High vs Low PEEP in Patients With ARDS Exhibiting Intense Inspiratory Effort During Assisted Ventilation: A Randomized Crossover Trial.

BACKGROUND: Positive end-expiratory pressure (PEEP) can potentially modulate inspiratory effort (ΔPes), which is the major determinant of self-inflicted lung injury. RESEARCH QUESTION: Does high PEEP reduce ΔPes in patients with moderate-to-severe ARDS on assisted ventilation? STUDY DESIGN AND METHODS: Sixteen patients with Pao2/Fio2 ≤ 200 mm Hg and ΔPes ≥ 10 cm H2O underwent a randomized sequence of four ventilator settings: PEEP = 5 cm H2O or PEEP = 15 cm H2O + synchronous (pressure support ventilation [PSV]) or asynchronous (pressure-controlled intermittent mandatory ventilation [PC-IMV]) inspiratory assistance. ΔPes and respiratory system, lung, and chest wall mechanics were assessed with esophageal manometry and occlusions. PEEP-induced alveolar recruitment and overinflation, lung dynamic strain, and tidal volume distribution were assessed with electrical impedance tomography. RESULTS: ΔPes was not systematically different at high vs low PEEP (pressure support ventilation: median, 20 cm H2O; interquartile range (IQR), 15-24 cm H2O vs median, 15 cm H2O; IQR, 13-23 cm H2O; P = .24; pressure-controlled intermittent mandatory ventilation: median, 20; IQR, 18-23 vs median, 19; IQR, 17-25; P = .67, respectively). Similarly, respiratory system and transpulmonary driving pressures, tidal volume, lung/chest wall mechanics, and pendelluft extent were not different between study phases. High PEEP resulted in lower or higher ΔPes, respiratory system driving pressure, and transpulmonary driving pressure according to whether this increased or decreased respiratory system compliance (r = -0.85, P < .001; r = -0.75, P < .001; r = -0.80, P < .001, respectively). PEEP-induced changes in respiratory system compliance were driven by its lung component and were dependent on the extent of PEEP-induced alveolar overinflation (r = -0.66, P = .006). High PEEP caused variable recruitment and systematic redistribution of tidal volume toward dorsal lung regions, thereby reducing dynamic strain in ventral areas (pressure support ventilation: median, 0.49; IQR, 0.37-0.83 vs median, 0.96; IQR, 0.62-1.56; P = .003; pressure-controlled intermittent mandatory ventilation: median, 0.65; IQR, 0.42-1.31 vs median, 1.14; IQR, 0.79-1.52; P = .002). All results were consistent during synchronous and asynchronous inspiratory assistance. INTERPRETATION: The impact of high PEEP on ΔPes and lung stress is interindividually variable according to different effects on the respiratory system and lung compliance resulting from alveolar overinflation. High PEEP may help mitigate the risk of self-inflicted lung injury solely if it increases lung/respiratory system compliance. TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT04241874; URL: www. CLINICALTRIALS: gov.

PRAME expression in 137 primary cutaneous melanomas and comparison with 38 related metastases.

Melanocytic lesions have always represented a diagnostic challenge for surgical pathologists. According to the literature, PRAME showed great promise as an immunohistochemical tool in the distinction between benign and malignant melanocytic lesions. In the present study, we retrospectively analyzed 137 thicker (Breslow > 1 mm) primary cutaneous melanomas with the aim to better understand the utility of PRAME immunohistochemistry in daily practice and also to investigate if PRAME could represent a prognostic biomarker for cutaneous melanomas. PRAME immunohistochemistry was performed in all melanomas and in the metastases with antibodies to PRAME (dilution 1:1000, clone Ab219650) on an automated immunostainer (Ventana Benchmark Ultra) using a brown chromogen (DAB). We found that melanomas (59.1%) show diffuse PRAME expression (score 4 +). 99 (72.3%) primary cutaneous melanoma had no relapse during the follow-up. Of this group of melanomas, 61/99 (61.6%) were diffusely positive for PRAME. 38 (27.7%) primary cutaneous melanoma had relapses. Of this group, 28/36 (77.7%) were diffusely positive. We did not find any statistical correlation between diffuse PRAME expression and the presence of driver mutation in BRAF gene (p = 0.927), NRAS gene (p = 0.496) or either of the two (p = 0.138). We did not find a prognostic significance of diffuse PRAME expression for relapse (p = 0.462) or survival rate (p = 0.245). The prognostic value of PRAME has been only reported in mucosal, uveal and cutaneous thin melanomas. Here, we show statistical analyses on PRAME expression for melanoma with Breslow > 1 mm based on survival rate and long-term follow-up. According to our results, PRAME is a useful immunohistochemical ancillary tool in daily practice diagnosis of melanocytic lesions.

