Cell Biochem Biophys DOI 10.1007/s12013-014-0377-7
ORIGINAL PAPER
Hyperperfusion Syndrome After Stenting for Intracranial Artery Stenosis Shancai Xu • Pei Wu • Huaizhang Shi Zhiyong Ji • Jiaxing Dai
•
Ó Springer Science+Business Media New York 2014
Abstract Hyperperfusion syndrome (HPS) is a rare but potentially devastating postoperative complication developing after endarterectomy and carotid stenting. Limited information is available about this complication. The aim of this study was to assess the incidence of HPS and risk factors leading to its development. We retrospectively reviewed 178 consecutive cases of patients who underwent stenting of intracranial artery revascularization. We analyzed the association between HPS and patient’s age, collateral vascular supply of the lesion, the interval between operation and the last occurrence of ischemic symptom, adequacy of blood pressure control after the operation, and other risk factors such as diabetes, smoking, hypertension, and gender. Of 178 included patients, we found HPS in six cases (3.4 %). Failure to strictly control postoperative blood pressure, a less than 3-week long interval between operation and the last occurrence of ischemic symptom, and poor collateral circulation were significantly associated with the development of HPS. The aforementioned factors are predictors for HPS. We argue that nitroprusside should not be used to control blood pressure after the operation because its use permits considerable blood pressure fluctuations. Keywords Intracranial hemorrhage Angioplasty Stent Hyperperfusion stenosis Hyperperfusion syndrome
Introduction The hyperperfusion syndrome (HPS) is a rare but potentially devastating postoperative complication of carotid endarterectomy or carotid artery angioplasty and stenting. HPS was initially described by Sundt et al. [1] in 1981 as a clinical syndrome involving ipsilateral migraine-like headache, transient focal seizure activity, and intracerebral hemorrhage after carotid endarterectomy. HPS is estimated to occur in about 0.3–1.2 % of patients after carotid endarterectomy [2–6] and in 1.1–6.8 % of patients following carotid artery stenting [7–10]. The clinical significance of HPS is increasingly recognized; therefore, the incidence, treatment, and pathophysiology of HPS, as well as the associated reperfusion injury, are in the focus of current research. There are still considerable knowledge gaps regarding the evolvement of HPS after stenting for intracranial artery stenosis. To date, only few cases have been reported [11– 13]. In the present report, we describe 6 cases of HPS observed among 178 consecutive patients who underwent the stenting for intracranial artery revascularization. We further discuss the incidence, clinical manifestations, and risk factors for this condition and provide suggestions to improving the clinical diagnosis and treatment.
Materials and Methods Patients and Operation S. Xu P. Wu H. Shi (&) Z. Ji J. Dai Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, No. 23 Youzheng Street, Nangang District, Harbin 150001, Heilongjiang, China e-mail:
[email protected];
[email protected]
We retrospectively reviewed 178 cases of consecutive intracranial artery angioplasties and stentings performed between December 17, 2006 and November 30, 2010. All procedures were performed at a single tertiary care center
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which serves a population of 10 million. We looked for HPS symptoms such as ipsilateral migraine-like headache, seizure, and non-thrombotic hemispheric neurological defects occurring within 7 days after revascularization. The mean (±SD) patient age was 54.9 ± 10.6 years. The degree of intracranial artery stenosis, defined according to the North American Symptomatic Carotid Endarterectomy Trial Collaborators criteria [10], was C70 % in 150 patients and 50–70 % in 28 patients. All patients were symptomatic, and the presentations varied from a history of previous stroke to transit ischemic attacks or acute stroke within the last 3 weeks. Poor collateral circulation was defined as a deficiency of pallium artery in anterior circulation or absence of posterior communicating artery in routine angioplasty. The patients’ blood pressure was not attempted to be lowered before the operation, because low blood pressure may lead to ischemic stroke in patients with intracranial artery stenosis. Nitroprusside was used to control the intraand postoperative blood pressure. During the first 24 h after the operation, all patients were monitored in a neurological unit with a high-level monitoring for neurological problems and blood pressure. Patients were treated to a BP \120/80 mmHg which was recommended by Abou-Chebl and colleagues [26] who found that comprehensive management of arterial hypertension can lower the incidence of ICH and HPS in high-risk patients following CAS, without additional complications or prolonged hospitalizations. The blood pressure control was defined as poor if a frequent dosage adjustment of nitroprusside was required for it was difficult to control BP \ 120/80 mmHg because of fluctuations. All patients received antiplatelet medication prior to and following the operation. The medication typically included 300 mg oral aspirin and 75 mg clopidogrel given for at least 3 days before 3 months after the operation. After that, clopidogrel was discontinued and 100 mg aspirin was prescribed to be used for more than 1 year (approx. 1–1.5 years on average). All angioplasty and stenting were performed by two neurosurgeons, using standard techniques. Procedures were conducted under general anesthesia under standard monitoring by an anesthetist. A bolus dose of intravenous heparin was administered during the procedure. Specifically, intravenous heparin was given at the dose of 100 IU/kg once the operation began. If the operation was not finished within an hour, intravenous heparin (1,000–2,000 IU) was given continuously every hour until the operation was finished. After the operation, heparin was not neutralized by protamine sulfate. CT scans were done in all patients 24 h after the operation with the purpose of excluding fresh ischemia or hemorrhage.
