Intensive mannitol slow infusion post‐stenting may attenuate stenting‐related early adverse effects in patients with cerebral venous sinus stenosis

Abstract Aims To analyze intensive slow mannitol poststenting on attenuating stenting‐related early adverse effects in cerebral venous sinus stenosis (CVSS). Methods This real‐world study enrolled subacute or chronic CVSS patients from January 2017 through March 2022 and divided them into DSA only and stenting post‐DSA groups. The later group was subdivided into control (without extra mannitol use) and intensive slow mannitol subgroup (immediate extra mannitol 250–500 mL, 2 mL/min infusion post‐stenting) after signed informed consent. All data were compared. Results A total of 95 eligible patients entered into final analysis, in which 37 cases underwent DSA only and 58 cases underwent stenting post‐DSA. Finally, 28 patients were entered into intensive slow mannitol subgroup and 30 in control. Stenting group vs. DSA group, HIT‐6 scores and WBC counts were higher in the former (both p < 0.001). Intensive slow mannitol subgroup vs. control on the third day post‐stenting, a statistically significant reductions were noticed in the former on WBC counts (6.19 ± 1.86 × 109/L vs. 9.59 ± 2.05 × 109/L); HIT‐6 scores (degree of headache) (40.00 (38.00–40.00) vs. 49.00 (41.75–55.25)) and brain edema surrounding the stent on CT maps (17.86% vs.96.67%), all p < 0.001. Conclusions Stenting‐related severe headache, inflammatory biomarkers elevation, and brain edema aggravation can be attenuated by intensive slow mannitol infusion.

11]15 In addition, the inflammatory process may cause restenosis of CVSS resulting in poor outcomes. 16,17 have noticed that even though the obstruction of venous reflow was corrected, and the mean pressure gradient (MPG) across the stenotic segment was diminished or even disappeared after stenting, patients had even higher serum levels of inflammatory biomarkers and increased brain edema in the initial days post-stenting compared to their baseline, which may explain why patients with CVSS had even more aggravated symptoms in the early period poststenting.Whereby, inhibiting stenting-related inflammation and brain edema may facilitate clinical outcomes. 18,19Herein, we aimed to explore a new strategy to attenuate the early adverse effects of stenting.

| Study design and patients' selection
The Ethics Committee of Xuanwu Hospital, Capital Medical University approved this single center real-world study, and all participates signed the informed consents prior to enrollment.A total of 95 patients with CVSS confirmed by imaging were enrolled from January

| Angiography process and venous sinus stenting
All patients with imaging confirmed CVSS further finished DSA with the help of local anesthesia to further identify the degree of the stenosis and to measure the MPG across the stenotic segment.Using the venography and manometry results, the same neurointerventional team stented stenotic segments when the trans-stenotic MPG was more than 8 mmHg and patients did not have vascular tortuosity, the presence of a long segment lesion, or severe thrombosis in stenotic sinus.Subsequently, the patients were divided into DSA group and stenting group.

| Postoperative management in stenting group
The routine dehydration strategy for all patients post-stenting was the same as that prior to stenting (4 mL/min, 125 mL, q6h).Moreover, patients in intensive slow mannitol subgroup underwent an immediate additional slow infusion of mannitol (2 mL/min, 250-500 mL, daily) for 2-3 days after signed the informed consents.Patients who declined to sign the informed consent form were assigned to the control subgroup (Figure 1).Serum inflammatory biomarkers, including the counts of white blood cell (WBC) and neutrophils, the percentage of neutrophils, interleukin-6 (IL-6), and high sensitivity C-reactive protein (hs-CRP) and headache intensity (HIT-6 scores), were assessed at baseline, immediately post-stenting and on days 1, 2, and 3 post-stenting.

