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.

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.

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.

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.

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.

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.

Physiological Comparison of High-Flow Nasal Cannula and Helmet Noninvasive Ventilation in Acute Hypoxemic Respiratory Failure.

Rationale: High-flow nasal cannula (HFNC) and helmet noninvasive ventilation (NIV) are used for the management of acute hypoxemic respiratory failure.Objectives: Physiological comparison of HFNC and helmet NIV in patients with hypoxemia.Methods: Fifteen patients with hypoxemia with PaO2/FiO2 < 200 mm Hg received helmet NIV (positive end-expiratory pressure ≥ 10 cm H2O, pressure support = 10-15 cm H2O) and HFNC (50 L/min) in randomized crossover order. Arterial blood gases, dyspnea, and comfort were recorded. Inspiratory effort was estimated by esophageal pressure (Pes) swings. Pes-simplified pressure-time product and transpulmonary pressure swings were measured.Measurements and Main Results: As compared with HFNC, helmet NIV increased PaO2/FiO2 (median [interquartile range]: 255 mm Hg [140-299] vs. 138 [101-172]; P = 0.001) and lowered inspiratory effort (7 cm H2O [4-11] vs. 15 [8-19]; P = 0.001) in all patients. Inspiratory effort reduction by NIV was linearly related to inspiratory effort during HFNC (r = 0.84; P < 0.001). Helmet NIV reduced respiratory rate (24 breaths/min [23-31] vs. 29 [26-32]; P = 0.027), Pes-simplified pressure-time product (93 cm H2O ⋅ s ⋅ min-1 [43-138] vs. 200 [168-335]; P = 0.001), and dyspnea (visual analog scale 3 [2-5] vs. 8 [6-9]; P = 0.002), without affecting PaCO2 (P = 0.80) and comfort (P = 0.50). In the overall cohort, transpulmonary pressure swings were not different between treatments (NIV = 18 cm H2O [14-21] vs. HFNC = 15 [8-19]; P = 0.11), but patients exhibiting lower inspiratory effort on HFNC experienced increases in transpulmonary pressure swings with helmet NIV. Higher transpulmonary pressure swings during NIV were associated with subsequent need for intubation.Conclusions: As compared with HFNC in hypoxemic respiratory failure, helmet NIV improves oxygenation, reduces dyspnea, inspiratory effort, and simplified pressure-time product, with similar transpulmonary pressure swings, PaCO2, and comfort.

Effect of Helmet Noninvasive Ventilation vs High-Flow Nasal Oxygen on Days Free of Respiratory Support in Patients With COVID-19 and Moderate to Severe Hypoxemic Respiratory Failure: The HENIVOT Randomized Clinical Trial.

Importance: High-flow nasal oxygen is recommended as initial treatment for acute hypoxemic respiratory failure and is widely applied in patients with COVID-19. Objective: To assess whether helmet noninvasive ventilation can increase the days free of respiratory support in patients with COVID-19 compared with high-flow nasal oxygen alone. Design, Setting, and Participants: Multicenter randomized clinical trial in 4 intensive care units (ICUs) in Italy between October and December 2020, end of follow-up February 11, 2021, including 109 patients with COVID-19 and moderate to severe hypoxemic respiratory failure (ratio of partial pressure of arterial oxygen to fraction of inspired oxygen ≤200). Interventions: Participants were randomly assigned to receive continuous treatment with helmet noninvasive ventilation (positive end-expiratory pressure, 10-12 cm H2O; pressure support, 10-12 cm H2O) for at least 48 hours eventually followed by high-flow nasal oxygen (n = 54) or high-flow oxygen alone (60 L/min) (n = 55). Main Outcomes and Measures: The primary outcome was the number of days free of respiratory support within 28 days after enrollment. Secondary outcomes included the proportion of patients who required endotracheal intubation within 28 days from study enrollment, the number of days free of invasive mechanical ventilation at day 28, the number of days free of invasive mechanical ventilation at day 60, in-ICU mortality, in-hospital mortality, 28-day mortality, 60-day mortality, ICU length of stay, and hospital length of stay. Results: Among 110 patients who were randomized, 109 (99%) completed the trial (median age, 65 years [interquartile range {IQR}, 55-70]; 21 women [19%]). The median days free of respiratory support within 28 days after randomization were 20 (IQR, 0-25) in the helmet group and 18 (IQR, 0-22) in the high-flow nasal oxygen group, a difference that was not statistically significant (mean difference, 2 days [95% CI, -2 to 6]; P = .26). Of 9 prespecified secondary outcomes reported, 7 showed no significant difference. The rate of endotracheal intubation was significantly lower in the helmet group than in the high-flow nasal oxygen group (30% vs 51%; difference, -21% [95% CI, -38% to -3%]; P = .03). The median number of days free of invasive mechanical ventilation within 28 days was significantly higher in the helmet group than in the high-flow nasal oxygen group (28 [IQR, 13-28] vs 25 [IQR 4-28]; mean difference, 3 days [95% CI, 0-7]; P = .04). The rate of in-hospital mortality was 24% in the helmet group and 25% in the high-flow nasal oxygen group (absolute difference, -1% [95% CI, -17% to 15%]; P > .99). Conclusions and Relevance: Among patients with COVID-19 and moderate to severe hypoxemia, treatment with helmet noninvasive ventilation, compared with high-flow nasal oxygen, resulted in no significant difference in the number of days free of respiratory support within 28 days. Further research is warranted to determine effects on other outcomes, including the need for endotracheal intubation. Trial Registration: ClinicalTrials.gov Identifier: NCT04502576.

