Abstract
Ischemic preconditioning (IP) uses transient ischemia to render tissues tolerant to subsequent, prolonged ischemia. This study sought to evaluate factors that contributed to the development of cerebral ischemia during PercuSurge balloon (Medtronic, Santa Rosa, CA) occlusion in patients undergoing carotid angioplasty and stenting (CAS). The PercuSurge occlusion balloon was used in 43 of 165 patients treated with CAS for high-grade stenosis; 20% were symptomatic. Symptoms of cerebral hypoperfusion during temporary occlusion of the internal carotid artery occurred in 10 of 43 patients and included dysarthria, agitation, decreased level of consciousness, and focal hemispheric deficit. The development of neurologic symptoms after initial PercuSurge balloon inflation and occluded internal carotid artery flow was associated with a decrease in the mean Glasgow Coma Scale (GCS) from 15 to 10 (range 9–14); the GCS returned to normal after occlusion balloon deflation. The mean time to spontaneous recovery of full neurologic function was 8 minutes (range 4–15 minutes). The mean subsequent procedure duration was 11.9 minutes (range 6–21 minutes). No recurrence of neurologic symptoms occurred when the occlusion balloon was reinflated. All 10 patients underwent successful CAS without occlusion, dissection, cerebrovascular accident, or death. Ischemic preconditioning can be used to enable CAS with embolic protection in patients who cannot tolerate initial interruption of antegrade cerebral perfusion by PercuSurge occlusion.
Introduction
The advent of carotid angioplasty and stenting (CAS) has been predicated on achieving low periprocedural cerebrovascular accident (CVA) rates that are equal to those of carotid endarterectomy (CEA).[1,2] The development of cerebral protection devices is believed to be integral to achieving acceptable periprocedural rates of CVA during CAS.[3-9] Cerebral protection devices are deployed in the internal carotid artery (ICA) distal to the index lesion. They are designed to prevent embolization of atheromatous debris that may be dislodged during CAS and thereby prevent periprocedural CVA.
Two techniques are currently being used in the United States: filter devices and temporary balloon occlusion.[10] Whereas filter-based cerebral protection devices maintain antegrade cerebral blood flow in the ipsilateral ICA during the CAS procedure, occlusion balloons require the temporary interruption of flow. A third technique used for embolic protection outside the United States uses reversal of flow in the ICA. The interruption of antegrade cerebral perfusion may induce cerebral ischemia. In patients undergoing CEA, 9 to 19% develop manifestations of cerebral ischemia that necessitate placement of a temporary intravascular shunt to maintain antegrade cerebral perfusion.[11-14] This number increases considerably when occlusion of the contralateral ICA is present, and up to 39% of patients with contralateral carotid occlusion require shunt placement during CEA.[15,16] Transient neurologic intolerance resulting from balloon occlusion of the ICA during CAS has also been reported.[10] This study sought to evaluate the use of a short reperfusion interval to acutely initiate ischemic preconditioning and induce neurologic tolerance in patients undergoing CAS with the PercuSurge occlusion balloon (Medtronic, Santa Rosa, CA) as a cerebral protection device. In addition, evaluation of the factors that contributed to the development of cerebral ischemia and of the techniques used to allow successful completion of the CAS procedure was performed.
Methods
Demographics
From January 2003 to January 2005, 165 patients (87 men, 78 women) with four carotid artery stenoses were treated with CAS. Prospective data collection was performed under the approval of the Institutional Review Board. All patients and procedures were entered prospectively into a computerized vascular registry.
