BACKGROUND:Blood lactate is a key biomarker of tissue hypoperfusion and metabolic distress, reflecting the balance between oxygen delivery and cellular metabolism. Early identification of rising lactate levels is critical for timely intervention in critically ill patients, yet existing predictive tools are static and limited to specific ICU subgroups. METHODS:We developed and externally validated two machine-learning models that provide hourly, real-time predictions of hyperlactatemia (lactate >2 mmol/L) within 6- and 12-hour horizons in general ICU populations. This retrospective, multi-cohort study used AmsterdamUMCdb and MIMIC-III for model development and internal validation, and eICU and HiRID for external validation. Adult ICU stays lasting ≥24 hours with lactate measurements ≤12 hours apart were included. Models based on routinely collected vital signs and laboratory data were trained using XGBoost and assessed for discrimination, calibration, decision-curve utility, and subgroup fairness. RESULTS:The development dataset included 13,573 ICU stays and 577,414 hourly samples. The 6-hour model achieved AUROC/AUPR of 0.87/0.384 (AmsterdamUMCdb) and 0.814/0.401 (MIMIC-III) internally, and 0.772/0.295 (eICU) and 0.823/0.246 (HiRID) externally. The 12-hour model showed consistent performance (AUROC ≥0.76 across all cohorts). Calibration and decision-curve analyses confirmed robust generalization and net clinical benefit without recalibration. CONCLUSIONS:These validated, continuously operating models enable real-time, near-future lactate risk assessment throughout the ICU stay, supporting earlier recognition of tissue hypoperfusion and metabolic shock in unselected critically ill populations.

Background Lung transplantation (LUTX) is frequently complicated by Primary Graft Dysfunction (PGD), a heterogeneous form of acute lung injury associated with multi-organ failure and rejection. We hypothesized that early, bedside plasma biomarkers could capture this biological heterogeneity, identifying phenotypes with differential clinical outcomes. Methods This two-year prospective single-center observational study enrolled 78 bilateral LUTX recipients. With a real-time point-of-care immunoanalyzer we measured IL-1β, IL-2, IL-6, IFN-γ, TNF, CCL-2, IL-15, Ferritin, and D-dimer 36 hours post-reperfusion. Outcome-agnostic Latent Profile Analysis (LPA) was applied to identify bio-signatures. PGD (grade 3) incidence and clinical outcomes were compared across classes. Results LPA identified three distinct classes, interpreted as biological sub-phenotypes. The Adaptive phenotype (68%) had the lowest inflammatory activation, shortest vasoactive support and Invasive Mechanical Ventilation (IMV) (both 1 day) and ICU stay (3 days), and lowest 72-hours PGD (8%) and Acute Kidney Injury (AKI) (28%) rates. The Hyperinflammatory phenotype (18%) showed the highest IL-6 and Ferritin levels with resolving PGD (69% to 23%, from 6 to 72 hours), but prolonged IMV (6 days), vasoactive support (3 days), ICU stay (7 days), with a high AKI rate (69%). The Coagulopathic phenotype (15%), requiring more intraoperative blood products, exhibited the highest TNF and D-dimer with persistent PGD (36% at 24 and 72 hours), intermediate vasoactive support (2 days), and AKI severity. Six-month rejection-free survival was similar across phenotypes. Conclusions This preliminary hypothesis-generating study suggests that point-of-care biomarkers after LUTX may identify biological phenotypes with potential clinical relevance. Future studies are needed to confirm such phenotyping. ### Competing Interest Statement Vittorio Scaravilli has received congress support from Biomerieux Italia S.p.a. (Bagno di Ripoli, Firenze, Italy) and Randox (Crumlin, UK) and serves as scientific consultant for U-Care Medical S.r.l. (Turin, Italy). Sebastiano Maria Colombo Vago has received congress support from AOP Health (Pisa, Italy). Valentina Vago has received congress support from Biomerieux (Bagno di Ripoli, Firenze, Italy). Francesco Blasi reports receipts of grants from AstraZeneca, GSK and Insmed; personal consulting fees from Menarini; personal fees for lectures, presentations, speakers bureaus, or educational events from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Grifols, Insmed, Menarini, OM Pharma, Pfizer, Vertex, and Zambon, outside the submitted work. Lieuwe Bos has received research grants from Santhera (Liestal, Switzerland) and ZonMW VIDI (The Hague, Netherlands); served on advisory boards for Sobi (Stockholm, Sweden), Exvastat (Cambridge, UK), Pfizer (New York, NY, USA), and AstraZeneca (Cambridge, UK); received consultancy fees from Santhera (Liestal, Switzerland); and served on the Data and Safety Monitoring Board for Aptarion (paid to institution). Giacomo Grasselli has received payments for scientific presentations from Drager Medical, Getinge, Fisher & Paykel, Mundipharma, and Cook Medical; participated in advisory board activities for GSK; and have received research grants from Fisher & Paykel and MSD. Margherita Brivio, Letizia Corinna Morlacchi, Leonardo Terranova, Margherita Carnevale-Schianca, Elena Trombetta, Lorenzo Rosso, Alberto Zanella, Mario Nosotti declare no conflict of interest. ### Funding Statement The study was (partially) supported by a Ricerca Corrente funds, Italian Ministry of Health, and Linea 2 Funds (G43C24002040001), Department of Biomedical, Surgical, and Dental Sciences ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This is a single-center, prospective, observational cohort study performed at an Italian tertiary referral center from June 1st, 2023, to June 30th, 2025, approved by the Regional Ethical Committee and registered on ClinicalTrials.gov (#[NCT06125535][1]). The study has been reviewed and approved by the Ethics Committee Milano Area 3. The initial approval was granted with opinion no. 1183\_2021, and subsequently amended and approved with opinion no. 881\_2022. All participants have provided written informed consent prior to enrollment in the study, in accordance with the approved ethical standards and relevant regulations. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT06125535&atom=%2Fmedrxiv%2Fearly%2F2025%2F12%2F01%2F2025.11.26.25340722.atom

