High-Dose Inhaled Nitric Oxide in Acute Hypoxemic Respiratory Failure Due to COVID-19: A Multicenter Phase II Trial.

Rationale: The effects of high-dose inhaled nitric oxide on hypoxemia in coronavirus disease (COVID-19) acute respiratory failure are unknown. Objectives: The primary outcome was the change in arterial oxygenation (PaO2/FiO2) at 48 hours. The secondary outcomes included: time to reach a PaO2/FiO2.300mmHg for at least 24 hours, the proportion of participants with a PaO2/FiO2.300mmHg at 28 days, and survival at 28 and at 90 days. Methods: Mechanically ventilated adults with COVID-19 pneumonia were enrolled in a phase II, multicenter, single-blind, randomized controlled parallel-arm trial. Participants in the intervention arm received inhaled nitric oxide at 80 ppm for 48 hours, compared with the control group receiving usual care (without placebo). Measurements and Main Results: A total of 193 participants were included in the modified intention-to-treat analysis. The mean change in PaO2/FiO2 ratio at 48 hours was 28.3mmHg in the intervention group and 21.4mmHg in the control group (mean difference, 39.1mmHg; 95% credible interval [CrI], 18.1 to 60.3). The mean time to reach a PaO2/FiO2.300mmHg in the interventional group was 8.7 days, compared with 8.4 days for the control group (mean difference, 0.44; 95% CrI, 23.63 to 4.53). At 28 days, the proportion of participants attaining a PaO2/FiO2.300mmHg was 27.7% in the inhaled nitric oxide group and 17.2% in the control subjects (risk ratio, 2.03; 95% CrI, 1.11 to 3.86). Duration of ventilation and mortality at 28 and 90 days did not differ. No serious adverse events were reported. Conclusions: The use of high-dose inhaled nitric oxide resulted in an improvement of PaO2/FiO2 at 48 hours compared with usual care in adults with acute hypoxemic respiratory failure due to COVID-19.

A Multidisciplinary Protocolized Approach for Ruptured Abdominal Aortic Aneurysm Management: A Retrospective Before-After Study.

OBJECTIVES: To investigate whether implementation of a multidisciplinary protocol for ruptured abdominal aortic aneurysm (rAAA) management reduces rates of adverse complications. DESIGN: A retrospective before-after study. SETTING: A tertiary-care academic hospital. PARTICIPANTS: Adult patients who underwent open or endovascular rAAA repair; data were stratified into before-protocol implementation (group 1: 2015-2018) and after-protocol implementation (group 2: 2019-2022) groups. INTERVENTION: The protocol details the workflow for vascular surgery, anesthesia, emergency department, and operating room staff for a rAAA case; training was accomplished through yearly workshops. MEASUREMENTS AND MAIN RESULTS: The primary outcome was in-hospital mortality. Secondary outcomes included all-cause morbidity and other major complications. Differences in postoperative complication rates between groups were assessed using Pearson's χ2 test. Of the 77 patients included undergoing rAAA repair, 41 (53.2%) patients were in group 1, and 36 (46.8%) patients were in group 2. Patients in group 2 had a significantly shorter median time to incision (1.0 v 0.7 hours, p = 0.022) and total procedure time (180.0 v 160.5 minutes, p = 0.039) for both endovascular and open repair. After protocol implementation, patients undergoing endovascular repair exhibited significantly lower rates of mortality (46.2% v 20.0%, p = 0.048), all-cause morbidity (65.4% v 44.0%, p = 0.050), and renal complications (15.4% v 0.0%, p = 0.036); patients undergoing open repair for a rAAA exhibited significantly lower rates of mortality (53.3% v 27.3%, p = 0.018) and bowel ischemia (26.7% v 0.0%, p = 0.035). CONCLUSIONS: Implementation of a multidisciplinary protocol for the management of a rAAA may reduce rates of adverse complications and improve the quality of care.

Veno-venous extracorporeal blood phototherapy increases the rate of carbon monoxide (CO) elimination in CO-poisoned pigs.

