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Subarachnoid Hemorrhage, AneurysmalPhase 2/3PENDULUMNCT05032118

Pilot Study of Ketamine Sedation for Aneurysmal Subarachnoid Hemorrhage

A Phase 2/3 study testing Ketamine Hydrochloride and Propofol in people with Subarachnoid Hemorrhage, Aneurysmal, run by Jenna L Leclerc MD, PhD.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 80 years
Conditions the study is for
Subarachnoid Hemorrhage, Aneurysmal
What is being tested?
Ketamine Hydrochloride and Propofol
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
No sites listed yet
Study dates
27 Apr 2023to 27 Apr 2023
Phase
Phase 2/3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 80 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Male or female 18 to 80 years old
  • Diagnosis of ruptured saccular aneurysm confirmed by cerebral angiography or computed tomography angiography (CTA)
  • Aneurysm securement via open neurosurgical clipping or endovascular coiling
  • Modified fisher grade 3 or 4 on admission cranial computed tomography scan
  • External ventricular drain placed as part of routine care
  • Mechanical ventilation requiring sedation
  • Ability to enroll within 72h following bleed
  • Informed consent

Who cannot join

  • Subarachnoid hemorrhage due to causes other than a saccular aneurysm (e.g. non-aneurysmal, traumatic, rupture of a fusiform or mycotic aneurysm)
  • Pregnancy or currently breast-feeding an infant
  • Forensic patient
  • Known significant baseline neurologic deficit
  • Glasgow coma scale 3 with fixed and dilated pupils or other signs of imminent death
  • Increased intracranial pressure >30mmHg in sedated patients lasting >4 hours anytime since the initial bleed
Show all 19Show fewer
  • Presence of systemic or CNS infection
  • Cardiopulmonary resuscitation after the initial bleed
  • Angiographic vasospasm prior to aneurysm repair, as documented by cerebral angiography or CTA
  • Surgical complication including but not limited to massive intraoperative hemorrhage, vascular occlusion, or inability to secure the ruptured aneurysm
  • 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
  • Heart failure or cardiomyopathy with ejection fracture <35%, symptoms or evidence of decompensated heart failure on admission or within preceding 6 months
  • 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)
  • Active psychotic symptoms, history of primary psychotic disorder (e.g. schizophrenia or schizoaffective disorder), or mania
  • History of ketamine dependence or abuse
  • Hypersensitivity to ketamine or any component of the formulation
  • Increased intraocular pressure or history of glaucoma
  • 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)
  • Severe kidney disease (e.g. plasma creatinine ≥2.5 mg/dL)

About this study

Official title: A Pilot Study of Ketamine Sedation Initiated Early After Aneurysmal Subarachnoid Hemorrhage: Effect on Vasospasm, Delayed Cerebral Ischemia, and Functional Outcomes

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.

Read the 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.

Being tested
Ketamine Hydrochloride, Propofol
Keywords
Ketamine, Vasospasm, Ischemic stroke, Delayed cerebral ischemia, Delayed neurological deficits, Cortical spreading depolarization
Medical subject headings
Subarachnoid Hemorrhage, Ischemic Stroke

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Ketamine HydrochlorideDrug

    Also called Ketalar

    Titratable ketamine infusion + low fixed-dose propofol.

  • PropofolDrug

    Also called Diprivan

    Standard of care titratable propofol infusion.

Study groups in NCT05032118
Study groupRoleWhat they receive
KetamineExperimentalIntravenous 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.
Receives: Drug: Ketamine Hydrochloride
Standard of CareActive comparatorIntravenous 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.
Receives: Drug: Propofol

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Days 4-12 post-bleed

Secondary outcomes (4)
  1. Lindegaard ratio (LR)

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

    Measured: Days 4-12 post-bleed

  2. 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.

    Measured: Days 4-12 post-bleed

  3. 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.

    Measured: Days 4-14 post-bleed

  4. 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).

