Nitric oxide: Clinical applications in critically ill patients

Abstract

Inhaled nitric oxide (iNO) acts as a selective pulmonary vasodilator and it is currently approved by the FDA for the treatment of persistent pulmonary hypertension of the newborn. iNO has been demonstrated to effectively decrease pulmonary artery pressure and improve oxygenation, while decreasing extracorporeal life support use in hypoxic newborns affected by persistent pulmonary hypertension. Also, iNO seems a safe treatment with limited side effects. Despite the promising beneficial effects of NO in the preclinical literature, there is still a lack of high quality evidence for the use of iNO in clinical settings. A variety of clinical applications have been suggested in and out of the critical care environment, aiming to use iNO in respiratory failure and pulmonary hypertension of adults or as a preventative measure of hemolysis-induced vasoconstriction, ischemia/reperfusion injury and as a potential treatment of renal failure associated with cardiopulmonary bypass. In this narrative review we aim to present a comprehensive summary of the potential use of iNO in several clinical conditions with its suggested benefits, including its recent application in the scenario of the COVID-19 pandemic. Randomized controlled trials, meta-analyses, guidelines, observational studies and case-series were reported and the main findings summarized. Furthermore, we will describe the toxicity profile of NO and discuss an innovative proposed strategy to produce iNO. Overall, iNO exhibits a wide range of potential clinical benefits, that certainly warrants further efforts with randomized clinical trials to determine specific therapeutic roles of iNO.

Keywords: COVID-19; Clinical applications; Critically ill; Ischemia/reperfusion injury; Nitric oxide; Pulmonary hypertension; Toxicology.

Fig. 1.

Clinical applications and effects of nitric oxide. Nitric oxide is currently approved by the FDA, with the sole indication for administration in patients with PPHN. iNO is sometimes used as a rescue therapy in severe ARDS. The other disease named in the figure represent potential target for iNO treatment. Clinical data are still poor. * diseases where only preclinical studies are available or clinical trials are ongoing. § conflicting data, see text for further details. Abbreviations: PVR, pulmonary vascular resistances; PPHN, persistent pulmonary hypertension of the newborn; ECMO, extracorporeal membrane oxygenation; ROSC, return of spontaneous circulation; LCOS, low cardiac output syndrome; ARDS, acute respiratory distress syndrome; V/Q, ventilation-to- perfusion ratio; PA, pulmonary artery; AKI, acute kidney injury; CPB, cardiopulmonary bypass; CKD, chronic kidney disease; pts, patients; NO, nitric oxide; PAH, pulmonary arterial hypertension.