PURPOSE: Secondary brain injury is a common cause of poor outcome after trauma, subarachnoid hemorrhage, and intracerebral hemorrhage, and optimizing treatment requires real-time insight into cerebral metabolism. Cerebra...PURPOSE: Secondary brain injury is a common cause of poor outcome after trauma, subarachnoid hemorrhage, and intracerebral hemorrhage, and optimizing treatment requires real-time insight into cerebral metabolism. Cerebral microdialysis (CMD) uniquely provides key related information, yet consensus on its use has not been updated since publication of the consensus statement from the 2014 International Microdialysis Forum. We aimed to assess expert consensus on the use of CMD in critical care and provide contemporary guidance to standardize practice and advance clinical implementation. METHODS: We conducted a 3-round modified Delphi study with international experts in CMD and neurocritical care. Consensus was defined as ≥ 75% agreement among non-abstaining respondents, with a minimum of 30 non-abstaining respondents required per statement. Statements not reaching consensus were iteratively revised based on panelist feedback. RESULTS: Forty of 67 invited experts (60%) from 9 countries participated. Sixty of 62 individual items achieved consensus (97%) across 9 domains: indications and patient selection, technical and procedural considerations, detecting deterioration and secondary injury, metabolic interpretation, treatment algorithms, glucose management, sampling frequency, core reporting items, and barriers to clinical implementation. CONCLUSION: This consensus statement provides updated, evidence-informed recommendations for the use of CMD in critical care. The panel reaffirmed many core recommendations from the 2014 consensus while making targeted advances: cautious extension of guidance to intracerebral hemorrhage, comprehensive reporting guidance addressing frequently omitted elements (19 items vs. 6 in 2014), and identification of 10 key barriers to routine clinical adoption.
Ughetto A, Schrage B, Vandenbriele C
… +21 more, Cherbi M, Beurton A, Fürholz M, Kuliczkowski W, Bonello L, Leurent G, Hurtado A, Gaudard P, Sundermeyer J, Hunziker L, Ouattara A, Tycinska A, Kociecka MZ, Pichené H, Lemarchand L, Jacomet M, Blaziak M, Klotzka A, Mansour A, Delmas C, IMPACT Investigators
BACKGROUND: Bleeding and thrombosis are major complications of micro-axial flow pump (mAFP) support in cardiogenic shock (CS), yet contemporary data on their incidence, temporal trends, and prognostic impact remain uncle...BACKGROUND: Bleeding and thrombosis are major complications of micro-axial flow pump (mAFP) support in cardiogenic shock (CS), yet contemporary data on their incidence, temporal trends, and prognostic impact remain unclear. METHODS: We retrospectively analyzed patients supported with mAFP between 2010 and 2023 across eleven high-volume European centers. Bleeding and thrombotic events during support were adjudicated and normalized to annual implant volumes. Kaplan–Meier analysis assessed 180-day survival, and multivariable logistic regression identified independent predictors of bleeding and thrombosis. RESULTS: Among 1,043 patients (61% acute myocardial infarction related CS), Impella CP was used in 72% and Impella 5 in 28%. Overall, 503 patients (48%) experienced ≥ 1 event: 252 bleeding only, 149 thrombosis only, and 102 both. Independent predictors of bleeding were post-cardiotomy CS (OR 2.64; 95% CI, 1.41–4.96; p = .003), Acute myocardial infarction related CS (AMICS) (OR 2.27; 95% CI, 1.38–3.74; p = .001), V-A ECMO unloading indication (OR 1.65; 95% CI, 1.14–2.39; p = .008) and renal replacement therapy at implantation (OR 1.56; 95% CI, 1.08–2.27; P = .019). Predictors of thrombosis were prior stroke (OR 2.51; 95% CI 1.40–4.51), AMI-CS (OR 2.06; 95% CI 1.42–3.00), and mAFP unloading with V-A ECMO (OR 2.03; 95% CI 1.38–2.98). Bleeding (OR 1.38; 95% CI 1.02–1.87) and thrombosis (OR 2.10; 95% CI 1.53–2.88) were independently associated with higher 180-day mortality. CONCLUSIONS: In this large European mAFP cohort, bleeding and thrombotic events were frequent and associated with mortality and adverse outcomes. Their distinct risk profiles support individualized prevention strategies and underscore the need for prospective randomized trials comparing anticoagulation regimens in risk-stratified patients.
