Name: a novel inhalation mask system to deliver high concentrations of nitric oxide gas in spontaneously breathing subjects
Uploaded: 2021-05-04T13:00:00
Description: Watch this Scientific Journal Video about A Novel Inhalation Mask System to Deliver High Concentrations of Nitric Oxide Gas in Spontaneously Breathing Subjects at JoVE.com

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.

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 inst...

<ol>
	<li>Roberts, I. D., Fineman, J. F., Zapol, W. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Inhaled+nitric+oxide+and+persistent+pulmonary+hypertension+of+the+newborn.">Inhaled nitric oxide and persistent pulmonary hypertension of the newborn.</a> Pneumologie. 52 (4), 239 (1998).</li><li>Rossaint, R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Inhaled+nitric+oxide+for+the+adult+respiratory+distress+syndrome.">Inhaled nitric oxide for the adult respiratory distress syndrome.</a> New England Journal of Medicine. 328 (6), 399-405 (1993).</li><li>Robinson, J. N., Banerjee, R., Landzberg, M. J., Thiet, M. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Inhaled+nitric+oxide+therapy+in+pregnancy+complicated+by+pulmonary+hypertension.">Inhaled nitric oxide therapy in pregnancy complicated by pulmonary hypertension.</a> American Journal of Obstetrics and Gynecology. 180 (4), 1045-1046 (1999).</li><li>Ichinose, F., Roberts, J. D., Zapol, W. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Inhaled+nitric+oxide:+a+selective+pulmonary+vasodilator:+current+uses+and+therapeutic+potential.">Inhaled nitric oxide: a selective pulmonary vasodilator: current uses and therapeutic potential.</a> Circulation. 109 (25), 3106-3111 (2004).</li><li>Miller, C. C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Inhaled+nitric+oxide+decreases+the+bacterial+load+in+a+rat+model+of+Pseudomonas+aeruginosa+pneumonia.">Inhaled nitric oxide decreases the bacterial load in a rat model of Pseudomonas aeruginosa pneumonia.</a> Journal of Cystic Fibrosis. 12 (6), 817-820 (2013).</li><li>&#197;kerstr&#246;m, S., Gunalan, V., Keng, C. T., Tan, Y. J., Mirazimi, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Dual+effect+of+nitric+oxide+on+SARS-CoV+replication:+Viral+RNA+production+and+palmitoylation+of+the+S+protein+are+affected.">Dual effect of nitric oxide on SARS-CoV replication: Viral RNA production and palmitoylation of the S protein are affected.</a> Virology. 395 (1), 1-9 (2009).</li><li>Deppisch, C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Gaseous+nitric+oxide+to+treat+antibiotic+resistant+bacterial+and+fungal+lung+infections+in+patients+with+cystic+fibrosis:+a+phase+I+clinical+study.">Gaseous nitric oxide to treat antibiotic resistant bacterial and fungal lung infections in patients with cystic fibrosis: a phase I clinical study.</a> Infection. 44 (4), 513-520 (2016).</li><li>Alvarez, R. A., Berra, L., Gladwin, M. T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Home+nitric+oxide+therapy+for+COVID-19.">Home nitric oxide therapy for COVID-19.</a> American Journal of Respiratory and Critical Care Medicine. 202 (1), 16-20 (2020).</li><li>Chen, L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Inhalation+of+nitric+oxide+in+the+treatment+of+severe+acute+respiratory+syndrome:+A+rescue+trial+in+Beijing.">Inhalation of nitric oxide in the treatment of severe acute respiratory syndrome: A rescue trial in Beijing.</a> Clinical Infectious Diseases. 39 (10), 1531-1535 (2004).</li><li>Keyaerts, E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Inhibition+of+SARS-coronavirus+infection+in+vitro+by+S-nitroso-N-+acetylpenicillamine,+a+nitric+oxide+donor+compound.">Inhibition of SARS-coronavirus infection in vitro by S-nitroso-N- acetylpenicillamine, a nitric oxide donor compound.</a> International Journal of Infectious Diseases. 8 (4), 223-226 (2004).</li><li>Rossi, G. A., Sacco, O., Mancino, E., Cristiani, L., Midulla, F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Differences+and+similarities+between+SARS-CoV+and+SARS-CoV-2:+spike+receptor-binding+domain+recognition+and+host+cell+infection+with+support+of+cellular+serine+proteases.">Differences and similarities between SARS-CoV and SARS-CoV-2: spike receptor-binding domain recognition and host cell infection with support of cellular serine proteases.</a> Infection. 48 (5), 665-669 (2020).</li><li>Berra, L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Protocol+for+a+randomized+controlled+trial+testing+inhaled+nitric+oxide+therapy+in+spontaneously+breathing+patients+with+COVID-19.">Protocol for a randomized controlled trial testing inhaled nitric oxide therapy in spontaneously breathing patients with COVID-19.</a> medRxiv. , (2020).</li><li>Lei, C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Protocol+for+a+randomized+controlled+trial+testing+inhaled+nitric+oxide+therapy+in+spontaneously+breathing+patients+with+COVID-19.">Protocol for a randomized controlled trial testing inhaled nitric oxide therapy in spontaneously breathing patients with COVID-19.</a> medRxiv. , (2020).</li><li>. Nitric oxide inhalation therapy for COVID-19 infections in the ED Available from: <a target="_blank" href="https://clinicaltrials.gov/ct2/show/NCT04338828">https://clinicaltrials.gov/ct2/show/NCT04338828</a> (2020)</li><li>Gianni, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Nitric+oxide+gas+inhalation+to+prevent+COVID-2019+in+healthcare+providers.">Nitric oxide gas inhalation to prevent COVID-2019 in healthcare providers.