Abstract
Background
Traumatic brain injury (TBI) is a significant cause of death and disability in young adults, but not much is known about the incidence and characteristics of blood–brain barrier (BBB) dysfunction in this group. In this proof of concept study, we sought to quantify the incidence of BBB dysfunction (defined as a cerebrospinal fluid (CSF)–plasma albumin quotient of ≥0.007) and examine the relationship between plasma and CSF levels of proteins and electrolytes, in patients with severe TBI.
Methods
We recruited 30 patients, all of whom were receiving hypertonic 20 % saline infusion for intracranial hypertension and had external ventricular drains in situ. Simultaneous CSF and blood samples were obtained. Biochemical testing was performed for sodium, osmolality, potassium, glucose, albumin, immunoglobulin-G, and total protein.
Results
Eleven patients (37 %) showed evidence of impairment of passive BBB function, with a CSF–plasma albumin quotient of ≥0.007. There were strong positive correlations seen among CSF–plasma albumin quotient and CSF–plasma immunoglobulin-G quotient and CSF–plasma total protein quotient (r = 0.967, P < 0.001 and r = 0.995, P < 0.001, respectively). We also found a higher maximum intracranial pressure (24 vs. 21 mmHg, P = 0.029) and a trend toward increased mortality (27 vs. 11 %, P = 0.33) in patients with BBB disruption.
Conclusions
In summary, passive BBB dysfunction is common in patients with severe TBI, and may have important implications for effectiveness of osmotherapy and long-term outcomes. Also, our results suggest that the CSF–plasma total protein quotient, a measurement which is readily available, can be used instead of the CSF–plasma albumin quotient for evaluating BBB dysfunction.





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References
- Coronado VG, McGuire LC, Sarmiento K, et al. Trends in traumatic brain injury in the U.S. and the public health response: 1995–2009. J Saf Res. 2012;43(4):299–307. 
- Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of Neurological Surgeons. Guidelines for the management of severe traumatic brain injury. II. Hyperosmolar therapy. J Neurotrauma. 2007;24(Suppl 1):S14–20. 
- Vialet R, Albanese J, Thomachot L, et al. Isovolume hypertonic solutes (sodium chloride or mannitol) in the treatment of refractory posttraumatic intracranial hypertension: 2 ml/kg 7.5% saline is more effective than 2 ml/kg 20% mannitol. Crit Care Med. 2003;31(6):1683–7. 
- Ware ML, Nemani VM, Meeker M, Lee C, Morabito DJ, Manley GT. Effects of 23.4% sodium chloride solution in reducing intracranial pressure in patients with traumatic brain injury: a preliminary study. Neurosurgery. 2005;57(4):727–36. 
- Kerwin AJ, Schinco MA, Tepas JJ 3rd, Renfro WH, Vitarbo EA, Muehlberger M. The use of 23.4% hypertonic saline for the management of elevated intracranial pressure in patients with severe traumatic brain injury: a pilot study. J Trauma. 2009;67(2):277–82. 
- Kamel H, Navi BN, Nakagawa K, Hemphill JC 3rd, Ko NU. Hypertonic saline versus mannitol for the treatment of elevated intracranial pressure: a meta-analysis of randomized clinical trials. Crit Care Med. 2011;39(3):554–9. 
- Lazaridis C, Neyens R, Bodle J, DeSantis SM. High-osmolarity saline in neurocritical care: systematic review and meta-analysis. Crit Care Med. 2013;41(5):1353–60. 
- Jeffcote T, Ho KM. Associations between cerebrospinal fluid concentrations, serum albumin concentrations and intracranial pressure in neurotrauma and intracranial haemorrhage. Anaesth Intensive Care. 2010;38:274–9. 
- The SAFE Study Investigators. Saline or albumin for fluid resuscitation in patients with traumatic brain injury. N Engl J Med. 2007;357:874–84. 
- Cooper DJ, Myburgh J, Heritier S, et al. Albumin resuscitation for traumatic brain injury: is intracranial hypertension the cause of increased mortality? J Neurotrauma. 2013;30(7):512–8. 
- Blyth BJ, Farhavar A, Gee C, et al. Validation of serum markers for blood–brain barrier disruption in traumatic brain injury. J Neurotrauma. 2009;26:1497–507. 
- Stahel PF, Morganti-Kossmann MC, Perez D, et al. Intrathecal levels of complement-derived soluble membrane attack complex (sC5b-9) correlate with blood–brain barrier dysfunction in patients with traumatic brain injury. J Neurotrauma. 2001;18(8):773–81. 
- Pleines UE, Stover JF, Kossmann T, Trentz O, Morganti-Kossmann MC. Soluble ICAM-1 in CSF coincides with the extent of cerebral damage in patients with severe traumatic brain injury. J Neurotrauma. 1998;15(6):399–409. 