BACKGROUND:Primary graft dysfunction (PGD) is a major cause of early morbidity and mortality after lung transplantation (LUTX), with limited early predictive markers. This study aimed to determine whether early postoperative bedside respiratory pathophysiology can predict severe PGD at 72 h. METHODS:In this prospective, single-center study, adult LUTX recipients underwent a decremental positive end-expiratory pressure (PEEP) trial (14, 10, 6 cm H 2 O) within 12 h after reperfusion. Gas exchange (venous admixture [Q s /Q T ], alveolar dead space), partitioned respiratory mechanics (respiratory system, chest wall, lung compliances-respiratory system compliance [Cpl RS ], chest wall compliance, lung compliance), and regional ventilation/perfusion ratio ( ) and collapse/overdistension ( via electrical impedance tomography) were assessed. Severe PGD was defined as Pa o2 /fraction of inspired oxygen ratio less than 200 mmHg at 72 h with bilateral infiltrates. RESULTS:Eight (17%) of 47 enrolled patients developed PGD. Compared to non-PGD patients, those with PGD exhibited significantly lower lung compliance (58 vs . 80 ml/cm H 2 O; P = 0.021) and Cpl RS (37 vs . 44 ml/cm H 2 O; P = 0.038), elevated Q s /Q T (21% vs . 5%; P < 0.001), higher alveolar dead space (15% vs . 12%; P = 0.010), and greater lung collapse ( P = 0.015). Non-PGD patients had more regions with high ( P = 0.036). In PGD, increasing PEEP reduced Q s /Q T (difference, -6.1%; 95% CI, -9.1 to -3.1; P = 0.001) and collapse (difference, -19.0%; 95% CI, -27.7 to -10.3; P = 0.002) without altering mechanics. In non-PGD, higher PEEP induced hyperinflation (difference 16.2%; 95% CI, 13.6 to 18.8; P < 0.001) and reduced Cpl RS (difference, -2.9 ml/cm H 2 O; 95% CI, -4.8 to -1.0; P = 0.008) and chest wall compliance (difference, -25.3 ml/cm H 2 O; 95% CI, -41.9 to -8.7; P = 0.024) while increasing physiologic dead space (difference, 2.9%; 95% CI, 1.2 to 4.6; P = 0.010). Q s /Q T showed the highest discriminative performance (area under the receiver operating characteristics curve, 0.92; 95% CI, 0.88 to 0.96) in predicting PGD development. CONCLUSIONS:Severe PGD is associated with early increases in venous admixture, reduced lung compliance, increased dead space, and patterns of collapse. These findings provide the rationale for studies exploring early pathophysiology-guided ventilatory management after LUTX.

