Effectiveness of Statins in Reducing the Rate of Severe

Sepsis: A Retrospective Evaluation

Christopher P. Martin, Pharm.D., M.S., Robert L. Talbert, Pharm.D., FCCP,
David S. Burgess, Pharm.D., FCCP, and Jay I. Peters, M.D.
Study Objectives. To determine whether use of 3-hydroxy-3-methylglutaryl
coenzyme A reductase inhibitors (statins) is associated with a reduced rate
of severe sepsis, and to further characterize the effect of statins on the
frequency of organ dysfunction in patients with severe sepsis.
Design. Retrospective cohort study.
Setting. University-associated teaching hospital.
Patients. Fifty-three patients admitted with sepsis; 16 were receiving statins
and 37 were not receiving statins (controls) before admission.
Measurements and Main Results. Patients were identified by the
International Classification of Diseases, Ninth Revision, Clinical Modification
codes. Patient demographics, vital signs, and laboratory values were
collected from their electronic medical records. The primary end point was
rate of severe sepsis, defined in accordance with guidelines from the
American College of Chest Physicians and the Society of Critical Care
Medicine. Secondary end points were in-hospital mortality rate and rate of
five categories of organ dysfunction (cardiovascular, renal, pulmonary,
hematologic, and metabolic). Preadmission statin therapy, compared with
no statin therapy, was associated with a 30% lower rate of severe sepsis
(56% vs 86%, p<0.02). In-hospital mortality was not significantly different
between groups (38% vs 49%, p=0.33); however, the rate of cardiovascular
dysfunction, defined as hypotension requiring vasopressor therapy, was
significantly lower in the statin group (38% vs 73%, p<0.02). No
significant differences in the other organ dysfunction categories were noted
between groups.
Conclusion. Statins appear to prevent sepsis from becoming severe, most
notably through prevention of sepsis-induced hypotension. This potential
role for statins in the prevention and treatment of severe sepsis should be
further evaluated in a randomized controlled trial.
Key Words: sepsis, severe sepsis, statins, 3-hydroxy-3-methylglutaryl
coenzyme A reductase inhibitors, HMG-CoA reductase inhibitors.
(Pharmacotherapy 2007;27(1):2026)
Sepsis, a syndrome of systemic inflammation
and immune system dysregulation, accounts for
an estimated 2% of all hospital admissions and
carries an absolute incidence of 5095
cases/100,000 people in the United States. 1, 2
Among patients admitted for sepsis, 924%
experience progression to severe sepsis, a serious
condition of sepsis with organ dysfunction.2, 3

Despite the availability of effective treatments,

severe sepsis remains deadly, with a mortality rate
of 2951%.2, 4, 5
The precise pathophysiology of sepsis and
severe sepsis has not been fully elucidated.
General consensus implicates immune system
dysregulation, although experts disagree as to the
relative roles of proinflammatory and antiinflam-

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EFFECTIVENESS OF STATINS IN PREVENTING SEVERE SEPSIS Martin et al