Thirty-Day Complications, Unplanned Hospital Encounters, and Mortality after Endosonography and/or Guided Bronchoscopy: A Prospective Study.

BACKGROUND AND OBJECTIVE: Limited data exist regarding the adverse events of advanced diagnostic bronchoscopy, with most of the available information derived from retrospective datasets that primarily focus on early complications. METHODS: We conducted a 15-month prospective cohort study among consecutive patients undergoing endosonography and/or guided bronchoscopy under general anesthesia. We evaluated the 30-day incidence of severe complications, any complication, unplanned hospital encounters, and deaths. Additionally, we analyzed the time of onset (immediate, within 1 h of the procedure; early, 1 h-24 h; late, 24 h-30 days) and identified risk factors associated with these events. RESULTS: Thirty-day data were available for 697 out of 701 (99.4%) enrolled patients, with 85.6% having suspected malignancy and multiple comorbidities (median Charlson Comorbidity Index (IQR): 4 (2-5)). Severe complications occurred in only 17 (2.4%) patients, but among them, 10 (58.8%) had unplanned hospital encounters and 2 (11.7%) died within 30 days. A significant proportion of procedure-related severe complications (8/17, 47.1%); unplanned hospital encounters (8/11, 72.7%); and the two deaths occurred days or weeks after the procedure. Low-dose attenuation in the biopsy site on computed tomography was independently associated with any complication (OR: 1.87; 95% CI 1.13-3.09); unplanned hospital encounters (OR: 2.17; 95% CI 1.10-4.30); and mortality (OR: 4.19; 95% CI 1.74-10.11). CONCLUSIONS: Severe complications arising from endosonography and guided bronchoscopy, although uncommon, have significant clinical consequences. A substantial proportion of adverse events occur days after the procedure, potentially going unnoticed and exerting a negative clinical impact if a proactive surveillance program is not implemented.

Physiological effects of awake prone position in acute hypoxemic respiratory failure.

BACKGROUND: The effects of awake prone position on the breathing pattern of hypoxemic patients need to be better understood. We conducted a crossover trial to assess the physiological effects of awake prone position in patients with acute hypoxemic respiratory failure. METHODS: Fifteen patients with acute hypoxemic respiratory failure and PaO2/FiO2 < 200 mmHg underwent high-flow nasal oxygen for 1 h in supine position and 2 h in prone position, followed by a final 1-h supine phase. At the end of each study phase, the following parameters were measured: arterial blood gases, inspiratory effort (ΔPES), transpulmonary driving pressure (ΔPL), respiratory rate and esophageal pressure simplified pressure-time product per minute (sPTPES) by esophageal manometry, tidal volume (VT), end-expiratory lung impedance (EELI), lung compliance, airway resistance, time constant, dynamic strain (VT/EELI) and pendelluft extent through electrical impedance tomography. RESULTS: Compared to supine position, prone position increased PaO2/FiO2 (median [Interquartile range] 104 mmHg [76-129] vs. 74 [69-93], p < 0.001), reduced respiratory rate (24 breaths/min [22-26] vs. 27 [26-30], p = 0.05) and increased ΔPES (12 cmH2O [11-13] vs. 9 [8-12], p = 0.04) with similar sPTPES (131 [75-154] cmH2O s min-1 vs. 105 [81-129], p > 0.99) and ΔPL (9 [7-11] cmH2O vs. 8 [5-9], p = 0.17). Airway resistance and time constant were higher in prone vs. supine position (9 cmH2O s arbitrary units-3 [4-11] vs. 6 [4-9], p = 0.05; 0.53 s [0.32-61] vs. 0.40 [0.37-0.44], p = 0.03). Prone position increased EELI (3887 arbitrary units [3414-8547] vs. 1456 [959-2420], p = 0.002) and promoted VT distribution towards dorsal lung regions without affecting VT size and lung compliance: this generated lower dynamic strain (0.21 [0.16-0.24] vs. 0.38 [0.30-0.49], p = 0.004). The magnitude of pendelluft phenomenon was not different between study phases (55% [7-57] of VT in prone vs. 31% [14-55] in supine position, p > 0.99). CONCLUSIONS: Prone position improves oxygenation, increases EELI and promotes VT distribution towards dependent lung regions without affecting VT size, ΔPL, lung compliance and pendelluft magnitude. Prone position reduces respiratory rate and increases ΔPES because of positional increases in airway resistance and prolonged expiratory time. Because high ΔPES is the main mechanistic determinant of self-inflicted lung injury, caution may be needed in using awake prone position in patients exhibiting intense ΔPES. Clinical trail registeration: The study was registered on clinicaltrials.gov (NCT03095300) on March 29, 2017.