Background Acute kidney injury (AKI) is common after lung transplantation (LUTX), with standard diagnostic criteria having limited early accuracy. We evaluated the AKI and postoperative outcomes risk-stratification performance of subclinical AKI and creatinine-independent kidney-injury phenotypes. Methods In this prospective single-center cohort including bilateral LUTX recipients, we measured urinary Tissue Inhibitor of Metalloproteinases-2 and Insulin-Like Growth Factor-Binding Protein 7 (u[TIMP-2]*[IGFBP-7]) and plasma Heart-Type Fatty Acid-Binding Protein (H-FABP), midkine, Soluble Tumor Necrosis Factor Receptor 1 (sTNFR1), and sTNFR2 at 6 and 36 hours after reperfusion, using point-of-care devices. AKI was defined by KDIGO criteria. Subclinical AKI was defined as u[TIMP-2]*[IGFBP-7]>0.3 without AKI criteria. Creatinine-independent phenotypes were identified with outcome-agnostic Latent Profile Analysis (LPA). Results Among 84 included patients, 30 (36%) developed AKI. u[TIMP-2]*[IGFBP-7] had modest AKI discrimination, with best AUROC 0.63 (95%CI 0.58-0.70) at 36 hours. Twenty-five patients had subclinical AKI, which had outcomes similar to those of patients without AKI. At 36 hours, plasma H-FABP, sTNFR1, and sTNFR2 were higher in patients with AKI. LPA identified 3 classes: low-risk (30%), intermediate-risk (51%), and high-risk (19%), with increasing rates of AKI (16%, 42%, 72%; p=0.006) and primary graft dysfunction grade 3 at 72 hours (4%, 13%, 35%; p=0.045). Compared with the low-risk class, the high-risk class had fewer organ support-free, ICU-free, and hospital-free days, and the lowest rejection-free survival. Conclusions After LUTX, u[TIMP-2]*[IGFBP-7] had limited risk-stratification performance, and subclinical AKI was not associated with a distinct clinical course. In contrast, plasma biomarker-derived risk phenotypes were associated with AKI severity and postoperative trajectory.

BACKGROUND:Ex vivo lung perfusion (EVLP) allows the evaluation of lungs that do not meet standard transplantation criteria. Current procedures do not permit the identification of regional functional deficits. We investigated the feasibility of assessing lobar gas exchange during EVLP in a swine model. METHODS:In five healthy swine, lungs were procured with beating heart and connected to an open-atrium EVLP circuit. Each pulmonary vein was cannulated for lobar perfusate sampling. After baseline assessment, the left inferior bronchus (LIB) and then the left superior bronchus (LSB) were temporarily clamped to simulate localized injury. At each step, perfusate gas analyses from each vein and the left atrium (LA), lung mechanics, pulmonary hemodynamics, and computed tomography (CT) were obtained. RESULTS:At baseline, no differences were observed between LA and lobar samples. Occlusion of LIB and LSB produced up to 95% non- or poorly aerated tissue in the affected lobe, with lobar shunt increasing to 97% [88%-103%] (LIB) and 97% [78%-106%] (LSB). Corresponding lobar PaO2/FiO2 fell to 47 [46-54] and 45 [43-67] mmHg, whereas LA-mixed venous blood maintained higher values (299 [188-373] and 349 [347-377] mmHg, respectively). Bronchial occlusions caused overall significant worsening of lung function, including increased pulmonary vascular resistance, and reduction in total air lung volume and normally aerated tissue on CT scan analysis. In Left Inferior Lobe (LIL), histological samples showed significant interstitial congestion and alveolar hemorrhage. CONCLUSIONS:Lobar-specific perfusate gas analysis during EVLP provides accurate functional assessment and enables the localization of lung injury, potentially improving graft evaluation before transplantation.

