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Association of CSF Biomarkers and Secondary Insults Following Severe Traumatic Brain Injury

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Abstract

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, S100β 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 S100β 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. S100β 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 (% ICP20) and cerebral perfusion pressure (CPP) < 60 mmHg (% CPP60), and cumulative “Pressure times Time Dose” (PTD) for episodes of ICP > 20 mmHg (PTD ICP20) and CPP < 60 mmHg (PTD CPP60). 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 S100β 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 S100β and NSE were found in all 223 CSF samples analyzed. ICH was found to be associated with PRE and POST S100β levels when measured as % ICP20 (r = 0.20 and r = 0.23, P < 0.01) and PTD ICP20 (r = 0.35 and r = 0.26, P < 0.001). POST increasing NSE levels were weakly correlated with increasing PTD ICP20 (r = 0.17, P = 0.01). PRE S100β levels were associated with episodes of CH as measured by % CPP60 (r = 0.20, P = 0.002) and both PRE and POST S100β levels were associated with PTD CPP60 (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 % CPP60 (r = 0.22 and r = 0.18, P < 0.01) and PTD CPP60 (r = 0.20 and r = 0.21, P < 0.01).

Conclusions

In this preliminary analysis, S100β 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.

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References

  1. Langlois J, Rutland-Brown W, Wald M. The epidemiology and impact of traumatic brain injury: a brief overview. J Head Trauma Rehabil. 2006;21(5):375–8.

    Article  PubMed  Google Scholar 

  2. Kraus JF, MacArthur DL. Epidemiology of brain injury. In: Evans RW, editor. Neurology and Trauma. New York, NY: Oxford University Press; 2006. p. 3–18.

  3. Ghajar J. Traumatic brain injury. Lancet. 2000;356:923–9.

    Article  PubMed  CAS  Google Scholar 

  4. Thurman D, Alverson C, Dunn K, Guerrero J, Sniezek J. Traumatic brain injury in the United States: a public health perspective. J Head Trauma Rehabil. 1999;14(6):602–15.

    Article  PubMed  CAS  Google Scholar 

  5. Kennedy CS, Moffatt M. Acute traumatic brain injury in children: exploring the cutting edge in understanding, therapy, and research. Clin Pediatr Emerg Med. 2004;5(4):224–38.

    Article  Google Scholar 

  6. Vos PE, Lamers KJB, Hendriks JCM, et al. Glial and neuronal proteins in serum predict outcome after severe traumatic brain injury. Neurology. 2004;62(8):1303–10.

    PubMed  CAS  Google Scholar 

  7. Miller JD, Sweet RC, Narayan R, et al. Early insults to the injured brain. JAMA. 1978;240:432–9.

    Google Scholar 

  8. Signorini DF, Andrews PJ, Jones PA, et al. Adding insult to injury: the prognostic value of early secondary insults to survival after traumatic brain injury. J Neurol Neurosurg Psychiatry. 1999;66:26–31.

    Article  PubMed  CAS  Google Scholar 

  9. Chambers IR, Treadwell L, Mendelow AD. The cause and incidence of secondary insults in severely head-injured adults and children. Br J Neurosurg. 2000;14:424–31.

    Article  PubMed  CAS  Google Scholar 

  10. Bratton SL, Chestnut RM, Ghajar J, et al. Guidelines for the management of severe traumatic brain injury. J Neurotrauma. 2007;24(Suppl 1):S37–44.

    PubMed  Google Scholar 

  11. Chestnut RM, Marshall LF, Klauber MR, et al. The role of secondary brain injury in determining outcome from severe head injury. J Trauma. 1993;34:216–22.

    Article  Google Scholar 

  12. Stocchetti N, Furlan A, Volta F. Hypoxemia and arterial hypotension at the accident scene in head injury. J Trauma. 1996;40(5):764–7.

    Article  PubMed  CAS  Google Scholar 

  13. Eisenberg H, Frankowski R, Contant C, et al. High dose barbiturate control of elevated intracranial pressure in patients with severe head injury. J Neurosurg. 1988;69:15–23.

    Article  PubMed  CAS  Google Scholar 

  14. Narayan R, Kishore P, Becker D, et al. Intracranial pressure: to monitor or not to monitor? A review of our experience with head injury. J Neurosurg. 1982;56:650–9.

