Regulation of Endocrine, Metabolic, Immune and Bioenergetic Responses in Sepsis
Regulation of Endocrine, Metabolic, Immune and Bioenergetic Responses in Sepsis
The hypothesis of this study is that bioenergetic failure in human sepsis, related to
 endocrine, metabolic and mitochondrial dysfunction, is a major determinant of defective host
 immune responses, increasing disease severity and risk of death. The objectives of this study
 are to examine the relationship between the severity of illness, and temporal changes in the
 activity of endocrine, metabolic and bioenergetic pathways, and consequent immune dysfunction
 in critically ill patients with sepsis and multiple organ failure in the Intensive Care Unit.
The objectives of this study are to examine the relationship between the severity of illness,
 and temporal changes in the activity of endocrine, metabolic and bioenergetic pathways, and
 consequent immune dysfunction in critically ill patients with sepsis and multiple organ
 failure in the Intensive Care Unit.

 This study will be undertaken using sequential blood sampling (until ICU discharge) and
 muscle biopsies (to a maximum of 5) in critically ill patients (a) with or (b) without sepsis
 plus a comparator group undergoing elective orthopaedic surgery. A variety of hormonal,
 cytokine, immune and mitochondrial measures wil lbe then made to assess whether any
 relationship exists between alterations in these different pathways, and whether eventual
 survivors and non-survivors can be distinguished.
Inclusion Criteria:

 -  Group 1: healthy control patients Patients undergoing elective total hip replacement
 will be eligible for enrollment in Group 1 after written informed consent has been
 obtained. Only 1 blood sample and 1 fat and muscle biopsy will be taken
 intra-operatively

 Group 2: non-septic, critically ill patients Patients requiring intensive care within 48
 hours of admission to hospital from home, for a non-septic/non-inflammatory pathology will
 be eligible for enrollment in the study after informed agreement has been obtained from the
 closest family member (see Consent below). At enrolment, Group 2 patients must have
 received mechanical ventilation commencing within 48 hours of admission to intensive care,
 should be likely to require mechanical ventilation for at least 48 hours, and must not
 fulfil the 2001 International Sepsis Definition Conference criteria for severe sepsis or
 septic shock

 Group 3: patients with severe sepsis or septic shock Patients requiring intensive care
 within 48 hours of admission to hospital from home, and evidence of severe sepsis (organ
 dysfunction due to infection) or septic shock as defined by the 2001 International Sepsis
 Definition Conference criteria, will be eligible for enrollment in the study after informed
 agreement has been obtained from their next-of-kin. Patients with underlying chronic liver
 disease are excluded from this group, and will be enrolled separately into Group 4.

 Group 4: patients with severe sepsis and underlying chronic liver disease Patients
 requiring intensive care admission, with underlying Child-Pugh Class A or B, biopsy-proven
 liver cirrhosis, within 24 h of the onset of severe sepsis (organ dysfunction due to
 infection) or septic shock as defined by the 2001 International Sepsis Definition
 Conference criteria), will be eligible for enrollment in the study after informed agreement
 has been obtained from their next-of-kin

 Exclusion Criteria:

 - Age <18 years

 Child-Pugh Class C liver disease

 Chronic dialysis-dependent renal failure

 Hepatitis B or C infection

 Immunosuppression (e.g. haematological malignancy, neutropenia, HIV infection)

 Immunosuppressive drug therapy within past 6 months

 Patient receiving oral or IV steroid therapy for greater than 1 week, within 6 months prior
 to ICU admission

 Muscle biopsy contraindicated in presence of coagulopathy (INR >2, platelet count <
 30,000)*

 Next-of-kin declines agreement / patient declines consent

 Patient receiving thyroid hormone therapy prior to ICU admission

 *This does not exclude enrolment into the study, particularly in the case of Group 4
 patients who frequently develop a coagulopathy as part of their underlying liver
 dysfunction