High-Dose Inhaled Nitric Oxide for the Treatment of Spontaneously Breathing Pregnant Patients With Severe Coronavirus Disease 2019 (COVID-19) Pneumonia

Carlo Valsecchi, Dario Winterton, Bijan Safaee Fakhr, Ai-Ris Y Collier, Ala Nozari, Jamel Ortoleva, Shivali Mukerji, Lauren E Gibson, Ryan W Carroll, Shahzad Shaefi, Riccardo Pinciroli, Carolyn La Vita, Jeanne B Ackman, Elizabeth Hohmann, Pankaj Arora, William H Barth Jr, Anjali Kaimal, Fumito Ichinose, Lorenzo Berra, DELiverly oF iNO (DELFiNO) Network Collaborators, Carlo Valsecchi, Dario Winterton, Bijan Safaee Fakhr, Ai-Ris Y Collier, Ala Nozari, Jamel Ortoleva, Shivali Mukerji, Lauren E Gibson, Ryan W Carroll, Shahzad Shaefi, Riccardo Pinciroli, Carolyn La Vita, Jeanne B Ackman, Elizabeth Hohmann, Pankaj Arora, William H Barth Jr, Anjali Kaimal, Fumito Ichinose, Lorenzo Berra, DELiverly oF iNO (DELFiNO) Network Collaborators

Abstract

Objective: To evaluate whether the use of inhaled nitric oxide (iNO)200 improves respiratory function.

Methods: This retrospective cohort study used data from pregnant patients hospitalized with severe bilateral coronavirus disease 2019 (COVID-19) pneumonia at four teaching hospitals between March 2020 and December 2021. Two cohorts were identified: 1) those receiving standard of care alone (SoC cohort) and 2) those receiving iNO200 for 30 minutes twice daily in addition to standard of care alone (iNO200 cohort). Inhaled nitric oxide, as a novel therapy, was offered only at one hospital. The prespecified primary outcome was days free from any oxygen supplementation at 28 days postadmission. Secondary outcomes were hospital length of stay, rate of intubation, and intensive care unit (ICU) length of stay. The multivariable-adjusted regression analyses accounted for age, body mass index, gestational age, use of steroids, remdesivir, and the study center.

Results: Seventy-one pregnant patients were hospitalized for severe bilateral COVID-19 pneumonia: 51 in the SoC cohort and 20 in the iNO200 cohort. Patients receiving iNO200 had more oxygen supplementation-free days (iNO200: median [interquartile range], 24 [23-26] days vs standard of care alone: 22 [14-24] days, P=.01) compared with patients in the SoC cohort. In the multivariable-adjusted analyses, iNO200 was associated with 63.2% (95% CI 36.2-95.4%; P<.001) more days free from oxygen supplementation, 59.7% (95% CI 56.0-63.2%; P<.001) shorter ICU length of stay, and 63.6% (95% CI 55.1-70.8%; P<.001) shorter hospital length of stay. No iNO200-related adverse events were reported.

Conclusion: In pregnant patients with severe bilateral COVID-19 pneumonia, iNO200 was associated with a reduced need for oxygen supplementation and shorter hospital stay.

Conflict of interest statement

Financial Disclosure: Lorenzo Berra receives salary support from K23 HL128882/NHLBI NIH as principal investigator for his work on hemolysis and nitric oxide. Lorenzo Berra receives technologies and devices from iNO Therapeutics LLC, Praxair Inc., and Masimo Corp. Lorenzo Berra receives grants from iNO Therapeutics LLC. Jamel Ortoleva received a compensation for a one-time meeting for La Jolla Pharmaceutical for angiotensin II. Ai-ris Y. Collier disclosed that money was paid to their institution from the Reproductive Scientist Development Program at the Eunice Kennedy Shriver National Institute of Child Health & Human Development and Burroughs Wellcome Fund HD000849. Carolyn La Vita disclosed receiving payment from the Orange Medical Nihon Kohden for honorariums for lectures to AARC. Jeanne B. Ackman disclosed that money was paid to her from Elsevier for royalties for associate editorship of a textbook and Celgene (a single consultancy fee in 2019). She also disclosed that this article discusses off-label use of nitric oxide to treat hypoxic pregnant patients with COVID-19. Ryan Carroll receives salary support from UNITAID for tuberculosis research in Uganda. The other authors did not report any potential conflicts of interest.

Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.

Figures

Fig. 1.
Fig. 1.
Flow chart. COVID-19, coronavirus disease 2019. Valsecchi. High-Dose Nitric Oxide in Severe COVID-19. Obstet Gynecol 2022.
Fig. 2.
Fig. 2.
Effect of inhaled nitric oxide (iNO)200 on respiratory rate, oxygenation (measured as SpO2/FiO2 ratio), and hemodynamics (data are mean, minimum–maximum). Linear mixed-model fit by maximum likelihood. A. Effect of iNO200 on SpO2/FiO2 ratio in patients with hypoxemia (defined as SpO2/FiO2 ratio 315 or lower) at the commencement of administration (n=56). B. Effect of iNO200 on respiratory rate, measured in breaths per minute (bpm) in patients with tachypnoea (defined as respiratory rate 24 bpm or higher) at the commencement of administration (n=94). C. Effect of iNO200 on mean arterial pressure, measured in mm Hg (n=139). D. Effect of iNO200 on heart rate, measured as beats per minute (bpm) (n=144) *P<.05 in the post hoc analysis (Tuckey’s range test) vs before (for additional statistical methods, see Appendix 2, available online at http://links.lww.com/AOG/C775). Valsecchi. High-Dose Nitric Oxide in Severe COVID-19. Obstet Gynecol 2022.
Fig. 3.
Fig. 3.
Methemoglobin levels (data are mean, minimum–maximum) during the administration of inhaled nitric oxide (iNO200). Linear mixed-model fit by maximum likelihood (n = 136). *P<.05 in the post hoc analysis (Tuckey’s range test) vs before; †P<.05 vs maximum levels during iNO. For additional statistical methods, see Appendix 2, available online at http://links.lww.com/AOG/C775. Valsecchi. High-Dose Nitric Oxide in Severe COVID-19. Obstet Gynecol 2022.

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