Skip to main content

Advertisement

SpringerLink
Log in

The Acute Phase of Experimental Subarachnoid Hemorrhage: Intracranial Pressure Dynamics and Their Effect on Cerebral Blood Flow and Autoregulation

  • Original Article
  • Published:
Translational Stroke Research Aims and scope Submit manuscript

Abstract

Clinical presentation and neurological outcome in subarachnoid hemorrhage (SAH) is highly variable. Aneurysmal SAH (aSAH) is hallmarked by sudden increase of intracranial pressure (ICP) and acute hypoperfusion contributing to early brain injury (EBI) and worse outcome, while milder or non-aneurysmal SAH with comparable amount of blood are associated with better neurological outcome, possibly due to less dramatic changes in ICP. Acute pressure dynamics may therefore be an important pathophysiological aspect determining neurological complications and outcome. We investigated the influence of ICP variability on acute changes after SAH by modulating injection velocity and composition in an experimental model of SAH. Five hundred microliters of arterial blood (AB) or normal saline (NS) were injected intracisternally over 1 (AB1, NS1), 10 (AB10, NS10), or 30 min (AB30) with monitoring for 6 h (n = 68). Rapid blood injection resulted in highest ICP peaks (AB1 median 142.7 mmHg [1.Q 116.7–3.Q 230.6], AB30 33.42 mmHg [18.8–38.3], p < 0.001) and most severe hypoperfusion (AB1 16.6% [11.3–30.6], AB30 44.2% [34.8–59.8]; p < 0.05). However, after 30 min, all blood groups showed comparable ICP elevation and prolonged hypoperfusion. Cerebral autoregulation was disrupted initially due to the immediate ICP increase in all groups except NS10; only AB1, however, resulted in sustained impairment of autoregulation, as well as early neuronal cell loss. Rapidity and composition of hemorrhage resulted in characteristic hyperacute hemodynamic changes, with comparable hypoperfusion despite different ICP ranges. Only rapid ICP increase was associated with pronounced and early, but sustained disruption of cerebral autoregulation, possibly contributing to EBI.

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
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Macdonald RL, Schweizer TA. Spontaneous subarachnoid haemorrhage. Lancet. 2017;389(10069):655–66.

    Article  PubMed  Google Scholar 

  2. Vergouwen MD, Vermeulen M, van Gijn J, Rinkel GJ, Wijdicks EF, 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(10):2391–5.

    Article  PubMed  Google Scholar 

  3. Schubert GA, Seiz M, Hegewald AA, Manville J, Thome C. Acute hypoperfusion immediately after subarachnoid hemorrhage: a xenon contrast-enhanced CT study. J Neurotrauma. 2009;26(12):2225–31.

    Article  PubMed  Google Scholar 

  4. Schubert GA, Seiz M, Hegewald AA, Manville J, Thome C. Hypoperfusion in the acute phase of subarachnoid hemorrhage. Acta Neurochir Suppl. 2011;110(Pt 1):35–8.

    PubMed  Google Scholar 

  5. Westermaier T, Jauss A, Eriskat J, Kunze E, Roosen K. Acute vasoconstriction: decrease and recovery of cerebral blood flow after various intensities of experimental subarachnoid hemorrhage in rats. J Neurosurg. 2009;110(5):996–1002.

    Article  PubMed  Google Scholar 

  6. Westermaier T, Jauss A, Eriskat J, Kunze E, Roosen K. Time-course of cerebral perfusion and tissue oxygenation in the first 6 h after experimental subarachnoid hemorrhage in rats. J Cereb Blood Flow Metab. 2009;29(4):771–9.

    Article  PubMed  Google Scholar 

  7. Bederson JB, Levy AL, Ding WH, Kahn R, DiPerna CA, Jenkins AL 3rd, et al. Acute vasoconstriction after subarachnoid hemorrhage. Neurosurgery. 1998;42(2):352–60 discussion 60-2.

    Article  CAS  PubMed  Google Scholar 

  8. Chen S, Feng H, Sherchan P, Klebe D, Zhao G, Sun X, et al. Controversies and evolving new mechanisms in subarachnoid hemorrhage. Prog Neurobiol. 2014;115:64–91.

