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Objectives: To compare heparin-based anticoagulation and bivalirudin-based anticoagulation within the context of critically ill patients with a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Design: An observational study. Setting: At the intensive care unit of a university hospital. Participants and interventions: Critically ill patients with a SARS-CoV-2 infection receiving full anticoagulation with heparin or bivalirudin. Measurements and main results: Twenty-three patients received full anticoagulation with bivalirudin and 60 with heparin. Despite patients in the bivalirudin group having higher mortality risk scores (SAPS II 60 ± 16 v 39 ±7, p < 0.001) and a higher need for extracorporeal support compared to the heparin group, hospital mortality was comparable (57% v 45, p=0.3). No difference in thromboembolic complications was observed, and bleeding events were more frequent in patients treated with bivalirudin (65% v 40%, p=0.01). Similar results were confirmed in the subgroup analysis of patients undergoing intravenous anticoagulation; in addition to comparable thrombotic complications occurrence and thrombocytopenia rate, however, no difference in the bleeding rate was observed (65% v 35%, p=0.08). Conclusions: Although heparin is the most used anticoagulant in the intensive care setting, bivalirudin-based anticoagulation was safe and effective in a cohort of critically ill patients with SARS-CoV-2. Bivalirudin may be given full consideration as an anticoagulation strategy for critically ill patients with SARS-CoV-2, especially in those with thrombocytopenia and on extracorporeal support.

Objective: To describe the experience with CytoSorb treatment in patients with refractory acute respiratory distress syndrome (ARDS) following SARS-CoV-2 infection. Methods: Retrospective observational study on 15 patients treated in a University Hospital. Results: All patients were male, with a mean age of 55 ± 14 years; eight patients (53%) were on venovenous extracorporeal membrane oxygenation (VV ECMO) due to refractory ARDS and all (100%) under mechanical ventilation at the time of CytoSorb use. We observed reduction in the level of C reactive protein (−52%, p = 0.002), total bilirubin (−46%, p = 0.03), direct bilirubin (−50%, p = 0.02), and D-dimers (−39%, p = 0.04) during CytoSorb treatment and a trend toward reduction in lactate dehydrogenase (−20%, p = 0.2), creatine phosphokinase (−38%, p = 0.1), and fibrinogen (−15%, p = 0.07). Eight patients died (53%) and seven (47%) were discharged from the ICU, of which five had recovery of the native lung function and two were successfully bridged to lung transplantation on VV ECMO support. No difference between survivors and non-survivors was present at baseline. Patients received three CytoSorb cycles on average: mean duration of CytoSorb cycle was 17 h 21 min, but premature circuit clotting despite appropriate level of systemic anticoagulation was frequently observed. Conclusions: CytoSorb treatment was effective in improving several laboratory parameters and inflammation in our experience and no treatment-related adverse effects were recorded. In the light of the unique pathophysiology of SARS-CoV-2 infection, CytoSorb treatment is extremely promising, since it might both reduce inflammation and activation of coagulation.

OBJECTIVE: The use of angiotensin II in invasively ventilated patients with coronavirus disease 2019 (COVID-19) is controversial. Its effect on organ function is unknown. DESIGN: Prospective observational study. SETTING: Intensive care unit (ICU) of a tertiary academic hospital in Milan, Italy. PARTICIPANTS: Adult patients receiving mechanical ventilation due to COVID-19. INTERVENTIONS: Use angiotensin II either as rescue vasopressor agent or as low dose vasopressor support. MAIN OUTCOME MEASURES: Patients treated before angiotensin II was available or treated in an adjacent COVID-19 ICU served as controls. For data analysis, we applied Bayesian modelling as appropriate. We assessed the effects of angiotensin II on organ function. RESULTS: We compared 46 patients receiving angiotensin II therapy with 53 controls. Compared with controls, angiotensin II increased the mean arterial pressure (median difference, 9.05 mmHg; 95% CI, 1.87–16.22; P = 0.013) and the Pao2/Fio2 ratio (median difference, 23.17; 95% CI, 3.46–42.88; P = 0.021), and decreased the odds ratio (OR) of liver dysfunction (OR, 0.32; 95% CI, 0.09–0.94). However, angiotensin II had no effect on lactate, urinary output, serum creatinine, C-reactive protein, platelet count, or thromboembolic complications. In patients with abnormal baseline serum creatinine, Bayesian modelling showed that angiotensin II carried a 95.7% probability of reducing the use of renal replacement therapy (RRT). CONCLUSIONS: In ventilated patients with COVID-19, angiotensin II therapy increased blood pressure and Pao2/Fio2 ratios, decreased the OR of liver dysfunction, and appeared to decrease the risk of RRT use in patients with abnormal baseline serum creatinine. However, all of these findings are hypothesis-generating only. TRIAL REGISTRATION: ClinicalTrials.gov NCT04318366.

In patients with severe or critical Coronavirus disease 2019 (COVID-19) manifestations, a thromboinflammatory syndrome, with diffuse microvascular thrombosis, is increasingly evident as the final step of pro-inflammatory cytokines storm. Actually, no proven effective therapies for novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection exist. Preliminary observations on anticoagulant therapy appear to be associated with better outcomes in moderate and severe COVID-19 patients with signs of coagulopathy and in those requiring mechanical ventilation. The pathophysiology underlying the prothrombotic state elicited by SARS-CoV-2 outlines possible protective mechanisms of antithrombotic therapy (in primis anticoagulants) for this viral illness. The indications for antiplatelet/anticoagulant use (prevention, prophylaxis, therapy) are guided by the clinical context and the COVID-19 severity. We provide a practical approach on antithrombotic therapy management for COVID-19 patients from a multidisciplinary point of view., Highlights • An endothelial thromboinflammatory syndrome is involved in severe COVID-19 manifestations. • A pathophysiological rationale (anti-inflammatory and direct antiviral effects) motivates the use of antithrombotic therapy • Anticoagulant therapy is associated with better outcomes in case of coagulopathy and mechanical ventilation. • A potential role for antithrombotic therapy in COVID-19 prevention and treatment needs further investigation.

