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Background and Objective: Population pharmacokinetic/pharmacodynamic (PK/PD) modelling of antibiotics including C-reactive protein (C-RP) dynamics could be helpful in predicting the efficacy of antimicrobials. We developed a PK/PD model for assessing the impact of continuous infusion (CI) meropenem PK/PD target attainment on C-RP dynamics in critically ill patients with documented Gram-negative hospital- (HAP) or ventilator-acquired pneumonia (VAP)., Methods: Patients were grouped according to the type of antibiotic treatment received [meropenem monotherapy; meropenem plus empirical anti-MRSA (methicillin-resistant Staphylococcus aureus) therapy; meropenem in combination with another anti-Gram-negative active agent; meropenem plus a targeted anti-MRSA therapy]. A one-compartment population PK model of CI meropenem was developed by including all patients. A full C-RP production inhibition model was developed for fitting the PD data by including only patients receiving meropenem monotherapy or meropenem plus empirical anti-MRSA therapy. Monte Carlo simulations explored the relationship between the type of PK/PD target attainment of CI meropenem, defined as optimal (steady-state plasma concentration [C ss ] to minimum inhibitory concentration [MIC] ratio = 4-8), quasi-optimal (C ss /MIC = 1-4) and sub-optimal (C ss /MIC < 1) and the magnitude of C-RP production inhibition over time., Results: A total of 64 patients providing 211 meropenem concentrations were included in the PK analysis, whereas 47 patients providing 328 C-RP data were included in the PD model. Simulations showed that optimal PK/PD target attainment was associated with the highest and most rapid C-RP production inhibition (44% and 56% at days 2 and 4, respectively). Conversely, sub-optimal PK/PD target attainment was shown to be almost ineffective (< 5% at day 4 and < 10% at day 10)., Conclusion: Our PK/PD model predicted that attaining optimal PK/PD target with CI meropenem may grant prompt and intense C-RP decrease among critically ill patients receiving targeted monotherapy for Gram-negative HAP/VAP, thus anticipating efficacy., Competing Interests: Declarations Ethics Approval and Consent to Participate The study was approved by the Local Ethics Committee (No. 308/2021/Oss/AOUBo on 24 May 2021). Consent for Publication Due to the retrospective nature of this investigation, informed written consent was waived. Availability of Data and Materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing Interests The authors declare that they have no competing interests. Funding This project has received funding from European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 861323. Authors' Contributions CT analyzed and wrote the initial manuscript; PGC wrote the manuscript and interpreted patient data; MR collected patient data; TT collected and analyzed patient data; AS collected and analyzed patient data; CvH, PV and FP supervised the project., (© 2024. The Author(s).)

Rationale: Lung-protective strategies using low Vt and moderate positive end-expiratory pressure (PEEP) are considered best practice in critical care, but interventional trials have never been conducted in patients with acute brain injuries because of concerns about carbon dioxide control and the effect of PEEP on cerebral hemodynamics. Objectives: To test the hypothesis that ventilation with lower VT and higher PEEP compared to conventional ventilation would improve clinical outcomes in patients with acute brain injury. Methods: In this multicenter, open-label, controlled clinical trial, 190 adult patients with acute brain injury were assigned to receive either a lung-protective or a conventional ventilatory strategy. The primary outcome was a composite endpoint of death, ventilator dependency, and acute respiratory distress syndrome (ARDS) at Day 28. Neurological outcome was assessed at ICU discharge by the Oxford Handicap Scale and at 6 months by the Glasgow Outcome Scale. Measurements and Main Results: The two study arms had similar characteristics at baseline. In the lung-protective and conventional strategy groups, using an intention-to-treat approach, the composite outcome at 28 days was 61.5% and 45.3% (relative risk [RR], 1.35; 95% confidence interval [CI], 1.03-1.79; P  = 0.025). Mortality was 28.9% and 15.1% (RR, 1.91; 95% CI, 1.06-3.42; P  = 0.02), ventilator dependency was 42.3% and 27.9% (RR, 1.52; 95% CI, 1.01-2.28; P  = 0.039), and incidence of ARDS was 30.8% and 22.1% (RR, 1.39; 95% CI, 0.85-2.27; P  = 0.179), respectively. The trial was stopped after enrolling 190 subjects because of termination of funding. Conclusions: In patients with acute brain injury without ARDS, a lung-protective ventilatory strategy, as compared with a conventional strategy, did not reduce mortality, percentage of patients weaned from mechanical ventilation, or incidence of ARDS and was not beneficial in terms of neurological outcomes. Because of the early termination, these preliminary results require confirmation in larger trials. Clinical trial registered with www.clinicaltrials.gov (NCT01690819).

Background: Age as an eligibility criterion for V-V ECMO is widely debated and varies among healthcare institutions. We examined how age relates to mortality in patients undergoing V-V ECMO for ARDS., Methods: Systematic review and meta-regression of clinical studies published between 2015 and June 2024. Studies involving at least 6 ARDS patients treated with V-V ECMO, with specific data on ICU and/or hospital mortality and patient age were included. The search strategy was executed in PubMed, limited to English-language. COVID-19 and non-COVID-19 populations were analyzed separately. Meta-regressions of mortality outcomes on age were performed using gender, BMI, SAPS II, APACHE II, Charlson comorbidity index or SOFA as covariates., Results: In non-COVID ARDS, the meta-regression of 173 studies with 56,257 participants showed a significant positive association between mean age and ICU/hospital mortality. In COVID-19 ARDS, a significant relationship between mean age and ICU mortality, but not hospital mortality, was found in 103 studies with 21,255 participants. Sensitivity analyses confirmed these findings, highlighting a linear relationship between age and mortality in both groups. For each additional year of mean age, ICU mortality increased by 1.2% in non-COVID ARDS and 1.9% in COVID ARDS., Conclusions: The relationship between age and ICU mortality is linear and shows no inflection point. Consequently, no age cut-off can be recommended for determining patient eligibility for V-V ECMO., (© 2024. The Author(s).)

Aim: To determine whether the duration of respiratory distress symptoms in severe COVID-19 pneumonia affects the need for invasive mechanical ventilation and clinical outcomes., Materials and Methods: An observational multicentre cohort study of patients hospitalised in five COVID-19-designated ICUs of the University Hospitals of Emilia-Romagna Region. Patients included were adults with pneumonia due to SARS-CoV-2 with PaO₂/FiO₂ ratio <300 mmHg, respiratory distress symptoms, and need for mechanical ventilation (invasive or non-invasive). Exclusion criteria were an uncertain time of respiratory distress, end-of-life decision, and mechanical respiratory support before hospital admission., Measurements and Main Results: We analysed 171 patients stratified into tertiles according to respiratory distress duration (distress time, DT) before application of mechanical ventilation support. The rate of patients requiring invasive mechanical ventilation was significantly different (p < 0.001) among the tertiles: 17/57 patients in the shortest duration, 29/57 in the intermediate duration, and 40/57 in the longest duration. The respiratory distress time significantly increased the risk of invasive ventilation in the univariate analysis (OR 5.5 [CI 2.48-12.35], p = 0.003). Multivariable regression analysis confirmed this association (OR 10.7 [CI 2.89-39.41], p < 0.001). Clinical outcomes (mortality and hospital stay) did not show significant differences between DT tertiles., Discussion: Albeit preliminary and retrospective, our data raised the hypothesis that the duration of respiratory distress symptoms may play a role in COVID-19 patients' need for invasive mechanical ventilation. Furthermore, our observations suggested that specific strategies may be directed towards identifying and managing early symptoms of respiratory distress, regardless of the levels of hypoxemia and the severity of the dyspnoea itself., (Copyright © 2022 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.)

Piperacillin/tazobactam (TZP) is administered intravenously in a fixed ratio (8:1) with the potential for inadequate tazobactam exposure to ensure piperacillin activity against Enterobacterales . Adult patients receiving continuous infusion (CI) of TZP and therapeutic drug monitoring (TDM) of both agents were evaluated. Demographic variables and other pertinent laboratory data were collected retrospectively. A population pharmacokinetic approach was used to select the best kidney function model predictive of TZP clearance (CL). The probability of target attainment (PTA), cumulative fraction of response (CFR) and the ratio between piperacillin and tazobactam were computed to identify optimal dosage regimens by continuous infusion across kidney function. This study included 257 critically ill patients (79.3% male) with intra-abdominal, bloodstream, and hospital-acquired pneumonia infections in 89.5% as the primary indication. The median (min-max range) age, body weight, and estimated glomerular filtration rate (eGFR) were 66 (23-93) years, 75 (39-310) kg, and 79.2 (6.4-234) mL/min, respectively. Doses of up to 22.5 g/day were used to optimize TZP based on TDM. The 2021 chronic kidney disease epidemiology equation in mL/min best modeled TZP CL. The ratio of piperacillin:tazobactam increased from 6:1 to 10:1 between an eGFR of <20 mL/min and >120 mL/min. At conventional doses, the PTA is below 90% when eGFR is ≥100 mL/min. Daily doses of 18 g/day and 22.5 g/day by CI are expected to achieve a >80% CFR when eGFR is 100-120 mL/min and >120-160 mL/min, respectively. Inadequate piperacillin and tazobactam exposure is likely in patients with eGFR ≥ 100 mL/min. Dose regimen adjustments informed by TDM should be evaluated in this specific population., Competing Interests: The authors declare no conflict of interest.

