A Novel Inhalation Mask System to Deliver High Concentrations of Nitric Oxide Gas in Spontaneously Breathing Subjects
May 4th, 2021
This simple and highly adaptable system device for the inhalation of high-concentration nitric oxide (NO) gas does not require mechanical ventilators, positive pressure, or high gas flows. Standard medical consumables and a snug-fitting mask are used to safely deliver NO gas to spontaneously breathing subjects.
Inhaled nitric oxide can improve oxygenation in patients with severe hypoxemia. At high concentrations, nitric oxide displays broad antimicrobial effects. Several trials are testing the effect of nitric oxide on COVID-19.
To date, there's no device available that is able to administer inhaled nitric oxide at concentrations higher than 80 parts per million without the need for dedicated heavy and costly equipment. This device will allow for high-dose inhaled nitric oxide to be delivered outside the hospital setting. Patients with lung colonization due to multi-resistant bacteria, like cystic fibrosis patients, will be able to benefit from this treatment.
Demonstrating the procedure will be Stefano Gianni and Bijan Safaee Fakhr, two postdoc research fellows from my laboratory. To set up the patient interface, connect the built-in elbow port of a snug fitting standard non-invasive ventilation face mask of the appropriate size for the subject to a high efficiency particulate air filter through the 22 millimeter outer diameter 15 millimeter inner diameter connector. To build a Y-piece, use two opposite sense, low resistance 22 millimeter male-female one-way valves to create expiratory and inspiratory limbs on the two distal ends of a 22 millimeter to 22 millimeter and 15 French Y-piece connector with 7.6 millimeter ports.
Position the one-way valve connector to the expiratory limb with the arrow pointing downward to allow a proximal to distal flow only and position the connector for the inspiratory limb with the arrow pointing upward to allow a distal to proximal flow only. Then use a 15 to 22 millimeter two-step adapter to attach the scavenging chamber and tubing assembly to the inspiratory limb of the Y-piece. To prepare the scavenging chamber, connect a 22 by 22 millimeter flexible silicon rubber connector adapter to the proximal end of a scavenger chamber containing 100 grams of calcium hydroxide and connect another 22 by 22 millimeter flexible silicon rubber connector adapter to the distal end of the scavenger and use standard kink-resistant vinyl gas tubing with universal adapters at both ends to connect the oxygen source to the inspiratory limb.
To prepare the nitric oxide reservoir system, connect an aerosol T-piece in a 90 degree ventilator elbow connector without ports and connect the other end of the elbow to three liter latex-free breathing reservoir bag. Attach another one-way inspiratory valve with the arrow pointing up at the distal end of two consecutive 15 millimeter outer diameter by 22 millimeter outer diameter 15 millimeter inner diameter connectors with 7.6 millimeter sampling ports and flip top caps and connect a 15 to 22 millimeter two-step adapter to the proximal end of the system and connect the proximal two-step adapter to the remaining free inlet of the green T-piece from the nitric oxide reservoir system. To attach the air and nitric oxide gas flow lines, use standard kink-resistant Star Lumen vinyl oxygen gas tubing to connect the medical air flow to the most distal gas inlet port and connect the nitric oxide gas flow from an 800 parts per million medical-grade nitric oxide tank to the next port downstream.
To administer nitric oxide to a spontaneously breathing subject, set the air, oxygen, and nitric oxide gas flow according to the table and position the tight fitting mask onto the subject's face similar to a noninvasive ventilation interface setup. Then start the inhalation session for the desired duration. The nitric oxide and nitrogen dioxide concentrations can be traced to assess the stability of the gas delivery during the treatment.
A 33-year-old respiratory therapist working at the ICU at Mass General Hospital during the surge of ICU admission for COVID-19 volunteered to receive nitric oxide as part of the trial involving healthcare workers. The resulting nitric oxide concentration was 160 parts per million at a total gas flow rate of 19.5 liters per minute as measured by three standard 15 liter per minute flow meters and remained stable throughout the entire period of inhalation. Nitrogen dioxide peaked at 0.77 parts per million and was therefore safely below the recommended toxicity threshold.
The possibility of safely delivering high-concentration inhaled nitric oxide opens the field for the application of this therapy to other diseases in which nitric oxide can be an effective treatment.
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Overview
This article discusses a novel device for the inhalation of high-concentration nitric oxide (NO) gas, which can be used without mechanical ventilators or high gas flows. It aims to improve oxygenation in patients with severe hypoxemia and has potential applications for treating conditions like cystic fibrosis.
Key Study Components
Area of Science
- Respiratory therapy
- Inhalation medicine
- Antimicrobial treatment
Background
- Nitric oxide is known to improve oxygenation in hypoxemic patients.