BACKGROUND AND OBJECTIVES: Carbon monoxide (CO) inhalation is the leading cause of poison-related deaths in the United States. CO binds to hemoglobin (Hb), displaces oxygen, and reduces oxygen delivery to tissues. The optimal treatment for CO poisoning in patients with normal lung function is the administration of hyperbaric oxygen (HBO). However, hyperbaric chambers are only available in medical centers with specialized equipment, resulting in delayed therapy. Visible light dissociates CO from Hb with minimal effect on oxygen binding. In a previous study, we combined a membrane oxygenator with phototherapy at 623 nm to produce a "mini" photo-ECMO (extracorporeal membrane oxygenation) device, which improved CO elimination and survival in CO-poisoned rats. The objective of this study was to develop a larger photo-ECMO device ("maxi" photo-ECMO) and to test its ability to remove CO from a porcine model of CO poisoning. STUDY DESIGN/MATERIALS AND METHODS: The "maxi" photo-ECMO device and the photo-ECMO system (six maxi photo-ECMO devices assembled in parallel), were tested in an in vitro circuit of CO poisoning. To assess the ability of the photo-ECMO device and the photo-ECMO system to remove CO from CO-poisoned blood in vitro, the half-life of COHb (COHb-t1/2 ), as well as the percent COHb reduction in a single blood pass through the device, were assessed. In the in vivo studies, we assessed the COHb-t1/2 in a CO-poisoned pig under three conditions: (1) While the pig breathed 100% oxygen through the endotracheal tube; (2) while the pig was connected to the photo-ECMO system with no light exposure; and (3) while the pig was connected to the photo-ECMO system, which was exposed to red light. RESULTS: The photo-ECMO device was able to fully oxygenate the blood after a single pass through the device. Compared to ventilation with 100% oxygen alone, illumination with red light together with 100% oxygen was twice as efficient in removing CO from blood. Changes in gas flow rates did not alter CO elimination in one pass through the device. Increases in irradiance up to 214 mW/cm2 were associated with an increased rate of CO elimination. The photo-ECMO device was effective over a range of blood flow rates and with higher blood flow rates, more CO was eliminated. A photo-ECMO system composed of six photo-ECMO devices removed CO faster from CO-poisoned blood than a single photo-ECMO device. In a CO-poisoned pig, the photo-ECMO system increased the rate of CO elimination without significantly increasing the animal's body temperature or causing hemodynamic instability. CONCLUSION: In this study, we developed a photo-ECMO system and demonstrated its ability to remove CO from CO-poisoned 45-kg pigs. Technical modifications of the photo-ECMO system, including the development of a compact, portable device, will permit treatment of patients with CO poisoning at the scene of their poisoning, during transit to a local emergency room, and in hospitals that lack HBO facilities.

Inhaled high dose nitric oxide is a safe and effective respiratory treatment in spontaneous breathing hospitalized patients with COVID-19 pneumonia.

BACKGROUND: Inhaled nitric oxide (NO) is a selective pulmonary vasodilator. In-vitro studies report that NO donors can inhibit replication of SARS-CoV-2. This multicenter study evaluated the feasibility and effects of high-dose inhaled NO in non-intubated spontaneously breathing patients with Coronavirus disease-2019 (COVID-19). METHODS: This is an interventional study to determine whether NO at 160 parts-per-million (ppm) inhaled for 30 min twice daily might be beneficial and safe in non-intubated COVID-19 patients. RESULTS: Twenty-nine COVID-19 patients received a total of 217 intermittent inhaled NO treatments for 30 min at 160 ppm between March and June 2020. Breathing NO acutely decreased the respiratory rate of tachypneic patients and improved oxygenation in hypoxemic patients. The maximum level of nitrogen dioxide delivered was 1.5 ppm. The maximum level of methemoglobin (MetHb) during the treatments was 4.7%. MetHb decreased in all patients 5 min after discontinuing NO administration. No adverse events during treatment, such as hypoxemia, hypotension, or acute kidney injury during hospitalization occurred. In our NO treated patients, one patient of 29 underwent intubation and mechanical ventilation, and none died. The median hospital length of stay was 6 days [interquartile range 4-8]. No discharged patients required hospital readmission nor developed COVID-19 related long-term sequelae within 28 days of follow-up. CONCLUSIONS: In spontaneous breathing patients with COVID-19, the administration of inhaled NO at 160 ppm for 30 min twice daily promptly improved the respiratory rate of tachypneic patients and systemic oxygenation of hypoxemic patients. No adverse events were observed. None of the subjects was readmitted or had long-term COVID-19 sequelae.

