Vasodilators and Angioplasty for Cerebral Vasospasm

10.1055/b-0034-80458

Vasodilators and Angioplasty for Cerebral Vasospasm

Pandey, Aditya S., Chaudhary, Neeraj, Fox\, W. Christopher, Thompson\, Byron Gregory, Gemmete\, Joseph J.

Pearls

Maximize cerebral perfusion pressure by increasing volume status, increasing mean arterial pressure, and reducing intracranial pressures.
Obtain a computed tomography (CT) scan of the head to evaluate for cerebral infarct or hemorrhage as explanations for clinical symptoms.
Proceed to cerebral angiography with chemical and mechanical angioplasty if medically refractory spasm persists; time is of the essence.

Cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH) is a delayed, reversible narrowing of the intracranial vasculature that occurs most commonly 4 to 14 days after aneurysmal SAH and can lead to permanent ischemic injury. Although it has been the focus of much research and clinical effort, vasospasm remains difficult to treat and is responsible for significant morbidity and mortality in patients with ruptured cerebral aneurysms. Angiographic spasm occurs in up to 70% of SAH patients, of whom half will become symptomatic secondary to ischemic changes. In the past, mortality rates from vasospasm have been reported to range from 30 to 70%, with 10 to 20% of patients experiencing severe neurologic deficits.1 ^, 2

With advancements in diagnostic and interventional technology, estimates of patients suffer significant morbidity/mortality, range from 5 to 9%, with vasospasm accounting for 12 to 17% of all fatalities or cases of disability after SAH.3 ^, 4 We have an incomplete understanding of the pathophysiology of vasospasm, and it is difficult to predict which patients will develop vasospasm after SAH. The Hunt and Hess grade, Fisher score, hypertension, smoking, cocaine use, age range of 40 to 59 years, and early rise in the middle cerebral artery blood flow on transcranial Doppler have been shown to be independent risk factors for vasospasm.4 Cerebral salt wasting has also been associated with vasospasm. This chapter discusses the multiple medical and endovascular therapies that are utilized to prevent or treat vasospasm.

♦ Vasospasm Prophylaxis and Medical Treatment

Prophylactic treatment for cerebral vasospasm following aneurysmal SAH is controversial and varies among institutions. Calcium channel blockers, intravenous magnesium, and 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) have all been used in attempts to prevent and treat vasospasm. In addition, triple-H (hypervolemia, hypertension, and hemodilution) therapy has been a mainstay of vasospasm treatment for years. At our institution, we initiate triple H therapy post-treatment of the cerebral aneurysm, as long as there are no medical contraindications such as congestive heart failure or severe pulmonary disease. We use prophylactic nimodipine and magnesium sulfate and are considering utilizing statins as new data emerge.

♦ Calcium Channel Antagonists

Calcium channel antagonists have been shown to decrease the overall incidence of cerebral infarction after SAH by 34% and the incidence of poor outcomes by 40%.5 The physiologic reasoning behind the use of calcium channel blockers is that the central event in vascular smooth muscle contraction is the influx of calcium into cells, which has been shown to occur after SAH.6 This, in turn, leads to several downstream events including free radical formation, production of vasoconstricting prostaglandins, and activation of the myosin light chain kinase that causes smooth muscle contraction. The most common calcium channel blocker used after SAH is nimodipine, which has a certain degree of specificity for the cerebral vessels. Multiple trials have shown its efficacy in improving outcomes, although it may not improve angiographic outcome.

♦ Magnesium

Obstetricians have used magnesium to treat eclampsia, as magnesium is thought to alter calcium physiology and thus alter vascular tone in the uterine circulation. Magnesium competes with calcium-binding sites, thus preventing muscular contraction and allowing vascular muscle relaxation. Level 1 evidence now exists for the usage of magnesium sulfate in the prevention of cerebral vasospasm. Westermaier et al7 have shown that magnesium sulfate significantly reduces cerebral ischemic events after SAH.

