High flow nasal oxygen vs. conventional oxygen therapy over respiratory oxygenation index after esophagectomy: an observational study.

Background: Postoperative pulmonary complications after esophagectomy still represent a matter of concern. High flow nasal cannula (HFNC) early after major abdominal and thoracic surgery has demonstrated some advantages over conventional oxygen therapy. Data about respiratory effect of HFNC after esophagectomy is scarce. The primary aim of this study is to investigate if the early use of HFNC after esophagectomy could enhance patients' postoperative respiratory oxygenation (ROX) index and, ultimately, reduce postoperative pneumonia. Methods: In this single center retrospective study all patients undergoing to esophagectomy for cancer from May 2020 to November 2022 were evaluated. Historical cohort (HC) received postoperative oxygen supplementation with Venturi mask or nasal goggles, and a cohort was put under HFNC (HFNC cohort). ROX index, blood gas analysis, radiological atelectasis score (RAS), post-operative complications' data and information on hospital stay have been collected and analyzed. Results: Seventy-one patients were included for the final statistical analysis, 31 in the HFNC and 40 in the HC cohort. Mean age was 64±10 years and body mass index (BMI) was 26 [24-29] kg/m2. ROX index was higher in the HFNC patients than in the HC, 20.8 [16.7-25.9] vs. 14.9 [10.8-18.2] (P<0.0001). In the HFNC cohort patients, pH was higher, 7.42 [7.40-7.44] vs. 7.39 [7.37-7.43] than HC, while PaCO2 was lower in HFNC cohort compared with HC, 39 [36-41] vs. 42 [39-45] mmHg, respectively (P=0.01). RAS was similar between the two cohorts of patients, 1.5±0.98 vs. 1.4±1.04 in the HFNC and the HC cohort, respectively (P=0.611). Lower acute respiratory failure (ARF) rate was recorded among HFNC than HC cohort, 0% vs. 13% respectively, P=0.06. No difference in pneumonia frequency between two cohorts was shown. Conclusions: HFNC improved the ROX index after esophagectomy through significant respiratory rate reduction. This tool should be considered for early respiratory support after extubation in this category of patients, not only as a rescue therapy for ARF, but also to optimize early postoperative respiratory function. Whether this will improve patients' outcomes requires further large randomized controlled trials.

Potential role of IgM-enriched immunoglobulin as adjuvant treatment in severe SARS-CoV-2 infection.

BACKGROUND: Severe COVID-19 patients are characterized by a dysregulated host response to an infection, with uncontrolled pro- and anti- inflammatory pathway activation. Consistent proportion of patients require admission in intensive care units and are at risk of progression to severe forms of disease. These patients are generally admitted during later stages of the disease, when effective antiviral and monoclonal antibody are not indicated. We aimed to assess the potential role of IgM-enriched intra venous immunoglobulins (IGAM) preparations in this setting. METHODS: This retrospective, observational case-controlled study was conducted at a single-center University Hospital of Udine in the Friuli Venezia Giulia Region of Italy. Patients referring to the center between March 2020 and April 2021 was included. During the study period, patient who received Pentaglobin® IGAM treatment (N.=56), administered as compassionate use, was compared with a control group (N.=169) to assess, by propensity score analysis, clinical outcome. RESULTS: Untreated controls required, respect to patient treated with IGAM therapy, longer time to hospitalization with no significant differences in death and orotracheal intubation requirement. Significant differences in the two cohort were in: SOFA was higher in treated, while D-dimer and P/F ratio was better in the treatment cohort. Multivariate logistic regression analysis performed on the "matched sample," obtained by a weighting propensity score approach, identify, as significant protective factor for death outcome, the Pentaglobin® treatment (0.820 [0.698-0.963], P=0.016) and low C-reactive protein (1.001 [1.000-1.002], P=0.031) value while the delay of onset hospitalization is associate with a worst outcome (0.983 [0.967-0.999], P=0.041). CONCLUSIONS: The present study offers a significant insight concerning the use of IgM-enriched immunoglobulin preparations in patients with SARS-CoV-2 severe infection and also could identifying the specific immunological and biochemical profile of the patient who can more benefit from this therapeutic option.

The role of asymmetric dimethylarginine (ADMA) in COVID-19: association with respiratory failure and predictive role for outcome.

