J Neurosurg 118:669675, 2013

AANS, 2013

Effect of rosuvastatin on cytokines after traumatic

head injury
Clinical article
*Martin Snchez-Aguilar, M.Sc.,1 J. Humberto Tapia-Prez, M.D., 2
Jos Juan Snchez-Rodrguez, M.D.,1,3 Juan Manuel Vias-Ros, M.D.,1,3
Patricia Martnez-Prez, N.P., 4 Esperanza de la Cruz-Mendoza, C.P., 5
Martin Snchez-Reyna, M.D.,1 Jaime Gerardo Torres-Corzo, M.D., 3
and Antonio Gordillo -Moscoso, Ph.D.1
Departments of 1Clinical Epidemiology and 5Nuclear Medicine Laboratory, Universidad Autnoma de San
Luis Potos; Departments of 3Neurosurgery and 4Neuropsychology and Rehabilitation, Hospital Central
Dr. Ignacio Morones Prieto, San Luis Potos, Mxico; and 2Klinik fr Neurochirurgie, Otto-von-Guericke
Universitt, Magdeburg, Germany
Object. The favorable effect of statin treatment after traumatic brain injury (TBI) has been shown in animal studies and is probably true in humans as well. The objective of this study was to determine whether acute statin treatment
following TBI could reduce inflammatory cytokines and improve functional outcomes in humans.
Methods. The authors performed a double-blind randomized clinical trial in patients with moderate to severe
TBI. Exclusion criteria were as follows: prior severe disability; use of modifiers of statin metabolism; multisystem
trauma; prior use of mannitol, barbiturates, corticosteroids, or calcium channel blockers; isolated brainstem lesions;
allergy to statins; previous hepatopathy or myopathy; previous treatment at another clinic; and pregnancy. Patients
were randomly selected to receive 20 mg of rosuvastatin or placebo for 10 days. The main goal was to determine the
effect of rosuvastatin on plasma levels of tumor necrosis factora, interleukin (IL)1b, IL-6, and IL-10 after 72 hours
of TBI. Amnesia, disorientation, and disability were assessed 3 and 6 months after TBI.
Results. Thirty-six patients were analyzed according to intention-to-treat analysis; 19 patients received rosuva
statin and 17 received placebo. The best-fit mixed model showed a significant effect of rosuvastatin on the reduction
of tumor necrosis factora levels (p = 0.004). Rosuvastatin treatment did not appear to affect the levels of IL-1b,
IL-6, and IL-10. The treatment was associated with a reduction in disability scores (p = 0.03), indicating a favorable
functional outcome. Life-threatening adverse effects were not observed.
Conclusions. The authors data suggest that statins may induce an antiinflammatory effect and may promote
recovery after TBI. The role of statins in TBI therapy should be confirmed in larger clinical trials. Clinical trial registration no.: NCT00990028.
(http://thejns.org/doi/abs/10.3171/2012.12.JNS121084)

Key Words traumatic brain injury rosuvastatin cytokine disability

raumatic brain injury continues to be a worldwide

health problem with devastating familial, social,
and economic consequences.7 The recovery phase

Abbreviations used in this paper: ALT = alanine transaminase;

AST = aspartate transaminase; CK = creatine kinase; DRS = Disability Rating Scale; GCS = Glasgow Coma Scale; GOAT = Galveston Orientation Amnesia Test; IL = interleukin; TBI = traumatic
brain injury; TCDB = Traumatic Coma Data Bank; TNFa = tumor
necrosis factora.
* Drs. Snchez-Aguilar and Tapia-Prez contributed equally to
this work.

J Neurosurg / Volume 118 / March 2013

includes many societal difficulties and loss of productivity. The available interventions do not clearly improve
long-term functional outcomes after TBI. Thus, the management of TBI remains largely supportive, directed toward control of cerebral edema and intracranial hypertension.24
The structural analogs of b-hydroxy-b-methylglutaryl coenzyme A (HMG CoA) reductase (statins) have
been assessed in the treatment of aneurysmal subarachnoid hemorrhage and spontaneous intracerebral hemorrhage in humans (for a review, see the article by TapiaPrez et al.21). Studies in animal models of TBI using
669