Preoperative patient demographic data are listed in Table 1 . Procedural details recorded included heart rate, blood pressure, medications given, degree of stenosis, size of native vessel, side of procedure, stent type and size, protection device used, and angioplasty balloon size. Postoperative data collected included heart rate, blood pressure, medications, cardiac enzymes, electrocardiographic changes, morbidity, mortality and length of stay. The PercuSurge occlusion balloon was employed in 43 of 165 patients treated with CAS for high-grade stenosis ( Table 2 ). All 43 patients were at increased risk for endarterectomy (7 restenosis, 3 irradiation, 3 contralateral occlusion, and 30 Goldman class II–III). Twenty-seven patients exhibited significant coronary artery disease, and three had severe chronic obstructive pulmonary disease, prohibiting intubation and administration of general anesthesia. The mean age of the patients treated in the study was 75.9 years (range 67–93 years). The degree of carotid stenosis was greater than 80% in all cases, with a mean stenosis of 90% (range 80–99%). Twenty percent of patients treated using the PercuSurge balloon were symptomatic from the carotid stenosis and 80% were asymptomatic. Fifteen patients were treated under the MavericII (Medtronic Inc., Santa Monica, CA) study protocol. The indications for using the occlusion balloon in the remaining patients included significant carotid tortuosity, heavily calcified high-grade lesions, and failure of delivery of a filter wire.
CAS Technique
All patients underwent CAS under local anesthesia without sedation. Procedures were performed by vascular surgeons in an angiography-equipped operating room using a fixed imaging system (Siemens AG, Munich, Germany). Femoral access was used in all cases. Cerebral protection devices were used in 162 of 165 cases, excluding 3 patients who had restenosis after CEA (n = 2) or CAS (n = 1). Microporous filters were used in the majority of cases (n = 119) and included the EPI FilterWire (Boston Scientific, Natick, MA), the Accunet (Guidant, Minneapolis, MN), and the Angioguard (Cordis, Warren, NJ). Prophylactic atropine (0.5–1.0 mg) was administered prior to simulation of the carotid baroreceptor by angioplasty balloon inflation. After the resultant increase in heart rate was observed, the lesion was predilated with a 4 × 40 mm monorail angioplasty balloon (Long VIVA, Boston Scientific). A self-expanding stent was then deployed across the lesion. Types of stents used included the Wallstent (Boston Scientific), AVE carotid stent (Medtronic), Acculink (Guidant), Precise (Cordis), and NexStent (Endotex, Cupertino, CA). Postdilatation with a monorail balloon 5 to 6 × 20 mm (Gazelle, Boston Scientific) was performed. Nitroglycerin (100–300 μg) was administered for treatment of spasm of the distal ICA in six cases and was not associated with hypotension or vasopressor use.
The PercuSurge occlusion balloon was employed in 43 patients treated with CAS for high-grade stenosis (Figure 1). The system is designed to contain and aspirate embolic material (thrombi/debris) while performing percutaneous transluminal angioplasty and stenting procedures. The PercuSurge has an inflation device, which can be set to inflate the occlusion balloon to sizes between 3 and 6 mm by 0.5 mm increments. The inflated balloon is positioned at least 3 cm distal to the stenosis to prevent interference with the distal tip of the self-expanding stent delivery system.
Cerebral Protection
The PercuSurge balloon was advanced across the index lesion. Use of an additional 0.014-inch guidewire to provide additional support (buddy wire) was required to permit passage of the PercuSurge wire in five patients with extensive tortuosity of the ICA (Figure 2). Dilatation of the carotid stenosis was not required prior to advancing the PercuSurge wire in any case. Once positioned in a straight portion of the ICA, the PercuSurge balloon was inflated to a diameter of 5 to 6 mm. Angiography was performed to confirm temporary occlusion of flow in the ICA. The PercuSurge system was used in five patients after failure of delivery of a filter wire cerebral protection device in heavily calcified high-grade lesions.
Figure 1. (click image to zoom)
Carotid artery angioplasty and stenting (CAS) using the PercuSurge GuardWire occlusion balloon for cerebral protection. A, The initial digital subtraction angiogram demonstrates a critical stenosis at the level of the carotid bifurcation. The arrow (shown in B) indicates the location of the occlusion balloon used for cerebral protection. B, Inflation of the PercuSurge occlusion balloon (arrow) in the straight segment of the internal carotid artery results in the cessation of arterial flow. C, After completion of the CAS procedure, the blood is evacuated from the internal carotid artery using the export catheter and the PercuSurge occlusion balloon is deflated. Resolution of the stenosis is achieved, with no residual stenosis.
Figure 2. (click image to zoom)
An additional 0.014-inch guidewire (arrows) used to provide additional support (buddy wire) was required to permit passage of the PercuSurge wire in patients with extensive tortuosity of the internal carotid artery. Previous attempts to position a cerebral protection microporous filter had been unsuccessful.
