Nitric Oxide for Acute Respiratory Distress Syndrome

Recruiting in Palo Alto (17 mi)

Overseen by Maurizio Cereda, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Academic

Recruiting

Sponsor: Massachusetts General Hospital

Disqualifiers: Pregnancy, Pneumothorax, Chronic lung disease, others

No Placebo Group

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

Acute respiratory distress syndrome (ARDS) is when a person's lungs become inflamed, which can be caused by infection, trauma, surgery, blood transfusion, or burn. ARDS often leads to a situation where the person cannot breathe independently and needs machines' help. Once the lungs are inflamed, the small air sacs responsible for exchanging gases (i.e., ventilation) and the blood flow in the lungs (i.e., perfusion) can be affected. In the past, most research focused on studying ventilation physiology and how to help people breathe with machines. Less was done on perfusion because it requires imaging techniques such as computed tomography with intravenous contrast and radiation. One treatment option for low oxygen levels is inhaled nitric oxide (iNO), a gas that can dilate the lung blood vessels and improve oxygenation; however, it is not always clear whether this treatment will work. Electrical Impedance Tomography (EIT) is a bedside and accessible imaging technique that is radiation-free and non-invasive and can potentially detect changes in lung perfusion. EIT can perform multiple measurements; it is portable and accessible. This prospective interventional study aims to assess changes in regional blood perfusion in the lungs of patients with ARDS in response to iNO utilizing EIT. The main questions it aims to answer are: 1. If EIT can measure lung regional perfusion response to an iNO challenge of 20ppm for 15 minutes. 2. If EIT is comparable to dual-energy computed tomography (DECT), the gold-standard method to detect changes in regional lung perfusion. 3. If EIT can be an imaging marker to identify ARDS severity Participants will be divided into two cohorts: 1. Cohort 1 (n=60): Participants will be asked to be monitored by EIT before, during, and after the administration of iNO (20 ppm) for 15 minutes (OFF-ON-OFF) 2. Cohort 2 (N=10): Participants will be asked to be monitored by EIT and DECT before and during the administration of iNO (20 ppm) for 15 minutes (OFF-ON).

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you are using devices with electric current generation, such as a pacemaker, you cannot participate in the trial.

What data supports the effectiveness of the drug nitric oxide for treating acute respiratory distress syndrome?

Research shows that inhaled nitric oxide can improve oxygen levels and reduce high blood pressure in the lungs for patients with acute respiratory distress syndrome by helping blood flow to better-ventilated areas of the lungs. ^{1 2 3 4 5}

Is inhaled nitric oxide generally safe for humans?

Inhaled nitric oxide (iNO) has been used in various medical conditions, but there are concerns about its safety, particularly regarding potential kidney issues and other side effects. Some studies have raised warnings about possible renal (kidney) dysfunction and toxicity from iNO and its derivatives. ^{6 7 8 9 10}

How does the drug nitric oxide work differently for acute respiratory distress syndrome?

Nitric oxide is unique because it is inhaled and acts as a selective pulmonary vasodilator, meaning it specifically widens blood vessels in the lungs to improve oxygenation. This is different from other treatments that may not target the lungs as directly or selectively. ^{1 4 8 11 12}

Research Team

Maurizio Cereda, MD

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

This trial is for adults over 18 who are in the ICU, intubated and on a ventilator due to mild to moderate ARDS. They must have an arterial line and central line already in place.

Inclusion Criteria

I have an arterial line and a central line in place.

I have been diagnosed with ARDS of mild to moderate severity.

I am an adult on a breathing machine in the ICU.

Exclusion Criteria

Left ventricle ejection fraction <20%

I am either younger than 18 or older than 80.

Hypernatremia (serum sodium > 150 mEq/L)

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive inhaled nitric oxide (iNO) challenge and are monitored using EIT and DECT

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Nitric Oxide (Vasodilator)

Trial Overview The study tests if inhaling nitric oxide (iNO) improves blood flow in the lungs of ARDS patients using Electrical Impedance Tomography (EIT), compared with dual-energy computed tomography (DECT).

