Inhaled Nitric Oxide in Acute Respiratory Distress Syndrome Subsets: Rationale and Clinical Applications

Abstract

Acute respiratory distress syndrome (ARDS) is a life-threatening condition, characterized by diffuse inflammatory lung injury. Since the coronavirus disease 2019 (COVID-19) pandemic spread worldwide, the most common cause of ARDS has been the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Both the COVID-19-associated ARDS and the ARDS related to other causes-also defined as classical ARDS-are burdened by high mortality and morbidity. For these reasons, effective therapeutic interventions are urgently needed. Among them, inhaled nitric oxide (iNO) has been studied in patients with ARDS since 1993 and it is currently under investigation. In this review, we aim at describing the biological and pharmacological rationale of iNO treatment in ARDS by elucidating similarities and differences between classical and COVID-19 ARDS. Thereafter, we present the available evidence on the use of iNO in clinical practice in both types of respiratory failure. Overall, iNO seems a promising agent as it could improve the ventilation/perfusion mismatch, gas exchange impairment, and right ventricular failure, which are reported in ARDS. In addition, iNO may act as a viricidal agent and prevent lung hyperinflammation and thrombosis of the pulmonary vasculature in the specific setting of COVID-19 ARDS. However, the current evidence on the effects of iNO on outcomes is limited and clinical studies are yet to demonstrate any survival benefit by administering iNO in ARDS.

Keywords: COVID-19; SARS-CoV-2; acute respiratory distress syndrome; inhaled nitric oxide.

FIG. 1.

iNO properties exerted in classic (left side) and COVID-19 (right side) ARDS. In classic ARDS, iNO exerts the following properties: (A) maintenance of patent pulmonary vessels thanks to antiplatelet properties; (B) enhancement of the V/Q match by diverting blood flow to ventilated lung units and therefore improvement of the respiratory gas exchange, thanks to selective pulmonary vasodilatory effect; (C) offloading of the right ventricle and prevention of its failure, because of pulmonary vasodilation, which determines a reduction in PAP and then a decrease of right ventricle afterload. In COVID-19 ARDS—together with the properties described in classic ARDS—iNO has the following properties: (D) replenishment of the depleted storage of endogenous NO in the presence of inflammatory induced endothelial dysfunction (i.e., eNOS dysfunction); (E) direct viricidal activity against SARS-CoV-2; (F) immune modulation and decreased lung inflammation and prevention of SARS-CoV-2-induced endothelial dysfunction thanks to anti-inflammatory properties. ARDS, acute respiratory distress syndrome; COVID-19, coronavirus disease 2019; eNOS, endothelial nitric oxide synthase; iNO, inhaled nitric oxide; PAP, pulmonary arterial pressure; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; V/Q, ventilation/perfusion.

FIG. 2.

Changes of PaO₂/FiO₂ ratio before and after iNO administration in patients with COVID-19 ARDS. (A) Studies that showed a significant change in PaO₂/FiO₂ ratio after iNO administration. (B) Studies that did not show a significant change in PaO₂/FiO₂ ratio after iNO administration. Data represent mean or median according to the data presentation in the original study.