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Pilot Study of Ketamine Sedation for Aneurysmal Subarachnoid Hemorrhage (PENDULUM)

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ClinicalTrials.gov Identifier: NCT05032118
Recruitment Status : Not yet recruiting
First Posted : September 2, 2021
Last Update Posted : September 2, 2021
Sponsor:
Information provided by (Responsible Party):
Jenna L Leclerc MD, PhD, Oregon Health and Science University

Tracking Information
First Submitted Date  ICMJE August 20, 2021
First Posted Date  ICMJE September 2, 2021
Last Update Posted Date September 2, 2021
Estimated Study Start Date  ICMJE September 2021
Estimated Primary Completion Date July 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 26, 2021)
Incidence of moderate and severe radiographic cerebral vasospasm (CV) [ Time Frame: Days 4-12 post-bleed ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: August 26, 2021)
  • Lindegaard ratio (LR) [ Time Frame: Days 4-12 post-bleed ]
    A change in the LRs on routine daily transcranial Doppler monitoring.
  • Incidence of delayed cerebral ischemia (DCI) [ Time Frame: Days 4-12 post-bleed ]
    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.
  • Incidence of CV/DCI-related Infarction [ Time Frame: Days 4-14 post-bleed ]
    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.
  • Functional outcomes [ Time Frame: Hospital discharge (on average days 14-21 post-bleed), and 3 and 6 months post-bleed ]
    Identified by the modified Rankin scale (mRS) and includes mortality (i.e. all-cause mortality and that directly resulting from aSAH or complications thereof).
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: August 26, 2021)
  • Vasopressor requirements [ Time Frame: Within 12 days post-bleed ]
    Change in vasopressor dosage required for induced hypertensive therapy.
  • Incidence of acute kidney injury [ Time Frame: Within 12 days post-bleed ]
    Defined as an absolute increase in serum creatinine of greater than or equal to 0.3mg/dL, increase in creatinine greater than or equal to 50%, or reduction in urine output less than 0.5ml/kg/h for greater than 6h.
  • Incidence of moderate to severe drug-induced liver injury [ Time Frame: Within 14 days post-bleed ]
    Defined based on the Cancer Therapy Evalutation Program of the National Cancer Institute of the National Institutes of Health, which is referred to as the Common Toxicity Criteria for Adverse Events, version 4.0: CTCAEv4.03.
  • Physiologic parameters: heart rate [ Time Frame: Days 3-10 post-bleed ]
    Defined as change in heart rate by more than 30 beats per minute.
  • Physiologic parameters: blood pressure [ Time Frame: Days 3-10 post-bleed ]
    Defined as change in blood pressure to over 200mmHg in absence of induced hypertensive therapy and felt as a result of ketamine administration.
  • Physiologic parameters: intracranial pressure [ Time Frame: Days 3-10 post-bleed ]
    Defined as change in ICP by 5mmHg.
  • Physiologic parameters: cerebral perfusion pressure [ Time Frame: Days 3-10 post-bleed ]
    Defined as a statistically significant change in cerebral perfusion pressure with ketamine administration.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Pilot Study of Ketamine Sedation for Aneurysmal Subarachnoid Hemorrhage
Official Title  ICMJE A Pilot Study of Ketamine Sedation Initiated Early After Aneurysmal Subarachnoid Hemorrhage: Effect on Vasospasm, Delayed Cerebral Ischemia, and Functional Outcomes
Brief Summary

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.

Detailed Description 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Prevention
Condition  ICMJE Subarachnoid Hemorrhage, Aneurysmal
Intervention  ICMJE
  • Drug: Ketamine Hydrochloride
    Titratable ketamine infusion + low fixed-dose propofol.
    Other Name: Ketalar
  • Drug: Propofol
    Standard of care titratable propofol infusion.
    Other Name: Diprivan
Study Arms  ICMJE
  • Experimental: Ketamine
    Intravenous ketamine will be initiated following aneurysm securement at 0.5mg/kg/h and will be titratable by 0.2mg/kg/h every 20min to a Richmond Agitation Sedation Scale (RASS) goal of 0 to -1 (or as otherwise clinically indicated). Ketamine boluses will be available at 0.5mg/kg every 1hr as needed for inadequate sedation or breakthrough agitation. An additional 0.5mg/kg bolus may be utilized prior to initiating the ketamine infusion, or as needed at the discretion of the clinician. The maximum ketamine infusion dose will be limited to 4mg/kg/h. A fixed-dose propofol infusion at 10mcg/kg/min will simultaneously be administered to minimize the potential psychomimetic side effects of ketamine. This sedation paradigm will continue for up to 10 days post-bleed or until the study participant no longer requires sedation, whichever occurs earlier. If the RASS goal is not met with this sedation regimen, additional agents will be at the discretion of the intensivist.
    Intervention: Drug: Ketamine Hydrochloride
  • Active Comparator: Standard of Care
    Intravenous titratable propofol will be initiated as needed per current standard of care, which generally consists of initiating the infusion at 10-20mcg/kg/min with titration parameters of 5-10mcg/kg/min every 5-10min for a RASS goal of 0 to -1 (or as otherwise clinically indicated). Propofol boluses are available at 10-20mg (or higher dosages if clinically required) every 15min as needed for inadequate sedation or breakthrough agitation. The maximum infusion dose is generally limited to 50mcg/kg/min. If the RASS goal is not met with this sedation regimen, additional agents will be at the discretion of the intensivist.
    Intervention: Drug: Propofol
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: August 26, 2021)
50
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 2023
Estimated Primary Completion Date July 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Jenna L Leclerc, MD, PhD 503-494-8840 leclercj@ohsu.edu
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT05032118
Other Study ID Numbers  ICMJE 00022844
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Jenna L Leclerc MD, PhD, Oregon Health and Science University
Study Sponsor  ICMJE Jenna L Leclerc MD, PhD
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Jenna L Leclerc, MD, PhD Oregon Health and Science University
PRS Account Oregon Health and Science University
Verification Date August 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP