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Brain Perfusion In Sepsis

Article in Current Vascular Pharmacology March 2013

Impact Factor: 2.97 DOI: 10.2174/1570161111311020007 Source: PubMed

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Fabio Silvio Taccone

Universit Libre de Bruxelles

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Sabino Scolletta

Universit degli Studi di Siena


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Federico Franchi

Universit degli Studi di Siena

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Katia Donadello

Universit Libre de Bruxelles


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2 Current Vascular Pharmacology, 2012, Vol. 10, No. 6 Taccone et al

ill patients [11, 12]. In a large cohort of mechanically venti-lated patients, mostly septic or with acute pneumonia, alteredmental state was observed in 66% of them at some pointduring the ICU stay [11]. In a prospective study of 1758 pa-tients admitted to a medical ICU, 217 of them experienced aneurological complication; encephalopathy was present inone third of patients, and SAE was the most frequent etiol-ogy [12]. In a series on 69 non-sedated patients with bacter-

aemia, 70% of them had clinical signs of brain dysfunctionand half of them showed severe encephalopathy [9]. In twolarge cohort studies of septic patients, acute mental state ab-normalities were described in more than 20% of them [13].The heterogeneity of SAE rate among these studies mayprobably be due to the different definitions of sepsis andSAE used. As such, more than 60% of patients with neuro-logical changes during critical illness patients also had evi-dence of brain lesions abnormalities on brain magnetic reso-nance and (EEG), including clinically silent epileptiformpatterns, were present in all septic patients, regardless of thepresence of clinical brain dysfunction [15, 16].

The most common manifestation of SAE is an alterationof mental state, ranging, from mild disorientation or lethargyto stupor and coma [17]. Most patients have fluctuantchanges in mental status, especially in the early course of theinfectious process where SAE may often be the first manifes-tation of severe sepsis [18]. Usually the neurological examdoes not show focal motor deficits. Myoclonus, asterixis andrigidity are rare and should raise the possibility of a toxic-metabolic encephalopathy. Focal asymmetric neurologicalsigns mandate to rule out structural brain lesions, either pri-mary or secondary to septic ischemic emboli. Cranial nervesare usually spared whereas clinical signs of peripheral nervealterations, like loss of tendon reflexes, should raise the pos-sibility of sepsis-associated critically ill polyneuromyopathy[19]. Finally, alteration of the neuro-endocrine axis (e.g. ad-renal and vasopressin insufficiency) and autonomic dysfunc-tion (e.g. blood pressure variations, arrhythmias, irregularbreathing) may be other manifestations of SAE [20]. Giventhe variable clinical manifestations of SAE, the ConfusionAssessment Method for the Intensive Care Unit (CAM-ICU)or the Assessment to Intensive Care Environment (ATICE)have been used to score altered mental state in this setting,however the Glasgow Coma Scale (GCS) remains the mostpopular tool and has been used to evaluate brain dysfunctionin septic patients with MOF [3, 21, 22].

There are no diagnostic tests with high specificity forSAE, so that the clinical, electrophysiological (Electroen-cephalogram, EEG; Somato Sensory Evoked Potentials,SSEPs), biochemical (neuron-specific enolase, NSE; S-100

protein) or imaging (Magnetic Resonance Imaging, MRI)criteria may be useful. Young et al. demonstrated that EEGis the most sensitive in the diagnosis of SAE, with mild dif-fuse slow waves even in patients without clinical abnormali-ties [15]. Also, EEG could be useful in the differential diag-nosis of coma in critically ill septic patients, especially todetect unexpected clinically silent non-convulsive status epi-lepticus [23]; in a large cohort of patients continuously moni-tored with EEG, septic patients had a higher rate of seizuresthan those without sepsis (32% vs. 9%) and sepsis on admis-sion was the only significant predictor of seizures and ofpoor outcome [24]. In one study using SSEPs, an increase of

peak latencies in cortical and sub-cortical component of dorsal column-medial lemniscus pathway (84% and 34% of alcases) was remarked. The impairment of these pathways wasassociated with severity of illness and had good correlationwith the degree of brain dysfunction [25]. Finally, serumlevels of NSE and S-100protein have been shown to correlate with poor outcome in septic shock patients [26]. Mag-netic resonance imaging (MRI) showed variable degrees o

vasogenic edema, related to blood-brain barrier (BBBbreakdown, or ischemic lesions surrounding the VirchowRobin spaces in septic brain [27]. Damage to the gray mattemay include bilateral lesions of basal ganglia and thalamusAlthough not specific for brain dysfunction during sepsisMRI can identify patients developing structural cerebral lesions during severe sepsis and septic shock and potentiallyhelp in patient prognostication.

1.3. Outcome and Therapy

Septic encephalopathy is not only an unpleasant confusion state but represents a severe organ dysfunction and maycontribute to poor outcome in septic patients [3, 13, 28]. Thegreatest the severity of SAE, as assessed by the GCS, thehighest the risk of death, with a mortality rate of 16% whenGCS was 15, 20% when GCS was 13-14, 50% when GCSwas 9-12, up to 63% in comatose patients (GCS < 9) [3]. Inanother study, septic patients with altered mental status had ahigher mortality than those without [13]. In a large cohort omechanically ventilated patients, the majority of them admitted for severe sepsis, it was demonstrated that ICU-relateddelirium was independently associated with longer hospitastay, worse cognitive recovery and higher mortality [11]. Iappears that SAE may also actively participate to the development of long-term cognitive dysfunction after critical illness [29]. Unfortunately, there is no specific treatment oSAE and outcome depends on the appropriate treatment othe underlying disease. Recently, the use of activated proteinC appeared to be beneficial on the evolution of SAE in septicpatients [30]. Several drugs, including dopexamine, inhibitors of inducible nitric oxide synthase (iNOS), corticosteroids, magnesium and antioxidants, have shown promisingresults in experimental sepsis, however no clinical data onthe efficacy of these interventions are currently available[31-34]. Given the absence of specific therapeutic interventions, treatment of SAE is mainly supportive, aimed to limiSAE-related secondary cerebral damage. Targeting brainperfusion and providing adequate oxygen and nutrients supply seem reasonable in this context.

