Endovascular Treatment of Medically Refractory Cerebral Vasospasm Following Aneurysmal Subarachnoid Hemorrhage

Discussion

This study examines our recent experience using PTA and IA verapamil to treat patients with aneurysmal SAH with medically refractory CV. We treated 189 patients during 349 treatment sessions, consisting of a single angioplasty, 286 IA verapamil infusions, and 59 combined therapies. In total, 151 vessel segments underwent PTA and 720 vessel segments were infused with verapamil. The procedural complication rate was 1.7% per procedure and 3.2% per patient. The clinically significant procedural complication rate was 0.6% per procedure and 1.1% per patient. Ultimately, 61% of patients had a good clinical outcome. To our knowledge, this constitutes the largest series of patients having undergone endovascular treatment for CV to date.

The goal of CV management is to prevent cerebral ischemia. Cerebral ischemia is likely a multifactorial process, but it is recognized that intracranial arterial luminal narrowing significantly reduces CBF.^3,23–25 This relationship is explained by the Poiseuille equation, which states that flow is directly proportional to the pressure gradient and radius to the fourth power and inversely proportional to the fluid viscosity and vessel length. This forms the basis for a hyperdynamic therapy that tries to optimize the pressure gradient and fluid viscosity to improve CBF.²⁶ However, there is a limit to how much these parameters can be modified before complications such as pulmonary edema, dilutional hyponatremia, and myocardial infarction occur.^26,27 PTA and IA verapamil infusion are invasive options for restoring luminal caliber by mechanical or pharmaceutical means, respectively.

The choice of endovascular treatment is dictated by the distribution and severity of CV. PTA is limited to vessels that can safely accommodate the balloon microcatheter: the major cerebral arteries at the base of the brain and their most proximal branches.¹⁴ We further restricted the use of PTA to those vessels demonstrating severe CV. Because PTA has previously been reported to have a 2%–5% risk of stroke and death,¹⁴ we believe the risk-to-benefit ratio is minimized when only severe disease is treated. However, the performance characteristics of low-compliance balloon microcatheters have improved, and our own level of experience has increased significantly during the past 2 decades. Thus, our current complication rate from PTA (1.7%, see the discussion below) is lower than that in an earlier series from our institution (7.1%).¹² In our current series, PTA was performed in 60 patients (67%) of 90 in whom there was severe proximal or severe proximal and distal CV (Table 1). This rate implies that 33% of cases were either inaccessible or unfavorable for treatment by PTA. Examples include CV of the A1 segment, which is difficult to cannulate with a balloon microcatheter^{9,10,12,28,29} or which may be hypoplastic at baseline and thus not safe to balloon dilate. If no prior angiogram existed demonstrating that the A1 segment was not hypoplastic at baseline, then PTA of the A1 segment was avoided. PTA of a vasospasm involving the vessel segment immediately adjacent to an aneurysm, which is associated with vessel rupture or surgical clip displacement,³⁰ was also considered to be contraindicated.

In cases in which PTA could not be performed, we infused IA verapamil. Verapamil has been used for about 10 years to treat CV, but optimal dosing remains in question.^31–35 We infused 2.0–30.0 mg per vessel segment. In our experience, these doses improved the luminal caliber in most cases; however, this finding cannot be confirmed on this retrospective study because delayed posttreatment DSA was not routinely performed in all patients. The efficacy of verapamil in improving the luminal caliber has been shown in earlier series: Feng et al³² found a 44% increase in vessel diameter following an average and maximum dose of 3 and 8 mg, respectively. Keuskamp et al³³ showed a significant increase in vessel diameter in 10 of 12 patients who were given ≥20 mg per vessel segment. Although Mazumdar et al³⁴ failed to show a significant increase in vessel diameter after 2.5–10.0 mg of verapamil, there was a trend to vasodilation in the most spastic vessels.

In our series, there was a direct correlation between the amount of verapamil infused and the severity of CV (Fig 3). Although this conclusion is intuitive and has been reported anecdotally in other studies,³² several confounding factors need to be considered. First, because CV severity was determined by visual inspection, there can be miscategorization, particularly in borderline cases. Second, even though our findings are statistically significant, they may not be clinically significant, given the wide overlap in doses between groups. Third, treatment bias is likely present because the amount of verapamil infused could be determined by operator experience rather than angiographic response. During the study period, all participating interventional neuroradiology attending physicians had 15–20 years of experience treating patients with SAH and CV. Finally, verapamil infusion is known to have an effect on spastic prearteriolar vessels, which are below the resolution of DSA.²² Functional measures such as CBF may thus be better end points for determining optimal verapamil dosing.^4,24,36

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Fig 3.

