Infectious Mediastinitis: A Retrospective Cohort Study.

Background: This study aimed to characterize the demographics, microbiology, management and treatment outcomes of mediastinitis according to the origin of the infection. Methods: This retrospective observational study enrolled patients who had mediastinitis diagnosed according to the criteria defined by the Centers for Disease Control and Prevention and were treated in Strasbourg University Hospital, France, between 1 January 2010 and 31 December 2020. Results: We investigated 151 cases, including 63 cases of poststernotomy mediastinitis (PSM), 60 cases of mediastinitis due to esophageal perforation (MEP) and 17 cases of descending necrotizing mediastinitis (DNM). The mean patient age (standard deviation) was 63 (14.5) years, and 109 of 151 patients were male. Microbiological documentation varied according to the origin of the infection. When documented, PSM cases were mostly monomicrobial (36 of 53 cases [67.9%]) and involved staphylococci (36 of 53 [67.9%]), whereas MEP and DNM cases were mostly plurimicrobial (38 of 48 [79.2%] and 8 of 12 [66.7%], respectively) and involved digestive or oral flora microorganisms, respectively. The median duration of anti-infective treatment was 41 days (interquartile range, 21-56 days), and 122 of 151 patients (80.8%) benefited from early surgical management. The overall 1-year survival rate was estimated to be 64.8% (95% confidence interval, 56.6%-74.3%), but varied from 80.1% for DNM to 61.5% for MEP. Conclusions: Mediastinitis represents a rare yet deadly infection. The present cohort study exhibited the different patterns observed according to the origin of the infection. Greater insight and knowledge on these differences may help guide the management of these complex infections, especially with respect to empirical anti-infective treatments.

Early chest tube removal on the 1st postoperative day protocol of an enhanced recovery after cardiac surgery programme is safe.

OBJECTIVES: The aim of this study was to assess the safety of early chest tube removal (CTR) protocol on the 1st postoperative day (POD1) of our Enhanced Recovery After Surgery (ERAS) programme by comparing the risk of postoperative pneumothorax, pleural and pericardial effusion requiring intervention and hospital mortality. METHODS: All consecutive patients undergoing elective coronary revascularization and/or valve surgery between 2015 and 2021 were assessed in terms of their perioperative management pathways: conventional standard of care (control group) versus standardized systematic perioperative ERAS programme including an early CTR on POD1 (ERAS group). A propensity score matching was applied. The primary end-point was a composite of postoperative pneumothorax, pleural and pericardial effusion requiring intervention and hospital mortality. RESULTS: A total of 3153 patients were included. Propensity score analysis resulted in 2 groups well-matched pairs of 1026 patients. CTR on POD1 was significantly increased from 29.5% in the control group to 70.3% in the ERAS group (P < 0.001). The incidence of the primary end-point was 6.4% in the control group and 6.9% in the ERAS group (P = 0.658). Patients in the ERAS group, as compared with control group, had significant lower incidence of bronchopneumonia (9.0% vs 13.5%; P = 0.001) and higher incidence of mechanical ventilation ≤6 h (84.6% vs 65.2%; P < 0.001), length of intensive care unit ≤1 day (61.2% vs 50.8%; P < 0.001) and hospital ≤6 days (67.3% vs.43.2%; P < 0.001). CONCLUSIONS: CTR on POD1 protocol can be safely incorporated into a standardized systematic ERAS programme, enabling early mobilization, and contributing to the improvement of postoperative outcomes. CLINICAL TRIAL REGISTRATION NUMBER: Ethics committee of the French Society of Thoracic and Cardio-Vascular Surgery (CERC-SFCTCV-2022-09-13_23140).

NButGT Reinforces the Beneficial Effects of Epinephrine on Cardiac Mitochondrial Respiration, Lactatemia and Cardiac Output in Experimental Anaphylactic Shock.

