The safety and efficacy of staged angioplasty for treating carotid stenosis with a high risk of hyperperfusion: A single-center retrospective study

Abstract

Objective

Hyperperfusion syndrome (HPS) following carotid artery stenting (CAS) is a rare but life-threatening complication. Staged angioplasty (SAP) is an alternative method that prevents HPS by preventing a sudden increase in cerebral blood flow. In this study, we investigated the safety and efficacy of SAP.

Methods

A total of 114 patients with carotid stenosis underwent CAS treatment in our hospital between September 2014 and September 2019. Patients with severe stenosis and poor collateral circulation shown on digital subtraction angiography (DSA) and hypoperfusion of the ipsilateral diseased blood vessel shown on computed tomography perfusion (CTP) imaging were subjected to SAP treatment (the SAP group), and other patients received regular CAS treatment (the RS group).

Results

Twenty-two patients (19.3%) with a high risk of HPS underwent SAP treatment, 1 of whom had carotid dissection after stage I balloon angioplasty and underwent regular CAS. This patient had HPS after surgery. None of the other patients in either group had HPS. One patient in the SAP group (4.5%) had hyperperfusion phenomenon (HPP) after stage II stenting, and 2 patients in the RS group (2.2%) had HPP. One patient in the SAP group (4.5%) and 4 patients in the RS group (4.3%) had symptomatic ischemic complications postoperatively. None of the differences between the 2 groups were statistically significant. Three patients had reduced modified Rankin Scale (mRS) scores at 90 days after discharge.

Conclusion

This research suggests that SAP appears to be an effective method to prevent HPS for patients with a high risk of HPS.

Introduction

Carotid artery stenting (CAS) and carotid endarterectomy (CEA) are common methods for treating carotid stenosis. Hyperperfusion syndrome (HPS) is a rare complication following CAS, with an overall incidence of 0.5-6.8%.^1,2 However, intracranial hemorrhage associated with HPS may cause devastating consequences.^3,4 Therefore, it is extremely important to prevent HPS through appropriate methods. Carotid stenosis higher than 90% is the main risk factor for the occurrence of HPS,^5–8 and other important risk factors include severe lesions of the contralateral carotid artery, poor collateral circulation, hypertension and recent stroke or ischemic incidence.⁹ The incidence of HPS ranges from 14.1% to 56%,^9–14 with the presence of more risk factors correlating to higher risks of HPS, and currently, no treatments have been proven to be effective for HPS except strict postoperative blood pressure control. Some scholars suggest that the incidence of HPS can be minimized by gradually restoring cerebral blood flow.¹⁵ Staged angioplasty (SAP), proposed by Yoshimura et al., is a treatment that involves 2 angioplasty stages, including balloon angioplasty for stage I and CAS for stage II.¹³ The goal of SAP is to prevent a sudden increase in cerebral blood flow (CBF) in areas with impaired cerebral hemodynamic reserve. Our study investigated the efficacy and safety of SAP for the prevention of HPS.

Materials and methods

This retrospective study was approved by the ethics committee of our institute. A total of 114 patients with carotid stenosis were treated with CAS. According to the relevant literature, we selected patients for 2 stage CAS according to the following criteria¹⁶: (1) patients with carotid stenosis of ≥70% according to the North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria; (2) patients with poor collateral circulation shown on digital subtraction angiography (DSA) and a collateral score of ≤2 according to the American Society of Intervention and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) collateral flow grading system; (3) patients with hypoperfusion ipsilateral to the diseased blood vessel shown on computed tomography perfusion imaging (CTP) and over 20% change in CBF, cerebral blood volume (CBV), mean transit time (MTT) and time to peak (TTP) on the ipsilateral side compared to the contralateral side. All criteria were required to be met for inclusion. Among the patients, 22 underwent SAP treatment, and 92 underwent regular CAS treatment. The baseline clinical data and relevant neurological events of each patient were recorded. The CBF of the middle cerebral artery was examined by CTP and transcranial Doppler ultrasound (TCD). postoperative diffusion-weighted magnetic resonance imaging (DWI) was used to assess postoperative DWI-positive conditions. All patients took aspirin (100 mg/d), clopidogrel (75 mg/g) and statins (20 mg/d) at least 1 week before surgery.

