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This study aimed at evaluating the efficacy and safety of high-dose (> 0.2 L/kg of treated plasma per day) coupled plasma filtration-adsorption (CPFA) in treating patients with septic shock. Multicentre, randomised, adaptive trial, performed in 12 Italian intensive care units (ICUs). Patients aged 14 or more, admitted to the ICU with septic shock, or had developed it during the stay were eligible. The final outcome was mortality at discharge from the last hospital at which the patient received care. Between May 2015, and October 2017, 115 patients were randomised. The first interim analysis revealed a number of early deaths, prompting an unplanned analysis. Last hospital mortality was non-significantly higher in the CPFA (55.6%) than in the control group (46.2%, p = 0.35). The 90-day survival curves diverged in favour of the controls early after randomisation and remained separated afterwards (p = 0.100). An unplanned analysis showed higher mortality in CPFA compared to controls among patients without severe renal failure (p = 0.025); a dose–response relationship was observed between treated plasma volume and mortality (p = 0.010). The COMPACT-2 trial was stopped due to the possible harmful effect of CPFA in patients with septic shock. The harmful effect, if present, was particularly marked in the early phase of septic shock. Patients not requiring renal replacement therapy seemed most exposed to the possible harm, with evidence of a dose–response effect. Until the mechanisms behind these results are fully understood, the use of CPFA for the treatment of patients with septic shock is not recommended.

PURPOSE: Severe coronavirus disease 2019 (COVID-19) is strongly related to interstitial pneumonia with frequent development of acute respiratory distress syndrome (ARDS). The role of corticosteroids (CS) treatment in these patients is still controversial. Some studies evidenced a possible role of an early short-term course of CS treatment in the treatment of severe pneumonia. PATIENTS AND METHODS: This is a single-center, retrospective study considering the patients with confirmed COVID-19 pneumonia admitted to our hospital between 9th March and 15th June 2020. Two groups were considered: early high-dose of methyl-prednisolone (eHDM; n ​= ​31) and the control group (n ​= ​52). Patients in the eHDM group received the dose of 5-8 ​mg/kg/day of methyl-prednisolone for 2 consecutive days. Primary outcome was the mortality evaluation; secondary outcomes were clinical improvement, side-effects and laboratory/radiographic changes. RESULTS: Significant differences between the two groups were: length of hospitalization (21.5 vs 28.4 days, p ​= ​0.026), length of non-invasive ventilation (NIV) or mechanical ventilation (11.5 vs 14.5 days, p ​= ​0.031), death (5 vs 12, p ​= ​0.006) and clinical improvement (16 vs 11, p=0.018). The following factors were related to in-hospital mortality in the multivariate analysis: comorbidities (OR ​= ​2.919; 95%CI ​= ​1.515-16.705; p

Noninvasive continuous positive airway pressure (NIV-CPAP) is effective in patients with hypoxemic respiratory failure. Building evidence during the COVID-19 emergency reported that around 50% of patients in Italy treated with NIV-CPAP avoided the need for invasive mechanical ventilation. Standard NIV-CPAP systems operate at high gas flow rates responsible for noise generation and inadequate humidification. Furthermore, open-configuration systems require a high concentration of oxygen to deliver the desired FiO2 . Concerns outlined the risk for aerosolization in the ambient air and the possible pressure drop in hospital supply pipes. A new NIV-CPAP system is proposed that includes automatic control of patient respiratory parameters. The system operates as a closed-loop breathing circuit that can be assembled, combining a sleep apnea machine with existing commercially available components. Analytical simulation of a breathing patient and simulation with a healthy volunteer at different FiO2 were performed. Inspired and expired oxygen fraction and inspired and expired carbon dioxide pressure were recorded at different CPAP levels with different oxygen delivery. Among the main findings, we report (a) a significant (up to 30-fold) reduction in oxygen feeding compared to standard open high flow NIV-CPAP systems, to assure the same FiO2 levels, and (b) a negligible production of the noise generated in ventilatory systems, and consequent minimization of patients' discomfort. The proposed NIV-CPAP circuit, reshaped in closed-loop configuration with the blower outside of the circuit, has the advantages of minimizing aerosol generation, environmental contamination, oxygen consumption, and noise to the patient. The system is easily adaptable and can be implemented using standard CPAP components.