We aimed to assess the potential role of Asymmetric dimethylarginine (ADMA) in conditioning respiratory function and pulmonary vasoregulation during Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) infection. Within 72 h from admission, samples from 90 COVID-19 patients were assessed for ADMA, SDMA, L-arginine concentrations. In addition to classical statistics, patients were also clustered by a machine learning approach according to similar features. Multivariable analysis showed that C-reactive protein (OR 1.012), serum ADMA (OR 4.652), white blood cells (OR = 1.118) and SOFA (OR = 1.495) were significantly associated with negative outcomes. Machine learning-based clustering showed three distinct clusters: (1) patients with low severity not requiring invasive mechanical ventilation (IMV), (2) patients with moderate severity and respiratory failure whilst not requiring IMV, and (3) patients with highest severity requiring IMV. Serum ADMA concentration was significantly associated with disease severity and need for IMV although less pulmonary vasodilation was observed by CT scan. High serum levels of ADMA are indicative of high disease severity and requirement of mechanical ventilation. Serum ADMA at the time of hospital admission may therefore help to identify COVID-19 patients at high risk of deterioration and negative outcome.

Barotrauma during Noninvasive Respiratory Support in COVID-19 Pneumonia Outside ICU: The Ancillary COVIMIX-2 Study.

BACKGROUND: Noninvasive respiratory support (NIRS) has been extensively used during the COVID-19 surge for patients with acute respiratory failure. However, little data are available about barotrauma during NIRS in patients treated outside the intensive care unit (ICU) setting. METHODS: COVIMIX-2 was an ancillary analysis of the previous COVIMIX study, a large multicenter observational work investigating the frequencies of barotrauma (i.e., pneumothorax and pneumomediastinum) in adult patients with COVID-19 interstitial pneumonia. Only patients treated with NIRS outside the ICU were considered. Baseline characteristics, clinical and radiological disease severity, type of ventilatory support used, blood tests and mortality were recorded. RESULTS: In all, 179 patients were included, 60 of them with barotrauma. They were older and had lower BMI than controls (p < 0.001 and p = 0.045, respectively). Cases had higher respiratory rates and lower PaO2/FiO2 (p = 0.009 and p < 0.001). The frequency of barotrauma was 0.3% [0.1-1.3%], with older age being a risk factor for barotrauma (OR 1.06, p = 0.015). Alveolar-arterial gradient (A-a) DO2 was protective against barotrauma (OR 0.92 [0.87-0.99], p = 0.026). Barotrauma required active treatment, with drainage, in only a minority of cases. The type of NIRS was not explicitly related to the development of barotrauma. Still, an escalation of respiratory support from conventional oxygen therapy, high flow nasal cannula to noninvasive respiratory mask was predictive for in-hospital death (OR 15.51, p = 0.001). CONCLUSIONS: COVIMIX-2 showed a low frequency for barotrauma, around 0.3%. The type of NIRS used seems not to increase this risk. Patients with barotrauma were older, with more severe systemic disease, and showed increased mortality.

Quality of Life in COVID-Related ARDS Patients One Year after Intensive Care Discharge (Odissea Study): A Multicenter Observational Study.

BACKGROUND: Investigating the health-related quality of life (HRQoL) after intensive care unit (ICU) discharge is necessary to identify possible modifiable risk factors. The primary aim of this study was to investigate the HRQoL in COVID-19 critically ill patients one year after ICU discharge. METHODS: In this multicenter prospective observational study, COVID-19 patients admitted to nine ICUs from 1 March 2020 to 28 February 2021 in Italy were enrolled. One year after ICU discharge, patients were required to fill in short-form health survey 36 (SF-36) and impact of event-revised (IES-R) questionnaire. A multivariate linear or logistic regression analysis to search for factors associated with a lower HRQoL and post-traumatic stress disorded (PTSD) were carried out, respectively. RESULTS: Among 1003 patients screened, 343 (median age 63 years [57-70]) were enrolled. Mechanical ventilation lasted for a median of 10 days [2-20]. Physical functioning (PF 85 [60-95]), physical role (PR 75 [0-100]), emotional role (RE 100 [33-100]), bodily pain (BP 77.5 [45-100]), social functioning (SF 75 [50-100]), general health (GH 55 [35-72]), vitality (VT 55 [40-70]), mental health (MH 68 [52-84]) and health change (HC 50 [25-75]) describe the SF-36 items. A median physical component summary (PCS) and mental component summary (MCS) scores were 45.9 (36.5-53.5) and 51.7 (48.8-54.3), respectively, considering 50 as the normal value of the healthy general population. In all, 109 patients (31.8%) tested positive for post-traumatic stress disorder, also reporting a significantly worse HRQoL in all SF-36 domains. The female gender, history of cardiovascular disease, liver disease and length of hospital stay negatively affected the HRQoL. Weight at follow-up was a risk factor for PTSD (OR 1.02, p = 0.03). CONCLUSIONS: The HRQoL in COVID-19 ARDS (C-ARDS) patients was reduced regarding the PCS, while the median MCS value was slightly above normal. Some risk factors for a lower HRQoL have been identified, the presence of PTSD is one of them. Further research is warranted to better identify the possible factors affecting the HRQoL in C-ARDS.

