Anticoagulation and Bleeding during Veno-Venous Extracorporeal Membrane Oxygenation: Insights from the PROTECMO Study.

Rationale: Definitive guidelines for anticoagulation management during veno-venous extracorporeal membrane oxygenation (VV ECMO) are lacking, whereas bleeding complications continue to pose major challenges. Objectives: To describe anticoagulation modalities and bleeding events in adults receiving VV ECMO. Methods: This was an international prospective observational study in 41 centers, from December 2018 to February 2021. Anticoagulation was recorded daily in terms of type, dosage, and monitoring strategy. Bleeding events were reported according to site, severity, and impact on mortality. Measurements and Main Results: The study cohort included 652 patients, and 8,471 days on ECMO were analyzed. Unfractionated heparin was the initial anticoagulant in 77% of patients, and the most frequently used anticoagulant during the ECMO course (6,221 d; 73%). Activated partial thromboplastin time (aPTT) was the most common test for monitoring coagulation (86% of days): the median value was 52 seconds (interquartile range, 39 to 61 s) but dropped by 5.3 seconds after the first bleeding event (95% confidence interval, -7.4 to -3.2; P < 0.01). Bleeding occurred on 1,202 days (16.5%). Overall, 342 patients (52.5%) experienced at least one bleeding event (one episode every 215 h on ECMO), of which 10 (1.6%) were fatal. In a multiple penalized Cox proportional hazard model, higher aPTT was a potentially modifiable risk factor for the first episode of bleeding (for 20-s increase; hazard ratio, 1.07). Conclusions: Anticoagulation during VV ECMO was a dynamic process, with frequent stopping in cases of bleeding and restart according to the clinical picture. Future studies might explore lower aPTT targets to reduce the risk of bleeding.

Severe Community-Acquired Pneumonia: Noninvasive Mechanical Ventilation, Intubation, and HFNT.

Severe acute respiratory failure (ARF) is a major issue in patients with severe community-acquired pneumonia (CAP). Standard oxygen therapy is the first-line therapy for ARF in the less severe cases. However, respiratory supports may be delivered in more severe clinical condition. In cases with life-threatening ARF, invasive mechanical ventilation (IMV) will be required. Noninvasive strategies such as high-flow nasal therapy (HFNT) or noninvasive ventilation (NIV) by either face mask or helmet might cover the gap between standard oxygen and IMV. The objective of all the supporting measures for ARF is to gain time for the antimicrobial treatment to cure the pneumonia. There is uncertainty regarding which patients with severe CAP are most likely to benefit from each noninvasive support strategy. HFNT may be the first-line approach in the majority of patients. While NIV may be relatively contraindicated in patients with excessive secretions, facial hair/structure resulting in air leaks or poor compliance, NIV may be preferable in those with increased work of breathing, respiratory muscle fatigue, and congestive heart failure, in which the positive pressure of NIV may positively impact hemodynamics. A trial of NIV might be considered for select patients with hypoxemic ARF if there are no contraindications, with close monitoring by an experienced clinical team who can intubate patients promptly if they deteriorate. In such cases, individual clinician judgement is key to choose NIV, interface, and settings. Due to the paucity of studies addressing IMV in this population, the protective mechanical ventilation strategies recommended by guidelines for acute respiratory distress syndrome can be reasonably applied in patients with severe CAP.

Respective Effects of Helmet Pressure Support, Continuous Positive Airway Pressure, and Nasal High-Flow in Hypoxemic Respiratory Failure: A Randomized Crossover Clinical Trial.