Pharmacologic Measures
All patients received clopidogrel (Sanofi-Synthelabo Pharmaceuticals, New York, NY) 5 days prior to the initiation of the CAS procedure and were maintained on clopidogrel for at least 30 days postoperatively. Anticoagulation with heparin sodium was maintained throughout the procedure with a target-activated clotting time of 250 to 350 seconds. Atropine (0.5–1.5 mg) was given prophylactically prior to balloon dilatation for the treatment of reflex bradycardia associated with dilatation of the carotid baroreceptor.
Intravenous vasoactive agents were used for management of hypotension (systolic blood pressure 1 < 90 mm Hg) in three cases involving the use of the PercuSurge balloon. Dopamine was used as the primary agent for hypotension; supplemental phenylephrine or norepinephrine was administered for refractory hypotension. In addition, fluid resuscitation was performed for all patients who experienced hypotension.
Statistical Analysis
Univariate testing was done using the Fisher exact test for analysis of dichotomous data and t-tests for continuous data analysis. Continuous data are expressed as mean ± standard deviation. Significance was assumed at p ≤ .05. Data were managed and analyzed by SPSS statistical software (version 13, SPSS Inc, Chicago, IL).
Results
Outcomes
The PercuSurge balloon was deployed and CAS was performed successfully in all 43 patients. No patient developed dissection of any of the access vessels. There were no instances of occlusion of the internal carotid or other arteries. Hematoma at the access site occurred in two patients but did not require blood transfusion. One pseudoaneurysm occurred at the femoral access site that required thrombin injection to correct. No patient required intubation or mechanical ventilatory support, and all patients were transferred to a monitored stepdown bed postoperatively. There were no cases of transient ischemic attacks (TIAs) or ischemic seizures. One patient developed postoperative headache that was alleviated by blood pressure control. There was no other clinical evidence of hyperperfusion syndrome. There were no CVAs or myocardial infarctions and no 30-day mortality. The length of stay ranged from 1 to 5 days, with a mean of 1.33 days.
Transient Neurologic Intolerance
Manifestations of neurologic intolerance occurred in 10 of 43 patients (23.3%) during PercuSurge balloon occlusion of antegrade flow in the ICA. In all cases, these symptoms resolved completely and spontaneously after CAS completion. Symptoms of cerebral ischemia in these patients were dysarthria (n = 7), decreased level of consciousness (n = 5), and hemispheric neurologic deficit (n = 3). In addition, six patients experienced altered mental status associated with agitation ( Table 3 ). The development of neurologic symptoms after initial PercuSurge inflation was associated with a decrease in the mean Glasgow Coma Scale (GCS) from an initial mean score of 15 to a mean minimum score of 10 (minimum score range 9–14); the GCS returned to 15 after balloon deflation and subsequent reinflation. The mean time 1 to spontaneous recovery of full neurologic function was 8 minutes (range 4–15 minutes). No thrombotic or embolic events were present on cerebral angiography, postoperative computed tomography (two patients), or magnetic resonance imaging (four patients).
Precipitating Factors
The development of cerebral ischemia with manifestations of transient neurologic intolerance was associated with distinct aspects of the CAS procedure in 10 patients ( Table 4 ). These factors were initial occlusion of the ICA by inflation of the PercuSurge balloon in five patients. There were no simultaneous associated hemodynamic changes. Neurologic intolerance developed with stimulation of the carotid baroreceptor during transluminal dilatation of the carotid stenosis in three patients. Neurologic intolerance was precipitated by the development of bradycardia to a heart rate less than 50 bpm and hypotension to a systolic blood pressure less than 80 mm Hg in these three patients. One patient developed symptoms during predilatation using the 4 × 40 mm angioplasty balloon and two developed symptoms during postdilatation with the 5.5 × 20 mm angioplasty balloon. Two patients developed transient neurologic intolerance in a delayed fashion 8 to 14 minutes after the initial PercuSurge balloon occlusion of the ICA. Neurologic intolerance in these instances appeared to result from the cumulative effects of cerebral ischemia and was not clearly attributable to a specific procedural factor or event.
