Abstract
Background
Post-hemorrhagic hydrocephalus (PHH) is a frequent complication of aneurysmal subarachnoid hemorrhage (aSAH), yet the relationship between serum magnesium (Mg) level and PHH remains unclear. To our knowledge, this is the first prospective study to specifically examine the association between admission serum Mg level and PHH in aSAH patients.
Methods
In this prospective, multicenter study (October 2019–October 2024), 131 patients with confirmed aSAH were enrolled from four neuro-intensive care units. Patients were stratified by admission serum Mg level as <2.2 mg/dl or ≥2.2 mg/dl. The primary outcome was PHH incidence; secondary outcomes were cerebral vasospasm (CV), delayed cerebral ischemia (DCI), and 30-day modified Rankin Scale (mRS) score.
Results
Baseline characteristics were similar between groups. Serum Mg ≥2.2 mg/dl was not significantly associated with reduced vasospasm, DCI, or poor functional outcome. However, serum Mg >2.5 mg/dl correlated with lower PHH incidence in univariate analysis (odds ratio, 0.36; P=0.027) but not in multivariate analysis (P=0.136). Independent predictors of PHH were posterior circulation aneurysm, high Fisher grade, and high Hunt and Hess grade. Poor 30-day mRS was independently associated with high Fisher and Hunt and Hess grades.
Conclusions
Admission serum Mg level was not independently associated with PHH, although a potential protective trend was noted at higher levels (>2.5 mg/dl). These findings suggest a possible role of Mg in PHH prevention. Further prospective trials are warranted to clarify the therapeutic potential of Mg and to establish optimal monitoring and correction strategies in aSAH management.
Keywords: cerebral aneurysm, hydrocephalus, magnesium, stroke, subarachnoid hemorrhage, surgery
INTRODUCTION
Cerebral aneurysmal subarachnoid hemorrhage (aSAH) accounts for approximately 5% of all stroke cases and is associated with substantial mortality and long-term neurological morbidity [1,2]. Despite significant advancements in diagnostic imaging and therapeutic interventions, the overall prognosis for patients with aSAH remains poor. The primary contributors to disability and mortality following aSAH are post-hemorrhagic complications, including rebleeding, cerebral vasospasm (CV), delayed cerebral ischemia (DCI), secondary cerebral infarction, and post-hemorrhagic hydrocephalus (PHH) [3,4].
PHH develops in approximately 20% of patients during the early phase of aSAH and is classified as either acute (within the first 3 days) or subacute (between 4 and 14 days) [4]. In contrast, chronic hydrocephalus (after 14 days) occurs in approximately 10%–20% of patients in the later stages of the disease course, typically beyond 2 weeks following the initial hemorrhage [4]. Acute hydrocephalus following aSAH often necessitates cerebrospinal fluid (CSF) diversion procedures, such as external ventricular drainage (EVD) or lumbar drainage (LD), to alleviate elevated intracranial pressure (ICP) and prevent secondary brain injury. Evidence from multiple studies suggests that up to 45% of these patients eventually require permanent CSF diversion through ventriculoperitoneal shunt placement [5,6]. Early CSF diversion can facilitate the clearance of blood breakdown products and proteinaceous debris from the subarachnoid space, reducing the risk of CSF flow obstruction and subsequent PHH [7,8].
Established risk factors for PHH following aSAH include poor clinical condition on admission (e.g., high Hunt and Hess grade), large hemorrhage volume (high Fisher grade), advanced age, rupture of posterior circulation aneurysms, and use of CSF diversion procedures [9-12]. More recently, serum and CSF magnesium (Mg) levels have been implicated in the overall prognosis of patients with aSAH [13-15]. However, the majority of these investigations has primarily focused on the neuroprotective properties of Mg, particularly its potential to reduce the incidence of CV and DCI.
Magnesium has been shown to exert anti-inflammatory effects, and a potential pathophysiological link between Mg levels and PHH is supported by a growing body of evidence implicating inflammation as a key contributor to the development of PHH. Inflammatory processes following aSAH—including cytokine release, leukocyte infiltration, and disruption of CSF absorption pathways [16-18]—may be modulated by systemic and central nervous system Mg concentrations. Thus, the role of Mg in attenuating neuroinflammation may extend beyond its established effects on CV and DCI, potentially influencing the risk or severity of PHH.
Despite the plausibility of a pathophysiological link between serum Mg level and PHH, few studies have specifically investigated this association in patients with aSAH. To address this gap in the literature, we initiated a study to evaluate the potential relationship between serum Mg level and PHH. In addition, our research seeks to determine the broader clinical implications of serum Mg concentration in neurological outcomes in patients with aSAH.
