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Improving Neurotrauma by Depolarization Inhibition With Combination Therapy: A Phase 2 Randomized Feasibility Trial
Jed A Hartings1, Jens P Dreier2,3,4,5,6, Laura B Ngwenya1
1Department of Neurosurgery, University of Cincinnati, Cincinnati , Ohio , USA.
Background And Objectives:
Spreading depolarizations (SDs) are a pathological mechanism that mediates lesion development in cerebral gray matter. They occur in ∼60% of patients with severe traumatic brain injury (TBI), often in recurring and progressive patterns from days 0 to 10 after injury, and are associated with worse outcomes. However, there are no protocols or trials suggesting how SD monitoring might be incorporated into clinical management. The objective of this protocol is to determine the feasibility and efficacy of implementing a treatment protocol for intensive care of patients with severe TBI that is guided by electrocorticographic monitoring of SDs.
Methods:
Patients who undergo surgery for severe TBI with placement of a subdural electrode strip will be eligible for enrollment. Those who exhibit SDs on electrocorticography during intensive care will be randomized 1:1 to either (1) standard care that is blinded to the further course of SDs or (2) a tiered intervention protocol based on efficacy to suppress further SDs. Interventions aim to block the triggering and propagation of SDs and include adjusted targets for management of blood pressure, CO 2 , temperature, and glucose, as well as ketamine pharmacotherapy up to 4 mg/kg/ hour. Interventions will be escalated and de-escalated depending on the course of SD pathology.
Expected Outcomes:
We expect to demonstrate that electrocorticographic monitoring of SDs can be used as a real- time diagnostic in intensive care that leads to meaningful changes in patient management and a reduction in secondary injury, as compared with standard care, without increasing medical complications or adverse events.
Discussion:
This trial holds potential for personalization of intensive care management by tailoring therapies based on monitoring and confirmation of the targeted neuronal mechanism of SD. Results are expected to validate the concept of this approach, inform refinement of the treatment protocol, and lead to larger-scale trials.
Insights
This study investigates using electrocorticography to monitor spreading depolarizations (SDs) in severe traumatic brain injury (TBI) patients. The goal is to personalize intensive care and reduce secondary brain injury by guiding treatment based on real-time SD activity.
Area of Science:
- Neuroscience
- Critical Care Medicine
- Neurological Surgery
Background:
- Spreading depolarizations (SDs) are a key mechanism in cerebral gray matter lesion development.
- SDs occur in approximately 60% of severe traumatic brain injury (TBI) patients, often progressively, and correlate with poor outcomes.
- Current clinical management lacks protocols for SD monitoring in TBI.
Purpose of the Study:
- To determine the feasibility and efficacy of an intensive care treatment protocol for severe TBI guided by electrocorticographic monitoring of SDs.
- To establish real-time diagnostic capabilities for SDs in intensive care settings.
- To reduce secondary injury in TBI patients through tailored management strategies.
Main Methods:
- Patients with severe TBI undergoing surgery with subdural electrode placement are eligible.
- Participants exhibiting SDs will be randomized to standard care or a tiered intervention protocol.
- Interventions include adjusted management of blood pressure, CO2, temperature, glucose, and ketamine, guided by SD activity.
Main Results:
- The study expects to show that SD monitoring enables meaningful changes in patient management.
- It anticipates a reduction in secondary injury compared to standard care.
- No increase in medical complications or adverse events is expected.
Conclusions:
- Electrocorticographic monitoring of SDs can serve as a real-time diagnostic tool in intensive care for TBI.
- This approach allows for personalized management, tailoring therapies to the specific neuronal mechanism of SD.
- Results are expected to validate this treatment concept and inform larger trials.
