Serum IL-6: a candidate biomarker for intracranial pressure elevation following isolated traumatic brain injury

Abstract

Background: Increased intracranial pressure (ICP) is a serious, life-threatening, secondary event following traumatic brain injury (TBI). In many cases, ICP rises in a delayed fashion, reaching a maximal level 48-96 hours after the initial insult. While pressure catheters can be implanted to monitor ICP, there is no clinically proven method for determining a patient's risk for developing this pathology.

Methods: In the present study, we employed antibody array and Luminex-based screening methods to interrogate the levels of inflammatory cytokines in the serum of healthy volunteers and in severe TBI patients (GCS<or=8) with or without incidence of elevated intracranial pressure (ICP). De-identified samples and ELISAs were used to confirm the sensitivity and specificity of IL-6 as a prognostic marker of elevated ICP in both isolated TBI patients, and polytrauma patients with TBI.

Results: Consistent with previous reports, we observed sustained increases in IL-6 levels in TBI patients irrespective of their ICP status. However, the group of patients who subsequently experienced ICP >or= 25 mm Hg had significantly higher IL-6 levels within the first 17 hours of injury as compared to the patients whose ICP remained <or=20 mm Hg. When blinded samples (n = 22) were assessed, a serum IL-6 cut-off of <5 pg/ml correctly identified 100% of all the healthy volunteers, a cut-off of >128 pg/ml correctly identified 85% of isolated TBI patients who subsequently developed elevated ICP, and values between these cut-off values correctly identified 75% of all patients whose ICP remained <or=20 mm Hg throughout the study period. In contrast, the marker had no prognostic value in predicting elevated ICP in polytrauma patients with TBI. When the levels of serum IL-6 were assessed in patients with orthopedic injury (n = 7) in the absence of TBI, a significant increase was found in these patients compared to healthy volunteers, albeit lower than that observed in TBI patients.

Conclusions: Our results suggest that serum IL-6 can be used for the differential diagnosis of elevated ICP in isolated TBI.

Figures

Figure 1

Identification of serum IL-6 as a marker of elevated ICP by antibody arrays. A. Time course of ICP in patients classified as having elevated ICP (ICP ≥ 25 mm Hg) versus that recorded in patients whose ICP remained below 20 mm Hg for the duration of the sampling period. B. Representative picture of a Ray Biosciences Cytokine array showing the immunoreactivity of interleukin family members in pooled samples (n = 7/pool) from healthy volunteers, TBI patients with elevated ICP, and TBI patients whose ICP remained below 20 mm Hg for the duration of the 5 day sampling period. C. Summary data (presented as % healthy volunteer(HV)) showing that the relative signal of IL-6 is significantly increased in patients with ICP ≥ 25 mm Hg compared to patients whose ICP remained below 20 mm Hg throughout the study period. Data is presented as mean ± SEM. ‡, significant difference by two-way ANOVA.

Figure 2

Early increase in serum IL-6 can be used to stratify TBI patients based on risk for developing elevated ICP. A. Time course of ICP in patients classified as having elevated ICP (ICP > 25 mm Hg) versus that recorded in patients whose ICP remained below 20 mm Hg for the duration of the sampling period. B. Standard curve showing the relationship between increasing IL-6 concentrations and the mean fluorescent intensity (MFI) detected by Luminex analysis. C. Summary data showing the levels of IL-6 detected in the serum of healthy volunteers (HV), from TBI patients with elevated ICP (ICP > 25 mm Hg), and from patients whose ICP remained below 20 mm Hg throughout the study period. D. Luminex data organized based on time of sample withdrawal relative to the subsequent increase in ICP. Day 0 represents the time point at which the ICP was recorded to surpass 25 mm Hg. Each patient with an elevation in ICP was paired with a patient whose ICP remained ≤20 mm Hg throughout the study period. Data is presented as mean ± SEM. ‡, significant difference by two-way ANOVA.

Figure 3

Representative ICP profiles for TBI patients. ICP profiles for TBI patients whose ICP A. remained ≤20 mm Hg throughout the 5 day study period and B. elevated to ≥25 mm Hg. Dotted line represents 20 mm Hg, the threshold for clinical intervention.

Figure 4

Orthopedic injury increases serum IL-6 levels. A. Summary data showing the mean serum IL-6 concentrations for healthy volunteers (HV) and orthopedic injury patients. Serum IL-6 levels were significantly lower in orthopedic injury patients compared to TBI patients with B. isolated brain injury and C. polytrauma. Data is presented as mean ± SEM. *, P < 0.05.