Purpose Perioperative myocardial dysfunction occurs frequently in cardiac surgery, and is a risk factor for morbidity and mortality. Levosimendan has been suggested to reduce mortality of patients with perioperative myocardial dysfunction. However, long-term outcome data on its efficacy in cardiac surgery are lacking. Materials and methods Cardiac surgery patients with perioperative myocardial dysfunction were randomized to levosimendan or placebo, in addition to standard inotropic care. One-year mortality data were collected. Results We randomized 506 patients (248 to levosimendan 258 to placebo). At 1-year follow-up, 41 patients (16.5%) died in the levosimendan group, while 47 (18.3%) died in the placebo group (absolute risk difference −1.8; 95% CI −8.4 to 4.9; P = .60). Female sex, history of chronic obstructive pulmonary disease, previous myocardial infarction, serum creatinine, hematocrit, mean arterial pressure, and duration of cardiopulmonary bypass were independently associated with 1-year mortality. Conclusions Levosimendan administration does not improve 1-year survival in cardiac surgery patients with perioperative myocardial dysfunction. One-year mortality in these patients is 17%. Six predictive factors for long-term mortality were identified. Study registration number NCT00994825 ( ClinicalTrials.gov ).

OBJECTIVES: In the general critical care patient population, restrictive transfusion regimen of RBCs has been shown to be safe and is yet implemented worldwide. However, in patients on venovenous extracorporeal membrane oxygenation, guidelines suggest liberal thresholds, and a clear overview of RBC transfusion practice is lacking. This study aims to create an overview of RBC transfusion in venovenous extracorporeal membrane oxygenation. DESIGN: Mixed method approach combining multicenter retrospective study and survey. SETTING: Sixteen ICUs worldwide. PATIENTS: Patients receiving venovenous extracorporeal membrane oxygenation between January 2018 and July 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the proportion receiving RBC, the amount of RBC units given daily and in total. Furthermore, the course of hemoglobin over time during extracorporeal membrane oxygenation was assessed. Demographics, extracorporeal membrane oxygenation characteristics, and patient outcome were collected. Two-hundred eight patients received venovenous extracorporeal membrane oxygenation, 63% male, with an age of 55 years (45-62 yr), mainly for acute respiratory distress syndrome. Extracorporeal membrane oxygenation duration was 9 days (5-14 d). Prior to extracorporeal membrane oxygenation, hemoglobin was 10.8 g/dL (8.9-13.0 g/dL), decreasing to 8.7 g/dL (7.7-9.8 g/dL) during extracorporeal membrane oxygenation. Nadir hemoglobin was lower on days when a transfusion was administered (8.1 g/dL [7.4-9.3 g/dL]). A vast majority of 88% patients received greater than or equal to 1 RBC transfusion, consisting of 1.6 U (1.3-2.3 U) on transfusion days. This high transfusion occurrence rate was also found in nonbleeding patients (81%). Patients with a liberal transfusion threshold (hemoglobin > 9 g/dL) received more RBC in total per transfusion day and extracorporeal membrane oxygenation day. No differences in survival, hemorrhagic and thrombotic complication rates were found between different transfusion thresholds. Also, 28-day mortality was equal in transfused and nontransfused patients. CONCLUSIONS: Transfusion of RBC has a high occurrence rate in patients on venovenous extracorporeal membrane oxygenation, even in nonbleeding patients. There is a need for future studies to find optimal transfusion thresholds and triggers in patients on extracorporeal membrane oxygenation.

Objective Patients with COVID-19 frequently develop acute respiratory distress syndrome (ARDS) requiring intensive care unit (ICU) admission. Data on long-term survival of these patients are lacking. We investigated 1-year survival, quality of life and functional recovery of COVID-19 ARDS patients requiring invasive mechanical ventilation Design Prospective observational study Setting Tertiary-care university hospital Participants All COVID-19 ARDS patients receiving invasive mechanical ventilation and discharged alive from hospital Interventions Patients were contacted by phone after 1-year. Functional, cognitive, and psychological outcomes were explored through a questionnaire and assessed using validated scales. Patients were offered the possibility to undergo a follow-up chest CT scan. Measurements and Main Results The study included all adult (age ≥ 18 years) patients with COVID-19-related ARDS admitted to an ICU of our institution between February 25th, 2020 - April 27th, 2020), who received at least one day of invasive mechanical ventilation (IMV). Of 116 patients who received IMV, 61 (52.6%) survived to hospital discharge. These survivors were assessed one year after discharge and 56 completed a battery of tests of cognition, activities of daily living and interaction with family members. They had overall good functional recovery, with >80% reporting good recovery and no difficulties in usual activities. A total of 52 (93%) of patients had no dyspnea at rest. Severe anxiety/depression was reported by five (8.9%) of patients. Comparing 2-months and 1-year data, we observed the most significant improvements in the areas of working status and exertional dyspnea. One-year Chest CT scans were available for 36 patients: fibrotic-like changes were present in four patients. Conclusions All patients who survived the acute phase of the COVID-19 disease and were discharged from the hospital were alive at the 1-year follow up and the vast majority of them had good overall recovery and quality of life. Study Registration ClinicalTrials.gov NCT04318366

