Incidence Coronary angiography has been and currently remains the gold standard for the diagnosis of coronary artery disease. It is an invasive procedure and is thus associated with various risks such as vascular and hemodynamic complications, contrast reaction, arrhythmias, myocardial infarction, stroke and death.1 Cardiac catheterization-related stroke has an incidence of 0.03% to 0.3% for diagnostic procedures2–4 and 0.3–0.4% for percutaneous coronary intervention (PCI).5,6 In patients undergoing percutaneous interventions, stiff, large-bore guiding catheters are used. These design characteristics can be more traumatic to the aorta than diagnostic catheters, which are more flexible and have smaller lumens and tapered tips. Causes of and Predisposing Factors for Stroke Patients with ischemic coronary artery disease often have generalized atherosclerosis. The use of guidewires and catheters may, therefore, cause fragmentation of atherosclerotic plaques with subsequent embolization.3,5,7,8 Other causes include air or cholesterol embolism and thrombus formation at the catheter tip.9,10 Some patient characteristics have been shown to increase the risk of a stroke due to cardiac catheterization. These include female gender, left ventricular hypertrophy,2 hypertension, diabetes mellitus, renal insufficiency and previous stroke.2,3,5,6,8 Large atherosclerotic burden, such as in those patients with advanced coronary artery disease, prior coronary artery bypass grafting (CABG), or extensive plaque on transesophageal echocardiography2,4 may also increase risk. Depressed ejection fraction has also been shown to increase risk, possibly by dislodgement of apical thrombus during left ventriculography.2 These patients should therefore be identified prior to the cardiac catheterization procedure as high risk for cerebrovascular complications. The procedure, equipment used and operative technique can also have an impact on the risk of stroke. Two recognized procedural risk features are longer fluoroscopic time3 and the use of larger-caliber catheters.11 Judkins left and Multipurpose guiding catheters have been shown to more frequently dislodge atheromatous debris from the aorta than other catheters. This is possibly because they are more traumatic to the aorta due to their long second-curve design. The use of smaller guiding catheters is recommended to avoid the risk of vascular embolization.11 Efforts should be made, especially in high-risk patients, to avoid prolonged fluoroscopy and to use catheters less likely to dislodge thrombi. Prolonged fluoroscopy may be a reflection of more complex or difficult procedures with the use of more interventional equipment. Microemboli have been frequently detected during invasive cardiovascular procedures.12,13 Solid microemboli are most likely due to mechanical fragmentation of atherosclerotic plaques or clots from the tip of the catheter. Gaseous emboli are usually caused by the entry of microbubbles during the injection of contrast and saline. While the majority (92%) of microemboli are gaseous, solid emboli have been more associated with cerebral injury.14 It has been shown, however, that larger volumes of intra-arterial air may also disturb brain metabolism.12 Vascular access through the radial artery instead of the femoral artery is being used increasingly for cardiac catheterization. The transradial approach gives rise to a higher number of solid cerebral microemboli than transfemoral catheterization, but there is no evidence showing whether these lead to cerebrovascular symptoms.14 When introduced from the right arm, the guidewire has to pass the apertures of the right vertebral and the right common carotid arteries. The guidewire may, at least in some cases, cause some mechanical force upon atherosclerotic plaques located near these apertures. Solid emboli generated during guidewire advancement from the femoral artery will be carried in the bloodstream to the abdominal viscera or the lower limbs. One study has shown that none of the patients who underwent brachial catheterization had an embolic event compared to 17% of patients who underwent femoral catheterization.7 The influence of the route of access on symptomatic embolization during coronary angiography has not been definitively established. Cerebral microemboli are predominantly detected during catheter advancement, catheter flushing, contrast injection and ventriculography.14 There is also a significant correlation between the number of microemboli and the volume of contrast used.14 Various studies have tried