Cerebral Vasospasm in Aneurysmal Subarachnoid Hemorrhage
Complications of TBA for cerebral vasospasm include vessel perforation (with microguidewire, microcatheter or balloon), vessel rupture (balloon), index artery dissection, index artery occlusion, ischemic stroke, hemorrhagic transformation of infarcted tissue, rebleeding from uncontrolled aneurysms and displacement of aneurysm clips.
Cerebral arterial rupture from over dilation is often lethal and most survivors have very poor clinical outcomes. The rate of cerebral arterial rupture in large case series has been reported to be as high as 4–5%. Contemporary estimates based on literature review suggest that the rupture rate is closer to 1% using modern devices and techniques.
Estimation of the true incidence of procedure related ischemic stroke in patients undergoing TBA is difficult because cerebral infarctions that are caused by the effects of PHCV alone are difficult to distinguish from those that are iatrogenic. Nevertheless, thromboembolic complications have been reported in as many as 4–5% of cases.
The long term angiographic results of TBA for PHCV have not been systematically evaluated. Long term development of flow limiting stenoses at the angioplasty site has been reported. The true incidence and prevalence of steno-occlusive sequelae due to intimal hyperplasia or dissection is unknown.
The risk of specific complications is modified to a significant degree by anatomical factors, disease related factors and technical factors. As with all surgical procedures, the physician should make every effort to minimize the risk of procedure related complications.
The target vessel selected for TBA represents one of the most important anatomical factors governing procedure related risk. PHCV frequently involves the large conducting subarachnoid arteries within and proximal to the circle of Willis at the base of the brain. These proximal cerebral vessels are often large with normal luminal calibers that range from 2 to 5 mm. Most clinical experience with TBA for PHCV has been restricted to these large proximal cerebral vessels (intracranial internal carotid artery, vertebral artery, basilar artery, M1, A1 and P1). Due to their small size and relative mural frailty, it is unclear to what extent the more distal vessels can be safely dilated with currently available balloon angioplasty catheters. It is not advisable to treat spastic vessels with baseline luminal diameters <1.5 mm by balloon angioplasty.
Technical factors that modify procedural risks relate to the use of anticoagulation. Intravascular stasis of blood, endothelial injury and a large profile intravascular foreign body surface are all factors that promote cerebral thromboembolism in this setting. Consequently, it is important to confirm effective anticoagulation before placing instrumentation in the spastic cerebral arteries with a guidewire or angioplasty balloon. In general, heparin is used because of its rapid onset of action, short half-life and ease of reversibility with protamine. An activated clotting time of 250–300 s is generally desirable. In theory, the risks of procedure related complications during microguidewire navigation and balloon inflation increase if the patient is moving. Consequently, most operators feel that procedural safety is optimized if patients are mechanically ventilated and paralyzed during TBA. Patient paralysis maximizes visibility of very small angioplasty balloons, and allows high quality digital subtraction angiograms to guide therapeutic decision making.
TBA for PHCV is currently performed with commercially available single and double lumen over the wire balloon catheters that track over 0.010 inch and 0.014 inch microguidewires, respectively. Coaxial navigation and balloon inflation can be safely performed using roadmap and fluoroscopic guidance. Control angiograms, performed through the guiding catheter after each balloon inflation cycle, provide important angiographic feedback to the operator. While single lumen balloon catheters are all compliant, double lumen balloon catheters may be compliant, semi-compliant or non-compliant.
It is prudent to under size balloons relative to the baseline normal vessel diameter (≤80–85%) to avoid over dilation. If possible, successive dilations are performed from distal to proximal to avoid crossing a fresh angioplasty site with balloon or wire, as this may inadvertently raise a dissection flap.
If possible, balloon length should be chosen to cover the longest contiguous straight segment of vessel to be treated, so that multiple dilations will not be necessary. When single lumen balloon occlusion microcatheters are subjected to multiple inflations, blood entering the balloon through the distal endhole can diminish balloon radio-opacity, decreasing the safety of inflation under fluoroscopic guidance and preventing timely balloon deflation. If the target segment is contiguous around a sharply angulated curve, a shorter balloon may be chosen and serial distal to proximal dilations performed to avoid forced straightening of the artery when the balloon is inflated. The limits of balloon inflation are determined by direct observation of balloon size and shape fluoroscopically, in addition to tracking the calculated inflation volumes.