MATERIALS AND METHODS
This study was conducted in accordance with the Declaration of Helsinki, and the study protocol was approved by the Institutional Review Board of Asan Medical Center (No. 2019-1299). Written informed consent was obtained from all patients, their family members, or legally authorized representatives prior to study enrollment.
Study Design and Setting
This prospective, multicenter study was conducted across multiple neuro-intensive care units (neuro-ICUs) in South Korea between October 2019 and October 2024. The selection of participating ICUs was coordinated through the Neuro-ICU Section of the Korean Society of Intensive Care Medicine.
The inclusion criteria for patient enrollment were as follows: (1) diagnosis of aSAH confirmed by computed tomography angiography (CTA), magnetic resonance angiography (MRA), or digital subtraction angiography (DSA); (2) age greater than 18 years and less than 85 years; (3) anticipated length of stay in the ICU exceeding 48 hours; and (4) presentation to the hospital within 6 hours of symptom onset. Exclusion criteria were (1) non-aneurysmal or traumatic SAH; (2) acute or chronic kidney injury; (3) preexisting bradycardia (heart rate < 50 beats per minute) or high-grade atrioventricular block; (4) known disease that may cause pseudo-hypomagnesemia like multiple myeloma and leukemia; (5) medications that can alter serum Mg level (e.g., proton pump inhibitors, aminoglycosides, calcineurin inhibitors) or further bleeding (antiplatelets, anticoagulation, etc.); (6) hemodynamic instability refractory to adequate fluid resuscitation and vasopressor support; (7) brain death or anticipated mortality within 48 hours of ICU admission; (8) pregnancy; (9) liver cirrhosis classified as Child-Pugh class C; and (10) Glasgow coma scale score less than 5. The primary outcome was incidence of PHH and its correlation with serum Mg level. Secondary outcomes included the incidence of CV, DCI, and functional outcomes as assessed by the hospital 30-day modified Rankin Scale (mRS) [19], all evaluated in relation to serum Mg level.
Data Collection and Definition
Data collection was conducted prospectively by a physician and a trained research nurse using a standardized data collection protocol. The following variables were assessed as potential predictors: (1) age; (2) sex; (3) comorbid conditions; (4) location of the ruptured aneurysm; (5) radiological characteristics associated with aSAH, including the Fisher scale, Hunt and Hess grade, and presence of hydrocephalus; (6) type of definitive treatment administered; and (7) admission data, including vital signs, laboratory test results (including serum Mg level), and neurological status.
PHH was defined as progressive ventricular enlargement on follow-up CT or MRI—characterized by an Evans’ index ≥0.30 [20], temporal horn dilation (>2 mm) [21], and/or periventricular edema—in the absence of cortical atrophy and accompanied by clinical signs of elevated ICP or neurological deterioration – observed following aSAH. CV was diagnosed using CTA, MRA, DSA, or Transcranial doppler (TCD) ultrasonography. Although DSA is considered the gold standard for the diagnosis of CV, it was not routinely performed in all patients due to its invasive nature and the associated clinical risk-benefit considerations in the context of serial monitoring. Instead, DSA was reserved for selective use based on specific clinical indications. TCD ultrasonography was adopted as the primary modality for routine surveillance of vasospasm in all enrolled patients. TCD examinations were conducted through the temporal bone window to evaluate cerebral blood flow velocity in the middle cerebral artery (MCA). In general, TCD monitoring commenced on hospital day (HD) 3 and was performed every other day until HD 15 by a certified vascular technologist. In patients diagnosed with CV, daily TCD monitoring was continued through HD 15. CV was defined as an MCA mean flow velocity exceeding 120 cm/sec in conjunction with a Lindegaard ratio greater than 3 [22]. DCI was defined as the occurrence of new focal neurological deficits or a reduction of at least two points on the GCS, either in the total score or in one of its component domains (i.e., eye opening, motor response on either side, or verbal response) [23]. Serum Mg level was assessed in all patients upon admission. In patients with low serum albumin level, where pseudo-hypomagnesemia was suspected, intravenous (IV) albumin replacement was administered, and serum Mg level was re-evaluated on the following day. Serum Mg replacement was indicated in patients with a serum Mg level <1.8 mg/dl. Intravenous Mg sulfate 10% (2 g/20 ml) was administered at a dose of one ampoule mixed with 100 ml of dextrose and infused over 15 minutes.
