Preventing effect of angiotensin-receptor-blocker for moderate to severe cerebral vasospasm after aneurysmal subarachnoid hemorrhage.

doi:10.21203/rs.3.rs-4932890/v1

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Preventing effect of angiotensin-receptor-blocker for moderate to severe cerebral vasospasm after aneurysmal subarachnoid hemorrhage.

https://doi.org/10.21203/rs.3.rs-4932890/v1

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Purpose

To verify the effectiveness of angiotensin-receptor blockers (ARBs) in preventing moderate to severe cerebral vasospasm, which may influence patient outcomes in cases of subarachnoid hemorrhage resulting from aneurysmal rupture.

Methods

Between 2016 and 2020, we treated a total of 210 patients. We obtained the clinical and radiological characteristics of patients through medical records and divided them into two groups: those who were administered ARBs (ARB group) and those who were not (no ARB group).

Results

One hundred eighty-one patients enrolled in this study. ARB group were 29 and no ARB group were 152. The overall incidence of moderate to severe vasospasm was 33.7%. The incidence of moderate to severe vasospasm in each group was 13.8% (4 patients) and 37.5% (57 patients), respectively. The independent risk factors for moderate to severe vasospasm included Fisher grade (III-IV) with an odds ratio (OR) of 2.732 (95% confidence interval [CI]: 1.343–5.560; P = 0.006), older age (OR = 0.963; 95% CI: 0.938–0.989; P = 0.006), and ARB administration (OR = 0.246; 95% CI: 0.079–0.771; P = 0.016).

Conclusions

Despite the potential adverse impacts associated with hypotension, the administration of ARBs may provide therapeutic benefits in preventing moderate to severe vasospasm. Age and volume of hemorrhage should be taken into consideration because of their association with the development of moderate to severe cerebral vasospasm.

Aneurysm

subarachnoid hemorrhage

angiotensin-receptor blocker

vasospasm

The incidence of cerebral vasospasm following subarachnoid hemorrhage due to aneurysmal rupture has been variably reported depending on the diagnostic methods and criteria used [10, 18, 20]. Angiographic vasospasm occurs up to 90% of aneurysmal subarachnoid hemorrhage (SAH) patients [20]. However, the prognosis can vary with the severity of angiographic vasospasm. It has been reported that the occurrence of delayed cerebral ischemia (DCI) or cerebral infarction varies depending on the grade of angiographic vasospasm. Moderate to severe cerebral vasospasm is associated with symptomatic vasospasm, DCI, and infarction, which can be related to neurological outcomes or prognosis [7, 16].

Recent study has shown that oral administration of nimodipine, a calcium channel blocker can decrease DCI, subsequently enhancing neurological outcomes without major side effects and is widely used for the prevention and treatment of cerebral vasospasm following aneurysmal SAH (Class I; Level of Evidence A). However, the mechanisms of its effect remain unclear [3]. Therefore, research into the mechanisms of cerebral vasospasm and more effective prevention and treatment strategies are being conducted. Several pathophysiological mechanisms of cerebral vasospasm, including prolonged arterial contraction, structural changes in the arterial wall, breakdown of blood products, and inflammatory response have been reported [18]. Up or down regulations of the renin–angiotensin–aldosterone (RAA) system and the endothelin (ET) system, involved in the pathophysiological mechanisms, can be considered important mechanisms in the development of cerebral vasospasm [1, 13, 15, 32]. Angiotensin-receptor blockers (ARBs), a type of antihypertensive drug, are commonly used in conjunction with calcium channel blockers (CCBs) for patients with hypertension and have been reported to be effective in preventing cerebral vasospasm through several animal experimental and clinical studies [30]. The purpose of this study is to verify the effectiveness of ARBs in preventing moderate to severe cerebral vasospasm, which may influence patient outcomes in cases of subarachnoid hemorrhage resulting from aneurysmal rupture.

Patient collection and baseline characteristics

The present study was approved by the institutional review board, which waived the need for informed consent.

Between 2016 and 2023, we conducted a retrospective analysis of the medical records of patients treated at our hospital for subarachnoid hemorrhage resulting from ruptured cerebral aneurysms. Excluded from the study cohort were patients who did not receive any interventions, those who succumbed within a week of treatment—thus precluding the assessment of cerebral vasospasm onset or progression, individuals for whom a comprehensive evaluation for cerebral vasospasm was not performed, and patients with cerebrovascular anomalies like Moyamoya disease, which rendered the assessment of cerebral vasospasm infeasible.

