http://infection.thelancet.com Vol 6 April 2006
Sepsis is an overwhelming systemic response to infection
characterised by systemic infl ammation and widespread
tissue injury (panel). Since many infl ammatory pathways
are triggered, merely blocking a single component is
likely to be insuffi cient to arrest the process.3 Indeed, the
modest success seen with approaches targeting individual
mediators may indicate that therapies modulating entire
families of mediators are more effi cacious.3–5
Excellent reviews have recently examined the
pathogenesis of sepsis.3,6 Here, we discuss the escalating
problem of sepsis and present the experimental and
clinical data supporting statins as a potential sepsis
prevention and treatment strategy.
Sepsis: an escalating problem
Sepsis is increasingly common. Surveillance data for the
USA indicate that approximately 751 000 individuals
developed severe sepsis in 1995 (300 cases per 100 000
population).6 Moreover, the incidence of sepsis appears
to be increasing. In one recent comprehensive study in
the USA the incidence of sepsis rose from 83 per 100 000
population in 1979 to 240 per 100 000 population in 2000,
an adjusted rate of increase of nearly 300%.7 Data from
France also suggest an increasing frequency over time.8
This increase likely refl ects the general population aging
and the improved survival of patients with chronic
diseases, which predisposes them to developing sepsis.
Sepsis is frequently lethal. Case fatality rates range
from 25% to 70% depending on defi nition, severity, and
comorbidity. To put this into perspective, severe sepsis
accounts for as many deaths each year as myocardial
infarction, and is the leading cause of death in critically
ill patients.9 Patients with septic shock have a 26-fold
increased risk of death compared with matched intensive
care patients without sepsis.8 Despite advances in
diagnosis and therapy, the number of in-hospital deaths
related to sepsis has tripled over the past 20 years.7
Sepsis is economically costly. Over two-thirds of
patients with sepsis are treated in critical care settings.
Additionally, about half of the survivors require long-
term institutional care.6,7 The mean cost of sepsis in a
recent Quebec study was $11 474 per episode of hospital
care.10 Long-term costs were even higher, averaging about
$27 481 from day 28 to 1 year for survivors. In the USA,
the direct costs of treating severe sepsis alone amount to
$16·7 billion annually.6
Few eff ective mediator targeted therapies are available.
Advances in the understanding of the pathogenesis and
natural history of sepsis have encouraged numerous
studies of novel therapeutics attempting to block key
steps in the cascade of infl ammatory processes leading to
tissue injury and organ dysfunction. Unfortunately, most
of these interventions have failed when tested in rigorous
trials in human beings.3,11,12 One exception is recombinant
activated protein C.11 Although eff ective in patients with
severe sepsis who are at high risk of death, it is expensive
(approximately $10 000 per treatment course), can cause
serious bleeding, and is reserved for those who have
multiple organ failure, a high risk of death, and a low risk
for bleeding. Exogenous glucocorticoid administration
for patients with vasopressor-dependent septic shock has
shown promising, albeit unconfi rmed, results.13,14 Results
from the recently completed, but as yet unreported,
Eurocorticus trial are eagerly awaited.
Lancet Infect Dis 2006; 6:
MT and TS are at the
Interdepartmental Division of
Critical Care Medicine,
Sunnybrook and Women’s
College Health Science Centre,
Toronto, Canada; YA is at the
Medical Intensive Care Unit,
Soroka University Medical
Centre, Faculty of Health
Sciences, Ben Gurion University,
Beer-Sheva, Israel; RSR is at the
Division of Cardiology,
Departments of Medicine and
Preventive Medicine, The
Feinberg School of Medicine,
Chicago, IL, USA; DGH is at the
Division of Clinical Pharmacology
and Toxicology, Sunnybrook and
Women’s College Health Sciences
Centre, and at the Institute for
Clinical Evaluative Sciences,
Dr Marius Terblanche,
Department of Critical Care
Medicine, Sunnybrook and
Women’s Health Science Centre,
2075 Bayview Ave, Toronto,
Ontario, Canada, M4N 3M5.
