Statins for the Treatment of Sepsis

US Pharm. 2008;33(2):HS-3-HS-15

Currently, sepsis--a systemic inflammatory response syndrome initiated secondary to an infection--is the tenth leading cause of death in the United States.¹ Approximately 750,000 patients develop sepsis each year.^2,3 Sepsis-related mortality ranges from 30% to 50%, with advancing age increasing the risk.^4,5 Two factors that contribute to a positive outcome in the treatment of sepsis are the timely diagnosis and identification of the offending pathogen. The four cornerstones of the therapeutic management of sepsis are hemodynamic monitoring, volume resuscitation, inotropic therapy, and red blood cell transfusions. Despite therapeutic advances, sepsis-related morbidity and mortality continue to increase.³

Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) are an integral part of the medication armamentarium for treating hyperlipidemia and reducing the risk of coronary artery disease. Their beneficial effects are due to statins' ability to inhibit the rate-limiting step of cholesterol biosynthesis, thereby decreasing the amount of circulating cholesterol in the body (FIGURE 1).⁶ These well-documented benefits are termed lipid-dependent effects. It has recently been discovered that statins possess effects beyond their lipid-lowering properties; these are termed lipid-independent or pleiotropic effects. Pleiotropic effects include anti-inflammatory, immunomodulatory, antioxidant, antithrombotic, and endothelium-stabilizing properties. Patients with sepsis syndrome experience dysfunction in all of these areas; therefore, statins theoretically would benefit them.⁶† The overall clinical impact of statins for treating sepsis is not fully delineated, however.

Rationale for Sepsis Improvement After Statin Use
Cytokines ^6,7: Sepsis activates an inflammatory cascade in which large amounts of cytokines are released into the body. Macrophages and endothelial cells are then hyperactivated by the unusually large quantity of circulating cytokines. The activation of macrophages and endothelial cells results in the release of more cytokines, exacerbating the inflammatory response. Statins have the ability to alter the expression of various cytokines (FIGURE 2). This alteration may lead to a reduction in the release of cytokines, thus breaking the chain between cytokine release and activation of macrophages and endothelial cells. These events potentially could culminate in the blunting of the inflammatory component associated with sepsis syndrome.

C-Reactive Protein^6,7 : C-reactive protein (CRP) is a nonspecific marker for inflammation in the body. Increased CRP levels have been associated with deleterious clinical outcomes. CRP, which is produced by the liver, is driven by the release of cytokines. As previously mentioned, sepsis precipitates an augmented chain of events that ultimately results in the release of a large amount of cytokines. CRP assists with endothelial-cell interaction, aids in the activation of complement, and induces tissue-factor expression. These actions work in concert to promote the formation of thrombi. Statins have the ability to deter cytokine release, thus leading to decreased amounts available to the liver for producing CRP. In theory, this action would reduce systemic inflammation and improve clinical outcomes in the septic patient.

Chemokines^6,7: Chemokines attract leukocytes to sites of infection or tissue damage. Statins have been shown to bind directly to the lymphocyte's cell surface, which prevents binding to the counterreceptor on the endothelial surface (FIGURE 3). Statins also reduce the production of chemoattractants. These actions result in a net decrease of inflammatory cells in the body. Statins also exert favorable effects on T lymphocytes. The Th-1 subclass of T lymphocytes promotes inflammation, which is inhibited by statins; the Th-2 subclass promotes anti-inflammation, which is expressed by statins (FIGURE 2). Therefore, statins are able to alter T lymphocytes, thereby halting an inflammatory effect and inducing a net anti-inflammatory effect.

Coagulation^6,7 : Sepsis-induced inflammation causes the downregulation of thrombomodulin and the upregulation of tissue factor on the surface of the endothelium. This shift results in endothelial dysfunction and favors thrombosis. Statins increase thrombomodulin on the endothelial surface and reduce tissue-factor expression in endothelial cells. This action has the potential to reduce the generation of thrombin. The increased amount of thrombomodulin on the surface of the endothelium allows it to be readily available to bind with thrombin. The net result of this binding is the activation of protein C. This activation will result in the initiation of the intrinsic anticoagulant cascade. Therefore, statins have the theoretical ability to blunt or reverse the procoagulant state that exists in sepsis syndrome (FIGURE 2).

Enzymes^6,7: Sepsis causes an increase in inducible nitric oxide (NO) synthase (NOS), which leads to the overproduction of NO. This overproduction leads to excessive vasodilatation, loss of systemic vascular resistance, and vascular leak. Statins modulate NOS activity and, consequently, NO levels by reducing inducible NOS expression and by maintaining or increasing endothelial constitutive NOS production. This reduction in the inducible NOS/endothelial constitutive NOS ratio may be clinically important since unselected NOS blockade is associated with increased mortality (FIGURE 2).