Acute acquired immune thrombocytopenia after cardiac surgery: A challenging case.

Thrombocytopenia is a common condition that recognizes an infinite number of possible causes, especially in specific settings like the one covered in this case report: the postoperative period of cardiac surgery. We report a case of an old male with multiple comorbidities who underwent a coronary angioplasty procedure and aortic valve replacement. He showed severe thrombocytopenia in the postoperative days. Differential diagnosis required a big effort, also for the experts in the field. Our goal was to aggressively treat the patient with prednisolone, platelets, and intravenous immunoglobulins to maximize the prognosis. Our patient developed no complications and was discharged successfully.

Ventilatory associated barotrauma in COVID-19 patients: A multicenter observational case control study (COVI-MIX-study).

BACKGROUND: The risk of barotrauma associated with different types of ventilatory support is unclear in COVID-19 patients. The primary aim of this study was to evaluate the effect of the different respiratory support strategies on barotrauma occurrence; we also sought to determine the frequency of barotrauma and the clinical characteristics of the patients who experienced this complication. METHODS: This multicentre retrospective case-control study from 1 March 2020 to 28 February 2021 included COVID-19 patients who experienced barotrauma during hospital stay. They were matched with controls in a 1:1 ratio for the same admission period in the same ward of treatment. Univariable and multivariable logistic regression (OR) were performed to explore which factors were associated with barotrauma and in-hospital death. RESULTS: We included 200 cases and 200 controls. Invasive mechanical ventilation was used in 39.3% of patients in the barotrauma group, and in 20.1% of controls (p<0.001). Receiving non-invasive ventilation (C-PAP/PSV) instead of conventional oxygen therapy (COT) increased the risk of barotrauma (OR 5.04, 95% CI 2.30 - 11.08, p<0.001), similarly for invasive mechanical ventilation (OR 6.24, 95% CI 2.86-13.60, p<0.001). High Flow Nasal Oxygen (HFNO), compared with COT, did not significantly increase the risk of barotrauma. Barotrauma frequency occurred in 1.00% [95% CI 0.88-1.16] of patients; these were older (p=0.022) and more frequently immunosuppressed (p=0.013). Barotrauma was shown to be an independent risk for death (OR 5.32, 95% CI 2.82-10.03, p<0.001). CONCLUSIONS: C-PAP/PSV compared with COT or HFNO increased the risk of barotrauma; otherwise HFNO did not. Barotrauma was recorded in 1.00% of patients, affecting mainly patients with more severe COVID-19 disease. Barotrauma was independently associated with mortality. TRIAL REGISTRATION: this case-control study was prospectively registered in clinicaltrial.gov as NCT04897152 (on 21 May 2021).

Identification of COVID-19 patients at risk of hospital admission and mortality: a European multicentre retrospective analysis of mid-regional pro-adrenomedullin.