(1) Background: The advantage of using carbapenems over beta-lactam/beta-lactamase inhibitor combinations in critically ill septic patients still remains a debated issue. We aimed to assess the comparative impact of an optimized pharmacokinetic/pharmacodynamic (PK/PD) target attainment of piperacillin-tazobactam vs. meropenem on the trend over time of both Sequential Organ Failure Assessment (SOFA) score and inflammatory biomarkers in critically ill patients receiving continuous infusion (CI) monotherapy with piperacillin-tazobactam or meropenem for treating documented Gram-negative bloodstream infections (BSI) and/or ventilator-associated pneumonia (VAP). (2) Methods: We performed a retrospective observational study comparing critically ill patients receiving targeted treatment with CI meropenem monotherapy for documented Gram-negative BSIs or VAP with a historical cohort of critical patients receiving CI piperacillin-tazobactam monotherapy. Patients included in the two groups were admitted to the general and post-transplant intensive care unit in the period July 2021-September 2023 and fulfilled the same inclusion criteria. The delta values of the SOFA score between the baseline of meropenem or piperacillin-tazobactam treatment and those at 48-h (delta 48-h SOFA score) or at 7-days (delta 7-days SOFA) were selected as primary outcomes. Delta 48-h and 7-days C-reactive protein (CRP) and procalcitonin (PCT), microbiological eradication, resistance occurrence, clinical cure, multi-drug resistant colonization at 90-day, ICU, and 30-day mortality rate were selected as secondary outcomes. Univariate analysis comparing primary and secondary outcomes between critically ill patients receiving CI monotherapy with piperacillin-tazobactam vs. meropenem was carried out. (3) Results: Overall, 32 critically ill patients receiving CI meropenem monotherapy were compared with a historical cohort of 43 cases receiving CI piperacillin-tazobactam monotherapy. No significant differences in terms of demographics and clinical features emerged at baseline between the two groups. Optimal PK/PD target was attained in 83.7% and 100.0% of patients receiving piperacillin-tazobactam and meropenem, respectively. No significant differences were observed between groups in terms of median values of delta 48-h SOFA (0 points vs. 1 point; p = 0.89) and median delta 7-days SOFA (2 points vs. 1 point; p = 0.43). Similarly, no significant differences were found between patients receiving piperacillin-tazobactam vs. meropenem for any of the secondary outcomes. (4) Conclusion: Our findings may support the contention that in critically ill patients with documented Gram-negative BSIs and/or VAP, the decreases in the SOFA score and in the inflammatory biomarkers serum levels achievable with CI piperacillin-tazobactam monotherapy at 48-h and at 7-days may be of similar extent and as effective as to those achievable with CI meropenem monotherapy provided that optimization on real-time by means of a TDM-based expert clinical pharmacological advice program is granted.

Background: Bloodstream infections (BSIs) by Gram-negative pathogens play a major role in intensive care patients, both in terms of prevalence and severity, especially if multi-drug resistant pathogens are involved. Early appropriate antibiotic therapy is therefore a cornerstone in the management of these patients, and growing evidence shows that implementation of a multidisciplinary team may improve patients' outcomes. Our aim was to evaluate the clinical and microbiological impact of the application of a multidisciplinary team on critically ill patients., Methods: Pre-post study enrolling critically ill patients with Gram negative bloodstream infection in intensive care unit. In the pre-intervention phase (from January until December 2018) patients were managed with infectious disease consultation on demand, in the post-intervention phase (from January until December 2022) patients were managed with a daily evaluation by a multidisciplinary team composed of intensivist, infectious disease physician, clinical pharmacologist and microbiologist., Results: Overall, 135 patients were enrolled during the study period, of them 67 (49.6%) in the pre-intervention phase and 68 (50.4%) in the post-intervention phase. Median age was 67 (58-75) years, sex male was 31.9%. Septic shock, the need for continuous renal replacement therapy and mechanical ventilation at BSI onset were similar in both groups, no difference of multidrug-resistant organisms (MDRO) prevalence was observed. In the post-phase, empirical administration of carbapenems decreased significantly (40.3% vs. 62.7%, p = 0.02) with an increase of appropriate empirical therapy (86.9% vs. 55.2%, p < 0.001) and a decrease of overall antibiotic treatment (12 vs. 16 days, p < 0.001). Despite no differences in delta SOFA and all-cause 30-day mortality, a significant decrease in microbiological failure (10.3% vs. 29.9%, p = 0.005) and a new-onset 30-day MDRO colonization (8.3% vs. 36.6%, p < 0.001) in the post-phase was reported. At multivariable analysis adjusted for main covariates, the institution of a multidisciplinary management team (MMT) was found to be protective both for new MDRO colonization [OR 0.17, 95%CI(0.05-0.67)] and microbiological failure [OR 0.37, 95%CI (0.14-0.98)]., Conclusions: The institution of a MMT allowed for an optimization of antimicrobial treatments, reflecting to a significant decrease in new MDRO colonization and microbiological failure among critically ill patients., (© 2024. The Author(s).)

Objectives: In patients with COVID-19 respiratory failure, controlled mechanical ventilation (CMV) is often necessary during the acute phases of the disease. Weaning from CMV to pressure support ventilation (PSV) is a key objective when the patient's respiratory functions improve. Limited evidence exists regarding the factors predicting a successful transition to PSV and its impact on patient outcomes., Design: Retrospective observational cohort study., Setting: Twenty-four Italian ICUs from February 2020 to May 2020., Patients: Mechanically ventilated ICU patients with COVID-19-induced respiratory failure., Intervention: The transition period from CMV to PSV was evaluated. We defined it as "failure of assisted breathing" if the patient returned to CMV within the first 72 hours., Measurements and Main Results: Of 1260 ICU patients screened, 514 were included. Three hundred fifty-seven patients successfully made the transition to PSV, while 157 failed. Pao 2 /Fio 2 ratio before the transition emerged as an independent predictor of a successful shift (odds ratio 1.00; 95% CI, 0.99-1.00; p = 0.003). Patients in the success group displayed a better trend in Pao 2 /Fio 2 , Paco 2 , plateau and peak pressure, and pH level. Subjects in the failure group exhibited higher ICU mortality (hazard ratio 2.08; 95% CI, 1.42-3.06; p < 0.001), an extended ICU length of stay (successful vs. failure 21 ± 14 vs. 27 ± 17 d; p < 0.001) and a longer duration of mechanical ventilation (19 ± 18 vs. 24 ± 17 d, p = 0.04)., Conclusions: Our study emphasizes that the Pao 2 /Fio 2 ratio was the sole independent factor associated with a failed transition from CMV to PSV. The unsuccessful transition was associated with worse outcomes., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

(1) Background: Piperacillin-tazobactam represents the first-line option for treating infections caused by full- or multi-susceptible Enterobacterales and/or Pseudomonas aeruginosa in critically ill patients. Several studies reported that attaining aggressive pharmacokinetic/pharmacodynamic (PK/PD) targets with beta-lactams is associated with an improved microbiological/clinical outcome. We aimed to assess the relationship between the joint PK/PD target attainment of continuous infusion (CI) piperacillin-tazobactam and the microbiological/clinical outcome of documented Gram-negative bloodstream infections (BSI) and/or ventilator-associated pneumonia (VAP) of critically ill patients treated with CI piperacillin-tazobactam monotherapy. (2) Methods: Critically ill patients admitted to the general and post-transplant intensive care unit in the period July 2021-September 2023 treated with CI piperacillin-tazobactam monotherapy optimized by means of a real-time therapeutic drug monitoring (TDM)-guided expert clinical pharmacological advice (ECPA) program for documented Gram-negative BSIs and/or VAP were retrospectively retrieved. Steady-state plasma concentrations (C ss ) of piperacillin and of tazobactam were measured, and the free fractions ( f ) were calculated according to respective plasma protein binding. The joint PK/PD target was defined as optimal whenever both the piperacillin f C ss /MIC ratio was >4 and the tazobactam f C ss /target concentration (C T ) ratio was > 1 (quasi-optimal or suboptimal whenever only one or none of the two weas achieved, respectively). Multivariate logistic regression analysis was performed for testing variables potentially associated with microbiological outcome. (3) Results: Overall, 43 critically ill patients (median age 69 years; male 58.1%; median SOFA score at baseline 8) treated with CI piperacillin-tazobactam monotherapy were included. Optimal joint PK/PD target was attained in 36 cases (83.7%). At multivariate analysis, optimal attaining of joint PK/PD target was protective against microbiological failure (OR 0.03; 95%CI 0.003-0.27; p = 0.002), whereas quasi-optimal/suboptimal emerged as the only independent predictor of microbiological failure (OR 37.2; 95%CI 3.66-377.86; p = 0.002). (4) Conclusion: Optimized joint PK/PD target attainment of CI piperacillin-tazobactam could represent a valuable strategy for maximizing microbiological outcome in critically ill patients with documented Gram-negative BSI and/or VAP, even when sustained by extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales . In this scenario, implementing a real-time TDM-guided ECPA program may be helpful in preventing failure in attaining optimal joint PK/PD targets among critically ill patients. Larger prospective studies are warranted to confirm our findings.