Bloodstream infections in COVID-19 patients undergoing extracorporeal membrane oxygenation in ICU: An observational cohort study.

BACKGROUND: COVID-19 patients undergoing ECMO are at highly increased risk of nosocomial infections. OBJECTIVES: To study incidence, clinical outcomes and microbiological features of bloodstream infections (BSI) occurring during ECMO in COVID-19 patients. METHODS: Observational prospective cohort study enrolling consecutive COVID-19 patients undergoing veno-venous-ECMO in an Italian ICU from March 2020 to March 2022. RESULTS: In the study population of 68 patients (age 53 [49-60] years, 82% males), 30 (44%) developed bloodstream infections (BSI group) while 38 did not (N-BSI group) with an incidence of 32 events/1000 days of ECMO. In BSI group pre-ECMO respiratory support was shorter (6 [4-9] vs 9 [5-12] days, p = 0.02) and ECMO treatment was longer (18 [10-29] vs 11 [7-18] days, p = 0.03) than in N-BSI group. The overall ECMO and ICU mortality were 50% and 59%, respectively, without any inter-group difference (p = 1.00). A longer ECMO treatment was independently correlated with higher rate of BSI (p = 0.04, OR [95% CI] 1.06 [1.02-1.11]). Sixteen primary and 14 secondary infectious events were documented. Gram-positive pathogens were more common in primary than secondary BSI (88% vs 43%, p = 0.02) and Enterococcus faecalis (56%) was the most frequent one. Conversely, Gram-negative microorganisms were more often isolated in secondary rather than primary BSI (57% vs 13%, p = 0.02), with Acinetobacter baumannii (21%) and Pseudomonas aeruginosa (21%) as most represented species. The administration of Sars-CoV-2 antiviral drug showed independent correlation with a reduced rate of ICU mortality (p = 0.01, OR [95% CI] 0.22 [0.07-0.73]). CONCLUSIONS: Bloodstream infections represented a frequent complication without worsening clinical outcomes in our COVID-19 patients undergoing ECMO. Primary and secondary BSI events showed peculiar microbiological profiles.

Recruitment-to-inflation Ratio Assessed through Sequential End-expiratory Lung Volume Measurement in Acute Respiratory Distress Syndrome.

BACKGROUND: Positive end-expiratory pressure (PEEP) benefits in acute respiratory distress syndrome are driven by lung dynamic strain reduction. This depends on the variable extent of alveolar recruitment. The recruitment-to-inflation ratio estimates recruitability across a 10-cm H2O PEEP range through a simplified maneuver. Whether recruitability is uniform or not across this range is unknown. The hypotheses of this study are that the recruitment-to-inflation ratio represents an accurate estimate of PEEP-induced changes in dynamic strain, but may show nonuniform behavior across the conventionally tested PEEP range (15 to 5 cm H2O). METHODS: Twenty patients with moderate-to-severe COVID-19 acute respiratory distress syndrome underwent a decremental PEEP trial (PEEP 15 to 13 to 10 to 8 to 5 cm H2O). Respiratory mechanics and end-expiratory lung volume by nitrogen dilution were measured the end of each step. Gas exchange, recruited volume, recruitment-to-inflation ratio, and changes in dynamic, static, and total strain were computed between 15 and 5 cm H2O (global recruitment-to-inflation ratio) and within narrower PEEP ranges (granular recruitment-to-inflation ratio). RESULTS: Between 15 and 5 cm H2O, median [interquartile range] global recruitment-to-inflation ratio was 1.27 [0.40 to 1.69] and displayed a linear correlation with PEEP-induced dynamic strain reduction (r = -0.94; P < 0.001). Intraindividual recruitment-to-inflation ratio variability within the narrower ranges was high (85% [70 to 109]). The relationship between granular recruitment-to-inflation ratio and PEEP was mathematically described by a nonlinear, quadratic equation (R2 = 0.96). Granular recruitment-to-inflation ratio across the narrower PEEP ranges itself had a linear correlation with PEEP-induced reduction in dynamic strain (r = -0.89; P < 0.001). CONCLUSIONS: Both global and granular recruitment-to-inflation ratio accurately estimate PEEP-induced changes in lung dynamic strain. However, the effect of 10 cm H2O of PEEP on lung strain may be nonuniform. Granular recruitment-to-inflation ratio assessment within narrower PEEP ranges guided by end-expiratory lung volume measurement may aid more precise PEEP selection, especially when the recruitment-to-inflation ratio obtained with the simplified maneuver between PEEP 15 and 5 cm H2O yields intermediate values that are difficult to interpret for a proper choice between a high and low PEEP strategy.