BACKGROUND: Mid-Regional pro-Adrenomedullin (MR-proADM) is an inflammatory biomarker that improves the prognostic assessment of patients with sepsis, septic shock and organ failure. Previous studies of MR-proADM have primarily focussed on bacterial infections. A limited number of small and monocentric studies have examined MR-proADM as a prognostic factor in patients infected with SARS-CoV-2, however there is need for multicenter validation. An evaluation of its utility in predicting need for hospitalisation in viral infections was also performed. METHODS: An observational retrospective analysis of 1861 patients, with SARS-CoV-2 confirmed by RT-qPCR, from 10 hospitals across Europe was performed. Biomarkers, taken upon presentation to Emergency Departments (ED), clinical scores, patient demographics and outcomes were collected. Multiclass random forest classifier models were generated as well as calculation of area under the curve analysis. The primary endpoint was hospital admission with and without death. RESULTS: Patients suitable for safe discharge from Emergency Departments could be identified through an MR-proADM value of ≤ 1.02 nmol/L in combination with a CRP (C-Reactive Protein) of ≤ 20.2 mg/L and age ≤ 64, or in combination with a SOFA (Sequential Organ Failure Assessment) score < 2 if MR-proADM was ≤ 0.83 nmol/L regardless of age. Those at an increased risk of mortality could be identified upon presentation to secondary care with an MR-proADM value of > 0.85 nmol/L, in combination with a SOFA score ≥ 2 and LDH > 720 U/L, or in combination with a CRP > 29.26 mg/L and age ≤ 64, when MR-proADM was > 1.02 nmol/L. CONCLUSIONS: This international study suggests that for patients presenting to the ED with confirmed SARS-CoV-2 infection, MR-proADM in combination with age and CRP or with the patient's SOFA score could identify patients at low risk where outpatient treatment may be safe.

Effect of heparin treatment on pulmonary embolism and in-hospital death in unvaccinated COVID-19 patients without overt deep vein thrombosis.

BACKGROUND: Pulmonary embolism (PE) without overt deep vein thrombosis (DVT) was common in hospitalized coronavirus-induced disease (COVID)-19 patients and represented a diagnostic, prognostic, and therapeutic challenge. The aim of this study was to analyze the prognostic role of PE on mortality and the preventive effect of heparin on PE and mortality in unvaccinated COVID-19 patients without overt DVT. METHODS: Data from 401 unvaccinated patients (age 68 ± 13 years, 33% females) consecutively admitted to the intensive care unit or the medical ward were included in a retrospective longitudinal study. PE was documented by computed tomography scan and DVT by compressive venous ultrasound. The effect of PE diagnosis and any heparin use on in-hospital death (primary outcome) was analyzed by a classical survival model. The preventive effect of heparin on either PE diagnosis or in-hospital death (secondary outcome) was analyzed by a multi-state model after having reclassified patients who started heparin after PE diagnosis as not treated. RESULTS: Median follow-up time was 8 days (range 1-40 days). PE cumulative incidence and in-hospital mortality were 27% and 20%, respectively. PE was predicted by increased D-dimer levels and COVID-19 severity. Independent predictors of in-hospital death were age (hazards ratio (HR) 1.05, 95% confidence interval (CI) 1.03-1.08, p < 0.001), body mass index (HR 0.93, 95% CI 0.89-0.98, p = 0.004), COVID-19 severity (severe versus mild/moderate HR 3.67, 95% CI 1.30-10.4, p = 0.014, critical versus mild/moderate HR 12.1, 95% CI 4.57-32.2, p < 0.001), active neoplasia (HR 2.58, 95% CI 1.48-4.50, p < 0.001), chronic obstructive pulmonary disease (HR 2.47; 95% CI 1.15-5.27, p = 0.020), respiratory rate (HR 1.06, 95% CI 1.02-1.11, p = 0.008), heart rate (HR 1.03, 95% CI 1.01-1.04, p < 0.001), and any heparin treatment (HR 0.35, 95% CI 0.18-0.67, p = 0.001). In the multi-state model, preventive heparin at prophylactic or intermediate/therapeutic dose, compared with no treatment, reduced PE risk and in-hospital death, but it did not influence mortality of patients with a PE diagnosis. CONCLUSIONS: PE was common during the first waves pandemic in unvaccinated patients, but it was not a negative prognostic factor for in-hospital death. Heparin treatment at any dose prevented mortality independently of PE diagnosis, D-dimer levels, and disease severity.

Transcranial Doppler in a child: A most valuable imaging modality.

Introduction: Pediatric brain injury is a common cause of emergency department (ED) referral. Although severe traumatic brain damage is less frequent, it could be primarily managed by non-pediatric critical care physicians called in for advice. Clinical evaluation is important, but radiology is of particular value in the case of severe brain injury. Transcranial Doppler may help the physician through neuromonitoring. Case Report: We report the case of a 3-year-old male child brought into the pediatric ED for a moderate head injury. His neurological status deteriorated rapidly, making endotracheal intubation and mechanical ventilation necessary. Computed tomography (CT) of the head revealed brain contusion and post-traumatic subarachnoidal hemorrhage. Discussion: Transcranial Doppler was performed at the standard transtemporal evaluation window, and it showed normal vascularization of the entire anterior brain. This result permitted performance of the control CT scan to be postponed. In this case, basic knowledge of transcranial ultrasound proved to be useful, and we believe it could also be useful to other colleagues faced with similar situations even if they are not dedicated to pediatric critically ill patients. Conclusion: Doppler ultrasound in the pediatric population is a valuable bedside tool. Together with clinical evaluation and radiology, it completes the set of techniques necessary for continuous neuromonitoring.

