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Purpose: Subarachnoid hemorrhage (SAH) is a rare but life-threatening clinical event for pediatric patients. Cerebral vasospasm is a common complication of SAH that often leads to poor outcomes. This case report describes the use of dual intraventricular (IVT) vasodilators in a pediatric patient., Summary: An 11-year-old male presented with traumatic diffuse SAH and cerebral vasospasm. Despite treatment with IVT nicardipine, intravenous (IV) milrinone by continuous infusion, enteral nimodipine, and intraarterial verapamil and milrinone given during digital subtraction angiography, transcranial Doppler (TCD) mean velocities continued to rise. IVT milrinone was then added to IVT nicardipine and IV milrinone. The combination of IVT nicardipine, IV milrinone, and rescue therapy with IVT milrinone was continued for a total of 7 days. TCD mean velocities decreased into the mild to moderate range within 2 days of the patient receiving this combined regimen and remained globally low thereafter., Conclusion: This case illustrates the potential benefit of using dual IVT vasodilators to improve outcomes for pediatric patients with refractory cerebral vasospasm., (© American Society of Health-System Pharmacists 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Subarachnoid hemorrhage (SAH) is a devastating type of stroke, leading to high mortality and morbidity rates. Cerebral vasospasm and delayed cerebral ischemia (DCI) are common complications following SAH that contribute significantly to the poor outcomes observed in these patients. Intrathecal (IT) nicardipine delivered via an existing external ventricular drain is an off-label intervention that has been shown to be correlated with reduced DCI and improved patient outcomes. The current study aims to characterize the population pharmacokinetic (popPK) properties of intermittent IT nicardipine. Following informed consent, serial cerebrospinal fluid (CSF) samples were obtained from 16 SAH patients (50.4 ± 9.3 years old; 13 females) treated with IT nicardipine every 6 h (q6h, n = 8) or every 8 h (q8h, n = 8) for an average of 72 ± 21 doses. High-performance liquid chromatography was used to quantify CSF concentration from each sample. Our popPK analysis showed that the CSF pharmacokinetics of IT nicardipine in the cohort was adequately described by a two-compartment model with a lag time. Model parameter estimates were reliable (relative standard error <50%). Intracranial pressure influenced both the total clearance and the central volume of nicardipine (i.e., negative correlation, P <-.001). Calculated PK parameters were similar between q6h and q8h dosing regimens. Despite a small cohort of SAH patients, we successfully developed a popPK model to describe the nicardipine disposition kinetics in the CSF following IT administration. These findings may help inform future clinical trials designed to examine the optimal dosing of IT nicardipine., (© 2024 The Author(s). The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Objectives: A paucity of treatments to prevent delayed cerebral ischemia (DCI) has stymied recovery after aneurysmal subarachnoid hemorrhage (aSAH). Nicardipine has long been recognized as a potent cerebrovascular vasodilator with a history off-label use to prevent vasospasm and DCI. Multiple centers have developed nicardipine prolonged release implants (NPRI) that are directly applied during clip ligation to locally deliver nicardipine throughout the vasospasm window. Here we perform a systematic review and meta-analysis to assess whether NPRI confers protection against DCI and improves functional outcomes after aSAH., Materials and Methods: A systematic search of PubMed, Ovid Embase, and Cochrane databases was performed for studies reporting the use of NPRI after aSAH published after January 1, 1980. We included all studies assessing the association of NPRI with DCI and or functional outcomes. Findings from studies with control arms were analyzed using a random effects model. A separate network meta-analysis was performed, including controlled NPRI studies, single-arm NPRI reports, and the control-arms of modern aSAH randomized clinical trials as additional comparators., Results: The search identified 214 unique citations. Three studies with 284 patients met criteria for the random effects model. The pooled summary odds ratio for the association of NPRI and DCI was 0.21 (95% CI 0.09-0.49, p = 0.0002) with no difference in functional outcomes (OR 1.80, 95% CI 0.63 - 5.16, p = 0.28). 10 studies of 866 patients met criteria for the network meta-analysis. The pooled summary odds ratio for the association of NPRI and DCI was 0.30 (95% CI 0.13-0.89,p = 0.017) with a trend towards improved functional outcomes (OR 1.68, 0.63 - 4.13 95% CI, p = 0.101)., Conclusions: In these meta-analyses, NPRI decreases the incidence of DCI with a non-significant trend towards improvement in functional outcomes. Randomized trials on the role of intrathecal calcium channel blockers are warranted to evaluate these observations in a prospective manner., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Cerebral vasospasm and delayed cerebral ischemia (DCI) contribute to poor outcome following subarachnoid hemorrhage (SAH). With the paucity of effective treatments, the authors describe their experience with intrathecal (IT) nicardipine for this indication., Methods: Patients admitted to the Emory University Hospital neuroscience ICU between 2012 and 2017 with nontraumatic SAH, either aneurysmal or idiopathic, were included in the analysis. Using a propensity-score model, this patient cohort was compared to patients in the Subarachnoid Hemorrhage International Trialists (SAHIT) repository who did not receive IT nicardipine. The primary outcome was DCI. Secondary outcomes were long-term functional outcome and adverse events., Results: The analysis included 1351 patients, 422 of whom were diagnosed with cerebral vasospasm and treated with IT nicardipine. When compared with patients with no vasospasm (n = 859), the treated group was significantly younger (mean age 51.1 ± 12.4 years vs 56.7 ± 14.1 years, p < 0.001), had a higher World Federation of Neurosurgical Societies score and modified Fisher grade, and were more likely to undergo clipping of the ruptured aneurysm as compared to endovascular treatment (30.3% vs 11.3%, p < 0.001). Treatment with IT nicardipine decreased the daily mean transcranial Doppler velocities in 77.3% of the treated patients. When compared to patients not receiving IT nicardipine, treatment was not associated with an increased rate of bacterial ventriculitis (3.1% vs 2.7%, p > 0.1), yet higher rates of ventriculoperitoneal shunting were noted (19.9% vs 8.8%, p < 0.01). In a propensity score comparison to the SAHIT database, the odds ratio (OR) to develop DCI with IT nicardipine treatment was 0.61 (95% confidence interval [CI] 0.44-0.84), and the OR to have a favorable functional outcome (modified Rankin Scale score ≤ 2) was 2.17 (95% CI 1.61-2.91)., Conclusions: IT nicardipine was associated with improved outcome and reduced DCI compared with propensity-matched controls. There was an increased need for permanent CSF diversion but no other safety issues. These data should be considered when selecting medications and treatments to study in future randomized controlled clinical trials for SAH.

