis. There is no biomarker available to determine the immune status of
patient. Thus, the need for early and definite diagnosis of immune status of patient with
sepsis, as well as the identification of patients at risk of evolving with severe organ
dysfunctions, is crucial.
Most important of all, speed is the key to survival. Therefore, it of crucial importance to
identify which patient characteristic determines the poor prognosis. Early intervention can
improve the prognosis. Investigators foresee an urgent need to identify predictors for
mortality in severe sepsis, including clinical factors or immune status. Recently, the PIRO
model has been proposed as a way of stratifying septic patients according to their
Predisposing condition, the severity of Infection, the Response to therapy and the degree of
Organ dysfunction. The immune status may be associated with above model. However, there is
paucity data addressing this issue. In this study, investigators will also analyze the
progression of patient condition during treatment and the associated immune status change. In
the future, Investigators hope the determination of immune status may contribute to this
model of classification rather than just being used as prognostic markers. Despite the
advances in the knowledge of the basic processes that trigger and sustain the systemic
inflammatory response in sepsis, the search for a "magic bullet" to treat this syndrome has
been frustrating. The incidence of severe sepsis and septic shock still remains quite high,
as does its mortality, which has decreased very little over the past decades.
Binding of TLRs to epitopes on microorganisms stimulates intracellular signaling, increasing
transcription of proinflammatory molecules such as tumor necrosis factor α (TNF-α) and
interleukin-1β, as well as antiinflammatory cytokines such as interleukin-10. Macrophage
dysfunction, as a component of immune suppression seen during trauma and sepsis, appears to
be one of the contributing factors to morbidity and mortality. Critically ill patients
demonstrating prolonged, severe reductions in monocyte HLA-DR expression or ex vivo tumor
necrosis factor alpha production are at high risk for nosocomial infection and death. Most
septic patients have decreasing cytokine levels at the time of treatment, suggesting a
transition from a hyperinflammatory to a hypo-inflammatory state. Immunoparalysis is a
potentially reversible risk factor for development of nosocomial infection in multiple organ
dysfunction syndrome. Whole-blood ex vivo TNF alpha response is a promising marker for
monitoring this condition. Investigators call it as "stimulated immune response". Toll-like
receptors (TLRs) are a recently described family of immune receptors involved in the
recognition of pathogen-associated molecular patterns (PAMPs). Lipopolysaccharide (LPS) is
present in the outer membranes of Gram-negative bacteria and has been demonstrated to be
responsible for the development of GNB-associated sepsis. Recognition of bacterial LPS by
macrophages is a key component of host defense against infection by Gram-negative bacteria. A
monocyte which encounters LPS should vigorously produce proinflammatory cytokines regardless
of whether or not it has been exposed to LPS in the past. Sepsis induces suppression of
macrophage function as determined by a reduction of pro-inflammatory cytokine production upon
re-exposure to lipopolysaccharide (LPS) in vitro. Whether further ground can be gained by
manipulating innate immunity is an important question waiting to be answered. Several
strategies to enhance innate immunity have been tried in normal subjects, including using
granulocyte colony-stimulating factor to increase the number and activation state of
circulating neutrophils, and IFN-γ to enhance macrophage dependent immunity. Investigators
will use this characteristic to assess patient's stimulated immune response. In addition,
differences in the nature of the initiating agent causing sepsis and the lack of
co-morbidities in the animal models probably contribute to some of the differences in animal
studies and clinical trials in sepsis. Investigators need to address these important issues
and work toward promoting immunologic homeostasis in the ICU. Here investigators performed a
systematic study aimed at evaluating
1. The diagnostic accuracy of stimulated immune response for predicting mortality;
2. Whether trend change in stimulated immune response more useful for above prediction;
3. Whether stimulated immune response can predict patients at risk of evolving with severe
organ dysfunctions (the presence or development of severe sepsis or progression of organ
dysfunctions within a 72-hr time period from biomarker checked along with treatment)
;
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