Intracranial Collateral Circulation
Incomplete collateral circulation to the cerebral hemisphere ipsilateral to the index carotid artery was present in the majority of patients who developed transient neurologic intolerance during occlusion of the carotid artery. An incomplete circle of Willis and/or contralateral carotid artery occlusion was present in 8 of 10 patients. Fifty-four percent of patients who experienced transient neurologic intolerance exhibited absence of the anterior communicating artery, the posterior communicating artery, or both. However, incomplete intracranial collateral arteries (anterior communicating, posterior communicating, or both) were also demonstrated in 39% of patients who did not experience neurologic intolerance. This difference failed to achieve statistical significance (p = not significant). Of note, occlusion of the contralateral ICA was observed in three patients in the study. Cerebral ischemia and neurologic intolerance occurred in two of these three patients. In addition, the total time of ICA occlusion by inflation of the PercuSurge balloon did not correlate with the development of neurologic intolerance (p = not significant).
Management of Neurologic Intolerance
Several techniques were employed to manage the development of neurologic intolerance and allow completion of the CAS procedure. In the five patients who developed immediate intolerance to initial PercuSurge balloon inflation, rapid deflation of the occlusion balloon was carried out. Symptoms resolved completely without permanent neurologic deficit in all cases. Once neurologic function returned to normal, the occlusion balloon was reinflated and the CAS procedure was completed. PercuSurge balloon reinflation was performed after a mean reperfusion interval of 10 minutes after full neurologic recovery (range 4–20 minutes). The mean subsequent procedure duration was 11.9 minutes (range 6–21 minutes). There were no instances of recurrence of neurologic symptoms after reinflation of the occlusion balloon. These findings were compatible with previously described models of neurologic tolerance induced by ischemic preconditioning. In the three patients in whom neurologic intolerance was precipitated by stimulation of the carotid baroreceptor by balloon dilatation, intravenous vasopressors were administered to alleviate hypotension. Vasopressor support with dopamine was used in all three patients. Supplemental phenylephrine was administered in one patient and norepinephrine was used in one other for refractory hypotension. Two of these patients developed complete asystole as a result of carotid balloon dilatation. These patients were instructed to cough forcefully to provide autocardiac compression. Forceful coughing resulted in generation of systolic pressures up to 60 mm Hg in these patients. No syncope developed in these two patients, and they were instructed to discontinue coughing after spontaneous restoration of a normal sinus rhythm. The development of bradycardia with a heart rate of less than 50 bpm was significantly reduced by the routine administration of atropine prior to the initial dilatation within the carotid bulb. All patients, including the two patients who developed cumulative ischemia without an evident precipitating factor, were managed by evacuation of the blood and any particulate matter from the ICA. This allowed for subsequent deflation of the PercuSurge occlusion balloon and restoration of antegrade cerebral perfusion. Once neurologic function returned to normal, the occlusion balloon was reinflated and the CAS procedure was completed. The mean subsequent procedure duration in these five patients was 7.9 minutes (range 5–9 minutes). Again, no recurrence of cerebral ischemia or neurologic intolerance occurred, suggesting the induction of neurologic tolerance by ischemic preconditioning. All 10 patients underwent successful dilatation of their carotid stenoses without occlusion, dissection, CVA, or cerebral hemorrhage.
Follow-Up
During the follow-up period (6–24 months, mean 15 months), none of the patients developed hemodynamically significant restenosis of the treated carotid artery. No patient has required reintervention on the index carotid artery. In addition, no patient has developed progression of disease in the contralateral carotid artery that required intervention. There have been no delayed neurologic events (CVA, TIA, or any other neurologic deficit) in the patients treated in the study. Hemodynamically significant stenosis of the external carotid artery occurred in three patients. There have been no instances of external carotid artery occlusion. In the patients who developed stenosis of the external carotid artery, no further intervention has been undertaken. These patients have remained free of clinical manifestations of the external carotid stenosis. There were no mortalities.