Tel +1 416 480 4522;
fax +1 416 480 4999;
Panel: Sepsis—spectrum of disease
The systemic infl ammatory response syndrome in response
to microbial invasion. Diagnostic criteria include numerous
variables relating to general signs, infl ammation,
haemodynamics, organ dysfunction, and tissue perfusion.1,2
Sepsis plus organ dysfunction, evidence of hypoperfusion, or
Severe sepsis with hypotension (systolic blood pressure
below 90 mmHg, a mean arterial pressure below 60 mmHg,
or a reduction in systolic blood pressure of more than
40 mmHg) persisting despite adequate fl uid resuscitation,
and in the absence of other causes of hypotension.
Statins: panacea for sepsis?
Marius Terblanche, Yaniv Almog, Robert S Rosenson, Terry S Smith, Daniel G Hackam
Sepsis occurs when the immune system responds to a localised infection at a systemic level, thereby causing tissue
damage and organ dysfunction. Statins have proven health benefi ts in many diseases involving vascular infl ammation
and injury. Recent animal data suggest that the administration of a statin before a sepsis-inducing insult reduces
morbidity and improves survival. The immunomodulatory and anti-infl ammatory eff ects of statins, collectively
referred to as pleiotropic eff ects, lend biological plausibility to such fi ndings. Limited human data hint at reduced
mortality rates in bacteraemic patients, and a reduced risk of sepsis in patients with bacterial infections concurrently
taking statins. These lines of evidence point to a potential new treatment and prevention modality for sepsis. The
stage is set for randomised controlled clinical trials that will determine whether statins represent a safe and benefi cial
treatment in critically ill, septic patients and whether statins are eff ective at preventing sepsis in high-risk clinical
http://infection.thelancet.com Vol 6 April 2006 243
3-hydroxy-3-methylglutaryl coenzyme A
(HMG-CoA) reductase inhibitors
Statins inhibit HMG-CoA reductase and have been
studied extensively in relation to atherosclerosis, an
infl ammatory disease of the vascular endothelium that
shares many similarities with the pathogenesis of sepsis.15
Numerous meta-analyses of clinical trials have provided
unequivocal evidence that statins are eff ective and safe in
preventing cardiovascular morbidity and mortality in
patients with and without pre-existing ischaemic heart
disease.16–22 Although the eff ects of statins were initially
attributed to a reduction in lipid levels, many benefi ts are
now considered to stem from eff ects other than lipid
Statins exert multiple eff ects on various cells through a
number of pathways. These so-called pleiotropic eff ects
are well described in relation to atherosclerosis.24–28 Very
early data from experimental animal and human models
of sepsis suggest that the pleiotropic mechanisms of
statins may benefi cially modulate the infl ammatory
cascades associated with sepsis (table 1). Furthermore,
observations indicate that statins directly aff ect the
infectivity and proliferation of a diverse array of
microorganisms. Although no randomised controlled
trials have tested the effi cacy of statins to prevent or treat
sepsis, interesting observational data support the
hypothesis of a benefi cial eff ect.
