Impact of Hydrocortisone Administration on White Blood Cell Gene Expression in Patients With Severe Sepsis

Sepsis Clinical Trial

Official title:

Pilot Study of White Blood Cell Gene Expression in Critically Ill Patients With Severe Sepsis and Relative Adrenal Insufficiency After Hydrocortisone Administration

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00185783
• Other study ID #: 95230
• Secondary ID: Stanford IRB Num
• Status: Completed
• Phase: Phase 1
• First received: September 12, 2005
• Last updated: April 7, 2011
• Start date: March 2005
• Est. completion date: November 2006

Study information

• Verified date: April 2011
• Source: Stanford University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Observational

Clinical Trial Summary

The purpose of this pilot study is to (1) examine the changes in gene expression in patients who suffer from severe sepsis and whose shock (inadequate oxygen delivery to vital organs) state does not respond to fluid and vasopressor administration, (2) to show that our sampling method of isolating RNA provides reliable and consistent data, (3) provide a basis for future gene expression studies in critically ill patients

Description:

Severe sepsis is characterized by inadequate perfusion of vital organs due to infection. More than 750,000 cases of severe sepsis occur each year in the United States. Mortality among patients with severe sepsis ranges from 7% to 50%. Initiation of antibiotic therapy within the first hour of diagnosis as well as fluid resuscitation and hemodynamic stabilization are primary goals of therapy.

Steroid administration has been shown to improve outcome in the subset of severe sepsis patients suffering from relative adrenal insufficiency. Although initial studies using high dose short course steroid therapy did not demonstrate efficacy, more recent studies of low dose longer duration hydrocortisone administration demonstrated a significant reduction in mortality at 28 days. The mechanism by which steroid administration affords protection is unclear. We hypothesize that steroid administration changes white blood cell gene and protein expression in severe sepsis patients from an immuno-inflammatory profile to a pattern consistent with healing.

Our first specific aim is to obtain plasma and total cellular RNA from leukocytes in the blood of ten patients admitted to Stanford Medical Center with the diagnosis of severe sepsis and adrenal insufficiency. Significant and distinct variations in whole blood leukocyte gene expression patterns occur depending upon the method of RNA isolation. We will attempt to demonstrate that our sampling method provides reliable and consistent data.

Our second specific aim is to begin an analysis of gene expression patterns in white blood cells before and after steroid administration in patients suffering from severe sepsis with relative adrenal insufficiency. We will use a protocol for assessment of gene expression that was developed by members of our research team.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 10
• Est. completion date: November 2006
• Est. primary completion date: November 2006
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Admission Diagnosis of Sepsis

• Evidence of Relative Adrenal Insufficiency

• Hypotension (Mean Arterial Pressure less than 60 mm Hg) Refractory to a. Fluid Resuscitation b. Dopamine infusion (greater than 5 micrograms/kg/min) c. Phenylephrine infusion (greater than 1 microgram/kg/min)

Exclusion Criteria:

• Use of Immunosuppressant Medications

• Immune Compromised Due to Disease (e.g., HIV infection)

• Transfusion of Blood Products within the past 7 Days

• Use of Cytokine Therapy (i.e., G-CSF)

• History of Bone Marrow Transplantation

Study Design

Observational Model: Cohort, Time Perspective: Prospective

Related Conditions & MeSH terms

• Adrenal Insufficiency
• Relative Adrenal Insufficiency
• Sepsis
• Toxemia

Intervention

Drug:
• Hydrocortisone Administration (Standard of Care Therapy)

Locations

Country	Name	City	State
United States	Stanford University Medical Center	Stanford	California

Sponsors (3)

Lead Sponsor	Collaborator
Stanford University	University of Colorado, Denver, University of Toronto

Country where clinical trial is conducted

United States, 

References & Publications (7)

Annane D, Sébille V, Charpentier C, Bollaert PE, François B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troché G, Chaumet-Riffaud P, Bellissant E. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002 Aug 21;288(7):862-71. Erratum in: JAMA. 2008 Oct 8;300(14):1652. Chaumet-Riffaut, Philippe [corrected to Chaumet-Riffaud, Philippe]. — View Citation

Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, Gea-Banacloche J, Keh D, Marshall JC, Parker MM, Ramsay G, Zimmerman JL, Vincent JL, Levy MM. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Intensive Care Med. 2004 Apr;30(4):536-55. Epub 2004 Mar 3. — View Citation

Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, Gea-Banacloche J, Keh D, Marshall JC, Parker MM, Ramsay G, Zimmerman JL, Vincent JL, Levy MM; Surviving Sepsis Campaign Management Guidelines Committee. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004 Mar;32(3):858-73. Review. Erratum in: Crit Care Med. 2004 Oct;32(10):2169-70. Crit Care Med. 2004 Jun;32(6):1448. Dosage error in article text. — View Citation

Dellinger RP. Cardiovascular management of septic shock. Crit Care Med. 2003 Mar;31(3):946-55. Review. — View Citation

Spiegelman JI, Mindrinos MN, Oefner PJ. High-accuracy DNA sequence variation screening by DHPLC. Biotechniques. 2000 Nov;29(5):1084-90, 1092. — View Citation

Steinmetz LM, Mindrinos M, Oefner PJ. Combining genome sequences and new technologies for dissecting the genetics of complex phenotypes. Trends Plant Sci. 2000 Sep;5(9):397-401. — View Citation

Wang QT, Piotrowska K, Ciemerych MA, Milenkovic L, Scott MP, Davis RW, Zernicka-Goetz M. A genome-wide study of gene activity reveals developmental signaling pathways in the preimplantation mouse embryo. Dev Cell. 2004 Jan;6(1):133-44. — View Citation