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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.

Background: As the global outbreak of COVID-19 continues to ravage the world, it is important to understand how frontline clinicians manage ventilatory support and the various limiting factors. / Methods: An online survey composed of 32 questions was developed and validated by an international expert panel. / Results: Overall, 502 respondents from 40 countries across six continents completed the survey. The mean number (±SD) of ICU beds was 64 ± 84. The most popular initial diagnostic tools used for treatment initiation were arterial blood gas (48%) and clinical presentation (37.5%), while the national COVID-19 guidelines were the most used (61.2%). High flow nasal cannula (HFNC) (53.8%), non-invasive ventilation (NIV) (47%), and invasive mechanical ventilation (IMV) (92%) were mostly used for mild, moderate, and severe COVID-19 cases, respectively. However, only 38.8%, 56.6% and 82.9% of the respondents had standard protocols for HFNC, NIV, and IMV, respectively. The most frequently used modes of IMV and NIV were volume control (VC) (36.1%) and continuous positive airway pressure/pressure support (CPAP/PS) (40.6%). About 54% of the respondents did not adhere to the recommended, regular ventilator check interval. The majority of the respondents (85.7%) used proning with IMV, with 48.4% using it for 12– 16 hours, and 46.2% had tried awake proning in combination with HFNC or NIV. Increased staff workload (45.02%), lack of trained staff (44.22%) and shortage of personal protective equipment (PPE) (42.63%) were the main barriers to COVID-19 management. / Conclusion: Our results show that general clinical practices involving ventilatory support were highly heterogeneous, with limited use of standard protocols and most frontline clinicians depending on isolated and varied management guidelines. We found increased staff workload, lack of trained staff and shortage of PPE to be the main limiting factors affecting global COVID-19 ventilatory support management.

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

AimWe aimed to characterise a large population of coronavirus disease 2019 (COVID-19) patients with moderate-to-severe hypoxaemic acute respiratory failure (ARF) receiving continuous positive airway pressure (CPAP) outside the intensive care unit (ICU), and to ascertain whether the duration of CPAP application increased the risk of mortality for patients requiring intubation.MethodsIn this retrospective, multicentre cohort study, we included adult COVID-19 patients, treated with CPAP outside ICU for hypoxaemic ARF from 1 March to 15 April, 2020. We collected demographic and clinical data, including CPAP therapeutic goal, hospital length of stay and 60-day in-hospital mortality.ResultsThe study included 537 patients with a median (interquartile range (IQR) age of 69 (60–76) years. 391 (73%) were male. According to the pre-defined CPAP therapeutic goal, 397 (74%) patients were included in the full treatment subgroup, and 140 (26%) in the do not intubate (DNI) subgroup. Median (IQR) CPAP duration was 4 (1–8) days, while hospital length of stay was 16 (9–27) days. 60-day in-hospital mortality was 34% (95% CI 0.304–0.384%) overall, and 21% (95% CI 0.169–0.249%) and 73% (95% CI 0.648–0.787%) for full treatment and DNI subgroups, respectively. In the full treatment subgroup, in-hospital mortality was 42% (95% CI 0.345–0.488%) for 180 (45%) CPAP failures requiring intubation, and 2% (95% CI 0.008–0.035%) for the remaining 217 (55%) patients who succeeded. Delaying intubation was associated with increased mortality (hazard ratio 1.093, 95% CI 1.010–1.184).ConclusionsWe described a large population of COVID-19 patients treated with CPAP outside ICU. Intubation delay represents a risk factor for mortality. Further investigation is needed for early identification of CPAP failures.

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.