Postoperative acute kidney injury (AKI) is frequent in cardiac surgery patients. Its pathophysiology is complex and involves decreased renal perfusion. Preliminary clinical evidence in critically ill patients shows that amino acids infusion increases renal blood flow and may decrease the incidence and severity of AKI. We designed a study to evaluate the effectiveness of perioperative continuous infusion of amino acids in decreasing AKI.This is a phase III, multi-center, randomized, double-blind, placebo-controlled trial. Adults undergoing cardiac surgery with cardiopulmonary bypass (CPB) are included. Patients are randomly assigned to receive either continuous infusion of a balanced mixture of amino acids in a dose of 2 g/kg ideal body weight/day or placebo (balanced crystalloid solution) from the operating room up to start of renal replacement therapy (RRT), or ICU discharge, or 72 h after the first dose. The primary outcome is the incidence of AKI during hospital stay defined by KDIGO (Kidney Disease: Improving Global Outcomes). Secondary outcomes include the need for, and duration of, RRT, mechanical ventilation; ICU and hospital length of stay; all-cause mortality at ICU, hospital discharge, 30, 90, and 180 days after randomization; quality of life at 180 days. Data will be analyzed in 3500 patients on an intention-to-treat basis.The trial is ongoing and currently recruiting. It will be one of the first randomized controlled studies to assess the relationship between amino acids use and kidney injury in cardiac surgery. If our hypothesis is confirmed, this practice could reduce morbidity in the studied population.This trial was registered on ClinicalTrials.gov with the trial identification NCT03709264 in October 2018.

BACKGROUND Consensus recommendations regarding the threshold levels of cardiac troponin elevations for the definition of perioperative myocardial infarction and clinically important periprocedural myocardial injury in patients undergoing cardiac surgery range widely (from >10 times to >= 70 times the upper reference limit for the assay). Limited evidence is available to support these recommendations. METHODS We undertook an international prospective cohort study involving patients 18 years of age or older who underwent cardiac surgery. High-sensitivity cardiac troponin I measurements (upper reference limit, 26 ng per liter) were obtained 3 to 12 hours after surgery and on days 1, 2, and 3 after surgery. We performed Cox analyses using a regression spline that explored the relationship between peak troponin measurements and 30-day mortality, adjusting for scores on the European System for Cardiac Operative Risk Evaluation II (which estimates the risk of death after cardiac surgery on the basis of 18 variables, including age and sex). RESULTS Of 13,862 patients included in the study, 296 (2.1%) died within 30 days after surgery. Among patients who underwent isolated coronary-artery bypass grafting or aortic-valve replacement or repair, the threshold troponin level, measured within 1 day after surgery, that was associated with an adjusted hazard ratio of more than 1.00 for death within 30 days was 5670 ng per liter (95% confidence interval [CI], 1045 to 8260), a level 218 times the upper reference limit. Among patients who underwent other cardiac surgery, the corresponding threshold troponin level was 12,981 ng per liter (95% CI, 2673 to 16,591), a level 499 times the upper reference limit. CONCLUSIONS The levels of high-sensitivity troponin I after cardiac surgery that were associated with an increased risk of death within 30 days were substantially higher than levels currently recommended to define clinically important periprocedural myocardial injury. (Funded by the Canadian Institutes of Health Research and others; VISION Cardiac Surgery ClinicalTrials.gov number, NCT01842568.)

BACKGROUND: COVID-19 is associated with elevated levels of inflammatory cytokines. We present the characteristics and outcomes of patients treated in the Intensive Care Unit (ICU) with immunosuppressive drugs, either tocilizumab or anakinra compared with controls. METHODS: A single-center observational prospective study on ICU invasively ventilated COVID-19 patients. The primary outcome was the clinical improvement at day 28. A Bayesian framework was employed, and all analyses were adjusted for confounders. RESULTS: Sixty-one consecutive invasively ventilated patients were included, nine (14.7%) received tocilizumab and 15 (24.6%) received anakinra. Over the first seven days, tocilizumab was associated with a greater decrease in C-reactive protein (P

BACKGROUND: COVID-19 disease can lead to severe functional impairments after discharge. We assessed the quality of life of invasively ventilated COVID-19 ARDS survivors. METHODS: We carried out a prospective follow-up study of the patients admitted to the Intensive Care Units (ICUs) of a teaching hospital. Patients affected by COVID-19 ARDS who required invasive ventilation and were successfully discharged home were assessed through the telephone administration of validated tests. We explored survival, functional outcomes, return to work, quality of life, cognitive and psychological sequelae. The main variables of interest were the following: demographics, severity scores, laboratory values, comorbidities, schooling, working status, treatments received during ICU stay, complications, and psychological, cognitive, functional outcomes. RESULTS: Out of 116 consecutive invasively ventilated patients, overall survival was 65/116 (56%) with no death occurring after hospital discharge. Forty-two patients were already discharged home with a median follow-up time of 61 (51-71) days after ICU discharge and 39 of them accepted to be interviewed. Only one patient (1/39) experienced cognitive decline. The vast majority of patients reported no difficulty in walking (32/35:82%), self-care (33/39:85%), and usual activities (30/39:78%). All patients were either malnourished (15/39:38%) or at risk for malnutrition (24/39:62%). Exertional dyspnea was present in 20/39 (51%) patients. 19/39 (49%) reported alterations in senses of smell and/or taste either before or after hospitalization. CONCLUSIONS: Invasively ventilated COVID-19 ARDS survivors have an overall good recovery at a 2-months follow-up which is better than what was previously reported in non-COVID-19 ARDS patients.

CytoSorb is a promising tool to treat severe inflammatory status with multiple mechanisms in the acute care setting. Its effect on drugs is, however, poorly documented in vivo, although removal of small molecules might translate into decreased blood levels of life-saving medications. The aim of this study was to assess the impact of CytoSorb on vancomycin and bivalirudin clearance in a large population of critically ill patients. We performed a single-center analysis of CytoSorb treatments performed between January 2018 and March 2019 in critically ill patients admitted to our intensive care unit. A total of 109 CytoSorb treatments were performed in 89 patients. A decrease in lactate dehydrogenase (P = .007), troponin T (P = .022), and creatine phosphokinase (P = .013) was reported during treatment. Vancomycin dose required significant adjustments during treatment (P < .001), but no significant change was necessary after the first 3 days. Similarly, the requirements of bivalirudin significantly changed over days (P < .001), but no dose adjustment was needed after the first 3 days of treatment. No differences in terms of vancomycin and bivalirudin dose need was observed between patients on extracorporeal membrane oxygenation and those who were not (P = .6 and P = .6, respectively), between patients with and without continuous veno-venous hemofiltration (P = .9 and P = .9, respectively), and between CytoSorb responders or not (P = .4 and P = .7, respectively). CytoSorb is effective in mitigating the systemic inflammatory response and safe with respect to vancomycin and bivalirudin administration. These preliminary data further support the use of CytoSorb as adjunct therapy in critically ill patients.

