A Novel Inhalation Mask System to Deliver High Concentrations of Nitric Oxide Gas in Spontaneously Breathing Subjects

Summary

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.

Abstract

Nitric Oxide (NO) is administered as gas for inhalation to induce selective pulmonary vasodilation. It is a safe therapy, with few potential risks even if administered at high concentration. Inhaled NO gas is routinely used to increase systemic oxygenation in different disease conditions. The administration of high concentrations of NO also exerts a virucidal effect in vitro. Owing to its favorable pharmacodynamic and safety profiles, the familiarity in its use by critical care providers, and the potential for a direct virucidal effect, NO is clinically used in patients with coronavirus disease-2019 (COVID-19). Nevertheless, no device is currently available to easily administer inhaled NO at concentrations higher than 80 parts per million (ppm) at various inspired oxygen fractions, without the need for dedicated, heavy, and costly equipment. The development of a reliable, safe, inexpensive, lightweight, and ventilator-free solution is crucial, particularly for the early treatment of non-intubated patients outside of the intensive care unit (ICU) and in a limited-resource scenario. To overcome such a barrier, a simple system for the non-invasive NO gas administration up to 250 ppm was developed using standard consumables and a scavenging chamber. The method has been proven safe and reliable in delivering a specified NO concentration while limiting nitrogen dioxide levels. This paper aims to provide clinicians and researchers with the necessary information on how to assemble or adapt such a system for research purposes or clinical use in COVID-19 or other diseases in which NO administration might be beneficial.

Introduction

NO inhalation therapy is regularly used as a life-saving treatment in several clinical settings^1,2,3. In addition to its well-known pulmonary vasodilator effect⁴, NO displays a broad antimicrobial effect against bacteria⁵, viruses⁶, and fungi⁷, particularly if administered at high concentrations (>100 ppm).⁸ During the 2003 Severe Acute Respiratory Syndrome (SARS) outbreak, NO showed potent antiviral activity in vitro and demonstrated therapeutic efficacy in patients infected with the SARS-Coronavirus (SARS-CoV)^9,10. The 2003 strain is structurally similar to SARS-Cov-2, the pathogen responsible for the current Coronavirus Disease-2019 (COVID-19) pandemic¹¹. Three randomized controlled clinical trials are ongoing in patients with COVID-19 to determine the potential benefits of breathing high-concentration NO gas to improve outcomes^12,13,14. In a fourth ongoing study, the prophylactic inhalation of high concentrations of NO is being investigated as a preventive measure against the development of COVID-19 in healthcare providers exposed to SARS-CoV-2-positive patients¹⁵.

The development of an effective and safe treatment for COVID-19 is a priority for the healthcare and scientific communities. To investigate the administration of NO gas at doses > 80 ppm in non-intubated patients and volunteering healthcare workers, the need to develop a safe and reliable non-invasive system became apparent. This technique aims to administer high NO concentrations at different fractions of inspired oxygen (FiO₂) to spontaneously breathing subjects. The methodology described here is currently in use for research purposes in spontaneously breathing COVID-19 patients at the Massachusetts General Hospital (MGH)^16,17. Following the guidelines of MGH's human research ethics committee, the proposed system is currently in use to conduct a series of randomized controlled trials to study the following effects of high concentrations of NO gas. First, the effect of 160 ppm NO gas is being studied in non-intubated subjects with mild-moderate COVID-19, admitted either in the Emergency Department (IRB Protocol #2020P001036)¹⁴ or as inpatients (IRB Protocol #2020P000786)¹⁸. Second, the role of high-dose NO is being examined to prevent SARS-CoV-2 infection and the development of COVID-19 symptoms in healthcare providers routinely exposed to SARS-CoV-2-positive patients (IRB Protocol # 2020P000831)¹⁹.

This simple device can be assembled with standard consumables routinely used for respiratory therapy. The proposed apparatus is designed to non-invasively deliver a mixture of NO gas, medical air, and oxygen (O₂). Nitrogen dioxide (NO₂) inhalation is minimized to reduce the risk of airway toxicity. The current NO₂ safety threshold set by the American Conference of Governmental Industrial Hygienists is 3 ppm over an 8-h time-weighted average, and 5 ppm is the short-term exposure limit. Conversely, the National Institute for Occupational Safety and Health recommends 1 ppm as a short-term limit of exposure²⁰. Given the increasing interest in high-dose NO gas therapy, the present report provides the necessary description of this novel device. It explains how to assemble its components to deliver a high concentration of NO for research purposes.

