Methemoglobin Concentration in High Dose Inhaled Nitric Oxide

Study Overview
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Brief Summary
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The goal of this clinical trial is to learn about the kinetic of methemoglobin in healthy subjects breathing high dose inhaled nitric oxide. The main questions it aims to answer are: What are the kinetics of methemoglobin formation at a maximum of 300 parts per million of nitric oxide and oxygen What are the kinetics of methemoglobin reduction after nitric oxide discontinuation Participants will be exposed to intermittent high dose inhaled nitric oxide at a maximum of 300 parts per million while being continuously monitored.

Detailed Description
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The current proposed physiologic study is a single center, open-label clinical trial in healthy subjects. The primary aim is to describe kinetics of methemoglobin (MetHb) formation and reduction during exposure to high dose inhaled nitric oxide (iNO) at a maximum of 300 parts per million in healthy volunteers. The investigators will also assess the contribution of increased cardiac output in relation to MetHb formation/reduction and of different inspired oxygen concentrations on the production of nitrogen dioxide (NO2). The study protocol consists of breathing iNO at a maximum of 300 parts per million (ppm) and two different FiO2 levels (i.e. 21% and 80%). The combination of iNO and FiO2 levels identifies 2 study cohorts; five different subjects will be enrolled for each cohort. The maximum number of volunteers enrolled in this clinical trial is 10 spontaneously breathing, awake, healthy subjects, divided in two groups (5 volunteers/group, 2 groups). The first 5 subjects will be exposed to iNO in a mixture of gas at 21% of FiO2, the second group of 5 patients will receive iNO a mixture of gas at 80% of FiO2. Each volunteer will be exposed to a maximum of 300 ppm of iNO at 3 times/day for 5 consecutive days. Thus, a maximum of 150 total iNO treatments will be administered (10 enrolled volunteers, 5 days, 3 treatments/day). On the fifth day of the study, the iNO administration will be performed during physical exercise that will increase the respiratory rate of the subject, in order to study the influence of the respiratory rate on the rate of MetHb formation. During each treatment period, a threshold of MetHb = 10% and/or inspiratory NO2 = 5 ppm (as defined by the OSHA, https://www.osha.gov/chemicaldata/21, last accessed on Oct 31, 2022) will be used as stopping criteria for gas inhalation. Also, iNO administration will be stopped at any time, regardless of the MetHb and NO2 levels, at the discretion of the subject.

Official Title
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Kinetics of Methemoglobin Concentration in Healthy Subjects Exposed to High Dose Inhaled Nitric Oxide

Conditions
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Healthy Subjects

Intervention / Treatment
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* Drug: Inhaled Nitric Oxide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 - 64 years-old volunteers. Body Mass Index (BMI) 18 - 30 kg/m2. Absence of current systemic and/or respiratory diseases. Capacity to consent to the study. Exclusion Criteria: Evidence of any physical, mental, and/or medical conditions that would make the proposed studies relatively more hazardous. Systemic and/or respiratory disease with or without any functional limitation. Left ventricle ejection fraction < 30%. Baseline MetHb ≥ 3% Other conditions of increased risk for MetHb formation: genetic diseases (e.g., glucose-6-phosphate dehydrogenase deficiency, cytochrome b5 reductase deficiency, sickle cell disease), significant anemia or baseline elevation in MetHb. History of transient ischemic attack or stroke. Active smoking and tobacco chewers. Volunteers may be enrolled if they quit smoking for more than 1 year and less than 10 pack years total. Any vaping/e-cigarettes use Excess alcohol use: more than ½ L/day of wine consumption or equivalent Current use of any recreational drugs (including the use of medical marijuana) or use of recreational drugs over the past year. Pregnancy determined by blood pregnancy test detecting presence of human chorionic gonadotropin (hCG). Less than six weeks postpartum. Any current medication uses except oral contraceptives. Lower respiratory infection within the last 30 days. Claustrophobia (inability to wear a facemask) or other active psychiatric conditions or unwillingness to cooperate with the investigators and other medical teams. Currently enrolled in another research study. Facial abnormalities that would preclude proper use of a face mask.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Interventional Model Description: Physiologic study in healthy volunteers
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nitric Oxide<br>High dose inhaled nitric oxide (targeting 250 ppm and not exceeding 300 ppm) in a nitrogen-oxygen-air mixture, at two different FiO2 levels (0.21 and 0.8) will be delivered intermittently with a dedicated system and a snug-fitting facemask to healthy volunteers three times per day for 5 days. The subjects will be monitored before, during and after the administration | Drug: Inhaled Nitric Oxide<br>* Inhaled nitric oxide (Medical grade, in NO/N2 tanks) will be delivered in a oxygen-air-nitrogen mixture for 30 minutes three times per day<br>* Other names: Gaseous Nitric Oxide;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Methemoglobin kinetics | Levels of methemoglobin formation and reduction during and after exposure to high dose inhaled nitric oxide | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nitric Oxide Metabolites | Measurement of Nitric Oxide metabolites (urinary and plasma) in subjects exposed to high dose iNO. | 7 days | 
| Nitrogen Dioxide | Inspiratory NO2 concentrations at different inspiratory concentrations of NO and O2 | 5 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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nitric oxide, methemoglobin, nitrogen dioxide