to estimate the significance of atherosclerotic aortic debris on cardiac catheterization. Atherosclerotic plaques of the thoracic aorta, as detected by transesophageal echocardiography, are a common finding in patients with coronary artery disease.15 These patients are at increased risk for catheter-related stroke or peripheral embolism, particularly in the presence of mobile atherosclerotic debris.7 The strongest clinical predictors of atherosclerotic aortic debris are advanced age and peripheral vascular disease.7 Karalis et al7 recommended the brachial approach instead of transfemoral cardiac caheterization in patients with mobile aortic plaque in order to prevent stroke or peripheral embolization. In summary, patients at risk for cerebrovascular complications of cardiac catheterization should be identified in advance. It also merits consideration whether transesophageal echocardiography should be used to identify at-risk patients who have mobile atherosclerotic plaques. Once these patients are identified, further measures should be undertaken to ensure that they are well hydrated prior to the procedure, as well as adopting techniques during the catheterization itself to minimize the chances of a stroke occurring. These include the use of atraumatic catheters, avoiding prolonged fluoroscopy time and not performing ventriculography if possible, especially if echocardiographic information is available. Clinical Features Pericoronary angiography strokes often occur during or immediately after the procedure when the femoral artery sheath is still in place,9 but the diagnosis can be delayed up to 36 hours in some cases.3 Common symptoms include visual disturbance, motor weakness, aphasia and altered mental status. There is vertebrobasilar involvement in almost half of the cases.2,3,5,6 Asymptomatic cerebral infarction following cardiac catheterization has been shown to occur in about 15% of patients.16 A 37-month study2 of about 6,500 patients who underwent invasive cardiac procedures such as left heart catheterization, balloon angioplasty and valvuloplasty, had an overall 0.4% incidence of neurological complications. The most common symptoms were visual disturbances (26%), hemiparesis (26%) and facial droop (26%). Deficits were localizable to the posterior circulation in 36% of patients and anterior in 64%. Al-Mubarak et al showed that most of the embolic strokes during catheterization procedures are associated with an embolus located in either the common carotid bifurcation or the proximal middle cerebral artery.17 In a recent 1-year study of pericoronary angiography strokes,10 the occluded vessel was the middle cerebral artery (MCA) in 24% of patients, the posterior cerebral artery in 19%, the basilar artery in 5%, the vertebral artery in 10% and occlusion in 2 anterior circulation branches (MCA, anterior cerebral artery, or both) in 43% patients. In another study of strokes complicating 20,900 cardiac catheterization procedures, the posterior circulation was affected in 21 of the 39 infarcts.3 The majority of patients who had a stroke following cardiac catheterization had an unfavorable outcome with a Rankin score of 3–6, i.e., moderate disability to coma, with a high inpatient mortality rate.3 The Rankin score is a measure of post-stroke handicap. Patients with large-vessel strokes tended to do worse.3 Investigations Computed tomography (CT) or magnetic resonance imaging (MRI), or both, have been performed in various studies investigating stroke post-cardiac catheterization. The contrast resolution of MRI is significantly higher than CT, making it far more sensitive than CT, especially in early cerebral ischemia.18 Diffusion-weighted (DWI) MRI is very sensitive for detecting cerebral ischemia within minutes after its onset, far exceeding any other imaging method available today.19 Studies using this imaging modality have shown that new cerebral lesions may be detected immediately after catheterization of stenotic aortic valves and CABG.20 Omran et al20 also found, after catheterization of stenotic aortic valves, that every acute cerebral DWI lesion was still present as a similar low-intensity lesion on conventional MRI sequences 3 months later. This strongly suggests that they represented irreversible ischemic injury. DWI with MRI has also shown multiple acute lesions (often tiny, cortical and in different vascular territories) distinct from the symptomatic lesion. This is consistent with a shower of embolic material.3 CT is still the most widely-used imaging option mainly to rule out hemorrhagic