Extracorporeal life support (ECLS) for acute respiratory failure encompasses veno-venous extracorporeal membrane oxygenation (V-V ECMO) and extracorporeal carbon dioxide removal (ECCO 2 R). V-V ECMO is primarily used to treat severe acute respiratory distress syndrome (ARDS), characterized by life-threatening hypoxemia or ventilatory insufficiency with conventional protective settings. It employs an artificial lung with high blood flows, and allows improvement in gas exchange, correction of hypoxemia, and reduction of the workload on the native lung. On the other hand, ECCO 2 R focuses on carbon dioxide removal and ventilatory load reduction ("ultra-protective ventilation") in moderate ARDS, or in avoiding pump failure in acute exacerbated chronic obstructive pulmonary disease. Clinical indications for V-V ECLS are tailored to individual patients, as there are no absolute contraindications. However, determining the ideal timing for initiating extracorporeal respiratory support remains uncertain. Current ECLS equipment faces issues like size and durability. Innovations include intravascular lung assist devices (ILADs) and pumpless devices, though they come with their own challenges. Efficient gas exchange relies on modern oxygenators using hollow fiber designs, but research is exploring microfluidic technology to improve oxygenator size, thrombogenicity, and blood flow capacity. Coagulation management during V-V ECLS is crucial due to common bleeding and thrombosis complications; indeed, anticoagulation strategies and monitoring systems require improvement, while surface coatings and new materials show promise. Moreover, pharmacokinetics during ECLS significantly impact antibiotic therapy, necessitating therapeutic drug monitoring for precise dosing. Managing native lung ventilation during V-V ECMO remains complex, requiring a careful balance between benefits and potential risks for spontaneously breathing patients. Moreover, weaning from V-V ECMO is recognized as an area of relevant uncertainty, requiring further research. In the last decade, the concept of Extracorporeal Organ Support (ECOS) for patients with multiple organ dysfunction has emerged, combining ECLS with other organ support therapies to provide a more holistic approach for critically ill patients. In this review, we aim at providing an in-depth overview of V-V ECMO and ECCO 2 R, addressing various aspects of their use, challenges, and potential future directions in research and development., (© 2023. The Author(s).)

(1) Objectives: to describe the pharmacokinetic/pharmacodynamic (PK/PD) profile of continuous infusion (CI) meropenem in critical patients with documented Gram-negative infections undergoing continuous veno-venous hemodiafiltration (CVVHDF) and to assess the relationship with microbiological outcome. (2) Methods: Data were retrospectively retrieved for patients admitted to the general and the post-transplant intensive care units in the period October 2022-May 2023 who underwent CVVHDF during treatment with CI meropenem optimized by means of a real-time therapeutic drug monitoring (TDM)-based expert clinical pharmacological advice (ECPA) program for documented Gram-negative infections. Steady-state meropenem plasma concentrations were measured, and the free fractions ( f C ss ) were calculated. Meropenem total clearance (CL tot ) was calculated at each TDM assessment, and the impact of CVVHDF dose intensity and of residual diuresis on CL tot was investigated by means of linear regression. Optimal meropenem PK/PD target attainment was defined as an f C ss /MIC ratio > 4. The relationship between meropenem PK/PD target attainment and microbiological outcome was assessed. (3) Results: A total of 24 critical patients (median age 68 years; male 62.5%) with documented Gram-negative infections were included. Median (IQR) meropenem f C ss was 19.9 mg/L (17.4-28.0 mg/L). Median (IQR) CL tot was 3.89 L/h (3.28-5.29 L/h), and median (IQR) CVVHDF dose intensity was 37.4 mL/kg/h (33.8-44.6 mL/kg/h). Meropenem dosing adjustments were provided in 20 out of 24 first TDM assessments (83.3%, all decreases) and overall in 26 out of the 51 total ECPA cases (51.0%). Meropenem PK/PD target attainment was always optimal, and microbiological eradication was achieved in 90.5% of assessable cases. (4) Conclusion: the real-time TDM-guided ECPA program was useful in attaining aggressive PK/PD targeting with CI meropenem in critically ill patients undergoing high-intensity CVVHDF and allowed microbiological eradication in most cases with dosing regimens ranging between 125 and 500 mg q6h over 6 h.

Purpose: To explore pharmacokinetic/pharmacodynamic (PK/PD) profile of continuous infusion (CI) ceftazidime-avibactam for treating difficult-to-treat resistant Gram-negative (DTR-GN) infections in critical patients undergoing continuous venovenous haemodiafiltration (CVVHDF)., Materials and Methods: Patients treated with CI ceftazidime-avibactam for DTR-GN infections during CVVHDF were retrospectively assessed. Ceftazidime and avibactam concentrations were measured at steady-state and the free fraction (fC ss ) was calculated. Total clearance (CL tot ) of both agents were calculated and the impact of CVVHDF intensity was assessed by linear regression. The joint PK/PD target of ceftazidime-avibactam was defined as optimal when both fC ss /MIC≥4 for ceftazidime and fC ss /C T  > 1 for avibactam were achieved. Relationship between ceftazidime-avibactam PK/PD targets and microbiological outcome was assessed., Results: Eight patients with DTR-GN infections were retrieved. Median fC ss were 84.5 (73.7-87.7 mg/L) for ceftazidime and 24.8 mg/L (20.7-25.8 mg/L) for avibactam. Median CL tot was 2.39 L/h (2.05-2.96 L/h) for ceftazidime and 2.56 L/h (2.12-2.98 L/h) for avibactam. Median CVVHDF dose was 38.6 mL/h/kg (35.9-40.0 mL/kg/h). CL tot were linearly correlated with CVVHDF dose (r = 0.53;p = 0.03, and r = 0.64;p = 0.006, respectively). The joint PK/PD targets were optimal granting microbiological eradication in all the assessable cases., Conclusion: CI administration of 1.25-2.5 g q8h ceftazidime-avibactam may allow prompt attainment and maintenance of optimal joint PK/PD targets during high-intensity CVVHDF., Competing Interests: Declaration of Competing Interest MG has received personal fees from Angelini and Shionogi, outside the submitted work. PV has served as a consultant for bioMérieux, Gilead, Merck Sharp & Dohme, Nabriva, Nordic Pharma, Pfizer, Thermo-Fisher, and Venatorx, and received payment for serving on the speaker's bureaus for Correvio, Gilead, Merck Sharp & Dohme, Nordic Pharma, and Pfizer, outside the submitted work. FP reports personal fees from Angelini, Basilea Pharmaceutica, Gilead, Hikma, MSD, Pfizer, Sanofi-Aventis, Shionogi, Thermo Fisher, and Accelerate Diagnostics, outside the submitted work; has participated in speaker's bureau for Accelerate Diagnostics, Angelini, Basilea Pharmaceutica, Gilead, Hikma, MSD, Pfizer, Sanofi-Aventis, Shionogi, Thermo Fisher, and as consultant for Angelini, Basilea Pharmaceutica, Gilead, MSD, Pfizer, Shionogi, outside the submitted work. The other authors report no potential conflicts of interest for this work., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Therapeutic drug monitoring (TDM) may be helpful in tailoring antimicrobial treatment, and expert interpretation of the results may make it more clinically useful., Methods: This study aimed to assess retrospectively the first-year impact (July 2021 to June 2022) of a newly established expert clinical pharmacological advice (ECPA) programme based on TDM results in tailoring therapy with 18 antimicrobials hospital-wide in a tertiary university hospital. All patients having ≥1 ECPA were grouped in five cohorts [haematology, intensive care unit (ICU), paediatrics, medical wards and surgical wards]. Four indicators of performance were identified: total ECPAs; total ECPAs recommending dosing adjustments/total ECPAs both at first and at subsequent assessments; and turnaround time (TAT) of ECPAs, defined as optimal (<12 h), quasi-optimal (12-24 h), acceptable (24-48 h) or suboptimal (>48 h)., Results: A total of 8484 ECPAs were provided for tailoring treatment in 2961 patients, mostly admitted in the ICU (34.1%) and medical wards (32.0%). The proportion of ECPAs recommending dosing adjustments was >40% at first assessment (40.9% haematology; 62.9% ICU; 53.9% paediatrics; 59.1% medical wards; and 59.7% surgical wards), and decreased consistently at subsequent TDM assessments (20.7% haematology; 40.6% ICU; 37.4% paediatrics; 32.9% medical wards; and 29.2% surgical wards). The overall median TAT of the ECPAs was optimal (8.11 h)., Conclusion: The TDM-guided ECPA programme was successful in tailoring treatment with a wide panel of antimicrobials hospital-wide. Expert interpretation by medical clinical pharmacologists, short TATs, and strict interaction with infectious diseases consultants and clinicians were crucial in achieving this., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: To assess the pharmacokinetics/pharmacodynamics (PK/PD) of cefiderocol administered by continuous infusion (CI) in a case series of critically ill patients with carbapenem-resistant Acinetobacter baumannii (CRAB) infections undergoing continuous venovenous haemodiafiltration (CVVHDF)., Methods: Critically ill patients receiving cefiderocol by CI during CVVHDF for documented bloodstream infections (BSIs), ventilator-associated pneumonia (VAP), and/or complicated intrabdominal infections (cIAIs) caused by CRAB and undergoing therapeutic drug monitoring (TDM) from February 2022 to January 2023 were retrospectively assessed. Cefiderocol concentrations were determined at steady-state, and the free fraction (fC ss ) was calculated. Cefiderocol total clearance (CL tot ) was determined at each TDM assessment. fC ss /MIC ratio was selected as a PD determinant of cefiderocol efficacy and defined as optimal (>4), quasi-optimal (1-4), and suboptimal (<1)., Results: Five patients with documented CRAB infections (two BSI+VAP, two VAP, and one BSI+cIAI) were included. The maintenance dose of cefiderocol was 2 g q8h over 8 h by CI. Median average fC ss was 26.5 mg/L (21.7-33.6 mg/L). Median CL tot was 4.84 L/h (2.04-5.22 L/h). Median CVVHDF dose was 41.1 mL/kg/h (35.5-44.9 mL/kg/h), and residual diuresis was reported in 4/5 cases. Optimal PK/PD target was attained in all cases, with a median cefiderocol fC ss /MIC ratio of 14.9 (6.6-33.6)., Conclusion: CI of full doses of cefiderocol could be a useful strategy to attain aggressive PK/PD targets for the treatment of severe CRAB infections in critically ill patients undergoing high-intensity CVVHDF and who have residual diuresis., (Copyright © 2023 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