Personalized Respiratory Support in ARDS: A Physiology-to-Bedside Review.

Acute respiratory distress syndrome (ARDS) is a leading cause of disability and mortality worldwide, and while no specific etiologic interventions have been shown to improve outcomes, noninvasive and invasive respiratory support strategies are life-saving interventions that allow time for lung recovery. However, the inappropriate management of these strategies, which neglects the unique features of respiratory, lung, and chest wall mechanics may result in disease progression, such as patient self-inflicted lung injury during spontaneous breathing or by ventilator-induced lung injury during invasive mechanical ventilation. ARDS characteristics are highly heterogeneous; therefore, a physiology-based approach is strongly advocated to titrate the delivery and management of respiratory support strategies to match patient characteristics and needs to limit ARDS progression. Several tools have been implemented in clinical practice to aid the clinician in identifying the ARDS sub-phenotypes based on physiological peculiarities (inspiratory effort, respiratory mechanics, and recruitability), thus allowing for the appropriate application of personalized supportive care. In this narrative review, we provide an overview of noninvasive and invasive respiratory support strategies, as well as discuss how identifying ARDS sub-phenotypes in daily practice can help clinicians to deliver personalized respiratory support and potentially improve patient outcomes.

GRM1 Gene Fusions as an Alternative Molecular Driver in Blue Nevi and Related Melanomas.

Activating mutations in GNAQ, GNA11, CYSLTR2, and PLCB4 genes are regarded as the main oncogenic drivers of blue nevi (BN) and blue malignant melanocytic tumors. Here we report 4 cases of blue melanocytic neoplasms devoid of these mutations but harboring GRM1 gene fusions. In this short series, there was no gender predominance (sex ratio, 1). The mean age at diagnosis was 40 years (range, 12-72). Tumors were located on the face (n = 2), forearm (n = 1), and dorsum of the foot (n = 1). Clinically, a plaque-like pre-existing BN was found in 2 cases, including a deep location; another case presented as an Ota nevus. Two cases were diagnosed as melanoma ex-BN, one as an atypical BN, and one as a plaque-like BN. Microscopic examination revealed a dermal proliferation of dendritic melanocytes in a sclerotic stroma. A dermal cellular nodule with atypia and mitotic activity was observed in 3 cases. Genetic investigation by whole exome RNA sequencing revealed MYO10::GRM1 (n = 2) and ZEB2::GRM1 (n = 1) fusions. A GRM1 rearrangement was identified by fluorescence in situ hybridization in the remaining case. SF3B1 comutations were present in the 2 melanomas, and both had a MYO10::GRM1 fusion. Array comparative genomic hybridization was feasible for 3 cases and displayed multiple copy number alterations in the 2 melanomas and limited copy number alterations in the atypical BN, all genomic profiles compatible with those of classical blue lesions. GRM1 was overexpressed in all cases compared with a control group of blue lesions with other typical mutations. Both melanomas rapidly developed visceral metastases following diagnosis, with a fatal outcome in one case and tumor progression under palliative care in the other. These data suggest that GRM1 gene fusions could represent an additional rare oncogenic driver in the setting of BN, mutually exclusive of classical canonical mutations, especially in plaque-type or Ota subtypes.

Long-term outcome of COVID-19 patients treated with helmet noninvasive ventilation vs. high-flow nasal oxygen: a randomized trial.

