Skip to main content

Advertisement

SpringerLink
Log in

Venous and arterial TNF-R1 predicts outcome and complications in acute subarachnoid hemorrhage

  • Original Article
  • Published:
Neurocritical Care Aims and scope Submit manuscript

Abstract

Background

There is increasing evidence for the role of inflammation in clinical outcome after subarachnoid hemorrhage (SAH). Specifically, the TNF-alfa(α) pathway seems to be relevant after SAH. Although the TNF-α main receptor, TNF-R1 is associated with aneurysm growth and rupture, its relation to prognosis is unknown.

We sought to compare TNF-R1 levels in peripheral venous blood and arterial blood closer to the ruptured aneurysm to study the association of TNF-R1 blood levels with poor prognosis (modified Rankin Scale  > 2 at discharge, 3 and 6 months) and complications (hydrocephalus or delayed cerebral ischemia/DCI) following SAH.

Methods

We included consecutive SAH patients admitted in the first 72 h of symptoms. Blood samples were simultaneously collected from a peripheral vein and from the main parent artery of the aneurysm. Levels of TNF-R1 were measured using enzyme-linked immunosorbent assays.

Results

We analyzed 58 patients. Arterial and venous levels of TNF-R1 were correlated (R = 0.706, p < 0.001). In multivariate regression analysis, venous TNF-R1 was an independent predictor of poor outcome at 6 months after adjusting by age and sex [odds ratio (OR) 11.63; 95% CI 2.09–64.7, p = 0.005] and after adjusting by Glasgow Coma Scale and Fisher scales (OR 8.74; 95% CI 1.45–52.7, p = 0.018). There was no association of TNF-R1 with DCI. A cut-off for arterial TNF-R1 of 1523.7 pg/mL had 75% sensitivity/66% specificity for the prediction of hydrocephalus.

Conclusion

Levels of venous TNF-R1 are associated with poor outcome in SAH. A specific association was found between levels of arterial TNF-R1 and hydrocephalus. These results are consistent with the role of TNF-α pathway in SAH and need to be validated in larger cohorts.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Hop JW, Rinkel GJE, Algra A, van Gijn J. Case-fatality rates and functional outcome after subarachnoid hemorrhage: a systematic review. Stroke. 1997;28(3):660–4.

    Article  CAS  PubMed  Google Scholar 

  2. Rosengart AJ, Schultheiss KE, Tolentino J, Macdonald RL. Prognostic factors for outcome in patients with aneurysmal subarachnoid hemorrhage. Stroke. 2007;38(8):2315–21.

    Article  PubMed  Google Scholar 

  3. Hijdra A, Van Gijn J, Nagelkerke NJD, Vermeulen M, Van Crevel H. Prediction of delayed cerebral ischemia, rebleeding, and outcome after aneurysmal subarachnoid hemorrhage. Stroke. 1988;19:1250–7.

    Article  CAS  PubMed  Google Scholar 

  4. Vergouwen MDI, Ilodigwe D, MacDonald RL. Cerebral infarction after subarachnoid hemorrhage contributes to poor outcome by vasospasm-dependent and -independent effects. Stroke. 2011;42(4):924–9.

    Article  PubMed  Google Scholar 

  5. Hong CM, Tosun C, Kurland DB, Gerzanich V. Biomarkers as outcome predictors in subarachnoid hemorrhage–a systematic review. Biomarkers. 2014;19(2):95–108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Jordan JD, Nyquist P. Biomarkers and Vasospasm after aneurysmal subarachnoid hemorrhage. Neurosurg Clin N Am. 2010;21(2):381–91.

    Article  PubMed  Google Scholar 

  7. Chou SH-Y, Feske SK, Simmons SL, et al. Elevated peripheral neutrophils and matrix metalloproteinase 9 as biomarkers of functional outcome following subarachnoid hemorrhage. Transl Stroke Res. 2011;2(4):600–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. McGirt MJ, Lynch JR, Blessing R, Warner DS, Friedman AH, Laskowitz DT. Serum von Willebrand factor, matrix metalloproteinase-9, and vascular endothelial growth factor levels predict the onset of cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Neurosurgery. 2002;51(5):1125–8.

    Article  Google Scholar 

  9. Seifert V, Loffler BM, Zimmermann M, Roux S, Stolke D. Endothelin concentrations in patients with aneurysmal subarachnoid hemorrhage. Correlation with cerebral vasospasm, delayed ischemic neurological deficits, and volume of hematoma. J Neurosurg. 1995;82(1):55–62.