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., (© 2023. The Author(s).)

Introduction: Extracellular vesicles (EVs) and particles (EPs) represent reliable biomarkers for disease detection. Their role in the inflammatory microenvironment of severe COVID-19 patients is not well determined. Here, we characterized the immunophenotype, the lipidomic cargo and the functional activity of circulating EPs from severe COVID-19 patients (Co-19-EPs) and healthy controls (HC-EPs) correlating the data with the clinical parameters including the partial pressure of oxygen to fraction of inspired oxygen ratio (PaO2/FiO2) and the sequential organ failure assessment (SOFA) score., Methods: Peripheral blood (PB) was collected from COVID-19 patients (n=10) and HC (n=10). EPs were purified from platelet-poor plasma by size exclusion chromatography (SEC) and ultrafiltration. Plasma cytokines and EPs were characterized by multiplex bead-based assay. Quantitative lipidomic profiling of EPs was performed by liquid chromatography/mass spectrometry combined with quadrupole time-of-flight (LC/MS Q-TOF). Innate lymphoid cells (ILC) were characterized by flow cytometry after co-cultures with HC-EPs or Co-19-EPs., Results: We observed that EPs from severe COVID-19 patients: 1) display an altered surface signature as assessed by multiplex protein analysis; 2) are characterized by distinct lipidomic profiling; 3) show correlations between lipidomic profiling and disease aggressiveness scores; 4) fail to dampen type 2 innate lymphoid cells (ILC2) cytokine secretion. As a consequence, ILC2 from severe COVID-19 patients show a more activated phenotype due to the presence of Co-19-EPs., Discussion: In summary, these data highlight that abnormal circulating EPs promote ILC2-driven inflammatory signals in severe COVID-19 patients and support further exploration to unravel the role of EPs (and EVs) in COVID-19 pathogenesis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Forte, Pellegrino, Trabanelli, Tonetti, Ricci, Cenerenti, Comai, Tazzari, Lazzarotto, Buratta, Urbanelli, Narimanfar, Alabed, Mecucci, La Manna, Emiliani, Jandus, Ranieri, Cavo, Catani and Palandri.)

Background: Veno-venous extracorporeal life support (V-V ECLS or V-V ECMO) has been adopted as a rescue support in severe cases of COVID-19 ARDS. Initial reports on the use of V-V ECLS in COVID-19 patients reported very high mortality rates (57%-94%), but subsequent studies showed much lower rates (30%-40%). The aim of this study is to analyze demographic features, clinical course and outcomes of COVID-19 treated with V-V ECLS during the Italian 'third wave', in which the alpha variant was prevalent in the country., Methods: Single-center, retrospective observational study conducted at the ECLS referral center of a teaching hospital in Italy from January 1st, 2021 and October 31st, 2021., Results: Between January and October 2021, 18 consecutive adult patients who underwent V-V ECLS for severe ARDS due to COVID-19 were enrolled. Thirteen patients (72.2%) were male, and their median age was 50 years; the median P/F ratio before V-V ECLS initiation was 43 mm Hg (IQR, 40; 56), and the median RESP score was 0.5 (IQR, -2.25; 1.0). The mortality rate at 90 days was 55.6, compared to 55.7% in non-COVID patients in our center (p > 0.05); the median duration of ECLS was 29 days (IQR, 11; 32), compared to 10 days (IQR, 8; 15), in non-COVID patients (p = 0.004). Incidence of complications was high., Conclusions: In patients with COVID-19 ARDS receiving V-V ECLS, unadjusted mortality was similar to pre-pandemic V-V ECLS cases, while the duration of ECLS was almost three times longer and with frequent complications. This could be partly explained by the selection of very sick patients at the baseline that evolved to multiorgan failure during the course of ECLS., (© 2022 International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Trehalose 6-phosphate (Tre6P), the intermediate of trehalose biosynthesis, is an essential signal metabolite in plants, linking growth and development to carbon status. Our current understanding of Tre6P metabolism and signaling pathways in plants is based almost entirely on studies performed with Arabidopsis thaliana, a model plant that performs C 3 photosynthesis. Conversely, our knowledge on the molecular mechanisms involved in Tre6P regulation of carbon partitioning and metabolism in C 4 plants is scarce. This topic is especially relevant due to the agronomic importance of crops performing C 4 photosynthesis, such as maize, sorghum and sugarcane. In this review, we focused our attention on recent developments related to Tre6P metabolism in C 4 species and raised some open questions that should be addressed in the near future to improve the yield of economically important crops., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The role of upper airways microbiota and its association with ventilator-associated pneumonia (VAP) development in mechanically ventilated (MV) patients is unclear. Taking advantage of data collected in a prospective study aimed to assess the composition and over-time variation of upper airway microbiota in patients MV for non-pulmonary reasons, we describe upper airway microbiota characteristics among VAP and NO-VAP patients., Methods: Exploratory analysis of data collected in a prospective observational study on patients intubated for non-pulmonary conditions. Microbiota analysis (trough 16S-rRNA gene profiling) was performed on endotracheal aspirates (at intubation, T0, and after 72 h, T3) of patients with VAP (cases cohort) and a subgroup of NO-VAP patients (control cohort, matched according to total intubation time)., Results: Samples from 13 VAP patients and 22 NO-VAP matched controls were analyzed. At intubation (T0), patients with VAP revealed a significantly lower microbial complexity of the microbiota of the upper airways compared to NO-VAP controls (alpha diversity index of 84 ± 37 and 160 ± 102, in VAP and NO&#95;VAP group, respectively, p-value < 0.012). Furthermore, an overall decrease in microbial diversity was observed in both groups at T3 as compared to T0. At T3, a loss of some genera (Prevotella 7, Fusobacterium, Neisseria, Escherichia-Shigella and Haemophilus) was found in VAP patients. In contrast, eight genera belonging to the Bacteroidetes, Firmicutes and Fusobacteria phyla was predominant in this group. However, it is unclear whether VAP caused dysbiosis or dysbiosis caused VAP., Conclusions: In a small sample size of intubated patients, microbial diversity at intubation was less in patients with VAP compared to patients without VAP., (© 2023. The Author(s).)