matory mechanisms. 6 Even so, most current
modalities for treating severe sepsis control or
prevent complications without addressing the
underlying immunopathology. This may explain
the continued high mortality rate from severe
sepsis. Of current treatments, only corticosteroids
and drotrecogin alfa have immune system
activity. Corticosteroids have been shown to
reduce the mortality rate at dose equivalents of
hydrocortisone 300 mg/day or lower,7 but higher
daily doses have actually increased the mortality
rate.8, 9 Therefore, sepsis treatments are needed
that attenuate the immune response enough to
protect the host without compromising the
response to infection and that can be administered earlier in the disease course to alleviate
and prevent complications.
The 3-hydroxy-3-methylglutaryl coenzyme A
(HMG-CoA) reductase inhibitors (statins) are
cholesterol-lowering drugs prescribed for
prevention of vascular events. Statins significantly reduce mortality and morbidity in patients
for whom primary or secondary prevention of
cardiovascular diseaserelated events is
indicated.1012 Statins are competitive antagonists
of HMG-CoA reductase, the catalyst enzyme for
the rate-limiting step in de novo synthesis of
cholesterol, the conversion of HMG-CoA to
mevalonate (Figure 1).13
Beyond this antihyperlipidemic activity, statins
possess immunomodulatory properties secondary
to reduced synthesis of farnesyl pyrophosphate
and geranylgeranyl pyrophosphate, the isoprenoid
derivatives of mevalonate. Isoprenoids mediate
important posttranslational modification of
proteins by attaching the lipophilic moieties that
provide a surface for attachment of the protein to
the cell membrane. Isoprenylation by farnesyl
pyrophosphate and geranylgeranyl pyrophosphate are essential for the function of Ras
guanosine triphosphatases, which operate in
signal transduction cascades for important
cellular processes in vascular endothelium and
From the Division of Pharmacotherapy, College of
Pharmacy, University of Texas at Austin, Austin, Texas (Drs.
Martin, Talbert, and Burgess); and the Departments of
Pharmacology (Drs. Martin, Talbert, and Burgess) and
Medicine (Drs. Talbert, Burgess, and Peters), University of
Texas Health Sciences Center at San Antonio, San Antonio,
Texas.
Presented at the annual meeting of the American College
of Clinical Pharmacy, San Francisco, California, October
2326, 2005.
Address reprint requests to Christopher P. Martin,
Pharm.D., M.S., College of Pharmacy, University of
Oklahoma, 4502 East 41st Street, Tulsa, OK 74135; e-mail:
Christopher-Martin@ouhsc.edu.

leukocytes.14, 15
Statin therapy has been associated with
reduced expression of E-selectin, P-selectin,
vascular cell adhesion molecule, and intracellular
adhesion molecule, all of which mediate
leukocyte interactions with vascular endothelium
and associated underlying tissues. 16, 17 In
addition, statins reduce expression of the major
transcription factor for the immune system,
nuclear factork B, 18 and proinflammatory
cytokines interleukin (IL)-6 and IL-1b.18, 19
The broad immunomodulatory properties of
statins may prove beneficial for patients with
sepsis. In murine sepsis models, pretreatment
with statins has improved survival.20, 21 In a
prospective cohort study, statins taken before
admission for pneumonia, cellulitis, or urinary
tract infection were associated with a lower rate
of severe sepsis than seen in patients who did not
receive a statin (2.4% vs 19%, 95% confidence
interval 0.030.52, p<0.001). 22 The rate of
admission to the intensive care unit (ICU) also
was lower for statin-treated patients (3.7% vs
12.2%, p=0.025). However, no significant
difference was noted between groups in the 28day mortality rate or score on the Acute
Physiology and Chronic Health Evaluation
(APACHE) II.
Our objective was to determine whether use of
statins is associated with a reduced rate of severe
sepsis in a population of patients with confirmed

Mevalonate

HMG-CoA

HMG-CoA
reductase

Isopentyl-PP

Statins
Geranylgeranyl-PP

Farnesyl-PP

Squalene

Geranylgeranyl
transferase

Farnesyl
transferase

(isoprenylation)

(isoprenylation)

Ras GTPases
(Rho, Ros, Rac, Rab)

Geranylgeranyl group + PP

Ras GTPases
(Rho, Ras)

Cholesterol

Farnesyl group + PP

Figure 1. Statins compete with 3-hydroxy-3-methylglutaryl

coenzyme A (HMG-CoA) for binding on the HMG-CoA
reductase enzyme and block production of mevalonate and
its derivatives, including cholesterol and the isoprenoids
geranylgeranyl pyrophosphate (PP) and farnesyl PP.
Reduced isoprenoid levels result in reduced availability of
functional Ras superfamily guanosine triphosphatase
(GTPases).

