Serum biomarkers and cerebral autoregulation as early warnings of delayed cerebral ischemia risk in patients after aneurysmal subarachnoid haemorrhage


      • Changes in serum S100B levels interacted with DCI occurrence after aSAH.
      • S100B concentration on day 3 following aSAH may predict DCI.
      • Worse cerebral autoregulation and elevated S100B increase the risk of DCI.
      • Monitoring of biomarkers and cerebral autoregulation support a prediction of DCI.



      Identifying patients at risk of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid haemorrhage (aSAH) remains challenging. This study aimed to evaluate the concentration of serum biomarkers along with cerebral autoregulation impairment on DCI.


      55 patients suffering from aSAH were enrolled in the study. Serum S100 protein B (S100B) was tested both on the day of admission and over three consecutive days following the occurrence of aSAH. Cerebral autoregulation was assessed using a tissue oxygenation index (TOxa) based on near-infrared spectroscopy.


      Changes in serum S100B levels interacted with DCI status (presence vs. absence): F = 3.84, p = 0.016. Patients with DCI had higher S100B concentration level on day 3 than those without DCI (3.54 ± 0.50 ng/ml vs. 0.58 ± 0.43 ng/ml, p = 0.001). S100B concentration on day 3 following aSAH predicted DCI (AUC = 0.77, p = 0.006). Raised level of serum S100B on day 3 was related with higher TOxa, thus with impaired cerebral autoregulation (rS = 0.52, p = 0.031). Multivariate logistic regression analysis showed that impaired cerebral autoregulation and elevated S100B concentration on day 3 increase the likelihood of DCI.


      Tracking changes in the serum biomarkers concentration along with monitoring of cerebral autoregulation, may play a role in early detection of patients at risk of DCI after aSAH. These results need to be validated in larger prospective cohorts.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of Clinical Neuroscience
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Etminan N.
        • Rinkel G.J.
        Unruptured intracranial aneurysms: development, rupture and preventive management.
        Nat Rev Neurol. 2016; 12: 699-713
        • Zheng K.
        • Zhong M.
        • Zhao B.
        • Chen S.Y.
        • Tan X.X.
        • Li Z.Q.
        • Xiong Y.
        • Duan C.
        Poor-grade aneurysmal subarachnoid hemorrhage: risk factors affecting clinical outcomes in intracranial aneurysm patients in a multi-center study.
        Front Neurol. 2019; 10: 123
        • Chen S.
        • Feng H.
        • Sherchan P.
        • Klebe D.
        • Zhao G.
        • Sun X.
        • Zhang J.
        • Tang J.
        • Zhang J.H.
        Controversies and evolving new mechanisms in subarachnoid hemorrhage.
        Prog Neurobiol. 2014; 115: 64-91
        • Rowland M.J.
        • Hadjipavlou G.
        • Kelly M.
        • Westbrook J.
        • Pattinson K.T.S.
        Delayed cerebral ischaemia after subarachnoid haemorrhage: Looking beyond vasospasm.
        Br J Anaesth. 2012; 109: 315-329
        • Lai P.M.R.
        • Du R.
        Association between S100B levels and long-term outcome after aneurysmal subarachnoid hemorrhage: systematic review and pooled analysis.
        PLoS ONE. 2016;
        • Hong C.M.
        • Tosun C.
        • Kurland D.B.
        • Gerzanich V.
        • Schreibman D.
        • Simard J.M.
        Biomarkers as outcome predictors in subarachnoid hemorrhage-a systematic review.
        Biomarkers. 2014; 19: 95-108
        • Bloomfield S.M.
        • McKinney J.
        • Smith L.
        • Brisman J.
        Reliability of S100B in predicting severity of central nervous system injury.
        Neurocrit Care. 2007; 6: 121-138
        • Goyal A.
        • Failla M.D.
        • Niyonkuru C.
        • Amin K.
        • Fabio A.
        • Berger R.P.
        • Wagner A.K.
        S100b as a prognostic biomarker in outcome prediction for patients with severe traumatic brain injury.
        J Neurotrauma. 2013; 30: 946-957
        • Zhang W.
        • Sun Ma L.L.
        • Li Z.
        Clinical significance of changes in IL-6, CRP and S100 in serum and NO in cerebrospinal fluid in subarachnoid hemorrhage and prognosis.
        Exp Ther Med. 2018; 16: 816-820
        • Kellermann I.
        • Kleindienst A.
        • Hore N.
        • Buchfelder M.
        • Brandner S.
        Early CSF and serum S100B concentrations for outcome prediction in traumatic brain injury and subarachnoid hemorrhage.
        Clin Neurol Neurosurg. 2016; 145: 79-83
        • Oh T.K.
        • Song I.A.
        • Lee J.H.
        Clinical usefulness of C-reactive protein to albumin ratio in predicting 30-day mortality in critically ill patients: a retrospective analysis.
        Sci Rep. 2018; 8: 14977
        • Jaeger M.
        • Soehle M.
        • Schuhmann M.U.
        • Meixensberger J.
        Clinical significance of impaired cerebrovascular autoregulation after severe aneurysmal subarachnoid hemorrhage.
        Stroke. 2012; 43: 2097-2101
        • Budohoski K.P.
        • Czosnyka M.
        • Kirkpatrick P.J.
        • Smielewski P.
        • Steiner L.A.
        • Pickard J.D.
        Clinical relevance of cerebral autoregulation following subarachnoid haemorrhage.
        Nat Rev Neurol. 2013; 9: 152-163
        • Lam J.M.K.
        • Smielewski P.
        • Czosnyka M.
        • Pickard J.D.
        • Kirkpatrick P.J.
        Predicting delayed ischemic deficits after aneurysmal subarachnoid hemorrhage using a transient hyperemic response test of cerebral autoregulation.
        Neurosurgery. 2000;
      1. Connolly ES, Rabinstein A, Carhuapoma JR, Derdeyn CP, Dion J, Higashida RT, Hoh BL, Kirkness CJ, Naidech AM, Ogilvy CS, Patel AB, Thompson BG, Vespa P. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/american Stroke Association, Stroke. 2012;43:1711–37. 10.1161/STR.0b013e3182587839.

