Intraarterial nimodipine for the treatment of symptomatic vasospasm after aneurysmal subarachnoid hemorrhage: A preliminary study
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.91356
Source of Support: None, Conflict of Interest: None
Objective: Despite dramatic advances in all medical era, cerebral vasospasm is still the major complication in patients with subarachnoid hemorrhage (SAH). The purpose of this study was to assess the influence of intraarterial (IA) nimodipine in the treatment of symptomatic vasospasm and in preventing neurological disabilities. Materials and Methods: We retrospectively reviewed 10 patients of SAH who received IA nimodipine in 15 procedures. The decision to perform angiography and endovascular treatment was based on the neurological examination, brain computed tomography (CT) and CT-angiography. The procedure reports, anesthesia records, neurological examination before and after the procedure, brain imaging and short- and long-term outcome were studied. Results: The average dose of nimodipine was 2 mg. The median change in mean arterial pressure at 10 min was -10 mmHg. No significant change of heart rate was observed at 10 min. There was radiological improvement in 80% of the procedures. Neurological improvement was noted after eight out of 12 procedures when nimodipine was used as the sole treatment and after 10 out of 15, overall. Six patients clinically improved after the treatment and had good outcome. In one patient, an embolus caused fatal anterior and middle cerebral arteries infarction. There was no other neurological deficit or radiological abnormality due to the nimodipine treatment itself. Conclusion: Low-dose IA nimodipine is a valid adjunct for the endovascular treatment of cerebral vasospasm. Beneficial effects are achieved in some patients, prompting a prospective control study.
Keywords: Cerebral vasospasm, nimodipine, subarachnoid hemorrhage
Delayed cerebral ischemia due to vasospasm is a major cause of morbidity and mortality for patients with subarachnoid hemorrhage (SAH). ,,,, Although balloon angioplasty is the treatment of choice for severe proximal cerebral arteries vasospasm, some vessels are not reachable with a balloon catheter because of the tortuosity of the carotid arteries or the distal position of pial arteries or perforators. ,, Intraarterial (IA) papaverine has been used with confounding results. ,, Some series showed temporary dilatation of the spastic vessels, , whereas others have shown worsening ischemia and subsequent neurological deterioration. ,, Cerebral blood flow studies have shown that papaverine can increase intracranial pressure without a significant effect on outcome, when administered intraarterially. , Another intraarterially administered vasodilator, nitroglycerin, has been shown to increase intracranial pressure, presumably by dilating the veins and therefore decreasing the cerebral perfusion pressure. , Verapamil, a calcium channel blocker, has been used as an IA agent in one series with some beneficial effects,  but needs to be evaluated in larger series to confirm its efficacy. One study has shown that calcium channel blocker (nimodipine) alleviates cerebral ischemia without clinical signs of intracranial hypertension and with no difference in cerebral perfusion pressure compared with the control group.  IA nimodipine has been used in a few clinical settings, and is shown to be effective and safe for the treatment of symptomatic vasospasm after SAH. ,, We started the use of nimodipine for patients with cerebral vasospasm either as an adjunct therapy to angioplasty or as the sole treatment depending on the angiographical and angioanatomical situation. This preliminary study was designed to assess the safety and efficacy of this treatment.
Between October 2004 and March 2006, 10 patients underwent IA injection of nimodipine for the treatment of SAH-induced vasospasm. Patients were classified according to the WFNS clinical grading. [Table 1] shows the summary of patients' characteristics with the aneurysm location and treatment.