Clinical features and natural history of coronavirus disease 2019 (COVID-19) differ widely among different countries and during different phases of the pandemia. Here, we aimed to evaluate the case fatality rate (CFR) and to identify predictors of mortality in a cohort of COVID-19 patients admitted to three hospitals of Northern Italy between March 1 and April 28, 2020. All these patients had a confirmed diagnosis of SARS-CoV-2 infection by molecular methods. During the study period 504/1697 patients died; thus, overall CFR was 29.7%. We looked for predictors of mortality in a subgroup of 486 patients (239 males, 59%; median age 71 years) for whom sufficient clinical data were available at data cut-off. Among the demographic and clinical variables considered, age, a diagnosis of cancer, obesity and current smoking independently predicted mortality. When laboratory data were added to the model in a further subgroup of patients, age, the diagnosis of cancer, and the baseline PaO2/FiO2 ratio were identified as independent predictors of mortality. In conclusion, the CFR of hospitalized patients in Northern Italy during the ascending phase of the COVID-19 pandemic approached 30%. The identification of mortality predictors might contribute to better stratification of individual patient risk.

Background The renal assist device (RAD) is a blood purification system containing viable renal tubular epithelial cells (TECs) that has been proposed for the treatment of acute kidney injury (AKI) and multiple organ failure. Perfluorocarbons (PFCs) are oxygen carriers used for organ preservation in transplantation. The aim of this study was to investigate the effect of PFCs on hypoxia- and sepsis-induced TEC injury and on renal CD133+ progenitor differentiation in a microenvironment similar to the RAD. Methods TECs were seeded in a polysulphone hollow fibre under hypoxia or cultured with plasma from 10 patients with sepsis-associated AKI in the presence or absence of PFCs and were tested for cytotoxicity (XTT assay), apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labeling assay, caspases, enzyme-linked immunosorbent assay, Fas/Fas Ligand pathway activation), mitochondrial activity, cell polarity [transepithelial electrical resistance (TEER)] and adenosine triphosphate production. The effect of PFCs on proliferation and differentiation of human CD133+ progenitors was also studied. Results In the presence of PFCs, TECs seeded into the polysulphone hollow fibre showed increased viability and expression of insulin-like growth factor 1, hepatocyte growth factor and macrophage-stimulating protein. Plasma from septic patients induced TEC apoptosis, disruption of oxidative metabolism, alteration of cell polarity and albumin uptake, down-regulation of the tight junction protein ZO-1 and the endocytic receptor megalin on the TEC surface. These detrimental effects were significantly reduced by PFCs. Moreover, PFCs induced CD133+ renal progenitor cell proliferation and differentiation towards an epithelial/tubular-like phenotype. Conclusions PFCs improved the viability and metabolic function of TECs seeded within a polysulphone hollow fibre and subjected to plasma from septic AKI patients. Additionally, PFCs promoted differentiation towards a tubular/epithelial phenotype of CD133+ renal progenitor cells.

Post-myocardial infarction ventricular septal rupture (VSR) is one of the most serious complications occurring in patients with ST elevation myocardial infarction. Although surgical repair with concurrent coronary artery bypass grafting (CABG) is considered the treatment of choice, it carries a very high morbidity and mortality rates. For this reason, surgical approach to all patients might not be reasonable, in particular when patients are critically ill or with multiple comorbidities. Percutaneous interventional approach appears to be safe and effective in patients with a chronic VSR or treated for a residual shunt after initial surgical closure. Immediate primary transcatheter closure in acute setting may also be considered an alternative and effective strategy in selected patients ensuring greater effectiveness and fewer complications compared to surgery. The timing of surgical or percutaneous intervention is critical: the presence of cardiogenic shock and closure in the acute phase after VSR diagnosis are important risk factors of mortality. Due to the high mortality rate, the use of percutaneous occluders has been investigated as an alternative approach. The treatment with dedicated device is in general successful with few procedure-related complications. This strategy is a less invasive alternative to surgical approach; however it needs to be applied on a case-by-case basis.