BACKGROUND: Long-term outcomes of patients treated with helmet noninvasive ventilation (NIV) are unknown: safety concerns regarding the risk of patient self-inflicted lung injury and delayed intubation exist when NIV is applied in hypoxemic patients. We assessed the 6-month outcome of patients who received helmet NIV or high-flow nasal oxygen for COVID-19 hypoxemic respiratory failure. METHODS: In this prespecified analysis of a randomized trial of helmet NIV versus high-flow nasal oxygen (HENIVOT), clinical status, physical performance (6-min-walking-test and 30-s chair stand test), respiratory function and quality of life (EuroQoL five dimensions five levels questionnaire, EuroQoL VAS, SF36 and Post-Traumatic Stress Disorder Checklist for the DSM) were evaluated 6 months after the enrollment. RESULTS: Among 80 patients who were alive, 71 (89%) completed the follow-up: 35 had received helmet NIV, 36 high-flow oxygen. There was no inter-group difference in any item concerning vital signs (N = 4), physical performance (N = 18), respiratory function (N = 27), quality of life (N = 21) and laboratory tests (N = 15). Arthralgia was significantly lower in the helmet group (16% vs. 55%, p = 0.002). Fifty-two percent of patients in helmet group vs. 63% of patients in high-flow group had diffusing capacity of the lungs for carbon monoxide < 80% of predicted (p = 0.44); 13% vs. 22% had forced vital capacity < 80% of predicted (p = 0.51). Both groups reported similar degree of pain (p = 0.81) and anxiety (p = 0.81) at the EQ-5D-5L test; the EQ-VAS score was similar in the two groups (p = 0.27). Compared to patients who successfully avoided invasive mechanical ventilation (54/71, 76%), intubated patients (17/71, 24%) had significantly worse pulmonary function (median diffusing capacity of the lungs for carbon monoxide 66% [Interquartile range: 47-77] of predicted vs. 80% [71-88], p = 0.005) and decreased quality of life (EQ-VAS: 70 [53-70] vs. 80 [70-83], p = 0.01). CONCLUSIONS: In patients with COVID-19 hypoxemic respiratory failure, treatment with helmet NIV or high-flow oxygen yielded similar quality of life and functional outcome at 6 months. The need for invasive mechanical ventilation was associated with worse outcomes. These data indicate that helmet NIV, as applied in the HENIVOT trial, can be safely used in hypoxemic patients. Trial registration Registered on clinicaltrials.gov NCT04502576 on August 6, 2020.

Usefulness of differential time to positivity between catheter and peripheral blood cultures for diagnosing catheter-related bloodstream infection: Data analysis from routine clinical practice in the intensive care unit.

PURPOSE: To assess the accuracy of differential time to positivity (DTP) method for the diagnosis of catheter-related bloodstream infections (CRBSI) in the routine practice of our intensive care unit (ICU). MATERIALS AND METHODS: Over a five-year study period, ICU patients with a central venous catheter in place for ≥48 h and undergoing DTP test with catheter tip culture were analyzed. We investigated: the accuracy of DTP test with the usual threshold of 120 min in confirming the clinical suspicion of CRBSI; the most accurate threshold value of DTP to detect CRBSI; the diagnostic accuracy of the ratio (rather than the difference) between times to positivity. RESULTS: Among 278 episodes of paired blood cultures, 13% were CRBSIs. DTP value ≥120 min used for the diagnosis of CRBSI yielded 41% sensitivity and 74% specificity. Performance of DTP values in predicting CRBSI was low (AUC = 0.60 [95%CI: 0.48-0.72]). Cutoff value of the ratio between times to positivity was 0.80, with 46% sensitivity and 79% specificity. CONCLUSIONS: The routine use of the DTP method at any cutoff point has inadequate accuracy in detecting CRBSI in the real every day clinical practice. Not even the ratio between times to positivity seems to be clinically useful.

Risk Factors Associated with Post-Operative Complications in Multidisciplinary Treatment of Descending Necrotizing Mediastinitis.

BACKGROUND: Descending necrotizing mediastinitis (DNM) is a severe, life-threatening complication of oropharyngeal infections with cervical necrotizing fasciitis. In this study, we aimed to identify any possible factors that correlate with favorable outcomes. METHODS: We retrospectively analyzed our series of 18 patients who underwent surgical treatment for DNM from a cervical abscess. Gender, age, symptoms, etiopathogenesis, comorbidities, time to surgery from diagnosis, degree of diffusion, identified microorganisms, surgical procedure, days in the intensive care unit, need for tracheostomy, complications, and surgical outcomes were reviewed. RESULTS: The main type of surgery was thoracotomy + cervicotomy in eight cases (50.0%), followed by cervicotomy +VATS in four (22.2%). Seven patients (38.9%) had two or more surgeries; a bilateral operation was necessary for four patients. Evaluating the risk factors associated with post-operative complications, age ≥ 60 years (p:0.031), cervicotomy alone as surgical approach (p = 0.040), and the bilateral approach (p = 0.048) resulted in significance in terms of the univariate analysis; age ≥ 60 years (p = 0.04) and cervical approach (p = 0.05) maintained their significance in terms of the multivariate analysis. CONCLUSIONS: The low mortality of our series emphasizes the importance of an extensive and immediate surgical drainage of both the neck and the mediastinum. Mediastinal drainage from cervicotomy seems to be a risk factor for post-operative complications. Minimally invasive surgery on the chest cavity, such as with Uniportal-VATS, could be a good approach above all in elderly patients and all those cases where bilateral access is required.

