Clusters of Cortical Spreading Depolarizations in a Patient with Intracerebral Hemorrhage: A Multimodal Neuromonitoring Study

Schiefecker, Alois Josef; Beer, Ronny; Pfausler, Bettina; Lackner, Peter; Broessner, Gregor; Unterberger, Iris; Sohm, Florian; Mulino, Miriam; Thomé, Claudius; Humpel, Christian; Schmutzhard, Erich; Helbok, Raimund

doi:10.1007/s12028-014-0050-4

Cited by 33 publications

(40 citation statements)

References 18 publications

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“…Univariate analysis found a significant correlation between therapy with S(+)-ketamine and the reduction of spreading depolarizations following traumatic brain damage, subarachnoid hemorrhage and malignant hemispheric infarction. In a recently published case report, Schiefecker et al presented a patient with severe intracerebral bleeding in whom both spreading depolarizations and the concentration of the excitatory neurotransmitter glutamate in the cerebral microdialysate were reduced on treatment with S(+)-ketamine [21]. A possible explanation could be that cortical spreading depolarizations may be suppressed and the cerebral energy utilization is improved by ketamine, which may help maintain the electrochemical ion gradient.…”

Section: Mechanism Of Action and Clinical Effectsmentioning

confidence: 99%

S(+)-ketamine

Trimmel

Helbok

Staudinger

et al. 2018

Wien Klin Wochenschr

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SummaryS(+)-ketamine, the pure dextrorotatory enantiomer of ketamine has been available for clinical use in analgesia and anesthesia for more than 25 years. The main effects are mediated by non-competitive inhibition of the N-methyl-D-aspartate (NMDA) receptor but S(+)-ketamine also interacts with opioid receptors, monoamine receptors, adenosine receptors and other purinergic receptors. Effects on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, metabotropic glutamate receptors (mGluR) and L‑type calcium chanels have also been described. S(+)-ketamine stimulates the sympathetic nerve system, making it an ideal drug for analgosedation or induction of anesthesia in instable patients. In addition, the neuroprotective properties, bronchodilatory, antihyperalgesic or antiepileptic effects provide interesting therapeutic options. In this article we discuss the numerous effects of S(+)-ketamine under pharmacological and clinical aspects especially for typical indications in emergency medicine as well as intensive care.

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Section: Mechanism Of Action and Clinical Effectsmentioning

confidence: 99%

S(+)-ketamine

Trimmel

Helbok

Staudinger

et al. 2018

Wien Klin Wochenschr

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“…The first prospective controlled trial of ketamine for SD inhibition recently confirmed this result in 8 patients with TBI and 2 with aSAH [30, 31]. Also, a case of spontaneous intracerebral hemorrhage has been reported in whom a cluster of SDs disappeared in response to ketamine and reappeared after discontinuation of ketamine [32]. In bedside-to-bench translation, results were further replicated in swine studies in which the active enantiomer, S(+) ketamine (s-ketamine), decreased the expansion, amplitude, and speed of SDs at a dosing of 2 mg/kg body weight (BW)/h.…”

Section: Introductionmentioning

confidence: 91%

Lasting s-ketamine block of spreading depolarizations in subarachnoid hemorrhage: a retrospective cohort study

et al. 2019

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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.

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“…Initial efforts have concentrated on the application of agents such as NMDA receptor (NMDAR) antagonists that block the initiation and propagation of SD. The dissociative anesthetic ketamine is an NMDAR antagonist that prevents SD in animal models (Hernandez-Caceres et al, 1987, Marrannes et al, 1988) and shows effectiveness in case reports (Sakowitz et al, 2009, Schiefecker et al, 2015). A retrospective review of medications used in the intensive care unit (ICU) also shows that ketamine infusion can reduce the frequency of SDs in brain injured patients (Hertle et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Ketamine reduces deleterious consequences of spreading depolarizations

Reinhart

Shuttleworth

2018

Experimental Neurology

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Recent work has implicated spreading depolarization (SD) as a key contributor the progression of acute brain injuries, however development of interventions selectively targeting SD has lagged behind. Initial clinical intervention efforts have focused on observations that relatively high doses of the sedative agent ketamine can completely suppress SD. However, blocking propagation of SD could theoretically prevent beneficial effects of SD in surrounding brain regions. Selective targeting of deleterious consequences of SD (rather than abolition) could be a useful adjunct approach, and be achieved with lower ketamine concentrations. We utilized a brain slice model to test whether deleterious consequences of SD could be prevented by ketamine, using concentrations that did not prevent the initiation and propagation of SD. Studies were conducted using murine brain slices, with focal KCl as an SD stimulus. Consequences of SD were assessed with electrophysiological and imaging measures of ionic and synaptic recovery. Under control conditions, ketamine (up to 30 μM) did not prevent SD, but significantly reduced neuronal Ca loading and the duration of associated extracellular potential shifts. Recovery of postsynaptic potentials after SD was also significantly accelerated. When SD was evoked on a background of mild metabolic compromise, neuronal recovery was substantially impaired. Under compromised conditions, the same concentrations of ketamine reduced ionic and metabolic loading during SD, sufficient to preserve functional recovery after repetitive SDs. These results suggest that lower concentrations of ketamine could be utilized to prevent damaging consequences of SD, while not blocking them outright and thereby preserving potentially protective effects of SD.

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Clusters of Cortical Spreading Depolarizations in a Patient with Intracerebral Hemorrhage: A Multimodal Neuromonitoring Study

Abstract: This novel association between clusters of CSDs, brain metabolic distress, and increased MMP-9 levels expands our knowledge about secondary brain injury after ICH. The role of ketamine after this devastating disorder needs further studies.

Cited by 33 publications

References 18 publications

S(+)-ketamine

S(+)-ketamine

Lasting s-ketamine block of spreading depolarizations in subarachnoid hemorrhage: a retrospective cohort study

Ketamine reduces deleterious consequences of spreading depolarizations

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