Severe sepsis Infections and Infestations Septicaemia
Conditions
Interventions
Patients will receive a single tablet of either simvastatin 40 mg or identical placebo daily for 7 days (removed from protocol as of 10/10/2007: or until discharge from intensive care, whichever occur
Sponsors
Oxford Radcliffe Hospitals NHS Trust (UK)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Patients eligible for inclusion: 1. Those admitted to the Adult Intensive Care Unit at John Radcliffe Hospital, Royal Sussex County Hospital and the Royal Berkshire Hospital (last two centres added 10/10/2007) 2. Severe sepsis or develop severe sepsis whilst in intensive care Patients must be randomised and receive the first dose of simvastatin within 24 hours of first organ dysfunction to be included in the study.
Exclusion criteria
Exclusion criteria: Patients will be excluded from the trial if they: 1. Are receiving simvastatin or another statin prior to admission 2. Refuse consent or their relatives refuse assent 3. Are less than 16 years of age 4. Are included in another interventional study 5. Have a known adverse reaction to statins 6. Have an indication or contraindication to treatment with a statin, according to the treating physician 7. Are unable to receive enteral medications 8. Are receiving drugs known to interact with simvastatin 9. Have active liver disease 10. Have severe renal impairment (anuria) (removed from protocol as of 10/10/2007: creatinine >400 µmol.l^-1 or requirement for renal replacement therapy despite adequate haemodynamic resuscitation) 11. Are at high risk of rhabdomyolysis [multiple trauma, crush injuries, extensive burns, baseline creatinine kinase (CK) =five-times upper limit of normal (ULN)] 12. Have a history of known or suspected porphyria 13. Are unlikely to survive more than 24 hours 14. Are unable to speak English (or whose relatives are unable to speak English) and a suitable interpreter cannot be found
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The difference in plasma IL-6 concentration between simvastatin and placebo treated groups, on day 3 of treatment. Plasma IL-6 will be measured using a commercially available enzyme linked immunosorbent assay (ELISA) kit. This technique has been used in other recent studies and is familiar to research staff in the department. | — |
Secondary
| Measure | Time frame |
|---|---|
| Inflammatory markers Change in: 1. IL-6 concentration from baseline on days 1, 3 and 7 of treatment 2. C-Reactive Protein (CRP) concentration from baseline on days 1, 3 and 7 of treatment 3. Neutrophil count from baseline on days 1, 3 and 7 of treatment 4. Procalcitonin concentration from baseline on days 1, 3, and 7 of treatment Infective complications 1. Antibiotic-free days during intensive care unit (ICU) admission 2. Number of new/nosocomial infections defined using National Institutes of Health (NIH) definitions Safety 1. Number of patients withdrawn due to suspected drug reaction 2. Number of patients withdrawn due to muscle complications (CK =five-times ULN, myalgia, myositis, myopathy) 3. Number of patients withdrawn due to elevated plasma aspartate levels 4. Difference in mean plasma CK between groups Mortality 1. ICU mortality 2. 30-day mortality 3. Hospital mortality Disease severity 1. SOFA scores days 1, 3 and 7 2. Length of stay 3. ICU length of stay 4. Hospital stay Compliance/efficacy 1. Plasma low density lipoprotein (LDL) concentration 2. High density lipoprotein (HDL)/LDL ratio | — |
Countries
United Kingdom
Outcome results
None listed