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted2 Sep 2021
  2. Study start27 Apr 2023
  3. Primary completion27 Apr 2023
  4. Study completion27 Apr 2023

Why it stopped: Institution change, no IRB approval

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2/3
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Masking
Single blind
Who is masked
Participant
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05032118
Sponsor's protocol ID
00022844
Acronym
PENDULUM
Status last verified
Apr 2023
First submitted
20 Aug 2021
Last updated
1 May 2023
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Carlson AP, Abbas M, Alunday RL, Qeadan F, Shuttleworth CW. Spreading depolarization in acute brain injury inhibited by ketamine: a prospective, randomized, multiple crossover trial. J Neurosurg. 2018 May 25;130(5):1513-1519. doi: 10.3171/2017.12.JNS171665. Print 2019 May 1.

    PubMed 29799344
  • Sakowitz OW, Kiening KL, Krajewski KL, Sarrafzadeh AS, Fabricius M, Strong AJ, Unterberg AW, Dreier JP. Preliminary evidence that ketamine inhibits spreading depolarizations in acute human brain injury. Stroke. 2009 Aug;40(8):e519-22. doi: 10.1161/STROKEAHA.109.549303. Epub 2009 Jun 11.

    PubMed 19520992
  • Groetzinger LM, Rivosecchi RM, Bain W, Bahr M, Chin K, McVerry BJ, Barbash I. Ketamine Infusion for Adjunct Sedation in Mechanically Ventilated Adults. Pharmacotherapy. 2018 Feb;38(2):181-188. doi: 10.1002/phar.2065. Epub 2018 Jan 10.

    PubMed 29193185
  • Schiefecker AJ, Beer R, Pfausler B, Lackner P, Broessner G, Unterberger I, Sohm F, Mulino M, Thome C, Humpel C, Schmutzhard E, Helbok R. Clusters of cortical spreading depolarizations in a patient with intracerebral hemorrhage: a multimodal neuromonitoring study. Neurocrit Care. 2015 Apr;22(2):293-8. doi: 10.1007/s12028-014-0050-4.

    PubMed 25142825
  • Hertle DN, Dreier JP, Woitzik J, Hartings JA, Bullock R, Okonkwo DO, Shutter LA, Vidgeon S, Strong AJ, Kowoll C, Dohmen C, Diedler J, Veltkamp R, Bruckner T, Unterberg AW, Sakowitz OW; Cooperative Study of Brain Injury Depolarizations (COSBID). Effect of analgesics and sedatives on the occurrence of spreading depolarizations accompanying acute brain injury. Brain. 2012 Aug;135(Pt 8):2390-8. doi: 10.1093/brain/aws152. Epub 2012 Jun 19.

    PubMed 22719001
  • Santos E, Olivares-Rivera A, Major S, Sanchez-Porras R, Uhlmann L, Kunzmann K, Zerelles R, Kentar M, Kola V, Aguilera AH, Herrera MG, Lemale CL, Woitzik J, Hartings JA, Sakowitz OW, Unterberg AW, Dreier JP. Lasting s-ketamine block of spreading depolarizations in subarachnoid hemorrhage: a retrospective cohort study. Crit Care. 2019 Dec 30;23(1):427. doi: 10.1186/s13054-019-2711-3.

    PubMed 31888772
  • Wanchoo S, Khazanehdari S, Patel A, Lin A, Rebeiz T, DeMatteo C, Ullman J, Ledoux D. Ketamine for empiric treatment of cortical spreading depolarization after subdural hematoma evacuation. Clin Neurol Neurosurg. 2021 Jan;200:106318. doi: 10.1016/j.clineuro.2020.106318. Epub 2020 Oct 17.

    PubMed 33268191
  • Von der Brelie C, Seifert M, Rot S, Tittel A, Sanft C, Meier U, Lemcke J. Sedation of Patients with Acute Aneurysmal Subarachnoid Hemorrhage with Ketamine Is Safe and Might Influence the Occurrence of Cerebral Infarctions Associated with Delayed Cerebral Ischemia. World Neurosurg. 2017 Jan;97:374-382. doi: 10.1016/j.wneu.2016.09.121. Epub 2016 Oct 11.

    PubMed 27742511

Questions about this trial

What is this clinical trial studying?

A Phase 2/3 study testing Ketamine Hydrochloride and Propofol in people with Subarachnoid Hemorrhage, Aneurysmal, run by Jenna L Leclerc MD, PhD.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 8 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 1 May 2023. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Incidence of moderate and severe radiographic cerebral vasospasm (CV) (time frame: Days 4-12 post-bleed). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05032118, which also lists 8 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 May 2023.

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