Zhang X, Chen Y, Liu R
… +41 more, Fang W, Qin B, Jiang R, Gao Y, Li W, Wu J, Zhao M, Yang Y, Ma X, Du B, Liu J, Song X, Zhang D, Gao X, Jin X, Liu J, Liu F, Liu L, Li J, Ma S, Peng Z, Sun Y, Shi S, Shen F, Shao H, Qin T, Wan X, Wang J, Wang H, Wu W, Wu H, Xu F, Xiong B, Yu X, Yang X, Zhang L, Zhao H, Zhang L, Guan X, Kang Y, Chen D
BACKGROUND: Critical care medicine plays a pivotal role in addressing life-threatening conditions; however, its development in China is hindered by resource scarcity and inequitable distribution. Existing studies have mo...BACKGROUND: Critical care medicine plays a pivotal role in addressing life-threatening conditions; however, its development in China is hindered by resource scarcity and inequitable distribution. Existing studies have mostly focused on ICU bed numbers or selected regions, and have rarely provided a comprehensive, nationwide assessment of ICU beds, staffing and equipment using standardized methods, nor have they systematically quantified population-based equity of ICU resources. To address this evidence gap and describe the current landscape of critical care capacity in China, we conducted a nationwide survey of critical care resources. The survey aimed to describe the current status of resources, quantify population-based equity, and explore regional and hierarchical disparities that may affect access to critical care. METHODS: This cross-sectional survey was conducted from January 1, 2021, to December 31, 2023, encompassing public comprehensive hospitals, private hospitals, and specialty hospitals across 31 provinces (including municipalities) in China. A total of 4,744 hospitals with a comprehensive ICU provided valid responses and were included in the analysis; the overall response rate among eligible hospitals invited through provincial health authorities was approximately 89.80%. The study focused on institutions with comprehensive intensive care units (ICUs). Hospitals were stratified by level, including tertiary A and B, secondary A and B, and county-level hospitals. Data were collected using the “Critical Care Medicine Resource Survey Form” via Wenjuanxing, an online survey platform. The survey evaluated spatial distribution (bed count and density), equipment availability (ventilators, ECMO, and CRRT), and human resources (staffing and qualification disparities). Responses were analyzed to identify regional and hierarchical variations in resource allocation and utilization. FINDINGS: Among the 4,744 hospitals, there were 83,632 operational ICU beds, corresponding to a national average of 5.95 ICU beds per 100,000 population. The total ICU workforce comprised 46,137 physicians (a physician-to-bed ratio of 0.55:1) and 134,056 nurses (a nurse-to-bed ratio of 1.60:1). Key equipment included 74,842 invasive ventilators, 13,389 non-invasive ventilators, 2,328 ECMO devices and 12,346 CRRT machines. ICU bed density varied from 2.29 to 10.53 beds per 100,000 population across provinces. The Gini coefficients for ICU beds, physicians and nurses allocated by population were all < 0.2, and there were no statistically significant differences in ICU beds or physician numbers per 100,000 population across provincial GDP or GDP per capita tiers. From 2015 to 2023, ICU beds increased by 80.0%, physicians by 73.4%, nurses by 61.5%, and ECMO devices by 512.8%. Although population-based distribution appeared relatively equitable, regions differed in absolute bed density, staffing ratios and geographic accessibility, and advanced technologies such as ECMO were available in 29.2% of hospitals. INTERPRETATION: Despite remarkable progress and optimization in ICU resource expansion, substantial gaps remain in China compared to developed countries, particularly regarding ICU bed densities and staffing ratios. Our analysis indicates relatively equitable distribution of ICU beds, physicians and nurses across provinces when assessed on a per population basis, as reflected by low Gini coefficients, but this population-based equity does not account for differences in disease burden, age structure, urban-rural composition or geographic accessibility. Accordingly, population-based equity of resources does not necessarily imply equity of access or adequacy of care. Moreover, this survey focused on resource quantity and did not assess perceived adequacy, organizational models or clinical outcomes, so no direct conclusions can be drawn about quality of care.These findings suggest that efforts to strengthen critical care in China should focus on improving resource density and staffing in underserved regions, enhancing accessibility in geographically vast areas, and promoting efficient use and regional sharing of advanced technologies such as ECMO through organized referral networks.
