BJA Advance Access originally published online on July 24, 2007
British Journal of Anaesthesia 2007 99(4):518-521; doi:10.1093/bja/aem201
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Elevated S100B levels do not correlate with the severity of encephalopathy during sepsis
1 Anestesia e Rianimazione, Università degli Studi di Napoli ‘Federico II’, via Pansini 5 (Ed 8), 80131 Napoli, Italy
2 Patologia Clinica, IRCCS Pascale, Napoli, Italy
* Corresponding author. E-mail: orpiazza{at}unina.it
Accepted for publication May 25, 2007.
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Abstract |
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Background: Sepsis-associated encephalopathy (SAE) is defined as a diffuse cerebral dysfunction induced by the systemic response to infection without any clinical or laboratory evidence of direct infectious involvement of the central nervous system. The astroglial protein S100B has been used as a marker of severity of brain injury and as a prognostic index in trauma patients and cardiac arrest survivors. We measured S100B serum levels in patients with severe sepsis to investigate if the severity of SAE correlated with an increase in S100B levels.
Methods: Twenty-one patients, with a diagnosis of severe sepsis, were included in this study. S100B levels were measured at intensive care unit (ICU) admission, 72 h and 7 days after admission. Their association with markers of brain dysfunction such as Glasgow coma scale (GCS), and EEG, and with sepsis-related organ failure assessment score (SOFA) and ICU mortality was investigated.
Results: Fourteen patients had elevated S100B levels. The levels did not correlate with GCS at admission, EEG pattern, or SOFA scores. Also, S100B levels did not differ between patients who recovered neurologically and those who did not (P = 0.62).
Conclusions: In severe sepsis, an increase in S100B does not allow the physicians to distinguish patients with severe impairment of consciousness from those with milder derangements or to prognosticate neurological recovery.
Keywords: brain, blood–brain barrier; brain, electroencephalography; complications, infections; complications, multiple organ dysfunction syndrome; complications, neurological
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Introduction |
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Sepsis-associated encephalopathy (SAE) is defined as a diffuse or multifocal cerebral dysfunction.1 It is a component of the systemic inflammatory response to an infection without clinical or laboratory evidence of direct brain infection. Acute alteration in mental status has been listed among the signs of hypoperfusion, the trademark of severe sepsis and septic shock,2 but the pathophysiology of SAE remains unclear. Metabolic derangements, endotoxin effects on the brain, altered amino acid profiles, and brain metabolism have been evaluated as possible causes.3 SAE is considered reversible, but survivors of severe sepsis often have long-lasting or irreversible cognitive and behavioural sequelae;4 it may be associated with an increased mortality rate in sepsis patients.3–6
The incidence of SAE ranges from 9% to 71%.6 Such a wide range is probably due to different definitions used by the different authors; when the Glasgow coma scale (GCS) was used to define mental alteration, 62% incidence and 39% mortality has been reported.5 GCS has been recommended to assess brain dysfunction in sepsis patients, even if problems related to the assessment in sedated patients are not yet resolved.7
EEG, the most widely used electrophysiology test in intensive care unit (ICU) patients, could be helpful in diagnosis and grading of SAE, but both EEG findings and neurological examination in sepsis patients are too often hampered by sedation and analgesia and by metabolic derangements. S100B protein is a dimeric acidic calcium-binding protein found intracellularly and extracellularly in the brain at subnanomolar–nanomolar concentrations.8
As a serum marker, which reflects the severity of brain damage, this astroglial protein has been proposed for the evaluation of post-cardiac arrest brain damage9 and to prognosticate neurological outcome after traumatic brain injury (Table 1).
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We have undertaken this study to evaluate the increase in S100B and its usefulness in diagnosis and prediction of neurological dysfunction in critically ill patients suffering from severe sepsis.
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Methods |
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The local ethic committee of Federico II University School of Medicine approved the study. Seventy-five patients were diagnosed with sepsis during the study period (January–December 2005). Only patients admitted to the ICU with severe sepsis10 were included in this retrospective analysis whereas patients with septic shock criteria were excluded. Clinical neurological examination was performed at the time of ICU admission, before any analgesic or sedative drugs were given. Patients already presenting with metabolic encephalopathy at hospital admission were excluded from the study. Further exclusion criteria were blunt or penetrating head trauma, intracerebral mass lesions, epilepsy, peripheral nervous system pathology, melanoma or other malignancy associated with S100B increase, cardiopulmonary resuscitation, shock of any origin, and causes of possible cerebral hypoxia.
Twenty-one patients [10 females, 11 males, mean (range) age 68.7 (49–84) yr] were considered eligible. Patients were characterized by gender, age, GCS, ICU mortality, and length of ICU stay. The sepsis-related organ failure assessment (SOFA) score and the GCS were calculated every day,11 12 including the day of S100B measurement. Neurological recovery was assessed daily during the ICU stay by clinical examination, after an adequate suspension of infusion of sedative drugs and at 90 days by Glasgow outcome scale (GOS).13 S100B was measured at ICU admission, after 72 h, and after 7 days, according to an internal protocol, independent of this study. EEG was recorded within 72 h after the diagnosis, after having stopped the sedation for at least 18 h. EEG findings were classified according to the Young score system.14 A computed tomography (CT) scan was performed at admission when the patients went for investigation of other problems and when the haemodynamic and respiratory conditions safely allowed it (n = 5).
