Inhaled Nitric Oxide for Microvascular Dysfunction in Traumatic Brain Injury

Sponsor

University of Pennsylvania (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05616910

Collaborator

(none)

Enrollment

Location

Arms

Anticipated Duration (Months)

1.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Traumatic brain injury (TBI) causes acute deficits in cerebral perfusion which may lead to secondary injury and worse outcomes. Inhaled nitric oxide (iNO) is a vasodilator that increases cerebral blood flow and is clinically used for hypoxic respiratory failure in neonates and adults. The investigators will perform a randomized controlled trial of iNO treatment in TBI patients acutely after injury. The investigators will then assess perfusion changes with optic neuromonitoring, blood biomarkers, and 6 month clinical outcomes.

Condition or Disease	Intervention/Treatment	Phase
Traumatic Brain Injury	Drug: inhaled nitric oxide	Phase 2

Detailed Description

The objective of this study is to show that inhaled nitric oxide can increase blood flow in the brain after traumatic brain injury, attenuating brain injury and resulting in improved long-term function.

The investigators will use optical brain monitoring to determine changes in cerebral perfusion and metabolism by iNO treatment in TBI subjects. Within 24 hours of enrollment, TBI subjects meeting the inclusion criteria without exclusion criteria will undergo 8 hour sessions of monitoring (4 hours on iNO, 4 hours on standard respiratory therapy) for 3 days. During this time, Noninvasive Neuro-optic Monitoring (NNOM) device will be placed on the scalp and cerebral perfusion and metabolism parameters will be monitored to assess for therapeutic effect of iNO. There will be within-subject comparison of cerebral perfusion and metabolism on and off iNO. Also, there will be within-group comparison of cerebral perfusion and metabolism on days when iNO is given first vs days when iNO is given at a second session. Additionally, these parameters from this group will compared to a parallel group of TBI patients receiving 8 hours of only standard respiratory therapy for 3 days.

The investigators will assess the safety profile of iNO use in TBI subjects. During the course of iNO therapy in the initial 3 days, study subjects will be monitored for methemoglobinemia, hypotension, neurological exam changes, and any other adverse events. These outcomes will be monitored for 2 weeks following the iNO treatment. Additionally, the investigators will assess blood-based biomarkers of injury with blood draws at the end of each iNO treatment session in TBI subjects for 3 days. During the initial three days of the trial, blood draws will be performed at the end of each session to detect biomarkers. Specifically, biomarkers that have been shown to correlate with injury severity such as GFAP, NFL, UCHL-1, tau, and S100B will be monitored at the end of iNO session and standard respiratory therapy session. This will be performed by using a novel assay termed SIMOA, a sensitive detection method for blood-based biomarkers.

As an exploratory aim, the investigators will compare 6-month GOS-E outcomes of the patients who received iNO to those who received standard respiratory therapy. Patients will be assessed for their functional status at the time of 6 month follow up. Each patient in this study will be compared to a patient who had similar demographic background, mechanism of injury (fall, motor vehicle crash, assault), and severity of injury (based on Glasgow Coma Scale) from an existing database.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

38 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Inhaled Nitric Oxide for Microvascular Dysfunction in Traumatic Brain Injury

Anticipated Study Start Date :

Aug 1, 2023

Anticipated Primary Completion Date :

Feb 1, 2026

Anticipated Study Completion Date :

Jul 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group A Subjects will receive iNO for 4 hours, followed by standard respiratory support (SRS) for 4 hours. This pattern will be reversed the next day (SRS then iNO). on the following day, the pattern will be reversed back to iNO for 4 hours and SRS for 4 hrs.	Drug: inhaled nitric oxide iNO will be provided by ventilator or nasal cannula for 4 hours each day. Other Names: standard respiratory therapy vs iNO
Experimental: Group B Subjects will receive iNO for 4 hours, followed by standard respiratory support (SRS) for 4 hours. This pattern will be reversed the next day (SRS then iNO). on the following day, the pattern will be reversed back to iNO for 4 hours and SRS for 4 hrs.	Drug: inhaled nitric oxide iNO will be provided by ventilator or nasal cannula for 4 hours each day. Other Names: standard respiratory therapy vs iNO

Arm

Intervention/Treatment

Experimental: Group A

Subjects will receive iNO for 4 hours, followed by standard respiratory support (SRS) for 4 hours. This pattern will be reversed the next day (SRS then iNO). on the following day, the pattern will be reversed back to iNO for 4 hours and SRS for 4 hrs.

Drug: inhaled nitric oxide

iNO will be provided by ventilator or nasal cannula for 4 hours each day.

Other Names:

standard respiratory therapy vs iNO

Experimental: Group B

Drug: inhaled nitric oxide

iNO will be provided by ventilator or nasal cannula for 4 hours each day.

Other Names:

standard respiratory therapy vs iNO

Outcome Measures

Primary Outcome Measures

Cerebral Metabolism assessed by Spectroscopy [3 days]
Metabolic Rate of oxygen consumption by the brain measured by diffuse correlation spectroscopy and time-resolved infrared-spectroscopy.

Secondary Outcome Measures

Incidence of Inhaled Nitric Oxide induced methemoglobinemia [14 days]
Methemoglobin levels of blood greater than 1%
Incidence of Inhaled Nitric Oxide induced hypotension [14 days]
Blood pressure less than 90/60 mmHg for 30 minutes or longer
Incidence of Inhaled Nitric Oxide induced neurological deterioration [14 days]
Glasgow coma scale decrease of 2 or more points.
Blood-based biomarkers of injury [3 days]
Levels of neurofilament-light, glial fibrillary acidic protein, tau, ubiquitin carboxy-terminal hydrolase L1 (all biomarkers are in units of pg/mL)
Long term functional outcome [6 months]
Glasgow Outcome Scale Extended (GOS-E) (range: 1-8, 1: death, 8: good recovery).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age 18-75 (inclusive)
Male or Female
GCS 9-12 or GCS 13-15 with an abnormal imaging scan
Loss of consciousness for 30 minutes to 24 hours
Post traumatic amnesia 1 day
Radiologic findings indicative of primarily diffuse TBI
Both Intubated and nonintubated patients

Exclusion Criteria:

Severe cardiac dysfunction (e.g. elevation of pulmonary edema on chest xray, large elevation of cardiac enzymes)
Large focal injury (subdural hematoma, epidural hematoma, intraparenchymal hematoma 30mL aggregate volume)
Need for immediate neurosurgical intervention
Pre-existing disabling psychiatric or neurological disorders such as cortical stroke, brain tumor, disabling multiple sclerosis, dementia, and severe TBI
Known intracranial large vessel disease
Acute Respiratory Distress Syndrome (ARDS) or pre-existing pulmonary hypertension
Cardiopulmonary resuscitation or cardioversion at admission
Transfusion at admission
Chronic Kidney Disease (Glomerular Filtration Rate 60mL/min/1.73m2)