Nimodipine reduces delayed cerebral vasospasm after intracranial tumour surgery: A Retrospective Study

Cerebral vasospasm (CVS) is a frequent and serious neurosurgical complication, without sufficient therapy. This retrospective study was performed to analyze if nimodipine can improve prognosis and reduce ischaemia secondary to delayed CVS after intracranial tumour surgery. A retrospective review was performed over the years 2011 to 2012 for patients with an anterior cranial fossa tumour and underwent intracranial tumour surgery. The surgical field was soaked with nimodipine solution or normal saline. Transcranial Doppler ultrasonography was used to measure velocity in the middle cerebral artery (MCA) and the distal extracranial internal carotid artery (eICA). Follow‐up was performed using the Glasgow Outcome Scale (GOS) after discharge. There were 94 patients that met the inclusion criteria. They included 50 males and 44 females, with a mean age of 49.6 years. In the nimodipine group, CVS occurred in 13 patients; 9 patients had CVS between 4 and 7 days, and 4 had CVS between 8 and 14 days. In the normal saline group, 19 patients had CVS, 3 presented with CVS within 3 days, 11 between 4–7 days and 5 between 8–14 days. A significant difference in the occurrence of CVS was observed between the two groups. Preoperative and postoperative the MCA velocities were compared, revealing a significant change in the normal saline group but not in the nimodipine group. Nimodipine markedly improves prognosis and significantly reduces ischaemia secondary to delayed CVS after intracranial tumour surgery, as well as the risks of mortality and morbidity.

regulate vasoconstriction. 9 Nimodipine is considered the first choice for the prevention of CVS after SAH and has been approved in some countries. 10 This study retrospectively analyzed the clinical data of 94 patients. Here, we report the effects of nimodipine on CVS after intracranial tumour surgery and the associated mechanisms.

| General information
A total of 94 patients were included in the study: 50 patients were male, and 44 were female. Patients ranged in age from 18 to 80 years, and the average age of these patients was 49.6 years. On the day after surgery, intracranial CT examination revealed no haematoma, ischaemia, and contusion or lacerated lesions in the brain.
No significant difference in the modified Fisher scale scores was found when five grades were compared separately between Group A and Group B (p > 0.05, Table 2).
In Group A, CVS was found in 13 patients, and none occurred during the first 3 days after the operation. Nine patients had CVS between 4 and 7 days, and four had CVS between 8 and 14 days.
TDU examination of Group A prior to surgery indicated that the MCA velocity was no more than 120 cm/s ( Figure 1A). MCA velocity was slightly higher in Group A after surgery than that prior to surgery; however, it was no more than 120 cm/s ( Figure 1B). In contrast, in Group B, 19 patients had CVS, three presented with CVS within 3 days, 11 within 4-7 days and five between 8 and 14 days. TDU examination of Group B prior to surgery indicated that the MCA velocity was no more than 120 cm/s ( Figure 2A). TDU examination of Group B after surgery revealed that the MCA velocity was more than 120 cm/s ( Figure 2B). A significant difference in the occurrence of CVS was observed between the two groups (p < 0.05).

| Comparison of the MCA velocity prior to surgery and after surgery in Group A and Group B
There was a significant change between preoperative and postoperative MCA velocity in Group B (Bonferroni correction at p < 0.01, Table 3); however, no significant changes were observed between preoperative and postoperative the MCA velocity in Group A.

| Comparison of prognoses between Group A and Group B
Grade V indicated a good prognosis, and grades I, II and III were defined as a poor prognosis. 11 A follow-up was performed patients were grade IV and 10 patients were grade V. (Table 4).
In Group A, 43 patients had a good prognosis, and 9 had a poor prognosis. In Group B, 27 had a good prognosis and 15 had a poor prognosis (p < 0.05; Table 4). The prognosis of group A was also better than that of group B at the 6-month postoperative followup (p < 0.05; Table 4).