2. PATHOGENESIS OF SAE: A SHORT OVERVIEW

Sepsis-associated encephalopathy is a poorly understoodcondition and little is known about this clinical process. Thepathophysiology is likely to be multifactorial (Fig. 1) [35]The concept of altered brain function related to the presencein the blood, and possibly in the brain, of micro-organisms otheir toxins is considered obsolete as altered CNS function iobserved also in patients without bacterial blood stream invasion [36]. Disseminated cerebral microabscesses havebeen suggested as a cause of SAE [37], although this has nobeen reported in more recent post-mortem studies [38]. Thespecific role of specific bacterial products like endotoxin isunlikely, as the incidence of SAE is similar in Gram-positiv


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Cerebral Hemodynamics in Sepsis Current Vascular Pharmacology, 2012, Vol. 10, No. 6

and Gram-negative bacteremia, as well as fungemia and evensepsis with unidentified pathogens [13]. Encephalopathyoccurs also in non-infectious conditions, such as pancreatitisor trauma, suggesting that it would be mostly related to thesystemic inflammatory response [39, 40].

The role of inflammation on brain dysfunction has beenwidely investigated in several in vitroor experimental mod-

els of sepsis; although some of the reported findings havealso been confirmed in the human setting, the pathogenesisof brain dysfunction mostly relies on laboratory data. Circu-lating pro-inflammatory mediators can promote vascularpermeability of the cerebral endothelium, which separatesthe blood from the brain parenchyma, thus permitting to sev-eral substances to exert toxic effects on neuronal cells. Tu-mor necrosis factor-alpha (TNF-) selectively altered BBBpermeability in brain microvessel endothelial cells withoutdisrupting tight junctions [41]. Endothelial cells treated withinterferon-gamma (IFN-) also exhibited significant morpho-logical changes with increased permeability [42]. Inflamma-

tory mediators have also direct effects on brain functions; thesubarachnoid injection of TNF- altered cerebral metabolism and increased cerebrospinal fluid lactate, by activatingthe production of nitric oxide (NO) [43]. Also, TNF- canupregulate the expression of aquaporin-4 channels and associated edema as well as astrocytosis through activation of itreceptor [44]. The intra-cerebral administration of interleukin-1 and IFN- in animals induced the same slow-wave

EEG patterns than those observed in patients with SAE [4546].

More importantly, sepsis-induced systemic inflammationcan directly affect brain homeostasis by triggering the twoimportant pathways that are implicated in the response tostress and in the immune system modulation: the circumventricular organs (CVOs), which lack a BBB and have a direccommunication with circulating mediators of sepsis and thevagus nerve, which is triggered by visceral inflammation [7]Once systemic and/or visceral inflammation are detected bythese pathways, an abnormal activation of brain signaling

Fig. (1). Schematic representation of mechanisms involved in the pathogenesis of sepsis-associated encephalopathy. Proinflammatory cyto-

kines are released during sepsis. They can either activate vagal fibres or enter the brain causing neurologic dysfunction (see text for details).5-HT, serotonin (5-hydroxytryptamine); Ach, acetylcholine; BBB, blood-brain barrier; CNS, central nervous system; CO, carbon monoxide;

CVOs = circumventricular organs; ECs, endothelial cells; GABA, gamma-aminobutyric acid; GLT, glutamate; HPA, hypothalamic-pituitary-

adrenocortical; HSF, heat-shock factors; IL, interleukin; LPS, lipopolysaccharide; NF-k, nuclear factor kappa B; NO, nitric oxide; NTS,

nucleus tractus solitarius; PAF, platelet activating factor; PG, prostaglandin; PVN, paraventricular nuclei; RAS, reticular activation system;

ROS, reactive oxygen species; TNF-, tumor necrosis factor-alpha.


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spread to behavioural, neuroendocrine and neurovegetativestructures, affecting directly microglial and neuronal cellsfunctions and modulating neurosecretion and neurotrasmis-sion [47, 48]. Inflammation rapidly alters the function ofhypothalamus, which regulates the endogenous production ofcorticosteroids and can modulate the inflammatory response[49] and may significantly impair the reticular activatingsystem functions, which control consciousness and attention

[50]. The cholinergic and serotoninergic releases are altered,while an increase in the -aminobutyric acid receptor densityis observed in the forebrain of septic rats [51, 52]. Brain tis-sular norepinephrine and epinephrine concentrations are de-creased in the forebrain and brain stem of septic animalstogether with the down-regulation of the cerebral -adrenergic system [53]. Also, a significant and early increaseof plasma aromatic aminoacids during abdominal murinesepsis was found to be associated with encephalopathy de-velopment [54]. The activation of CVO also promotes theentry of leucocytes into the CNS, with further increase oflocal inflammation [55].

Several other mechanisms may be involved in the devel-opment of SAE. Sepsis produces an imbalance between theproduction of reactive oxygen species (ROS) and the corre-sponding repair system, the so-called oxidative stress. Reac-tive oxygen species trigger lipid peroxidation in the cerebralvessels and the surrounding parenchyma, which eventuallycause structural membrane damage and promote inflamma-tion [56]. Cerebral oxidative stress can also be triggered bythe decrease of heat-shock factors or by hyperglycemia [57,58]. Bacterial endotoxin and inflammatory cytokines in-crease cerebral tissue levels of glutamate via the up-regulation of iNOS; glutamate can trigger brain cells damageby allowing high intracellular levels of calcium and the acti-vation of several enzymes that alter cell structures, such ascomponents of the cytoskeleton, membrane, and DNA [59].Within the brain parenchyma, the activation of astrocytes viathe toll-like receptors by the mediators of inflammation [60]can further increase the vulnerability of neurons to glutamateand free radical-mediated injuries [56, 61, 62]. Moreover,sepsis also alters the synthesis of ascorbate, which may pro-vide antioxidant and protective effects on neurons in re-sponse to glutamate and ROS release [63]. The complementsystem, which normally contributes to eliminate bacteria,may be excessively activated during sepsis and have delete-rious effect through the activation of glial cells, secretion ofproinflammatory cytokines and generation of other toxicproducts on brain function [64]. Edema formation could befurther promoted by the activation of aquaporin channels,which regulate the presence of water in the brain tissue and

may altered during sepsis [65]. Alterations in the glucoseuptake and metabolism or regional deregulation of intracellu-lar calcium homeostasis have also been suggested to contrib-ute to the pathogenesis of SAE [50, 66]. All these pathwayscause mitochondrial dysfunction by inhibiting the mitochon-drial electron transport chain and uncoupling oxidative phos-phorylation, which ultimately leads to bioenergetic failureand apoptosis of brain cells [38, 58].