    Article  CAS  PubMed  Google Scholar 

  10. Schebesch K-M, Brawanski A, Bele S, et al. Neuropeptide Y—an early biomarker for cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Neurol Res. 2013;35(10):1038–43.

    Article  CAS  PubMed  Google Scholar 

  11. Wang J, Wang J-F, Hu X-M. Caspase-3 in serum predicts outcome after aneurysmal subarachnoid hemorrhage. Clin Chim Acta. 2016;460:196–202.

    Article  CAS  PubMed  Google Scholar 

  12. Frijns CJM, Rinkel GJE, Castigliego D, Van Gijn J, Sixma JJ, Fijnheer R. Endothelial cell activation after subarachnoid hemorrhage. Neurosurgery. 2002;50(6):1223–30.

    PubMed  Google Scholar 

  13. Mathiesen T, Edner G, Ulfarsson E, Andersson B. Cerebrospinal fluid interleukin-1 receptor antagonist and tumor necrosis factor-alpha following subarachnoid hemorrhage. J Neurosurg. 1997;87(2):215–20.

    Article  CAS  PubMed  Google Scholar 

  14. Chou SH, Feske SK, Atherton J, et al. Early elevation of serum TNFα is associated with poor outcome in subarachnoid hemorrhage. J Investig Med. 2012;60(7):1054–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Young AMH, Karri SK, You W, Ogilvy CS. Specific TNF-alpha inhibition in cerebral aneurysm formation and subarachnoid hemorrhage. Curr Drug Saf. 2012;7(3):190–6.

    Article  CAS  PubMed  Google Scholar 

  16. Rogy MA, Coyle SM, Oldenburg HS, et al. Persistently elevated soluble tumor necrosis factor receptor and interleukin-1 receptor antagonist levels in critically ill patients. J Am Coll Surg. 1994;178(2):132–8.

    CAS  PubMed  Google Scholar 

  17. Frontera JA, Claassen J, Schmidt JM, et al. Prediction of symptomatic vasospasm after subarachnoid hemorrhage: the modified fisher scale. Neurosurgery. 2006;59(1):21–7.

    Article  PubMed  Google Scholar 

  18. Hijdra A, Brouwers PJ, Vermeulen M, van Gijn J. Grading the amount of blood on computed tomograms after subarachnoid hemorrhage. Stroke. 1990;21(8):1156–61.

    Article  CAS  PubMed  Google Scholar 

  19. van Gijn J, Hijdra A, Wijdicks EF, Vermeulen M, van Crevel H. Acute hydrocephalus after aneurysmal subarachnoid hemorrhage. J Neurosurg. 1985;63(3):355–62.

    Article  PubMed  Google Scholar 

  20. Frontera JA, Fernandez A, Schmidt JM, et al. Defining vasospasm after subarachnoid hemorrhage: What is the most clinically relevant definition? Stroke. 2009;40(6):1963–8.

    Article  PubMed  Google Scholar 

  21. Vergouwen MDI, Vermeulen M, Muizelaar JP, et al. Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies proposal of a multidisciplinary research group. Stroke. 2010;41:2391–5.

    Article  Google Scholar 

  22. Janssen PM, Visser NA, Dorhout Mees SM, Klijn CJM, Algra A, Rinkel GJE. Comparison of telephone and face-to-face assessment of the modified Rankin Scale. Cerebrovasc Dis. 2010;29(2):137–9.

    Article  PubMed  Google Scholar 

  23. Aoki T, Fukuda M, Nishimura M, Nozaki K, Narumiya S. Critical role of TNF-alpha-TNFR1 signaling in intracranial aneurysm formation. Acta Neuropathol Commun. 2014;2(1):34.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Gruber A, Rössler K, Graninger W, Donner A, Illievich MU, Czech T. Ventricular cerebrospinal fluid and serum concentrations of sTNFR-I, IL-1ra, and IL-6 after aneurysmal subarachnoid hemorrhage. J Neurosurg Anesthesiol. 2000;12(4):297–306.

    Article  CAS  PubMed  Google Scholar 

  25. Sedger LM, McDermott MF. TNF and TNF-receptors: from mediators of cell death and inflammation to therapeutic giants—past, present and future. Cytokine Growth Factor Rev. 2014;25(4):453–72.

