Intra-Arterial Nicardipine Infusion Improves CT Perfusion–Measured Cerebral Blood Flow in Patients with Subarachnoid Hemorrhage–Induced Vasospasm

Materials and Methods

Results

The patient data including time of treatment in relation to the aSAH, age, sex, Hunt and Hess grade, Fisher group, location and treatment of the aneurysm, location and severity of the vasospasm, IA nicardipine dosage per location, and pre- and posttreatment CTP data are summarized in the Table.

A total of 15 vessels were successfully treated in 6 patients. One patient underwent PTA in addition to IA nicardipine infusion. The remaining patients were treated only with IA nicardipine. The total dose ranged from 6 to 30 mg per patient. In 1 patient, we were unable to quantify improvement in flow parameters, due to section-selection differences between the pre- and posttreatment CTP examinations. This patient was not included in our quantitative analysis; however, subjective analysis of the 2 closest pre- and posttreatment sections was suggestive of posttreatment improvement.

A total of 16 vascular territories were analyzed in the remaining 5 patients, including bilateral MCA and ACA territories in 2 patients, bilateral MCA and PCA territories in 1 patient, and bilateral MCA territories in 2 patients. One patient (case 4) had near-complete occlusion of the M2 segment of the right MCA on angiographic evaluation. She was treated with 8 mg of nicardipine infusion in the right ICA, resulting in only minimal angiographic response. In another patient (case 5), only the left ICA was treated because the procedure had to be aborted due to seizures. In the remaining 14 vascular territories, treatment resulted in satisfactory angiographic response.

Both CBF and MTT improved significantly in the affected regions in response to IA nicardipine therapy. Mean CBF increased from 38.2 ± 13.1 mL/100 g/min in the pretreatment CTP scan to 50.7 ± 12.9 mL/100 g/min in the posttreatment CTP scan. This translates into a relative CBF increase of 41.3 ± 42.9% (range, −9%–162%; P = .0004). Mean MTT decreased from 6.0 ± 1.2 seconds in the pretreatment CTP scan to 4.3 ± 1.3 seconds in the posttreatment CTP scan, resulting in a relative MTT reduction of 26.2 ± 24.2% (range, 0%–70%; P = .0002). The CBV response was quite variable and did not show any specific pattern; mean CBV was 2.8 ± 0.7 mL/100 g in the pretreatment CTP scan and 2.9 ± 0.8 mL/100 g in the posttreatment CTP scan (relative CBV change, 4.0 ± 20.6%; range, −44%–34%; P = .63). Fig 1 illustrates the effects of IA nicardipine infusion on DSA and MTT maps.

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Fig 1.

Panels 1, 2, and 3 illustrate cases 1, 2, and 3, respectively. Panels A–D show pre- and posttreatment angiograms and MTT maps, respectively. Panel 1: A, Severe vasospasm of the left PCA, which had a marked response to nicardipine infusion in the basilar artery (1B) resulting in 28% reduction in MTT (1C, -D) and 62% increase in CBF (not shown) at the left PCA territory. Panel 2: A, Severe vasospasm of the left ACA, which had a marked response to PTA of the A1 segment and nicardipine infusion (2B), resulting in 68% reduction in MTT (2C, -D) and 89% increase in CBF (not shown) at the left ACA territory. Panel 3: A, Moderate vasospasm of the left MCA, which had only a mild angiographic response to nicardipine infusion (3B). C and D, Despite the suboptimal angiographic result, there was a 37% reduction in MTT and 69% increase in CBF (not shown) at the left MCA territory. This likely reflects the nicardipine effect in the microcirculation.

To assess the possibility that the aforementioned benefit was mostly related to PTA, we performed a second analysis excluding the 4 vascular territories (case 2) that were also treated with PTA. The improvement in cerebral hemodynamics remained statistically significant, with a relative CBF increase of 25.7 ± 25.9% (range, −9%–69%; P = .01) and a relative MTT reduction of 13.8 ± 10.5% (range, 0%–37%; P = .026).

Discussion

In the present study, we have described the direct effects of IA nicardipine on reduced CBF in patients with hemodynamically significant vasospasm after aSAH by using first-pass quantitative cine CTP. The principal findings of the study are: 1) the characterization of the acute CBF response to IA nicardipine infusion; and 2) the validation of the use of CTP in the assessment of new treatment modalities for vasospasm.

