Ketamine for Traumatic Brain Injury

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: University of Texas Southwestern Medical Center

Disqualifiers: Schizophrenia, Hypertension, Tachycardia, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 1 day

10 Participants Needed

Trial Summary

What is the purpose of this trial?

Traumatic brain injury (TBI) accounts for approximately 2.5 million visits to emergency departments in the United States each year. After decades of research, management strategies for severe TBI (sTBI) patients are still evolving. Optimizing intracranial pressure (ICP) and cerebral perfusion pressure (CPP) are paramount in the management of these patients and placement of these monitors is the current standard-of-care. However, monitoring brain oxygenation (PbtO2) with invasive intraparenchymal monitors is currently under investigation in the management of severe TBI and placement of these monitors is gaining widespread use. This has opened the door for the use of tiered therapy to optimize ICP and PbtO2 simultaneously. Current evidence indicates that correction of ICP, CPP and PbtO2 in sTBI requires optimized analgesia and sedation. Ketamine is one of the few drugs available that has both sedative and analgesic properties and does not commonly compromise respiratory drive like opioids and sedative-hypnotics. However, traditionally, ketamine has been viewed as contraindicated in the setting of TBI due to concerns for elevation in ICP. Yet, new data has cast this long-held assumption into significant doubt. Hence the present pilot study will characterize the neurophysiological response to a single dose of ketamine in critically-ill TBI patient with ICP and PbtO2 monitoring.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What evidence supports the effectiveness of ketamine for treating traumatic brain injury?

Research suggests that ketamine may be safe for use in patients with brain injuries, as it does not increase intracranial pressure and may improve blood flow to the brain. Additionally, ketamine has shown protective effects on the brain in laboratory studies, which could be beneficial after a brain injury. ^{1 2 3 4 5}

Is ketamine generally safe for humans?

Ketamine is generally considered safe for humans, but common side effects include dissociation (feeling detached from reality) and increased blood pressure and heart rate. Different formulations and ways of taking ketamine can affect how often these side effects happen. ^{6 7 8 9 10}

How does the drug ketamine differ from other treatments for traumatic brain injury?

Ketamine is unique for traumatic brain injury because it can improve blood flow to the brain and has anti-inflammatory properties, which may help in recovery. Unlike other treatments, ketamine can be used safely without increasing pressure in the brain when administered under controlled conditions. ^{1 2 11 12 13}

Research Team

Anna Bashmakov, D.O.

Principal Investigator

UT Southwestern Medical Center

Eligibility Criteria

This trial is for adults over 18 with severe traumatic brain injury (sTBI) who have had a device placed to monitor intracranial pressure and brain tissue oxygenation. It's not suitable for those who don't meet these specific conditions.

Inclusion Criteria

I have had a severe brain injury.

I have a device in my head to monitor brain pressure and oxygen levels.

Exclusion Criteria

Systolic blood pressure > 180, diastolic blood pressure > 120

Documented history of schizophrenia

Sinus tachycardia with sustained heart rate >120

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive a single dose of ketamine to assess neurophysiological response in severe TBI patients

1 day

1 visit (in-person)

Monitoring

Participants are monitored for brain tissue oxygenation and intracranial pressure for 3 hours post-treatment

3 hours

Continuous monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

1-2 weeks

Treatment Details

Interventions

• Ketamine

Trial Overview The study is testing the effects of a single dose of ketamine on patients with sTBI. Ketamine, known for its sedative and pain-relieving properties, will be evaluated to see how it affects brain pressure and oxygen levels in critically ill TBI patients.

Ketamine is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Ketalar for:

• Anesthesia
• Treatment-resistant depression

Approved in European Union as Ketalar for:

• Anesthesia
• Treatment-resistant depression

Approved in United States as Spravato for:

• Treatment-resistant depression

Approved in European Union as Spravato for:

• Treatment-resistant depression

Approved in Canada as Spravato for:

• Treatment-resistant depression

Who Is Running the Clinical Trial?

University of Texas Southwestern Medical Center

Lead Sponsor

Trials

1,102

Recruited

1,077,000+

Findings from Research

In a study using rat models of traumatic brain injury caused by maxillofacial impact, ketamine treatment significantly improved recovery time, with treated rats recovering about 2 days faster than the control group.

