are critically ill and is associated with higher mor-
tality and long-term cognitive impairment (LTCI),
which is akin to a dementia-like cognitive disability. 1-7
This acquired cognitive impairment—critical illness
brain injury—has important public health implications
for both younger and older patients (the latter an
increasingly larger proportion of the population),
threatening the functional independence and quality
of life of millions of ICU survivors in the coming
decades. Given that delirium in the ICU represents
early brain dysfunction during critical illness and can
be easily assessed using validated bedside instruments, 1,8
novel therapies that prevent or treat delirium may
prevent its associated immediate and long-term
Findings from animal and human studies suggest a
neuroinfl ammatory pathogenesis of delirium and long-
term brain dysfunction associated with critical illness.
We propose a testable hypothesis, based on existing
elirium is a manifestation of acute brain dys-
function that occurs in up to 80% of patients who
data, that the pleiotropic effects of statin medications
can mitigate the mechanisms of delirium and LTCI
associated with critical illness. Specifi cally, that statins
may modify two processes leading to brain injury:
neuroinfl ammation and activation of proinfl amma-
Effects on Neuroinflammation
During Critical Illness
An intense systemic infl ammatory response to ill-
ness or injury is a key mediator of organ dysfunction
during critical illness. Several conditions that often
lead to an ICU admission are examples of the delete-
rious effects of systemic infl ammation (eg, severe
sepsis, trauma, acute respiratory distress syndrome).
Proinfl ammatory cytokines (eg, tumor necrosis factor
[TNF]- a and IL-1 b ) and chemokines (eg, monocytic
chemoattractant protein [MCP]-1) activate leuko-
cytes and endothelial cells (which express leukocyte
Delirium is a frequent form of acute brain dysfunction in patients who are critically ill and is
associated with poor clinical outcomes, including a critical illness brain injury that may last for
months to years. Despite widespread recognition of signifi cant adverse outcomes, pharmacologic
approaches to prevent or treat delirium during critical illness remain unproven. We hypothesize
that commonly prescribed statin medications may prevent and treat delirium by targeting molecular
pathways of infl ammation (peripheral and central) and microglial activation that are central to
the pathogenesis of delirium. Systemic infl ammation, a principal mechanism of injury, for exam-
ple, in sepsis, acute respiratory distress syndrome, and other critical illnesses, can cause neuronal
apoptosis, blood-brain barrier injury, brain ischemia, and microglial activation. We hypothesize
that the known pleiotropic effects of statins, which attenuate such neuroinfl ammation, may redi-
rect microglial activation and promote an antiinfl ammatory phenotype, thereby offering the
potential to reduce the public health burden of delirium and its associated long-term cognitive
injury. CHEST 2011; 140(3):580–585
Abbreviations: BBB 5 blood-brain barrier; eNOS 5 endothelial nitric oxide synthase ; iNOS 5 inducible nitric oxide
synthase; LPS 5 lipopolysaccharide; LTCI 5 long-term cognitive impairment; MCP 5 monocytic chemoattractant protein;
TBI 5 traumatic brain injury; TNF 5 tumor necrosis factor
Statins and Brain Dysfunction
A Hypothesis to Reduce the Burden of Cognitive
Impairment in Patients Who Are Critically Ill
Alessandro Morandi , MD, MPH ; Christopher G. Hughes , MD ;
Timothy D. Girard , MD , MSCI ; Danny F. McAuley , MD ;
E. Wesley Ely , MD , MPH , FCCP; and Pratik P. Pandharipande , MD , MSCI
CHEST / 140 / 3 / SEPTEMBER, 2011 581
contributing to ongoing neuroinfl ammation, with resul-
tant neurodegeneration manifesting as severe pro-
longed delirium and LTCI.