Tuberculosis: the sanatorium season in the early 20th century.

The creation of hospitals providing specialist care is not a prerogative of our time. As the world wonders how to cope with new pandemics and the age-old problems of the transmission of infections and the isolation of the sick, while the COVID-19 pandemic has been raging, it might be worth glancing back at the period - just over a century ago - when sanatoriums were set up in Italy as part of the fight against consumption.

Remdesivir plus Dexamethasone in COVID-19: A cohort study of severe patients requiring high flow oxygen therapy or non-invasive ventilation.

INTRODUCTION: Remdesivir and Dexamethasone represent the cornerstone of therapy for critically ill patients with acute hypoxemic respiratory failure caused by Coronavirus Disease 2019 (COVID-19). However, clinical efficacy and safety of concomitant administration of Remdesivir and Dexamethasone (Rem-Dexa) in severe COVID-19 patients on high flow oxygen therapy (HFOT) or non-invasive ventilation (NIV) remains unknown. MATERIALS AND METHODS: Prospective cohort study that was performed in two medical Intensive Care Units (ICUs) of a tertiary university hospital. The clinical impact of Rem-Dexa administration in hypoxemic patients with COVID-19, who required NIV or HFOT and selected on the simplified acute physiology score II, the sequential organ failure assessment score and the Charlson Comorbidity Index score, was investigated. The primary outcome was 28-day intubation rate; secondary outcomes were end-of-treatment clinical improvement and PaO2/FiO2 ratio, laboratory abnormalities and clinical complications, ICU and hospital length of stay, 28-day and 90-day mortality. RESULTS: We included 132 patients and found that 28-day intubation rate was significantly lower among Rem-Dexa group (19.7% vs 48.5%, p<0.01). Although the end-of-treatment clinical improvement was larger among Rem-Dexa group (69.7% vs 51.5%, p = 0.05), the 28-day and 90-day mortalities were similar (4.5% and 10.6% vs. 15.2% and 16.7%; p = 0.08 and p = 0.45, respectively). The logistic regression and Cox-regression models showed that concomitant Rem-Dexa therapy was associated with a reduction of 28-day intubation rate (OR 0.22, CI95% 0.05-0.94, p = 0.04), in absence of laboratory abnormalities and clinical complications (p = ns). CONCLUSIONS: In COVID-19 critically ill patients receiving HFO or NIV, 28-day intubation rate was lower in patients who received Rem-Dexa and this finding corresponded to lower end-of-treatment clinical improvement. The individual contribution of either Remdesevir or Dexamethasone to the observed clinical effect should be further investigated.

Bracket Bonding to All-Ceramic Materials with Universal Adhesives.

The need for bracket bonding to ceramic restorations is increasing. The aim of this study was to evaluate the effect of universal adhesives on bracket adhesion to polished or glazed lithium disilicate (LDS) and monolithic zirconia (MZ) surfaces. One hundred and twenty brackets (N = 10) were bonded to either polished or glazed LDS (e.max CAD B32, Ivoclar Vivadent, Schaan, Liechtenstein) and MZ (In-Ceram® YZ, VITA, Bad Sackingen, Germany) blocks using three different adhesives combined with Transbond™ XT Paste (3M Unitek, Monrovia, CA, USA). Tested universal adhesives were Scotchbond™ Universal Adhesive (SU, 3M St. Paul, MN, USA) and Assure Plus (AP, Reliance, Itasca, IL, USA). Transbond™ XT Primer (XTP, 3M Unitek, Monrovia, CA, USA) served as a control adhesive. Bracket bond strength was measured in shear mode (SBS). Failure type was determined by the Modified Adhesive Remnant Index (ARI). Data were statistically analyzed. On polished LDS, SU yielded bracket SBS significantly superior to those of AP and XTP. On polished MZ, the use of SU and AP significantly enhanced bracket retention as compared with XTP. Low SBS values, below the threshold of clinical acceptability, were reached by all tested adhesives on glazed LDS and MZ specimens. SBS measurements corresponded with failure type observations. Universal adhesives SU and AP could be considered for use on polished LDS and MZ surfaces.

