Use of defibrotide in COVID-19 pneumonia: comparison of a phase II study and a matched real-world cohort control.

The coronavirus disease 2019 (COVID-19) pandemic led to an unprecedented burden on healthcare systems around the world and a severe global socioeconomic crisis, with more than 750 million confirmed cases and at least 7 million deaths reported by 31st December 2023. The DEFI-VID19 study (ClinicalTrials.gov NCT04335201), a phase II, single-arm, multicenter, open-label trial was designed in mid-2020 to assess the safety and efficacy of defibrotide in treating patients with COVID-19 pneumonia. Defibrotide was administered at a dose of 25 mg/kg/d intravenously, divided into four daily doses over a planned 14-day period for patients with COVID-19 pneumonia receiving non-invasive ventilation. The primary endpoint was Respiratory Failure Free Survival (RFFS); Overall Survival (OS), the number of post-recovery days, and adverse events were the secondary endpoints. For comparison, a contemporaneous control cohort receiving standard of care only was retrospectively selected by applying the eligibility criteria of the DEFI-VID19 trial. To adjust for the imbalance between the two cohorts in terms of baseline variable distributions, an outcome regression analysis was conducted. In adjusted analysis, patients receiving defibrotide reported a trend towards higher RFFS (HR=0.71[0.95CI: 0.34 to 1.29, P= .138]) and OS (HR=0.78[0.95CI: 0.33 to 1.53, P= .248]) and showed a significantly increased number of post-recovery days (difference in means: 3.61[ 0.95CI: 0.97 to 6.26, P= .0037]). Despite concomitant thromboprophylaxis with low molecular weight heparin, the safety profile of defibrotide proved to be favorable. Taken together, our findings suggest that defibrotide may represent a valuable addition to the COVID-19 therapeutic options.

A cytokine/PTX3 prognostic index as a predictor of mortality in sepsis.

Background: Early prognostic stratification of patients with sepsis is a difficult clinical challenge. Aim of this study was to evaluate novel molecules in association with clinical parameters as predictors of 90-days mortality in patients admitted with sepsis at Humanitas Research Hospital. Methods: Plasma samples were collected from 178 patients, diagnosed based on Sepsis-3 criteria, at admission to the Emergency Department and after 5 days of hospitalization. Levels of pentraxin 3 (PTX3), soluble IL-1 type 2 receptor (sIL-1R2), and of a panel of pro- and anti-inflammatory cytokines were measured by ELISA. Cox proportional-hazard models were used to evaluate predictors of 90-days mortality. Results: Circulating levels of PTX3, sIL-1R2, IL-1ß, IL-6, IL-8, IL-10, IL-18, IL-1ra, TNF-α increased significantly in sepsis patients on admission, with the highest levels measured in shock patients, and correlated with SOFA score (PTX3: r=0.44, p<0.0001; sIL-1R2: r=0.35, p<0.0001), as well as with 90-days mortality. After 5 days of hospitalization, PTX3 and cytokines, but not sIL-1R2 levels, decreased significantly, in parallel with a general improvement of clinical parameters. The combination of age, blood urea nitrogen, PTX3, IL-6 and IL-18, defined a prognostic index predicting 90-days mortality in Sepsis-3 patients and showing better apparent discrimination capacity than the SOFA score (AUC=0.863, 95% CI: 0.780-0.945 vs. AUC=0.727, 95% CI: 0.613-0.840; p=0.021 respectively). Conclusion: These data suggest that a prognostic index based on selected cytokines, PTX3 and clinical parameters, and hence easily adoptable in clinical practice, performs in predicting 90-days mortality better than SOFA. An independent validation is required.

Neurological counterparts of hyponatremia: pathological mechanisms and clinical manifestations.

Hyponatremia, defined as a serum sodium concentration <135 mEq/L, represents the most frequent electrolyte disorder in older hospitalized patients. Early recognition of hyponatremia is mandatory, since it represents an independent risk factor that increases hospital mortality by 40 %. Delayed correction of hyponatremia may worsen brain edema, resulting in different degrees of neural damage. However, an overly rapid correction of serum sodium levels can lead to osmotic demyelination syndrome (ODS), a dreadful neurological picture. In recent years, hyponatremia and ODS have received growing attention both in terms of clinical management and pathophysiology, leading to the discovery of new drugs and treatment algorithms. In this review, we recapitulate the pathogenetic background, clinical manifestations, and treatment guidelines of hyponatremia, focusing on the neurological alterations. Neurological symptoms may be neglected when they manifest as early signs of mild hyponatremia, while brain damage can irremediably affect patients' conditions in the context of ODS.

Different cardiovascular responses to hemodialysis-induced fluid depletion and blood pressure compliance.

