Pilot Study of Ketamine Sedation for Aneurysmal Subarachnoid Hemorrhage

NCT05032118 | Withdrawn Phase 2 FDA Drug

• 1 other identifier: 00022844
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Subarachnoid Hemorrhage, Aneurysmal

Keywords

Ketamine; Vasospasm; Ischemic stroke; Delayed cerebral ischemia; Delayed neurological deficits; Cortical spreading depolarization

Outcome Measures

Primary Outcomes (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.

  Days 4-12 post-bleed

Secondary Outcomes (4)

• Lindegaard ratio (LR)

  Days 4-12 post-bleed

• Incidence of delayed cerebral ischemia (DCI)

  Days 4-12 post-bleed

• Incidence of CV/DCI-related Infarction

  Days 4-14 post-bleed

• Functional outcomes

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

Other Outcomes (7)

• Vasopressor requirements

  Within 12 days post-bleed

• Incidence of acute kidney injury

  Within 12 days post-bleed

• Incidence of moderate to severe drug-induced liver injury

  Within 14 days post-bleed

Study Arms (2)

Ketamine

EXPERIMENTAL

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.

Drug: Ketamine Hydrochloride

Standard of Care

ACTIVE COMPARATOR

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.

Drug: Propofol

Interventions

Ketamine Hydrochloride DRUG

Titratable ketamine infusion + low fixed-dose propofol.

Also known as: Ketalar

Ketamine

Propofol DRUG

Standard of care titratable propofol infusion.

Also known as: Diprivan

Standard of Care

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Jenna L Leclerc MD, PhD: lead

Related Publications (8)

• 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.

  PMID: 29799344 BACKGROUND

• 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.

  PMID: 19520992 BACKGROUND

• 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.

  PMID: 29193185 BACKGROUND

• 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.

  PMID: 25142825 BACKGROUND

• 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.

  PMID: 22719001 BACKGROUND

• 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.

  PMID: 31888772 BACKGROUND

• 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.

  PMID: 33268191 BACKGROUND

• 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.

  PMID: 27742511 BACKGROUND

MeSH Terms

Conditions

Subarachnoid Hemorrhage; Ischemic Stroke

Interventions

Ketamine; Propofol

Condition Hierarchy (Ancestors)

Intracranial Hemorrhages; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Hemorrhage; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Stroke

Intervention Hierarchy (Ancestors)

Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic

Study Officials

• Jenna L Leclerc, MD, PhD

  Oregon Health and Science University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Anesthesiology Critical Care Fellow

Study Record Dates

• First Submitted: August 20, 2021
• First Posted: September 2, 2021
• Study Start: April 27, 2023
• Primary Completion: April 27, 2023
• Study Completion: April 27, 2023
• Last Updated: May 1, 2023

Record last verified: 2023-04

Data Sharing

• IPD Sharing: Will not share