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 (Pa O 2 )/fraction of inspired oxygen (F i O 2 ) ratio <150 mm Hg. Higher C-reactive protein and lower Pa O 2 /F i O 2 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, Pa O 2 /F i O 2 , and platelet counts were independently associated with increased risk of NIV failure. Clinical trial registered with ClinicalTrials.gov (NCT04382235).

The mammalian brain is highly vulnerable to oxygen deprivation, yet the mechanism underlying the brain’s sensitivity to hypoxia is incompletely understood. Hypoxia induces accumulation of hydrogen sulfide, a gas that inhibits mitochondrial respiration. Here, we show that, in mice, rats, and naturally hypoxia-tolerant ground squirrels, the sensitivity of the brain to hypoxia is inversely related to the levels of sulfide:quinone oxidoreductase (SQOR) and the capacity to catabolize sulfide. Silencing SQOR increased the sensitivity of the brain to hypoxia, whereas neuron-specific SQOR expression prevented hypoxia-induced sulfide accumulation, bioenergetic failure, and ischemic brain injury. Excluding SQOR from mitochondria increased sensitivity to hypoxia not only in the brain but also in heart and liver. Pharmacological scavenging of sulfide maintained mitochondrial respiration in hypoxic neurons and made mice resistant to hypoxia. These results illuminate the critical role of sulfide catabolism in energy homeostasis during hypoxia and identify a therapeutic target for ischemic brain injury.

Background Mechanical chest compression (CC) is currently suggested to deliver sustained high‐quality CC in a moving ambulance. This study compared the hemodynamic support provided by a mechanical piston device or manual CC during ambulance transport in a porcine model of cardiopulmonary resuscitation. Methods and Results In a simulated urban ambulance transport, 16 pigs in cardiac arrest were randomized to 18 minutes of mechanical CC with the LUCAS (n=8) or manual CC (n=8). ECG, arterial and right atrial pressure, together with end‐tidal CO 2 and transthoracic impedance curve were continuously recorded. Arterial lactate was assessed during cardiopulmonary resuscitation and after resuscitation. During the initial 3 minutes of cardiopulmonary resuscitation, the ambulance was stationary, while then proceeded along a predefined itinerary. When the ambulance was stationary, CC‐generated hemodynamics were equivalent in the 2 groups. However, during ambulance transport, arterial and coronary perfusion pressure, and end‐tidal CO 2 were significantly higher with mechanical CC compared with manual CC (coronary perfusion pressure: 43±4 versus 18±4 mmHg; end‐tidal CO 2 : 31±2 versus 19±2 mmHg, P <0.01 at 18 minutes). During cardiopulmonary resuscitation, arterial lactate was lower with mechanical CC compared with manual CC (6.6±0.4 versus 8.2±0.5 mmol/L, P <0.01). During transport, mechanical CC showed greater constancy compared with the manual CC, as represented by a higher CC fraction and a lower transthoracic impedance curve variability ( P <0.01). All animals in the mechanical CC group and 6 (75%) in the manual one were successfully resuscitated. Conclusions This model adds evidence in favor of the use of mechanical devices to provide ongoing high‐quality CC and tissue perfusion during ambulance transport.

Background: While supportive treatment for traumatic brain injury (TBI) has progressed, specific neuroprotective interventions are still lacking. Models of ischaemic heart and brain injury show a therapeutic potential for Argon gas, but it is still not known whether inhaled Argon (iAr) is protective in TBI. We tested the effects of iAr administered acutely to TBI mice on brain oedema, tissue microenvironmental changes, neurological functions and structural outcome.Methods: Anaesthetized adult C57BL/6J mice were subjected to severe TBI by controlled cortical impact. Ten minutes after TBI, mice were randomized to 24h treatment with iAr 70%-O2 30% or air (iCtr). Sensorimotor deficits were evaluated up to six weeks post-TBI by three independent tests.Cognitive function was evaluated by Barnes maze test at four weeks. Magnetic resonance imaging (MRI) was done to examine brain oedema at three days and white matter damages at five weeks.Microglia/macrophage activation and functional commitment was evaluated at one week after TBI by immunohistochemistry.Results: iAr significantly accelerated sensorimotor recovery and improved cognitive deficits one month after TBI, with less white matter damage in the ipsilateral fimbria and body of the corpus callosum. Early changes underpinning protection included a reduction of pericontusional vasogenic oedema and action on the inflammatory response. iAr significantly reduced microglial activation with increases in ramified cells and the M2-like marker YM1. Conclusion: iAr accelerates recovery of sensorimotor function and improves cognitive and structural outcome one-month after severe TBI in mice. Early effects include a reduction of brain oedema and neuroinflammation in the contused tissue.