In vitro and human studies have shown that, in addi-
tion to their effect on cholesterol synthesis, statins have
complex pleiotropic effects, including antiinfl ammatory,
immunomodulatory, endothelial function-enhancing,
and anticoagulant effects. 15 These pleiotropic effects
may prevent or attenuate delirium during critical ill-
ness by acting on causative mechanisms, including
neuroinfl ammation, BBB injury, neuronal apoptosis,
ischemia and hemorrhage, and microglial activation
( Fig 1 ). 9,10 Specifi cally, in vitro and animal studies
have shown that statins suppress upregulation of toll-
like receptors (which trigger infl ammation in response
to infection) and reduce the release of TNF- a , IL-1 b ,
and MCP-1 as well as leukocyte adhesion molecules
involved in the development of endothelial damage
and BBB alterations. 15,16 Statins also reduce iNOS
expression, thereby reducing neuronal apoptosis and
increasing BP and cerebral blood fl ow, and they
increase endothelial nitric oxide synthase (eNOS)
expression, preserving microcirculatory blood fl ow
via local vasodilation. 17 Lastly, statins counteract the
procoagulant cascade promoted by infl ammation
through the following mechanisms: blunting mono-
cytic expression of tissue factor, increasing thrombo-
modulin availability (important in the activation of
protein C), and reducing levels of plasminogen acti-
vator inhibitor-1, which impairs the fi brinolytic system. 15
Though no studies to date have evaluated the effect
of statins on delirium in patients in the ICU, this drug
class has been examined in models of traumatic brain
injury (TBI), 18 which involves pathophysiologic changes
(eg, neuronal damage and apoptosis, neuroinfl amma-
tion, and BBB injury) similar to those observed in other
types of critical illness, including sepsis and acute
respiratory distress syndrome. The benefi ts of statins
observed in animal studies of TBI include increased
hippocampal neuron survival and improved neuro-
logic function. 18-22 In humans, one clinical trial reported
a reduction in amnesia and increased orientation in
patients with TBI who were treated with rosuvasta-
tin. 23 Studies investigating the effect of statins on
patients with postoperative delirium, a population
with different clinical profi les than patients in the
ICU, have yielded inconsistent results. 24,25 One retro-
spective study 25 reported an increased risk of post-
operative delirium for patients who had elective
surgery and were taking statins, whereas a prospec-
tive study 24 found a signifi cant reduction in postop-
erative delirium for patients who had cardiac surgery
and were taking statins. Well-designed, randomized,
placebo-controlled trials are required to determine
the true effect of statins on delirium during critical
adhesion molecules), resulting in endothelial damage
and tissue factor expression that initiate a procoagu-
lant cascade, ultimately leading to microvascular throm-
bosis, impaired blood fl ow, and end-organ damage
( Fig 1 ). In addition, cytokines trigger production of
inducible nitric oxide synthase (iNOS), which causes
nitric oxide-mediated hypotension, further infl am-
mation, and apoptosis. Ultimately, the characteristic
infl ammatory state of critical illness causes multiple
mechanisms of injury in the brain, including vascular
damage, ischemia, breakdown of the blood-brain
barrier (BBB), local neuroinfl ammation, and apoptosis,
all of which are observed, for example, in animal
models of sepsis and in humans with sepsis-associated
delirium. 9,10 In addition to directly injuring neurons,
this neuroinfl ammation activates quiescent microglia,
the resident macrophages in the brain ( Fig 1 ), 10-12 a
process that van Gool and colleagues 13 proposed as
pivotal to CNS damage from systemic infl ammation.
Microglia are usually activated to clear apoptotic cells
resulting from an injury. 14 Their overactivation, how-
ever, can be responsible for an exaggerated infl am-
matory response. 14 Van Gool and colleagues, 13 in fact,
postulated that impaired cholinergic inhibition of
microglia is responsible for overactivation of microglia
that can persist for months following critical illness,
Manuscript received November 2, 2010; revision accepted March
Affi liations: From the Center for Quality of Aging (Drs Morandi ,
Girard, and Ely), the Center for Health Services Research
(Drs Morandi, Girard, and Ely), the Division of Allergy, Pulmo-
nary, and Critical Care Medicine, the Department of Medicine
(Drs Morandi, Girard, and Ely), and the Department of Anesthesiol-
ogy, Division of Critical Care Medicine (Drs Hughes and Pandhari-
pande), Vanderbilt University School of Medicine; the Anesthesia
Service (Dr Pandharipande) and the Geriatric Research, Education,
and Clinical Center Service (Drs Girard and Ely), Department
of Veterans Affairs Medical Center, Tennessee Valley Healthcare
System, Nashville, TN; and the Regional Intensive Care Unit
(Dr McAuley), Royal Victoria Hospital, and the Centre for Infec-
tion and Immunity (Dr McAuley), the Queen’s University of Belfast,
Belfast, Northern Ireland.
Funding /Support: Dr Hughes is supported by the Foundation
for Anesthesia Education and Research Mentored Research
Training Grant. Dr Girard is supported by the National Institutes
of Health [Grant AG034257]. Dr McAuley is supported by the
Northern Ireland Public Health Agency Research and Develop-
ment Division Translational Research Group for Critical Care.