Objective To determine the incidence, predictors, and outcome of pneumothorax (PNX)/pneumomediastinum (PMD) in coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome (ARDS). Design Observational study. Setting Tertiary-care university hospital. Participants One hundred sixteen consecutive critically ill, invasively ventilated patients with COVID-19 ARDS. Interventions The authors collected demographic, mechanical ventilation, imaging, laboratory, and outcome data. Primary outcome was the incidence of PNX/PMD. Multiple logistic regression analyses were performed to identify predictors of PNX/PMD. Measurements and Main Results PNX/PMD occurred in a total of 28 patients (24.1%), with 22 patients developing PNX (19.0%) and 13 developing PMD (11.2%). Mean time to development of PNX/PMD was 14 ± 11 days from intubation. The authors found no significant difference in mechanical ventilation parameters between patients who developed PNX/PMD and those who did not. Mechanical ventilation parameters were within recommended limits for protective ventilation in both groups. Ninety-five percent of patients with PNX/PMD had the Macklin effect (linear collections of air contiguous to the bronchovascular sheaths) on a baseline computed tomography scan, and tended to have a higher lung involvement at intensive care unit (ICU) admission (Radiographic Assessment of Lung Edema score 32.2 ± 13.4 v 18.7 ± 9.8 in patients without PNX/PMD, p = 0.08). Time from symptom onset to intubation and time from total bilirubin on day two after ICU admission were the only independent predictors of PNX/PMD. Mortality was 60.7% in patients who developed PNX/PMD versus 38.6% in those who did not (p = 0.04). Conclusion PNX/PMD occurs frequently in COVID-19 patients with ARDS requiring mechanical ventilation, and is associated with increased mortality. Development of PNX/PMD seems to occur despite use of protective mechanical ventilation and has a radiologic predictor sign.

Background: There is no information on acute kidney injury (AKI) and continuous renal replacement therapy (CRRT) among invasively ventilated coronavirus disease 2019 (COVID-19) patients in Western healthcare systems. Objective: To study the prevalence, characteristics, risk factors and outcome of AKI and CRRT among invasively ventilated COVID-19 patients. Methods: Observational study in a tertiary care hospital in Milan, Italy. Results: Among 99 patients, 72 (75.0%) developed AKI and 17 (17.7%) received CRRT. Most of the patients developed stage 1 AKI (33 [45.8%]), while 15 (20.8%) developed stage 2 AKI and 24 (33.4%) a stage 3 AKI. Patients who developed AKI or needed CRRT at latest follow-up were older, and among CRRT treated patients a greater proportion had preexisting CKD. Hospital mortality was 38.9% for AKI and 52.9% for CRRT patients. Conclusions: Among invasively ventilated COVID-19 patients, AKI is very common and CRRT use is common. Both carry a high risk of in-hospital mortality.

Objective Meropenem is a β-lactam, carbapenem antibacterial agent with antimicrobial activity against gram-negative, gram-positive and anaerobic micro-organisms and is important in the empirical treatment of serious infections in Intensive Care Unit (ICU) patients. Multi-drug resistant gram-negative organisms, coupled with scarcity of new antibiotic classes, forced healthcare community to optimize the therapeutic potential of available antibiotics. Our aim is to investigate the effect of continuous infusion of meropenem against bolus administration, as indicated by a composite outcome of reducing death and emergence of extensive or pan drug-resistant pathogens in a population of ICU patients. Design Double blind, double dummy, multicenter randomized controlled trial (1:1 allocation ratio). Setting Tertiary and University hospitals. Interventions 600 ICU patients with sepsis or septic shock, needing by clinical judgment antibiotic therapy with meropenem, will be randomized to receive a continuous infusion of meropenem 3 g/24 h or an equal dose divided into three daily boluses (i.e. 1g q8h). Measurements The primary endpoint will be a composite outcome of reducing death and emergence of extensive or pan drug-resistant pathogens. Secondary endpoints will be death from any cause at day 90, antibiotic-free days at day 28, ICU-free days at day 28, cumulative SOFA-free (Sequential Organ Failure Assessment) score from randomization to day 28 and the two, separate, components of the primary endpoint. We expect a primary outcome reduction from 52 to 40% in the continuous infusion group. Conclusions The trial will provide evidence for choosing intermittent or continuous infusion of meropenem for critically ill patients with multi-drug resistant gram-negative infections.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has spread worldwide determining dramatic impacts on healthcare systems. Early identification of high-risk parameters is required in order to provide the best therapeutic approach. Coronary, thoracic aorta and aortic valve calcium can be measured from a non-gated chest computer tomography (CT) and are validated predictors of cardiovascular events and all-cause mortality. However, their prognostic role in acute systemic inflammatory diseases, such as COVID-19, has not been investigated. OBJECTIVES: The aim was to evaluate the association of coronary artery calcium and total thoracic calcium on in-hospital mortality in COVID-19 patients. METHODS: 1093 consecutive patients from 16 Italian hospitals with a positive swab for COVID-19 and an admission chest CT for pneumonia severity assessment were included. At CT, coronary, aortic valve and thoracic aorta calcium were qualitatively and quantitatively evaluated separately and combined together (total thoracic calcium) by a central Core-lab blinded to patients' outcomes. RESULTS: Non-survivors compared to survivors had higher coronary artery [Agatston (467.76 ​± ​570.92 vs 206.80 ​± ​424.13 ​mm2, p ​