Background: Cerebral arterial vasospasm and delayed ischemic neurological deficits are significant contributors to morbidity and mortality following aneurysmal subarachnoid hemorrhage. Additional treatment modalities are needed. Intraventricular nicardipine has been suggested as a potential therapy for the treatment of cerebral vasospasm. It is an appealing option for multiple reasons: many of these patients already have ventricular drains in place, it can be safely administered at the bedside, and can be used in patients for whom conventional therapies are either not effective or not tolerated., Methods: Retrospective case series of all patients who received intraventricular nicardipine for the treatment of cerebral vasospasm from January 2006 to June 2007 at a university tertiary care hospital., Results: Sixty-four patients received intraventricular nicardipine during the study period. Forty-two patients met inclusion criteria. Intraventricular nicardipine administration was associated with a reduction of the mean cerebral blood flow velocity of 26.3 cm/s in the middle cerebral artery and 7.4 cm/s in the anterior cerebral artery. This reduction was maintained over 24 h with continued administration., Conclusions: Intraventricular nicardipine was associated with a significant and sustained reduction in mean cerebral blood flow velocity as measured by transcranial Doppler when used in the treatment of suspected cerebral vasospasm following aneurysmal subarachnoid hemorrhage. We do not find significant safety concerns related to elevations of intracranial pressure or ventricular catheter related infections. Further prospective studies are warranted to better determine the efficacy and safety of this therapy.

Background: Cerebral vasospasm leading to delayed ischemia is a common and serious complication of aneurysmal subarachnoid hemorrhage that often results in increased morbidity and mortality. Treatments for cerebral vasospasm, including triple-H therapy (therapeutic hypervolemia, hypertension, and hemodilution), nimodipine, balloon angioplasty, and intra-arterial vasodilators have limitations in their efficacy and safety profiles. Nicardipine, a calcium channel blocker, is available for intravenous administration for blood pressure reduction. A recent study reported its efficacy in the treatment of cerebral vasospasm when given intrathecally (IT). We present our experiences with IT nicardipine for treatment of cerebral vasospasm., Methods: IT nicardipine was administered to six patients with aneurysmal subarachnoid hemorrhage after prophylactic and aggressive therapeutic management for vasospasm failed., Results: In these patients, IT nicardipine treatment was followed within 8 hours by a 43.1 +/- 31.0 cm/s decrease in middle cerebral arterial flow velocity, as measured by transcranial Doppler ultrasound., Conclusions: Based on these positive results, we believe that larger scale studies evaluating the safety and efficacy of IT nicardipine for the management of cerebral vasospasm are warranted.

One of the common complications of non-traumatic subarachnoid hemorrhage (SAH) is delayed cerebral ischemia (DCI). Intrathecal (IT) administration of nicardipine, a calcium channel blocker (CCB), upon detection of large-artery cerebral vasospasm holds promise as a treatment that reduces the incidence of DCI. In this observational study, we prospectively employed a non-invasive optical modality called diffuse correlation spectroscopy (DCS) to quantify the acute microvascular cerebral blood flow (CBF) response to IT nicardipine (up to 90min) in 20 patients with medium-high grade non-traumatic SAH. On average, CBF increased significantly with time post-administration. However, the CBF response was heterogeneous across subjects. A latent class mixture model was able to classify 19 out of 20 patients into two distinct classes of CBF response: patients in Class 1 (n = 6) showed no significant change in CBF, while patients in Class 2 (n = 13) showed a pronounced increase in CBF in response to nicardipine. The incidence of DCI was 5 out of 6 in Class 1 and 1 out of 13 in Class 2 (p < 0.001). These results suggest that the acute (<90min) DCS-measured CBF response to IT nicardipine is associated with intermediate-term (up to 3 weeks) development of DCI. [ABSTRACT FROM AUTHOR]