Introduction
Severe sepsis is a common cause of critical illness and death on the intensive care unit (ICU). It is estimated that severe sepsis accounts for more than 9 % of all annual deaths in the United States, comparable to the figure for myocardial infarction.
Interestingly, recent human studies suggested that 3-hydroxy-3-methylglutaryl coen- zyme A (HMG-CoA) reductase inhibitors or statins, widely used in the treatment of hypercholesterolemia and atherosclerosis, have some protective effects in bacter- emia, sepsis, and related problems, independent of their cholesterol-lowering effects [1 – 17]. The growing body of evidence gives rise to the question of whether statins have a role in established sepsis as an adjuvant therapy, in the primary prevention of sepsis or both, and what the mechanisms of action are.
In this chapter, an update is given on the possible mechanisms whereby statins might affect sepsis and related disorders, such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). There will be some considerations regarding adverse events and withdrawal of statin therapy.
Statin Therapy Reduces the Incidence of and Mortality from Sepsis
In recent years, several observational reports have been published regarding prior statin therapy and sepsis [4, 12], bacteremia [2, 9, 11], multiple organ dysfunction syndrome (MODS) [10], pneumonia [6], and ICU-acquired infections [14]. The larg- est observational study was recently reported by Hackam et al. [12]. The authors included 69,168 patients in their population-based cohort analysis of whom half received a statin and half did not. They showed that the use of statins in patients with atherosclerosis was associated with a reduced risk of subsequent sepsis (hazard ratio 0.81; 95 % CI 0.72 – 0.90 if adjusted for demographic characteristics, sepsis risk factors, comorbidities, and health-care use) even in high risk subgroups (Fig. 1).
Reductions in severe sepsis were also observed. The reduction in the development of severe sepsis needing intensive care was confirmed by Almog et al. [4]. Obviously, all statin-using patients had cardiovascular disease. Results are, therefore, hard to inter- prete and to extrapolate to patients not suffering from cardiovascular disease.
Indeed, hyperlipoproteinemic mice are more susceptible to sepsis than wild-type mice [15], so that patients with cardiovascular disease or hyperlipoproteinemia might be more susceptible to sepsis. The protective effect of statins is, therefore, likely to be under- rather than overestimated.
Fig. 1. Decreased risk of sepsis in high-risk subgroups. The protective association between statins and sepsis persisted in high-risk sub- groups, including patients with dia- betes mellitus, chronic renal failure, or a history of infections. Hazard ratios represent ratio of risk of patients treated with statins to patients not treated with statins as the reference group. Horizontal lines show 95 % CI. From [12] with per- mission.
Furthermore, prior statin therapy decreased mortality in patients with bacter- emia, relatively independent of underlying disease [2, 9, 11]. However, Thomsen et al. [11] reported that statin use did not have an effect on short-term mortality after bacteremia, but in contrast, was associated with a decreased mortality between 31 and 180 days after bacteremia, while Liappis et al. [2] and Kruger et al. [9] found that statin use was associated with a survival benefit already (at 28 days) in the hos- pital. In addition, statin use appeared to be associated with a decreased 28-day mor- tality in patients developing MODS [10] and decreased 30-day mortality in patients hospitalized for community-acquired pneumonia (CAP), seemingly independent of comorbidity [6]. In contrast to these, often retrospective, observational studies reporting beneficial effects of statins on mortality, Fernandez et al. [14] found higher hospital mortality in patients using statins (61 % vs 42 %) even after adjust- ment for predicted risk on the basis of the APACHE II score. The authors concluded that statin therapy may be a marker rather than a mediator of a worse outcome, probably because of incomplete mortality prediction by scoring systems [14].
Until now, no randomized clinical trials have been performed to support the potentially beneficial effects of statins in the prevention and adjuvant treatment of sepsis, by decreasing its prevalence, severity, and mortality. The prospective evi- dence available regarding the use of statins as adjuvant therapy is limited to studies on other inflammatory diseases and to animal work. Statins have been tried in the treatment of rheumatoid arthritis and multiple sclerosis. In a randomized clinical trial in patients with rheumatoid arthritis, treatment with statins decreased disease activity, C-reactive protein (CRP), and the erythrocyte sedimentation rate [16]. Six months of simvastatin treatment in multiple sclerosis decreased the number and volume of brain lesions on magnetic resonance imaging (MRI) [17]. These results underline the anti-inflammatory properties of statins.