Rationale: The respective effects of positive end-expiratory pressure (PEEP) and pressure support delivered through the helmet interface in patients with hypoxemia need to be better understood. Objectives: To assess the respective effects of helmet pressure support (noninvasive ventilation [NIV]) and continuous positive airway pressure (CPAP) compared with high-flow nasal oxygen (HFNO) on effort to breathe, lung inflation, and gas exchange in patients with hypoxemia (PaO2/FiO2 ⩽ 200). Methods: Fifteen patients underwent 1-hour phases (constant FiO2) of HFNO (60 L/min), helmet NIV (PEEP = 14 cm H2O, pressure support = 12 cm H2O), and CPAP (PEEP = 14 cm H2O) in randomized sequence. Measurements and Main Results: Inspiratory esophageal (ΔPES) and transpulmonary pressure (ΔPL) swings were used as surrogates for inspiratory effort and lung distension, respectively. Tidal Volume (Vt) and end-expiratory lung volume were assessed with electrical impedance tomography. ΔPES was lower during NIV versus CPAP and HFNO (median [interquartile range], 5 [3-9] cm H2O vs. 13 [10-19] cm H2O vs. 10 [8-13] cm H2O; P = 0.001 and P = 0.01). ΔPL was not statistically different between treatments. PaO2/FiO2 ratio was significantly higher during NIV and CPAP versus HFNO (166 [136-215] and 175 [158-281] vs. 120 [107-149]; P = 0.002 and P = 0.001). NIV and CPAP similarly increased Vt versus HFNO (mean change, 70% [95% confidence interval (CI), 17-122%], P = 0.02; 93% [95% CI, 30-155%], P = 0.002) and end-expiratory lung volume (mean change, 198% [95% CI, 67-330%], P = 0.001; 263% [95% CI, 121-407%], P = 0.001), mostly due to increased aeration/ventilation in dorsal lung regions. During HFNO, 14 of 15 patients had pendelluft involving >10% of Vt; pendelluft was mitigated by CPAP and further by NIV. Conclusions: Compared with HFNO, helmet NIV, but not CPAP, reduced ΔPES. CPAP and NIV similarly increased oxygenation, end-expiratory lung volume, and Vt, without affecting ΔPL. NIV, and to a lesser extent CPAP, mitigated pendelluft. Clinical trial registered with clinicaltrials.gov (NCT04241861).

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.

Incidence of bloodstream infections due to multidrug-resistant pathogens in ordinary wards and intensive care units before and during the COVID-19 pandemic: a real-life, retrospective observational study.

PURPOSE: SARS-COV-2 pandemic led to antibiotic overprescription and unprecedented stress on healthcare systems worldwide. Knowing the comparative incident risk of bloodstream infection due to multidrug-resistant pathogens in COVID ordinary wards and intensive care-units may give insights into the impact of COVID-19 on antimicrobial resistance. METHODS: Single-center observational data extracted from a computerized dataset were used to identify all patients who underwent blood cultures from January 1, 2018 to May 15, 2021. Pathogen-specific incidence rates were compared according to the time of admission, patient's COVID status and ward type. RESULTS: Among 14,884 patients for whom at least one blood culture was obtained, a total of 2534 were diagnosed with HA-BSI. Compared to both pre-pandemic and COVID-negative wards, HA-BSI due to S. aureus and Acinetobacter spp. (respectively 0.3 [95% CI 0.21-0.32] and 0.11 [0.08-0.16] new infections per 100 patient-days) showed significantly higher incidence rates, peaking in the COVID-ICU setting. Conversely, E. coli incident risk was 48% lower in COVID-positive vs COVID-negative settings (IRR 0.53 [0.34-0.77]). Among COVID + patients, 48% (n = 38/79) of S. aureus isolates were resistant to methicillin and 40% (n = 10/25) of K. pneumoniae isolates were resistant to carbapenems. CONCLUSIONS: The data presented here indicate that the spectrum of pathogens causing BSI in ordinary wards and intensive care units varied during the pandemic, with the greatest shift experienced by COVID-ICUs. Antimicrobial resistance of selected high-priority bacteria was high in COVID positive settings.

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.

Pneumocystis jirovecii pneumonia in intensive care units: a multicenter study by ESGCIP and EFISG.

BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) is an opportunistic, life-threatening disease commonly affecting immunocompromised patients. The distribution of predisposing diseases or conditions in critically ill patients admitted to intensive care unit (ICU) and subjected to diagnostic work-up for PJP has seldom been explored. MATERIALS AND METHODS: The primary objective of the study was to describe the characteristics of ICU patients subjected to diagnostic workup for PJP. The secondary objectives were: (i) to assess demographic and clinical variables associated with PJP; (ii) to assess the performance of Pneumocystis PCR on respiratory specimens and serum BDG for the diagnosis of PJP; (iii) to describe 30-day and 90-day mortality in the study population. RESULTS: Overall, 600 patients were included in the study, of whom 115 had presumptive/proven PJP (19.2%). Only 8.8% of ICU patients subjected to diagnostic workup for PJP had HIV infection, whereas hematological malignancy, solid tumor, inflammatory diseases, and solid organ transplants were present in 23.2%, 16.2%, 15.5%, and 10.0% of tested patients, respectively. In multivariable analysis, AIDS (odds ratio [OR] 3.31; 95% confidence interval [CI] 1.13-9.64, p = 0.029), non-Hodgkin lymphoma (OR 3.71; 95% CI 1.23-11.18, p = 0.020), vasculitis (OR 5.95; 95% CI 1.07-33.22, p = 0.042), metastatic solid tumor (OR 4.31; 95% CI 1.76-10.53, p = 0.001), and bilateral ground glass on CT scan (OR 2.19; 95% CI 1.01-4.78, p = 0.048) were associated with PJP, whereas an inverse association was observed for increasing lymphocyte cell count (OR 0.64; 95% CI 0.42-1.00, p = 0.049). For the diagnosis of PJP, higher positive predictive value (PPV) was observed when both respiratory Pneumocystis PCR and serum BDG were positive compared to individual assay positivity (72% for the combination vs. 63% for PCR and 39% for BDG). Cumulative 30-day mortality and 90-day mortality in patients with presumptive/proven PJP were 52% and 67%, respectively. CONCLUSION: PJP in critically ill patients admitted to ICU is nowadays most encountered in non-HIV patients. Serum BDG when used in combination with respiratory Pneumocystis PCR could help improve the certainty of PJP diagnosis.

Clinical implications of endotoxin activity and Polymyxin-B hemoperfusion in critically ill patients with septic cardiomyopathy: A single-center, retrospective, observational study.

BACKGROUND: To explore the association between endotoxin activity (EA) and septic cardiomyopathy (SCM), the relationship between endotoxin removal by Polymyxin-B hemoperfusion (PMX-HP) and recovery from SCM (R-SCM), and the correlation between R-SCM and the 28-day mortality in septic patients admitted to the intensive care unit (ICU). METHODS: Observational study that included patients admitted to two ICUs of a tertiary university hospital between April 2011 and December 2019, who received PMX-HP for sepsis/septic shock. The SCM and R-SCM were assessed by transthoracic echocardiography. RESULTS: Among 148 patients, SCM was diagnosed in 60 (46%) of them and had no relationship with median EA (SCM group: 0.73; no-SCM group: 0.66, p = 0.48). Recovery from SCM was observed in 24 patients (49%) and was independently associated with the PMX-HP (OR 4.19, 95%CI [1.22, 14.3]; p = 0.02) and the SAPS2 II score (OR 0.94, 95%CI [0.9, 0.98]; p = 0.006). In the SCM group, the 28-day mortality was 60% and was independently predicted by R-SCM (OR 0.02, 95%CI [0.001, 0.3] p = 0.005) and SAPS II score (OR 1.11, 95%CI [1.01, 1.23] p = 0.037). CONCLUSIONS: In septic patients, EA was not associated with SCM. However, endotoxin removal by Polymyxin-B hemoperfusion was associated with recovery from cardiomyopathy, which was a predictor of lower 28-day mortality.

Prediction of ventilator-associated pneumonia outcomes according to the early microbiological response: a retrospective observational study.