The results suggest that ketamine may be an effective intervention for enhancing recovery following traumatic brain injuries, indicating its potential therapeutic role in similar human injuries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Animal experiment of the ketamine effects on traumatic brain injury resulting from impact maxillofacial injury]. Zhang, C., Li, H., Liao, W., et al.[2013]

Ketamine can be safely used in patients with neurological impairments when administered under controlled conditions, as it does not increase intracranial pressure and may improve cerebral perfusion.

In addition to its safety profile, ketamine shows neuroprotective effects in laboratory settings, suggesting potential benefits for brain injury recovery, although caution is needed due to possible neurotoxic effects at high doses in certain animal studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Revising a dogma: ketamine for patients with neurological injury? Himmelseher, S., Durieux, ME.[2022]

Ketamine is a promising medication for managing sedation and pain in patients with traumatic brain injury (TBI), as it does not increase intracranial pressure and may even lower it.

Its favorable safety profile makes ketamine a reliable option for use in prehospital settings during the acute phase of TBI, although careful consideration of its benefits and potential drawbacks is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine in acute phase of severe traumatic brain injury "an old drug for new uses?" Godoy, DA., Badenes, R., Pelosi, P., et al.[2021]

In a study of 4,183 combat casualties with head injuries, there was no significant association between prehospital ketamine administration and worse survival outcomes after controlling for factors like airway intervention and injury mechanism.

Although overall survival rates were similar between ketamine recipients and non-recipients, those who received ketamine and died had a higher risk ratio for time to death, suggesting a potential impact on the timing of mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine Administration in Prehospital Combat Injured Patients With Traumatic Brain Injury: A 10-Year Report of Survival. Torres, AC., Bebarta, VS., April, MD., et al.[2020]

Oral ketamine has shown effectiveness in treating severe depression, including treatment-resistant cases and those with suicidal ideation, based on various studies including randomized controlled trials with doses ranging from 0.25 to 7 mg/kg.

Despite its lower bioavailability (20%-25% reaching the bloodstream), oral ketamine is well tolerated and can be adjusted for individual needs, making it a practical option for depression treatment alongside conventional antidepressants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral Ketamine for Depression, 1: Pharmacologic Considerations and Clinical Evidence. Andrade, C.[2019]

A retrospective analysis of 449 administrations of ketamine by critical care paramedics showed that it is safely used for trauma, primarily for lower limb injuries, with median doses aligning with national guidelines.

Reported side effects were consistent with known frequencies, indicating that ketamine can be administered safely in a pre-hospital setting, although further prospective studies are needed to confirm its efficacy and safety in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective analysis of ketamine administration by critical care paramedics in a pre-hospital care setting. Cowley, A., Williams, J., Westhead, P., et al.[2022]

An extended release oral ketamine tablet was found to be safe and well tolerated in a study of seven patients with treatment-resistant depression/anxiety, with no significant changes in vital signs and only one brief report of dissociation.

All patients experienced over 50% improvements in mood ratings over 96 hours, suggesting that while the onset of mood improvement is slightly delayed compared to injectable forms, this oral formulation could be a promising option for treating resistant depression and anxiety disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of extended release ketamine tablets in patients with treatment-resistant depression and anxiety: open label pilot study. Glue, P., Medlicott, NJ., Neehoff, S., et al.[2022]

In a study involving 9 children with refractory convulsive status epilepticus (RSE), intravenous ketamine was found to be effective in resolving RSE in 6 of the patients, demonstrating its potential as a treatment option.

The treatment was deemed safe, as none of the patients experienced serious adverse events, suggesting that ketamine could be a viable alternative for children who do not respond to conventional anesthetics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of ketamine in refractory status epilepticus in children. Rosati, A., L'Erario, M., Ilvento, L., et al.[2022]

A review of 41 treatment arms from 21 studies found that ketamine formulations that maximize first pass metabolism and delay the time to peak concentration (Tmax) are associated with better safety and tolerability, particularly in reducing side effects like dissociation and increased blood pressure.

The study revealed strong correlations between the ketamine:norketamine ratio and both dissociation ratings and blood pressure changes, suggesting that careful formulation can help minimize adverse effects while maintaining the antidepressant efficacy of ketamine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of formulation and route of administration on ketamine's safety and tolerability: systematic review. Glue, P., Russell, B., Medlicott, NJ.[2021]

There is currently no standardized safety monitoring protocol for off-label use of generic ketamine, and safety monitoring for intranasal esketamine varies by jurisdiction, leading to potential gaps in patient safety.

