Clinical trial NCT03900182: The Role of Hyperbaric Oxygen and Neuropsychological Therapy in Cognitive Function Following Traumatic Brain Injury
Official title: The Role of Hyperbaric Oxygen and Neuropsychological Therapy in Cognitive Function Following Traumatic Brain Injury
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Brain Injuries, Traumatic
Neuropsychology
Keywords: Traumatic brain injury
hyperbaric oxygen therapy
neuropsychological treatment
cognitive function
biomarkers.
Lead sponsor: Chang Gung Memorial Hospital
Sponsor class: OTHER
First posted: 2019-04-02
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: After signing an informed consent form, the patients were invited for baseline evaluation. Included patients were randomized into two groups. The neuropsychological functions were the primary endpoints of the study. Secondary end point included quality of life evaluation. Evaluations were made by medical and neuropsychological practitioners who were blinded to patients' inclusion in the control-crossed or the treated groups.

Patients in the treated group were evaluated three - at baseline, after 6 weeks of HBOT and after 6 weeks of neuropsychological treatment or no treatment. Patients in the crossover group were evaluated three times: baseline, after 6 weeks control period of no treatment, and after subsequent 6 weeks of HBOT. The post-HBOT neuropsycological evaluations were performed more than 1 week (1-2 weeks) after the end of the HBOT protocol. The following HBOT protocol was practiced: 30 daily sessions, 5 days/week, 60 minutes each, 100% oxygen at 1.5ATA.
Primary purpose: TREATMENT

Brief summary: Traumatic brain injury (TBI) caused by accidents is a very important public health problem in Taiwan. There are many people with brain damage and cognitive dysfunction caused by traumatic brain injury every year. Currently, there is no effective treatment for cognitive dysfunction caused by traumatic brain injury. Evidence from clinical studies in recent years suggests that hyperbaric oxygen therapy may be a treatment for repairing nerves after brain injury.

Many studies have shown that oxidative stress and inflammatory responses play an important role in the pathogenesis of the central nervous system. In recent years, our research team has shown that oxidative stress and inflammatory response are significantly associated with the prognosis of patients with traumatic brain injury, cerebral hemorrhage, and stroke patients. More and more evidences also show that oxidative stress and inflammatory response play an important role in the neuropathological changes of mental cognitive sequelae after traumatic brain injury. This injury may be gradual from the time of head trauma. This process begins with the generation of oxidative stress and free radicals. When the cell repair and free radical scavenging system can not effectively overcome the excessive production of free radicals, an oxidative damage reaction will occur, causing a series of inflammatory cells and cytokines to be activated. Studies have also shown that when inhibiting those free radicals that produce oxidative stress, the neurological function and cognitive function of the head after trauma can be significantly improved.

It is becoming widely acknowledged that the combined action of hyperoxia and hyperbaric pressure leads to significant improvement in tissue oxygenation while targeting both oxygenand pressure-sensitive genes, resulting in improved mitochondrial metabolism with anti-apoptotic and anti-inflammatory effects. The investigators published an article this year showing that hyperbaric oxygen therapy can improve the prognosis of patients with acute stroke and increase endothelial progenitor cells in the systemic circulation.

The investigators plan to conduct this research project through hyperbaric oxygen therapy and neuropsychological therapy, and using scientific tests and neurocognitive function assessments. The investigators hope to answer the following questions: (1) Whether the treatment of hyperbaric oxygen can improve oxidative stress and inflammatory response after brain injury, and observe changes in biomarker concentration; (2) Whether hyperbaric oxygen therapy and neuropsychological therapy can improve cognitive function after brain injury; and (3) which biomarkers are factors that influence cognitive function prognosis.

Detailed description: Research Methodology A prospective cohort study will be conducted. The follow-up periods are 18 weeks.

Diagnostic criteria of mild and moderate traumatic brain injury. Diagnostic criteria of traumatic brain injury will be according to (1) American Association of Neurosurgical Surgeons (AANS) Guidelines for The Management of Severe Head Injury; (2) YOUMANS Neurological Surgery Fifth Edition Guidelines for Traumatic Brain Injury.

Definitions and classifications Traumatic brain injury is defined as damage to the brain resulting from external mechanical force, such as rapid acceleration or deceleration, impact, blast waves, or penetration by a projectile. Consequently to the injury, brain function is temporarily or permanently impaired and structural damage may or may not be detectable with current imaging technology. TBI is usually classified based on severity, anatomical features of the injury, and the cause of the injury. The severity is assessed according to the loss of consciousness (LOC) duration, the post-traumatic amnesia (PTA), and the Glasgow coma scale (GCS) grading of the level of consciousness. Approximately (70-90%) of the TBI in the US are classified as mild TBI (mTBI) or concussion - LOC duration of 0-30 minutes, PTA duration of less than a day and GCS grade of 13-15. Post concussion syndrome (PCS) is a set of symptoms succeeding mTBI in most patients. The PCS symptoms include headache, dizziness, neuropsychiatric symptoms, and cognitive impairments. In most patients, PCS may continue for weeks or months, and up to 25% of the patients may experience prolonged PCS (PPCS) in which the symptoms last for over six months. Such individuals are at high risk for emotional and cognitive dysfunction, culminating in inability to carry out ordinary daily activities, work responsibilities and standard social relationships.