Long-term sequelae associated with COVID-19 are currently poorly defined, specifically in patients who have been discharged from intensive care units. We hypothesized that functional and pulmonary capacity, as well as mental health and cognitive function, would remain outside the normal range for up to 12 months after ICU discharge. Methods This is an international multicenter, prospective follow-up study of patients admitted to ICU due to COVID-19 (1). At 3, 6 and 12 months after ICU discharge, the following assessments were done: 6-minute walking test, Barthel Index Score (BIS), WHODAS score, spirometry, lung diffusion capacity for carbon monoxide (DLCO), Hospital Anxiety and Depression Scale (HADS), Patient Health Questionnaire-9 (PHQ-9) and the Montreal Cognitive Assessment (MoCA). Normalized test results at any follow-up assessment were not repeated at subsequent visits. Results 354 patients from 9 sites in 6 countries (Ireland, Spain, Italy, USA, Singapore, Colombia) admitted to ICU from January 2021 to December 2022 for COVID-19 were included. Median (IQR) age was 60 years (SD 13.3y), 32.5% were females, and 22 patients (6.2%) died during follow-up. The 6-min walking test was outside a normal range in 97.7%, 98% and 99.1% of the patients at 3, 6 and 12 months, with a mean walking distance of 359, 392 and 433 meters, respectively (Fig.1A). The BIS score was not normalized in 12.4%, 23.5% and 28% (Fig.1B), the WHODAS score in 22.2%, 56.4% and 45.2% (Fig.1C) at 3, 6 and 12 months, respectively. FVC and FEV1 were outside normal limits in 64.3% of the patients at 3 months, 34.7% and 32.9% at 6 months, 33.8% and 27.7% at 12 months (Fig.1D/E). DLCO was abnormal in 62.4%, 78.4% and 80.6% (Fig.1F) of patients, at 3, 6 and 12 months. As shown by the HADS, anxiety was present in 28.9%, 26.9% and 32.7% (Fig.1G) of the patients, while 30.2%, 26.9% and 32.7% (Fig.1H) had significant depression at 3, 6 and 12 months. The PHQ-9 was outside normal range in 66.4%, 66.2% and 72.2% (Fig 1I) of the patients, while the MOCA test revealed cognitive impairment in 40.8%, 30% and 32.5% of the patients at 3, 6 and 12 months. Conclusion The assessment of COVID-19 patients up to 12 months post-ICU discharge indicates that pulmonary function and mental health remain outside the normal range in a significant proportion of patients, with one-third of patients experiencing cognitive impairment. A comprehensive evaluation of the pre-ICU admission status is currently underway.

Acute kidney injury (AKI) is common after liver transplantation, but difficult to diagnose with serum creatinine and urinary output. This study evaluated the early risk stratification capability of urinary tissue inhibitor of metalloproteinases-2 and insulin-like growth factor binding protein-7 (u[TIMP-2]*[IGFBP-7]) in a prospective adult liver transplantation cohort. u[TIMP-2]*[IGFBP-7] was measured 6 and 36 hours after graft reperfusion, with AKI and acute kidney disease diagnosed according to KDIGO and ADQI criteria at 7-day and 90-day windows. Subclinical AKI was defined as u[TIMP-2]*[IGFBP-7] >0.30 without clinical AKI. Among 78 included patients, AKI occurred in 45% (10.3%, 11.7%, and 23.4% for stages 1, 2, and 3). At 6 hours, 46% had u[TIMP-2]*[IGFBP-7] >0.30, predicting AKI (stage ≥1) with an OR of 3.23 ( p =0.01); at 36 hours, 37% had u[TIMP-2]*[IGFBP-7] >0.30, predicting stage 3 AKI with an OR of 4.22 ( p =0.009). Serum creatinine/urinary output criteria predicted AKI only in 10% and 18% at 6 and 36 hours, respectively. Subclinical patients with AKI (24%) had higher risks of acute kidney disease (42% vs. 26%), early allograft dysfunction (32% vs. 18%), graft loss (16% vs. 4%), and longer intensive care unit stays. u[TIMP-2]*[IGFBP-7] is a valuable biomarker for early AKI risk stratification after liver transplantation, with subclinical AKI representing a distinct, clinically relevant phenotype.

Regional citrate anticoagulation (RCA) is the most widespread technique which allows to perform extracorporeal treatments, avoiding the complications of systemic anticoagulation. Due to limited citrate clearance, RCA may be applied only to low extracorporeal blood flows (i.e., BF < 200 ml/min). In this proof of concept study, we developed an innovative RCA technique based on Ion Exchange Resin (i-ER) technology capable of regionally anticoagulating BF up to 500 mL/min. Six healthy swine (41.0 ± 3.1 kg) were sedated, mechanically ventilated, and connected to a prototype extracorporeal circuit for continuous renal replacement therapy featuring a citrate-removal stage based on absorbent materials and replacement fluids. Blood flow was 500 ml/min. Sodium citrate was continuously infused at the circuit inlet (5 mmol/L). Heparin was continuously infused. Citrate concentration and Kaolin Heparinase thromboelastography (KH-TEG) were measured on arterial blood, extracorporeal blood downstream the citrate infusion port, and downstream the citrate-removal stage. Samples were collected at baseline, 2, 8, 15, 30, 45, 60, 90, and 120 min for citrate and at baseline, 2, 30, 60, and 120 min for KH–TEG. Calcium chloride was infused to maintain systemic ionized calcium within the physiological range. The experiment lasted 2 h. During the whole experiment, KH–TEG in the artery showed normal coagulation: reaction time (R) was 8.30[6.80–10.10] min, with Maximum Amplitude (MA) of 71.70[67.90–77.00] mm, while in the extracorporeal circuit, KH–TEG showed no sign of clot formation R > 60 min, MA = 0 mm. Citrate concentrations in blood samples were stable within 30 min, then slowly increased. The efficacy of the citrate-removal dropped from 93.8 ± 3.4

