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Method Article
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.
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.
NO inhalation therapy is regularly used as a life-saving treatment in several clinical settings1,2,3. 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 outcomes12,13,14. 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.
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
2. Building the Y-piece and preparation of the O2 supply
3. Building and attaching the scavenging chamber
4. Building and attaching the NO reservoir system
5. Building the NO and medical air supply 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.
7. Use in spontaneously breathing subjects
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 workers15,19. 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...
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 elsewhere16<...
L.B. receives salary support from K23 HL128882/NHLBI NIH as a principal investigator for his work on hemolysis and nitric oxide. L.B. receives technologies and devices from iNO Therapeutics LLC, Praxair Inc., Masimo Corp. L.B. receives a grant from iNO Therapeutics LLC. A.F. and L.T. reported funds from the German Research Foundation (DFG) F.I. 2429/1-1; TR1642/1-1. WMZ receives a grant from NHLBI B-BIC/NCAI (#U54HL119145), and he is on the scientific advisory board of Third Pole Inc., which has licensed patents on electric NO generation from MGH. All other authors have nothing to declare.
This study was supported by the Reginald Jenney Endowment Chair at Harvard Medical School to L.B., by L.B. Sundry Funds at MGH, and by laboratory funds of the Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care and Pain Medicine at MGH.
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 |
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