M. Snchez-Aguilar et al.
statins showed quicker absorption of bleeding contusions
and improvement of spatial orientation and neurological
function in statin-treated animals than in controls.12,13,15,23
Previously, we suggested that acute therapy with rosuvastatin could help reduce the duration of posttraumatic
amnesia and disorientation.22 A recently published study
showed that statin users had lower mortality rates and
better functional outcomes 12 months after TBI.20 The
apparent neuroprotective effect of statins seems to be related to the regulation of inflammatory processes and the
induction of neurorestorative cellular mechanisms.6,21,25
After trauma, astrocytes and microglia release IL1b and TNFa, which activate an inflammatory cascade.
Clinical studies showed high levels of TNFa, IL-10, and
IL-6 in TBI patients.4,10,14,16 The negative effects of IL-1b
and TNFa after TBI are clear.14 The role of IL-6 is more
ambiguous because it has both pro- and antiinflammatory
effects. Interleukin-10 is generally considered an antiinflammatory cytokine.10,14 In animals, simvastatin selectively reduces IL-1b expression, which seems to inhibit
activation of microglial cells and astrocytes.12
Based on these data, we designed a randomized placebo-controlled clinical investigation. The purpose of the
study was to assess the systemic acute antiinflammatory
effects of statins after TBI. We hypothesized that rosuvastatin would reduce or prevent the elevation of plasma
levels of TNFa, IL-1b, IL-6, and IL-10.

Methods
Patient Population

We conducted this randomized clinical placebo-controlled study at one hospital (Hospital Central Dr. Ignacio Morones Prieto, San Luis Potos, Mxico). Eligible
patients ranged in age from 16 to 60 years with moderate
to severe TBI (GCS score < 13) and intracranial lesions,
as noted on CT scanning. Eligible patients were available
for randomization within the first 24 hours after TBI.
Exclusion criteria were predated head injury or severe disability due to neurological or psychiatric disease.
Other exclusion criteria were as follows: administration of
fibrates, niacin, cyclosporine, azoles, macrolides, protease
inhibitors, nefazodone, verapamil, diltiazem, or amiodarone in the past 24 hours; poor chances of survival; multisystem trauma; administration of mannitol, barbiturates,
corticosteroids, indomethacin, or calcium channel blockers before recruitment; isolated brainstem lesions; allergy
to statins; history of hepatopathy or myopathy; prior treatment at another clinic; and pregnancy. We also excluded
patients who died within 72 hours of TBI and those who
died of causes unrelated to brain injury. Patients families were informed of the study objectives, and signed
informed consent was obtained. The study was approved
by the local ethics committee and was registered with the
local health agency and with clinical trials (clinical trial
registration no.: NCT00990028).

Management and Intervention Protocol

Patients were managed in accordance with the Advanced Trauma Life Support (ATLS) guidelines. Once

670

patients were stable and the inclusion criteria were met,

they were randomly allocated to receive either oral administration of rosuvastatin (20 mg Crestor, AstraZeneca) or placebo (tablets with the same appearance and
base) for a period of 10 days. Nasogastric or orogastric
catheters were placed as needed.
Routine treatment at admission included administration of saline solution (0.9%), a gastric protector (omeprazole 40 mg/day), an analgesic (ketorolac 30 mg/12 hours),
and an anticonvulsant agent for a period of 48 hours (diphenylhydantoin; loading dose of 15 mg/kg, maintenance
at 100 mg/8 hours). Haloperidol was used as an antipsychotic drug in case of agitation. For intubation, we used
diazepam (2-10 mg) plus rocuronium (0.6 mg/kg).
Demographic, clinical, and laboratory values were
recorded on admission. The variables included age, sex,
mechanism of trauma, associated lesions, time between
trauma and first statin dose, pupillary symmetry, and responsiveness at admission. We also analyzed basal systolic and diastolic arterial blood pressure (mm Hg), hematocrit level (%), total leukocyte count (cells/mm3), and
plasma glucose levels (mg/dl). The CT findings were classified according to the TCDB classification.17 Drug safety
was evaluated by monitoring plasma levels of hepatic
enzymes (ALT and AST) and CK for muscular toxicity
every 3rd day.
Patient Randomization

Drugs were prepared according to a list of randomized sequential numbers (blocks of 4) prior to the beginning of the study. Random sequential numbers were
generated using R-2.12.1 software for Windows. Packets
containing tablets were provided to the infirmary staff
who delivered the tablets to the patients.