AbstractOpen-lung ventilation during cardiopulmonary bypass (CPB) in patients undergoing heart transplantation (HTx) is a potential strategy to mitigate postoperative acute respiratory distress syndrome (ARDS). We utilized an ovine HTx model to investigate whether open-lung ventilation during CPB reduces postoperative lung damage and complications. Eighteen sheep from an ovine HTx model were included, with ventilatory interventions randomly assigned during CPB: the OPENVENT group received low tidal volume (VT) of 3 mL/kg and positive end-expiratory pressure (PEEP) of 8 cm H20, while no ventilation was provided in the NOVENT group as per standard of care. The recipient sheep were monitored for 6 h post-surgery. The primary outcome was histological lung damage, scored at the end of the study. Secondary outcomes included pulmonary shunt, driving pressure, hemodynamics and inflammatory lung infiltration. All animals completed the study. The OPENVENT group showed significantly lower histological lung damage versus the NOVENT group (0.22 vs 0.27, p = 0.042) and lower pulmonary shunt (19.2 vs 32.1%, p = 0.001). In addition, the OPENVENT group exhibited a reduced driving pressure (9.6 cm H2O vs. 12.8 cm H2O, p = 0.039), lower neutrophil (5.25% vs 7.97%, p ≤ 0.001) and macrophage infiltrations (11.1% vs 19.6%, p < 0.001). No significant differences were observed in hemodynamic parameters. In an ovine model of HTx, open-lung ventilation during CPB significantly reduced lung histological injury and inflammatory infiltration. This highlights the value of an open-lung approach during CPB and emphasizes the need for further clinical evidence to decrease risks of lung injury in HTx patients.

BACKGROUND:The commonest echocardiographic measurement, left ventricular ejection fraction, can not necessarily predict mortality of recipients following heart transplantation potentially due to afterload dependency. Afterload-independent left ventricular stroke work index (LVSWI) is alternatively recommended by the current guideline; however, pulmonary artery catheters are rarely inserted in organ donors in most jurisdictions. We propose a novel non-invasive echocardiographic parameter, Pressure-Strain Product (PSP), as a potential surrogate of catheter-based LVSWI. This study aimed to investigate if PSP could correlate with catheter-based LVSWI in an ovine model of brain stem death (BSD) donors. The association between PSP and myocardial mitochondrial function in the post-transplant hearts was also evaluated. METHODS:Thirty-one female sheep (weight 47 ± 5 kg) were divided into two groups; BSD (n = 15), and sham neurologic injury (n = 16). Echocardiographic parameters including global circumferential strain (GCS) and global radial strain (GRS) and pulmonary artery catheter-based LVSWI were simultaneously measured at 8-timepoints during 24-h observation. PSP was calculated as a product of GCS or GRS, and mean arterial pressure for PSPcirc or PSPrad, respectively. Myocardial mitochondrial function was evaluated following 6-h observation after heart transplantation. RESULTS:In BSD donor hearts, PSPcirc (n = 96, rho = .547, p < .001) showed the best correlation with LVSWI among other echocardiographic parameters. PSPcirc returned AUC of .825 to distinguish higher values of cardiomyocyte mitochondrial function (cut-off point; mean value of complex 1,2 O2 Flux) in post-transplant hearts, which was greater than other echocardiographic parameters. CONCLUSIONS:PSPcirc could be used as a surrogate of catheter-based LVSWI reflecting mitochondrial function.

Background Lung transplantation (LUTX) is often complicated by primary graft dysfunction (PGD). Plasma biomarkers hold potential for PGD phenotyping and targeted therapy. This scoping review aims to collect the available literature in search of serum biomarkers for PGD phenotyping. Methods Following JBI and PRISMA guidelines, we conducted a systematic review searching MEDLINE, Web of Science, EMBASE and The Cochrane Library for papers reporting the association between serum biomarkers measured within 72 h of reperfusion and PGD, following International Society for Heart and Lung Transplantation (ISHLT) guidelines. We extracted study details, patient demographics, PGD definition and timing, biomarker concentration, and their performance in identifying PGD cases. Results Among the 1050 papers screened, 25 prospective observational studies were included, with only nine conducted in the last decade. These papers included 1793 unique adult patients (1195 double LUTX, median study size 100 (IQR 44–119)). Most (n=21) compared PGD grade 3 to less severe PGD, but only four adhered to 2016 PGD definitions. Enzyme-linked immunosorbent assays and the multiplex bead array technique were utilised in 23 and two papers, respectively. In total, 26 candidate biomarkers were identified, comprising 13 inflammatory, three endothelial activation, three epithelial injury, three cellular damage and two coagulation dysregulation markers. Only five biomarkers (sRAGE, ICAM-1, PAI-1, SP-D, FSTL-1) underwent area under the receiver operating characteristic curve analysis, yielding a median value of 0.58 (0.51–0.78) in 406 patients (276 double LUTX). Conclusions Several biomarkers exhibit promise for future studies aimed at PGD phenotyping after LUTX. To uncover the significant existing knowledge gaps, further international prospective studies incorporating updated diagnostic criteria, modern platforms and advanced statistical approaches are essential.

