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Published in: Journal of Neuroinflammation 1/2016

Open Access 01-12-2016 | Research

Multivariate projection method to investigate inflammation associated with secondary insults and outcome after human traumatic brain injury: a pilot study

Authors: Anna Teresa Mazzeo, Claudia Filippini, Rosalba Rosato, Vito Fanelli, Barbara Assenzio, Ian Piper, Timothy Howells, Ilaria Mastromauro, Maurizio Berardino, Alessandro Ducati, Luciana Mascia

Published in: Journal of Neuroinflammation | Issue 1/2016

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Abstract

Background

Neuroinflammation has been proposed as a possible mechanism of brain damage after traumatic brain injury (TBI), but no consensus has been reached on the most relevant molecules. Furthermore, secondary insults occurring after TBI contribute to worsen neurological outcome in addition to the primary injury. We hypothesized that after TBI, a specific pattern of cytokines is related to secondary insults and outcome.

Methods

A prospective observational clinical study was performed. Secondary insults by computerized multimodality monitoring system and systemic value of different cytokines were collected and analysed in the first week after intensive care unit admission. Neurological outcome was assessed at 6 months (GOSe). Multivariate projection technique was applied to analyse major sources of variation and collinearity within the cytokines dataset without a priori selecting potential relevant molecules.

Results

Twenty-nine severe traumatic brain injury patients undergoing intracranial pressure monitoring were studied. In this pilot study, we demonstrated that after TBI, patients who suffered of prolonged and severe secondary brain damage are characterised by a specific pattern of cytokines. Patients evolving to brain death exhibited higher levels of inflammatory mediators compared to both patients with favorable and unfavorable neurological outcome at 6 months. Raised ICP and low cerebral perfusion pressure occurred in 21 % of good monitoring time. Furthermore, the principal components selected by multivariate projection technique were powerful predictors of neurological outcome.

