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Lasting s-ketamine block of spreading depolarizations in subarachnoid hemorrhage: a retrospective cohort study
Critical Care ( IF 8.8 ) Pub Date : 2019-12-01 , DOI: 10.1186/s13054-019-2711-3
Edgar Santos 1 , Arturo Olivares-Rivera 1 , Sebastian Major 2, 3, 4 , Renán Sánchez-Porras 1 , Lorenz Uhlmann 5 , Kevin Kunzmann 5 , Roland Zerelles 1 , Modar Kentar 1 , Vasilis Kola 2 , Adrian Hernández Aguilera 1 , Mildred Gutierrez Herrera 1 , Coline L Lemale 4 , Johannes Woitzik 6 , Jed A Hartings 7, 8 , Oliver W Sakowitz 1, 9 , Andreas W Unterberg 1 , Jens P Dreier 2, 3, 4, 10, 11
Affiliation  

ObjectiveSpreading depolarizations (SD) are characterized by breakdown of transmembrane ion gradients and excitotoxicity. Experimentally, N-methyl-d-aspartate receptor (NMDAR) antagonists block a majority of SDs. In many hospitals, the NMDAR antagonist s-ketamine and the GABAA agonist midazolam represent the current second-line combination treatment to sedate patients with devastating cerebral injuries. A pressing clinical question is whether this option should become first-line in sedation-requiring individuals in whom SDs are detected, yet the s-ketamine dose necessary to adequately inhibit SDs is unknown. Moreover, use-dependent tolerance could be a problem for SD inhibition in the clinic.MethodsWe performed a retrospective cohort study of 66 patients with aneurysmal subarachnoid hemorrhage (aSAH) from a prospectively collected database. Thirty-three of 66 patients received s-ketamine during electrocorticographic neuromonitoring of SDs in neurointensive care. The decision to give s-ketamine was dependent on the need for stronger sedation, so it was expected that patients receiving s-ketamine would have a worse clinical outcome.ResultsS-ketamine application started 4.2 ± 3.5 days after aSAH. The mean dose was 2.8 ± 1.4 mg/kg body weight (BW)/h and thus higher than the dose recommended for sedation. First, patients were divided according to whether they received s-ketamine at any time or not. No significant difference in SD counts was found between groups (negative binomial model using the SD count per patient as outcome variable, p = 0.288). This most likely resulted from the fact that 368 SDs had already occurred in the s-ketamine group before s-ketamine was given. However, in patients receiving s-ketamine, we found a significant decrease in SD incidence when s-ketamine was started (Poisson model with a random intercept for patient, coefficient − 1.83 (95% confidence intervals − 2.17; − 1.50), p < 0.001; logistic regression model, odds ratio (OR) 0.13 (0.08; 0.19), p < 0.001). Thereafter, data was further divided into low-dose (0.1–2.0 mg/kg BW/h) and high-dose (2.1–7.0 mg/kg/h) segments. High-dose s-ketamine resulted in further significant decrease in SD incidence (Poisson model, − 1.10 (− 1.71; − 0.49), p < 0.001; logistic regression model, OR 0.33 (0.17; 0.63), p < 0.001). There was little evidence of SD tolerance to long-term s-ketamine sedation through 5 days.ConclusionsThese results provide a foundation for a multicenter, neuromonitoring-guided, proof-of-concept trial of ketamine and midazolam as a first-line sedative regime.

中文翻译:

持久的氯胺酮阻断蛛网膜下腔出血扩散去极化:一项回顾性队列研究

目的传播去极化 (SD) 的特征是跨膜离子梯度的破坏和兴奋性毒性。实验上,N-甲基-d-天冬氨酸受体 (NMDAR) 拮抗剂可阻断大多数 SD。在许多医院,NMDAR 拮抗剂 s-氯胺酮和 GABAA 激动剂咪达唑仑代表了目前用于镇静破坏性脑损伤患者的二线联合治疗。一个紧迫的临床问题是,在检测到 SDs 的需要镇静的个体中,这种选择是否应该成为第一线,但充分抑制 SDs 所需的 s-氯胺酮剂量尚不清楚。此外,使用依赖性耐受性可能是临床中 SD 抑制的一个问题。方法我们从前瞻性收集的数据库中对 66 名动脉瘤性蛛网膜下腔出血 (aSAH) 患者进行了回顾性队列研究。66 名患者中有 33 名在神经重症监护中对 SD 进行皮层电图神经监测期间接受了 s-氯胺酮。给予s-氯胺酮的决定取决于对更强镇静的需要,因此预计接受s-氯胺酮的患者的临床结果会更差。结果在aSAH后4.2±3.5天开始应用S-氯胺酮。平均剂量为 2.8 ± 1.4 mg/kg 体重 (BW)/h,因此高于推荐的镇静剂量。首先,根据是否在任何时间接受s-氯胺酮对患者进行划分。未发现组间 SD 计数存在显着差异(使用每位患者的 SD 计数作为结果变量的负二项式模型,p = 0.288)。这很可能是因为在给予 s-氯胺酮之前,s-氯胺酮组中已经发生了 368 个 SD。然而,在接受 s-氯胺酮治疗的患者中,我们发现在开始使用 s-氯胺酮时 SD 发生率显着降低(泊松模型对患者进行随机截距,系数 − 1.83(95% 置信区间 − 2.17; − 1.50),p < 0.001;逻辑回归模型,优势比 (OR) 0.13 (0.08; 0.19),p < 0.001)。此后,数据进一步分为低剂量 (0.1–2.0 mg/kg BW/h) 和高剂量 (2.1–7.0 mg/kg/h) 段。高剂量 s-氯胺酮导致 SD 发生率进一步显着降低(泊松模型,- 1.10(- 1.71;- 0.49),p < 0.001;逻辑回归模型,OR 0.33(0.17;0.63),p < 0.001)。几乎没有证据表明 SD 对 5 天的长期 s-氯胺酮镇静有耐受性。结论这些结果为多中心、神经监测指导的、
更新日期:2019-12-01
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