Therapeutic Effects of Inhaled Nitric Oxide Therapy in COVID-19 Patients

Abstract

The global COVID-19 pandemic has become the largest public health challenge of recent years. The incidence of COVID-19-related acute hypoxemic respiratory failure (AHRF) occurs in up to 15% of hospitalized patients. Antiviral drugs currently available to clinicians have little to no effect on mortality, length of in-hospital stay, the need for mechanical ventilation, or long-term effects. Inhaled nitric oxide (iNO) administration is a promising new non-standard approach to directly treat viral burden while enhancing oxygenation. Along with its putative antiviral affect in COVID-19 patients, iNO can reduce inflammatory cell-mediated lung injury by inhibiting neutrophil activation, lowering pulmonary vascular resistance and decreasing edema in the alveolar spaces, collectively enhancing ventilation/perfusion matching. This narrative review article presents recent literature on the iNO therapy use for COVID-19 patients. The authors suggest that early administration of the iNO therapy may be a safe and promising approach for the treatment of COVID-19 patients. The authors also discuss unconventional approaches to treatment, continuous versus intermittent high-dose iNO therapy, timing of initiation of therapy (early versus late), and novel delivery systems. Future laboratory and clinical research is required to define the role of iNO as an adjunct therapy against bacterial, viral, and fungal infections.

Keywords: COVID-19; acute respiratory syndrome coronavirus 2; endothelium; inhaled nitric oxide therapy; nitric oxide.

Figure 1

Illustrates the continuum of intrapulmonary pathophysiology at the early stages of COVID-19 pneumonia, highlighting the putative beneficial effects of NO. Part I. The effects of iNO are etiopathogenetic. iNO may reduce viral load while halting the intrapulmonary cascade of inflammation, decreasing alveolar dead space, and thus optimizing ventilation-perfusion. In addition, a decrease in respiratory rate, improvement of gas exchange, and enhanced respiratory comfort may prevent the development of self-induced lung injury (SILI). iNO may also prevent co- and superinfection (CSI), including those involving hospital antibiotic-resistant flora. To this end, it is important to consider administering iNO therapy at the early stage of disease, before the development of irreversible changes in the lungs. Part II. Persistent SILI and CSI contribute to transition of disease into a self-maintaining and self-sustained process. The continuum of intrapulmonary pathophysiology is mediated by local and systemic hyper-inflammatory reactions, even after virus elimination. There is an increase in elastance and a decrease in aerated lung, an increase in intra-alveolar exudation, a transition to low compliance phenotype, mirroring the known pathogenesis ARDS. The NO-mediated impact at this stage is aimed at optimizing V/Q matching. Considering the transition of functional changes in the lungs to morphological changes, therapeutic effects of iNO would be quite limited, represent last-resort treatment, and do not consistently result in improved outcomes. Part III. iNO-mediated cardio-respiratory interactions to reduce the risk of right ventricular failure. Prevention of acute cor pulmonale development by reducing right ventricular afterload. Prevention of group 3 pulmonary hypertension due to prolonged antifibrotic effects of iNO in the lungs.