Study Objectives

Our main objective was to determine whether rosuvastatin administration within the first 24 hours of TBI
could acutely influence the performance of TNFa, IL1b, IL-6, and IL-10 measured in plasma after 72 hours.
Venous blood samples were collected at admission and
after 72 hours. Samples were immediately centrifuged for
15 minutes at 1957g at 4C. The plasma was decanted
and stored at -80C until measurement. Plasma levels of
TNFa and IL-1b were determined using IMMULITE
1000 (Siemens). Interleukin-6 and IL-10 levels were measured using Quantikine (R&D Systems).
A secondary objective was to explore the functional
outcome in patients on the basis of the DRS and for amnesia and disorientation determined using the GOAT. The
DRS is derived from the GCS and evaluates the patients
cognitive understanding of daily activities, degree of assistance and supervision required, and employability.18
The DRS scores range from 0 to 30, with higher values indicating greater disability. A score of 30 indicates
death. A GOAT score of more than 75 points indicates
improvement in amnesia and disorientation.11 These tests
were performed at discharge from the hospital and at 3
and 6 months after TBI. Scoring was blinded and was assessed by the same neuropsychologist (P.M.P.).
J Neurosurg / Volume 118 / March 2013

Rosuvastatin after traumatic brain injury

Sample Size

Sample size was estimated based on a change of 15%

in cytokine levels using data from our previous study,23
with 80% power and a significance level of 0.05 for comparing 2 independent samples. A sufficiently powered
analysis required 18 patients per group.
Statistical Analysis

We used SPSS for Windows (version 19, IBM SPSS,

Inc.) for statistical analyses. We compared the characteristics by using the chi-square test for binomial and categorical variables and the Student t-test or Mann-Whitney
U-test for continuous variables, depending on the data
distribution.
We analyzed the effect of statin on the serum markers of interest (cytokines, hepatic enzymes, and CK) by
using mixed models, accounting for repeated measures
and first-order (autoregressive) covariance structures.
Variables that yielded a p value < 0.2 in direct comparisons between treated and untreated patients were incorporated into the fitted models. For hepatic parameters and
CK levels, we used a logarithmic transformation to obtain
a normal distribution and equal variance between different groups. Mixed models were fitted to determine the relationship of therapy with changes in functional outcome
according to patient DRS scores. The models included
possible confounders, namely, admission GCS score, surgical treatment, and laboratory parameters. Coefficients
of regression with 95% confidence intervals are presented
where necessary.

Results

Between August 2009 and June 2011, 39 of 79 patients who had sustained a TBI were recruited at our hospital. Three patients were excluded from the analysis, as
explained in Fig. 1. Rosuvastatin treatment was paused on
the 4th day due to increasing CK values in 1 patient.
Group Characteristics

Nineteen patients received rosuvastatin and 17 received placebo. Table 1 shows the demographic, clinical,
laboratory, and radiological findings upon admission. The
time between TBI and the first dose of the drug was 10.63
hours (95% CI 8.3912.87 hours) in the rosuvastatin
group and 12.82 hours (95% CI 9.9715.67 hours) in the
placebo group (p = 0.20).
The lesions observed in the rosuvastatin group were
as follows: cervical whiplash (in 2 patients) and ocular
injury, scalp injury, anterior skull base fracture, middle
skull base fracture, and lung contusion with atelectasis (in
1 patient each). In the control group we observed extracranial hematoma (in 3 patients); cervical whiplash and
middle skull base fractures (in 2 patients each); and left
femur fracture, humerus fracture, right clavicle fracture,
scalp injury, and carotid cavernous fistula (in 1 patient
each).

Inpatient Evolution

Ten patients in the rosuvastatin group and 7 in the con-

J Neurosurg / Volume 118 / March 2013

trol group were intubated within the first 24 hours. The

median intubation time was 1 day (range 015 days) for
statin-treated patients and 0 days (range 010 days) in control patients. Three patients were surgically treated in each
group for hematoma drainage. Regarding complications, in
the rosuvastatin group we observed pneumonia (in 2 patients) and seizures in the acute follow-up phase, hydrocephalus, treatment-resistant increased intracranial pressure, and persistent CK increase without renal repercussion
(in 1 patient each). In the control group, we observed urinary tract infection, treatment-resistant increased intracranial pressure, and pneumonia (in 1 patient each).
Cytokine Measurements

Table 2 shows cytokine levels on Days 0 and 3. The

data showed that rosuvastatin therapy significantly reduced
TNFa levels. We observed no impact on IL-1b levels and
minimal effects on IL-6 and IL-10 levels (Table 3).