Protocol

NOTE: See the Table of Materials for the materials needed to assemble the delivery system. Sources of medical air, O₂, and NO gases should also be available on site. The device has been developed for investigation use in research protocols that underwent rigorous review by the local Institutional Review Board (IRB). Under no circumstances should providers operate solely based on the indications included in this manuscript, assembling and using this device without seeking prior appropriate institutional regulatory approval. Starting from the proximal end of the device, assemble the pieces in the following order (Figure 1).

1. Building the patient interface

1. Take a snug-fitting, standard, non-invasive ventilation face mask of the appropriate size for the subject.
2. Connect the mask's built-in elbow port to a high-efficiency particulate air (highly hydrophobic bacterial/viral filter, HEPA class 13) filter through the 22 mm outer diameter (O.D.)/15 mm inner diameter (I.D.) connector.
3. (Optional) To facilitate the subject's movement and reduce the risk of disconnection, add a 15 mm O.D. x 22 mm O.D./15 mm I.D. (length 5 cm-6.5 cm) flexible patient connector for an endotracheal or tracheostomy tube between the mask interface and the HEPA filter.
   ​NOTE: Make every effort to avoid leakage of the mask interface. The "patient end" of the device could also consist of a mouthpiece. A nose clip must be added in such a configuration.

2. Building the Y-piece and preparation of the O₂ supply

1. Take a 22 mm to 22 mm and 15 F Y-piece connector with 7.6 mm ports. Create the circuit's expiratory and inspiratory limbs on the two distal ends of the Y-piece through two opposite-sense, low-resistance, 22 mm male/female, one-way valves.
   1. Expiratory limb: On one end of the Y-piece, place the one-way valve connector allowing a proximal-to-distal flow only (arrow pointing downward).
   2. Inspiratory limb: On the other end of the Y-piece, connect a one-way valve allowing a distal-to-proximal flow only (arrow pointing upward).
2. Connect the proximal end of the Y to the HEPA filter.
3. Using standard, kink-resistant, vinyl gas tubing with universal adaptors at both ends, connect the O₂ source to the Y-piece's inspiratory limb. Choose tubing of appropriate length considering the distance between the patient and the source of the gas.
   ​NOTE: The Y-piece connector must have a sampling port on the inspiratory limb. If not, an additional straight connector with a sampling port must be used to supply O₂.

3. Building and attaching the scavenging chamber

1. Connect a 22 mm x 22 mm silicon rubber, flexible connector adapter to the proximal end of a scavenger chamber (internal diameter = 60 mm, internal length = 53 mm, volume = 150mL) containing 100 g of calcium hydroxide (Ca(OH)₂).
2. Attach a 15 mm O.D. x 22 mm O.D./15 mm I.D., 5 cm-6.5 cm, flexible, corrugated tube to the silicon rubber adapter.
3. Connect another 22 mm x 22 mm silicon rubber, flexible connector adapter to the distal end of the scavenger.
4. Add the scavenging chamber and tubing assembly to the Y piece's inspiratory limb using a 15 mm-22 mm two-step adapter.

4. Building and attaching the NO reservoir system

1. Assemble a 3-L latex-free breathing reservoir bag and a 90° ventilator elbow connector without ports (22 mm ID x 22 mm).
2. Connect the other end of the elbow to the central opening of the aerosol T-piece (horizontal ports 22 mm O.D., vertical port 11 mm I.D./22 mm O.D.).
3. Attach the T-piece to the scavenging chamber's distal end by advancing it until it fits the silicon rubber connector tightly.

5. Building the NO and medical air supply system

1. Build the NO/air gas supply system by attaching two consecutive 15 mm O.D. x 15 mm I.D./22 mm O.D. connectors with 7.6 mm sampling ports and flip-top caps.
   NOTE: Once the caps are removed, the sampling accesses will function as gas inlet ports.
2. At the distal end of the NO/air supply system, attach another one-way inspiratory valve (arrow pointing upwards).
3. At the proximal end of the NO/air supply system, connect a 15/22 mm two-step adapter.
4. Connect the proximal two-step adapter to the remaining free inlet of the green T-piece from the NO reservoir system.

6. Attach the air and NO gas flow lines by using standard, kink-resistant, star-lumen vinyl oxygen gas tubing for the following steps.