Angioplasty can be safely performed using compliant, semi-compliant and non-compliant balloons. Most double lumen balloon catheters suitable for intracranial angioplasty are designed for the treatment of coronary artery atherosclerotic vascular disease. These balloons reach nominal diameters at pressures in the range of 6–18 atmospheres. Generally, a much lower balloon pressure is needed to counter the contractile force generated by a cerebral artery in spasm, and restore normal luminal caliber. The critical threshold for vessel rupture is determined by vessel radius and wall tension, rather than balloon pressure. When a non-compliant balloon bridges mismatched arterial segments, the relatively rigid balloon will disproportionately stretch the smaller segment. The smaller segment will be at greatest risk of rupture. When a compliant balloon bridges mismatched arterial segments, the balloon will preferentially expand into the larger segment. This results because at the same balloon pressure a higher wall tension is required to resist balloon expansion in the larger segment according to Laplace's law. Consequently, the larger caliber segment is at greatest risk of rupture. Balloon inflation should be limited to approximately 85% of the baseline luminal diameter of any target segment.
Disease related factors that modify procedural risks encompass both end organ disease and vessel wall disease. Reperfusion of completed cerebral infarctions can lead to significant neurological deterioration owing to hemorrhagic transformation. Consequently, it is inadvisable to perform TBA of vessels supplying the territory of a large completed cerebral infarction. TBA performed adjacent to clipped ruptured aneurysms has been associated with fatal rupture of the parent artery. Angioplasty of vessel segments that may be structurally compromised should be avoided.
IAVT can be administered through selective (≥4 French) or superselective (≤3 French) transarterial catheters. Infusions given through superselective microcatheters placed within affected pial arteries ensure that an effective dose is delivered to the target circulation. This may be advantageous in specific situations where two circulations are competing for flow at a bifurcation. For example, if the intent is to treat anterior cerebral artery spasm in the setting of a tightly constricted A1 and widely patent M1, drug administered into the internal carotid artery would run off to the lower resistance middle cerebral artery circulation substantially reducing the dose delivered to the anterior cerebral artery. Another specific example in which superselective infusion is advantageous relative to selective infusion relates to the risk of transient and permanent blindness as a result of papaverine infusion into the internal carotid artery. There is evidence that the risk is significantly higher when papaverine infusions are given through catheters placed proximal to the ophthalmic artery. In many patients, however, effective treatment can be administered by infusing vasodilators through selective catheters positioned in the extracranial internal carotid artery or vertebral artery. Vasodilators infused into the cerebral arterial circulation in this way can produce vasodilatation at all levels of the cerebral arterial tree without the associated risks of pial vessel instrumentation. In theory, continuous infusions delivered at a constant rate may be asymmetrically distributed to downstream vascular territories when flow is laminar. Consequently, some operators administer infusions as a series of rapid pulsatile bursts to ensure uniform dispersal of drug in the anterograde bloodstream. IAVT procedures are safe for the management of PHCV involving the distal cerebral arteries beyond the circle of Willis, a commonly encountered problem. In addition, IAVT can be safely performed in awake patients that are independently breathing. Nevertheless, IAVT procedures are not without risk. The procedure related risks encompass all the risks of DSA, including the small risk of cervicocerebral arterial dissection and stroke. Treatment specific risks depend to some degree on the vasodilator agent selected. All agents have occasionally been associated with seizures, intra-cranial hypertension and systemic hypotension. The onset of action for intra-arterial vasodilators is often delayed and the therapeutic effects are short lived. Consequently, repeated procedures are often necessary to manage relapsing symptoms with the cumulative risks accruing over time.
For more than 20 years, papaverine, a phosphodiesterase inhibitor, was the most widely used agent employed in IAVT procedures. It is infrequently used in current clinical practice because of concerns about the potential neurotoxicity of papaverine or its commonly used preservative chlorobutanol. These concerns were sparked by a report documenting the development of symptomatic brain lesions in five patients treated with intra-arterial papaverine for PHCV in San Francisco when all patients became symptomatic immediately after the initiation of intra-arterial papaverine and all developed gray matter lesions in the irrigated vascular territories on brain MRI. Histological findings in one patient were consistent with selective gray matter necrosis, a feature more closely associated with the effect of metabolic toxins rather than ischemic tissue damage. Intra-arterial papaverine is commonly administered in normal saline as a 0.3% solution at a dose of 300 mg per arterial territory infused over a 30 min period. Compared with other vasodilators used for the treatment of PHCV, papaverine is much more insoluble and has a strong tendency for precipitation in aqueous solutions. Mixing of papaverine solutions with iodinated contrast or heparin solutions may promote precipitation. The formation of insoluble crystals in clinical preparations of papaverine can lead to clinically significant embolic complications. Intracranial hypertension has been reported to be a significant problem after treatment of multiple vascular territories by intra-arterial papaverine infusion. This presumably occurs due to the augmentation of cerebral blood volume produced by widespread cerebral vasodilatation. Seizures, mydriasis and transient hemiparesis have also been reported. Transient and rarely permanent monocular blindness has been reported after intra-arterial papaverine infusion through catheters placed in the internal carotid artery proximal to the origin of the ophthalmic artery. Cardiac dysfunction and respiratory arrest have been reported with posterior circulation infusions of papaverine. Milrinone, another phosphodiesterase inhibitor, has been used for IAVT in small case series.