Patient hesitancy in perioperative clinical trial enrollment during the COVID-19 pandemic.

The COVID-19 pandemic has caused tremendous disruptions to non-COVID-19 clinical research. However, there has been little investigation on how patients themselves have responded to clinical trial recruitment during the COVID-19 pandemic. To investigate the effect of the COVID-19 pandemic on rates of patient consent to enrollment into non-COVID-19 clinical trials, we carried out a cross-sectional study using data from the Nitric Oxide/Acute Kidney Injury (NO/AKI) and Minimizing ICU Neurological Dysfunction with Dexmedetomidine-Induced Sleep (MINDDS) trials. All patients eligible for the NO/AKI or MINDDS trials who came to the hospital for cardiac surgery and were approached to gain consent to enrollment were included in the current study. We defined "Before COVID-19" as the time between the start of the relevant clinical trial and the date when efforts toward that clinical trial were deescalated by the hospital due to COVID-19. We defined "During COVID-19" as the time between trial de-escalation and trial completion. 5,015 patients were screened for eligibility. 3,851 were excluded, and 1,434 were approached to gain consent to enrollment. The rate of consent to enrollment was 64% in the "Before COVID-19" group and 45% in the "During COVID-19" group (n = 1,334, P<0.001) (RR = 0.70, 95% CI 0.62 to 0.80, P<0.001). Thus, we found that rates of consent to enrollment into the NO/AKI and MINDDS trials dropped significantly with the onset of the COVID-19 pandemic. Patient demographic and socioeconomic status data collected from electronic medical records and patient survey data did not shed light on possible explanations for this observed drop, indicating that there were likely other factors at play that were not directly measured in the current study. Increased patient hesitancy to enroll in clinical trials can have detrimental effects on clinical science, patient health, and patient healthcare experience, so understanding and addressing this issue during the COVID-19 pandemic is crucial.

Pronation Reveals a Heterogeneous Response of Global and Regional Respiratory Mechanics in Patients With Acute Hypoxemic Respiratory Failure.

OBJECTIVES: Experimental models suggest that prone position and positive end-expiratory pressure (PEEP) homogenize ventral-dorsal ventilation distribution and regional respiratory compliance. However, this response still needs confirmation on humans. Therefore, this study aimed to assess the changes in global and regional respiratory mechanics in supine and prone positions over a range of PEEP levels in acute respiratory distress syndrome (ARDS) patients. DESIGN: A prospective cohort study. PATIENTS: Twenty-two intubated patients with ARDS caused by COVID-19 pneumonia. INTERVENTIONS: Electrical impedance tomography and esophageal manometry were applied during PEEP titrations from 20 cm H2O to 6 cm H2O in supine and prone positions. MEASUREMENTS: Global respiratory system compliance (Crs), chest wall compliance, regional lung compliance, ventilation distribution in supine and prone positions. MAIN RESULTS: Compared with supine position, the maximum level of Crs changed after prone position in 59% of ARDS patients (n = 13), of which the Crs decreased in 32% (n = 7) and increased in 27% (n = 6). To reach maximum Crs after pronation, PEEP was changed in 45% of the patients by at least 4 cm H2O. After pronation, the ventilation and compliance of the dorsal region did not consistently change in the entire sample of patients, increasing specifically in a subgroup of patients who showed a positive change in Crs when transitioning from supine to prone position. These combined changes in ventilation and compliance suggest dorsal recruitment postpronation. In addition, the subgroup with increased Crs postpronation demonstrated the most pronounced difference between dorsal and ventral ventilation distribution from supine to prone position (p = 0.01), indicating heterogeneous ventilation distribution in prone position. CONCLUSIONS: Prone position modifies global respiratory compliance in most patients with ARDS. Only a subgroup of patients with a positive change in Crs postpronation presented a consistent improvement in dorsal ventilation and compliance. These data suggest that the response to pronation on global and regional mechanics can vary among ARDS patients, with some patients presenting more dorsal lung recruitment than others.