The aim of this retrospective multicenter observational study is to test the feasibility and safety of a combined extracorporeal CO 2 removal (ECCO 2 R) plus renal replacement therapy (RRT) system to use an ultraprotective ventilator setting while maintaining (1) an effective support of renal function and (2) values of pH within the physiologic limits in a cohort of coronavirus infectious disease 2019 (COVID-19) patients. Among COVID-19 patients admitted to the intensive care unit of 9 participating hospitals, 27 patients with acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI) requiring invasive mechanical ventilation undergoing ECCO 2 R-plus-RRT treatment were included in the analysis. The treatment allowed to reduce V T from 6.0 ± 0.6 mL/kg at baseline to 4.8 ± 0.8, 4.6 ± 1.0, and 4.3 ± 0.3 mL/kg, driving pressure (ΔP) from 19.8 ± 2.5 cm H 2 O to 14.8 ± 3.6, 14.38 ± 4.1 and 10.2 ± 1.6 cm H 2 O after 24 hours, 48 hours, and at discontinuation of ECCO 2 R-plus-RRT (T3), respectively ( p < 0.001). PaCO 2 and pH remained stable. Plasma creatinine decreased over the study period from 3.30 ± 1.27 to 1.90 ± 1.30 and 1.27 ± 0.90 mg/dL after 24 and 48 hours of treatment, respectively ( p < 0.01). No patient-related events associated with the extracorporeal system were reported. These data show that in patients with COVID-19-induced ARDS and AKI, ECCO 2 R-plus-RRT is effective in allowing ultraprotective ventilator settings while maintaining an effective support of renal function and values of pH within physiologic limits., Competing Interests: Disclosure: The authors have no conflicts of interest to declare., (Copyright © ASAIO 2022.)

Background: Environmental contamination by SARS-CoV-2 from patients with COVID-19 undergoing noninvasive ventilation (NIV) in the ICU is still under investigation. This study set out to investigate the presence of SARS-CoV-2 on surfaces near subjects receiving NIV in the ICU under controlled conditions (ie, use of dual-limb circuits, filters, adequate room ventilation)., Methods: This was a single-center, prospective, observational study in the ICU of a tertiary teaching hospital. Four surface sampling areas, at increasing distance from subject's face, were identified; and each one was sampled at fixed intervals: 6, 12, and 24 h. The presence of SARS-CoV-2 was detected with real-time reverse transcriptase-polymerase-chain-reaction (RT-PCR) test on environmental swabs; the RT-PCR assay targeted the SARS-CoV-2 virus nucleocapsid N1 and N2 genes and the human RNase P gene as internal control., Results: In a total of 256 collected samples, none were positive for SARS-CoV-2 genetic material, whereas 21 samples (8.2%) tested positive for RNase P, thus demonstrating the presence of genetic material unrelated to SARS-CoV-2., Conclusions: Our data show that application of NIV in an appropriate environment and with correct precautions leads to no sign of surface environmental contamination. Accordingly, our data support the idea that use of NIV in the ICU is safe both for health care workers and for other patients., Competing Interests: The authors have disclosed no conflicts of interest., (Copyright © 2023 by Daedalus Enterprises.)

After fluid status optimization, norepinephrine infusion represents the cornerstone of septic shock treatment. De-escalation of vasopressors should be considered with caution, as hypotension increases the risk of mortality. In this prospective observational study including 42 patients, we assess the role of dynamic elastance (EaDyn), i.e., the ratio between pulse pressure variation and stroke volume variation, which can be measured noninvasively by the MostCare monitoring system, to predict a mean arterial pressure (MAP) drop > 10% 30 min after norepinephrine reduction. Patients were divided into responders (MAP falling > 10%) and non-responders (MAP falling < 10%). The receiver-operating-characteristic curve identified an area under the curve of the EaDyn value to predict a MAP decrease > 10% of 0.84. An EaDyn cut-off of 0.84 predicted a MAP drop > 10% with a sensitivity of 0.71 and a specificity of 0.89. In a multivariate logistic regression, EaDyn was significantly and independently associated with MAP decrease (OR 0.001, 95% confidence interval 0.00001−0.081, p < 0.001). The nomogram model for the probability of MAP decrease > 10% showed a C-index of 0.90. In conclusion, in a septic shock cohort, EaDyn correlates well with the risk of decrease of MAP > 10% after norepinephrine reduction.

Background: Therapeutic drug monitoring (TDM) may represent an invaluable tool for optimizing antimicrobial therapy in septic patients, but extensive use is burdened by barriers. The aim of this study was to assess the impact of a newly established expert clinical pharmacological advice (ECPA) program in improving the clinical usefulness of an already existing TDM program for emerging candidates in tailoring antimicrobial therapy among critically ill patients., Methods: This retrospective observational study included an organizational phase (OP) and an assessment phase (AP). During the OP (January-June 2021), specific actions were organized by MD clinical pharmacologists together with bioanalytical experts, clinical engineers, and ICU clinicians. During the AP (July-December 2021), the impact of these actions in optimizing antimicrobial treatment of the critically ill patients was assessed. Four indicators of performance of the TDM-guided real-time ECPA program were identified [total TDM-guided ECPAs July-December 2021/total TDM results July-December 2020; total ECPA dosing adjustments/total delivered ECPAs both at first assessment and overall; and turnaround time (TAT) of ECPAs, defined as optimal (< 12 h), quasi-optimal (12-24 h), acceptable (24-48 h), suboptimal (> 48 h)]., Results: The OP allowed to implement new organizational procedures, to create a dedicated pathway in the intranet system, to offer educational webinars on clinical pharmacology of antimicrobials, and to establish a multidisciplinary team at the morning bedside ICU meeting. In the AP, a total of 640 ECPAs were provided for optimizing 261 courses of antimicrobial therapy in 166 critically ill patients. ECPAs concerned mainly piperacillin-tazobactam (41.8%) and meropenem (24.9%), and also other antimicrobials had ≥ 10 ECPAs (ceftazidime, ciprofloxacin, fluconazole, ganciclovir, levofloxacin, and linezolid). Overall, the pre-post-increase in TDM activity was of 13.3-fold. TDM-guided dosing adjustments were recommended at first assessment in 61.7% of ECPAs (10.7% increases and 51.0% decreases), and overall in 45.0% of ECPAs (10.0% increases and 35.0% decreases). The overall median TAT was optimal (7.7 h) and that of each single agent was always optimal or quasi-optimal., Conclusions: Multidisciplinary approach and timely expert interpretation of TDM results by MD Clinical Pharmacologists could represent cornerstones in improving the cost-effectiveness of an antimicrobial TDM program for emerging TDM candidates., (© 2022. The Author(s).)

The use of donor management protocols has significantly improved recovery rates; however, the inherent instability of lungs after death results in low utilization rates of potential donor lungs. Donor lungs are susceptible to direct trauma, aspiration, neurogenic edema, ventilator-associated barotrauma, and ventilator-associated pneumonia. After irreversible brain injury and determination of futility of care, the goal of medical management of the donor shifts to maintaining hemodynamic stability and maximizing the likelihood of successful organ recovery., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Rationale: The "Berlin definition" of acute respiratory distress syndrome (ARDS) does not allow inclusion of patients receiving high-flow nasal oxygen (HFNO). However, several articles have proposed that criteria for defining ARDS should be broadened to allow inclusion of patients receiving HFNO. Objectives: To compare the proportion of patients fulfilling ARDS criteria during HFNO and soon after intubation, and 28-day mortality between patients treated exclusively with HFNO and patients transitioned from HFNO to invasive mechanical ventilation (IMV). Methods: From previously published studies, we analyzed patients with coronavirus disease (COVID-19) who had Pa O 2 /Fi O 2 of ⩽300 while treated with ⩾40 L/min HFNO, or noninvasive ventilation (NIV) with positive end-expiratory pressure of ⩾5 cm H 2 O (comparator). In patients transitioned from HFNO/NIV to invasive mechanical ventilation (IMV), we compared ARDS severity during HFNO/NIV and soon after IMV. We compared 28-day mortality in patients treated exclusively with HFNO/NIV versus patients transitioned to IMV. Measurements and Main Results: We analyzed 184 and 131 patients receiving HFNO or NIV, respectively. A total of 112 HFNO and 69 NIV patients transitioned to IMV. Of those, 104 (92.9%) patients on HFNO and 66 (95.7%) on NIV continued to have Pa O 2 /Fi O 2 ⩽300 under IMV. Twenty-eight-day mortality in patients who remained on HFNO was 4.2% (3/72), whereas in patients transitioned from HFNO to IMV, it was 28.6% (32/112) ( P  < 0.001). Twenty-eight-day mortality in patients who remained on NIV was 1.6% (1/62), whereas in patients who transitioned from NIV to IMV, it was 44.9% (31/69) ( P  < 0.001). Overall mortality was 19.0% (35/184) and 24.4% (32/131) for HFNO and NIV, respectively ( P  = 0.2479). Conclusions: Broadening the ARDS definition to include patients on HFNO with Pa O 2 /Fi O 2 ⩽300 may identify patients at earlier stages of disease but with lower mortality.

