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Hyperoxemia and Cerebral Vasospasm in Aneurysmal Subarachnoid Hemorrhage

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Abstract

Background

Cerebral vasospasm is a major contributor to disability and mortality after aneurysmal subarachnoid hemorrhage. Oxidation of cell-free hemoglobin plays an integral role in neuroinflammation and is a suggested source of tissue injury after aneurysm rupture. This study sought to determine whether patients with subarachnoid hemorrhage and cerebral vasospasm were more likely to have been exposed to early hyperoxemia than those without vasospasm.

Methods

This single-center retrospective cohort study included adult patients presenting with aneurysmal subarachnoid hemorrhage to Vanderbilt University Medical Center between January 2007 and December 2017. Patients with an ICD-9/10 diagnosis of aneurysmal subarachnoid hemorrhage were initially identified (N = 441) and subsequently excluded if they did not have intracranial imaging, arterial PaO2 values or died within 96 h post-rupture (N = 96). The final cohort was 345 subjects. The degree of hyperoxemia was defined by the highest PaO2 measured within 72 h after aneurysmal rupture. The primary outcome was development of cerebral vasospasm, which included asymptomatic vasospasm and delayed cerebral ischemia (DCI). Secondary outcomes were mortality and modified Rankin Scale.

Results

Three hundred and forty five patients met inclusion criteria; 218 patients (63%) developed vasospasm. Of those that developed vasospasm, 85 were diagnosed with delayed cerebral ischemia (DCI, 39%). The average patient age of the cohort was 55 ± 13 years, and 68% were female. Ninety percent presented with Fisher grade 3 or 4 hemorrhage (N = 310), while 42% presented as Hunt–Hess grade 4 or 5 (N = 146). In univariable analysis, patients exposed to higher levels of PaO2 by quintile of exposure had a higher mortality rate and were more likely to develop vasospasm in a dose-dependent fashion (P = 0.015 and P = 0.019, respectively). There were no statistically significant predictors that differentiated asymptomatic vasospasm from DCI and no significant difference in maximum PaO2 between these two groups. In multivariable analysis, early hyperoxemia was independently associated with vasospasm (OR = 1.15 per 50 mmHg increase in PaO2 [1.03, 1.28]; P = 0.013), but not mortality (OR = 1.10 [0.97, 1.25]; P = 0.147) following subarachnoid hemorrhage.

Conclusions

Hyperoxemia within 72 h post-aneurysmal rupture is an independent predictor of cerebral vasospasm, but not mortality in subarachnoid hemorrhage. Hyperoxemia is a variable that can be readily controlled by adjusting the delivered FiO2 and may represent a modifiable risk factor for vasospasm.

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References

  1. Etminan N, Chang HS, Hackenberg K, 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(5):588–97.

    Article  Google Scholar 

  2. Vergouwen MD, Jong-Tjien-Fa AV, Algra A, et al. Time trends in causes of death after aneurysmal subarachnoid hemorrhage: a hospital-based study. Neurology. 2016;86(1):59–63.

    Article  CAS  Google Scholar 

  3. Al-Khindi T, Macdonald RL, Schweizer TA. Cognitive and functional outcome after aneurysmal subarachnoid hemorrhage. Stroke. 2010;41(8):e519–36.

    Article  Google Scholar 

  4. Allen GS. Role of calcium antagonists in cerebral arterial spasm. Am J Cardiol. 1985;55(3):149b–53b.

    Article  CAS  Google Scholar 

  5. Francoeur CL, Mayer SA. Management of delayed cerebral ischemia after subarachnoid hemorrhage. Crit Care. 2016;20(1):277.

    Article  Google Scholar 

  6. Patel AS, Griessenauer CJ, Gupta R, et al. Safety and efficacy of noncompliant balloon angioplasty for the treatment of subarachnoid hemorrhage-induced vasospasm: a multicenter study. World Neurosurg. 2017;98:189–97.

    Article  Google Scholar 

  7. Kwon HJ, Lim JW, Koh HS, et al. Stent-retriever angioplasty for recurrent post-subarachnoid hemorrhagic vasospasm—a single center experience with long-term follow-up. Clin Neuroradiol. 2018.

  8. Zimmermann M, Seifert V. Endothelin and subarachnoid hemorrhage: an overview. Neurosurgery. 1998;43(4):863–875; discussion 875–866.

  9. Pasqualin A. Epidemiology and pathophysiology of cerebral vasospasm following subarachnoid hemorrhage. J Neurosurg Sci. 1998;42(Suppl 1):15–21.

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  11. Frontera JA, Claassen J, Schmidt JM, et al. Prediction of symptomatic vasospasm after subarachnoid hemorrhage: the modified fisher scale. Neurosurgery. 2006;59(1):21–27; discussion 21–27.

