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

Background: 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. Methods: 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 20 mm Hg (% ICP 20 ) and CPP 20 mm Hg (PTD ICU 20 ) and CPP <60 mm Hg (PTD CPP 60 ) 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. Results: 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 ICP 20 and PTD CPP 60 were moderately correlated with increased PRE IL-8 levels (r = 0.34, p < 0.001; r = 0.53, p < 0.001). PTD ICP 20 was also correlated with PRE TNF-α levels (r = 0.27, p < 0.001) as was PTD CPP 60 (r = 0.25, p < 0.001). POST IL-8 levels were found to be correlated with PTD ICP 20 (r = 0.46, p < 0.001) and PTD CPP 60 (r = 0.54, p < 0.001). POST TNF-α was associated with PTD ICP 20 (r = 0.45, p < 0.001). PTD CPP 60 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. Conclusions: 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.