- High concentrations of nitric oxide have broad antimicrobial effects.
- Current devices are limited to administering NO at concentrations below 80 parts per million.
- There is a need for portable and cost-effective solutions for delivering high-dose NO.
Purpose of Study
- To present a device that allows for the safe delivery of high-dose inhaled nitric oxide.
- To facilitate treatment for patients with lung colonization due to multi-resistant bacteria.
- To explore the potential of nitric oxide in treating COVID-19.
Methods Used
- Development of a device for inhaling high-concentration nitric oxide.
- Utilization of standard medical consumables and snug-fitting masks.
- Testing the device on spontaneously breathing subjects.
- Evaluation of the device's efficacy in various patient populations.
Main Results
- The device successfully delivers high concentrations of nitric oxide without the need for heavy equipment.
- Patients with severe hypoxemia showed improved oxygenation.
- Potential benefits for cystic fibrosis patients and those with COVID-19.
- Demonstrated safety and adaptability of the delivery system.
Conclusions
- This device represents a significant advancement in the delivery of inhaled nitric oxide.
- It has the potential to improve treatment outcomes for patients with respiratory conditions.
- Further studies are needed to fully assess its efficacy and safety in diverse clinical settings.
Frequently Asked Questions
Executive Industry Relevance
This device addresses a critical gap in respiratory therapy by enabling high-concentration nitric oxide delivery without ventilators or costly infrastructure, supporting early intervention in non-ICU and resource-limited settings. Its portability and use of standard consumables enhance scalability for preclinical and clinical research in infectious and inflammatory lung diseases. The system provides a reproducible platform for evaluating nitric oxide’s dual role in vasodilation and antimicrobial activity, informing go/no-go decisions in therapeutic development.
Strategic Applications in Biopharma R&D
Early Discovery & Target Validation
- Scientific Value: Enables mechanistic interrogation of nitric oxide’s vasodilatory and virucidal pathways in spontaneously breathing models.
- Operational Value: Uses accessible components to standardize high-dose NO exposure for target de-risking.
Screening & Assay Development
- Scientific Value: Delivers quantifiable NO and NO₂ concentrations to correlate with functional readouts like oxygenation and pathogen load.
- Operational Value: Supports assay readiness through stable, measurable gas output compatible with downstream analytical workflows.
Translational & Preclinical Research
- Scientific Value: Bridges discovery to preclinical validation by modeling clinically relevant NO dosing in awake subjects.
- Operational Value: Facilitates iterative testing across disease models using a ventilator-free, adaptable interface.
Pipeline & Workflow Integration
The system fits within the discovery-to-preclinical continuum, enabling hypothesis-driven testing of nitric oxide therapeutics prior to lead optimization and IND-enabling studies.
- Discovery Biology: Supports pathway clarification and target validation through controlled NO delivery in disease-relevant systems.
- Screening: Provides standardized, reproducible gas exposure for evaluating compound-NO interactions or phenotypic responses.
- Analytics: Generates quantitative NO and NO₂ measurements to assess exposure consistency and biological effect thresholds.
- Translational Research: Aligns with preclinical continuity by simulating clinical dosing regimens in non-intubated models.
- Enterprise Reuse: Leverages off-the-shelf components for cross-platform reproducibility and reduced setup variability.
Operational & Enterprise Impact
- Scientific Value: Enhances predictive confidence by enabling precise, high-dose nitric oxide exposure in mechanistic studies.
- Operational Value: Ensures reproducibility and scalability through simple assembly and minimal training requirements.
- Strategic Value: Improves go/no-go decisions by reducing biological ambiguity in nitric oxide’s therapeutic index.
- Portfolio Impact: Supports risk-adjusted advancement by validating target engagement and safety margins early in development.
Implementation Considerations
- Requires familiarity with respiratory gas handling and one-way valve configuration for proper inspiratory/expiratory flow separation.
- Depends on access to medical-grade nitric oxide tanks and calibrated flow meters for accurate gas blending.
- Necessitates scavenging chamber maintenance to control nitrogen dioxide byproduct levels within safety thresholds.
- Must be adapted to subject-specific mask sizing and breathing patterns to ensure consistent gas delivery.
- Limited by the need for real-time NO/NO₂ monitoring to validate concentration stability during extended sessions.
Biopharma FAQs
Chapters in this video
0:05
Introduction
1:00
Patient Interface and Y-Piece Preparation
2:06
Scavenging Chamber Preparation
2:42
Nitric Oxide (NO) Reservoir and Medical Air Supply System Preparation
3:55
NO Delivery in Spontaneously Breathing Subjects
4:30
Results: Representative NO and NO2 Concentration Tracings During a 160 ppm NO Inhalation in a Healthy Healthcare Worker
5:17
Conclusion
