Review

Pathophysiology of septic encephalopathy: A review

Marios C. Papadopoulos, MD, FRCS; D. Ceri Davies, PhD; Ray F. Moss; Derek Tighe, PhD; E. David Bennett, FRCP

Objectives: Encephalopathy is a common complication of sepsis. This review describes the different pathologic mechanisms that may be involved in its etiology. Data Sources: The studies described here were derived from the database PubMed (http:\\www.nlm.nih.gov) and from references identied in the bibliographies of pertinent articles and books. The citations are largely conned to English language articles between 1966 and 1998. Older publications were used if they were of historical signicance. Study Selection: All investigations in which any aspect of septic encephalopathy was reported were included. This selection encompasses clinical, animal, and in vitro cell culture work. Data Extraction: The literature cited was published in peerreviewed clinical or basic science journals or in books.

Data Synthesis: Contradictions between the results of published studies are discussed. Conclusions: The most immediate and serious complication of septic encephalopathy is impaired consciousness, for which the patient may require ventilation. The etiology of septic encephalopathy involves reduced cerebral blood ow and oxygen extraction by the brain, cerebral edema, and disruption of the bloodbrain barrier that may arise from the action of inammatory mediators on the cerebrovascular endothelium, abnormal neurotransmitter composition of the reticular activating system, impaired astrocyte function, and neuronal degeneration. Currently, there is no treatment. (Crit Care Med 2000; 28:3019 3024) KEY WORDS: astrocytes; blood-brain barrier; brain edema; cerebrovascular circulation; inammation; intensive care; leukocytes; neurons; sepsis; vascular endothelium

ncephalopathy is a deterioration of mental state or level of consciousness initiated by a disease process extrinsic to the brain. The word encephalopathy originates from the Greek (inside), (head), and os (suffering). Sepsis (Greek s) literally means putrefaction, but is now dened as clinical evidence of infection, with systemic sequelae such as increased respiratory rate, increased heart rate, abnormal body temperature, and inadequate organ perfusion (1). Recognition of the association between infection and impaired brain function dates back 2,500 yrs to Hippocrates, who described patients with fevers, abscesses or spreading redness, and swelling of the limbs that developed phrenitis (2). Subsequently, Galen (approximately 200 AD) pointed out that inammation often affected the mind sympathetically, causing delirium (3) and more recently Sir William Osler (1892) noted that sepsis impaired brain function

From the Departments of Anaesthetics and Intensive Care Medicine (Drs. Papadopoulos, Tighe, Bennett), Anatomy and Developmental Biology (Dr. Davies), and Electron Microscopy (Mr. Moss), St. Georges Hospital Medical School, London, UK. Copyright 2000 by Lippincott Williams & Wilkins

(4). The encephalopathy of sepsis can be classied as either early or septic encephalopathy, that presents before multiple organ failure occurs or late encephalopathy that is accompanied by multiple organ failure, hypotension, and other systemic phenomena. The concept of early or septic encephalopathy as an entity that cannot be explained by hepatic or renal dysfunction, hypotension, or hypoxia is relatively new. Septic encephalopathy was originally dened as altered brain function related to the presence of microorganisms or their toxins in the blood (5). However, this denition is inaccurate because neither microorganisms nor their products can be isolated from the blood of many septic patients (1, 6). Septic encephalopathy probably arises from the action of inammatory mediators on the brain or a cytotoxic response by brain cells to these mediators. Sepsis and its sequelae, sepsis syndrome, septic shock, and acute respiratory distress syndrome, are the leading causes of mortality in intensive care units, accounting for 10% to 50% of deaths (7, 8). Septic encephalopathy has been reported to occur in 8% to 70% of septic patients (6, 8, 9) and is the most common form of encephalopathy among patients in intensive care units (10). The

large variation in the reported incidence of septic encephalopathy probably results from the different denitions of sepsis and encephalopathy used. Septic encephalopathy is probably underdiagnosed because many critically ill patients receive treatments such as sedation, mechanical ventilation, or neuromuscular junction blockade that mask the signs of neural dysfunction. Septic patients may also have renal or liver failure, acute respiratory distress syndrome, electrolyte disturbances, acid-base alterations, hypo/ hyperglycemia, hypotension, hypoxemia, hypo/hyperthermia, or endocrine abnormalities (11). These associated conditions make it difcult for the effects of sepsis on the brain to be studied in isolation. Nevertheless, the onset of encephalopathy often precedes these abnormalities (12), suggesting that septic encephalopathy is not caused by them.