Dr Ely is supported by the US Department of Veterans Affairs
Clinical Science Research and Development Service [Merit Review
Award] and the National Institutes of Health [Grant AG027472].
Drs Ely and Girard are both supported by the US Department of
Veterans Affairs Tennessee Valley Geriatric Research, Education,
and Clinical Center. Dr Pandharipande is supported by the US
Department of Veterans Affairs Clinical Science Research and
Development Service [Career Development Award].
Correspondence to: Alessandro Morandi, MD, MPH, 1211
21st Ave S, Ste 6100, Nashville, TN 37212; e-mail: morandi.
© 2011 American College of Chest Physicians. Reproduction
of this article is prohibited without written permission from the
American College of Chest Physicians ( http://www.chestpubs.org/
acetylcholine receptors, in particular the nicotinic
receptor a 7, supporting the hypothesis that a central
antiinfl ammatory cholinergic pathway may limit the
response of microglia in the periphery via release of
acetylcholine by neurons. 31,32
Systemic infl ammation can infl uence acute and
chronic microglial activation, promoting the proinfl am-
matory rather than the antiinfl ammatory phenotype. 26,27
In fact, exposure to LPS has been shown in a rat model
of Parkinson disease to shift the primed microglia to
a proinfl ammatory phenotype with increased secre-
tion of IL-1 b . 27 Additionally, a peripheral infection in
animal models of prion disease with primed microglia
led to a switching to a proinfl ammatory phenotype. 33
Hughes and colleagues, 34 however, raised the ques-
tion of whether microglia activated by LPS actually
led to an enhanced infl ammatory state. In this study 34
conducted on microglia in animals with prion disease,
it was found that microglia engaged in phagocytosis
of apoptotic cells remain in an antiinfl ammatory state,
at least with regard to the lack of production of the
proinfl ammatory IL-1B, when exposed to LPS. These
data suggest that a phagocytic state does not neces-
sarily imply the production of infl ammatory media-
tors by microglia.
Statins may counteract the infl ammation-induced
action of proinfl ammatory-phenotype microglial acti-
vation during critical illness. Their actions favor a
switch toward antiinfl ammatory phenotypes that may
contribute to neuronal healing rather than damage
( Fig 2 ), a process observed in studies of animal models
and cultured mouse microglial cells. Li et al 35 reported
that mice treated with simvastatin had signifi cantly
Effects on Microglial Activation
and Phenotype Switching
The effects of acute systemic infl ammation on delir-
ium might be explained through the activation of primed
microglia. 13,26,27 Perry and colleagues 28 described how
microglia in the brain can already be activated as a
result of an ongoing brain pathology (eg, Alzheimer
disease, Parkinson disease, or prion disease) or aging.
These microglia are named primed microglia, and their
stimulation by central or systemic challenges (eg, an
infection) can lead to exaggerated and long-lasting
infl ammatory responses compared with those of
subjects who have unprimed microglia. In fact,
van Gool et al 13 hypothesized that a cholinergic impair-
ment from systemic infl ammation may cause uncon-
trolled activation of brain microglia that can last for
months, especially in patients with primed microglia,
and can eventually lead to or worsen neurodegenera-
tion. In a model of prion disease, lipopolysaccharide
(LPS) exposure led to activation of microglia, with
expression of IL-1 b , IL-6, TNF- a , and iNOS, and
eventual neuronal death. 26
While the hypothesis of impaired cholinergic inhibi-
tory control of the brain microglia still needs to be
proven, the cholinergic effects on peripheral mac-
rophages have been well described in animal models
using the term “infl ammatory refl ex.” 29,30 It has been
reported that the release of acetylcholine through vagal
nerve stimulation in response to endotoxin exposure
suppresses proinfl ammatory cytokine release (eg, IL-6,
TNF-a, IL-1, IL-18) without affecting the production
of the antiinfl ammatory cytokine IL-10. 29 Addition-
ally, in vitro studies have shown that microglia express
Figure 1. The systemic infl ammatory cascade, effects of delirium, and sites of action for statins in critical illness. The systemic infl amma-
tory cascade in critical illness is one of the main drivers of delirium. Different clinical conditions that often lead to an ICU admission could
be used as examples of systemic infl ammation (eg, severe sepsis, acute respiratory distress syndrome). This fi gure describes the principal
mechanisms responsible for brain injury in critical illness. Consequently, we show the proven pleiotropic effect of statins on the systemic
infl ammatory cascade, representing the basis by which statins may reduce delirium and its long-term neurologic sequelae in ICU survivors.