Objective To assess whether the administration of the ultra-short–acting β-blocker esmolol in cardiac surgery could have a cardioprotective effect that translates into improved postoperative outcomes. Design Single-center, double-blinded, parallel-group randomized controlled trial. Setting A tertiary care referral center. Participants Patients undergoing elective cardiac surgery with preoperative evidence of left ventricular end-diastolic diameter >60 mm and/or left ventricular ejection fraction Interventions Patients were assigned randomly to receive either esmolol (1 mg/kg as a bolus before aortic cross-clamping and 2 mg/kg mixed in the cardioplegia solution) or placebo in a 1:1 allocation ratio. Measurements and Main Results The primary composite endpoint of prolonged intensive care unit stay and/or in-hospital mortality occurred in 36/98 patients (36%) in the placebo group versus 27/102 patients (27%) in the esmolol group (p = 0.13). In the esmolol group, a reduction in the maximum inotropic score during the first 24 postoperative hours was observed (10 [interquartile range 5-15] v 7 [interquartile range 5-10.5]; p = 0.04), as well as a trend toward a reduction in postoperative low-cardiac-output syndrome (13/98 v 6/102; p = 0.08) and the rate of hospital admission at one year (26/95 v 16/96; p = 0.08). A trend toward an increase in the number of patients with ejection fraction ≥60% at hospital discharge also was observed (4/95 v 11/92; p = 0.06). Conclusions In the present trial, esmolol as a cardioplegia adjuvant enhanced postoperative cardiac performance but did not reduce a composite endpoint of prolonged intensive care unit stay and/or mortality.

Cardiac arrest is the cessation of cardiac mechanical activity, as confirmed by the absence of signs of circulation [1]. It represents a serious worldwide public health concern [1, 2]. In the United States, the incidence of out-of-hospital cardiac arrest (OHCA) in adults is about 141 per 100,000 people (347,322 per year) while in-hospital cardiac arrest (IHCA) is near 1.99 per 1000 hospitalization days. Millions more occur across the rest of North America, Europe, and Asia [2, 3]. While global survival after OHCA has significantly increased in the past 40 years, it remains unacceptably low at hospital discharge, accounting of 8.8% (95% confidence interval (CI), 8.2–9.4%) [4]. Survival at hospital discharge does not exceed 20% in IHCA according to the actual largest studies [5].

Background. Myocarditis lacks systematic characterization in COVID-19 patients. Methods. We enrolled consecutive patients with newly diagnosed myocarditis in the context of COVID-19 infection. Diagnostic and treatment strategies were driven by a dedicated multidisciplinary disease unit for myocarditis. Multimodal outcomes were assessed during prospective follow-up. Results. Seven consecutive patients (57% males, age 51 ± 9 y) with acute COVID-19 infection received a de novo diagnosis of myocarditis. Endomyocardial biopsy was of choice in hemodynamically unstable patients (n = 4, mean left ventricular ejection fraction (LVEF) 25 ± 9%), whereas cardiac magnetic resonance constituted the first exam in stable patients (n = 3, mean LVEF 48 ± 10%). Polymerase chain reaction (PCR) analysis revealed an intra-myocardial SARS-CoV-2 genome in one of the six cases undergoing biopsy: in the remaining patients, myocarditis was either due to other viruses (n = 2) or virus-negative (n = 3). Hemodynamic support was needed for four unstable patients (57%), whereas a cardiac device implant was chosen in two of four cases showing ventricular arrhythmias. Medical treatment included immunosuppression (43%) and biological therapy (29%). By the 6-month median follow-up, no patient died or experienced malignant arrhythmias. However, two cases (29%) were screened for heart transplantation. Conclusions. Myocarditis associated with acute COVID-19 infection is a spectrum of clinical manifestations and underlying etiologies. A multidisciplinary approach is the cornerstone for tailored management.

Objectives During severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, dramatic endothelial cell damage with pulmonary microvascular thrombosis have been was hypothesized to occur. The aim was to assess whether pulmonary vascular thrombosis (PVT) is due to recurrent thromboembolism from peripheral deep vein thrombosis or to local inflammatory endothelial damage, with a superimposed thrombotic late complication. Design Observational study. Setting Medical and intensive care unit wards of a teaching hospital. Participants The authors report a subset of patients included in a prospective institutional study (CovidBiob study) with clinical suspicion of pulmonary vascular thromboembolism. Interventions Computed tomography pulmonary angiography and evaluation of laboratory markers and coagulation profile. Measurements and Main Results Twenty-eight of 55 (50.9%) patients showed PVT, with a median time interval from symptom onset of 17.5 days. Simultaneous multiple PVTs were identified in 22 patients, with bilateral involvement in 16, mostly affecting segmental/subsegmental pulmonary artery branches (67.8% and 96.4%). Patients with PVT had significantly higher ground glass opacity areas (31.7% [22.9-41] v 17.8% [10.8-22.1], p < 0.001) compared with those without PVT. Remarkably, in all 28 patients, ground glass opacities areas and PVT had an almost perfect spatial overlap. D-dimer level at hospital admission was predictive of PVT. Conclusions The findings identified a specific radiologic pattern of coronavirus disease 2019 (COVID-19) pneumonia with a unique spatial distribution of PVT overlapping areas of ground-glass opacities. These findings supported the hypothesis of a pathogenetic relationship between COVID-19 lung inflammation and PVT and challenged the previous definition of pulmonary embolism associated with COVID-19 pneumonia., Graphical abstract Computed Tomography Pulmonary Angiography (CTPA) imaging demonstrating, in three different clinical scenarios, eventual filling defects in branches of the pulmonary arteries (white arrows) and their spatial distribution according to the corresponding ventilation maps (white asterisks indicate normal lung parenchyma). In (a) [non COVID-19 pneumonia] and (c) [non COVID-19 ARDS] filling defects are electively found in the branches of the pulmonary arteries accountable for the vascularization of healthy lung segments. On the contrary, in (b) [COVID-19 pneumonia] there is an almost perfect topographical overlap between filling defects distribution and pneumonia extent.Image, graphical abstract