Amnesia and Disorientation

We found that 3 of 19 patients in the rosuvastatin

group achieved positive GOAT scores at the time of discharge from the hospital. In the placebo group 5 of 17
patients had positive GOAT scores upon discharge. Three
months after TBI, 12 of 19 patients in the rosuvastatin
group and 13 of 16 patients in the control group recovered (GOAT scores > 75). Six months after TBI, 5 of 17
patients in the rosuvastatin group and 2 of 14 in the control group did not recover. Statistically significant results
were not observed at any time.

Disability at Discharge and at 3 and 6 Months After TBI

The median DRS score at discharge in the rosuva

statin group was 9 (range 1.530) and 6 (range 330) in the
placebo group. Three months after TBI, the median DRS
score was 3 (range 0.5-30) in the rosuvastatin group and
3 (range 1-30) in the control group. After a follow-up of 6
months, a median DRS score of 2.5 (range 030) was observed in the rosuvastatin group, whereas the median DRS
score was 1.7 (range 0.530) in the placebo group. A mixed
model explaining the influence of the treatment throughout
the follow-up period is summarized in Table 4.

Drug Safety

Hepatic failure and renal complications were not observed. Levels of AST and ALT were not significantly
different between the treatment groups. As mentioned
above, rosuvastatin treatment in 1 patient was stopped because of a substantial increase in the CK levels (10,000
U/L). Upon follow-up, we did not find evidence of renal
failure. Excluding the CK values of this patient, no differences were observed between the therapy groups. The
data describing these parameters are shown in Fig. 2.

Discussion

The main objective of this study was to determine

whether statins inhibited systemic inflammation. We
therefore measured plasma levels of cytokines after acute
TBI. The argument that inflammation is a contributor to
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M. Snchez-Aguilar et al.

Fig. 1. Diagram of the recruitment phase. a = this patient was in the rosuvastatin group; b = both patients were in the placebo
group; RVS = rosuvastatin.

secondary damage after TBI is widely accepted.19 Interleukin-1b and TNFa lead to the activation of an inflammatory cascade after TBI and negatively influence the
evolution of trauma patients.14 Despite the unclear role
of IL-6, it may be a useful biomarker for TBI in children.1 In animal models, simvastatin reduced IL-1b expression, thereby inhibiting the activation of microglial
cells and astrocytes.12 The reduction of this inflammatory
agent seems to be related to inhibition of TLR4/nuclear

factor kBmediated inflammatory response.3 Our study

detected a significant effect of rosuvastatin treatment on
TNFa levels and a slight (but not significant) reduction
of IL-6 levels. An increase in IL-1b levels was observed
in control patients, but patients who were given statins
did not exhibit an increase in the levels of this cytokine
after 3 days. However, this effect was not significant. Our
results suggest that statins induce some antiinflammatory
effects after TBI. These results should be considered in

Fig. 2. Graphs showing the log mean with 95% CIs of AST, ALT, and CK levels on Days 0, 3, and 7 after administration of
rosuvastatin or placebo.

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Rosuvastatin after traumatic brain injury

TABLE 1: Characteristics of treatment groups*
Group
Characteristic
sex (male)
mean age (yrs)
mechanism of lesion
violence
motor vehicle
fall
other
median GCS score
GCS score <9
pupillary asymmetry
absence of pupillary response
side of lesion
rt
lt
bilat
mean SBP (mm Hg)
mean DBP (mm Hg)
MABP (mm Hg)
mean heart rate (bpm)
laboratory parameters
mean WBC count (103/l)
mean hematocrit (%)
mean glucose (mg/dl)
median AST (U/L)
median ALT (U/L)
median CK (U/L)
TCDB score
II
III
IV
intracranial lesion
SAH
contusion
swelling
EDH
SDH

Rosuvastatin (n = 19)

Placebo (n = 17)

p Value

18 (94.7)
26.3 (20.731.9)

16 (94.1)
24.1 (18.929.2)