Statins and sepsis
Statins exert anti-infl ammatory eff ects by modifying
leucocyte–endothelium interactions and by altering the
responses of monocytes/macrophages and T cells.32,34–38,40–42,51
Statins further modulate infl ammatory cell signalling and
infl ammatory gene expression, thereby reducing the
release of infl ammatory cytokines and acute phase
antioxidant eff ects through a variety of mechanisms.49,50,61–67
Intriguing data demonstrate the antithrombotic properties
of statins through eff ects on platelet function, coagulation,
and fi brinolysis, while these agents also improve
endothelial function by enhancing the expression of
endothelial constitutive nitric oxide and by inhibiting
apoptosis.31,37,38,45–48,52,68–78 Lastly, statins also directly inhibit
MHC class II expression induced by interferon gamma,
thereby modifying T-cell activity.44 Such pleiotropic
properties may therefore be responsible for the benefi cial
eff ects of statins observed in clinical trials of other
infl ammatory, immune-mediated diseases such as
multiple sclerosis and rheumatoid arthritis.79,80
also have important
Prevention in animal models
A number of animal models of sepsis provide data
supporting the notion that statins may be eff ective in the
prevention of sepsis. Mice rendered septic while receiving
simvastatin survived four times longer than controls
while cardiac and haemodynamic function was
completely preserved.81 Responsiveness to dobutamine
was preserved by statin pre-treatment. Similarly, in
response to lipopolysaccharide stimulation, plasma
nitrate levels rose less while the response to phenylephrine
was preserved in male
The mesentery of rats treated with simvastatin before
injection of Staphylococcus aureus alpha toxin exhibited
changes in leucocyte–endothelium interactions as
observed by intravital microscopy.38 Exotoxin-induced
leucocyte rolling, adherence, and leucocyte transmigration
were signifi cantly reduced (p<0·01, p<0·01, and p<0·05,
respectively). Similarly, P-selectin
endothelial cell surfaces was reduced by 50%. Signifi cantly
enhanced expression of endothelial constitutive nitric
oxide synthase was also noted (p<0·05). Furthermore,
mice receiving cerivastatin before lipopolysaccharide
injection expressed signifi cantly reduced serum levels of
tissue necrosis factor-alpha and interleukin 1-beta at
2 hours (both p<0·05), and nitrite and nitrate at 8 hours
(p<0·05). These changes translated into a survival benefi t
with 7-day survival rates signifi cantly improved in treated
mice (26·7% vs 73·3%, p=0·016).43
Finally, a 1-week period of simvastatin treatment was
suffi cient to prevent infection-induced muscarinic
dysfunction of the coronary circulation in mature swine
with acute Chlamydia pneumoniae infection.83 Following
intra-coronary acetylcholine injection (1 × 10–⁶ mol/L),
intra-coronary fl ow was reduced in non-treated animals,
but increased in statin-treated animals. Both groups
demonstrated vasoconstriction at higher doses of
acetylcholine (1 × 10–⁵ mol/L) but vasoconstriction was
signifi cantly more prolonged in the non-treated group
(p<0·01). These benefi ts accrued independent of
simvastatin’s eff ects on lipids and infl ammation, and
point toward a direct eff ect on the coronary circulation in
Wistar rats receiving
Treatment in animal models
Limited early data suggest that statins may provide a
novel treatment modality for established sepsis. Mice
treated with a number of diff erent statins (simvastatin,
atorvastatin, pravastatin, fl uvastatin) 6 hours after a septic
insult demonstrated signifi cantly increased survival
times (p<0·05, except fl uvastatin: p=0·759) due to the
restoration of cardiac function and haemodynamic status
(p<0·005, except fl uvastatin: p<0·05).84 This eff ect was
diminished compared with the eff ects seen in the pre-
treatment (ie, prevention) model.81 Response to
dobutamine stimulation was also signifi cantly improved
in the statin group (p<0·001). Fluvastatin again
underperformed compared with the other agents.