[Novel immunological aspects of pediatric kidney transplantation]. / Nuovi aspetti immunologici del trapianto di rene in eta' pediatrica.

Pediatric kidney transplantation has been a serious challenge from the outset. The main reason lies in the immune system of children, which presents significant differences in terms of lymphocyte subpopulation distribution and alloimmune response activation from the adult immune system. These differences are greatest between neonates and adults, while they decrease in a linear and age-dependent fashion. In the past, kidney transplantation in children was a courageous initiative, given the poorer outcomes compared with adult recipients. Today, thanks to advances in therapy protocols and a better knowledge of the pediatric immune system, graft survival in pediatric patients has significantly improved and transplantation is the standard of care for the treatment of chronic organ failure in children. Moreover, there is growing interest in the field of pediatric transplantation because of the recipients' peculiar infective risk profile, the underestimated cardiovascular risk, and the necessity to identify both new non-invasive diagnostic techniques and the characteristics that make the pediatric immune system so peculiar. Acquiring new knowledge in those fields may slow down the adoption of new therapies but, on the other hand, it may represent a starting point to provide pediatric allograft recipients with diagnostic and therapeutic advantages and ultimately achieve allograft tolerance.

Chemiluminescence-based Assays for Detection of Nitric Oxide and its Derivatives from Autoxidation and Nitrosated Compounds.

Nitric oxide (NO) activity in vivo is the combined results of its direct effects, the action of its derivatives generated from NO autoxidation, and the effects of nitrosated compounds. Measuring NO metabolites is essential to studying NO activity both at vascular levels and in other tissues, especially in the experimental settings where exogenous NO is administered. Ozone-based chemiluminescence assays allow precise measurements of NO and NO metabolites in both fluids (including plasma, tissue homogenates, cell cultures) and gas mixtures (e.g., exhaled breath). NO reacts with ozone to generate nitrogen dioxide in an excited state. The consequent light emission allows photodetection and the generation of an electric signal reflecting the NO content of the sample. Aliquots from the same sample can be used to measure specific NO metabolites, such as nitrate, nitrite, S-nitrosothiols, and iron-nitrosyl complexes. In addition, NO consumed by cell-free hemoglobin is also quantified with chemiluminescence analysis. An illustration of all these techniques is provided.

A Novel Inhalation Mask System to Deliver High Concentrations of Nitric Oxide Gas in Spontaneously Breathing Subjects.

Nitric Oxide (NO) is administered as gas for inhalation to induce selective pulmonary vasodilation. It is a safe therapy, with few potential risks even if administered at high concentration. Inhaled NO gas is routinely used to increase systemic oxygenation in different disease conditions. The administration of high concentrations of NO also exerts a virucidal effect in vitro. Owing to its favorable pharmacodynamic and safety profiles, the familiarity in its use by critical care providers, and the potential for a direct virucidal effect, NO is clinically used in patients with coronavirus disease-2019 (COVID-19). Nevertheless, no device is currently available to easily administer inhaled NO at concentrations higher than 80 parts per million (ppm) at various inspired oxygen fractions, without the need for dedicated, heavy, and costly equipment. The development of a reliable, safe, inexpensive, lightweight, and ventilator-free solution is crucial, particularly for the early treatment of non-intubated patients outside of the intensive care unit (ICU) and in a limited-resource scenario. To overcome such a barrier, a simple system for the non-invasive NO gas administration up to 250 ppm was developed using standard consumables and a scavenging chamber. The method has been proven safe and reliable in delivering a specified NO concentration while limiting nitrogen dioxide levels. This paper aims to provide clinicians and researchers with the necessary information on how to assemble or adapt such a system for research purposes or clinical use in COVID-19 or other diseases in which NO administration might be beneficial.

