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Copyright of Anaesthesist is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Anaesthesist is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Anaesthesist is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Recruitment maneuvers have been proposed as an adjunct to mechanical ventilation to re-expand collapsed lung regions. Although, in most patients recruitment maneuvers improve gas exchange a controversial discussion on recruitment maneuvers remains. This article reviews the physiological and patho-physiological backgrounds of recruitment maneuvers. The different recruitment maneuvers and possible monitoring are discussed as well as the influence of recruitment on other organs. Furthermore, we discuss whether recruitment maneuvers are useful if patients with acute lung injury or acute respiratory distress syndrome are ventilated with a lung-protective strategy. [ABSTRACT FROM AUTHOR]

Abstract Tracheostomy is a generally accepted procedure that assures free access to the airways in long-term lung ventilation. Apart from surgical tracheostomy, percutaneous dilational tracheostomy (PDT) has been increasingly employed in intensive care units. Presently, five dilatation methods are available, all equally allowing the performance of a secure and low-risk, bedside tracheostomy in the intensive care unit. Exact knowledge of the anatomy of the neck region and of the entire procedure are preconditions for a safe intervention. Percutaneous procedures offer advantages over surgical tracheostomy in terms of complications. To minimize the risks, expertise in airway management during PDT and knowledge of the particularities of cannula replacement in dilational tracheostoma, are compulsory. Endoscopic control assures that the tracheostoma can be placed correctly and that possible complications can be recognised early. The incidence of a serious tracheal stenosis after PDT is low. [ABSTRACT FROM AUTHOR]

Understanding migratory patterns is important for predicting and mitigating unwanted consequences of environmental change or anthropogenic challenges on vulnerable species. Wild Atlantic salmon undergo challenging migrations between freshwater and marine environments, and the numbers of salmon returning to their natal rivers to reproduce have declined over several decades. Mortality from sea lice linked to fish farms within their seaward migration routes is proposed as a contributing factor to these declines. Here, we used 31 microsatellite markers to establish a genetic baseline for the main rivers in the Hardangerfjord, western Norway. Mixed stock analysis was used to assign Atlantic salmon post-smolts caught in trawls in 2013–2017 back to regional reporting units. Analyses demonstrated that individuals originating from rivers located in the inner region of the fjord arrived at the outer fjord later than individuals from middle and outer fjord rivers. Therefore, as post-smolts originating from inner rivers also have to migrate longer distances to exit the fjord, these data suggest that inner fjord populations are more likely to be at risk of mortality through aquaculture-produced sea lice, and other natural factors such as predation, than middle or outer fjord populations with earlier exit times and shorter journeys. These results will be used to calibrate models estimating mortality from sea lice on wild salmon for the regulation of the Norwegian aquaculture industry.

A 33-year-old woman sought medical attention for a painful swelling of the left ankle. Plain radiographs revealed an osteolytic lesion involving the left distal tibia. An excisional biopsy provided the diagnosis of leiomyosarcoma in the tibia. A staging work-up was performed and an abdominal CT showed 4 liver hypodense lesions in both lobes with peripheral contrast enhancement. A liver biopsy confirmed the diagnosis of epithelioid hemangioendothelioma of the liver. No association between these two entities has been described before. This case introduces the importance of the pathological confirmation of apparent metastatic lesions in low grade sarcomas and provides a review of the literature of both tumours.

En este artículo se resume la experiencia de nuestro grupo de investigación en el campo de los efectos de un disruptor endocrino androgenizante (el tributilo de estaño, más conocido como TBT por su abreviatura del inglés tributyltin) en gasterópodos marinos del litoral gallego. Nuestras investigaciones sobre este tema comenzaron en 1996 y continúan en la actualidad. Después de una breve introducción sobre qué es el TBT y su problemática, se resumen los principales hallazgos conseguidos con nuestro trabajo, que se basan principalmente en el estudio de los efectos en el gasterópodo carnívoro Nucella lapillus con alguna información adicional para otras especies como el carroñero Nassarius reticulatus. Nuestro trabajo abarca tanto la bioacumulación de contaminante, la manifestación de un biomarcador específico de los efectos del TBT (masculinización de hembras, conocido como imposex) en poblaciones naturales y en experiencias de trasplante, el estudio de la presencia de individuos genéticamente más resistentes a los efectos del TBT y algunos datos de ecología molecular sobre la estructuración poblacional y capacidad de dispersión de Nucella lapillus.

Kidney response to acute and mechanically induced variation in ventilation associated with different levels of PEEP has not been investigated. We aimed to quantify the effect of ventilatory settings on renal acid-base compensation. Forty-one pigs undergoing hypo- (<0.2 Lkg -1  min -1 , PEEP 25 cmH 2 O), intermediate (0.2-0.4 Lkg -1  min -1 with either PEEP 5 or 25 cmH 2 O), or hyper-ventilation (>0.4 Lkg -1  min -1 , PEEP 5 cmH 2 O) for 48 h were retrospectively included. The decrease in pH paralleled the decrease in plasma strong ion difference (SID) in hyper- and intermediately ventilated groups with lower PEEP. In contrast, the plasma SID remained nearly constant in hypo- and intermediately ventilated groups with higher PEEP. Changes in plasma chloride concentration accounted for the changes in plasma SID (conditional R 2  = 0.86). The plasma SID changes were paralleled by mirror changes in urinary SID. Higher PEEP (25 cmH 2 O), compared to lower PEEP (5 cmH 2 O) dampened or abolished the renal compensation through its effect on hemodynamics (higher central venous and mean pulmonary pressures), irrespective of minute ventilation. During mechanical ventilation, the compensatory renal response to respiratory derangement is immediate and progressive but can be dampened by high PEEP levels., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Background: The individual components of mechanical ventilation may have distinct effects on kidney perfusion and on the risk of developing acute kidney injury; we aimed to explore ventilatory predictors of acute kidney failure and the hemodynamic changes consequent to experimental high-power mechanical ventilation., Methods: Secondary analysis of two animal studies focused on the outcomes of different mechanical power settings, including 78 pigs mechanically ventilated with high mechanical power for 48 h. The animals were categorized in four groups in accordance with the RIFLE criteria for acute kidney injury (AKI), using the end-experimental creatinine: (1) NO AKI: no increase in creatinine; (2) RIFLE 1-Risk: increase of creatinine of > 50%; (3) RIFLE 2-Injury: two-fold increase of creatinine; (4) RIFLE 3-Failure: three-fold increase of creatinine; RESULTS: The main ventilatory parameter associated with AKI was the positive end-expiratory pressure (PEEP) component of mechanical power. At 30 min from the initiation of high mechanical power ventilation, the heart rate and the pulmonary artery pressure progressively increased from group NO AKI to group RIFLE 3. At 48 h, the hemodynamic variables associated with AKI were the heart rate, cardiac output, mean perfusion pressure (the difference between mean arterial and central venous pressures) and central venous pressure. Linear regression and receiving operator characteristic analyses showed that PEEP-induced changes in mean perfusion pressure (mainly due to an increase in CVP) had the strongest association with AKI., Conclusions: In an experimental setting of ventilation with high mechanical power, higher PEEP had the strongest association with AKI. The most likely physiological determinant of AKI was an increase of pleural pressure and CVP with reduced mean perfusion pressure. These changes resulted from PEEP per se and from increase in fluid administration to compensate for hemodynamic impairment consequent to high PEEP., (© 2024. The Author(s).)

(1) Background: Patients with sepsis following surgical intervention may exhibit fundamental distinctions from those experiencing sepsis without prior surgery. Despite the potential clinical importance of distinguishing these two sepsis subpopulations, dissimilarities, particularly in outcome, between surgical and non-surgical patients have been subject to limited scientific investigations in the existing literature. This study aimed to investigate the differences in mortality and sepsis-associated organ dysfunction between these two groups. (2) Methods: A retrospective analysis was conducted using data from a large cohort of prospectively enrolled patients with sepsis (n = 737) admitted to three intensive care units at University Medical Center Goettingen; patients were categorized into surgical (n = 582) and non-surgical sepsis groups (n = 155). The primary outcomes assessed were 28- and 90-day mortality rates, and secondary endpoints were multiple clinical parameters and measures of sepsis-associated organ dysfunction. (3) Results: Non-surgical patients presented a significantly higher 90-day mortality (37%) compared to surgical sepsis patients (30%, p = 0.0457). Moreover, the non-surgical sepsis group exhibited increased sepsis-associated organ dysfunction, as evidenced by higher average SOFA scores ( p < 0.001), elevated levels of serum Procalcitonin ( p = 0.0102), and a higher utilization of organ replacement therapies such as ventilation (p < 0.001), vasopressor treatment ( p < 0.001), and renal replacement therapy ( p = 0.0364). Additionally, non-surgical sepsis patients had higher organ-specific SOFA respiratory ( p < 0.001), cardiovascular ( p < 0.001), renal ( p < 0.001), coagulation (0.0335), and central nervous system ( p = 0.0206) subscores. (4) Conclusions: These results suggested that patients with non-surgical sepsis may face distinct challenges and a higher risk of adverse outcomes compared to patients with sepsis following surgical intervention. These findings have important implications for clinical decision-making, patient management, and resource allocation in sepsis care.