Merx et al. [18] studied treatment with statins after the onset of sepsis in mice.
They showed that treatment, starting 6 h after induction of sepsis by cecal ligation and perforation (CLP), improved survival by preservation of cardiac function and hemodynamics. This could be attributed to improved endothelial nitric oxide (NO) synthase (NOS) function and reduced endothelial adhesion of leukocytes [18]. In
perfusion, increased permeability, renal dysfunction, tubular injury and mortality.
Mechanisms of the Beneficial Effects of Statins during Sepsis and Acute Lung Injury
Increasing evidence suggests that statins have beneficial effects beyond lowering of serum cholesterol, the so-called pleiotropic effects, including immunomodulation and endothelial protection (Fig. 2). Furthermore, statins may have antibacterial, antifungal, and antiviral properties and could thereby limit an influenza pandemic, for instance [18, 20 – 22]. Pleiotropic effects can be explained by the isoprenoid inter- mediates playing a role in the cholesterol pathway. Cholesterol synthesis begins with the transportation of acetyl-CoA from the mitochondria to the cytosol, which is then converted to HMG-CoA. The conversion of HMG-CoA to mevalonate by the enzyme HMG-CoA reductase is rate limiting and can be inhibited by statins. This does not only disrupt cholesterol synthesis, but also the synthesis of the isoprenoid intermediates (Fig. 3). Isoprenoid intermediates are necessary for the addition of the farnesyl or geranylgeranyl groups (prenylation) to several proteins involved in fun- damental cellular processes such as regulation of actin filament (F-actin) cytoskele- ton, apoptosis, proliferation, migration, and gene expression.
Statins are able to modulate the immune response and ameliorate inflammation by a variety of mechanisms. For example, they repress major histocompatibility complex II (MHC II)-mediated T-cell activation, inhibit the interaction between leu- kocytes and endothelial cells by reduction of the expression of various adhesion molecules, shift the T-helper (Th)-1/2 balance towards Th2 leading to suppressed secretion of pro-inflammatory cytokines interleukin (IL)-2, -6, -12, interferon (IFN)- gamma and tumor necrosis factor (TNF)-[ [5, 23, 24]. Furthermore, Niessner et al.
[13] showed that statin treatment of healthy volunteers blunted monocyte, lipopoly- saccharide (LPS)-induced activation of Toll-like receptors (TLR)-4 and -2. Steiner et al. [7] showed in healthy volunteers that simvastatin was able to inhibit LPS-induced elevation of serum high-sensitive CRP and monocyte chemoattractant protein-1 (MCP-1). In addition, they reported that statin pretreatment blunted the expression of monocyte tissue factor expression in response to LPS, attenuating activation of coagulation by LPS. Statins may also increase fibrinolytic activity in the endothe- lium. In contrast to anti-inflammatory effects, Erikstrup et al. [25] reported that simvastatin treatment had no effect on the rise in circulating cytokines and leuko- cyte counts in response to endotoxemia in healthy volunteers.
Fig. 2. Pleiotropic effects of statins.
Statins are most often prescribed for their cholesterol-lowering effects, but they have also a variety of cholesterol-independent effects, including immunomodulatory, anti- inflammatory, anti-oxidative, endo- thelium-protective, and antimicro- bial properties. EC: endothelial cell
Fig. 3. Pathway of cholesterol biosynthesis.
Acetyl-CoA is converted to 3-hydroxy-3-methyl- glutaryl-CoA (HMG-CoA) by HMG-CoA reductase.
This enzyme can be inhibited by statins. By doing so, statins do not only inhibit the synthesis of cholesterol, but also of the isoprenoid intermedi- ates, which are necessary for the prenylation of several vital proteins, such as RhoA.
