Non-invasive Measurement of Cerebrovascular Reactivity After Traumatic Brain Injury

Terminated

• Conditions: TBI
• Interventions: Drug: Sildenafil citrate; Device: Functional Near Infared Spectroscopy; Other: Hypercapnia Challenge

• Registration Number: NCT02990078
• Lead Sponsor: University of Pennsylvania

Brief Summary

The investigators will longitudinally measure cerebrovascular reactivity (CVR) by functional near-infrared spectroscopy (fNIRS) in acute (≤3 days from injury), subacute, and chronic phases after TBI as a biomarker of TCVI as compared to healthy controls. CVR will be measured by fNIRS response to hypercapnia. The investigators hypothesize that CVR will be decreased after TBI and that these decreases will correlate with clinical outcomes. Furthermore, the investigators predict that administration of a vasodilatory medication (sildenafil) will augment CVR after TBI.

Detailed Description

Not available

Study Timeline

• Study Start: 2016-12
• Study First Submitted: 2016-12-05
• Study First Submitted QC: 2016-12-07
• Study First Posted: 2016-12-12
• Primary Completion: 2022-06-30
• Study Completion: 2022-09-30
• Status Verified: 2022-10
• Last Update Submitted: 2022-10-10
• Last Update Posted: 2022-10-13

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 26

Inclusion Criteria

1. Men and women, aged ≥18

2. CT evidence of TBI-linked abnormality

   • Traumatic subarachnoid hemorrhage
   • Intracerebral hemorrhage/contusion
   • Subdural/epidural hematoma

3. Ability to undergo fNIRS testing with hypercapnia challenge

4. Subject able to provide informed consent

5. Attending of record agrees to include subject in study

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Exclusion Criteria

1. Unstable respiratory or hemodynamic status

2. Evidence of penetrating brain injury

3. TBI requiring craniotomy or craniectomy

4. Evidence or risk of ICP crisis

5. History of disabling pre-existing neurologic disorder (e.g. dementia, uncontrolled epilepsy, multiple sclerosis, strokes, brain tumors, prior severe TBI, or other disorder that confounds interpretation of NIRS testing or neuropsychological results)

6. History of pre-existing disabling mental illness (e.g. major depression or schizophrenia)

7. Exclusion criteria for sildenafil administration:

   • History of melanoma
   • current use of organic nitrate vasodilators
   • current use of ritonavir (HIV-protease inhibitor)
   • current use of erythromycin, ketoconazole, or itraconazole; current use of cimetidine
   • current use of alpha-blockers such as doxazosin (Cardura), tamsulosin (Flomax), and terazosin (Hytrin) prazosin (Minipres)
   • resting hypotension (systolic BP <90)
   • severe renal insufficiency
   • hepatic cirrhosis
   • acute ischemic stroke within past 2 months
   • acute myocardial infarction within past 2 months
   • unstable angina pectoris
   • acute or chronic heart failure
   • retinitis pigmentosa
   • pregnant or breastfeeding female
   • known hypersensitivity or allergy to sildenafil