BACKGROUND: Ventilator-associated pneumonia (VAP) is a leading infectious cause of morbidity in critically ill patients, yet current guidelines offer no indications for follow-up cultures. We aimed to evaluate the role of follow-up cultures and microbiological response 3 days after diagnosing VAP as predictors of short- and long-term outcomes. METHODS: We performed a retrospective analysis of a cohort prospectively collected from 2004 to 2017. VAP was diagnosed based on clinical, radiographical and microbiological criteria. For microbiological identification, a tracheobronchial aspirate was performed at diagnosis and repeated after 72 h. We defined three groups when comparing the two tracheobronchial aspirate results: persistence, superinfection and eradication of causative pathogens. RESULTS: 157 patients were enrolled in the study, among whom microbiological persistence, superinfection or eradication was present in 67 (48%), 25 (16%) and 65 (41%), respectively, after 72 h. Those with superinfection had the highest mortalities in the intensive care unit (p=0.015) and at 90 days (p=0.036), while also having the fewest ventilator-free days (p=0.019). Multivariable analysis revealed shock at VAP diagnosis (OR 3.43, 95% CI 1.25-9.40), Staphylococcus aureus isolation at VAP diagnosis (OR 2.87, 95% CI 1.06-7.75) and hypothermia at VAP diagnosis (OR 0.67, 95% CI 0.48-0.95, per +1°C) to be associated with superinfection. CONCLUSIONS: Our retrospective analysis suggests that VAP short- and long-term outcomes may be associated with superinfection in follow-up cultures. Follow-up cultures may help guide antibiotic therapy and its duration. Further prospective studies are necessary to verify our findings.

Use of an innovative cuff pressure control and subglottic secretions drainage system in COVID-19 ARDS patients undergoing pronation.

We conducted a proof of concept study where Anapnoguard endotracheal tubes and its control unit were used in 15 patients with COVID-19 acute respiratory distress syndrome. Anapnoguard system provides suction, venting, rinsing of subglottic space and controls cuff pressure detecting air leakage through the cuff. Alpha-amylase and pepsin levels, as oropharyngeal and gastric microaspiration markers, were assessed from 85 tracheal aspirates in the first 72 h after connection to the system. Oropharyngeal microaspiration occurred in 47 cases (55%). Episodes of gastric microaspiration were not detected. Patient positioning, either prone or supine, did not affect alpha-amylase and pepsin concentration in tracheal secretions. Ventilator-associated pneumonia (VAP) rate was 40%. The use of the AG system provided effective cuff pressure control and subglottic secretions drainage. Despite this, no reduction in the incidence of VAP has been demonstrated, compared to data reported in the current COVID-19 literature. The value of this new technology is worth of being evaluated for the prevention of ventilator-associated respiratory tract infections.

Ceftazidime-Avibactam Use for Klebsiella pneumoniae Carbapenemase-Producing K. pneumoniae Infections: A Retrospective Observational Multicenter Study.

BACKGROUND: A growing body of observational evidence supports the value of ceftazidime-avibactam (CAZ-AVI) in managing infections caused by carbapenem-resistant Enterobacteriaceae. METHODS: We retrospectively analyzed observational data on use and outcomes of CAZ-AVI therapy for infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp) strains. Multivariate regression analysis was used to identify variables independently associated with 30-day mortality. Results were adjusted for propensity score for receipt of CAZ-AVI combination regimens versus CAZ-AVI monotherapy. RESULTS: The cohort comprised 577 adults with bloodstream infections (n = 391) or nonbacteremic infections involving mainly the urinary tract, lower respiratory tract, and intra-abdominal structures. All received treatment with CAZ-AVI alone (n = 165) or with ≥1 other active antimicrobials (n = 412). The all-cause mortality rate 30 days after infection onset was 25% (146/577). There was no significant difference in mortality between patients managed with CAZ-AVI alone and those treated with combination regimens (26.1% vs 25.0%, P = .79). In multivariate analysis, mortality was positively associated with presence at infection onset of septic shock (P = .002), neutropenia (P < .001), or an INCREMENT score ≥8 (P = .01); with lower respiratory tract infection (LRTI) (P = .04); and with CAZ-AVI dose adjustment for renal function (P = .01). Mortality was negatively associated with CAZ-AVI administration by prolonged infusion (P = .006). All associations remained significant after propensity score adjustment. CONCLUSIONS: CAZ-AVI is an important option for treating serious KPC-Kp infections, even when used alone. Further study is needed to explore the drug's seemingly more limited efficacy in LRTIs and potential survival benefits of prolonging CAZ-AVI infusions to ≥3 hours.