Discussion
Cerebral ischemia during temporary occlusion of the ICA develops in a significant proportion of patients during the performance of CEA.[11-16] However, the reported experience with CAS using the PercuSurge balloon has been more limited,[17-19] and the associated cerebral hypoxia has not been fully characterized. Ischemic preconditioning is an endogenous cellular protective mechanism whereby brief, noninjurious periods of ischemia render a tissue more resistant to a subsequent, more prolonged ischemic insult. Its protective effect has been initially described in the myocardium and had been shown to decrease infarct size, increase functional recovery, and abrogate ischemia and reperfusion-induced arrhythmias and myocardial stunning.[20-26] In the myocardium, the initial response to the ischemic stimulus lasts 2 to 3 hours and results from rapid post-translational modification of preexisting proteins. IP has also been described in animal models in which transient spinal cord ischemia reduces neurologic injury after experimental aortic occlusion.[27,28] This neuroprotective effect has also been described in a murine model of both global and focal cerebral ischemia and is demonstrated acutely after a very short 3-minute initial sublethal insult that is followed by 30 minutes of reperfusion.[29-33] It is thought to be mediated through increased release of endothelial nitric oxide and upregulation of inducible nitric oxide synthase (iNOS).[34,35]
The observation of initial neurologic intolerance to PercuSurge balloon inflation with subsequent tolerance following a short reperfusion interval is similar to the phenomenon of ischemic preconditioning demonstrated in animal models of spinal cord ischemia and cerebral hypoperfusion. The exact mechanism by which the ischemic preconditioning effect is mediated remains unknown but is believed to similarly involve several mediators, such as adenosine and nitric oxide.[27,34-37]
Several genes are known to have hypoxia-responsive elements in their promoters and can be activated by a short hypoxic insult. These include genes that regulate vasomotor control: iNOS, β-adrenergic receptor, endothelin; angiogenesis–vascular endothelial growth factor; erythropoiesis erythropoietin; cell death-notch intramembrane proteolysis (NIP)3, Nix; and energy metabolism-glucose transporters 1 and 3, lactate dehydrogenase, and aldolases.[38,39] Therefore, hypoxia may activate a large number of target genes that would act to increase cerebral perfusion, increase lactate and glucose delivery to cells, and promote rapid glycolysis during hypoxia and other cellular adaptations that renders the cells resistant to subsequent ischemic insults. Although several target genes are likely to account for hypoxia-induced changes, there are likely to be other factors that also mediate hypoxia-induced changes, including nontranscriptional and nontranslational changes occurring in various enzymes, ion pumps, and neurotransmitter systems that provide adaptive improvements in cell survival in the brain.
Although evidence from clinical trials published in the cardiac literature suggests that ischemic preconditioning occurs in humans,[20-25] the evidence for ischemic preconditioning in the human brain is less firm. Some studies suggest that patients with a stroke who had a previous TIA have milder neurologic deficits at presentation and better functional recovery,[40,41] although the mechanisms at play remain controversial.[40]
Of considerable interest was the occurrence of neurologic intolerance immediately on initial inflation of the occlusion balloon in the ICA. This immediate onset of cerebral ischemia occurred in five patients and was alleviated by deflation of the PercuSurge balloon and restoration of antegrade cerebral perfusion. The cerebral ischemia induced by the initial balloon occlusion appeared to induce ischemic preconditioning since reinflation and reocclusion of the ICA did not induce any further manifestations of neurologic intolerance.
No measurements of cerebral perfusion, such as electroencephalography or sensory evoked potentials, were obtained in this study. It is therefore not possible to completely characterize the mechanisms occurring in the adult brain that lead to ischemic preconditioning. Physiologic monitoring during CAS may allow the prediction of ischemic preconditioning in patients undergoing complete interruption of unilateral antegrade cerebral blood flow. Although positron emission tomography is an attractive tool to evaluate functional changes in cerebral activity, it is not possible to obtain intraoperatively during CAS. Other potential tests include intraoperative transcranial Doppler monitoring that may reveal a change in regional cerebral blood flow in patients experiencing ischemic preconditioning following transient occlusion of their ICA. However, cerebral blood flow as measured by laser-Doppler flowmetry did not differ during occlusion and reperfusion in a murine model of preconditioning despite a reduction in infarct size in the preconditioned group.[35] Electroencephalographic (EEG) monitoring with evaluation of frequency delays during periods of cerebral hypoxia could also be used. EEG changes associated with ischemic preconditioning are not fully characterized but can be inferred by the improvement in depolarization activity associated with cerebral hypoxia.