CLINICAL FEATURES
A diagnosis of septic encephalopathy requires evidence of extracranial infection and impaired mental state. Extracranial infection may be apparent from the history and examination, but blood cultures are positive in 50% of septic patients and a focus on infection may be
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difcult to nd (13). A group of 69 septic patients showed impaired attention, orientation, concentration and writing, and (in more severe cases) delirium and coma (9). In contrast to structural brain lesions, encephalopathy is characterized by symmetrical neurologic ndings. The asterixis, tremor, and multifocal myoclonus found in encephalopathy resulting from liver, kidney, or endocrine gland failures are infrequent in sepsis (9). Hypoxemia, hypotension, peripheral organ failure, and the presence of exogenous drugs should be excluded. Meningitis, encephalitis, brain abscess, and subdural empyema are important differentials to exclude using lumbar puncture, computed tomography, or magnetic resonance imaging. Electroencephalography is more sensitive than bedside testing in identifying septic encephalopathy (14) and may be valuable in intensive care units where clinical assessment is difcult. The severity of encephalopathy, which can be graded by the degree of electroencephalographic abnormality (14, 15) or in more severe cases by the Glasgow Coma Scale score (16), correlates with mortality.

PATHOGENESIS
The pathophysiology of septic encephalopathy is likely to be multifactorial. Early reports suggested that septic encephalopathy may be caused by disseminated cerebral microabscesses (17, 18), but a more recent postmortem study (10) failed to nd microabscesses in the brains of four patients with septic encephalopathy. Similar proportions of septic patients with Gram-negative bacteremia, Grampositive bacteremia, fungemia, or with no identied causative organism develop septic encephalopathy (6). These ndings, together with the fact that encephalopathy occurs in noninfectious conditions such as pancreatitis (19), suggest that infecting organisms and/or their toxins do not directly cause encephalopathy. The systemic inammation resulting from infection or other causes, appears more likely to be the cause of septic encephalopathy (20). Inammatory mediators released by leukocytes in sepsis have profound effects on endothelial cells and astrocytes; damage to these cells results in impaired neuronal function. Therefore, this review concentrates on four cell types that play a crucial role in the pathogenesis of septic encephalopathy: leuko3020

cytes, cerebral microvessel endothelial cells, astrocytes, and neurons. Leukocytes. The sequence of events leading to systemic inammation has been reviewed elsewhere (20). Although inammation is initially a local process, in severe infections, massive tissue injury, and in the presence of large amounts of necrotic tissue, a systemic release of inammatory mediators occurs (systemic inammatory response syndrome) that has adverse effects on the liver, lung, kidney, and heart (2124). These organs suffer panendothelial injury that causes reduced patency of microvessels (25). The lungs, liver, and spleen are underperfused (24) and accumulate activated leukocytes (22) that release lysosomal enzymes and oxygen free radicals. In contrast to organs of the reticuloendothelial system, the brain is resistant to leukocyte accumulation (26). Intracerebral injection of platelet activating factor, interleukin-8, interleukin-1, or tumor necrosis factor- fails to cause leukocyte exudation into the brain parenchyma in mice (27). There are a number of reasons for this (28, 29). First, the central nervous system is devoid of a lymphatic system that sequestrates potential antigens. Second, the central nervous system is protected from inammatory cell inltration by the blood-brain barrier. Although cerebrovascular endothelial cell pinocytosis increases in sepsis (30 32), allowing immunologically relevant molecules to pass through, the intercellular tight junctions remain morphologically intact (30 33) and thus, probably constitute a barrier to inammatory cells. Third, cells of the central nervous system express very low levels of the major histocompatibility complex antigens, which play a fundamental role in the induction and regulation of immune responses. Finally, the cerebrovascular endothelium expresses very low levels of leukocyte adhesion molecules such as VCAM-1 and ICAM-1 compared with the peripheral vascular endothelium (28, 29). Although leukocyte accumulation does not occur in the brain during sepsis, inammatory mediators cross the bloodbrain barrier and have adverse effects on the brain. Tumor necrosis factor- and interferon- increase the permeability of cultured bovine (30) and human (31) cerebral endothelial cells by promoting pinocytosis without apparently affecting the intercellular tight junctions. Intracerebral injection of interleukin-1 or interleukin-2 into experimental animals has