We obtained the clinical and radiological characteristics of patients through medical records and divided them into two groups: those who were administered ARBs (ARB group) and those who were not (no ARB group). The characteristics analyzed included age, sex, smoking history, hypertension, initial Glasgow Coma Scale (GCS) score, magnesium therapy, statin use, Hunt-Hess grade, Fisher grade, location of the aneurysm, M1/intenal carotid artery (ICA) ratio and M1 diameter (measured at admission and on day 7 post-treatment), mean blood velocity and peak blood velocity by transcranial Doppler (TCD) ultrasonography (measured at admission, on day 7 and 10 days post-treatment), presence or absence of cerebral vasospasm, performing angioplasty, modified Rankin Scale (mRS) score at admission and discharge, and treatment modalities (clipping and coil embolization).

Patient management

After treatment, all patients were admitted to the intensive care unit for management. Postoperative systolic blood pressure was maintained within the range of 120–150 mmHg. Nimodipine was administered intravenously at a dosage of 20 mg/kg/h. Once the fasting period was concluded, the medication was switched to oral administration and continued for at least two weeks. Efforts were made to maintain a normal body temperature. To monitor for the occurrence of hydrocephalus and the status of bleeding, brain computed tomography (CT) scans were conducted every 7 days. On the seventh day following the hemorrhage, either magnetic resonance angiography (MRA) with time of flight (TOF) image or transfemoral cerebral angiography (TFCA) was performed to assess the presence of vasospasm and the state of treatment. An initial TCD ultrasonography was conducted within 3 days after the subarachnoid hemorrhage to evaluate the vascular condition, and TCD ultrasonography was performed daily for two weeks, unless there were special events, to monitor the condition of the vessels. In cases of moderate or severe cerebral vasospasm or symptomatic vasospasm, chemical angioplasty was performed.

Definition of moderate to severe vasospasm and DCI from cerebral vasospasm.

All patients underwent a preoperative evaluation with TFCA to assess the initial state of the vessels. Baseline values measured by TCD ultrasonography were established within 3 days, and to track vascular status, TCD ultrasonography was performed over the course of 2 weeks post-treatment, with both the peak velocity and mean velocity of the middle cerebral artery (MCA) being monitored. Occurrence of cerebral vasospasm was investigated during two periods: around seventh day the maximum values were observed, and around tenth day the maximum values were noted. Moderate to severe vasospasm was identified based on a 150% increase from the baseline mean blood flow velocity or a 200% increase from the peak blood flow velocity measured by TCD ultrasonography. The M1/ICA ratio and degree of M1 segment stenosis calculated from an MRA Time-of-Flight image or TFCA performed at Seventh day post-treatment was used to determine; a vasospasm was defined as moderate to severe if there was a reduction of more than 33% in the ratio or if there was more than 33% stenosis in the M1 segment itself. DCI is defined as: 1) symptomatic vasospasm, which includes clinical deterioration, a new focal deficit, decrease in level of consciousness, or both; and 2) infarction attributable to vasospasm, indicated by a new infarct visible on CT and/or MRI scans that was not present on the admission or immediate postoperative scan.

Statistical analysis

All statistical analyses were conducted using IBM SPSS Statistics version 22.0 (IBM Corp., Armonk, New York, USA). Continuous variables were reported as mean ± standard deviation. The Chi-square test was utilized for categorical variables. Results were deemed statistically significant if the P-value was less than 0.05. A univariate analysis was carried out to determine the association between risk factors and the occurrence of moderate to severe vasospasm. Following this, a multivariate logistic regression analysis was performed on factors that achieved a P-value of less than 0.2 in the univariate analysis, to identify independent risk factors for moderate to severe vasospasm. A factor was considered an independent risk factor for moderate to severe vasospasm if it had a P-value of less than 0.05 in the multivariate analysis. The GPower 3.1 software is a commonly used power analysis program in the social sciences, utilized to calculate the effect size or the required sample size in statistical tests [14]. For a power analysis using linear multiple regression analysis, with an effect size of 0.15, an alpha of 0.05, a power of 0.80, and 11 predictors, the minimum required sample size is 123. Our sample size is 181, which is greater than the minimum sample size required for the power analysis. This meets Cohen's (1988) standard of a power level of 0.8 or higher, indicating that the results of our study are statistically significant.

