This was a single-center, non-randomized, non-blinded, single-arm trial conducted at the First Affiliated Hospital of Xi’an Jiaotong University (registered on ClinicalTrials.gov with NCT 04358445 on March 16, 2020) and approved by the Ethics Committee of the hospital (approval NO. XJYFY-2019 N28). All participants provided informed consent to participate in the study and shared their clinical data. All study-related documents were securely stored in the research center, and research data were collected in a limited manner. The entire research process was supervised and monitored by the clinical research center of our hospital. The study followed the SPIRIT reporting guidelines (11).

We enrolled 71 eligible patients with aSAH between March 2020 and March 2022. The MACSF group comprised patients who received MACSF as an intraoperative irrigation fluid, while the NS group consisted of patients who underwent surgery with NS as the irrigation fluid and were enrolled before March 2020. Patients were required to meet the following inclusion criteria: (1) age between 18 and 80 years, (2) aSAH diagnosed by CTA or DSA, (3) admission within 72 h after symptom onset, (4) aneurysm clipped within 36 h after admission, and (5) provided written informed consent. To avoid the influence of the modified Rankin Scale (mRS) score before aSAH onset on the prognostic evaluation, we added additional exclusion criteria after registration. These exclusion criteria included severe craniocerebral trauma, mRS score > 2 before the onset of aSAH, or severe concomitant diseases.

MACSF was prepared by trained medical personnel from the Department of Pharmacy Intravenous Admixture Services (PIAS) on a laminar flow clean bench. MACSF consists of a finished intravenous medication consisting of 0.9% sodium chloride injection, sterilized water for injection, 10% potassium chloride injection, 25% magnesium sulfate injection, 5% sodium bicarbonate injection, and 5% glucose injection. Freshly prepared MACSF was promptly transferred to the operating room in a designated container through a specific channel. The entire procedure was strictly to aseptic principles. A comparison of the compositions and properties of NS, MACSF, other ACSFs, and physiological CSF is shown in Table 1 (9).

From March 2020 to March 2022, eligible patients were recruited into the MACSF group and received MACSF as an intraoperative irrigation fluid. From March 2019 to March 2020, patients with aSAH who used NS as an irrigation fluid in surgery met the aforementioned criteria, and had complete case data, were recruited in the NS group as historical controls. Patients in the MACSF group were irrigated with MACSF after opening the skull and cerebral dura mater, whereas patients in the NS group were irrigated with NS throughout the surgery. All the patients underwent surgery and were managed by the same neurosurgical team. The remaining treatments in both groups strictly adhered to the clinical guidelines.

Demographic data, including sex, age, smoking and alcohol consumption history, and medical history, were recorded in detail. Vital signs, Hunt-Hess Scale scores, modified Fisher grades, and World Federation of Neurosurgical Societies (WFNS) scores were evaluated by a neurologist at admission. Cranial computed tomography was performed on admission and the day after surgery. The blood flow velocity of the intracranial arteries was dynamically evaluated using TCD performed by an experienced technician to determine the occurrence and severity of CVS every alternate day until 14 days after surgery. The Acute Physiology and Chronic Health Evaluation II (APACHE II) score of 15 was used as the criteria for admission and discharge from the ICU. Prognosis was assessed 90 days after disease onset using the mRS (12–14). All TCD examinations and clinical assessments were performed free of charge.

Initially, we compared the mRS scores between the MACSF and NS groups at 1, 3, and 6 months after aSAH onset. Considering the representativeness and universality of the 90-day mRS evaluation in short-term prognosis, combined with the results of this study, we only chose 90 days as the final time point for prognostic evaluation. The prognosis was evaluated 90 days after ictus using the mRS, a 7-point scale ranging from 0 (no symptoms) to 6 (death). The mRS was dichotomized into favorable (mRS ≤ 2) and unfavorable (mRS > 2) prognosis (12, 15). Follow-up was conducted via telephone interviews by a trained neurologist blinded to the treatment assignments. If a patient was unavailable, a proxy was interviewed (16).

Ideally, cerebral angiography should be used as a diagnostic criterion for cerebral vasospasm. However, based on practical feasibility considerations, CVS was diagnosed using TCD in this study (17). The Lindeggard Index (LI) and mean blood flow velocity (MBF) are the main parameters used to evaluate the occurrence and severity of CVS. However, since some physiological or pathological conditions can also cause the increase of MBF without vasospasm, we eliminated the diagnostic criteria of “MBF of tested arteries is higher than 120 cm/s” to reduce the false-positive rate in diagnosing CVS. Therefore, the final criteria for diagnosing CVS by TCD are as follows (18, 19): (1) LI ≥ 3 or (2) Increase in MBF of tested arteries by more than 15 cm/s or 20% compared with the previous time. The severity of CVS is briefly described as follows (20–22): If the LI is greater than 6, severe CVS can be directly diagnosed. When LI ranges from 3 to 6, the severity of CVS can be classified by MBF as mild (120–139 cm/s), moderate (140–199 cm/s) or severe (≥200 cm/s).