22

PHARMACOTHERAPY Volume 27, Number 1, 2007

sepsis, and to further characterize the effect of

statins on the frequency of organ dysfunction in
patients with severe sepsis.
Methods
Study Design
This retrospective cohort study, conducted at
University Hospital, University Health System,
San Antonio, Texas, evaluated the effectiveness of
statins taken before hospital admission for sepsis
in reducing the rate of severe sepsis. The project
was approved by the hospitals research department as well as the institutional review board of
the University of Texas Health Sciences Center at
San Antonio.
Study Patients
Data from patients admitted to the hospital
between October 1, 2003, and September 30,
2004, were reviewed. Patients then were
identified using the International Classification of
Diseases, Ninth Revision, Clinical Modification
(ICD-9-CM) codes for septicemia or systemic
inflammatory response syndrome (Table 1).
Patients who met the criteria for sepsis were
eligible for inclusion in the study. Sepsis was
defined, according to the American College of
Chest Physicians and the Society of Critical Care
Medicine (ACCP-SCCM), as suspected or proven
infection with at least two of the four systemic
inflammatory response syndrome criteria (Table
2). 23 Eligibility was determined by review of
laboratory data and vital signs contained in the
patients electronic medical record. Outpatient
pharmacy records and the admission history and
physical examination results in the electronic
medical record were used to determine whether
patients had been taking statins before
admission. Patients for whom this information
could not be obtained were excluded from the
study.
Patients were also excluded if they had not
taken a statin before but were prescribed one
during their hospital course. Other exclusion
criteria were malignancy, solid-organ transplant,
human immunodeficiency virus infection,
neutropenia (absolute neutrophil count of < 1000
cells/mm3), and receiving immunocompromising
drugs. Patients who experienced cardiopulmonary
arrest within 24 hours of hospital arrival were
excluded because ischemic injury sustained
during resuscitation efforts would confound their
disease course. Those younger than 40 years

Table 1. ICD-9-CM Codes Used for Patient Identification

Code
Description
038.0
Septicemia
038.9
Unspecified septicemia
995.91
Systemic inflammatory response syndrome
without organ dysfunction
995.92
Systemic inflammatory response syndrome
with organ dysfunction
ICD-9-CM = International Classification of Diseases, Ninth Revision,
Clinical Modification.

Table 2. Systemic Inflammatory Response Syndrome Criteriaa

Criteria
Definition
Fever or
hypothermia
Temperature > 100.4F or < 98.6F
Tachypnea
Respiratory rate > 20 breaths/min
Tachycardia
Heart rate > 90 beats/min
Leukocytosis or
White blood cell count > 12 or
leukopenia
< 4 x 103/mm3, or > 10% bands
a

Systemic inflammatory response syndrome is defined as the presence

of two or more of these criteria.

were also excluded since they were not likely to

be taking statins. Also excluded were patients
whose medical records were unavailable for their
entire hospital stay, as in the case of a patient
who was transferred from another facility.
Baseline laboratory values, blood culture
results, medical histories, and vital signs were
collected for the first 24 hours of ICU admission
to define potential differences between the cohort
of patients who had taken statins before
admission and the cohort of patients who had
not. If a patient was not admitted to the ICU,
information was gathered from the hospital
admission data regardless of which medical
service admitted the patient. If numerous values
were recorded on the day of admission, the
patients most deviant value from the mean of the
normal range was recorded in accordance with
the APACHE scoring methods. Overall disease
severity at baseline was evaluated with the
APACHE III score.
End Points
The primary end point was occurrence of
severe sepsis, defined according to ACCP-SCCM
guidelines as sepsis with evidence of least one
organ dysfunction category. 23 Because it is
difficult to ascertain retrospectively what
constitutes adequate fluid resuscitation, the
definitions of cardiovascular and renal
dysfunction categories for this study were

EFFECTIVENESS OF STATINS IN PREVENTING SEVERE SEPSIS Martin et al

Table 3. Definitions of Organ Dysfunction Categories
Category
Definition
Cardiovascular
Hypotension requiring vasopressor therapy
Renal
Urine output < 0.5 ml/kg/hr
Pulmonary
PaO2:FiO2 ratio 250 or 200 with
no other organ dysfunction
Hematologic
Platelet count 80 x 103/mm3 or
decreased by 50% over 3 days
Metabolic
pH 7.30 and plasma lactate level
1.5 x ULN
PaO2 = partial pressure of oxygen in arterial blood; FiO2 = fraction
of inspired oxygen; ULN = upper limits of normal.