  12. Hosoda K, Fujita S, Kawaguchi T, et al. Effect of clot removal and surgical manipulation on regional cerebral blood flow and delayed vasospasm in early aneurysm surgery for subarachnoid hemorrhage. Surg Neurol. 1999;51(1):81–8.

    Article  CAS  Google Scholar 

  13. Macdonald RL, Weir BK. A review of hemoglobin and the pathogenesis of cerebral vasospasm. Stroke. 1991;22(8):971–82.

    Article  CAS  Google Scholar 

  14. Hugelshofer M, Sikorski CM, Seule M, et al. Cell-free oxyhemoglobin in cerebrospinal fluid after aneurysmal subarachnoid hemorrhage: biomarker and potential therapeutic target. World Neurosurg. 2018;120:e660–6.

    Article  Google Scholar 

  15. Bulters D, Gaastra B, Zolnourian A, et al. Haemoglobin scavenging in intracranial bleeding: biology and clinical implications. Nat Rev Neurol. 2018;14(7):416–32.

    Article  CAS  Google Scholar 

  16. Shaver CM, Wickersham N, McNeil JB, et al. Cell-free hemoglobin promotes primary graft dysfunction through oxidative lung endothelial injury. JCI Insight. 2018;3(2).

  17. Yang Y, Chen S, Zhang JM. The updated role of oxidative stress in subarachnoid hemorrhage. Curr Drug Deliv. 2017;14(6):832–42.

    CAS  PubMed  Google Scholar 

  18. Jeon SB, Choi HA, Badjatia N, et al. Hyperoxia may be related to delayed cerebral ischemia and poor outcome after subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry. 2014;85(12):1301–7.

    Article  Google Scholar 

  19. Roden DM, Pulley JM, Basford MA, et al. Development of a large-scale de-identified DNA biobank to enable personalized medicine. Clin Pharmacol Ther. 2008;84(3):362–9.

    Article  CAS  Google Scholar 

  20. De Marchis GM, Schaad C, Fung C, et al. Gender-related differences in aneurysmal subarachnoid hemorrhage: a hospital based study. Clin Neurol Neurosurg. 2017;157:82–7.

    Article  Google Scholar 

  21. Krishnamurthy S, Kelleher JP, Lehman EB, et al. Effects of tobacco dose and length of exposure on delayed neurological deterioration and overall clinical outcome after aneurysmal subarachnoid hemorrhage. Neurosurgery. 2007;61(3):475–480; discussion 480–471.

  22. Lantigua H, Ortega-Gutierrez S, Schmidt JM, et al. Subarachnoid hemorrhage: who dies, and why? Crit Care. 2015;19:309.

    Article  Google Scholar 

  23. Harris PA, Taylor R, Thielke R, et al. Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377–81.

    Article  Google Scholar 

  24. van Swieten JC, Koudstaal PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1988;19(5):604–7.

    Article  Google Scholar 

  25. Hunt WE, Hess RM. Surgical risk as related to time of intervention in the repair of intracranial aneurysms. J Neurosurg. 1968;28(1):14–20.

    Article  CAS  Google Scholar 

  26. van der Steen WE, Leemans EL, van den Berg R, et al. Radiological scales predicting delayed cerebral ischemia in subarachnoid hemorrhage: systematic review and meta-analysis. Neuroradiology. 2019;61(3):247–56.

    Article  Google Scholar 

  27. Little R, Rubin D. Statistical analysis with missing data. New York: Wiley; 1987.

    Google Scholar 

  28. Torbey MT, Hauser TK, Bhardwaj A, et al. Effect of age on cerebral blood flow velocity and incidence of vasospasm after aneurysmal subarachnoid hemorrhage. Stroke. 2001;32(9):2005–11.

    Article  CAS  Google Scholar 

  29. Helmerhorst HJ, Arts DL, Schultz MJ, et al. Metrics of arterial hyperoxia and associated outcomes in critical care. Crit Care Med. 2017;45(2):187–95.

    Article  Google Scholar 

  30. Peixoto MS, de Oliveira Galvao MF, Batistuzzo de Medeiros SR. Cell death pathways of particulate matter toxicity. Chemosphere. 2017;188:32–48.

  31. Gorrini C, Harris IS, Mak TW. Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov. 2013;12(12):931–47.

    Article  CAS  Google Scholar 

  32. Liochev SI. Reactive oxygen species and the free radical theory of aging. Free Radic Biol Med. 2013;60:1–4.

    Article  CAS  Google Scholar 

  33. Lucke-Wold BP, Logsdon AF, Manoranjan B, et al. Aneurysmal subarachnoid hemorrhage and neuroinflammation: a comprehensive review. Int J Mol Sci. 2016;17(4):497.

    Article  Google Scholar 

  34. Gaetani P, Lombardi D. Brain damage following subarachnoid hemorrhage: the imbalance between anti-oxidant systems and lipid peroxidative processes. J Neurosurg Sci. 1992;36(1):1–10.