The Maugeri daily activity profile: a tool to assess physical activity in patients with chronic obstructive pulmonary disease.

Patients with chronic obstructive pulmonary disease (COPD) report reduced physical activity (PA). There are only few tools available to assess PA and sedentary behavior in these patients, and none of them aims to differentiate between sedentary and active patterns. The aim of the study was to evaluate an easy tool to profile daily activity time in a cohort of patients with COPD, compared to healthy subjects; the study was set at the Istituti Clinici Scientifici Maugeri (ICS), IRCCS of Tradate and Lumezzane, Italy, and at the Ente Ospedaliero Cantonale Novaggio, Switzerland (Italian Speaking). The populations were inpatients with COPD, healthy subjects. The items of the Maugeri Daily Activity (MaDA) profile were chosen based on literature, interviews with patients and health professionals. Time spent during sleep (ST), when awake (AT), active (ACT) or in sedentary behavior (SET) were recorded. Lung function tests, arterial blood gases, the modified Medical Research Council (mMRC), the six-minute walking distance test (6MWD), the COPD Assessment Test (CAT), and the body-mass index, airflow obstruction, dyspnea, and exercise capacity (BODE) index were also assessed in patients. Sixty patients with COPD and 60 healthy controls filled in the questionnaire. As compared to controls, patients showed longer AT and SET. Active time of patients was significantly correlated with mMRC, CAT, Bode Index and 6MWD, but not with demographics, anthropometrics or stages of disease. Using this tool, we found that patients with COPD spent longer time awake and in sedentary behavior. The MaDA may be useful to evaluate PA in patients with COPD.

(1,3)-ß-D-Glucan-based empirical antifungal interruption in suspected invasive candidiasis: a randomized trial.

BACKGROUND: (1,3)-ß-D-Glucan has been widely used in clinical practice for the diagnosis of invasive Candida infections. However, such serum biomarker showed potential to guide antimicrobial therapy in order to reduce the duration of empirical antifungal treatment in critically ill septic patients with suspected invasive candidiasis. METHODS: This was a single-centre, randomized, open-label clinical trial in which critically ill patients were enrolled during the admission to the intensive care unit (ICU). All septic patients who presented invasive Candida infection risk factors and for whom an empirical antifungal therapy was commenced were randomly assigned (1:1) in those stopping antifungal therapy if (1,3)-ß-D-glucan was negative ((1,3)-ß-D-glucan group) or those continuing the antifungal therapy based on clinical rules (control group). Serum 1,3-ß-D-glucan was measured at the enrolment and every 48/72 h over 14 days afterwards. The primary endpoint was the duration of antifungal treatment in the first 30 days after enrolment. RESULTS: We randomized 108 patients into the (1,3)-ß-D-glucan (n = 53) and control (n = 55) groups. Median [IQR] duration of antifungal treatment was 2 days [1-3] in the (1,3)-ß-D-glucan group vs. 10 days [6-13] in the control group (between-group absolute difference in means, 6.29 days [95% CI 3.94-8.65], p < 0.001). Thirty-day mortality was similar (28.3% [(1,3)-ß-D-glucan group] vs. 27.3% [control group], p = 0.92) as well as the overall rate of documented candidiasis (11.3% [(1,3)-ß-D-glucan group] vs. 12.7% [control group], p = 0.94), the length of mechanical ventilation (p = 0.97) and ICU stay (p = 0.23). CONCLUSIONS: In critically ill septic patients admitted to the ICU at risk of invasive candidiasis, a (1,3)-ß-D-glucan-guided strategy could reduce the duration of empirical antifungal therapy. However, the safety of this algorithm needs to be confirmed in future, multicentre clinical trial with a larger population. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03117439 , retrospectively registered on 18 April 2017.

