Mitochondrial Function of Immune Cells in Sepsis (MitoSepsis)
Introduction: Evidence suggests that sepsis and septic shock severely impair mitochondria and that the resulting mitochondrial dysfunction is related to the severity and outcome of the resulting organ dysfunction. In sepsis mitochondrial abnormalities - biochemical and ultrastructural - have been recognized in multiple organs, including liver, kidney, skeletal and heart muscle tissue and blood cells. Circulating immune cells play an important role in the pathophysiology of sepsis. Stimulation of the immune system alters the energy requirements of immune cells; down-regulation of immune-cell activity has been associated with prolonged sepsis and unfavourable outcome. The aim of the project is to comprehensively investigate changes in mitochondrial function of immune cells in patients with severe sepsis and septic shock. The following main hypotheses will be evaluated:
- Severe sepsis and septic shock leads to increased energy requirements of immune cells and to an increase in mitochondrial enzyme activities and energy production.
- Changes of mitochondrial function in human immune cells are associated with alterations in clinical and laboratory markers of severity of sepsis.
- Prolonged sepsis and unfavourable outcome is associated with down regulation of mitochondrial function.
Methods: A total of 30 adult patients admitted to the intensive care unit (ICU) due to severe sepsis or septic shock will be included in the study; 30 healthy volunteers serve as controls. Patients with any type of chronic infectious, inflammatory or autoimmune diseases, after transplantations or receiving immunosuppressive agents are excluded.
Collected baseline characteristics include patient demographics, diagnosis and severity of illness scores at the time of admission. Daily collected follow up data include clinical and laboratory parameters of organ dysfunction, use of vasopressors/inotropes, use of antibiotics, use of steroids and results of microbiological cultures/stains.
Negative identification and isolation of monocytes, B cells and CD4 T cells will be performed daily from ICU admission to discharge using an antibody-antigen mediated immunomagnetic cell isolation procedure that depletes all blood cells except the specific target cells. Mitochondrial function of immune cells will be assessed by measurement of mitochondrial complex activity for complexes I to IV by a standard titration protocol. Additionally, the levels of pro- and anti-inflammatory cytokines (Interleukin (IL)-1, IL-6, IL-10, TNF-α) will be assessed throughout the stay in the ICU. For comparison mitochondrial function of of monocytes, B cells and CD4 T cells and cytokine levels will be measured in a group of 10 healthy volunteers.
Analysis plan: Changes in mitochondrial function of immune cells over time compared to a healthy control group and during the course of severe sepsis and septic shock is the main outcome parameter of this study. Assessed predictors are determined by the severity of the underlying septic condition and include clinical and laboratory evidence for dysfunction of vital organ systems and changes in levels of inflammatory and anti-inflammatory cytokines.
|Study Design:||Observational Model: Cohort
Time Perspective: Prospective
|Official Title:||Mitochondrial Function of Immune Cells in Severe Sepsis and Septic Shock - a Prospective Observational Cohort Study|
- Mitochondrial function of immune cells [ Time Frame: At the time of ICU admission ] [ Designated as safety issue: No ]
- Change from baseline in mitochondrial function of immune cells [ Time Frame: 24 hours after ICU admission ] [ Designated as safety issue: No ]
- Change from baseline in mitochondrial function of immune cells [ Time Frame: 48 hours after ICU admission ] [ Designated as safety issue: No ]
- Change from baseline in mitochondrial function of immune cells [ Time Frame: At time of resoltion of sepsis, expected to be after 5 days ] [ Designated as safety issue: No ]
- Levels of cytokines (of IL-1, IL-6, IL-10 and TNFa) [ Time Frame: At ICU admission, 24h and 48h after admission, & at time of resolution of sepsis (expected to be after 5 days) ] [ Designated as safety issue: No ]
- ICU mortality [ Time Frame: At time of dismissal from ICU, expected to be after 7 days ] [ Designated as safety issue: No ]
Biospecimen Retention: Samples With DNA
Serum, isolated B-cells, T-cells, Monocytes
|Study Start Date:||May 2012|
|Estimated Study Completion Date:||June 2014|
|Estimated Primary Completion Date:||December 2013 (Final data collection date for primary outcome measure)|
Patients with severe sepsis / septic shock
30 Adult patients (age > 18years), with severe sepsis or septic shock as defined by the 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference guidelines at the time of admission to ICU.
Other: blood sampling
Blood samples will be taken at ICU admission, and 24h and 48h after admission, and at time of resolution of sepsis
Other: blood sampling
Blood samples will be taken twice at a 7 day interval
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|Contact: Tobias M Merzfirstname.lastname@example.org|
|Department of Intensive Care Medicine, Bern University Hospital (Inselspital) and University of Bern||Not yet recruiting|
|Bern, Switzerland, 3010|
|Contact: Siamak Djafarzadeh 0041 31 632 21 11 email@example.com|
|Principal Investigator: Tobias M Merz|
|Sub-Investigator: Siamak Djafarzadeh|
|Sub-Investigator: Stephan M Jakob|
|Sub-Investigator: Jukka Takala|
|Study Chair:||Tobias Merz||Department of Intensive Care Medicine, Bern University Hospital (Inselspital) and University of Bern|