Statins in Sepsis

Abstract

Sepsis is a common intensive care unit event occurring in approximately 750 000 patients annually, with a case mortality rate approaching 50%. Sepsis is characterized by a chaotic and excessive release of inflammatory cytokines and procoagulants including tumor necrosis factor, interleukin (IL)-1, IL-6, IL-8, platelet-activating factor, and tissue factor. Efforts to inhibit individual cytokines in order to modify poor outcomes have been generally disappointing, suggesting the need to target multiple inflammatory mediators to obtain clinical benefit. Statins lower lipids by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which in turn inhibits the rate-limiting step in cholesterol biosynthesis. In addition to lowering total cholesterol, statins have pleiotropic effects on inflammation and immunity. Instead of impacting a single entity in the sepsis syndrome, statins may have positive effects on multiple inflammatory, immunomodulating, and coagulation targets involved in the development of infection and sepsis. There have been a number of institutional- and population-based studies that have evaluated the impact of statins in patients with infection and sepsis. Most of these studies, but not all, have demonstrated a number of positive outcomes in patients with statins, including reduction in mortality. Based on these data, statins are a promising therapy in the management of patients with sepsis and warrant larger and more rigorous clinical trials.

Association between statin therapy and outcomes in critically ill patients: a nested cohort study

“…A similar finding was noted by Christensen et al [19]. This result might be related to the higher lipophilicity of simvastatin, which enables it to better penetrate cells [29]. However, large sample size is required to confirm these findings.…”

Is There Potential for Repurposing Statins as Novel Antimicrobials?

“…Sepsis is a serious infection-induced whole-body inflammatory state, and, due to the immunomodulatory activity of statins, several studies have been carried out to evaluate the benefit of statin therapy in the prevention or treatment of the disease. While the type, design, size, and measured outcomes of the studies have been varied and overall results conflicting, in recent years extensive reviews evaluating these clinical studies have been published (21)(22)(23)(24)(25)(26)(27). The majority of clinical studies to date have been retrospective cohort studies evaluating the impact of prior treatment with statins on disease progression and mortality.…”

Statins and sepsis: A magic bullet or just shooting blanks?*

“…There are 750,000 cases of sepsis annually accounting for almost 2% of all hospital admissions and a hospital mortality rate of approximately 30% (1)(2)(3). Sepsis is the tenth leading cause of death in the United States (4,5), with an estimated annual cost of $16.7 billion (3,6).…”

“…ALI/ARDS is mediated by an intense inflammatory response with associated oxidative injury (8). The presence of invading microorganisms and their toxins results in systemic inflammation, production of inflammatory mediators, endothelial dysfunction, and excessive release of proinflammatory cytokines, tumor necrosis factor, C-reactive protein, interleukins, and procoagulants (1,2,4,6,9,10). Sepsis is characterized by endothelial dysfunction, systemic inflammation, immune system dysregulation, and inability to regulate the intense inflammatory response (1,2,4,6,9,10).…”

“…These trials were all negative (2)(3)(4) or even associated with an increased mortality rate in the treatment group. Indeed, sepsis induces changes in arginine metabolism, leading to a complex picture deducted from the findings of clinical trials.…”