The mechanism by which aSAH-induced vasospasm occurs is not yet fully understood; however, both experimental and clinical data strongly suggest the efficacy of calcium antagonists in the treatment and prevention of vasospasm.^13–15 Nimodipine, an oral dihydropyridine calcium antagonist, has been shown to reduce the incidence of vasospasm-induced cerebral infarction by 34% and the rate of poor outcomes by 40%.¹⁶ Nicardipine is another dihydropyridine calcium antagonist, which has more selective effects on vascular smooth muscle than on cardiac muscle. Several studies have demonstrated that continuous intravenous nicardipine infusion significantly decreases the incidence of symptomatic, angiographic, and TCD vasospasm.^15,17,18 However, the efficacy of this regimen has been limited by prolonged hypotension, pulmonary edema, and renal dysfunction.

Badjatia et al⁶ have previously demonstrated that IA nicardipine infusion improves angiographic vasospasm with an effect more sustained than what has been reported with papaverine. However, it is clear that factors other than angiographic response play a role in the clinical response to vasospasm treatment as demonstrated by the lack of correlation between angiographic and clinical improvement in many situations. For instance, patients treated with IA papaverine may still have further neurologic deterioration despite angiographic improvement.¹⁹ Conversely, patients treated with IA nimodipine may demonstrate remarkable clinical improvement despite unchanged angiographic vasospasm.⁷ Similarly, IA infusion of L-arginine has been shown to markedly increase CBF in a primate model of SAH, despite the lack of any angiographic changes.²⁰ Changes in perfusion at the microvasculature level probably account for this clinicoangiographic dissociation. Therefore, assessment of cerebral perfusion as opposed to angiographic results alone should be considered when evaluating novel therapies for vasospasm.

As an example, Firlik et al¹⁹ have demonstrated that IA papaverine may fail to improve CBF despite reversal of angiographic vasospasm. These authors reported a series of 15 patients with symptomatic vasospasm who underwent a total of 23 IA papaverine treatments (including combined angioplasty on 5 occasions). Angiographic vasospasm was at least partially reversed following treatment on 18 of 23 occasions (78%). Associated clinical improvement was major on 6 occasions, but either minor or none on 17. Pre- and posttreatment CBF was assessed by stable xenon-enhanced CT on 13 occasions but showed improvement in previously ischemic areas in only 6 of these (46%).¹⁹

CTP has been shown to be a useful tool in the selection of proper candidates for acute stroke thrombolysis²¹ and has more recently been used to diagnose and guide medical and endovascular therapy in patients with delayed cerebral ischemia after aSAH.^8,9,22 The application of CTP to assess the response to vasospasm treatment has also been previously reported. Ono et al²³ performed CTP in 8 patients with aSAH-induced vasospasm before, immediately after, and 4.5–6 hours after IA infusion of fasudil hydrochloride with an average CBF in the infused hemisphere of 41.6 ± 3.56, 46.4 ± 5.82, and 41.6 ± 7.42 mL/100 g/min, respectively. The authors concluded that, though initially effective, fasudil hydrochloride is a short-lived treatment for vasospasm.²³ In our study, pretreatment and immediately posttreatment mean CBF was 38.2 ± 13.1 and 50.7 ± 12.9 mL/100 g/min, respectively.

Our analysis is somewhat limited by its overall small sample size and by the fact that PTA was performed in 1 of our patients, and differences in section selection did not allow the inclusion of that last patient in the analysis. In addition, our work carries all the limitations of a retrospective methodology. Finally, although we proved the effectiveness of IA nicardipine in increasing CBF in patients with vasospasm, we did not assess the duration of this effect due to concerns about the additional contrast and radiation exposure that would be necessary for another CTP examination. Despite these limitations, we were able to demonstrate a statistically significant improvement in CBF and MTT immediately after IA nicardipine infusion.

Conclusion

IA nicardipine infusion improves CBF and MTT in ischemic regions in patients with aSAH-induced vasospasm. Our data complement, at the tissue level, the previously reported favorable effects of IA nicardipine seen with angiographic studies. In addition, this study reinforces that CTA/CTP is a safe and promising technique for the evaluation of aSAH-induced vasospasm. Indeed, quantitative CTP may provide a surrogate marker for monitoring the success of treatment strategies in patients with aSAH-induced vasospasm. Future studies with larger sample sizes are required to confirm our results and to answer the questions about the duration of the treatment effect as well as its overall impact in clinical outcomes.