Participant Groups

Group I: Electrical Impedance Tomography and Dual-Energy Computed Tomography Experimental Treatment 1 Intervention

In a subset of 10 subjects (cohort 2), EIT and DECT will be performed in a row at the same type of bed and body position. In cohort 2, the measurements will be before nitric oxide (iNO) and during iNO. The OFF-ON fashion for DECT imaging is to minimize the subject's exposure to radiation and reduce the time spent in the CT room.

Group II: Electrical Impedance Tomography Experimental Treatment 1 Intervention

A total of 60 subjects (cohort 1) will receive an inhaled nitric oxide (iNO) challenge (20 ppm) for 15 min. The investigators will measure ventilation and perfusion distributions using EIT before iNO ("OFF1"), after 15 min on iNO ("ON"), and after 15 min washout ("OFF2") to confirm baseline stability.

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

Dr. William Curry

Massachusetts General Hospital

Chief Medical Officer

MD from Harvard Medical School

Dr. Anne Klibanski

Massachusetts General Hospital

Chief Executive Officer since 2019

MD from Harvard Medical School

Findings from Research

Inhaled nitric oxide can improve oxygenation in patients with acute respiratory distress syndrome (ARDS) by vasodilating well-ventilated areas of the lung, making it a potential therapeutic option.

Despite its benefits, nitric oxide is a highly reactive molecule with both positive and negative biological effects, and its use in ARDS remains experimental, highlighting the need for further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy of inhaled nitric oxide in the treatment of acute respiratory distress syndrome. An evidence-based medicine approach. Greene, JH., Klinger, JR.[2019]

Inhaled nitrogen monoxide (NO) significantly improved levels of key angiokinetic factors and clinical symptoms in patients with acute high altitude disease, as shown in a study of 47 patients comparing NO treatment to routine medical care.

The treatment with inhaled NO led to a notable increase in serum NO and 6-Keto-PGF(1a) levels, while decreasing harmful factors like endothelin and thromboxane B(2), suggesting a beneficial mechanism for managing high altitude sickness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The effect of inhaled nitric oxide on endothelium-derived angiokinetic factors in patients with acute high altitude disease]. Zheng, BH., Li, SZ., He, Y., et al.[2013]

Inhaled nitric oxide (NO) significantly improved oxygen levels and reduced pulmonary artery pressure in 6 patients with severe ARDS during a 30-minute treatment, indicating its potential benefits for gas exchange and pulmonary hypertension.

The study suggests that short-term inhalation of NO is likely safe, as toxic byproducts remained below harmful levels, but further research is needed to assess the safety and efficacy of long-term NO use in ARDS patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Nitrous oxide (NO) in the treatment of adult respiratory distress syndrome]. Ricou, B., Grandin, S., Jolliet, P., et al.[2020]

Inhaled nitric oxide (NO) has shown promise in selectively dilating blood vessels in the lungs, which could help manage acute respiratory distress syndrome (ARDS) based on research over the past decade.

However, while inhaled NO may benefit lung injuries, its effects on multi-system failure are still unclear, and more clinical trials are needed to assess its safety, side effects, and overall effectiveness in treating ARDS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhaled nitric oxide: a possible therapy for ARDS. Camsooksai, J.[2020]

In a study involving anesthetized pigs with endotoxin-induced lung injury, lower levels of endothelin-1 (ET-1) were associated with a lack of response to inhaled nitric oxide (INO), suggesting ET-1 may play a role in determining who benefits from INO treatment.

The research indicates that monitoring ET-1 levels could help predict which patients are likely to respond to INO, as responders had significantly higher ET-1 levels compared to nonresponders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association between inflammatory mediators and response to inhaled nitric oxide in a model of endotoxin-induced lung injury. Trachsel, S., Deby-Dupont, G., Maurenbrecher, E., et al.[2018]

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]

Nitric oxide (NO) is identified as a key endothelium-derived relaxing factor (EDRF) that regulates smooth muscle tone and platelet behavior, with its release being significantly inhibited by N omega-Monomethylarginine (N-MeArg), suggesting its crucial role in vascular relaxation.

