Use of serum biomarkers to predict cerebral hypoxia after severe traumatic brain injury.

The management of severe traumatic brain injury (TBI) focuses on prevention and treatment of secondary insults such as cerebral hypoxia (CH). There are a number of biomarkers that are thought to play a part in secondary injury following severe TBI. This study evaluates the association between S100ß, neuron-specific enolase (NSE), and glial fibrillary acidic protein (GFAP), detected in the serum of severe TBI patients and CH as measured by brain tissue oxygen partial pressure (Pbo(2)). Patients with severe TBI were prospectively enrolled. Pressure times time (PTD; mm Hg*h), measuring the depth and duration of CH, was calculated for 12-h periods for episodes of moderate (Pbo(2) < 20 mm Hg) and severe (Pbo(2) < 15 mm Hg) CH, and compared to serum levels of S100ß, NSE, and GFAP drawn prior to periods of monitoring. An adjusted mixed model analysis was applied as was receiver operating characteristic (ROC) curve analysis. Of 76 patients enrolled, 24 had Pbo(2) monitoring. One hundred and thirty serum samples were matched with 12-h periods of monitoring. Significant associations were found in adjusted analyses between increasing serum levels of S100ß (coefficient=0.57, 0.56; p<0.001), NSE (coefficient=0.48, 0.52; p<0.001), and GFAP (coefficient=0.29, 0.30; p=0.003 and 0.002), and increasing PTD of moderate (Pbo(2)<20 mm Hg) and severe (Pbo(2)<15 mm Hg) CH. AUCs for the prediction of moderate and severe CH were 0.62 and 0.66 for S100ß, 0.55 and 0.71 for NSE, and 0.50 and 0.62 for GFAP, respectively. Specificities were between 76% and 90% for S100ß and NSE. S100ß, NSE, and GFAP demonstrate promise as candidate serum markers of impending CH. The fact that these biomarker elevations occur prior to the onset of clinical manifestations suggests that we may be able to predict imminent events following TBI. Given the morbidity of CH, early intervention and prevention may have a significant impact on outcomes and help guide decisions about the timing of interventions.

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<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)-1ß, 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. 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 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. 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.

Association of CSF biomarkers and secondary insults following severe traumatic brain injury.

BACKGROUND: Management of severe traumatic brain injury (TBI) focuses on mitigating secondary insults. There are a number of biomarkers that are thought to play a part in secondary injury following severe TBI. Two of these, S100ß and neuron-specific enolase (NSE), have been extensively studied in the setting of neurological injury. This pilot study was undertaken to investigate the relationship of S100ß and NSE to clinical markers of severity and poor outcome: intracranial hypertension (ICH), and cerebral hypoperfusion (CH). METHODS: Patients at the R Adams Cowley Shock Trauma Center were prospectively enrolled over an 18-month period. Inclusion criteria were: age > 18, admission within the first 6 h after injury, Glasgow Coma Scale (GCS) < 9 on admission, isolated TBI, and placement of an intraventricular catheter (IVC). Patients were managed according to an institutional protocol based on the Brain Trauma Foundation Guidelines. CSF was collected from the IVC on admission and twice daily for 7 days. S100ß and NSE levels were analyzed by ELISA. CSF levels drawn before (PRE) and after (POST) 12-h time periods were compared to percentage time intracranial pressure (ICP) > 20 mmHg (% ICP(20)) and cerebral perfusion pressure (CPP) < 60 mmHg (% CPP(60)), and cumulative "Pressure times Time Dose" (PTD) for episodes of ICP > 20 mmHg (PTD ICP(20)) and CPP < 60 mmHg (PTD CPP(60)). Statistical analysis was performed using the Student's t test to compare means and non-parametric Wilcoxon statistic to compare ranked data. Linear regression methods were applied to compare levels of S100ß and NSE with ICP and CPP(.) RESULTS: Twenty-three patients were enrolled. The cohort of patients was severely injured and neurologically compromised on admission (admission GCS = 5.6 ± 3.1, Injury Severity Score (ISS) = 31.9 ± 10.6, head Abbreviated Injury Scale (AIS) = 4.4 ± 0.7, Marshall score = 2.6 ± 0.9). Elevated levels of S100ß and NSE were found in all 223 CSF samples analyzed. ICH was found to be associated with PRE and POST S100ß levels when measured as % ICP(20) (r = 0.20 and r = 0.23, P < 0.01) and PTD ICP(20) (r = 0.35 and r = 0.26, P < 0.001). POST increasing NSE levels were weakly correlated with increasing PTD ICP(20) (r = 0.17, P = 0.01). PRE S100ß levels were associated with episodes of CH as measured by % CPP(60) (r = 0.20, P = 0.002) and both PRE and POST S100ß levels were associated with PTD CPP(60) (r = 0.24 and r = 0.23, P < 0.001). PRE and POST NSE levels were also associated with episodes of CH as measured by % CPP(60) (r = 0.22 and r = 0.18, P < 0.01) and PTD CPP(60) (r = 0.20 and r = 0.21, P < 0.01). CONCLUSIONS: In this preliminary analysis, S100ß levels were associated with ICH and CH over a full week of ICP monitoring. We also found associations between CH and NSE levels in CSF of patients with severe TBI. Our results suggest that there is an association between levels of ICH and CH and these biomarkers when measured before episodes of clinically significant secondary insults. These markers of neuronal cell death demonstrate promise as both indicators of impending clinical deterioration and targets of future therapeutic interventions.

The prevalence of abnormal results of conventional coagulation tests on admission to a trauma center.

BACKGROUND: Several groups have reported that a fraction of severely injured patients have abnormal coagulation tests at presentation to trauma centers, even in the absence of significant crystalloid resuscitation. These patients have high mortality, but their prevalence in trauma populations is not clear from the reports. STUDY DESIGN AND METHODS: Records of all patients admitted to a large urban trauma center during 2000 through 2006 were searched for early measures of common coagulation tests and in-hospital mortality. RESULTS: Abnormal coagulation tests were increasingly frequent with increasing injury severity, ranging from 5 to 43 percent for the prothrombin time as the injury severity scores (ISSs) increased from 5 to more than 45 and 4 to 18 percent for platelet counts of less than 150 x 10(9) per L. Abnormal coagulation tests were associated with excess mortality even below conventional transfusion triggers and this was especially true for the partial thromboplastin time. CONCLUSIONS: Abnormal coagulation tests are common in severely injured patients. Even in the moderately injured, they are associated with higher mortality.