The complex signaling network that is implicated inthese phenomena include the production of nitric oxide(NO), through the activation of the inducible form of NOsynthase (iNOS) [67, 68], the release of pro-inflammatory

cytokines and their receptors from neurons, astrocytes andmicroglial cells [69, 70], as well as the production of prostaglandins, which are key mediators in the brain response toinflammatory stimuli [71, 72]. Finally, a number of othermediators are involved in the cerebral brain response to sys-temic inflammation, such as chemokines, macrophagemigrating inhibitory factor, angiotensin, endothelin, plateleactivating factor, superoxide radicals and carbon

monoxide [73].

3. ALTERATIONS IN BRAIN PERFUSION DURINGSEPSIS

A decrease in brain perfusion has been evoked as a majodeterminant of SAE [74]. Alterations of systemic blood flowassociated with tissue hypo-perfusion and poor oxygen distribution, are a key feature of sepsis [2]; indeed, several studies have tried to evaluate the link between cerebral perfusionabnormalities and brain dysfunction in sepsis. As brain perfusion is dependent, amongst all, from mean arterial pressure(MAP), which is generally reduced in severe sepsis and septic shock, it would be important to monitor the adequacy ocerebral blood flow (CBF) and oxygenation during sepsis awell as to evaluate the integrity of flow regulation, in orderto adapt blood pressure levels and avoid the development osecondary brain ischemic events in such patients [38].

3.1. Cerebral Blood Flow: Normal Ranges, Physiologyand Regulation

Cerebral blood flow is the blood supply to the brain in agiven time. In an adult, CBF is typically 750 mL (or 50-55mL/100 g of brain tissue/min) and represents roughly 15% othe cardiac output. It ranges from 20 mL/100g/min in thewhite matter to more than 70 mL/100g/min in the grey matter and is tightly regulated to meet cerebral metabolic demands [75]. Cerebral blood flow regulation is extremely

complex and is determined by a number of factors, such aviscosity of blood, the diameter of cerebral blood vessels andthe net pressure of the blood flow into the brain, known ascerebral perfusion pressure (CPP), which is calculated as thedifference between mean arterial pressure (MAP) and intracranial pressure (ICP) or the central venous pressure (CVP)whichever is the higher [76]. Cerebral vessels are able tomaintain CBF constant through a wide range of MAP (from50 to 150 mmHg) by altering their diameters in a processcalled cerebral autoregulation (CA); in normal conditionsa raise of MAP induce vasoconstriction whereas a reductionof MAP produces vasodilatation (Fig. 2) [77]. This procesis extremely important because when CBF exceed cellularequirements (a condition known as hyperemia), then the

intracranial pressure (ICP) may rise and potentially damagebrain tissue. On the other hand, low CBF (


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The control of CBF is dependent not only on MAP butalso on four other major determinants, including chemical,metabolic, neural and myogenic factors (Fig. 3) [77]. Al-though this division may be somewhat artificial and thesecontrol mechanisms probably operate in concert, it is usefulto consider each separately. CBF is extremely sensitive tochanges in arterial PaCO2 (chemical), displaying markedincreases during moderate hypercapnia and reduction during

hypocapnia. Changes in CBF in response to changes inPaCO2 are referred to as cerebral CO2-reactivity (COR).

The magnitude of cerebral circulatory response is ap-proximately 5% change in CBF for each 1 mmHg change inPaCO2, within a range of 25 to 60 mmHg [83]. In contrast,acidosis and alcalosis, for blood pH values ranging from 6.7to 7.6, have little effect upon the CBF [84]. Changes inPaCO2 are detected by carotid artery chemoreceptors andthis regulatory mechanism can be altered by a lesion of thetegmental reticular formation [77]. The effect of PaCO2seems to be related to changes in local brain perivascular pHrather than direct carbon dioxide action on smooth vascularcells, but could also be mediated by K+-dependent channelsor adenosine, while vasodilatation induced by hypercapnia

can be abolished by prostaglandin synthesis inhibition [85-89]. Astrocytes contribute in maintaining the homeostasis ofthe extracellular compartment in CNS and may profoundlyinfluence central CO2 chemoreactivity and respiratory con-trol [90]. Importantly, cerebrovascular dilatation induced byhypercapnia is markedly attenuated by moderate hypoten-sion, which contributes to exhaust the capacity of cerebralvessels to further dilate [83]. On the opposite, with markedhypercapnia, the capacity to maintain a constant CBF duringhypotension is lost, and CBF will decline as CPP declines[91]. Finally, CBF is less sensitive to changes in arterialoxygen tension (PaO2) over the normal physiological ranges.

If arterial PaO2 falls below 50 mmHg, pronounced increaseof CBF occurs (at 30 mmHg CBF is almost double than a100 mmHg PaO2). Conflicting results have been publishedon the effects of hyperoxia on cerebral perfusion; moderatehyperoxia induced a mild decrease in CBF in healthy volun-teers [92], while ventilation with 100% of oxygen has onlyminimal effects upon CBF in patients with traumatic braininjury [93].

