Ketamine Infusion in Neurologic Deficit

NCT02636218 | Completed Phase 2 DMC

• 1 other identifier: KTM-3007
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

Brief Summary

Subarachnoid hemorrhage (SAH) or bleeding in the brain as a result of ruptured aneurysm is a devastating type of stroke. Many patients who undergo emergent neurosurgery to repair the aneurysm and remove the bleeding suffer from complications in their subsequent hospital stay, the most frequent and morbid of which is delayed cerebral ischemia (DCI) or small strokes resulting from impaired blood flow to certain vital brain centers. This occurs because of changes to the brain's blood vessels that occur after the bleed. The arteries can become narrow (spasm) or small clots can form within the vasculature that disrupts normal blood flow. Patients are left with profound neurologic deficits from these secondary complications. Anesthesiologists, neurosurgeons, and intensivists are in need of a way to protect the brain during this vulnerable period following aneurysm repair. One drug that may provide such protection is ketamine, a compound frequently used in operating rooms and intensive care units to provide anesthesia and analgesia. Ketamine works by blocking glutamate receptor ion channels that play a pivotal role in promoting brain cell death during strokes by flooding the brain with too much calcium and dangerous chemicals. This project is designed to test the efficacy of ketamine in protecting the brain following aneurysm repair by using a controlled infusion of the drug in the intensive care unit (ICU) when patients return from their operation.

Conditions

Subarachnoid Hemorrhage

Keywords

Ketamine

Outcome Measures

Primary Outcomes (1)

• Changes in physiologic parameters as specified below

  Temperature, heart rate (HR), mean arterial pressure (MAP), intracranial pressure (ICP), central venous pressure (CVP) if available, peak airway pressure (PAP) if available, end-tidal carbon dioxide (ETCO2) will be evaluated during infusion. Collected measurement data will be analyzed based on the occurrence of adverse events such as increase in ICP by more than 3 mmHg, increase in HR by more than 30 bpm, increase in partial pressure of CO2 (pCO2) by more than 20 mmHg, increase in lactate by more than 0.5, drop in pH by more than 0.2, increase in systolic blood pressure (SBP0 to over 200 mmHg, or any other unforeseen event that is deemed to be related to the drug treatment with adverse effects on the patient.

  During infusion and 1 hour post-infusion

Secondary Outcomes (8)

• Biologic samples

  Day 1-2 post-infusion

• Neurocognitive test Montreal Cognitive Assessment Scale (MoCA)

  Day 30 or Day 60 post-DCI

• Neurocognitive test modified Rankin Scale (mRS)

  Day 30 or Day 60 post-DCI

• Brain imaging using Magnetic Resonance Imaging (MRI)

  Day 30 or Day 60 post-DCI

• Hospital anxiety and depression score

  Day 30 or Day 60 post-DCI

Study Arms (2)

0.9% NaCl control

ACTIVE COMPARATOR

Normal saline

Drug: 0.9% NaCl

Ketamine

EXPERIMENTAL

Anesthetic

Drug: Ketamine

Interventions

Ketamine DRUG

500 ml of ketamine (0.2 mg/ml) infused at 5 ug/kg/min for 4 hours.

Also known as: Ketamine HCl

Ketamine

0.9% NaCl DRUG

500 ml of 0.9% NaCl infused at 5 ug/kg/min for 4 hours.

Also known as: NS

0.9% NaCl control

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.
• World Federation of Neurological Surgeons (WFNS) grade 2 to 4, obtained after resuscitation and prior to dosing.
• SAH on admission cranial computed tomography (CT) scan (diffuse clot present in both hemispheres, thin or thick \[\>4 mm\], or local thick SAH (\>4 mm).
• Ruptured saccular aneurysm, confirmed by catheter angiography (CA) or CT angiography (CTA) and treated by neurosurgical clipping or endovascular coiling.
• External ventricular drain placed as part of routine care.
• Able to be dosed within 4 hours of new neurologic deficit.
• Historical modified Rankin score of 0 or 1.
• Hemodynamically stable after resuscitation (systolic blood pressure \> 100 mm Hg)
• Haemoglobin \>85 g/L, platelets \>125,000 cells/mm3
• Informed consent.
• New neurologic deficits that were not present previously, identified by 1) a decrease of 2 points on the modified Glasgow coma scale (mGCS) or 2) an increase in 2 points on the National Institute of Health Stroke Scale (NIHSS). i.e., a CODE VASOSPASM initiated in the ICU.

