Endotoxemia-induced inflammation and the effect on the human brain

Mark van den Boogaard, Bart P Ramakers, Nens van Alfen, Sieberen P van der Werf, Wilhelmina F Fick, Cornelia W Hoedemaekers, Marcel M Verbeek, Lisette Schoonhoven, Johannes G van der Hoeven, Peter Pickkers, Mark van den Boogaard, Bart P Ramakers, Nens van Alfen, Sieberen P van der Werf, Wilhelmina F Fick, Cornelia W Hoedemaekers, Marcel M Verbeek, Lisette Schoonhoven, Johannes G van der Hoeven, Peter Pickkers

Abstract

Introduction: Effects of systemic inflammation on cerebral function are not clear, as both inflammation-induced encephalopathy as well as stress-hormone mediated alertness have been described.

Methods: Experimental endotoxemia (2 ng/kg Escherichia coli lipopolysaccharide [LPS]) was induced in 15 subjects, whereas 10 served as controls. Cytokines (TNF-alpha, IL-6, IL1-RA and IL-10), cortisol, brain specific proteins (BSP), electroencephalography (EEG) and cognitive function tests (CFTs) were determined.

Results: Following LPS infusion, circulating pro- and anti-inflammatory cytokines, and cortisol increased (P < 0.0001). BSP changes stayed within the normal range, in which neuron specific enolase (NSE) and S100-beta changed significantly. Except in one subject with a mild encephalopathic episode, without cognitive dysfunction, endotoxemia induced no clinically relevant EEG changes. Quantitative EEG analysis showed a higher state of alertness detected by changes in the central region, and peak frequency in the occipital region. Improved CFTs during endotoxemia was found to be due to a practice effect as CFTs improved to the same extent in the reference group. Cortisol significantly correlated with a higher state of alertness detected on the EEG. Increased IL-10 and the decreased NSE both correlated with improvement of working memory and with psychomotor speed capacity. No other significant correlations between cytokines, cortisol, EEG, CFT and BSP were found.

Conclusions: Short-term systemic inflammation does not provoke or explain the occurrence of septic encephalopathy, but primarily results in an inflammation-mediated increase in cortisol and alertness.

Trial registration: NCT00513110.

Figures

Figure 1
Figure 1
LPS-induced changes in cytokine plasma concentrations, cortisol and brain specific proteins. Time -0- reflects baseline concentrations. Administration of lipopolysaccharide (LPS) resulted in a marked increase in TNF-α, IL-6, IL-10, IL-1Ra and cortisol concentrations. All changes in cytokine and the cortisol concentrations were significant (P < 0.001). Concentrations of neuron specific enolase (NSE) decreased after administration of LPS (P < 0.001) and S100-β showed a significant biphasic change (P = 0.038). All data are expressed as mean ± standard error of the mean (n = 15). GFAP, glial fibrillary acidic protein; S100β, S100 Calcium Binding Protein B. * P < 0.05. ** P < 0.001.
Figure 2
Figure 2
Increase of the EEG occipital peak frequencies, relative alpha band power and absolute alpha and beta band power two to three hours after LPS infusion. Data of peak frequency are absolute numbers, data of absolute and relative band power are expressed as percentage changes. Time -0- reflects baseline measurements. (standard error of the means were omitted for reasons of clarity). * P < 0.05. ** P < 0.001. (a) Peak frequency in occipital region. Friedman analysis of variance revealed changes in P4O2 and P3O1 (both P < 0.001). (b) Percentage change compared to baseline in absolute band power (ABP) of alpha activity in occipital and central region. Friedman analysis of variance revealed changes for alpha activity in P4O, P3O1 and F4C4, F3C3 all P < 0.001. (c) Percentage change compared with baseline in absolute band power (ABP) and relative band power (RBP) of beta activity in occipital region. Friedman analysis of variance revealed changes of RBP for beta activity in P4O2 (P = 0.017), P3O1 (P = 0.575) and ABP for beta activity in P4O and P3O1 (both P < 0.001).

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