Despite significant advancements in the understanding of pulmonary vascular permeability and the preclinical development of compounds targeting pulmonary vascular permeability, their translation into clinical therapies f...Despite significant advancements in the understanding of pulmonary vascular permeability and the preclinical development of compounds targeting pulmonary vascular permeability, their translation into clinical therapies for acute respiratory distress syndrome (ARDS) has remained unsuccessful. Among others, this translational gap can be attributed to limitations in measuring pulmonary vascular permeability in the clinical setting. This review aims to evaluate current and near-future modalities for quantifying pulmonary edema and their potential application in research settings. We first outline the definition of ARDS and the pathophysiology of pulmonary edema, focusing on pulmonary vascular mechanisms and therapeutic targets to reducing vascular leakage. Next, we examine techniques for assessing pulmonary edema, including gravimetry (the preclinical gold standard), transpulmonary thermodilution (the clinical gold standard), as well as newer modalities such as lung ultrasound and chest CT. Finally, we discuss how pulmonary edema measurements may serve as meaningful endpoints in early-phase clinical trials. The use of pulmonary edema as a primary endpoint in clinical trials may carry significant advantages, including more direct parameters for translation of pre-clinical studies on vascular leakage into clinical application, and possibly a higher success rate for transition to large phase III trials. Amidst the era of personalized medicine, the quantification of pulmonary edema holds promise in guiding clinical pharmacological trials for ARDS.
BACKGROUND: Percutaneous veno-arterial extracorporeal membrane oxygenation (VA-ECMO) implantation reduces infectious complications compared with surgical cannulation. However, arterial decannulation using manual compress...BACKGROUND: Percutaneous veno-arterial extracorporeal membrane oxygenation (VA-ECMO) implantation reduces infectious complications compared with surgical cannulation. However, arterial decannulation using manual compression remains associated with bleeding, vascular injury, and infection. We evaluated a fully percutaneous decannulation strategy (FP-D) combining MANTA® and Femoseal® devices. METHODS: All patients undergoing FP-D between October 2020 and May 2022 in our institution were included. Outcomes were compared with a historical cohort decannulated using manual compression (MC). The primary endpoint was surgical revision after decannulation. Secondary endpoints included major bleeding, transfusion, vascular complications, infection, and 30-day survival. A propensity score weighting approach was performed to adjust for baseline differences. RESULTS: Among 497 patients treated with percutaneous VA-ECMO, 250 underwent FP-D and 247 MC. After propensity score, FP-D significantly reduced surgical revision (3.9% vs. 7.2%; RR 0.55, 95% CI 0.32–0.94; p = 0.0311), infection requiring surgery (3.7% vs. 8.4%; RR 0.44, 95% CI 0.25–0.77; p = 0.004), and major bleeding (1.4% vs. 11%; RR 0.13, 95% CI 0.06–0.30; p < 0.0001), with lower transfusion requirements (7.1% vs. 45.7%; RR 0.16, 95% CI 0.11–0.22; p < 0.0001). Thirty-day death was comparable between groups (8,2% vs. 5,57%; p = 0.1316). Systematic CT scans revealed frequent but mostly silent arterial lesions after FP-D. CONCLUSION: FP-D markedly reduced bleeding, transfusion, infection, and surgical revision compared with manual compression, while preserving short-term survival. Systematic imaging identified frequent subclinical vascular lesions, supporting targeted surveillance and endovascular management when appropriate.