modified from the ACCP-SCCM definitions,

removing any mention of fluid resuscitation
(Table 3). The definitions of pulmonary, hematologic, and metabolic dysfunction remained
unaltered.
Secondary end points were in-hospital mortality
rate and rate of each organ dysfunction category
considered separately.
Statistical Analysis
Statistical analyses were performed using SAS
JMP (SAS Institute Inc., Cary, NC). Continuous
variables, including laboratory values, vital signs,
and APACHE III scores, were evaluated for
normality with the Shapiro-Wilk W test.
Normally distributed continuous variables were
analyzed by the Student t test, nonnormal
variables by the Wilcoxon t test. Nominal
variables, including primary and secondary end
points, were evaluated by the Fisher exact test.
Baseline characteristics were analyzed for
correlation with end points using univariate
logistic regression. Baseline characteristics
identified as disparate between the two cohorts
and those identified by univariate logistic
regression were evaluated in a multivariate
logistic regression model.
Results
Patients
A total of 180 patients matched the requested
ICD-9-CM codes. Almost half of these patients
were excluded because they were younger than
40 years or because the presence or absence of a
statin in their drug regimen before admission
could not be established. A total of 127 patients
were excluded (Table 4); of the 53 remaining, 16
were assigned to the statin cohort and 37 to the
control (no statin) cohort. Most patients in the
statin group were taking pravastatin (75%),

23

Table 4. Reasons for Exclusion in the 127 Patients

No. (%)
Exclusion Criteria
of Patients
Age < 40 yrs
34 (26.8)
Statin status unknown
29 (22.8)
Malignancy
28 (22.1)
Solid organ transplant
13 (10.2)
Cardiac arrest 24 hrs of admission
9 (7.1)
Human immunodeficiency virus
5 (3.9)
Patient transferred during care
4 (3.2)
In-hospital statin therapy started
3 (2.4)
Neutropenia
2 (1.6)

followed by atorvastatin (13%), then simvastatin

(6%) and lovastatin (6%).
Baseline characteristics of the 53 study patients,
including demographics, medical history,
laboratory values, and vital signs, are shown in
Table 5. Average age of the statin cohort was
almost 10 years older than that of the controls.
More statin-treated patients than controls had a
history of stroke and diabetes mellitus. In
contrast, significantly more control patients than
statin-treated patients had a history of cirrhosis.
Serum bilirubin levels were higher in the control
cohort, but serum albumin levels and platelet
count were higher in the statin group.
No significant differences in baseline vital signs
were noted between groups. In all the study
patients, the four most common types of
infection were pulmonary (33%), skin and soft
tissue (24%), urinary tract (18%), and abdominal
(11%). Overall, 27 patients (51%) had a positive
blood culture, with gram-positive bacteria the
most common isolate (57%), followed by gramnegative (29%) and mixed infections (14%).
Primary and Secondary End Points
Statin use was associated with a 30% absolute
reduction in the rate of severe sepsis (56% vs
86% for statin-treated patients vs controls,
p<0.02; Figure 2). The in-hospital mortality rate
did not differ significantly between cohorts (38%
vs 49%, p=0.33); however, the rate of cardiovascular dysfunction was significantly lower in
the statin-treated patients versus controls (38%
vs 73%, p<0.02; Figure 3). No significant
differences were noted between groups in the
renal, pulmonary, hematologic, or metabolic
organ dysfunction categories.
Covariates
Univariate logistic regression indicated that
bilirubin concentration (p=0.02) and the