Noninvasive ventilation and high-flow oxygen therapy for severe community-acquired pneumonia.

PURPOSE OF REVIEW: We review the evidence on the use of noninvasive respiratory supports (noninvasive ventilation and high-flow nasal cannula oxygen therapy) in patients with acute respiratory failure because of severe community-acquired pneumonia. RECENT FINDINGS: Noninvasive ventilation is strongly advised for the treatment of hypercapnic respiratory failure and recent evidence justifies its use in patients with hypoxemic respiratory failure when delivered by helmet. Indeed, such interface allows alveolar recruitment by providing high level of positive end-expiratory pressure, which improves hypoxemia. On the other hand, high-flow nasal cannula oxygen therapy is effective in patients with hypoxemic respiratory failure and some articles support its use in patients with hypercapnia. However, early identification of noninvasive respiratory supports treatment failure is crucial to prevent delayed orotracheal intubation and protective invasive mechanical ventilation. SUMMARY: Noninvasive ventilation is the first-line therapy in patients with acute hypercapnic respiratory failure because of pneumonia. Although an increasing amount of evidence investigated the application of noninvasive respiratory support to hypoxemic respiratory failure, the optimal ventilatory strategy in this setting is uncertain. Noninvasive mechanical ventilation delivered by helmet and high-flow nasal cannula oxygen therapy appear as promising tools but their role needs to be confirmed by future research.

Protective effect of SARS-CoV-2 preventive measures against ESKAPE and Escherichia coli infections.

BACKGROUND/OBJECTIVES: We investigated whether behavioral precautions adopted during Coronavirus disease (COVID-19) pandemic also influenced the spreading and multidrug resistance (MDR) of ESKAPEEc (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii [AB], Pseudomonas aeruginosa, Enterobacter spp and Escherichia Coli, [EC]) among Intensive Care Unit (ICU) patients. SUBJECTS/METHODS: We performed a single-center retrospective study in adult patients admitted to our COVID-19-free surgical ICU. Only patients staying in ICU for more than 48 hours were included. The ESKAPEEc infections recorded during the COVID-19 period (June 1, 2020 - February 28, 2021) and in the corresponding pre-pandemic period (June 1, 2019 - February 28, 2020) were compared. An interrupted time series analysis was performed to rule out possible confounders. RESULTS: Overall, 173 patients in the COVID-19 period and 132 in the pre-COVID-19 period were investigated. The ESKAPEEc infections were documented in 23 (13.3%) and 35 (26.5%) patients in the pandemic and the pre-pandemic periods, respectively (p = 0.005). Demographics, diagnosis, comorbidities, type of surgery, Simplified Acute Physiology Score II, length of mechanical ventilation, hospital and ICU length of stay, ICU death rate, and 28-day hospital mortality were similar in the two groups. In comparison with the pre-pandemic period, no AB was recorded during COVID-19 period, (p = 0.017), while extended-spectrum beta-lactamase-producing EC infections significantly decreased (p = 0.017). Overall, the ESKAPEEc isolates during pandemic less frequently exhibited multidrug-resistant (p = 0.014). CONCLUSIONS: These findings suggest that a robust adherence to hygiene measures together with human contact restrictions in a COVID-19 free ICU might also restrain the transmission of ESKAPEEc pathogens.

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.

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.

Hemadsorption.

PURPOSE OF REVIEW: To review pathophysiological pathways of immune system response to infections, which may justify mediators removal by extracorporeal blood purification therapies (EBPTs) in critically ill septic patients. Moreover, we presented an overview of the EBPTs mostly used in clinical practice with the aim to modulate immune system dysfunction in sepsis. RECENT FINDINGS: Sepsis is a life-threatening disease and recent findings showed that its pathophysiology relies on dysregulated immune system response to pathogen invasion of the body. In the light of this view, EBPTs have been demonstrated effective to remove specific mediators and foster balance between pro- and anti-inflammatory pathways. SUMMARY: EBPTs have been widely used in clinical practice, with the aim to modulate immune system dysfunction by the removal of pathogens and inflammatory mediators in critically ill patients with sepsis. Such therapies are characterised by specific structural features, which allow selective and nonselective removal of mediators by adsorption. However, few evidences support their role in the management of critically ill patients with sepsis. Accordingly, an evidence-based and personalized approach to EBPTs in sepsis is strongly advocated, in order to solve controversies in this field and optimise the management of critically ill septic patients.