Antioxidant Effects ^6,7: Reactive oxygen levels are increased in patients with sepsis. It has been reported that oxidative stress is an important factor associated with morbidity and mortality in patients with sepsis and multisystem organ failure. Statins inhibit phorbol myristate acetateñinduced oxygen radical production in monocytes through NADPH oxidase inactivation. Activation of this enzyme is largely responsible for the production of reactive oxygen species in sepsis ( FIGURE 2).

Studies Addressing Statin Therapy and Sepsis
Liappis et al conducted a single-center, retrospective, cohort trial to compare mortality and clinical findings in patients taking statins with those of patients not receiving statins at the time of their bacteremic episode.⁸ Of the 388 subjects, 35 were taking a statin; the rest (n = 353) were not. The authors found a significant reduction in overall hospital mortality rates among patients taking statins, with a mortality rate of 6% in the statin group and a rate of 28% in the nonstatin group. Mortality rates that could be attributed to the infection were lower in the statin group (3%) than in the nonstatin group (20%). The authors concluded that statins might prove beneficial in the treatment of infections, but that prospective studies were needed to validate this potential benefit. This trial had several weaknesses, including a small number of subjects in the statin group, unbalanced baseline characteristics, and a questionable study design.

The association between statin administration and mortality in bacteremic patients requiring hospital admission was assessed by Kruger et al in a single-center, retrospective, cohort trial.⁹ This study involved 438 patients, 66 of whom were receiving statin therapy upon admission (the remaining 372 were not). Compared with the group that did not receive statins, the statin group had a significantly lower incidence of hospital mortality (10.6% versus 23.1%) and bacteremia-related mortality (6.1% versus 18.3%). There also was a reduction in all-cause hospital mortality (1.8% versus 23.1%) and in death related to bacteremia (1.8 versus 18.3%), which was more pronounced in patients who continued to receive statin therapy after the diagnosis of bacteremia. The authors concluded that statin administration provided a significant survival benefit and recommended that more trials be conducted to evaluate statin utilization in critically ill patients. Two weaknesses of this trial were the small number of patients in the statin group and the inability to extrapolate to a larger patient population.

Fernandez et al conducted a single-center, retrospective, cohort trial of 438 subjects to assess the impact of previous statin therapy on hospital mortality and determine whether the impact is due to a protective effect against ICU-acquired infections. ¹⁰ Prior to ICU admission, 38 subjects were receiving statin therapy and the remaining 400 were not. This trial found no difference with respect to ICU-acquired infections between subjects who were taking statins preadmission and those who were not receiving statin therapy. Paradoxically, there was a higher rate of mortality in the statin group. The authors concluded that the higher occurrence of mortality in the statin group might have been related to the greater severity of illness in that group. The authors also suggested the need for prospective, randomized trials in order to validate their findings. Weaknesses of this trial were generalized inclusion criteria, no reason listed for ICU admission, and differences in baseline characteristics between the two groups that may have led to skewed results.

A single-center, prospective, observational, cohort study undertaken by Almog et al evaluated whether patients treated with statins developed severe sepsis less frequently and whether this presumed protective effect might reduce the rate of admission to the ICU.¹¹ The study included 361 subjects, 82 of whom were receiving statin therapy prior to hospital admission; the rest (n = 279) were not receiving statin therapy. Severe sepsis developed in 2.4% of subjects receiving prior statin therapy and in 19% of those not receiving it--a statistical and clinical difference between the two groups. The subjects receiving statin therapy also had a significantly reduced incidence of ICU admission (3.7%) compared with the nonstatin group (12.2%). The investigators found that therapy with statins for at least one month before the onset of an acute bacterial infection is probably associated with a reduced rate of severe sepsis and ICU admission. They reiterated a need for future prospective, controlled trials to verify their results and to determine the clinical significance of statins as a preventative approach to sepsis. Weaknesses of this trial included unbalanced baseline characteristics, a relatively smaller statin group, and the study design.

A population-based, retrospective, cohort analysis was conducted by Thomsen et al to investigate statin use and mortality due to bacteremia.¹² This trial involved 5,353 subjects, 176 who had received statin therapy and 5,177 who had not. Up to 30 days, mortality between the two groups was similar. However, between days 31 and 180, the statin group experienced a significantly lower incidence of mortality than the non-statin group. These results suggested that statins may not possess short-term benefits in the treatment of bacteremia, but may cause a reduction in long-term mortality. The researchers concluded that, due to the trial's weaknesses, the benefits of statin therapy for bacteremia were difficult to interpret. Two weaknesses were the relatively small size of the statin group and the study design (observational).