Gas conditioning during helmet noninvasive ventilation: effect on comfort, gas exchange, inspiratory effort, transpulmonary pressure and patient-ventilator interaction.

BACKGROUND: There is growing interest towards the use of helmet noninvasive ventilation (NIV) for the management of acute hypoxemic respiratory failure. Gas conditioning through heat and moisture exchangers (HME) or heated humidifiers (HHs) is needed during facemask NIV to provide a minimum level of humidity in the inspired gas (15 mg H2O/L). The optimal gas conditioning strategy during helmet NIV remains to be established. METHODS: Twenty patients with acute hypoxemic respiratory failure (PaO2/FiO2 < 300 mmHg) underwent consecutive 1-h periods of helmet NIV (PEEP 12 cmH2O, pressure support 12 cmH2O) with four humidification settings, applied in a random order: double-tube circuit with HHs and temperature set at 34 °C (HH34) and 37 °C (HH37); Y-piece circuit with HME; double-tube circuit with no humidification (NoH). Temperature and humidity of inhaled gas were measured through a capacitive hygrometer. Arterial blood gases, discomfort and dyspnea through visual analog scales (VAS), esophageal pressure swings (ΔPES) and simplified pressure-time product (PTPES), dynamic transpulmonary driving pressure (ΔPL) and asynchrony index were measured in each step. RESULTS: Median [IqR] absolute humidity, temperature and VAS discomfort were significantly lower during NoH vs. HME, HH34 and HH37: absolute humidity (mgH2O/L) 16 [12-19] vs. 28 [23-31] vs. 28 [24-31] vs. 33 [29-38], p < 0.001; temperature (°C) 29 [28-30] vs. 30 [29-31] vs. 31 [29-32] vs 32. [31-33], p < 0.001; VAS discomfort 4 [2-6] vs. 6 [2-7] vs. 7 [4-8] vs. 8 [4-10], p = 0.03. VAS discomfort increased with higher absolute humidity (p < 0.01) and temperature (p = 0.007). Higher VAS discomfort was associated with increased VAS dyspnea (p = 0.001). Arterial blood gases, respiratory rate, ΔPES, PTPES and ΔPL were similar in all conditions. Overall asynchrony index was similar in all steps, but autotriggering rate was lower during NoH and HME (p = 0.03). CONCLUSIONS: During 1-h sessions of helmet NIV in patients with hypoxemic respiratory failure, a double-tube circuit with no humidification allowed adequate conditioning of inspired gas, optimized comfort and improved patient-ventilator interaction. Use of HHs or HME in this setting resulted in increased discomfort due to excessive heat and humidity in the interface, which was associated with more intense dyspnea. Trail Registration Registered on clinicaltrials.gov (NCT02875379) on August 23rd, 2016.

Compassionate use of anti-IL6 receptor antibodies in critically ill patients with acute respiratory distress syndrome due to SARS-CoV-2.

BACKGROUND: COVID-19 patients developing the acute respiratory distress syndrome (ARDS) show increased production of pro-inflammatory cytokines, including interleukin-6 (IL-6). The use of humanized monoclonal antibody against interleukin-6 receptor (IL-6R) may represent a potential treatment strategy. We analyzed the effects of compassionate use of tocilizumab and sarilumab on clinical outcome of patients affected by ARDS due COVID-19. METHODS: This single-center, observational, exploratory study was performed during the acute phase of COVID-19 outbreak, between March 7th and April 21st, 2020 in a University Hospital in Rome, Italy. All consecutive adult patients admitted to the intensive care unit with laboratory-confirmed COVID-19 and fulfilling ARDS criteria were enrolled. Patients who were treated with anti-IL-6R therapy were compared to those who were not, as per clinical decision. Inverse probability weights were applied to weight individual's contribution to survival curves and in the multivariate regression model. RESULTS: Among 105 ARDS patients, 65 received compassionate treatment with anti-IL-6R therapy (43 [66%] Tocilizumab [Hoffmann-La Roche, Basel, Switzerland] and 22 [34%] Sarilumab, respectively], with oxygenation improvement. In the multivariable Cox proportional regression hazards model with propensity score inverse probability weighting, patients who received anti-IL-6R treatment had lower risk of death compared to those who did not, with a hazard ration of 0.34 [95% confidence interval 0.17-0.74], P=0.001. CONCLUSIONS: Our data suggested that immune modulator therapy based on anti-human IL-6 receptor monoclonal antibodies might lead to improved outcome in patients with ARDS due to COVID-19. These data support the need for confirmatory randomized trials to assess the effect of immune modulator therapies on mortality.