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Table 1 Patient demographics and baseline characteristics Hyperperfusion syndrome
Present
Absent
Mean age
57.67 ± 10.23
54.77 ± 10.65
Pvalue 0.59
Female, n (%)
0
47 (27.33)
0.34
Poor collateral circulation, n (%) Interval \ 3 weeks, n (%)
6 (100)
74 (43.02)
0.01
6 (100)
30 (17.44)
\0.01
Poor control of BP, n (%)
6 (100)
43 (25.0)
\0.01
Smoker, n (%)
4 (66.67)
121 (70.35)
1.0
Hypertension, n (%)
5 (83.33)
125 (72.67)
0.34
Diabetes, n (%)
3 (50.0)
106 (61.63)
0.68
Anterior circulation, n (%)
5 (83.33)
93 (54.07)
0.13
Statistical Analysis Data are expressed as mean ± SD or absolute numbers (%). Statistical analysis was performed using the SPSS statistical software (SPSS Inc., Chicago, USA). The Wilcoxon rank sum test or Fisher exact test was used to test the associations between the occurrence of HPS and the patients’ age, collateral vascular supply of the lesion, interval between the operation and last occurrence of ischemic symptoms, adequacy of blood control after the operation, and risk factors, such as diabetes, smoking, hypertension, and gender. The differences were considered significant at p \ 0.05.
Results Patient demographics and baseline characteristics are presented in Table 1. Of 178 patients who underwent angioplasty and stenting, HPS was observed in 6 (3.4 %) cases. The age of these 6 patients was 57.7 ± 10.2 years. All patients were male, with the preoperative degree of stenosis of more than 70 %. All patients had poor collateral circulation, poor control of blood pressure after procedure, and the interval between the operation and last occurrence of ischemic symptoms of less than 3 weeks. Five patients underwent stenting of middle cerebral artery, while the remaining one patient had stenting of basilar artery. Local intra-arterial thrombolysis was performed before stenting in the patient with the basilar artery stenosis to attenuate acute occlusion of the artery. All HPS patients experienced intracerebral hemorrhage; three of the patients eventually died, making the overall mortality rate of 1.7 % (3/178 patients). The other three patients were conscious with no detectable neurological impairments. The hemorrhages occurred between 1 and 3 h after the stent placement procedure was completed and were manifested with a sudden
Cell Biochem Biophys Fig. 1 a Stent and hemorrhage in the left temporal lobe and lateral ventricles. b Fatal hemorrhage in the central region on the left side after the middle cerebral artery stenting
onset of massive neurological dysfunction, e.g., hemiparesis and disturbance of consciousness. Brain CT scans, performed every 24 h, demonstrated fatal intracerebral hemorrhages in the areas supplied by the artery following stent placement (Fig. 1). The remaining three patients were asymptomatic, and few small intracerebral hemorrhages were detected by brain CT scans (Fig. 2). In these three patients, once CT scans demonstrated hemorrhage, aspirin and clopidogrel were discontinued and blood pressure was strictly controlled. CT scans were repeated 1 week after the hemorrhage episode and showed no increase in the hemorrhage and absorption of the previous hemorrhage. The patients were discharged 2 weeks after the operation. After 3 months, patients did not have any detectable neurological abnormalities. We believe the six intracerebral hemorrhage cases were caused by HPS due to two reasons: Firstly, we reviewed this operation video carefully and found no guide wire perforation. Secondly, brain CT scans exhibited hemorrhage occurred in the areas where the guide wire was not able to reach. Thirdly, the CT scans which were performed 24 h after operation showed no fresh infarction which may lead to hemorrhage. The age, gender, smoking history, and the presence of hypertension or diabetes did not differ between patients with HPS and other patients (Table 1). However, failure to strictly control postoperative blood pressure, a less than 3-week long interval between the operation and the last occurrence of ischemic symptoms, and poor collateral circulation were significantly (p \ 0.05) associated with the development of HPS. Further, HPS tended to occur predominantly in the anterior circulation (5/6 patients; 83.3 %) as opposed to posterior circulation (1/6 patients; 16.7 %).