Mechanically ventilated patients suffering from acute respiratory distress syndrome (ARDS) frequently receive aerosolized iloprost. Because of prostacyclin's short half-life, prolonged inhalative administration might improve its clinical efficacy. But, this is technically challenging. A solution might be the use of inspiration-synchronized vibrating mesh nebulizers (VMN syn ), which achieve high drug deposition rates while showing prolonged nebulization times. However, there are no data comparing prolonged to bolus iloprost nebulization using a continuous vibrating mesh nebulizer (VMN cont ) and investigating the effects of different ventilation modes on inspiration-synchronized nebulization. Therefore, in an in vitro model of mechanically ventilated adults, a VMN syn and a VMN cont were compared in volume-controlled (VC-CMV) and pressure-controlled continuous mandatory ventilation (PC-CMV) regarding iloprost deposition rate and nebulization time. During VC-CMV, the deposition rate of the VMN syn was comparable to the rate obtained with the VMN cont , but 10.9% lower during PC-CMV. The aerosol output of the VMN syn during both ventilation modes was significantly lower compared to the VMN cont , leading to a 7.5 times longer nebulization time during VC-CMV and only to a 4.2 times longer nebulization time during PC-CMV. Inspiration-synchronized nebulization during VC-CMV mode therefore seems to be the most suitable for prolonged inhalative iloprost administration in mechanically ventilated patients.

Background: Despite recent advances in the clinical management and understanding of sepsis and septic shock, these complex clinical syndromes continue to have high mortality rates. The effect of sex on these diseases' mortality, clinical presentation and morbidity remains controversial. This study aimed to investigate the association of sex with mortality and organ dysfunction in patients with sepsis and septic shock., Methods: Prospectively enrolled patients with clinically defined sepsis and septic shock in three intensive care units at University Medical Center Göttingen, Germany, were investigated. The primary outcomes were 28- and 90-day mortality, while the secondary endpoints included the evaluation of organ dysfunction as measured by clinical scores and laboratory parameters., Results: A total of 737 septic patients were enrolled, including 373 in septic shock, 484 males, and 253 females. No significant differences in 28- and 90-day mortality were observed in the cohort. However, men with sepsis had significantly higher SOFA scores, SOFA respiratory and renal subscores, bilirubin and creatinine values, and lower weight-adapted urine outputs, indicating higher organ dysfunction compared to women., Conclusions: Our findings revealed notable differences in organ dysfunction between male and female patients, with males exhibiting more pronounced dysfunction across multiple clinical indicators. These results highlight the potential influence of sex on sepsis disease severity and suggest the need for tailored approaches in sepsis management according to patient sex.

Rationale: In the EOLIA (ECMO to Rescue Lung Injury in Severe ARDS) trial, oxygenation was similar between intervention and conventional groups, whereas [Formula: see text]e was reduced in the intervention group. Comparable reductions in ventilation intensity are theoretically possible with low-flow extracorporeal CO 2 removal (ECCO 2 R), provided oxygenation remains acceptable. Objectives: To compare the effects of ECCO 2 R and extracorporeal membrane oxygenation (ECMO) on gas exchange, respiratory mechanics, and hemodynamics in animal models of pulmonary (intratracheal hydrochloric acid) and extrapulmonary (intravenous oleic acid) lung injury. Methods: Twenty-four pigs with moderate to severe hypoxemia (Pa O 2 :Fi O 2  ⩽ 150 mm Hg) were randomized to ECMO (blood flow 50-60 ml/kg/min), ECCO 2 R (0.4 L/min), or mechanical ventilation alone. Measurements and Main Results: [Formula: see text]o 2 , [Formula: see text]co 2 , gas exchange, hemodynamics, and respiratory mechanics were measured and are presented as 24-hour averages. Oleic acid versus hydrochloric acid showed higher extravascular lung water (1,424 ± 419 vs. 574 ± 195 ml; P  < 0.001), worse oxygenation (Pa O 2 :Fi O 2  = 125 ± 14 vs. 151 ± 11 mm Hg; P  < 0.001), but better respiratory mechanics (plateau pressure 27 ± 4 vs. 30 ± 3 cm H 2 O; P  = 0.017). Both models led to acute severe pulmonary hypertension. In both models, ECMO (3.7 ± 0.5 L/min), compared with ECCO 2 R (0.4 L/min), increased mixed venous oxygen saturation and oxygenation, and improved hemodynamics (cardiac output = 6.0 ± 1.4 vs. 5.2 ± 1.4 L/min; P  = 0.003). [Formula: see text]o 2 and [Formula: see text]co 2 , irrespective of lung injury model, were lower during ECMO, resulting in lower Pa CO 2 and [Formula: see text]e but worse respiratory elastance compared with ECCO 2 R (64 ± 27 vs. 40 ± 8 cm H 2 O/L; P  < 0.001). Conclusions: ECMO was associated with better oxygenation, lower [Formula: see text]o 2 , and better hemodynamics. ECCO 2 R may offer a potential alternative to ECMO, but there are concerns regarding its effects on hemodynamics and pulmonary hypertension.

The accumulation of Bile Acids (BA) in serum is a common finding in critically ill patients and has been found in patients with Acute Respiratory Distress Syndrome (ARDS), where liver and biliary function could be essentially affected by the underlying disease process and subsequent therapeutic measures. We hypothesized that the glycine-to-taurine conjugation ratio (G/T-ratio) is predictive of outcome in ARDS patients and would support our previously published hypothesis that the BA profile reflects a (mal-) adaptive response of bile acid production when suffering from a disease or syndrome such as ARDS. In 70 patients with ARDS, we determined conjugated BA fractions from protein precipitated serum samples using a LC-MS/MS method and calculated the G/T-ratios, which were then compared with a healthy control group. In patients with ARDS, the G/T-ratio was markedly lower compared to the control group, due to an increase in taurine-conjugated BA. The G/T ratio was lowest on the day of diagnosis and increased steadily during the following days (control = 3.80 (2.28-4.44); day 0 = 1.79 (1.31-3.86); day 3 = 2.91 (1.71-5.68); day 5 = 2.28 (1.25-7.85), significant increases were found between day 0 and day 3 (p = 0.019) and between day 0 and day 5 (p = 0.031). G/T-ratio was significantly correlated with SAPS II score on day 0 (p = 0.009) and day 3 (p = 0.036) and with survival (p = 0.006). Regarding survival, the receiver-operator characteristic revealed an area-under-the-curve of 0.713 (CI 0.578-0.848), the Youden index revealed a G/T-ratio cut-off level of 2.835 (sensitivity 78.4%, specificity 63.2%). Our findings further support our previously published hypothesis that alterations in BA profiles represent adaptive mechanisms in states of severe disease. Our current study adds the finding of an increase in taurine-conjugated BA expressed by a decrease in the G/T-ratio of conjugated BA in serum. The G/T-ratio on day 3 using a threshold G/T-ratio of 2.8 was even associated with survival (p = 0.006); these results are yet to be confirmed by subsequent studies., (© 2022. The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI).)

Background: Ventilatory ratio (VR) has been proposed as an alternative approach to estimate physiological dead space. However, the absolute value of VR, at constant dead space, might be affected by venous admixture and CO 2 volume expired per minute (VCO 2 )., Methods: This was a retrospective, observational study of mechanically ventilated patients with acute respiratory distress syndrome (ARDS) in the UK and Italy. Venous admixture was either directly measured or estimated using the surrogate measure Pa O 2 /FiO 2 ratio. VCO 2 was estimated through the resting energy expenditure derived from the Harris-Benedict formula., Results: A total of 641 mechanically ventilated patients with mild (n=65), moderate (n=363), or severe (n=213) ARDS were studied. Venous admixture was measured (n=153 patients) or estimated using the Pa O 2 /FiO 2 ratio (n=448). The VR increased exponentially as a function of the dead space, and the absolute values of this relationship were a function of VCO 2 . At a physiological dead space of 0.6, VR was 1.1, 1.4, and 1.7 in patients with VCO 2 equal to 200, 250, and 300, respectively. VR was independently associated with mortality (odds ratio [OR]=2.5; 95% confidence interval [CI], 1.8-3.5), but was not associated when adjusted for V D /V Tphys , VCO 2 , Pa O 2 /FiO 2 (OR adj =1.2; 95% CI, 0.7-2.1). These three variables remained independent predictors of ICU mortality (V D /V Tphys [OR adj =17.9; 95% CI, 1.8-185; P<0.05]; VCO 2 [OR adj =0.99; 95% CI, 0.99-1.00; P<0.001]; and Pa O 2 /FiO 2 (OR adj =0.99; 95% CI, 0.99-1.00; P<0.001])., Conclusions: VR is a useful aggregate variable associated with outcome, but variables not associated with ventilation (VCO 2 and venous admixture) strongly contribute to the high values of VR seen in patients with severe illness., (Copyright © 2022 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: Acute respiratory distress syndrome is a life-threatening condition with a hospital mortality rate of up to 40%. Biomarkers related to the pathophysiology of ARDS may not only identify patients at risk but may also serve as potential therapeutic targets. This study examined the association between the proteolytic C-terminal 42-peptide fragment of alpha-1 antitrypsin and ARDS severity., Methods: The 42-peptide fragment and interleukin-6 levels were measured in 21 patients with mild-to-moderate ARDS and 47 patients with moderate-to-severe ARDS on days 1, 3, and 5 after diagnosis/admission to the intensive care unit. To elucidate the association between both biomarkers and the PaO 2 /FiO 2 ratio, the concentrations of both biomarkers were compared between the two groups, and a multivariate regression analysis was performed., Results: The concentrations of both biomarkers were higher in patients with moderate-to-severe ARDS. While the PaO 2 /FiO 2 ratio increased from day 1 to day 3, the concentrations of both biomarkers decreased. Multivariate regression analysis revealed negative associations between the PaO 2 /FiO 2 ratio and both the C-terminal 42-peptide of alpha-1 antitrypsin and interleukin-6 on day 1 (beta: -0.138, p = 0.052; beta: -0.096, p = 0.004) and on day 3 (beta: -0.157, p = 0.045; beta: -0.106, p = 0.043)., Interpretation: The C-terminal 42-peptide of alpha-1 antitrypsin is a new biomarker associated with ARDS severity. Its predictive value in identifying patients at risk of developing moderate-to-severe ARDS must be investigated in additional, independent prospective studies., 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 © 2022. Published by Elsevier Inc.)