Anaphylactic shock (AS) is the most severe form of acute systemic hypersensitivity reaction. Although epinephrine can restore patients' hemodynamics, it might also be harmful, supporting the need for adjuvant treatment. We therefore investigated whether NButGT, enhancing O-GlcNAcylation and showing beneficial effects in acute heart failure might improve AS therapy. Ovalbumin-sensitized rats were randomly allocated to six groups: control (CON), shock (AS), shock treated with NButGT alone before (AS+pre-Nbut) or after (AS+post-Nbut) AS onset, shock treated with epinephrine alone (AS+EPI) and shock group treated with combination of epinephrine and NButGT (AS+EPI+preNBut). Induction of shock was performed with an intravenous (IV) ovalbumin. Cardiac protein and cycling enzymes O-GlcNAcylation levels, mean arterial pressure (MAP), heart rate, cardiac output (CO), left ventricle shortening fraction (LVSF), mitochondrial respiration, and lactatemia were evaluated using Western blotting experiments, invasive arterial monitoring, echocardiography, mitochondrial oximetry and arterial blood samples. AS decreased MAP (-77%, p < 0.001), CO (-90%, p < 0.001) and LVSF (-30%, p < 0.05). Epinephrine improved these parameters and, in particular, rats did not die in 15 min. But, cardiac mitochondrial respiration remained impaired (complexes I + II -29%, p < 0.05 and II -40%, p < 0.001) with hyperlactatemia. NButGT pretreatment (AS+pre-Nbut) efficiently increased cardiac O-GlcNAcylation level as compared to the AS+post-Nbut group. Compared to epinephrine alone, the adjunction of NButGT significantly improved CO, LVSF and mitochondrial respiration. MAP was not significantly increased but lactatemia decreased more markedly. Pretreatment with NButGT increases O-GlcNAcylation of cardiac proteins and has an additive effect on epinephrine, improving cardiac output and mitochondrial respiration and decreasing blood lactate levels. This new therapy might be useful when the risk of AS cannot be avoided.

Enhanced recovery after surgery program for patients undergoing isolated elective coronary artery bypass surgery improves postoperative outcomes.

OBJECTIVE: To evaluate the effect of a perioperative systematic standardized enhanced recovery after surgery (ERAS) program for patients undergoing isolated elective coronary artery bypass grafting (CABG) in terms of mortality, hospital morbidities, and length of stay. METHODS: From January 2015 to September 2020, 1101 patients underwent isolated elective CABG. Our standardized systematic ERAS program was implemented in November 2018. Propensity score matching resulted in well-matched pairs of 362 patients receiving standard perioperative care (control group) and 362 patients on the ERAS program (ERAS group). There were no significant intergroup differences in preoperative and operative data except for the normothermia rate, which was significantly greater in the ERAS group (P < .001). The primary outcome was 3-year mortality. The secondary outcomes were hospital morbidities and length of stay. RESULTS: In-hospital and 3-year mortality did not differ between the 2 groups. The ERAS program was associated with a significant relative risk decrease in mechanical ventilation duration (-53.1%, P = .003), length of intensive care unit stay (-28.0%, P = .015), length of hospital stay (-10.5%, P = .046), bronchopneumonia (-51.5%, P < .001), acute respiratory distress syndrome (-50.8%, P = .050), postoperative delirium (-65.4%, P = .011), moderate-to-severe acute kidney injury (-72.0%, P = .009), 24-hour chest tube output (-26.4%, P < .001), and overall red blood cell transfusion rate (-32.4%, P = .005) compared with the control group. CONCLUSIONS: A systematic standardized ERAS program for low-risk patients undergoing isolated elective CABG was associated with a significant improvement in postoperative outcomes, reduction in red blood cell transfusion, shorter lengths of intensive care unit and hospital stays, and comparable long-term mortality.

An enhanced recovery programme significantly improves postoperative outcomes after surgical aortic valve replacement.

OBJECTIVES: Evidence regarding the benefits of an enhanced recovery after cardiac surgery (ERACS) programme is lacking. The aim of this study was to analyse the impact of a systematic standardized ERACS programme for patients undergoing isolated elective surgical aortic valve replacement (SAVR) for aortic stenosis in terms of hospital mortality and morbidity, patient blood management and length of stay. METHODS: Patients undergoing isolated elective SAVR for aortic stenosis between 2015 and 2020 were identified from our database (n = 941). The standardized systematic ERACS programme was implemented in November 2018. Propensity score matching indicated that 259 patients would receive standard perioperative care (control group) and 259 patients would receive the ERACS programme (ERACS group). The primary outcome was hospital mortality. The secondary outcomes were hospital morbidity, patient blood management and length of stay. RESULTS: Both groups had similar hospital mortality rates (0.4%). The ERACS group had a significantly lower troponin I peak level (P < 0.001), a larger proportion of improved perioperative left ventricular ejection fractions (P = 0.001), a lower incidence of bronchopneumonia (P = 0.030), a larger proportion of patients with mechanical ventilation <6 h (P < 0.001), a lower incidence of delirium (P = 0.028) and less acute renal failure (P = 0.013). The ERACS group had a significantly lower rate of red blood cell transfusions (P = 0.002). The intensive care unit stay was significantly shorter in the ERACS group than in the control group (P = 0.039). CONCLUSIONS: The standardized systematic ERACS programme significantly improved postoperative outcomes and should become the reference for the perioperative care pathway for patients undergoing SAVR.

