Inhaled Nitric Oxide for Traumatic Brain Injury

Overseen By Ramon Diaz-Arrastia

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Pennsylvania

Must not be taking: Nitric oxide donors

Disqualifiers: Severe cardiac dysfunction, Large focal injury, Disabling psychiatric disorders, Intracranial vessel disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 4 days

38 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it mentions possible drug interactions with nitric oxide donors like prilocaine, sodium nitroprusside, and nitroglycerin. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug inhaled nitric oxide for traumatic brain injury?

Inhaled nitric oxide has been reported to help decrease intracranial pressure (pressure inside the skull) in patients with traumatic brain injury and acute respiratory distress syndrome, possibly by reducing inflammation, which may lead to better outcomes. ^{1 2 3 4 5}

Is inhaled nitric oxide generally safe for humans?

Inhaled nitric oxide (iNO) has been used safely in various medical settings, including critical care transport and treatment of premature infants. Some studies have noted potential side effects like low blood pressure and kidney issues, but these are often manageable with proper medical supervision. ^{2 3 4 6 7}

How does the drug inhaled nitric oxide differ from other treatments for traumatic brain injury?

Inhaled nitric oxide is unique because it may reduce inflammation and decrease intracranial pressure in patients with traumatic brain injury, especially when complicated by acute respiratory distress syndrome. This anti-inflammatory mechanism and its administration as an inhaled gas set it apart from other treatments. ^{1 3 4 5 8}

Research Team

Samuel Shin

Principal Investigator

Assistant Professor

Eligibility Criteria

Adults aged 18-75 with moderate traumatic brain injury (TBI), evidenced by specific criteria such as post-traumatic amnesia, loss of consciousness for a certain time, and particular radiologic findings. Patients both on breathing support and not are included. Excluded are those with severe heart issues, known large vessel brain disease, lung conditions like ARDS or pulmonary hypertension, serious kidney disease, immediate need for brain surgery, or pre-existing major psychiatric/neurological disorders.

Inclusion Criteria

I experienced memory loss for a day after an injury.

Loss of consciousness for 30 minutes to 24 hours

Radiologic findings indicative of primarily diffuse TBI

Exclusion Criteria

I do not have severe heart problems.

I currently have a respiratory infection.

I have a large brain bleed.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

Within 24 hours

Treatment

Participants receive inhaled nitric oxide (iNO) treatment and standard respiratory therapy in alternating 4-hour sessions over 4 days

4 days

Daily monitoring sessions

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of blood-based biomarkers and functional status

6 months

1 visit (in-person) at 6 months

Treatment Details

Interventions

• Inhaled Nitric Oxide

Trial Overview The trial is testing inhaled nitric oxide (iNO), a gas that widens blood vessels to improve blood flow in the brain after TBI. Participants will be randomly assigned to receive iNO soon after their injury. The study will monitor changes in blood flow using optic neuromonitoring and measure recovery outcomes up to six months later.

Participant Groups

Group I: Group B Experimental Treatment 1 Intervention

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.

Group II: Group A Experimental Treatment 1 Intervention

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.

Inhaled Nitric Oxide is already approved in United States, European Union for the following indications:

Approved in United States as INOmax for:

• Hypoxic respiratory failure
• Pulmonary hypertension

Approved in United States as Genosyl for:

• Hypoxic respiratory failure
• Pulmonary hypertension

Approved in European Union as INOmax for:

• Persistent pulmonary hypertension of the newborn
• Acute hypoxic respiratory failure

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

Findings from Research

Inhaled nitric oxide (iNO) significantly improved oxygen levels in patients with severe hypoxemia, with arterial oxygen partial pressure (PaO2) increasing from 60.7 to 72.3 mm Hg after treatment (P=.008).

The use of iNO allowed for safe transport of patients to a tertiary care center, with 60.2% of those treated surviving to discharge, compared to a 50% survival rate in patients transported without iNO.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhaled nitric oxide to improve oxygenation for safe critical care transport of adults with severe hypoxemia. Teman, NR., Thomas, J., Bryner, BS., et al.[2020]

The implementation of clinical guidelines for inhaled nitric oxide (iNO) therapy in a pediatric intensive care unit led to a significant reduction in the duration of iNO treatment, from a median of 162 hours to 76 hours, without compromising patient care.

Following the guidelines, there was a notable cost savings of $4,600 per patient, demonstrating that standardized protocols can enhance efficiency and reduce unnecessary expenses in iNO therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Quality Improvement Initiative to Standardize Use of Inhaled Nitric Oxide in the PICU. Karsies, TJ., Evans, L., Frost, R., et al.[2022]

Inhaled nitric oxide (iNO) can be safely managed by trained nurses during the transport of critically ill patients, as demonstrated by a study involving patients transported from March 2020 to August 2022.

Out of the patients studied, only 16.7% experienced hypotension, which was manageable and resolved with medication adjustments, while no serious adverse events like worsening hypoxemia or cardiac arrest were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of Nurse-Managed Inhaled Nitric Oxide During Critical Care Interfacility Transport. Troncoso, R., Garfinkel, EM., Kaul, K., et al.[2023]

In a study of 860 premature infants under 32 weeks, low-dose inhaled nitric oxide (iNO) did not significantly improve intact survival at 28 days compared to placebo, with survival rates of 61.4% for iNO and 61.1% for controls.

The use of iNO was found to be safe, showing no significant differences in major complications like intraventricular hemorrhage, necrotizing enterocolitis, or patent ductus arteriosus compared to controls, suggesting it does not increase the risk of these side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety and efficacy of nitric oxide therapy in premature infants. Hascoet, JM., Fresson, J., Claris, O., et al.[2016]

Inhaled nitric oxide (iNO) therapy significantly increases the risk of renal dysfunction in patients with acute respiratory distress syndrome (ARDS), with an adjusted hazard ratio of 1.59 after accounting for confounding factors.

Older patients (aged 65 and above) are particularly vulnerable to kidney injury associated with iNO therapy, highlighting the need for careful monitoring in this demographic.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhaled nitric oxide and the risk of renal dysfunction in patients with acute respiratory distress syndrome: a propensity-matched cohort study. Ruan, SY., Wu, HY., Lin, HH., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Inhaled nitric oxide to improve oxygenation for safe critical care transport of adults with severe hypoxemia. [2020]

2. United States pubmed.ncbi.nlm.nih.gov

A Quality Improvement Initiative to Standardize Use of Inhaled Nitric Oxide in the PICU. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Safety of Nurse-Managed Inhaled Nitric Oxide During Critical Care Interfacility Transport. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Inhaled nitric oxide in premature infants: effect on tracheal aspirate and plasma nitric oxide metabolites. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Successful use of inhaled nitric oxide to decrease intracranial pressure in a patient with severe traumatic brain injury complicated by acute respiratory distress syndrome: a role for an anti-inflammatory mechanism? [2021]

6. United States pubmed.ncbi.nlm.nih.gov

The safety and efficacy of nitric oxide therapy in premature infants. [2016]

7. England pubmed.ncbi.nlm.nih.gov

Inhaled nitric oxide and the risk of renal dysfunction in patients with acute respiratory distress syndrome: a propensity-matched cohort study. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

The influence of inhaled nitric oxide on cerebral blood flow and metabolism in a child with traumatic brain injury. [2019]