J Korean Med Sci.  2025 Apr;40(14):e45. 10.3346/jkms.2025.40.e45.

Administration of Calcium and Magnesium in Acute Intracerebral Hemorrhage Patients: Assessing Safety and Feasibility

• Kim M
• Park W
• Hwang JH
• Kim JH
• Chung Y
• Lee SU
• Byun J
• Park JC
• Ahn JS
• Lee S

• KMID: 2566829
• DOI: http://doi.org/10.3346/jkms.2025.40.e45

Abstract

Background
Serum calcium and magnesium levels are a key factor of the coagulation cascade and may potentially contribute to the pathophysiology of intracerebral hemorrhage (ICH) expansion. The aim of this study was to attain and sustain target levels of serum calcium and magnesium for three days following admission.
Methods
A single-blind, prospective, multicenter randomized study was conducted from 2019 to 2022 years, enrolling acute ICH patients aged 18–80 years, with radiological diagnosis and without surgical intervention. Participants were randomly assigned in a 1:1 ratio to either the study group or the control group. In the study group, the target serum levels of calcium (9–10.2 mg/dL) and magnesium (2–3 mg/dL) were actively achieved and maintained for a duration of 3 days following admission. The primary outcome was the expansion of ICH volume within the first 3 days between the study group and the control groups.
Results
After implementing inclusion/exclusion criteria, 105 of 354 patients remained in the study. There were no significant differences in ICH volume on hospital days 2 and 3 between the groups. Admission factors including Glasgow coma scale score, hemoglobin level, ICH volume, and spot sign showed significant correlations in multivariate analysis. On the third day of hospitalization, admission serum magnesium levels showed a significant correlation with ICH expansion, whereas calcium levels did not.
Conclusion
Admission serum magnesium levels were found to correlate with hematoma expansion in patients with acute ICH. While magnesium itself may not be a direct therapeutic target, it could serve as a valuable indicator for identifying potential therapeutic strategies aimed at preventing ICH volume increase.

Keyword

Magnesium; Calcium; Cerebrovascular Hematoma; Intracerebral Hemorrhage; Stroke

Figure

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  Fig. 1 ICH volume measurements in CT. We measured the volume of the ICH on hospital days 1 (= admission), 2, and 3. The ICH volume was measured using CT scans with slices ranging from 3 to 5 mm in thickness. These slices were processed using in-house software called AsanJ, which is based on a plug-in package for ImageJ (available at https://rsbweb.nih.gov/ij). To minimize measurement errors, the ICH volume measurements were conducted by a board-certified neurosurgeon and a board-certified neuroradiologist. Both individuals were blinded to the treatment assignments, and the mean value of the measurements was recorded to ensure accuracy and consistency. CT angiography was performed in all patients and the presence of the spot sign was documented. Acute ICH was observed in the left occipital lobe. The volume of ICH was assessed by measuring the volume for each slice from the CT scan, which revealed a total volume of approximately 25 cc.ICH = intracerebral hemorrhage, CT = computed tomography.

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  Fig. 2 Enrollment, randomization, and follow-up for study patients.ICU = intensive care units, ICH = intracerebral hemorrhage.

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  Fig. 3 The 30-day mRS between study and control groups.mRS = modified Rankin Scale.

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  Fig. 4 Changes in seum calcium and magnesium levels following administration. Black and gray bars denote the study and control groups, respectively.HD = hospital day.

Reference

1. Rymer MM. Hemorrhagic stroke: intracerebral hemorrhage. Mo Med. 2011; 108(1):50–54. PMID: 21462612.

2. Feigin VL, Lawes CM, Bennett DA, Barker-Collo SL, Parag V. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol. 2009; 8(4):355–369. PMID: 19233729.

3. Kim JY, Bae HJ. Spontaneous intracerebral hemorrhage: management. J Stroke. 2017; 19(1):28–39. PMID: 28178413.

4. Inoue Y, Miyashita F, Toyoda K, Minematsu K. Low serum calcium levels contribute to larger hematoma volume in acute intracerebral hemorrhage. Stroke. 2013; 44(7):2004–2006. PMID: 23674530.