Cerebral perfusion using ASL in patients with COVID-19 and neurological manifestations: A retrospective multicenter observational study.

BACKGROUND AND PURPOSE: Cerebral hypoperfusion has been reported in patients with COVID-19 and neurological manifestations in small cohorts. We aimed to systematically assess changes in cerebral perfusion in a cohort of 59 of these patients, with or without abnormalities on morphological MRI sequences. METHODS: Patients with biologically-confirmed COVID-19 and neurological manifestations undergoing a brain MRI with technically adequate arterial spin labeling (ASL) perfusion were included in this retrospective multicenter study. ASL maps were jointly reviewed by two readers blinded to clinical data. They assessed abnormal perfusion in four regions of interest in each brain hemisphere: frontal lobe, parietal lobe, posterior temporal lobe, and temporal pole extended to the amygdalo-hippocampal complex. RESULTS: Fifty-nine patients (44 men (75%), mean age 61.2 years) were included. Most patients had a severe COVID-19, 57 (97%) needed oxygen therapy and 43 (73%) were hospitalized in intensive care unit at the time of MRI. Morphological brain MRI was abnormal in 44 (75%) patients. ASL perfusion was abnormal in 53 (90%) patients, and particularly in all patients with normal morphological MRI. Hypoperfusion occurred in 48 (81%) patients, mostly in temporal poles (52 (44%)) and frontal lobes (40 (34%)). Hyperperfusion occurred in 9 (15%) patients and was closely associated with post-contrast FLAIR leptomeningeal enhancement (100% [66.4%-100%] of hyperperfusion with enhancement versus 28.6% [16.6%-43.2%] without, p = 0.002). Studied clinical parameters (especially sedation) and other morphological MRI anomalies had no significant impact on perfusion anomalies. CONCLUSION: Brain ASL perfusion showed hypoperfusion in more than 80% of patients with severe COVID-19, with or without visible lesion on conventional MRI abnormalities.

Mortality and Delays of Management of Acute Mesenteric Ischemia: The Need of a Dedicated Program.

BACKGROUND: To study the mortality and delays of management of patients with acute mesenteric ischemia (AMI) admitted to the emergency department of a tertiary hospital and identify risk factors for 1-month mortality. METHODS: A single-center and retrospective study including all consecutive patients treated for AMI from January 2008 to December 2018 was conducted. Short- and medium-term survival was studied with a Kaplan-Meier analysis. Delays before diagnosis and surgical intervention were collected. To determine factors associated with mortality at 1 month postoperatively, univariate and multivariate analyzes were performed. RESULTS: The survival rate of the 67 included patients was 55.22% at 1 month and 37.31% at 1 year. In-hospital mortality was 50.74%. The average delay between admission and diagnosis was 4.83 ± 5.03 hr (95% confidence interval [CI], 3.60-6.05), and the delay between admission and surgical treatment was 10.64 ± 8.80 hr (95% CI, 8.49-12.79). The independent variables associated with an increased mortality at 1 month postoperatively in the univariate analysis were age >65 years old (odds ratio [OR] = 3.52; P = 0.046), lactate >3.31 mmol/l at admission (H0) (OR = 7.38; P < 0.001), lactate >3.32 mmol/l on day 1 (H24) (OR = 5.60; P = 0.002), creatinine >95.9 µmol/l at H0 (OR = 4.66; P = 0.004), aspartate aminotransferase (AST) >59 U/l at H0 (OR = 3.55; P = 0.017), and having hypertension as comorbidity (OR = 9.32; P = 0.040). Early curative anticoagulation (z = -2.4; P = 0.016) was an independent protective factor for mortality, and lactate >3.31 mmol/l at H0 (z = 2.62; P = 0.009) was an independent predictor factor of mortality at 1 month postoperatively in the multivariate analysis. CONCLUSION: AMI remains a serious and lethal condition with delays of surgical management remaining too long due to a lack of a dedicated therapeutic protocol allowing an early diagnosis.