8. Unstable cardiac status that constitutes a contraindication to sexual activity

9. Inability to read and communicate in English (necessary to obtain reliable neuropsychometric data)

10. Nursing mothers

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Acute TBI	Sildenafil citrate	Subjects will be recruited from the neurointensive care unit within 72 hours of their injury. At the time of informed consent, the investigators will perform fNIRS testing with a hypercapnia challenge, fNIRS with hypercapnia challenge 60 minutes after a single oral dose of 50mg sildenafil citrate, outcome qustionaires and symptom checklists (including: Glasgow Outcomes Scale-Extended, Rivermead Post-Concussive Symptom Questionnaire, Brief Symptom Inventory, Alcohol Consumption Questionnaire, Patient Health Questionnaire, and Insomnia Severity Index). This will all be administered again at 14 days, 90 days, 180 days, 1 year, 2 years, 3 years, and 4 years after injury.
Sub-acute/Chronic TBI	Sildenafil citrate	Subjects who suffered a TBI previously and have now entered a subacute or chronic phase of their TBI will be approached by the research team at their clinic visit with a TBI specialist. In those subjects, study timing will be based on the time of their original injury, therefore will start study visits at the next possible time point.
Healthy Controls	Sildenafil citrate	The investigators will also enroll healthy "peer controls". These control subjects will be family members and friends of TBI subjects. These peer controls are likely to have similar environmental and socioeconomic exposures/support which may impact recovery after TBI and may also impact CVR. These control subjects will meet the same inclusion/exclusion criteria as TBI subjects without the requirement for an injury or acute brain imaging. These subjects will be tested in the same way as both TBI groups, but will only have one visit.
Sub-acute/Chronic TBI	Hypercapnia Challenge	Subjects who suffered a TBI previously and have now entered a subacute or chronic phase of their TBI will be approached by the research team at their clinic visit with a TBI specialist. In those subjects, study timing will be based on the time of their original injury, therefore will start study visits at the next possible time point.
Healthy Controls	Functional Near Infared Spectroscopy	The investigators will also enroll healthy "peer controls". These control subjects will be family members and friends of TBI subjects. These peer controls are likely to have similar environmental and socioeconomic exposures/support which may impact recovery after TBI and may also impact CVR. These control subjects will meet the same inclusion/exclusion criteria as TBI subjects without the requirement for an injury or acute brain imaging. These subjects will be tested in the same way as both TBI groups, but will only have one visit.
Healthy Controls	Hypercapnia Challenge	The investigators will also enroll healthy "peer controls". These control subjects will be family members and friends of TBI subjects. These peer controls are likely to have similar environmental and socioeconomic exposures/support which may impact recovery after TBI and may also impact CVR. These control subjects will meet the same inclusion/exclusion criteria as TBI subjects without the requirement for an injury or acute brain imaging. These subjects will be tested in the same way as both TBI groups, but will only have one visit.
Acute TBI	Functional Near Infared Spectroscopy	Subjects will be recruited from the neurointensive care unit within 72 hours of their injury. At the time of informed consent, the investigators will perform fNIRS testing with a hypercapnia challenge, fNIRS with hypercapnia challenge 60 minutes after a single oral dose of 50mg sildenafil citrate, outcome qustionaires and symptom checklists (including: Glasgow Outcomes Scale-Extended, Rivermead Post-Concussive Symptom Questionnaire, Brief Symptom Inventory, Alcohol Consumption Questionnaire, Patient Health Questionnaire, and Insomnia Severity Index). This will all be administered again at 14 days, 90 days, 180 days, 1 year, 2 years, 3 years, and 4 years after injury.
Acute TBI	Hypercapnia Challenge	Subjects will be recruited from the neurointensive care unit within 72 hours of their injury. At the time of informed consent, the investigators will perform fNIRS testing with a hypercapnia challenge, fNIRS with hypercapnia challenge 60 minutes after a single oral dose of 50mg sildenafil citrate, outcome qustionaires and symptom checklists (including: Glasgow Outcomes Scale-Extended, Rivermead Post-Concussive Symptom Questionnaire, Brief Symptom Inventory, Alcohol Consumption Questionnaire, Patient Health Questionnaire, and Insomnia Severity Index). This will all be administered again at 14 days, 90 days, 180 days, 1 year, 2 years, 3 years, and 4 years after injury.
Sub-acute/Chronic TBI	Functional Near Infared Spectroscopy	Subjects who suffered a TBI previously and have now entered a subacute or chronic phase of their TBI will be approached by the research team at their clinic visit with a TBI specialist. In those subjects, study timing will be based on the time of their original injury, therefore will start study visits at the next possible time point.

Primary Outcome Measures

Name	Time	Method
Change in CVR prior to sildenafil administration	< 72hrs, 14 days, 90 days, 180 days, 1 year, 2 years, 3 years, 4 years

Secondary Outcome Measures

Name	Time	Method
Change CVR after sildenafil administration	<72 hours, 14 days, 90 days, 180 days, 1 year, 2 years, 3 years, 4 years
Relationship of CVR with symptom reports, as measured by the Neurobehavioral Symptom Inventory (NBSI).	< 72hrs, 14 days, 90 days, 180 days, 1 year, 2 years, 3 years, 4 years

Trial Locations

Locations (1)

Penn Presbyterian Medical Center; 🇺🇸 Philadelphia, Pennsylvania, United States