SAH Management and CSF Diversion
All enrolled patients with aSAH were managed according to standard clinical protocols [1,24]. This included blood pressure regulation, optimization of intravascular volume status, transfusion as needed, ICP monitoring, and other supportive measures, all in accordance with established clinical guidelines. CSF diversion (EVD or LD) was performed in all patients diagnosed with PHH associated with impaired consciousness. The indications, management strategies, and weaning protocols for CSF diversion were implemented in accordance with established clinical guidelines [1,25,26].
Clinical Assessment
The patients were divided into two groups using a serum Mg cutoff value of 2.2 mg/dl based on the upper limit of the normal physiological range. This choice is consistent with previous studies in aSAH populations [27,28], which suggest that Mg >2.0–2.5 mg/dl may be associated with improved neurologic outcomes and reduced complications such as vasospasm or DCI. For statistical analysis, the severity grading scales used to assess aSAH were dichotomized into favorable and unfavorable categories. Fisher grades 1–2 were classified as favorable, while grades 3–4 were considered unfavorable. Similarly, Hunt and Hess grades 1–3 were categorized as favorable, whereas grades 4–5 were deemed unfavorable. Neurological outcomes were assessed using the mRS. All patients were followed for a period of 30 days from hospital admission. In cases where the patient remained alive but was no longer hospitalized within 30 days of the initial event, neurological status was evaluated via a structured telephone interview with a family member, conducted by a trained research nurse.
Statistical Analysis
Baseline characteristics were summarized as mean±standard deviation for continuous variables with a normal distribution and as median with interquartile range (IQR) for non-normally distributed continuous variables. Categorical variables were expressed as absolute numbers with corresponding percentages. Statistical significance was defined as a two-sided P-value <0.05. To identify factors associated with unfavorable clinical outcomes, univariate and multivariate logistic regression analyses were performed. Variables with clinical relevance or a P-value <0.1 in univariate analysis were included in the multivariate model. All statistical analyses were conducted using IBM SPSS version 29.0 (IBM Corp.), SAS version 9.4 (SAS Institute), and R software version 4.3.0 (The R Foundation for Statistical Computing), incorporating R packages including rms and receiver operating characteristic. The precision of the estimates was reported with a 95% CI, and P-values <0.05 were considered statistically significant.
RESULTS
Characteristics of Study Patients
A total of 249 patients with aSAH who were admitted to four neuro-ICUs between October 2019 and October 2024 was prospectively screened. After applying predefined inclusion and exclusion criteria, 131 patients were included in the final analysis. These patients were stratified into two groups based on their serum Mg level at the time of admission: serum Mg <2.2 mg/dl (n=50) and ≥ 2.2 mg/dl (n=81) (Figure 1). No significant differences were observed between the two groups in terms of baseline demographic or clinical characteristics of age, sex, comorbidities, aneurysm location, and radiological severity as determined by Fisher grade. However, the admission serum Mg level differed significantly between the two groups (median [IQR]: 1.7 mg/dl [1.5–1.8] vs. 2.5 mg/dl [2.3–2.6], P<0.002). Additionally, there was no significant difference in treatment modality or extent of subarachnoid clot removal during surgery (Table 1).
Figure 1.
Enrollment, inclusion, and exclusion of study patients. SAH: subarachnoid hemorrhage; Mg: magnesium; GCS: Glasgow coma scale; ICU: Intensive care unit.
Table 1.