</a> medRxiv. , (2020).</li><li>Safaee Fakhr, B., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=High+concentrations+of+nitric+oxide+inhalation+therapy+in+pregnant+patients+with+severe+coronavirus+disease+2019+(COVID-19).">High concentrations of nitric oxide inhalation therapy in pregnant patients with severe coronavirus disease 2019 (COVID-19).</a> Obstetrics &amp; Gynecology. , (2020).</li><li>Gianni, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Ideation+and+assessment+of+a+nitric+oxide+delivery+system+for+spontaneously+breathing+subjects.">Ideation and assessment of a nitric oxide delivery system for spontaneously breathing subjects.</a> Nitric Oxide. 104-105, 29-35 (2020).</li><li>. Nitric oxide gas inhalation therapy for mild/moderate COVID-19 Available from: <a target="_blank" href="https://clinicaltrials.gov/ct2/show/NCT04305457">https://clinicaltrials.gov/ct2/show/NCT04305457</a> (2020)</li><li>. NO prevention of COVID-19 for healthcare providers Available from: <a target="_blank" href="https://clinicaltrials.gov/ct2/show/NCT04312243?term=Berra&amp;draw=2&amp;rank=7">https://clinicaltrials.gov/ct2/show/NCT04312243?term=Berra&amp;draw=2&amp;rank=7</a> (2020)</li><li>. 1988 OSHA PEL Project-Nitrogen Dioxide|NIOSH|CDC Available from: <a target="_blank" href="https://www.cdc.gov/niosh/pel88/10102-44.html">https://www.cdc.gov/niosh/pel88/10102-44.html</a> (2020)</li><li>Yu, B., Zapol, W. M., Berra, L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Electrically+generated+nitric+oxide+from+air:+a+safe+and+economical+treatment+for+pulmonary+hypertension.">Electrically generated nitric oxide from air: a safe and economical treatment for pulmonary hypertension.</a> Intensive Care Medicine. 45 (11), 1612-1614 (2019).</li><li>Yu, B., Muenster, S., Blaesi, A. H., Bloch, D. B., Zapol, W. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Producing+nitric+oxide+by+pulsed+electrical+discharge+in+air+for+portable+inhalation+therapy.">Producing nitric oxide by pulsed electrical discharge in air for portable inhalation therapy.</a> Science Translational Medicine. 7 (294), (2015).</li><li>Lovich, M. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Generation+of+purified+nitric+oxide+from+liquid+N2O4+for+the+treatment+of+pulmonary+hypertension+in+hypoxemic+swine.">Generation of purified nitric oxide from liquid N2O4 for the treatment of pulmonary hypertension in hypoxemic swine.</a> Nitric Oxide - Biology and Chemistry. 37 (1), 66-72 (2014).</li><li>Cortazzo, J. A., Lichtman, A. D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Methemoglobinemia:+A+review+and+recommendations+for+management.">Methemoglobinemia: A review and recommendations for management.</a> Journal of Cardiothoracic and Vascular Anesthesia. 28 (4), 1043-1047 (2014).</li><li>Christenson, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+incidence+and+pathogenesis+of+cardiopulmonary+deterioration+after+abrupt+withdrawal+of+inhaled+nitric+oxide.">The incidence and pathogenesis of cardiopulmonary deterioration after abrupt withdrawal of inhaled nitric oxide.</a> American Journal of Respiratory and Critical Care Medicine. 161 (5), 1443-1449 (2000).</li><li>Yu, B., Ichinose, F., Bloch, D. B., Zapol, W. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Inhaled+nitric+oxide.">Inhaled nitric oxide.</a> British Journal of Pharmacology. 176 (2), 246-255 (2019).</li><li>INO Therapeutics. INOMAX - nitric oxide gas. Food and Drug Administration (FDA) Available from: <a target="_blank" href="https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020845s014lbl.pdf">https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020845s014lbl.pdf</a> (2013)</li><li>Klinger, J. R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Therapy+for+pulmonary+arterial+hypertension+in+adults:+Update+of+the+CHEST+Guideline+and+Expert+Panel+Report.">Therapy for pulmonary arterial hypertension in adults: Update of the CHEST Guideline and Expert Panel Report.</a> Chest. 155 (3), 565-586 (2019).</li><li>Cornfield, D. N., Milla, C. E., Haddad, I. Y., Barbato, J. E., Park, S. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Safety+of+inhaled+nitric+oxide+after+lung+transplantation.">Safety of inhaled nitric oxide after lung transplantation.</a> Journal of Heart and Lung Transplantation. 22 (8), 903-907 (2003).</li><li>Bhorade, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Response+to+inhaled+nitric+oxide+in+patients+with+acute+right+heart+syndrome.">Response to inhaled nitric oxide in patients with acute right heart syndrome.</a> American Journal of Respiratory and Critical Care Medicine. 159 (2), 571-579 (1999).</li><li>Mizutani, T., Layon, A. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Clinical+applications+of+nitric+oxide.">Clinical applications of nitric oxide.</a> Chest. 110 (2), 506-524 (1996).</li><li>. Nitric oxide gas inhalation in Severe Acute Respiratory Syndrome in COVID-19 Available from: <a target="_blank" href="https://clinicaltrials.gov/ct2/show/NCT04306393">https://clinicaltrials.gov/ct2/show/NCT04306393</a> (2020)</li></ol>