BBB 5 blood-brain barrier; BDNF 5 brain-derived neurotrophic factor; eNOS 5 endothelial nitric oxide synthase; iNOS 5 inducible nitric
oxide synthase; LOS 5 length of stay; LTCI 5 long-term cognitive impairment; MCP 5 monocytic chemoattractant protein; PAI 5 plasmi-
nogen activator inhibitor; TNF 5 tumor necrosis factor; VEGF 5 vascular endothelial growth factor.
CHEST / 140 / 3 / SEPTEMBER, 2011 583
infl ammatory status, as described in the fi rst section
of this article.
Thus, statins might redirect the pathophysiologic
response of the CNS to infl ammation during critical
illness, promoting an antiinflammatory response,
enhancing apoptotic cell cleaning and synapse strip-
ping, and leading to a reduction in delirium and
LTCI. Additionally, statins can reduce the immediate
increase in neuroinfl ammation secondary to activa-
tion of quiescent and primed microglia. This hypothesis
could be tested in animal models of sepsis, correlat-
ing the biologic fi ndings of microglial switching with
behavioral assessments indicative of delirium.
Effects of Statins and Clinical Outcomes
In clinical trials, statins given late in life have not
prevented or delayed the onset of dementia, 43 but
these results do not preclude a benefi cial effect of sta-
tins on delirium or LTCI due to critical illness. The use
of statins during an immediate infl ammatory response,
as witnessed in patients who were critically ill, might
have different consequences than the use of statins
on the low-grade chronic infl ammation related to
Importantly, animal and human studies have also
shown that abrupt discontinuation of statins can lead
to an acute rebound infl ammation and worsening of
clinical outcomes. 44-48 Animal studies have demon-
strated that short-term withdrawal of statin therapy
leads to suppressed eNOS production, elevated oxygen
free-radical production, and increased endothelial
dysfunction as soon as 2 days after discontinuation. 49,50
These changes supersede the benefi cial effects of sta-
tin therapy on platelet function and neuronal cell
A proinfl ammatory rebound is reported within 5 days
of statins interruption in patients with myocardial
infarction. 44 The observed proinfl ammatory state was
found to be threefold higher in those patients than
in patients not receiving statin therapy before or
during hospitalization. 44 Demonstrating its impor-
tance, infl ammation after myocardial infarction has
been associated with ventricular dysfunction and
sudden death up to 2 years after the initial event. 52,53
Heeschen et al 47 found an increased cardiac risk in
patients who were long-term statin users and who
were admitted for acute coronary syndromes in which
statins were withdrawn, abrogating the benefi cial
effect of these drugs on the clinical outcomes. A large
case-control study reported that statin withdrawal
(within 30 days) led to a twofold increase in the risk
of subarachnoid hemorrhage. 48 Finally, a randomized
clinical trial tested the effects of statin withdrawal
during the fi rst 3 days of admission on clinical outcomes
fewer activated microglia after TBI than mice treated
with placebo. Famer and colleagues 36 reported
a signifi cant reduction in microglia activation in
animal models treated with rosuvastatin. Similarly,
Townsend et al 37 found that lovastatin signifi cantly
reduced CD40 expression (a marker of microglial acti-
vation) in primary culture microglial cells by indirectly
blocking the expression of proinfl ammatory media-
tors. In addition, lovastatin signifi cantly increased
microglial phagocytic function, an indicator of the
antiinfl ammatory phenotype and a process inhibited
by CD40 activation.
Microglial activation leads to the induction of
iNOS, a deleterious component of the infl ammatory
cascade involved in neuronal damage. 38 Statins have
been shown to reduce the production of iNOS from
activated microglial cells and macrophages. 39,40 Addi-
tionally, lovastatin was also shown to signifi cantly
reduce prostaglandin E2 release from microglia,
either under basal conditions or after stimulation by
IL-1B, in primary cultures of rat cortical microglia. 41
Statins have also been shown in rats and human micro-
glia to reduce the production of the proinfl ammatory
cytokine IL-6. 36,42
Circulating cytokines released as the result of an
infl ammatory response can cross the BBB and activate
quiescent microglia or cause an exaggerated infl am-
matory response in primed microglia. Statins can also
counteract the deleterious effects associated with micro-
glial activation through their effects on the peripheral
Figure 2. The microglia phenotypes, effects of delirium, and
hypothesized mechanism of action of statins in critical illness. A
systemic infl ammatory cascade caused by infection (eg, sepsis) or
by other critical illnesses (eg, acute respiratory distress syndrome)
may result in a microglial proinfl ammatory phenotype potentially
leading to worse neurologic outcomes as manifested by delirium
and LTCI. The pleiotropic effect of statins might redirect the
microglia to an antiinfl ammatory phenotype, activating mecha-
nisms responsible for brain protection and therefore possibly
leading to better immediate and long-term neurologic outcomes
for survivors of critical illness. See Figure 1 legend for expansion
of the abbreviation.