The following protocol is used at our institution to manage a clinically symptomatic vasospasm after aneurysmal SAH. When vasospasm is suspected clinically, a brain computed tomography (CT) along with CT-angiography is performed to confirm, firstly, the presence or absence of ischemia and, secondly, the presence of vasospasm. If the vasospasm is mild (<25% of arterial diameter reduction) and the patient has minor symptoms, triple -H therapy is administered and the patient is transferred to the Intensive Care Unit (ICU). In case of any worsening of neurological status, cerebral angiography with endovascular treatment will be considered. If there is moderate to severe vasospasm (25-50% arterial diameter reduction or >50%, respectively) or in the presence of significant neurological deficit, immediate angiography with attempt for cerebral vessel dilatation is performed. In this setting, nimodipine is administered if (1) there is moderate to severe vasospasm that could not be safely treated with balloon angioplasty for technical or anatomical reasons, (2) vasospasm is present on the distal vessel with delay in arterial circulation or (3) in combination with balloon angioplasty in order to prevent the catheter-induced vasospasm.
We retrospectively reviewed angiography reports, anesthesia records, neurological examination, brain CT before and after treatment and the short- and long-term outcome of these 10 consecutive patients who received IA administration of nimodipine. The anesthesia was performed with rapifen and midazolam. The angiography was performed using a 5F diagnostic catheter and a 4F catheter was used in the carotid or vertebral arteries at the cervical level to inject nimodipine. A super-selective catheterization was also performed according to the neurological evaluation pre-operatively and the location of vasospasm. Nimodipine was diluted in a solution of NaCl 0.9% to obtain a 25% concentration. The dose administered was 1-4 mg (5-20 ml) per vessel with the maximum rate of 2 ml/min.
Because the major undesirable effects of IV nimodipine are hypotension and bradycardia, blood pressure and heart rate were used as parameters for systemic side-effects. The average blood pressure and heart rate measured within 5 min before nimodipine injection were used as baseline measures. The hemodynamic parameters at 10 min were used as the measurement of the systemic effect of nimodipine. The procedure was planned to be stopped if a significant drop in the systolic BP (>40 mmHg) had occurred or if there were signs of intracranial hypertension (hypertension, bradycardia or neurologic signs). A repeat angiography was performed to control the effect of chemical angioplasty after 10 min. The frontal projections of the arterial phase of these angiograms were digitized and were magnified 200% and the diameters of the treated internal carotid artery (ICA), M1 segment of middle cerebral artery (MCA) and A1 segment of anterior cerebral artery (ACA) were compared with the pre-treatment status. The neurologic examinations were compared before and after treatment for all patients and patients were admitted to the ICU and underwent critical neurological evaluation by the neurosurgery team. The post-angioplasty neurologic examinations were determined as improved, stable or worse. Brain CT scans obtained before and after treatment were compared to identify unexpected neurologic complications such as edema, infarction, hemorrhage or hydrocephalus.
The short-term and long-term (1 year or longer) outcome of these patients was evaluated using Glasgow Outcome Scores.
Five patients had WFNS grade I, two had grade II, one had grade III and two had grade V. A total of 15 procedures were performed. The average dose of nimodipine per patient was 2 ± 0.6 mg or 0.5 mcg/kg. There was no correlation between the dose and the degree of vasospasm. The largest single dose per vessel was 4 mg. In four procedures, there was an association of mechanical (balloon) and chemical (nimodipine) angioplasty. In 11 procedures, nimodipine was administered as the sole treatment: in three of them for distal vasospasm [Figure 1] and [Figure 2] and in the remaining for technical difficulties that contraindicated a mechanical dilatation of spastic vessels due to a high procedural risk. Treatment was repeated in three patients 1-6 days after the first treatment. Two patients received three separate treatments. Thirteen procedures were performed under general anesthesia and two under local anesthesia. [Table 2] shows the location and degree of vasospasm and post-nimodipine infusion data in these 10 patients.
