Role of endovascular super selective intra-arterial injection of CA channel blocker agent (nimodipine) in management of cerebral vasospasm following aneurysmal SAH: a single institution experience

Abstract

Background

Vasospasm is a grave complication of aneurysmal subarachnoid hemorrhage (SAH) with a significant rate of morbidity and mortality. Endovascular intra-arterial injection of Ca channel blocker agent (Nimodipine) may offer a promising solution in refractory vasospasm.

Results

During the period between April 2017 and May 2019, 120 patients who presented with SAH due to a ruptured intracranial aneurysm were admitted to the neurosurgery department at Alexandria University Hospitals. Among them, 30 patients developed refractory vasospasm and were subjected to endovascular super selective intraarterial injection of nimodipine. The angiographic improvement was excellent in three (10%), good in 14 (46%) and poor in the remaining 13 procedures (43%). Clinical improvement was achieved in 15 cases while 15 cases showed no improvement on Modified Rankin Scale. No cases deteriorated following the injection.

Conclusions

Endovascular chemical angioplasty using a ca channel blocker agent (Nimodipine) is a safe and efficient method for the treatment of refractory post aneurysmal SAH vasospasm. The quest is still needed for developing a better efficient agent to overcome the vasospasm dilemma.

Background

Aneurysmal subarachnoid hemorrhage (SAH) is a catastrophic health burden with a high fatality rate and permanent disability complications. The incidence of SAH is 9/ 100,000 persons/year with regional variation with a 30 days fatality rate of 42%. It is an overwhelming problem with an overall prognosis depending on the volume of the initial bleeding, re-bleeding, vasospasm, the degree of delayed cerebral ischemia (DCI), hydrocephalus, and electrolyte disturbance. The extracranial complications may include myocardial ischemia with arrhythmias and neurogenic pulmonary edema [1,2,3].

Vasospasm is a major complication with increased rates of permanent disability and mortality following SAH. A deeper understanding of the pathophysiology and pathogenesis of the cerebral vasospasm is mandatory in dealing with DCI and making it one of the main targets of therapeutic goals [4,5]. Oral and intravenous vasodilators are not always sufficient for most cases. For this reason, endovascular treatment of refractory cerebral vasospasm has become part of the standard treatment protocol in many neurosurgical centers. The most frequently used techniques aim to achieve arterial vessel dilatation using endovascular super selective intra-arterial administration of pharmacological agents, mechanical balloon angioplasty, or a combination of both. Endovascular balloon angioplasty techniques can be applied to only proximal vessel segments [5,6].

The purpose of our study was to assess the safety and efficacy of endovascular intra-arterial injection of ca channel blocker agent (Nimodipine) in the management of cerebral vasospasm following spontaneous SAH.

Methods

During the period between April 2017 and May 2019, 120 patients who presented with SAH due to a ruptured intracranial aneurysm were admitted to the neurosurgery department of Alexandria Main University Hospital. Among, them 30 patients experienced refractory symptomatic cerebral vasospasm. Digital subtraction Angiography (DSA) was done showing radiological vasospasm and so the patients were subjected to the treatment.

The thirty-patient were included in the study, among them 10 females and 20 males. The age ranged from 40 to 63 years. Among the 30 patients, the aneurysm was treated by surgical clipping in 28 (93.3%), whereas 2 patients (6.7%) underwent endovascular treatment using simple coiling.

Aneurysmal treatment was performed within the first 10 days of hemorrhage in all patients due to being referred from other institutions. Thirty-two endovascular procedures were performed from day 4 through day 15 after SAH (mean number of days after SAH, 7.3 days). One patient required 3 endovascular sessions.

The patient’s neurologic condition was assessed by using the Hunts and Huss (H&H) grading scale on admission. Non-enhanced computed tomography (NECT) scans were evaluated according to the Fisher classification (Table 1).

Table 1 Patients’ characteristics

On admission to the neurosurgical intensive care unit, standard medical management was initiated including preventive, well-monitored hypertensive, hypervolemic, and hemodilution (triple-H) therapy which was maximized to the point of elevating systolic arterial pressure to 150–170 mm Hg. All patients received oral nimodipine (Nimotop, Bayer Pharma AG, Leverkusen, Germany). This treatment was continued until the 21st day in patients developing vasospasm. In those refractory cases, intravenous administration of 2 mg of nimodipine per hour using continuous infusion beginning was tried in some of them. The drug was suspended only if refractory hypotension developed.

Patients were considered eligible for endovascular nimodipine injection if they showed at least one of the following conditions:

• 1. Altered consciousness or clinical worsening based on Glasgow Coma Scale scores

• 2. New motor deficits (mono/hemiparesis or cranial nerve palsy)

• 3. Speech disturbances (aphasia-dysphasia)

When vasospasm was suspected, cerebral CT scanning was first performed to exclude other causes of clinical deficits, such as hydrocephalus, infarction, or rebleeding.

