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 (χ = 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).
Background: Spinal anesthesia is a safe anesthetic technique commonly practiced. However, it is associated with hypotension (33%), bradycardia (13%), and shivering which are induced by hypovolemia, sympathetic blockade, and Bezold–Jarisch reflex through intracardiac serotonin (5HT3) receptors and vagus nerve. Aim: To study the effect of intravenous (i.v.) ondansetron on hypotension and bradycardia induced by spinal anesthesia. Setting and Design: This was a randomized controlled double-blinded study done in a tertiary care teaching hospital. Methods: Of 140 patients, 70 in Group A received 2 mL of i.v. ondansetron 4 mg and 70 in the Group B received 2 mL of i.v. normal saline. 3 mL of 0.5% hyperbaric bupivacaine was injected intrathecally. Measurements of blood pressure and heart rate (HR) were taken every 3 min for 30 min after spinal anesthesia was performed. Mean arterial pressure (MAP) drop more than 20% was considered as incidence of hypotension and ephedrine 6 mg i.v. was given. HR drop >20% was regarded as bradycardia and atropine 0.5 mg i.v. was given. Statistical Tests: Quantitative data were analyzed using ANOVA test and qualitative data were analyzed using Chi-square test. Results: Both groups are comparable in demographic data. Four (5.7%) patients in Group B and no patients in Group A had incidence of bradycardia and atropine requirement ( P = 0.120). There was no statistically significant difference in systolic blood pressure, diastolic blood pressure, and MAP. 19 (27%) patients in Group A and 33 (47.1%) in Group B required ephedrine with P = 0.029. 12 (17.1%) in Group B and no patients in Group A had shivering with P = 0.0001. Conclusion: Our study indicates that prophylactic use of ondansetron before spinal anesthesia significantly reduces the requirement of ephedrine and shivering.
INTRODUCTION Retrospective clinical data support a therapeutic effect of ketamine in suppression of CSD. Animal and slice data strongly support this targeted efficacy on CSD. We present the results of the first prospective clinical trial testing the role of ketamine used for clinical sedation on occurrence of CSD after brain injury. METHODS 10 subjects with aneurysmal subarachnoid hemorrhage (SAH) or severe traumatic brain injury (TBI) or were recruited. A 1 × 6 ECog strip was placed at the time of craniotomy and subjects were then placed on a randomized alternating 6 hour schedule of ketamine or other sedation agent. Ketamine dose was adjusted to clinical effect and left at a subanesthetic basal dose if no sedation was required (0.1mg/kg/h.) CSD was scored using standard criteria, blinded to ketamine dosing. Occurrence of CSD was then compared to the hourly dose of ketamine to determine the effect of ketamine on CSD occurrence. RESULTS >Successful ECog recordings were obtained in all 10 subjects 8 with SAH and 2 with TBI. There was a total of 1642 hours of observations with adequate ECog 833 off ketamine and 809 on ketamine. Hours on doses of less than 1.15 mg/kg/h were associated with a highly significant increased risk of CSD compared with hours on doses of 1.15 mg/kg/h or more (OR = 13.838, 95% CI = 1.99-1000). A decrease of 0.15 mg/kg/h in dose was found to be associated with two-fold increase in the odds of CSDs (OR = 1.973, 95% CI = 1.265-3.503). There was no significant effect of ketamine on the mean duration of depression after CSD (F = 2.62, P = 0.11). CONCLUSION Ketamine effectively inhibits CSD after acute neurologic injury (SAH and TBI) in a dose dependent fashion. These data also demonstrate the feasibility of using CSD as a surrogate measure in future studies prior to large-scale studies of CSD directed therapy on outcome.
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