Preoperative assessment

All patients underwent DSA examination prior to angioplasty, and the severity of carotid stenosis and compensation were assessed according to NASCET criteria. All patients received DWI scans after balloon angioplasty and CAS to assess postoperative DWI-positive conditions. All patients underwent CTP examination before and after surgery to evaluate the perfusion of the blood supply area ipsilateral to the diseased vessel. Hypoperfusion was defined as ipsilateral CBF lower than 20% that of contralateral CBF on CTP. The asymmetry index of the CBF on the 2 sides was calculated. The relative changes in the peak cerebral arterial systolic flow rate before and after surgery was assessed by TCD. The systolic blood pressure of the patients was maintained at over 140 mmHg during this period. Hyperperfusion phenomenon (HPP) was defined as increased cerebral arterial blood flow (over 100% increase in the peak systolic blood flow rate) detected by TCD or an asymmetry index of CBF of more than 120% compared to the contralateral side on CTP.¹⁷ HPS refers to HPP-induced headache, epilepsy, consciousness disorder or focal neurological deficit. Previous study suggests that Willis rings can be divided into four types according to whether the anterior and posterior circulation is complete. Type I: the anterior and posterior circulation are complete, type II: the anterior circulation is complete, the posterior circulation is incomplete, type III: the anterior circulation is incomplete, the posterior circulation is complete, type IV: the anterior and posterior circulation are incomplete.¹⁸ In Table 1, ‘normal’ refers to type I and ‘abnormal’ includes type II, type III and type IV.

Table 1.

Baseline characteristics of the 2 groups.

Variables	RS group (n = 92)	SAP group (n = 22)	P value
Age	71.3±6.5	69.4±6.5	0.18
Sex (male/female)	59/33	15/7	0.721
Risk factors, n(%)
Hypertension	64 (69.6)	17 (77.3)	0.474
Diabetes	40 (43.5)	9 (40.9)	0.827
Coronary disease	19 (20.7)	5 (22.7)	1.0
Atrial fibrillation	4 (4.3)	2 (9.1)	0.716
Smoke	41 (44.6)	9 (40.9)	0.756
Stenosis ≧70%, n (%)	2 (2.2)	22 (100)	<0.01
Contralateral stenosis
≧50%	11 (12.0)	3 (13.6)	1.00
≧70%	1 (1.1)	2 (9.1)	0.172
≧90%	0	0
Contralateral occlusion	5 (5.4)	1 (4.5)	1.00
Willis ring
Normal	58 (56.9)	13 (59.1)	0.848
Abnormal	34 (37.0)	9 (40.9)	0.731
CTP, n (%)
Hypoperfusion	2 (2.2)	22 (100)	<0.0148
Normal	90 (97.8)	0	<0.01
Stent type
Close cell	48 (52.2)	12 (54.5)	0.841
Open cell	44 (47.8)	10 (45.5)	0.841

Normal willis ring: complete circle of Willis; Abnormal willis ring: incomplete anterior or posterior halves of the circle of Willis.

Staged angioplasty

Stage I balloon angioplasty

An 8F guiding catheter was placed in the common carotid artery. An appropriate embolization protection device was placed at the distal end of the stenosis according to the diameter of the internal carotid artery. Then, a balloon (3 mm*2 cm/3 mm*3 cm) was inserted into the stenotic lesion for inflation. The procedure was considered successful if the luminal diameter at the stenosis exceeded 2 mm on postoperative angiography. All patients underwent successful surgery.

Stage II CAS

Stage II CAS was performed 3–4 weeks after stage I balloon angioplasty. An embolization protection device was placed at the distal end of the stenosis. A self-expanding carotid stent was deployed at the stenosis based on the condition of the diseased blood vessel. When necessary, an appropriate balloon was selected for postdilation.