A review of the anesthesia records of all patients did not reveal any secondary sign of increased intracranial pressure. In two patients who had the treatment under local anesthesia, we did not observe sudden deterioration of consciousness or other neurological deficit. Neurological examination after the treatment was improved in six (60%) patients, stable in three (30%) patients and was worse in one (10%) patient. In one patient, where nimodipine was effective in relieving spasm, the patient died due to aneurysm rebleeding from a small residual part (2 mm). In the only patient with worsening of clinical examination, there was a thromboembolic fatal complication with occlusion of the carotid bifurcation and subsequent anterior and middle cerebral artery territory ischemia. This dramatic complication was related to the procedure but was not due to nimodipine itself. Patients who were receiving triple -H therapy (seven patients) had a similar response to nimodipine as that of patients who were not receiving triple -H therapy (three patients). A comparison of brain CT scan before and after the treatment with nimodipine revealed no evidence of worsening cerebral edema, increase in hydrocephalus, new ischemia or hemorrhage. The only procedure-related complication was the abovementioned case with MCA and ACA territory ischemia. The short-term and long-term outcomes were good in seven cases (GOS I or II) [Table 2]. The mortality as shown here in this series was not directly related to the administration of nimodipine.
Notable vascular dilatation was observed in 11 (73%) of the 15 procedures and in seven patients. A partial result was observed in one patient in whom the A1 segment did not respond to nimodipine but the M1 segment showed remarkable dilatation (overall 80% good results). Angiographic results were judged as poor in three procedures (20%). Vasospasm never worsened after the selective injection of IA nimodipine.
Administration of IA nimodipine had little systemic effect, and seemed to be dose dependent. The average changes of mean arterial pressure at 10 min were -5 ± 1 mmHg. The changes were clinically relevant in two patients who presented with moderate hypotension after the treatment, who necessitate the administration of moderate doses of amines. In these two patient, the systolic BP dropped to 130 mmHg (from 155 mmHg) and to 120 mmHg (from 140 mmHg), respectively. There was no severe bradycardia that warranted treatment. In no patient did a significant elevation of intracranial pressure occur during or immediately after the procedure.
Of the seven patients with radiological resolution of spasm after the procedure, six (85%) had clinical improvement. Of the three patients with no radiological response, none had clinical improvement. Of the four patients who remained clinically unchanged after the treatment, two had vascular dilatation on immediate post-procedural angiogram. Among the six patients with good long-term outcomes, five (83%) experienced clinical improvement after the procedure. Only one (10%) patient with no clinical improvement and no angiographic dilatation had good outcome.
Angioplasty is widely considered to be the most effective endovascular procedure because of the excellent and nearly always permanent reversal of vasospasm, which is often followed by high rates of clinical improvement. ,,,, Among the serious complications of this procedure are vessel rupture, branch occlusion, displacement of aneurysm clip or rerupture of an untreated aneurysm. ,, Because this procedure is technically demanding, it should be performed in centers with experiences in endovascular therapy and, moreover, it can be applied only to proximal, segmental vasospasm in the ICA, the M1 segment and, less often, the A1 or M2 segment. 
Because of fewer technical difficulties, IA administration of vasodilators has become an attractive alternative to mechanical angioplasty. Papaverine has long been used as the only available treatment with efficiency, especially in distal vessels. Reported complications include monoocular blindness, brainstem dysfunction, transient focal neurological deficit and emboli. ,,,,,, Rebound effect can occur with need for repeated procedures and related risks.  Other agents such as milrinone, , verapamil,  neuropeptide, susbtance P and intestinal peptide  have been used or are under investigation, but their efficacy has yet to be determined. Administration of nimodipine by the arterial route has previously been reported in a few very small series , and only one relatively larger series.  Biondi et al. assessed the efficacy in 25 patients who underwent IA injection of nimodipine and demonstrated that 76% of the patients showed clinical improvement, 63% had notable vascular dilatation after the procedure and 72% had a favorable outcome, with no complication related to this treatment. They concluded that IA nimodipine is effective and safe for the treatment of symptomatic vasospasm after SAH.
