Pilot Study of Ketamine Sedation for Aneurysmal Subarachnoid Hemorrhage

Jenna L Leclerc MD, PhD

Overview

Aneurysmal subarachnoid hemorrhage (aSAH) is bleeding into the space between the brain and the tissues that surround the brain as a result of a ruptured aneurysm and is a type of stroke associated with high morbidity and mortality. Those that survive the initial bleed are critically ill and require prolonged intensive care unit stays since they are at risk for a multitude of secondary insults that can further worsen functional outcomes. An especially feared secondary insult is delayed cerebral ischemia (DCI), which is a lack of blood flow to a particular portion of the brain that can result in an ischemic stroke and produce profound neurologic deficits. How DCI develops in some people after aSAH and not others is unknown, but many have hypothesized various mechanisms such as 1) cerebral vasospasm, a focal anatomic narrowing of the blood vessels in the brain that could decrease downstream blood flow, 2) abnormal electrical activity, and 3) microthrombi, or the formation of small blood clots. It is vitally important to identify a therapy that could protect the brain from these secondary insults that happen days after the initial brain bleed. Ketamine is a drug used in the majority of hospitals around the world for various indications, including general anesthesia, sedation, and for pain. Ketamine blocks a specific receptor that is present within the brain and in doing so could play a critical protective role against these secondary insults after aSAH by blocking the flow of dangerous chemicals. Ketamine may provide the following beneficial properties after aSAH: 1) pain control, 2) seizure prevention, 3) blood pressure support, 4) dilation of the brain blood vessels, 5) sedation, 6) anti-depressant, and 7) anti-inflammatory. This project is designed to test whether ketamine sedation in the intensive care unit after aneurysm repair provides better outcomes than the currently used sedation regimen.

Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating form of hemorrhagic stroke associated with high morbidity and mortality, which has been linked to the development of cerebral vasospasm (CV) and delayed cerebral ischemia (DCI). Two prominent mechanisms by which CV and DCI have been proposed to occur include cortical spreading depolarizations (CSDs) and neuroinflammation. Ketamine is a NMDA receptor antagonist that is in widespread and common clinical use as a general anesthetic, sedative, analgesic and anti-depressant, among other indications. The investigators hypothesize that early initiation of ketamine sedation following aneurysm securement in lieu of the usual propofol-based sedation regimen will improve aSAH outcomes via a multifactorial mechanism. Many potential mechanisms exist by which ketamine could be beneficial following aSAH, including but not limited to: 1) direct cerebrovasodilation, 2) inhibiting the development of and terminating ongoing CSDs, 3) reducing neuronal hyperexcitability and glutamate-mediated excitotoxicity, 4) positively modulating a plethora of neuroinflammatory cascades, and 5) reduced vasopressor requirements owing to intrinsic sympathomimetic properties. This study is a prospective randomized single-blind pilot and feasibility study to begin investigating whether early ketamine administration after aSAH attenuates CV, DCI, DCI-associated infarctions, and improves functional outcomes.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Male or female 18 to 80 years old 2. Diagnosis of ruptured saccular aneurysm confirmed by cerebral angiography or computed tomography angiography (CTA) 3. Aneurysm securement via open neurosurgical clipping or endovascular coiling 4. Modified fisher grade 3 or 4 on admission cranial computed tomography scan 5. External ventricular drain placed as part of routine care 6. Mechanical ventilation requiring sedation 7. Ability to enroll within 72h following bleed 8. Informed consent Exclusion Criteria: 1. Subarachnoid hemorrhage due to causes other than a saccular aneurysm (e.g. non-aneurysmal, traumatic, rupture of a fusiform or mycotic aneurysm) 2. Pregnancy or currently breast-feeding an infant 3. Forensic patient 4. Known significant baseline neurologic deficit 5. Glasgow coma scale 3 with fixed and dilated pupils or other signs of imminent death 6. Increased intracranial pressure \>30mmHg in sedated patients lasting \>4 hours anytime since the initial bleed 7. Presence of systemic or CNS infection 8. Cardiopulmonary resuscitation after the initial bleed 9. Angiographic vasospasm prior to aneurysm repair, as documented by cerebral angiography or CTA 10. Surgical complication including but not limited to massive intraoperative hemorrhage, vascular occlusion, or inability to secure the ruptured aneurysm 11. Severe coronary artery disease (e.g. obstructive disease with stenosis \>50% of any vessel on coronary angiography), angina, symptoms or evidence of myocardial ischemia, myocardial infarction within 3 months of study enrollment 12. Heart failure or cardiomyopathy with ejection fracture \<35%, symptoms or evidence of decompensated heart failure on admission or within preceding 6 months 13. Tachyarrhythmia (e.g. history or evidence of any symptomatic ventricular tachycardia, ventricular fibrillation, atrial fibrillation or flutter with rapid ventricular rate, or any supraventricular tachycardia) 14. Active psychotic symptoms, history of primary psychotic disorder (e.g. schizophrenia or schizoaffective disorder), or mania 15. History of ketamine dependence or abuse 16. Hypersensitivity to ketamine or any component of the formulation 17. Increased intraocular pressure or history of glaucoma 18. Known or suspected cirrhosis or evidence of moderate-severe liver dysfunction on laboratory evaluation (e.g. ALT and AST\>3x upper limit of normal, alkaline phosphatase and gamma-glutamyl transferase\>2.5x upper limit of normal, and/or bilirubin\>1.5x upper limit of normal) 19. Severe kidney disease (e.g. plasma creatinine ≥2.5 mg/dL)

Outcomes

Primary Outcomes

Incidence of moderate and severe radiographic cerebral vasospasm (CV)

Identified on standard of care repeat CTA or cerebral angiography where moderate and severe are defined as 33-66% and \>66% reduction in vessel diameter, respectively.

Time frame: Days 4-12 post-bleed

Secondary Outcomes

Lindegaard ratio (LR)

A change in the LRs on routine daily transcranial Doppler monitoring.

Time frame: Days 4-12 post-bleed

Incidence of delayed cerebral ischemia (DCI)

Defined as acute mental status change and/or new neurologic deficits that were not previously present after excluding for other causes (e.g. metabolic, hydrocephalus, fever, infection, seizure) with clinical improvement after initiation of hypertensive therapy or anti-vasospasm therapy (e.g. intra-arterial verapamil, balloon angioplasty), and/ or brain imaging demonstrating ischemia in the absence of surgical complication.

Time frame: Days 4-12 post-bleed

Incidence of CV/DCI-related Infarction

Identified on standard of care follow-up imaging scans (e.g. CT or MRI) in the presence of moderate-severe radiographic vasospasm or DCI (as defined above) and in the absence of surgical complication.

Time frame: Days 4-14 post-bleed

Functional outcomes

Identified by the modified Rankin scale (mRS) and includes mortality (i.e. all-cause mortality and that directly resulting from aSAH or complications thereof).

Time frame: Hospital discharge (on average days 14-21 post-bleed), and 3 and 6 months post-bleed

Pilot Study of Ketamine Sedation for Aneurysmal Subarachnoid Hemorrhage

Overview

Conditions

Interventions

Eligibility

Outcomes

Primary Outcomes

Secondary Outcomes