Non-invasive Measurement of Cerebrovascular Reactivity After Traumatic Brain Injury

Sponsor

University of Pennsylvania (Other)

Overall Status

Recruiting

CT.gov ID

NCT02990078

Collaborator

(none)

168

Enrollment

Location

120

Anticipated Duration (Months)

1.4

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
TBI	Drug: Sildenafil citrate Device: Functional Near Infared Spectroscopy Other: Hypercapnia Challenge

Study Design

Study Type:

Observational

Anticipated Enrollment :

168 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

Cerebrovascular Reactivity Assessed With Functional Near-infrared Spectroscopy as a Biomarker of Traumatic Microvascular Injury After Moderate-severe Traumatic Brain Injury

Actual Study Start Date :

Dec 1, 2016

Anticipated Primary Completion Date :

Jan 1, 2026

Anticipated Study Completion Date :

Dec 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Acute TBI 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.	Drug: Sildenafil citrate Sildenafil is a potent and specific PDE5 inhibitor, which was initially developed for the treatment of hypertension and angina. Its effectiveness as a treatment for male erectile dysfunction became apparent during Phase I clinical trials, and the focus of drug development shifted to this indication. In patients with cerebrovascular dysfunction, a few preliminary studies have used sildenafil to increase CVR. Participants in the pilot study had CVR tested in response to hypercapnia measured twice, at baseline and then 1 hour after administration of sildenafil citrate, 50 mg by mouth. The investigators have an IND exemption for the uses in this study. Other Names: Viagra Device: Functional Near Infared Spectroscopy Functional near-infrared spectroscopy (fNIRS) will be used to measure regional cerebral blood flow and cerebrovascular reactivity. are connected to the scalp and surrounding detectors a few cm away detect the light as it scatters through the underlying tissues. The technique is able to detect changes in the absorption spectrum of the tissue corresponding to the concentrations of oxyhemoglobin (HbO2) and deoxyhemoglobin (HbR), and indicate local perfusion changes. Other Names: fNIRS Other: Hypercapnia Challenge The study device is a Douglas Bag that traditionally is designed to measure respiratory exchange. It consists of large bag attached to a mouthpiece utilized to hold either expired air from the subject or filled with different concentrations of air to be aspired. For the purposes of this study, the Douglas Bag will be utilized to induce hypercapnia in the subject. The bag is equipped with a switch that allows rapid shifting from room air to 5% CO2 each minute over 7 minutes.
Sub-acute/Chronic TBI 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.	Drug: Sildenafil citrate Sildenafil is a potent and specific PDE5 inhibitor, which was initially developed for the treatment of hypertension and angina. Its effectiveness as a treatment for male erectile dysfunction became apparent during Phase I clinical trials, and the focus of drug development shifted to this indication. In patients with cerebrovascular dysfunction, a few preliminary studies have used sildenafil to increase CVR. Participants in the pilot study had CVR tested in response to hypercapnia measured twice, at baseline and then 1 hour after administration of sildenafil citrate, 50 mg by mouth. The investigators have an IND exemption for the uses in this study. Other Names: Viagra Device: Functional Near Infared Spectroscopy Functional near-infrared spectroscopy (fNIRS) will be used to measure regional cerebral blood flow and cerebrovascular reactivity. are connected to the scalp and surrounding detectors a few cm away detect the light as it scatters through the underlying tissues. The technique is able to detect changes in the absorption spectrum of the tissue corresponding to the concentrations of oxyhemoglobin (HbO2) and deoxyhemoglobin (HbR), and indicate local perfusion changes. Other Names: fNIRS Other: Hypercapnia Challenge The study device is a Douglas Bag that traditionally is designed to measure respiratory exchange. It consists of large bag attached to a mouthpiece utilized to hold either expired air from the subject or filled with different concentrations of air to be aspired. For the purposes of this study, the Douglas Bag will be utilized to induce hypercapnia in the subject. The bag is equipped with a switch that allows rapid shifting from room air to 5% CO2 each minute over 7 minutes.
Healthy Controls 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.	Drug: Sildenafil citrate Sildenafil is a potent and specific PDE5 inhibitor, which was initially developed for the treatment of hypertension and angina. Its effectiveness as a treatment for male erectile dysfunction became apparent during Phase I clinical trials, and the focus of drug development shifted to this indication. In patients with cerebrovascular dysfunction, a few preliminary studies have used sildenafil to increase CVR. Participants in the pilot study had CVR tested in response to hypercapnia measured twice, at baseline and then 1 hour after administration of sildenafil citrate, 50 mg by mouth. The investigators have an IND exemption for the uses in this study. Other Names: Viagra Device: Functional Near Infared Spectroscopy Functional near-infrared spectroscopy (fNIRS) will be used to measure regional cerebral blood flow and cerebrovascular reactivity. are connected to the scalp and surrounding detectors a few cm away detect the light as it scatters through the underlying tissues. The technique is able to detect changes in the absorption spectrum of the tissue corresponding to the concentrations of oxyhemoglobin (HbO2) and deoxyhemoglobin (HbR), and indicate local perfusion changes. Other Names: fNIRS Other: Hypercapnia Challenge The study device is a Douglas Bag that traditionally is designed to measure respiratory exchange. It consists of large bag attached to a mouthpiece utilized to hold either expired air from the subject or filled with different concentrations of air to be aspired. For the purposes of this study, the Douglas Bag will be utilized to induce hypercapnia in the subject. The bag is equipped with a switch that allows rapid shifting from room air to 5% CO2 each minute over 7 minutes.