Demographic and clinical characteristics of the study population
| Characteristics | Serum Mg level <2.2 (n=50) | Serum Mg level ≥2.2 (n=81) | P-value |
|---|---|---|---|
| Age (yr) | 59.45±14.9 | 63.85±11.4 | 0.105 |
| Female sex | 32 (64) | 49 (60.5) | 0.832 |
| Comorbidity | |||
| Hypertension | 19 (38) | 37 (45.7) | 0.454 |
| Diabetes | 14 (28) | 19 (23.5) | 0.562 |
| Chronic renal disease | 4 (8) | 6 (7.4) | 0.982 |
| Stroke (ischemic) | 6 (12) | 8 (9.9) | 0.781 |
| Stroke (hemorrhagic) | 4 (8) | 6 (7.4) | 0.973 |
| Ruptured aneurysm location | |||
| Anterior circulation | |||
| ACA | 11 (22) | 16 (19.8) | 0.881 |
| MCA | 12 (24) | 14 (17.3) | 0.541 |
| ICA | 20 (40) | 36 (44.4) | 0.701 |
| Posterior circulation | 7 (14) | 15 (18.5) | 0.401 |
| Fisher scale | 0.682 | ||
| 1 | 0 | 0 | |
| 2 | 11 (22) | 23 (28.4) | |
| 3 | 23 (46) | 37 (45.7) | |
| 4 | 16 (32) | 21 (25.9) | |
| Hunt and Hess classification | 0.652 | ||
| 1 | 2 (4) | 5 (6.2) | |
| 2 | 9 (18) | 14 (17.3) | |
| 3 | 14 (28) | 21 (25.9) | |
| 4 | 16 (32) | 24 (29.6) | |
| 5 | 9 (18) | 17 (21) | |
| Admission GCS | 9 (6–13) | 8 (7–14) | 0.292 |
| Admission SBP (mm Hg) | 152 (132–178) | 155 (138–175) | 0.583 |
| Admission DBP (mm Hg) | 84 (75–102) | 88 (79–108) | 0.451 |
| Admission laboratory data | |||
| Hemoglobin (g/dl) | 10.8 (9.5–12.2) | 11.9 (10.2–13.2) | 0.182 |
| Platelet (×103/ul) | 222 (187–243) | 198 (176–244) | 0.128 |
| INR | 1.05 (0.96–1.23) | 0.97 (0.89–1.31) | 0.152 |
| Glucose (mg/dl) | 148 (121–184) | 142 (117–185) | 0.652 |
| Calcium (mg/dl) | 8.5 (8.1–9.4) | 8.8 (8.3–9.7) | 0.527 |
| Magnesium (mg/dl) | 1.7 (1.5–1.8) | 2.5 (2.3 –2.6) | 0.002 |
| Types of treatment | |||
| Craniotomy with clipping | 21 (42) | 33 (40.7) | 0.892 |
| Endovascular treatment | 28 (56) | 44 (54.3) | 0.915 |
| Medical management only | 1 (1.7) | 4 (4.9) | 0.647 |
| Postoperative SAH removal extent (n=54)a) | 0.412 | ||
| 1 (Total, >90%) | 2 (9.5) | 4 (12.1) | |
| 2 (Subtotal, 50%–90%) | 4 (19.0) | 11 (33.3) | |
| 3 (Partial, 20%–50%) | 11 (52.4) | 15 (45.5) | |
| 4 (Merely, <20%) | 4 (19.0) | 3 (9.1) | |
| Hydrocephalus on admission | 12 (24) | 22 (27.2) | 0.713 |
| CSF diversion (EVD or LD) | 11 (22) | 20 (24.7) | 0.774 |
Values are presented as mean±standard deviation, number (%), or median (interquartile range).
Mg: magnesium; ACA: anterior cerebral artery; MCA: middle cerebral artery; ICA: internal carotid artery; GCS: Glasgow coma scale; SBP: systolic blood pressure; DBP: diastolic blood pressure; INR: international normalized ratio; SAH: subarachnoid hemorrhage; CSF: cerebrospinal fluid; EVD: external ventricular drainage; LD: lumbar drainage.
Limited to patients who underwent open surgical procedures (craniotomy and clipping, n=54).
Clinical Outcomes Associated with Serum Mg Level
We analyzed clinical factors potentially associated with serum Mg level at the time of admission. There were no significant differences between the two groups in the incidence of CV (15/50 [30%] vs. 26/81 [32.1%], P=0.762), the need for chemical cerebral angioplasty (10 [20%] vs. 15 [18.5%], P=0.871), or the occurrence of DCI (9 [18%] vs. 15 [18.5%], P=0.891) during the first 14 days of hospitalization. Similarly, there were no significant differences in the length of ICU stay (median [IQR]: 10.2 days [8.9–12.1] vs. 10.8 days [8.5–12.5], P=0.092), total hospital stay (median [IQR]: 19.5 days [15.5–23.2] vs. 18.8 days [14.5–22.8], P=0.682), or 30-day mRS (median [IQR]: 3 [2–5] vs. 3 [1–5], P=0.445) between the low- and high-serum-Mg groups (Table 2).
Table 2.
Clinical outcomes associated with the serum magnesium level
| Serum Mg level <2.2 (n=50) | Serum Mg level ≥2.2 (n=81) | P-value | |
|---|---|---|---|
| Vasospasm | 15 (30) | 26 (32.1) | 0.762 |
| Chemical cerebral angioplasty | 10 (20) | 15 (18.5) | 0.871 |
| DCI | 9 (18) | 15 (18.5) | 0.891 |
| The length of ICU stays (day) | 10.2 (8.9–12.1) | 10.8 (8.5–12.5) | 0.092 |
| The length of hospital stays (day) | 19.5 (15.5–23.2) | 18.8 (14.5–22.8) | 0.682 |
| 30-Day mRS | 3 (2–5) | 3 (1–5) | 0.445 |
Values are presented as number (%) or median (interquartile range).
