Mitochondrial Function of Immune Cells in Sepsis

NCT01600989 | Completed

• 1 other identifier: 015/10
• Study Type: observational
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Shock, Septic

Keywords

shock septic; monocytes; lymphocytes; mitochondria; interleukins; Tumor Necrosis Factor-alpha; Hypoxia-Inducible Factor 1, alpha Subunit

Outcome Measures

Primary Outcomes (1)

• Mitochondrial function of immune cells

  At the time of ICU admission

Secondary Outcomes (5)

• Change from baseline in mitochondrial function of immune cells

  24 hours after ICU admission

• Change from baseline in mitochondrial function of immune cells

  48 hours after ICU admission

• Change from baseline in mitochondrial function of immune cells

  At time of resoltion of sepsis, expected to be after 5 days

• Levels of cytokines (of IL-1, IL-6, IL-10 and TNFa)

  At ICU admission, 24h and 48h after admission, & at time of resolution of sepsis (expected to be after 5 days)

• ICU mortality

  At time of dismissal from ICU, expected to be after 7 days

Study Arms (2)

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

Healthy volunteers

Healthy volunteers

Other: blood sampling

Interventions

blood sampling OTHER

Blood samples will be taken at ICU admission, and 24h and 48h after admission, and at time of resolution of sepsis

Patients with severe sepsis / septic shock

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

30 patients with severe sepsis or septic shock at ICU admission

You may qualify if:

• Adult patients (age \> 18years)
• 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.

You may not qualify if:

• Patients with any type of chronic infectious, inflammatory or autoimmune diseases
• Patients after hematopoietic or solid organ transplantation
• Patients receiving long term treatment with steroids or other immunosuppressive agents

Sponsors & Collaborators

• Insel Gruppe AG, University Hospital Bern: lead

Study Sites (1)

Department of Intensive Care Medicine, Bern University Hospital (Inselspital) and University of Bern

Bern, 3010, Switzerland

Location

Biospecimen

Retention: SAMPLES WITH DNA

Serum, isolated B-cells, T-cells, Monocytes

MeSH Terms

Conditions

Shock, Septic

Interventions

Blood Specimen Collection

Condition Hierarchy (Ancestors)

Sepsis; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Tobias Merz

  Department of Intensive Care Medicine, Bern University Hospital (Inselspital) and University of Bern

  STUDY CHAIR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 11, 2012
• First Posted: May 17, 2012
• Study Start: May 1, 2012
• Primary Completion: October 1, 2013
• Study Completion: November 1, 2013
• Last Updated: April 25, 2014

Record last verified: 2014-04

Locations

CH (1)