Serum lactate and acute mesenteric ischaemia: An observational, controlled multicentre study.

BACKGROUND: Early diagnosis and prompt management of acute mesenteric ischaemia (AMI) are key to survival but remain extremely difficult, due to vague and non-specific symptoms. Serum lactate (SL) is commonly presented as a useful biomarker for the diagnosis or prognosis of AMI. The aim of our study was test SL (1) as a diagnostic marker and (2) as a prognostic marker for AMI. STUDY DESIGN: This was an ancillary multicentre case-control study. Patients with AMI at intensive care unit (ICU) admission were included (AMI group) and matched to ICU patients without AMI (control group). SL was measured and compared on day 0 (D0) and day 1 (D1). Diagnosis and prognosis accuracy were assessed by receiver operating characteristic (ROC) and their area under the curve (AUC). RESULTS: Each group consisted of 137 matched ICU patients. There was no significant difference of SL between the two groups at D0 or at D1 (p = 0.26 and p = 0.29 respectively). SL was a poor marker of AMI: at D0 and D1, AUC were respectively 0.57 [0.51; 0.63] and 0.60 [0.53; 0.67]. SL at D0 and D1 correctly predicted ICU mortality, independently of AMI (AUC D0: 0.69 [0.59; 0.79] vs. 0.74 [0.65; 0.82]; p = 0.51 and D1: 0.74 [0.64; 0.84] vs. 0.76 [0.66; 0.87]; p = 0.77, respectively, for control and AMI groups]. CONCLUSIONS: SL has no specific link with AMI, both for diagnosis and prognosis. SL should not be used for the diagnosis of AMI but, despite its lack of specificity, it may help to assess severity.

Impaired Myocardial Mitochondrial Function in an Experimental Model of Anaphylactic Shock.

Anaphylactic shock (AS) is associated with a profound vasodilation and cardiac dysfunction. The cellular mechanisms underlying AS-related cardiac dysfunction are unknown. We hypothesized that myocardial mitochondrial dysfunction may be associated with AS cardiac dysfunction. In controls and sensitized Brown Norway rats, shock was induced by ovalbumin i.v bolus, and abdominal aortic blood flow (ABF), systemic mean arterial pressure (MAP), and lactatemia were measured for 15 min. Myocardial mitochondrial function was assessed with the evaluation of mitochondrial respiration, oxidative stress production by reactive oxygen species (ROS), reactive nitrogen species (RNS), and the measurement of superoxide dismutases (SODs) activity. Oxidative damage was assessed by lipid peroxidation. The mitochondrial ultrastructure was assessed using transmission electronic microscopy. AS was associated with a dramatic drop in ABF and MAP combined with a severe hyperlactatemia 15 min after shock induction. CI-linked substrate state (197 ± 21 vs. 144 ± 21 pmol/s/mg, p < 0.05), OXPHOS activity by complexes I and II (411 ± 47 vs. 246 ± 33 pmol/s/mg, p < 0.05), and OXPHOS activity through complex II (316 ± 40 vs. 203 ± 28 pmol/s/mg, p < 0.05) were significantly impaired. ROS and RNS production was not significantly increased, but SODs activity was significantly higher in the AS group (11.15 ± 1.02 vs. 15.50 ± 1.40 U/mL/mg protein, p = 0.02). Finally, cardiac lipid peroxidation was significantly increased in the AS group (8.50 ± 0.67 vs. 12.17 ± 1.44 µM/mg protein, p < 0.05). No obvious changes were observed in the mitochondrial ultrastructure between CON and AS groups. Our experimental model of AS results in rapid and deleterious hemodynamic effects and was associated with a myocardial mitochondrial dysfunction with oxidative damage and without mitochondrial ultrastructural injury.

Evolution of Neuroimaging Findings in Severe COVID-19 Patients with Initial Neurological Impairment: An Observational Study.