    Article  PubMed  Google Scholar 

  9. Sehba FA, Hou J, Pluta RM, Zhang JH. The importance of early brain injury after subarachnoid hemorrhage. Prog Neurobiol. 2012 Apr;97(1):14–37.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Foreman B. The pathophysiology of delayed cerebral ischemia. J Clin Neurophysiol. 2016;33(3):174–82.

    Article  PubMed  Google Scholar 

  11. Rouchaud A, Lehman VT, Murad MH, Burrows A, Cloft HJ, Lindell EP, et al. Nonaneurysmal perimesencephalic hemorrhage is associated with deep cerebral venous drainage anomalies: a systematic literature review and meta-analysis. AJNR Am J Neuroradiol. 2016;37(9):1657–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Suwatcharangkoon S, Meyers E, Falo C, Schmidt JM, Agarwal S, Claassen J, et al. Loss of consciousness at onset of subarachnoid hemorrhage as an important marker of early brain injury. JAMA Neurol. 2016;73(1):28–35.

    Article  PubMed  Google Scholar 

  13. Marbacher S, Neuschmelting V, Andereggen L, Widmer HR, von Gunten M, Takala J, et al. Early brain injury linearly correlates with reduction in cerebral perfusion pressure during the hyperacute phase of subarachnoid hemorrhage. Intensive Care Med Exp. 2014;2(1):30.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Prunell GF, Svendgaard NA, Alkass K, Mathiesen T. Delayed cell death related to acute cerebral blood flow changes following subarachnoid hemorrhage in the rat brain. J Neurosurg. 2005;102(6):1046–54.

    Article  PubMed  Google Scholar 

  15. Santos GA, Petersen N, Zamani AA, Du R, LaRose S, Monk A, et al. Pathophysiologic differences in cerebral autoregulation after subarachnoid hemorrhage. Neurology. 2016;86(21):1950–6.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Budohoski KP, Czosnyka M, Smielewski P, Kasprowicz M, Helmy A, Bulters D, et al. Impairment of cerebral autoregulation predicts delayed cerebral ischemia after subarachnoid hemorrhage: a prospective observational study. Stroke. 2012;43(12):3230–7.

    Article  PubMed  Google Scholar 

  17. Jaeger M, Soehle M, Schuhmann MU, Meixensberger J. Clinical significance of impaired cerebrovascular autoregulation after severe aneurysmal subarachnoid hemorrhage. Stroke. 2012;43(8):2097–101.

    Article  PubMed  Google Scholar 

  18. Budohoski KP, Czosnyka M, Kirkpatrick PJ, Smielewski P, Steiner LA, Pickard JD. Clinical relevance of cerebral autoregulation following subarachnoid haemorrhage. Nat Rev Neurol. 2013;9(3):152–63.

    Article  CAS  PubMed  Google Scholar 

  19. Schmieder K, Moller F, Engelhardt M, Scholz M, Schregel W, Christmann A, et al. Dynamic cerebral autoregulation in patients with ruptured and unruptured aneurysms after induction of general anesthesia. Zentralblatt fur Neurochirurgie. 2006;67(2):81–7.

    Article  CAS  PubMed  Google Scholar 

  20. Jaeger M, Schuhmann MU, Soehle M, Nagel C, Meixensberger J. Continuous monitoring of cerebrovascular autoregulation after subarachnoid hemorrhage by brain tissue oxygen pressure reactivity and its relation to delayed cerebral infarction. Stroke. 2007;38(3):981–6.

    Article  PubMed  Google Scholar 

  21. Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol. 2010;8(6):e1000412.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Schubert GA, Poli S, Mendelowitsch A, Schilling L, Thome C. Hypothermia reduces early hypoperfusion and metabolic alterations during the acute phase of massive subarachnoid hemorrhage: a laser-Doppler-flowmetry and microdialysis study in rats. J Neurotrauma. 2008;25(5):539–48.