Simvastatin may also be benefi cial in lung injury. A dose
of 20 mg/kg (much higher than used clinically) has been
shown to off er signifi cant
lipopolysaccharide-induced pulmonary vascular leaks
(p<0·05) and infl ammation in a murine infl ammatory
model of acute lung injury.33
http://infection.thelancet.com Vol 6 April 2006
Eff ects on microorganisms
Statins infl uence a broad array of pathogenic
microorganisms. Lovastatin reduces the intracellular
growth of Salmonella typhimurium
macrophages, while atorvastatin does the same in a
mouse model.85 Lovastatin also caused a fi ve-fold increase
in terminal deoxytransferase end-labelling-positive
S typhimurium-infected cells (25% vs 5% in untreated
cells), implicating host cell death as a potential
mechanism for lovastatin’s inhibition of intracellular
bacterial proliferation. Lovastatin also reduces HIV-1 viral
loads and increases CD4+ cell counts in acute infection
models and patients with chronic infection.86 Viral entry
and exit of cells are blocked. Lovastatin additionally
reduces Candida albicans gene expression, and
consequently the organism’s growth, by inhibiting the
sterol pathway.87 Finally, quantitative PCR analysis of
human umbilical vein endothelial cells infected with
cytomegalovirus and co-incubated with fl uvastatin
demonstrated signifi cant reductions in cytomegalovirus
DNA in fl uvastatin-treated supernatants (p<0·01).88 Viral
particle concentrations were up to 30 times lower
(p<0·001). Taken together, it appears that statins decrease
the infectivity and replication rates of a number of
microorganisms. These interesting fi ndings may have
important implications for patients at high risk of
Human experimental data
Early data suggest that the eff ects of statins in animal
models of sepsis may also occur in human beings with
sepsis. A study analysing superoxide anion production in
healthy volunteers (n=14) and non-septic (n=14) and
septic (n=14) intensive care patients found higher oxygen
radical levels in the septic group.66 Simvastatin and
vitamin E reduced oxygen radical production ex vivo by
40% and 20%, respectively. This fi nding is interesting
since oxidative stress appears to be an important factor of
morbidity and mortality in patients with sepsis and
The eff ects of pre-treatment for 4 days with simvastatin
on lipopolysaccharide-induced infl ammatory markers in
vivo was assessed in a double-blind, placebo-controlled
study in 20 healthy men.37 Levels of high sensitivity C-
reactive protein and monocyte chemotactic protein-1 were
signifi cantly reduced (p<0·01 and p<0·05, respectively).
Both these proteins are known tissue factor inducers.
Furthermore, the expression of tissue factor by monocytes,
and prothrombin fragment levels, was signifi cantly
reduced (p<0·05). Of note, increases in tissue factor
expression and disruption of the thrombomodulin–protein
C interaction during sepsis tilt the coagulation system
towards a prothrombotic state.92 Inhibition of tissue factor
expression and improved thrombomodulin–protein C
function may therefore counteract the formation of
microvascular thrombi. Indeed, improved outcomes have
been demonstrated with recombinant thrombomodulin in
animal models of sepsis, and activated protein C in human
beings with sepsis and organ failure.93,94 Importantly,
atorvastatin and simvastatin strongly increase the
expression and functional activity of thrombomodulin in
human umbilical vein endothelial cells, human coronary
artery endothelial cells, and EA.hy926 endothelial cells.45
No data from randomised trials of statins and sepsis are
available, but observational studies lend support to a
potentially important preventive and/or treatment eff ect
(table 2). The largest study to date is a population-based
cohort study involving the linked administrative databases
in Ontario, Canada, and included a matched cohort of
69 168 patients.95 The incidence of sepsis was substantially
lower among patients receiving statins (hazard ratio [HR]
0·81; 95% CI 0·72–0·91). The protective association
between statins and sepsis persisted in high-risk subgroups
including patients with diabetes mellitus, malignancy, and
Actions of statins Reference
Infl ammatory cell signalling and gene expression
Increased NFIκB activity
Inhibition of NFκB, AP1
Decreased lipopolysaccharide-mediated gene expression
Decreased MCP1, RANTES, interleukin 8
Kleeman et al,29 Wang et al,30 Dichtl et al31
Dichtl et al31
Grip et al32
Jacobson et al33
Grip et al,32 Diomede et al,34 Kothe et al,35
Romano et al,36 Steiner et al37
Pruefer et al38
Pruefer et al,38 Bickel et al39