      2. Dorhout Mees SM, Rinkel GJE, Feigin VL, Algra A, van den Bergh WM, Vermeulen M, van Gijn J. Calcium antagonists for aneurysmal subarachnoid haemorrhage., Cochrane Database Syst. Rev. 2007;18:CD000277. 10.1002/14651858.CD000277.pub3.

        • Francoeur C.L.
        • Mayer S.A.
        Management of delayed cerebral ischemia after subarachnoid hemorrhage.
        Crit Care. 2016; 20: 277
        • Purkayastha S.
        • Sorond F.
        Transcranial doppler ultrasound: Technique and application.
        Semin Neurol. 2012; 32: 411-420
        • Budohoski K.P.
        • Czosnyka M.
        • Smielewski P.
        • Varsos G.V.
        • Kasprowicz M.
        • Brady K.M.
        • Pickard J.D.
        • Kirkpatrick P.J.
        Cerebral autoregulation after subarachnoid hemorrhage: comparison of three methods.
        J Cereb Blood Flow Metab. 2012; 33: 449-456
        • Blanca M.J.
        • Alarcón R.
        • Arnau J.
        • Bono R.
        • Bendayan R.
        Non-normal data: Is ANOVA still a valid option?.
        Psicothema. 2017;
        • Nishikawa H.
        • Suzuki H.
        mplications of periostin in the development of subarachnoid hemorrhage-induced brain injuries.
        Neural Regen Res. 2017; 12: 1982-1984
        • Dadas A.
        • Washington J.
        • Marchi N.
        • Janigro D.
        Improving the clinical management of traumatic brain injury through the pharmacokinetic modeling of peripheral blood biomarkers.
        Fluids Barriers CNS. 2016; 13: 21
        • Blyth B.J.
        • Farhavar A.
        • Gee C.
        • Hawthorn B.
        • He H.
        • Nayak A.
        • Stöcklein V.
        • Bazarian J.J.
        Validation of serum markers for blood-brain barrier disruption in traumatic brain injury.
        J Neurotrauma. 2009;
      3. Balança B, Ritzenthaler T, Gobert F, Richet C, Bodonian C, Carrillon R, Terrie A, Desmurs L, Perret-Liaudet A, Dailler F. Significance and diagnostic accuracy of early s100b serum concentration after aneurysmal subarachnoid hemorrhage, J Clin Med 2020;9:1746. 10.3390/jcm9061746 LK -