Introduction In addition to the directly attributed mortality, COVID-19 is also likely to increase mortality indirectly. In this systematic review, we investigate the direct and indirect effects of COVID-19 on out-of-hospital cardiac arrests. Methods We searched PubMed, BioMedCentral, Embase and the Cochrane Central Register of Controlled Trials for studies comparing out-of-hospital cardiac arrests occurring during the pandemic and a non-pandemic period. Risk of bias was assessed with the ROBINS-I tool. The primary endpoint was return of spontaneous circulation. Secondary endpoints were bystander-initiated cardiopulmonary resuscitation, survival to hospital discharge, and survival with favourable neurological outcome. Results We identified six studies. In two studies, rates of return of spontaneous circulation and survival to hospital discharge decreased significantly during the pandemic. Especially in Europe, bystander-witnessed cases, bystander-initiated cardiopulmonary resuscitation and resuscitation attempted by emergency medical services were reduced during the pandemic. Also, ambulance response times were significantly delayed across all studies and patients presenting with non-shockable rhythms increased in two studies. In 2020, 3.9–5.9% of tested patients were SARS-CoV-2 positive and 4.8–26% had suggestive symptoms (fever and cough or dyspnoea). Conclusions Out-of-hospital cardiac arrests had worse short-term outcomes during the pandemic than a non-pandemic period suggesting direct effects of COVID-19 infection and indirect effects from lockdown and disruption of healthcare systems. Patients at high risk of deterioration should be identified outside the hospital to promptly initiate treatment and reduce fatalities. Study registration PROSPERO CRD42020195794.

Background: The use of angiotensin II (ANGII) in invasively ventilated COVID-19 patients is controversial. Its effect on markers of organ function is unknown.Methods: We used ANGII either as rescue vasopressor agent or as low dose vasopressor support. Patients treated before ANGII availability or in an adjacent COVID-19 ICU served as controls. For data analysis, we applied Bayesian modelling as appropriate. We assessed the effects of ANG on markers of organ function.Results: We compared 46 ANGII patients with 53 controls. Compared with controls, ANGII increased MAP (median difference, 9.05 mmHg [95% confidence interval, 1.87 to 16.22]; p = 0.013) and PaO2/FiO2 ratio (median difference, 23.17 [95% confidence interval, 3.46 to 42.88]; p = 0.021). ANGII had no effect on lactate, urinary output, serum creatinine, C-Reactive protein, platelet count, or thromboembolic complications. However, it significantly decreased the odd ratio of liver dysfunction (odds ratio: 0.32; 0.09 to 0.94) and, on Bayesian modelling, in patients with abnormal baseline serum creatinine, ANGII carried a 95.7% probability of decreasing renal replacement therapy use. Conclusions: In ventilated COVID-19 patients, ANGII therapy was associated with increased blood pressure and PaO2/FiO2 ratios, decreased odds ratio of liver dysfunction, and a high probability of decreasing renal replacement therapy use in patients with abnormal baseline serum creatinine.

Background Tracheal intubation in patients at risk for secondary spinal cord injury is potentially difficult and risky. Objectives To compare tracheal intubation techniques in adult patients at risk for secondary cervical spinal cord injury undergoing surgery. Primary outcome was first-attempt failure rate. Secondary outcomes were time to successful intubation and procedure complications. Design Systematic review and meta-analysis of randomized controlled trials (RCTs) with trial sequential analysis (TSA). Data sources Databases searched up to July 2019. Eligibility Randomized controlled trials comparing different intubation techniques. Results We included 18 trials enrolling 1972 patients. Four studies used the "awake" approach, but no study compared awake versus non-awake techniques. In remaining 14 RCTs, intubation was performed under general anesthesia. First-attempt failure rate was similar when comparing direct laryngoscopy or fiberoptic bronchoscopy versus other techniques. A better first-attempt failure rate was found with videolaryngoscopy and when pooling all the fiberoptic techniques together. All these results appeared not significant at TSA, suggesting inconclusive evidence. Intubating lighted stylet allowed faster intubation. Postoperative neurological complications were 0.34% (no significant difference among techniques). No life-threatening adverse event was reported; mild local complications were common (19.5%). The certainty of evidence was low to very low mainly due to high imprecision and indirectness. Conclusions Videolaryngoscopy and fiberoptic-assisted techniques might be associated with higher first-attempt failure rate over controls. However, low to very low certainty of evidence does not allow firm conclusions on the best tracheal intubation in patients at risk for cervical spinal cord injury.

Objective: To assess whether a restrictive strategy of RBC transfusion reduces 28-day mortality when compared with a liberal strategy in cancer patients with septic shock. Design: Single center, randomized, double-blind controlled trial. Setting: Teaching hospital. Patients: Adult cancer patients with septic shock in the first 6 hours of ICU admission. Interventions: Patients were randomized to the liberal (hemoglobin threshold, < 9 g/dL) or to the restrictive strategy (hemoglobin threshold, < 7 g/dL) of RBC transfusion during ICU stay. Measurements and Main Results: Patients were randomized to the liberal (n = 149) or to the restrictive transfusion strategy (n = 151) group. Patients in the liberal group received more RBC units than patients in the restrictive group (1 [0-3] vs 0 [0-2] unit; p < 0.001). At 28 days after randomization, mortality rate in the liberal group (primary endpoint of the study) was 45% (67 patients) versus 56% (84 patients) in the restrictive group (hazard ratio, 0.74; 95% CI, 0.53-1.04; p = 0.08) with no differences in ICU and hospital length of stay. At 90 days after randomization, mortality rate in the liberal group was lower (59% vs 70%) than in the restrictive group (hazard ratio, 0.72; 95% CI, 0.53-0.97; p = 0.03). Conclusions: We observed a survival trend favoring a liberal transfusion strategy in patients with septic shock when compared with the restrictive strategy. These results went in the opposite direction of the a priori hypothesis and of other trials in the field and need to be confirmed.

