Skip to main content

Advertisement

SpringerLink
Log in

Relevance of Cerebral Interleukin-6 After Aneurysmal Subarachnoid Hemorrhage

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

Abstract

Background

This study examines the inflammatory response via interleukin-6 (IL-6) in aneurysmal subarachnoid hemorrhage (aSAH) patients and its association with their clinical course (occurrence of acute focal neurological deficits, AFND; and delayed cerebral ischemia, DCI).

Methods

A total of 38 consecutive aSAH patients were studied prospectively within 14 days after admission and classified as asymptomatic (n = 9; WFNS grade 1 (1–2), median and quartiles) and symptomatic (n = 29; WFNS grade 4 (2–5)); the latter presenting with AFND (n = 13), DCI (n = 10) or both (n = 6). Levels of pro-inflammatory cytokine IL-6 were determined in cerebral extracellular fluid (ECF, using cerebral microdialysis), cerebrospinal fluid (CSF) and plasma for 10 days after aSAH. Additionally, C-reactive protein (CRP) levels were measured in plasma.

Results

High IL-6 levels in CSF, ECF and plasma were found in all patients, reflecting a pronounced local inflammatory response after aSAH, followed only in symptomatic patients by a delayed systemic inflammation (CRP P < 0.025, days 7–9 after aSAH). In all compartments, IL-6 levels appeared to be higher in symptomatic patients, accompanied also by a higher ECF lactate–pyruvate ratio (P = 0.04). Cerebral, but not plasma IL-6, levels were indicative of the development of DCI in symptomatic patients (ECF P = 0.003; CSF P = 0.001).

Conclusions

A pronounced initial cerebral inflammatory state was observed in patients of all WFNS grades, suggesting that IL-6 elevations are not necessarily detrimental. Cerebral, but not plasma IL-6, levels were predictive of the development of delayed ischemic deficits in symptomatic patients, suggesting that CSF or ECF are the best sampling media for future studies.

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.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Chamorro A, Hallenbeck J. The harms and benefits of inflammatory and immune responses in vascular disease. Stroke. 2006;37:291–3.

    Article  PubMed  Google Scholar 

  2. Vila N, Castillo J, Davalos A, Esteve A, Planas AM, Chamorro A. Levels of anti-inflammatory cytokines and neurological worsening in acute ischemic stroke. Stroke. 2003;34:671–5.

    Article  CAS  PubMed  Google Scholar 

  3. Chamorro A, Urra X, Planas AM. Infection after acute ischemic stroke: a manifestation of brain-induced immunodepression. Stroke. 2007;38:1097–103.

    Article  PubMed  Google Scholar 

  4. 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;8:101–5.

    Article  PubMed  Google Scholar 

  5. Sercombe R, Dinh YR, Gomis P. Cerebrovascular inflammation following subarachnoid hemorrhage. Jpn J Pharmacol. 2002;88:227–49.

    Article  CAS  PubMed  Google Scholar 

  6. Acalovschi D, Wiest T, Hartmann M, Farahmi M, Mansmann U, Auffarth GU, et al. Multiple levels of regulation of the interleukin-6 system in stroke. Stroke. 2003;34:1864–9.

    Article  CAS  PubMed  Google Scholar 

  7. Schoch B, Regel JP, Wichert M, Gasser T, Volbracht L, Stolke D. Analysis of intrathecal interleukin-6 as a potential predictive factor for vasospasm in subarachnoid hemorrhage. Neurosurgery. 2007;60:828–36.

    Article  PubMed  Google Scholar 

  8. Fassbender K, Hodapp B, Rossol S, Bertsch T, Schmeck J, Schutt S, et al. Inflammatory cytokines in subarachnoid haemorrhage: association with abnormal blood flow velocities in basal cerebral arteries. J Neurol Neurosurg Psychiatry. 2001;70:534–7.

    Article  CAS  PubMed  Google Scholar 

  9. Rothoerl RD, Ringel F. Molecular mechanisms of cerebral vasospasm following aneurysmal SAH. Neurol Res. 2007;29:636–42.

    Article  CAS  PubMed  Google Scholar 

  10. Mathiesen T, Andersson B, Loftenius A, von Holst H. Increased interleukin-6 levels in cerebrospinal fluid following subarachnoid hemorrhage. J Neurosurg. 1993;78:562–7.