Local cerebral blood flow (CBF) is also tightly coupledto neuronal activity (metabolic) so that CBF may adjust tothe level of energy generation in the brain (neurometaboliccoupling). The regional cerebral metabolic activity is represented by the metabolism of oxygen (CMRO2) and glucose[94]. The precise mechanisms responsible for this couplingremain elusive and alterations in the concentrations of locametabolites or the generation of several vasoactive chemicasubstances (i.e., H and K ions, adenosine, vasoactive intestinal peptide-VIP or products of arachidonic acid) have beenproposed as pivotal mediators [95, 96]. Astrocytic processeextensively unsheathe cerebral arterioles and, through thelink between neuronal synapses and the cerebral vasculatureare in a strategic position to convey cellular signals to the

blood vessels [97]. The brain metabolism can also significantly affect the magnitude of CBF modification to changeof PaCO2; indeed, factors that reduce neurons activity (egsedation reduces oxygen and glucose consumption) reducethe cerebral circulation response to hypercapnia [98], whilemild hypercapnia itself may cause a suppression of cerebrametabolic rate of oxygen up to 13% [99]. Importantly, somediscrepancies exist in the relationship between CBF and glucose metabolism and oxygen consumption; one hypothesis isthat part of cerebral metabolism would use lactate generatedby the metabolism of glucose in the astrocytes, through theactivation of glycolitic pathways [100]; lactate itself showed

Fig. (2). Schematic representation of cerebral blood flow (CBF) variations associated with changes in mean arterial pressure (MAP, red line),

arterial carbon dioxide tension (PaCO2, green dotted line) and arterial oxygen tension (PaO2, bleu dotted line).
https://www.researchgate.net/publication/5993616_Mitochondrial_transport_proteins_of_the_brain?el=1_x_8&enrichId=rgreq-0f6637ac36911799d9ef3f408cc2087a-XXX&enrichSource=Y292ZXJQYWdlOzIzNjA1ODk2ODtBUzoxNzMyMjgzNTgxMTk0MjRAMTQxODMxMjI2NzQ5Mg==https://www.researchgate.net/publication/5993616_Mitochondrial_transport_proteins_of_the_brain?el=1_x_8&enrichId=rgreq-0f6637ac36911799d9ef3f408cc2087a-XXX&enrichSource=Y292ZXJQYWdlOzIzNjA1ODk2ODtBUzoxNzMyMjgzNTgxMTk0MjRAMTQxODMxMjI2NzQ5Mg==


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some vasodilating effect on cerebral arterioles and couldcontribute to modulated brain perfusion in response to cere-bral cells demand [101,102].

The third factor implicated in CBF regulation is the peri-vascular innervation (neuro-vascular reactivity) (Fig. 3),which depends not only on the extrinsic nerve supply fromthe cranial ganglia to the cerebral vasculature, but also on theintracerebral neurons linked to these vessels. Most of theextrinsic neuron fibers are sympathetic and can be summa-rized in three different types, each with distinct origins andneurotransmitters. The first consists of sympathetic neuronsarising principally from the superior cervical ganglion (pro-ducing norepinephrine and neuropeptide-Y, thus vasocon-striction); the second consists of parasympathetic neurons in

the spheno-palatine and otic ganglia (producing acetylcho-line and VIP); the third consists of sensory fibers originatingin the trigeminal ganglion (producing substance P and calci-tonin gene-related peptide, thus vasodilation) [103]. Never-theless, attempts to manipulate CBF by either cervical sym-pathectomy or symphathetic stimulation resulted in variablesCBF changes in experimental models [104, 105]. Also, theparasympathetic nerves may have some effect only in pain-mediated cerebral vasodilatation while trigeminal fibers cansubstantially affect CBF only in particular conditions, suchas hypertension and seizures [103]. Thus, CBF appears to beprimarily regulated by local metabolism with only minor

modulation by extrinsic nerves. Among local neuromodulators, dopaminergic axons innervate the intra-parenchymamicrovessels and dopamine may directly regulate corticablood flow [106].

Bayliss et al. were the first to present the myogenic basiof CA, showing that modifications of the arteriolar smoothmuscle tone are elicited by changes in transmural pressure[107]. Accordingly, an increase in the transmural pressurewould stretch the smooth muscle of the vascular wall, stimulating the reflex contraction of radial fibers, which eventuallyresult in vasoconstriction [108]. A growing body of evidencesuggests that endothelium-dependent pathways are the primary mediators of myogenic control of CA [109]. The endothelium appears to act as the transducer of transmural forces

that would stimulate the release of vasodilating substancessuch as NO and L-arginine [110,111]. The role of NO hasbeen confirmed by the vasodilatation of large cerebral arteries and pial arterioles in response to the application of ace-tylcholine in vivo [112]; this process was dependent on theNOS activity and could be blocked by NOS antagonist, suchas N-monomethyl-L-arginine (L-NMMA) [113].

Autoregulation can be totally lost during some acutecerebrovascular disease or preserved but shifted (normallytowards the right and higher values, for example in chronichypertension) [114-117]. In such abnormal conditions, the

Fig. (3).Schematic representation of multiple mechanisms of cerebrovascular control. The control of cerebral blood flow is dependent on

five major determinants: mean arterial pressure, and chemical, metabolic, neural and myogenic factors (see text for details).