Left ventricle (LV) unloading during VenoArterial ExtraCorporeal Membrane Oxygenation (VA-ECMO) reduces the risk of LV distention, stagnation and pulmonary congestion resulting from the increased afterload. Lacking direct comparisons between unloading strategies we used network meta-analysis to indirectly compare different unloading approaches.A literature research was performed to include all studies on VA-ECMO reporting data on mechanical LV unloading. The pre-specified outcome was in-hospital death.Literature search identified 389 studies: 16 were included in the analysis (3930 patients). Two strategies of mechanical LV unloading were compared: afterload reduction (IABP) and preload reduction (Impella pump, right upper pulmonary/trans-septal catheters, LV surgical vents). Any LV unloading strategy was associated with mortality reduction with overall OR = 0.54; 95% CI 0.42-0.70; p .001. Targeting afterload was associated with reduced mortality (OR = 0.61 95% CI 0.46-0.81; p .001; IAny unloading strategy in VA-ECMO patients was associated with lower mortality as compared to no-unloading. Preload reduction strategies resulted superior to afterload reduction.

In the publication of this article [1], there was an error in a contributors Family Name. This has now been updated in the original article.

Awake fiberoptic intubation is one of the recommended strategies for surgical patients with anticipated difficult airway, especially when concurrent difficult ventilation is expected. We performed the first systematic review of randomized controlled trials assessing different protocols for awake fiberoptic intubation in anticipated difficult airway, including studies investigating elective awake fiberoptic intubation for scheduled surgery; randomized controlled trials comparing different methods for performing awake fiberoptic intubation; and adult patients with anticipated difficult airway. We excluded studies in the nonoperating theater settings, randomized controlled trials comparing awake fiberoptic intubation with other techniques, and studies based on simulation. Primary outcomes were success rate and death; secondary outcomes were major adverse events. Thirty-seven randomized controlled trials evaluating 2045 patients and 4 areas were identified: premedication, local anesthesia, sedation, and ancillary techniques to facilitate awake fiberoptic intubation. Quality of evidence was moderate-low and based on small-sampled randomized controlled trials. Overall, 12 of 2045 intubation failures (0.59%) and 7 of 2045 severe adverse events (0.34%) occurred, with no permanent consequences or death. All evaluated methods to achieve local anesthesia performed similarly well. No differences were observed in success rate with different sedatives. Dexmedetomidine resulted in fewer desaturation episodes compared to propofol and opioids with or without midazolam (relative risk, 0.51 [95% CI, 0.28-0.95]; P = .03); occurrence of desaturation was similar with remifentanil versus propofol, while incidence of apnoea was lower with sevoflurane versus propofol (relative risk, 0.43 [95% CI, 0.22-0.81]; P = .01). A high degree of efficacy and safety was observed with minimal differences among different protocols; dexmedetomidine might offer a better safety profile compared to other sedatives.

The authors aimed to identify interventions documented by randomized controlled trials (RCTs) that reduce mortality in adult critically ill and perioperative patients, followed by a survey of clinicians' opinions and routine practices to understand the clinicians' response to such evidence. The authors performed a comprehensive literature review to identify all topics reported to reduce mortality in perioperative and critical care settings according to at least 2 RCTs or to a multicenter RCT or to a single-center RCT plus guidelines. The authors generated position statements that were voted on online by physicians worldwide for agreement, use, and willingness to include in international guidelines. From 262 RCT manuscripts reporting mortality differences in the perioperative and critically ill settings, the authors selected 27 drugs, techniques, and strategies (66 RCTs, most frequently published by the New England Journal of Medicine [13 papers], Lancet [7], and Journal of the American Medical Association [5]) with an agreement ≥67% from over 250 physicians (46 countries). Noninvasive ventilation was the intervention supported by the largest number of RCTs (n = 13). The concordance between agreement and use (a positive answer both to "do you agree" and "do you use") showed differences between Western and other countries and between anesthesiologists and intensive care unit physicians. The authors identified 27 clinical interventions with randomized evidence of survival benefit and strong clinician support in support of their potential life-saving properties in perioperative and critically ill patients with noninvasive ventilation having the highest level of support. However, clinician views appear affected by specialty and geographical location.

Background Acute respiratory failure (ARF) is a common cause of presentation to the Emergency Department (ED). High flow nasal cannula (HFNC) has been introduced as an alternative way to administer oxygen. Objectives We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing HFNC with conventional oxygen therapy (COT) and noninvasive ventilation (NIV) exclusively in the ED setting. Methods Inclusion criteria were: RCTs on adults with ARF admitted to the ED, investigating HFNC vs. COT or other modes of ventilation. Trials that compared HFNC support outside the ED, were published as an abstract, or nonrandomized were excluded. Results Four RCTs comparing HFNC with COT and one HFNC to NIV met the criteria. Overall, 775 patients were included. The meta-analysis of the studies comparing HFNC and COT showed no differences in intubation requirement, treatment failure, hospitalization, or mortality. Intolerance was significantly higher with HFNC (risk ratio 6.81 95% confidence interval 1.18–39.19; p = 0.03). In the only available RCT comparing HFNC with NIV, no difference was found for intubation rate, treatment failure, tolerance, and dyspnea. Conclusions We did not find any benefit of HFNC compared with COT and NIV in terms of intubation requirement, treatment failure, hospitalization, and mortality; COT was better tolerated.