Situations often arise in intensive care units (ICUs) for which only sparse primary evidence or guidelines are applicable or to which existing evidence cannot be applied owing to interactions of multiple disease states. To improve and guide intensive care management in complex scenarios, ultrasonography and echocardiography are invaluable. In five clinical scenarios involving acute deterioration, serial ultrasound examinations of the respiratory system, general critical care ultrasound (GCCUS), and non-invasive haemodynamic critical care echocardiography (CCE) were used routinely. Ultrasonographic results were used to guide further management and initiate experimental therapy or transition from curative to supportive care. The process of initiation of ultrasound examinations to clinical decision-making in these complex scenarios is outlined. These case vignettes highlight the utility of ultrasound and echocardiography. When clinical management is not clear, or evidence is not available, the use of ultrasound for the evaluation of the respiratory system, GCCUS, and non-invasive haemodynamic CCE can help to guide management, reveal newly developed pathologies, lead to clinical management changes, and support the decision for employing experimental therapy approaches in a dynamic way of which few other imaging modalities or monitoring tools are currently capable.

The amount of energy delivered to the respiratory system is recognized as a cause of ventilator-induced lung injury (VILI). How energy dissipation within the lung parenchyma causes damage is still a matter of debate. Expiratory flow control has been proposed as a strategy to reduce the energy dissipated into the respiratory system during expiration and, possibly, VILI. We studied 22 healthy pigs (29 ± 2 kg), which were randomized into a control ( n = 11) and a valve group ( n = 11), where the expiratory flow was controlled through a variable resistor. Both groups were ventilated with the same tidal volume, positive end-expiratory pressure (PEEP), and inspiratory flow. Electric impedance tomography was continuously acquired. At completion, lung weight, wet-to-dry ratios, and histology were evaluated. The total mechanical power was similar in the control and valve groups (8.54 ± 0.83 J·min -1 and 8.42 ± 0.54 J·min -1 , respectively, P = 0.552). The total energy dissipated within the whole system (circuit + respiratory system) was remarkably different (4.34 ± 0.66 vs. 2.62 ± 0.31 J/min, P < 0.001). However, most of this energy was dissipated across the endotracheal tube (2.87 ± 0.3 vs. 1.88 ± 0.2 J/min, P < 0.001). The amount dissipated into the respiratory system averaged 1.45 ± 0.5 in controls versus 0.73 ± 0.16 J·min -1 in the valve group, P < 0.001. Although respiratory mechanics, gas exchange, hemodynamics, wet-to-dry ratios, and histology were similar in the two groups, the decrease of end-expiratory lung impedance was significantly greater in the control group ( P = 0.02). We conclude that with our experimental conditions, the reduction of energy dissipated in the respiratory system did not lead to appreciable differences in VILI. NEW & NOTEWORTHY Energy dissipation within the respiratory system is a factor promoting ventilator-induced lung injury (VILI). In this animal study, we modulated the expiratory flow, reducing the energy dissipated in the system. However, this reduction happened mostly across the endotracheal tube, and only partly in the respiratory system. Therefore, in healthy lungs, the advantage in energy dissipation does not reduce VILI, but the advantages might be more relevant in diseased lungs under injurious ventilation.

The aim of the current paper is to summarize the results of the International CytoSorb Registry. Data were collected on patients of the intensive care unit. The primary endpoint was actual in-hospital mortality compared to the mortality predicted by APACHE II score. The main secondary endpoints were SOFA scores, inflammatory biomarkers and overall evaluation of the general condition. 1434 patients were enrolled. Indications for hemoadsorption were sepsis/septic shock (N = 936); cardiac surgery perioperatively (N = 172); cardiac surgery postoperatively (N = 67) and "other" reasons (N = 259). APACHE-II-predicted mortality was 62.0±24.8%, whereas observed hospital mortality was 50.1%. Overall SOFA scores did not change but cardiovascular and pulmonary SOFA scores decreased by 0.4 [-0.5;-0.3] and -0.2 [-0.3;-0.2] points, respectively. Serum procalcitonin and C-reactive protein levels showed significant reduction: -15.4 [-19.6;-11.17] ng/mL; -17,52 [-70;44] mg/L, respectively. In the septic cohort PCT and IL-6 also showed significant reduction: -18.2 [-23.6;-12.8] ng/mL; -2.6 [-3.0;-2.2] pg/mL, respectively. Evaluation of the overall effect: minimal improvement (22%), much improvement (22%) and very much improvement (10%), no change observed (30%) and deterioration (4%). There was no significant difference in the primary outcome of mortality, but there were improvements in cardiovascular and pulmonary SOFA scores and a reduction in PCT, CRP and IL-6 levels. Trial registration: ClinicalTrials.gov Identifier: NCT02312024 (retrospectively registered)., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: KT has received honoraria for lectures and consultations from CytoSorbents Europe (Berlin, Germany); KK has received honoraria for lectures and consultations from CytoSorbents Europe (Berlin, Germany); AF has received honoraria for lectures and consultations from CytoSorbents Europe (Berlin, Germany); FMB has received honoraria for lectures and consultations from CytoSorbents Europe (Berlin, Germany); ZM has received honoraria for lectures and consultations and he also functions as medical director at CytoSorbents Europe (Berlin, Germany). This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Rationale: Weaning from venovenous extracorporeal membrane oxygenation (VV-ECMO) is based on oxygenation and not on carbon dioxide elimination. Objectives: To predict readiness to wean from VV-ECMO. Methods: In this multicenter study of mechanically ventilated adults with severe acute respiratory distress syndrome receiving VV-ECMO, we investigated a variable based on CO 2 elimination. The study included a prospective interventional study of a physiological cohort ( n  = 26) and a retrospective clinical cohort ( n  = 638). Measurements and Main Results: Weaning failure in the clinical and physiological cohorts were 37% and 42%, respectively. The main cause of failure in the physiological cohort was high inspiratory effort or respiratory rate. All patients exhaled similar amounts of CO 2 , but in patients who failed the weaning trial, [Formula: see text]e was higher to maintain the Pa CO 2 unchanged. The effort to eliminate one unit-volume of CO 2 , was double in patients who failed (68.9 [42.4-123] vs. 39 [20.1-57] cm H 2 O/[L/min]; P  = 0.007), owing to the higher physiological Vd (68 [58.73] % vs. 54 [41.64] %; P  = 0.012). End-tidal partial carbon dioxide pressure (Pet CO 2 )/Pa CO 2 ratio was a clinical variable strongly associated with weaning outcome at baseline, with area under the receiver operating characteristic curve of 0.87 (95% confidence interval [CI], 0.71-1). Similarly, the Pet CO 2 /Pa CO 2 ratio was associated with weaning outcome in the clinical cohort both before the weaning trial (odds ratio, 4.14; 95% CI, 1.32-12.2; P  = 0.015) and at a sweep gas flow of zero (odds ratio, 13.1; 95% CI, 4-44.4; P  < 0.001). Conclusions: The primary reason for weaning failure from VV-ECMO is high effort to eliminate CO 2 . A higher Pet CO 2 /Pa CO 2 ratio was associated with greater likelihood of weaning from VV-ECMO.

Objectives: Lung damage during mechanical ventilation involves lung volume and alveolar water content, and lung ultrasound (LUS) and electrical impedance tomography changes are related to these variables. We investigated whether these techniques may detect any signal modification during the development of ventilator-induced lung injury (VILI)., Design: Experimental animal study., Setting: Experimental Department of a University Hospital., Subjects: Forty-two female pigs (24.2 ± 2.0 kg)., Interventions: The animals were randomized into three groups (n = 14): high tidal volume (TV) (mean TV, 803.0 ± 121.7 mL), high respiratory rate (RR) (mean RR, 40.3 ± 1.1 beats/min), and high positive-end-expiratory pressure (PEEP) (mean PEEP, 24.0 ± 1.1 cm H2O). The study lasted 48 hours. At baseline and at 30 minutes, and subsequently every 6 hours, we recorded extravascular lung water, end-expiratory lung volume, lung strain, respiratory mechanics, hemodynamics, and gas exchange. At the same time-point, end-expiratory impedance was recorded relatively to the baseline. LUS was assessed every 12 hours in 12 fields, each scoring from 0 (presence of A-lines) to 3 (consolidation)., Measurements and Main Results: In a multiple regression model, the ratio between extravascular lung water and end-expiratory lung volume was significantly associated with the LUS total score (p < 0.002; adjusted R2, 0.21). The variables independently associated with the end-expiratory difference in lung impedance were lung strain (p < 0.001; adjusted R2, 0.18) and extravascular lung water (p < 0.001; adjusted R2, 0.11)., Conclusions: Data suggest as follows. First, what determines the LUS score is the ratio between water and gas and not water alone. Therefore, caution is needed when an improvement of LUS score follows a variation of the lung gas content, as after a PEEP increase. Second, what determines the end-expiratory difference in lung impedance is the strain level that may disrupt the intercellular junction, therefore altering lung impedance. In addition, the increase in extravascular lung water during VILI development contributed to the observed decrease in impedance., Competing Interests: Dr. Gattinoni reports to be a consultant for General Electrics and SIDAM (Mirandola, Modena, Italy). He also receives lectures fees from Estor and Dimar. He received support for article research from departmental sources and Sartorius AG (Otto-BrennerStraße 20, 37079, Göttingen, Germany). Dr. Saager reports financial relationships with Medtronic, Ferrer Deutschland, and Merck. Part of the salary support for the author Dr. Busana was provided by an unrestricted research grant from Sartorius, Göttingen, Germany. Dr. Lazzari disclosed work for hire. Dr. Moerer’s institution received funding from the National CEOsys Network Germany, funded by the Federal Ministry of Education and Research (FKZ 01KX2021) and an unrestricted grant from CSL Behring and Pulsion Medical Systems SE; he received funding from Pulsion Medial Systems SE and CSL Behring. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