"Hematocrit: The Neglected Variable of Extracorporeal CO2 Removal." American Journal of Respiratory and Critical Care Medicine, 209(5), pp. 595–598

Purpose: This study aimed to investigate the effects of inspired oxygen fraction (FiO2) and positive end-expiratory pressure (PEEP) on gas exchange in mechanically ventilated patients with COVID-19. Methods: Two FiO2 (100%, 40%) were tested at 3 decreasing levels of PEEP (15, 10, and 5 cmH2O). At each FiO2 and PEEP, gas exchange, respiratory mechanics, hemodynamics, and the distribution of ventilation and perfusion were assessed with electrical impedance tomography. The impact of FiO2 on the intrapulmonary shunt (delta shunt) was analyzed as the difference between the calculated shunt at FiO2 100% (shunt) and venous admixture at FiO2 40% (venous admixture). Results: Fourteen patients were studied. Decreasing PEEP from 15 to 10 cmH2O did not change shunt (24 [21-28] vs 27 [24-29]%) or venous admixture (18 [15-26] vs 23 [18-34]%) while partial pressure of arterial oxygen (FiO2 100%) was higher at PEEP 15 (262 [198-338] vs 256 [147-315] mmHg; P < .05). Instead when PEEP was decreased from 10 to 5 cmH2O, shunt increased to 36 [30-39]% (P < .05) and venous admixture increased to 33 [30-43]% (P < .05) and partial pressure of arterial oxygen (100%) decreased to 109 [76-177] mmHg (P < .05). At PEEP 15, administration of 100% FiO2 resulted in a shunt greater than venous admixture at 40% FiO2, ((24 [21-28] vs 18 [15-26]%, P = .005), delta shunt 5.5% (2.3-8.8)). Compared to PEEP 10, PEEP of 5 and 15 cmH2O resulted in decreased global and pixel-level compliance. Cardiac output at FiO2 100% resulted higher at PEEP 5 (5.4 [4.4-6.5]) compared to PEEP 10 (4.8 [4.1-5.5], P < .05) and PEEP 15 cmH2O (4.7 [4.5-5.4], P < .05). Conclusion: In this study, PEEP of 15 cmH2O, despite resulting in the highest oxygenation, was associated with overdistension. PEEP of 5 cmH2O was associated with increased shunt and alveolar collapse. Administration of 100% FiO2 was associated with an increase in intrapulmonary shunt in the setting of high PEEP. Trial registration: NCT05132933.

Mortality and morbidity of Acute Respiratory Distress Syndrome (ARDS) are largely unaltered. A possible new approach to treatment of ARDS is offered by the discovery of inflammatory subphenotypes. In an ovine model of ARDS phenotypes, matching key features of the human subphenotypes, we provide an imaging characterization using computer tomography (CT). Nine animals were randomized into (a) OA (oleic acid, hypoinflammatory; n = 5) and (b) OA-LPS (oleic acid and lipopolysaccharides, hyperinflammatory; n = 4). 48 h after ARDS induction and anti-inflammatory treatment, CT scans were performed at high (H) and then low (L) airway pressure. After CT, the animals were euthanized and lung tissue was collected. OA-LPS showed a higher air fraction and OA a higher tissue fraction, resulting in more normally aerated lungs in OA-LPS in contrast to more non-aerated lung in OA. The change in lung and air volume between H and L was more accentuated in OA-LPS, indicating a higher recruitment potential. Strain was higher in OA, indicating a higher level of lung damage, while the amount of lung edema and histological lung injury were largely comparable. Anti-inflammatory treatment might be beneficial in terms of overall ventilated lung portion and recruitment potential, especially in the OA-LPS group.