You may not qualify if:

• Subarachnoid hemorrhage due to causes other than a saccular aneurysm (e.g., trauma or rupture of fusiform or infective aneurysm).
• WFNS Grade 1 or 5 assessed after the completion of aneurysm repair.
• Increased intracranial pressure (ICP) \>30 mm Hg in sedated patients lasting \>4 hours anytime since admission.
• Intraventricular or intracerebral hemorrhage in absence of SAH or with only local, thin SAH.
• Angiographic vasospasm prior to aneurysm repair procedure, as documented by catheter angiogram or CT angiogram.
• Major complication during aneurysm repair such as, but not limited to, massive intraoperative hemorrhage, brain swelling, arterial occlusion, or inability to secure the ruptured aneurysm.
• Aneurysm repair requiring flow diverting stent or stent-assisted coiling and dual antiplatelet therapy.
• Hemodynamically unstable prior to administration of study drug (i.e., SBP \<90 mm Hg, requiring \>6 L colloid or crystalloid fluid resuscitation).
• Cardiopulmonary resuscitation was required following SAH.
• Female patients with positive pregnancy test (blood or urine) at screening.
• History within the past 6 months and/or physical finding on admission of decompensated heart failure (New York Heart Association \[NYHA\] Class III and IV or heart failure requiring hospitalization).
• Acute myocardial infarction within 3 months prior to the administration of the study drug.
• Symptoms or electrocardiogram (ECG)-based signs of acute myocardial infarction or unstable angina pectoris on admission.
• Electrocardiogram evidence and/or physical findings compatible with second or third degree heart block or of cardiac arrhythmia associated with hemodynamic instability.
• Echocardiogram, if performed as part of standard-of-care before treatment, revealing a left ventricular ejection fraction (LVEF) \<40%.

Sponsors & Collaborators

• Unity Health Toronto: lead
• Defence Research and Development Canada: collaborator

Study Sites (1)

St Michael's Hospital

Toronto, Ontario, M5B 1W8, Canada

Location

Related Publications (4)

• Etminan N, Vergouwen MD, Ilodigwe D, Macdonald RL. Effect of pharmaceutical treatment on vasospasm, delayed cerebral ischemia, and clinical outcome in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. J Cereb Blood Flow Metab. 2011 Jun;31(6):1443-51. doi: 10.1038/jcbfm.2011.7. Epub 2011 Feb 2.

  PMID: 21285966 BACKGROUND

• Nilsson OG, Saveland H, Boris-Moller F, Brandt L, Wieloch T. Increased levels of glutamate in patients with subarachnoid haemorrhage as measured by intracerebral microdialysis. Acta Neurochir Suppl. 1996;67:45-7. doi: 10.1007/978-3-7091-6894-3_10.

  PMID: 8870801 BACKGROUND

• Beal MF. Mechanisms of excitotoxicity in neurologic diseases. FASEB J. 1992 Dec;6(15):3338-44.

  PMID: 1464368 BACKGROUND

• Forder JP, Tymianski M. Postsynaptic mechanisms of excitotoxicity: Involvement of postsynaptic density proteins, radicals, and oxidant molecules. Neuroscience. 2009 Jan 12;158(1):293-300. doi: 10.1016/j.neuroscience.2008.10.021. Epub 2008 Nov 1.

  PMID: 19041375 BACKGROUND

MeSH Terms

Conditions

Subarachnoid Hemorrhage

Interventions

Ketamine; Saline Solution

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

Intervention Hierarchy (Ancestors)

Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• Andrew Baker, MD, FRCPC

  Unity Health Toronto

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 8, 2015
• First Posted: December 21, 2015
• Study Start: January 26, 2016
• Primary Completion: March 31, 2021
• Study Completion: November 15, 2023
• Last Updated: August 16, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)