stroke. Transcranial Doppler (TCD) is also an established noninvasive method which can be used to detect cerebral microemboli.21 If the femoral sheath is still in place, however, cerebral angiography is a quicker and more sensitive investigative modality. Diagnostic cerebral angiography in patients with acute stroke can better define the thrombus morphology, degree of occlusion by the offending thrombus and presence or absence of collateral pathways.22 This investigation requires involvement of an interventional neuroradiologist. It may become necessary for cardiologists to develop this skill, in view of the fact that many cardiac centers do not have access to an interventional neuroradiologist. The degree of vessel occlusion has been classified by using the thrombolysis in myocardial infarction (TIMI) score. TIMI 0 is complete occlusion, TIMI 1 is contrast material passage through the clot with minimal perfusion, TIMI 2 is partial flow and/or recanalization, and TIMI 3 is complete flow and/or recanalization.23 A “TICI score” in stroke studies specifies “cerebral” rather than “myocardial” perfusion with corresponding grade definitions. Although cerebral angiography carries a finite risk of complications due to the procedure itself, the relative risk is considered to be low in the setting of acute stroke.24 Treatment Cardiologists managing acute ischemic stroke complicating cardiac catheterization should compare its treatment to the evolution of management strategies for acute myocardial infarction. Very early recanalization of occluded arteries is the critical step for treatment of both diseases. Although there are parallels between treatments of ischemic stroke and myocardial infarction, differences exist that make effective treatment of acute ischemic stroke particularly challenging.25 Acute platelet-rich thrombi that form on an atherosclerotic plaque are usually the culprit lesion for ischemia in myocardial infarction. In contrast, many ischemic strokes are due to emboli from thrombi formed in a proximal extracranial artery or in the heart.26 This is especially true in the context of pericoronary angiography stroke. These emboli are likely to vary substantially in composition, and may consist of much older and harder clots that might be less likely to respond to thrombolytic agents alone.25 Secondly, the volume of clot in some patients with ischemic stroke may be substantially greater that that seen in acute myocardial infarction. Clot may occlude the internal carotid as well as the middle cerebral artery trunk and beyond. Such extensive clot is unlikely to be lysed by intravenous thrombolytic therapy alone during the first few critical hours after stroke onset in the vast majority of cases. Thirdly, extracranial arteries to the brain can be quite tortuous, particularly in the elderly, and the intracranial carotid arteries traverse through bony canals. These factors can make intra-arterial delivery of mechanical devices to remove clot, and even maneuvering of guide catheters, difficult and time-consuming. In addition, the brain does not tolerate perforation of distal vessels by guidewires. Due to these substantial differences in the pathophysiology of stroke complicating cardiac catheterization, it is imperative to seek early assistance from stroke physicians to assess the anatomical and clinical correlates of the lesion to enable decision-making regarding the type of management needed. Thrombolysis for acute ischemic stroke has sparked much debate since the landmark NINDS-tPA (National Institute of Neurological Disorders and Stroke) trial in 1995.27–29 As the benefits of thrombolysis have been shown to outweigh the risks, systemic intravenous (IV) tPA (at a dose of 0.9 mg/kg, not exceeding 90 mg, given as a 10% bolus followed by continuous infusion of the remaining 90% over 60 minutes) has been an established treatment for spontaneous acute ischemic stroke of less than 3 hours’ duration.27,28 Due to the low incidence of stroke complicating cardiac catheterization, no defined standard of acute therapeutic options exists.29,30 In most cases, the etiology is felt to be embolic due to atherosclerotic debris and not thrombus,3,4,6,7 and therefore acute therapy with systemic thrombolysis is not routinely performed. The outcome of untreated stroke complicating cardiac catheterization has been shown to be poor.3 Hence, definitive management strategies are essential for recanalization to reestablish cerebral blood flow. Treatment modalities via the IV or intra-arterial (IA) route for this iatrogenic