Iwasaki Y, Kinoshita T, Yoshimura J
… +18 more, Maruyama S, Ohshimo S, Murao S, Watanabe M, Uchida K, Igarashi Y, Nishimoto Y, Katayama S, Kurosawa H, Inoue Y, Kodate A, Iyama K, Inoue S, Kaneda K, Ito Y, Kobayashi H, Nakataki E, Shime N
BACKGROUND: The Sequential Organ Failure Assessment (SOFA)-2 score was developed to better reflect contemporary critical care practice by incorporating modern organ support modalities and updated thresholds based on rece...BACKGROUND: The Sequential Organ Failure Assessment (SOFA)-2 score was developed to better reflect contemporary critical care practice by incorporating modern organ support modalities and updated thresholds based on recent data. However, the generalizability of this framework to intensive care unit (ICU) populations beyond the development cohort, particularly across organ support subgroups and major disease categories, remains uncertain. We aimed to evaluate the external validity of SOFA-2 using the OneICU database, a large Japanese critical care database with comprehensive domain-level data. METHODS: Adult ICU stays between February 2013 and August 2025 were included and classified into two cohorts: those with complete SOFA-1 and SOFA-2 component data on the day of ICU admission, and those with complete SOFA-2 data on that day. Discriminatory performance for ICU mortality was evaluated using the area under the receiver operating characteristic curve (AUROC) and compared between SOFA-1 and SOFA-2 using the DeLong test. Subgroup analyses were performed by major organ support device use and across disease categories. RESULTS: Among 152,883 eligible ICU stays, 67,116 had complete SOFA-1 and SOFA-2 data, and 121,443 had complete SOFA-2 data. SOFA-2 showed a slightly higher AUROC for ICU mortality than SOFA-1 (0.859 vs. 0.853; p < 0.001), although the absolute difference was small. Across subgroups defined by mechanical circulatory support use, SOFA-2 showed higher discrimination than SOFA-1. Discrimination was similar in other device-defined subgroups and in patients readmitted to the ICU. SOFA-2 also demonstrated good discrimination across major diagnostic groups. CONCLUSIONS: SOFA-2 showed similar discrimination for ICU mortality compared with SOFA-1 and maintained broadly comparable performance across clinically relevant subgroups, supporting its applicability for early severity assessment in heterogeneous ICU populations.
BACKGROUND: Intensive care medicine has increasingly embraced shared decision-making and advance care planning as core components of good clinical practice. Nonetheless, clinical reasoning is sometimes implicitly framed...BACKGROUND: Intensive care medicine has increasingly embraced shared decision-making and advance care planning as core components of good clinical practice. Nonetheless, clinical reasoning is sometimes implicitly framed as a linear, biologically driven process. In contexts of prognostic uncertainty, this framing risks obscuring a structural feature of decision-making: the constitutive role of value-based judgments in shaping prognosis and outcomes. MAIN BODY: This paper introduces the concept of conditional outcomes to clarify a structural feature of certain clinical situations, in which survival or death does not follow from biology alone but is co-determined within the range of biologically possible trajectories by value-based choices made by patients, families, and clinicians regarding whether and how to intervene. Using the case of Mrs. Elizabeth, a woman with advanced amyotrophic lateral sclerosis, we show how an identical clinical state may be framed as either terminal or amenable to escalation, not because it is assessed differently, but because values and goals are interpreted and enacted differently. Even when shared decision-making is practiced, the way value judgments shape prognostic determinations often remains implicit. Making these assumptions explicit complements shared decision-making and advance care planning, clarifying how clinical outcomes are logically dependent on prior value-based commitments that shape judgments about benefit, burden, and the goals of care. CONCLUSIONS: Making the conditional structure of outcomes explicit clarifies that value-based judgments are not ancillary to prognosis but structurally shape prognostic determinations and subsequent outcomes. Recognizing the conditional nature of prognostication strengthens clinical reasoning by integrating biological knowledge with ethical commitments in end-of-life care.
BACKGROUND: Large-scale combat operations (LSCO) pose unique logistical and clinical challenges to haemorrhagic casualty management. The existing French military transfusion doctrine, originally designed for low-intensit...BACKGROUND: Large-scale combat operations (LSCO) pose unique logistical and clinical challenges to haemorrhagic casualty management. The existing French military transfusion doctrine, originally designed for low-intensity conflicts (LIC), does not meet the demands of LSCO. This work aimed to develop a revised, consensus-based transfusion doctrine integrating operational, medical, and safety requirements for LSCO environments. METHODS: At the request of the Central Directorate of the Military Health Service, a Delphi-based consensus process was conducted between November 2024 and April 2025. Eight senior military physicians—anaesthesiologist-intensivists, emergency and operational clinicians, and medical biologists with over five years of specialty experience—reviewed eleven thematic domains identified for revision. Drafts, developed from doctrinal texts, operational feedback, and international literature (including systematic reviews), were iteratively refined through three Delphi cycles until full consensus (100%) was reached. This consensus reflects expert doctrinal guidance for LSCO operational preparedness under limited/heterogeneous evidence rather than proof of clinical efficacy. The resulting doctrine was compared with the previous LIC framework and international LSCO transfusion strategies. RESULTS: The new doctrine establishes a scalable, safety-focused system integrating forward whole-blood resuscitation, enhanced logistical autonomy, and reinforced haemovigilance. Cold-stored whole blood will be prioritised as the primary resuscitation product for Roles 1 and 2, while Role 3 will employ component therapy. A new dedicated operational medical unit will oversee in-theatre collection, testing, and distribution. Forward transfusion by trained nurses using universal blood products under predefined criteria will be authorised, with strict traceability and targeted training ensuring transfusion safety in LSCO. CONCLUSIONS: This consensus defines the modern French transfusion doctrine for LSCO, combining operational flexibility with rigorous safety oversight and alignment with international standards.