L-arg, L-arginine; NO, nitric oxide; PaCO2, arterial carbon dioxide tension; VIP, vasoactive intestinal peptide.
https://www.researchgate.net/publication/49776881_Bidirectional_control_of_arteriole_diameter_by_astrocytes?el=1_x_8&enrichId=rgreq-0f6637ac36911799d9ef3f408cc2087a-XXX&enrichSource=Y292ZXJQYWdlOzIzNjA1ODk2ODtBUzoxNzMyMjgzNTgxMTk0MjRAMTQxODMxMjI2NzQ5Mg==https://www.researchgate.net/publication/23439554_Brain_metabolism_dictates_the_polarity_of_astrocyte_control_over_arterioles_Nature?el=1_x_8&enrichId=rgreq-0f6637ac36911799d9ef3f408cc2087a-XXX&enrichSource=Y292ZXJQYWdlOzIzNjA1ODk2ODtBUzoxNzMyMjgzNTgxMTk0MjRAMTQxODMxMjI2NzQ5Mg==https://www.researchgate.net/publication/21215113_Ide_H_Effect_of_chemical_sympathectomy_on_cerebral_blood_flow_in_rats?el=1_x_8&enrichId=rgreq-0f6637ac36911799d9ef3f408cc2087a-XXX&enrichSource=Y292ZXJQYWdlOzIzNjA1ODk2ODtBUzoxNzMyMjgzNTgxMTk0MjRAMTQxODMxMjI2NzQ5Mg==https://www.researchgate.net/publication/23671476_Sympathetic_withdrawal_augments_cerebral_blood_flow_during_acute_hypercapnia_in_sleeping_lambs?el=1_x_8&enrichId=rgreq-0f6637ac36911799d9ef3f408cc2087a-XXX&enrichSource=Y292ZXJQYWdlOzIzNjA1ODk2ODtBUzoxNzMyMjgzNTgxMTk0MjRAMTQxODMxMjI2NzQ5Mg==https://www.researchgate.net/publication/240495863_Dopa_-_minergic_regulation_of_cerebral_microcirculation?el=1_x_8&enrichId=rgreq-0f6637ac36911799d9ef3f408cc2087a-XXX&enrichSource=Y292ZXJQYWdlOzIzNjA1ODk2ODtBUzoxNzMyMjgzNTgxMTk0MjRAMTQxODMxMjI2NzQ5Mg==https://www.researchgate.net/publication/283435332_On_the_local_reactions_of_the_arterial_wall_to_changes_in_arterial_pressure?el=1_x_8&enrichId=rgreq-0f6637ac36911799d9ef3f408cc2087a-XXX&enrichSource=Y292ZXJQYWdlOzIzNjA1ODk2ODtBUzoxNzMyMjgzNTgxMTk0MjRAMTQxODMxMjI2NzQ5Mg==https://www.researchgate.net/publication/19123402_Influence_of_transmural_pressure_on_myogenic_responses_of_isolated_cerebral_arteries_of_the_rat?el=1_x_8&enrichId=rgreq-0f6637ac36911799d9ef3f408cc2087a-XXX&enrichSource=Y292ZXJQYWdlOzIzNjA1ODk2ODtBUzoxNzMyMjgzNTgxMTk0MjRAMTQxODMxMjI2NzQ5Mg==https://www.researchgate.net/publication/7043460_Altered_cerebrovascular_responses_after_exposure_to_venoarterial_extracorporeal_membrane_oxygenation_Role_of_the_nitric_oxide_pathway?el=1_x_8&enrichId=rgreq-0f6637ac36911799d9ef3f408cc2087a-XXX&enrichSource=Y292ZXJQYWdlOzIzNjA1ODk2ODtBUzoxNzMyMjgzNTgxMTk0MjRAMTQxODMxMjI2NzQ5Mg==https://www.researchgate.net/publication/7544506_Paravicini_TM_Miller_AA_Drummond_GR_Sobey_CGFlow-induced_cerebral_vasodilatation_in_vivo_involves_activation_of_phosphatidylinositol-3_kinase_NADPH-oxidase_and_nitric_oxide_synthase_J_Cereb_Blood_Flow?el=1_x_8&enrichId=rgreq-0f6637ac36911799d9ef3f408cc2087a-XXX&enrichSource=Y292ZXJQYWdlOzIzNjA1ODk2ODtBUzoxNzMyMjgzNTgxMTk0MjRAMTQxODMxMjI2NzQ5Mg==https://www.researchgate.net/publication/15670423_Lipopolysaccharide-induced_hypotension_and_vascular_hyporeactivity_in_the_rat_Tissue_analysis_of_nitric_oxide_synthase_mRNA_and_protein_expression_in_the_presence_and_absence_of_dexamethasone_NG-monom?el=1_x_8&enrichId=rgreq-0f6637ac36911799d9ef3f408cc2087a-XXX&enrichSource=Y292ZXJQYWdlOzIzNjA1ODk2ODtBUzoxNzMyMjgzNTgxMTk0MjRAMTQxODMxMjI2NzQ5Mg==https://www.researchgate.net/publication/49826841_Favorable_Outcome_in_Traumatic_Brain_Injury_Patients_With_Impaired_Cerebral_Pressure_Autoregulation_When_Treated_at_Low_Cerebral_Perfusion_Pressure_Levels?el=1_x_8&enrichId=rgreq-0f6637ac36911799d9ef3f408cc2087a-XXX&enrichSource=Y292ZXJQYWdlOzIzNjA1ODk2ODtBUzoxNzMyMjgzNTgxMTk0MjRAMTQxODMxMjI2NzQ5Mg==https://www.researchgate.net/publication/47395257_Pathogenesis_and_Clinical_Physiology_of_Hypertension?el=1_x_8&enrichId=rgreq-0f6637ac36911799d9ef3f408cc2087a-XXX&enrichSource=Y292ZXJQYWdlOzIzNjA1ODk2ODtBUzoxNzMyMjgzNTgxMTk0MjRAMTQxODMxMjI2NzQ5Mg==https://www.researchgate.net/publication/26707006_Autoregulation_after_ischaemic_stroke?el=1_x_8&enrichId=rgreq-0f6637ac36911799d9ef3f408cc2087a-XXX&enrichSource=Y292ZXJQYWdlOzIzNjA1ODk2ODtBUzoxNzMyMjgzNTgxMTk0MjRAMTQxODMxMjI2NzQ5Mg==https://www.researchgate.net/publication/240495863_Dopa_-_minergic_regulation_of_cerebral