All the patients showed positive cultures (Gram-positive bacteria in five, Gram-negative bacteria in 10, and fungus in six patients). Sixteen patients suffered from pneumonia, two had a central venous catheter-related infection, and three a surgical wound infection. Six patients suffered from bacteraemia and four from candidaemia.
The normal S100B value is <0.15 µg litre–1 in adults.9 A commercial kit (LIAISON Sangect 100) was used to measure the S100B concentration; the detection limit of the kit is 0.02 µg litre–1
All results are presented as mean (SD). Student's t-test, Kruskal–Wallis, Spearman correlation, and 
2 tests were used for statistical analysis.
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Results |
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The patient characteristics are presented in Tables 2 and 3. Nine patients showed evidence of severe impairment of consciousness (GCS
8). Five patients showed milder neurological dysfunction (GCS=9–12) and seven patients showed agitation and confusion but scored a GCS of 14 or 15.
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Mean serum S100B was increased to 0.334 (0.274) µg litre–1; S100B >0.5 µg litre–1 was found in 14 patients. The values of S100B levels during the stay in the ICU at 72 h and 7 days were stable (Table 4). In seven patients, S100B was in the normal range (<0.15 µg litre–1), and three of these seven patients had severe impairment of consciousness (GCS
8). Overall, the GCS score did not correlate with the S100B levels (r = 0.082) and the severity of brain damage could not be defined on the basis of this protein serum levels at ICU admission.
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Postoperative surgical patients showed a higher S100B value [0.36 (0.29)] than medical patients [0.27 (0.23) µg litre–1]; this difference was not statistically significant (P > 0.05 on Student's t-test).
The ICU mortality was 42% (nine patients out of 21 died within 28 days). Among survivors at 28 days, six patients died within 90 days after the severe sepsis; in these patients, GOS at ICU discharge was 3. Only six patients out of 21 survived long enough to allow the neurological evaluation at 90 days. Complete recovery of consciousness was achieved in five patients (GOS 5); one patient (no. 14, Table 3) was severely disabled (GOS 3).
The GCS score at the admission of the patients who completely recovered consciousness was higher than the GCS of the patients who did not completely regain consciousness [13.3 (1.9) vs 8.4 (3.8); P = 0.009]. All the patients who had a GCS<8 at admission died during the following 90 days period.
S100B serum levels on diagnosis of severe sepsis (at admission) did not differ between patients who recovered neurological status [0.268 (0.131)] and the patients who did not [0.286 (0.315) µg litre–1, P = 0.624]. Also the SOFA score and S100B levels did not correlate (r = 0.124). EEGs findings were abnormal in all cases, with a large range of inter-individual variability, and we did not find any correlation between EEG patterns (Young score system) and S100B serum levels (P = 0.553, Table 5).
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CT scan was performed in five patients, and they did not show any evidence of cerebral lesions associated with SAE.
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Discussion |
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The main finding of this study is that S100B levels are increased in severe sepsis, without a clear relationship with GCS or EEG. So far, the aetiology of SAE has not been clearly described, but the mechanism is probably multifactorial; the alteration of consciousness as a direct effect of the hypoperfusion seems an oversimplified explanation.15 We excluded patients with septic shock from the analysis in order to avoid the possibility of prolonged ischaemic insults.16 Alterations of blood–brain barrier permeability with subsequent brain oedema formation are common features in experimental models.17 Also, inflammatory cytokines [tumour necrosis factor (TNF) and interleukin-1 (IL-1)] are produced by neurons and they participate in a bidirectional communication between the nervous and the immune system.18
S100B is included in the large family of calcium-binding proteins: other S100 proteins, the S100A8, and the A9 act, as chemotactic molecules in inflammation.19 Hayakata and colleagues20 reported an increase in S100B and IL-1 in cerebrospinal fluid in early phases of severe TBI. This study confirmed the results of Liu and colleagues21 who showed increases in IL-1 induced by S100B in microglial and neuronal cells in Alzheimer cell cultures. In vitro experiments have shown that TNF increased the release of S100B from astrocyte cultures without damaging the cells.22 Therefore, increased S100B in sepsis can be interpreted as a proinflammatory response of the brain. Although we cannot exclude this possibility, damaged skeletal muscles and cartilage and adipocytes stimulated by catecholamines might also release relatively large quantities of S100B during sepsis.
In our study, an increase in S100B did not allow us to distinguish patients with severe impairment of consciousness from those with milder derangements. Also, the prognostic role of this protein could not be deduced because of the small sample size.
In conclusion, we have shown a significant increase in S100B in severe sepsis. However, this increase did not correlate with the severity of neurological dysfunction or the patient's neurological outcome.