Calcium channel blockers have been infused directly into the cerebral arteries to treat PHCV. Nimodipine was the first agent used in this way. The use of intra-arterial verapamil and nicardipine are being increasingly reported in the literature. Verapamil is typically administered as a bolus infusion whereas nicardipine is delivered slowly in a prolonged infusion for up to 90 min periods. Prolonged infusions involving indwelling transarterial catheters are theoretically associated with a greater risk of thromboembolism. Although there are reports of prolonged infusions through transarterial intracranial microcatheters lasting as long as 20 h (median 8 h), further study is necessary to establish the safety of this approach. Significant increases in intracranial pressure and decreases in cerebral perfusion pressure lasting for several hours have been reported with high dose intra-arterial verapamil infusion. Systemic hypotension is rarely seen with verapamil; however, doses exceeding 35 mg per procedure have been associated with significant decreases in mean arterial pressure, often in delayed fashion as long as 5–7 h after the procedure. Intra-arterial nicardipine is more often associated with hypotension, particularly with high doses. Initial reports of intra-arterial verapamil described doses of 2–5 mg per vessel treated. Although many operators currently use 10–20 mg per vessel, little is known about the dose–response relationship. We have observed seizures in patients treated with high doses of intra-arterial verapamil (≥15 mg/vessel). High dose intra-arterial verapamil has also been associated with hypotension in more than 50% of patients. Nicardipine has been given in doses of 0.5–0.6 mg per vessel but doses higher than 15 mg per vessel are also reported.
Modality Specific Procedural Safety
Transluminal Balloon Angioplasty
Complications of TBA for cerebral vasospasm include vessel perforation (with microguidewire, microcatheter or balloon), vessel rupture (balloon), index artery dissection, index artery occlusion, ischemic stroke, hemorrhagic transformation of infarcted tissue, rebleeding from uncontrolled aneurysms and displacement of aneurysm clips.
Cerebral arterial rupture from over dilation is often lethal and most survivors have very poor clinical outcomes. The rate of cerebral arterial rupture in large case series has been reported to be as high as 4–5%. Contemporary estimates based on literature review suggest that the rupture rate is closer to 1% using modern devices and techniques.
Estimation of the true incidence of procedure related ischemic stroke in patients undergoing TBA is difficult because cerebral infarctions that are caused by the effects of PHCV alone are difficult to distinguish from those that are iatrogenic. Nevertheless, thromboembolic complications have been reported in as many as 4–5% of cases.
The long term angiographic results of TBA for PHCV have not been systematically evaluated. Long term development of flow limiting stenoses at the angioplasty site has been reported. The true incidence and prevalence of steno-occlusive sequelae due to intimal hyperplasia or dissection is unknown.
The risk of specific complications is modified to a significant degree by anatomical factors, disease related factors and technical factors. As with all surgical procedures, the physician should make every effort to minimize the risk of procedure related complications.
The target vessel selected for TBA represents one of the most important anatomical factors governing procedure related risk. PHCV frequently involves the large conducting subarachnoid arteries within and proximal to the circle of Willis at the base of the brain. These proximal cerebral vessels are often large with normal luminal calibers that range from 2 to 5 mm. Most clinical experience with TBA for PHCV has been restricted to these large proximal cerebral vessels (intracranial internal carotid artery, vertebral artery, basilar artery, M1, A1 and P1). Due to their small size and relative mural frailty, it is unclear to what extent the more distal vessels can be safely dilated with currently available balloon angioplasty catheters. It is not advisable to treat spastic vessels with baseline luminal diameters <1.5 mm by balloon angioplasty.
