Low Serum Calcium and Magnesium Levels and Rupture of Intracranial Aneurysms

Abstract

Background and Purpose

Both low serum calcium and magnesium levels have been associated with the extent of bleeding in patients with intracerebral hemorrhage suggesting hypocalcemia and hypomagnesemia induced coagulopathy as a possible underlying mechanism. We hypothesized that serum albumin-corrected total calcium and magnesium levels are associated with ruptured intracranial aneurysms.

Methods

The medical records of 4,701 patients, including 1,201 prospective patients, diagnosed at the Brigham and Women’s Hospital and Massachusetts General Hospital between 1990 and 2016 were reviewed and analyzed. 1,275 patients had available serum calcium, magnesium, and albumin values within 1 day of diagnosis. Individuals were divided into cases with ruptured aneurysms and controls with unruptured aneurysms. Univariable and multivariable logistic regression analyses were performed to determine the association between serum albumin-corrected total calcium and magnesium levels, and ruptured aneurysms.

Results

In multivariable analysis both albumin-corrected calcium (OR 0.33, 95% CI 0.27–0.40) and magnesium (OR 0.40, 95% CI 0.28–0.55) were significantly and inversely associated with ruptured intracranial aneurysms.

Conclusions

In this large case-control study, hypocalcemia and hypomagnesemia at diagnosis were significantly associated with ruptured aneurysms. Impaired hemostasis due to hypocalcemia and hypomagnesemia may explain this association.

Introduction

Recently, both hypocalcemia and hypomagnesemia have been significantly associated with extent of bleeding in patients with intracerebral hemorrhage (ICH).^1–3 Since both calcium and magnesium are involved in platelet function and the coagulation cascade, impaired hemostasis due to hypocalcemia and hypomagnesemia may explain this association.^{2, 4–6} In addition, hypomagnesemia has been associated with severity of aneurysmal subarachnoid hemorrhage (aSAH) and related complications such as delayed cerebral ischemia⁷, although conflicting results have been reported.⁸ However, studies investigating this association in the context of intracranial aneurysm rupture risk are lacking. Here we present a large case-control study investigating the association between albumin-corrected total calcium and magnesium values at admission, and the risk of aSAH.

Methods

The data that support the findings of this study are available from the corresponding author upon reasonable request. 4,701 patients who were diagnosed with an intracranial aneurysm between 1990 and 2016 at the Brigham and Women’s Hospital and Massachusetts General Hospital were identified with both machine learning algorithms and manual medical chart review. This study was approved by our Institutional Review Board and considered minimal risk. Patient consent was, therefore, waived by the board. Patients were identified both prospectively on clinical presentation (2007–2016) and retrospectively using natural language processing (NLP) in conjunction with the Partners Healthcare Research Patients Data Registry (RPDR).⁹ Detailed methods are provided in the online supplement (please see http://stroke.ahajournals.org). Inclusion criteria were limited to patients with available serum total calcium, magnesium, and albumin measurements within 1 day of diagnosis, leading to a final total number of 1,275 eligible patients.

Univariable and multivariable logistic regression models were implemented to test for effects of serum total calcium, albumin, and magnesium. All statistical analyses were performed using the Stata statistical software package (version 14, StataCorp. College Station, TX).

Results

Patient demographics and characteristics, as well as laboratory values, are shown in Supplemental Tables I and II. A total of 1,275 patients with 1,704 aneurysms were included, of which 900 (70.6%) were ruptured. Patients with hypocalcemia (albumin-corrected) were significantly more frequently diagnosed with ruptured aneurysms, and also had lower magnesium values. When albumin-corrected calcium and magnesium values from within 1 year prior to rupture were compared to values within 1 day after rupture in the same patient, there were no significant differences for both albumin-corrected calcium (p=0.13) and magnesium levels (0.99), indicating that lower calcium and magnesium levels after rupture were not primarily due to the rupture itself. Given the association of calcium and the anticoagulation pathway, we examined a subgroup of patients without oral anticoagulation therapy. In this subgroup, INR values were higher in patients with hypocalcemia (INR 1.30, 95% CI 1.17–1.43) compared to patients without hypocalcemia (INR 1.15, 95% CI 1.00–1.30) but the difference was not statistically significant.

Table 1 shows the results of the univariable and multivariable analyses. In multivariable analysis, younger age, black race, Asian race, current alcohol use, and current tobacco use were significantly associated with aSAH. In contrast, coronary artery disease (OR 0.51, 95% CI 0.29–0.91), higher albumin-corrected total calcium (OR 0.33, 95% CI 0.27–0.40), and higher magnesium (OR 0.50, 95% CI 0.34–0.75) were significantly associated with a lower rupture risk. The direction and significance of all coefficients remained similar in the sensitivity analyses using complete cases only (Supplemental Table III). Figure 1 shows the proportion of ruptured aneurysms stratified according to serum albumin-corrected total calcium levels and magnesium levels within 1 day of diagnosis.

Table 1.

Univariable and multivariable logistic regression for rupture status including serum laboratory values within 1 day of diagnosis (N=1,275). Multiple imputation (40 imputations) with chained equations was used for missing data.

