Comment: Cerebrospinal Fluid Pharmacokinetics of Nicardipine Following Intrathecal Administration in Subarachnoid Hemorrhage Patients

To the Editor,

We recently read with great interest the article by Sadan et al.¹ This study, using data from 16 subarachnoid hemorrhage (SAH) patients, successfully developed a population pharmacokinetic (popPK) model to describe the nicardipine disposition kinetics in the cerebrospinal fluid (CSF) following intrathecal (IT) administration. However, we noted that the authors may have overlooked several important factors during the execution of the study. We want to offer the following suggestions for the author's consideration.

First, there are issues concerning the details of sample collection, storage, and analysis. We observed discrepancies in the reported times of CSF and blood collection. Additionally, the storage conditions and analysis timing of the samples were not specified. Considering that CSF was collected hourly, up to 6 or 8 h, the authors should clarify whether the samples were stored at −80°C and analyzed collectively once all samples were collected. These details are crucial as they may affect the concentration measurements of nicardipine and the comparability of samples, which could impact the reliability of the experimental model.

Second, the study indicates that IT nicardipine may cause side effects such as hydrocephalus, leading to an increased need for CSF shunting procedures.^{2, 3} However, the study did not mention the occurrence of hydrocephalus in these 16 patients in either the short or the long term. This omission limits the ability to analyze the correlation between CSF nicardipine concentrations and the incidence of hydrocephalus. Furthermore, as noted by the authors, there is not enough high-level evidence to support the improvement of SAH patient outcomes with IT nicardipine.^{3, 4} However, the study lacks specific clinical outcome data for these 16 patients (e.g., neurological recovery and survival rates), which restricts the clinical relevance and applicability of the findings. These factors should be considered in future research designs.

Third, research suggests that cisternal nicardipine (CN) is more effective than the external ventricular drain (EVD) route, but the mechanism remains unclear.⁵ CN is typically used in patients treated by coiling, while EVD is used for those treated by microsurgical clipping. We propose that the superior efficacy of nicardipine in patients treated with coiling compared to those undergoing microsurgical clipping may be due to the fact that the blood–brain barrier in the former is not disrupted, thereby preventing systemic hypotension from CSF nicardipine leakage. Future studies incorporating a CN group based on the study protocol of Sadan et al. could help validate this mechanism. Additionally, since every 12-h administration of 4 mg nicardipine is the most common dosing regimen, future research might consider this dosing scheme to avoid frequent IT administration.⁴

In summary, we commend Sadan et al. for their work on determining the optimal dose of IT nicardipine. However, studying the pharmacokinetics of nicardipine without considering its clinical effects and practical applications may be insufficient. To more comprehensively evaluate the efficacy and safety of the optimal dose of IT nicardipine, larger and more rigorously designed studies are needed.

Xiaolin Du and Guangtang Chen both wrote the article.

The authors declare no conflicts of interest.

This work was supported by the project for clinical research, the Affiliated Hospital of Guizhou Medical University [gyfygcc-2023-01].