Two hundred-ten patients were treated in our institution due to aneurysmal subarachnoid hemorrhage from 2016 to 2020. Among them, 11 patients were expired within a week due to initial poor clinical condition. Since one patient had moyamoya disease, we could not confirm whether the vasospasm was presented during hospital course. There were 17 patients who could not estimate vascular condition according to poor temporal window leading a failure measuring initial or following values measured by TCD ultrasonography or absence of following radiologic evaluation. Finally, 181 patients enrolled in this study (Fig. 1).

Baseline characteristics.

Of 181 patients enrolled this study, 29 were administrated ARB during hospital course (ARB group) and the other 152 did not (non-ARB group). In patient data, there were no statistical differences between ARB and non-ARB group except for statin use. In radiologic data, only proportion of higher Fisher grade at admission was greater in ARB group than non-ARB group. Although the Fisher grade at admission was greater than in ARB group, clinical outcome according to the mRS score at discharge were better in non-ARB group than ARB group (Table 1). In ARB group, one patient, who had a preoperative mRS score 2, died from rebleeding of coiled vertebral artery dissection aneurysm during rehabilitation. And clinical outcome of two patients were deteriorated according to unexplained increase of postoperative hematoma and procedure related complication (cerebral infarction due to coil stretch).

Table 1

baseline characteristics
Variables	No ARB (n = 152)	ARB (n = 29)	P-value
Age (mean ± SD), years	58.19 ± 13.136	63.31 ± 11.430	0.051
Sex (female), n (%)	96 (63.2)	19 (65.5)	0.809
Smoking, n (%)	48 (31.6)	8 (27.6)	0.670
HTN, n (%)	25 (16.4)	29 (100)	0.941
Initial GCS < 8	17 (11.2)	7 (24.1)	0.059
Treated with magnesium, n (%)	147 (96.7)	29 (100.0)	1.000
Statin use, n (%)	23 (15.1)	9 (31.0)	0.040
HH grade (≥ 3), n (%)	67 (44.1)	13 (44.8)	0.941
Fisher grade (≥ 3), n (%)	85 (55.9)	22 (75.9)	0.045
Location of aneurysm, n (%)			0.079
Ant. Circulation	145 (95.4)	25 (86.2)
Post. Circulation	7 (4.6)	4 (13.8)
M1/ICA ratio
Initial	0.547 ± 0.110	0.524 ± 0.115	0.283
At POD # 7	0.492 ± .0.129	0.485 ± 0.120	0.800
TCD Mean Velocity
Initial	41.578 ± 27.611	39.43 ± 26.536	0.685
At POD #7	71.148 ± 37.915	63.198 ± 23.829	0.308
At POD #10	75.854 ± 38.015	61.769 ± 27.525	0.102
TCD Peak velocity
Initial	62.155 ± 44.418	60.596 ± 44.866	0.856
At POD #7	105.089 ± 55.234	90.986 ± 37.729	0.253
At POD #10	106.526 ± 53.002	88.299 ± 41.728	0.132
Vasospasm, n (%)	57 (37.5)	4 (13.8)	0.013
Angioplasty, n (%)	25 (16.4)	3(10.3)	0.577
DCI, n (%)	19 (12.5)	0 (0)	0.047
Pre mRS (≤ 2), n (%)	83 (54.6)	14 (48.3)	0.858
mRS at discharge (≤ 2), n (%)	117 (77.0)	16 (55.2)	0.015
Surgical clipping, n (%)	15 (9.9)	1 (3.4)	0.475
Coil embolization, n (%)	137 (90.1)	28 (96.6)	0.475
ARB angiotensin-receptor blocker, SD standard deviation, HTN hypertension, GCS Glasgow Coma Scale, HH hunt-Hess, ant. anterior, post. Posterior, ICA internal carotid artery, POD postoperative day, TCD transcranial Doppler ultrasonography, DCI delayed cerebral ischemia, mRS modified Rankin Scale.

Incidence of moderate to severe vasospasm.

Overall incidence of moderate to severe vasospasm was 33.7%. Fifty-seven patients (37.5%) suffered vasospasm in non-ARB group. Among them, intra-arterial chemical angioplasty was performed in 25 (16.4%) patients. Four patients (13.8%) suffered vasospasm in ARB group. And three patients (10.3%) were treated with angioplasty. The difference in the incidence of moderate to severe vasospasm between the two groups was statistically significant. DCI occurred in 19 patients (12.5%) in the non-ARB group and did not occur in the ARB group. This difference was statistically significant (Table 1).

