Effect of Nicardipine Prolonged-Release Implants on Cerebral Vasospasm and Clinical Outcome After Severe Aneurysmal Subarachnoid Hemorrhage

Abstract

Background and Purpose-The purpose of this study was to investigate the effect of nicardipine prolonged-release implants (NPRIs) on cerebral vasospasm and clinical outcome after severe subarachnoid hemorrhage. Methods-Thirty-two patients with severe subarachnoid hemorrhage and undergoing aneurysm clipping were included into this single center, randomized, double-blind trial. Sixteen patients received NPRIs implanted into the basal cisterns in direct contact to the exposed proximal blood vessels; in 16 control patients, the basal cisterns were opened and washed out only without leaving implants. Angiography was performed preoperatively and at day 8Ϯ1. Computed tomography imaging was analyzed for the incidence of territorial infarcts unrelated to surgery. Patient outcome was assessed using the modified Rankin and National Institute of Health Stroke scales. Results-The incidence of angiographic vasospasm in proximal vessel segments was significantly reduced after implantation of NPRIs (73% control versus 7% NPRIs). Significant differences occurred also for the majority of distal vessel segments. Computed tomography scans revealed a lower incidence of delayed ischemic lesions (47% control versus 14% NPRIs). The NPRI group demonstrated more favorable modified Rankin and National Institute of Health Stroke scales as well as a significantly lower incidence of deaths (38% control versus 6% NPRIs). Conclusions-Implantation of NPRIs reduces the incidence of cerebral vasospasm and delayed ischemic deficits and improves clinical outcome after severe subarachnoid hemorrhage. Key Words: nicardipine prolonged-release implants Ⅲ SAH Ⅲ stroke Ⅲ vasospasm C erebral vasospasm remains one of the most serious complications after aneurysmal subarachnoid hemorrhage (SAH). Over the past decades, several pharmacological approaches have been investigated for the prevention of cerebral vasospasm. Among those, the most prominent is the use of voltage-gated calcium channel antagonists such as nimodipine and nicardipine. Experimental data support the concept that voltage-gated calcium channel antagonists are capable of preventing cerebral vasospasm if administered in high enough doses to the vessel wall. 1 However, when administered intravenously or orally, the doses necessary to exert maximum pharmacological effect cannot be achieved as a result of the side effects of the drug. [2][3][4] Recently, this limitation in the delivery of voltage-gated calcium channel antagonists has been overcome by the introduction of nicardipine prolonged-release implants (NPRIs). These nicardipine-loaded polymers are implanted into the basal cisterns in close contact to the proximal cerebrovascular system at the time of aneurysm clipping and release the drug over 14 days. Thereby, nicardipine is delivered locally at a high and constant concentration to the cerebral blood vessel wall, at the same time avoiding systemic side effects.The initial preclinical and clinical experiences with NPRIs have been promising and have failed to show toxicity. [2][3][4] In a re...

Intra-Arterial Nimodipine for Severe Cerebral Vasospasm after Aneurysmal Subarachnoid Hemorrhage: Influence on Clinical Course and Cerebral Perfusion

“…[1][2][3][4] The current strategies for preventing vasospasm comprise the systemic administration of the calcium channel blocker nimodipine. [5][6][7] Moreover, the use of intracisternal thrombolysis 8 and the intracisternal application of nicardipine-prolonged implants 9,10 demonstrated effectiveness in preventing cerebral vasospasm. Despite these treatment methods, 6,11 the rate of vasospasmrelated permanent disability is estimated as totaling 10%-20%.…”

A Site-Specific, Sustained-Release Drug Delivery System for Aneurysmal Subarachnoid Hemorrhage

“…Despite this and unlike other vasodilator drugs [24,25], it improved clinical outcome. In addition to being a potent vasodilator, even of arteries with angiographic vasospasm [12,26], it was later noted that nimodipine inhibited other delayed effects of SAH that may contribute to DCI, such as cortical spreading ischemia [27], and that it had fibrinolytic activity that could reduce microthromboemboli [23]. Other vasodilators may not have these pleiotrophic effects [28].…”

“…There have been prior reports of sustained-release formulations of dihydropyridines and other drugs administered into the subarachnoid space for SAH [12,13,29,30]. While there has been some evidence that these may be effective, these formulations have had limitations, including lack of characterization of pharmacokinetics, stability, and injectability, use of materials with known or unknown toxicity, and limited data on efficacy of the active drug.…”

“…Clinically, however, the dose that can be administered is limited because L-type calcium channels are located on arteries throughout the brain and body, and doses that dilate the cerebral arteries have some dilatory effect on systemic arteries, causing potentially deleterious adverse effects such as hypotension. Surgically placing pellets containing nicardipine, another dihydropyridine, into the subarachnoid space after aneurysmal SAH reduced DCI and cerebral infarction and improved outcome in experimental and clinical studies of aneurysmal SAH [11,12]. However, the pellets can only be implanted during a craniotomy conducted for aneurysm repair and currently at least 50 % of aneurysms are repaired endovascularly.…”

Nicardipine Prolonged-release Implants - A Potential Tool for the Prevention of Cerebral Vasospasm?

“…9 Given all of the above-mentioned promising results, our group initiated a single-centre prospective randomised Phase IIa study (NPRI versus no NPRI) in 32 patients. 10 All patients were considered high risk (Hunt & Hess grade 3-4, Fisher grade 3) and, when randomised into the treatment arm, received a fixed number of 10 pellets. Digital subtraction angiography (DSA) was analysed in a blinded fashion by an outside institution, and a diameter increase of 115 % was observed in those vessels immediately adjacent to the pellets.…”