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

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.

Amplitude Spectrum Area of ventricular fibrillation to guide defibrillation: a small open-label, pseudo-randomized controlled multicenter trial.

BACKGROUND: Ventricular fibrillation (VF) waveform analysis has been proposed as a potential non-invasive guide to optimize timing of defibrillation. METHODS: The AMplitude Spectrum Area (AMSA) trial is an open-label, multicenter randomized controlled study reporting the first in-human use of AMSA analysis in out-of-hospital cardiac arrest (OHCA). The primary efficacy endpoint was the termination of VF for an AMSA ≥ 15.5 mV-Hz. Adult shockable OHCAs randomly received either an AMSA-guided cardiopulmonary resuscitation (CPR) or a standard-CPR. Randomization and allocation to trial group were carried out centrally. In the AMSA-guided CPR, an initial AMSA ≥ 15.5 mV-Hz prompted for immediate defibrillation, while lower values favored chest compression (CC). After completion of the first 2-min CPR cycle, an AMSA < 6.5 mV-Hz deferred defibrillation in favor of an additional 2-min CPR cycle. AMSA was measured and displayed in real-time during CC pauses for ventilation with a modified defibrillator. FINDINGS: The trial was early discontinued for low recruitment due to the COVID-19 pandemics. A total of 31 patients were recruited in 3 Italian cities, 19 in AMSA-CPR and 12 in standard-CPR, and included in the data analysis. No difference in primary outcome was observed between the two groups. Termination of VF occurred in 74% of patients in the AMSA-CPR compared to 75% in the standard CPR (OR 0.93 [95% CI 0.18-4.90]). No adverse events were reported. INTERPRETATION: AMSA was used prospectively in human patients during ongoing CPR. In this small trial, an AMSA-guided defibrillation provided no evidence of an improvement in termination of VF. TRIAL REGISTRATION: NCT03237910. FUNDING: European Commission - Horizon 2020; ZOLL Medical Corp., Chelmsford, USA (unrestricted grant); Italian Ministry of Health - Current research IRCCS.

Inhaled nitric oxide: role in the pathophysiology of cardio-cerebrovascular and respiratory diseases.

Nitric oxide (NO) is a key molecule in the biology of human life. NO is involved in the physiology of organ viability and in the pathophysiology of organ dysfunction, respectively. In this narrative review, we aimed at elucidating the mechanisms behind the role of NO in the respiratory and cardio-cerebrovascular systems, in the presence of a healthy or dysfunctional endothelium. NO is a key player in maintaining multiorgan viability with adequate organ blood perfusion. We report on its physiological endogenous production and effects in the circulation and within the lungs, as well as the pathophysiological implication of its disturbances related to NO depletion and excess. The review covers from preclinical information about endogenous NO produced by nitric oxide synthase (NOS) to the potential therapeutic role of exogenous NO (inhaled nitric oxide, iNO). Moreover, the importance of NO in several clinical conditions in critically ill patients such as hypoxemia, pulmonary hypertension, hemolysis, cerebrovascular events and ischemia-reperfusion syndrome is evaluated in preclinical and clinical settings. Accordingly, the mechanism behind the beneficial iNO treatment in hypoxemia and pulmonary hypertension is investigated. Furthermore, investigating the pathophysiology of brain injury, cardiopulmonary bypass, and red blood cell and artificial hemoglobin transfusion provides a focus on the potential role of NO as a protective molecule in multiorgan dysfunction. Finally, the preclinical toxicology of iNO and the antimicrobial role of NO-including its recent investigation on its role against the Sars-CoV2 infection during the COVID-19 pandemic-are described.

Nitric oxide: Clinical applications in critically ill patients.

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.

Development of a Critical Care Response - Experiences from Italy During the Coronavirus Disease 2019 Pandemic.

Italy was the first western country facing an outbreak of coronavirus disease 2019 (COVID-19). The first Italian patient diagnosed with COVID-19 was admitted, on Feb. 20, 2020, to the intensive care unit (ICU) in Codogno (Lodi, Lombardy, Italy), and the number of reported positive cases increased to 36 in the next 24 hours, and then exponentially for 18 days. This triggered a response that resulted in a massive surge in ICU bed capacity. The COVID19 Lombardy Network organized a structured logistic response and provided scientific evidence to highlight information on COVID-19 associated respiratory failure.

Noninvasive Ventilatory Support of Patients with COVID-19 outside the Intensive Care Units (WARd-COVID).

Rationale: Treatment with noninvasive ventilation (NIV) in coronavirus disease (COVID-19) is frequent. Shortage of intensive care unit (ICU) beds led clinicians to deliver NIV also outside ICUs. Data about the use of NIV in COVID-19 is limited.Objectives: To describe the prevalence and clinical characteristics of patients with COVID-19 treated with NIV outside the ICUs. To investigate the factors associated with NIV failure (need for intubation or death).Methods: In this prospective, single-day observational study, we enrolled adult patients with COVID-19 who were treated with NIV outside the ICU from 31 hospitals in Lombardy, Italy.Results: We collected data on demographic and clinical characteristics, ventilatory management, and patient outcomes. Of 8,753 patients with COVID-19 present in the hospitals on the study day, 909 (10%) were receiving NIV outside the ICU. A majority of patients (778/909; 85%) patients were treated with continuous positive airway pressure (CPAP), which was delivered by helmet in 617 (68%) patients. NIV failed in 300 patients (37.6%), whereas 498 (62.4%) patients were discharged alive without intubation. Overall mortality was 25%. NIV failure occurred in 152/284 (53%) patients with an arterial oxygen pressure (PaO2)/fraction of inspired oxygen (FiO2) ratio <150 mm Hg. Higher C-reactive protein and lower PaO2/FiO2 and platelet counts were independently associated with increased risk of NIV failure.Conclusions: The use of NIV outside the ICUs was common in COVID-19, with a predominant use of helmet CPAP, with a rate of success >60% and close to 75% in full-treatment patients. C-reactive protein, PaO2/FiO2, and platelet counts were independently associated with increased risk of NIV failure.Clinical trial registered with ClinicalTrials.gov (NCT04382235).