The primary outcome measures included the incidence of CVS within 14 days after surgery and the mRS score at 90 days after onset. Secondary prognostic indicators included length of total hospital stay, length of intensive care unit (ICU) stay, and mortality within 90 days of onset. The safety index was defined as the incidence of hypermagnesemia, meningitis, or hydrocephalus within 14 days after surgery.

According to previous epidemiological investigations, the incidence of CVS in the NS group was 60% (1, 2). Owing to the lack of studies related to ACSF, we hypothesized that using MACSF for intraoperative irrigation during clipping would reduce the incidence of CVS by 50%. Based on this assumption, with a two-sided significance level of 0.05 and power of 90%, at least 27 patients were recruited into the MACSF group. Furthermore, 33 patients were required when the loss-to-follow-up rate was empirically assumed to be 20%. However, we set the ratio of the control group to the experimental group at more than 1:1.

All statistical analyses were performed using SPSS 23.0. Data are presented as mean ± standard deviation ( X ¯ ± s) for continuous symmetric distribution variables, median (M) and interquartile range (IQR) for continuous skewed distribution variables, and percentages for categorical variables. Group comparisons were performed using Analysis of Variance or independent Student’s t-test for continuous variables and chi-squared test for categorical variables. The Mann–Whitney U non-parametric test was used for variables that did not meet the conditions of the parameter test. p < 0.05 was considered statistically significant.

Data were recorded and stored using both paper forms and electronic databases. Supporting data for the findings of this study are available from the corresponding author upon request.

All patients completed 90-day follow-up examinations. The distribution of the mRS scores 90 days after onset is presented in Figure 1. A favorable outcome (mRS ≤ 2) at 90 days after onset was significantly more common in the MACSF group (82.35%) than in the NS group (59.46%; p = 0.035). There was also a significant difference in the mortality rate 90 days after onset between the two groups (8.82% vs. 27.03%; p = 0.048) (Table 3).

When analyzing the incidence of CVS, six patients were excluded because of TCD examinations less than 3 times (two cases in the MACSF group and four cases in the NS group). The overall incidence of CVS was 80.00%. There was no significant difference in the duration of anti-CVS drug use (days) between the MACSF (12.63 ± 6.54) and NS groups (14.15 ± 7.94; p = 0.402). The incidence and severity of CVS in the two groups are shown in Figure 2. Statistical analysis revealed that the incidence of CVS was significantly lower in the MACSF group (22 out of 32, 68.75%) than in the NS group (30 out of 33, 90.91%; p = 0.026), and the incidence of moderate-to-severe CVS was also significantly lower in the MACSF group (5 out of 32, 15.63%) than in the NS group (13 out of 33, 39.39%; p = 0.032).

Three and 10 patients in the MACSF and NS groups, respectively, were excluded because of voluntary discharge. As is shown in Figure 3, the median length of total hospital stay was significantly shorter in the MACSF group (M 15.00, IQR 11.00–22.00) than in the NS group (M 22.00, IQR 18.00–27.00; p = 0.008), and the median length of ICU stay was also significantly shorter in the MACSF group (M 2.00, IQR 0.00–5.00) than in the NS group (M 4.00, IQR 3.00–15.00; p = 0.018).

Serum Mg²⁺ and Ca²⁺ concentrations were measured on admission and within 24 h after surgery. In the MACSF group, the mean serum concentrations of Mg²⁺ and Ca²⁺ at admission were 0.93 ± 0.11 mmol/L and 2.29 ± 0.12 mmol/L, respectively. In the NS group, they were 0.96 ± 0.10 mmol/L and 2.33 ± 0.16 mmol/L. No significant differences were observed between the groups. The postoperative serum concentrations of Mg²⁺ and Ca²⁺ compared to those at admission were not significantly different in either the MACSF or NS groups.

The incidence of hypermagnesemia was not significantly different between the MACSF (0 out of 34, 0.00%) and NS groups (2 out of 37, 5.41%; p = 0.494). Additionally, the incidence of meningitis did not differ significantly between the two groups (MACSF group [15 out of 34, 44.12%] vs. NS group [16 out of 37, 43.24%]; p = 0.941). Furthermore, the difference in the incidence of hydrocephalus was not significant (MACSF group [3 out of 34, 8.82%] vs. NS group [2 out of 37, 5.41%]; p = 0.665) (Table 4).