Abstract
Objective
To determine if statin therapy reduces the incidence of severe sepsis and the levels of inflammatory cytokines in patients with acute bacterial infection.
Design
Double-blind placebo controlled randomized clinical trial.
Setting
Department of medicine and medical intensive care unit in a tertiary university medical center.
Patients and participants
A total of 83 patients with suspected or documented bacterial infection were enrolled. We randomly assigned 42 patients to receive 40 mg of simvastatin orally, followed by 20 mg of simvastatin, and 41 to receive matching placebo.
Measurements and results
The study was prematurely terminated due to slow recruitment rate. Here we report the analysis of the secondary outcome: change in cytokines levels at 72 h. Both groups were evenly matched in terms of co-morbidity and severity of illness on admission. Four of the 83 patients enrolled developed severe sepsis, two in each group. No difference was observed in other clinical variables and there were no mortalities. Cytokine levels were randomly assessed in 40 patients (20 in each group). Both TNF-α and IL-6 levels were significantly reduced in the simvastatin group (p = 0.02 and p = 0.02, respectively), while no such difference was observed in the placebo group (p = 0.35 and 0.39, respectively).
Conclusions
Statin therapy may be associated with a reduction in the levels of inflammatory cytokines in patients with acute bacterial infections. Large controlled trials will determine if this reduction will translate into a clinical benefit.
References
Blanco-Colio LM, Tunon J, Martin-Ventura JL, Egido J (2003) Anti-inflammatory and immunomodulatory effects of statins. Kidney Int 63:12–23
Terblanche M, Almog Y, Rosenson RS, Smith TS, Hackam DG (2007) Statins and sepsis: multiple modifications at multiple levels. Lancet Infect Dis 7:358–368
Takemoto M, Liao JK (2001) Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler Thromb Vasc Biol 21:1712–1719
Almog Y (2003) Statins, inflammation, and sepsis: hypothesis. Chest 124:740–743
Novack V, Terblanche M, Almog Y (2006) Do statins have a role in preventing or treating sepsis? Crit Care 10:113
Almog Y, Shefer A, Novack V, Maimon N, Barski L, Eizinger M, Friger M, Zeller L, Danon A (2004) Prior statin therapy is associated with a decreased rate of severe sepsis. Circulation 110:880–885
Hackam D, Mamdani M, Li P, Redelmeier D (2006) Statins and sepsis in patients with cardiovascular disease: a population-based cohort analysis. Lancet 367:413–418
Almog Y, Novack V, Eisinger M, Porath A, Novack L, Gilutz H (2007) The effect of statin therapy on infection-related mortality in patients with atherosclerotic diseases. Crit Care Med 35:372–378
Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fischer CJ Jr (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344:699–709
Charlson ME, Pompei P, Ales KL, MacKenzie CR (1987) A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 40:373–383
Panacek E, Marshall JC, Albertson TE, Johnson DH, Johnson S, MacArthur RD, Miller M, Barchuk WT, Fischkoff S, Kaul M, Teoh L, Van Meter L, Daum L, Lemeshow S, Hicklin G, Doig C (2004) Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab’)2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels. Crit Care Med 32:2173–2182
Alberti C, Brun-Buisson C, Chevret S, Antonalli M, Goodman SV, Martin C, Moreno R, Ochagavia AR, Palazzo M, Werdan K, Le Gall JR (2005) Systemic inflammatory response and progression to severe sepsis in critically ill infected patients. Am J Respir Crit Care Med 171:461–468
Farmer JA (2000) Pleiotropic effects of statins. Curr Atheroscler Rep 2:208–217
Terblanche M, Almog Y, Rosenson R, Smith T, Hackam D (2006) Statins: panacea for sepsis? Lancet Infect Dis 6:242–248
Stoll LL, McCormick ML, Denning GM, Weintraub NL (2004) Antioxidant effects of statins. Drugs Today (Barc) 40:975–990
Rikitake Y, Liao JK (2005) Rho GTPases, statins, and nitric oxide. Circ Res 97:1232–1235
Pleiner J, Schaller G, Mittermayer F, Zorn S, Marsik C, Polterauer S, Kapiotis S, Woltz M (2004) Simvastatin prevents vascular hyporeactivity during inflammation. Circulation 110:3349–3354
Paumelle R, Blanquart C, Briand O, Barbier O, Duhem C, Woerly G, Percevault F, Fruchart JC, Dombrowicz D, Glineur C, Staels B (2006) Acute Antiinflammatory Properties of Statins Involve Peroxisome Proliferator-Activated Receptor-{alpha} via Inhibition of the Protein Kinase C Signaling Pathway. Circ Res 98:361–369
Almog Y, Terblanche M (2008) Pleiotropic effects of statins: implications for critical care. Contemp Crit Care 5:1–12
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Novack, V., Eisinger, M., Frenkel, A. et al. The effects of statin therapy on inflammatory cytokines in patients with bacterial infections: a randomized double-blind placebo controlled clinical trial. Intensive Care Med 35, 1255–1260 (2009). https://doi.org/10.1007/s00134-009-1429-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00134-009-1429-0