Purpose To describe the effect of renal sympathetic denervation (RDN) on renal arteries immediately after the procedure and at follow-up. Case report A 52-year-old woman with severe resistant hypertension underwent RDN. A transient spasm occurred in the left renal artery immediately after radiofrequency energy delivery, with subsequent complete resolution without any additional therapy. At 6-month follow-up, the blood pressure increased, and imaging revealed a tight stenosis in the left renal artery, which was successfully treated with a stent. In the next days, there was an immediate significant blood pressure reduction. Conclusion Renal denervation can be complicated by local tissue injury at the ablation sites that could be a possible trigger of late arterial disease.

Background Surgery in patients affected by amyotrophic lateral sclerosis (ALS) presents a particular anesthetic challenge because of the risk of post-operative pulmonary complications. Aims of the study We report on the use of non-invasive ventilation (NIV) to prevent post-operative pulmonary complications (PPCs) in nine patients affected by ALS enrolled in a phase-1 clinical trial with stem cell transplantation. Methods All patients were treated with autologous mesenchymal stem cells implanted into the spinal cord with a surgical procedure. Anesthesia was induced with propofol and maintained with remifentanil and sevoflurane. No muscle relaxant was used. After awakening and regain of spontaneous breathing, patients were tracheally extubated. Non-invasive ventilation through nasal mask was delivered and non-invasive positive pressure ventilation and continuous positive pressure ventilation were started. Results The average time on NIV after surgery was 3 h and 12 min. All patients regained stable spontaneous breathing after NIV discontinuation and had no episodes of respiratory failure until the following day. Conclusions Our case series suggest that the use of NIV after surgery can be a safe strategy to prevent PPCs in patients affected by ALS. The perioperative procedure we chose for these patients appeared safe even in patients with advanced functional stage of the disease.

Introduction Chemical, biological, radiological, and nuclear (CBRN) emergencies need particular hospital preparedness and resources availability. Also, specific skills and capabilities are required for efficient response to these types of events. The aim of this study was to develop an assessment tool to evaluate hospital preparedness and response performance with respect to CBRN emergencies. Methods An evaluation tool was developed using the Delphi technique. A panel of experts from 10 countries, both European and non-European, with more than 5 years of experience in research or practice in CBRN emergency management was involved in this study. The study was run online, and the experts were asked to evaluate a list of items on hospital preparedness and response in CBRN emergencies. A threshold of 85% agreement level was defined as the consensus of experts in this study. Results The first-round questionnaire was answered by 13 experts. Consensus on the preparedness section was reached for all 29 items during the first round and one item was also added by the experts. Consensus on the response performance indicators were reached in 51 out of the 59 items, during the first round, and eight items were modified and then approved in the second round by the experts. Conclusion Hospitals need a specific level of preparedness to enable an effective response to CBRN emergencies. The assessment tool, developed through experts' consensus in this study, provides a standardized method for the evaluation of hospital preparedness and response performance with respect to CBRN emergencies. The feasibility and reliability of this assessment tool could be evaluated before and during simulated exercises in a standardized manner.