Background Ventilation with the noble gas argon (Ar) has shown neuroprotective and cardioprotective properties in different in vitro and in vivo models. Hence, the neuroprotective effects of Ar were investigated in a severe, preclinically relevant porcine model of cardiac arrest. Methods and Results Cardiac arrest was ischemically induced in 36 pigs and left untreated for 12 minutes before starting cardiopulmonary resuscitation. Animals were randomized to 4‐hour post‐resuscitation ventilation with: 70% nitrogen–30% oxygen (control); 50% Ar–20% nitrogen–30% oxygen (Ar 50%); and 70% Ar–30% oxygen (Ar 70%). Hemodynamic parameters and myocardial function were monitored and serial blood samples taken. Pigs were observed up to 96 hours for survival and neurological recovery. Heart and brain were harvested for histopathology. Ten animals in each group were successfully resuscitated. Ninety‐six‐hour survival was 60%, 70%, and 90%, for the control, Ar 50%, and Ar 70% groups, respectively. In the Ar 50% and Ar 70% groups, 60% and 80%, respectively, achieved good neurological recovery, in contrast to only 30% in the control group ( P <0.0001). Histology showed less neuronal degeneration in the cortex ( P <0.05) but not in the hippocampus, and less reactive microglia activation in the hippocampus ( P =0.007), after Ar compared with control treatment. A lower increase in circulating biomarkers of brain injury, together with less kynurenine pathway activation ( P <0.05), were present in Ar‐treated animals compared with controls. Ar 70% pigs also had complete left ventricular function recovery and smaller infarct and cardiac troponin release ( P <0.01). Conclusions Post‐resuscitation ventilation with Ar significantly improves neurologic recovery and ameliorates brain injury after cardiac arrest with long no‐flow duration. Benefits are greater after Ar 70% than Ar 50%.

The noninvasive CO estimation with esCCO and ICON exhibited limited accuracy and precision, despite with reasonable trending ability, when compared to TDCO, during OLT. The inaccuracy of esCCO and ICON is especially large when SVR and Ea were decreased during the neohepatic phase. Further refinement of the technology is desirable before noninvasive techniques can replace TDCO during OLT.

Background: The biological effects of nitric oxide are mediated via protein S-nitrosylation. Levels of S-nitrosylated protein are controlled in part by the denitrosylase, S-nitrosoglutathione reductase (GSNOR). The objective of this study was to examine whether GSNOR inhibition improves outcomes after cardiac arrest and cardiopulmonary resuscitation (CA/CPR). Methods: Adult wild-type C57BL/6 and GSNOR-deleted (GSNOR −/− ) mice were subjected to potassium chloride-induced CA and subsequently resuscitated. Fifteen minutes after a return of spontaneous circulation, wild-type mice were randomized to receive the GSNOR inhibitor, SPL-334.1, or normal saline as placebo. Mortality, neurological outcome, GSNOR activity, and levels of S-nitrosylated proteins were evaluated. Plasma GSNOR activity was measured in plasma samples obtained from post-CA patients, preoperative cardiac surgery patients, and healthy volunteers. Results: GSNOR activity was increased in plasma and multiple organs of mice, including brain in particular. Levels of protein S-nitrosylation were decreased in the brain 6 hours after CA/CPR. Administration of SPL-334.1 attenuated the increase in GSNOR activity in brain, heart, liver, spleen, and plasma, and restored S-nitrosylated protein levels in the brain. Inhibition of GSNOR attenuated ischemic brain injury and improved survival in wild-type mice after CA/CPR (81.8% in SPL-334.1 versus 36.4% in placebo; log rank P =0.031). Similarly, GSNOR deletion prevented the reduction in the number of S-nitrosylated proteins in the brain, mitigated brain injury, and improved neurological recovery and survival after CA/CPR. Both GSNOR inhibition and deletion attenuated CA/CPR-induced disruption of blood brain barrier. Post-CA patients had higher plasma GSNOR activity than did preoperative cardiac surgery patients or healthy volunteers ( P <0.0001). Plasma GSNOR activity was positively correlated with initial lactate levels in postarrest patients (Spearman correlation coefficient=0.48; P =0.045). Conclusions: CA and CPR activated GSNOR and reduced the number of S-nitrosylated proteins in the brain. Pharmacological inhibition or genetic deletion of GSNOR prevented ischemic brain injury and improved survival rates by restoring S-nitrosylated protein levels in the brain after CA/CPR in mice. Our observations suggest that GSNOR is a novel biomarker of postarrest brain injury as well as a molecular target to improve outcomes after CA.

Synopsis 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 the 20 th of February 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 prompt, coordinated response of the ICUs in the epicenter region of the outbreak - COVID19 Lombardy Network - that resulted in a massive surge in the ICU bed capacity. The COVID19 Lombardy Network organized a structured logistic response. Furthermore, it provided a significant amount of scientific evidence to highlight globally useful information on the clinical history of COVID-19 associated respiratory failure. The Italian experience was characterized by a significant use of helmet cPAP and prone positioning in awake patients to cope with the resource limitations during the pandemic outbreak. Specific national recommendations were structured to help clinicians during the hard choices of resource allocation. Humanitarian and educational programs were developed within the Italian population to promote awareness about patients and healthcare providers’ conditions during the pandemic.