Purpose: COVID-19-related acute respiratory distress syndrome (ARDS) is characterized by the presence of signs of microvascular involvement at the CT scan, such as the vascular tree in bud (TIB) and the vascular enlargement pattern (VEP). Recent evidence suggests that TIB could be associated with an increased duration of invasive mechanical ventilation (IMV) and intensive care unit (ICU) stay. The primary objective of this study was to evaluate whether microvascular involvement signs could have a prognostic significance concerning liberation from IMV., Material and Methods: All the COVID-19 patients requiring IMV admitted to 16 Italian ICUs and having a lung CT scan recorded within 3 days from intubation were enrolled in this secondary analysis. Radiologic, clinical and biochemical data were collected., Results: A total of 139 patients affected by COVID-19 related ARDS were enrolled. After grouping based on TIB or VEP detection, we found no differences in terms of duration of IMV and mortality. Extension of VEP and TIB was significantly correlated with ground-glass opacities (GGOs) and crazy paving pattern extension. A parenchymal extent over 50% of GGO and crazy paving pattern was more frequently observed among non-survivors, while a VEP and TIB extent involving 3 or more lobes was significantly more frequent in non-responders to prone positioning., Conclusions: The presence of early CT scan signs of microvascular involvement in COVID-19 patients does not appear to be associated with differences in duration of IMV and mortality. However, patients with a high extension of VEP and TIB may have a reduced oxygenation response to prone positioning., Trial Registration: NCT04411459., (© 2022. Italian Society of Medical Radiology.)

Purpose of Review: To review current evidence on the pathophysiology of COVID-19-related acute respiratory distress syndrome (ARDS) and on the implementation of lung protective ventilation., Recent Findings: Although multiple observations and physiological studies seem to show a different pathophysiological behaviour in COVID-19-ARDS compared with 'classical' ARDS, numerous studies on thousands of patients do not confirm these findings and COVID-19-ARDS indeed shares similar characteristics and interindividual heterogeneity with ARDS from other causes. Although still scarce, present evidence on the application of lung protective ventilation in COVID-19-ARDS shows that it is indeed consistently applied in ICUs worldwide with a possible signal towards better survival at least in one study. The levels of positive end-expiratory pressure (PEEP) usually applied in these patients are higher than in 'classical' ARDS, proposing once again the issue of PEEP personalization in hypoxemic patients. In the absence of robust evidence, careful evaluation of the patient is needed, and empiric settings should be oriented towards lower levels of PEEP., Summary: According to the present evidence, a lung protective strategy based on low tidal volume and plateau pressures is indicated in COVID-19-ARDS as in ARDS from other causes; however, there are still uncertainties on the appropriate levels of PEEP., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: In acute respiratory distress syndrome (ARDS), response to positive end-expiratory pressure (PEEP) is variable according to different degrees of lung recruitability. The search for a tool to individualize PEEP based on patients' individual response is warranted. End-expiratory lung volume (EELV) assessment by nitrogen washing-washout aids bedside estimation of PEEP-induced alveolar recruitment and may therefore help titrate PEEP on patient's individual recruitability. We designed a randomized trial to test whether an individualized PEEP setting protocol driven by EELV measurement may improve a composite clinical outcome in patients with moderate-to-severe ARDS (IPERPEEP trial)., Methods: IPERPEEP is an open-label, multicenter, randomized trial that will be conducted in 10 intensive care units in Italy and will enroll 132 ARDS patients showing PaO 2 /FiO 2 ratio ≤ 150 mmHg within 24 h from endotracheal intubation while on mechanical ventilation with PEEP 5 cmH 2 O. To standardize lung volumes at study initiation, all patients will undergo mechanical ventilation with tidal volume of 6 ml/kg of predicted body weight and PEEP set to obtain a plateau pressure within 28 and 30 cmH 2 O for 30 min (EXPRESS PEEP). Afterwards, a 5-step decremental PEEP trial will be conducted (EXPRESS PEEP to PEEP 5 cmH 2 O), and EELV will be measured at each step. Recruitment-to-inflation ratio will be calculated for each PEEP range from EELV difference. Patients will be then randomized to receive mechanical ventilation with PEEP set according to the optimal recruitment observed in the PEEP trial (IPERPEEP arm) trial or to achieve a plateau pressure of 28-30 cmH 2 O (control arm, EXPRESS strategy). In both groups, tidal volume size, use of prone positioning and neuromuscular blocking agents, and weaning from PEEP and from mechanical ventilation will be standardized. The primary endpoint of the study is a composite clinical outcome incorporating in-ICU mortality, 60-day ventilator-free days, and serum interleukin-6 concentration over the course of the initial 72 h of treatment., Discussion: The IPERPEEP study is a randomized trial powered to elucidate whether an individualized PEEP setting protocol based on bedside assessment of lung recruitability can improve a composite clinical outcome during moderate-to-severe ARDS., Trial Registration: ClinicalTrials.gov NCT04012073 . Registered 9 July 2019., (© 2022. The Author(s).)

Introduction: optimal treatment of Gram-negative infections in critically ill patients is challenged by changing pathophysiological conditions, reduced antimicrobial susceptibility and limited therapeutic options. The aim of this study was to assess the impact of maximizing Css/MIC ratio on efficacy of continuous infusion (CI) meropenem in treating documented Gram-negative infections in critically ill patients and to perform a population pharmacokinetic/pharmacodynamic analysis to support treatment optimization. Materials and Methods: Classification and regression tree (CART) analysis was used to identify whether a cutoff of steady-state meropenem concentration (Css)-to-minimum inhibitory concentration (MIC) (Css/MIC) ratio correlated with favorable clinical outcome. A non-parametric approach with Pmetrics was used for pharmacokinetic analysis and covariate evaluation. The probability of target attainment (PTA) of the identified Css/MIC ratio was calculated by means of Monte Carlo simulations. Cumulative fraction of response (CFRs) were calculated against common Enterobacterales, P. aeruginosa and A. baumannii as well. Results: a total of 74 patients with 183 meropenem Css were included. CART analysis identified a Css/MIC ratio ≥4.63 as cutoff value significantly associated with favorable clinical outcomes. Multivariate regression analysis confirmed the association [OR (95%CI): 20.440 (2.063-202.522); p < 0.01]. Creatinine clearance (CL CR ) was the only covariate associated with meropenem clearance. Monte Carlo simulations showed that, across different classes of renal function, dosages of meropenem ranging between 0.5 and 2 g q6h over 6 h (namely by CI) may grant PTAs of Css/MIC ratios ≥4.63 against susceptible pathogens with an MIC up to the EUCAST clinical breakpoint of 2 mg/L. The CFRs achievable with these dosages were very high (>90%) against Enterobacterales across all the classes of renal function and against P. aeruginosa among patients with CL CR < 30 ml/min/1.73 m 2 , and quite lower against A. baumannii . Discussion: our findings suggest that Css/MIC ratio ≥4.63 may be considered the pharmacodynamic target useful at maximizing the efficacy of CI meropenem in the treatment of Gram-negative infections in critically ill patients. Dosages ranging between 0.5 g q6h and 2 g q6h by CI may maximize the probability of favorable clinical outcome against meropenem-susceptible Gram-negative pathogens among critically ill patients having different degrees of renal function ., Competing Interests: FP has participated in speaker bureaus for Angelini, Basilea Pharmaceutica, Gilead, Hikma, Merck Sharp and Dohme, Nordic Pharma, Pfizer and Sanofi Aventis, and in advisory boards for Angelini, Basilea, Pharmaceutica, Correvio, Gilead, Hikma, Merck Sharp and Dohme, Nordic Pharma, Novartis, Pfizer, Shionogi and Thermo-Fisher, outside the submitted work. PV has served as a consultant for bioMérieux, Gilead, Merck Sharp and Dohme, Nabriva, Nordic Pharma, Pfizer, Thermo-Fisher, and Venatorx, and received payment for serving on the speaker’s bureaus for Correvio, Gilead, Merck Sharp and Dohme, Nordic Pharma, and Pfizer, outside the submitted work. MG has received personal fees from Angelini, outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cojutti, Gatti, Rinaldi, Tonetti, Laici, Mega, Siniscalchi, Giannella, Viale and Pea.)