        • Ruiyan L.
        • Jianlong L.
        • Qingbin L.
        • Qinghua Y.
        • Chen M.
        • Yan F.
        • Yongli L.
        • Xiaoyan L.
        • Zhongfei H.
        • Mingli L.
        • Jinquan C.
        • Chuanlu J.
        CSF S100B in patients treated by endovascular coiling or surgical clipping after aneurysmal subarachnoid hemorrhage and its correlation to cerebral vasospasm.
        Chinese Neurosurg J. 2017; 3: 24
        • Kiiski H.
        • Långsjö J.
        • Tenhunen J.
        • Ala-Peijari M.
        • Huhtala H.
        • Hämäläinen M.
        • Moilanen E.
        • Peltola J.
        S100B, NSE and MMP-9 fail to predict neurologic outcome while elevated S100B associates with milder initial clinical presentation after aneurysmal subarachnoid hemorrhage.
        J Neurol Sci. 2018;
        • Herrmann M.
        • Vos P.
        • Wunderlich M.T.
        • De Bruijn C.H.M.M.
        • Lamers K.J.B.
        Release of glial tissue-specific proteins after acute stroke: a comparative analysis of serum concentrations of protein S-100B and glial fibrillary acidic protein.
        Stroke. 2000;
        • Jung C.S.
        • Lange B.
        • Zimmermann M.
        • Seifert V.
        CSF and serum biomarkers focusing on cerebral vasospasm and ischemia after subarachnoid hemorrhage.
        Stroke Res Treat. 2013;
        • Suzuki H.
        • Nishikawa H.
        • Kawakita F.
        Matricellular proteins as possible biomarkers for early brain injury after aneurysmal subarachnoid hemorrhage.
        Neural Regen Res. 2018; 13: 1175-1178
        • Lam J.M.K.
        • Smielewski P.
        • Czosnyka M.
        • Pickard J.D.
        • Kirkpatrick P.J.
        Predicting delayed ischemic deficits after aneurysmal subarachnoid hemorrhage using a transient hyperemic response test of cerebral autoregulation.
        Neurosurgery. 2000; 47: 819-825
      4. Budohoski KP, Czosnyka M, Smielewski P, Kasprowicz M, Helmy A, Bulters D, Pickard JD, Kirkpatrick PJ. Impairment of cerebral autoregulation predicts delayed cerebral ischemia after subarachnoid hemorrhage: a prospective observational study., Stroke. 2012;43:3230–7. 10.1161/STROKEAHA.112.669788.

      5. Budohoski KP, Czosnyka M, Smielewski P, Varsos GV, Kasprowicz M, Brady KM, Pickard JD, Kirkpatrick PJ. Monitoring cerebral autoregulation after subarachnoid hemorrhage, Acta Neurochir Suppl 2016;33:449–56. 10.1007/978-3-319-22533-3_40.

        • Carandang R.A.
        The role of invasive monitoring in traumatic brain injury.
        Curr Trauma Rep. 2015; 27: 509-517
        • Evensen K.B.
        • Eide P.K.
        Measuring intracranial pressure by invasive, less invasive or non-invasive means: limitations and avenues for improvement.
        Fluids Barriers CNS. 2020; 17: 34
        • Rivera-Lara L.
        • Geocadin R.
        • Zorrilla-Vaca A.
        • Healy R.
        • Radzik B.R.
        • Palmisano C.
        • Mirski M.
        • Ziai W.C.
        • Hogue C.
        Validation of near-infrared spectroscopy for monitoring cerebral autoregulation in comatose patients.
        Neurocrit Care. 2017; 27: 362-369
        • Park J.J.
        • Kim C.
        • Jeon J.P.
        Monitoring of delayed cerebral ischemia in patients with subarachnoid hemorrhage via near-infrared spectroscopy.
        J Clin Med. 2020; 9: 1595
      6. Jabbarli R, Pierscianek D, Darkwah Oppong M, Sato T, Dammann P, Wrede KH, Kaier K, Köhrmann M, Forsting M, Kleinschnitz C, Roos A, Sure U. Laboratory biomarkers of delayed cerebral ischemia after subarachnoid hemorrhage: a systematic review, Neurosurg Rev 2020;43:825–83. 10.1007/s10143-018-1037-y.

        • Zheng Y.K.
        • Dong X.Q.
        • Du Q.
        • Wang H.
        • Yang D.B.
        • Zhu Q.
        • Che Z.H.
        • Shen Y.F.
        • Jiang L.
        • Hu W.
        • Wang K.Y.
        • Yu W.H.
        Comparison of plasma copeptin and multiple biomarkers for assessing prognosis of patients with aneurysmal subarachnoid hemorrhage.
        Clin Chim Acta. 2017;
        • Kaplan M.
        • Ates I.
        • Akpinar M.Y.
        • Yuksel M.
        • Kuzu U.B.
        • Kacar S.
        • Coskun O.
        • Kayacetin E.
        Predictive value of C-reactive protein/albumin ratio in acute pancreatitis.
        Hepatobiliary Pancreat Dis Int. 2017; 16: 424-430
        • Park J.
        • Chung K.
        • Song J.
        • Kim S.
        • Kim E.
        • Jung J.
        • Kang Y.
        • Park M.
        • Kim Y.
        • Chang J.
        • Leem A.
        The C-Reactive Protein/Albumin Ratio as a Predictor of Mortality in Critically Ill Patients.
        J Clin Med. 2018; 7: 333
        • Zhang D.
        • Yan H.
        • Wei Y.
        • Liu X.
        • Zhuang Z.
        • Dai W.
        • Li J.
        • Li W.
        • Hang C.
        C-reactive protein/albumin ratio correlates with disease severity and predicts outcome in patients with aneurysmal subarachnoid hemorrhage.
        Front Neurol. 2019; 10: 1186