Summary Improvements in the control of haemorrhage after trauma have resulted in the survival of many people who would otherwise have died from the initial loss of blood. However, the danger is not ...over once bleeding has been arrested and blood pressure restored. Two-thirds of patients who die following major trauma now do so as a result of causes other than exsanguination. Trauma evokes a systemic reaction that includes an acute, non-specific, immune response associated, paradoxically, with reduced resistance to infection. The result is damage to multiple organs caused by the initial cascade of inflammation aggravated by subsequent sepsis to which the body has become susceptible. This Series examines the biological mechanisms and clinical implications of the cascade of events caused by large-scale trauma that leads to multiorgan failure and death, despite the stemming of blood loss. Furthermore, the stark and robust epidemiological finding—namely, that age has a profound influence on the chances of surviving trauma irrespective of the nature and severity of the injury—will be explored. Advances in our understanding of the inflammatory response to trauma, the impact of ageing on this response, and how this information has led to new and emerging treatments aimed at combating immune dysregulation and reduced immunity after injury will also be discussed.
Abstract Background The 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. Methods Neutrophils 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. Findings Neutrophils 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. Interpretation Neutrophil 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. Funding British Journal of Anaesthesia, Royal College of Anaesthetists.
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