Pre-emptive or early adjuvant simvastatin therapy in elderly patients with infection and sepsis

Abstract

BackgroundThe incidence, severity, morbidity, and mortality associated with sepsis increases with age, and statin treatment improves outcomes during infection. We characterised the effect of age and acute infection on key neutrophil functions, assessed whether physiologically relevant doses of simvastatin altered neutrophil functions, and, if benefits were seen, when statins could be used during septic infection. MethodsNeutrophils extracted from the whole blood of healthy volunteers and patients with a lower respiratory tract infection (LRTI), pneumonia, or sepsis were assessed for migratory accuracy, phagocytosis, and production of neutrophil extracellular traps (NET) before and after in-vitro treatment with simvastatin. In addition, neutrophil function was assessed in healthy elderly volunteers, who were receiving simvastatin (80 mg/day for 2 weeks) or placebo as part of a crossover, double-blind, randomised controlled trial. Here we present data for neutrophil migration. FindingsNeutrophils from healthy volunteers (n=70, aged 21–94 years) showed preserved chemokinesis (random movement) but reduced chemotaxis (directed migration) (r2=−0·48, p<0·0001) towards the chemo-attractant interleukin 8. Neutrophil chemotaxis, measured as mean difference (MD) in migration, decreased in volunteers aged over 65 years (comparison ≤35 years vs ≥65, MD 1·25 μm/min, p=0·02). Elderly patients with a LRTI (n=10, age 24–73), pneumonia (n=5, 66–73), or severe sepsis (n=22, 23–89) showed a progressive decrease in neutrophil chemotaxis compared with healthy controls (LRTI, MD 0·7 μm/min, p=0·04; pneumonia, 1·1 μm/min, p=0·02; sepsis 1·6 μm/min, p=0·01) with neutrophils associated with sepsis unable to perform targeted chemotaxis. Improvements in chemotaxis to baseline values were seen after recovery in patients who survived their illness. In-vitro treatment with simvastatin (1μM) of neutrophils taken from healthy elderly patients restored old neutrophil chemotaxis to that of young cells. Simvastatin also restored neutrophil migration in older patients with LRTI and pneumonia to baseline values but not in patients with sepsis. 2 weeks of oral simvastatin in healthy elderly volunteers (≥65 years, n=20) increased the accuracy of neutrophil migration in vitro (MD 1·68 μm/min, p=0·02) replicating in-vitro work. InterpretationNeutrophil function in elderly people is compromised in health, and deteriorates further during infective episodes in accordance with the severity of the disease. Migratory accuracy can be improved with short-term in-vitro simvastatin therapy in health and mild infection but not in sepsis. Our data suggest that statin therapy might be a preventive or an early adjuvant intervention rather than a treatment in established sepsis. We are testing in a clinical trial whether simvastatin 80 mg for 7 days modifies neutrophil responses in elderly patients with pneumonia and sepsis. FundingBritish Journal of Anaesthesia, Royal College of Anaesthetists.