Conclusions

The multivariate projection method represents a valuable methodology to study neuroinflammation pattern occurring after secondary brain damage in severe TBI patients, overcoming multiple putative interactions between mediators and avoiding any subjective selection of relevant molecules.
Literature
1.
go back to reference Kossmann T, Hans V, Imhof HG, Trentz O, Morganti-Kossmann MC. Interleukin-6 released in human cerebrospinal fluid following traumatic brain injury may trigger nerve growth factor production in astrocytes. Brain Res. 1996;713(1–2):143–52.CrossRefPubMed Kossmann T, Hans V, Imhof HG, Trentz O, Morganti-Kossmann MC. Interleukin-6 released in human cerebrospinal fluid following traumatic brain injury may trigger nerve growth factor production in astrocytes. Brain Res. 1996;713(1–2):143–52.CrossRefPubMed
2.
go back to reference Kossmann T, Stahel PF, Lenzlinger PM, Redl H, Dubs RW, Trentz O, et al. Interleukin-8 released into the cerebrospinal fluid after brain injury is associated with blood–brain barrier dysfunction and nerve growth factor production. J Cereb Blood Flow Metab. 1997;17(3):280–9. doi:10.1097/00004647-199703000-00005.CrossRefPubMed Kossmann T, Stahel PF, Lenzlinger PM, Redl H, Dubs RW, Trentz O, et al. Interleukin-8 released into the cerebrospinal fluid after brain injury is associated with blood–brain barrier dysfunction and nerve growth factor production. J Cereb Blood Flow Metab. 1997;17(3):280–9. doi:10.​1097/​00004647-199703000-00005.CrossRefPubMed
3.
go back to reference Morganti-Kossmann MC, Rancan M, Stahel PF, Kossmann T. Inflammatory response in acute traumatic brain injury: a double-edged sword. Curr Opin Crit Care. 2002;8(2):101–5.CrossRefPubMed Morganti-Kossmann MC, Rancan M, Stahel PF, Kossmann T. Inflammatory response in acute traumatic brain injury: a double-edged sword. Curr Opin Crit Care. 2002;8(2):101–5.CrossRefPubMed
6.
go back to reference Santarsieri M, Kumar RG, Kochanek PM, Berga S, Wagner AK. Variable neuroendocrine-immune dysfunction in individuals with unfavorable outcome after severe traumatic brain injury. Brain Behav Immun. 2015;45. Santarsieri M, Kumar RG, Kochanek PM, Berga S, Wagner AK. Variable neuroendocrine-immune dysfunction in individuals with unfavorable outcome after severe traumatic brain injury. Brain Behav Immun. 2015;45.
7.
9.
go back to reference Helmy A, Carpenter KL, Menon DK, Pickard JD, Hutchinson PJ. The cytokine response to human traumatic brain injury: temporal profiles and evidence for cerebral parenchymal production. J Cereb Blood Flow Metab. 2011;31(2):658–70.CrossRefPubMed Helmy A, Carpenter KL, Menon DK, Pickard JD, Hutchinson PJ. The cytokine response to human traumatic brain injury: temporal profiles and evidence for cerebral parenchymal production. J Cereb Blood Flow Metab. 2011;31(2):658–70.CrossRefPubMed
10.
go back to reference Helmy A, Guilfoyle MR, Carpenter KL, Pickard JD, Menon DK, Hutchinson PJ. Recombinant human interleukin-1 receptor antagonist promotes M1 microglia biased cytokines and chemokines following human traumatic brain injury. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2015; doi:0271678X15620204 . Helmy A, Guilfoyle MR, Carpenter KL, Pickard JD, Menon DK, Hutchinson PJ. Recombinant human interleukin-1 receptor antagonist promotes M1 microglia biased cytokines and chemokines following human traumatic brain injury. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2015; doi:0271678X15620204 .
11.
go back to reference Miller JD, Sweet RC, Narayan R, Becker DP. Early insults to the injured brain. JAMA. 1978;240(5):439–42.CrossRefPubMed Miller JD, Sweet RC, Narayan R, Becker DP. Early insults to the injured brain. JAMA. 1978;240(5):439–42.CrossRefPubMed
12.
go back to reference Andrews PJ, Piper IR, Dearden NM, Miller JD. Secondary insults during intrahospital transport of head-injured patients. Lancet. 1990;335(8685):327–30.CrossRefPubMed Andrews PJ, Piper IR, Dearden NM, Miller JD. Secondary insults during intrahospital transport of head-injured patients. Lancet. 1990;335(8685):327–30.CrossRefPubMed
13.