been reported to mimic the electroencephalographic changes and soporic effects of septic encephalopathy (34 36) and to cause fever by their effect on the hypothalamus (37). Subarachnoid injection of tumor necrosis factor- in rabbits reduces cerebral oxygen uptake and cerebral blood ow and increases intracranial pressure and cerebrospinal uid lactate (38). Tumor necrosis factor- enhances the production of endothelin and inhibits the formation of nitric oxide by cultured cerebral endothelial and smooth muscle cells (39). Activated leukocytes in the circulation generate oxygen free radicals that react with erythrocyte cell membranes and reduce the deformability of normal human erythrocytes treated with endotoxin (40, 41), erythrocytes in septic patients (42), erythrocytes in dogs infused with Escherichia Coli (43), and erythrocytes in rats after cecal ligation and puncture (44 46). Erythrocytes in cerebral microvessels appear enlarged and rounded in pigs with fecal peritonitis (33). These abnormally-shaped erythrocytes may be unable to squeeze through microvessels, thus exacerbating the cerebral hypoperfusion that occurs in sepsis (47, 48). Inotropes improve cardiac output that may be suppressed in the later stages of sepsis. 2 adrenergic agents are also antiinammatory (49 52), but 1-adrenergic agents are proinammatory (53, 54). In pigs with faecal peritonitis, dopexamine (a 2 adrenoceptor, vascular DA1 receptor, and prejunctional DA2 receptor agonist) protects against cerebral edema (55) and attenuates the leukostasis that occurs in the liver (56). Further studies are required to assess whether inotropes with 1 activity aggravate septic encephalopathy in humans, whereas inotropes with 2 activity offer protection against septic encephalopathy in humans. Cerebral Endothelial Cells. Blood is separated from the brain parenchyma by the blood-brain barrier, which depends on the integrity of cerebral microvessel endothelial cells. Normal cerebral microvessel endothelium, in contrast to that of most other tissues, has no fenestrations, possesses intercellular tight junctions, and contains few pinocytotic vesicles (57, 58). Septic encephalopathy appears to be associated with breakdown of the blood-brain barrier because patients with septic encephalopathy have high protein levels in the cerebrospinal uid (14) and colloidal iron oxide (32), 14 C-amino acids (59), and 125I-albumin
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(24) pass from the circulation into the brain parenchyma in septic rodents. Normally, low doses of circulating catecholamines have no effect on cerebral blood vessels because they are excluded from the central nervous system by the blood-brain barrier (60, 61). Higher concentrations of circulating catecholamines may result in dilation of cerebral blood vessels resulting from an increase in arterial blood pressure and thus, distension of the vascular walls. Disruption of the blood-brain barrier allows the high levels of endogenous catecholamines that occur in sepsis (61) and the various vasopressors administered in intensive care units to directly inuence cerebral vascular resistance (62). Agents with 1-adrenoceptor activity, such as norepinephrine, have been reported to cross the blood-brain barrier and cause cerebral vasoconstriction in sepsis (63). In contrast, during hemorrhagic shock, where blood-brain barrier permeability is unaffected, norepinephrine has no effect on the cerebral vasculature (64). Impaired blood-brain barrier function may also explain why cerebral oxygen consumption is 33% of normal in septic patients and remains constant when the cerebral blood ow is increased (47, 48). The cerebral