Septic-associated encephalopathy - everything starts at a microlevel
Septic-associated encephalopathy - everything starts at a microlevel
Tarek Sharshar 0 2
Andrea Polito 0 2
Anthony Checinski 0 2
Robert D Stevens 1
0 Department of Intensive Care Medicine, Raymond Poincare teaching Hospital and University of Versailles Saint-Quentin en Yvelines , 104 Boulevard Raymond Poincare, 92380 Garches , France
1 Department of Anesthesiology Critical Care Medicine, Johns Hopkins University School of Medicine , Meyer 8-140, 600 N Wolfe St, Baltimore, MD 21287 , USA
2 Department of Intensive Care Medicine, Raymond Poincare teaching Hospital and University of Versailles Saint-Quentin en Yvelines , 104 Boulevard Raymond Poincare, 92380 Garches , France
Sepsis-associated encephalopathy is associated with increased mortality and morbidity. Its pathophysiology remains insufficiently elucidated, although there is evidence for a neuroinflammatory process sequentially involving endothelial activation, blood-brain barrier alteration and cellular dysfunction and alteration in neurotransmission. Experimental studies have shown that microcirculatory dysfunction, a consequence of endothelial activation, is an early pathogenic step. To date, we do not know whether it is present in septic patients, whether it accounts for clinical features and whether it is treatable.
The experimental study by Taccone and colleagues
recently published in Critical Care  aims to
determine whether sepsis is associated with early cerebral
micro-circulatory failure, which is believed to play a role
in the pathophysiology of sepsis-associated
encephalopathy (SAE). SAE is a frequent and severe complication of
sepsis as it is associated with increased mortality,
morbidity and plausibly with diminished long-term cognitive
performance [2,3]. Evidence suggests that SAE results
from an alteration of neurotransmission, the
mechanisms of which are insufficiently elucidated.
One pathophysiologic scenario is an inflammatory
process that starts by cerebral endothelial activation ,
which directly releases or, through alteration of the
blood-brain barrier, facilitates the passage of
inflammatory mediators (that is, cytokines, chemokines) into the
parenchyma. Increased permeability of the blood-brain
barrier has been extensively documented in
experimental models of sepsis, has been linked to complement
activation , and has been observed in septic patients
using magnetic resonance imaging (MRI) . In turn,
these inflammatory mediators will affect all brain cells.
Van Gool and colleagues  proposed that
sepsisinduced microglial activation plays a role in delirium.
Inflammatory mediators are able to alter cellular
metabolism by inducing oxidative stress and mitochondrial
dysfunction , resulting in pathologic abnormalities
that range from alterations of neurotransmission to
apoptosis . It has been shown that experimental
sepsis, via inflammatory mediators, alters brain cholinergic
, beta-adrenergic, gamma-aminobutyric acid and
serotoninergic signalling, predominately in the neocortex
and hippocampus . This feature may account for the
electroencephalographic disturbances reported in septic
patients . Additional factors that compound this
neuroinflammatory process include the release of
excitatory amino acids, hyperglycemia, exposure to neurotoxic
pharmacologic agents, hemodynamic alterations,
coagulopathy, and hypoxemia .
One major consequence of endothelial activation is
that it may compromise regional brain tissue perfusion
by altering microcirculation. Microcirculatory
dysfunction (MD) has previously been experimentally assessed,
notably by measuring neurovascular coupling. This
consists of assessing changes in cortical flow velocity during
somatosensory activation . Interestingly, this MD
preceded both neurophysiologic and macrocirculatory
alterations, indicating that it is an early step in the
pathogenesis of SAE. Taccone and colleagues 
provide a convincing visual demonstration of this
phenomenon. Using cortical videomicroscopy in an ovine
peritonitis model, they found evidence of a reduced
density of perfused and functional capillaries. But if the
occurrence of MD during experimental sepsis is
established, it remains to be seen whether this phenomenon
is present in septic patients, whether it accounts for
clinical features of SAE and whether it is treatable. The
microcirculation has not been evaluated in septic
patients; in contrast, several studies have examined
macrocirculatory changes with inconsistent results .
One argument may be the impairment of autoregulation
reported in some studies of septic patients ,
although autoregulation is primarily determined by
arterioles, which lie outside micro-circulation.
Neuropathologic findings of diffuse ischemic damages and
micro-haemorrhages support this hypothesis .
