Relationship of Serum and Cerebrospinal Fluid Biomarkers With Intracranial Hypertension and Cerebral Hypoperfusion After Severe Traumatic Brain Injury

Abstract

There is little that can be done to treat or reverse the primary injury that occurs at the time of a traumatic brain injury (TBI). Initial management of the patient with severe TBI focuses on prevention of subsequent secondary insults, namely, intracranial hypertension (ICH) and cerebral hypoperfusion (CH). Currently, there is no reliable way to predict which patients will develop ICH and CH other than clinical acumen; therefore, indicators of impending secondary intracranial insults may be useful in predicting these events and allowing for prevention and early intervention. This study was undertaken to investigate the relationship of cytokine levels with intracranial pressure (ICP) and cerebral perfusion pressure (CPP) in patients with severe TBI. Patients at the R Adams Cowley Shock Trauma Center were prospectively enrolled for a 6-month period. Inclusion criteria were older than 17 years, admission within the first 6 hours after injury, Glasgow Coma Scale<9 on admission, and placement of a clinically indicated ICP monitor. Serum and cerebrospinal fluid, when available, were collected on admission and twice daily for 7 days. Cytokine levels of interleukin (IL)-1β, IL-6, IL-8, IL-10, and tumor necrosis factor (TNF)-α were analyzed by multiplex bead array assays. Hourly values for ICP and CPP were recorded, and means, minimum (for CPP) or maximum (for ICP) values, percentage time ICP>20 mm Hg (%ICP20) and CPP<60 mm Hg (%CPP60), and cumulative Pressure Times Time Dose (PTD; mm Hg·h) for ICP>20 mm Hg (PTD ICP20) and CPP<60 mm Hg (PTD CPP60) were compared with the serum and cerebrospinal fluid levels that were drawn before 12-hour time periods (PRE) and after 12-hour time periods (POST) of monitoring. Twenty-four patients were enrolled. In-hospital mortality was 12.5%, and good functional outcome was noted in 58%. Two hundred and seventy-five serum samples were taken and analyzed. IL-6 levels in the serum were found in the highest concentration of the cytokines measured. PTD ICP20 and PTD CPP60 were moderately correlated with increased PRE IL-8 levels (r=0.34, p<0.001; r=0.53, p<0.001). PTD ICP20 was also correlated with PRE TNF-α levels (r=0.27, p<0.001) as was PTD CPP60 (r=0.25, p<0.001). POST IL-8 levels were found to be correlated with PTD ICP20 (r=0.46, p<0.001) and PTD CPP60 (r=0.54, p<0.001). POST TNF-α was associated with PTD ICP20 (r=0.45, p<0.001). PTD CPP60 was also moderately correlated with POST TNF-α levels (r=0.26, p<0.001). When comparing patients with good versus poor outcome, median daily serum IL-8 levels were associated with poor outcome. IL-8 and, to a lesser extent, TNF-α demonstrated the most promise in this study to be candidate serum markers of impending ICH and CH. The clinical relevance of this is the suggestion that we may be able to predict impending secondary insults after TBI before the clinical manifestation of these events. Given the known morbidity of ICH and CH, early intervention and prevention may have a significant impact on outcome. This becomes even more important when decisions must be made about timing of interventions. Increased levels of IL-8 and TNF-α in the serum during episodes of ICH and CH imply there are significant systemic effects of these events. These serum biomarkers are promising as diagnostic targets. In addition, further study of the precise role of these molecules may have significant implications for inflammatory system manipulation in the management of severe TBI.