Intra-arterial catheter injection of nimodipine

A single 5 Fr arterial sheath was placed into the right common femoral artery under local anesthesia (xylocaine). A 5 Fr diagnostic catheter was then advanced to perform a 4 vessels DSA, depending on the vascular territory being treated.

A bolus of 1 mg (5 ml) of nimodipine was administered slowly (was infused after it was diluted with 15 ml of normal saline to obtain a 25% dilution), followed by a second bolus application 5 min later. The follow-up angiography was performed 10 min later. In cases of minor angiographic effect after the second bolus injection, the patients were considered for continuous IAN for 2 h (4 mg/h). Micro-catheters (Echelon 10) were advanced using microwires to the affected vasospastic small vessels to deliver the nimodipine more distally and selectively.

The internal carotid artery on the side of vasospastic cerebral vessels was infused in 29 of 30 procedures. Nimodipine was injected into one vertebral artery because of associated posterior circulation vasospasm.

Because of the reported undesirable effects of some vasoactive drugs on systemic blood pressure and intracranial pressure, routine physiologic monitoring was always performed while the patients were being treated. Arterial blood pressure was continuously monitored to record the maximum systolic blood pressure and the total decrease from the beginning of the procedure.

Post-treatment clinical evaluation

After the procedure, all patients returned to the neurosurgical intensive care unit, and standard parameters were continuously monitored. Clinical assessments were performed over the first 24 h. Triple-H therapy was continued after nimodipine intra-arterial infusion. Also, there was continued intra-venous infusion with nimodipine at a rate of 2 mg/h. All patients remained in the neurosurgical intensive care unit until they recovered or their clinical criteria stabilized. They were then transferred to the neurosurgical ward. Clinical follow-up data were obtained from the case notes for each patient on their discharge from the hospital.

Results:

Angiographic results

Vasospasm was assessed subjectively by two neurosurgery consultants and graded as mild when arterial narrowing was 25% (5 cases), moderate when 25–50% (5 cases), and severe when narrowing was > 50% (20 cases). Vasospasm involved the MCA, ACA, and their perforators in 29 patients. Post circulation was only affected in one patient.

Notable vascular dilatation was observed in 17 cases (56%) of 30 procedures. The angiographic response was excellent in three cases (10%) and good in 14 cases (46%) of the 30 endovascular procedures. Angiographic responses were judged poor in the remaining 13 procedures (43%). Vasospasm was not worsened after the selective injection of intra-arterial nimodipine.

Systolic blood pressure did not decrease by more than 40 mm Hg during nimodipine infusion and was never below 100 mm Hg. Hypotension was rapidly normalized within a short time (5–10 min) after the end of the procedure. No hypertension happened during or immediately after the endovascular treatment. No clinically evident complications or deaths could be linked to the system (Table 2).

Table 2 Angiographic and clinical results

Clinical results

Fifteen (50%) patients had a stable improvement in their clinical condition during the 24 h following vasospasm treatment with intra-arterial nimodipine. 12 cases didn’t show any clinical improvement following the intra-arterial injection of nimodipine and 3 cases died during the following week (who had a Low GCS on admission). Fifteen patients had clinical improvement and long-term better function on both GOS and Modified Rankin scores. Two patients (6%) had no clinical improvement despite the notable vascular dilatation on the post-treatment angiogram. No patients with poor vascular dilatation experienced clinical improvement after the procedure (Tables 2 and 3).

Table 3 Angiographic-clinical correlation

Follow up

After a follow-up of 3 months, 15 patients (50%) showed a good GOS score (14 with a score of 4, and 1 had a GOS score of 5). Seven patients had a GOS of 3 and 5 patients had a GOS of 2. Three patients died.

On the modified Rankin scale score one patient with a score of 0, nine patients with a score of 2, and five patients with a score of 3. Seven patients had a severe disability, while three patients died.

Discussion

Cerebral vasospasm is a devastating sequel causing patient deterioration and loss after perfect aneurysm clipping or coiling. Many therapeutic interventions were studied to beat this major enemy after securing ruptured intracranial aneurysms. local, oral, and parenteral pharmaceutical agents were tried to prevent cerebral vasospasm. [5,6]Balloon angioplasty is a well-known method of treatment in the case of refractory cerebral vasospasm and reverses its symptoms. Balloon Angioplasty is an effective endovascular procedure with permanent effect to some extent, yet it is invasive and technically challenging and restricted to a proximal arterial tree with focal segments of vasospasm. It requires an experienced neuro-interventionist. The materials used are expensive. Also, it may result in vessel rupture. Restenosis may occur after vasodilation. [5]

Papaverine is an opium alkaloid with a smooth muscle relaxing effect. It is used for its effective vasodilator action. It can be used locally during the clipping process and intraarterial application using an endovascular approach. Papaverine has a lot of complications including monocular blindness, brain stem dysfunction, and transient focal neurologic deficits and convulsions. The vasodilator effect is temporary with rebound vasoconstriction. [6,7,8]

In our institution, we studied the angiographic and clinical effect of endovascular Intra-arterial injection of Nimodipine (IAN) on cerebral vasospasm after aneurysmal SAH that was resistant to systemic therapy. Nimodipine is a Calcium antagonist with a cerebral vasodilator effect and to some extent little systemic effect. [9,10,11,12,13,14]

In the present study 15 (50%) patients had a stable improvement in their clinical condition during the 24 h following vasospasm treatment with intra-arterial nimodipine. Twelve cases didn’t show any clinical improvement following the intra-arterial injection of nimodipine and 3 cases died during the following week. The mortality was related to the bad initial presentation and the refractory vasospasm.