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<...

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 (&#62;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 &#62; 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&#39;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.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>90&#176; ventilator elbow connector without ports 22 mm ID x 22 mm OD</td>
			<td>Teleflex, Wayne, PA, USA</td>
			<td>1641</td>
			<td></td>
		</tr>
		<tr>
			<td>Aerosol tee connector: horizontal ports 22 mm OD, vertical port 11 mm ID/22 mm OD</td>
			<td>Teleflex, Wayne, PA, USA</td>
			<td>1077</td>
			<td></td>
		</tr>
		<tr>
			<td>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)</td>
			<td>Vyaire Medical Inc., Mettawa, IL, USA</td>
			<td>3215</td>
			<td></td>
		</tr>
		<tr>
			<td>High-efficiency particulate air (highly hydrophobic bacterial/viral filter,&#160; HEPA class 13) filter (22 mm ID/15 mm OD x 22 mm OD/15 mm ID connector)</td>
			<td>Teleflex, Wayne, PA, USA</td>
			<td>28012</td>
			<td></td>
		</tr>
		<tr>
			<td>Latex-free 3-L breathing reservoir bag</td>
			<td>CareFusion, Yorba Linda, CA, USA</td>
			<td>5063NL</td>
			<td></td>
		</tr>
		<tr>
			<td>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)</td>
			<td>Praxair, Bethlehem PA, USA</td>
			<td>MM NO800NI-AQ</td>
			<td></td>
		</tr>
		<tr>
			<td>One-way valve 22 mm male/female (arrow pointing towards female end)</td>
			<td>Teleflex, Wayne, PA, USA</td>
			<td>1664</td>
			<td>N=2 inspiratory limb (upward arrow)</td>
		</tr>
		<tr>
			<td>One-way valve 22 mm male/female (arrow pointing towards male end)</td>
			<td>Teleflex, Wayne, PA, USA</td>
			<td>1665</td>
			<td>N=1 expiratory limb (downward arrow)</td>
		</tr>
		<tr>
			<td>Rad-57 Handheld Pulse Oximeter with Rainbow SET Technology</td>
			<td>Masimo Corporation, Irvine, CA, USA</td>
			<td>3736</td>
			<td>Including SpMet Option</td>
		</tr>
		<tr>
			<td>Scavenger (ID = 60 mm, internal length = 53 mm, volume = 150 mL) containing 100 g of calcium hydroxide</td>
			<td>Spherasorb, Intersurgical Ltd, Berkshire, UK</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Silicon rubber flexible connectors 22 mm F x 22 mm F</td>
			<td>Tri-anim Health Services, Dublin, OH, USA</td>
			<td>301-9000</td>
			<td></td>
		</tr>
		<tr>
			<td>Snug-fit standard face mask of appropriate size</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Star Lumen standard medical grade vynil oxygen tubing with universal connectors</td>
			<td>Teleflex, Morrisville, NC, USA</td>
			<td>1115</td>
			<td>Variable length according to distance from source of gas. 2.1 m length used in protocol</td>
		</tr>
		<tr>
			<td>Straight connector with a 7.6 mm sampling port (15 mm OD x 15 mm ID/22 mm OD)</td>
			<td>Mallinckrodt, Bedminster, NJ, USA</td>
			<td>502041</td>
			<td></td>
		</tr>
		<tr>
			<td>Two-step adapter (15 mm to 22 mm)</td>
			<td>Airlife Auburndale, FL, USA</td>
			<td>1824</td>
			<td></td>
		</tr>
		<tr>
			<td>Y-piece connector with 7.6 mm ports (22 mm to 22 mm and 15 F)</td>
			<td>Vyaire Medical Inc., Mettawa, IL, USA</td>
			<td>1831</td>
			<td></td>
		</tr>
	</tbody>
</table>