go back to reference Jones PA, Andrews PJ, Midgley S, Anderson SI, Piper IR, Tocher JL, et al. Measuring the burden of secondary insults in head-injured patients during intensive care. J Neurosurg Anesthesiol. 1994;6(1):4–14.CrossRefPubMed Jones PA, Andrews PJ, Midgley S, Anderson SI, Piper IR, Tocher JL, et al. Measuring the burden of secondary insults in head-injured patients during intensive care. J Neurosurg Anesthesiol. 1994;6(1):4–14.CrossRefPubMed
15.
go back to reference McHugh GS, Engel DC, Butcher I, Steyerberg EW, Lu J, Mushkudiani N, et al. Prognostic value of secondary insults in traumatic brain injury: results from the IMPACT study. J Neurotrauma. 2007;24(2):287–93. doi:10.1089/neu.2006.0031.CrossRefPubMed McHugh GS, Engel DC, Butcher I, Steyerberg EW, Lu J, Mushkudiani N, et al. Prognostic value of secondary insults in traumatic brain injury: results from the IMPACT study. J Neurotrauma. 2007;24(2):287–93. doi:10.​1089/​neu.​2006.​0031.CrossRefPubMed
17.
go back to reference Chesnut RM, Marshall LF, Klauber MR, Blunt BA, Baldwin N, Eisenberg HM, et al. The role of secondary brain injury in determining outcome from severe head injury. J Trauma. 1993;34(2):216–22.CrossRefPubMed Chesnut RM, Marshall LF, Klauber MR, Blunt BA, Baldwin N, Eisenberg HM, et al. The role of secondary brain injury in determining outcome from severe head injury. J Trauma. 1993;34(2):216–22.CrossRefPubMed
18.
go back to reference Signorini DF, Andrews PJ, Jones PA, Wardlaw JM, Miller JD. Adding insult to injury: the prognostic value of early secondary insults for survival after traumatic brain injury. J Neurol Neurosurg Psychiatry. 1999;66(1):26–31.CrossRefPubMedPubMedCentral Signorini DF, Andrews PJ, Jones PA, Wardlaw JM, Miller JD. Adding insult to injury: the prognostic value of early secondary insults for survival after traumatic brain injury. J Neurol Neurosurg Psychiatry. 1999;66(1):26–31.CrossRefPubMedPubMedCentral
20.
go back to reference McKeating EG, Andrews PJ, Signorini DF, Mascia L. Transcranial cytokine gradients in patients requiring intensive care after acute brain injury. Br J Anaesth. 1997;78(5):520–3.CrossRefPubMed McKeating EG, Andrews PJ, Signorini DF, Mascia L. Transcranial cytokine gradients in patients requiring intensive care after acute brain injury. Br J Anaesth. 1997;78(5):520–3.CrossRefPubMed
21.
go back to reference Hergenroeder GW, Moore AN, McCoy Jr JP, Samsel L, Ward III NH, Clifton GL, et al. Serum IL-6: a candidate biomarker for intracranial pressure elevation following isolated traumatic brain injury. J Neuroinflammation. 2010;7:19.CrossRefPubMedPubMedCentral Hergenroeder GW, Moore AN, McCoy Jr JP, Samsel L, Ward III NH, Clifton GL, et al. Serum IL-6: a candidate biomarker for intracranial pressure elevation following isolated traumatic brain injury. J Neuroinflammation. 2010;7:19.CrossRefPubMedPubMedCentral
23.
go back to reference Mussack T, Biberthaler P, Kanz KG, Wiedemann E, Gippner-Steppert C, Mutschler W, et al. Serum S-100B and interleukin-8 as predictive markers for comparative neurologic outcome analysis of patients after cardiac arrest and severe traumatic brain injury. Crit Care Med. 2002;30(12):2669–74. doi:10.1097/01.CCM.0000037963.51270.44.CrossRefPubMed Mussack T, Biberthaler P, Kanz KG, Wiedemann E, Gippner-Steppert C, Mutschler W, et al. Serum S-100B and interleukin-8 as predictive markers for comparative neurologic outcome analysis of patients after cardiac arrest and severe traumatic brain injury. Crit Care Med. 2002;30(12):2669–74. doi:10.​1097/​01.​CCM.​0000037963.​51270.​44.CrossRefPubMed
24.
go back to reference Yan EB, Satgunaseelan L, Paul E, Bye N, Nguyen P, Agyapomaa D, et al. Post-traumatic hypoxia is associated with prolonged cerebral cytokine production, higher serum biomarker levels, and poor outcome in patients with severe traumatic brain injury. J Neurotrauma. 2014;31(7):618–29. doi:10.1089/neu.2013.3087.CrossRefPubMedPubMedCentral Yan EB, Satgunaseelan L, Paul E, Bye N, Nguyen P, Agyapomaa D, et al. Post-traumatic hypoxia is associated with prolonged cerebral cytokine production, higher serum biomarker levels, and poor outcome in patients with severe traumatic brain injury. J Neurotrauma. 2014;31(7):618–29. doi:10.​1089/​neu.​2013.​3087.CrossRefPubMedPubMedCentral