In sepsis, dysregulation of the immune response leads to rapid multiorgan failure and death. Accurate and timely diagnosis is lifesaving and should discriminate sepsis from the systemic inflammatory response syndrome (SIRS) caused by non-infectious agents. Osteopontin acts as an extracellular matrix component or a soluble cytokine in inflamed tissues. Its exact role in immune response and sepsis remains to be elucidated. Therefore, we investigated the role of osteopontin in SIRS and sepsis.Prospective, observational study.Intensive care unit of a university hospital.Fifty-six patients with SIRS or sepsis and 56 healthy subjects were enrolled.We analyzed the serum levels of osteopontin and TH1-TH2 cytokines and investigated the role of osteopontin on interleukin 6 secretion by monocytes.Serum osteopontin levels were strikingly higher in patients than in controls and in sepsis than in SIRS, and decreased during the resolution of both the disorders. Receiver operating characteristic curves showed that osteopontin levels have discriminative power between SIRS and sepsis with an area under the curve of 0.796. Osteopontin levels directly correlated with those of interleukin 6 and in vitro, recombinant osteopontin increased interleukin 6 secretion by monocytes in both the absence and presence of high doses of lipopolysaccharide.These data suggest that osteopontin might be a mediator involved in the pathogenesis of SIRS and sepsis, possibly by supporting interleukin 6 secretion.45. SIRS/Sepsis: clinical studies.

The objective was to examine the effect of repeated applications of coupled plasmafiltration-adsorption on the hemodynamic response in septic shock patients hospitalized in intensive care units (ICUs).Prospective, intention-to-treat.General ICU of a tertiary care, non-teaching, 400-bed, city hospital.Twelve consecutive mechanically ventilated septic shock patients, with or without concomitant acute renal failure (ARF).A median of 10 consecutive sessions (prescribed treatment time: 10 h/session; delivered duration: 8.43+/-1.37 h/min) of coupled plasmafiltration-adsorption for each patient.Mean arterial pressure (77.2+/-12.5 [CI 95%; 74.5-79.8] vs. 83.3+/-14.1 [CI 95%; 80.3-86.3] mm Hg; [ p0.001]), cardiac index (4.03+/-0.89 [CI 95%; 3.83-4.22] vs. 3.46+/-0.82 [CI 95%; 3.28-3.64] L/m(2)/min; [ p0.001]), systemic vascular resistance index (1,388+/-496 [CI 95%; 1,278-1,497] vs. 1,753+/-516 [CI 95%; 1,639-1,867] dynes x s/cm(5); [ p0.001]), PO2/FIO2 ratio (204+/-87 [CI 95%; 185-223] vs. 238+/-82 [CI 95%; 220-256]; [ p0.001]), significantly improved during 100 global treatments (pre- vs. post-treatment values). Intra-thoracic blood volume and extra-vascular lung water did not change across treatments. Vasopressor requirement was reduced: norepinephrine decrease from an infusion rate of 0.13+/-0.07 (CI 95%; 0.06-0.16) to 0 gamma/kg/min after a mean of 5.3+/-2.7 sessions. C reactive protein (CRP) significantly decreased (from 29.3+/-7.3 vs. 7.9+/-4.8; p0.0001) during treatment. Survival was 90% at day 28 and 70% at day 90.Coupled plasmafiltration-adsorption was a feasible and safe extracorporeal treatment and exerted a remarkable improvement in the hemodynamics, the pulmonary function, and the outcome in septic shock patients with or without concomitant ARF.

Patients who fail noninvasive ventilation are generally intubated and are then subjected to complications of invasive mechanical ventilation. With transtracheal open ventilation, ventilator support is delivered through an uncuffed small bore minitracheostomy tube, which eliminates pooling of secretions above the cuff and thus reduces the risk of tracheobronchial microbial colonization.To compare transtracheal open ventilation (treatment group) with conventional invasive ventilation (control group) in patients with exacerbation of chronic obstructive pulmonary disease who initially failed noninvasive ventilation.Patients were randomized to receive trans-tracheal open ventilation (n=19) or conventional invasive ventilation (n=20).There was no difference in arterial blood gases after 1 and 30 h between the two groups. Two patients receiving transtracheal open ventilation and 13 undergoing conventional ventilation had complications (p0.0001). Compared with conventional ventilation, transtracheal open ventilation significantly decreased both the duration of mechanical ventilation (7.6+/-4.7 vs. 18.6+/-10.6 d, p0.0001) and length of stay in the intensive care unit (10.2+/-4.5 vs. 21.3+/-9.7 d, p0.0001).Transtracheal open ventilation was as effective as conventional ventilation in maintaining adequate gas exchange and reducing complications, duration of mechanical ventilation, and intensive care unit length of stay.