1 . Bergeron N , Dubois MJ , Dumont M , Dial S , Skrobik Y .
Intensive care delirium screening checklist: evaluation of a new
screening tool . Intensive Care Med . 2001 ; 27 ( 5 ): 859 - 864 .
2 . Ely EW , Shintani A , Truman B , et al . Delirium as a predictor
of mortality in mechanically ventilated patients in the inten-
sive care unit . JAMA . 2004 ; 291 ( 14 ): 1753 - 1762 .
3 . Girard TD , Jackson JC , Pandharipande PP , et al . Delirium as
a predictor of long-term cognitive impairment in survivors of
critical illness . Crit Care Med . 2010 ; 38 ( 7 ): 1513 - 1520 .
4 . Jackson JC , Gordon SM , Hart RP , Hopkins RO , Ely EW . The
association between delirium and cognitive decline: a review of
the empirical literature . Neuropsychol Rev . 2004 ; 14 ( 2 ): 87 - 98 .
5 . MacLullich AM , Beaglehole A , Hall RJ , Meagher DJ .
Delirium and long-term cognitive impairment . Int Rev
Psychiatry . 2009 ; 21 ( 1 ): 30 - 42 .
6 . Pisani MA , Kong SY , Kasl SV , Murphy TE , Araujo KL ,
Van Ness PH . Days of delirium are associated with 1-year
mortality in an older intensive care unit population . Am J
Respir Crit Care Med . 2009 ; 180 ( 11 ): 1092 - 1097 .
7 . Shehabi Y , Riker RR , Bokesch PM , Wisemandle W, Shintani A,
Ely EW; SEDCOM (Safety and Effi cacy of Dexmedetomidine
Compared with Midazolam) Study Group. Delirium duration
and mortality in lightly sedated, mechanically ventilated inten-
sive care patients. Crit Care Med . 2010 ;38(12):2311-2318.
8 . Ely EW , Inouye SK , Bernard GR , et al . Delirium in mechani-
cally ventilated patients: Validity and reliability of the confusion
assessment method for the intensive care unit (CAM-ICU) .
JAMA . 2001 ; 286 ( 21 ): 2703 - 2710 .
9 . Ebersoldt M , Sharshar T , Annane D . Sepsis-associated
delirium . Intensive Care Med . 2007 ; 33 ( 6 ): 941 - 950 .
10 . Semmler A , Hermann S , Mormann F , et al . Sepsis causes
neuroinfl ammation and concomitant decrease of cerebral
metabolism . J Neuroinfl ammation . 2008 ; 5 : 38 .
11. Cerejeira J , Firmino H , Vaz-Serra A , Mukaetova-Ladinska EB.
The neuroinfl ammatory hypothesis of delirium. Acta
Neuropathol . 2010 ;119(6):737-754.
12 . Perry VH , Nicoll JA , Holmes C . Microglia in neurodegenera-
tive disease . Nat Rev Neurol . 2010 ; 6 ( 4 ): 193 - 201 .
13 . van Gool WA , van de Beek D , Eikelenboom P . Systemic
infection and delirium: when cytokines and acetylcholine
collide . Lancet . 2010 ; 375 ( 9716 ): 773 - 775 .
14 . Mosser DM , Edwards JP . Exploring the full spectrum of mac-
rophage activation . Nat Rev Immunol . 2008 ; 8 ( 12 ): 958 - 969 .
15 . Terblanche M , Almog Y , Rosenson RS , Smith TS , Hackam DG .
Statins and sepsis: multiple modifi cations at multiple levels .
Lancet Infect Dis . 2007 ; 7 ( 5 ): 358 - 368 .
16 . Niessner A , Steiner S , Speidl WS , et al . Simvastatin sup-
presses endotoxin-induced upregulation of toll-like receptors
4 and 2 in vivo . Atherosclerosis . 2006 ; 189 ( 2 ): 408 - 413 .