The Ketamine Side Effect Tool (KSET) is recommended as a comprehensive tool for monitoring both acute and long-term side effects of ketamine and esketamine treatments, addressing the lack of agreed frameworks for safety monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Ketamine Side Effect Tool (KSET): A comprehensive measurement-based safety tool for ketamine treatment in psychiatry. Bayes, A., Short, B., Zarate, CA., et al.[2023]

In a study involving 118 mice with traumatic brain injury, ketamine treatment significantly increased microglial proliferation in the hippocampus shortly after injury, which may play a role in the brain's recovery process.

Despite reducing overall neurogenesis, ketamine administration improved cognitive performance in a memory task, indicating that it may have beneficial effects on behavioral outcomes following traumatic brain injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine Alters Hippocampal Cell Proliferation and Improves Learning in Mice after Traumatic Brain Injury. Peters, AJ., Villasana, LE., Schnell, E.[2019]

A single intravenous (IV) infusion of sub-anesthetic doses of ketamine showed dose-dependent effects on inflammatory cytokine levels in male and female rats, indicating its potential immunomodulatory properties.

The study found that ketamine reduced levels of certain inflammatory markers like TNF-α and IL-6, but these effects varied by sex and were mostly temporary, suggesting that further research is needed to explore ketamine's therapeutic potential in inflammatory conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of an intravenous ketamine infusion on inflammatory cytokine levels in male and female Sprague-Dawley rats. Spencer, HF., Berman, RY., Boese, M., et al.[2022]

In a study using a rat model of mild traumatic brain injury (mTBI), intravenous ketamine infusion was found to reduce inflammatory cytokines and alter locomotor activity without causing adverse effects on behavioral outcomes or neuroinflammation in the days following the injury.

Ketamine demonstrated a dose-dependent effect on reducing specific inflammatory markers (KC/GRO, TNF-α, and IL-1β) after mTBI, suggesting its potential as a therapeutic intervention to mitigate post-injury inflammation and improve recovery outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of a Subanesthetic Ketamine Infusion on Inflammatory and Behavioral Outcomes after Closed Head Injury in Rats. Spencer, HF., Boese, M., Berman, RY., et al.[2023]

References

1. China pubmed.ncbi.nlm.nih.gov

[Animal experiment of the ketamine effects on traumatic brain injury resulting from impact maxillofacial injury]. [2013]

2. United States pubmed.ncbi.nlm.nih.gov

Revising a dogma: ketamine for patients with neurological injury? [2022]

3. England pubmed.ncbi.nlm.nih.gov

Ketamine in acute phase of severe traumatic brain injury "an old drug for new uses?" [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Ketamine Administration in Prehospital Combat Injured Patients With Traumatic Brain Injury: A 10-Year Report of Survival. [2020]

5. United States pubmed.ncbi.nlm.nih.gov

Oral Ketamine for Depression, 1: Pharmacologic Considerations and Clinical Evidence. [2019]

6. England pubmed.ncbi.nlm.nih.gov

A retrospective analysis of ketamine administration by critical care paramedics in a pre-hospital care setting. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Safety and efficacy of extended release ketamine tablets in patients with treatment-resistant depression and anxiety: open label pilot study. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Efficacy and safety of ketamine in refractory status epilepticus in children. [2022]

9. Germany pubmed.ncbi.nlm.nih.gov

Influence of formulation and route of administration on ketamine's safety and tolerability: systematic review. [2021]

10. Netherlands pubmed.ncbi.nlm.nih.gov

The Ketamine Side Effect Tool (KSET): A comprehensive measurement-based safety tool for ketamine treatment in psychiatry. [2023]

11. United States pubmed.ncbi.nlm.nih.gov

Ketamine Alters Hippocampal Cell Proliferation and Improves Learning in Mice after Traumatic Brain Injury. [2019]

12. England pubmed.ncbi.nlm.nih.gov

Effects of an intravenous ketamine infusion on inflammatory cytokine levels in male and female Sprague-Dawley rats. [2022]

13. Switzerland pubmed.ncbi.nlm.nih.gov

Effects of a Subanesthetic Ketamine Infusion on Inflammatory and Behavioral Outcomes after Closed Head Injury in Rats. [2023]