Inhaled high dose nitric oxide is a safe and effective respiratory treatment in spontaneous breathing hospitalized patients with COVID-19 pneumonia

Bijan Safaee Fakhr, Raffaele Di Fenza, Stefano Gianni, Steffen B Wiegand, Yusuke Miyazaki, Caio C Araujo Morais, Lauren E Gibson, Marvin G Chang, Ariel L Mueller, Josanna M Rodriguez-Lopez, Jeanne B Ackman, Pankaj Arora, Louie K Scott, Donald B Bloch, Warren M Zapol, Ryan W Carroll, Fumito Ichinose, Lorenzo Berra, Nitric Oxide Study Investigators, Eizo Marutani, Takamitsu Ikeda, Vibhu Parcha, Benjamin Corman, Grant Larson, Eduardo Diaz Delgado, Hatus V Wanderley, Kimberley Hutchinson, Elizabeth I Caskey, Martin Capriles, Lisa Traeger, Anna Fischbach, Robert M H Grange, Kathryn Hibbert, Peggy S Lai, Oluwaseun Akeju, Riccardo Pinciroli, Stuart N Harris, Edward A Bittner, Reginald E Greene, Robert M Kacmarek, Bijan Safaee Fakhr, Raffaele Di Fenza, Stefano Gianni, Steffen B Wiegand, Yusuke Miyazaki, Caio C Araujo Morais, Lauren E Gibson, Marvin G Chang, Ariel L Mueller, Josanna M Rodriguez-Lopez, Jeanne B Ackman, Pankaj Arora, Louie K Scott, Donald B Bloch, Warren M Zapol, Ryan W Carroll, Fumito Ichinose, Lorenzo Berra, Nitric Oxide Study Investigators, Eizo Marutani, Takamitsu Ikeda, Vibhu Parcha, Benjamin Corman, Grant Larson, Eduardo Diaz Delgado, Hatus V Wanderley, Kimberley Hutchinson, Elizabeth I Caskey, Martin Capriles, Lisa Traeger, Anna Fischbach, Robert M H Grange, Kathryn Hibbert, Peggy S Lai, Oluwaseun Akeju, Riccardo Pinciroli, Stuart N Harris, Edward A Bittner, Reginald E Greene, Robert M Kacmarek

Abstract

Background: Inhaled nitric oxide (NO) is a selective pulmonary vasodilator. In-vitro studies report that NO donors can inhibit replication of SARS-CoV-2. This multicenter study evaluated the feasibility and effects of high-dose inhaled NO in non-intubated spontaneously breathing patients with Coronavirus disease-2019 (COVID-19).

Methods: This is an interventional study to determine whether NO at 160 parts-per-million (ppm) inhaled for 30 min twice daily might be beneficial and safe in non-intubated COVID-19 patients.

Results: Twenty-nine COVID-19 patients received a total of 217 intermittent inhaled NO treatments for 30 min at 160 ppm between March and June 2020. Breathing NO acutely decreased the respiratory rate of tachypneic patients and improved oxygenation in hypoxemic patients. The maximum level of nitrogen dioxide delivered was 1.5 ppm. The maximum level of methemoglobin (MetHb) during the treatments was 4.7%. MetHb decreased in all patients 5 min after discontinuing NO administration. No adverse events during treatment, such as hypoxemia, hypotension, or acute kidney injury during hospitalization occurred. In our NO treated patients, one patient of 29 underwent intubation and mechanical ventilation, and none died. The median hospital length of stay was 6 days [interquartile range 4-8]. No discharged patients required hospital readmission nor developed COVID-19 related long-term sequelae within 28 days of follow-up.

Conclusions: In spontaneous breathing patients with COVID-19, the administration of inhaled NO at 160 ppm for 30 min twice daily promptly improved the respiratory rate of tachypneic patients and systemic oxygenation of hypoxemic patients. No adverse events were observed. None of the subjects was readmitted or had long-term COVID-19 sequelae.

Keywords: COVID-19; Nitric oxide; Viral pneumonia.