Immune Modulation in Critically Ill Septic Patients.

Sepsis is triggered by infection-induced immune alteration and may be theoretically improved by pharmacological and extracorporeal immune modulating therapies. Pharmacological immune modulation may have long lasting clinical effects, that may even worsen patient-related outcomes. On the other hand, extracorporeal immune modulation allows short-term removal of inflammatory mediators from the bloodstream. Although such therapies have been widely used in clinical practice, the role of immune modulation in critically ill septic patients remains unclear and little evidence supports the role of immune modulation in this clinical context. Accordingly, further research should be carried out by an evidence-based and personalized approach in order to improve the management of critically ill septic patients.

Ventilator-associated pneumonia diagnosis: a prioritization exercise based on multi-criteria decision analysis.

The aim was to provide global experts ranking on priorities in diagnostic tools for VAP in clinical practice. A multiple criteria decision analysis (MCDA) was performed to identify diagnosis tools for VAP diagnosis. Priority factors were identified after literature review. An international, multidisciplinary expert panel reviewed variables and ranked diagnostic tools. Experts from ten European hospitals participated. Regarding bedside clinical practices, seven required chest X-ray use in all patients, whereas six reported the use of blood cultures and endotracheal aspirate in all patients. Invasive techniques were routinely performed in seven sites. CRP, PCT, and Gram stains were performed in all patients by 5, 2, and 8, respectively. Impact on patient outcomes, safety, and impact on the decision to start antibiotic therapy were ranked as the top three relevant concerns (7.7/10, 7/10, and 6.9/10, respectively). Chest X-ray was ranked as the most important imaging technique to diagnose VAP (score 251.7). Apart from blood cultures, endotracheal aspirate culture was identified as the main collection method for the microbiological testing (scores of 274.8 and 246.8, respectively). Mini-BAL was the preferred invasive technique with a score of 208. Top three biomarkers were CRP (score 184.3), PCT (181.3), and WBC (166.4). Gram stain (192.5) was prioritized among laboratory diagnostic techniques. Using MCDA, it is recommended to perform a combination of diagnostic techniques including images (chest X-ray), culture of clinical specimens (blood cultures and endotracheal aspirate), and biomarkers (CRP or PCT) for VAP diagnosis at the bedside. Gram stain was ranked as the preferred laboratory technique.

The importance of airway and lung microbiome in the critically ill.

During critical illness, there are a multitude of forces such as antibiotic use, mechanical ventilation, diet changes and inflammatory responses that could bring the microbiome out of balance. This so-called dysbiosis of the microbiome seems to be involved in immunological responses and may influence outcomes even in individuals who are not as vulnerable as a critically ill ICU population. It is therefore probable that dysbiosis of the microbiome is a consequence of critical illness and may, subsequently, shape an inadequate response to these circumstances.Bronchoscopic studies have revealed that the carina represents the densest site of bacterial DNA along healthy airways, with a tapering density with further bifurcations. This likely reflects the influence of micro-aspiration as the primary route of microbial immigration in healthy adults. Though bacterial DNA density grows extremely sparse at smaller airways, bacterial signal is still consistently detectable in bronchoalveolar lavage fluid, likely reflecting the fact that lavage via a wedged bronchoscope samples an enormous surface area of small airways and alveoli. The dogma of lung sterility also violated numerous observations that long predated culture-independent microbiology.The body's resident microbial consortia (gut and/or respiratory microbiota) affect normal host inflammatory and immune response mechanisms. Disruptions in these host-pathogen interactions have been associated with infection and altered innate immunity.In this narrative review, we will focus on the rationale and current evidence for a pathogenic role of the lung microbiome in the exacerbation of complications of critical illness, such as acute respiratory distress syndrome and ventilator-associated pneumonia.

(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.