a novel inhalation mask system to deliver high concentrations of nitric oxide gas in 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.

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...

Watch this Scientific Journal Video about A Novel Inhalation Mask System to Deliver High Concentrations of Nitric Oxide Gas in Spontaneously Breathing Subjects at JoVE.com

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

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 ...

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.

Research

JoVE Journal

Medicine

Expired CO2 Measurement in Intubated or Spontaneously Breathing Patients from the Emergency Department

Expired CO2 Measurement in Intubated or Spontaneously Breathing Patients from the Emergency Department

Carbon dioxide (CO2) along with oxygen (O2) share the role of being the most important gases in the human body. The measuring of expired CO2 at the mouth ...

Analytical Techniques for Assaying Nitric Oxide Bioactivity

Nitric oxide (NO) is a diatomic free radical that is extremely short lived in biological systems (less than 1 second in circulating blood)1. NO may be ...

Use of Animal Model of Sepsis to Evaluate Novel Herbal Therapies

Sepsis refers to a systemic inflammatory response syndrome resulting from a microbial infection. It has been routinely simulated in animals by several ...

Intraoperative Detection of Subtle Endometriosis: A Novel Paradigm for Detection and Treatment of Pelvic Pain Associated with the Loss of Peritoneal Integrity

Endometriosis is a  common disease affecting 40 to 70% of reproductive-aged women with chronic  pelvic pain (CPP) and/or infertility. The purpose of this ...

5/6th Nephrectomy in Combination with High Salt Diet and Nitric Oxide Synthase Inhibition to Induce Chronic Kidney Disease in the Lewis Rat

Chronic kidney disease (CKD) is a global problem. Slowing CKD progression is a major health priority. Since CKD is characterized by complex derangements ...

Performing Subretinal Injections in Rodents to Deliver Retinal Pigment Epithelium Cells in Suspension

The conversion of light into electrical impulses occurs in the outer retina and is accomplished largely by rod and cone photoreceptors and retinal pigment ...

MRI Mapping of Cerebrovascular Reactivity via Gas Inhalation Challenges

The brain is a spatially heterogeneous and temporally dynamic organ, with different regions requiring different amount of blood supply at different time. ...

Dry Powder and Nebulized Aerosol Inhalation of Pharmaceuticals Delivered to Mice Using a Nose-only Exposure System

Obstructive respiratory diseases like asthma and chronic obstructive pulmonary disease (COPD) are currently treated by inhaled anti-inflammatory and ...

Comparing the Effects of Electronic Cigarette Vapor and Cigarette Smoke in a Novel In Vivo Exposure System

Comparing the Effects of Electronic Cigarette Vapor and Cigarette Smoke in a Novel In Vivo Exposure System

Electronic cigarettes (E-cigarettes) are being widely used, and growing in popularity. It is estimated that more than 9 million adults use them regularly. ...

Novel Methods for Intranasal Administration Under Inhalation Anesthesia to Evaluate Nose-to-Brain Drug Delivery

Intranasal administration has been reported to be a potential pathway for nose-to-brain delivery of therapeutic agents that circumvents the blood-brain ...