In this prospective observational study, non-invasive critical care echocardiography (CCE) was used to obtain quantitative hemodynamic parameters in 107 intensive care unit (ICU) patients; the parameters were then visualized in a novel web graph approach to increase the understanding and impact of CCE abnormalities, as an alternative to thermodilution techniques. Visualizing the CCE hemodynamic data in six-dimensional web graph plots was feasible in almost all ICU patients. In 23.1% of patients, significant tricuspid regurgitation prevented correlation between thermodilution techniques and echocardiographic hemodynamics. Two parameters of longitudinal right ventricular function (TAPSE and S') did not correlate in ICU patients. Clinical surrogate parameters of hemodynamic compromise did not correlate with measured hemodynamics. 26.2% of the patients with mean arterial pressures above 60 mmHg had cardiac indices (CI) below 2.5 L min -1 ·m -2 . A CI below 2.2 L·min -1 ·m -2 was associated with a significant ICU survival disadvantage. CCE was feasible in addition or as an alternative to thermodilution techniques for the hemodynamic evaluation of ICU patients. Six-dimensional web graph plots visualized the hemodynamic states and were especially useful in conditions in which thermodilution methods were not reliable. Hemodynamic CCE identified patients with previously unknown low CI, which correlated with a higher ICU mortality., (© 2022. The Author(s).)

Objectives: Cholestasis and elevated serum bile 1 acid levels are common in critically ill patients. This study aims to define the specific pattern of bile acids associated with acute respiratory distress syndrome (ARDS) and the changes in pattern over time., Methods: Prospective observational study. Serum samples of 70 ARDS patients were analyzed for primary bile acids (cholic acid, chenodeoxycholic acid) and secondary bile acids (deoxycholic acid, litocholic acid, and ursodeoxycholic acid) as well as their glycine and taurine glycation products., Results: Primary bile acid levels increased from day zero to day five by almost 50% (p<0.05). This change bases on a statistically significant increase in all primary bile acids between day 0 and day 5 (cholic acid [CA] p=0.001, taurocholic acid [TCA] p=0.004, glycocholic acid [GCA] p<0.001, chenodeoxycholic acid [CDCA] p=0.036, taurochenodeoxycholic acid [TCDCA] p<0.001, glycochenodeoxycholic acid [GCDCA] p<0.001). Secondary bile acids showed predominantly decreased levels on day 0 compared to the control group and remained stable throughout the study period; the differences between day zero and day five were not statistically significant. Non-survivors exhibited significantly higher levels of TCDCA on day 5 (p<0.05) than survivors. This value was also independently associated with survival in a logistic regression model with an odds ratio of 2.24 (95% CI 0.53-9.46)., Conclusions: The individual bile acid profile of this ARDS patient cohort is unique compared to other disease states. The combination of changes in individual bile acids reflects a shift toward the acidic pathway of bile acid synthesis. Our results support the concept of ARDS-specific plasma levels of bile acids in a specific pattern as an adaptive response mechanism., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

The extent of ventilator-induced lung injury may be related to the intensity of mechanical ventilation--expressed as mechanical power. In the present study, we investigated whether there is a safe threshold, below which lung damage is absent. Three groups of six healthy pigs (29.5 ± 2.5 kg) were ventilated prone for 48 h at mechanical power of 3, 7, or 12 J/min. Strain never exceeded 1.0. PEEP was set at 4 cmH 2 O. Lung volumes were measured every 12 h; respiratory, hemodynamics, and gas exchange variables every 6. End-experiment histological findings were compared with a control group of eight pigs which did not undergo mechanical ventilation. Functional residual capacity decreased by 10.4% ± 10.6% and 8.1% ± 12.1% in the 7 J and 12 J groups (p = 0.017, p < 0.001) but not in the 3 J group (+1.7% ± 17.7%, p = 0.941). In 3 J group, lung elastance, PaO 2 and PaCO 2 were worse compared to 7 J and 12 J groups (all p < 0.001), due to lower ventilation-perfusion ratio (0.54 ± 0.13, 1.00 ± 0.25, 1.78 ± 0.36 respectively, p < 0.001). The lung weight was lower (p < 0.001) in the controls (6.56 ± 0.90 g/kg) compared to 3, 7, and 12 J groups (12.9 ± 3.0, 16.5 ± 2.9, and 15.0 ± 4.1 g/kg, respectively). The wet-to-dry ratio was 5.38 ± 0.26 in controls, 5.73 ± 0.52 in 3 J, 5.99 ± 0.38 in 7 J, and 6.13 ± 0.59 in 12 J group (p = 0.03). Vascular congestion was more extensive in the 7 J and 12 J compared to 3 J and control groups. Mechanical ventilation (with anesthesia/paralysis) increase lung weight, and worsen lung histology, regardless of the mechanical power. Ventilating at 3 J/min led to better anatomical variables than at 7 and 12 J/min but worsened the physiological values., (© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Purpose: This study aimed at investigating the mechanisms underlying the oxygenation response to proning and recruitment maneuvers in coronavirus disease 2019 (COVID-19) pneumonia., Methods: Twenty-five patients with COVID-19 pneumonia, at variable times since admission (from 1 to 3 weeks), underwent computed tomography (CT) lung scans, gas-exchange and lung-mechanics measurement in supine and prone positions at 5 cmH 2 O and during recruiting maneuver (supine, 35 cmH 2 O). Within the non-aerated tissue, we differentiated the atelectatic and consolidated tissue (recruitable and non-recruitable at 35 cmH 2 O of airway pressure). Positive/negative response to proning/recruitment was defined as increase/decrease of PaO 2 /FiO 2 . Apparent perfusion ratio was computed as venous admixture/non aerated tissue fraction., Results: The average values of venous admixture and PaO 2 /FiO 2 ratio were similar in supine-5 and prone-5. However, the PaO 2 /FiO 2 changes (increasing in 65% of the patients and decreasing in 35%, from supine to prone) correlated with the balance between resolution of dorsal atelectasis and formation of ventral atelectasis (p = 0.002). Dorsal consolidated tissue determined this balance, being inversely related with dorsal recruitment (p = 0.012). From supine-5 to supine-35, the apparent perfusion ratio increased from 1.38 ± 0.71 to 2.15 ± 1.15 (p = 0.004) while PaO 2 /FiO 2 ratio increased in 52% and decreased in 48% of patients. Non-responders had consolidated tissue fraction of 0.27 ± 0.1 vs. 0.18 ± 0.1 in the responding cohort (p = 0.04). Consolidated tissue, PaCO 2 and respiratory system elastance were higher in patients assessed late (all p < 0.05), suggesting, all together, "fibrotic-like" changes of the lung over time., Conclusion: The amount of consolidated tissue was higher in patients assessed during the third week and determined the oxygenation responses following pronation and recruitment maneuvers., (© 2021. The Author(s).)

Background: Impaired liver function and cholestasis are frequent findings in critically ill patients and are associated with poor outcomes. We tested the hypothesis that hypoxic liver injury and hypoxic cholangiocyte injury are detectable very early in patients with ARDS, may depend on the severity of hypoxemia, and may be aggravated by the use of rescue therapies (high PEEP level and prone positioning) but could be attenuated by extracorporeal membrane oxygenation (ECMO)., Methods: In 70 patients with ARDS, aspartate-aminotransferase (AST), alanin-aminotransferase (ALT) and gamma glutamyltransferase (GGT) were measured on the day of the diagnosis of ARDS and three more consecutive days (day 3, day 5, day 10), total bile acids were measured on day 0, 3, and 5., Results: AST levels increased on day 0 and remained constant until day 5, then dropped to normal on day 10 (day 0: 66.5 U/l; day 3: 60.5 U/l; day 5: 63.5 U/l, day 10: 32.1 U/l), ALT levels showed the exact opposite kinetic. GGT was already elevated on day 0 (91.5 U/l) and increased further throughout (day 3: 163.5 U/l, day 5: 213 U/l, day 10: 307 U/l), total bile acids levels increased significantly from day 0 to day 3 ( p = 0.019) and day 0 to day 5 ( p < 0.001), but not between day 3 and day 5 ( p = 0.217). Total bile acids levels were significantly correlated to GGT on day 0 ( p < 0.001), day 3 ( p = 0.02), and in a trend on day 5 ( p = 0.055). PEEP levels were significantly correlated with plasma levels of AST (day 3), ALT (day 5) and GGT (day 10). Biomarker levels were not associated with the use of ECMO, prone position, the cause of ARDS, and paO 2 ., Conclusions: We found no evidence of hypoxic liver injury or hypoxic damage to cholangiocytes being caused by the severity of hypoxemia in ARDS patients during the very early phase of the disease. Additionally, mean PEEP level, prone positioning, and ECMO treatment did not have an impact in this regard. Nevertheless, GGT levels were elevated from day zero and rising, this increase was not related to paO 2 , prone position, ECMO treatment, or mean PEEP, but correlated to total bile acid levels.