Aneurysmal subarachnoid hemorrhage (SAH) is associated with high morbidity and mortality. In SAH patients, plasma osteopontin (OPN) has been shown to independently predict poor outcome. The aim of the study is to investigate, in a selected population with severe SAH, OPN time course in cerebrospinal fluid (CSF) and plasma during the first week after aneurism rupture, and OPN prognostic value. We included 44 patients with the following criteria: (1) age 18 and 80 years, (2) diagnosis of SAH from cerebral aneurysm rupture, (3) insertion of external ventricular drain. Plasma and CSF were sampled at day 1, 4, and 8. OPN levels, in CSF and plasma, displayed a weak correlation on day 1 and were higher, in CSF, in all time points. Only in poor prognosis patients, OPN levels in CSF significantly increased at day 4 and day 8. Plasma OPN at day 1 and 4 was predictor of poor outcome. In conclusion, plasma and CSF OPN displays a weak correlation, on day 1. The higher levels of OPN found in the CSF compared to plasma, suggest OPN production within the CNS after SAH. Furthermore, plasma OPN, at day 1 and 4, seems to be an independent predictor of poor outcome.

BACKGROUND: Coronary artery disease is a major cause of morbidity and mortality worldwide, and is a consequence of acute thrombotic events involving activation of platelets and coagulation proteins. Factor Xa inhibitors and aspirin each reduce thrombotic events but have not yet been tested in combination or against each other in patients with stable coronary artery disease.METHODS: In this multicentre, double-blind, randomised, placebo-controlled, outpatient trial, patients with stable coronary artery disease or peripheral artery disease were recruited at 602 hospitals, clinics, or community centres in 33 countries. This paper reports on patients with coronary artery disease. Eligible patients with coronary artery disease had to have had a myocardial infarction in the past 20 years, multi-vessel coronary artery disease, history of stable or unstable angina, previous multi-vessel percutaneous coronary intervention, or previous multi-vessel coronary artery bypass graft surgery. After a 30-day run in period, patients were randomly assigned (1:1:1) to receive rivaroxaban (2·5 mg orally twice a day) plus aspirin (100 mg once a day), rivaroxaban alone (5 mg orally twice a day), or aspirin alone (100 mg orally once a day). Randomisation was computer generated. Each treatment group was double dummy, and the patients, investigators, and central study staff were masked to treatment allocation. The primary outcome of the COMPASS trial was the occurrence of myocardial infarction, stroke, or cardiovascular death. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants.FINDINGS: Between March 12, 2013, and May 10, 2016, 27 395 patients were enrolled to the COMPASS trial, of whom 24 824 patients had stable coronary artery disease from 558 centres. The combination of rivaroxaban plus aspirin reduced the primary outcome more than aspirin alone (347 [4%] of 8313 vs 460 [6%] of 8261; hazard ratio [HR] 0·74, 95% CI 0·65-0·86, pINTERPRETATION: In patients with stable coronary artery disease, addition of rivaroxaban to aspirin lowered major vascular events, but increased major bleeding. There was no significant increase in intracranial bleeding or other critical organ bleeding. There was also a significant net benefit in favour of rivaroxaban plus aspirin and deaths were reduced by 23%. Thus, addition of rivaroxaban to aspirin has the potential to substantially reduce morbidity and mortality from coronary artery disease worldwide.FUNDING: Bayer AG.

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.

To evaluate the performance of a new helmet (NH) recently introduced into clinical use relative to that of the standard helmet (SH) in terms of delivering non-invasive continuous positive airway pressure (nCPAP) and pressure support ventilation (nPSV).This was a bench study using a mannequin connected to an active lung simulator. The SH was fastened to the mannequin by armpit braces, which are not needed to secure the NH.The inspiratory and expiratory variations in nCPAP delivered with two different simulated efforts (Pmus), were determined relative to the preset CPAP level. nPSV was applied at two simulated respiratory rates (RR) and two cycling-off flow thresholds. We measured inspiratory trigger delay (Delay trinsp), expiratory trigger delay (Delay trexp), time of synchrony (Time sync), trigger pressure drop (ΔP trigger), airway pressure-time product during the triggering phase (PTPt), the initial 200 ms from the onset of the ventilator pressurization (PTP 200), and the initial 300 and 500 ms from the onset of the simulated effort; this two latter parameters were expressed as the percentage of the area of ideal pressurization (PTP 300-index and PTP 500-index, respectively).In nCPAP, at both Pmus, the differences between the two interfaces at both Pmus were small and clinically irrelevant. In nPSV, regardless of the setting, NH resulted in significantly smaller trigger delays, ΔP trigger, and PTPt. Time sync, PTP 200, PTP 300-index, and PTP 500-index were also significantly higher with the NH compared to the SH, irrespective of the setting.Compared to the SH, the NH is equally effective in delivering nCPAP and more effective in delivering nPSV, and it is used to avoid the need for armpit braces.