Mg: magnesium; DCI: delayed cerebral ischemia; ICU: intensive care unit; mRS: modified Rankin scale.
Independent Clinical and Laboratory Factors of PHH
Univariate logistic regression analysis identified several factors significantly associated with the development of PHH. These included ruptured aneurysm location in the posterior circulation (odds ratio, [OR], 3.05; 95% CI, 1.30–7.16; P=0.011), Fisher grade 3–4 (OR, 4.22; 95% CI, 1.45–12.33; P=0.008), Hunt and Hess grade 4–5 (OR, 2.76; 95% CI, 1.15–6.64; P=0.023), and admission serum Mg level >2.5 mg/dl (OR, 0.36; 95% CI, 0.14–0.89; P=0.027). Multivariate logistic regression analysis revealed that posterior circulation aneurysm (OR, 2.84; 95% CI, 1.12–7.21; P=0.028), Fisher grade 3–4 (OR, 3.89; 95% CI, 1.29–11.74; P=0.015), and Hunt and Hess grade 4–5 (OR, 2.48; 95% CI, 1.02–6.03; P=0.046) were independently associated with the development of PHH. In the univariate analysis, both predefined (≥2.2 mg/dl) and exploratory (>2.5 mg/dl) Mg thresholds were assessed for potential association with PHH. Because the >2.5 mg/dl cutoff demonstrated a stronger inverse relationship with PHH incidence (P=0.027), only this variable was included in the multivariate logistic regression model. Admission serum Mg level, while showing a significant inverse association in univariate analysis when >2.5 mg/dl, did not remain significant in the multivariate model (P=0.136) (Table 3).
Table 3.
Independent clinical and laboratory factors of post-hemorrhagic hydrocephalus
| Univariate analysis | Multivariate analysis | |||||
|---|---|---|---|---|---|---|
| OR | 95% CI | P-value | OR | 95% CI | P-value | |
| Age (yr) | 1.01 | 0.98–1.04 | 0.482 | |||
| Female sex | 0.92 | 0.45–1.88 | 0.818 | |||
| Comorbidity | ||||||
| Hypertension | 1.17 | 0.56-2.45 | 0.674 | |||
| Diabetes | 0.86 | 0.36-2.05 | 0.730 | |||
| Chronic renal disease | 1.08 | 0.24-4.79 | 0.918 | |||
| Stroke (ischemic) | 1.12 | 0.36-3.44 | 0.844 | |||
| Stroke (hemorrhagic) | 1.04 | 0.27-3.95 | 0.956 | |||
| Ruptured aneurysm location | ||||||
| ACA | 1 | |||||
| MCA | 0.86 | 0.38–1.95 | 0.717 | |||
| ICA | 1.02 | 0.50–2.12 | 0.952 | |||
| Posterior circulation | 3.05 | 1.30–7.16 | 0.011 | 2.84 | 1.12–7.21 | 0.028 |
| Fisher grade | ||||||
| 1, 2 | 1 | |||||
| 3, 4 | 4.22 | 1.45–12.33 | 0.008 | 3.89 | 1.29–11.74 | 0.015 |
| Hunt and Hess grade | ||||||
| 1, 2, 3 | 1 | |||||
| 4, 5 | 2.76 | 1.15–6.64 | 0.023 | 2.48 | 1.02–6.03 | 0.046 |
| Admission blood test | ||||||
| Hemoglobin (g/dl) | 1.04 | 0.90–1.20 | 0.589 | |||
| Platelet (×103/ul) | 0.99 | 0.97–1.01 | 0.289 | |||
| INR | 1.42 | 0.46–4.35 | 0.538 | |||
| Glucose (mg/dl) | 1.03 | 0.96–1.10 | 0.408 | |||
| Calcium (mg/dl) | 0.95 | 0.63–1.44 | 0.812 | |||
| Admission serum Mg (mg/dl) | ||||||
| < 2 (n=50) | 0.84 | 0.38–1.88 | 0.671 | 0.91 | 0.39–2.13 | 0.827 |
| 2–2.5 (n=61) | 0.93 | 0.42–2.04 | 0.859 | 1.01 | 0.44–2.32 | 0.982 |
| 2.5 (n=20) | 0.36 | 0.14–0.89 | 0.027 | 0.48 | 0.18–1.27 | 0.136 |
OR: odds ratio; ACA: anterior cerebral artery; MCA: middle cerebral artery; ICA: internal carotid artery; INR: international normalized ratio; Mg: magnesium.