Recent advances in MRI are enabling important
inferences regarding the cerebral microcirculation; however,
simpler techniques are needed to directly assess and
monitor cerebral microcirculation or correlated markers
at the bedside. It would be of interest to determine
whether cerebral MD is correlated with
micro-circulatory disturbances in other organs that are more easily
amenable to direct assessment. The neurological
consequence of MD is unknown, although one study
interestingly showed that delirium in septic patients is
associated with disturbed autoregulation rather than
with altered cerebral blood flow or tissue oxygenation
The clinical importance of cerebral microcirculatory
impairment in sepsis might be confirmed by assessing
the effects of therapeutic intervention. Prominent
micro-circulatory effects of various agents have been
tested in septic animals, including curcumin, bradykinin,
inducible nitric oxide synthase (iNOS) inhibitors,
anticytokines or complement antibodies and glucocorticoids
. The effects of glucocorticoids and that of other
therapeutic agents used in sepsis (that is, activated
protein C) on SAE are unknown. One other major
unanswered issue is whether targeting higher systemic blood
pressures will improve cerebral perfusion and
oxygenation in the presence of MD.
One may argue that MD is merely one feature in the
complex pathogenesis of SAE. In the experimental
setting it will be important to develop agents or strategies
that modulate what ostensibly is an early pathogenic
phenomenon rather than targeting later events that may
not be reversible. In patients, we need more evidence of
the role of microcirculation in SAE. This will require
techniques to measure and monitor the cerebral
microcirculation at the bedside.
1. Taccone FS , Su F , Pierrakos C , He X , James S , Dewitte O , Vincent JL , De Backer D : Cerebral microcirculation is impaired during sepsis: an experimental study . Crit Care 2010 , 14 : R140 .
2. Eidelman LA , Putterman D , Putterman C , Sprung CL : The spectrum of septic encephalopathy . Definitions , etiologies, and mortalities. JAMA 1996 , 275 : 470 - 473 .
3. Iacobone E , Bailly-Salin J , Polito A , Friedman D , Stevens RD , Sharshar T : Sepsis-associated encephalopathy and its differential diagnosis . Crit Care Med 2009 , 37 : S331 - S336 .
4. Flierl M , Stahel P , Rittirsch D , Huber-Lang M , Niederbichler AD , Hoesel LM , Touban BM , Morgan SJ , Smith WR , Ward PA , Ipaktchi K : Inhibition of complement C5a prevents breakdown of the blood-brain barrier and pituitary dysfunction in experimental sepsis . Crit Care 2009 , 13 : R12 .
5. Sharshar T , Carlier R , Bernard F , Guidoux C , Brouland JP , Nardi O , de la Grandmaison GL , Aboab J , Gray F , Menon D , Annane D : Brain lesions in septic shock: a magnetic resonance imaging study . Intensive Care Med 2007 , 33 : 798 - 806 .
6. van Gool WA , van de Beek D , Eikelenboom P : Systemic infection and delirium: when cytokines and acetylcholine collide . Lancet 2010 , 375 : 773 - 775 .
7. Messaris E , Memos N , Chatzigianni E , Konstadoulakis MM , Menenakos E , Katsaragakis S , Voumvourakis C , Androulakis G : Time-dependent mitochondrial-mediated programmed neuronal cell death survival in sepsis . Crit Care Med 2004 , 32 : 1764 - 1770 .
8. Sharshar T , Gray F , Lorin de la Grandmaison GL , Hopkinson NS , Ross E , Dorandeu A , Orlikowski D , Raphael JC , Gajdos P , Annane D : Apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock . Lancet 2003 , 362 : 1799 - 1805 .
9. Semmler A , Frisch C , Debeir T , Ramanathan M , Okulla T , Klockgether T , Heneka MT : Long-term cognitive impairment, neuronal loss and reduced cortical cholinergic innervation after recovery from sepsis in a rodent model . Exp Neurol 2007 , 204 : 733 - 740 .
10. Hellstrom IC , Danik M , Luheshi GN , Williams S : Chronic LPS exposure produces changes in intrinsic membrane properties and a sustained IL-dependent increase in GABAergic inhibition in hippocampal CA1 pyramidal neurons . Hippocampus 2005 , 15 : 656 - 664 .
11. Oddo M , Carrera E , Claassen J , Mayer SA , Hirsch LJ : Continuous electroencephalography in the medical intensive care unit . Crit Care Med 2009 , 37 : 2051 - 2056 .
12. Rosengarten B , Wolff S , Klatt S , Schermuly RT : Effects of inducible nitric oxide synthase inhibition or norepinephrine on the neurovascular coupling in an endotoxic rat shock model . Crit Care 2009 , 13 : R139 .
13. Pfister D , Siegemund M , Dell-Kuster S , Smielewski P , Regg S , Strebel SP , Marsch SC , Pargger H , Steiner LA : Cerebral perfusion in sepsis-associated delirium . Crit Care 2008 , 12 : R63 .
14. Sharshar T , Annane D , de la Gradmaison GL , Brouland JP , Hopkinson NS , Franoise G : The Neuropathology of Septic Shock . Brain Pathol 2004 , 14 : 21 - 33 .
15. Vachharajani V , Vital S , Russell J , Scott LK , Granger DN : Glucocorticoids Inhibit the Cerebral Microvascular Dysfunction Associated with Sepsis in Obese Mice . Microcirculation 2006 , 13 : 477 - 487 .