perimicrovessel edema, seen in pigs after fecal peritonitis (33) and in rabbits with endotoxemia (32), is likely to limit the diffusion and hence utilization of oxygen, nutrients, and cellular waste across the microvessel wall. In dogs (65), pigs (63), and humans (47, 48), endotoxic shock has been shown to cause a reduction in cerebral blood ow that cannot be increased by improving the mean arterial pressure with vasopressors, suggesting that cerebral edema may increase intracranial pressure in sepsis, thus opposing the increase in cerebral blood ow after elevation of mean arterial pressure. This hypothesis is also supported by the fact that endotoxemia in pigs causes intracranial hypertension despite arterial hypotension (66). Systemic administration of E. Coli endotoxin to healthy volunteers did not affect cerebral blood ow or the rate of cerebral oxygen metabolism, despite replicating many of the systemic and hemodynamic features of sepsis (67). Although this model of sepsis (67) avoids many of the confounding variables present in critically ill patients, the lack of effect of E. Coli endotoxin on the cerebral circulation probably reects the low dose of endotoxin used. Another
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cause of impaired cerebral oxygen utilization during sepsis may be the inhibition of mitochondrial function. There is evidence from rat liver, smooth muscle, and pulmonary epithelium that endotoxemia and proinammatory cytokines cause mitochondrial dysfunction, probably by nitric oxide-mediated mechanisms (68). Alternatively, the reduced brain oxygen extraction in sepsis may be caused by, rather than be the cause of, the reduced brain activity in sepsis. In pigs with fecal peritonitis (33) and rabbits with endotoxemia (32), the interendothelial cell tight junctions appear to remain morphologically intact, although the permeability of the blood-brain barrier was increased. Therefore, the functional status of the tight junctions is unclear and requires investigation. Because the molecular structure of tight junctions has recently been elucidated (69), it would be interesting to use immunohistochemistry to investigate whether the glue-like tight junction protein occludin and its intracellular anchor ZO-1 are functionally disrupted in sepsis. Astrocytes. The perivascular endfeet of cortical astrocytes are disrupted in pigs with fecal peritonitis (33) and in rabbits injected with endotoxin (32). Astrocytes are important supportive and homeostatic cells in the central nervous system (70) and their injury may exacerbate neuronal damage by several mechanisms. First, in regions of high neuronal activity, there is a potassium ux from neurons to the extracellular space. The potassium is taken up by astrocytes and transferred to endothelial cells. It is then secreted into the vascular lumen to dilate local blood vessels (70, 71). Astrocyte damage may thus impair the regulation of local blood ow. Second, astrocytes transport energy substrates from microvessels to neurons in proportion to the level of synaptic activity (72). Injury to astrocyte endfeet may impair this coupling process and therefore reduce synaptic activity. Third, astrocytes are important in inducing blood-brain barrier properties in the cerebral endothelium (73) and their damage may exacerbate the increased bloodbrain barrier permeability in sepsis. Astrocytes possess receptors for inammatory mediators (74). In human astrocyte cultures, recombinant human -interferon and interleukin-1 induce the formation of reactive oxygen intermediates (75) that are toxic (76). Free radical scavengers inhibit the electrophysiological changes seen after addition of

