Cerebral vasospasm (CV) represents the most crucial complication encountered following an aneurysmal subarachnoid hemorrhage (aSAH). However, despite the use of different therapeutic procedures, 16-65% of these patients consequently develop delayed cerebral ischemia (DCI). The early detection of CV in aSAH may be difficult both clinically and radiographically (1).

Despite all existing treatment approaches, aSAH, and the ensuing CV and DCI are the leading causes of morbidity and mortality in affected patients (1,2). Although 40-70% of patients exhibit substantial arterial narrowing (on a doppler ultrasound or in angiography), only 20 to 30% of these patients present with DCI (3,4). Intra-arterial digital subtraction angiography (DSA) is commonly used as a screening device for the identification of CV and focal cerebral ischemia (CI) (5). Furthermore, DSA allows for therapeutic endovascular interventions, such as balloon angioplasty and stenting in each intracranial artery if required (5). Still, the detailed delineation of the vessels may not be obtained when multiple stenoses are present, and DSA also constitutes an invasive method. By contrast, computed tomography (CT) perfusion (CTP) can identify damage which is not recognized by other methods and may be beneficial for assessing CI related to aSAH (6). CTP allows for the early detection of CI and provides essential information on the ischemic penumbra, which is of utmost importance for the early identification and management of CI (7). In addition, CTP can be used in daily practice, or it can be used as a separate diagnostic tool without the need for magnetic resonance imaging (MRI) data to predict the outcomes of patients with aSAH (7,8). With conventional MRI, performed pre- and post-contrast administration, irreversibly damaged brain tissue cannot be discriminated from infarcted brain tissue (penumbra), which is under the risk of ischemia (7). Even though a conventional MRI provides anatomical details, it does not provide functional details on the dynamic process of ischemia and its elongation. Thus, CTP has currently become an important technique (7). However, there are insufficient data on its association with other non-invasive techniques, such as transcranial Doppler (TCD) ultrasound (3,9,10).

Although several studies have only confirmed the efficacy of nimodipine in patients with CV and subsequent CI, multiple centers have included papaverine, hemodynamic (triplex) therapy and balloon angioplasty in their treatment algorithms for severe CV, despite the fact that these have yet to be established as life-saving therapies (2,11,12). In addition, since 1982, the effect of locally applied nimodipine on vasospasm has been widely used and is well-known (13). However, to the best of our knowledge, no study to date has demonstrated the efficacy of combined intrathecal (IT) and intravenous (IV) nimodipine therapy for cerebral vasospasm. In this respect, the present retrospective study aimed to evaluate the efficacy of combined IV and IT nimodipine therapy for preventing permanent neurological deterioration in patients with severe post-hemorrhagic CV. The present study also aimed to assess the effectiveness of this technique in the clinical outcomes of patients with aSAH.

A total of 14 patients were enrolled in the study (Table II). Of these, 7 patients were males (50%), and the mean age of the patients was 50.9 years (SD ±19 years). Of these, 8 patients (57.1%) underwent surgical and 6 patients (42.8%) underwent endovascular procedures. The outcomes and baseline characteristics of the participants are presented in Table II. Overall, 6 patients [42.8%; 5 (35.7%) from the IV group and 1 (7.1%) from the IV + IT group], who experienced clinical symptoms with severe CV, such as a decline in the level of consciousness, were administered hypervolemic hypertensive and intra-arterial calcium channel therapy or IT nimodipine following the early identification of symptomatic vasospasm with CTP or TCD findings. These patients presented with permanent neurological deficits, as detected using a CT scan following 1 month of follow-up. The TCD and CTP data of the patients are presented in Tables II and III. In the 6 patients (42.8%) who presented with permanent neurological deficits due to vasospasm, CTP revealed reduced a CBF and prolonged MTT. However, TCD also revealed elevated PSV and PI values in the same patients (Table III).

The of the findings present study suggested that the combined use of IT nimodipine with IV therapy in post-aSAH patients who develop severe CV is a safe procedure that may prevent permanent neurological deterioration and delay unfavorable ischemic incidents. Until 2008, the only clinical trial evaluating the effectiveness of the local IT administration of nimodipine was reported by Auer et al (13). In the present study, a 2.4x10^-5 M solution of nimodipine was applied either during the surgery directly to the cerebral vessels or through a catheter post-operatively, with favorable results for vasospasm (13). To date, the effectiveness of IT applied nimodipine has been tested in other clinical trials, demonstrating a notable improvement in cerebral perfusion as detected using CTP and follow-up DSA in the majority of patients (12,20-22). However, no significant adverse effects have been observed following the IT administration of calcium blocking agents (nimodipine/nicardipine) or magnesium sulfate (13). Although the present study included a small sample size, the results obtained with the IT nimodipine administration using an EVD demonstrated a favorable outcome in patients who developed severe CV following aSAH. Moreover, avoiding the risks of the invasive DSA procedure, the utility of CTP and TCD are the most common and studied imaging techniques (3,23).

According to previous studies, the use of IT vasodilating agents is time-dependent, with better effects associated with early drug placement (24). In the present study, the IT bolus was repeated every 24 h during the first 7 days of the event with positive results. Pharmacodynamics diverge between the CSF and the systemic installation, and thus, drug efficacy may vary considerably (25). Although an IT drug placement has numerous benefits, such as direct access to affected vessels, a thick clot may block the stream of drugs from the ventricle to basal blood vessels in vasospasm (26). Moreover, no existing technique can evaluate the effectiveness of nimodipine administered IT vs. systemically. To the best of our knowledge, no study to date, has demonstrated the efficacy of combined IT and IV nimodipine therapy for CV. The present study evaluated two groups of patients depending on IT nimodipine therapy uptake. The clinical outcomes without ischemic damage in CTP at 1 month of follow-up were related to those of the group treated with a combination of IV and IT nimodipine therapy administered in Ringer's solution at a concentration of 2 mg/100 ml. By contrast, the group treated with only IV nimodipine administration exhibited unfavorable clinical outcomes with ischemic damage shown in the CTP and TCD.

The present study has certain limitations. First, the present study was a small, single-center study. Another limitation is its retrospective design. Therefore, firm conclusions regarding the role of IT nimodipine in managing severe vasospasm following aSAH cannot be reached. However, the findings presented herein may serve as a basis for more extensive clinical studies in the future.

In conclusion, although in recent years, notable efforts have been made to gain a better understanding of the mechanisms of CV and the further development of therapeutic agents, IT nimodipine administration is not yet considered a mainstream standard of care. The findings of the present study suggest that the combination of IT and IV nimodipine therapy may be a viable option for treating CV following aSAH. However, the findings of the present small study should be interpreted cautiously and serve as a basis for a future, more extensive clinical investigations.