BACKGROUND AND OBJECTIVES: Cerebral complications related to the COVID-19 were documented by brain MRIs during the acute phase. The purpose of the present study was to describe the evolution of these neuroimaging findings (MRI and FDG-PET/CT) and describe the neurocognitive outcomes of these patients. METHODS: During the first wave of the COVID-19 outbreak between 1 March and 31 May 2020, 112 consecutive COVID-19 patients with neurologic manifestations underwent a brain MRI at Strasbourg University hospitals. After recovery, during follow-up, of these 112 patients, 31 (initially hospitalized in intensive care units) underwent additional imaging studies (at least one brain MRI). RESULTS: Twenty-three men (74%) and eight women (26%) with a mean age of 61 years (range: 18-79) were included. Leptomeningeal enhancement, diffuse brain microhemorrhages, acute ischemic strokes, suspicion of cerebral vasculitis, and acute inflammatory demyelinating lesions were described on the initial brain MRIs. During follow-up, the evolution of the leptomeningeal enhancement was discordant, and the cerebral microhemorrhages were stable. We observed normalization of the vessel walls in all patients suspected of cerebral vasculitis. Four patients (13%) demonstrated new complications during follow-up (ischemic strokes, hypoglossal neuritis, marked increase in the white matter FLAIR hyperintensities with presumed vascular origin, and one suspected case of cerebral vasculitis). Concerning the grey matter volumetry, we observed a loss of volume of 3.2% during an average period of approximately five months. During follow-up, the more frequent FDG-PET/CT findings were hypometabolism in temporal and insular regions. CONCLUSION: A minority of initially severe COVID-19 patients demonstrated new complications on their brain MRIs during follow-up after recovery.

Combining predictive markers for severe COVID-19: Torquetenovirus DNA load and SARS-CoV-2 RNAemia.

RATIONALE/OBJECTIVES: SARS-CoV-2 is the cause of worldwide COVID-19, which severity has been linked to the immune and inflammatory response. Here, we investigate Torquetenovirus (TTV) DNA load - a marker reflecting the intensity of the overall immune response - as well as SARS-CoV-2 RNAemia and IgM/IgG antibodies in COVID-19-positive patients. METHODS: Two hundred and fifteen COVID-19-positive patients were enrolled, including 87 severe cases and 128 mild-moderate cases. SARS-CoV-2 RNAemia and IgM/IgG antibodies, as well as TTV DNA loads, were measured on longitudinal plasma samples. RESULTS: The rate of severe cases was higher in patients with low TTV DNA load in plasma considering a threshold of 700 copies/mL. In severe patients, SARS-CoV-2 RNAemia positivity rates were higher than those in mild-moderate cases at any timepoint. When combined, TTV DNA load and SARS-CoV-2 RNAemia allowed to predict the outcome of COVID-19 infection, with a higher risk (HR=12.4) of ICU admission in patients with low TTV DNA load and positive SARS-CoV-2 RNAemia. CONCLUSIONS: TTV DNA load and SARS-CoV-2 RNAemia may be effective, non-invasive markers reflecting disease severity and poor outcome that could be conveniently measured in a clinical laboratory setting, as soon as COVID-19 diagnosis is made.

Identification of driver genes for critical forms of COVID-19 in a deeply phenotyped young patient cohort.

The drivers of critical coronavirus disease 2019 (COVID-19) remain unknown. Given major confounding factors such as age and comorbidities, true mediators of this condition have remained elusive. We used a multi-omics analysis combined with artificial intelligence in a young patient cohort where major comorbidities were excluded at the onset. The cohort included 47 "critical" (in the intensive care unit under mechanical ventilation) and 25 "non-critical" (in a non-critical care ward) patients with COVID-19 and 22 healthy individuals. The analyses included whole-genome sequencing, whole-blood RNA sequencing, plasma and blood mononuclear cell proteomics, cytokine profiling, and high-throughput immunophenotyping. An ensemble of machine learning, deep learning, quantum annealing, and structural causal modeling were used. Patients with critical COVID-19 were characterized by exacerbated inflammation, perturbed lymphoid and myeloid compartments, increased coagulation, and viral cell biology. Among differentially expressed genes, we observed up-regulation of the metalloprotease ADAM9. This gene signature was validated in a second independent cohort of 81 critical and 73 recovered patients with COVID-19 and was further confirmed at the transcriptional and protein level and by proteolytic activity. Ex vivo ADAM9 inhibition decreased severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uptake and replication in human lung epithelial cells. In conclusion, within a young, otherwise healthy, cohort of individuals with COVID-19, we provide the landscape of biological perturbations in vivo where a unique gene signature differentiated critical from non-critical patients. We further identified ADAM9 as a driver of disease severity and a candidate therapeutic target.

Impact of COVID-19 and lockdown regarding blood transfusion.