Haitsma Mulier JLG, van Leer B, Beijer-Verduin JJ
… +12 more, de Grooth HS, Lavalaye J, Noordzij PG, Pater N, Pool SE, Rettig TCD, van Stee CP, Pillay J, Balink H, Cremer OL, Braat AJAT, Derde LPG
BACKGROUND: [18F]-fluorodeoxyglucose Positron Emission Tomography combined with Computed Tomography ([18F]FDG PET/CT) is widely used to detect focal inflammation. However, its diagnostic performance and utility in the IC...BACKGROUND: [18F]-fluorodeoxyglucose Positron Emission Tomography combined with Computed Tomography ([18F]FDG PET/CT) is widely used to detect focal inflammation. However, its diagnostic performance and utility in the ICU remain unclear. We aimed to identify factors influencing diagnostic yield and scan quality of [18F]FDG PET/CT in critically ill patients suspected of infection or inflammation. METHODS: We retrospectively evaluated [18F]FDG PET/CT scans performed in adult ICU patients across four Dutch hospitals (2013–2023). The primary endpoint was diagnostic yield: new conclusive diagnoses and/or therapy changes within 72 h. Secondary endpoints were scan quality and adequacy of myocardial suppression. Logistic regression was used to identify determinants of each endpoint. RESULTS: We analyzed 169 scans for 162 clinical indications in 151 patients. A conclusive diagnosis was established for 109 indications (67%), including 79 new diagnoses (49%), most frequently involving the musculoskeletal system (n = 39; 24%) and the respiratory tract (n = 31; 19%). [18F]FDG PET/CT prompted a therapy change in 70 indications (43%). Diabetes (aOR 0.35 [95% CI: 0.15–0.80]) and partial-body imaging versus total-body imaging (aOR 0.48 [CI 0.24–0.99]) were associated with fewer new diagnoses. A longer pre-scan ICU stay predicted therapy change (aOR 1.03 [1.01–1.05]). Higher BMI (aOR 1.08 [1.00–1.17]) and lower serum creatinine (log-transformed aOR 0.36 [0.20–0.68]) were associated with improved scan quality. Male sex (aOR 0.45 [0.21–0.96]) and pre-scan unfractionated heparin (aOR 0.43 [0.19–0.98]) were associated with suboptimal myocardial suppression. CONCLUSIONS: [18F]FDG PET/CT has a high diagnostic yield in critically ill patients. Diagnostic yield, scan quality and myocardial suppression are influenced by patient characteristics and preparation. Optimizing these factors may further enhance its utility in the ICU.
