Why did atorvastatin show no biological or clinical evidence of efficacy in statin-naïve patients with established sepsis in this well-designed and conducted study? However, it is worth considering the treatment regimen used in this study. To date, most statins have demonstrated pleiotropic effects, but no studies have directly compared the immunomodulatory effects of different types of statins. In addition, there are limited data demonstrating statin efficacy in clinically relevant human models or critically ill patients to provide information on the optimal statin, dose, and duration of treatment for these studies. Interestingly, in a recent nested cohort study, statin therapy reduced in-hospital mortality in patients with sepsis, but a reduction in mortality was observed only with simvastatin, but not with atorvastatin. Most of the reduction in was observed with higher dose statins. The finding that higher doses may be more effective compared pretreatment with two doses of simvastatin (5 or 20 mg/kg) in a lipopolysaccharide (LPS)-induced mouse model of acute lung injury (ALI). Only high doses were effective in reducing lung injury. Pretreatment with simvastatin 40 and 80 mg for 4 days reduced the inflammatory response to inhaled LPS in healthy subjects. Although there was no difference between the 40 mg and 80 mg simvastatin groups in this study, he did not design this study to determine whether there was a difference between the two simvastatin doses. Two recent studies support long-term use of high-dose statins. In his ASEPSIS study in sepsis patients, taking atorvastatin 40 mg daily during hospitalization reduced the rate of sepsis progressing to severe sepsis during hospitalization. In a small proof-of-concept study in his ALI patients, half of whom had sepsis, simvastatin 80 mg daily for up to 14 days improved scores for serial organ failure. However, the improvement was only significant on day 14 and not on day 7, suggesting that longer treatment is needed. In the current study, the median dose of atorvastatin 20 mg administered Only 4 times. Although the atorvastatin levels achieved are adequate for the cholesterol-lowering effects of statins, it is unclear if these levels are sufficient to achieve the pleiotropic antiinflammatory effects of statins. Another possible explanation for the absence of an effect in statin-naive patients with established sepsis is that the timing of statin use may have been too late to modulate the inflammatory changes of sepsis. The majority of data indicate that statins are effective when used as a pretreatment in animal models of sepsis and ALI. A metaanalysis of 13 studies involving 254,950 patients found that treatment with statins in community-acquired pneumonia was associated with improved survival but that the effect was more pronounced if treatment was initiated in the community prior to hospital admission. This is supported by data showing that pretreatment with simvastatin attenuated systemic and pulmonary inflammatory responses to LPS in healthy subjects. Statin users included patients diagnosed with sepsis who were taking statins continuously for 30 days prior to the index date. The control group consisted of patients diagnosed with sepsis who had not used statins continuously for 30 days prior to the index date. Our analysis was based on the intent-to-treat principle. That is, statin users and non-users who switched to other treatment groups or failed follow-up during the study period will continue to be part of the treatment. To clarify the effects of each dose-response relationship, he divided statin users into two groups. Patients treated with high-potency statins (at least 10 mg rosuvastatin, at least 20 mg atorvastatin, or at least 40 mg simvastatin) and patients treated with low-potency statins (all other statin treatments). Septic patients treated with both high- and low-potency statins were classified as high-potency statin users in the analysis.