- Maier B, Schwerdtfeger K, Mautes A, et al. Differential release of interleukines 6, 8, and 10 in cerebrospinal fluid and plasma after traumatic brain injury. Shock. 2001;15(6):421–6. 
- Csuka E, Morganti-Kossmann MC, Lenzlinger PM, Joller H, Trentz O, Kossmann T. IL-10 levels in cerebrospinal fluid and serum of patients with severe traumatic brain injury: relationship to IL-6, TNF-alpha, TGF-beta1 and blood–brain barrier function. J Neuroimmunol. 1999;101:211–21. 
- Morganti-Kossmann MC, Hans VH, Lenzlinger PM, et al. TGF-beta is elevated in the CSF of patients with severe traumatic brain injuries and parallels blood–brain barrier function. J Neurotrauma. 1999;16(7):617–28. 
- National Health and Medical Research Council, Australian research council, Australian Vice-Chancellor’s Committee. National statement on ethical conduct in human research. Canberra: Australian Government; 2007. 
- Privitera MD, Zakaria T, Khatri R. Nervous system. In: Kaplan LA, Pesce AJ, editors. Clinical chemistry theory, analysis, correlation. 5th ed. St Louis: Elsevier; 2010. p. 907–8, 923. 
- Reiber H, Peter JB. Cerebrospinal fluid analysis: disease-related data patterns and evaluation programs. J Neurol Sci. 2001;184:101–22. 
- Marshall LF, Eisenberg H, Jane JA, Marshall SB, Klauber MR. A new classification of head injury based on computerized tomography. J Neurosurg. 1991;75(Suppl):S14–20. 
- Steyerberg EW, Mushkudiani N, Perel P, et al. Predicting outcome after traumatic brain injury: development and internal validation of prognostic scores based on admission characteristics. PLoS Med. 2008;5(8):e165. 
- Ho KM. Ten caveats of interpreting correlation coefficient in anaesthesia and intensive care research. Anaesth Intensive Care. 2012;40(4):595–7. 
- Polderman KH, van de Kraats G, Dixon JM, Vandertop WP, Girbes ARJ. Increases in spinal fluid osmolarity induced by mannitol. Crit Care Med. 2003;31(2):584–90. 
- Von Holst H, Mathiesen T. Electrolyte concentrations in serum and CSF following subarachnoid haemorrhage. Br J Neurosurg. 1990;4:123–6. 
- Harrington MG, Salomon RM, Pogoda JM, et al. Cerebrospinal fluid sodium rhythms. Cerebrospinal Fluid Res. 2010;7:3–11. 
- Gagliardi RJ. Prognostic value of potassium and sodium levels in cerebrospinal fluid and blood in patients with coma. Study of 55 cases. Arq Neuropsiquiatr. 1982;40:230–8. 
- Baldy-Moulinier M. Cerebral blood flow and membrane ionic pump. Eur Neurol. 1972;6:107–13. 
- Iliff JJ, Wang M, Liao Y, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med. 2012;4(147):147ra111. 
- Tanno H, Nockels RP, Pitts LH, Noble LJ. Breakdown of the blood–brain barrier after fluid percussive brain injury in the rat. Part 1: distribution and time course of protein extravasation. J Neurotrauma. 1992;9(1):21–32. 
- Tanno H, Nockels RP, Pitts LH, Noble LJ. Breakdown of the blood–brain barrier after fluid percussion brain injury in the rat: Part 2: effect of hypoxia on permeability to plasma proteins. J Neurotrauma. 1992;9(4):335–47. 
- Jiang JY, Lyeth BG, Kapasi MZ, Jenkins LW, Povlishock JT. Moderate hypothermia reduces blood–brain barrier disruption following traumatic brain injury in the rat. Acta Neuropathol. 1992;84:495–500. 
- Fukuda K, Tanno H, Okimura Y, Nakamura M, Yamaura A. The blood–brain barrier disruption to circulating proteins in the early period after fluid percussion brain injury in rats. J Neurotrauma. 1995;12(3):315–24. 
Acknowledgments
JRB was supported by a Practitioner Fellowship from the Royal Perth Hospital Medical Research Foundation.
Conflict of interest
Melanie M. Saw, Jenny Chamberlain, Michelle Barr, Matt P.G. Morgan, John R. Burnett, and Kwok M. Ho declare that they have no conflict of interest.
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Saw, M.M., Chamberlain, J., Barr, M. et al. Differential Disruption of Blood–Brain Barrier in Severe Traumatic Brain Injury. Neurocrit Care 20, 209–216 (2014). https://doi.org/10.1007/s12028-013-9933-z
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