Weber et al,40 Yoshida et al41
Kallen et al42
Decreased exotoxin-induced leucocyte rolling
Decreased P-selectin expression
Decreased CD11a, CD18, VLA4
Direct blocking of LFA1
Release of infl ammatory cytokines and acute phase proteins
Decreased interleukin 1, TNFα, interleukin 6
Decreased C-reactive protein
Direct inhibition of MHC class II
Coagulation and fi brinolysis
Decreased tissue factor expression
Decreased von Willebrand factor
Increased thrombomodulin activity
Decreased PAI1 and increased tissue plasminogen activator activity
Increased ecNOS and decreased iNOS
Antioxidant eff ects
Diomede et al,34 Ando et al43
Kleeman et al,29 Wang et al,30 Steiner et al37
Kwak et al44
Steiner et al37
Bickel et al39
Shi et al45
Bourcier and Libby46
Madonna et al47
Degraeve et al48
Landmesser et al49
Increased haemoxygenase 1Grosser et al50
AP1=activator protein 1; CD=cluster of diff erentiation; COX2=cyclooxygenase 2; ecNOS=endothelial constitutive nitric oxide
synthase; ecSOD=endothelial constitutive superoxide dismutase; iNOS=inducible nitric oxide synthase; LFA1=leucocyte function
antigen 1; MCP1=monocyte chemotactic protein; NFκB=nuclear factor kappa B; NFIκB=inhibitory nuclear factor kappa B;
PAI1=plasminogen activator inhibitor 1; PPAR=peroxisome proliferator-activated receptor; RANTES=regulated upon activation,
normal T cells expressed and secreted; TNFα=tumour necrosis factor α; VLA4, very late antigen, also known as integrin alpha(4)
Table 1: Actions of statins in sepsis models
http://infection.thelancet.com Vol 6 April 2006 245
those receiving oral steroids. Signifi cant reductions in
severe sepsis (HR 0·83; 95% CI 0·70–0·97) and fatal sepsis
(HR 0·75; 95% CI 0·61–0·93) were also observed.
Almog and colleagues96 provided further evidence in a
prospective observational cohort study investigating the
rates of severe sepsis and requirement for intensive care
unit admission in 361 consecutive patients admitted to
hospital with presumed or confi rmed bacterial infections.
Prior statin treatment (n=82) was associated with
signifi cant reductions in the incidence of severe sepsis
(2·4% vs 9%; RR 0·07, 95% CI 0·01–0·51) and need for
intensive care unit admission (3·7% vs 12·2%, p<0·025).
As expected, mortality rates were signifi cantly higher in
patients who developed severe sepsis (p<0·01), but no
statistically signifi cant diff erence was found between
statin-treated and non-treated patients.
A single-centre, retrospective review of 388 patients
with S aureus and Gram-negative bacteraemia demon-
strated signifi cant reductions in both overall (6% vs 28%,
p=0·002) and attributable (3% vs 20%, p=0·01) mortality
in patients receiving statin treatment before admission.97
These diff erences existed despite higher rates of diabetes
mellitus, hypertension, and coronary artery disease in
the statin group, arguing against major confounding by
Retrospective cohort data from two US teaching
hospitals provided information on 787 patients with a
discharge diagnosis of pneumonia.98 Patients were
deemed to be on a statin if it was prescribed at admission.
30-day and 90-day mortality were 9·2% and 13·6%,
respectively. After adjusting for confounders, including
using propensity analysis (a statistical technique to ensure
that patients in both groups are equally likely to be
prescribed a particular intervention, in this instance a
statin), its use at presentation was associated with an odds
ratio for death at 30 days of 0·36 (95% CI 0·14–0·92).
Finally, a retrospective cohort analysis analysed data
from 438 patients requiring hospitalisation for an episode
of bacteraemia between 2000 and 2003.100 Mortality (all-
cause 10·6% vs 23·1%, p=0·022; attributable 6·1% vs
18·3%, p=0·014) was signifi cantly reduced in patients
receiving statins at the time of hospitalisation. More
intriguing is the fi nding of higher reductions in mortality
in patients who continued to receive a statin after the
diagnosis of bacteraemia (1·8% vs 23·1%, p=0·002; 1·8%
vs 18·3%, p=0·0018, respectively). This study provides
the fi rst evidence pointing to a potential treatment benefi t
in septic human patients.
However, not all the data point toward a benefi t. In a
recent study,99 the investigators did an assessment of the
eff ects of statin treatment, before or during intensive
care unit admission, in 438 patients ventilated for more
than 96 hours. Although there was a trend toward lower
rates and delayed onset of infection in statin-treated
patients, these did not reach statistical signifi cance.
Hospital mortality was, however, higher in statin-treated
patients (61% vs 42%, p=0·03).
