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

Andrew P. Carlson, Mohammad Abbas, Robert L. Alunday, Fares Qeadan, and C. William Shuttleworth

OBJECTIVE

Retrospective 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.

METHODS

Ten 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.

RESULTS

Successful 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.

CONCLUSIONS

Ketamine 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)

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Spreading depolarization may represent a novel mechanism for delayed fluctuating neurological deficit after chronic subdural hematoma evacuation

Laila M. Mohammad, Mohammad Abbas, C. William Shuttleworth, Rosstin Ahmadian, Annapoorna Bhat, Deirdre A. Hill, and Andrew P. Carlson

OBJECTIVE

Most patients with chronic subdural hematoma (cSDH) recover after surgical evacuation with a straightforward course. There is a subset of patients who develop transient and fluctuating deficits not explained by seizures, stroke, or mass effect after evacuation. The objective of this study was to investigate whether these postoperative neurological deficits may be related to temporary brain dysfunction caused by cortical spreading depolarizations (SDs).

METHODS

The authors conducted a prospective observational study of 40 patients who underwent cSDH evacuation. At the time of surgery, a 1 × 6 subdural electrode strip was placed on the cortex parallel to the subdural drain. Clinical outcomes were assessed utilizing the Markwalder Grading Scale, need for clinical EEG for new deficit, and presence of new deficits.

RESULTS

Definitive SD was detected in 6 (15%) of 40 patients. Baseline and cSDH characteristics did not differ between patients with and without SD. More patients experienced postoperative neurological deterioration if they had SD (50%) compared to those without SD (8.8%; p = 0.03). Only 2 patients in the entire cohort demonstrated early neurological deterioration, both of whom had SD. One of these cases demonstrated a time-locked new focal neurological deficit (aphasia) at the start of a series of multiple clusters of SD.

CONCLUSIONS

This is the first observation of SD occurring after cSDH evacuation. SD occurred at a rate of 15% and was associated with neurological deterioration. This may represent a novel mechanism for otherwise unexplained fluctuating neurological deficit after cSDH evacuation. This could provide a new therapeutic target, and SD-targeted therapies should be evaluated in prospective clinical trials.

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Spreading depolarization may represent a novel mechanism for delayed fluctuating neurological deficit after chronic subdural hematoma evacuation

Laila M. Mohammad, Mohammad Abbas, C. William Shuttleworth, Rosstin Ahmadian, Annapoorna Bhat, Deirdre A. Hill, and Andrew P. Carlson

OBJECTIVE

Most patients with chronic subdural hematoma (cSDH) recover after surgical evacuation with a straightforward course. There is a subset of patients who develop transient and fluctuating deficits not explained by seizures, stroke, or mass effect after evacuation. The objective of this study was to investigate whether these postoperative neurological deficits may be related to temporary brain dysfunction caused by cortical spreading depolarizations (SDs).

METHODS

The authors conducted a prospective observational study of 40 patients who underwent cSDH evacuation. At the time of surgery, a 1 × 6 subdural electrode strip was placed on the cortex parallel to the subdural drain. Clinical outcomes were assessed utilizing the Markwalder Grading Scale, need for clinical EEG for new deficit, and presence of new deficits.

RESULTS

Definitive SD was detected in 6 (15%) of 40 patients. Baseline and cSDH characteristics did not differ between patients with and without SD. More patients experienced postoperative neurological deterioration if they had SD (50%) compared to those without SD (8.8%; p = 0.03). Only 2 patients in the entire cohort demonstrated early neurological deterioration, both of whom had SD. One of these cases demonstrated a time-locked new focal neurological deficit (aphasia) at the start of a series of multiple clusters of SD.

CONCLUSIONS

This is the first observation of SD occurring after cSDH evacuation. SD occurred at a rate of 15% and was associated with neurological deterioration. This may represent a novel mechanism for otherwise unexplained fluctuating neurological deficit after cSDH evacuation. This could provide a new therapeutic target, and SD-targeted therapies should be evaluated in prospective clinical trials.