Pilot Study of Ketamine Sedation for Aneurysmal Subarachnoid Hemorrhage

Subarachnoid Hemorrhage, Aneurysmal Clinical Trial

— PENDULUM  

Official title:

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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT05032118
• Other study ID #: 00022844
• Status: Withdrawn
• Phase: Phase 2/Phase 3
• Start date: April 27, 2023
• Est. completion date: April 27, 2023

Study information

• Verified date: April 2023
• Source: Oregon Health and Science University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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. 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.

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: April 27, 2023
• Est. primary completion date: April 27, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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)

Related Conditions & MeSH terms

• Hemorrhage
• Subarachnoid Hemorrhage
• Subarachnoid Hemorrhage, Aneurysmal

Intervention

Drug:
• Ketamine Hydrochloride
Titratable ketamine infusion + low fixed-dose propofol.
• Propofol
Standard of care titratable propofol infusion.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Jenna L Leclerc MD, PhD

References & 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 25:1-7. doi: 10.3171/2017.12.JNS171665. Online ahead of print. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Vasopressor requirements	Change in vasopressor dosage required for induced hypertensive therapy.	Within 12 days post-bleed
Other	Incidence of acute kidney injury	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.	Within 12 days post-bleed
Other	Incidence of moderate to severe drug-induced liver injury	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.	Within 14 days post-bleed
Other	Physiologic parameters: heart rate	Defined as change in heart rate by more than 30 beats per minute.	Days 3-10 post-bleed
Other	Physiologic parameters: blood pressure	Defined as change in blood pressure to over 200mmHg in absence of induced hypertensive therapy and felt as a result of ketamine administration.	Days 3-10 post-bleed
Other	Physiologic parameters: intracranial pressure	Defined as change in ICP by 5mmHg.	Days 3-10 post-bleed
Other	Physiologic parameters: cerebral perfusion pressure	Defined as a statistically significant change in cerebral perfusion pressure with ketamine administration.	Days 3-10 post-bleed
Primary	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	Lindegaard ratio (LR)	A change in the LRs on routine daily transcranial Doppler monitoring.	Days 4-12 post-bleed
Secondary	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.	Days 4-12 post-bleed
Secondary	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.	Days 4-14 post-bleed
Secondary	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).	Hospital discharge (on average days 14-21 post-bleed), and 3 and 6 months post-bleed