Neurally adjusted ventilatory assist (NAVA) has been shown to improve patient-ventilator interaction and reduce asynchronies in intubated patients, as opposed to pressure support ventilation (PSV). This is a short-term head-to-head physiologic comparison between PSV and NAVA in delivering noninvasive ventilation through a helmet (h-NIV), in patients with postextubation hypoxemic acute respiratory failure.Ten patients underwent three 20-min trials of h-NIV in PSV, NAVA, and PSV again. Arterial blood gases (ABGs) were assessed at the end of each trial. Diaphragm electrical activity (EAdi) and airway pressure (P (aw)) were recorded to derive neural and mechanical respiratory rate and timing, inspiratory (delay(TR-insp)) and expiratory trigger delays (delay(TR-exp)), time of synchrony between diaphragm contraction and ventilator assistance (time(synch)), and the asynchrony index (AI).ABGs, peak EAdi, peak P (aw), respiratory rate, either neural or mechanical, neural timing, and delay(TR-exp) were not different between trials. Compared with PSV, with NAVA the mechanical expiratory time was significantly shorter, while the inspiratory time and duty cycle were greater. Time(synch) was 0.79 ± 0.35 s in NAVA versus 0.60 ± 0.30 s and 0.55 ± 0.29 s during the PSV trials (p 0.01 for both). AI exceeded 10% during both PSV trials, while not in NAVA (p 0.001).Compared with PSV, NAVA improves patient-ventilator interaction and synchrony, with no difference in gas exchange, respiratory rate, and neural drive and timing.

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.

Because non-invasive mechanical ventilation (NIV) is increasingly used, new devices, both ventilators and interfaces, have been continuously proposed for clinical use in recent years. To provide the clinicians with valuable information about ventilators and interfaces for NIV, several bench studies evaluating and comparing the performance of NIV devices have been concomitantly published, which may influence the choice in equipment acquisition. As these comparisons, however, may be problematic and sometimes lacking in consistency, in the present article we review and discuss those technical aspects that may explain discrepancies. Studies concerning bench evaluations of devices for NIV were reviewed, focusing on some specific technical aspects: lung models and simulation of inspiratory demand and effort, mechanical properties of the virtual respiratory system, generation and quantification of air leaks, ventilator modes and settings, assessment of the interface-ventilator unit performance. The impact of the use of different test lung models is not clear and warrants elucidation; standard references for simulated demand and effort, mode of generation and extent of air leaks, resistance and compliance of the virtual respiratory system, and ventilator settings are lacking; the criteria for assessment of inspiratory trigger function, inspiration-to-expiration (I:E) cycling, and pressurization rate vary among studies; finally, the terminology utilized is inconsistent, which may also lead to confusion. Consistent experimental settings, uniform terminology, and standard measurement criteria are deemed to be useful to enhance bench assessment of characteristics and comparison of performance of ventilators and interfaces for NIV.

Traumatic injury and trauma deaths have been worldwide considered a major health problem [1]. The World Health Organization estimates that 16 000 people die everyday from trauma injuries, and for every person who dies, several thousands more are injured, many of them with permanent sequelae. Injury accounts for 16% of the global burden of disease [2].

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.

Noninvasive neurally adjusted ventilatory assist by helmet (hNAVA) was shown to improve, compared with pressure support ventilation by helmet (hPSV), patient-ventilator interaction and synchrony in patients with acute respiratory failure without affecting peak electrical activity of the diaphragm (EAdipeak) [1]. Recently, a new helmet is available, which improves pressurization during hPSV. We propose a new setting of hNAVA (hNAVA15) to achieve further improvement. We compare hPSV, hNAVA and hNAVA15, all delivered using the new helmet, with respect to patient's dyspnea, assessed by a visual analogue scale (VASd), arterial blood gases (ABGs), EAdipeak, rate of ventilator pressurization and triggering performance.

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.

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