Reactive oxygen species (ROS) are involved in the pathogenesis and manifestations of sepsis. They react with various biological substrates causing membrane dysfunc- tion, tissue damage and ultimately, perhaps, MODS. Durant et al. [3] reported that superoxide anion production upon neutrophil stimulation was greater in critically ill, septic patients than in non-septic patients and healthy volunteers and that simva- statin reduced in vitro superoxide production by 40 %, through inactivation of NADPH oxidase, as also found by others [5, 26, 27]. Landmesser et al. [8] reported that statin treatment of patients with chronic heart failure doubled the activity of superoxide dismutase (SOD), thereby reducing oxidative stress and improving flow- dependent dilation, as compared to low density lipoprotein (LDL) cholesterol lower- ing by a non-statin drug. Recently, the pro-inflammatory effects of statins, via T cells secreting IFN* , have been described also [28].
Endothelium
The endothelium is the first organ that comes into contact with circulating bacterial toxins in sepsis and it coordinates the inflammatory response. Dysfunction of the endothelium is thought to play a major role in the pathogenesis of sepsis. Leukocyte adherence and activation, vasodilation and vasoconstriction, the balance between coagulation and fibrinolysis, and microvascular permeability changes during sepsis, are regulated by the endothelium. A major problem in sepsis is endothelial barrier dysfunction and increased vascular leakage, for instance in the lungs, thought to be associated with ALI/ARDS. Indeed, a number of sepsis-related factors such as LPS, cytokines, and thrombin can impair endothelial barrier function in vitro [29, 30].
One of the pathways that may contribute to barrier dysfunction by activation of the F-actin cytoskeleton is the RhoA/Rho-kinase pathway [30]. RhoA has a geranylgera- nyl anchor required for translocation from the cytosol to the membrane upon acti- vation. We have shown that simvastatin attenuated thrombin-induced hyperperme- ability in endothelial cell monolayers by prevention of translocation of RhoA to the membrane, resulting in reduced formation of stress fibers and conserved focal adhe- sions [29]. In addition, Dell’Omo et al. [1] showed that pre-treatment with simvasta- tin normalized the increased permeability of capillary endothelium in hypercholes- terolemic, atherosclerotic men. Furthermore, several recent experimental in vitro and in vivo studies have reported that statins attenuate increased vascular leak, by preventing RhoA activation [1, 29 – 32].
rate the mildly increased pulmonary leak index (PLI) in 37 patients using statins and 27 patients not using statins, after cardiac or major vascu- lar surgery. The PLI was supranormal (80.014: values above this line are considered elevated) in 21 (57 %) and 16 (59 %) patients, respectively.
Individual data are shown; horizontal bars represent mean and vertical bars the 95 % confidence interval.
From [32] with permission.
In murine, intratracheal LPS-induced ALI, statin pretreatment ameliorated lung vas- cular leak and inflammation, but impaired host defense [33, 34]. Jacobson et al. [31]
treated mice with simvastatin prior to and concomitantly with intratracheally- administered LPS and found protection of barrier function of the lung vessels and prevention of changes in a variety of genes involved in the inflammatory and immune response. In ischemia/reperfusion models, both of lungs and remote organs, prior statin therapy seemed to ameliorate ALI, inflammation, and increased permeability [27]. In a clinical, prospective and observational study involving 64 patients after cardiac and major vascular surgery, known risk factors for increased permeability in the lungs and ALI/ARDS [32], prior statins had been administered in 68 and 44 % of patients, respectively. Prior statin therapy did not ameliorate mildly increased pulmonary permeability after surgery, as measured using a non- invasive radionuclide method [32] (Fig. 4). Since the patients did not fulfil ALI/
ARDS criteria, it cannot be excluded that statins have beneficial effects when perme- ability is severely increased, during sepsis for instance.
RhoA does not only play a role in endothelial dysfunction by activation of the F- actin cytoskeleton, but also by negatively affecting eNOS mRNA expression and impairing release of NO. Endothelium-derived NO mediates vasodilation and inhib- its leukocyte adhesion, platelet aggregation, and smooth muscle proliferation. Sta- tins improve endothelial function by upregulating eNOS, downregulating vasocon- striction endothelin, and increasing responses to vasodilators, also in endotoxin- challenged humans [1, 5, 27, 35]. Statins may also reduce NO scavenging by ROS [26]. Statins may ameliorate endotoxin-induced inducible NO expression mitigating vasoconstrictor responses, in animals and man [5, 36].