	Univariable*		Multivariable*
Characteristics	OR (95% CI)	P	OR (95% CI)	P
Female	1.02 (0.78–1.34)	0.87	1.25 (0.92–1.71)	0.16
Black race (vs. white race)	1.34 (0.85–2.11)	0.21	1.91 (1.13–3.23)	0.02
Hispanic race (vs. white race)	0.87 (0.54–1.38)	0.55	0.85 (0.50–1.45)	0.54
Asian race (vs. white race)	2.01 (0.88–4.62)	0.10	2.65 (1.04–6.74)	0.04
Other/unknown race (vs. white race)	1.52 (0.88–2.61)	0.13	1.75 (0.95–3.22)	0.07
Age at diagnosis	0.97 (0.96–0.98)	<0.01	0.98 (0.97–0.99)	<0.01
Coronary artery disease	0.40 (0.25–0.65)	<0.01	0.51 (0.29–0.91)	0.02
Myocardial infarction	0.47 (0.28–0.79)	0.01	0.69 (0.37–1.27)	0.24
Hypertension	0.64 (0.50–0.82)	<0.01	0.87 (0.65–1.16)	0.35
Atrial fibrillation	0.44 (0.26–0.75)	<0.01	0.69 (0.37–1.28)	0.24
Number of aneurysms	1.04 (0.89–1.23)	0.50	1.02 (0.85–1.23)	0.80
Family history aneurysms	0.90 (0.62–1.30)	0.57	0.85 (0.55–1.30)	0.44
Current tobacco use	2.31 (1.75–3.04)	<0.01	2.13 (1.55–2.92)	<0.01
Current alcohol use	1.70 (1.32–2.19)	<0.01	1.66 (1.23–2.23)	<0.01
Albumin-corrected total calcium (mg/dL)	0.34 (0.28–0.41)	<0.01	0.33 (0.27–0.40)	<0.01
Magnesium (mg/dL)	0.40 (0.28–0.55)	<0.01	0.50 (0.34–0.75)	<0.01

Figure 1.

Percentage of ruptured aneurysms stratified according to serum albumin-corrected total calcium and magnesium levels at diagnosis.

Discussion

Inoue et al. demonstrated a relationship between low admission serum calcium levels and larger hematoma volume among patients with acute ICH.³ This finding was confirmed in another cohort study where hypocalcemia was associated with larger baseline ICH volumes and hematoma expansion.¹ The authors hypothesized that low levels of calcium may lead to hematoma enlargement due to calcium’s role in platelet function and the coagulation cascade.¹ Since oral anticoagulation therapy may affect coagulation physiology, we examined patients who were not on oral anticoagulants at the time of diagnosis.¹ In this subgroup, patients with hypocalcemia (albumin-corrected calcium <8.4mg/dL) had higher INR values than non-hypocalcemic patients. Although the difference was not significant, the trend suggests that hypocalcemia-induced subtle alterations of the coagulation pathway may predispose aneurysms to increased risk of rupture. Another possible mechanism by which hypocalcemia could lead to aSAH is vasoconstriction and subsequent elevation of blood pressure by affecting vascular reactivity.^10–13 However, hypertension was not significantly more common among hypocalcemic patients in our cohort. This is consistent with the study by Morotti et al. that also failed to show an association between calcium values and hypertension.¹

Although administration of magnesium in patients with acute stroke did not demonstrate functional outcome benefits in a randomized controlled trial¹⁴, Liotta et al. recently found in an observational cohort study that lower magnesium levels at admission were associated with larger ICH volumes, hematoma growth, and worse functional outcome.² Interestingly, it has been shown that magnesium also plays a crucial role in the coagulation pathway, platelet activation, and hemostasis, possibly supporting the hypothesis that hypomagnesemia induced coagulopathy may have implications in the pathophysiology of intracranial aneurysm rupture. Sekiya et al. showed that magnesium ions significantly augment the biological activities of factor IX.⁶ However, the question remains whether hypomagnesemia is associated with the cause or the effect of aSAH.⁷ Another possible mechanism for hypomagnesemia after acute stroke or SAH is acidosis-associated increase in intracellular brain magnesium levels, with a subsequent decrease in serum magnesium levels.^{7, 15} Taken together, our findings suggest that hypocalcemia and hypomagnesemia related impairment of the coagulation cascade could explain the increased association with rupture of intracranial aneurysms. However, these mechanistic links need to be further explored in future studies.

Some of the major strengths of our study are the high-quality standardized database, the large sample size, and the presence of a large control group. The main limitations include the retrospective design for a portion of the patients, the lack of pre-rupture measurements in the majority of patients, and the lack of ionized calcium values. However, we have albumin values to account for the effects of albumin on serum calcium. In some cases of aSAH, history of tobacco and alcohol consumption was obtained from relatives of patients, possibly leading to information bias. Finally, while there was no significant difference in the albumin-corrected calcium levels before and after rupture, there is a trend towards hypocalcemia after rupture. It is possible that the hypocalcemia may be secondary to the hemorrhage, and the lack of statistical significance may be due to insufficient power.

Summary

Our data showed that hypocalcemia and hypomagnesemia at diagnosis were significantly associated with ruptured aneurysms, which may be explained by impaired hemostasis. Further large prospective trials are needed to confirm our findings.