Introduction
Delayed cerebral ischemia is caused by vasospasm. This is frequently observed in patients with aneurysmal subarachnoid hemorrhage (SAH), and this is a major cause of morbidity and mortality.22) Four to 14 days after the rupture of a cerebral aneurysm, angiographically confirmed vasospasm occurs in about two-thirds of these patients. In the remaining one-third, complications such as cerebral infarction develop due to the impaired cerebral blood flow; in the worst of these cases, 5~10% of the patients die.22) Various studies have assessed alternative forms of treatment for vasospasm that is refractory to medical approaches such as triple H therapy (induced hypertension, hypervolemia and hemodilution). Among them, some of the studies have examined the administration of intra-arterial papaverine and using low-pressure balloon angioplasty.6-8)16)17)20) Yet all of these alternatives also have their disadvantages. Papaverine can induce seizure and elevate the intracranial pressure and it can cause serious neurological deterioration.7)8)17) Low-pressure balloon angioplasty dilates only the proximal vessels and this procedure carries a risk of vascular rupture.20) Many studies have recently described the intra-arterial injection of a calcium antagonist to treat vasospasm; positive results regarding the safety and effect of nicardipine have been reported among these papers.1)3)6)10-12)18)19)22) In this study, the safety and usefulness of low-dose nicardipine for the treatment of vasospasm were examined based on the outcomes of 32 patients who were treated with intra-arterial nicardipine angioplasty for vasospasm that occurred after aneurysmal SAH.
Materials and Methods
1. Patients
A retrospective study was performed on 32 patients who had undergone intra-arterial nicardipine angioplasty to treat symptomatic vasospasm that was refractory to medical treatments. The study period extended from January 2007 to February 2011. Microsurgical clipping was performed in 50% of the patients and endovascular coiling was performed in the other half, and both procedures were done within 24 hours of the patient’s admission to the hospital due to aneurysmal SAH. All the patients were subsequently managed in the intensive care unit (ICU) where intravenous nimodipine was administered to prevent vasospasm.4) When the patient’s consciousness decreased or any neurologic deficit developed, brain computed tomography angiography (CTA) was then performed. The patients with suspected vasospasm, as determined based on a comparison with the initial brain CTA, were evaluated by cerebral angiography. Angiographic confirmation of the vasospasm was followed by performing angioplasty, which consisted exclusively of injecting nicardipine into the spasmodic vessel with excluding administering papaverine or performing balloon angioplasty.
 
2. Methods
The 32 patients underwent a total of 55 angioplasty sessions. All the procedures were performed by one endovascular neurosurgeon and with the patients under local anesthesia. Intravenous remifentanil or midazolam was administered to three patients for sedation. Angioplasty was performed without sedatives in the remaining patients. During the procedure, the blood pressure (BP), EKG, SaO2 and heart rate were continuously monitored. When vasospasm was observed, nicardipine, which was prepared by diluting 10mg of the drug in 90ml of normal saline (1 mg nicardipine = 10ml diluted nicardipine), was administered through a 1ml syringe attached to a microcatheter that was placed at the affected site, i.e., the anterior cerebral artery (ACA), middle cerebral artery (MCA), internal carotid artery (ICA) or vertebral artery (VA). The maximum dose of nicardipine per vessel was 3mg, and this was administered at a rate of 1 mg/3min (0.33 mg/min) with the total dose not exceeding 12mg per angioplasty. If the systolic BP decreased by 30% or more before treatment was completed, then the injection was stopped and normal saline was provided up to a maximum volume of 500ml. The nicardipine injection was continued following the recovery of the systolic BP. A mixture of heparin (2,000IU) and normal saline (1,000 ml) was continuously injected into the affected artery via a catheter during angioplasty to prevent thromboembolism. Within 30min after the administration of nicardipine, angiography was performed again to evaluate the degree of vasospasm. The patients were transferred to the ICU and triple H therapy was continued. After the angioplasty, the sheath was maintained in position for up to 3 days. If additional treatment was no longer required, then the sheath was removed and manual compression on the insertion site was performed to achieve hemostasis.
 
3. Data Analysis
The data was retrospectively collected and analyzed together with the medical records of the patients. The data was comprised of the GCS score, the H-H grade and Fisher's grade at the time of the patient‘s admission, the GCS score at the time that angiography was performed, newly developed neurologic deficits, the onset and degree of vasospasm, the administered dose of nicardipine and its administration site, the pre- and post-systolic BP, the improved GCS score after angioplasty, the time between angioplasty and the improved GCS score, the number of angioplasty procedures performed and the mRS at the time of the patient’s discharge and the medical complications. Vasospasm was classified as mild (<40%), moderate (40~75%) or severe (?75%) based on a comparison of the inner diameter of the proximal and distal normal segments of the narrowed site.3)
Results
Between January 2007 and February 2011, 248 patients presented with aneurysmal SAH. Thirty-two of these patients underwent nicardipine angioplasty after cerebral angiographic confirmation of vasospasm, which presented as decreased consciousness and neurologic deficit despite triple H therapy and intravenous nimodipine administration. The ruptured cerebral aneurysm involved the anterior circulation in 29 patients (90.6%) and the posterior circulation in three patients (9.4%).