26.
go back to reference Brain Trauma Foundation A, CNS, AANS/CNS. Guidelines for the Management of Severe Traumatic Brain Injury. J Neurotrauma. 2007;24:S1–S106.CrossRef Brain Trauma Foundation A, CNS, AANS/CNS. Guidelines for the Management of Severe Traumatic Brain Injury. J Neurotrauma. 2007;24:S1–S106.CrossRef
27.
go back to reference Piper I, Citerio G, Chambers I, Contant C, Enblad P, Fiddes H, et al. The BrainIT group: concept and core dataset definition. Acta Neurochir (Wien). 2003;145(8):615–28. doi:10.1007/s00701-003-0066-6. discussion 28–9.CrossRef Piper I, Citerio G, Chambers I, Contant C, Enblad P, Fiddes H, et al. The BrainIT group: concept and core dataset definition. Acta Neurochir (Wien). 2003;145(8):615–28. doi:10.​1007/​s00701-003-0066-6. discussion 28–9.CrossRef
28.
go back to reference Nyholm L, Howells T, Enblad P, Lewen A. Introduction of the Uppsala Traumatic Brain Injury register for regular surveillance of patient characteristics and neurointensive care management including secondary insult quantification and clinical outcome. Ups J Med Sci. 2013;118(3):169–80. doi:10.3109/03009734.2013.806616.CrossRefPubMedPubMedCentral Nyholm L, Howells T, Enblad P, Lewen A. Introduction of the Uppsala Traumatic Brain Injury register for regular surveillance of patient characteristics and neurointensive care management including secondary insult quantification and clinical outcome. Ups J Med Sci. 2013;118(3):169–80. doi:10.​3109/​03009734.​2013.​806616.CrossRefPubMedPubMedCentral
29.
go back to reference Elf K, Nilsson P, Ronne-Engstrom E, Howells T, Enblad P. Cerebral perfusion pressure between 50 and 60 mm Hg may be beneficial in head-injured patients: a computerized secondary insult monitoring study. Neurosurgery. 2005;56(5):962–71. discussion −71.PubMed Elf K, Nilsson P, Ronne-Engstrom E, Howells T, Enblad P. Cerebral perfusion pressure between 50 and 60 mm Hg may be beneficial in head-injured patients: a computerized secondary insult monitoring study. Neurosurgery. 2005;56(5):962–71. discussion −71.PubMed
30.
go back to reference Wilson JT, Pettigrew LE, Teasdale GM. Emotional and cognitive consequences of head injury in relation to the glasgow outcome scale. J Neurol Neurosurg Psychiatry. 2000;69(2):204–9.CrossRefPubMedPubMedCentral Wilson JT, Pettigrew LE, Teasdale GM. Emotional and cognitive consequences of head injury in relation to the glasgow outcome scale. J Neurol Neurosurg Psychiatry. 2000;69(2):204–9.CrossRefPubMedPubMedCentral
31.
go back to reference Wilson JT, Pettigrew LE, 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.CrossRefPubMed Wilson JT, Pettigrew LE, 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.CrossRefPubMed
32.
go back to reference Vignali DA. Multiplexed particle-based flow cytometric assays. J Immunol Methods. 2000;243(1–2):243–55.CrossRefPubMed Vignali DA. Multiplexed particle-based flow cytometric assays. J Immunol Methods. 2000;243(1–2):243–55.CrossRefPubMed
34.
go back to reference Hutchinson PJ, O’Connell MT, Rothwell NJ, Hopkins SJ, Nortje J, Carpenter KL, et al. Inflammation in human brain injury: intracerebral concentrations of IL-1alpha, IL-1beta, and their endogenous inhibitor IL-1ra. J Neurotrauma. 2007;24(10):1545–57. doi:10.1089/neu.2007.0295.CrossRefPubMed Hutchinson PJ, O’Connell MT, Rothwell NJ, Hopkins SJ, Nortje J, Carpenter KL, et al. Inflammation in human brain injury: intracerebral concentrations of IL-1alpha, IL-1beta, and their endogenous inhibitor IL-1ra. J Neurotrauma. 2007;24(10):1545–57. doi:10.​1089/​neu.​2007.​0295.CrossRefPubMed
35.
go back to reference Das M, Mohapatra S, Mohapatra SS. New perspectives on central and peripheral immune responses to acute traumatic brain injury. J Neuroinflammation. 2012;9:236.CrossRefPubMedPubMedCentral Das M, Mohapatra S, Mohapatra SS. New perspectives on central and peripheral immune responses to acute traumatic brain injury. J Neuroinflammation. 2012;9:236.CrossRefPubMedPubMedCentral
36.