Respiratory physiology of COVID-19-induced respiratory failure compared to ARDS of other etiologies.

BACKGROUND: Whether respiratory physiology of COVID-19-induced respiratory failure is different from acute respiratory distress syndrome (ARDS) of other etiologies is unclear. We conducted a single-center study to describe respiratory mechanics and response to positive end-expiratory pressure (PEEP) in COVID-19 ARDS and to compare COVID-19 patients to matched-control subjects with ARDS from other causes. METHODS: Thirty consecutive COVID-19 patients admitted to an intensive care unit in Rome, Italy, and fulfilling moderate-to-severe ARDS criteria were enrolled within 24 h from endotracheal intubation. Gas exchange, respiratory mechanics, and ventilatory ratio were measured at PEEP of 15 and 5 cmH2O. A single-breath derecruitment maneuver was performed to assess recruitability. After 1:1 matching based on PaO2/FiO2, FiO2, PEEP, and tidal volume, COVID-19 patients were compared to subjects affected by ARDS of other etiologies who underwent the same procedures in a previous study. RESULTS: Thirty COVID-19 patients were successfully matched with 30 ARDS from other etiologies. At low PEEP, median [25th-75th percentiles] PaO2/FiO2 in the two groups was 119 mmHg [101-142] and 116 mmHg [87-154]. Average compliance (41 ml/cmH2O [32-52] vs. 36 ml/cmH2O [27-42], p = 0.045) and ventilatory ratio (2.1 [1.7-2.3] vs. 1.6 [1.4-2.1], p = 0.032) were slightly higher in COVID-19 patients. Inter-individual variability (ratio of standard deviation to mean) of compliance was 36% in COVID-19 patients and 31% in other ARDS. In COVID-19 patients, PaO2/FiO2 was linearly correlated with respiratory system compliance (r = 0.52 p = 0.003). High PEEP improved PaO2/FiO2 in both cohorts, but more remarkably in COVID-19 patients (p = 0.005). Recruitability was not different between cohorts (p = 0.39) and was highly inter-individually variable (72% in COVID-19 patients and 64% in ARDS from other causes). In COVID-19 patients, recruitability was independent from oxygenation and respiratory mechanics changes due to PEEP. CONCLUSIONS: Early after establishment of mechanical ventilation, COVID-19 patients follow ARDS physiology, with compliance reduction related to the degree of hypoxemia, and inter-individually variable respiratory mechanics and recruitability. Physiological differences between ARDS from COVID-19 and other causes appear small.

Early nasal high-flow versus Venturi mask oxygen therapy after lung resection: a randomized trial.