Postoperative blood pressure management

All of the patients treated by regular CAS or SAP were subjected to blood pressure monitoring for 72 hours after surgery. The postoperative pressure was controlled at 20% less than the preoperative pressure and maintained for 3 weeks. After postoperative blood pressure control treatment, patients were discharged and followed-up once every week.

Postoperative assessment

The incidences of HPP and HPS following balloon angioplasty and CAS were assessed. The attending physician and the radiologist examined whether each patient had new positive lesions on cranial DWI at 1 day after balloon angioplasty and CAS. In the SAP group, the DWI-positive rate was defined as the total lesions detected after all treatment stages. We also assessed the incidence of symptomatic ischemic complications and the incidence of modified Rankin Scale (mRS) score reduction at 90 days after discharge. Symptomatic ischemic complications were defined as postoperative symptoms lasting for at least 24 hours.

Statistical analysis

The data were analyzed using SPSS software. Continuous variables were expressed as the mean±standard deviation. Categorical variables were reported as number (%). Continuous variables in paired samples were analyzed by a paired Student t test. The unpaired Student’s t-test was used to compare the unpaired continuous variables. Categorical variables were analyzed with a chi square test. Differences with P≤0.05 were considered statistically significant.

Results

Among the 114 patients undergoing CAS treatment, 22 patients (19.3%) underwent SAP treatment according to our recruitment criteria for patients with a high hyperperfusion risk. The baseline characteristics of the patients in the RS and SAP groups are shown in Table 1. The stenosis rate for the SAP group was significantly higher than that for the RS group. In the SAP group, 1 patient had carotid dissection after stage I balloon angioplasty, underwent regular CAS and had HPS after the procedure. The other 21 patients showed significantly improved blood flow in the hypoperfusion regions after stage I treatment as indicated by CTP and TCD. CTP showed that CBF increased from 0.83±0.04 before the procedure to 0.98±0.06 after the procedure; CBV increased from 0.96±0.02 before the procedure to 0.994±0.025 after the procedure; MTT shortened from 1.16±0.06 before the procedure to 1.05±0.04 after the procedure; and TTP shortened from 1.21±0.07 before the procedure to 1.03±0.06 after the procedure. The differences in these parameters were statistically significant. Additionally, there were also large changes in CBF, CBV, MTT and TTP before and after stage II CAS (Table 2). Significant changes in the peak systolic blood flow rate before and after the 2 stages were detected by TCD (Table 3). The postoperative cranial DWI-positive rate for the RS group was 8.7% (8 cases), and that for the SAP group was 13.6% (3 cases), with the positive rate in the SAP group higher than that of the RS group. Univariate analysis showed that older patients and patients using open loop stents had more positive lesions on DWI, but the differences were not statistically significant. Three patients had reduced mRS scores at 90 days after discharge. One patient in the SAP group and 2 patients in the RS group had HPP. A total of 5 patients in the 2 groups had symptomatic ischemic surgery complications, but the differences were not statistically significant (Table 4).

Table 2.

Changes in perfusion parameters on CTP in patients with carotid stenosis during the operation.

	RS group (n = 92)		SAP group (n = 22)			P	P1	P2
	Preoperative	Postoperative	Preoperative	Stage I	Stage II
CBF	0.92±0.06	1.01±0.08	0.83±0.04	0.98±0.06	1.02±0.08	<0.05	<0.01	<0.01
CBV	0.994±0.023	0.998±0.021	0.96±0.02	0.994±0.025	0.998±0.022	0.83	0.72	0.85
MTT	1.05±0.05	1.01±0.04	1.16±0.06	1.05±0.04	1.01±0.05	<0.05	<0.01	<0.01
TTP	1.04±0.06	0.99±0.05	1.21±0.07	1.03±0.06	0.98±0.06	<0.05	<0.01	<0.01

CBF: cerebral blood flow; CBV: cerebral blood volume; MTT: mean transit time; TTP: time to peak; CTP: CT perfusion imaging. P: RS group: Preoperative vs postoperative. P1: SAP group: Preoperative vs stage I. P2: SAP group: Preoperative vs stage II.