Background: The use of ultrasonography in the intensive care unit (ICU) is steadily increasing but is usually restricted to examinations of single organs or organ systems. In this study, we combine the ultrasound approaches the most relevant to ICU to design a whole-body ultrasound (WBU) protocol. Recommendations and training schemes for WBU are sparse and lack conclusive evidence. Our aim was therefore to define the range and prevalence of abnormalities detectable by WBU to develop a simple and fast bedside examination protocol, and to evaluate the value of routine surveillance WBU in ICU patients., Methods: A protocol for focused assessments of sonographic abnormalities of the ocular, vascular, pulmonary, cardiac and abdominal systems was developed to evaluate 99 predefined sonographic entities on the day of admission and on days 3, 6, 10 and 15 of the ICU admission. The study was a clinical prospective single-center trial in 111 consecutive patients admitted to the surgical ICUs of a tertiary university hospital., Results: A total of 3003 abnormalities demonstrable by sonography were detected in 1275 individual scans of organ systems and 4395 individual single-organ examinations. The rate of previously undetected abnormalities ranged from 6.4 ± 4.2 on the day of admission to 2.9 ± 1.8 on day 15. Based on the sonographic findings, intensive care therapy was altered following 45.1% of examinations. Mean examination time was 18.7 ± 3.2 min, or 1.6 invested minutes per detected abnormality., Conclusions: Performing the WBU protocol led to therapy changes in 45.1% of the time. Detected sonographic abnormalities showed a high rate of change in the course of the serial assessments, underlining the value of routine ultrasound examinations in the ICU. Trial registration The study was registered in the German Clinical Trials Register (DRKS, 7 April 2017; retrospectively registered) under the identifier DRKS00010428., (© 2021. The Author(s).)

(1) Background: Sepsis is a leading cause of death and a global public health problem. Accordingly, deciphering the underlying molecular mechanisms of this disease and the determinants of its morbidity and mortality is pivotal. This study examined the effect of the rs951818 SNP of the negative costimulatory lymphocyte-activation gene 3 (LAG-3) on sepsis mortality and disease severity. (2) Methods: 707 consecutive patients with sepsis were prospectively enrolled into the present study from three surgical ICUs at University Medical Center Goettingen. Both 28- and 90-day mortality were analyzed as the primary outcome, while parameters of disease severity served as secondary endpoints. (3) Results: In the Kaplan-Meier analysis LAG-3 rs951818 AA-homozygote patients showed a significantly lower 28-day mortality (17.3%) compared to carriers of the C-allele (23.7%, p = 0.0476). In addition, these patients more often received invasive mechanical ventilation (96%) during the course of disease than C-allele carriers (92%, p = 0.0466). (4) Conclusions: Genetic profiling of LAG-3 genetic variants alone or in combination with other genetic biomarkers may represent a promising approach for risk stratification of patients with sepsis. Patient-individual therapeutic targeting of immune checkpoints, such as LAG-3, may be a future component of sepsis therapy. Further detailed investigations in clinically relevant sepsis models are necessary.

Coronavirus disease 2019 (COVID-19) pneumonia is an evolving disease. We will focus on the development of its pathophysiologic characteristics over time, and how these time-related changes determine modifications in treatment. In the emergency department: the peculiar characteristic is the coexistence, in a significant fraction of patients, of severe hypoxaemia, near-normal lung computed tomography imaging, lung gas volume and respiratory mechanics. Despite high respiratory drive, dyspnoea and respiratory rate are often normal. The underlying mechanism is primarily altered lung perfusion. The anatomical prerequisites for PEEP (positive end-expiratory pressure) to work (lung oedema, atelectasis, and therefore recruitability) are lacking. In the high-dependency unit: the disease starts to worsen either because of its natural evolution or additional patient self-inflicted lung injury (P-SILI). Oedema and atelectasis may develop, increasing recruitability. Noninvasive supports are indicated if they result in a reversal of hypoxaemia and a decreased inspiratory effort. Otherwise, mechanical ventilation should be considered to avert P-SILI. In the intensive care unit: the primary characteristic of the advance of unresolved COVID-19 disease is a progressive shift from oedema or atelectasis to less reversible structural lung alterations to lung fibrosis. These later characteristics are associated with notable impairment of respiratory mechanics, increased arterial carbon dioxide tension ( P aCO 2 ), decreased recruitability and lack of response to PEEP and prone positioning., Competing Interests: Conflicts of interest: L. Gattinoni reports consultancy fee from General Electrics and SIDAM. He also received lecture fees from Estor and Dimar. Conflicts of interest: S. Gattarello has nothing to disclose. Conflicts of interest: I. Steinberg has nothing to disclose. Conflicts of interest: M. Busana has nothing to disclose. Conflicts of interest: P. Palermo has nothing to disclose. Conflicts of interest: S. Lazzari has nothing to disclose. Conflicts of interest: F. Romitti has nothing to disclose. Conflicts of interest: M. Quintel has nothing to disclose. Conflicts of interest: K. Meissner has nothing to disclose. Conflicts of interest: J.J. Marini has nothing to disclose. Conflicts of interest: D. Chiumello has nothing to disclose. Conflicts of interest: L. Camporota has nothing to disclose., (Copyright ©The authors 2021.)

Purpose: We investigated if the stress applied to the lung during non-invasive respiratory support may contribute to the coronavirus disease 2019 (COVID-19) progression., Methods: Single-center, prospective, cohort study of 140 consecutive COVID-19 pneumonia patients treated in high-dependency unit with continuous positive airway pressure (n = 131) or non-invasive ventilation (n = 9). We measured quantitative lung computed tomography, esophageal pressure swings and total lung stress., Results: Patients were divided in five subgroups based on their baseline PaO 2 /FiO 2 (day 1): non-CARDS (median PaO 2 /FiO 2 361 mmHg, IQR [323-379]), mild (224 mmHg [211-249]), mild-moderate (173 mmHg [164-185]), moderate-severe (126 mmHg [114-138]) and severe (88 mmHg [86-99], p < 0.001). Each subgroup had similar median lung weight: 1215 g [1083-1294], 1153 [888-1321], 968 [858-1253], 1060 [869-1269], and 1127 [937-1193] (p = 0.37). They also had similar non-aerated tissue fraction: 10.4% [5.9-13.7], 9.6 [7.1-15.8], 9.4 [5.8-16.7], 8.4 [6.7-12.3] and 9.4 [5.9-13.8], respectively (p = 0.85). Treatment failure of CPAP/NIV occurred in 34 patients (24.3%). Only three variables, at day one, distinguished patients with negative outcome: PaO 2 /FiO 2 ratio (OR 0.99 [0.98-0.99], p = 0.02), esophageal pressure swing (OR 1.13 [1.01-1.27], p = 0.032) and total stress (OR 1.17 [1.06-1.31], p = 0.004). When these three variables were evaluated together in a multivariate logistic regression analysis, only the total stress was independently associated with negative outcome (OR 1.16 [1.01-1.33], p = 0.032)., Conclusions: In early COVID-19 pneumonia, hypoxemia is not linked to computed tomography (CT) pathoanatomy, differently from typical ARDS. High lung stress was independently associated with the failure of non-invasive respiratory support., (© 2021. The Author(s).)

Knowledge of gas volume, tissue mass and recruitability measured by the quantitative CT scan analysis (CT-qa) is important when setting the mechanical ventilation in acute respiratory distress syndrome (ARDS). Yet, the manual segmentation of the lung requires a considerable workload. Our goal was to provide an automatic, clinically applicable and reliable lung segmentation procedure. Therefore, a convolutional neural network (CNN) was used to train an artificial intelligence (AI) algorithm on 15 healthy subjects (1,302 slices), 100 ARDS patients (12,279 slices), and 20 COVID-19 (1,817 slices). Eighty percent of this populations was used for training, 20% for testing. The AI and manual segmentation at slice level were compared by intersection over union (IoU). The CT-qa variables were compared by regression and Bland Altman analysis. The AI-segmentation of a single patient required 5-10 s vs. 1-2 h of the manual. At slice level, the algorithm showed on the test set an IOU across all CT slices of 91.3 ± 10.0, 85.2 ± 13.9, and 84.7 ± 14.0%, and across all lung volumes of 96.3 ± 0.6, 88.9 ± 3.1, and 86.3 ± 6.5% for normal lungs, ARDS and COVID-19, respectively, with a U-shape in the performance: better in the lung middle region, worse at the apex and base. At patient level, on the test set, the total lung volume measured by AI and manual segmentation had a R 2 of 0.99 and a bias -9.8 ml [CI: +56.0/-75.7 ml]. The recruitability measured with manual and AI-segmentation, as change in non-aerated tissue fraction had a bias of +0.3% [CI: +6.2/-5.5%] and -0.5% [CI: +2.3/-3.3%] expressed as change in well-aerated tissue fraction. The AI-powered lung segmentation provided fast and clinically reliable results. It is able to segment the lungs of seriously ill ARDS patients fully automatically., 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 © 2021 Herrmann, Busana, Cressoni, Lotz, Moerer, Saager, Meissner, Quintel and Gattinoni.)