Recently it has been shown in animal models of amyotrophic lateral sclerosis (ALS) that stem cells significantly slow the progression of the disease and prolong survival. We have evaluated the feasibility and safety of a method of intraspinal cord implantation of autologous mesenchymal stem cells (MSCs) in a few well-monitored patients with ALS.Bone marrow collection was performed according to the standard procedure by aspiration from the posterior iliac crest. Ex vivo expansion of mesenchymal stem cells was induced according to Pittenger's protocol. The cells were suspended in 2 ml of autologous cerebrospinal fluid and transplanted into the spinal cord by a micrometric pump injector.No patient manifested major adverse events such as respiratory failure or death. Minor adverse events were intercostal pain irradiation (4 patients) which was reversible after a mean period of three days after surgery, and leg sensory dysesthesia (5 patients) which was reversible after a mean period of six weeks after surgery. No modification of the spinal cord volume or other signs of abnormal cell proliferation were observed.Our results appear to demonstrate that the procedures of ex vivo expansion of autologous mesenchymal stem cells and of transplantation into the spinal cord of humans are safe and well tolerated by ALS patients.

The management of refractory post-traumatic cerebral oedema remains a frustrating endeavour for the neurosurgeon and the intensivist. Mortality and morbility rates remain high, despite refinements in medical and pharmacological means of controlling intracranial hypertension.

Multi-organ dysfunction syndrome (MODS) is the most frequent cause of death in patients admitted to intensive care units. Severe sepsis and septic shock are the primary causes of MODS and develop as a result of the host response to infection and to bacterial wall components, such as the lipid-A containing lipopolysaccharide (LPS). The host response involves both the cellular and humoral arms of the immune system and the generation of pro- and anti-inflammatory molecules. The anti-inflammatory response may lead to a state of 'immunoparalysis'. Continuous renal replacement therapies (CRRT) remove several soluble pro- and anti-inflammatory mediators simultaneously, albeit at low rates. However, large pore membranes, such as those used for plasmafiltration, may enhance cytokine removal and clearance. We recently observed that the use of coupled plasma filtration adsorption (CPFA) improved survival in a rabbit model of septic shock [1]. The outcome was not correlated with single cytokines or mediators (such as TNFa, platelet-activating factor or endotoxin), but rather with a global sepsis severity score. The results of this study suggested that a non-selective removal of various septic mediators was beneficial. A pilot, prospective, cross-over study tested the hypothesis that CPFA combined with hemodialysis might exert similar beneficial effects on hemodynamics and leukocyte responsiveness in humans with established septic shock and that it might prove superior to continuous veno-venous hemodiafiltration (CVVHDF) alone [2].

Elevated level of osteoprotegerin (OPG), a pleiotropic cytokine involved in bone metabolism, has been associated with coronary heart disease and higher cardiovascular mortality. Because cardiovascular disorders are recognized risk factors for dementia, the study of OPG as a disease marker in vascular dementia (VaD) and Alzheimer's disease (AD) seemed worthy of investigation. OPG concentration was determined by ELISA in an Italian cohort consisting of 39 VaD patients, 36 AD patients, and 39 non-demented controls strictly matched for age and gender. Plasma OPG levels were positively related to age in both demented and non-demented persons. OPG concentrations were significantly higher in both VaD (median: 4.75 pmol/l; interquartile range: 3.42-6.85 pmol/l; P