BACKGROUND: Data on high-flow nasal oxygen after thoracic surgery are limited and confined to the comparison with low-flow oxygen. Different from low-flow oxygen, Venturi masks provide higher gas flow at a predetermined fraction of inspired oxygen (FiO2). We conducted a randomized trial to determine whether preemptive high-flow nasal oxygen reduces the incidence of postoperative hypoxemia after lung resection, as compared to Venturi mask oxygen therapy. METHODS: In this single-center, randomized trial conducted in a teaching hospital in Italy, consecutive adult patients undergoing thoracotomic lung resection, who were not on long-term oxygen therapy, were randomly assigned to receive high-flow nasal or Venturi mask oxygen after extubation continuously for two postoperative days. The primary outcome was the incidence of postoperative hypoxemia (i.e., ratio of the partial pressure of arterial oxygen to FiO2 (PaO2/FiO2) lower than 300 mmHg) within four postoperative days. RESULTS: Between September 2015 and April 2018, 96 patients were enrolled; 95 patients were analyzed (47 in high-flow group and 48 in Venturi mask group). In both groups, 38 patients (81% in the high-flow group and 79% in the Venturi mask group) developed postoperative hypoxemia, with an unadjusted odds ratio (OR) for the high-flow group of 1.11 [95% confidence interval (CI) 0.41-3] (p = 0.84). No inter-group differences were found in the degree of dyspnea nor in the proportion of patients needing oxygen therapy after treatment discontinuation (OR 1.34 [95% CI 0.60-3]), experiencing pulmonary complications (OR 1.29 [95% CI 0.51-3.25]) or requiring ventilatory support (OR 0.67 [95% CI 0.11-4.18]). Post hoc analyses revealed that PaO2/FiO2 during the study was not different between groups (p = 0.92), but patients receiving high-flow nasal oxygen had lower arterial pressure of carbon dioxide, with a mean inter-group difference of 2 mmHg [95% CI 0.5-3.4] (p = 0.009), and were burdened by a lower risk of postoperative hypercapnia (adjusted OR 0.18 [95% CI 0.06-0.54], p = 0.002). CONCLUSIONS: When compared to Venturi mask after thoracotomic lung resection, preemptive high-flow nasal oxygen did not reduce the incidence of postoperative hypoxemia nor improved other analyzed outcomes. Further adequately powered investigations in this setting are warranted to establish whether high-flow nasal oxygen may yield clinical benefit on carbon dioxide clearance. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02544477 . Registered 9 September 2015.

High dose tigecycline in critically ill patients with severe infections due to multidrug-resistant bacteria.

INTRODUCTION: The high incidence of multidrug-resistant (MDR) bacteria among patients admitted to ICUs has determined an increase of tigecycline (TGC) use for the treatment of severe infections. Many concerns have been raised about the efficacy of this molecule and increased dosages have been proposed. Our purpose is to investigate TGC safety and efficacy at higher than standard doses. METHODS: We conducted a retrospective study of prospectively collected data in the ICU of a teaching hospital in Rome. Data from all patients treated with TGC for a microbiologically confirmed infection were analyzed. The safety profile and efficacy of high dosing regimen use were investigated. RESULTS: Over the study period, 54 patients (pts) received TGC at a standard dose (SD group: 50 mg every 12 hours) and 46 at a high dose (HD group: 100 mg every 12 hours). Carbapenem-resistant Acinetobacter.baumannii (blaOXA-58 and blaOXA-23 genes) and Klebsiella pneumoniae (blaKPC-3 gene) were the main isolated pathogens (n = 79). There were no patients requiring TGC discontinuation or dose reduction because of adverse events. In the ventilation-associated pneumonia population (VAP) subgroup (63 patients: 30 received SD and 33 HD), the only independent predictor of clinical cure was the use of high tigecycline dose (odds ratio (OR) 6.25; 95% confidence interval (CI) 1.59 to 24.57; P = 0.009) whilst initial inadequate antimicrobial treatment (IIAT) (OR 0.18; 95% CI 0.05 to 0.68; P = 0.01) and higher Sequential Organ Failure Assessment (SOFA) score (OR 0.66; 95% CI 0.51 to 0.87; P = 0.003) were independently associated with clinical failure. CONCLUSIONS: TGC was well tolerated at a higher than standard dose in a cohort of critically ill patients with severe infections. In the VAP subgroup the high-dose regimen was associated with better outcomes than conventional administration due to Gram-negative MDR bacteria.

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.

Noninvasive ventilation: practical advice.

PURPOSE OF REVIEW: This critical review discusses the key points that would be of practical help for the clinician who applies noninvasive ventilation (NIV) for treatment of patients with acute respiratory failure (ARF). RECENT FINDINGS: In recent years, the growing role of NIV in the acute care setting has led to the development of technical innovations to overcome the problems related to gas leakage and dead space. A considerable amount of research has been conducted to improve the quality of the devices as well as optimize ventilation modes used to administer NIV. As a result, also mechanical ventilators have been implemented with modalities aimed at delivering NIV. SUMMARY: The success of NIV in patients with ARF depends on several factors, including the skills of the clinician, selection of patient, choice of interface, selection of ventilation mode and ventilator setting, monitoring, and the motivation of the patient. Recent advances in the understanding of the physiological aspects of using NIV through different interfaces and ventilator settings have led to improve patient-machine interaction, enhancing favorable NIV outcome.