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Admission serum high mobility group box 1 (HMGB1) protein predicts delayed cerebral ischemia following aneurysmal subarachnoid hemorrhage

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Abstract

High mobility group box 1 protein (HMGB1) is a prototypical damage associated particle and acts as a key player in aseptic inflammation. HMGB1 appears critical for the crosstalk of a prothrombotic and proinflammatory state that is implicated in mediating and exacerbating ischemic brain injury. The role of HMGB1 in aneurysmal subarachnoid hemorrhage (aSAH) remains to be elucidated. A prospective, single blinded observational study was designed to investigate the role of HMGB1 in aSAH. Serial serum HMGB1 level quantification on admission day 0, 4, 8, and 12 was performed. Primary outcome measures were delayed cerebral ischemia (DCI — new infarction on CT) and poor functional outcome (90-day modified Rankin Scale 4–6). The role of HMGB1 levels for DCI, functional outcome and radiological vasospasm prediction was analyzed. Collectively, 83 aSAH patients were enrolled. Five patients died within 48 h. In 29/78 patients (37.2%), DCI was identified. In multivariable analysis, radiological vasospasm and admission HMGB1 were independent predictors for DCI. Younger age and higher white blood cell count, but not insult burden (World Federation of Neurosurgical Societies scale, modified Fisher scale, intraparenchymal or intraventricular hematoma existence) correlated with admission HMGB1 levels. Serial HMGB1 levels did not differ between patients with or without DCI, poor functional outcome or radiological vasospasm development. Admission serum HMGB1 does not reflect initial insult burden but serves as an independent biomarker predictive of DCI. Further studies are warranted to disentangle the role of HMGB1 surrounding the sequelae of aSAH.

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Data are available upon reasonable request, initiation requires contacting the corresponding author.

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Abbreviations

aSAH :

Aneurysmal subarachnoid hemorrhage

AUC :

Area under the curve

CVS :

Clinical vasospasm

CRP :

C-reactive protein

CTA :

CT-angiography

DAM :

Damage associated particle

DIND :

Delayed ischemic neurological deficit

DSA :

Digital subtraction angiography

DCI :

Delayed cerebral ischemia

EBI :

Early brain injury

HIMOBASH :

High mobility group box 1 in aneurysmal subarachnoid hemorrhage

HMGB1 :

High mobility group box 1 protein

IPH :

Intraparenchymal hematoma

IVH :

Intraventricular hemorrhage

RAGE :

Receptor for advanced glycation endproduct

mRS :

Modified Rankin Scale

NETs :

Neutrophil extracellular traps

RVS :

Radiological vasospasm

TLR :

Toll-like-receptor

TCD :

Transcranial doppler studies

WBC :

White blood cell

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Acknowledgements

The authors highly appreciate the generous support of Wolfgang Thomann, and the technical support of Birgit Beilmann-Höh and Tim Schmidt. The authors would like to specifically thank the nursing staff of the neurosurgical intensive and intermediate care units (NC-01, NC-05) for their strong support of the study. The authors appreciate funding support from the Homburger Forschungsförderung (HOMFOR 2018) and the Dr. Theiss Research Award 2017.

Funding

This study was financially supported by intramural research grants to PH obtained from the Homburger Forschungsförderung (HOMFOR 2018) and the Dr. Theiss Research Award 2017.

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Authors and Affiliations

  1. Department of Neurosurgery, Saarland University Medical Center, Homburg/Saar, Germany

    Sina Hemmer, Sebastian Senger, Joachim Oertel & Philipp Hendrix

  2. Department of Neurosurgery, Geisinger, Danville, PA, USA

    Christoph J. Griessenauer & Philipp Hendrix

  3. Research Institute of Neurointervention, Paracelsus Medical University, Salzburg, Austria

    Christoph J. Griessenauer

  4. Department of Neuroradiology, Saarland University Medical Center, Homburg/Saar, Germany

    Andreas Simgen

  5. Department of Clinical Chemistry and Laboratory Medicine, Saarland University Medical Center, Homburg/Saar, Germany

    Jürgen Geisel

  6. Klinik für Neurochirurgie, Medizinische Fakultät, Universität des Saarlandes, 66421, Homburg, Germany

    Philipp Hendrix

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  1. Sina Hemmer
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Contributions

SH and PH performed data analysis, discussed results, created figures, and wrote the manuscript. SH, SS, PH collected patient data and blood samples. JG analyzed samples and provided technical supervision. CG, AS, JG, JO provided technical and administrative support. PH designed the study. JO and PH provided clinical supervision. All authors reviewed and edited the manuscript for content.

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Correspondence to Philipp Hendrix.

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The study was approved by the ethics committee of the Saarland Medical Association 118/17. The study was performed in accordance with the Declaration of Helsinki. All patients or their legal representatives gave informed consent. All patients or their legal representatives gave informed consent.

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N/A, no identifiable information.

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Hemmer, S., Senger, S., Griessenauer, C.J. et al. Admission serum high mobility group box 1 (HMGB1) protein predicts delayed cerebral ischemia following aneurysmal subarachnoid hemorrhage. Neurosurg Rev 45, 807–817 (2022). https://doi.org/10.1007/s10143-021-01607-0

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