Hackam et al engaged in a large, population-based, retrospective, cohort study of 69,168 patients that investigated the use of statins and their effect on sepsis.¹³ The statin group and the nonstatin group each comprised 34,584 patients. The authors found that the rate of sepsis was significantly lower in patients receiving statin therapy prior to hospital admission compared with patients not receiving statin therapy prior to admission. The design of this study was considered a weakness due to the possibility that confounding factors had been introduced.

A small, single-center, retrospective, cohort trial of 53 subjects was carried out by Martin et al. ¹⁴ Sixteen subjects were receiving statin therapy and 37 controls were not receiving statin therapy prior to admission. The trial investigated whether the use of statins is associated with a reduced rate of severe sepsis in a population of patients with confirmed sepsis; it also aimed to further characterize the effect of statins on the frequency of organ dysfunction in patients with severe sepsis. The authors established that statins were associated with a significantly lower instance of severe sepsis (56%, versus 86% for the nonstatin group). No difference in mortality was noted between the two groups (38% in the statin group and 49% in the non-statin group), however. The statin group had a significant reduction in the rate of cardiovascular dysfunction compared with controls (38% versus 73%). The authors concluded that statins may provide an interventional strategy in patients with severe sepsis or septic shock. They suggested further investigation in the form of randomized, prospective, placebo-controlled trials involving patients with sepsis. Weaknesses of this trial were its small sample size, analysis of a single center, and retrospective evaluation.

Yang et al conducted a retrospective study involving patients with sepsis.¹⁵ The objective was to define the effect of statins on 30-day mortality in an Asian population with sepsis. Of the 454 patients studied, 104 received a statin at least 30 days before hospital admission and during the course of the septic event. The other 350 patients were considered controls and did not receive statin therapy prior to admission. There was no significant difference in 30-day sepsis-related mortality between the two groups (19.2% versus 18.9%). The investigators concluded that there were no marked beneficial or harmful effects of statin therapy during sepsis in terms of 30-day survival rates of bloodstream infections in this population. Weaknesses of this trial were unbalanced baseline characteristics and restrictive inclusion criteria.

Summary
The pleiotropic effects associated with statin therapy are well documented and are gaining increased attention. Sepsis is associated with inflammatory processes, coagulopathies, oxidative stress, and vascular dysfunction. These deleterious effects theoretically could be modified by statin therapy, which leads to the assumption that statins may have beneficial effects in patients diagnosed with sepsis. However, due to weak methodology and conflicting results, current trials are unable to provide a definitive answer to this interesting question. The available literature does suggest a positive association between statin therapy and improved patient outcomes, but this must be validated by large, randomized, double-blind, controlled trials. Statins cannot presently be recommended as a therapeutic modality in the treatment or prevention of sepsis.

References

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7. Ray KK, Cannon CP. The potential relevance of the multiple lipid-independent (pleiotropic) effects of statins in the management of acute coronary syndromes. J Am Coll Cardiol. 2005;46:1425-1433.

8. 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.

9. Kruger P, Fitzsimmons K, Cook D, et al. Statin therapy is associated with fewer deaths in patients with bacteraemia. Intensive Care Med. 2006;32:75-79.

10. Fernandez R, De Pedro VJ, Artigas A. Statin therapy prior to ICU admission: protection against infection or a severity marker? Intensive Care Med. 2006;32:160-164.

11. Almog Y, Shefer A, Novack V, et al. Prior statin therapy is associated with a decreased rate of severe sepsis. Circulation. 2004;110: 880-885.

12. Thomsen RW, Hundborg HH, Johnsen SP, et al. Statin use and mortality within 180 days after bacteremia: a population-based cohort study. Crit Care Med. 2006;34:1080-1086.

13. Hackam DG, Mamdani M, Li P, Redelmeier DA. Statins and sepsis in patients with cardiovascular disease: a population-based cohort analysis. Lancet. 2006;367:413-418.

14. Martin CP, Talbert RL, Burgess DS, Peters JI. Effectiveness of statins in reducing the rate of severe sepsis: a retrospective evaluation. Pharmacotherapy. 2007;27:20-26.

15. Yang KC, Chien JY, Tseng WK, et al. Statins do not improve short-term survival in an oriental population with sepsis. Am J Emerg Med. 2007;25:494-501.

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