Diaphragm thickening fraction predicts noninvasive ventilation outcome: a preliminary physiological study.

BACKGROUND: A correlation between unsuccessful noninvasive ventilation (NIV) and poor outcome has been suggested in de-novo Acute Respiratory Failure (ARF) patients. Consequently, it is of paramount importance to identify accurate predictors of NIV outcome. The aim of our preliminary study is to evaluate the Diaphragmatic Thickening Fraction (DTF) and the respiratory rate/DTF ratio as predictors of NIV outcome in de-novo ARF patients. METHODS: Over 36 months, we studied patients admitted to the emergency department with a diagnosis of de-novo ARF and requiring NIV treatment. DTF and respiratory rate/DTF ratio were measured by 2 trained operators at baseline, at 1, 4, 12, 24, 48, 72 and 96 h of NIV treatment and/or until NIV discontinuation or intubation. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the ability of DTF and respiratory rate/DTF ratio to distinguish between patients who were successfully weaned and those who failed. RESULTS: Eighteen patients were included. We found overall good repeatability of DTF assessment, with Intra-class Correlation Coefficient (ICC) of 0.82 (95% confidence interval 0.72-0.88). The cut-off values of DTF for prediction of NIV failure were < 36.3% and < 37.1% for the operator 1 and 2 (p < 0.0001), respectively. The cut-off value of respiratory rate/DTF ratio for prediction of NIV failure was > 0.6 for both operators (p < 0.0001). CONCLUSION: DTF and respiratory rate/DTF ratio may both represent valid, feasible and noninvasive tools to predict NIV outcome in patients with de-novo ARF. Trial registration ClinicalTrials.gov Identifier: NCT02976233, registered 26 November 2016.

Staphylococcus aureus ventilator-associated pneumonia in patients with COVID-19: clinical features and potential inference with lung dysbiosis.

BACKGROUND: Hospitalized patients with COVID-19 admitted to the intensive care unit (ICU) and requiring mechanical ventilation are at risk of ventilator-associated bacterial infections secondary to SARS-CoV-2 infection. Our study aimed to investigate clinical features of Staphylococcus aureus ventilator-associated pneumonia (SA-VAP) and, if bronchoalveolar lavage samples were available, lung bacterial community features in ICU patients with or without COVID-19. METHODS: We prospectively included hospitalized patients with COVID-19 across two medical ICUs of the Fondazione Policlinico Universitario A. Gemelli IRCCS (Rome, Italy), who developed SA-VAP between 20 March 2020 and 30 October 2020 (thereafter referred to as cases). After 1:2 matching based on the simplified acute physiology score II (SAPS II) and the sequential organ failure assessment (SOFA) score, cases were compared with SA-VAP patients without COVID-19 (controls). Clinical, microbiological, and lung microbiota data were analyzed. RESULTS: We studied two groups of patients (40 COVID-19 and 80 non-COVID-19). COVID-19 patients had a higher rate of late-onset (87.5% versus 63.8%; p = 0.01), methicillin-resistant (65.0% vs 27.5%; p < 0.01) or bacteremic (47.5% vs 6.3%; p < 0.01) infections compared with non-COVID-19 patients. No statistically significant differences between the patient groups were observed in ICU mortality (p = 0.12), clinical cure (p = 0.20) and microbiological eradication (p = 0.31). On multivariable logistic regression analysis, SAPS II and initial inappropriate antimicrobial therapy were independently associated with ICU mortality. Then, lung microbiota characterization in 10 COVID-19 and 16 non-COVID-19 patients revealed that the overall microbial community composition was significantly different between the patient groups (unweighted UniFrac distance, R2 0.15349; p < 0.01). Species diversity was lower in COVID-19 than in non COVID-19 patients (94.4 ± 44.9 vs 152.5 ± 41.8; p < 0.01). Interestingly, we found that S. aureus (log2 fold change, 29.5), Streptococcus anginosus subspecies anginosus (log2 fold change, 24.9), and Olsenella (log2 fold change, 25.7) were significantly enriched in the COVID-19 group compared to the non-COVID-19 group of SA-VAP patients. CONCLUSIONS: In our study population, COVID-19 seemed to significantly affect microbiological and clinical features of SA-VAP as well as to be associated with a peculiar lung microbiota composition.