BACKGROUND: On the basis of cardiovascular compliance, hemodialysis (HD) patients can be classified as hypotension prone (HP) or hypotension resistant (HR). METHODS: We compare the hemodynamic behavior and myocardial performances in 6 HP and 6 HR patients before and after an isolated ultrafiltration (IU) session removing 3% of total body water. RESULTS: HP show higher basal plasma angiotensin II levels during IU (p<0.01), whereas angiotensin II remained unchanged in HR patients (p<0.001 between groups). The percentage changes of plasma volume (PV) was similar in the 2 groups. A significant reduction of cardiac index was observed only in the HP group (p<0.001 between groups). The mean values of heart rate remained significantly higher, whereas total peripheral resistances significantly fell in the HP in comparison with the HR group (p<0.001 between groups). During IU, the mean arterial pressure (MAP) changes were -10 +/- 3 mm Hg in the HP vs. -3.3 +/- 2 mm Hg in the HR group (p<0.001). Echocardiography data were collected before and after IU. All enrolled patients presented left ventricular hypertrophy; following IU, HP patients showed a reduction of mean left ventricular diameter (p<0.01), left atrial diameters and right atrial diameter, and a change in percentage of right atrium ejection fraction (p<0.001, p<0.01). CONCLUSIONS: In comparison with HR patients, HP patients before and after IU showed a defective arteriovenous tone adjustment to the PV changes, with a hemodynamic picture of abnormal sympathetic stimulation. Moreover, a reduced cardiac preload with both atrial and ventricular underfilling in these patients is at risk for a sudden drop in MAP.

Minimal focal steatosis of liver after islet transplantation in humans: a long-term study.

Several reports have been published on islet transplantation in humans, but few data are available on the effect of islet infusion on the hepatic structure. Our aim was to evaluate in a longitudinal study the impact on the liver of intrahepatic islet transplantation. Clinical outcome and liver imaging were evaluated in 31 cases of islet-kidney transplantation (follow-up 38 +/- 4 months, range 12-96 months). Patients were divided into three groups: full function (FF, 9 cases: established insulin independence); partial function (PF, 16 cases: transient insulin independence, prolonged C-peptide secretion): no function (NF, 6 cases: exhaustion of C-peptide secretion within the first year). Upper abdomen sonogram was regularly performed during the whole follow-up period. Percutaneous liver biopsy was performed in case of echographic abnormalities. Multiple small areas of focal hyperechogenicity were observed in nine cases after 6-12 months. These findings were observed only in FF (two) and in PF (seven) patients. Fasting C-peptide levels at the time of echography were higher in negative than in positive patients (2.42 +/- 0.16 vs. 1.51 +/- 0.10 ng/ml, p = 0,0001). Liver biopsies showed focal macrovesicular steatosis, surrounded by normal liver parenchyma. Normal liver function was maintained. In conclusion, our results indicate that islet transplantation can lead to structural changes of the liver parenchyma (focal steatosis). It is more often observed in patients with partial function. Sonogram can be considered a specific method to reveal liver changes after islet transplantation.

Normalization of multiple hemostatic abnormalities in uremic type 1 diabetic patients after kidney-pancreas transplantation.

To evaluate the effects of kidney-pancreas transplantation on hemostatic abnormalities in uremic type 1 diabetic patients, we conducted a cross-sectional study involving 12 type 1 diabetic patients, 30 uremic type 1 diabetic patients, 27 uremic type 1 diabetic patients who had a kidney-pancreas transplant, 12 uremic type 1 diabetic patients who had a kidney-alone transplant, and 13 healthy control subjects. We evaluated platelet and clotting system. Platelets in the group of uremic type 1 diabetic patients were significantly larger than platelets in the other groups. Resting calcium levels were significantly higher in the uremic type 1 diabetic patients and uremic type 1 diabetic patients who had a kidney-alone transplant than in the type 1 diabetic patients who had a kidney-pancreas transplant and control subjects. CD41 expression was significantly reduced in platelets from the uremic type 1 diabetic patients compared with the other groups. Levels of hypercoagulability markers in the type 1 diabetic patients who had a kidney-pancreas transplant and, to a lesser extent, the uremic type 1 diabetic patients who had a kidney-alone transplant but not the uremic type 1 diabetic patients were similar to those of the control subjects. A reduction in natural anticoagulants was evident in the uremic type 1 diabetic patients, whereas near-normal values were observed in the type 1 diabetic patients who had a kidney-pancreas transplant and uremic type 1 diabetic patients who had a kidney-alone transplant. Hemostatic abnormalities were not observed in type 1 diabetic patients who had a kidney-pancreas transplant. This finding might explain the lower cardiovascular death rate observed in type 1 diabetic patients who had a kidney-pancreas transplant compared with uremic type 1 diabetic patients who had a kidney-alone transplant or uremic type 1 diabetic patients.