Published by Elsevier Inc.

Figures

Fig. 1
Fig. 1
Delivery system description. In summary, a non-rebreathing circuit composed of standard respiratory circuit connectors, a reservoir bag, a scavenging chamber containing calcium hydroxide, and a snug-fitting mask was used to reach 160 ppm NO gas. Nitric oxide balanced in nitrogen (Praxair, Inc. Danbury, Connecticut, United States) was blended with medical air and oxygen to obtain the desired mixture, based on in vitro measurements. The delivery system allows stability of administered concentration of NO, with NO2 levels always below the Occupational Safety and Health Administration (OSHA) threshold.
Fig. 2
Fig. 2
Effect of nitric oxide (NO) inhalation on respiratory rate (RR) and oxygenation. Linear mixed model fit by maximum likelihood. (A) SpO2(%)/ FiO2(%) (n = 33 treatments) improved by 49 [95% CI: 29–70] during treatment, and by 22 [95% CI: 1–42] after treatment in all patients with hypoxemia (SpO2/FiO2 < 315) before NO gas administration. (B) RR (n = 75 treatments) was reduced by 2 [95% CI: 2–3] breaths/min during NO treatment (Rx) and remained reduced by 2 [95% CI: 1–3] breaths/min after treatment in all patients with tachypnea (RR at baseline >24 breaths/min) at the commencement of the administration. (C) RR was reduced during hospitalization by 1 [95% CI: 0 to 1] breath/min for each day of treatment. At 48 h, the RR was lower by 3 [95%CI: 2–5] breaths/min. *P < 0.05 vs Before. $ P < 0.05 vs Day 0.
Fig. 3
Fig. 3
Methemoglobin during nitri oxide (NO) inhalation therapy (Rx). Linear mixed model fit by maximum likelihood. *P 