Hypotheses and Purpose:

In this study, the investigators hypothesize that the hyperbaric oxygen therapy in neurotherapeutics, in light of recent persuasive evidence for hyperbaric oxygen therapy efficacy in brain repair and of new understanding of brain energy management and response to damage. The investigators discuss the optimal timing of treatment, optimal dose-response curve (oxygenpressure levels), suitable candidates and promising future directions. The investigators speculate that these changes of biomarkers correlated with the hyperbaric oxygen therapy efficacy and the progression of neuropsychological testing during the 18 weeks follow-up.

The investigators plan to conduct this research project through hyperbaric oxygen therapy and neuropsychological therapy and using scientific tests and neurocognitive function assessments. The scientific tests including flow cytometry to evaluate the fraction of circulating activated platelets, the proportion of leukocytosis apoptosis, Erythrocyte assay of antioxidant enzymes and Enzyme-Linked Immunosorbent Assay (ELISA) for inflammatory markers.

Purpose:

1. To evaluate that whether the treatment of hyperbaric oxygen can improve oxidative stress and inflammatory response after brain injury, and observe changes in biomarker concentration.
2. To evaluate that whether hyperbaric oxygen therapy and neuropsychological therapy can improve cognitive function after brain injury.
3. To evaluate that which biomarkers are factors that influence the prognosis of cognitive function.

Eligibility criteria: Inclusion Criteria:

* Traumatic brain injury, mild and moderated.
* Age between 18 and 65 years old

Exclusion Criteria:

1. Penetrating injury, including gunshot injury
2. Combined with other major trauma which had unstable hemodynamics
3. Major systemic disease, such ESRD, liver cirrhosis, CHF, or a malignant disease
4. Evidence for alcoholism or any other addictive disorders, or known affective or other psychiatric disease or use of sedatives or neuroleptic medication
5. Known neurological disorders potentially affecting the central nervous system or severe recent life events that might have interfered with neuropsychological testing.

Primary outcomes:
measure: Neuropsychological testing- Wechsler Adult Intelligence scale-III (WAIS-III)
timeFrame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
measure: Neuropsychological testing- Cognitive Ability Screening Instrument (CASI)
timeFrame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
measure: Neuropsychological testing- mini-mental state examination (MMSE)
timeFrame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
measure: Neuropsychological testing- Short Form 36 questionnaire
timeFrame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
measure: Neuropsychological testing- The World Health Organization Quality of Life questionnaire (WHOQOL-BREF)
timeFrame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
measure: Neuropsychological testing- Beck Depression Inventory
timeFrame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
Secondary outcomes:
measure: oxidative damage markers: Erythrocyte superoxide dismutase (SOD) activity
timeFrame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
measure: oxidative damage markers: Erythrocyte glutathione peroxidase (GPx) activity
timeFrame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
measure: oxidative damage markers: serum malondialdehyde (MDA) content
timeFrame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
measure: oxidative damage markers: serum free thiol content
timeFrame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
measure: Cytokines (IL-1β) by Enzyme-linked immunosorbent assays
timeFrame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
measure: Cytokines (IL-6) by Enzyme-linked immunosorbent assays
timeFrame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
measure: Cytokines (IL-10) by Enzyme-linked immunosorbent assays
timeFrame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
measure: Cytokines (TNF-α) by Enzyme-linked immunosorbent assays
timeFrame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
measure: endothelium-leukocyte activation (ICAM-1)
timeFrame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
measure: endothelium-leukocyte activation ( VCAM-1)
timeFrame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
measure: endothelium-leukocyte activation (E-selectin)
timeFrame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
measure: endothelium-leukocyte activation (L-selectin)
timeFrame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
measure: neural inflammation markers (S-100)
timeFrame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
measure: neural inflammation markers (tau protein)
timeFrame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
measure: neural inflammation markers (MMP-2)
timeFrame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
measure: neural inflammation markers (MMP-9)
timeFrame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
measure: plasma cell-free DNA by Real-time quantative PCR
timeFrame: Change from baseline, at after 6 weeks of HBOT and at after 6 times of neuropsychological treatment.
Other outcomes:
Locations:
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Chang Gung Memorial Hospital
Study officials:
affiliation: Chang Gung Medical Foundation
name: Tsang-Tang Hsieh, MD
role: STUDY_CHAIR
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