Background: Ventilator-induced lung injury (VILI) via respiratory mechanics is deeply interwoven with hemodynamic, kidney and fluid/electrolyte changes. We aimed to assess the role of positive fluid balance in the framework of ventilation-induced lung injury. Methods: Post-hoc analysis of seventy-eight pigs invasively ventilated for 48 h with mechanical power ranging from 18 to 137 J/min and divided into two groups: high vs. low pleural pressure (10.0 ± 2.8 vs. 4.4 ± 1.5 cmH 2 O; p < 0.01). Respiratory mechanics, hemodynamics, fluid, sodium and osmotic balances, were assessed at 0, 6, 12, 24, 48 h. Sodium distribution between intracellular, extracellular and non-osmotic sodium storage compartments was estimated assuming osmotic equilibrium. Lung weight, wet-to-dry ratios of lung, kidney, liver, bowel and muscle were measured at the end of the experiment. Results: High pleural pressure group had significant higher cardiac output (2.96 ± 0.92 vs. 3.41 ± 1.68 L/min; p < 0.01), use of norepinephrine/epinephrine (1.76 ± 3.31 vs. 5.79 ± 9.69 mcg/kg; p < 0.01) and total fluid infusions (3.06 ± 2.32 vs. 4.04 ± 3.04 L; p < 0.01). This hemodynamic status was associated with significantly increased sodium and fluid retention (at 48 h, respectively, 601.3 ± 334.7 vs. 1073.2 ± 525.9 mmol, p < 0.01; and 2.99 ± 2.54 vs. 6.66 ± 3.87 L, p < 0.01). Ten percent of the infused sodium was stored in an osmotically inactive compartment. Increasing fluid and sodium retention was positively associated with lung-weight ( R 2 = 0.43, p < 0.01; R 2 = 0.48, p < 0.01) and with wet-to-dry ratio of the lungs ( R 2 = 0.14, p < 0.01; R 2 = 0.18, p < 0.01) and kidneys ( R 2 = 0.11, p = 0.02; R 2 = 0.12, p = 0.01). Conclusion: Increased mechanical power and pleural pressures dictated an increase in hemodynamic support resulting in proportionally increased sodium and fluid retention and pulmonary edema., Competing Interests: LG reports a consultancy for General Electrics and SIDAM. He also receives lectures fees from Estor and Dimar. LS reports financial relationships with Medtronic, Ferrer Deutschland and Merck. Part of the salary support for the author MB was provided by an unrestricted research grant from Sartorius Inc. Göttingen, Germany. 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 Gattarello, Pasticci, Busana, Lazzari, Palermo, Palumbo, Romitti, Steinberg, Collino, Vassalli, Langer, Moerer, Saager, Herrmann, Cadringher, Meissner, Quintel and Gattinoni.)

Inflammation and oxidative stress characterize sepsis and determine its severity. In this study, we investigated the relationship between albumin oxidation and sepsis severity in a selected cohort of patients from the Albumin Italian Outcome Study (ALBIOS). A retrospective analysis was conducted on the oxidation forms of human albumin [human mercapto-albumin (HMA), human non-mercapto-albumin form 1 (HNA1) and human non-mercapto-albumin form 2 (HNA2)] in 60 patients with severe sepsis or septic shock and 21 healthy controls. The sepsis patients were randomized (1:1) to treatment with 20% albumin and crystalloid solution or crystalloid solution alone. The albumin oxidation forms were measured at day 1 and day 7. To assess the albumin oxidation forms as a function of oxidative stress, the 60 sepsis patients, regardless of the treatment, were grouped based on baseline sequential organ failure assessment (SOFA) score as surrogate marker of oxidative stress. At day 1, septic patients had significantly lower levels of HMA and higher levels of HNA1 and HNA2 than healthy controls. HMA and HNA1 concentrations were similar in patients treated with albumin or crystalloids at day 1, while HNA2 concentration was significantly greater in albumin-treated patients ( p < 0.001). On day 7, HMA was significantly higher in albumin-treated patients, while HNA2 significantly increased only in the crystalloids-treated group, reaching values comparable with the albumin group. When pooling the septic patients regardless of treatment, albumin oxidation was similar across all SOFA groups at day 1, but at day 7 HMA was lower at higher SOFA scores. Mortality rate was independently associated with albumin oxidation levels measured at day 7 (HMA log-rank = 0.027 and HNA2 log-rank = 0.002), irrespective of treatment group. In adjusted regression analyses for 90-day mortality, this effect remained significant for HMA and HNA2. Our data suggest that the oxidation status of albumin is modified according to the time of exposure to oxidative stress (differences between day 1 and day 7). After 7 days of treatment, lower SOFA scores correlate with higher albumin antioxidant capacity. The trend toward a positive effect of albumin treatment, while not statistically significant, warrants further investigation., Competing Interests: MC, FM, and AP are full-time employees of Grifols, a manufacturer of plasma derivatives. Grifols had no access to clinical data from ALBIOS and did not perform statistical analyses of data, but only provided editorial support. Publication costs of this manuscript were sustained by Grifols. LG and PC received honoraria from Grifols., (Copyright © 2021 Bonifazi, Meessen, Pérez, Vasques, Busana, Vassalli, Novelli, Bernasconi, Signori, Masson, Romitti, Giosa, Macrì, Pasticci, Palumbo, Mota, Costa, Caironi, Latini, Quintel and Gattinoni.)

Objectives: Early diagnosis of infections is pivotal in critically ill patients. Innovative gene expression-based approaches promise to deliver precise, fast, and clinically practicable diagnostic tools to bedside. This study aimed to validate the SepsisMetaScore, an 11-gene signature previously reported by our study group, in a representative longitudinal cohort of trauma patients., Design: Prospective observational cohort study., Setting: Surgical ICUs of the University Medical Center Goettingen, Germany., Patients: Critically ill patients with severe traumatic injuries., Interventions: None., Measurements and Main Results: Paired box gene (PAXgene) RNA blood tubes were drawn at predefined time points over the course of disease. The performance of the SepsisMetaScore was tested using targeted polymerase chain reaction and compared with Procalcitonin using area under the receiver operating characteristics analyses. The SepsisMetaScore showed significant differences between infected and noninfected patients (n = 52). It was able to accurately discriminate infectious from noninfectious acute inflammation with an area under the receiver operating characteristics of 0.92 (95% CI, 0.85-0.99) and significantly outperformed Procalcitonin (area under the receiver operating characteristics curve = 0.53; 95% CI, 0.42-0.64) early in the course of infection (p = 0.014)., Conclusions: We demonstrated the clinical utility for diagnosis of infections with higher accuracy using the SepsisMetaScore compared with Procalcitonin in a prospective cohort of severe trauma patients. Future studies should assess whether the SepsisMetaScore may substantially improve clinical practice by accurate differentiation of infections from sterile inflammation and identification of patients at risk for sepsis. Our results support further investigation of the SepsisMetaScore for the development of tailored precision treatment of critically ill patients., Competing Interests: Drs. Thair and Sweeney are employees of, and shareholders in, Inflammatix, Inc. Drs. Thair, Sweeney, and Khatri received funding from Inflammatix, Inc, Burlingame, CA. Inflammatix is developing the SepsisMetaScore as part of a broader test for commercial use (HostDx-Sepsis; Inflammatix). Dr. Quintel also received funding from Xenies/Fresenius, B.Braun, and Baxter. Dr. Khatri is a shareholder in and a consultant to Inflammatix; he is funded, in part, by the Bill and Melinda Gates Foundation (OPP1113682); the National Institute of Allergy and Infectious Diseases grants 1U19AI109662, U19AI057229, and 5R01AI125197; Department of Defense contracts W81XWH-18-1-0253 and W81XWH1910235; and the Ralph & Marian Falk Medical Research Trust. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: Mechanical ventilation (MV) is the cornerstone in the management of the acute respiratory distress syndrome (ARDS). Recent research suggests that decreasing the intensity of MV using lung protective ventilation (LPV) with lower tidal volume (Vt) and driving pressure (∆P) could improve survival. Extra-corporal CO 2 removal (ECCO 2 R) precisely enables LPV by allowing lower Vt, ∆P and mechanical power while maintaining PaCO 2 within a physiologic range. This study evaluates the potential cost-effectiveness of ECCO 2 R-enabled LPV in France., Methods: We modelled the distribution over time of ventilated ARDS patients across 3 health-states (alive & ventilated, alive & weaned from ventilation, dead). We compared the outcomes of 3 strategies: MV (no ECCO 2 R), LPV (ECCO 2 R when PaCO 2  > 55 mmHg) and Ultra-LPV (ECCO 2 R for all). Patients characteristics, ventilation settings, survival and lengths of stay were derived from a large ARDS epidemiology study. Survival benefits associated with lower ∆P were taken from the analysis of more than 3000 patients enrolled in 9 randomized trials. Health outcomes were expressed in quality-adjusted life years (QALYs). Incremental cost-effectiveness ratios (ICERs) were computed with both Day 60 cost and Lifetime cost., Results: Both LPV and ULPV as enabled by ECCO2R provided favorable results at Day 60 as compared to MV. Survival rates were increased with the protective strategies, notably with ULPV that provided even more manifest benefits as compared to MV. LPV and ULPV produced +0.162 and + 0.627 incremental QALYs as compared to MV, respectively. LPV and ULPV costs were augmented because of their survival benefits. Nonetheless, ICERs of LPV and ULPV vs. MV were all well below the €50,000 threshold. ULPV also presented with favorable ICERs as compared to LPV (i.e. less than €25,000/QALY)., Conclusions: ECCO 2 R-enabled LPV strategies might provide cost-effective survival benefit. Additional data from interventional and observational studies are needed to support this preliminary model-based analysis., Competing Interests: Declaration of Competing Interest OE, AMD, PM, MQ and AC have received reimbursements and consulting fees from Baxter in the conduct of the study and the preparation of the manuscript. JG and KH are employees of Baxter and own stocks or shares of the company. This study was funded by Baxter. The sponsor had no influence on the design of the model and the choice of sources to feed it. Authors are grateful to Dilip Makhija and Stephen Russel for their valuable inputs at the study inception., (Copyright © 2021. Published by Elsevier Inc.)

