A new role for statins in sepsis

Several studies have shown promising results regarding the use of statins as an adjunctive treatment for sepsis. Most of those studies were retrospective or observational in nature. The ASEPSIS trial has reported that the administration of atorvastatin reduced clinical progression of sepsis but did not improve mortality. These findings are promising and further multicenter trials are needed to confirm these outcomes and to establish whether this class of medications will offer utility in this regard.


Introduction
In the previous issue of Critical Care, Patel and colleagues report the result of a single-center study that randomized septic patients to atorvastatin or placebo. Th e authors found that patients treated with statins had less transition to severe sepsis although mortality was no diff erent between the treated and untreated patients [1]. Th ese fi ndings, although promising, need to be confi rmed in larger, multicenter trials.
Sepsis is a systemic infl ammatory response syndrome triggered by infection, while severe sepsis is organ dysfunction due to infection. Severe sepsis is associated with high rates of morbidity and mortality. Th e incidence of sepsis has increased over the last few decades and in the United States currently aff ects more than 750,000 patients annually [1]. Sepsis is estimated to be directly responsible for more than 200,000 deaths and results in $17 billion of costs annually [2,3]. An impressive amount of research has been devoted to understanding the pathophysiology of sepsis, and to the testing of potential treatments. Despite signifi cant advances, 30 to 40% of patients with severe sepsis still die in the ICU [2].

Main text
Th e primaum mauvens in severe sepsis is thought to be an uncontrolled proinfl ammatory response triggered by infectious agents that leads to organ dysfunction. Th is response starts when microbial antigenic structures bind to specifi c receptors on leukocytes and induce a highly complex cascade of biochemical reactions Th is induction then results in generation of a myriad of proinfl ammatory and pro coagu lant agents [4]. In addition to the lipidlowering and cardiovascular protective eff ects of statins, a signifi cant body of evidence supports their potential role in the amelioration of the proinfl ammatory process of sepsis. Th is evidence includes in vitro biologic plausibility studies, animal models, and human trials.

Biologic plausibility
HMG CoA inhibitors (statins) decrease the production of isoprenoid lipid and inhibit the activation of GTPase protein via their eff ects on prenylation [5]. Statins have been shown to act on several crucial steps in sepsis: the generation of proinfl ammatory cytokines (IL-6, IL-8, and TNFα), modulation of leukocyte and monocyte func tions, and reduction of oxidative stress as well as improvement in endothelial function and platelet activity. In one trial, simvastatin reduced the systemic response to endotoxin administration and decreased expression of Toll-like receptors that hold a key early role in sepsis [6]. In addition, an antimicrobial eff ect of statins on methicillinsensitive Staphylococcus aureus and methicillin-resistant S. aureus has been reported [7].

Animal models
Animal models on statin use in the setting of sepsis have shown some promising results. In a cecal ligation and puncture mouse model of sepsis, treatment with simvastatin, atorvastatin, and pravastatin but not fl uvastatin prolonged survival primarily by improvement of cardiac function and systemic hemodynamics [8].

Human studies
A signifi cant body of evidence indicates that there may be a role for statins in the treatment of sepsis. Although most of the trials are retrospective and observational in nature, their conclusions are promising. Th e trial fi ndings indicate that statins may decrease the level of infl am matory cytokines, the incidence of de-novo sepsis, the worsen ing of ongoing sepsis, and possibly also sepsis mortality.
Novack and colleagues randomized 83 patients with acute bacterial infections to simvastatin or placebo and showed that treatment with statins reduced cytokine levels at 72 hours [9].
A retrospective study of 787 patients admitted with pneumonia showed that pretreatment with statins was associated with improved mortality [10].
Some authors have cautioned against the use of statins in the treatment of sepsis due to concerns of myopathy and hepatotoxicity [11]. Prospective randomized controlled trials are therefore needed to defi nitively establish the appropriate adjunctive role for statins in sepsis and to adequately estimate the magnitude of any possible adverse events.
In the previous issue of Critical Care, Patel and colleagues take a step toward answering the question of whether or not statins are of utility in the prevention of severe sepsis. Within their randomized control setting, the authors minimized biases inherent to retrospective trials. Th e selection of statin-naïve patients was appropriate but may have hindered some of their potential fi ndings, especially if a prolonged pretreatment period is needed to durably aff ect outcomes. Showing clinical outcome benefi ts of statins in a fl oor population of hospital patients with lower acuity of illness will probably be diffi cult to demonstrate in the absence of very large trials. Th e great majority of patients with sepsis do not progress to severe sepsis and therefore prophylactic treatment to prevent severe sepsis would require treatment of a large number of patients who may not benefi t. Treatment that shows a decrease in progression to a disease state linked to increased mortality without an eff ect on decreasing this mortality is also problematic.

Conclusion
Th ere are some important take-home messages from this study. First, there is a need for larger, multicenter random ized controlled trials in patients with variable degrees of severity of illness, analyzing hard endpoints to establish any role for statins in septic patients. Second, clinicians should probably avoid, if possible, stopping statins in critically ill patients with sepsis who are already taking statins at the time of admission. Given our small armamentarium of agents in sepsis, statins could prove a useful addition.