Simvastatin and Survival in Sepsis
To the Editor:
I read with great interest the recent article by Merx and colleagues1 that described their finding that mice treated with simvastatin before the induction of sepsis had dramatic reductions in mortality.
Although I agree with the authors’ assertion that their work warrants further investigation, I believe the readers of this article may have been done a disservice by the authors’ review of the literature. The authors state that this study was the first to demonstrate that statins significantly improve survival in sepsis. However, Ando and colleagues2 previously reported that mice pretreated with cerivastatin had significant reductions in mortality relative to untreated control animals in a lipopolysaccharide-induced model of sepsis (73% survival in treated animals versus 27% survival in untreated animals at 7 days; P=0.016).
Merx and coworkers1 also suggest that retrospective studies in humans with sepsis who are coincidentally using a statin could pave the way toward prospective clinical trials. The reader should be aware that a retrospective study of this nature has already been published. Liappis and colleagues3 previously reported a retrospective review of 388 bacteremic intensive care unit patients admitted to one medical center. This review demonstrated that those patients using a statin at the time of admission to the intensive care unit with either aerobic Gram-negative bacilli or Staphylococcus aureus bacteremia had a significant reduction in in-hospital mortality (6% versus 28%; P=0.002) relative to controls not using a statin, despite a higher incidence of diabetes mellitus, hypertension, and cardiovascular disease in the statin group.
The work of Merx and colleagues is an important addition to the growing literature describing the pleiotropic effects of statins. The sum of available studies, both animal and human, that detail the benefit of statins in sepsis should give impetus to further investigations that may lead toward improved clinical outcomes.
The views expressed herein are those of the author and do not represent the opinions of the government.
Merx MW, Liehn EA, Janssens U, Lutticken R, Schrader J, Hanrath P, Weber C. HMG-CoA reductase inhibitor simvastatin profoundly improves survival in a murine model of sepsis. Circulation. 2004; 109: 2560–2565.
Ando H, Takamura T, Ota T, Nagai Y, Kobayashi K. Cerivastatin improves survival of mice with lipopolysaccharide-induced sepsis. J Pharmacol Exp Ther. 2000; 294: 1043–1046.
Liappis AP, Kan VL, Rochester CG, Simon GL. The effect of statins on mortality in patients with bacteremia. Clin Infect Dis. 2001; 33: 1352–1357.
We are grateful to Dr Stamm for his knowledgeable comments and for highlighting the important work of Ando et al.1 Although his findings are very much in accordance with ours,2 we would like to point out that the treatment with lipopolysaccharide used as a surrogate for sepsis in this elegant experimental series represents an approach focused on direct induction of inducible NO synthetase and elevation of cytokine levels. Cecal ligation and perforation, in contrast, involve a more complex pathophysiological scenario with an upregulation and activation of multiple inflammatory mediators, thus likely emulating the septic disease encountered in patients more closely (for review, see Deitch et al3). This also is reflected by the pronounced hemodynamic dysregulation documented in our model. Furthermore, sepsis was considerably less severe in the model reported by Ando et al, with a survival rate >70% in the untreated group at 36 hours, compared with 10% in our study. In light of these significant differences in methodology, it is all the more promising that statins proved to be beneficial in both models.
We are aware of the encouraging retrospective bacteremia study by Liappis et al.4 However, bacteremia does not constitute sepsis (see consensus criteria for sepsis5) and thus does not necessarily imply that the patient was actually suffering from sepsis, including all its hemodynamic and other implications. We therefore continue to believe that retrospective studies on the use of statins and their benefit quo ad vitam in patients afflicted by sepsis could indeed facilitate prospective trials, and we join Dr Stamm in hoping that further investigations in this promising field are stimulated and eventually will benefit patients.
Ando H, Takamura T, Ota T, et al. Cerivastatin improves survival of mice with lipopolysaccharide-induced sepsis. J Pharmacol Exp Ther. 2000; 294: 1043–1046.
Merx MW, Liehn EA, Janssens U, et al. HMG-CoA reductase inhibitor simvastatin profoundly improves survival in a murine model of sepsis. Circulation. 2004; 110: 2560–2565.
Liappis AP, Kan VL, Rochester CG, et al. The effect of statins on mortality in patients with bacteremia. Clinical Infectious Diseases. 2001; 33: 1352–1357.