    Article  CAS  PubMed  Google Scholar 

  11. Osuka K, Suzuki Y, Tanazawa T, Hattori K, Yamamoto N, Takayasu M, et al. Interleukin-6 and development of vasospasm after subarachnoid haemorrhage. Acta Neurochir (Wien). 1998;140:943–51.

    Article  CAS  Google Scholar 

  12. Hillman J, Aneman O, Persson M, Andersson C, Dabrosin C, Mellergard P. Variations in the response of interleukins in neurosurgical intensive care patients monitored using intracerebral microdialysis. J Neurosurg. 2007;106:820–5.

    Article  CAS  PubMed  Google Scholar 

  13. Hanafy KA, Grobelny B, Fernandez L, Kurtz P, Connolly ES, Mayer SA, et al. Brain interstitial fluid TNF-alpha after subarachnoid hemorrhage. J Neurol Sci. 2010;291:69–73.

    Article  CAS  PubMed  Google Scholar 

  14. Drake C. Report of World Federation of Neurological Surgeons Committee on a Universal Subarachnoid Hemorrhage Grading Scale. J Neurosurg. 1988;68:985–6.

    Google Scholar 

  15. Fisher CM, Kistler JP, Davis JM. Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning. Neurosurgery. 1980;6:1–9.

    Article  CAS  PubMed  Google Scholar 

  16. Sarrafzadeh AS, Nagel A, Czabanka M, Denecke T, Vajkoczy P, Plotkin M. Imaging of hypoxic-ischemic penumbra with (18)F-fluoromisonidazole PET/CT and measurement of related cerebral metabolism in aneurysmal subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2010;30:36–45.

    Article  CAS  PubMed  Google Scholar 

  17. Claassen J, Bernardini GL, Kreiter K, Bates J, Du YE, Copeland D, et al. Effect of cisternal and ventricular blood on risk of delayed cerebral ischemia after subarachnoid hemorrhage: the Fisher scale revisited. Stroke. 2001;32:2012–20.

    Article  CAS  PubMed  Google Scholar 

  18. Frontera JA, Fernandez A, Schmidt JM, Claassen J, Wartenberg KE, Badjatia N, et al. Defining vasospasm after subarachnoid hemorrhage: what is the most clinically relevant definition? Stroke. 2009;40:1963–8.

    Article  PubMed  Google Scholar 

  19. Lindegaard KF, Nornes H, Bakke SJ, Sorteberg W, Nakstad P. Cerebral vasospasm diagnosis by means of angiography and blood velocity measurements. Acta Neurochir (Wien). 1989;100:12–24.

    Article  CAS  Google Scholar 

  20. Sarrafzadeh AS, Sakowitz OW, Kiening KL, Benndorf G, Lanksch WR, Unterberg AW. Bedside microdialysis: a tool to monitor cerebral metabolism in subarachnoid hemorrhage patients? Crit Care Med. 2002;30:1062–70.

    Article  PubMed  Google Scholar 

  21. Sarrafzadeh A, Haux D, Kuchler I, Lanksch WR, Unterberg AW. Poor-grade aneurysmal subarachnoid hemorrhage: relationship of cerebral metabolism to outcome. J Neurosurg. 2004;100:400–6.

    Article  PubMed  Google Scholar 

  22. Sarrafzadeh A, Haux D, Sakowitz O, Benndorf G, Herzog H, Kuechler I, et al. Acute focal neurological deficits in aneurysmal subarachnoid hemorrhage: relation of clinical course, CT findings, and metabolite abnormalities monitored with bedside microdialysis. Stroke. 2003;34:1382–8.

    Article  CAS  PubMed  Google Scholar 

  23. Jennett B, Bond M. Assessment of outcome after severe brain damage. Lancet. 1975;1:480–4.

    Article  CAS  PubMed  Google Scholar 

  24. Hutchinson PJ, O’Connell MT, Al-Rawi PG, Maskell LB, Kett-White R, Gupta AK, et al. Clinical cerebral microdialysis: a methodological study. J Neurosurg. 2000;93:37–43.

    Article  CAS  PubMed  Google Scholar 

  25. Graetz D, Nagel A, Schlenk F, Sakowitz O, Vajkoczy P, Sarrafzadeh A. High ICP as trigger of proinflammatory IL-6 cytokine activation in aneurysmal subarachnoid hemorrhage. Neurol Res. 2009 (Epub ahead of print).

  26. Schlenk F, Graetz D, Nagel A, Schmidt M, Sarrafzadeh AS. Insulin-related decrease in cerebral glucose despite normoglycemia in aneurysmal subarachnoid hemorrhage. Crit Care. 2008;12:R9.