Background: We evaluated the incidence of invasive pulmonary aspergillosis among intubated patients with critical COVID-19 and evaluated different case definitions of invasive aspergillosis., Methods: Prospective, multicenter study in adult patients with microbiologically confirmed COVID-19 receiving mechanical ventilation. All included participants underwent a screening protocol for invasive pulmonary aspergillosis with bronchoalveolar lavage galactomannan and cultures performed on admission at 7 days and in case of clinical deterioration. Cases were classified as coronavirus-associated pulmonary aspergillosis (CAPA) according to previous consensus definitions. The new definition was compared with putative invasive pulmonary aspergillosis (PIPA)., Results: 108 patients were enrolled. Probable CAPA was diagnosed in 30 (27.7%) patients after a median of 4 (2-8) days from intensive care unit (ICU) admission. Kaplan-Meier curves showed a significantly higher 30-day mortality rate from ICU admission among patients with either CAPA (44% vs 19%, P = .002) or PIPA (74% vs 26%, P < .001) when compared with patients not fulfilling criteria for aspergillosis. The association between CAPA (OR, 3.53; 95% CI, 1.29-9.67; P = .014) or PIPA (OR, 11.60; 95% CI, 3.24-41.29; P < .001) with 30-day mortality from ICU admission was confirmed, even after adjustment for confounders with a logistic regression model. Among patients with CAPA receiving voriconazole treatment (13 patients; 43%) a trend toward lower mortality (46% vs 59%; P = .30) and reduction in galactomannan index in consecutive samples were observed., Conclusions: We found a high incidence of CAPA among critically ill COVID-19 patients and its occurrence seems to change the natural course of disease., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

C4 photosynthesis is typically characterized by the spatial compartmentalization of the photosynthetic reactions into mesophyll (M) and bundle sheath (BS) cells. Initial carbon fixation within M cells gives rise to C4 acids, which are transported to the BS cells. There, C4 acids are decarboxylated so that the resulting CO2 is incorporated into the Calvin cycle. This work is focused on the study of Setaria viridis, a C4 model plant, closely related to several major feed and bioenergy grasses. First, we performed the heterologous expression and biochemical characterization of Setaria isoforms for chloroplastic NADP-malic enzyme (NADP-ME) and mitochondrial NAD-malic enzyme (NAD-ME). The kinetic parameters obtained agree with a major role for NADP-ME in the decarboxylation of the C4 acid malate in the chloroplasts of BS cells. In addition, mitochondria-located NAD-ME showed regulatory properties that could be important in the context of the operation of the C4 carbon shuttle. Secondly, we compared the proteomes of M and BS compartments and found 825 differentially accumulated proteins that could support different metabolic scenarios. Most interestingly, we found evidence of metabolic strategies to insulate the C4 core avoiding the leakage of intermediates by either up-regulation or down-regulation of chloroplastic, mitochondrial, and peroxisomal proteins. Overall, the results presented in this work provide novel data concerning the complexity of C4 metabolism, uncovering future lines of research that will undoubtedly contribute to the expansion of knowledge on this topic., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Health-related quality of life (HRQoL) impairment is often reported among COVID-19 ICU survivors, and little is known about their long-term outcomes. We evaluated the HRQoL trajectories between 3 months and 1 year after ICU discharge, the factors influencing these trajectories and the presence of clusters of HRQoL profiles in a population of COVID-19 patients who underwent invasive mechanical ventilation (IMV). Moreover, pathophysiological correlations of residual dyspnea were tested., Methods: We followed up 178 survivors from 16 Italian ICUs up to one year after ICU discharge. HRQoL was investigated through the 15D instrument. Available pulmonary function tests (PFTs) and chest CT scans at 1 year were also collected. A linear mixed-effects model was adopted to identify factors associated with different HRQoL trajectories and a two-step cluster analysis was performed to identify HRQoL clusters., Results: We found that HRQoL increased during the study period, especially for the significant increase of the physical dimensions, while the mental dimensions and dyspnea remained substantially unchanged. Four main 15D profiles were identified: full recovery (47.2%), bad recovery (5.1%) and two partial recovery clusters with mostly physical (9.6%) or mental (38.2%) dimensions affected. Gender, duration of IMV and number of comorbidities significantly influenced HRQoL trajectories. Persistent dyspnea was reported in 58.4% of patients, and weakly, but significantly, correlated with both DLCO and length of IMV., Conclusions: HRQoL impairment is frequent 1 year after ICU discharge, and the lowest recovery is found in the mental dimensions. Persistent dyspnea is often reported and weakly correlated with PFTs alterations., Trial Registration: NCT04411459., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Emerging data suggest that more aggressive beta-lactam PK/PD targets could minimize the occurrence of microbiological failure and/or resistance development. This study aims to assess whether a PK/PD target threshold of continuous infusion (CI) beta-lactams may be useful in preventing microbiological failure and/or resistance development in critically ill patients affected by documented Gram-negative infections., Methods: Patients admitted to intensive care units from December 2020 to July 2021 receiving continuous infusion beta-lactams for documented Gram-negative infections and having at least one therapeutic drug monitoring in the first 72 h of treatment were included. A receiver operating characteristic (ROC) curve analysis was performed using the ratio between steady-state concentration and minimum inhibitory concentration (C ss /MIC) ratio as the test variable and occurrence of microbiological failure as the state variable. Area under the curve (AUC) and 95% confidence interval (CI) were calculated. Independent risk factors for the occurrence of microbiological failure were investigated using logistic regression., Results: Overall, 116 patients were included. Microbiological failure occurred in 26 cases (22.4%). A C ss /MIC ratio ≤ 5 was identified as PK/PD target cut-off with sensitivity of 80.8% (CI 60.6-93.4%) and specificity of 90.5% (CI 74.2-94.4%), and with an AUC of 0.868 (95%CI 0.793-0.924; p < 0.001). At multivariate regression, independent predictors of microbiological failure were C ss /MIC ratio ≤ 5 (odds ratio [OR] 34.54; 95%CI 7.45-160.11; p < 0.001) and Pseudomonas aeruginosa infection (OR 4.79; 95%CI 1.11-20.79; p = 0.036)., Conclusions: Early targeting of CI beta-lactams at C ss /MIC ratio > 5 during the treatment of documented Gram-negative infections may be helpful in preventing microbiological failure and/or resistance development in critically ill patients.

Background: Hypercapnic exacerbations are severe complications of chronic obstructive pulmonary disease (COPD), characterized by negative impact on prognosis, quality of life and healthcare costs. The present standard of care for acute exacerbations of COPD is non-invasive ventilation; when it fails, the use of invasive mechanical ventilation is inevitable, but is associated with extremely poor prognosis. Extracorporeal circuits designed to remove CO 2 (ECCO 2 R) may enhance the efficacy of NIV to remove CO 2 and avoid the worsening of respiratory acidosis, which inevitably leads to failure of non-invasive ventilation. Although the use of ECCO 2 R for acute exacerbations of COPD is steadily increasing, solid evidence on its efficacy and safety is scarce, thus the need for a randomized controlled trial., Methods: multicenter randomized controlled unblinded clinical trial including 284 (142 per arm) patients with acute hypercapnic respiratory failure caused by exacerbation of COPD, requiring respiratory support with NIV. The primary outcome is event free survival at 28 days, a composite outcome defined by survival in absence of prolonged mechanical ventilation, severe hypoxemia, septic shock and second episode of COPD exacerbation. Secondary outcomes are incidence of endotracheal intubation and tracheostomy, intensive care and hospital length-of-stay and 90-day mortality., Discussion: Acute exacerbations of COPD represent a significant burden in terms of prognosis, quality of life and healthcare costs. Lack definite evidence despite increasing use of ECCO 2 R justifies a randomized trial to evaluate whether patients with acute hypercapnic acidosis not responsive to NIV should undergo invasive mechanical ventilation (with all serious related risks) or be treated with ECCO 2 R to avoid invasive ventilation but be exposed to possible adverse events of ECCO 2 R. Owing to its pragmatic nature, sample size and composite primary outcome, this trial aims at providing valuable answers to relevant questions for clinical treatment of acute exacerbations of COPD., Trial Registration: ClinicalTrials.gov , NCT04582799 . Registered 12 October 2020, ., (© 2021. The Author(s).)

Competing Interests: The authors have no funding or conflicts of interest to disclose.

