Subarachnoid hemorrhage (SAH) or bleeding in the brain as a result of ruptured aneurysm is a devastating type of stroke. Many patients who undergo emergent neurosurgery to repair the aneurysm and remove the bleeding suffer from complications in their subsequent hospital stay, the most frequent and morbid of which is delayed cerebral ischemia (DCI) or small strokes resulting from impaired blood flow to certain vital brain centers. This occurs because of changes to the brain's blood vessels that occur after the bleed. The arteries can become narrow (spasm) or small clots can form within the vasculature that disrupts normal blood flow. Patients are left with profound neurologic deficits from these secondary complications. Anesthesiologists, neurosurgeons, and intensivists are in need of a way to protect the brain during this vulnerable period following aneurysm repair. One drug that may provide such protection is ketamine, a compound frequently used in operating rooms and intensive care units to provide anesthesia and analgesia. Ketamine works by blocking glutamate receptor ion channels that play a pivotal role in promoting brain cell death during strokes by flooding the brain with too much calcium and dangerous chemicals. This project is designed to test the efficacy of ketamine in protecting the brain following aneurysm repair by using a controlled infusion of the drug in the intensive care unit (ICU) when patients return from their operation.
Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating type of stroke, with significant long-term morbidity for patients who survive the initial bleed. The most frequent and morbid complication is delayed cerebral ischemia (DCI) resulting from angiographic vasospasm of the arteries of the circle of Willis. At present, there is no protective therapy aimed at neuronal preservation during this period of ischemia. The standard medical care is primarily to maintain intravascular volume status to improve cerebral perfusion during arterial narrowing, or calcium channel blockers for smooth muscle relaxation on the arterial wall. Experimental and clinical data suggest a primary mechanism of neuronal injury during ischemia is excitotoxicity, glutamate-induced cell death resulting from overstimulation of ionotropic N-methyl-D-aspartate (NMDA) receptors and resultant excessive calcium influx. Ketamine is a dissociative anesthetic with a mechanism of action of non-competitive antagonism of the NMDA receptor, routinely used in operating rooms and intensive care units as an analgesic and anesthetic. In addition to its anesthetic properties, ketamine is also an anti-inflammatory agent and a sympathomimetic, maintaining sedation without the adverse effects of hemodynamic instability. Identification of a neuroprotective entity for DCI following SAH would vastly improve the quality of life and shorten hospital stay for patients with a ruptured intracerebral aneurysm. It is critical to identify such agents so that patients survive their injury, spend shorter time in the ICU, and can return to work and maintain relationships.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
9
St Michael's Hospital
Toronto, Ontario, Canada
Changes in physiologic parameters as specified below
Temperature, heart rate (HR), mean arterial pressure (MAP), intracranial pressure (ICP), central venous pressure (CVP) if available, peak airway pressure (PAP) if available, end-tidal carbon dioxide (ETCO2) will be evaluated during infusion. Collected measurement data will be analyzed based on the occurrence of adverse events such as increase in ICP by more than 3 mmHg, increase in HR by more than 30 bpm, increase in partial pressure of CO2 (pCO2) by more than 20 mmHg, increase in lactate by more than 0.5, drop in pH by more than 0.2, increase in systolic blood pressure (SBP0 to over 200 mmHg, or any other unforeseen event that is deemed to be related to the drug treatment with adverse effects on the patient.
Time frame: During infusion and 1 hour post-infusion
Biologic samples
Blood and cerebrospinal fluid (CSF) samples will be collected and analyzed for biomarker levels which would indicate extent of neuronal injury.
Time frame: Day 1-2 post-infusion
Neurocognitive test Montreal Cognitive Assessment Scale (MoCA)
Neurocognitive function will be assessed using the MoCA to determine preliminary effects of ketamine on neurocognitive outcome.
Time frame: Day 30 or Day 60 post-DCI
Neurocognitive test modified Rankin Scale (mRS)
Neurocognitive function will be assessed using the mRS determine preliminary effects of ketamine on neurocognitive outcome.
Time frame: Day 30 or Day 60 post-DCI
Brain imaging using Magnetic Resonance Imaging (MRI)
Structural and functional brain imaging will be conducted using Tesla MRI system to assess white matter integrity.
Time frame: Day 30 or Day 60 post-DCI
Hospital anxiety and depression score
Assessments for neuro-cognitive outcomes and correlation with MRI findings
Time frame: Day 30 or Day 60 post-DCI
EQ-5D-5L
Neurocognitive outcome assessment and correlation with MRI results
Time frame: Day 30 or Day 60 post-DCI
Trail making test
Neurocognitive outcome assessment and correlation with MRI results
Time frame: Day 30 or Day 60 post-DCI
Verbal fluency tests
Neurocognitive outcome assessment and correlation with MRI results
Time frame: Day 30 or Day 60 post-DCI
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.