gms | German Medical Science

Objective: Electrical and hemodynamic characteristics of spreading depolarizations (SD) can be affected by the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine, which has been shown to produce neuroprotection in animals with lissencephalic brains. The effectiveness of SD-targeted neuroprotective therapies could be evaluated in real time by measuring SD incidence. We investigated the effect of s-ketamine on SD characteristics in two translational porcine models and in patients with aneurysmal subarachnoid hemorrhage (aSAH) in whom multimodal neuromonitoring was performed.

Methods: In both animal models, SDs were monitored using electrocorticography (ECoG) and large field-of-view movement-compensated intrinsic optical signal (IOS) imaging, which enabled us to perform a long-term analysis of blood volume signals in regions of interest. In the first animal model (n=15), SDs were induced with drops of 1M KCl in both hemispheres at 1h-intervals during 18h (Group 1: control, Group 2: ketamine 2mg/kg/h, Group 3: 4mg/kg/h, each n=5). In a second model, the left middle cerebral artery was occluded (MCAo) which subsequently induced SDs. Animals were randomly assigned to either receive 5mg/kg/h ketamine or not (Groups 4 and 5, each n=5) and were monitored over 30h. 67 aSAH patients were prospectively monitored, including ECoG (mean 11 days). We retrospectively compared relevant variables of patients who received ketamine (n=31) vs. no-ketamine.

Results: Ketamine reduced the incidence of SDs in both porcine models (reduction to 35.7% in the KCl and 68.7% in the MCAo model using ketamine 4mg/kg/h). We also found significant changes in the electrical and hemodynamic characteristics (amplitude, duration, expansion, etc.). Following MCAo, SDs appeared, originating in the ischemic center and concentrically invading penumbra and normally perfused, surrounding tissue, subsequent SDs were generated at the rim of the permanently depolarized core. Ketamine was less effective in reducing the SD incidence, but it decreased the hypoemic and increased the hyperemic components. In patients, a mean of 2.7mg/kg/h s-ketamine reduced the SD incidence from 1.87 to 0.68 SDs/day (reduction to 36.6%) (Wilcoxon p<0.001). Doses above the recommended therapeutic range (>2mg/kg/h) were more effective. In patients with CT-proven brain infarcts the efficacy of ketamine was lower than in patients without.

Conclusion: Ketamine has the capability to reduce the incidence and characteristics of SDs in gyrencephalic brain of both porcine model and aSAH patients. Most effective doses are above the recommended therapeutic range for sedation. More information is required before proceeding to a clinical trial.