Skip to main content

Rethinking brain injury after subarachnoid hemorrhage

Introduction

Aneurysmal subarachnoid hemorrhage (aSAH) has an annual incidence of six cases per 100,000 persons, with a high incidence of long-term poor neurological outcome [1, 2]. Several complications may occur after the aneurysm rupture, such as global cerebral ischemia, re-bleeding, medical complications (i.e., infections, anemia and hyponatremia) and the occurrence of secondary brain injury [2]. As such, poor outcome is strongly related to the occurrence of initial (i.e., early brain injury) or delayed events (i.e., delayed cerebral ischemia). However, the nomenclature of these events and their diagnosis/management need to be better specified.

Early brain injury

The concept of “early brain injury” (EBI) after SAH has been recently introduced and encompasses several disorders occurring within the first 72 h following the aneurysm rupture [3]. Definition of EBI is heterogeneous, as mainly based on experimental data, and includes the evaluation of initial clinical symptoms, neuroimaging findings, as well as metabolic and/or electrophysiological variables using multimodal neuromonitoring (i.e., cortical spreading depolarizations [CSDs], which are detected by intracerebral electroencephalography, iEEG; tissue hypoxia; metabolic distress, which is detected by cerebral microdialysis, cMD) [3]. EBI results primarily from extravasation of blood into the subarachnoid space and increased intracranial pressure (ICP), which result in reduced cerebral blood flow (CBF) and transient global cerebral ischemia [4, 5]. These processes could be further aggravated by cerebral vasoconstriction, disruption of the brain blood barrier (BBB), neuro-inflammation, early seizures or loss of CBF autoregulation [6, 7], which will further contribute to increase ICP and brain ischemia. Although not proven in large randomized clinical trials, several interventions might be initiated (i.e., modulation of MAP, osmotic therapies, anticonvulsive therapy and normothermia) to minimize the extent of EBI in these patients [8].

Delayed cerebral ischemia: towards a new definition?

Regardless of the initial clinical presentation, aSAH patients may present a delayed neurological deterioration. In 2010, a definition of “clinical deterioration caused by delayed cerebral ischemia” (DCI) was proposed, as “the occurrence of focal neurological impairment, such as hemiparesis, aphasia, apraxia, hemianopsia, or neglect, or a decrease of at least 2 points on the Glasgow Coma Scale…” [9]. However, this definition presents several limitations. First, it does not take into account other more subtle clinical signs, such as those related to frontal (mood changes) or posterior cerebral areas (i.e., dysgraphia and dyscalculia). Second, this definition is of limited use in unconscious or sedated patients, in whom clinical assessment is unreliable. Third, the presence of an already established cerebral ischemia on neuroimaging would not allow physicians to initiate adequate therapies to avoid tissue hypoxia. Forth, the definition of clinical deterioration after DCI does not provide information on the underlying mechanisms; even though cerebral vasospasm has been considered for decades as the main determinant of DCI [10], other pathological phenomena could be involved [11], including also systemic medical complications [12].

Therefore, as the pathophysiology of delayed neuro-worsening of SAH patients includes also “non-ischemic” processes, secondary brain injury should be more specifically defined as a “Delayed Brain Injury” (DBI). As such, DBI diagnosis should be based on repeated clinical examinations and/or neuro-monitoring tools (i.e., altered brain hemodynamics, oxygenation or metabolism—Fig. 1) [13]. When delayed brain injury is suspected, biological and microbiological tests as well as systemic monitoring should be used to rule out different causes of DBI, either cerebral (i.e., delayed hydrocephalus, arachnoiditis, seizures, ventriculitis, loss of autoregulation and/or cerebral vasospasm and cerebral thromboembolic events) or systemic (i.e., dysglycemia, electrolytic derangements, cardiovascular and respiratory failure or sepsis). As such, multimodal monitoring, such as direct measuring of intracranial pressure (ICP), brain tissue oxygen evaluation (PbtO2) and cerebral microdialysis (cMD), together with continuous EEG monitoring (cEEG), transcranial Doppler (TCD) and near-infrared spectroscopy (NIRS) are available real-time tools that might adequately characterize the cerebral etiologies of DBI, help to target therapy and to quantify brain response to therapeutic interventions [14].

Fig. 1
figure 1

Practical approach to the identification of delayed brain injury after subarachnoid hemorrhage and some of the potential etiologies, according to different diagnostic approaches

Importantly, as different neuromonitoring tool provide non-redundant and complementary information, the use of a multimodal approach could further improve the understanding of the pathophysiology of DBI in this setting. As an example, TCD could early detect the alterations of cerebral blood flow velocities, while NIRS and PbtO2 may effectively assess regional oxygenation, either noninvasively or invasively. The occurrence of seizures can be adequately identified by the use of cEEG, while cMD would help to diagnose altered neuronal metabolism [15]. Although potentially useful, cerebral blood flow and autoregulation assessment have a limited role for routine bedside. Finally, cerebral computed tomography (CT), together with CT-angiography (CTA) and perfusion (CTP) are accurate tools to provide a definitive diagnosis of cerebral hypoperfusion [2] and microvascular dysfunction.