Independent Factors Associated with 30-Day Functional Outcome Assessed by mRS
Univariate analyses demonstrated that advanced age, posterior circulation aneurysm, and higher Fisher and Hunt and Hess grades were associated with poor 30-day outcomes. After adjustment, only high Fisher and Hunt and Hess grades remained independently correlated with unfavorable functional status (mRS ≥3). Serum Mg level, regardless of cutoff, was not significantly related to 30-day neurological outcome in either univariate or multivariate model. These findings indicate that initial hemorrhage burden and clinical severity, rather than admission Mg concentration, primarily determine short-term recovery after aSAH (Table 4).
Table 4.
Independent factors associated with 30-day functional outcome assessed by mRS
| Univariate Analysis | Multivariate Analysis | |||||
|---|---|---|---|---|---|---|
| OR | 95% CI | P-value | OR | 95% CI | P-value | |
| Age (yr) | 1.18 | 1.02–1.35 | 0.027 | 1.12 | 0.96–1.30 | 0.125 |
| Female sex | 0.98 | 0.49–1.97 | 0.96 | |||
| Comorbidity | ||||||
| Hypertension | 1.24 | 0.62–2.47 | 0.558 | |||
| Diabetes | 1.42 | 0.63–3.22 | 0.392 | |||
| Chronic renal disease | 2.32 | 0.59–9.18 | 0.236 | |||
| Stroke (ischemic) | 1.75 | 0.51–5.96 | 0.373 | |||
| Stroke (hemorrhagic) | 1.98 | 0.52–7.48 | 0.312 | |||
| Ruptured aneurysm location | ||||||
| ACA | 1 | |||||
| MCA | 1.05 | 0.43–2.53 | 0.912 | |||
| ICA | 0.89 | 0.37–2.15 | 0.794 | |||
| Posterior circulation | 2.54 | 1.02–6.29 | 0.045 | 2.12 | 0.85–5.29 | 0.108 |
| Fisher grade | ||||||
| 1, 2 | 1 | |||||
| 3, 4 | 3.38 | 1.04–11.24 | 0.036 | 2.91 | 1.02–9.52 | 0.047 |
| Hunt and Hess grade | ||||||
| 1, 2, 3 | 1 | |||||
| 4, 5 | 4.25 | 1.79–10.1 | 0.001 | 3.69 | 1.39–9.79 | 0.009 |
| Admission blood test | ||||||
| Hemoglobin (g/dl) | 1.14 | 0.92–1.41 | 0.236 | |||
| Platelet (×103/ul) | 0.99 | 0.98–1.01 | 0.324 | |||
| INR | 1.88 | 0.62–5.74 | 0.263 | |||
| Glucose (mg/dl) | 1.03 | 0.98–1.08 | 0.234 | |||
| Calcium (mg/dl) | 0.95 | 0.59–1.54 | 0.821 | |||
| Admission serum Mg (mg/dl) | ||||||
| <2 (n=50) | 0.88 | 0.42–1.85 | 0.742 | |||
| 2–2.5 (n=61) | 0.76 | 0.36–1.61 | 0.483 | |||
| >2.5 (n=20) | 0.42 | 0.22–1.71 | 0.356 | |||
mRS: modified Rankin scale; OR: odds ratio; ACA: anterior cerebral artery; MCA: middle cerebral artery; ICA: internal carotid artery; INR: international normalized ratio; Mg: magnesium.
DISCUSSION
To the best of our knowledge, this is the first prospective study to explore the association between serum Mg level on admission and the development of PHH in patients with aSAH. Our findings suggest that, while higher admission serum Mg level (>2.5 mg/dl) demonstrated a significant inverse association with PHH in univariate analysis, this relationship did not remain significant in multivariate analysis. Nevertheless, this trend may indicate a potential protective role of elevated serum Mg, warranting further investigation into the optimal therapeutic range for Mg in the acute management of aSAH.
The potential association between higher serum Mg level and lower incidence of PHH is not yet fully established, but there are several biological mechanisms and emerging evidence that suggest Mg might play a neuroprotective and anti-inflammatory role. PHH is believed to be, in part, a consequence of inflammatory responses within the subarachnoid space and arachnoid granulations, leading to fibrosis and impaired CSF absorption [29,30]. Pro-inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) play key roles in this process [31]. Magnesium has demonstrated anti-inflammatory properties, including the ability to suppress the release of IL-1β and TNF-α, potentially reducing fibrotic changes that contribute to CSF outflow obstruction [32]. Also, Mg acts as a calcium antagonist and promotes cerebral vasodilation [33]. In those ways, it can help protect microvasculature and reduce endothelial injury, limiting secondary damage from ischemia or vasospasm that can exacerbate PHH development [34,35]. Hypomagnesemia increases the risk of delirium in critically ill patients as well [36].