0.93
0.53
0.37

3 (15.8)
10 (52.6)
6 (31.6)
0
10 (412)
4
5 (26.3)
2 (10.5)

1 (5.9)
8 (47.1)
6 (35.3)
2 (11.8)
10 (612)
3
3 (17.6)
2 (11.8)

0.33
0.79
0.53
1.00

6 (31.6)
4 (21.1)
9 (47.4)
117.5 (107.7127.3)
75.4 (70.480.3)
97.03 (89.9104.1)
95.4 (86.7104.2)

6 (35.3)
2 (11.8)
9 (52.9)
121.9 (116.4127.4)
76.0 (72.279.8)
101.7 (95.4108.07)
94.1 (86.4101.8)

1.00
0.66
1.00
0.43
0.84
0.30
0.81

15.9 (13.0218.95)
40.1 (35.544.7)
165.9 (131.8200.03)
58 (17218.6)
37 (12183.5)
823 (532140)

14.2 (10.717.7)
38.2 (35.640.89)
133.4 (111.7155.1)
44 (12170)
45 (9148)
565 (1425934)

0.42
0.47
0.10
0.77
0.90
0.80

9 (47.4)
6 (31.6)
8 (42.1)

6 (35.3)
8 (47.1)
3 (17.6)

0.51
0.49
0.15

5 (26.3)
7 (36.8)
3 (15.8)
1 (5.3)
0

4 (23.5)
8 (47.1)
2 (11.8)
2 (11.8)
1 (5.9)

1.00
0.73
1.00
0.59
0.47

* DBP = diastolic blood pressure; EDH = epidural hematoma; MABP = mean arterial blood pressure; SAH = subarachnoid hemorrhage; SBP = systolic blood pressure; SDH = subdural hematoma; WBC = white blood cell.
Mean values are presented as the mean (95% CI). Median values are presented as the median (range). All other values are the
number of patients (%).

light of the limitations of our study. First, even if cytokine levels correspond to outcome after TBI, there are
multiple mechanisms by which plasma markers can be
confounded.9 Second, new evidence strongly suggests
that the biologically relevant compartment for the study
of cytokines in TBI should be the extracellular brain and
not plasma or CSF.8 Third, the time between the TBI and
the measurement of cytokines, as well as the repetition of
the measurement, could be a source of bias. Finally, our
J Neurosurg / Volume 118 / March 2013

study included a small number of patients. This sample

size was calculated considering the scarce available information in the literature regarding the effects of statin
use after TBI in humans. The possibility that the study
was underpowered cannot be excluded.
Regarding the clinical outcomes, the proportion of
patients with positive GOAT scores (improved amnesia
and disorientation) between groups was not statistically
significant. In comparison with our previous study, 22 we
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M. Snchez-Aguilar et al.
TABLE 2: Levels of cytokines on Days 0 and 3
Mean (95% CI)
Rosuvastatin (n = 19)
Cytokine
TNF
IL-1
IL-6
IL-10

Day 0

Placebo (n = 17)
Day 3

18.13 (12.8823.37)*
4.39 (2.296.50)
1.26 (0.771.74)
0.14 (0.110.18)

15.17 (10.2220.13)
4.55 (2.496.60)
0.85 (0.501.19)
0.11 (0.100.12)

Day 0

Day 3

11.44 (9.7113.18)*
2.69 (1.853.52)
0.86 (0.621.09)
0.12 (0.090.16)

12.57 (9.0716.07)
9.83 (2.25 to 21.91)
0.84 (0.381.29)
0.11 (0.090.13)

* p < 0.05.

did not assess the global time to achieve some improvement. In this way, we could not know whether statintreated patients recovered more quickly than controls.
The mixed model analyzing the disability suggested a
trend toward improving functional scale (DRS) score.
Our data agree with the findings of a recent retrospective
cohort study. The authors of that study showed a lowered
risk of in-hospital death and increased chances of achieving good functional recovery 12 months after injury in
older adults who were given statins prior to a head injury.20 Major limitations of this study are the larger number
of deaths in the statin group and patients lost to follow-up
in the placebo group.
For this trial, we selected rosuvastatin because of
the positive results it has had on posttraumatic amnesia
observed in our previous study. Differences in the type
of statin dose and duration of therapy could help explain
some of the inconclusive results. More recent experimental evidence favors the use of simvastatin, a natural lipophilic statin, which displays a better distribution in the
CNS and thus has a better effect after TBI.2 Nevertheless,
a new analysis of the safety of simvastatin questions its
use, because it carries a greater risk of rhabdomyolysis
than do other statins.5 Dose escalation and pharmacological studies in humans that measure drug concentration in
brain tissue and comparing safety of different statins are
necessary to define the role of statins in the management
of TBI.
TABLE 3: Mixed models related to the change of TNF, IL-6, and
IL-10
Cytokine
TNF
rosuvastatin
surgical intervention
interaction btwn treatment & TCDB score
IL-6
rosuvastatin
TCDB score
GCS score <9
IL-10
rosuvastatin
GCS score <9
interaction btwn treatment & GCS score

