Spreading depolarization in acute brain injury inhibited by ketamine: a prospective, randomized, multiple crossover trial

Abstract

OBJECTIVERetrospective clinical data and case studies support a therapeutic effect of ketamine in suppression of spreading depolarization (SD) following brain injury. Preclinical data strongly support efficacy in terms of frequency of SD as well as recovery from electrocorticography (ECoG) depression. The authors present the results of the first prospective controlled clinical trial testing the role of ketamine used for clinical sedation on occurrence of SD.METHODSTen patients with severe traumatic brain injury (TBI) or aneurysmal subarachnoid hemorrhage (SAH) were recruited for this pilot trial. A standard ECoG strip was placed at the time of craniotomy, and the patients were then placed on an alternating every-6-hour schedule of ketamine or other sedation agent. The order of treatment was randomized. The ketamine dose was adjusted to clinical effect or maintained at a subanesthetic basal dose (0.1 mg/kg/hr) if no sedation was required. SD was scored using standard criteria, blinded to ketamine dosing. Occurrence of SD was compared with the hourly dose of ketamine to determine the effect of ketamine on SD occurrence.RESULTSSuccessful ECoG recordings were obtained in all 10 patients: 8 with SAH and 2 with TBI. There were a total of 1642 hours of observations with adequate ECoG: 833 hours off ketamine and 809 hours on ketamine. Analysis revealed a strong dose-dependent effect such that hours off ketamine or on doses of less than 1.15 mg/kg/hr were associated with an increased risk of SD compared with hours on doses of 1.15 mg/kg/hr or more (OR 13.838, 95% CI 1.99-1000). This odds ratio decreased with lower doses of 1.0 mg/kg/hr (OR 4.924, 95% CI 1.337-43.516), 0.85 mg/kg/hr (OR 3.323, 95% CI 1.139-16.074), and 0.70 mg/kg/hr (OR 2.725, 95% CI 1.068-9.898) to a threshold of no effect at 0.55 mg/kg/hr (OR 1.043, 95% CI 0.565-2.135). When all ketamine data were pooled (i.e., on ketamine at any dose vs off ketamine), a nonsignificant overall trend toward less SD during hours on ketamine (χ2 = 3.86, p = 0.42) was observed.CONCLUSIONSKetamine effectively inhibits SD over a wide range of doses commonly used for sedation, even in nonintubated patients. These data also provide the first prospective evidence that the occurrence of SD can be influenced by clinical intervention and does not simply represent an unavoidable epiphenomenon after injury. These data provide the basis for future studies assessing clinical improvement with SD-directed therapy.Clinical trial registration no.: NCT02501941 (clinicaltrials.gov).

Keywords: DC = direct current; ECoG = electrocorticography; ICP = intracranial pressure; SAH = subarachnoid hemorrhage; SD = spreading depolarization; TBI = traumatic brain injury; delayed cerebral ischemia; spreading depolarization; spreading depression; subarachnoid hemorrhage; traumatic brain injury; vascular disorders; vasospasm.

Conflict of interest statement

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Figures

FIG. 1.

Example patient and SD. A: Lateral scout CT scan demonstrating the location of the electrode strip on the cortical surface. Each lead is labeled 1–6. B: Full-spectrum, referential DC recordings from the electrode strip. The data are condensed to the scale shown at the bottom. The double arrows show 2 definite DC shifts of SD in electrodes 3 and 4. There are more irregular DC shifts on the other channels, which also likely represent continuation of the SD wave. C: Filtered data on the same 6 electrodes over the same time interval as in B. Note that the start of the depression of the high-frequency data (double arrows) occurs simultaneously with the DC shift, defining the SD.

FIG. 2.

Plot of frequency of SD occurrences per hour (circles) versus dose of ketamine. All SD occurrences were at doses below 1.15 mg/kg/hr. A further trend toward less frequent occurrence (SD/hr) can also be clearly noted, though the numbers with > 2 SD/hr are small.

FIG. 3.

Individual linear regression analysis of each of the 9 patients with ICP monitoring regarding the effect of ketamine on ICP. The overall mixed-effects model showed no significant association. Note that in individual patients, the trends are quite variable, with some patients showing a negative association.