Send Reprints Orders on reprints@benthamscience.org Current Vascular Pharmacology, 2012, 10, 000-000 1 1570-1611/12 $58.00+.00 © 2012 Bentham Science Publishers Brain Perfusion In Sepsis Fabio Silvio Taccone* ,1 , Sabino Scolletta 1 , Federico Franchi 2 , Katia Donadello 1 and Mauro Oddo 3 1 Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles (ULB), Route de Lennik, 808, 1070 Brussels, Belgium; 2 Department of Anaesthesia and Intensive Care, University of Siena, Viale Bracci, 1, 53100 Siena, Italy; 3 Department of Intensive Care Medicine, Centre Hospitalier Universitaire Vaudois, Rue du Bugnon 21, 1011 Lausanne, Vaud, Switzerland Abstract: Brain dysfunction is a frequent complication of sepsis, usually defined as “sepsis-associated encephalopathy” (SAE). Its pathophysiology is complex and related to numerous processes and pathways, while the exact mechanisms pro- ducing neurological impairment in septic patients remain incompletely elucidated. Alterations of the cerebral blood flow (CBF) may represent a key component for the development of SAE. Reduction of CBF may be caused by cerebral vaso- constriction, either induced by inflammation or hypocapnia. Endothelial dysfunction associated with sepsis leads to im- pairment of microcirculation and cerebral metabolic uncoupling that may further reduce brain perfusion so that CBF be- comes inadequate to satisfy brain cellular needs. The natural autoregulatory mechanisms that protect the brain from re- duced/inadequate CBF can be impaired in septic patients, especially in those with shock or delirium, and this further con- tributes to cerebral ischemia if blood pressure drops below critical thresholds. Sedative agents alter cerebro-vascular reac- tivity and may significantly reduce CBF. Although disorders of brain perfusion and alteration of CBF and cerebral autoregulation are frequently observed in humans with sepsis, their exact role in the pathogenesis of SAE remains un- known. Brain perfusion can further become inadequate due to cerebral microcirculatory dysfunction, as evidenced in the experimental setting. Microvascular alterations can be implicated in the development of electrophysiological abnormali- ties observed during sepsis and contribute to neurological alterations in septic animals. The aim of this review is to pro- vide an update on the pathophysiology of brain perfusion in sepsis, with a particular focus on human clinical investigation and novel tools for CBF monitoring in septic patients. Keywords: Sepsis, encephalopathy, brain dysfunction, cerebral hemodynamics, autoregulation, cerebral blood flow, carbon dioxide, microcirculation. 1. BRAIN DYSFUNCTION DURING SEPSIS 1.1. Definition of Sepsis-Associated Encephalopathy (SAE) Septic shock and related multi-organ failure (MOF) re- main a major cause of morbidity and mortality in intensive care units (ICUs) worldwide [1]. The infectious stimuli, as- sociated with a widespread reaction characterized by the release of numerous circulating pro-inflammatory molecules, can potentially impair the function of several organs [2]. Brain dysfunction occurs early during sepsis and is com- monly characterized by the development of an altered mental state; however, cerebral abnormalities are also described in late course of sepsis, often accompanied by MOF, hypoten- sion and other systemic events [3, 4]. Hippocrates first re- ported the association between infections and cerebral dysfunction more than 2500 years ago [5], and sir William Osler also described, later on, the occurrence of “delirium” in patients with ongoing sepsis [6]. Nevertheless, concomi- tant hepatic or renal failure, electrolyte and metabolic distur- bances, altered glucose homeostasis, hypotension, *Address correspondence to this author at the Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, ULB), Route de Lennik, 808, 1070 Brussels, BELGIUM; Tel: +322 555 5587; Fax: +322 555 4698; E-mail: ftaccone@ulb.ac.be hypoxemia, hypothermia or neurological side-effects of differ- ent pharmacological agents may concomitantly occur in septic patients, rendering the discrimination between sepsis-related brain dysfunction and encephalopathy from other causes a potentially difficult task [7]. Sepsis-associated encephalopathy (SAE) can be defined as a diffuse or multifocal brain dysfunction associated with an infectious illness (a) without clinical and laboratory evidence of intracranial infection and/or (b) without conditions unre- lated to the infectious process that would significantly alter brain function [8]. The diagnosis should therefore exclude structural brain lesions or primary pathologies of the central nervous system (i.e. meningitis or stroke), other neurological diseases (i.e. epilepsy), a toxic-metabolic cause, fat embolism syndrome and anoxic brain injury [9]. Moreover, acute in- flammatory encephalopathies, such as acute disseminated en- cephalomyelitis or acute hemorrhagic leucoencephalopathy, should be also considered apart from SAE, because of their specific immuno-mediated inflammation of central nervous system (CNS) structures and response to corticosteroids [10]. 1.2. Epidemiology, Clinical Features and Diagnosis The occurrence of SAE is variable but is one of the most common forms of encephalopathy encountered in critically