Nitric Oxide for Acute Respiratory Distress Syndrome

Overseen By Roberta Ribeiro De Santis Santiago, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Massachusetts General Hospital

Disqualifiers: Pregnancy, Pneumothorax, Chronic lung disease, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 1 day

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if inhaled nitric oxide, a gas that helps open lung blood vessels, can improve oxygen levels in people with acute respiratory distress syndrome (ARDS), where inflamed lungs struggle to function properly. The study will use Electrical Impedance Tomography (EIT) to observe changes in lung blood flow with this treatment. Researchers will compare EIT with a more complex imaging method to assess if EIT can effectively track changes in lung health. Suitable candidates for this trial are adults in intensive care who are on a ventilator and have mild to moderate ARDS. As an unphased trial, this study offers a unique opportunity to contribute to innovative research that could enhance ARDS treatment.

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 prior data suggests that Electrical Impedance Tomography is safe for measuring lung perfusion in ARDS patients?

Research has shown that inhaled nitric oxide (iNO) is generally safe for patients with acute respiratory distress syndrome (ARDS), though some risks exist. In certain cases, iNO has been linked to a higher chance of kidney problems. However, a study with 50 patients, including 39 with ARDS related to COVID-19, found iNO to be practical and safe. While iNO can improve oxygen levels by widening blood vessels in the lungs, potential side effects should be considered. Those with kidney concerns should consult the trial team before deciding to join. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about using nitric oxide for Acute Respiratory Distress Syndrome (ARDS) because it offers a unique way to improve lung function. Unlike standard treatments that often involve mechanical ventilation and supportive care, nitric oxide is inhaled and works by directly relaxing the blood vessels in the lungs, which can enhance oxygenation quickly. This localized effect means it might help improve breathing in a targeted manner without systemic side effects. Additionally, the use of techniques like Electrical Impedance Tomography (EIT) and Dual-Energy Computed Tomography (DECT) in monitoring this treatment offers a new way to visualize and understand lung function, potentially leading to more personalized and effective treatment strategies.

What evidence suggests that this trial's treatments could be effective for ARDS?

Research has shown that inhaled nitric oxide (iNO) can aid individuals with acute respiratory distress syndrome (ARDS). Studies have found that iNO improves the coordination of air and blood flow in the lungs, raising blood oxygen levels. In severe ARDS cases, iNO increased arterial oxygen, easing patients' breathing. Additionally, iNO may reduce heart stress by enhancing lung blood flow. In this trial, participants will receive iNO to evaluate its effects on ventilation and perfusion distributions, offering a promising option for those with severe breathing issues due to ARDS. ^{1 2 3 4 6}

Who Is on the Research Team?

Maurizio Cereda, MD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

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%

Hypernatremia (serum sodium > 150 mEq/L)

Suspected pregnancy, pregnancy or less than six weeks postpartum

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Nitric Oxide

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).

How Is the Trial Designed?

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.

Nitric Oxide is already approved in United States for the following indications:

Approved in United States as Inomax for:

• Hypoxic respiratory failure in term and near-term neonates with pulmonary hypertension

Approved in United States as Noxivent for:

• Hypoxic respiratory failure in term and near-term neonates with pulmonary hypertension

Approved in United States as GeNOsyl for:

• Hypoxic respiratory failure in term and near-term neonates with pulmonary hypertension

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

Published Research Related to This Trial

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]

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 (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]

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]

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) 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]

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) 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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10402704/

Inhaled Nitric Oxide in Acute Respiratory Distress ... iNO seems a promising agent as it could improve the ventilation/perfusion mismatch, gas exchange impairment, and right ventricular failure, which are reported ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6464789/

Inhaled nitric oxide for acute respiratory distress syndrome ... The primary objective was to examine the effects of administration of inhaled nitric oxide on mortality in adults and children with ARDS.

3. sciencedirect.com sciencedirect.com/science/article/pii/S1130634323002568

Inhaled nitric oxide in adult patients with acute respiratory ... This review focuses on the therapeutic use of iNO in adult ARDS patients. We set out some recommendations for its use as rescue therapy against refractory ...

4. annalsofintensivecare.springeropen.com annalsofintensivecare.springeropen.com/articles/10.1186/s13613-023-01150-9

Inhaled nitric oxide in patients with acute respiratory distress ... Our study reports the benefits of iNO in improving arterial oxygenation in C-ARDS patients. This improvement seems more relevant in the most severe cases.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT06249633

Inhaled Nitric Oxide for ARDS-related Pulmonary ... Open-label pilot study of early inhaled nitric oxide (iNO) for patients developing de novo pulmonary hypertension during Acute Respiratory Distress Syndrome ( ...

6. atsjournals.org atsjournals.org/doi/10.1164/rccm.202304-0637OC

High-Dose Inhaled Nitric Oxide in Acute Hypoxemic ... The beneficial effects of inhaled NO therapy have been attributed to its ability to reduce intrapulmonary shunting (6), resulting in improved ...