17 . McGown CC , Brown NJ , Hellewell PG , Reilly CS , Brookes ZL .
Benefi cial microvascular and anti-infl ammatory effects of
pravastatin during sepsis involve nitric oxide synthase III .
Br J Anaesth . 2010 ; 104 ( 2 ): 183 - 190 .
18 . Wible EF , Laskowitz DT . Statins in traumatic brain injury .
Neurotherapeutics . 2010 ; 7 ( 1 ): 62 - 73 .
19 . Lu D , Goussev A , Chen J , et al . Atorvastatin reduces neuro-
logical defi cit and increases synaptogenesis, angiogenesis, and
neuronal survival in rats subjected to traumatic brain injury .
J Neurotrauma . 2004 ; 21 ( 1 ): 21 - 32 .
20 . Wang H , Lynch JR , Song P , et al . Simvastatin and atorvastatin
improve behavioral outcome, reduce hippocampal degen-
eration, and improve cerebral blood fl ow after experimental
traumatic brain injury . Exp Neurol . 2007 ; 206 ( 1 ): 59 - 69 .
21 . Lu D , Mahmood A , Goussev A , et al . Atorvastatin reduction
of intravascular thrombosis, increase in cerebral microvascular
in patients admitted for acute stroke. 45 Patients for
whom statins were withdrawn had a signifi cant 8.67-
fold increase in the risk of neurologic deterioration and
a 4.66-fold increase in the combined risk of functional
dependency and death. 45
Observational studies are, therefore, warranted to
examine whether the continuation vs discontinuation
of statins during critical illness alters infl ammatory
biomarkers and the course of delirium and, subse-
quently, the development of LTCI. Additionally, if the
results of observational studies are promising, ran-
domized, placebo-controlled trials could investigate
the effi cacy of statins initiated early during an ICU
stay for the prevention or treatment of delirium and
the related neurocognitive sequelae coupled with stan-
dard clinical outcomes. Because differential effects on
neuroinfl ammation during critical illness might result
from treatment with lipophilic vs hydrophilic statins,
both types of drugs should be tested in clinical trials.
The safety profi le of drugs administered during criti-
cal illness is always a concern because of alterations in
kidney and liver function and other factors predispos-
ing patients to adverse reactions; statins, fortunately,
are generally safe, resulting in a very low incidence of
myopathy (0.01%) and liver enzyme abnormalities
(0.1%) at standard doses. 54 Also, an intervention
intended to prevent or treat delirium in patients in
the ICU needs to work quickly (over hours rather than
days or weeks). Animal models of TBI have shown
that statins produce pleiotropic effects within a few
hours of administration, making them attractive agents
for study during critical illness. 20 Finally, the effects
of statins on the mechanisms of neuronal injury dur-
ing critical illness can be studied using anatomic and
functional neuroimaging to examine brain volumes
and functional activation to help understand whether
statins promote switching from microglia activation
to an antiinfl ammatory phenotype with reduction in
brain atrophy and preservation of brain function. 37,55
In conclusion, statins are ideal candidates to investi-
gate in the hope of mitigating the rapidly growing
public health problem of ICU delirium and the acqui-
sition of long-term critical illness brain injury affect-
ing thousands of survivors of critical illness annually.
Financial /nonfi nancial disclosures: The authors have reported
to CHEST the following confl icts of interest: Dr Girard has
received honoraria from Hospira Inc. Dr McAuley has received
consultant fees and served on advisory boards for GlaxoSmithKline
for acute lung injury and has received lecture fees for organized
meetings from AstraZeneca. Dr Ely has received honoraria from
GlaxoSmithKline, Pfi zer, Lilly, Hospira, Cumberland, and Aspect.
Drs Morandi, Hughes, and Pandharipande have reported that no
potential confl icts of interest exist with any companies/organizations
whose products or services may be discussed in this article.
www.chestpubs.org Download full-text
CHEST / 140 / 3 / SEPTEMBER, 2011 585
of neurons in the rat CNS in vivo . J Neurosci . 1998 ; 18 ( 6 ):
2161 - 2173 .
39 . Cordle A , Landreth G . 3-Hydroxy-3-methylglutaryl-coenzyme
A reductase inhibitors attenuate beta-amyloid-induced micro-
glial infl ammatory responses . J Neurosci . 2005 ; 25 ( 2 ): 299 - 307 .