F I G U R E 1
The brain computerized tomography (CT) was assessed at baseline prior to stenting, the immediate post-stenting, and on post operative day 2.

| Observation and quantification of clinical indicators
To access the negative effects of headache on normal activities, the headache intensity was measured by the short-form Headache Impact Test-6 (HIT-6). 20Brain edema presented in CT scans was evaluated by a semi-quantitative approach.A score 0 was assigned to a CT scan if the sulci cerebri in the local area surrounding the stent disappeared completely.If the sulci cerebri could be found in the area, a score of 1 was assigned to the CT scan.Intracranial pressure (ICP) was defined as the opening pressure of the cerebrospinal fluid (CSF) obtained through a lumbar puncture.The trans-stenotic pressure gradient was represented by MPG measured in DSA.About 58 out of the 95 patients underwent stenting post-DSA (stenting group); the remaining 37 cases underwent DSA only without any stenting (DSA group).The serum inflammatory markers and the results of CT were compared between the two groups immediately following the operation.

| Statistical analysis
In the stenting group, 28 patients into the intensive slow mannitol subgroup and 30 patients in control.Serum inflammatory markers and follow-up CT results between the two subgroups were compared immediately post-stenting and within 3 days post-stenting.

| Serum inflammatory biomarkers fluctuation
Complete blood counts, IL-6 and hs-CRP in patients were, respectively, tested prior to the operation and immediately after operation with or without stenting.

| ICP and MPG
Baseline ICP in all patients, represented by the opening pressure of cerebrospinal fluid (CSF), exceeded the normal upper cut-off levels and had no statistical difference between the DSA group [330.00 (230.00-330.00)mmH2O] and the stenting group [330.00 (307.50-330.00)mmH2O], p = 0.073.
Baseline MPG, measured during DSA, was significantly higher in the stenting group [11.2).

| Bleeding events and inpatient duration post-stenting
In this study, no bleeding events occurred in the intensive slow mannitol subgroup (0.00%), while four patients (13.33%) experienced bleeding in the control subgroup post-stenting.One patient had a hematoma located at right parietal lobe, another patient experienced hemorrhagic transformation inside the area of CVT induced infarction, and two patients had subdural hemorrhages (Figure 3D), details are shown in Table 5.Second, both the elevated serum inflammatory biomarkers and brain edema decreased more rapidly in the intensive slow mannitol subgroup compared to the control subgroup (Table 5, Figures 2 and 3C).Finally, the percentage, severity (HIT-6 scores), and the duration of headache after intensive slow mannitol infusion post-stenting were better than that in the control subgroup.All of these factors reduced the time of hospital stay in the intensive slow mannitol subgroup [4.50 (3.00-6.00)days] compared to the control subgroup [7.00 (6.00-9.00)days] (p < 0.001), details are displayed in Table 5.

| CVSS related IH and treatment
It is well-known that the etiologies of CVSS include thrombotic and non-thrombotic causes, the former comes from incomplete recanalization after thrombosis, although the patients have undergone standardized anticoagulation with enough duration. 7Nonthrombotic CVSS mainly occurs due to giant arachnoid granule obstruction in cerebral venous sinus, lesions of cerebral venous sinus wall, or both. 21One of the most fatal complications of either

TA B L E 5
The fluctuation of the inflammatory biomarkers in plasma and the HIT-6 scores, the duration of headache, the follow-up CT, bleeding events and inpatient time post-stenting.
Stenting related severe headache, brain edema, and even bleeding events that seriously affected clinical outcomes and prolong their hospital stay often occurred in clinical setting, which remains an urgent entity that needs to be solved at present.

| Endovascular interventions induce inflammation
During the endovascular intervention processes, vascular endothelial injuries induced by the crawling of guide wire catheter in the vascular lumen, contrast injection, and stent placement are probable mechanisms that induce or augment the complex inflammatory responses.5][26] Whereby, it is expected that serum inflammatory biomarkers will significantly increase after endovascular interventions, which is consistent with our research. 24,26,27

| The probable mechanisms of brain edema post-stenting
][6][7][9][10][11]28 These conclusions are in line with our observations.However, the brain edema, especially in the local area surrounding the stent, presented on follow-up CTs in almost all patients post-stenting seems not to conform with the decreased ICP and MPG.The definite mechanism underlying this edema remains unclear.In our observations, baseline ICP in both DSA group and stenting group were both higher than the normal cutoff value with no statistical difference between them.Therefore, it is possible that the causes of brain edema were mainly related to stent implantation rather than baseline elevated observed, but brain edema formation is enhanced, [29][30][31] which may be related to the asymmetric response of the brain parenchyma to decreased ICP throughout the open cranium. 29The hyperperfusion of the local decompressed area and the increased tissue pressure gradient of the whole brain result in the development of brain edema. 30 addition, the impairment of cerebral autoregulation, failure of cerebral energy metabolism, and increased cerebral inflammation after craniectomy can also contribute to aggravation of brain edema. 31erefore, routine dehydration therapy post-stenting should not only be continued, but also used more intensively.