In our department, IA nimodipine has been used since October 2004 as an alternative for the treatment of medically intractable vasospasm in 10 patients and for 15 procedures. Balloon angioplasty was used in three patients (four procedures) among them. Our results showed that in nearly 80% of the procedures, there was an immediate notable vascular dilatation and, among patients with good radiological response to nimodipine, 85% had clinical improvement. Conversely, there was no clinical improvement in patients without response to nimodipine. Nevertheless, one of these patient presented good clinical outcome at long-term follow-up. There was no significant hemodynamic instability and no complications directly due to nimodipine infusion. All our patients received nimodipine orally for prophylactic measure. One could raise the question regarding the utility of IA injection of nimodipine in patients receiving the drug orally. We believe that the cerebral concentration of nimodipine might be higher when injected locally, and this could allow the persistence of therapeutic drug concentration for longer periods than per oral administration. The positive effect of nimodipine is exerted by several mechanisms; direct neuroprotective properties induced by the blockage of free radical attack on the intraneuronal mitochondria, an improvement of CO 2 reactivity and cerebral oxygen metabolism and reduction of tissue damage caused by calcium overload at perfusion. ,,,,,,
The efficacy of intravenous nimodipine is controversial. One analysis failed to show a statistically significant reduction in angiographically detected cerebral vasospasm among patients treated with intravenous nimodipine.  One in vitro study confirmed this finding.  Some investigators have shown that after nimodipine, the magnitude of vasodilatation in isolated rat arterioles was greater and the duration of dilation after washout longer in intracerebral penetrating arteries than in pial arteries. , One can assume that in humans, nimodipine could be more effective in dilating small perforating branches than angiographically visible large arteries. However, in our study, a significant reduction of angiographic cerebral vasospasm was found in 73% of the procedures, with 83% clinical improvement after nimodipine among patients with good outcome. This was comparable to the series from Biondi et al., which showed 63% significant cerebral vasospasm reduction and 72% clinical improvement. Firat et al. recently published an experimental study evaluating the efficacy of selective IA nimodipine in a rabbit model of chronic vasospasm due to SAH. Their conclusions confirm the positive effect of IA nimodipine in relieving spasm. The same study showed that IA nimodipine is more effective than IA papaverine.  Roda et al. found that a maximized dose of intraarterially injected nimodipine given just before and during reperfusion reduced the cortical infarct volume in rats subjected to partially reversible focal cerebral ischemia.  On the basis of the data from previous series and ours, we can hypothesize that nimodipine injected directly into the territories where vasospasm has developed improves the survival of patients with hypoperfused cerebral tissue.
In the present series, multiple treatments were performed in three patients whose conditions were unchanged after endovascular treatment or when they showed a new deterioration and worsening of neurological status despite the first infusion of nimodipine with good result. The treatment was repeated in an attempt to prevent progressive deterioration. Our findings regarding the systemic effect of IA nimodipine on BP and heart rate are in correlation with Biondi et al., showing no significant adverse effect.
This is a preliminary study. The collection of data is retrospective and the series is small. There is no control group. All the abovementioned limitations represent a flaw to the real value of conclusions retrieved from this evaluation. Long-term clinical efficacy of this treatment may be influenced by many factors and, therefore, the positive trend toward symptom reversal and good outcome is not sufficient to claim the relative efficacy of this treatment. The real efficacy of this treatment in preventing ischemia should be assessed by simultaneous cerebral blood flow monitoring, which was not included in the evaluation of this preliminary series. Although our data have obvious limitations, we can conclude from the results of this retrospective analysis that (1) nimodipine is effective in relieving vasospasm in cases where intensive medical therapy fails, with good radiological results (73%) and relatively good clinical results (60%), (2) this technique could be done in the same setting with angioplasty for relieving distal spasm or to prepare vessels before mechanical dilatation, (3) the effect of nimodipine is temporary and may need repeated procedures and (4) the complications in this series are not directly related to IA nimodipine infusion but are related to the risk of the endovascular technique itself. Ideally, this study should be run in a prospective randomized trial along with the evaluation of cerebral blood flow to confirm the results shown here, but a long time would be required to gather enough patients at a single institution or a small group of institutions to achieve adequate statistical power.
[Figure 1], [Figure 2]
[Table 1], [Table 2]