Phosphocreatine (PCr) plays an important role in the energy metabolism of the heart and a decrease in its intracellular concentration results in alteration of myocardium energetics and work. We conducted a meta-analysis of all randomized and matched trials that compared PCr with placebo or standard treatment in patients with coronary artery disease or chronic heart failure or in those undergoing cardiac surgery. We systematically searched PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials and Google Scholar up to 1 November 2015, for pertinent trials. The primary outcome was all-cause mortality. Secondary outcomes included inotrope use, ejection fraction (EF), peak creatinine kinase-myocardial band (CK-MB) release and the incidence of major arrhythmias, as well as spontaneous recovery of the heart performance in the subgroup of patients undergoing cardiac surgery with cardiopulmonary bypass. We pooled odds ratio (OR) and mean difference (MD) using fixed- and random effects models. We identified 41 controlled trials, of them 32 were randomized. Patients receiving PCr had lower all-cause mortality when compared with the control group [61/1731 (3.5%) vs 177/1667 (10.6%); OR: 0.71, 95% CI: 0.51-0.99; P = 0.04; I(2) = 0%; with 3400 patients and 22 trials included]. Phosphocreatine administration was associated with higher LVEF (MD: 3.82, 95% CI: 1.18-6.46; P = 0.005; I(2) = 98%), lower peak CK-MB release (MD: -6.08, 95% CI: -8.01, -4.15; P < 0.001; I(2) = 97%), lower rate of major arrhythmias (OR: 0.42; 95% CI: 0.27-0.66; P < 0.001; I(2) = 0%), lower incidence of inotropic support (OR: 0.39, 95% CI: 0.25-0.61; P < 0.001; I(2) = 56%) and a higher level of spontaneous recovery of the heart performance after cardiopulmonary bypass (OR: 3.49, 95% CI: 2.28-5.35; P < 0.001; I(2) = 49%) when compared with the control group. In a mixed population of patients with coronary artery disease, chronic heart failure or in those undergoing cardiac surgery, PCr may reduce all-cause short-term mortality. In addition, PCr administration was associated with improved cardiac outcomes. Owing to the pharmacological plausibility of this effect and to the concordance of the beneficial effects of PCr on several secondary but important outcomes and survival, there is urgent need for a large multicentre randomized trial to confirm these findings.

Purpose CytoSorb treatment is a promising tool to treat severe inflammatory status in the acute care setting. Its effect on drugs is, however, poorly documented in vivo, although unselective and unpredictable removal of small molecules might translate into decreased blood levels of potentially life-saving medications. The aim of this study was to assess the impact of Cytosorb treatment on clereance of small drug molecules, measured as dose adjustements need, in a large population of critically ill patients. Methods Single-center analysis of Cytosorb treatments performed between 01-2018 and 03-2019 in patients with cardiogenic shock of several origins. Results 109 Cytosorb treatments were performed in 86 patients. A decrease in LDH (p=0.007), troponin T (p=0.022) and CPK (p=0.013), together with a trend toward lower need of inotropes, was reported during treatment, supporting its clinical efficacy in the study population. Vancomycin dose was significantly changed during the days of treatment (p Conclusion Cytosorb therapy was effective in improving shock parameters in a large population of cardiogenic shock patients, without affecting the dose need of vancomycin and bivalirudin after reaching target concentration. The results of this study further support the role of Cytosorb in the treatment of critically ill.

Left ventricle (LV) unloading during VA-ECMO reduces the detrimental effect of increased afterload. Lacking direct comparisons between unloading strategies we used network metanalysis to indirectly compare different unloading approaches. A literature research was performed to include all studies on

The aim of this study was to evaluate the efficacy of perioperative intra-aortic balloon pump use in high-risk cardiac surgery patients.A single-center randomized controlled trial and a meta-analysis of randomized controlled trials.Heart Institute of São Paulo University.High-risk patients undergoing elective coronary artery bypass surgery.Patients were randomized to receive preskin incision intra-aortic balloon pump insertion after anesthesia induction versus no intra-aortic balloon pump use.The primary outcome was a composite endpoint of 30-day mortality and major morbidity (cardiogenic shock, stroke, acute renal failure, mediastinitis, prolonged mechanical ventilation, and a need for reoperation). A total of 181 patients (mean [SD] age 65.4 [9.4] yr; 32% female) were randomized. The primary outcome was observed in 43 patients (47.8%) in the intra-aortic balloon pump group and 42 patients (46.2%) in the control group (p = 0.46). The median duration of inotrope use (51 hr [interquartile range, 32-94 hr] vs 39 hr [interquartile range, 25-66 hr]; p = 0.007) and the ICU length of stay (5 d [interquartile range, 3-8 d] vs 4 d [interquartile range, 3-6 d]; p = 0.035) were longer in the intra-aortic balloon pump group than in the control group. A meta-analysis of 11 randomized controlled trials confirmed a lack of survival improvement in high-risk cardiac surgery patients with perioperative intra-aortic balloon pump use.In high-risk patients undergoing cardiac surgery, the perioperative use of an intra-aortic balloon pump did not reduce the occurrence of a composite outcome of 30-day mortality and major complications compared with usual care alone.

Background Perioperative goal-directed hemodynamic therapy (GDHT) has been advocated in high-risk patients undergoing noncardiac surgery to reduce postoperative morbidity and mortality. We hypothesized that using cardiac index (CI)-guided GDHT in the postoperative period for patients undergoing high-risk surgery for cancer treatment would reduce 30-day mortality and postoperative complications. Methods A randomized, parallel-group, superiority trial was performed in a tertiary oncology hospital. All adult patients undergoing high-risk cancer surgery who required intensive care unit admission were randomly allocated to a CI-guided GDHT group or to a usual care group. In the GDHT group, postoperative therapy aimed at CI ≥ 2.5 L/min/m2 using fluids, inotropes and red blood cells during the first 8 postoperative hours. The primary outcome was a composite endpoint of 30-day all-cause mortality and severe postoperative complications during the hospital stay. A meta-analysis was also conducted including all randomized trials of postoperative GDHT published from 1966 to May 2017. Results A total of 128 patients (64 in each group) were randomized. The primary outcome occurred in 34 patients of the GDHT group and in 28 patients of the usual care group (53.1% vs 43.8%, absolute difference 9.4 (95% CI, − 7.8 to 25.8); p = 0.3). During the 8-h intervention period more patients in the GDHT group received dobutamine when compared to the usual care group (55% vs 16%, p