| Headache and intracranial hemorrhage post-stenting
There has been numerous research analyzing the adverse effects related to stenting, and the first diagnostic criteria for post-stenting headache has been proposed in the International Classification of Headache Disorders (3rd edition). 7,32,33r study also observed that stenting-related headache could either be a considerable worsening of a prior headache or a new onset headache after stenting.
The mechanisms of stenting-related headache remain unclear.It may be correlated with stent implantation leading to stretching of the venous sinus wall to stimulate intracranial pain-sensitive structures. 7,33 addition, the brain edema, especially in the local area surrounding the stent, found in our study could be also a plausible reasoning for the headache in the early postoperative period after stenting.
There has been increasing attention towards cerebral bleeding post-stenting, such as cerebral or subdural hematoma and subarachnoid hemorrhage. 6,7,9,10,28,34For patients with residual thrombus in the stenotic sinus, the thrombus disruption after stenting might promote activation of local inflammation and coagulation dysfunction, contributing to endothelial cell injuries.This can result in a friable venous wall that is prone to damage and hemorrhage from endovascular maneuvers. 7,35,36Moreover, our previous study demonstrated that hemorrhage usually occurred in the brain region contralateral to the side of the stent due to transient pressure differences between the two sides that leads to the contralateral perforating vein being pulled and injured. 15 the present study, 4 patients suffered bleeding events in the control subgroup.The bleeding events included a hemorrhage in right parietal lobe, subdural hemorrhages in the right pare, and intracranial hemorrhage in the preoperative infarcted lesion.It is important to optimize treatment strategies after venous sinus stenting to avoid these complications.

| Significance of intensive slow mannitol use post-stenting
8][39] It exerts influence on blood viscosity by increasing plasma osmolality and pulling water intravascularly from tissue. 37,38In addition to, mannitol may decrease the cerebrospinal fluid (CSF) formation rate to reduce the ICP. 37Apart from the salutary effect on brain swelling and ICP, mannitol is also highly valid for quelling the inflammatory reactions in brain injury and may be cytoprotective through scavenging free radicals released during the inflammation process. 38,39In this study, all patients underwent continuous mannitol therapy pre-stenting, and on this basis, patients in the intensive mannitol subgroup underwent extra mannitol slow infusion post-stenting.We found for the first time that extra slow infusion of mannitol could further alleviate brain edema prominently and rapidly than a routine mannitol strategy.Moreover, this therapy could also rapidly decrease the levels of abnormal elevated serum inflammatory biomarkers, which effectively attenuates stentingrelated severe headache and may even inhibit the onset of cerebral bleeding events.The probable mechanism may be slow infusion of mannitol prolongs its retention time in the blood circulation, which dehydrates swollen vascular endothelial cells, inhibits inflammatory reactions, and scavenges free radicals.Furthermore, slow infusion of mannitol has weak dehydration effects on brain tissue, so it has little impact on ICP and thus avoids the low intracranial pressure headache caused by excessive rapid dehydration.

| Long-term adverse effects and outcomes post-stenting
Although stenting-related inflammatory process is transient, the release of reactive oxygen species and/or cytokines from inflammatory cells contribute to cell proliferation and vascular remodeling, and further increase the risk for restenosis within or adjacent to the stent.Furthermore, the injured endothelial cells post-stenting lead to platelet adherence, aggregation and activation, which promote the coagulation cascade by inducing thrombin formation.Subsequently, thrombin formation causes thrombosis within or nearby the stent leading to sinus restenosis for patients with intracranial venous stenting. 3,7,25,27,28,33,35,36However, this study mainly compared the early adverse effects of post-stenting prior to discharge between the intensive slow mannitol subgroup and the control subgroup.
Follow-up for long-term adverse effects and clinical outcomes are still ongoing for these patients.