♦ Triple-H Therapy

Hypervolemia, hypertension, and hemodilution therapy (triple-H) has long been a mainstay of medical therapy in patients with aneurysmal SAH. The rationale behind triple-H therapy is that maintenance of high circulating blood volume, increased perfusion pressures, and decreased blood viscosity will enhance cerebral blood flow in the setting of vasoconstriction. Although in healthy adults changes in cardiac output do not change the local cerebral flow, they do impact cerebral blood flow in patients suffering from cerebral vasospasm. Our goal is to maintain euvolemia as defined by the specific central venous/wedge pressure which allows for the highest cardiac output.

The vast majority of our SAH patients receive central lines so that central venous pressures can be closely monitored to achieve optimized volume expansion without causing pulmonary edema. We prefer central venous pressures in the range of 8 to 12 mm Hg, but these are highly individualized and must be closely monitored in relation to the clinical findings in each patient. Patients with cardiopulmonary disease may need to be evaluated with a Swan Ganz catheter, as the ideal venous pressure in these patients needs to be related to the ideal cardiac output.8 One series or 184 patients reported a 13% risk of device-related sepsis in patients with pulmonary artery catheters, as well as a 2% risk of congestive heart failure, 1.3% risk of subclavian vein thrombosis, and 1% risk of pneumothorax.8 Most SAH patients require invasive blood pressure monitoring. In the post-clipping or -coiling vasospasm period, we often allow patients to autoregulate with systolic blood pressure in the range of 200 mm Hg. The role of red blood cell transfusion is not well studied, but transfusion could certainly increase the oxygen carrying capacity.

Endovascular Therapy

Endovascular treatment with intraarterial infusion of a vasodilator or balloon angioplasty is indicated in patients with symptomatic vasospasm refractory to medical therapy to prevent neurologic deficits referable to the vascular territory of the angiographic vasospasm. Any patient who is a candidate for cerebral angioplasty in the context of cerebral vasospasm must be evaluated with a computed tomography (CT) scan of the head to evaluate for hemorrhage as well as the presence of hypodensity within the vascular territory at question for vasospasm. A vessel diameter reduction between 25% and 50% from the initial angiographic diameter is usually treated with intraarterial infusion of vasodilators. Vessel diameter reductions greater than 50% from the initial angiographic diameter are treated with a combination of mechanical and chemical angioplasty. The timing of endovascular intervention for vasospasm is critical, and a 2-hour window from the time of symptoms may exist for restoration of blood flow to the region affected by vasospasm.9

Intraarterial Vasodilators (Table 34.1)

Papaverine

The most studied intraarterial pharmacologic agent to date is papaverine. It is an opium alkaloid that is thought to alter adenosine 3′,5′–cyclic monophosphate levels in smooth muscles.10 The half-life is approximately 2 hours. Hoh and Ogilvy,11 in a review of intraarterial agents for treatment of cerebral vasospasm, reported that papaverine produced clinical improvement in only 43% of the treated patients. The effectiveness of treatment was short given its half-life; therefore, multiple treatments were required, which led to a variable and increased risk of complications. Platz et al12 more recently reported a case of spontaneous hemorrhage following intraarterial use of papaverine. They hypothesized that local increased levels of infused papaverine possibly led to a blood–brain barrier (BBB) breakdown with subsequent intracranial hemorrhage. Furthermore, there has been a recent report from Pennings et al13 that they observed an abnormal response to topical application of papaverine on the cerebral cortical microvasculature during aneurysm surgery. They noted rebound vasoconstriction in two of 14 cases. In the cases where there was some increase in vessel diameter compared with baseline, it did not reach statistical significance.

**Table 34.1** Intraarterial Agents for the Treatment of Vasospasm
Agent	Typical Intraarterial Dose	Half-Life (Hours)	Side Effects
Papaverine	300 mg per vascular territory at 0.3% concentration over 20 minutes.	2	Cortical necrosis, permanent neurologic deficits, raised intracranial pressure, systemic hypotension
Verapamil	1- to 2-mg bolus over 2 minutes with maximum of 10 mg per vascular territory	7	Increased intracranial pressure
Nimodipine	1 to 3 mg at 25% dilution over 10 to 30 minutes in each vascular territory; maximum dose 5 mg	9	Increased intracranial pressure
Nicardipine	0.2 to 0.5 mg/mL in 1-mL aliquots; maximum dose of 20 mg per vascular territory	16	Increased intracranial pressure

There is wide variation in the intraarterial use of papaverine in terms of dosage and duration of infusion.13 Firlik et al14 demonstrated no correlation with the clinical response and angiographic picture in cases of vasospasm from aneurysmal SAH treated with intraarterial papaverine. In their cohort of 15 patients they had 23 intraarterial (IA) treatments with papaverine, leading to partial angiographic reversal in 18 of the 23 IA treatments. However, major clinical improvement was seen in only six treatments and minor improvement or none in 17.