Among 181 patients, 61 patients suffered vasospasm during hospital course. There were no statistical differences between non-vasospasm and vasospasm group for initial M1/ICA ratio, initial mean blood flow velocity, and initial peak blood flow velocity measured by TCD ultrasonography. However, M1/ICA ratio, mean blood flow velocity and peak blood flow velocity at 7 and 10 days after operation were statistically different (Table 2).

Table 2

Differences of M1/ICA ratio and TCD velocities between non-vasospasm and vasospasm groups.
Variables	Non-vasospasm (n = 120)	Vasospasm (n = 61)	P-value
M1/ICA ratio (mean ± SD)
Initial	0.546 ± 0.0963	0.539 ± 0.116	0.655
At POD # 7	0.525 ± .0.121	0.302 ± 0.154	0.000
TCD Mean Velocity (mean ± SD)
Initial	51.848 ± 18.974	50.276 ± 23.110	0.680
At POD #7	58.286 ± 18.153	187.477 ± 46.699	0.000
At POD #10	58.672 ± 21.888	191.572 ± 43.621	0.000
TCD Peak velocity (mean ± SD)
Initial	79.315 ± 34.577	70.563 ± 37.853	0.185
At POD #7	89.466 ± 37.760	222.321 ± 67.201	0.002
At POD #10	86.466 ± 37.760	225.094 ± 61.352	0.000
ICA internal carotid artery, SD standard deviation, POD postoperative day, TCD transcranial Doppler ultrasonography.

Risk factors for moderate to severe vasospasm.

Univariate analysis showed that older age and ARB administration associated with vasospasm (P = 0.011 and P = 0.019). Multiple logistic regression analysis, using factors associated with vasospasm, showed that Fisher grade (III-IV) (OR = 2.732; 95%CI = 1.343–5.560; P = 0.006) independently increased the risk of vasospasm. And older age (odds ratio [OR] = 0.963; 95% CI = 0.938–0.989; P = 0.006) and ARB administration (OR = 0.246; 95%CI = 0.079–0.771; P = 0.016) independently decreased the risk for vasospasm (Table 3).

Table 3

Univariate and multivariate analyses of the risk factors for cerebral vasospasm.
Factors	Univariate	P-value	Multivariate	P-Value
	Odd ratio (95% CI)		Odd ratio (95% CI)
Age	0.968 (0.944–0.993)	0.011	0.963 (0.938–0.989)	0.006
Sex	0.923 (0.487–1.747)	0.805
Smoking	1.784 (0.928–3.430)	0.083	1.552 (0.773–3.116)	0.217
HTN	0.522 (0.254–1.072)	0.076	1.322 (0.473–3.699)	0.595
Magnesium	0.756 (0.123–4.651)	0.763
Statin use	0.873 (0.384–1.984)	0.747
ARB	0.267 (0.088–0.805)	0.019	0.246 (0.079–0.771)	0.016
Additional CCB	0.394 (0.153–1.018)	0.054	0.515 (0.189–1.405)	0.195
Fisher grade (III-IV)	1.870 (0.976–3.583)	0.059	2.732 (1.343–5.560)	0.006
HH grade	1.497 (0.805–2.783)	0.202
Tx. Modality (clip)	1.130 (0.374–3.413)	0.828
HTN hypertension, ARB angiotensin-receptor-blocker, CCB calcium-channel blocker, HH Hunt-Hess, Tx. treatment.

Case illustration

A fifty-year-old female patient with a severe headache visited our emergency room. She had hypertension and had been taking a calcium channel blocker. Initial brain CT and CT angiography revealed an aneurysmal subarachnoid hemorrhage (Hunt-Hess grade:2 and modified Fisher grade:3) due to ruptured left MCA bifurcation aneurysm (Fig. 2A). Emergent TFCA was performed, revealing the aneurysm to have a maximal size of 6.21mm and a neck size of 3.21mm. Emergent coil embolization using double microcatheters technique was successfully performed. The ruptured aneurysm occluded completely without procedural complications (Fig. 2B). We inserted a lumbar drain to treat mild hydrocephalus, and the patient was admitted to the ICU for intracranial pressure control and vasospasm prevention. Initial TCD ultrasonography was conducted the day after coil embolization (Fig. 2C and 2D). TCD ultrasonography monitoring continued for 2 weeks to detect vasospasm. The blood flow velocity of left MCA was increased slowly. However, the patient experienced no clinical symptoms except for a headache. Seven days after coil embolization, she complained of severe headache and left-side visual disturbance. Immediate follow-up TCD ultrasonography revealed severe vasospasm, the mean blood flow velocity having doubled (Fig. 2E and 2F). TFCA was conducted to confirm and treat the vasospasm. TFCA revealed severe vasospasm in the cerebral vessels of the left hemisphere (Fig. 2G, the white arrow and circle denote regions of decreased blood flow attributable to vasospasm). Intra-arterial nimodipine angioplasty was performed for 4 days, after which the vasospasm and her symptoms gradually improved (Fig. 2H, 2I, 2J, the white arrow and circle highlight areas of restored blood flow following intra-arterial nimodipine angioplasty). She was discharged at 3 weeks after coil embolization without neurologic symptoms. Her mRS score at 6months post-embolization was 0.