_microcirculation?el=1_x_8&enrichId=rgreq-0f6637ac36911799d9ef3f408cc2087a-XXX&enrichSource=Y292ZXJQYWdlOzIzNjA1ODk2ODtBUzoxNzMyMjgzNTgxMTk0MjRAMTQxODMxMjI2NzQ5Mg==https://www.researchgate.net/publication/283435332_On_the_local_reactions_of_the_arterial_wall_to_changes_in_arterial_pressure?el=1_x_8&enrichId=rgreq-0f6637ac36911799d9ef3f408cc2087a-XXX&enrichSource=Y292ZXJQYWdlOzIzNjA1ODk2ODtBUzoxNzMyMjgzNTgxMTk0MjRAMTQxODMxMjI2NzQ5Mg==https://www.researchgate.net/publication/23439554_Brain_metabolism_dictates_the_polarity_of_astrocyte_control_over_arterioles_Nature?el=1_x_8&enrichId=rgreq-0f6637ac36911799d9ef3f408cc2087a-XXX&enrichSource=Y292ZXJQYWdlOzIzNjA1ODk2ODtBUzoxNzMyMjgzNTgxMTk0MjRAMTQxODMxMjI2NzQ5Mg==https://www.researchgate.net/publication/23671476_Sympathetic_withdrawal_augments_cerebral_blood_flow_during_acute_hypercapnia_in_sleeping_lambs?el=1_x_8&enrichId=rgreq-0f6637ac36911799d9ef3f408cc2087a-XXX&enrichSource=Y292ZXJQYWdlOzIzNjA1ODk2ODtBUzoxNzMyMjgzNTgxMTk0MjRAMTQxODMxMjI2NzQ5Mg==https://www.researchgate.net/publication/21215113_Ide_H_Effect_of_chemical_sympathectomy_on_cerebral_blood_flow_in_rats?el=1_x_8&enrichId=rgreq-0f6637ac36911799d9ef3f408cc2087a-XXX&enrichSource=Y292ZXJQYWdlOzIzNjA1ODk2ODtBUzoxNzMyMjgzNTgxMTk0MjRAMTQxODMxMjI2NzQ5Mg==https://www.researchgate.net/publication/49776881_Bidirectional_control_of_arteriole_diameter_by_astrocytes?el=1_x_8&enrichId=rgreq-0f6637ac36911799d9ef3f408cc2087a-XXX&enrichSource=Y292ZXJQYWdlOzIzNjA1ODk2ODtBUzoxNzMyMjgzNTgxMTk0MjRAMTQxODMxMjI2NzQ5Mg==https://www.researchgate.net/publication/26707006_Autoregulation_after_ischaemic_stroke?el=1_x_8&enrichId=rgreq-0f6637ac36911799d9ef3f408cc2087a-XXX&enrichSource=Y292ZXJQYWdlOzIzNjA1ODk2ODtBUzoxNzMyMjgzNTgxMTk0MjRAMTQxODMxMjI2NzQ5Mg==https://www.researchgate.net/publication/47395257_Pathogenesis_and_Clinical_Physiology_of_Hypertension?el=1_x_8&enrichId=rgreq-0f6637ac36911799d9ef3f408cc2087a-XXX&enrichSource=Y292ZXJQYWdlOzIzNjA1ODk2ODtBUzoxNzMyMjgzNTgxMTk0MjRAMTQxODMxMjI2NzQ5Mg==https://www.researchgate.net/publication/23564035_The_brain_in_acute_liver_failure_A_tortuous_path_from_hyperammonemia_to_cerebral_edema?el=1_x_8&enrichId=rgreq-0f6637ac36911799d9ef3f408cc2087a-XXX&enrichSource=Y292ZXJQYWdlOzIzNjA1ODk2ODtBUzoxNzMyMjgzNTgxMTk0MjRAMTQxODMxMjI2NzQ5Mg==https://www.researchgate.net/publication/49826841_Favorable_Outcome_in_Traumatic_Brain_Injury_Patients_With_Impaired_Cerebral_Pressure_Autoregulation_When_Treated_at_Low_Cerebral_Perfusion_Pressure_Levels?el=1_x_8&enrichId=rgreq-0f6637ac36911799d9ef3f408cc2087a-XXX&enrichSource=Y292ZXJQYWdlOzIzNjA1ODk2ODtBUzoxNzMyMjgzNTgxMTk0MjRAMTQxODMxMjI2NzQ5Mg==https://www.researchgate.net/publication/15670423_Lipopolysaccharide-induced_hypotension_and_vascular_hyporeactivity_in_the_rat_Tissue_analysis_of_nitric_oxide_synthase_mRNA_and_protein_expression_in_the_presence_and_absence_of_dexamethasone_NG-monom?el=1_x_8&enrichId=rgreq-0f6637ac36911799d9ef3f408cc2087a-XXX&enrichSource=Y292ZXJQYWdlOzIzNjA1ODk2ODtBUzoxNzMyMjgzNTgxMTk0MjRAMTQxODMxMjI2NzQ5Mg==https://www.researchgate.net/publication/7544506_Paravicini_TM_Miller_AA_Drummond_GR_Sobey_CGFlow-induced_cerebral_vasodilatation_in_vivo_involves_activation_of_phosphatidylinositol-3_kinase_NADPH-oxidase_and_nitric_oxide_synthase_J_Cereb_Blood_Flow?el=1_x_8&enrichId=rgreq-0f6637ac36911799d9ef3f408cc2087a-XXX&enrichSource=Y292ZXJQYWdlOzIzNjA1ODk2ODtBUzoxNzMyMjgzNTgxMTk0MjRAMTQxODMxMjI2NzQ5Mg==https://www.researchgate.net/publication/7043460_Altered_cerebrovascular_responses_after_exposure_to_venoarterial_extracorporeal_membrane_oxygenation_Role_of_the_nitric_oxide_pathway?el=1_x_8&enrichId=rgreq-0f6637ac36911799d9ef3f408cc2087a-XXX&enrichSource=Y292ZXJQYWdlOzIzNjA1ODk2ODtBUzoxNzMyMjgzNTgxMTk0MjRAMTQxODMxMjI2NzQ5Mg==https://www.researchgate.net/publication/19123402_Influence_of_transmural_pressure_on_myogenic_responses_of_isolated_cerebral_arteries_of_the_rat?el=1_x_8&enrichId=rgreq-0f6637ac36911799d9ef3f408cc2087a-XXX&enrichSource=Y292ZXJQYWdlOzIzNjA1ODk2ODtBUzoxNzMyMjgzNTgxMTk0MjRAMTQxODMxMjI2NzQ5Mg==