1. Connect medical air to the most distal gas inlet port.
2. Connect NO gas from an 800 ppm medical-grade NO tank (size AQ aluminum cylinders containing 2239 L of 800 ppm of NO gas at standard temperature and pressure, balanced with nitrogen; delivered volume 2197 L) to the next port downstream.
   ​NOTE: Tubing must be of appropriate length to reach the gases' sources comfortably. Different tanks or generators of NO can be used as sources of gas.

7. Use in spontaneously breathing subjects

1. Set the air, O₂, and NO gas flow according to the desired FiO₂ and NO concentration.
   NOTE: The recommended flow rates for administering NO at 80, 160, or 250 ppm are listed in Table 1 (applicable to 800 ppm cylinders only).
2. Position the tight-fitting mask on the patient's face, similar to a non-invasive ventilation interface setup.
3. Start the inhalation session for the desired duration.

Results

A 33-year-old respiratory therapist working at the ICU at MGH during the surge of ICU admission for COVID-19 volunteered to receive NO as part of the trial involving healthcare workers^15,19. The trial tested the efficacy of 160 ppm of NO as a virucidal agent, thereby preventing disease occurrence in lungs at risk for viral contamination. The first session of the inhalation prophylaxis was administered before starting a shift throu...

Discussion

Given the increasing interest in NO gas therapy for non-intubated patients, including those with COVID-19⁸, the present report describes a novel custom device and how to assemble its components to deliver NO at concentrations as high as 250 ppm. The proposed system is built out of inexpensive consumables and safely delivers a reproducible concentration of NO gas in spontaneously breathing patients. The ease of assembly and use, together with the safety data published elsewhere^16<...

Materials

Name	Company	Catalog Number	Comments
90° ventilator elbow connector without ports 22 mm ID x 22 mm OD	Teleflex, Wayne, PA, USA	1641
Aerosol tee connector: horizontal ports 22 mm OD, vertical port 11 mm ID/22 mm OD	Teleflex, Wayne, PA, USA	1077
Flexible patient connector for endotracheal or tracheostomy tube (15 mm OD x 22 mm OD/15 mm ID, length 5 cm to 6.5 cm)	Vyaire Medical Inc., Mettawa, IL, USA	3215
High-efficiency particulate air (highly hydrophobic bacterial/viral filter,  HEPA class 13) filter (22 mm ID/15 mm OD x 22 mm OD/15 mm ID connector)	Teleflex, Wayne, PA, USA	28012
Latex-free 3-L breathing reservoir bag	CareFusion, Yorba Linda, CA, USA	5063NL
Nitric Oxide tank 800 ppm medical-grade (size AQ aluminum cylinders containing 2239 L at STP of 800 ppm NO gas balanced with nitrogen, volume 2197 L)	Praxair, Bethlehem PA, USA	MM NO800NI-AQ
One-way valve 22 mm male/female (arrow pointing towards female end)	Teleflex, Wayne, PA, USA	1664	N=2 inspiratory limb (upward arrow)
One-way valve 22 mm male/female (arrow pointing towards male end)	Teleflex, Wayne, PA, USA	1665	N=1 expiratory limb (downward arrow)
Rad-57 Handheld Pulse Oximeter with Rainbow SET Technology	Masimo Corporation, Irvine, CA, USA	3736	Including SpMet Option
Scavenger (ID = 60 mm, internal length = 53 mm, volume = 150 mL) containing 100 g of calcium hydroxide	Spherasorb, Intersurgical Ltd, Berkshire, UK
Silicon rubber flexible connectors 22 mm F x 22 mm F	Tri-anim Health Services, Dublin, OH, USA	301-9000
Snug-fit standard face mask of appropriate size
Star Lumen standard medical grade vynil oxygen tubing with universal connectors	Teleflex, Morrisville, NC, USA	1115	Variable length according to distance from source of gas. 2.1 m length used in protocol
Straight connector with a 7.6 mm sampling port (15 mm OD x 15 mm ID/22 mm OD)	Mallinckrodt, Bedminster, NJ, USA	502041
Two-step adapter (15 mm to 22 mm)	Airlife Auburndale, FL, USA	1824
Y-piece connector with 7.6 mm ports (22 mm to 22 mm and 15 F)	Vyaire Medical Inc., Mettawa, IL, USA	1831