Diagnosic modalities and criteria of cerebral vasospasm

This study diagnosed vasospasm using TCD ultrasonography and angiographic imaging, including MRA with TOF image and TFCA. Various methods are employed to diagnose cerebral vasospasm, among which TCD ultrasonography, angiographic imaging including MRA, CT Angiography, TFCA, and dynamic perfusion CT are commonly utilized to date [2, 4, 7, 9, 12, 16, 21, 23, 27]. TCD ultrasonography, being non-invasive and repeatable, is considered a useful tool for the early detection of vasospasm when considering its accuracy [2]. Recent studies indicate that measuring the blood flow velocity in the Middle Cerebral Artery (MCA) via TCD ultrasonography is particularly effective in diagnosing vasospasm [21, 23]. In study evaluating the accuracy of TCD ultrasonography, it was reported that the mean blood flow velocity in the MCA exceeding 120 cm/sec yielded a negative predictive value of 87%, while velocities greater than 200 cm/sec demonstrated a positive predictive value of 87% [4]. Li et al. reported no significant difference in the incidence of vasospasm measured through both TCD ultrasonography and TFCA, with incidences of 87.78% and 83.33%, respectively [22].

In this study, the diagnostic criteria for moderate to severe vasospasm were based on a 150% increase from the baseline mean blood flow velocity or a 200% increase from the baseline peak blood flow velocity measured by TCD ultrasonography, and more than a 33% constriction of the MCA as observed in angiographic image studies using MRA and TFCA. Diagnostic criteria for vasospasm vary among studies, but research employing angiographic imaging has diagnosed moderate degree vasospasm with a 25–33% or more reduction in lumen diameter.[2, 7, 16, 25] Studies using TCD ultrasonography have suspected vasospasm when the mean blood flow velocity exceeded 120 cm/sec, diagnosing moderate degree vasospasm or higher when blood flow velocities were between 140–150 cm/sec or above [21, 22]. The mean blood flow velocity in TCD ultrasonography is calculated based on the formula MFV = (PSV + 2×EDV) / 3 (cm/s) [15], with maximum blood flow velocities of over 200 cm/sec reported to be associated with cerebral ischemia and infarction [5]. Based on these findings, our study diagnosed moderate to severe vasospasm, which we consider to be substantiated by sufficient evidence.

Incidence and risk factors of Cerebral vasospasm

Cerebral vasospasm incidence is significantly elevated between 4–6 days post-subarachnoid hemorrhage (SAH) compared to the 1–3 days following the event, peaks at 7–9 days, and then diminishes at 10–12 days post-event [22]. Accordingly, this study analyzed the M1/ ICA ratio and M1 diameter upon admission and on the 7th day post-treatment, as well as blood flow velocities measured by TCD ultrasonography upon admission, and on the 7th and 10th days post-treatment. Recent research suggests that cerebral vasospasm occurs in up to 90% of cases, with the incidence of moderate to severe vasospasm reported between 31%-45% [7, 8, 16, 22, 24, 25]. These figures align closely with our study's findings.

Reasonable risk factors for cerebral vasospasm include age, history of cigarette smoking, the severity of SAH clot observed on CT, hypertension, and the clinical grade upon admission [20]. In our study on moderate to severe vasospasm, independent risk factors identified were age, Fisher grade (indicating the severity of the SAH clot on CT), and the administration of ARBs.