Once the diagnosis is made, several therapeutic options could be considered, according to the underlying cause, which may include, among all, induced hypertension, intra-arterial vasodilators, intracranial angioplasty for cerebral vasospasm, electrolytes replacement, optimization of systemic oxygen and hemoglobin, as well as antiepileptic therapy or surgical treatment for hydrocephalus. However, for microvascular dysfunction and cortical depolarization as causes of secondary brain injuries after SAH, no standardized therapies have been reported yet.

In summary, the concept of DBI should be implemented in the current management of SAH diagnosis and management. The advantages of this new approach are:

  • The use of a more comprehensive term including different etiologies of delayed neurological deterioration and a more comprehensive description of the pathophysiology underlying this phenomenon;

  • A more careful attention to non-ischemic and systemic processes which can lead to secondary brain injury and, eventually, to poor outcome;

  • The need of a standardized multimodal neuromonitoring approach, using both invasive and noninvasive tools, to assess cerebral causes of DBI following SAH.

Further research is warranted to assess whether this new definition of pathological events occurring after the aneurysm rupture can favor a more precise characterization of therapeutic strategies aiming to improve patients’ management and outcome in this setting.

Availability of data materials

Not Applicable.

References

  1. Etminan N, Chang H-S, Hackenberg K, de Rooij NK, Vergouwen MDI, Rinkel GJE, et al. Worldwide incidence of aneurysmal subarachnoid hemorrhage according to region, time period, blood pressure, and smoking prevalence in the population: a systematic review and meta-analysis. JAMA Neurol. 2019;76:588–97.

    Article  Google Scholar 

  2. Connolly ES, Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, Higashida RT, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage. Stroke. 2012;43:1711–37.

    Article  Google Scholar 

  3. Rass V, Helbok R. Early brain injury after poor-grade subarachnoid hemorrhage. Curr Neurol Neurosci Rep. 2019;19:78.

    Article  Google Scholar 

  4. Siuta M, Zuckerman SL, Mocco J. Nitric oxide in cerebral vasospasm: theories, measurement, and treatment. Neurol Res Int. 2013;213:972417.

    Google Scholar 

  5. Kusaka G, Ishikawa M, Nanda A, Granger DN, Zhang JH. Signaling pathways for early brain injury after subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2004;24:916–25.

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  7. Cahill WJ, Calvert JH, Zhang JH. Mechanisms of Early Brain Injury after Subarachnoid Hemorrhage. J Cereb Blood Flow Metab. 2006;26:1341–53.

    Article  CAS  Google Scholar 

  8. Francoeur CL, Mayer SA. Management of delayed cerebral ischemia after subarachnoid hemorrhage. Crit Care. 2016;20:277.

    Article  Google Scholar 

  9. Vergouwen MDI, Vermeulen M, van Gijn J, Rinkel GJE, 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. Stroke. 2010;41:2391–5.

    Article  Google Scholar 

  10. Lin C-L, Dumont AS, Zhang JH, Zuccarello M, Muroi C. Cerebral vasospasm after aneurysmal subarachnoid hemorrhage: mechanism and therapies. Biomed Res Int. 2014;2014:679014.

    PubMed  PubMed Central  Google Scholar 

  11. Budohoski KP, Guilfoyle M, Helmy A, Huuskonen T, Czosnyka M, Kirollos R, et al. The pathophysiology and treatment of delayed cerebral ischaemia following subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry. 2014;85:1343–53.

    Article  Google Scholar 

  12. Taccone FS, De Oliveira Manoel AL, Robba C, Vincent J-L. Use a “GHOST-CAP” in acute brain injury. Crit Care. 2020;24:89.

    Article  Google Scholar 

  13. Wartenberg KE. Update on the management of subarachnoid hemorrhage. Future Neurol. 2013;8:205–24.

    Article  CAS  Google Scholar 

  14. Wartenberg KE, Schmidt JM, Mayer SA. Multimodality monitoring in neurocritical care. Crit Care Clin. 2007;23:507–38.

    Article  CAS  Google Scholar 

  15. Schulz MK, Wang LP, Tange M, Bjerre P. Cerebral microdialysis monitoring: determination of normal and ischemic cerebral metabolisms in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg. 2000;93:808–14.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

None.

Funding

None.

Author information

Authors and Affiliations

Authors

Contributions

CR and SA wrote the first draft of the manuscript. CR, PB and FST participated in the concept of the study, and supervision. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Fabio Silvio Taccone.

Ethics declarations

Ethical approval and consent to participate

Not Applicable.

Consent for publication

Not Applicable.

Competing interests

None.

Additional information

Publisher's Note

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

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Amodio, S., Bouzat, P., Robba, C. et al. Rethinking brain injury after subarachnoid hemorrhage. Crit Care 24, 612 (2020). https://doi.org/10.1186/s13054-020-03342-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13054-020-03342-2