Due to their observational nature, the studies presented
above may suff er from selection bias and hidden
confounding, and we should interpret these results with
caution. Taken together, however, these early data suggest
that statins may, in human beings, contribute to
preventing sepsis and have a role in the treatment of
Potential adverse eff ects
Statins have the potential for adverse eff ects. Some
evidence suggests that low cholesterol levels may
predispose to infection and resultant mortality.101,102 Serum
lipoproteins may protect against the lethal eff ects of
endotoxinaemia by binding
endotoxin.103–106 Furthermore, a low serum cholesterol
concentration is an independent predictor of infectious
complications and mortality in hospitalised patients.107–111
In addition, in a large community-based cohort of 55 300
men and 65 271 women followed for 15 years, a one
standard deviation increase in total serum cholesterol
was associated with a reduction in risk of infection
(excluding respiratory and HIV) of 8% in both men (95%
CI 4–12 %) and women (95% CI 5–11%).101 Individuals in
the lowest quintile of cholesterol had a 40% increased
risk for infection compared with patients in the highest
Additionally, statins are associated with serious organ
specifi c side-eff ects, such as muscle and hepatic toxicity.
In a comprehensive, individual patient-based meta-
analysis, the incidence of rhabdomyolysis was extremely
low (5-year excess 0·01%, SE 0·01).22 Hospitalisation for
rhabdomyolysis is sometimes needed, while recurrent
muscle pain is common on statin re-challenge.112 The
incidence of hepatotoxicity is also very low. For example,
for lovastatin, the fi rst of the statins to receive regulatory
approval, the rate of elevation in serum alanine
aminotransferase levels is 1 for every 1·14 million patient-
Study design SettingNumber of
Statin eff ect
Elderly patients with cardiovascular
disease hospitalised for sepsis
Patient admitted to hospital with
suspected or confi rmed bacterial
Patients admitted to hospital with
Patient with discharge diagnosis of
Intensive care patients ventilated
more than 96 hours
Patient requiring hospital admission
Decreased sepsis, severe sepsis and
Decreased incidence of severe
sepsis* and need for intensive care
Decreased mortality in statin-
Decreased 30-day mortality*
438Decreased mortality with
Decreased mortality when
treatment continued after
*Statistically signifi cant (all p values less than 0·05).
Table 2: Summary of human observational data in sepsis
http://infection.thelancet.com Vol 6 April 2006
treatment years,113 which is approximately equal to the
background rate of idiopathic acute liver failure.
The extension of therapy to new patient populations
opens up the potential for the development of currently
unknown side-eff ects. Indeed, some have been described
already following statin use, including peripheral
neuropathy, tendinopathy, a lupus-like syndrome, the
exacerbation of myasthenia gravis, and a disorder
resembling Guillain-Barré syndrome.114–119 These side-
eff ects are quite rare, and usually resolve with either a
reduction in dose, or cessation of treatment. However,
the safety profi le of statins in critically ill patients
remains to be established and clinicians using these
agents in novel ways should monitor for unusual
Potential therapeutic implications
Positive, convincing results from well-designed trials
would have four immediate implications for patient care
and further research. First, a widely available, inexpensive
treatment option would be available to prevent or treat a
common and frequently fatal human disease. Second,
patients with concurrent infections already prescribed
statins would be discouraged from discontinuing their
medications, and physicians might be encouraged to
continue these drugs during a patient’s hospitalisation.
Third, patients at high risk for developing sepsis might
receive statin therapy during the period of highest risk.
Fourth, pharmaceutical companies may be stimulated to
develop intravenous forms of statins for parenteral
We therefore argue that a research agenda is needed to
answer the following clinically important questions: are
statins eff ective at preventing sepsis in high-risk clinical
settings, and are statins a safe and benefi cial treatment in
critically ill septic patients?
Confl icts of interest
MT, YA, TSS, and DGH declare that they have no confl icts of interest.
RSR has received research grants from Astra Zeneca, Bristol Myers
Squibb, Merck, and Pfi zer, and has received speaker’s fees from Astra
Zeneca, Bristol Myers Squibb, and Merck.
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