    Article  PubMed  Google Scholar 

  23. Steimers A, Gramer M, Takagaki M, Graf R, Lindauer U, Kohl-Bareis M. Simultaneous imaging of cortical blood flow and haemoglobin concentration with LASCA and RGB reflectometry. Adv Exp Med Biol. 2013;789:427–33.

    Article  CAS  PubMed  Google Scholar 

  24. Sugawara T, Ayer R, Jadhav V, Zhang JH. A new grading system evaluating bleeding scale in filament perforation subarachnoid hemorrhage rat model. J Neurosci Methods. 2008;167(2):327–34.

    Article  PubMed  Google Scholar 

  25. Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9(7):671–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Czosnyka M, Smielewski P, Kirkpatrick P, Laing RJ, Menon D, Pickard JD. Continuous assessment of the cerebral vasomotor reactivity in head injury. Neurosurgery. 1997;41(1):11–7 discussion 7-9.

    Article  CAS  PubMed  Google Scholar 

  27. Donnelly J, Budohoski KP, Smielewski P, Czosnyka M. Regulation of the cerebral circulation: bedside assessment and clinical implications. Crit Care. 2016;20(1):129.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Sanchez-Porras R, Santos E, Czosnyka M, Zheng Z, Unterberg AW, Sakowitz OW. ‘Long’ pressure reactivity index (L-PRx) as a measure of autoregulation correlates with outcome in traumatic brain injury patients. Acta Neurochir. 2012;154(9):1575–81.

    Article  PubMed  Google Scholar 

  29. Salary M, Quigley MR, Wilberger JE Jr. Relation among aneurysm size, amount of subarachnoid blood, and clinical outcome. J Neurosurg. 2007;107(1):13–7.

    Article  PubMed  Google Scholar 

  30. Konczalla J, Schmitz J, Kashefiolasl S, Senft C, Seifert V, Platz J. Non-aneurysmal subarachnoid hemorrhage in 173 patients: a prospective study of long-term outcome. Eur J Neurol. 2015;22(10):1329–36.

    Article  CAS  PubMed  Google Scholar 

  31. Raya A, Zipfel GJ, Diringer MN, Dacey RG Jr, Derdeyn CP, Rich KM, et al. Pattern not volume of bleeding predicts angiographic vasospasm in nonaneurysmal subarachnoid hemorrhage. Stroke. 2014;45(1):265–7.

    Article  PubMed  Google Scholar 

  32. Kapadia A, Schweizer TA, Spears J, Cusimano M, Macdonald RL. Nonaneurysmal perimesencephalic subarachnoid hemorrhage: diagnosis, pathophysiology, clinical characteristics, and long-term outcome. World Neurosurg. 2014;82(6):1131–43.

    Article  PubMed  Google Scholar 

  33. Dickinson CJ. Reappraisal of the Cushing reflex: the most powerful neural blood pressure stabilizing system. Clin Sci. 1990;79(6):543–50.

    Article  CAS  Google Scholar 

  34. Sorrentino E, Diedler J, Kasprowicz M, Budohoski KP, Haubrich C, Smielewski P, et al. Critical thresholds for cerebrovascular reactivity after traumatic brain injury. Neurocrit Care. 2012;16(2):258–66.

    Article  CAS  PubMed  Google Scholar 

  35. Bijlenga P, Czosnyka M, Budohoski KP, Soehle M, Pickard JD, Kirkpatrick PJ, et al. “Optimal cerebral perfusion pressure” in poor grade patients after subarachnoid hemorrhage. Neurocrit Care. 2010;13(1):17–23.

    Article  PubMed  Google Scholar 

  36. Ebel H, Rust DS, Leschinger A, Ehresmann N, Kranz A, Hoffmann O, et al. Vasomotion, regional cerebral blood flow and intracranial pressure after induced subarachnoid haemorrhage in rats. Zentralblatt fur Neurochirurgie. 1996;57(3):150–5.

    CAS  PubMed  Google Scholar 

  37. Steiner L, Lofgren J, Zwetnow NN. Lethal mechanism in repeated subarachnoid hemorrhage in dogs. Acta Neurol Scand. 1975;52(4):268–93.