5. Sun J, Liu W, Zhu R, Wu Y, Yang L. The relationship between low serum calcium level and intracerebral hemorrhage hematoma expansion: a protocol of systematic review and meta-analysis. Medicine (Baltimore). 2020; 99(3):e18844. PMID: 32011500.

6. Goyal N, Tsivgoulis G, Malhotra K, Houck AL, Khorchid YM, Pandhi A, et al. Serum magnesium levels and outcomes in patients with acute spontaneous intracerebral hemorrhage. J Am Heart Assoc. 2018; 7(8):e008698. PMID: 29654197.

7. van den Besselaar AM. Magnesium and manganese ions accelerate tissue factor-induced coagulation independently of factor IX. Blood Coagul Fibrinolysis. 2002; 13(1):19–23. PMID: 11994563.

8. Letson HL, Dobson GP. Correction of acute traumatic coagulopathy with small-volume 7.5% NaCl adenosine, lidocaine, and Mg2+ occurs within 5 minutes: a ROTEM analysis. J Trauma Acute Care Surg. 2015; 78(4):773–783. PMID: 25807406.

9. Liotta EM, Prabhakaran S, Sangha RS, Bush RA, Long AE, Trevick SA, et al. Magnesium, hemostasis, and outcomes in patients with intracerebral hemorrhage. Neurology. 2017; 89(8):813–819. PMID: 28747450.

10. Loggini A, El Ammar F, Mansour A, Kramer CL, Goldenberg FD, Lazaridis C. Association between electrolyte levels at presentation and hematoma expansion and outcome in spontaneous intracerebral hemorrhage: a systematic review. J Crit Care. 2021; 61:177–185. PMID: 33181414.

11. Elkhatib TH, Shehta N, Bessar AA. Hematoma expansion predictors: laboratory and radiological risk factors in patients with acute intracerebral hemorrhage: a prospective observational study. J Stroke Cerebrovasc Dis. 2019; 28(8):2177–2186. PMID: 31133486.

12. Can A, Rudy RF, Castro VM, Dligach D, Finan S, Yu S, et al. Low serum calcium and magnesium levels and rupture of intracranial aneurysms. Stroke. 2018; 49(7):1747–1750. PMID: 29844027.

13. Tan G, Yuan R, Wei C, Xu M, Liu M. Serum magnesium but not calcium was associated with hemorrhagic transformation in stroke overall and stroke subtypes: a case-control study in China. Neurol Sci. 2018; 39(8):1437–1443. PMID: 29804167.

14. Dorhout Mees SM, Algra A, Vandertop WP, van Kooten F, Kuijsten HA, Boiten J, et al. Magnesium for aneurysmal subarachnoid haemorrhage (MASH-2): a randomised placebo-controlled trial. Lancet. 2012; 380(9836):44–49. PMID: 22633825.

15. Saver JL, Starkman S, Eckstein M, Stratton SJ, Pratt FD, Hamilton S, et al. Prehospital use of magnesium sulfate as neuroprotection in acute stroke. N Engl J Med. 2015; 372(6):528–536. PMID: 25651247.

16. Muir KW, Lees KR, Ford I, Davis S. Intravenous Magnesium Efficacy in Stroke (IMAGES) Study Investigators. Magnesium for acute stroke (intravenous magnesium efficacy in stroke trial): randomised controlled trial. Lancet. 2004; 363(9407):439–445. PMID: 14962524.

17. Greenberg SM, Ziai WC, Cordonnier C, Dowlatshahi D, Francis B, Goldstein JN, et al. 2022 guideline for the management of patients with spontaneous intracerebral hemorrhage: a guideline from the American Heart Association/American Stroke Association. Stroke. 2022; 53(7):e282–e361. PMID: 35579034.

18. Wada R, Aviv RI, Fox AJ, Sahlas DJ, Gladstone DJ, Tomlinson G, et al. CT angiography “spot sign” predicts hematoma expansion in acute intracerebral hemorrhage. Stroke. 2007; 38(4):1257–1262. PMID: 17322083.