24

PHARMACOTHERAPY Volume 27, Number 1, 2007

Table 5. Baseline Characteristics of the Study Patients
Statin Group
Control Group
Characteristic
(n=16)
(n=37)
No. (%)
Sex
Male
10 (62.5)
22 (59.5)
Female
6 (37.5)
15 (40.5)
Medical history
Chronic heart failure
3 (18.8)
3 (8.1)
Cirrhosis
0 (0)
10 (27.3)
Chronic kidney disease
7 (43.8)
8 (21.6)
COPD
2 (12.5)
2 (5.4)
Diabetes mellitus
13 (81.3)
13 (35.1)
Stroke
4 (25.0)
1 (2.7)
Mean SD
Age (yrs)
65.9 9.8
56.7 11.9
Maximum temperature (F)
99.3 1.9
100.1 2.4
Serum sodium (mEq/L)
132 6
133 9
Serum potassium (mEq/L)
4.2 1
4.2 1
Serum bicarbonate (mEq/L)
18 6
19 7
Serum albumin (g/dl)
3.0 0.7
2.4 0.6
Hematocrit (%)
31.5 5.7
32.9 6.8
Arterial pH
7.33 0.16
7.31 0.11
APACHE III score
95 31
87 30
Median (range)
Heart rate (beats/min)
108 (57178)
120 (60199)
Mean arterial pressure
(mm Hg)
77 (37124)
64 (42163)
Serum creatinine (mg/dl)
2.9 (0.68.4)
2.1 (0.213.9)
Serum glucose (mg/dl)
180 (461011)
125 (342200)
Serum bilirubin (mg/dl)
0.6 (0.23.4)
1.5 (0.321.6)
WBC count (x 103/mm3)
11.9 (3.866.9)
14.8 (2.743.5)
Platelet count (x 103/mm3)
231 (55525)
131 (40569)
PaO2 (mm Hg)
112 (44237)
109 (32247)
PaCO2 (mm Hg)
33 (1761)
34 (1689)

p Value
0.120

0.250
0.017
0.097
0.574
0.003
0.025
0.005
0.190
0.800
0.982
0.453
0.029
0.437
0.733
0.482
0.177
0.522
0.610
0.150
0.002
0.433
0.019
0.922
0.855

COPD = chronic obstructive pulmonary disease; APACHE = Acute Physiology and Chronic Health
Evaluation; PaO2 = partial pressure of oxygen in arterial blood; PaCO2 = partial pressure of carbon
dioxide in arterial blood; WBC = white blood cell.

APACHE III score (p=0.04) were independent

predictors of severe sepsis. No other continuous
variables were predictive, although a trend was
seen for mean arterial pressure (p=0.08), heart
rate (p=0.07), and maximum body temperature
(p=0.08). A multivariate logistic regression
model including age, serum albumin concentration, platelet count, bilirubin concentration,
and APACHE III score failed to identify any
factor associated with the outcome of severe
sepsis. Sex and medical history variables had no
effect on the outcome of severe sepsis when
analyzed by the Fisher exact test.
Since a significant difference was noted
between groups in the frequency of cirrhosis, and
since elevated bilirubin levels were associated
with severe sepsis, patients with cirrhosis were
excluded from an analysis of the primary end
point to ensure that this did not affect the results.

When the 10 control patients with cirrhosis were

excluded, statins were still associated with a
reduced rate of severe sepsis (56% of statintreated patients vs 85% of controls, p<0.05).
Discussion
Our study findings were in agreement with the
findings of another study22 in that the rate of
severe sepsis was significantly lower in patients
who received statin therapy before hospital
admission. Neither investigation observed a
significant reduction in mortality rate; however,
this may be related to the small sample sizes in
each study. Studies with larger numbers of
patients may show a benefit in mortality rate,
especially considering that the death rate from
severe sepsis is an estimated 2951%. 2, 4, 5
Differences between these two investigations

