Institute for Clinical Chemistry, Medical Faculty Mannheim of the University of Heidelberg, University Hospital Mannheim, Mannheim, Germany.
Department of Neurosurgery, Medical Faculty Mannheim of the University of Heidelberg University Hospital Mannheim, Mannheim, Germany.
J Clin Pharm Ther. 2020 Feb;45(1):81-87. doi: 10.1111/jcpt.13028. Epub 2019 Aug 17.
Delayed cerebral ischaemia is an important cause of morbidity and mortality after aneurysmal subarachnoid haemorrhage (aSAH). Nimodipine is the only drug approved by the FDA for improving outcome after aSAH. Clinically, however, there are no specific values of this drug in cerebrospinal fluid (CSF) during aSAH treatment that could be associated to outcome improvement. Furthermore, the neurotransmitter glutamate acts as a secondary marker for brain injury. The aim was to establish a method to measure nimodipine and glutamate concentrations simultaneously in CSF of patients after aSAH.
From June 2017 to June 2018, we prospectively collected clinical data of patients with aSAH admitted to our neurointensive care unit. All included patients received nimodipine orally (60 mg every 4 hours). Patients, who developed clinical vasospasm during their in-hospital stay, underwent intra-arterial application of nimodipine (IAN), followed by angiographic control. A method using high-performance liquid chromatography coupled with mass spectrometric analysis (LC-MS/MS) was established for quantification of both analytes in CSF.
In 15 (60%) of 25 patients, nimodipine and glutamate concentrations were measured. After IAN for treatment of vasospasms, CSF nimodipine concentrations were slightly higher than in patients who received nimodipine only orally (0.60 ± 0.27 ng/mL vs 0.48 ± 0.18 ng/mL). Patients developing vasospasm exhibited higher glutamate concentrations than patients without vasospasm (188.84 ng/mL vs136.07 ng/mL).
The developed method allowed the simultaneous quantification of nimodipine and glutamate in CSF. Furthermore, we demonstrated that IAN resulted in higher concentrations in CSF, when compared to oral application only.
迟发性脑缺血是蛛网膜下腔出血（aSAH）后发病率和死亡率的重要原因。尼莫地平是美国食品和药物管理局（FDA）批准的唯一一种改善 aSAH 后结果的药物。然而，临床上，在 aSAH 治疗期间，脑脊液（CSF）中没有特定的尼莫地平值与结果改善相关。此外，神经递质谷氨酸是脑损伤的二级标志物。目的是建立一种同时测量 aSAH 后患者 CSF 中尼莫地平与谷氨酸浓度的方法。
从 2017 年 6 月至 2018 年 6 月，我们前瞻性地收集了我院神经重症监护病房收治的 aSAH 患者的临床数据。所有纳入的患者均接受尼莫地平口服（每 4 小时 60mg）。在住院期间出现临床血管痉挛的患者接受了动脉内尼莫地平应用（IAN），随后进行血管造影控制。建立了一种使用高效液相色谱-质谱联用（LC-MS/MS）定量 CSF 中两种分析物的方法。
在 25 例患者中，有 15 例（60%）测量了尼莫地平与谷氨酸浓度。IAN 治疗血管痉挛后，CSF 尼莫地平浓度略高于仅口服尼莫地平的患者（0.60±0.27ng/mL 比 0.48±0.18ng/mL）。发生血管痉挛的患者谷氨酸浓度高于无血管痉挛的患者（188.84ng/mL 比 136.07ng/mL）。
所开发的方法允许同时定量 CSF 中的尼莫地平与谷氨酸。此外，我们证明与仅口服应用相比，IAN 导致 CSF 中浓度更高。