Cholesterol-dependent Effects
Statins might not only be beneficial in sepsis because of the pleiotropic effects, but also because of their ability to raise high-density lipoprotein (HDL) cholesterol lev- els while decreasing total and LDL cholesterol, and triglyceride levels. Accumulating evidence indicates the protective role of plasma lipoproteins such as HDL cholesterol in sepsis. HDL cholesterol has higher binding capacity for LPS than other lipopro- teins, via LPS-binding protein [37]. Berbee et al. [38] described that the protein moi- eties of lipoproteins, the apolipoproteins, are responsible for modulating effects of
LPS. HDL-associated apolipoprotein CI [38] enhances the early inflammatory response to sepsis and improves survival, while apolipoprotein E [39] and apolipro- tein A-I [40] reduce the LPS-induced production of cytokines and ameliorate hemo- dynamic changes, ALI and mortality, in animal models. Interestingly, Chien et al.
[41] reported that patients who died within 30 days had lower levels of HDL choles- terol and apolipoprotein A-I during the first four days of severe sepsis, as compared to survivors. Furthermore, HDL cholesterol correlated inversely with IL-6 and TNF – [ levels. A low serum level of HDL cholesterol was an independent predictor of 30-day mortality rate. Furthermore, infusion of recombinant HDL in animal mod- els or healthy volunteers blocks many of the pathophysiological effects of endotoxe- mia or sepsis, but a positive clinical trial has not yet been reported [42]. In addition to raising the level of HDL cholesterol and thereby increasing the binding capacity for LPS, Spitzer and Harris. [43] hypothesized that statins enhance LPS clearance from the circulation and attenuate the septic response by promoting the expression of LDL receptors enhancing the uptake of lipoprotein-LPS complexes. This may result in inhibition of nuclear factor-kappa B (NF-κB) nuclear translocation and thereby amelioration of the pro-inflammatory response [43]. Finally, HDL choles- terol in particular may be a precursor for adequate cortisol synthesis, necessary to cope with stress.
Adverse Events and Withdrawal of Statins
Statins have an excellent safety profile, because more than 50,000 individuals, pri- marily middle-aged and older persons, have been randomized to either placebo or statin in several trials and no severe morbidity or increased mortality was observed in the drug treatment group [44]. Reported adverse effects are neuromuscular, including rhabdomyolysis, axonal neuropathy, myopathy, elevations of hepatic enzymes, without clinically significant liver disease and, possibly in the long term, cancer [45]. The dose of statins should be well balanced, because for most of the pleiotropic Rho-dependent effects, high doses are necessary, while, on the other hand, neuromuscular adverse effects are more likely to occur at higher statin doses.
Rhabdomyolysis is a severe, but fortunately very rare adverse event [44]. The adverse neuromuscular effects might contribute to the development of critical illness polyneuromyopathy, if statin administration is continued throughout critical illness [46]. Patients with sepsis may be more susceptible to statin-associated neuromuscu- lar disease due to a reduced statin metabolism, the additive effect of other processes inhibiting neuromuscular function and the use of drugs associated with increased toxicity of statins. Other risk factors may also apply, such as those described before [44], including advanced age, frailty, multisystem disease, multiple medications, and peri-operative periods.
Despite the growing evidence that statin therapy lowers the incidence, severity, and mortality of sepsis [12], little is known about the effects of statin withdrawal in patients. Recent studies have suggested that acute withdrawal of statin therapy may result in deterioration of endothelial function with resultant propensity for throm- bosis and impaired vasodilation [35, 47, 48]. In addition, Fonarow et al. [49]
reported an increased risk of mortality in patients whose statin therapy was discon- tinued during the first 24 hours of hospitalization for acute myocardial infarction.
This may be explained by a rebound-like increase in oxidative stress, decrease in NO bioavailability, and increase in coagulability [26, 35, 50]. The implication for the sep-
Conclusion
Prospective randomized clinical trials, also in normocholesterolemic patients, are necessary to study the effect of statins in the prevention and treatment of sepsis.
Study variables might include fluid balance, lung permeability, occurrence and severity of ALI/ARDS, and pro-inflammatory factors, among others. Prior statin therapy should not be discontinued in the critically ill (postoperative) patient with sepsis. Continuation, however, carries the presumably small risk of aggravation of critical illness polyneuromyopathy, however.
Acknowledgement: G.P. van Nieuw Amerongen was supported by Netherlands Heart Foundation (The Hague, the Netherlands) grant 2003T032
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