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Association Between Ionized Calcium Level and Neurological Outcome in Endovascularly Treated Patients with Spontaneous Subarachnoid Hemorrhage: A Retrospective Cohort Study

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Abstract

Background

Spontaneous subarachnoid hemorrhage (SSAH) is associated with significant morbidity and mortality. Pathophysiological processes following initial bleeding are complex and not fully understood. In this study, we aimed to determine whether a low level of ionized calcium (Ca++), an essential cofactor in the coagulation cascade and other cellular processes, is associated with adverse neurological outcome, development of early hydrocephalus, and symptomatic vasospasm among patients with SSAH.

Methods

This was a retrospective single-center cohort study of all patients admitted for SSAH between January 1, 2009, and April 31, 2020. The primary outcome was an unfavorable neurological status at discharge, defined as a modified Rankin Scale score greater than or equal to 3. Secondary outcomes were the development of early hydrocephalus and symptomatic vasospasm. Multivariable logistic regression was performed to determine whether Ca++ was an independent predictor of these outcomes.

Results

A total of 255 patients were included in the final analysis. Hypocalcemia, older age, admission Glasgow Coma Scale (GCS) score, and admission Hunt–Hess classification scale (H&H) grades IV and V were independently associated with unfavorable neurological outcome, with adjusted odds ratios (ORs) of 1.93 (95% confidence interval [CI] 1.1–3.4; p = 0.02) for each 0.1 mmol L−1 decrease in the Ca++ level, 1.04 (95% CI 1.01–1.08; p = 0.02) for each year increase, 0.82 (95% CI 0.68–0.99; p = 0.04), and 6.29 (95% CI 1.14–34.6; p = 0.03), respectively. Risk factors for the development of hydrocephalus were hypocalcemia and GCS score, with ORs of 1.85 (95% CI 1.26–2.71; p = 0.002) for each 0.1 mmol L−1 decrease in the Ca++ level and 0.83 (95% CI 0.73–0.94; p = 0.005), respectively. Ca++ was not associated with symptomatic vasospasm (OR 1.04 [95% CI 0.76–1.41]; p = 0.81). Among patients with admission H&H grade I–III bleeding, hypocalcemia was independently associated with unfavorable neurological outcome at discharge, with an adjusted OR of 1.99 (95% CI 1.03–3.84; p = 0.04) for each 0.1 mmol L−1 decrease in the Ca++ level. Hypocalcemia was also an independent risk factor for the development of early hydrocephalus, with an adjusted OR of 2.95 (95% CI 1.49–5.84; p = 0.002) for each 0.1 mmol L−1 decrease in the Ca++ level. Ca++ was not associated with symptomatic vasospasm. No association was found between Ca++ and predefined outcomes among patients with admission H&H grade IV and V bleeding.

Conclusions

Our study shows that hypocalcemia is associated with worse neurological outcome at discharge and development of early hydrocephalus in endovascularly treated patients with SSAH. Potential mechanisms include calcium-induced coagulopathy and higher blood pressure. Trials are needed to assess whether correction of hypocalcemia will lead to improved outcomes.

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Author information

Author notes

  1. Danny Epstein and Yaacov Freund have contributed equally as first authors.

Authors and Affiliations

  1. Critical Care Division, Rambam Health Care Campus, Haifa, Israel

    Danny Epstein & Tarek Diab

  2. Ruth and Bruce Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Efron St 1, Haifa, 35254, Israel

    Yaacov Freund, Aeyal Raz & Ami Neuberger

  3. Department of Cardiology, Rambam Health Care Campus, Haifa, Israel

    Erez Marcusohn

  4. Department of Neurosurgery, Rambam Health Care Campus, Haifa, Israel

    Tarek Diab

  5. Department of Diagnostic Imaging, Rambam Health Care Campus, Haifa, Israel

    Erez Klein

  6. Department of Anesthesiology, Rambam Health Care Campus, Haifa, Israel

    Aeyal Raz

  7. Infectious Diseases Unit, Rambam Health Care Campus, Haifa, Israel

    Ami Neuberger

  8. Department of Internal Medicine B, Rambam Health Care Campus, Haifa, Israel

    Ami Neuberger

  9. Medical Intensive Care Unit, Rambam Health Care Campus, Haifa, Israel

    Asaf Miller

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Contributions

DE conceived the idea for the study, designed the study, collected and analyzed the data, performed the statistical analysis, drafted the manuscript, and approved the final manuscript as submitted; YF conceived the idea for the study, designed the study, collected and analyzed the data, drafted the manuscript, and approved the final manuscript as submitted. Contributed equally as first author. EM conceived the idea for the study, critically reviewed the manuscript, and approved the final manuscript as submitted; TD conceived the idea for the study, analyzed the data, critically reviewed the manuscript, and approved the final manuscript as submitted; EK collected and analyzed the data, drafted the manuscript, and approved the final manuscript as submitted; AR conceived the idea for the study, designed the study, critically reviewed the manuscript, and approved the final manuscript as submitted; AN conceived the idea for the study, designed the study, drafted the manuscript, critically reviewed the final version of the manuscript, and approved the final manuscript as submitted; AM conceived the idea for the study, designed the study, critically reviewed the manuscript, and approved the final manuscript as submitted.

Corresponding author

Correspondence to Yaacov Freund.

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Conflict of interests

AR is a consultant for Medtronic and is supported by the United States–Israel Binational Science Foundation (not related to this study). All the other authors declare no conflicts interest.

Ethical Approval/Informed Consent

The study was performed in concordance with the Helsinki declaration and was approved by the Institutional Review Board at Rambam Health Care Campus (approval number RMB-0181-20). The need for written informed consent was waived because of the retrospective study design.

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Epstein, D., Freund, Y., Marcusohn, E. et al. Association Between Ionized Calcium Level and Neurological Outcome in Endovascularly Treated Patients with Spontaneous Subarachnoid Hemorrhage: A Retrospective Cohort Study. Neurocrit Care 35, 723–737 (2021). https://doi.org/10.1007/s12028-021-01214-3

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