40 . Huang KC , Chen CW , Chen JC , Lin WW . HMG-CoA
reductase inhibitors inhibit inducible nitric oxide synthase gene
expression in macrophages . J Biomed Sci . 2003 ; 10 ( 4 ): 396 - 405 .
41 . Tringali G , Vairano M , Dello Russo C , Preziosi P , Navarra P .
Lovastatin and mevastatin reduce basal and cytokine-stimulated
production of prostaglandins from rat microglial cells in vitro:
Evidence for a mechanism unrelated to the inhibition of
hydroxy-methyl-glutaryl CoA reductase . Neurosci Lett . 2004 ;
354 ( 2 ): 107 - 110 .
42 . Lindberg C , Crisby M , Winblad B , Schultzberg M . Effects of
statins on microglia . J Neurosci Res . 2005 ; 82 ( 1 ): 10 - 19 .
43 . McGuinness B , Craig D , Bullock R , Passmore P . Statins for
the prevention of dementia . Cochrane Database Syst Rev .
2009 ;( 2 ): CD003160 .
44 . Sposito AC , Carvalho LS , Cintra RM , et al ; Brasilia Heart
Study Group . Rebound infl ammatory response during the
acute phase of myocardial infarction after simvastatin with-
drawal . Atherosclerosis . 2009 ; 207 ( 1 ): 191 - 194 .
45 . Blanco M , Nombela F , Castellanos M , et al . Statin treatment
withdrawal in ischemic stroke: A controlled randomized study .
Neurology . 2007 ; 69 ( 9 ): 904 - 910 .
46 . Gertz K , Laufs U , Lindauer U , et al . Withdrawal of statin
treatment abrogates stroke protection in mice . Stroke . 2003 ;
34 ( 2 ): 551 - 557 .
47 . Heeschen C , Hamm CW , Laufs U , Snapinn S , Böhm M ,
White HD ; Platelet Receptor Inhibition in Ischemic
Syndrome Management (PRISM) Investigators . Withdrawal
of statins increases event rates in patients with acute coronary
syndromes . Circulation . 2002 ; 105 ( 12 ): 1446 - 1452 .
48 . Risselada R , Straatman H , van Kooten F , et al . Withdrawal
of statins and risk of subarachnoid hemorrhage . Stroke . 2009 ;
40 ( 8 ): 2887 - 2892 .
49 . Laufs U , Endres M , Custodis F , et al . Suppression of
endothelial nitric oxide production after withdrawal of statin
treatment is mediated by negative feedback regulation of
rho GTPase gene transcription . Circulation . 2000 ; 102 ( 25 ):
3104 - 3110 .
50 . Vecchione C , Brandes RP . Withdrawal of 3-hydroxy-3-
methylglutaryl coenzyme A reductase inhibitors elicits oxi-
dative stress and induces endothelial dysfunction in mice .
Circ Res . 2002 ; 91 ( 2 ): 173 - 179 .
51 . Brandes RP , Beer S , Ha T , Busse R . Withdrawal of cerivas-
tatin induces monocyte chemoattractant protein 1 and tissue
factor expression in cultured vascular smooth muscle cells .
Arterioscler Thromb Vasc Biol . 2003 ; 23 ( 10 ): 1794 - 1800 .
52 . Anzai T , Yoshikawa T , Shiraki H , et al . C-reactive protein
as a predictor of infarct expansion and cardiac rupture
after a fi rst Q-wave acute myocardial infarction . Circulation .
1997 ; 96 ( 3 ): 778 - 784 .
53 . Pietilä KO , Harmoinen AP , Jokiniitty J , Pasternack AI . Serum
C-reactive protein concentration in acute myocardial infarc-
tion and its relationship to mortality during 24 months
of follow-up in patients under thrombolytic treatment .
Eur Heart J . 1996 ; 17 ( 9 ): 1345 - 1349 .
54 . Armitage J . The safety of statins in clinical practice . Lancet .
2007 ; 370 ( 9601 ): 1781 - 1790 .
55 . Blinzinger K , Kreutzberg G . Displacement of synaptic ter-
minals from regenerating motoneurons by microglial cells .
Z Zellforsch Mikrosk Anat . 1968 ; 85 ( 2 ): 145 - 157 .
patency and integrity, and enhancement of spatial learn-
ing in rats subjected to traumatic brain injury . J Neurosurg .
2004 ; 101 ( 5 ): 813 - 821 .
