The Effect of Propofol vs. Isoflurane Anesthesia on Postoperative Changes in Cerebrospinal Fluid Cytokine Levels: Results from a Randomized Trial

Abstract

Introduction: Aside from direct effects on neurotransmission, inhaled and intravenous anesthetics have immunomodulatory properties. In vitro and mouse model studies suggest that propofol inhibits, while isoflurane increases, neuroinflammation. If these findings translate to humans, they could be clinically important since neuroinflammation has detrimental effects on neurocognitive function in numerous disease states.

Materials and methods: To examine whether propofol and isoflurane differentially modulate neuroinflammation in humans, cytokines were measured in a secondary analysis of cerebrospinal fluid (CSF) samples from patients prospectively randomized to receive anesthetic maintenance with propofol vs. isoflurane (registered with http://www.clinicaltrials.gov, identifier NCT01640275). We measured CSF levels of EGF, eotaxin, G-CSF, GM-CSF, IFN-α2, IL-1RA, IL-6, IL-7, IL-8, IL-10, IP-10, MCP-1, MIP-1α, MIP-1β, and TNF-α before and 24 h after intracranial surgery in these study patients.

Results: After Bonferroni correction for multiple comparisons, we found significant increases from before to 24 h after surgery in G-CSF, IL-10, IL-1RA, IL-6, IL-8, IP-10, MCP-1, MIP-1α, MIP-1β, and TNF-α. However, we found no difference in cytokine levels at baseline or 24 h after surgery between propofol- (n = 19) and isoflurane-treated (n = 21) patients (p > 0.05 for all comparisons). Increases in CSF IL-6, IL-8, IP-10, and MCP-1 levels directly correlated with each other and with postoperative CSF elevations in tau, a neural injury biomarker. We observed CSF cytokine increases up to 10-fold higher after intracranial surgery than previously reported after other types of surgery.

Discussion: These data clarify the magnitude of neuroinflammation after intracranial surgery, and raise the possibility that a coordinated neuroinflammatory response may play a role in neural injury after surgery.

Keywords: anesthesia; cerebrospinal fluid; cytokine; inflammation; isoflurane; neuroinflammation; propofol; surgery.

Figures

Figure 1

CONSORT diagram/flow chart of the study population. CSF, cerebrospinal fluid.

Figure 2

Cerebrospinal fluid (CSF) cytokine levels at 0 and 24 h after surgery for patients randomized to propofol and isoflurane. Wilcoxon rank sum tests showed that was no differences in cytokine levels between propofol and isoflurane-treated patients at either 0 or 24 h (p > 0.05 for all, prior to Bonferroni correction). Data points represent anesthetic group means; error bars represent standard error of the mean. (A) EGF, (B) Eotaxin, (C) G-CSF, (D) GM-CSF, (E) IFN-α2, (F) IL-10, (G) IL-1RA, (H) IL-6, (I) IL-7, (J) IL-8, (K) IP-10, (L) MCP-1, (M) MIP-1α, (N) MIP-1β, and (O) TNF-α.

Figure 3

Heat map of Spearman correlations between change in cerebrospinal fluid (CSF) cytokine levels from 0 to 24 h after surgery. (A) All colored cells are significant at p < 0.05. Bolded cells are significant after Bonferroni correction (25). Color bar ranges from yellow (R = 0.36 or smallest significant spearman correlation) to red (R = 0.92 or largest significant spearman correlation). (B)p Values for each comparison in part A [values <0.05 highlighted in blue and values significant after Bonferroni correction are bolded (25)].