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References |
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1 Young GB, Bolton CF, Austin TW, Archibald YM, Gonder J, Wells GA. The encephalopathy associated with septic illness. Clin Invest Med (1990) 13:297–304.[Web of Science][Medline]
2 ACCP/SSCM Medicine Consensus Committee. Definition of sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med (1992) 20:864–74.[Web of Science][Medline]
3 Consales G, De Gaudio AR. Sepsis associated encephalopathy. Minerva Anestesiol (2005) 71:39–52.[Medline]
4 Wilson JX, Young GB. Sepsis-associated encephalopathy: evolving concepts. Can J Neurol Sci (2003) 30:98–105.[Web of Science][Medline]
5 Eidelmann LA, Putterman D, Putterman C, Sprung L. The spectrum of septic encephalopathy. Definitions, etiologies, and mortalities. JAMA (1996) 14:470–3.
6 Bleck TP, Smith MC, Pierre-Louis SJ, Jares JJ, Murray J, Hansen CA. Neurologic complications of critical medical illnesses. Crit Care Med (1993) 21:98–103.[Web of Science][Medline]
7 Bolton CF, Prough DS, Sprung CL, Young GB. Shock, Sepsis, and Organ Failure: Brain Damage Secondary to Hemorrhagic-Traumatic Shock–Sepsis–Traumatic Brain Injury—Schlag G, Redl H, Traber D, eds. (1997) Springer Verlag.
8 Donato R. Intracellular and extracellular roles of S100 proteins. Microsc Res Tech (2003) 60:540–51.[CrossRef][Web of Science][Medline]
9 Piazza O, Cotena S, Esposito G, De Robertis E, Tufano R. S100B is a sensitive but non specific prognostic index in comatose patients after cardiac arrest. Minerva Chir (2005) 60:477–80.[Medline]
10 Levy MM, Fink MP, Marshall JC, et al, SCCM/ESICM/ACCP/ATS/SIS. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med (2003) 31:1250–6.[CrossRef][Web of Science][Medline]
11 Gogos CA, Lekkou A, Papageorgiou O, Siagris D, Skoutelis A, Bassaris HP. Clinical prognostic markers in patients with severe sepsis: a prospective analysis of 139 consecutive cases. J Infect (2003) 47:300–6.[CrossRef][Web of Science][Medline]
12 Vincent JL, Moreno R, Takala J, et al. The SOFA (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med (1996) 22:707–10.[Web of Science][Medline]
13 Jennet B, Bond M. Assessment of outcome after severe brain damage. Lancet (1975) I:480–4.
14 Young GB, Bolton CF, Archibald YM, Austin TW, Wells GA. The electroencephalogram in sepsis-associated encephalopathy. J Clin Neurophysiol (1992) 9:145–52.[Web of Science][Medline]
15 Pollard V, Conroy B, Prough DS, Deyo DJ, Traber L, Traber D. Shock, Sepsis, and Organ Failure: Brain Damage Secondary to Hemorrhagic-Traumatic Shock–Sepsis–Traumatic Brain Injury—Schlag G, Redl H, Traber D, eds. (1997) Springer Verlag.
16 Sharshar T, Annane D, de la Grandmaison GL, Brouland JP, Hopkinson NS, Francoise G. The neuropathology of septic shock. Brain Pathol (2004) 14:21–3.[Web of Science][Medline]
17 Esen F, Erdem T, Aktan D, et al. Effect of magnesium sulfate administration on blood–brain barrier in a rat model of intraperitoneal sepsis: a randomized controlled experimental study. Crit Care (2005) 9:R18–23.[CrossRef][Web of Science][Medline]
18 Tracey KJ. The inflammatory reflex. Nature (2002) 420:853–9.[CrossRef][Medline]
19 Marenholz I, Heizman CW, Fritz G. S100 proteins in mouse and man: from evolution to function and pathology (including an update of the nomenclature). Biochem Biophys Res Commun (2004) 322:1111–22.[CrossRef][Web of Science][Medline]
20 Hayakata T, Shiozaki T, Tasaki O, et al. Changes in CSF S100B and cytokine concentrations in early-phase severe traumatic brain injury. Shock (2004) 22:102–7.[CrossRef][Web of Science][Medline]
21 Liu L, Li Y, Van Eldik LJ, Griffin WS, Barger SW. S100B-induced microglial and neuronal IL-1 expression is mediated by cell type-specific transcription factors. J Neurochem (2005) 92:546–53.[CrossRef][Web of Science][Medline]
22 Edwards M, Robinson SR. TNF alpha affects the expression of GFAP and S100B: implications in Alzheimer's disease. J Neural Transm (2006) 113:1709–15.[CrossRef][Web of Science][Medline]
23 Cotena S, Piazza O, Storti M. The S100B protein and traumatic brain injury. J Neurosurg (2006) 104:435–6.[Web of Science][Medline]
24 Russo E, Cotena S, Rossi R, et al. The brain is wider than the sky. Minerva Anestesiol (2006) 72:217.[Web of Science][Medline]
25 Piazza O, Palomba R, Esposito G. S100B serum levels increase in postoperative patients. Acute Pain (2006) 8:87–8.[CrossRef]
26 Piazza O, Cotena S, De Robertis E, Esposito G, Servillo G. S100B in Guillain–Barré syndrome. Br J Anaesth (2006) 96:141–2.
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