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upper and lower ranges of MAP/CPP or PaCO2, amongwhich CBF remain constant, can be much narrower than innormal conditions. Such ranges may be different among pa-tients and change over time within the same subject, so thatoptimal MAP targets to maintain adequate brain perfusionmay be difficult to predict. In sepsis, several mechanisms areimplicated in altered brain perfusion and CBF regulation inseptic patients.

3.2. Effects of Endothelial Dysfunction and Inflammationon Brain During Sepsis

Alterations of brain perfusion and microcirculation dur-ing sepsis are mostly mediated by the changes induced bysystemic inflammation on cerebral endothelial cells [118]. Innormal conditions, the cerebral endothelium has tight inter-cellular junctions, no fenestrations and few pynocyticvesicules, which separate blood from the brain parenchyma.The abnormal brain stimulation occurring during sepsis canactivate the endothelium [119, 120], causing the expressionof adhesion molecules with subsequent aggregation of circu-lating white blood cells and increased permeability to vari-ous neurotoxic agents [121]. The breakdown of the endothe-lial barrier during sepsis has been directly demonstrated bythe intracerebral accumulation of radioactive tracers in sev-eral experimental studies [119]. The activation of cerebralendothelial cells is mediated by endotoxin and pro-inflammatory cytokines that, through activation of nuclearfactor (NF)-kB, induce the over-expression of iNOS thatfurther increases BBB permeability [122, 123]. This wouldalso allow high brain concentrations of vasoactive agents,acting directly on intracerebral vessels and inducing vaso-constriction and reduction of CBF [124]. Reduction of localblood flow as well as impairment of microcirculation cancontribute to leucocytes accumulation and local productionof lysosomial enzymes and oxygen free radicals [125]. Reac-tive products of leukocytes can interact with erythrocytesmembrane and reduce their deformability, which in turn fa-cilitates red blood cells impaction in microvessels and exac-erbates cerebral hypoperfusion [126]. The result of all theseevents is the development of perivascular edema that con-tributes to altered brain perfusion and is associated with neu-ronal injury [127, 128].

Low brain flow levels are a feature of the response toendotoxin [129]. Early reductions of CBF during experimen-tal endotoxemia are due to cerebral vasoconstriction, both innewborn and adult animals, and these changes are not linkedto hypotensive events [129,130]. Importantly, endotoxin cansuppress neuronal activity and cerebral metabolic rate [131,132]; thus, as cerebral blood flow remains closely coupled to

cerebral metabolic requirements, a concomitant reduction ofbrain perfusion and metabolic rates have been observed inexperimental sepsis [133]. Elevated levels of TNF-occur-ring during endotoxemia have powerful vasoactive effects oncerebral vessels [134]. Injection of TNF- into the cisternamagna of rabbits produced a rapid reduction in cerebral oxy-gen uptake and a more prolonged reduction in CBF; this wasaccompanied by an increase in intracranial pressure and anincrease in cerebrospinal fluid lactate [43]. Although TNF-can both modulate vasodilatation of superficial cerebral arte-rioles and vasoconstriction of intraparenchymal cerebral ves-sels, endotoxin can impair endothelium-dependent vasodila-

tor pathways, such as NO [135], thus promoting vessels constriction viaprostanoids and endothelin pathways [136,137]Persistent exposure to endotoxin may mitigate its effects onCBF [129].

The excessive production of NO by the endotheliumthrough the activation of iNOS is responsible for the vasodilatation found in several vascular beds during sepsis, including the brain, which may ultimately counteract the early

vasoconstrictor response [138]. This complex endotheliasignaling has further been highlighted in experimentastudies, which showed conflicting results on the effects oiNOS inhibition on brain perfusion during sepsis did noaffect CBF [43, 139-141], suggesting that CBF is also controlled by other mechanisms than NO during systemic inflammation [73].

3.3. Alteration of Brain Microcirculation During Sepsis

Microcirculatory perfusion is responsible for the finetuning of oxygen supply to organs [142]and microcirculatory alterations may play a key role in the pathogenesis osepsis-related organ dysfunction [143,144]. Moreover, cere

bral endothelial cells play an important regulatory role inbrain vasoregulation [145] and in maintaining a constanenergy supply to brain cells [146]. Sepsis-associated microcirculatory alterations have been reported in the sublinguaarea, as well as in striated muscle, small bowel mucosa andliver [147-150]. Vachhrajani et al. showed that microvascular flow abnormalities were secondary to a marked adhesionof platelets and leukocytes to the vascular endothelium obrain venules already four hours after induced sepsis, withexaggerated response in obese mice compared to the leananimals [151]. In another study on peritonitis induced insheep, Taccone et al. showed that cortical cerebral microcirculation was altered and microcirculatory abnormalities became significant at the onset of septic shock and were no

prevented by aggressive fluid administration [152]. Moreover, changes in the cerebral microcirculation were not relatedto changes in MAP, CI or lactate, suggesting that these alterations in the brain may occur even when systemic pressureis maintained into normal ranges. Indirect data suggest thesealterations may have important consequences on brain cellsand function. In endotoxic animals, microcirculatory failureoccurred in the early phase of sepsis, and preceded changesin evoked potential responses, indicating that altered perfusion of active neurons is responsible for electrophysiologicaabnormalities [153]. Microcirculatory alterations in the cortex were associated with changes in brain tissue PO2, impaired oxygen delivery and cell energy crisis (Taccone FS eal., Abstract - 39th SCCM Congress, 2010, Miami, USA), al

of which contribute to secondary cerebral damage after sepsis. Using intravital microscopy, Comim et al. [154]showeda progressive increase in leucocytes and platelets adhesionwithin brain microcirculation, especially in the deeper brainstructures, and microvascular disturbances were associatedwith a local production of pro-inflammatory cytokines andwith the development of abnormalities in locomotor functions in septic rats. Importantly, microvascular abnormalitiewere attenuated by selectively blocking adhesion moleculessuch as P-selectin, CD18, or intercellular adhesion molecule(ICAM)-1, or by the administration of curcumin, whichblocks the interaction of leucocytes with endothelial cell
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[151, 155]. Other therapeutical interventions, such as dex-amethasone, magnesium or hypertonic solutions significantlyimproved brain microcirculation in experimental sepsis,while iNOS inhibition and norepinephrine administration didnot affect capillary abnormalities in endotoxemic rats [34,156-158]. Unfortunately, brain microcirculation is still im-possible to monitor and visualize in the clinical practicewithout direct exposure of cerebral cortex after craniectomy

and data on microvascular abnormalities are still lacking inthe human setting.