BACKGROUND: The outbreak of a SARS-CoV-2 resulted in a massive afflux of patients in hospital and intensive care units with many challenges. Blood transfusion was one of them regarding both blood banks (safety, collection, and stocks) and consumption (usual care and unknown specific demand of COVID-19 patients). The risk of mismatch was sufficient to plan blood transfusion restrictions if stocks became limited. STUDY DESIGN AND METHODS: Analyses of blood transfusion in a tertiary hospital and blood collection in the referring blood bank between February 24 and May 31, 2020. RESULTS: Withdrawal of elective surgery and non-urgent care and admission of 2291 COVID-19 patients reduced global activity by 33% but transfusion by 17% only. Only 237 (10.3) % of COVID-19 patients required blood transfusion, including 45 (2.0%) with acute bleeding. Lockdown and cancellation of mobile collection resulted in an 11% reduction in blood donation compared to 2019. The ratio of reduction in blood transfusion to blood donation remained positive and stocks were slightly enhanced. DISCUSSION: Reduction of admissions due to SARS-CoV-2 pandemic results only in a moderate decrease of blood transfusion. Incompressible blood transfusions concern urgent surgery, acute bleeding (including some patients with COVID-19, especially under high anticoagulation), or are supportive for chemotherapy-induced aplasia or chronic anemia. Lockdown results in a decrease of blood donation by cancellation of mobile donation but with little impact on a short period by mobilization of usual donors. No mismatch between demand and donation was evidenced and no planned restriction to blood transfusion was necessary.

French multicentre observational study on SARS-CoV-2 infections intensive care initial management: the FRENCH CORONA study.

AIM: Describing acute respiratory distress syndrome patterns, therapeutics management, and outcomes of ICU COVID-19 patients and indentifying risk factors of 28-day mortality. METHODS: Prospective multicentre, cohort study conducted in 29 French ICUs. Baseline characteristics, comorbidities, adjunctive therapies, ventilatory support at ICU admission and survival data were collected. RESULTS: From March to July 2020, 966 patients were enrolled with a median age of 66 (interquartile range 58-73) years and a median SAPS II of 37 (29-48). During the first 24 h of ICU admission, COVID-19 patients received one of the following respiratory supports: mechanical ventilation for 559 (58%), standard oxygen therapy for 228 (24%) and high-flow nasal cannula (HFNC) for 179 (19%) patients. Overall, 721 (75%) patients were mechanically ventilated during their ICU stay. Prone positioning and neuromuscular blocking agents were used in 494 (51%) and 460 (48%) patients, respectively. Bacterial co-infections and ventilator-associated pneumonia were diagnosed in 79 (3%) and 411 (43%) patients, respectively. The overall 28-day mortality was 18%. Age, pre-existing comorbidities, severity of respiratory failure and the absence of antiviral therapy on admission were identified as independent predictors of 28-day outcome. CONCLUSION: Severity of hypoxaemia on admission, older age (> 70 years), cardiovascular and renal comorbidities were associated with worse outcome in COVID-19 patients. Antiviral treatment on admission was identified as a protective factor for 28-day mortality. Ascertaining the outcomes of critically ill COVID-19 patients is crucial to optimise hospital and ICU resources and provide the appropriate intensity level of care.

Liposomal encapsulation of trans-crocetin enhances oxygenation in patients with COVID-19-related ARDS receiving mechanical ventilation.

Current therapeutic treatments improving the impaired transportation of oxygen in acute respiratory distress syndrome (ARDS) have been found to be relevant and beneficial for the therapeutic treatment of COVID-19 patients suffering from severe respiratory complications. Hence, we report the preclinical and the preliminary results of the Phase I/II clinical trial of LEAF-4L6715, a liposomal nanocarrier encapsulating the kosmotropic agent trans-crocetin (TC), which, once injected, enhance the oxygenation of vascular tissue and therefore has the potential to improve the clinical outcomes of ARDS and COVID-19 in severely impacted patients. We demonstrated that the liposomal formulation enabled to increase from 30 min to 48 h the reoxygenation properties of free TCs in vitro in endothelial cells, but also to improve the half-life of TC by 6-fold in healthy mice. Furthermore, we identified 25 mg/kg as the maximum tolerated dose in mice. This determined concentration led to the validation of the therapeutic efficacy of LEAF-4 L6715 in a sepsis mouse model. Finally, we report the preliminary outcomes of an open-label multicenter Phase I/II clinical trial (EudraCT 2020-001393-30; NCT04378920), which was aimed to define the appropriate schedule and dosage of LEAF-4L6715 and to confirm its tolerability profile and preliminary clinical activity in COVID-19 patients treated in intensive care unit.