Transpulmonary pressure can be estimated using esophageal balloon (EB) catheters, which come in a variety of manufacturing configurations. We assessed the performance of novel polyurethane EB designs, Aspisafe NG and NG+, against existing alternatives. We created a biomechanical model of the chest cavity using a plastic chamber and an ex-vivo porcine esophagus. The chamber was pressurized (− 20 and + 20 cmH2O) to simulate pleural pressures. We conducted tests with various EB inflation volumes and measured transesophageal pressure (TEP). TEP measurement was defined as accurate when the difference between pressure within the EB and chamber was 0 ± 1 cmH2O. We computed the minimal (Vaccuracy-min) and maximal (Vaccuracy-max) EB inflation volumes of accuracy. Inflation volumes were further validated using a surrogate method derived by the clinically validated positive pressure occlusion test (PPOT). When the esophageal balloons were filled with inflation volumes within the range provided by the manufacturers, the accuracy of TEP measurements was marginal. Our tests found median Vaccuracy-min across EB of 0.00–0.50 mL (p = 0.130), whereas Vaccuracy-max ranged 0.50–2.25 mL (p = 0.002). Post PPOT validation, median TEP was − 0.4 cmH2O (− 1.5 to 0.3) (p < 0.001 among catheters). The Aspisafe NG and NG+ were accurate in 81.7% and 77.8% of the measurements, respectively. We characterized two new EBs, which demonstrated good benchtop accuracy in TEP measurements. However, accuracy was notably influenced by the precise selection of EB inflation volumes.

Abstract Background Transpulmonary pressure is the effective pressure across the lung parenchyma and has been proposed as a guide for mechanical ventilation. The pleural pressure is challenging to directly measure in clinical setting and esophageal manometry using esophageal balloon catheters was suggested for estimation. However, the accuracy of using esophageal pressure to estimate pleural pressure is debated due to variability in the mechanical properties of respiratory system, esophagus and esophageal catheter. Furthermore, while a vertical pleural pressure gradient exists across lung regions, esophageal pressure balloon provides a single value, representing, at most, the pressure surrounding the esophagus. Methods In a swine model with a preserved esophagus and a single homogenous, easily measurable intrathoracic pressure, we evaluated esophageal pressure’s agreement with intrathoracic pressure at different positive end-expiratory pressure (PEEP) levels (0, 5, 10, 15 cmH2O). We assessed the improvement of measurement accuracy by correcting absolute esophageal values using a previously described technique, that accounts for the pressure generated by the esophageal wall in response to esophageal balloon inflation. The study involved five swine, wherein two different esophageal catheters were used alongside the four distinct PEEP levels. Swings, uncorrected and corrected absolute esophageal pressures (end-inspiratory, end-expiratory) were compared with their respective intrathoracic pressures. The effect of correction technique was assessed with manual incremental step inflation procedure. Results We found that both catheters significantly overestimated absolute esophageal pressure compared to intrathoracic pressure (5.01 ± 3.32 and 6.06 ± 5.62 cmH2O at end-expiration and end-inspiration, respectively), with error increasing at higher positive end-expiratory pressure levels (end-expiration: 2.36 ± 2.03, 3.77 ± 1.37, 6.24 ± 2.51 and 7.69 ± 4.02 for each PEEP level, P < 0.0001; end-inspiration: 1.71 ± 2.10, 3.70 ± 1.73, 7.67 ± 3.62 and 11.14 ± 7.60 for each PEEP level, P = 0.0004). Applying the correction technique significantly improved agreement for absolute values (0.82 ± 1.62 and 1.86 ± 3.94 cmH2O at end-expiration and end-inspiration, respectively). Esophageal pressure swings accurately estimated intrathoracic pressure swings at low-medium intrathoracic pressures (-0.64 ± 0.62, -0.07 ± 0.53, 1.43 ± 1.51, and 3.45 ± 3.94 at PEEP 0, 5, 10 and 15 cmH2O, respectively; P = 0.0197). Conclusions The correction technique, based on the mechanical response of esophageal wall to the balloon inflation, is fundamental for obtaining reliable estimations of absolute intrathoracic pressure values, and for ensuring its correct application in clinical setting.