In 3 of the 10 patients, the onset of cerebral ischemia resulting in neurologic intolerance was directly associated with bradycardia and hypotension that resulted from balloon dilatation of the carotid sinus baroreceptor. Early in the study period, atropine was administered selectively for the development of bradycardia and hypotension. However, with increased experience, routine prophylactic administration was initiated for all patients with primary carotid lesions prior to angioplasty of the carotid bulb. Balloon dilatation was initiated only after the intrinsic heart rate had increased by 10 to 20 bpm. Administration of an additional prophylactic dose of atropine was performed in patients whose heart rate had returned to baseline or in whom the systolic blood pressure was less than 120 mm Hg. The patients who received selective administration of atropine were compared with those who received routine administration. The patients receiving routine atropine administration experienced a significant reduction in the incidence of bradycardia.[41,42] Consequently, routine administration of atropine prior to balloon dilatation of the carotid baroreceptor has been adopted for all patients with primary carotid stenosis.
Previous angiographic studies of the intracranial circulation have indicated that the need for use of an intravascular shunt may be predicted based on the status of the collateral circulation to the hemisphere ipsilateral to the index carotid stenosis.[43] In the current study, incomplete intracranial collateral vessels, that is, an absent anterior or posterior communicating artery, was present in 54% of patients who developed neurologic intolerance. Interestingly, incomplete intracranial collaterals were present in 39% of patients who did not experience neurologic intolerance. As a likely result of the relatively small sample size, these figures did not achieve statistical significance. Although it seems intuitively likely that incomplete collateral arterial communication may contribute to the development of neurologic intolerance during CAS using the PercuSurge balloon, the results of the current study are not able to confirm this supposition.
The duration of PercuSurge occlusion balloon inflation did not correlate with the development of cerebral ischemia and neurologic intolerance. The average duration of balloon occlusion of the ICA was relatively limited at 11.9 minutes and the maximum duration was 21 minutes. These durations are shorter than the time typically reported for performance of CEA. Despite this, the incidence of neurologic intolerance was relatively high in the current study. Of additional potential significance is the finding that two of the three patients with occlusion of the contralateral ICA did develop neurologic intolerance.
The etiology of cerebral ischemia resulting in neurologic intolerance during CAS with the PercuSurge balloon appears to be multifactorial in nature. Incomplete collateral circulation or occlusion of the contralateral ICA may be contributing factors. Hypotension resulting from angioplasty of the carotid bulb appears to be significant as well. Although balloon occlusion time did not correlate directly with the development of neurologic intolerance, it has the potential to be one of the multifactorial elements contributing to neurologic intolerance. Consideration of these factors during the performance of CAS with the PercuSurge occlusion balloon for cerebral protection is prudent. The avoidance of hypotension and asystole by routine atropine pretreatment prior to angioplasty and the ready availability of intravenous vasopressors for administration are two factors that may be directly controlled. Limiting balloon inflation time to the extent possible is also likely to be worthwhile. The status of the contralateral carotid artery and the anterior and posterior communicating arteries, although not modifiable, may identify patients at high risk for developing neurologic intolerance following interruption of antegrade carotid perfusion.
In conclusion, ischemic preconditioning seems to occur in the human brain and follows a short period of cerebral hypoperfusion during CAS using the PercuSurge occlusion balloon. As such, interventions based on the mechanisms of ischemic tolerance could be used in preventive or treatment strategies. It can be used to enable CAS in patients who cannot tolerate initial interruption of antegrade cerebral perfusion by PercuSurge occlusion. Ischemic tolerance after the initial transient ischemic event may be mediated by a protective cellular mechanism invoked during a short reperfusion interval. Although not characterized at the molecular level in patients undergoing CAS, ischemic preconditioning seen with the PercuSurge balloon makes this cerebral protection device a valuable tool in the armamentarium of CAS.
Reviewed by Dr. Ramaz Mitaishvili