    Article  PubMed  CAS  Google Scholar 

  15. Schreiber MA, Aoki N, Scott B, et al. Determination of mortality in patients with severe blunt head injury. Arch Surg. 2002;137:285–90.

    Article  PubMed  Google Scholar 

  16. Changaris DG, McGraw CP, Richardson JD, et al. Correlation of cerebral perfusion pressure and Glasgow Coma Scale to outcome. J Trauma. 1987;27:1007–13.

    Article  PubMed  CAS  Google Scholar 

  17. Robertson CS, Valadka AB, Hannay HJ, et al. Prevention of secondary ischemic insults after severe head injury. Crit Care Med. 1999;27:2086–95.

    Article  PubMed  CAS  Google Scholar 

  18. Zimmer DB, Cornwall EH, Landar A, et al. The S100 protein family: history, function, and expression. Brain Res Bull. 1995;37:417–29.

    Article  PubMed  CAS  Google Scholar 

  19. Marangos PJ, Schmechel DE. Neuron specific enolase, a clinically useful marker for neurons and neuroendocrine cells. Annu Rev Neurosci. 1987;10:269–95.

    Article  PubMed  CAS  Google Scholar 

  20. Vos PE, Lamers KJB, Hendriks JCM, et al. Glial and neuronal proteins in serum predict outcome after severe traumatic brain injury. Neurology. 2004;62:1303–10.

    PubMed  CAS  Google Scholar 

  21. Nguyen DN, Spapen H, Su F, et al. Elevated serum levels of S-100β protein and neuron-specific enolase are associated with brain injury in patients with severe sepsis and septic shock. Crit Care Med. 2006;34(7):1967–74.

    Article  PubMed  CAS  Google Scholar 

  22. Pelinka L, Kroepfl A, Leixnering M, et al. GFAP versus S100B in serum after traumatic brain injury: relationship to brain damage and outcome. J Neurotrauma. 2004;21(11):1553–61.

    Article  PubMed  Google Scholar 

  23. Pleines U, Moragnti-Kossman C, Rancan M, et al. S-100B reflects the extent of injury and outcome, whereas neuronal specific enolase is a better indicator of neuroinflammation in patients with severe traumatic brain injury. J Neurotrauma. 2001;18(5):491–8.

    Article  PubMed  CAS  Google Scholar 

  24. Spinella PC, Dominguez T, Drott HR, et al. S-100B protein-serum levels in healthy children and its association with outcome in pediatric traumatic brain injury. Crit Care Med. 2003;31(3):939–45.

    Article  PubMed  CAS  Google Scholar 

  25. Hayakata T, Shiozaki T, Tasaki O, et al. Changes in CSF S100B and cytokine concentrations in early-phase severe traumatic brain injury. Shock. 2004;22(2):102–7.

    Article  PubMed  CAS  Google Scholar 

  26. Berger RP, Pierce MC, Wisniewski SR, et al. Neuron specific enolase and S100B in cerebrospinal fluid after severe traumatic brain injury in infants and children. Pediatrics. 2002;109(2):E31.

    Article  PubMed  Google Scholar 

  27. Kirchhoff C, Buhmann S, Braunstein V, et al. Cerebrospinal S100-B: a potential marker for progressive intracranial hemorrhage in patients with severe traumatic brain injury. Eur J Med Res. 2008;13(11):511–6.

    PubMed  CAS  Google Scholar 

  28. Association for the advancement of automotive medicine. Abbreviated Injury Scale, 2005. Barrington, IL: AAAM; 2005.

  29. Boyd CR, Tolson MA, Copes WS. Evaluating trauma care: the TRISS method. Trauma score and the injury severity score. J Trauma. 1987;27:370–8.

    Article  PubMed  CAS  Google Scholar 

  30. Marshall LF, Bowers-Marshall S, Klauber MR, et al. A new classification of head injury based on computerized tomography. J Neurosurg. 1991;75(Suppl):S14–20.

    Google Scholar 

  31. Wilson JTL, Pettigrew LEL, Teasdale GM. Structured interviews for the Glasgow Outcome Scale and the extended Glasgow Outcome Scale: guidelines for their use. J Neurotrauma. 1998;15(8):573–85.