25

EFFECTIVENESS OF STATINS IN PREVENTING SEVERE SEPSIS Martin et al

were noted in the rate of severe sepsis in control
patients and the absolute risk reduction. The
reason for these differences is unknown; they
may result from the lack of random treatment
assignment in these investigations.
We believe our study is the first to evaluate the
effect of statins on the frequency of organ
dysfunction. The reduced rate of severe sepsis in
the statin cohort was driven in large part by the
reduced rate of cardiovascular dysfunction,
defined in our study as hypotension requiring
vasopressor therapy. Previous studies have
demonstrated that statins reduce levels of the
integrins P-selectin, E-selectin, and both vascular
cell adhesion molecule and intracellular adhesion
molecule. 16, 17 Diminished expression, and
perhaps even functionality of these proteins, may
reduce leukocyte diapodesis and prevent damage
to the vascular endothelium and smooth muscle
cells. This offers a possible mechanistic
explanation for the efficacy of statins in patients
with sepsis that should be evaluated in future
investigations.
In addition, the reduction in hypotension
requiring vasopressor therapy in the statin cohort
supports the findings of a study that used a
murine model of sepsis. 20 The authors found
that mice exposed to simvastatin were resistant to
reductions in cardiac output and mean arterial
pressure when sepsis was induced. The authors
also demonstrated that simvastatin administration
restored sensitivity to dobutamine and thus
recovery of cardiac output in sham-treated mice.
Therefore, statins may provide an interventional
strategy in patients with severe sepsis or even

septic shock, and should be investigated more

formally in that regard.
Limitations
Retrospective evaluations are intrinsically
poorly controlled; therefore, the results of our
study must be considered with a few caveats.
Potential uncontrolled confounders in this study
were the administration of other treatments, such
as antibiotics or other drugs, which may have
differed between groups. Statin therapy was
associated with a reduced rate of severe sepsis,
but this does not prove that statins reduce the
progression to severe sepsis from sepsis. Many of
the study patients presented with severe sepsis;
therefore, it is unclear whether their disease
course would have abated if proper treatment had
been sought earlier. The disparate rate of
cirrhosis, hyperbilirubinemia, hypoalbuminemia,
and thrombocytopenia in the control group could
independently affect morbidity; however, no
effect on morbidity materialized after subgroup
analysis. Therefore these confounders did not
alter the conclusions of our study.
Future Directions
Given the results of this retrospective study as
well as those of another study,22 statin use as an
interventional strategy for sepsis deserves further
evaluation. Statins should be evaluated in a
randomized, prospective, placebo-controlled trial
involving patients with sepsis; the primary end
point should be mortality rate. Furthermore,
considering the significant reduction in the rate
of cardiovascular dysfunction with statins in our

100

100

80

Statin group
Control group

Percentage of Patients

Percentage of Patients

Statin group
Control group

60
40
20
0
Severe Sepsis

In-Hospital Mortality

Figure 2. Primary end point results. Nine (56%) of the 16

statin-treated patients developed severe sepsis versus 32
(86%) of the 37 control patients (p<0.02). No significant
difference in mortality was noted between groups; six (38%)
statin-treated patients and 18 (49%) controls died during
their hospital stay (p=0.33).

80
60
40
20
0

Cardiovascular

Renal

Pulmonary

Hematologic

Metabolic

Figure 3. Rates of organ dysfunction by category for the

two groups. Significantly fewer statin-treated patients (6 of
16 [38%]) than controls (27 of 37 [73%]) experienced
cardiovascular dysfunction (p<0.02). No significant
difference in any other category was noted between groups.

26

PHARMACOTHERAPY Volume 27, Number 1, 2007

investigation as well as in a study in mice,20

statins should also be evaluated in patients with
septic shock to determine the effect on hemodynamic parameters.
Conclusion
Few effective treatment strategies exist for
severe sepsis, a serious condition with a high
mortality rate. Many therapies administered in
patients with severe sepsis manage the
complications involved without addressing the
underlying immunopathology of the disorder.
Statins have broad immunomodulatory properties
that may be protective. In our study, statin use
before hospital admission was associated with a
reduced frequency of severe sepsis. Our findings
need to be replicated in randomized, prospective,
placebo-controlled trials to further elucidate the
potential of statins as a preventive or therapeutic
strategy in patients with sepsis.
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