complication have mainly been derived from case reports and small trials.17,29–33 Full recovery after IV urokinase or rtPA has also been reported in isolated anterior and posterior circulation strokes during the pericoronary angiography period.30–32 Due to the paucity of trials of IV thrombolysis for ischemic stroke complicating cardiac catheterization, outcomes have to be extrapolated from other trials of thrombolysis for ischemic strokes. Three trials of streptokinase for stroke thrombolysis were stopped because of high rates of acute mortality and intracranial bleeding,34–36 hence clinical interest is presently focused on urokinase and rtPA. A 2004 update of the Cochrane review of thrombolysis using urokinase (UK), streptokinase, recombinant pro-UK, or rtPA for acute ischemic stroke included 18 trials comprising 5,727 patients.37 For treatment up to 3 hours after stroke (1,311 patients, 50% of whom came from the National Institute of Neurological Disorders and Stroke [NINDS] trial), thrombolytic therapy appeared more effective in reducing poor functional outcomes (all agents OR, 0.66; 95% CI, 0.53, 0.83; rtPA OR, 0.64; 95% CI, 0.5, 0.83) with no significant mortality adverse events at the end of follow up (all agents OR, 1.13; 95% CI, 0.86, 1.48; rtPA OR, 0.97; 95% CI, 0.69, 1.36), but still an excess of symptomatic intracranial hemorrhage (rtPA OR, 3.40; 95% CI 1.48 to 7.84). While the landmark NINDS trial of IV tPA for ischemic stroke required a neurodeficit measurable on NIHSS (National Institute of Health Stroke Scale), the PROACT (Prolyse in Acute Cerebral Thromboembolism) IA thrombolysis trials required a minimum NIHSS of 4 to be eligible for thrombolysis.37,38 Recovery in the NINDS-tPA trial was defined as an improvement in NIHSS of 4 from baseline at 24 hours after onset of symptoms.27,39 The principal goal of ischemic stroke treatment is to rapidly restore cerebral blood flow. Pericoronary angiography strokes which often occur during or immediately after the procedure when the femoral artery sheath is still in place, do provide a unique opportunity for rapid initiation of IA thrombolysis and catheter-based intervention.9 IV thrombolysis appears to be better suited to the recanalization of smaller distal emboli as opposed to large intracranial vessel occlusions that can be successfully lysed with local intra-arterial infusion.40 Rates of recanalization in the proximal MCA are higher with IA thrombolysis than with IV thrombolysis, with recanalization rates of 70% and 31%, respectively.41 Technical advances in the design of softer, more compliant microcatheters and steerable guidewires have made intracranial endovascular access increasingly feasible and safe. The theoretical advantages of IA thrombolysis include direct infusion of the medication into the occluding thrombus with higher local drug concentrations, lower systemic concentration of thrombolytic agent and less risk of extracranial hemorrhagic complications. It also allows precise depiction of the arterial anatomy including morphology of thrombus, assessment of treatment effect and extent of collateral circulation, and the possible use of mechanical means to disrupt the clot with the use of guidewires, microcatheters or other devices.22 The disadvantages of this approach are the time delays required for angiography and microcatheter placement before therapy is commenced. If the femoral sheath is still in place, there is an opportunity to minimize some of these delays for IA thrombolysis. The additional risks of the endovascular procedure itself include intracranial arterial embolization, subarachnoid hemorrhage, arterial perforation, hemorrhagic infarction, retroperitoneal hematoma and groin hematoma.42 Such complications occur in less than 5% of patients treated.42 Two major trials of IA thrombolysis for ischemic stroke, PROACT 1 and PROACT 2, used 6–9 mg of r-pro-UK via a microcatheter embedded in the proximal third of the thrombus or in close proximity to the clot, followed by IV heparin for 4 hours in patients within 6 hours of symptom onset. These trials showed that IA administration of thrombolytic agents appears to have better recanalization and clinical outcomes than IV t-PA, and the rate of intracerebral hemorrhage is similar to that seen in the NINDS t-PA Stroke trial.25 A recently published retrospective, multicenter study of 21 patients who received IA thrombolysis for pericoronary angiography (10 diagnostic and 11 interventional) ischemic stroke found arterial occlusion in 14 (66.7%) and 7 (33.3%) of the anterior and