Lasting s-ketamine block of spreading depolarizations in subarachnoid hemorrhage: a retrospective cohort study
Edgar Santos,
Arturo Olivares-Rivera,
Sebastian Major,
Renán Sánchez-Porras,
Lorenz Uhlmann,
Kevin Kunzmann,
Roland Zerelles,
Modar Kentar,
Vasilis Kola,
Adrian Hernández Aguilera,
Mildred Gutierrez Herrera,
Coline L. Lemale,
Johannes Woitzik,
Jed A. Hartings,
Oliver W. Sakowitz,
Andreas W. Unterberg,
Jens P. Dreier
Affiliations
Edgar Santos
Neurosurgery Department, Heidelberg University Hospital- Ruprecht-Karls-Universität Heidelberg
Arturo Olivares-Rivera
Neurosurgery Department, Heidelberg University Hospital- Ruprecht-Karls-Universität Heidelberg
Sebastian Major
Center for Stroke Research Berlin, Charité–Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health
Renán Sánchez-Porras
Neurosurgery Department, Heidelberg University Hospital- Ruprecht-Karls-Universität Heidelberg
Lorenz Uhlmann
Institute of Medical Biometry and Informatics, Ruprecht-Karls-University Heidelberg
Kevin Kunzmann
Institute of Medical Biometry and Informatics, Ruprecht-Karls-University Heidelberg
Roland Zerelles
Neurosurgery Department, Heidelberg University Hospital- Ruprecht-Karls-Universität Heidelberg
Modar Kentar
Neurosurgery Department, Heidelberg University Hospital- Ruprecht-Karls-Universität Heidelberg
Vasilis Kola
Center for Stroke Research Berlin, Charité–Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health
Adrian Hernández Aguilera
Neurosurgery Department, Heidelberg University Hospital- Ruprecht-Karls-Universität Heidelberg
Mildred Gutierrez Herrera
Neurosurgery Department, Heidelberg University Hospital- Ruprecht-Karls-Universität Heidelberg
Coline L. Lemale
Department of Experimental Neurology, Charité–Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health
Johannes Woitzik
Evangelisches Krankenhaus Oldenburg, University of Oldenburg
Jed A. Hartings
UC Gardner Neuroscience Institute, University of Cincinnati (UC) College of Medicine
Oliver W. Sakowitz
Neurosurgery Department, Heidelberg University Hospital- Ruprecht-Karls-Universität Heidelberg
Andreas W. Unterberg
Neurosurgery Department, Heidelberg University Hospital- Ruprecht-Karls-Universität Heidelberg
Jens P. Dreier
Center for Stroke Research Berlin, Charité–Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health
Abstract Objective Spreading 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. Methods We 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. Results S-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. Conclusions These results provide a foundation for a multicenter, neuromonitoring-guided, proof-of-concept trial of ketamine and midazolam as a first-line sedative regime.