    Article  PubMed  CAS  Google Scholar 

  32. Joseph DK, Dutton RP, Aarabi B, Scalea TM. Decompressive laparotomy to treat intractable intracranial hypertension after traumatic brain injury. J Trauma. 2004;57(4):687–93. (discussion 693–695).

    Article  PubMed  Google Scholar 

  33. Scalea TM, Bochicchio GV, Habashi N, McCunn M, Shih D, McQuillan K, Aarabi B. Increased intra-abdominal, intrathoracic, and intracranial pressure after severe brain injury: multiple compartment syndrome. J Trauma. 2007;62(3):647–56. (discussion 656).

    Article  PubMed  Google Scholar 

  34. Kahraman S, Hu P, Xiao Y, Dutton RP, Aarabi B, Stein DM, Scalea TM. Pressure-time dose of automated ICP and CPP data predicts outcomes in severe TBI. J Trauma. 2010;69:110–8.

    Article  PubMed  Google Scholar 

  35. Vik A, Nag T, Fredriksli OA, et al. Relationship of “dose” of intracranial hypertension to outcome in severe traumatic brain injury. J Neurosurg. 2008;109:678–84.

    Article  PubMed  Google Scholar 

  36. Kramer M. R2 statistics for mixed models. Stat Med. 2008;27(29):6137–57.

    Article  Google Scholar 

  37. Xu R. Measuring explained variation in linear mixed effects models. Stat Med. 2003;22:3527–41.

    Article  PubMed  Google Scholar 

  38. Fano G, Biocca S, Fulle S, et al. The S-100 protein family in search of a function. Prog Neurobiol. 1995;46:71–82.

    Article  PubMed  CAS  Google Scholar 

  39. McAdory BS, van Eldik LJ, Norden JJ. S-100B, a neurotrophic protein that modulates neuronal protein phosphorylation, is upregulated during lesion induced collateral sprouting and reactive synaptogenesis. Brain Res. 1998;813:211–7.

    Article  PubMed  CAS  Google Scholar 

  40. Donato R. S100: a multigenic family of calcium-modulated proteins of the EF-hand type with intracellular and extracellular functional roles. Int J Biochem Cell Biol. 2001;33:637–68.

    Article  PubMed  CAS  Google Scholar 

  41. Persson L, Hardemark HG, Gustafsson J, et al. S-100 protein and neuron-specific enolase in cerebrospinal fluid and serum; markers of cell damage in human central nervous system. Stroke. 1987;18:911–8.

    PubMed  CAS  Google Scholar 

  42. Bridges E, Biever K. Joint combat casualty research team and joint theater trauma system. AACN Adv Critical Care. 2010;21:260–76.

    Article  Google Scholar 

  43. Goodman MD, Makley AT, Lentsch AB, et al. Traumatic brain injury and aeromedical evacuation: when is the brain fit to fly? J Surg Res. 2010;164:286–93.

    Google Scholar 

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Acknowledgment

This study was funded in part by W81XWH-07-2-0118.

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Authors and Affiliations

  1. Division of Critical Care/Program in Trauma, R Adams Cowley Shock Trauma Center, University of Maryland School of Medicine, 22 South Greene Street, Baltimore, MD, 21201, USA

    Deborah M. Stein, Jay Menaker, Grant V. Bochicchio, Bizhan Aarabi & Thomas M. Scalea

  2. The Shock, Trauma and Anesthesiology Research Organized Research Center, University of Maryland School of Medicine, Baltimore, MD, USA

    Deborah M. Stein, Joseph A. Kufera, Allison Lindell, Karen R. Murdock, Jay Menaker, Grant V. Bochicchio & Thomas M. Scalea

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  1. Deborah M. Stein
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  2. Joseph A. Kufera
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Correspondence to Deborah M. Stein.

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Stein, D.M., Kufera, J.A., Lindell, A. et al. Association of CSF Biomarkers and Secondary Insults Following Severe Traumatic Brain Injury. Neurocrit Care 14, 200–207 (2011). https://doi.org/10.1007/s12028-010-9496-1

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  • DOI: https://doi.org/10.1007/s12028-010-9496-1

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