Platelet Dysfunction in Cardiac Surgery: When is the Best Time to Assess It? An Observational Single Center Study.

Purpose. Cardiac surgery is characterized by a high risk of complications related to perioperative bleeding. Guidelines suggest the use of local algorithms based on perioperative point-of-care tests to assess and manage potential coagulation abnormalities. We investigated whether heparin reversal administration affects the adenosine-5-diphosphate (ADP) test values, thus identifying the earliest time point following cardio-pulmonary bypass that permits the promptest detection and treatment of potential platelet dysfunctions. Methods. This was a retrospective, single-center, observational study enrolling cardiac surgery patients requiring cardiac bypass. ADP-tests at 4 different time-points during surgery (T0: baseline, T1: at aortic de-clamping, T2: 10 minutes after protamine administration, and T3: at the end of surgery) were performed. Results. 63 patients undergoing elective cardiac surgery were studied. Baseline ADP-test values were almost constantly greater than intraoperative values, and end of surgery values were often greater than previous intraoperative values. The only difference that proved to be not statistically significant was between T1 and T2, with a clinically insignificant mean difference of -.2 U (95%CI of difference: -6.9 - 6.5 U). There was no correlation between the variation in ADP-test values pre- and post-protamine administration and the protamine-to-heparin ratio. Conclusion. The results of the present study support the hypothesis that the ADP-test could be performed early, at aortic de-clamping before protamine administration. This approach allows for the promptest assessment of a potential impairment in platelet function, and its timely correction.

Bronchoscopic suspect of Herpesvirus infection in critically ill COVID-19 patients: two case reports and brief literature review.

Herpesviridae infection in COVID-19 patients has been reported, particularly muco-cutaneous lesions. Little is known about Herpesviridae lung infection in critically ill COVID-19 patients. Typical scattered lesions seen through fiberoptic bronchoscopy in these patients should raise the question as to whether to start empirically acyclovir treatment while a Herpesviridae diagnostics result becomes available.

Pericardial Cytokine "Storm" in a COVID-19 Patient: the Confirmation of a Hypothesis.

Novel Coronavirus Disease in most cases produces mild symptoms which resolve after a few days. Some authors hypothesized that SARS-CoV-2 infection could trigger excessive cytokine production leading to a severe multi-organ disease requiring intensive care admission. Respiratory and neurological symptoms are the most frequently reported manifestation of the disease. Indeed, cardiac involvement is reported mostly as a part of a systemic disease. Few isolated cardiac manifestations of COVID-19 infection have been described. We report herein a case of SARS-CoV-2 related severe isolated pericardial involvement requiring ICU admission due to cardiac tamponade needing urgent drainage. Analysis of pericardial fluid from drainage demonstrated a higher cytokine concentration than blood values. Other causes of pericardial disease, such as autoimmunity, bacterial or other than COVID-19 infection, neoplasms or acute myocardial infarction were also evaluated, but all tests confirmed negative results. The suspicion of isolated involvement of the pericardium was therefore demonstrated by the analysis of cytokines which strongly support our hypothesis.

Peri-operative approach to esophagectomy: a narrative review from the anesthesiological standpoint.

OBJECTIVE: This review summarizes the peri-operative anesthesiological approaches to esophagectomy considering the best up-to-date, evidence-based medicine, discussed from the anesthesiologist's standpoint. BACKGROUND: Esophagectomy is the only curative therapy for esophageal cancer. Despite the many advancements made in the surgical treatment of this tumour, esophagectomy still carries a morbidity rate reaching 60%. Patients undergoing esophagectomy should be referred to high volume centres where they can receive a multidisciplinary approach to treatment, associated with better outcomes. The anesthesiologist is the key figure who should guide the peri-operative phase, from diagnosis through to post-surgery rehabilitation. We performed an updated narrative review devoted to the study of anesthesia management for esophagectomy in cancer patients. METHODS: We searched MEDLINE, Scopus and Google Scholar databases from inception to May 2021. We used the following terms: "esophagectomy", "esophagectomy AND pre-operative evaluation", "esophagectomy AND protective lung ventilation", "esophagectomy AND hemodynamic monitoring" and "esophagectomy AND analgesia". We considered only articles with abstract written in English and available to the reader. We excluded single case-reports. CONCLUSIONS: Pre-operative anesthesiological evaluation is mandatory in order to stratify and optimize any medical condition. During surgery, protective ventilation and judicious fluid management are the cornerstones of intraoperative "protective anesthesia". Post-operative care should be provided by an intensive care unit or high-dependency unit depending on the patient's condition, the type of surgery endured and the availability of local resources. The provision of adequate post-operative analgesia favours early mobilization and rapid recovery. Anesthesiologist has an important role during the peri-operative care for esophagectomy. However, there are still some topics that need to be further studied to improve the outcome of these patients.