    Article  CAS  Google Scholar 

  26. Lotocki G, Alonso OF, Dietrich WD, Keane RW. Tumor necrosis factor receptor 1 and its signaling intermediates are recruited to lipid rafts in the traumatized brain. J Neurosci. 2004;24(49):11010–6.

    Article  CAS  PubMed  Google Scholar 

  27. Lucke-Wold BP, Logsdon AF, Manoranjan B, et al. Aneurysmal subarachnoid hemorrhage and neuroinflammation: a comprehensive review. Int J Mol Sci. 2016;17(4):1–17.

    Article  CAS  Google Scholar 

  28. Sehba FA, Pluta RM, Zhang JH. Metamorphosis of subarachnoid hemorrhage research: from delayed vasospasm to early brain injury. Mol Neurobiol. 2011;43(1):27–40.

    Article  CAS  PubMed  Google Scholar 

  29. Pantoni L, Sarti C, Inzitari D. Cytokines and cell adhesion molecules in cerebral ischemia: experimental bases and therapeutic perspectives. Arterioscler Thromb Vasc Biol. 1998;18(4):503–13.

    Article  CAS  PubMed  Google Scholar 

  30. 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.

    Article  CAS  PubMed  Google Scholar 

  31. Hirashima Y, Nakamura S, Endo S, Kuwayama N, Naruse Y, Takaku A. Elevation of platelet activating factor, inflammatory cytokines, and coagulation factors in the internal jugular vein of patients with subarachnoid hemorrhage. Neurochem Res. 1997;22(10):1249–55.

    Article  CAS  PubMed  Google Scholar 

  32. Tuttolomondo A, Pecoraro R, Pinto A. Studies of selective TNF inhibitors in the treatment of brain injury from stroke and trauma: a review of the evidence to date. Drug Des Dev Ther. 2014;8:2221–39.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We thank the Clinical Pathology Laboratory of Hospital São José, CHLC, for careful preparation of the blood samples.

Funding

Dr Fragata was supported by Sociedade Portuguesa de AVC/Tecnifar. Dr Bustamante is supported by a Juan Rodes research contract (JR16/00008) from Instituto de Salud Carlos III.

Author information

Authors and Affiliations

  1. Neuroradiology Department, Centro Hospitalar Lisboa Central, Rua Jose Antonio Serrano, 1150-099, Lisbon, Portugal

    Isabel Fragata

  2. Neurovascular Research Laboratory, Vall d’Hebron Institute of Research (VHIR), Barcelona, Spain

    Alejandro Bustamante, Anna Penalba & Joan Montaner

  3. Unidade Cérebro-Vascular, Centro Hospitalar Lisboa Central, Lisbon, Portugal

    Patrícia Ferreira & Ana Paiva Nunes

  4. Neurology Department, Centro Hospitalar Lisboa Norte, Lisbon, Portugal

    Patrícia Canhão

  5. Faculdade de Medicina, Instituto de Medicina Molecular, Universidade de Lisboa, Lisbon, Portugal

    Patrícia Canhão

  6. Institute de Biomedicine of Seville, IBiS/Hospital Universitario Virgen del Rocío/CSIC/University of Seville, Seville, Spain

    Joan Montaner

  7. Department of Neurology, Hospital Universitario Virgen Macarena, Seville, Spain

    Joan Montaner

Authors
  1. Isabel Fragata
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alejandro Bustamante
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anna Penalba
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Patrícia Ferreira
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ana Paiva Nunes
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Patrícia Canhão
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Joan Montaner
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

IF, AB, PC, JM contributed to project design; IF, AB, AP, PF, APN contributed to data collection; AB, IF performed data analysis; IF, AB, JM, PC contributed to Writing. All authors reviewed and approved the final manuscript.

Corresponding author

Correspondence to Isabel Fragata.

Ethics declarations

Conflicts of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

Institutional review board approval was obtained for this study. Informed consent obtained from patient or legal representative.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Figure 1

Flowchart depicting patients enrolled, included, and excluded in the study (TIFF 80095 kb)

Supplementary material 2 (DOCX 13 kb)

Supplementary material 3 (DOCX 13 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fragata, I., Bustamante, A., Penalba, A. et al. Venous and arterial TNF-R1 predicts outcome and complications in acute subarachnoid hemorrhage. Neurocrit Care 31, 107–115 (2019). https://doi.org/10.1007/s12028-019-00669-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12028-019-00669-9

Keywords

Search

Navigation