Data from a large series by Biondi et al. [12] demonstrated that IAN is effective and safe for the treatment of vasospasm after SAH. In their trial, 25 patients treated with IAN were retrospectively reviewed and analyzed. Clinical improvement was observed in 76% of the patients. Angiographic vessel dilation occurred in 43% of all the IAN sessions, and 18 of 25 patients had a favorable outcome (MRS 0–2). No complications were observed.

Hanggi et al. [14] studied the effectiveness of IAN by investigating cerebral perfusion by repeated perfusion CT scan (PCT). Their results provided a survey of the immediate and lasting efficacy of IAN. Eleven (61.1%) of 18 patients with some immediate effects of IAN were clinically assessable. In 7 patients, the neurologic condition remained unchanged, whereas 2 patients demonstrated an immediate neurologic improvement. Nevertheless, 2 patients showed a decreasing GCS. Their results are not like the study by Biondi et al. who demonstrated a clinical improvement in 76% of the patients after IAN. Also, the clinical improvement in our series reached 50%.

In our institution, the dose of the nimodipine was adjusted to work on reversing the angiographical vasospasm, to the same extent to avoid the hypotensive complication of the drug. In general, all patients received dosing ranging from 5- 8 mg as a total dose (1 to 2 mg loading as an initial dose and 4 mg/h as a maintenance dose provided no hypotension is monitored). There was no complication during all procedures other than hypotension which was rapidly corrected by intravenous fluids and vasoactive materials. The effect of IAN was monitored clinically, and the improved cases didn’t need another endovascular treatment session which reflects the durable effect of IAN. The same effect was proved by Hanggi et al.study.^[[(12)]]

Hypotension is well known as the most dominant side effect of systemically applied nimodipine. In our study population, 5 patients experienced an arterial blood pressure decrease of 20 mm Hg systolic after the initial bolus, despite the already-instituted hypertensive and hypervolemic therapy. In all patients, this effect was temporary and could easily be treated within minutes by adjusting the vasoactive medication. Nevertheless, this demonstrated that patients always need to be monitored during and after the IAN procedure.

One limitation of the study is the lack of a control group. The application of IAN was introduced exclusively as rescue therapy. Because of imminent infarction, no control group was included in the study. A further limitation is presented by the small sample size, precluding subgroup analysis. In addition, the absences of CT Brain Perfusion pre and post-injection of intra-arterial nimodipine to assess the effect of the ca channel blockers in reversing vasospasm and reperfusion of the ischemic parts (Figs. 1, 2, 3).

Fig. 1

A case of 50-year-old female presented with a left MCA aneurysm. Coiling of the aneurysm was done. A anteroposterior view of the Lt ICA showing severe spasm of both ACA and MCA and the coiled MCA bifurcation aneurysm. Poor distal and parenchyma flow is observed. B Left ICA angiogram in the AP view showing dilatation of the ACA and MCA. Better distal and parenchymal flow is observed

Fig. 2

A case of 45-year-old male presented with an Acom aneurysm. A anteroposterior view of the RT ICA showing severe spasm of both ACA and MCA and the clipped Acom aneurysm. Poor distal and parenchyma flow is observed. B right ICA angiogram in the AP view showing dilatation of the ACA and MCA. Better distal and parenchymal flow is observed

Fig. 3

A case of 52-year-old male presented with an RT MCA aneurysm. coiling of the aneurysm was done. A anteroposterior view of the RT ICA showing severe spasm of both ACA and MCA and the coiled MCA bifurcation aneurysm. The ACA is not seen with Poor distal and parenchyma flow observed. B right ICA angiogram in the AP view showing vasodilatation of the ACA and MCA. Better distal and parenchymal flow is observed

Conclusions

In conclusion, according to our study, IAN has a direct positive response in most patients with refractory vasospasm after standard therapy, improving both angiographic and clinical vasospasm. Although our data have some limits regarding the absence of PCT to assess the cerebral perfusion after the first 24 h yet results of the analysis suggest that intra-arterial nimodipine is effective and safe in selected cases of vasospasm following aneurysmal SAH. The search for better alternative dosing and ca channel blockers treatment strategies to reduce cerebral vasospasm and improve patients’ outcomes must be continued.