References

    1. Sartini C., Tresoldi M., Scarpellini P., Tettamanti A., Carcò F., Landoni G., Zangrillo A. Respiratory parameters in patients with COVID-19 after using noninvasive ventilation in the prone position outside the intensive care unit. J. Am. Med. Assoc. 2020;323:2338–2340. doi: 10.1001/jama.2020.7861.
    1. Raoof S., Nava S., Carpati C., Hill N.S. High-flow, noninvasive ventilation and awake (nonintubation) proning in patients with COVID-2019 with respiratory failure. Chest. 2020 doi: 10.1016/j.chest.2020.07.013.
    1. Ichinose F., Roberts J.D., Zapol W.M. Inhaled nitric oxide: a selective pulmonary vasodilator: current uses and therapeutic potential. Circulation. 2004;109:3106–3111. doi: 10.1161/01.CIR.0000134595.80170.62.
    1. Gebistorf F., Karam O., Wetterslev J., Afshari A. Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) in children and adults. Cochrane Database Syst. Rev. 2016:CD002787. doi: 10.1002/14651858.CD002787.pub3.
    1. Kacmarek R.M., Ripple R., Cockrill B.A., Bloch K.J., Zapol W.M., Johnson D.C. Inhaled nitric oxide. A bronchodilator in mild asthmatics with methacholine-induced bronchospasm. Am. J. Respir. Crit. Care Med. 1996;153:128–135. doi: 10.1164/ajrccm.153.1.8542105.
    1. Moreno I., Mir A., Vicente R., Pajares A., Ramos F., Vicente J.L., Barbera M. Analysis of interleukin-6 and interleukin-8 in lung transplantation: correlation with nitric oxide administration. Transplant. Proc. 2008;40:3082–3084. doi: 10.1016/j.transproceed.2008.08.124.
    1. Samama C.M., Diaby M., Fellahi J.L., Mdhafar A., Eyraud D., Arock M., Guillosson J.J., Coriat P., Rouby J.J. Inhibition of platelet aggregation by inhaled nitric oxide in patients with acute respiratory distress syndrome. Anesthesiology. 1995;83:56–65. doi: 10.1097/00000542-199507000-00007.
    1. Goldbart A., Golan-Tripto I., Pillar G., Livnat-Levanon G., Efrati O., Spiegel R., Lubetzky R., Lavie M., Carmon L., Nahum A. Inhaled nitric oxide therapy in acute bronchiolitis: a multicenter randomized clinical trial. Sci. Rep. 2020;10:9605. doi: 10.1038/s41598-020-66433-8.
    1. Chen L., Liu P., Gao H., Sun B., Chao D., Wang F., Zhu Y., Hedenstierna G., Wang C.G. Inhalation of nitric oxide in the treatment of severe acute respiratory syndrome: a rescue trial in Beijing. Clin. Infect. Dis. 2004;39:1531–1535. doi: 10.1086/425357.
    1. Akerström S., Gunalan V., Keng C.T., Tan Y.-J., Mirazimi A. Dual effect of nitric oxide on SARS-CoV replication: viral RNA production and palmitoylation of the S protein are affected. Virology. 2009;395:1–9. doi: 10.1016/j.virol.2009.09.007.
    1. Akaberi D., Krambrich J., Ling J., Luni C., Hedenstierna G., Järhult J.D., Lennerstrand J., Lundkvist Å. Mitigation of the replication of SARS-CoV-2 by nitric oxide in vitro. Redox Biology. 2020:101734. doi: 10.1016/j.redox.2020.101734.
    1. Ferrari M., Santini A., Protti A., Andreis D.T., Iapichino G., Castellani G., Rendiniello V., Costantini E., Cecconi M. Inhaled nitric oxide in mechanically ventilated patients with COVID-19. J. Crit. Care. 2020;60:159–160. doi: 10.1016/j.jcrc.2020.08.007.
    1. Tavazzi G., Marco P., Mongodi S., Dammassa V., Romito G., Mojoli F. Inhaled nitric oxide in patients admitted to intensive care unit with COVID-19 pneumonia. Crit. Care. 2020;24:1–2. doi: 10.1186/s13054-020-03222-9.
    1. Abou-Arab O., Huette P., Debouvries F., Dupont H., Jounieaux V., Mahjoub Y. Inhaled nitric oxide for critically ill Covid-19 patients: a prospective study. Crit. Care. 2020;24 doi: 10.1186/s13054-020-03371-x.
    1. Gianni S., Morais C.C.A., Larson G., Pinciroli R., Carroll R., Yu B., Zapol W.M., Berra L. Ideation and assessment of a nitric oxide delivery system for spontaneously breathing subjects. Nitric Oxide. 2020;104–105:29–35. doi: 10.1016/j.niox.2020.08.004.
    1. Wiegand S.B., Safaee Fakhr B., Carroll R.W., Zapol W.M., Kacmarek R.M., Berra L. Rescue treatment with high-dose gaseous nitric oxide in spontaneously breathing patients with severe coronavirus disease 2019. Crit Care Explor. 2020;2:e0277. doi: 10.1097/CCE.0000000000000277.