End-Stage Respiratory Failure Secondary to Bronchiolitis Obliterans Syndrome Induced by Toxic Epidermal Necrosis, Also Known as Lyell Syndrome: A Case Report.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but serious dermatologic diseases. They can be associated with systemic manifestations such as bronchiolitis obliterans syndrome (BOS). SJS/TEN-induced BOS is associated with a poor prognosis, and no guidelines exist regarding its management. Several case reports have described the association between SJS/TEN and BOS, with few patients undergoing lung transplantation as a last resort therapy. Unfortunately, in the published reports, none of the transplanted patients were observed for a long period of time after the transplantation; therefore, the long-term mortality as well as the risk of recurrence of BOS could not be inferred from these reports. CASE REPORT: We present the case of a young patient diagnosed with SJS complicated by BOS and end-stage respiratory failure refractory to corticosteroid therapy. She underwent bilateral lung transplantation with an outstanding outcome at 5-year follow-up. CONCLUSION: SJS/TEN-induced BOS might have a favorable evolution and long-term outcomes following lung transplantation. However, prospective studies are needed to confirm this finding.

Perioperative hemodynamic optimization: from guidelines to implementation-an experts' opinion paper.

Despite a large body of evidence, the implementation of guidelines on hemodynamic optimization and goal-directed therapy remains limited in daily routine practice. To facilitate/accelerate this implementation, a panel of experts in the field proposes an approach based on six relevant questions/answers that are frequently mentioned by clinicians, using a critical appraisal of the literature and a modified Delphi process. The mean arterial pressure is a major determinant of organ perfusion, so that the authors unanimously recommend not to tolerate absolute values below 65 mmHg during surgery to reduce the risk of postoperative organ dysfunction. Despite well-identified limitations, the authors unanimously propose the use of dynamic indices to rationalize fluid therapy in a large number of patients undergoing non-cardiac surgery, pending the implementation of a "validity criteria checklist" before applying volume expansion. The authors recommend with a good agreement mini- or non-invasive stroke volume/cardiac output monitoring in moderate to high-risk surgical patients to optimize fluid therapy on an individual basis and avoid volume overload. The authors propose to use fluids and vasoconstrictors in combination to achieve optimal blood flow and maintain perfusion pressure above the thresholds considered at risk. Although purchase of disposable sensors and stand-alone monitors will result in additional costs, the authors unanimously acknowledge that there are data strongly suggesting this may be counterbalanced by a sustained reduction in postoperative morbidity and hospital lengths of stay. Beside existing guidelines, knowledge and explicit clinical reasoning tools followed by decision algorithms are mandatory to implement individualized hemodynamic optimization strategies and reduce postoperative morbidity and duration of hospital stay in high-risk surgical patients.

Reduced Flow-Mediated Dilatation Is Not Related to COVID-19 Severity Three Months after Hospitalization for SARS-CoV-2 Infection.

The coronavirus disease 2019 (COVID-19) pandemic has spread rapidly worldwide, with more than two million deaths. Evidence indicates the critical role of the vascular endothelium in its pathophysiology but, like potential changes in functional vasodilation, the vascular effect of SARS-CoV-2 at a given distance from the acute infection is largely unknown. We assessed brachial artery flow-mediated dilatation (FMD) in 27 COVID-19 patients needing conventional or intensive care unit hospitalization, three months after SARS-CoV-2 infection diagnosis and in nine age- and sex- matched control subjects. Interestingly, the FMD was lower in COVID-19 patients as compared to controls (8.2 (7.2-8.9) vs. 10.3 (9.1-11.7)); p = 0.002, and half of the hospitalized COVID-19 survivors presented with a reduced FMD < 8% at three months of COVID-19 onset. Impaired FMD was not associated with severe or critical SARS-CoV-2 infection, reflected by ICU hospitalization, total hospitalization duration, or severity of lung damage. In conclusion, reduced FMD is often observed even three months after hospitalization for SARS-CoV-2 infection, but such alteration predominantly appears to not be related to COVID-19 severity. Longer and larger follow-up studies will help to clarify the potential prognosis value of FMD among COVID-19 patients, as well as to further determine the mechanisms involved.