| LI M ITATI O N S
Limitations of this study may as follows: a single-center real-world study.There is a need to conduct a greater prospective multicenter study in the future.Second, CT follow-up in stenting group was monitored dynamically prior to discharge without identical cut-off points, as such the lack of consistent cut off times may act as a confounding factor when it comes to brain edema.Third, the pathological mechanism of brain edema, especially in areas surrounding the stent, is still unclear, and there is no published 2017 through March 2022 consecutively, and all of them underwent digital subtraction angiography (DSA).Medical data were derived from the inpatient database and analyzed by two experienced neurologists and radiologists, respectively.The endovascular interventions were performed by the same experienced surgical team.Inclusion criteria: (1) the CVSS was confirmed by contrastenhanced magnetic resonance venography (CE-MRV), computed tomographic venography (CTV), or DSA; (2) sub-acute or chronic CVSS, defined as the interval time from the onset of signs and symptoms until enrollment was ≥4 weeks; (3) persistently or worsening clinical symptoms despite undergoing regular treatment with medications.Exclusion criteria: (1) a confirmed acute or chronic infection preoperatively; (2) intracranial hypertension (IH) secondary to other reasons, which include (a) drug-induced IH, (b) cerebrospinal fluid shunt history, (c) intracranial mass occupation, (d) arteriovenous malformations, (e) traumatic brain injury, and (f) acute arterial stroke; (3) and incomplete clinical data or disagreement with the clinical decision making.

| 3 of 11 HAN
Flow chart of the study.CVSS, cerebral venous sinus stenosis; DSA, digital subtraction angiography.et al.

TA B L E 3 F I G U R E 2 3 . 5 |slow mannitol subgroup versus control post-stenting 3 . 5 . 1 |
The ratios of inflammatory markers elevation in DSA group and stenting group [(post-DSA-baseline)/ baseline or (post-stenting-baseline)/ baseline].Dynamic fluctuation of serum inflammatory biomarkers post-stenting in the two stenting subgroups [Two-way RM ANOVA with Sidak's multiple comparisons test (* versus control subgroup)].WBC, white blood cell.Intensive Brain edema in local area surroundingthe stent, HIT-6 scores and the duration of headache continued Patients in the stenting group were further subdivided into an intensive slow mannitol subgroup and a control subgroup.Following the CT scan post-stenting, brain edema was noticed in almost all patients in both subgroups immediate post-stenting.In the following days, all patients underwent CT scans of their brain every 1 or 2 days until discharge.The degree of brain edema dissipation, especially those with a score of 0, in the two subgroups was remarkably different.In the control subgroup, 29 patients (96.67%) had brain edema in the local area surrounding the stent, which remained present from 4 to 5 days post stenting and, in some cases, until the seventh day prior to discharge; in the intensive slow mannitol subgroup, the brain edema disappeared within 2 days in a majority of patients with only five patients (17.86%) continuing to have brain edema in the local area surrounding the stent on the third day post-stenting, p < 0.001

TA B L E 4
Baseline ICP and MPG, postoperative HIT-6 scores and CT follow up.F I G U R E 3 (A) The CT scanned immediate post-DSA or post-stenting.(a-d) CT scanned immediate post-DSA; (e-h) CT scanned immediate post-stenting.(B) Follow-up CT of the patient in control subgroup.(a-d) Immediate post-stenting.(e-h) At Day 2 after stenting.(C) Followup CT of the patient in intensive slow mannitol subgroup.(a-d) Immediate post-stenting.(e-h) At Day 2 after stenting.(D) Intracranial hemorrhage post-stenting on CT maps (red arrows): (a) Right parietal lobe hemorrhage; (b) Hemorrhagic transformation within infarcted area; (c, d) Subdural hemorrhage.
ICPs.It is well known that stenting in venous sinus stenosis is different than that in arterial disease.Arterial diseases have a normal ICP environment, whereas venous sinus stenosis induces a high-pressure environment in the whole brain.When the stent is released successfully, the intracranial pressure of both the local segment and entire brain drops suddenly, causing the local brain tissue to be pulled and the whole brain tissue to suddenly decompress; this may be the main reason for early brain edema after stenting.The possible mechanism is similar to decompression craniectomy.After patients undergo decompressive craniectomy, a significant reduction in ICP has been F I G U R E 4 Kaplan-Meier curve of the headache post-stenting in two stenting subgroups (log-rank test, p < 0.001).