Background: Fluid warming, recommended for fluid rates of > 500 ml h -1 , is an integral part of patient temperature management strategies. Fluid warming devices using an uncoated aluminium containing heating element have been reported to liberate aluminium resulting in critical aluminium concentrations in heated fluids. We investigated saline solution (0.9%), artificially spiked with organic acids to determine the influence of fluid composition on aluminium release using the uncoated enFlow® device. Additionally, the Level1® as a high volume fluid warming device and the ThermoSens® device were investigated with artificial spiked fluid at high risk for aluminum release and a clinically used crystalloid solution., Results: Saline solution spiked with lactate more than acetate, especially at a non neutral pH, led to high aluminium release. Next to the enFlow® device, aluminium release was observed for the Level1® device, but not for the coated ThermoSens®-device., Conclusion: Uncoated aluminium containing fluid warming devices lead to potentially toxic levels of aluminium in heated fluids, especially in fluids with non-neutral pH containing organic acids and their salts like balanced electrolyte solutions.

Background: The physiological dead space is a strong indicator of severity and outcome of acute respiratory distress syndrome (ARDS). The "ideal" alveolar PCO 2 , in equilibrium with pulmonary capillary PCO 2 , is a central concept in the physiological dead space measurement. As it cannot be measured, it is surrogated by arterial PCO 2 which, unfortunately, may be far higher than ideal alveolar PCO 2 , when the right-to-left venous admixture is present. The "ideal" alveolar PCO 2 equals the end-tidal PCO 2 (P ET CO 2 ) only in absence of alveolar dead space. Therefore, in the perfect gas exchanger (alveolar dead space = 0, venous admixture = 0), the P ET CO 2 /PaCO 2 is 1, as P ET CO 2 , P A CO 2 and PaCO 2 are equal. Our aim is to investigate if and at which extent the P ET CO 2 /PaCO 2 , a comprehensive meter of the "gas exchanger" performance, is related to the anatomo physiological characteristics in ARDS., Results: We retrospectively studied 200 patients with ARDS. The source was a database in which we collected since 2003 all the patients enrolled in different CT scan studies. The P ET CO 2 /PaCO 2 , measured at 5 cmH 2 O airway pressure, significantly decreased from mild to mild-moderate moderate-severe and severe ARDS. The overall populations was divided into four groups (~ 50 patients each) according to the quartiles of the P ET CO 2 /PaCO 2 (lowest ratio, the worst = group 1, highest ratio, the best = group 4). The progressive increase P ET CO 2 /PaCO 2 from quartile 1 to 4 (i.e., the progressive approach to the "perfect" gas exchanger value of 1.0) was associated with a significant decrease of non-aerated tissue, inohomogeneity index and increase of well-aerated tissue. The respiratory system elastance significantly improved from quartile 1 to 4, as well as the PaO 2 /FiO 2 and PaCO 2 . The improvement of P ET CO 2 /PaCO 2 was also associated with a significant decrease of physiological dead space and venous admixture. When PEEP was increased from 5 to 15 cmH 2 O, the greatest improvement of non-aerated tissue, PaO 2 and venous admixture were observed in quartile 1 of P ET CO 2 /PaCO 2 and the worst deterioration of dead space in quartile 4., Conclusion: The ratio P ET CO 2 /PaCO 2 is highly correlated with CT scan, physiological and clinical variables. It appears as an excellent measure of the overall "gas exchanger" status.

Aerosol therapy in patients suffering from acute respiratory distress syndrome (ARDS) has so far failed in improving patients' outcomes. This might be because dependent lung areas cannot be reached by conventional aerosols. Due to their physicochemical properties, semifluorinated alkanes (SFAs) could address this problem. After induction of ARDS, 26 pigs were randomized into three groups: (1) control (Sham), (2) perfluorohexyloctane (F6H8), and (3) F6H8-ibuprofen. Using a nebulization catheter, (2) received 1 mL/kg F6H8 while (3) received 1 mL/kg F6H8 with 6 mg/mL ibuprofen. Ibuprofen plasma and lung tissue concentration, bronchoalveolar lavage (BAL) fluid concentration of TNF-α, IL-8, and IL-6, and lung mechanics were measured. The ibuprofen concentration was equally distributed to the dependent parts of the right lungs. Pharmacokinetic data demonstrated systemic absorption of ibuprofen proofing a transport across the alveolo-capillary membrane. A significantly lower TNF-α concentration was observed in (2) and (3) when compared to the control group (1). There were no significant differences in IL-8 and IL-6 concentrations and lung mechanics. F6H8 aerosol seemed to be a suitable carrier for pulmonary drug delivery to dependent ARDS lung regions without having negative effects on lung mechanics.

COVID-19 infection may lead to acute respiratory distress syndrome (CARDS) where severe gas exchange derangements may be associated, at least in the early stages, only with minor pulmonary infiltrates. This may suggest that the shunt associated to the gasless lung parenchyma is not sufficient to explain CARDS hypoxemia. We designed an algorithm (Vent ri Q lar ), based on the same conceptual grounds described by J.B. West in 1969. We set 498 ventilation-perfusion (V A /Q) compartments and, after calculating their blood composition (PO 2 , PCO 2 , and pH), we randomly chose 10 6 combinations of five parameters controlling a bimodal distribution of blood flow. The solutions were accepted if the predicted PaO 2 and PaCO 2 were within 10% of the patient's values. We assumed that the shunt fraction equaled the fraction of non-aerated lung tissue at the CT quantitative analysis. Five critically-ill patients later deceased were studied. The PaO 2 /FiO 2 was 91.1 ± 18.6 mmHg and PaCO 2 69.0 ± 16.1 mmHg. Cardiac output was 9.58 ± 0.99 L/min. The fraction of non-aerated tissue was 0.33 ± 0.06. The model showed that a large fraction of the blood flow was likely distributed in regions with very low V A /Q (Q mean  = 0.06 ± 0.02) and a smaller fraction in regions with moderately high V A /Q. Overall LogSD, Q was 1.66 ± 0.14, suggestive of high V A /Q inequality. Our data suggest that shunt alone cannot completely account for the observed hypoxemia and a significant V A /Q inequality must be present in COVID-19. The high cardiac output and the extensive microthrombosis later found in the autopsy further support the hypothesis of a pathological perfusion of non/poorly ventilated lung tissue. NEW & NOTEWORTHY Hypothesizing that the non-aerated lung fraction as evaluated by the quantitative analysis of the lung computed tomography (CT) equals shunt (V A /Q = 0), we used a computational approach to estimate the magnitude of the ventilation-perfusion inequality in severe COVID-19. The results show that a severe hyperperfusion of poorly ventilated lung region is likely the cause of the observed hypoxemia. The extensive microthrombosis or abnormal vasodilation of the pulmonary circulation may represent the pathophysiological mechanism of such V A /Q distribution.

Background: Hospital-acquired pneumonia (HAP) is a common problem in intensive care medicine and the patient outcome depends on the fast beginning of adequate antibiotic therapy. Until today pathogen identification is performed using conventional microbiological methods with turnaround times of at least 24 h for the first results. It was the aim of this study to investigate the potential of headspace analyses detecting bacterial species-specific patterns of volatile organic compounds (VOCs) for the rapid differentiation of HAP-relevant bacteria., Methods: Eleven HAP-relevant bacteria (Acinetobacter baumanii, Acinetobacter pittii, Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis, Staphylococcus aureus, Serratia marcescens) were each grown for 6 hours in Lysogeny Broth and the headspace over the grown cultures was investigated using multi-capillary column-ion mobility spectrometry (MCC-IMS) to detect differences in the VOC composition between the bacteria in the panel. Peak areas with changing signal intensities were statistically analysed, including significance testing using one-way ANOVA or Kruskal-Wallis test (p < 0.05)., Results: 30 VOC signals (23 in the positive ion mode and 7 in the negative ion mode of the MCC-IMS) showed statistically significant differences in at least one of the investigated bacteria. The VOC patterns of the bacteria within the HAP panel differed substantially and allowed species differentiation., Conclusions: MCC-IMS headspace analyses allow differentiation of bacteria within HAP-relevant panel after 6 h of incubation in a complex fluid growth medium. The method has the potential to be developed towards a feasible point-of-care diagnostic tool for pathogen differentiation on HAP.