    Article  CAS  PubMed  Google Scholar 

  38. Lee JY, Sagher O, Keep R, Hua Y, Xi G. Comparison of experimental rat models of early brain injury after subarachnoid hemorrhage. Neurosurgery. 2009;65(2):331–43 discussion 43.

    Article  PubMed  Google Scholar 

  39. Fragata I, Canto-Moreira N, Canhao P. Comparison of cerebral perfusion in perimesencephalic subarachnoid hemorrhage and aneurysmal subarachnoid hemorrhage. Neuroradiology. 2018;60(6):609–16.

    Article  PubMed  Google Scholar 

  40. Bederson JB, Germano IM, Guarino L. Cortical blood flow and cerebral perfusion pressure in a new noncraniotomy model of subarachnoid hemorrhage in the rat. Stroke. 1995;26(6):1086–91 discussion 91-2.

    Article  CAS  PubMed  Google Scholar 

  41. Ansar S, Edvinsson L. Equal contribution of increased intracranial pressure and subarachnoid blood to cerebral blood flow reduction and receptor upregulation after subarachnoid hemorrhage. Laboratory investigation. J Neurosurg. 2009 Nov;111(5):978–87.

    Article  PubMed  Google Scholar 

  42. Boedtkjer E. Acid-base regulation and sensing: accelerators and brakes in metabolic regulation of cerebrovascular tone. J Cereb Blood Flow Metab. 2017:271678X17733868.

  43. Schain AJ, Melo-Carrillo A, Strassman AM, Burstein R. Cortical spreading depression closes paravascular space and impairs glymphatic flow: implications for migraine headache. J Neurosci. 2017;37(11):2904–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Balbi M, Koide M, Schwarzmaier SM, Wellman GC, Plesnila N. Acute changes in neurovascular reactivity after subarachnoid hemorrhage in vivo. J Cereb Blood Flow Metab. 2015;16.

  45. Balbi M, Koide M, Wellman GC, Plesnila N. Inversion of neurovascular coupling after subarachnoid hemorrhage in vivo. J Cereb Blood Flow Metab. 2017:271678X16686595.

  46. Springborg JB, Ma X, Rochat P, Knudsen GM, Amtorp O, Paulson OB, et al. A single subcutaneous bolus of erythropoietin normalizes cerebral blood flow autoregulation after subarachnoid haemorrhage in rats. Br J Pharmacol. 2002;135(3):823–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Yamamoto S, Nishizawa S, Tsukada H, Kakiuchi T, Yokoyama T, Ryu H, et al. Cerebral blood flow autoregulation following subarachnoid hemorrhage in rats: chronic vasospasm shifts the upper and lower limits of the autoregulatory range toward higher blood pressures. Brain Res. 1998;782(1–2):194–201.

    Article  CAS  PubMed  Google Scholar 

  48. Friedrich V, Flores R, Sehba FA. Cell death starts early after subarachnoid hemorrhage. Neurosci Lett. 2012;512(1):6–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hollig A, Weinandy A, Nolte K, Clusmann H, Rossaint R, Coburn M. Experimental subarachnoid hemorrhage in rats: comparison of two endovascular perforation techniques with respect to success rate, confounding pathologies and early hippocampal tissue lesion pattern. PLoS One. 2015;10(4):e0123398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Schneider UC, Davids AM, Brandenburg S, Muller A, Elke A, Magrini S, et al. Microglia inflict delayed brain injury after subarachnoid hemorrhage. Acta Neuropathol. 2015;130(2):215–31.

    Article  PubMed  Google Scholar 

  51. Hop JW, Rinkel GJ, Algra A, van Gijn J. Initial loss of consciousness and risk of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. Stroke. 1999;30(11):2268–71.

    Article  CAS  PubMed  Google Scholar 

  52. Konczalla J, Platz J, Schuss P, Vatter H, Seifert V, Guresir E. Non-aneurysmal non-traumatic subarachnoid hemorrhage: patient characteristics, clinical outcome and prognostic factors based on a single-center experience in 125 patients. BMC Neurol. 2014;14:140.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Shimoda M, Hoshikawa K, Shiramizu H, Oda S, Yoshiyama M, Osada T, et al. Early infarction detected by diffusion-weighted imaging in patients with subarachnoid hemorrhage. Acta Neurochir. 2010;152(7):1197–205.