Introduction Extracorporeal membrane oxygenation (ECMO) is known to influence all blood components. Reduction in leukocyte numbers during ECMO and their slow recovery ECMO have been associated with poorer prognosis. However, few studies on leukocyte fate have been conducted on adult patients on ECMO and are predominately cardiogenic shock-specific cohorts. Here, we attempt to examine the leukocyte profiles of ECMO-supported adult patients with both heart and/or lung failure and their associations with mortality and morbidity. Methods This multicenter, retrospective study included adult patients with refractory cardiac and/or respiratory failure supported by veno-arterial (VA) and veno-venous (VV) ECMO between 2016 and 2017. Data were collected from intensive care units of five ECMO centers in Australia, Italy, Japan, Hong Kong, and Germany. The primary outcome was the temporal trend of differential peripheral blood leukocyte numbers pre, during and post ECMO cannulation and survival in patients receiving venovenous and/or venoarterial ECMO. In addition, we evaluated the associations between leukocyte numbers and bleeding, infection, and organ dysfunction. Results Among 164 ECMO patients, mean age was 51 ± 16 years, and 67.7% of patients were male. 58.5% were placed on VA-ECMO, 39% on VV-ECMO, and 2.4% on VA/VV ECMO. Sixty-six patients who underwent ECMO (40.2%) did not survive hospitalization, and 96.9% of deaths occurred during ICU stay. In univariate analysis, a lower monocyte count (HR 0.45, 95% CI 0.21–0.93, p = 0.032), lower platelet count (HR 0.99, 95% CI 0.99-1.00, p = 0.009), higher lymphocyte count (HR 1.10, 95% CI 1.007–1.19, p = 0.033) and higher International Normalised Ratio (HR 3.98, 95% CI 2.64–5.99, p < 0.001) peri-ECMO were associated with increased risk of death. An elevated neutrophil count (HR 1.19, 95% CI 1.04–1.36, p = 0.013), age and lactate dehydrogenase were associated with mortality in multivariate analysis. There were no correlations between leukocyte variables and the development of infectious or bleeding complications. Integrated Discrimination Improvement index showed that SAPS II score with the addition of peri-ECMO lymphocyte (p = 0.001) or monocyte (p < 0.001) numbers have a better predictive value for death in ICU than SAPS II score alone. Conclusions Assessment of ECMO-related monocyte and lymphocyte numeric changes may be useful outcome prognosticators when used in conjunction with SAPS II score. Further investigation with larger patient cohorts will be required.

Editor—Several assisted ventilatory modes are available for invasive mechanical ventilation. Pressure support ventilation (PSV) is one of the most frequently used,1 in which inspiration is triggered by a pneumatic signal (i.e. flow or pressure),2 while expiration is cycled when the inspiratory flow decreases to a predetermined fraction of peak inspiratory flow.3 Neurally adjusted ventilatory assist (NAVA) ventilation is a partial ventilatory mode using a specialised nasogastric probe that measures diaphragmatic electrical activity, which in turn is used to trigger inspiration, cycle expiration, and provide proportional ventilatory assistance.

BACKGROUND:Extracorporeal carbon dioxide removal (ECCO2R) promotes protective ventilation in patients with acute respiratory failure, but devices with high CO2 extraction capacity are required for clinically relevant impact. This study evaluates three novel low-flow techniques based on dialysate acidification, also combined with renal replacement therapy, and metabolic control. METHODS:Eight swine were connected to a low-flow (350 mL/min) extracorporeal circuit including a dialyzer with a closed-loop dialysate circuit, and two membrane lungs on blood (MLb) and dialysate (MLd), respectively. The following 2-hour steps were performed: 1) MLb-start (MLb ventilated); 2) MLbd-start (MLb and MLd ventilated); 3) HLac (lactic acid infusion before MLd); 4) HCl-NaLac (hydrochloric acid infusion before MLd combined with renal replacement therapy and reinfusion of sodium lactate); 5) HCl-βHB-NaLac (hydrochloric acid infusion before MLd combined with renal replacement therapy and reinfusion of sodium lactate and sodium 3-hydroxybutyrate). Caloric and fluid inputs, temperature, blood glucose and arterial carbon dioxide pressure were kept constant. RESULTS:The total MLs CO2 removal in HLac (130±25 mL/min), HCl-NaLac (130±21 mL/min) and HCl-βHB-NaLac (124±18 mL/min) were higher compared with MLbd-start (81±15 mL/min, P<0.05) and MLb-start (55±7 mL/min, P<0.05). Minute ventilation in HLac (4.3±0.9 L/min), HCl-NaLac (3.6±0.8 L/min) and HCl-βHB-NaLac (3.6±0.8 L/min) were lower compared to MLb-start (6.2±1.1 L/min, P<0.05) and MLbd-start (5.8±2.1 L/min, P<0.05). Arterial pH was 7.40±0.03 at MLb-start and decreased only during HCl-βHB-NaLac (7.35±0.03, P<0.05). No relevant changes in electrolyte concentrations, hemodynamics and significant adverse events were detected. CONCLUSIONS:The three techniques achieved a significant extracorporeal CO2 removal allowing a relevant reduction in minute ventilation with a sufficient safety profile.