Ultrasound diaphragmatic excursion during non-invasive ventilation in ICU: a prospective observational study.

BACKGROUND AND AIM: Diaphragmatic dysfunction is seen in up to 60% of critically ill patients with respiratory failure, and it is associated with worse outcomes. The functionality of the diaphragm can be studied with simple and codified bedside ultrasound evaluation. Diaphragm excursion is one of the most studied parameters. The aim of this study was to assess the prevalence of diaphragmatic dysfunction in critically ill non-intubated patients admitted to a general intensive care unit with acute respiratory failure. METHODS: We collected data, including ultrasound diaphragm excursion, at 2 time points: at T0 (at the time of recruitment, just before starting NIV) and at T1 (after one hour of NIV). RESULTS: A total of 47 patients were enrolled. The prevalence of diaphragm dysfunction was 42.5% (95% CI 28, 3 - 57,8). Surgical patients showed a higher incidence (relative risk of 1.97) than medical patients. Mean DE was not significantly different between NIV responders (1,35 ± 0.78 cm) and non-responders (1.21 ± 0.85 cm, p 0,6). Patients with diaphragmatic dysfunction responded positively to NIV in 60% (95% CI 36.0 - 80.9%) of cases, while patients without diaphragmatic dysfunction responded positively to the NIV trial in 70.4% (95% CI 49.8 - 86.2%) of cases (p = 0.54). Taking the use of ultrasound diaphragm excursion as a potential predictor of NIV response, the corresponding ROC curve had an area under the curve of 0.53; the best balance between sensitivity (58.1%) and specificity (62.5%) was obtained with a cut-off diaphragm excursion of 1.37 cm. CONCLUSIONS: Diaphragm dysfunction is particularly frequent in critically ill patients with respiratory failure. The functionality of the diaphragm can be effectively and easily tested by bedside ultrasound examination. Overall, our results point towards tentative evidence of a trend of a different response to NIV in patients with vs without diaphragmatic dysfunction.

CORonavirus-19 mild to moderate pneumonia Management with blood Ozonization in patients with Respiratory failure (CORMOR) multicentric prospective randomized clinical trial.

BACKGROUND: Following positive experience on the use of blood ozonation in SARS-CoV-2, the CORMOR randomized trial was designed to evaluate the adjuvant role of oxygen/ozone therapy in mild to moderate SARS-CoV-2 pneumonia. METHODS: The trial (ClinicalTrial.gov NCT04388514) was conducted in four different Italian centers (April-October 2020). Patients were treated according to best available standard of care (SoC) therapy, with or without O3-autohemotherapy (O3-AHT). RESULTS: A total of 92 patients were enrolled: SoC + O3-AHT (48 patients) were compared to the SoC treatment (44 patients). The two groups differed in steroids therapy administration (72.7% in SoC arm vs. 50.0% in O3-AHT arm; p = 0.044). Steroid therapy was routinely started when it was subsequently deemed as effective for the treatment of COVID-19 disease. No significant differences in mortality rates, length of hospital stay, mechanical ventilation requirement and ICU admission were observed. Clinical improvement in patients with pneumonia was assessed according to a specifically designed score (decrease in SIMEU class, improvement in radiology imaging, improvement in PaO2/FiO2, reduction in LDH and requirement of oxygen therapy ≤ 5 days). Score assessment was performed on day-3 (T3) and day-7 (TEnd) of O3-AHT treatment. A significant increase in the score was reported at TEnd, in the O3-AHT treatment arm (0 [0-1] in the SoC arm vs. 2 [1-3] the O3-AHT arm; p = 0.018). No adverse events related O3-AHT treatment was observed. CONCLUSION: In mild-to-moderate pneumonia due to SARS-CoV-2, adjuvant oxygen/ozone therapy did not show any effect on mortality, or mechanical intubation but show a clinical improvement a day 7 from randomization in a composite clinical endpoint. Larger Randomized prospective studies alone or in combination with steroids are needed to confirm our results.