Arm

Intervention/Treatment

Acute TBI

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.

Drug: Sildenafil citrate

Sildenafil is a potent and specific PDE5 inhibitor, which was initially developed for the treatment of hypertension and angina. Its effectiveness as a treatment for male erectile dysfunction became apparent during Phase I clinical trials, and the focus of drug development shifted to this indication. In patients with cerebrovascular dysfunction, a few preliminary studies have used sildenafil to increase CVR. Participants in the pilot study had CVR tested in response to hypercapnia measured twice, at baseline and then 1 hour after administration of sildenafil citrate, 50 mg by mouth. The investigators have an IND exemption for the uses in this study.

Other Names:

Viagra

Device: Functional Near Infared Spectroscopy

Functional near-infrared spectroscopy (fNIRS) will be used to measure regional cerebral blood flow and cerebrovascular reactivity. are connected to the scalp and surrounding detectors a few cm away detect the light as it scatters through the underlying tissues. The technique is able to detect changes in the absorption spectrum of the tissue corresponding to the concentrations of oxyhemoglobin (HbO2) and deoxyhemoglobin (HbR), and indicate local perfusion changes.

Other Names:

fNIRS

Other: Hypercapnia Challenge

The study device is a Douglas Bag that traditionally is designed to measure respiratory exchange. It consists of large bag attached to a mouthpiece utilized to hold either expired air from the subject or filled with different concentrations of air to be aspired. For the purposes of this study, the Douglas Bag will be utilized to induce hypercapnia in the subject. The bag is equipped with a switch that allows rapid shifting from room air to 5% CO2 each minute over 7 minutes.

Sub-acute/Chronic TBI

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.

Drug: Sildenafil citrate

Other Names:

Viagra

Device: Functional Near Infared Spectroscopy

Other Names:

fNIRS

Other: Hypercapnia Challenge

Healthy Controls

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.

Drug: Sildenafil citrate

Other Names:

Viagra

Device: Functional Near Infared Spectroscopy

Other Names:

fNIRS

Other: Hypercapnia Challenge

Outcome Measures

Primary Outcome Measures

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

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Men and women, aged ≥18
CT evidence of TBI-linked abnormality

Traumatic subarachnoid hemorrhage
Intracerebral hemorrhage/contusion
Subdural/epidural hematoma

Ability to undergo fNIRS testing with hypercapnia challenge
Subject able to provide informed consent
Attending of record agrees to include subject in study

Exclusion Criteria:

Unstable respiratory or hemodynamic status
Evidence of penetrating brain injury
TBI requiring craniotomy or craniectomy
Evidence or risk of ICP crisis
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)
History of pre-existing disabling mental illness (e.g. major depression or schizophrenia)
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

Unstable cardiac status that constitutes a contraindication to sexual activity
Inability to read and communicate in English (necessary to obtain reliable neuropsychometric data)
Nursing mothers