    Article  PubMed  Google Scholar 

  54. Prunell GF, Mathiesen T, Diemer NH, Svendgaard NA. Experimental subarachnoid hemorrhage: subarachnoid blood volume, mortality rate, neuronal death, cerebral blood flow, and perfusion pressure in three different rat models. Neurosurgery. 2003;52(1):165–75 discussion 75-6.

    PubMed  Google Scholar 

Download references

Acknowledgments

We cordially thank Ekaterina Harder, Jörn Iwertowski (Translational Neurosurgery and Neurobiology) and Birgit Nellessen (Dept. of Anesthesiology, RWTH Aachen University) for technical assistance. Further technical support was provided by the Immunohistochemistry Facility, a core facility of the Interdisciplinary Center for Clinical Research (IZKF) Aachen within the Faculty of Medicine at RWTH Aachen University.

Funding

This study was supported by grants from DFG (FOR 2591) and by grants from the Foundation of Neurosurgical Research (German Society of Neurosurgery, 2016).

Author information

Authors and Affiliations

  1. Department of Neurosurgery, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany

    Catharina Conzen, Walid Albanna, Miriam Weiss, Hans Clusmann, Ute Lindauer & Gerrit A. Schubert

  2. Translational Neurosurgery and Neurobiology, RWTH Aachen University, Aachen, Germany

    Catharina Conzen, Katrin Becker, Annika Bach, Nyanda Lushina, Sarah Pinkernell & Ute Lindauer

  3. Institute for Occupational Safety and Health of the German Social Accident Insurance, Sankt Augustin, Germany

    André Steimers

Authors
  1. Catharina Conzen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Katrin Becker
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Walid Albanna
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Miriam Weiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Annika Bach
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nyanda Lushina
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. André Steimers
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sarah Pinkernell
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hans Clusmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ute Lindauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Gerrit A. Schubert
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceived and designed the experiments and the study protocol: CC, GAS, UL. Performed the experiments: CC, KB. Analyzed the data: CC, UL, GAS, WA. Interpretation of the data: CC, GAS, UL. Designed and performed immunohistochemistry: CC, AB, KB. Blinded cell counting: NL. Blinded analysis of successful SAH: MW. Contributed reagents/materials/analysis tools: AS, WA, CC, UL, HC, GAS, SP, MW, KB. Wrote the paper: CC, KB, GAS. Critical review of the manuscript: UL, HC, MW, AS, WA, AB, KB.

Corresponding author

Correspondence to Gerrit A. Schubert.

Ethics declarations

Ethical Approval

All applicable international, national, and institutional guidelines for the care and use of animals were followed. All experimental protocols were approved by the responsible state authorities in line with the EU Directive 2010/63/EU on the protection of animals used for scientific purposes (Landesamt für Natur, Umwelt und Verbraucherschutz (LANUV) Nordrhein – Westfalen, Recklinghausen, Germany; AZ 84-02.04.2015.A412) and were performed in accordance with the ARRIVE Guidelines [21].

Conflict Interests

The authors declare that there is no conflict of interest.

Electronic supplementary material

Tables with raw data for CBF, CPP, ABP, ICP and PRx, a figure illustrating blood distribution, a figure showing time courses of EEG and ICP from a representative animal from AB1,a figure illustrating the sequence of CBF analysis from laser speckle images and two tables showing values of blood gas analysis are provided in the supplementary material section.

ESM 1

(DOCX 3254 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Conzen, C., Becker, K., Albanna, W. et al. The Acute Phase of Experimental Subarachnoid Hemorrhage: Intracranial Pressure Dynamics and Their Effect on Cerebral Blood Flow and Autoregulation. Transl. Stroke Res. 10, 566–582 (2019). https://doi.org/10.1007/s12975-018-0674-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12975-018-0674-3

Keywords

Search

Navigation