IA verapamil dose by CV severity. Only IA infusions into the ICA and vertebral arteries are considered (n = 680, 94% of total vessel segments infused). X indicates the median verapamil dose.

There are limited data related to the durability of endovascular treatments. In our study, repeat treatments were performed in 102 patients (54%); 17% of cases treated with PTA and IA verapamil and 51% of cases treated with IA verapamil alone required repeat treatments. PTA had excellent durability in our series, with only a single vessel segment (2%) requiring repeat PTA. This is in keeping with other series that have shown that vessel segments treated with angioplasty rarely re-stenose to the point of warranting further therapy.^10,37 The durability of PTA has been explained by the ultrastructural changes that occur within the media of the mechanically dilated vessel wall.^38,39

The length of therapeutic effect of IA verapamil in CV is not known. Although the biologic half-life of intravenous verapamil is 110 minutes,⁴⁰ the persistence of its vasodilatory effect on the cerebral arteries is poorly understood. The coronary artery literature is not particularly instructive because coronary vasospasm tends to be much shorter lived (minutes) than CV (days to weeks).¹⁸ Whereas coronary vasospasm will resolve on its own in less than the half-life of verapamil, CV often persists well beyond the expected half-life of verapamil in the cerebral circulation. Thus, IA verapamil may have to be re-administered multiple times during a course of protracted CV to maintain CBF and prevent ischemia. The optimal time interval between IA verapamil infusions is not known, though most patients treated repeatedly with IA verapamil at our institution had a mean of 3 days in between. Prolonged IA verapamil infusion (for ≤20.5 hours) with in-dwelling catheters has recently been described and provides a novel mode of administration.³¹

Our recent experience demonstrates the safety of endovascular vasospasm therapy by using PTA and/or IA verapamil infusion. There were no treatment-related deaths, and of the 6 procedural complications, only 2 resulted in patient clinical deterioration. Distal embolization following PTA is a recognized complication and, in our patient, resulted in short-term disability with later full recovery. However, to our knowledge, intractable ICP elevation following IA verapamil has not been previously reported. Albanese et al³¹ described a single patient with transient ICP elevation during prolonged IA verapamil infusion that resolved on treatment cessation. Other studies have shown that IA verapamil has a negligible effect on ICP at similar or higher doses than that used to treat our patient.^32–34 Although this case may represent refractory cerebral edema in a critically ill patient with SAH, given its temporal relationship to IA verapamil infusion, vigilant ICP monitoring is warranted.

Although endovascular vasospasm therapies are safe, their efficacy remains poorly characterized. Both PTA and IA verapamil have been shown to improve neurologic status in the short term, but their long-term benefits remain inconclusive. In our series, 61% of patients had a good outcome, 29% had a poor outcome, and 10% died. Historically, mortality rates after SAH have been reported to be as high as 67% with up to a third requiring lifelong care.⁴¹ In the modern era, mortality and morbidity have steadily decreased and the ISAT reported the following outcomes after 1 year: 72% good, 18% poor, and 9% dead.⁴² However, the patient population of that trial differs significantly from the patient population in the current series. Specifically, ISAT included many patients who did not have medically refractory CV, thus constituting a less morbid cohort than that presented our series. Thus, the outcomes in our tertiary care referral center may be similar, if not better, than other published clinical trials.

Ultimately, safety without efficacy is meaningless, and in the absence of efficacy, any patient risk is unwarranted. To our knowledge, there are no randomized studies of the effect of endovascular treatment for CV on outcomes. Small uncontrolled studies report a wide range of clinical improvement: 10%–80%.⁴³ More rigorously controlled trials of CV therapies are, therefore, warranted. Given the current paradigm that CV causes ischemia and disabling infarction in ≤20% of patients with SAH, comparison of PTA and/or IA verapamil or other vasodilators with a pure placebo (ie, sham endovascular treatment) would be unethical. Trials comparing IA vasodilators of differing pharmacologic actions, such as verapamil and milrinone, would be an appropriate next step in the further elucidation of safe and efficacious prevention of CV-induced cerebral infarction.