19. Newcommon NJ, Green TL, Haley E, Cooke T, Hill MD. Improving the assessment of outcomes in stroke: use of a structured interview to assign grades on the modified Rankin Scale. Stroke. 2003; 34(2):377–378. PMID: 12574545.

20. Tu L, Liu X, Li T, Yang X, Ren Y, Zhang Q, et al. Admission serum calcium level as a prognostic marker for intracerebral hemorrhage. Neurocrit Care. 2019; 30(1):81–87. PMID: 29995185.

21. Liu M, Xiong Y, Hua X, Huang L, He W, You C, et al. Prognostic value of day-of-event serum calcium and magnesium for predicting 1-year prognosis after intracerebral hemorrhage. Neurol Sci. 2023; 44(11):3957–3965. PMID: 37291394.

22. Roh DJ, Albers DJ, Magid-Bernstein J, Doyle K, Hod E, Eisenberger A, et al. Low hemoglobin and hematoma expansion after intracerebral hemorrhage. Neurology. 2019; 93(4):e372–e380. PMID: 31209179.

23. Morotti A, Charidimou A, Phuah CL, Jessel MJ, Schwab K, Ayres AM, et al. Association between serum calcium level and extent of bleeding in patients with intracerebral hemorrhage. JAMA Neurol. 2016; 73(11):1285–1290. PMID: 27598746.

24. Lin JY, Chung SY, Lin MC, Cheng FC. Effects of magnesium sulfate on energy metabolites and glutamate in the cortex during focal cerebral ischemia and reperfusion in the gerbil monitored by a dual-probe microdialysis technique. Life Sci. 2002; 71(7):803–811. PMID: 12074939.

25. Nowak L, Bregestovski P, Ascher P, Herbet A, Prochiantz A. Magnesium gates glutamate-activated channels in mouse central neurones. Nature. 1984; 307(5950):462–465. PMID: 6320006.

26. Can A, Du R. Calcium, magnesium, and subarachnoid hemorrhage. Aging (Albany NY). 2018; 10(9):2212–2213. PMID: 30171765.

27. Kim BJ, Lee SH, Ryu WS, Kang BS, Kim CK, Yoon BW. Low level of low-density lipoprotein cholesterol increases hemorrhagic transformation in large artery atherothrombosis but not in cardioembolism. Stroke. 2009; 40(5):1627–1632. PMID: 19286585.

28. Wong GK, Lam CW, Chan MT, Gin T, Poon WS. The effect of hypermagnesemic treatment on cerebrospinal fluid magnesium level in patients with aneurysmal subarachnoid hemorrhage. Magnes Res. 2009; 22(2):60–65. PMID: 19658274.

29. Moramarco S, Morciano L, Morucci L, Messinese M, Gualtieri P, Carestia M, et al. Epidemiology of hypoalbuminemia in hospitalized patients: a clinical matter or an emerging public health problem? Nutrients. 2020; 12(12):3656. PMID: 33261019.

30. Hu S, Sheng W, Hu Y, Ma Q, Li B, Han R. A nomogram to predict early hematoma expansion of hypertensive cerebral hemorrhage. Medicine (Baltimore). 2021; 100(7):e24737. PMID: 33607818.

31. Sporns PB, Schwake M, Kemmling A, Minnerup J, Schwindt W, Niederstadt T, et al. Comparison of spot sign, blend sign and black hole sign for outcome prediction in patients with intracerebral hemorrhage. J Stroke. 2017; 19(3):333–339. PMID: 29037015.

32. Cascella M, Vaqar S. Hypermagnesemia. Treasure Island, FL, USA: StatPearls Publishing;2023.

33. Sadiq NM, Naganathan S, Badireddy M. Hypercalcemia. Treasure Island, FL, USA: StatPearls Publishing;2023.

34. Veldurthy V, Wei R, Oz L, Dhawan P, Jeon YH, Christakos S. Vitamin D, calcium homeostasis and aging. Bone Res. 2016; 4:16041. PMID: 27790378.

35. Baird GS. Ionized calcium. Clin Chim Acta. 2011; 412(9-10):696–701. PMID: 21238441.