674

F Value

p Value

9.68
4.61
4.72

0.004
0.04
0.004

3.034
6.501
6.881

0.091
0.004
0.013

2.37
4.83
13.33

0.134
0.035
<0.001

Therapy with 20 mg of rosuvastatin for 10 days was,

in general, safe. We did not observe acute hepatic failure
or rhabdomyolysis with renal failure. The main complication was a massive elevation in CK levels, which caused
us to stop treatment in 1 patient. We did not detect further
complications upon follow-up in this patient. A statistically significant difference in the levels of hepatic enzymes or CK was not observed; therefore, we believe that
the therapy was well tolerated.

Conclusions

Statin therapy administrated after acute TBI seems

to induce some antiinflammatory systemic effects. In addition, it could be related to functional improvement. Further clinical trials targeting aspects such as specific effect
in the immunological brain networks and the improvement of functionality need to be performed to design a
larger multicenter clinical trial.
Disclosure
This study was supported by the Programa Integral de Fortalecimiento Institucional de la Universidad Autonma de San Luis
Potos (C1O-PIFI-09-12.41 and C1O-PIFI-03-06.06). The medication was provided by AstraZeneca.
Author contributions to the study and manuscript preparation
include the following. Conception and design: Snchez-Aguilar,
Tapia-Prez, Torres-Corzo, Gordillo-Moscoso. Acquisition of data:
Snchez-Rodrguez, Vias-Ros, Martnez-Prez, de la Cruz-Mendoza, Snchez-Reyna. Analysis and interpretation of data: SnchezAguilar, Tapia-Prez, Snchez-Rodrguez, de la Cruz-Mendoza,
Torres-Corzo. Drafting the article: Snchez-Aguilar, Tapia-Prez,
Snchez-Rodrguez, Vias-Ros. Critically revising the article: all
TABLE 4: Mixed models related to performance on the DRS
during a follow-up time of 6 months
Parameter

Beta (95% CI)

p Value

rosuvastatin
surgery
baseline SBP
basal plasma glucose
male sex
IL-6
baseline IL-10
baseline TNF

7.01 (13.35 to 0.67)

10.86 (0.1521.56)
0.31 (0.58 to 0.056)
0.12 (0.060.17)
22.95 (11.3834.51)
5.38 (9.59 to 1.17)
1.13 (2.04 to 0.22)
0.76 (0.381.13)

0.031
0.047
0.019
<0.001
<0.001
0.014
0.016
<0.001

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Rosuvastatin after traumatic brain injury

authors. Reviewed submitted version of manuscript: all authors.
Approved the final version of the manuscript on behalf of all authors:
Snchez-Aguilar. Statistical analysis: Tapia-Prez. Administrative/
technical/material support: de la Cruz-Mendoza, Snchez-Reyna.
Study supervision: Snchez-Aguilar, Torres-Corzo, Gordillo-Moscoso.
Acknowledgments
The authors thank Ing. Olga Elias-Chalita for her logistical
assistance during the recruitment phase, Dr. Nora Sauceda Elenes
for her help during the recruitment, and Arlene Salazar Aldrete for
technical assistance with cytokine measurement.
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Manuscript submitted May 28, 2012.
Accepted December 3, 2012.
Please include this information when citing this paper: published online January 4, 2013; DOI: 10.3171/2012.12.JNS121084.
Address correspondence to: Martin Snchez-Aguilar, M.Sc.,
Department of Clinical Epidemiology, Universidad Autnoma de
San Luis Potos, Av. Venustiano Carranza 2405, San Luis Potos
78210, Mxico. email: jemarsan7@hotmail.com.

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