Learning from the Italian experience during COVID-19 pandemic waves: be prepared and mind some crucial aspects.

COVID-19 pandemic has rapidly spread worldwide causing a serious challenge to the global medical community. Italy was struck hard during the first wave earlier this year and several weaknesses as well as general unpreparedness of the national healthcare system were acknowledged. Learning essential lessons from the past, we realized how implementing contingency response measures, human resources and social dynamics could have changed the outcome if promptly adopted. This review translates the previous experience into strategic actions that has to be considered when developing appropriate national and regional operational plans to respond to a pandemic.

Cerebral fat embolism after traumatic bone fractures: a structured literature review and analysis of published case reports.

BACKGROUND: The incidence of cerebral fat embolism (CFE) ranges from 0.9-11%, with a mean mortality rate of around 10%. Although no univocal explanation has been identified for the resulting fat embolism syndrome (FES), two hypotheses are widely thought: the 'mechanical theory', and the 'chemical theory'. The present article provides a systematic review of published case reports of FES following a bone fracture. METHODS: We searched MEDLINE, Web of Science and Scopus to find any article related to FES. Inclusion criteria were: trauma patients; age ≥ 18 years; and the clinical diagnosis of CFE or FES. Studies were excluded if the bone fracture site was not specified. RESULTS: One hundred and seventy studies were included (268 cases). The male gender was most prominent (81.6% vs. 18.4%). The average age was 33 years (±18). The mean age for males (29 ± 14) was significantly lower than for females (51 ± 26) (p < 0.001). The femur was the most common fracture site (71% of cases). PFO was found in 12% of all cases. Univariate and multivariate regression analyses showed the male gender to be a risk factor for FES: RR 1.87 and 1.41, respectively (95%CI 1.27-2.48, p < 0.001; 95%CI 0.48-2.34, p < 0.001). CONCLUSIONS: FES is most frequent in young men in the third decades of life following multiple leg fractures. FES may be more frequent after a burst fracture. The presence of PFO may be responsible for the acute presentation of cerebral embolisms, whereas FES is mostly delayed by 48-72 h.

MR-proADM as prognostic factor of outcome in COVID-19 patients.

Mid Regional pro-ADM (MR-proADM) is a promising novel biomarker in the evaluation of deteriorating patients and an emergent prognosis factor in patients with sepsis, septic shock and organ failure. It can be induced by bacteria, fungi or viruses. We hypothesized that the assessment of MR-proADM, with or without other inflammatory cytokines, as part of a clinical assessment of COVID-19 patients at hospital admission, may assist in identifying those likely to develop severe disease. A pragmatic retrospective analysis was performed on a complete data set from 111 patients admitted to Udine University Hospital, in northern Italy, from 25th March to 15th May 2020, affected by SARS-CoV-2 pneumonia. Clinical scoring systems (SOFA score, WHO disease severity class, SIMEU clinical phenotype), cytokines (IL-6, IL-1b, IL-8, TNF-α), and MR-proADM were measured. Demographic, clinical and outcome data were collected for analysis. At multivariate analysis, high MR-proADM levels were significantly associated with negative outcome (death or orotracheal intubation, IOT), with an odds ratio of 4.284 [1.893-11.413], together with increased neutrophil count (OR = 1.029 [1.011-1.049]) and WHO disease severity class (OR = 7.632 [5.871-19.496]). AUROC analysis showed a good discriminative performance of MR-proADM (AUROC: 0.849 [95% Cl 0.771-0.730]; p < 0.0001). The optimal value of MR-proADM to discriminate combined event of death or IOT is 0.895 nmol/l, with a sensitivity of 0.857 [95% Cl 0.728-0.987] and a specificity of 0.687 [95% Cl 0.587-0.787]. This study shows an association between MR-proADM levels and the severity of COVID-19. The assessment of MR-proADM combined with clinical scoring systems could be of great value in triaging, evaluating possible escalation of therapies, and admission avoidance or inclusion into trials. Larger prospective and controlled studies are needed to confirm these findings.