Technical factors that modify procedural risks relate to the use of anticoagulation. Intravascular stasis of blood, endothelial injury and a large profile intravascular foreign body surface are all factors that promote cerebral thromboembolism in this setting. Consequently, it is important to confirm effective anticoagulation before placing instrumentation in the spastic cerebral arteries with a guidewire or angioplasty balloon. In general, heparin is used because of its rapid onset of action, short half-life and ease of reversibility with protamine. An activated clotting time of 250–300 s is generally desirable. In theory, the risks of procedure related complications during microguidewire navigation and balloon inflation increase if the patient is moving. Consequently, most operators feel that procedural safety is optimized if patients are mechanically ventilated and paralyzed during TBA. Patient paralysis maximizes visibility of very small angioplasty balloons, and allows high quality digital subtraction angiograms to guide therapeutic decision making.
TBA for PHCV is currently performed with commercially available single and double lumen over the wire balloon catheters that track over 0.010 inch and 0.014 inch microguidewires, respectively. Coaxial navigation and balloon inflation can be safely performed using roadmap and fluoroscopic guidance. Control angiograms, performed through the guiding catheter after each balloon inflation cycle, provide important angiographic feedback to the operator. While single lumen balloon catheters are all compliant, double lumen balloon catheters may be compliant, semi-compliant or non-compliant.
It is prudent to under size balloons relative to the baseline normal vessel diameter (≤80–85%) to avoid over dilation. If possible, successive dilations are performed from distal to proximal to avoid crossing a fresh angioplasty site with balloon or wire, as this may inadvertently raise a dissection flap.
If possible, balloon length should be chosen to cover the longest contiguous straight segment of vessel to be treated, so that multiple dilations will not be necessary. When single lumen balloon occlusion microcatheters are subjected to multiple inflations, blood entering the balloon through the distal endhole can diminish balloon radio-opacity, decreasing the safety of inflation under fluoroscopic guidance and preventing timely balloon deflation. If the target segment is contiguous around a sharply angulated curve, a shorter balloon may be chosen and serial distal to proximal dilations performed to avoid forced straightening of the artery when the balloon is inflated. The limits of balloon inflation are determined by direct observation of balloon size and shape fluoroscopically, in addition to tracking the calculated inflation volumes.
Angioplasty can be safely performed using compliant, semi-compliant and non-compliant balloons. Most double lumen balloon catheters suitable for intracranial angioplasty are designed for the treatment of coronary artery atherosclerotic vascular disease. These balloons reach nominal diameters at pressures in the range of 6–18 atmospheres. Generally, a much lower balloon pressure is needed to counter the contractile force generated by a cerebral artery in spasm, and restore normal luminal caliber. The critical threshold for vessel rupture is determined by vessel radius and wall tension, rather than balloon pressure. When a non-compliant balloon bridges mismatched arterial segments, the relatively rigid balloon will disproportionately stretch the smaller segment. The smaller segment will be at greatest risk of rupture. When a compliant balloon bridges mismatched arterial segments, the balloon will preferentially expand into the larger segment. This results because at the same balloon pressure a higher wall tension is required to resist balloon expansion in the larger segment according to Laplace's law. Consequently, the larger caliber segment is at greatest risk of rupture. Balloon inflation should be limited to approximately 85% of the baseline luminal diameter of any target segment.
Disease related factors that modify procedural risks encompass both end organ disease and vessel wall disease. Reperfusion of completed cerebral infarctions can lead to significant neurological deterioration owing to hemorrhagic transformation. Consequently, it is inadvisable to perform TBA of vessels supplying the territory of a large completed cerebral infarction. TBA performed adjacent to clipped ruptured aneurysms has been associated with fatal rupture of the parent artery. Angioplasty of vessel segments that may be structurally compromised should be avoided.