    1. Safaee Fakhr B., Wiegand S.B., Pinciroli R., Gianni S., Morais C.C.A., Ikeda T., Miyazaki Y., Marutani E., Di Fenza R., Larson G.M., Parcha V., Gibson L.E., Chang M.G., Arora P., Carroll R.W., Kacmarek R.M., Ichinose F., Barth W.H., Kaimal A., Hohmann E.L., Zapol W.M., Berra L. Obstet Gynecol; 2020. High Concentrations of Nitric Oxide Inhalation Therapy in Pregnant Patients with Severe Coronavirus Disease 2019 (COVID-19)
    1. Budts W., Van Pelt N., Gillyns H., Gewillig M., Van de Werf F., Janssens S. Residual pulmonary vasoreactivity to inhaled nitric oxide in patients with severe obstructive pulmonary hypertension and Eisenmenger syndrome. Heart. 2001;86:553–558. doi: 10.1136/heart.86.5.553.
    1. Tsapenko M.V., Tsapenko A.V., Comfere T.B., Mour G.K., Mankad S.V., Gajic O. Arterial pulmonary hypertension in noncardiac intensive care unit. Vasc. Health Risk Manag. 2008;4:1043–1060. doi: 10.2147/vhrm.s3998.
    1. Hare S.S., Tavare A.N., Dattani V., Musaddaq B., Beal I., Cleverley J., Cash C., Lemoniati E., Barnett J. Validation of the British Society of Thoracic Imaging guidelines for COVID-19 chest radiograph reporting. Clin. Radiol. 2020;75:710. doi: 10.1016/j.crad.2020.06.005. e9-710.e14.
    1. Rice T.W., Wheeler A.P., Bernard G.R., Hayden D.L., Schoenfeld D.A., Ware L.B. Comparison of the SpO2/FIO2 ratio and the PaO 2/FIO2 ratio in patients with acute lung injury or ARDS. Chest. 2007;132:410–417. doi: 10.1378/chest.07-0617.
    1. Rossaint R., Falke K.J., López F., Slama K., Pison U., Zapol W.M. Inhaled nitric oxide for the adult respiratory distress syndrome. N. Engl. J. Med. 1993;328:399–405. doi: 10.1056/NEJM199302113280605.
    1. Raut M.S., Maheshwari A. Inhaled nitric oxide, methemoglobinemia, and route of delivery. Saudi J. Anaesth. 2017;11:364. doi: 10.4103/sja.SJA_82_17.
    1. Donnelly J.P., Wang X.Q., Iwashyna T.J., Prescott H.C. Readmission and death after initial hospital discharge among patients with COVID-19 in a large multihospital system. J. Am. Med. Assoc. 2021;325:304–306. doi: 10.1001/jama.2020.21465.
    1. Lavery A.M. Characteristics of hospitalized COVID-19 patients discharged and experiencing Same-hospital readmission — United States, March–August 2020. MMWR Morb. Mortal. Wkly. Rep. 2020;69 doi: 10.15585/mmwr.mm6945e2.
    1. Ayoubkhani D., Khunti K., Nafilyan V., Maddox T., Humberstone B., Diamond I., Banerjee A. Post-covid syndrome in individuals admitted to hospital with covid-19: retrospective cohort study. BMJ. 2021;372:n693. doi: 10.1136/bmj.n693.
    1. Roberts J.D., Fineman J.R., Morin F.C., Shaul P.W., Rimar S., Schreiber M.D., Polin R.A., Zwass M.S., Zayek M.M., Gross I., Heymann M.A., Zapol W.M. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. The Inhaled Nitric Oxide Study Group. N. Engl. J. Med. 1997;336:605–610. doi: 10.1056/NEJM199702273360902.
    1. Alvarez R.A., Berra L., Gladwin M.T. Home NO therapy for COVID-19. Am. J. Respir. Crit. Care Med. 2020 doi: 10.1164/rccm.202005-1906ED.
    1. Santamarina M.G., Boisier D., Contreras R., Baque M., Volpacchio M., Beddings I. COVID-19: a hypothesis regarding the ventilation-perfusion mismatch. Crit. Care. 2020;24:395. doi: 10.1186/s13054-020-03125-9.
    1. Ignarro L.J. Inhaled NO and COVID-19. Br. J. Pharmacol. 2020;177:3848–3849. doi: 10.1111/bph.15085.
    1. Miller C., Miller M., McMullin B., Regev G., Serghides L., Kain K., Road J., Av-Gay Y. A phase I clinical study of inhaled nitric oxide in healthy adults. J. Cyst. Fibros. 2012;11:324–331. doi: 10.1016/j.jcf.2012.01.003.
    1. Hu J., Spina S., Zadek F., Kamenshchikov N.O., Bittner E.A., Pedemonte J., Berra L. Effect of nitric oxide on postoperative acute kidney injury in patients who underwent cardiopulmonary bypass: a systematic review and meta-analysis with trial sequential analysis. Ann. Intensive Care. 2019;9:129. doi: 10.1186/s13613-019-0605-9.

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