    CAS  PubMed  Google Scholar 

  35. Nishihashi T, Trandafir CC, Wang A, et al. Hypersensitivity to hydroxyl radicals in rat basilar artery after subarachnoid hemorrhage. J Pharmacol Sci. 2006;100(3):234–6.

    Article  CAS  Google Scholar 

  36. Pyne-Geithman GJ, Caudell DN, Prakash P, et al. Glutathione peroxidase and subarachnoid hemorrhage: implications for the role of oxidative stress in cerebral vasospasm. Neurol Res. 2009;31(2):195–9.

    Article  CAS  Google Scholar 

  37. Ciurea AV, Palade C, Voinescu D, et al. Subarachnoid hemorrhage and cerebral vasospasm—literature review. J Med Life. 2013;6(2):120–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Kallet RH, Matthay MA. Hyperoxic acute lung injury. Respir Care. 2013;58(1):123–41.

    Article  Google Scholar 

  39. Deuber C, Terhaar M. Hyperoxia in very preterm infants: a systematic review of the literature. J Perinat Neonatal Nurs. 2011;25(3):268–74.

    Article  Google Scholar 

  40. Janz DR, Hollenbeck RD, Pollock JS, et al. Hyperoxia is associated with increased mortality in patients treated with mild therapeutic hypothermia after sudden cardiac arrest. Crit Care Med. 2012;40(12):3135–9.

    Article  CAS  Google Scholar 

  41. Damiani E, Adrario E, Girardis M, et al. Arterial hyperoxia and mortality in critically ill patients: a systematic review and meta-analysis. Crit Care. 2014;18(6):711.

    Article  Google Scholar 

  42. Fujita M, Oda Y, Yamashita S, et al. Early-stage hyperoxia is associated with favorable neurological outcomes and survival after severe traumatic brain injury: a post-hoc analysis of the brain hypothermia study. J Neurotrauma. 2017.

  43. Yokoyama S, Hifumi T, Kawakita K, et al. Early hyperoxia in the intensive care unit is significantly associated with unfavorable neurological outcomes in patients with mild-to-moderate aneurysmal subarachnoid hemorrhage. Shock. 2019;51(5):593–8.

    Article  Google Scholar 

  44. Lang M, Raj R, Skrifvars MB, et al. Early moderate hyperoxemia does not predict outcome after aneurysmal subarachnoid hemorrhage. Neurosurgery. 2016;78(4):540–5.

    Article  Google Scholar 

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Acknowledgements

The authors would like to thank the REDCap team for assistance with secure data storage.

Funding

Dr. Ware was funded by NIH HL103836. Drs. Ware and Bastarache are funded by HL135849.

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Authors and Affiliations

  1. Department of Neurological Surgery, Vanderbilt University Medical Center, 1161 21st Avenue South, T4224 Medical Center North, Nashville, TN, 37232-2380, USA

    Rebecca A. Reynolds & Reid C. Thompson

  2. Vanderbilt University School of Medicine, Nashville, TN, USA

    Shaunak N. Amin, Sumeeth V. Jonathan, Alan R. Tang & Matthews Lan

  3. Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Chunxue Wang

  4. Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, and Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA

    Julie A. Bastarache & Lorraine B. Ware

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  1. Rebecca A. Reynolds
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Contributions

RAR contributed to study conception, data collection, and manuscript preparation. SNA, SVJ, ART, and ML contributed to data collection and manuscript preparation. CW assisted with statistical analysis and critical revision of the manuscript. JAB, LBW, and RCT contributed to study conception and critical review of the manuscript.

Corresponding author

Correspondence to Rebecca A. Reynolds.

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Conflict of Interest

Author LB Ware has received research support from Global Blood Therapeutics, CSL Behring, and Boehringer Ingelheim in the past and currently receives research support from Genentech. She also has received consulting fees from Citius, Foresee, Boehringer Ingelheim, Quark, CSL Behring and Merck.

Ethical Approval

An Institutional Review Board waiver was granted by Vanderbilt University as the study did not meet the definition of human subjects research.

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Supplemental Fig. 1.

Flowchart of study population (JPEG 38 kb)

Supplemental Fig. 2.

Maximum PaO2 and modified Rankin Scale. Boxplot summary of maximum PaO2 in the first 3 days by modified Rankin Scale at discharge among survivors (N = 336). Nine patients without available modified Rankin Scales were excluded. P = 0.067 by Kruskal–Wallis test (JPEG 68 kb)

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Reynolds, R.A., Amin, S.N., Jonathan, S.V. et al. Hyperoxemia and Cerebral Vasospasm in Aneurysmal Subarachnoid Hemorrhage. Neurocrit Care 35, 30–38 (2021). https://doi.org/10.1007/s12028-020-01136-6

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  • DOI: https://doi.org/10.1007/s12028-020-01136-6

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