Scaglione G, Colaneri M, Offer M
… +11 more, Montrucchio G, Genovese C, Viaggi B, Dore F, Tricella G, Dalfino L, Monti G, Gori A, Palomba E, Finazzi S, Italian Group for Evaluation of Interventions in Intensive Care Medicine
UNLABELLED: This multicenter study focuses on the latest (2020-2024) trends in candidemia in 155 Italian ICUs, stressing its frequency and lethality, with a shift toward non-albicans, fluconazole-resistant species, namel...UNLABELLED: This multicenter study focuses on the latest (2020-2024) trends in candidemia in 155 Italian ICUs, stressing its frequency and lethality, with a shift toward non-albicans, fluconazole-resistant species, namely C. parapsilosis. In this study, resistance to fluconazole prolonged ICU stays without increasing mortality, while non-catheter-related episodes had a more severe prognosis. RATIONALE: Candidemia is the leading fungal bloodstream infection (BSI) in the ICU and carries high mortality. After the COVID-19 pandemic, non-albicans, fluconazole-resistant species increased in Europe, yet contemporary ICU-acquired data are scarce. The primary outcome of this study was to evaluate the incidence of ICU-acquired candidemia per 1,000 "at risk" ICU admissions (ICU length of stay [LOS] ≥ 48 h). Secondary analyses compared ICU-acquired candidemia with ICU-acquired bacterial BSI and assessed species distribution, fluconazole susceptibility, and outcomes by fluconazole resistance and by source of infection. METHODS: Data were drawn from the PROSAFE network, a prospective multicentric observational project conducted across 192 Italian ICUs (2014-2023). RESULTS: Among 179,590 ICU admissions, 95,662 were at risk. ICU-acquired candidemia occurred in 373 patients (3.9‰ of at-risk admissions). Compared with ICU-acquired bacterial BSI, candidemia patients had longer intra-ICU and hospital LOS (32 vs 24 days and 44 vs 36 days, respectively; p < 0.001) and higher mortality (intra-ICU 41.3% vs 28.7%; intra-hospital 50.3% vs 34.1%; p < 0.001). Candida albicans was isolated in 47.2% of episodes, followed by Candida parapsilosis at 33.0%; the latter is often fluconazole-resistant (53.7%). Mortality did not increase in fluconazole-resistant episodes, but ICU LOS did (36 vs 31 days; p = 0.016). Non-catheter-related infections (197/373, 52.8%) had higher intra-hospital mortality rates (57.0% vs 42.9%; p = 0.007). CONCLUSIONS: ICU-acquired candidemia in Italy remains frequent and lethal, with a worrisome shift in epidemiology and resistance; the latter prolongs ICU stay without increasing mortality. Non-catheter-related episodes had a poorer prognosis. Findings support enhanced surveillance, catheter care, and earlier antifungal therapy.
BACKGROUND: Nasal antimicrobial photodynamic therapy (aPDT) is a non-antibiotic decolonization strategy with potential to reduce ICU-acquired infections without contributing to antimicrobial resistance. We conducted a fe...BACKGROUND: Nasal antimicrobial photodynamic therapy (aPDT) is a non-antibiotic decolonization strategy with potential to reduce ICU-acquired infections without contributing to antimicrobial resistance. We conducted a feasibility pilot to evaluate implementation of intranasal aPDT in critically ill adults and to generate preliminary estimates of microbiologic and clinical outcomes to inform a future definitive trial. DESIGN: Prospective, single-center, non-randomized feasibility pilot study with sequential control and intervention phases. SETTING: Adult mixed medical–surgical intensive care units at a tertiary academic hospital. PATIENTS: Adults ≥ 19 years with an expected ICU stay > 48 h. INTERVENTION: During the intervention phase, patients received intranasal aPDT every 48 h until ICU discharge. Control-phase patients received standard ICU care without nasal decolonization. Nasal swabs were obtained at ICU admission and every four days. MAIN FEASIBILITY OUTCOMES: Recruitment rate, protocol adherence, safety, data completeness, and ability to adjudicate pneumonia events using blinded, rule-based criteria aligned with CDC/NHSN definitions. RESULTS: A total of 227 patients were analyzed (126 control, 101 intervention). Recruitment targets were met. Adherence to scheduled nasal swab collection was 97.7%. During the intervention phase, 57.8% of scheduled aPDT treatments were delivered in full and 12.0% partially delivered. No intervention-related serious adverse events were observed. Pneumonia adjudication was completed with high inter-system concordance and minimal missing data, supporting adequacy of data capture tools. Exploratory analyses demonstrated significantly lower early cumulative nasal pathogen burden in the intervention group (p < 0.01). The incidence of adjudicated VAP/HAP was 9.0 per 1,000 ICU patient-days during the intervention phase compared with 14.9 per 1,000 ICU patient-days during the control phase (incidence rate ratio 0.61, 95% CI 0.31–1.17, a difference that was not statistically significant). A hierarchical composite endpoint incorporating pneumonia, microbiologic clearance, and cumulative pathogen burden yielded a win ratio of 1.29 (95% CI 0.74–2.31) favoring treatment. CONCLUSIONS: Implementation of nasal aPDT in the ICU was feasible and safe, with high sampling adherence and successful blinded adjudication. Exploratory signals of reduced pathogen burden and lower though not statistically significant, pneumonia incidence provide preliminary support for progression to a multicenter randomized trial powered for clinical endpoints. TRIAL REGISTRATION: NCT06867458 clinicaltrials.gov, Registration date March 6, 2025.