Transthoracic Echocardiography in Prone Patients With Acute Respiratory Distress Syndrome: A Feasibility Study.

OBJECTIVES: Patients with acute respiratory distress syndrome are at risk for developing cardiac dysfunction which is independently associated with worse outcomes. Transthoracic echocardiography is an ideal imaging modality for goal-directed assessment and optimization of cardiac function and volume status. Prone positioning, while demonstrated to improve oxygenation, offload the right ventricle, and reduce short-term mortality in acute respiratory distress syndrome, has previously precluded transthoracic echocardiography on these patients. The purpose of this study was to assess the ability to perform focused transthoracic echocardiography examinations on acute respiratory distress syndrome patients in the prone position. DESIGN: We performed a cross-sectional study of critically ill patients hospitalized for acute respiratory distress syndrome due to coronavirus disease 2019. SETTING: This study was conducted in medical and surgical intensive units in a tertiary hospital. PATIENTS: We examined 27 mechanically ventilated and prone patients with acute respiratory distress syndrome due to coronavirus disease 2019. Participants were examined at the time of enrollment in an ongoing clinical trial (NCT04306393), and no patients were excluded from echocardiographic analysis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We were able to perform transthoracic echocardiography and obtain satisfactory images for quantitative assessment of right ventricular function in 24 out of 27 (88.9%) and left ventricular function in 26 out of 27 (96.3%) of patients in the prone position, including many who were obese and on high levels of positive end-expiratory pressure (≥ 15 cm H2O). CONCLUSIONS: Transthoracic echocardiography can be performed at the prone patient's bedside by critical care intensivists. These findings encourage the use of focused transthoracic echocardiography for goal-directed cardiac assessment in acute respiratory distress syndrome patients undergoing prone positioning.

Protocol for a randomized controlled trial testing inhaled nitric oxide therapy in spontaneously breathing patients with COVID-19.

Introduction: the current worldwide outbreak of Coronavirus disease 2019 (COVID-19) due to a novel coronavirus (SARS-CoV-2) is seriously threatening the public health. The number of infected patients is continuously increasing and the need for Intensive Care Unit admission ranges from 5 to 26%. The mortality is reported to be around 3.4% with higher values for the elderly and in patients with comorbidities. Moreover, this condition is challenging the healthcare system where the outbreak reached its highest value. To date there is still no available treatment for SARS-CoV-2. Clinical and preclinical evidence suggests that nitric oxide (NO) has a beneficial effect on the coronavirus-mediated acute respiratory syndrome, and this can be related to its viricidal effect. The time from the symptoms' onset to the development of severe respiratory distress is relatively long. We hypothesize that high concentrations of inhaled NO administered during early phases of COVID-19 infection can prevent the progression of the disease. Methods and analysis: This is a multicenter randomized controlled trial. Spontaneous breathing patients admitted to the hospital for symptomatic COVID-19 infection will be eligible to enter the study. Patients in the treatment group will receive inhaled NO at high doses (140-180 parts per million) for 30 minutes, 2 sessions every day for 14 days in addition to the hospital care. Patient in the control group will receive only hospital care. The primary outcome is the percentage of patients requiring endotracheal intubation due to the progression of the disease in the first 28 days from enrollment in the study. Secondary outcomes include mortality at 28 days, proportion of negative test for SARS-CoV-2 at 7 days and time to clinical recovery. Ethics and dissemination: The trial protocol has been approved at the Investigation Review Boards of Xijing Hospital (Xi'an, China) and The Partners Human Research Committee of Massachusetts General Hospital (Boston, USA) is pending. Recruitment is expected to start in March 2020. Results of this study will be published in scientific journals, presented at scientific meetings, and on related website or media in fighting this widespread contagious disease.

High Concentrations of Nitric Oxide Inhalation Therapy in Pregnant Patients With Severe Coronavirus Disease 2019 (COVID-19).