posterior circulation, respectively.10 Mean time-to-therapy was 36 ± 12 minutes from the time the neurological deficit was noted. rtPA was used in 9 (43%) patients, and UK in 12 (57%) patients. The median rtPA dose was 23 mg (range 12–34). The median UK dose was 1,000,000 U (range 50,000–1,500,000). No heparin was allowed for 24 hours after IA thrombolysis. Recanalization (TIMI 1, 2 and 3) occurred in 14 (66.7%) patients: complete (TIMI 3) in 5 (24%) and partial (TIMI 1 and 2) in 9 (43%); no recanalization (TIMI 0) occurred in 7 (33.3%) patients. Ten patients (48%) had good outcomes at discharge. The recanalization rate and mortality (19% — a quarter of which was due to intracranial hemorrhage, and the rest were due to large stroke or severe coronary artery disease) were similar to previous trials of intra-arterial thrombolysis.9 Younger age, shorter time-to-treatment and lack of intracranial hemorrhage showed a trend for improved outcomes. Though there was no statistically significant difference with regard to gender, race, thrombolytic agent used or NIHSS, patients with good outcomes had a numerically lower median NIHSS score than patients with bad outcomes (15 versus 18).9 Patients with large-vessel strokes who tend to do worse might be candidates for IA thrombolysis, and if such an endovascular approach is chosen, mechanical disruption of athero-embolic material rather than pharmacologic clot lysis may be necessary to achieve vessel patency.3 Al-Mubarak et al reported a 75% success rate for a complete or near-complete improvement in neurological deficit using catheter-based neurovascular rescue for stroke during invasive coronary procedures.17 Mechanical embolus disruption can be used as an adjunctive technique during IA thrombolytic therapy,17,43,44 especially when there is no improvement in flow after the initial dose of thrombolytic agent. Balloon angioplasty with or without thrombolysis may also be an effective method for reperfusion.33,45 Other techniques that have been tried for recanalization for ischemic stroke include devices that deliver laser energy, ultrasound devices46 and the Neurojet (a modified version of the Angiojet catheter currently approved for the removal of clot in the coronary circulation).47 Angioplasty and stenting have been performed in a series of 8 patients with symptomatic intracranial vertebrobasilar atherosclerosis reported by Rasmussen et al at the Cleveland Clinic.38 The procedure was technically successful in 7 patients, and they were asymptomatic up to 8 months later. Stroke physicians will in all likelihood follow the steps of cardiologists who have used a multipronged approach to reopen occluded coronary arteries that involves drugs and mechanical devices, and that depends on the availability of technology and expertise at a given hospital. Conclusion Stroke is a rare but devastating complication of cardiac catheterization. Both patient characteristics and procedural risk factors have been identified which increase the risks of this complication. Patients may have to be better risk-stratified with investigations using technologies such as transesophageal echocardiography prior to subjecting them to cardiac catheterization. This iatrogenic complication offers a unique opportunity for rapid treatment due to the short event-to-treatment time, availability of resources for rapid imaging and the possibility of neurovascular rescue if the femoral sheath is still in place. A catheter-based technique may be an optimal reperfusion strategy for acute stroke during cardiac catheterization, and may provide an improved outcome of a potentially debilitating complication of the procedure, but this clinical pathway is appropriate only when experienced personnel and equipment are available.36 It may be important for cardiovascular specialists to be familiar with cerebrovascular anatomy and angiographic technique in order to improve our manpower to provide emergency care such as acute stroke management. This is important, as intra-arterial reperfusion may become the preferred therapy in acute stroke when compared to systemic thrombolysis, particularly in this iatrogenic condition. It is also imperative to involve the stroke team early, and management decisions should be made jointly by the cardiologist and stroke physician. Well-defined protocols are thus necessary in every cardiac catheterization lab for the management of stroke complicating cardiac catheterization. One such protocol we suggest is shown in Figures 1 and 2.
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