Table 3.

Changes in TCD perfusion parameters in the 2 stages of the operation in the SAP group.

	Stage I	Stage II
TCD	42.28±6.15	68.54±8.26
	68.54±8.26	103.35±12.18
P value	<0.01	<0.01

TCD: transcranial Doppler.

Table 4.

Comparison of clinical outcome between the 2 groups.

Factors	RS (n = 92)	SAP (n = 22)	P value
Efficacy
HPP(%)	2(2.2)	1(4.5)	1.00
HPS(%)	1(1.1)	0	1.00
Safety
DWI-positive high spots(%)	8(8.7)	3(13.6)	0.762
After balloon angioplasty	–	0	–
After CAS	–	3(13.6)	–
Ischemic complication	4(4.3)	1(4.5)	1.00
mRS decrease at 90 days(%)	2(2.2)	1(4.5)	1.00

Discussion

In this study, we performed SAP in 22 patients with a high risk of hyperperfusion according to the severity of carotid stenosis, distal collateral compensation and the ipsilateral perfusion status of the diseased blood vessel. In the SAP group, 1 patient had carotid dissection after stage I balloon angioplasty, underwent regular CAS and had HPS after the procedure. This surgery was completed by a highly experienced physician. Fifty percent residual stenosis was retained after stenting, and the postoperative blood pressure was maintained at 30% lower than that before the procedure. However, the patient still had HPS. HPP was observed in 1 patient in the SAP group and 2 patients in the RS group, but the difference in the HPP incidence between the 2 groups was not statistically significant. Of the 2 patients with HPP in the RS group, the baseline data showed that although they had moderate carotid stenosis, they had poor collateral compensation, and CTP showed that they had distal hypoperfusion, indicating that preoperative ipsilateral hypoperfusion is the main cause of postoperative hyperperfusion. The incidences of positive lesions in DWI and symptomatic ischemic surgery complications in the SAP group were not higher than those in the RS group. These results indicate that among the patients with a confirmed high risk of hyperperfusion, SAP can prevent HPS and is safe.

Hyperperfusion is caused by a sudden increase in CBF with impaired brain autoregulation functions in regions with chronic cerebral hypoperfusion.^19–21 One mechanism for preventing hyperperfusion may be that mild to moderate angioplasty can prevent a sudden increase in CBF, which helps restore the impaired cerebral microvascular autoregulation. Mo et al.²² evaluated hemodynamic changes after SAP with CTP and TCD and found that there were significant changes in CBF, CBV, MTT and TTP between before and after the first and second stages of treatments. In our study, we found that CBF on CTP increased from 83% to 96% at the first stage and to 102% after the second stage, which was consistent with the findings reported by Mo et al. Additionally, the symptoms of patients with symptomatic carotid stenosis were significantly alleviated after stage I surgery. Uchida et al.²³ reported that the asymmetry index of CBF increased suddenly from 84.1% to 123% after regular CAS. In contrast, the index only increased from 84.1% to 96.1% after SAP. Dividing CAS into 2 stages prevented a sudden increase in CBF. These data indicate that stage I balloon angioplasty not only increases CBV but also improves the impaired cerebral autoregulation function, which helps prevent hyperperfusion.