Papaverine hydrochloride is supplied as a 3% concentration, 30 mg/mL, in an acidic mixture maintained at a pH of 3.3. Papaverine may form crystal precipitates, with crystal size up to 100 μm, when mixed with human serum at 3% or 0.3% concentrations. A precipitate has also been seen when 3% papaverine solution was mixed with heparinized saline in concentrations of 2000 to 10,000 units of heparin per liter. The typical papaverine concentration infused is 0.3%, produced by diluting 300 mg of papaverine in 100 mL of normal saline. The entire dose (300 mg) is given in a vascular territory over 20 to 30 minutes. If more than one vascular territory is involved, additional infusions of 300 mg can be given. The catheter for infusion in the anterior circulation should be placed past the ophthalmic artery to prevent possible precipitate being introduced into the retina. In the posterior circulation the catheter should be positioned past the origin of the anterior inferior cerebellar artery to prevent respiratory arrest and the potential of cardiac dysfunction due to transient depression of the medullary respiratory and cardiovascular nuclei. Papaverine can cause systemic hypotension and elevation of intracranial pressure during infusion; therefore, these parameters should be monitored closely.

Side effects from intraarterial infusion of papaverine also included transient neurologic deficits such as mydriasis, transient hemiparesis, and respiratory depression. Given the short half-life, the transient effect on the local cerebral vasculature, and significant side effects, we no longer utilize papaverine for chemical angioplasty at our institution.

Calcium Channel Antagonists

With the complications associated with papaverine, use of calcium channel antagonists (verapamil, nimodipine, nicardipine) for the treatment of cerebral vasospasm has become more popular. These agents are still not approved by the Food and Drug Administration (FDA) in the United States for intraarterial use in the cerebral vasculature.

Verapamil

Verapamil is a phenylalkylamine calcium channel blocker that inhibits voltage-gated calcium channels in the arterial wall smooth muscle cells, resulting in vasodilatation. The half-life is approximately 7 hours. Feng et al15 reported on the intraarterial use of verapamil in 29 patients who underwent 34 procedures; 52% were treated with verapamil alone, which resulted in 44% experiencing increased vessel diameters and 33% exhibiting neurologic improvements without complications or intracranial pressure (ICP) issues. The vasodilation effects of verapamil are still transient and poorly sustained, and no studies thus far have demonstrated significant patient outcome benefit.

Verapamil is usually infused in a 1- to 2-mg bolus over 2 minutes, with a total maximal dose of 10 mg administered into each vascular territory. In their small cohort of 10 patients, Keuskamp et al16 have demonstrated the efficacy of using high doses of verapamil (total 41 ± 29 mg per procedure) without significant alteration of ICP, cerebral perfusion pressure, or other side effects. In their series, the neurologic deficits that prompted endovascular treatment of vasospasm improved in eight of 12 procedures. In a recent report of a case series of again 12 patients, Albanese et al17 have documented the use of ultrahigh doses of verapamil for treatment of vasospasm. They used an average dose of 164.6 mg of verapamil per vessel for infiltration through an indwelling microcatheter. They have demonstrated improvement in nine of 12 patients. Only one patient had the infusion stopped due to ICP increasing beyond 20 cm H₂O.

Major complications of intravenous verapamil are hyptension and bradycardia; however, no significant changes in blood pressure or heart rate have been reported with intraarterial infusion. No prolonged or dramatic increase in intracranial pressure has been reported, as mentioned above. Intraarterial verapamil administration appears to be safe with few systemic effects in the limited number of patients studied.

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