Alterations in the cerebral artery wall can be induced by age, lifestyle habits, and underlying health conditions. As age advances and with continuous smoking, alongside conditions like atherosclerosis and hypertension, vascular wall degeneration may occur, leading to changes in vascular wall compliance. Therefore, vascular wall degeneration can influence the occurrence of cerebral vasospasm and its treatment outcomes. Vasoconstriction risk may decrease in the presence of vascular degeneration, and the response to antivasospasm agents may also diminish in cases of vasospasm [20, 26, 29]. Our study uniquely found that age independently influenced the occurrence of vasospasm, with an increased age correlating with a reduced risk of moderate to severe cerebral vasospasm.

The severity of the SAH clot on CT is known in numerous studies as the most influential independent risk factor [17, 18, 20, 26]. Cerebral vasospasm can be initiated and exacerbated by spasmogenic substances, one of the breakdown products of extravasated blood post-SAH [18]. In cases with a high Fisher grade (III-IV), indicating a substantial SAH clot, the risk of developing cerebral vasospasm increases, even with the use of antivasospasm agents, as does the risk for moderate to severe cerebral vasospasm.

In the RAA system and the ET system, angiotensin-II-type-1-receptor and endothelin-1 are involved in mediating vasoconstriction, whereas angiotensin-II-type-2-receptor is implicated in facilitating vasorelaxation. In the pathophysiological condition of SAH, elevated Angiotensin-II-type-1-receptors can increase the risk of a long-lasting contraction induced by endothelin-1. ARBs, by intervening in this process, can suppress vasoconstriction, thus potentially preventing or aiding in the treatment of cerebral vasospasm [15, 19, 30–32]. Inflammatory response is one of the pathophysiology of cerebral vasospasm. The PGF2α/prostacyclin/thromboxane system appears to play a role in the complex mechanisms leading to cerebral inflammation and vasospasm following subarachnoid hemorrhage (SAH), indicating its significance within the multifaceted process [6, 28]. ARB, also seem to have positive effect for not only mitigating this inflammatory response but also in its prevention or reduction [11, 31]. Despite ARB being antihypertensive agents with the effect of lowering systemic blood pressures, their use in the treatment of patients with aneurysmal SAH may have adverse effects. Nevertheless, their involvement in the modulation of vasoconstriction and inflammation warrants further exploration for potential therapeutic benefits in this context. Our study verified a statistically significant lower incidence of moderate to severe cerebral vasospasm in patients administered ARBs, confirming that ARB intake is an independent factor in reducing the risk of vasospasm.

Limitation of the study

This study has several limitations. First, this study may exhibit potential selection bias due to its retrospective nature. The patients included were treated at a single institution, employing a nearly identical surgical procedure. However, the values measured by TCD ultrasonography during the hospital course could be influenced by the patient's condition, including hyperemia and unstable vital status. Second, the angiographic evaluation conducted on the seventh day of hospitalization may not have been entirely accurate in some respects due to the lack of uniformity in the method used, as it was performed using either MRA or TFCA, rather than a single standardized approach. Third, while the preventive effect of ARBs on moderate to severe vasospasm was observed, the group not administered ARBs surprisingly showed better clinical outcomes. This discrepancy could be attributed to the relatively smaller size of the ARB group, in which a higher rate of unexpected complications during the treatment process might have skewed the accurate assessment of clinical outcomes, as represented by the mRS score.

This study highlights that, in the initial management of SAH patients, particular attention should be given to age and volume of hemorrhage due to their association with the development of moderate to severe cerebral vasospasm. Despite the potential adverse impacts associated with hypotension, the administration of ARBs may offer therapeutic benefits in treating SAH patients, owing to their capacity to prevent moderate to severe cerebral vasospasm through diverse mechanisms.

ARB

Angiotensin-receptor blocker

CCB

calcium channel blocker

computed tomography

DCI

delayed cerebral ischemia

endothelin

GCS

Glasgow Coma Scale

ICA

internal carotid artery

MCA

middle cerebral artery

MRA

magnetic resonance angiography

mRS

modified Rankin Scale

RAA

renin–angiotensin–aldosterone

SAH

subarachnoid hemorrhage

TCD

transcranial Doppler

TFCA

transfemoral cerebral angiography

Ethical approval: The study was approved by our institutional review board (CNUSH-IRB 2021-01-001)

Acknowledgments: None

Competing Interests and Funding: The authors declare no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

submissions that do not include relevant declarations will be returned as incomplete.

Disclosures: None

Data availability: Available upon reasonable request from the corresponding author.

Code availability: Not applicable.

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Preventing effect of angiotensin-receptor-blocker for moderate to severe cerebral vasospasm after aneurysmal subarachnoid hemorrhage.

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