3.4. Brain Perfusion and Autoregulation in ExperimentalSepsis

Several experimental papers have investigated cerebralperfusion during sepsis. In one study on dogs, CBF showed a30% decrease within 15 min after endotoxin administration,while the arterial blood pressure was still not markedlychanged [129]. In a second canine study, CBF decreasedimmediately after the administration of endotoxin and con-sistently remained below control values [159]. Cerebrovas-cular resistances (CVR) initially decreased, then progres-sively increased to levels significantly higher than normaland were associated with the lowest CBF levels in the laterstages of shock. Nevertheless, other studies also demon-strated that CBF was unchanged during sepsis induced in ratsand sheep, while others reported an increased CBF [139,140,160,161]. These seemingly controversial findings maybe related to different models (endotoxin vs. bacteria) andspecies used.

Cerebro-vascular reactivity to pressure changes was wellmaintained in several experimental model of sepsis [129,138, 159], but in others reactivity to PaCO2 changes wasaltered [162, 163]. In one study, Hinkelbein et al. [164]found no significant difference in the global CBF betweennon-septic and septic animals, despite the presence of sig-

nificant hypocapnia in the sepsis group. Although one possi-ble explanation to these findings is that the cerebrovasculartone becomes unresponsive to carbon dioxide stimuli,authors also suggested that, during the hyperdynamic phaseof sepsis, brain hyperemia might develop, which counteractshypocapnia-mediated reduction of CBF. The role of PaCO2is also essential in maintaining normal CA during sepsis; inone study, septic normocapnic animals showed higher in-crease in CMRO2 than hypocapnic animals, suggesting lossof CA and uncoupling between CBF and cerebral metabo-lism during sepsis at normal or high PaCO2 levels [129].

Another important factor influencing brain autoregulationin experimental models is the local inflammation. In one

study, CBF was increased with preserved autoregulation inrats with pneumococcal sepsis, even if there was a right shiftof the lower threshold of MAP at which CBF was kept con-stant [165]. Importantly, if these animals had also a directbrain injury, represented by concomitant bacterial meningi-tis, CA was completely impaired, suggesting that pneumo-coccal bacteraemia itself can trigger only cerebral vasodilata-tion but does not affect CA in the absence of direct braininflammation. The importance of inflammation on brainautoregulation was also underlined in a paper by Rosengar-ten et al., in which cerebral hyperemia induced by transientcarotid compression in septic rats was significantly impaired

in those animals receiving high dose endotoxin and havinglower MAP [166].

Although some controversy still exists, previous studiesappear to demonstrate that sepsis significantly impair brainperfusion and CBF regulation. Whether modulating brainperfusion with hemodynamic augmentation and the use ovasopressors may improve brain perfusion after sepsis is stilunclear. In one study on a model of sepsis induced by con-

tinuous infusion of Pseudomonas aeruginosa [138], CBFremained stable during the hypotension phase even if a redistribution of cardiac output in other organs than the brain waobserved. Interestingly, when norepinephrine was used torestore normal MAP, cerebral perfusion was unaffected, andthe same results were found after the administration of N-monomethyl L-Arginine (L-NMMA), which inhibited theNO production from iNOS. As Meyer and Lingnau [139140]observed a significant decrease in CBF after NOS inhibition using N-nitro-L-Arginine-Methylester (L-NAME), iis still possible that more selective iNOS inhibitors like LNMMA, when compared to L-NAME, would leave the constitutive NOS untouched and thus prevent excessive vasoconstriction.

Finally, a significant reduction of cortical CBF despitestable cardiac output was observed in a murine model oendotoxemic sepsis; this reduction of brain perfusion occurred in parallel with decreased EEG activity and was associated with reduced glucose uptake, measured by PET-scanand increased inflammation [167]. These data suggested thaan early drop of CBF could be related to regional changes inneuronal activity and energy demand and may be independent from MAP changes in septic animals. Although differenareas of the brain showed significant differences in cerebrametabolic changes during sepsis (i.e. an increase of 27 to 33% in the septal nucleus and raphe nucleus and a decrease o14 to 27 % in the auditory cortex, lateral geniculate, superio

colliculus, hippocampus, parietal cortex, and locus coeruleus) [50], the influence of cerebral metabolic changes onbrain perfusion during a septic process may add a new key ointerpretation.

4. BRAIN PERFUSION IN HUMAN SEPSIS

The first study supporting the concept of reduced cerebraperfusion as a major determinant in SAE developmenshowed, in a retrospective analysis, that hypotension was theonly predictor of delirium in patients developing sepsis aftesurgery [168]. Moreover, in an autoptic study analyzing thebrain of patients who died from sepsis, multiple ischemiclesions could be identified in different areas of the brain and

were attributed to hypotensive events, which may occur inpresence of preexisting cerebrovascular disease as well as incase of impairment of CBF autoregulation [38].

4.1. How to Monitor Cerebral Perfusion and Autoregulation in Septic Patients

Cerebral perfusion has been initially evaluated using theKety-Schmidt technique, which applies the Fick principle(arterial and bulb jugular venous content at different timepoints of a tracer is proportional to the global blood flow) tocalculate CBF; different tracers, such as N2O, xenon or argonhave been used [169]. Using the same Fick principle, the
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