Although no prior clinical studies have directly examined the relationship between serum Mg level and PHH in adults, limited experimental and pediatric evidence suggests a potential mechanistic link. In a rodent model of kaolin-induced hydrocephalus, a study reported that Mg sulfate therapy conferred mild neuroprotective effects, including reduced astroglial activation and modest attenuation of ventricular enlargement, although it did not significantly prevent white matter damage or halt disease progression [37]. Another study described two infants with primary hypomagnesemia who developed external hydrocephalus, both of whom demonstrated clinical and radiological improvement following Mg correction, suggesting a possible role of Mg in CSF regulation [38]. Together, these findings imply that Mg may influence CSF dynamics and neuroinflammation, supporting the hypothesis that higher serum Mg level could have a protective effect against PHH. Unlike these limited case reports and experimental models, our study is the first clinical investigation to evaluate the association between admission serum Mg level and PHH in aSAH patients. While the inverse relationship between higher serum Mg level and PHH did not reach significance in multivariate analysis, the observed trend supports the biologic plausibility suggested by prior preclinical data and highlights the need for further prospective studies to determine whether Mg supplementation could modulate PHH risk in this population.
We also assessed the relationships between serum Mg level and other clinically relevant outcomes, including CV, chemical cerebral angioplasty, and DCI. In our cohort, there were no significant differences in these outcomes based on admission serum Mg level. This is in contrast to prior studies that reported a correlation between lower serum Mg level and increased incidence of CV or DCI [34,39-41]. One possible explanation is that Mg level was only assessed at admission in our study. Previous data suggest that serial Mg monitoring throughout the hospitalization period, particularly during the high-risk vasospasm window (days 3–14), can provide more clinically relevant insights [41]. Furthermore, active correction of hypomagnesemia during this critical period might influence these secondary complications, which our study did not address. Additionally, no significant association was observed between admission serum Mg level and other key outcomes, including length of ICU or hospital stay and 30-day functional status as assessed by the mRS. These findings imply that a single measurement of serum Mg at admission has limited prognostic utility for functional recovery in the early post-aSAH period. These findings underscore the limitations of relying solely on a single Mg measurement at admission and suggest that serum Mg level may need to be dynamically monitored and maintained within a therapeutic range to achieve meaningful clinical benefit. Therefore, there is a clear need to establish evidence-based protocols that define both the optimal timing and target range for serum Mg level in patients with aSAH, particularly in relation to secondary complications such as PHH, vasospasm, and DCI.
Consistent with previous studies, our results reaffirm that posterior circulation aneurysm rupture, higher Fisher grade, and higher Hunt and Hess grade are independent predictors of PHH [42-44]. Although the association between serum Mg >2.5 mg/dl and reduced PHH incidence did not retain significance in multivariate analysis, the observed trend supports the hypothesis that Mg influences CSF dynamics or neuroinflammatory processes, contributing to PHH pathophysiology. Future research should investigate whether maintaining serum Mg within an optimized range during the acute phase of aSAH can reduce the incidence of PHH. In terms of functional outcome, our findings demonstrate that 30-day mRS scores were significantly associated with posterior circulation aneurysm rupture, high Fisher grade, and high Hunt and Hess grade, which aligns with established predictors of poor neurologic recovery in aSAH populations. These results further emphasize the importance of initial hemorrhage burden and clinical severity on patient prognosis.
An additional exploratory finding in our analysis was that a serum Mg level exceeding 2.5 mg/dl demonstrated a significant inverse association with PHH incidence in univariate analysis, although this relationship did not persist in the adjusted multivariate model. This observation suggests that a modestly higher Mg concentration—above the conventional physiological range—is required to elicit measurable neuroprotective or anti-inflammatory effects in the setting of aSAH. The threshold of 2.5 mg/dl is consistent with therapeutic ranges proposed in previous neuroprotection and vasospasm-prevention studies [13,27,28], which targeted serum Mg levels between approximately 2.0 and 3.0 mg/dl to achieve cerebral vasodilation and attenuation of excitotoxic or inflammatory cascades. While our study was not designed to evaluate treatment thresholds, this exploratory trend suggests that maintaining serum Mg near or above 2.5 mg/dl could confer additional protection against secondary complications such as PHH. Although higher admission Mg concentrations (>2.5 mg/dl) demonstrated an inverse trend with PHH incidence in univariate analysis, this relationship did not retain statistical significance after adjustment for confounding clinical and radiologic variables (P=0.136). Therefore, the present findings should not be interpreted as evidence of a preventive or therapeutic effect of Mg. Rather, they suggest a possible pathophysiologic link that warrants further exploration.
