Ninety-three percent of patients with aSAH admitted to the critical care areas at our institution received less than the guideline recommended dose and duration of nimodipine. The recommendation for nimodipine is largely based on a review conducted by Mees and colleagues which demonstrated nimodipine reduced the composite “poor outcome” of death or dependence on help for activities of daily living and secondary ischemia when compared to placebo.9 The four trials analyzed for this outcome studied nimodipine for a duration of 21 days but multiple limitations, including significant heterogeneity, may hinder generalizability to our study population.9 Three of the four trials excluded patients with renal, cardiac or hepatic insufficiency.12–15 None of the evaluations included patients undergoing endovascular coiling unlike the vast majority in our study.12–15
Our median treatment duration was 11.6 days (0-25.2) which may arguably still provide some protection against CV, as the incidence peaks at seven to ten days, should that be a contributing mechanism.1 In contrast, Hernández-Durán and colleagues conducted a retrospective analysis of 170 patients admitted to the Department of Neurosurgery at a university hospital which found that nimodipine interruption was correlated with greater incidence of DCI (p = 0.431, P < 0.001).16 Forty-four percent of our patients experienced vasospasm demonstrated on imaging compared to 70% of patients in the literature.1 Our approximations of imaging-confirmed vasospasm may be underestimated as we do not employ CT as part of routine vasospasm screening, as well as the timing of our imaging depends on the availability of the CT scanners and staffing. Our mortality rate was found to be 44%, which is higher than the North American incidence of 32%.2 This could be due to our study taking place in a critical care setting.
Most commonly reported reasons for a delay in initiation included an unavailable enteral route (65%) and transfer from another hospital (47%). Prioritizing early confirmed enteral access and improved communication and education with referring hospital sites regarding the importance of timely nimodipine therapy may help expedite nimodipine initiation. Of the patients who discontinued nimodipine early, fourteen percent did not have nimodipine continued on discharge or transfer. Pharmacist-led medication reconciliation may potentially improve continuity of care with nimodipine and has been shown to reduce medication errors during transfers and discharge.17 Twenty-four percent of patients received an alternative nimodipine dosing regimen because the blood pressure was below target. However, patients also received a median of two other medications with the potential to lower blood pressure. Clinical pharmacists can play a pivotal role in mitigating these interactions by optimizing medication management without potentially compromising nimodipine therapy.18
Vasospasm requiring a higher blood pressure target was a common reason for alternative dosing (33%) and early discontinuation or treatment interruption (12%). Upon vasospasm onset, guidelines recommend induction of hypertension unless blood pressure or cardiac status precludes it.4 Requiring a higher blood pressure target may challenge continued nimodipine therapy due to its antihypertensive properties.10–11 Intravenous milrinone, a phosphodiesterase-3 inhibitor, is an investigational medication in the treatment of vasospasm in the setting of aneurysmal subarachnoid hemorrhage.19 Lakhal and colleagues conducted a controlled observational study evaluating milrinone therapy for cerebral vasospasm against historical controls treated with induced hypertension alone.19 Both groups received nimodipine.19 Investigators concluded that intravenous milrinone was independently associated with lower odds of six month functional disability (defined as a score between two and six on modified Rankin score) and vasospasm-related brain infarction on imaging.19 Patients receiving milrinone also demonstrated a reduced odds of requiring endovascular angioplasty.19 Although this study was conducted in an intensive care unit, only 17% of patients had a WFNS score of V compared to 35% in our analysis.19 Initiation of milrinone was associated with hypotension and subsequent increases in norepinephrine infusions to maintain blood pressure targets.19 As nimodipine was continued in both groups, milrinone may only be considered an adjunctive treatment from this evaluation. Only five percent of patients in our study received milrinone but this information was only collected within 24 hours of nimodipine dosage change, interruption, discontinuation limiting our ability to capture such data.
In a study conducted by Barfejani and colleagues, thirty-six of 109 included patients with aSAH received guideline-recommended dose and duration of nimodipine in a Neurointensive Care Unit at a tertiary care center.10 Only 1% of patients in our study received guideline-recommended dose and duration of nimodipine which may be explained by 3% of patients dying in the aforementioned study compared to 44% in our evaluation.10 Patients in our cohort generally presented with a higher severity of illness denoted by 52% scoring as a WFNS III to IV as opposed to 33% in the Barfejani analysis.10 Surgical interventions used in this study were not reported. Sandow and colleagues reported 96 of 220 included patients with aSAH received full daily dose of nimodipine in a Neurointensive Care Unit in Germany.11 However, investigators only collected nimodipine data for the first 14 days following diagnosis of aSAH.11 Furthermore, sixty-five percent of patients were treated with clipping as surgical intervention whereas eight percent of our patients were treated with clipping.11 Although choice of neurosurgical intervention is highly individualized, guidelines recommend endovascular coiling for most patient populations.4–5
Our study is limited in its retrospective design, restricting the accuracy and completeness of our data sets to the quality of documentation available. Additionally, some of our data collection was further limited in its cross-sectional nature.
In conclusion, despite the inherent limitations in the evidence, our best guidance in the treatment of aSAH still advocates unadulterated nimodipine therapy for 21 days, with the avoidance of interruptions. From our evaluation, the integrity of nimodipine treatment is most vulnerable during transfers and establishment of oral access at initial diagnosis, as well as during the management of patient-specific blood pressure targets. Clinical pharmacists are uniquely poised to optimize nimodipine therapy through the education of transferring sites, advocating for better blood pressure management and protection of nimodipine therapy, and facilitating medication reconciliation on transfer and discharge.