Discussion To our knowledge, there are currently no published reports on the incidence of HPS after intracranial artery angioplasty and stenting. The incidence of 3.4 % observed in our study is within the ranges of the previously reported incidence of 1.1–6.8 % [7–10, 14–16]. The pathophysiological mechanism of the cerebral HPS is linked to the failure of normal cerebral autoregulation and long-term changes in the perfusion pressure [16]. Cerebral autoregulation has myogenic and neurogenic components. In myogenic autoregulation, increased intravascular pressure results in depolarization of vascular smooth muscles and vasoconstriction of small arterioles at high systemic blood pressure. When blood pressure exceeds the limit of myogenic autoregulation, the remaining autoregulation in large arterioles and small arterioles is dependent on sympathetic autonomic innervation in the adventitia. These vascular changes, resulting from neural innervations, are called neurovascular coupling. The restoration of perfusion pressure after stenting in a previously hypoperfused area may lead to hyperperfusion. In addition, free oxygen radicals produced during angioplasty and stenting may cause damage to cerebrovascular endothelium, resulting in the breakdown of the blood–brain barrier, thus contributing to the development of HPS [14, 16]. In our study, intracerebral hemorrhage was the main manifestation of HPS following intracranial artery stenting. By contrast, headache and focal seizure were not observed. We speculate that there can be two possible explanations for this phenomenon. First, in case of the carotid artery stenting, blood pressure may drop after the operation as a function of baroreceptors located in the adventitia of the carotid bifurcation. These baroreceptors detect the pressure
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Cell Biochem Biophys Fig. 2 A 64-year-old patient with a 60 % stenosis of the middle cerebral artery presented with asymptomatic intracerebral hemorrhage. a, b CT scan shows no fresh infarct or hemorrhage 24 h before the stenting. c, d CT scan shows hemorrhage in the area supplied by the middle cerebral artery. e, f CT scan shows resolution of the hemorrhage 1 week after the stenting
change and appropriately adjust sympathetic and parasympathetic activity. By contrast, in case of intracranial artery stenting, blood pressure does not change prior to or
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following the operation because of the deficiency of baroreceptors in intracranial artery. The high perfusion pressure is mostly defined by high blood pressure after
Cell Biochem Biophys
endovascular revascularization and may lead to intracerebral hemorrhage. Second, mechanical expansion of the intracranial artery resulting from angioplasty and stenting may damage the ability of the perforator arteries to constrict, which, in turn, can promote a breakthrough autoregulation in the downstream vessels. We believe that other potential causes, such as intracerebral hemorrhage caused by the guide wire perforation, can be excluded because all patients were conscious and exhibited no new neurological defects immediately after the operation. Furthermore, brain CT scans exhibited fatal intracerebral hemorrhages in the areas where the guide wire was not able to reach. In addition, the guide wire perforations often lead to subarachnoid but not intracerebral hemorrhages. Other conditions that may predispose for HPS following the carotid artery stenting or carotid endarterectomy include patient’s age ([75 years), long history of hypertension, diabetes, severe stenosis, poor collateralization, history of stroke, and inadequate control of postoperative blood pressures [15–19]. We also found that poor collateralization may be another potential risk factor for intracranial HPS. Coutt et al. [2] reported five patients lacking collateralization in a group of seven patients presented with HPS after stenting. A recently published study [10] on carotid artery stenting or carotid endarterectomy showed that 64 % of patients with HPS exhibit deficient collateralization. Terada et al. [10] also suggest that HPS may occur after operation in patients without sufficient collateralization. Our results are in line with these reports. Moreover, we want to emphasize that HPS may preferably occur in anterior circulation (5/6 patients with anterior circulation vs. 1/6 patients with posterior circulation), although the observed difference did not reach statistical significance in our study. We speculate that this phenomenon is attributable to better perfusion of the brain via posterior circulation. The posterior communicating artery may act as a supply artery for posterior circulation in