sepsis and septic patients with encephalopathy have a higher mortality than those without encephalopathy. These ndings suggest that encephalopathy may be a cause of death in septic patients.

ncephalopathy is often the rst manifestation of

various interferons to hippocampal slices (77). The results of experiments using rodent cell cultures suggest that astrocytes inuence the vulnerability of neurons to hypoxic (78), excitotoxic (79), and free radical-mediated (80) injuries. Therefore, the role of astrocytes in modulating neuronal damage in sepsis merits further study. Neurons. Septic encephalopathy is associated with disturbances of the reticular activating system that controls consciousness and attention. Cecal ligation and puncture in rats has been shown to increase glucose utilization by the raphe nuclei (81) and to increase the turnover of serotonin throughout the brain (82). In the same animal model of sepsis, glucose utilization by the locus ceruleus (81) and the norepinephrine content of the whole brain were found to be reduced (83). Enhanced serotoninergic and reduced noradrenergic neurotransmission have also been reported in hepatic (84) and uremic (85) encephalopathy and may, therefore, be universal features of the encephalopathies (86, 87). However, it is unclear whether these changes in neurotransmission are causes of encephalopathy or epiphenomena. Altered levels of tyrosine, tryptophan, and phenylalanine might explain the changes in neurotransmission found in sepsis, although the data should be interpreted with caution because such alterations may be secondary to the liver and renal failure that occurs in sepsis. The
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plasma and brain concentrations of these aromatic amino acids are increased in septic patients (88, 89) and in rats after cecal ligation and puncture (59), because they are released into the circulation from muscle breakdown (90, 91). In humans, the severity of septic encephalopathy can be predicted from the plasma concentrations of these amino acids (89, 92), suggesting that they contribute to its pathophysiology. Increased brain levels of the serotonin precursor tryptophan may be responsible for the potentiation of the reticular activating system serotonergic pathways. Intracarotid infusion of tryptophan has been shown to induce drowsiness and sleepiness in dogs (93). The high concentrations of tyrosine and phenylalanine in septic brains have been reported to cause increased levels of their breakdown products, -phenylethylamine and octopamine (91, 92, 94). These false neurotransmitters may be responsible for the inhibition of the central noradrenergic pathways (91, 94). Furthermore, administration of phenylalanine to dogs (93) and mice (95) has been shown to induce hypoactivity, ingestion of phenylalanine by a human volunteer caused lethargy (96), and congenital disorders of phenylalanine metabolism lead to encephalopathy (97). Branched-chain amino acids compete with aromatic amino acids for transport across the blood-brain barrier (88 93). They are used as energy sources in sepsis, causing a fall in their plasma and brain levels (88 93). Administration of branched chain amino acid-rich solutions to a group of septic patients has been reported to normalize plasma amino acid levels and to reverse encephalopathy (88, 91). However, these results must be treated with caution because the patients were also subjected to antibiotic treatment and abscess drainage. Dark, shrunken, apparently degenerating neurons are present in the frontal cortices of hemodynamically controlled pigs after only 8 hrs of fecal peritonitis (33). This is an important nding because septic encephalopathy was previously thought to be reversible (12, 86). Neuronal injury was not reported in rabbits injected with endotoxin, (32) suggesting possible differences between species or in the severity of sepsis. It is not known whether neuronal injury occurs in septic humans. However, because the duration of sepsis is typically considerably 8 hrs
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in critically ill patients, their neuronal damage might be even more severe than that observed in the pig model. Although septic encephalopathy occurs before cerebral hypoperfusion, cerebral hypoxia/ischemia could potentially contribute to neuronal death in sepsis. In septic patients, cerebral blood ow is reduced to 62% of normal (47, 48). This decrease does not appear to be enough to threaten neuronal viability or to cause electroencephalographic changes (98, 99) because cerebral blood ow needs to fall to 45% before the electroencephalogram is affected and to 33% for anoxic depolarization of neurons to occur (98, 99). Even if cerebral blood ow in sepsis is sufcient for the baseline energy requirements of neurons, it may become functionally limiting during high synaptic activity. Impaired cerebral blood ow may therefore inhibit the processing of complex information and thus contribute to the symptoms of septic encephalopathy, unless it is the reduced neuronal activity that occurs in sepsis, which causes the decrease in cerebral blood ow. In a study of eight septic patients (47), the cerebrovascular response to changes in the arterial partial pressure of carbon dioxide was found to remain intact, despite the depression of cerebral blood ow. However, it is not clear whether hyperventilation in sepsis would further compromise cerebral blood ow and thus exacerbate the encephalopathy. Augmentation of -amino butyric acid-mediated neurotransmission by endogenous benzodiazepine ligands may contribute to the impaired motor function and decreased consciousness in hepatic encephalopathy (100); the role of the -amino butyric acid system in septic encephalopathy awaits identication. Glutamate is considered to be the neurotransmitter in 40% of the synapses in the brain (101). Glutamate, released by damaged neurons and by reverse transport of the astrocyte glutamate carrier (102, 103), causes neuronal injury (excitotoxicity) in many disorders, including hepatic encephalopathy (102). Its role in septic encephalopathy has not been evaluated. There are no published studies of the genetic response of neurons to sepsis, despite the sizeable literature that shows the importance of gene products such as hsp-70, bcl-2, p53, HO-1, and the caspases in other forms of brain damage such as ischemia (103).

CONCLUSIONS
Encephalopathy is often the rst manifestation of sepsis (12, 86) and septic patients with encephalopathy have a higher mortality than those without encephalopathy (6, 9, 10, 15). These ndings suggest that encephalopathy may be a cause of death in septic patients. Although often unrecognized, it would appear that brain injury occurs in sepsis at least as frequently as damage to other organs. Free radicals produced by leukocytes damage erythrocytes and thus limit oxygen delivery to the brain. Inammatory mediators released by leukocytes impair mitochondrial function and oxygen extraction by the brain. These mediators also open the blood-brain barrier, resulting in perimicrovessel edema and disruption of astrocyte endfeet. Aromatic amino acids enter the brain parenchyma and disturb the neurotransmitter content of the brain. Ultimately, these changes appear to cause extensive neuronal injury and thus, the possibility exists that patients who recover from sepsis may have long-term neuropsychiatric/ neurologic decits.

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