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Original Investigation |

Association Between Serum Calcium Level and Extent of Bleeding in Patients With Intracerebral Hemorrhage ONLINE FIRST

Andrea Morotti, MD1,2,3; Andreas Charidimou, MD, PhD3; Chia-Ling Phuah, MD2,3; Michael J. Jessel, BS3; Kristin Schwab, BA3; Alison M. Ayres, BA3; Javier M. Romero, MD4; Anand Viswanathan, MD, PhD3; M. Edip Gurol, MD, MSc3; Steven M. Greenberg, MD, PhD3; Christopher D. Anderson, MD, MMSc2,3; Jonathan Rosand, MD, MSc2,3; Joshua N. Goldstein, MD, PhD2,3,5
[+] Author Affiliations
1Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
2Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General Hospital, Boston
3J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston
4Neuroradiology Service, Department of Radiology, Massachusetts General Hospital, Boston
5Department of Emergency Medicine, Massachusetts General Hospital, Boston
JAMA Neurol. Published online September 06, 2016. doi:10.1001/jamaneurol.2016.2252
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Importance  Calcium is a key cofactor of the coagulation cascade and may play a role in the pathophysiology of intracerebral hemorrhage (ICH).

Objective  To investigate whether a low serum calcium level is associated with an increase in the extent of bleeding in patients with ICH as measured by baseline hematoma volume and risk of hematoma expansion.

Design, Setting, and Participants  Prospective cohort study of 2103 consecutive patients with primary ICH ascertained during the period between 1994 and 2015 at an academic medical center. The statistical analysis was performed in January 2016.

Main Outcomes and Measures  Total calcium level was measured on admission, and hypocalcemia was defined as a serum calcium level of less than 8.4 mg/dL. Baseline and follow-up hematoma volumes, detected by noncontrast computed tomography, were measured using a computer-assisted semiautomatic analysis. Hematoma expansion was defined as an increase of more than 30% or 6 mL from baseline ICH volume. Associations between serum calcium level and baseline hematoma volume and between serum calcium level and ICH expansion were investigated in multivariable linear and logistic regression models, respectively.

Results  A total of 2123 patients with primary ICH were screened, and 2103 patients met the inclusion criteria (mean [SD] age, 72.7 [12.5] years; 54.3% male patients), of whom 229 (10.9%) had hypocalcemia on admission. Hypocalcemic patients had a higher median baseline hematoma volume than did normocalcemic patients (37 mL [IQR, 15-72 mL] vs 16 mL [IQR, 6-44 mL]; P < .001). Low calcium levels were independently associated with higher baseline ICH volume (β = −0.13, SE = .03, P < .001). A total of 1393 patients underwent follow-up noncontrast computed tomography and were included in the ICH expansion analysis. In this subgroup, a higher serum calcium level was associated with reduced risk of ICH expansion (odds ratio, 0.55 [95% CI, 0.35-0.86]; P = .01), after adjusting for other confounders.

Conclusions and Relevance  Hypocalcemia correlates with the extent of bleeding in patients with ICH. A low calcium level may be associated with a subtle coagulopathy predisposing to increased bleeding and might therefore be a promising therapeutic target for acute ICH treatment trials.

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Figure 1.
Cohort Selection Flowchart

ICH indicates intracerebral hemorrhage; IVH, intraventricular hemorrhage.

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Figure 2.
Association Between Total Calcium Level, Baseline Hematoma Volume, and Predicted Probability of Hematoma Expansion

Scatterplots showing relationships between total calcium level and baseline hematoma volume (A) and total calcium level and predicted probability of hematoma expansion (B). The solid lines represent the linear regression fit across all patients.

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