vertebrobasilar artery stenosis patients, which is in contrast to patients with the middle cerebral artery stenosis that is only compensated by small pallium arteries. In addition, we found that patients with poor control of blood pressure were at higher risk of developing HPS after revascularization of intracranial artery. This finding is similar to the breakthrough (i.e., the phenomenon when cerebral blood flow breaks through autoregulation and rapidly increases) in hypertensive encephalopathy [16]. The postoperative fluctuation of blood pressure may lead to changes in intracranial perfusion pressure which is relevant to the etiology of HPS. Thus, some authors speculate that aggressive control of blood pressure may be associated with clinical and radiological improvement. Ogasawara et al. [9] evaluated patients with carotid artery stenosis who underwent carotid artery stenting or carotid endarterectomy
and suggested that a strict control of postoperative blood pressure prevents intracranial hemorrhage in patients with HPS after carotid endarterectomy. However, these authors did not observe any relationship between blood pressure control and intracranial hemorrhage. Kaku et al. [17] confirmed that initial careful monitoring and control of blood pressure is helpful to prevent HPS in the at-risk patients identified by single-photon emission CT (SPECT). We, therefore, hypothesize that the observed high incidence of intracerebral hemorrhage among our study patients may be related to the use of nitroprusside. First, since the half-life of nitroprusside is very short, its dosage needs to be frequently adjusted before blood pressure normalizes. Therefore, the use of this drug inadvertently causes fluctuations of blood pressure. Second, nitroprusside may worsen HPS by impairing cerebral vasoconstriction, which is essential for intracranial artery autoregulation. By contrast, the mixed a- and b-adrenergic antagonist labetalol has no direct effects on cerebral blood flow and decreases the cerebral perfusion pressure and mean arterial pressure by about 30 % [20]. Therefore, it should be used as a routine drug instead of nitroprusside for management of blood pressure in patients with stenting. Grunwald et al. [21] reported a significant correlation between pre-existing lesions and occurrence of HPS. These authors suggest that the presence of microvascular changes indicates a higher risk of developing hyperperfusion injury. In our study, we observed that the less than 3-week long interval between the operation and the last occurrence of ischemic symptoms is also a good predictive factor for HPS. Furthermore, all patients who developed HPS had an extensive small vessel disease with old territorial infarcts. Although brain CT scan performed in 4/6 patients 24 h before the operation showed no freshly demarked lesions, we believe that recently occurred lacunar infarcts may increase permeability of cerebral vessels and thus lead to HPS. Although HPS is a rare complication of intracranial artery revascularization, patients with this syndrome may suffer from a poor prognosis. Many methods for the detection of preoperative hypoperfusion and flow-related factors were tested to identify the patients at risk [19, 22, 23]. By contrast, little is known about the treatment of HPS. Ogasawara et al. [24] reported that the administration of a free-radical scavenger edaravone was able to prevent cerebral hyperperfusion after carotid endarterectomy. Further, Rezende et al. [12] described staged angioplasty as a relatively simple and effective method to avoid HPS in patients at high risk of hyperperfusion after carotid revascularization. In the staged angioplasty group, none of the 8 patients treated this method developed HPS [12]. By contrast, 6/10 patients who underwent regular carotid artery
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stenting developed HPS as detected by SPECT [12]. However, vascular wall dissection caused by balloon angioplasty during the stage-1 procedure significantly limits its use in intracranial artery angioplasty and stenting. In addition, Ge et al. [25] demonstrated in animal study that ischemic post-conditioning can potentially be effective to prevent cerebral HPS. However, clinical usability of this method to prevent HPS in patients needs further exploration. In conclusion, failure to strictly control postoperative blood pressure, a less than 3-week long interval between the operation and the last occurrence of ischemic symptoms, and poor collateral circulation may be the predictors of HPS after intracranial artery stent placement. Further, nitroprusside should not be used for the control of blood pressure after operation.
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