The mean age of the 17 female patients (53.1%) and 15 male (46.9%) patients was 52.8 years (range : 22~79). The Glasgow Coma Scale (GCS) score, which was measured at the time of the patient’s admission to the hospital, was 3~6 in four patients (12.5%), 7~11 in four patients (12.5%) and 12~15 in 24 patients (75%). There were 39 aneurysms in total with two aneurysms observed in seven patients and one aneurysm observed in 25 patients. The Hunt and Hess grade (H-H grade), Fisher's grade and the GCS score measured at the time of the patient’s admission were retrospectively examined to assess the initial condition of the patients. The prognosis was evaluated using the modified Rankin Scale (mRS),15) and this was measured at discharge (Table 1). A mRS of 0~2 points indicated a good prognosis and a mRS of 3~6 points indicated a poor prognosis. The initial H-H grade was I in two patients, II in eight patients, III in 15 patients and IV in seven patients.
The onset of the vasospasm was less than 6 days in 12 patients (37.5%), 7~12 days in 17 patients (53.1%) and 13 days or more in three patients (9.4%) (Table 2). The degree of vasospasm was severe in 19 patients (59.4%), moderate in five (15.6%) and mild in eight (25%). The mean systolic BP before and after angioplasty was 164 mmHg (range: 140~190) and 125 mmHg (range: 84~150), respectively (Table 3). The rate of systolic BP reduction after angioplasty was less than 10% in 2 patients (6.3%), 10~20% in 9 (28.1%), 20~30% in 12 (37.5%), 30~40% in 8 (25%) and 40% or more in 1 patient (3.2%). The mean time required for the post-angioplasty recovery of the systolic BP was 124 minutes. Persistently low systolic BP following the administration of nicardipine was not observed in any patient. The mean time required for one session of angioplasty was 50 minutes, with longer times required as the dose of nicardipine increased. Angiographic improvement was observed after the procedure (Fig. 1) with improvements of the GCS score in all the patients (a mean increase of 2.4 points, range: 1~5). The mean time required for significant improvement of the GCS score was 10.5 hours (range: 2~39 hours), with improvements of the GCS score observed within 12 hours in 24 (75%) of the 32 patients (Table 2). The neurologic deficits that developed before angioplasty were paresis (five patients) and aphasia (seven patients). In one of the five patients, right-sided paresis occurred during clipping of the aneurysm and this clipping included the left M2 branch of the MCA. The paresis remained in the form of a sequela in this patient, although the GCS score improved after angioplasty. In the remaining four patients who had paresis and in the seven patients with aphasia, an optimal postoperative condition was eventually recovered.
The clinical symptoms improved in 15 (46.9%) of the 32 patients after one session of angioplasty and active triple H therapy, which made additional angioplasty unnecessary. Yet additional angioplasty was required in the other 17 (53.1%) patients despite triple H therapy after angioplasty. Of these 17 patients, 11 (34.4%) underwent two sessions of angioplasty, five patients (15.6%) underwent three sessions and one patient (3.1%) underwent four sessions. The mean interval between the sessions was 2.7 days (Table 4). The maximum dose of nicardipine administered per angioplasty was 12 mg. Of the total 55 angioplasty sessions, less than 5 mg of nicardipine was administered in 24 sessions (43.6%), 5~9 mg was administered in 28 sessions (50.9%) and 10 mg or more was administered in three sessions (5.5%). In 55 sessions, the mean nicardipine dose was 5.2 mg (range: 2~12 mg); in 52 sessions (94.0%), less than 10 mg per session was used (Table 5). During angioplasty, no complication related to the procedure occurred such as thromboembolic events or acute transitory spasm. Follow-up was not possible in 2 of the 32 patients as one was transferred to another hospital and the other died of sepsis. The clinical outcomes were assessed with mRS at the time of discharge. Of the 30 patients, 19 (63.3%) had good outcomes (mRS: 0~2), and 11 (36.7%) had poor outcomes (mRS: 3~6). Among the latter group, 8 had a poor mental status (a H-H grade of III-IV) and 3 had limited improvement due to complications related to surgery.