| DISCUSS ION
In the present study, we showed that administration of nimodipine during and after surgery can effectively prevent the occurrence of delayed CVS and improves the prognosis of CVS. After resecting was soaked into the surgical field for 10 minutes, and then nimodipine was continuously infused via a micropump. CVS is caused by an extreme contraction of the arteries and tense vascular smooth muscle. 12 The mechanisms underlying CVS remain unclear; it may be multifactorial and involve a complicated pathological process.
Potential causes of CVS are as follows: 1, mechanical stimulation lead to the blood flowing into the subarachnoid space and subsequent occurrence of CVS occurs; 13 2, vascular wall injury caused by compression of the vascular wall and vascular wall malnutrition; 14  vessels caused by vasoactive substances; 16 5, increased intracranial pressure, the overdose of dehydration drugs and insufficient supply of blood volume; 17 and 6, inflammation and immune reactions of blood vessel walls. 5,18,19 The common final pathway arising from all the above factors stated is an increase in calcium influx, and the release of calcium ions from intracellular calcium stores, leading to an overload of free calcium in the cytosol. 20 When a critical constriction concentration is reached following the opening of calcium channels, extracellular calcium enters the cells and is released from the calcium stores, leading to an increase in the concentration of free calcium in the cytosol; thus, vasospasm occurs. 21 Therefore, calcium overload is believed to be the most important phenomenon during the generation of vasospasm.
There are two types of calcium channels, voltage-dependent and receptor-operated. 22 The former is located in the cell membrane of heterologous multimeric transmembrane proteins. These channels are activated at depolarized membrane potentials and are the source of the "voltage-dependent" epithet. Activation of particular voltage-dependent calcium channels (VDCCs) allows calcium (Ca 2 + ions) to rush into the cell, which depending on the cell type, results in activation of calcium-sensitive potassium channels, muscular contraction, excitation of neurons, upregulation of gene expression, or release of hormones or neurotransmitters, 23 which in turn leads to the development of arterial tone and vasoconstriction. 24 The opening of this type of channel is related to voltage and occurs due to the depolarization of the smooth muscle cell membrane after the channel is activated and excited. 25 The opening of the latter channel is caused by the stimulation of receptors of the cell membrane by certain substances, such as 5-hydroxytryptamine (5-HT) and adrenalin. It has been shown that nimodipine significantly reduced symptoms caused by secondary ischaemia after SAH. 28 Currently, nimodipine is considered as the first choice for the prevention of CVS after SAH. Nimodipine is a second-generation dihydrotestosterone pyridine class calcium antagonist with the highest lipid solubility. 29 High lipophilicity of nimodipine facilitates its movement through the blood-brain barrier, and nimodipine is also highly selective for vascular smooth muscle due to the dihydrotestosterone pyridine ring. 30  In addition, nimodipine can significantly improve cerebral blood circulation after brain injury, preventing secondary brain damage and promoting brain function recovery. Nimodipine lavage can effectively improve the prognosis of secondary cerebral vasospasm after SAH. [33][34][35] Our findings revealed that infusion and oral intake of nimodipine after nimodipine lavage during surgery are effective in the prevention of the development of delayed CVS after intracranial tumour craniotomy. The incidence of CVS in the nimodipine group (25%) was significantly lower than that in the normal saline group (45%). In addition, the MCA velocity was significantly lower in the nimodipine group than in the normal saline group after surgery. Prognoses appeared to be remarkably improved in the nimodipine group.
To date, regarding the diagnosis of CVS after intracranial tumour craniotomy, digital subtraction angiography (DSA) and TDU are believed to be effective CVS detection methods. DSA had been a gold standard for the diagnosis of CVS. 36 However, if the blood vessel is too small to be detected by DSA, misdiagnosis of CVS might occur. 37 Because DSA is an invasive examination and could produce risks such as iatrogenic stroke and rupture of the blood vessels, the application of DSA is limited for the detection of CVS. 38,39 Additionally, TDU has the advantage of being economical, noninvasive, real-time, and repeatable, offering continuous monitoring with high sensitivity and specificity; thus, TDU has become the first-line procedure in the detection of CVS. 40 In this study, blood flow velocity prior to CVS was measured as baseline velocity and was compared with that after surgery at different time points. Furthermore, comparing changes in blood flow velocity in the MCA allows the objective detection of CVS. However, different operators of TDU might obtain different results due to unavoidable subjective factors such as the variable angle of the ultrasound probe that was used. In this study, the same doctor performed TDU examinations in all patients, and the experiment was singleblinded to make the examination data reliable. Our results showed that TDU can be effectively used for the diagnosis of CVS after intracranial tumour surgery. If the flow velocity in the MCA is more than 120 cm/s, and Lindegaard index is more than 3, a diagnosis of CVS is confirmed.
We showed that the application of nimodipine during and after surgery can effectively prevent the occurrence of delayed CVS and improve the prognosis of CVS. Notably, the retrospective cases in our study were limited. If larger sample sizes are available, the preventive effect of nimodipine on CVS can be studied more clearly.

| MATERIAL AND ME THODS
Patients with anterior cranial fossa (ACF) tumours who were treated in our hospital from 2011 to 2012 were included in this study, and the prognosis of the included patients was followed up after discharge. Inclusion criteria were as follows: confirmed diagnosis of an ACF tumour; consent to undergo intracranial tumour surgery; ≥18 years and ≤80 years. Exclusion criteria were as follows: severe

| Modified Fisher scale
Brain CT was performed on the day of surgery. Classification of the amount and distribution of SAH was based on the modified Fisher scale. 43

| Prognosis
Follow-up was performed using the GOS three months after discharge. 44

| Statistical analyses
Demographic factors, including age and sex, among the two groups and clinical characteristics, were evaluated using SPSS 23.0. The Student's t test was used to analyze any statistical difference in the Fisher classification score, GOS between groups A and B, as well as postoperative MCA velocity compared with preoperative MCA velocity in each group. The chi-square test was used for comparing the rate of CVS and no CVS between Group A and Group B. Statistical significance levels were set to a p-value, 0.05 (Table 3).
We chose partial correlations as the measure of association between the CVS and nimodipine assessed by the MCA velocity (1, 3, 5, 7, 14 days), and Bonferroni correction was performed for multiple comparisons in correlation testing, statistical significance; p < 0.05/5 (Table 4).

ACK N OWLED G EM ENTS
None.

CO N FLI C T O F I NTE R E S T
The authors declare no conflicts of interest.

AUTH O R CO NTR I B UTI O N S
All authors contributed to the study conception and design. methodology, software, formal analysis: Ying Yu, Shuai Zhao, Xuan Xie; writing-original draft preparation: Fan Chen; writing-review and editing: Yunqian Li, Zheng Jin, Fan Chen; all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.