Purpose: The onset of the coronavirus disease 19 (COVID-19) pandemic in Italy induced a dramatic increase in the need for intensive care unit (ICU) beds for a large proportion of patients affected by COVID-19-related acute respiratory distress syndrome (ARDS). The aim of the present study was to describe the health-related quality of life (HRQoL) at 90 days after ICU discharge in a cohort of COVID-19 patients undergoing invasive mechanical ventilation and to compare it with an age and sex-matched sample from the general Italian and Finnish populations. Moreover, the possible associations between clinical, demographic, social factors, and HRQoL were investigated., Methods: COVID-19 ARDS survivors from 16 participating ICUs were followed up until 90 days after ICU discharge and the HRQoL was evaluated with the 15D instrument. A parallel cohort of age and sex-matched Italian population from the same geographic areas was interviewed and a third group of matched Finnish population was extracted from the Finnish 2011 National Health survey. A linear regression analysis was performed to evaluate potential associations between the evaluated factors and HRQoL., Results: 205 patients answered to the questionnaire. HRQoL of the COVID-19 ARDS patients was significantly lower than the matched populations in both physical and mental dimensions. Age, sex, number of comorbidities, ARDS class, duration of invasive mechanical ventilation, and occupational status were found to be significant determinants of the 90 days HRQoL. Clinical severity at ICU admission was poorly correlated to HRQoL., Conclusion: COVID-19-related ARDS survivors at 90 days after ICU discharge present a significant reduction both on physical and psychological dimensions of HRQoL measured with the 15D instrument., Trial Registration: NCT04411459., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The synergic combination of D-dimer (as proxy of thrombotic/vascular injury) and static compliance (as proxy of parenchymal injury) in predicting mortality in COVID-19-ARDS has not been systematically evaluated. The objective is to determine whether the combination of elevated D-dimer and low static compliance can predict mortality in patients with COVID-19-ARDS. A "training sample" (March-June 2020) and a "testing sample" (September 2020-January 2021) of adult patients invasively ventilated for COVID-19-ARDS were collected in nine hospitals. D-dimer and compliance in the first 24 h were recorded. Study outcome was all-cause mortality at 28-days. Cut-offs for D-dimer and compliance were identified by receiver operating characteristic curve analysis. Mutually exclusive groups were selected using classification tree analysis with chi-square automatic interaction detection. Time to death in the resulting groups was estimated with Cox regression adjusted for SOFA, sex, age, PaO 2 /FiO 2 ratio, and sample (training/testing). "Training" and "testing" samples amounted to 347 and 296 patients, respectively. Three groups were identified: D-dimer ≤ 1880 ng/mL (LD); D-dimer > 1880 ng/mL and compliance > 41 mL/cmH 2 O (LD-HC); D-dimer > 1880 ng/mL and compliance ≤ 41 mL/cmH 2 O (HD-LC). 28-days mortality progressively increased in the three groups (from 24% to 35% and 57% (training) and from 27% to 39% and 60% (testing), respectively; p < 0.01). Adjusted mortality was significantly higher in HD-LC group compared with LD (HR = 0.479, p < 0.001) and HD-HC (HR = 0.542, p < 0.01); no difference was found between LD and HD-HC. In conclusion, combination of high D-dimer and low static compliance identifies a clinical phenotype with high mortality in COVID-19-ARDS.

Background: Few small studies have described hospital-acquired infections (HAIs) occurring in patients with COVID-19., Research Question: What characteristics in critically ill patients with COVID-19 are associated with HAIs and how are HAIs associated with outcomes in these patients?, Study Design and Methods: Multicenter retrospective analysis of prospectively collected data including adult patients with severe COVID-19 admitted to eight Italian hub hospitals from February 20, 2020, through May 20, 2020. Descriptive statistics and univariate and multivariate Weibull regression models were used to assess incidence, microbial cause, resistance patterns, risk factors (ie, demographics, comorbidities, exposure to medication), and impact on outcomes (ie, ICU discharge, length of ICU and hospital stays, and duration of mechanical ventilation) of microbiologically confirmed HAIs., Results: Of the 774 included patients, 359 patients (46%) demonstrated 759 HAIs (44.7 infections/1,000 ICU patient-days; 35% multidrug-resistant [MDR] bacteria). Ventilator-associated pneumonia (VAP; n = 389 [50%]), bloodstream infections (BSIs; n = 183 [34%]), and catheter-related BSIs (n = 74 [10%]) were the most frequent HAIs, with 26.0 (95% CI, 23.6-28.8) VAPs per 1,000 intubation-days, 11.7 (95% CI, 10.1-13.5) BSIs per 1,000 ICU patient-days, and 4.7 (95% CI, 3.8-5.9) catheter-related BSIs per 1,000 ICU patient-days. Gram-negative bacteria (especially Enterobacterales) and Staphylococcus aureus caused 64% and 28% of cases of VAP, respectively. Variables independently associated with infection were age, positive end expiratory pressure, and treatment with broad-spectrum antibiotics at admission. Two hundred thirty-four patients (30%) died in the ICU (15.3 deaths/1,000 ICU patient-days). Patients with HAIs complicated by septic shock showed an almost doubled mortality rate (52% vs 29%), whereas noncomplicated infections did not affect mortality. HAIs prolonged mechanical ventilation (median, 24 days [interquartile range (IQR), 14-39 days] vs 9 days [IQR, 5-13 days]; P < .001), ICU stay (24 days [IQR, 16-41 days] vs 9 days [IQR, 6-14 days]; P = .003), and hospital stay (42 days [IQR, 25-59 days] vs 23 days [IQR, 13-34 days]; P < .001)., Interpretation: Critically ill patients with COVID-19 are at high risk for HAIs, especially VAPs and BSIs resulting from MDR organisms. HAIs prolong mechanical ventilation and hospitalization, and HAIs complicated by septic shock almost double mortality., Trial Registry: ClinicalTrials.gov; No.: NCT04388670; URL: www.clinicaltrials.gov., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

During the COVID-19 pandemic, a shortage of mechanical ventilators was reported and ventilator sharing between patients was proposed as an ultimate solution. Two lung simulators were ventilated by one anesthesia machine connected through two respiratory circuits and T-pieces. Five different combinations of compliances (30-50 mL × cmH 2 O -1 ) and resistances (5-20 cmH 2 O × L -1 × s -1 ) were tested. The ventilation setting was: pressure-controlled ventilation, positive end-expiratory pressure 15 cmH 2 O, inspiratory pressure 10 cmH 2 O, respiratory rate 20 bpm. Pressures and flows from all the circuit sections have been recorded and analyzed. Simulated patients with equal compliance and resistance received similar ventilation. Compliance reduction from 50 to 30 mL × cmH 2 O -1 decreased the tidal volume (V T ) by 32% (418 ± 49 vs. 285 ± 17 mL). The resistance increase from 5 to 20 cmH 2 O × L -1 × s -1 decreased V T by 22% (425 ± 69 vs. 331 ± 51 mL). The maximal alveolar pressure was lower at higher compliance and resistance values and decreased linearly with the time constant (r² = 0.80, p < 0.001). The minimum alveolar pressure ranged from 15.5 ± 0.04 to 16.57 ± 0.04 cmH 2 O. Cross-flows between the simulated patients have been recorded in all the tested combinations, during both the inspiratory and expiratory phases. The simultaneous ventilation of two patients with one ventilator may be unable to match individual patient's needs and has a high risk of cross-interference.

COVID-19 infection may predispose to secondary bacterial infection which is associated with poor clinical outcome especially among critically ill patients. We aimed to characterize the lower respiratory tract bacterial microbiome of COVID-19 critically ill patients in comparison to COVID-19-negative patients. We performed a 16S rRNA profiling on bronchoalveolar lavage (BAL) samples collected between April and May 2020 from 24 COVID-19 critically ill subjects and 24 patients with non-COVID-19 pneumonia. Lung microbiome of critically ill patients with COVID-19 was characterized by a different bacterial diversity (PERMANOVA on weighted and unweighted UniFrac Pr(> F) = 0.001) compared to COVID-19-negative patients with pneumonia. Pseudomonas alcaligenes, Clostridium hiranonis, Acinetobacter schindleri, Sphingobacterium spp., Acinetobacter spp. and Enterobacteriaceae, characterized lung microbiome of COVID-19 critically ill patients (LDA score > 2), while COVID-19-negative patients showed a higher abundance of lung commensal bacteria (Haemophilus influenzae, Veillonella dispar, Granulicatella spp., Porphyromonas spp., and Streptococcus spp.). The incidence rate (IR) of infections during COVID-19 pandemic showed a significant increase of carbapenem-resistant Acinetobacter baumannii (CR-Ab) infection. In conclusion, SARS-CoV-2 infection and antibiotic pressure may predispose critically ill patients to bacterial superinfection due to opportunistic multidrug resistant pathogens.

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.