Given the limitations of our single-time-point measurement and the observational nature of this study, these findings should be regarded as hypothesis-generating, warranting confirmation in future prospective or interventional trials incorporating serial Mg monitoring and controlled supplementation protocols to determine the optimal therapeutic target for neurovascular protection in aSAH.
This study has several limitations that should be acknowledged. First, although the data were collected prospectively, the relatively small sample size might limit the generalizability of our findings and reduce the statistical power to detect rare clinical outcomes or subtle associations. Second, the mean age of the study population was relatively high (59.45 years), and some patients might have had preexisting ventricular enlargement due to age-related brain atrophy. This could potentially introduce diagnostic bias in differentiating true PHH from chronic ventriculomegaly. Last, we clarify that Mg homeostasis can vary considerably during the first two weeks post-aSAH, especially within the critical vasospasm window (days 3–14). Consequently, a single baseline measurement might not accurately reflect sustained Mg exposure or the cumulative biological effects relevant to delayed complications such as PHH, CV, and DCI. Additionally, we added a potential confounding impact of institutional Mg replacement protocols for patients with hypomagnesemia (Mg <1.8 mg/dl). Because these correction protocols were applied as part of standard care, post-admission Mg levels may have differed from the initial measurement, potentially attenuating the observed associations between baseline Mg and later outcomes. We emphasize that future studies should incorporate serial Mg monitoring and standardized supplementation protocols to more accurately evaluate temporal and dose–response relationships between Mg dynamics and neurovascular complications.
In this prospective multicenter study, admission serum Mg level was not independently associated with the development of PHH in patients with aSAH. This study did not establish an independent association between admission serum Mg level and PHH following aSAH While a trend toward lower PHH incidence was observed at higher Mg levels (>2.5 mg/dl), the effect was not confirmed in multivariate analysis (P=0.136). Established predictors—including posterior circulation aneurysm, high Fisher grade, and high Hunt and Hess grade—remained dominant determinants of PHH risk. Further prospective and interventional studies are needed to validate these observations, clarify underlying mechanisms, and determine whether targeted Mg management can provide therapeutic benefit in the prevention of PHH after aSAH.
KEY MESSAGES
▪ This is the first prospective, multicenter study to examine the association between admission serum magnesium (Mg) level and post-hemorrhagic hydrocephalus (PHH) in patients with aneurysmal subarachnoid hemorrhage.
▪ While Mg ≥2.2 mg/dl was not independently associated with PHH or other major outcomes, Mg >2.5 mg/dl at admission showed a significant association with reduced PHH incidence in univariate analysis, suggesting a possible protective effect.
▪ Posterior circulation aneurysm, high Fisher grade, and high Hunt and Hess grade were identified as independent predictors of PHH, emphasizing the importance of hemorrhage severity and aneurysm characteristics over baseline Mg level in current risk stratification.
Footnotes
CONFLICT OF INTEREST
No potential conflict of interest relevant to this article was reported.
FUNDING
This research was supported by the Basic Science Research Program through the National Research Foundation of Korea, funded by the Ministry of Science and ICT (grant No. 2022R1A2C2011941, RS-2022-NR070396). Additional support was provided by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea (grant No. RS-2024-00438911), and by the Asan Institute for Life Sciences, Asan Medical Center (Seoul, Republic of Korea) under grant numbers 2025IP0031-1 and 2025IF0001-1 to Seungjoo Lee.
ACKNOWLEDGMENTS
None.
AUTHOR CONTRIBUTIONS
Conceptualization: MK, SL, HJ. Methodology: MK, SL, JHH, HJ, YC, YS, JHK, JB, AC, WP, JCP, JSA. Formal analysis: MK. Data curation: MK, SL, HJ, SBK, JHH, HJ, YC, YS, JHK, JB, AC, WP, JCP, JSA. Visualization: MK, SL, HJ, SBK. Project administration: MK, SL, HJ. Funding acquisition: MK, SL. Writing - original draft: MK. Writing - review & editing: MK, SL. All authors read and agreed to the published version of the manuscript.
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