Another critical problem is the safety of SAP. SAP is carried out in 2 stages, which may increase surgery-related complications, especially symptomatic ischemic complications. Several large-scale prospective CAS studies showed that the incidence of perioperative complications was 3.3-5.2%.^24–26 In our study, 1 patient in the SAP group (4.5%) had symptomatic ischemic complications; the incidence rate was similar to that for conventional CAS reported in the literature.²⁷ The study by Uchida et al.²³ showed that the incidence rates of ischemic complications in the SAP and RS groups were 9.8% and 9.3% respectively, with no significant difference between the 2 groups. The DWI-positive rate for the SAP group was slightly higher than that for the RS group, but the difference was not statistically significant. Additionally, the incidences of symptomatic ischemic complications caused by positive lesions on DWI did not differ significantly between the 2 groups. This is consistent with the results reported by Hayakawa et al.²⁸ The administration of statins prior to CAS can significantly reduce the incidence of perioperative ischemic complications. A recent study reported the effect of atorvastatin in preventing ischemic complications after CAS, confirming that perioperative statin treatment is effective for reducing the number and incidence of ischemic lesions on DWI.²⁹ The second aspect related to the safety of the procedure is the interval between stage I balloon angioplasty and stage II CAS, with no consensus being reached so far. If the interval between the 2 stages is too long, ischemic complications can occur due to elastic retraction. Nagashima et al.³⁰ reported that according to acetazolamide single photon emission computed tomography (SPECT), impaired cerebral vascular reactivity (CVR) improved within a few days after stage I angioplasty; therefore, they suggested at least a week between the 2 stages of treatments. However, Yoshimura et al.¹³ believed that cerebral perfusion returned to normal at 1 month after stage I angioplasty and suggested 1 month between the 2 stages. In our study, the median interval between the 2 stages was 3–4 weeks. The incidence of elastic retraction at the dilatation site shown by angiography before stage II surgery was 10.6%, but we did not detect any ischemic symptoms related to elastic retraction.

Currently, there is no consensus on the balloon diameter for stage I balloon angioplasty. In our study, we found that balloons with a diameter of 3 mm were safe and effective. Yoshimura et al.¹³ even believed that 3 mm might be the optimal size for balloon angioplasty. Smaller balloons are do not effectively improve stenosis and perfusion, while larger balloons may cause dissection during dilatation. In the SAP group in our study, 1 patient had carotid dissection after stage I balloon angioplasty. However, Mo et al.²⁰ also reported that 1 patient had dissection after stage I balloon angioplasty. Therefore, we believe that the occurrence of dissection is related to not only the size of the balloon but also the structure of the lesion.

Hypertension following carotid interventional treatment is an important factor leading to hyperperfusion.¹⁰ Among our cases, the postoperative systolic blood pressure was controlled at 20% lower than the baseline pressure. However, HPP was still detected by TCD after surgery in 3 patients, suggesting that HPS may occur in patients with normal blood pressure; therefore, HPS cannot be completely prevented by simply controlling postoperative blood pressure.

Although our treatment was successful, this study has some limitations. First, this is a single-center retrospective study with a small sample size. Second, the SAP group inclusion criteria were patients with severe carotid stenosis, poor collateral compensation and hypoperfusion ipsilateral to the diseased vessel. These criteria were very strict because it is possible that patients with nonsevere carotid stenosis had hypoperfusion on CTP and that these patients might also have a high risk of hyperperfusion. Third, the interval between the 2 stages of treatment was not completely uniform, and therefore, the optimal interval needs to be determined by a multicenter prospective study.

Conclusion

Our research shows that SAP appears to be a safe and effective method to prevent HPS in patients with carotid stenosis and a high risk of hyperperfusion.

Authors’ contribution

Yue Wan, Hui Wang, Qi Fang: conception, design. Yue Wan, Dapeng Wang, Hao Tian, Jing Zuo: data acquisition, data analysis. Yue Wan: drafting the manuscript. Hao Tian, Qi Fang: revising the manuscript. Yue Wan, Hui Wang, Dapeng Wang, Hao Tian, Jing Zuo, Qi Fang: final approval of the submitted manuscript.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethics approval

According to the guidelines of our local ethics committees, ethical approval was given when necessary for this anonymous retrospective study, which was conducted in accordance to the Declaration of Helsinki. A patient’s consent for treatment was obtained according to the individual institutional guidelines. Due to the retrospective nature of the study additional informed consent was deemed unnecessary.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Yue Wan https://orcid.org/0000-0001-7909-1125

Qi Fang https://orcid.org/0000-0002-9762-2687