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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT02887274
Other study ID # CMRPG8B1073
Secondary ID
Status Recruiting
Phase
First received
Last updated
Start date July 2013
Est. completion date December 2018

Study information

Verified date August 2018
Source Chang Gung Memorial Hospital
Contact Cheryl Huang, Bachelor
Phone 886077317123
Email cheryl60286@gmail.com
Is FDA regulated No
Health authority
Study type Observational

Clinical Trial Summary

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.


Description:

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)


Recruitment information / eligibility

Status Recruiting
Enrollment 300
Est. completion date December 2018
Est. primary completion date December 2018
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility Inclusion Criteria:

- Severe sepsis

- Septic shock

Exclusion Criteria:

- Patients are < 18 yrs

- Patients are immunocompromised (treatment with corticosteroids >1 mg/kg equivalent prednisone)

- Bone marrow or organ transplant recipients,

- Leucopenia [white blood cells count< 109/L] or neutropenia [polymorphonuclear granulocyte count <0.5 109/L]

- Hematologic malignancy

Study Design


Related Conditions & MeSH terms


Locations

Country Name City State
Taiwan Chang Gung Memorial Hospital Kaohsiung

Sponsors (1)

Lead Sponsor Collaborator
Chang Gung Memorial Hospital

Country where clinical trial is conducted

Taiwan, 

References & Publications (10)

Frazier WJ, Hall MW. Immunoparalysis and adverse outcomes from critical illness. Pediatr Clin North Am. 2008 Jun;55(3):647-68, xi. doi: 10.1016/j.pcl.2008.02.009. Review. — View Citation

Hall MW, Knatz NL, Vetterly C, Tomarello S, Wewers MD, Volk HD, Carcillo JA. Immunoparalysis and nosocomial infection in children with multiple organ dysfunction syndrome. Intensive Care Med. 2011 Mar;37(3):525-32. doi: 10.1007/s00134-010-2088-x. Epub 201 — View Citation

Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G; SCCM/ESICM/ACCP/ATS/SIS. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med. 2003 Apr;31(4):1250-6. Review. — View Citation

Marshall JC, Charbonney E, Gonzalez PD. The immune system in critical illness. Clin Chest Med. 2008 Dec;29(4):605-16, vii. doi: 10.1016/j.ccm.2008.08.001. Review. — View Citation

Neveu H, Kleinknecht D, Brivet F, Loirat P, Landais P. Prognostic factors in acute renal failure due to sepsis. Results of a prospective multicentre study. The French Study Group on Acute Renal Failure. Nephrol Dial Transplant. 1996 Feb;11(2):293-9. — View Citation

Nguyen HB, Corbett SW, Steele R, Banta J, Clark RT, Hayes SR, Edwards J, Cho TW, Wittlake WA. Implementation of a bundle of quality indicators for the early management of severe sepsis and septic shock is associated with decreased mortality. Crit Care Med — View Citation

Phua J, Koh Y, Du B, Tang YQ, Divatia JV, Tan CC, Gomersall CD, Faruq MO, Shrestha BR, Gia Binh N, Arabi YM, Salahuddin N, Wahyuprajitno B, Tu ML, Wahab AY, Hameed AA, Nishimura M, Procyshyn M, Chan YH; MOSAICS Study Group. Management of severe sepsis in — View Citation

Sakr Y, Burgett U, Nacul FE, Reinhart K, Brunkhorst F. Lipopolysaccharide binding protein in a surgical intensive care unit: a marker of sepsis? Crit Care Med. 2008 Jul;36(7):2014-22. doi: 10.1097/CCM.0b013e31817b86e3. — View Citation

Shiramizo SC, Marra AR, Durão MS, Paes ÂT, Edmond MB, Pavão dos Santos OF. Decreasing mortality in severe sepsis and septic shock patients by implementing a sepsis bundle in a hospital setting. PLoS One. 2011;6(11):e26790. doi: 10.1371/journal.pone.002679 — View Citation

Vincent JL, Abraham E, Annane D, Bernard G, Rivers E, Van den Berghe G. Reducing mortality in sepsis: new directions. Crit Care. 2002 Dec;6 Suppl 3:S1-18. Epub 2002 Dec 5. Review. — View Citation

Outcome

Type Measure Description Time frame Safety issue
Other Whether stimulated immune response can predict patients at risk of evolving with severe organ dysfunctions 4 weeks, up to 24 weeks
Primary The diagnostic accuracy of stimulated immune response for predicting mortality 4 weeks, up to 24 weeks
Secondary Whether trend change in stimulated immune response more useful for prediction mortality 4 weeks, up to 24 weeks
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