Inhaled nitric oxide in patients with acute respiratory distress syndrome caused by COVID-19: treatment modalities, clinical response, and outcomes

Armand Mekontso Dessap; Laurent Papazian; Manuella Schaller; Saad Nseir; Bruno Megarbane; Luc Haudebourg; Jean-François Timsit; Jean-Louis Teboul; Khaldoun Kuteifan; Marc Gainnier; Michel Slama; Patrick Houeto; Laurent Lecourt; Alain Mercat; Antoine Vieillard-Baron

doi:10.1186/s13613-023-01150-9

Inhaled nitric oxide in patients with acute respiratory distress syndrome caused by COVID-19: treatment modalities, clinical response, and outcomes

Ann Intensive Care. 2023 Jun 27;13(1):57. doi: 10.1186/s13613-023-01150-9.

Authors

Armand Mekontso Dessap^{1

2

3}, Laurent Papazian⁴, Manuella Schaller⁵, Saad Nseir⁶, Bruno Megarbane⁷, Luc Haudebourg⁸, Jean-François Timsit⁹, Jean-Louis Teboul¹⁰, Khaldoun Kuteifan¹¹, Marc Gainnier¹², Michel Slama¹³, Patrick Houeto⁵, Laurent Lecourt⁵, Alain Mercat¹⁴, Antoine Vieillard-Baron^{15

16}

Affiliations

¹ Service de Médecine Intensive Réanimation, Hôpitaux Universitaires Henri-Mondor, AP-HP, 94010, Créteil, France. armand.dessap@aphp.fr.
² CARMAS research group, Univ Paris Est Créteil, Faculté de Santé, 94010, Créteil, France. armand.dessap@aphp.fr.
³ IMRB, INSERM, Univ Paris Est Créteil, 94010, Créteil, France. armand.dessap@aphp.fr.
⁴ Médecine Intensive Réanimation, Centre d'Etudes et de Recherches sur les Services de Santé et Qualité de vie EA 3279, Hôpital Nord, Assistance Publique-Hôpitaux de Marseille, Aix-Marseille University, 13015, Marseille, France.
⁵ Air Liquide Sante International, 92220, Bagneux, France.
⁶ Department of Intensive Care Medicine, Critical Care Center, CHU of Lille, 59000, Lille, France.
⁷ Department of Medical and Toxicological Critical Care, Lariboisière Hospital, INSERM MURS-1144, University of Paris, AP-HP, 2 Rue Ambroise Paré, 75010, Paris, France.
⁸ Service de Pneumologie et Réanimation Médicale du Département R3S, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, AP-HP, Paris, France.
⁹ Medical and Infectious Diseases Intensive Care Unit, Bichat-Claude Hospital and U1137, IAME Université Paris-Cité, AP-HP, 75018, Paris, France.
¹⁰ Service de Medecine Intensive-Reanimation, Hôpital de Bicêtre, AP-HP, 78, rue du Général Leclerc, 94270, Le Kremlin-Bicêtre, France.
¹¹ Service de Réanimation Médicale, Groupe Hospitalier de la Région Mulhouse Sud Alsace, 68100, Mulhouse, France.
¹² Réanimation des Urgences, Hôpital de La Timone, Assistance Publique des Hôpitaux de Marseille, Marseille, France.
¹³ Medical Intensive Care Unit, CHU Sud Amiens, Amiens, France.
¹⁴ Department of Intensive Care, University of Angers, Angers, France.
¹⁵ Medical Intensive Care Unit, Ambroise Paré Hospital, AP-HP, Boulogne-Billancourt, France.
¹⁶ Inserm UMR 1018, Équipe 5, CESP, Villejuif, France.

Abstract

Background: Inhaled nitric oxide (iNO) has been widely used in patients with COVID-19-related acute respiratory distress syndrome (C-ARDS), though its physiological effects and outcome are debated in this setting. The objective of this cohort study was to describe the modalities of iNO use, clinical response, and outcomes in a large cohort of C-ARDS patients.

Methods: Multicentre, retrospective cohort study conducted in France.

Results: From end February to December 2020, 300 patients (22.3% female) were included, 84.5% were overweight and 69.0% had at least one comorbidity. At ICU admission, their median (IQR) age, SAPS II, and SOFA score were 66 (57-72) years, 37 (29-48), and 5 (3-8), respectively. Patients were all ventilated according to a protective ventilation strategy, and 68% were prone positioned before iNO initiation. At iNO initiation, 2%, 37%, and 61% of patients had mild, moderate, and severe ARDS, respectively. The median duration of iNO treatment was 2.8 (1.1-5.5) days with a median dosage of 10 (7-13) ppm at initiation. Responders (PaO₂/FiO₂ ratio improving by 20% or more) represented 45.7% of patients at 6 h from iNO initiation. The severity of ARDS was the only predictive factor associated with iNO response. Among all evaluable patients, the crude mortality was not significantly different between responders at 6 h and their counterparts. Of the 62 patients with refractory ARDS (who fulfilled extracorporeal membrane oxygenation criteria before iNO initiation), 32 (51.6%) no longer fulfilled these criteria after 6 h of iNO. The latter showed significantly lower mortality than the other half (who remained ECMO eligible), including after confounder adjustment (adjusted OR: 0.23, 95% CI 0.06, 0.89, p = 0.03).

Conclusions: Our study reports the benefits of iNO in improving arterial oxygenation in C-ARDS patients. This improvement seems more relevant in the most severe cases. In patients with ECMO criteria, an iNO-driven improvement in gas exchange was associated with better survival. These results must be confirmed in well-designed prospective studies.

Keywords: Acute respiratory distress syndrome; COVID-19; ECMO; Inhaled nitric oxide; Refractory hypoxaemia.