Discussion
The pathophysiology of vasospasm that occurs after aneurysmal SAH is still poorly understood. The prevention and treatment of vasospasm have been examined in several studies. Low-pressure balloon angioplasty, which is widely used, is limited by the fact that vasodilation is only local and there is a risk of vascular rupture with this procedure.13)20) Angioplasty involving the administration of intra-arterial papaverine results in serious adverse events such as seizure, increased intracranial pressure, paradoxical vasospasm, worsening of ischemia and profound neurological deterioration.7)8)16)17) Therefore, the administration of a calcium antagonist as an alternative approach to the treatment of vasospasm has been the focus of several recent studies and all these studies have reported its usefulness.1)2)9)10)
Nimodipine is a calcium antagonist and a member of the dihydropyridine family, and it has been used for many years as medical therapy for vasospasm due to aneurysmal SAH and this is based on nimodipine's demonstrated ability to reduce the incidence of brain infarcts by 34~40% and to improve the clinical outcome.4)19) Nicardipine is another calcium antagonist and it acts more selectively with greater effects on vascular smooth muscles than on the myocardium. The continuous intravenous administration of nicardipine reportedly reduces the prevalence of symptomatic vasospasm and vasospasm as revealed by angiography or transcranial Doppler (TCD).9)10)12) However, the prolonged intravenous infusion of nicardipine has several disadvantages such as persistent hypotension, pulmonary edema and renal impairment.10) By contrast, many recent studies have reported the efficacy of intra-arterial administration of nicardipine. Badjatia et al.3) reported the immediate vasodilation effect seen on angiography after the administration of nicardipine through an artery. TCD performed within 4 days after the infusion showed mean peak systolic velocities that were significantly reduced from their pretreatment values. Nogueria et al.18) documented that according to cine computed tomography perfusion, the intra-arterial administration of nicardipine improved both the cerebral blood flow and the mean transit time in the ischemic region.
Based on previous studies, we performed only nicardipine angioplasty, with omitting balloon or papaverine angioplasty, on vasospasms that occurred after aneurysmal SAH. With this approach, the GCS score improved (mean: 2.4, range: 1~5) in all 32 patients. The 12 patients who had paresis or aphasia due to vasospasm eventually regained their pre-vasospasm condition. These results indicate that nicardipine angioplasty is effective even at low doses of the drug. Indeed, our results are comparable to those reported in the above-mentioned studies. Additionally, the systolic BP, which decreased during the procedure due to the administration of nicardipine, recovered within a mean of 2 hours to the pre-angioplasty level; any clinical symptoms related to the decrease of the systolic BP were not observed. Thus, we conclude that the administration of low-dose nicardipine is not only an effective alternative to balloon angioplasty and papaverine administration, but it also reduces the duration of the procedure and helps to avoid complications such as thromboembolic events.
According to Linfante et al.14) as the amount of nicardipine injection increases, a greater vasodilation effect is achieved; however, unstable hemodynamics follow. For achieving hemodynamic stability, our study used only low dose nicardipine even if multiple sessions were necessary. Considering the half-life of nicardipine,23) additional angioplasty was performed when no clinical improvement was observed within 24 hours after the procedure or the patient's recovered consciousness worsened. Badjatia et al.3) demonstrated the use of 1~5mg of intra-arterially administered nicardipine per vessel without performing additional sessions in 18 patients with vasospasm. Clinical improvement was observed in 42% of the treated patients. In our study, multiple sessions of angioplasty were carried out in 17 patients (53.2%) and the GCS score after angioplasty improved in all the patients without any particular complications. Among the 30 patients who were followed, 19 (63.3%) had good outcomes (mRS: 0~2) (Table 3). Therefore, when low dose nicardipine is used together with multiple sessions of angioplasty, both hemodynamic safety and effectiveness could be obtained.
Despite the good outcomes achieved by the patients, this study has several limitations. First, the degree of improvement was not objectively measured because not all the patients underwent TCD monitoring before and after the angioplasty, which is a consequence of the study being retrospectively performed. The data on the difference of the intracranial pressure pre- and post-angioplasty and the intra-operative change of the pressure was not available because ventriculostomy was not performed in all of the patients. These aspects need to be taken into account in future studies.
Conclusion
In this study, angioplasty consisting only of the intra-arterial administration of low-dose nicardipine was performed for the treatment of vasospasm refractory to medical treatment. The outcomes were better than those reported in other studies using balloon and papaverine angioplasty. Additionally, the relatively low dose of nicardipine shortened the procedure time, and there was faster recovery of systolic BP and fewer procedure-related complications. These results support the use of low-dose nicardipine angioplasty with multiple sessions, if necessary, as an effective, hemodynamically safe treatment for vasospasm. Further studies with a larger number of patients are still necessary to determine the optimal dose of nicardipine needed to achieve adequate treatment.
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