Intra-arterial Vasodilator Infusion Therapy
IAVT can be administered through selective (≥4 French) or superselective (≤3 French) transarterial catheters. Infusions given through superselective microcatheters placed within affected pial arteries ensure that an effective dose is delivered to the target circulation. This may be advantageous in specific situations where two circulations are competing for flow at a bifurcation. For example, if the intent is to treat anterior cerebral artery spasm in the setting of a tightly constricted A1 and widely patent M1, drug administered into the internal carotid artery would run off to the lower resistance middle cerebral artery circulation substantially reducing the dose delivered to the anterior cerebral artery. Another specific example in which superselective infusion is advantageous relative to selective infusion relates to the risk of transient and permanent blindness as a result of papaverine infusion into the internal carotid artery. There is evidence that the risk is significantly higher when papaverine infusions are given through catheters placed proximal to the ophthalmic artery. In many patients, however, effective treatment can be administered by infusing vasodilators through selective catheters positioned in the extracranial internal carotid artery or vertebral artery. Vasodilators infused into the cerebral arterial circulation in this way can produce vasodilatation at all levels of the cerebral arterial tree without the associated risks of pial vessel instrumentation. In theory, continuous infusions delivered at a constant rate may be asymmetrically distributed to downstream vascular territories when flow is laminar. Consequently, some operators administer infusions as a series of rapid pulsatile bursts to ensure uniform dispersal of drug in the anterograde bloodstream. IAVT procedures are safe for the management of PHCV involving the distal cerebral arteries beyond the circle of Willis, a commonly encountered problem. In addition, IAVT can be safely performed in awake patients that are independently breathing. Nevertheless, IAVT procedures are not without risk. The procedure related risks encompass all the risks of DSA, including the small risk of cervicocerebral arterial dissection and stroke. Treatment specific risks depend to some degree on the vasodilator agent selected. All agents have occasionally been associated with seizures, intra-cranial hypertension and systemic hypotension. The onset of action for intra-arterial vasodilators is often delayed and the therapeutic effects are short lived. Consequently, repeated procedures are often necessary to manage relapsing symptoms with the cumulative risks accruing over time.
For more than 20 years, papaverine, a phosphodiesterase inhibitor, was the most widely used agent employed in IAVT procedures. It is infrequently used in current clinical practice because of concerns about the potential neurotoxicity of papaverine or its commonly used preservative chlorobutanol. These concerns were sparked by a report documenting the development of symptomatic brain lesions in five patients treated with intra-arterial papaverine for PHCV in San Francisco when all patients became symptomatic immediately after the initiation of intra-arterial papaverine and all developed gray matter lesions in the irrigated vascular territories on brain MRI. Histological findings in one patient were consistent with selective gray matter necrosis, a feature more closely associated with the effect of metabolic toxins rather than ischemic tissue damage. Intra-arterial papaverine is commonly administered in normal saline as a 0.3% solution at a dose of 300 mg per arterial territory infused over a 30 min period. Compared with other vasodilators used for the treatment of PHCV, papaverine is much more insoluble and has a strong tendency for precipitation in aqueous solutions. Mixing of papaverine solutions with iodinated contrast or heparin solutions may promote precipitation. The formation of insoluble crystals in clinical preparations of papaverine can lead to clinically significant embolic complications. Intracranial hypertension has been reported to be a significant problem after treatment of multiple vascular territories by intra-arterial papaverine infusion. This presumably occurs due to the augmentation of cerebral blood volume produced by widespread cerebral vasodilatation. Seizures, mydriasis and transient hemiparesis have also been reported. Transient and rarely permanent monocular blindness has been reported after intra-arterial papaverine infusion through catheters placed in the internal carotid artery proximal to the origin of the ophthalmic artery. Cardiac dysfunction and respiratory arrest have been reported with posterior circulation infusions of papaverine. Milrinone, another phosphodiesterase inhibitor, has been used for IAVT in small case series.
Calcium channel blockers have been infused directly into the cerebral arteries to treat PHCV. Nimodipine was the first agent used in this way. The use of intra-arterial verapamil and nicardipine are being increasingly reported in the literature. Verapamil is typically administered as a bolus infusion whereas nicardipine is delivered slowly in a prolonged infusion for up to 90 min periods. Prolonged infusions involving indwelling transarterial catheters are theoretically associated with a greater risk of thromboembolism. Although there are reports of prolonged infusions through transarterial intracranial microcatheters lasting as long as 20 h (median 8 h), further study is necessary to establish the safety of this approach. Significant increases in intracranial pressure and decreases in cerebral perfusion pressure lasting for several hours have been reported with high dose intra-arterial verapamil infusion. Systemic hypotension is rarely seen with verapamil; however, doses exceeding 35 mg per procedure have been associated with significant decreases in mean arterial pressure, often in delayed fashion as long as 5–7 h after the procedure. Intra-arterial nicardipine is more often associated with hypotension, particularly with high doses. Initial reports of intra-arterial verapamil described doses of 2–5 mg per vessel treated. Although many operators currently use 10–20 mg per vessel, little is known about the dose–response relationship. We have observed seizures in patients treated with high doses of intra-arterial verapamil (≥15 mg/vessel). High dose intra-arterial verapamil has also been associated with hypotension in more than 50% of patients. Nicardipine has been given in doses of 0.5–0.6 mg per vessel but doses higher than 15 mg per vessel are also reported.