    Article  PubMed  Google Scholar 

  27. Goodman JC, Robertson CS. Microdialysis: is it ready for prime time? Curr Opin Crit Care. 2009;15:110–7.

    Article  PubMed  Google Scholar 

  28. Nakahara T, Tsuruta R, Kaneko T, Yamashita S, Fujita M, Kasaoka S, et al. High-mobility group box 1 protein in CSF of patients with subarachnoid hemorrhage. Neurocrit Care. 2009;11:362–8.

    Article  CAS  PubMed  Google Scholar 

  29. Dirnagl U, Klehmet J, Braun JS, Harms H, Meisel C, Ziemssen T, et al. Stroke-induced immunodepression: experimental evidence and clinical relevance. Stroke. 2007;38:770–3.

    Article  PubMed  Google Scholar 

  30. Takizawa T, Tada T, Kitazawa K, Tanaka Y, Hongo K, Kameko M, et al. Inflammatory cytokine cascade released by leukocytes in cerebrospinal fluid after subarachnoid hemorrhage. Neurol Res. 2001;23:724–30.

    Article  CAS  PubMed  Google Scholar 

  31. Meisel C, Schwab JM, Prass K, Meisel A, Dirnagl U. Central nervous system injury-induced immune deficiency syndrome. Nat Rev Neurosci. 2005;6:775–86.

    Article  CAS  PubMed  Google Scholar 

  32. Banks WA, Kastin AJ, Broadwell RD. Passage of cytokines across the blood–brain barrier. Neuroimmunomodulation. 1995;2:241–8.

    Article  CAS  PubMed  Google Scholar 

  33. Buller KM. Role of circumventricular organs in pro-inflammatory cytokine-induced activation of the hypothalamic-pituitary-adrenal axis. Clin Exp Pharmacol Physiol. 2001;28:581–9.

    Article  CAS  PubMed  Google Scholar 

  34. Smith CJ, Emsley HC, Gavin CM, Georgiou RF, Vail A, Barberan EM, et al. Peak plasma interleukin-6, other peripheral markers of inflammation in the first week of ischaemic stroke correlate with brain infarct volume, stroke severity, long-term outcome. BMC Neurol. 2004;4:2.

    Article  PubMed  Google Scholar 

  35. Woiciechowsky C, Schoning B, Cobanov J, Lanksch WR, Volk HD, Docke WD. Early IL-6 plasma concentrations correlate with severity of brain injury and pneumonia in brain-injured patients. J Trauma. 2002;52:339–45.

    Article  CAS  PubMed  Google Scholar 

  36. Asadullah K, Woiciechowsky C, Docke WD, Liebenthal C, Wauer H, Kox W, et al. Immunodepression following neurosurgical procedures. Crit Care Med. 1995;23:1976–83.

    Article  CAS  PubMed  Google Scholar 

  37. van der Poll T, Keogh CV, Guirao X, Buurman WA, Kopf M, Lowry SF. Interleukin-6 gene-deficient mice show impaired defense against pneumococcal pneumonia. J Infect Dis. 1997;176:439–44.

    Article  PubMed  Google Scholar 

  38. Wong GK, Poon WS, Chan MT, Boet R, Gin T, Ng SC, et al. Intravenous magnesium sulphate for aneurysmal subarachnoid hemorrhage (IMASH): a randomized, double-blinded, placebo-controlled, multicenter phase III trial. Stroke. 2010;41:921–6.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors acknowledge outstanding technical assistance by Sabine Seidlitz and Jasmin Kopetzki and the excellent support of the ICU team.

Financial Disclosure

The authors have no financial interest in the monitoring device described.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Campus Virchow Medical Center, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany

    Asita Sarrafzadeh, Florian Schlenk & Peter Vajkoczy

  2. Institute for Biometry and Clinical Epidemiology, Charité—Universitätsmedizin Berlin, Berlin, Germany

    Christine Gericke

Authors
  1. Asita Sarrafzadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Florian Schlenk
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christine Gericke
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peter Vajkoczy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Asita Sarrafzadeh.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sarrafzadeh, A., Schlenk, F., Gericke, C. et al. Relevance of Cerebral Interleukin-6 After Aneurysmal Subarachnoid Hemorrhage. Neurocrit Care 13, 339–346 (2010). https://doi.org/10.1007/s12028-010-9432-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12028-010-9432-4

Keywords

Search

Navigation