The study demonstrated that the relaxation effect induced by histamine and acetylcholine in the guinea pig pulmonary artery is dependent on EDRF, and that this effect can be reversed by L-arginine, indicating that EDRF likely originates from arginine metabolism in the endothelium.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of arginine as a precursor of endothelium-derived relaxing factor. Sakuma, I., Stuehr, DJ., Gross, SS., et al.[2022]

The study demonstrates that endothelium-derived relaxing factor (EDRF) is chemically and biologically identical to nitric oxide (NO), as both substances produce similar effects on vascular smooth muscle relaxation and cyclic GMP accumulation.

Both EDRF and NO are unstable and share similar mechanisms of action, being inactivated by certain agents and stabilized by superoxide dismutase, indicating that NO is likely the primary mediator of EDRF's vasodilatory effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Ignarro, LJ., Buga, GM., Wood, KS., et al.[2022]

Inhaled nitric oxide (iNO) significantly improved oxygenation in children with acute respiratory distress syndrome (ARDS), with no significant difference in effectiveness between low (1 ppm) and higher concentrations (10 and 20 ppm).

The study found no evidence of toxicity from methaemoglobinaemia or nitrogen dioxide during iNO administration, suggesting that using lower concentrations may help minimize potential side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomised trial of three doses of inhaled nitric oxide in acute respiratory distress syndrome. Tang, SF., Sherwood, MC., Miller, OI.[2019]

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]

Nitric oxide (NO) in solution can relax blood vessels similarly to the endothelium-derived relaxant factor (EDRF), suggesting a potential role for NO in vascular health.

However, evidence indicates that NO and EDRF may not be the same, as they show different effects in non-vascular smooth muscles and interact differently with certain materials, raising questions about their identities and mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

What is the relationship between the endothelium derived relaxant factor and nitric oxide? Long, CJ., Berkowitz, BA.[2019]

Inhaled nitric oxide (NO) therapy was safely administered to 11 burned children with severe acute respiratory distress syndrome (ARDS), showing an average improvement of 162% in the PaO2/FiO2 ratio, which indicates better oxygenation.

The study suggests that a quick response to inhaled NO, measured by the improvement in the PaO2/FiO2 ratio within the first hour, may be linked to higher survival rates, as 73% of the children survived the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-dose inhaled nitric oxide in acutely burned children with profound respiratory failure. Sheridan, RL., Zapol, WM., Ritz, RH., et al.[2017]

References

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

The efficacy of inhaled nitric oxide in the treatment of acute respiratory distress syndrome. An evidence-based medicine approach. [2019]

2. China pubmed.ncbi.nlm.nih.gov

[The effect of inhaled nitric oxide on endothelium-derived angiokinetic factors in patients with acute high altitude disease]. [2013]

3. Switzerland pubmed.ncbi.nlm.nih.gov

[Nitrous oxide (NO) in the treatment of adult respiratory distress syndrome]. [2020]

4. England pubmed.ncbi.nlm.nih.gov

Inhaled nitric oxide: a possible therapy for ARDS. [2020]

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

Association between inflammatory mediators and response to inhaled nitric oxide in a model of endotoxin-induced lung injury. [2018]

6. 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]

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

Identification of arginine as a precursor of endothelium-derived relaxing factor. [2022]

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

Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Randomised trial of three doses of inhaled nitric oxide in acute respiratory distress syndrome. [2019]

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

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

11. Netherlands pubmed.ncbi.nlm.nih.gov

What is the relationship between the endothelium derived relaxant factor and nitric oxide? [2019]

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

Low-dose inhaled nitric oxide in acutely burned children with profound respiratory failure. [2017]