22 . Lu D , Qu C , Goussev A , et al . Statins increase neurogenesis
in the dentate gyrus, reduce delayed neuronal death in the
hippocampal CA3 region, and improve spatial learning in
rat after traumatic brain injury . J Neurotrauma . 2007 ; 24 ( 7 ):
1132 - 1146 .
23 . Tapia-Perez JH , Sanchez-Aguilar M , Torres-Corzo JG , et al .
Effect of rosuvastatin on amnesia and disorientation after
traumatic brain injury (NCT003229758) . J Neurotrauma . 2008 ;
25 ( 8 ): 1011 - 1017 .
24 . Katznelson R , Djaiani GN , Borger MA , et al . Preoperative
use of statins is associated with reduced early delirium rates
after cardiac surgery . Anesthesiology . 2009 ; 110 ( 1 ): 67 - 73 .
25 . Redelmeier DA , Thiruchelvam D , Daneman N . Delirium
after elective surgery among elderly patients taking statins .
CMAJ . 2008 ; 179 ( 7 ): 645 - 652 .
26 . Cunningham C , Wilcockson DC , Campion S , Lunnon K ,
Perry VH . Central and systemic endotoxin challenges exac-
erbate the local infl ammatory response and increase neu-
ronal death during chronic neurodegeneration . J Neurosci .
2005 ; 25 ( 40 ): 9275 - 9284 .
27 . Pott Godoy MC , Tarelli R , Ferrari CC , Sarchi MI , Pitossi FJ .
Central and systemic IL-1 exacerbates neurodegeneration
and motor symptoms in a model of Parkinson’s disease . Brain .
2008 ; 131 ( pt 7 ): 1880 - 1894 .
28 . Perry VH , Newman TA , Cunningham C . The impact of sys-
temic infection on the progression of neurodegenerative dis-
ease . Nat Rev Neurosci . 2003 ; 4 ( 2 ): 103 - 112 .
29 . Borovikova LV , Ivanova S , Zhang M , et al . Vagus nerve stimu-
lation attenuates the systemic infl ammatory response to
endotoxin . Nature . 2000 ; 405 ( 6785 ): 458 - 462 .
30 . Tracey KJ . The infl ammatory refl ex . Nature . 2002 ; 420 ( 6917 ):
853 - 859 .
31 . De Simone R , Ajmone-Cat MA , Carnevale D , Minghetti L .
Activation of alpha7 nicotinic acetylcholine receptor by nicotine
selectively up-regulates cyclooxygenase-2 and prostaglandin E2
in rat microglial cultures . J Neuroinfl ammation . 2005 ; 2 ( 1 ): 4 .
32 . Shytle RD , Mori T , Townsend K , et al . Cholinergic modula-
tion of microglial activation by alpha 7 nicotinic receptors .
J Neurochem . 2004 ; 89 ( 2 ): 337 - 343 .
33 . Combrinck MI , Perry VH , Cunningham C . Peripheral infec-
tion evokes exaggerated sickness behaviour in pre-clinical
murine prion disease . Neuroscience . 2002 ; 112 ( 1 ): 7 - 11 .
34 . Hughes MM , Field RH , Perry VH , Murray CL , Cunningham C .
Microglia in the degenerating brain are capable of phagocy-
tosis of beads and of apoptotic cells, but do not effi ciently
remove PrPSc, even upon LPS stimulation . Glia . 2010 ;
58 ( 16 ): 2017 - 2030 .
35 . Li B , Mahmood A , Lu D , et al . Simvastatin attenuates micro-
glial cells and astrocyte activation and decreases interleukin-
1beta level after traumatic brain injury . Neurosurgery . 2009 ;
65 ( 1 ): 179 - 185, discussion 185-186.
36 . Famer D , Wahlund LO , Crisby M . Rosuvastatin reduces
microglia in the brain of wild type and ApoE knockout mice on a
high cholesterol diet; implications for prevention of stroke and
AD . Biochem Biophys Res Commun . 2010 ; 402 ( 2 ): 367 - 372 .
37 . Townsend KP , Shytle DR , Bai Y , et al . Lovastatin modulation
of microglial activation via suppression of functional CD40
expression . J Neurosci Res . 2004 ; 78 ( 2 ): 167 - 176 .
38 . Weldon DT , Rogers SD , Ghilardi JR , et al . Fibrillar beta-
amyloid induces microglial phagocytosis, expression of induc-
ible nitric oxide synthase, and loss of a select population