go back to reference Ziebell JM, Morganti-Kossmann MC. Involvement of pro- and anti-inflammatory cytokines and chemokines in the pathophysiology of traumatic brain injury. Neurotherapeutics. 2010;7(1):22–30.CrossRefPubMed Ziebell JM, Morganti-Kossmann MC. Involvement of pro- and anti-inflammatory cytokines and chemokines in the pathophysiology of traumatic brain injury. Neurotherapeutics. 2010;7(1):22–30.CrossRefPubMed
37.
go back to reference Perez-Barcena J, Ibanez J, Brell M, Crespi C, Frontera G, Llompart-Pou JA, et al. Lack of correlation among intracerebral cytokines, intracranial pressure, and brain tissue oxygenation in patients with traumatic brain injury and diffuse lesions. Crit Care Med. 2011;39(3):533–40. doi:10.1097/CCM.0b013e318205c7a4.CrossRefPubMed Perez-Barcena J, Ibanez J, Brell M, Crespi C, Frontera G, Llompart-Pou JA, et al. Lack of correlation among intracerebral cytokines, intracranial pressure, and brain tissue oxygenation in patients with traumatic brain injury and diffuse lesions. Crit Care Med. 2011;39(3):533–40. doi:10.​1097/​CCM.​0b013e318205c7a4​.CrossRefPubMed
38.
go back to reference Helmy A, Guilfoyle MR, Carpenter KL, Pickard JD, Menon DK, Hutchinson PJ. Recombinant human interleukin-1 receptor antagonist in severe traumatic brain injury: a phase II randomized control trial. J Cereb Blood Flow Metab. 2014;34(5):845–51.CrossRefPubMedPubMedCentral Helmy A, Guilfoyle MR, Carpenter KL, Pickard JD, Menon DK, Hutchinson PJ. Recombinant human interleukin-1 receptor antagonist in severe traumatic brain injury: a phase II randomized control trial. J Cereb Blood Flow Metab. 2014;34(5):845–51.CrossRefPubMedPubMedCentral
39.
go back to reference Stocchetti N, Zanaboni C, Colombo A, Citerio G, Beretta L, Ghisoni L, et al. Refractory intracranial hypertension and "second-tier" therapies in traumatic brain injury. Intensive Care Med. 2008;34(3):461–7. doi:10.1007/s00134-007-0948-9.CrossRefPubMed Stocchetti N, Zanaboni C, Colombo A, Citerio G, Beretta L, Ghisoni L, et al. Refractory intracranial hypertension and "second-tier" therapies in traumatic brain injury. Intensive Care Med. 2008;34(3):461–7. doi:10.​1007/​s00134-007-0948-9.CrossRefPubMed
40.
go back to reference Zanier ER, Ortolano F, Ghisoni L, Colombo A, Losappio S, Stocchetti N. Intracranial pressure monitoring in intensive care: clinical advantages of a computerized system over manual recording. Crit Care. 2007;11(1):R7.CrossRefPubMedPubMedCentral Zanier ER, Ortolano F, Ghisoni L, Colombo A, Losappio S, Stocchetti N. Intracranial pressure monitoring in intensive care: clinical advantages of a computerized system over manual recording. Crit Care. 2007;11(1):R7.CrossRefPubMedPubMedCentral
41.
go back to reference Guiza F, Depreitere B, Piper I, Citerio G, Chambers I, Jones PA, et al. Visualizing the pressure and time burden of intracranial hypertension in adult and paediatric traumatic brain injury. Intensive Care Med. 2015;41:1067–76. doi:10.1007/s00134-015-3806-1.CrossRefPubMed Guiza F, Depreitere B, Piper I, Citerio G, Chambers I, Jones PA, et al. Visualizing the pressure and time burden of intracranial hypertension in adult and paediatric traumatic brain injury. Intensive Care Med. 2015;41:1067–76. doi:10.​1007/​s00134-015-3806-1.CrossRefPubMed
43.
go back to reference Unterberg A, Kiening K, Schmiedek P, Lanksch W. Long-term observations of intracranial pressure after severe head injury. The phenomenon of secondary rise of intracranial pressure. Neurosurgery. 1993;32(1):17–23. discussion −4.CrossRefPubMed Unterberg A, Kiening K, Schmiedek P, Lanksch W. Long-term observations of intracranial pressure after severe head injury. The phenomenon of secondary rise of intracranial pressure. Neurosurgery. 1993;32(1):17–23. discussion −4.CrossRefPubMed
44.
Metadata
Title
Multivariate projection method to investigate inflammation associated with secondary insults and outcome after human traumatic brain injury: a pilot study
Authors
Anna Teresa Mazzeo
Claudia Filippini
Rosalba Rosato
Vito Fanelli
Barbara Assenzio
Ian Piper
Timothy Howells
Ilaria Mastromauro
Maurizio Berardino
Alessandro Ducati
Luciana Mascia
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2016
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-016-0624-5

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