BACKGROUND: Rescue therapies to treat or prevent progression of coronavirus disease 2019 (COVID-19) hypoxic respiratory failure in pregnant patients are lacking. METHOD: To treat pregnant patients meeting criteria for severe or critical COVID-19 with high-dose (160-200 ppm) nitric oxide by mask twice daily and report on their clinical response. EXPERIENCE: Six pregnant patients were admitted with severe or critical COVID-19 at Massachusetts General Hospital from April to June 2020 and received inhalational nitric oxide therapy. All patients tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A total of 39 treatments was administered. An improvement in cardiopulmonary function was observed after commencing nitric oxide gas, as evidenced by an increase in systemic oxygenation in each administration session among those with evidence of baseline hypoxemia and reduction of tachypnea in all patients in each session. Three patients delivered a total of four neonates during hospitalization. At 28-day follow-up, all three patients were home and their newborns were in good condition. Three of the six patients remain pregnant after hospital discharge. Five patients had two negative test results on nasopharyngeal swab for SARS-CoV-2 within 28 days from admission. CONCLUSION: Nitric oxide at 160-200 ppm is easy to use, appears to be well tolerated, and might be of benefit in pregnant patients with COVID-19 with hypoxic respiratory failure.

Clinical signature and pathogenetic factors of diabetes associated with pancreas disease (T3cDM): a prospective observational study in surgical patients.

To characterize the clinical signature and etiopathogenetic factors of diabetes associated with pancreas disease [type 3 diabetes mellitus (T3cDM)]. To estimate incidence and identify predictors of both diabetes onset and remission after pancreatic surgery. A prospective observational study was conducted. From January 2008 to December 2012, patients (n = 651) with new diagnosis of pancreatic disease admitted to the Pancreatic Surgery Unit of the San Raffaele Scientific Institute were evaluated. Hospital and/or outpatient medical records were reviewed. Blood biochemical values including fasting blood glucose, insulin and/or C-peptide, glycosylated hemoglobin and anti-islet antibodies were determined. Diabetes onset was assessed after surgery and during follow-up. At baseline, the prevalence of diabetes was 38 % (age of onset 64 ± 11 years). In most cases, diabetes occurred within 48 months from pancreatic disease diagnosis. Among different pancreatic diseases, minor differences were observed in diabetes characteristics, with the exception of the prevalence. Diabetes appeared associated with classical risk factors for type 2 diabetes (i.e., age, sex, family history of diabetes and body mass index), and both beta-cell dysfunction and insulin resistance appeared relevant determinants. The prevalence of adult-onset autoimmune diabetes was as previously reported within type 2 diabetes. Within a few days after surgery, either diabetes remission or new-onset diabetes was observed. In patients with pancreatic cancer, no difference in diabetes remission was observed after palliative or resective surgery. Classical risk factors for type 2 diabetes were associated with the onset of diabetes after surgery. T3cDM appeared as a heterogeneous entity strongly overlapped with type 2 diabetes.

Strategies to reverse endothelial progenitor cell dysfunction in diabetes.

Bone-marrow-derived cells-mediated postnatal vasculogenesis has been reported as the main responsible for the regulation of vascular homeostasis in adults. Since their discovery, endothelial progenitor cells have been depicted as mediators of postnatal vasculogenesis for their peculiar phenotype (partially staminal and partially endothelial), their ability to differentiate in endothelial cell line and to be incorporated into the vessels wall during ischemia/damage. Diabetes mellitus, a condition characterized by cardiovascular disease, nephropathy, and micro- and macroangiopathy, showed a dysfunction of endothelial progenitor cells. Herein, we review the mechanisms involved in diabetes-related dysfunction of endothelial progenitor cells, highlighting how hyperglycemia affects the different steps of endothelial progenitor cells lifetime (i.e., bone marrow mobilization, trafficking into the bloodstream, differentiation in endothelial cells, and homing in damaged tissues/organs). Finally, we review preclinical and clinical strategies that aim to revert diabetes-induced dysfunction of endothelial progenitor cells as a means of finding new strategies to prevent diabetic complications.