Inhaled Nitric Oxide for Microvascular Dysfunction in Traumatic Brain Injury

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.

Study Overview

• Status: Enrolling by invitation
• Conditions: Traumatic Brain Injury
• Intervention / Treatment: Drug: inhaled nitric oxide

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 4 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 4 days.

The investigators will assess the safety profile of iNO use in TBI subjects. During the course of iNO therapy in the initial 4 days, study subjects will be monitored for methemoglobinemia, hypotension, renal failure, neurological exam changes, and any other adverse events. 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 4 days. During the initial 4 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 and injury biomarkers 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.

• Study Type: Interventional
• Enrollment (Estimated): 38
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Penn Presbyterian Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Aged 18-75 (inclusive)
2. GCS 9-12 or GCS 13-15 with an abnormal imaging scan
3. Radiologic findings indicative of primarily diffuse TBI

Exclusion Criteria:

1. Severe cardiac dysfunction (e.g. elevation of pulmonary edema on chest xray, large elevation of cardiac enzymes)
2. Large focal injury (subdural hematoma, epidural hematoma, intraparenchymal hematoma, >30mL aggregate volume).
3. Need for immediate neurosurgical intervention
4. Pre-existing disabling psychiatric or neurological disorders such as cortical stroke, brain tumor, disabling multiple sclerosis, dementia, and severe TBI
5. Known intracranial vessel disease
6. Acute Respiratory Distress Syndrome (ARDS) or pre-existing pulmonary hypertension
7. Cardiopulmonary resuscitation or cardioversion at admission
8. Chronic Kidney Disease (Glomerular Filtration Rate <60mL/min/1.73m2)
9. Respiratory Infection
10. Prisoners, patients in police custody, pregnant women
11. Possible drug interactions (nitric oxide donors: prilocaine, sodium nitroprusside, nitroglycerin)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group iNO; 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
Sham Comparator: Group SRS; Subjects will receive standard respiratory support (SRS) for 8 hours.	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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cerebral Metabolism assessed by Spectroscopy	Metabolic Rate of oxygen consumption by the brain measured by diffuse correlation spectroscopy and time-resolved infrared-spectroscopy.	4 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Long term functional outcome	Glasgow Outcome Scale Extended (GOS-E) (range: 1-8, 1: death, 8: good recovery).	6 months
Incidence of Inhaled Nitric Oxide induced methemoglobinemia	Methemoglobin levels of blood greater than 1%	4 days
Incidence of Inhaled Nitric Oxide induced hypotension	Blood pressure less than 90/60 mmHg for 30 minutes or longer	4 days
Incidence of Inhaled Nitric Oxide induced neurological deterioration	Glasgow coma scale decrease of 2 or more points.	4 days
Blood-based biomarkers of injury	Levels of neurofilament-light, glial fibrillary acidic protein, tau, ubiquitin carboxy-terminal hydrolase L1 (all biomarkers are in units of pg/mL)	4 days, 6 months

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Investigators: Principal Investigator: Samuel Shin, Assistant Professor

Study record dates

Study Major Dates

• Study Start (Actual): April 6, 2025
• Primary Completion (Estimated): March 28, 2028
• Study Completion (Estimated): March 28, 2028

Study Registration Dates

• First Submitted: October 31, 2022
• First Submitted That Met QC Criteria: November 8, 2022
• First Posted (Actual): November 15, 2022

Study Record Updates

• Last Update Posted (Actual): June 17, 2026
• Last Update Submitted That Met QC Criteria: June 16, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: traumatic brain injury; nitric oxide; cerebral blood flow; hypoperfusion
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Craniocerebral Trauma; Trauma, Nervous System; Brain Injuries; Brain Injuries, Traumatic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Neurotransmitter Agents; Antioxidants; Protective Agents; Respiratory System Agents; Free Radical Scavengers; Anti-Asthmatic Agents; Bronchodilator Agents; Vasodilator Agents; Endothelium-Dependent Relaxing Factors; Gasotransmitters; Nitric Oxide
• Other Study ID Numbers: 851809

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No