Rationale: Understanding the physiology of CO 2 stores mobilization is a prerequisite for intermittent extracorporeal CO 2 removal (ECCO 2 R) in patients with chronic hypercapnia. Objectives: To describe the dynamics of CO 2 stores. Methods: Fifteen pigs (61.7 ± 4.3 kg) were randomized to 48 hours of hyperventilation (group "Hyper," n  = 4); 48 hours of hypoventilation (group "Hypo," n  = 4); 24 hours of hypoventilation plus 24 hours of normoventilation (group "Hypo-Baseline," n  = 4); or 24 hours of hypoventilation plus 24 hours of hypoventilation plus ECCO 2 R (group "Hypo-ECCO 2 R," n  = 3). Forty-eight hours after randomization, the current [Formula: see text]e was reduced by 50% in every pig. Measurements and Main Results: We evaluated [Formula: see text]co 2 , [Formula: see text]o 2 , and metabolic [Formula: see text]co 2 ([Formula: see text]o 2 times the metabolic respiratory quotient). Changes in the CO 2 stores were calculated as [Formula: see text]co 2  - metabolic V̇co 2 . After 48 hours, the CO 2 stores decreased by 0.77 ± 0.17 l kg -1 in group Hyper and increased by 0.32 ± 0.27 l kg -1 in group Hypo ( P  = 0.030). In group Hypo-Baseline, they increased by 0.08 ± 0.19 l kg -1 , whereas in group Hypo-ECCO 2 R, they decreased by 0.32 ± 0.24 l kg -1 ( P  = 0.197). In the second 24-hour period, in groups Hypo-Baseline and Hypo-ECCO 2 R, the CO2 stores decreased by 0.15 ± 0.09 l kg -1 and 0.51 ± 0.06 l kg -1 , respectively ( P  = 0.002). At the end of the experiment, the 50% reduction of [Formula: see text]e caused a Pa CO 2 rise of 9.3 ± 1.1, 32.0 ± 5.0, 16.9 ± 1.2, and 11.7 ± 2.0 mm Hg h -1 in groups Hyper, Hypo, Hypo-Baseline, and Hypo-ECCO 2 R, respectively ( P  < 0.001). The Pa CO 2 rise was inversely related to the previous CO 2 stores mobilization ( P  < 0.001). Conclusions: CO 2 from body stores can be mobilized over 48 hours without reaching a steady state. This provides a physiological rationale for intermittent ECCO 2 R in patients with chronic hypercapnia.

Acute respiratory distress syndrome (ARDS) represents an acute diffuse inflammation of the lungs triggered by different causes, uniformly leading to a noncardiogenic pulmonary edema with inhomogeneous densities in lung X-ray and lung CT scan and acute hypoxemia. Edema formation results in "heavy" lungs, inducing loss of compliance and the need to spend more energy to "move" the lungs. Consequently, an ARDS patient, as long as the patient is breathing spontaneously, has an increased respiratory drive to ensure adequate oxygenation and CO 2 removal. One would expect that, once the blood gases get back to "physiological" values, the respiratory drive would normalize and the breathing effort return to its initial status. However, in many ARDS patients, this is not the case; their respiratory drive appears to be upregulated and fully or at least partially detached from the blood gas status. Strikingly, similar alteration of the respiratory drive can be seen in patients suffering from SARS, especially SARS-Covid-19. We hypothesize that alterations of the renin-angiotensin-system (RAS) related to the pathophysiology of ARDS and SARS are involved in this dysregulation of chemosensitive control of breathing., 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 © 2021 Hülsmann, Khabbazzadeh, Meissner and Quintel.)

Background: Albumin is a key regulator of fluid distribution within the extracellular space and has several properties beyond its oncotic activity. The accumulating evidence suggests that supplementation of albumin may provide survival advantages only when the insult is severe as in patients with septic shock., Methods/design: The randomized controlled multicentre study of albumin replacement therapy in septic shock (ARISS) investigates whether the replacement with albumin and the maintenance of its serum levels of at least 30 g/l for 28 days improve survival in patients with septic shock compared to resuscitation and volume maintenance without albumin. Adult patients (≥ 18 years) with septic shock are randomly assigned within a maximum of 24 h after the onset of septic shock after obtaining informed consents to treatment or control groups. Patients assigned to the treatment group receive a 60-g loading dose of human albumin 20% over 2-3 h. Serum albumin levels are maintained at least at 30 g/l in the ICU for a maximum of 28 days following randomization using 40-80 g human albumin 20% infusion. The control group is treated according to the usual practice with crystalloids as the first choice for the resuscitation and maintenance phase of septic shock. The primary endpoint is 90 days mortality and secondary endpoints include 28-day, 60-day, ICU, and in-hospital mortality, organ dysfunction/failure, total amount of fluid administration and total fluid balance in the ICU, and lengths of ICU and hospital stay. In total, 1412 patients need to be analysed, 706 per group. For the sample size estimation, a 15% reduction in 90-day mortality is assumed, i.e. an absolute reduction of 7.5% points to 42.5% (relative risk 1.18). Assuming a dropout rate of 15%, a total of 1662 patients need to be allocated., Discussion: The results of the clinical trial may influence the treatment of patients with septic shock. The expected improvement in patient survival may result in a reduction in the resources currently used in the treatment of these patients and in the socioeconomic burden of this disease., Trial Registration: ClinicalTrials.gov NCT03869385 . Registration on 18 July 2019. Protocol version: Final 3.0.

Purpose: To investigate whether COVID-19-ARDS differs from all-cause ARDS., Methods: Thirty-two consecutive, mechanically ventilated COVID-19-ARDS patients were compared to two historical ARDS sub-populations 1:1 matched for PaO 2 /FiO 2 or for compliance of the respiratory system. Gas exchange, hemodynamics and respiratory mechanics were recorded at 5 and 15 cmH 2 O PEEP. CT scan variables were measured at 5 cmH 2 O PEEP., Results: Anthropometric characteristics were similar in COVID-19-ARDS, PaO 2 /FiO 2 -matched-ARDS and Compliance-matched-ARDS. The PaO 2 /FiO 2 -matched-ARDS and COVID-19-ARDS populations (both with PaO 2 /FiO 2 106 ± 59 mmHg) had different respiratory system compliances (Crs) (39 ± 11 vs 49.9 ± 15.4 ml/cmH 2 O, p = 0.03). The Compliance-matched-ARDS and COVID-19-ARDS had similar Crs (50.1 ± 15.7 and 49.9 ± 15.4 ml/cmH 2 O, respectively) but significantly lower PaO 2 /FiO 2 for the same Crs (160 ± 62 vs 106.5 ± 59.6 mmHg, p < 0.001). The three populations had similar lung weights but COVID-19-ARDS had significantly higher lung gas volume (PaO 2 /FiO 2 -matched-ARDS 930 ± 644 ml, COVID-19-ARDS 1670 ± 791 ml and Compliance-matched-ARDS 1301 ± 627 ml, p < 0.05). The venous admixture was significantly related to the non-aerated tissue in PaO 2 /FiO 2 -matched-ARDS and Compliance-matched-ARDS (p < 0.001) but unrelated in COVID-19-ARDS (p = 0.75), suggesting that hypoxemia was not only due to the extent of non-aerated tissue. Increasing PEEP from 5 to 15 cmH 2 O improved oxygenation in all groups. However, while lung mechanics and dead space improved in PaO 2 /FiO 2 -matched-ARDS, suggesting recruitment as primary mechanism, they remained unmodified or worsened in COVID-19-ARDS and Compliance-matched-ARDS, suggesting lower recruitment potential and/or blood flow redistribution., Conclusions: COVID-19-ARDS is a subset of ARDS characterized overall by higher compliance and lung gas volume for a given PaO 2 /FiO 2 , at least when considered within the timeframe of our study.

Background : Previous studies have reported the fundamental role of immunoregulatory proteins in the clinical phenotype and outcome of sepsis. This study investigated two functional single nucleotide polymorphisms (SNPs) of T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), which has a negative stimulatory function in the T cell immune response. Methods : Patients with sepsis ( n = 712) were prospectively enrolled from three intensive care units (ICUs) at the University Medical Center Goettingen since 2012. All patients were genotyped for the TIM-3 SNPs rs1036199 and rs10515746. The primary outcome was 28-day mortality. Disease severity and microbiological findings were secondary endpoints. Results : Kaplan-Meier survival analysis demonstrated a significantly lower 28-day mortality for TIM-3 rs1036199 AA homozygous patients compared to C-allele carriers (18% vs. 27%, p = 0.0099) and TIM-3 rs10515746 CC homozygous patients compared to A-allele carriers (18% vs. 26%, p = 0.0202). The TIM-3 rs1036199 AA genotype and rs10515746 CC genotype remained significant predictors for 28-day mortality in the multivariate Cox regression analysis after adjustment for relevant confounders (adjusted hazard ratios: 0.67 and 0.70). Additionally, patients carrying the rs1036199 AA genotype presented more Gram-positive and Staphylococcus epidermidis infections, and rs10515746 CC homozygotes presented more Staphylococcus epidermidis infections. Conclusion : The studied TIM-3 genetic variants are associated with altered 28-day mortality and susceptibility to Gram-positive infections in sepsis.

Objective: To investigate the behavior of pentraxin-3 (PTX3), troponin T (hsTnT), N-terminal pro-B type Natriuretic Peptide (NT-proBNP) in sepsis and their relationships with sepsis severity and oxygen transport/utilization impairment., Design: Retrospective analysis of PTX3, hsTnT, NT-proBNP levels at day 1, 2, and 7 after admission in the intensive care unit in a subset of the Albumin Italian Outcome Sepsis database., Setting: Forty Italian intensive care units., Patients: Nine hundred fifty-eight septic patients enrolled in the randomized clinical trial comparing albumin replacement plus crystalloids and crystalloids alone., Interventions: The patients were divided into sextiles of lactate (marker of severity), ScvO2 (marker of oxygen transport), and fluid balance (marker of therapeutic strategy)., Measurements and Main Results: PTX3 and hsTnT were remarkably similar in the two treatment arms, while NT-proBNP was almost double in the albumin treatment group. However, as the distribution of all these biomarkers was similar between control and treatment arms, for the sake of clarity, we analyzed the patients as a single cohort. PTX3 (71.8 [32.9-186.3] ng/mL), hsTnT (50.4 [21.6-133.6] ng/L), and NT-proBNP (4,393 [1,313-13,837] ng/L) were abnormally elevated in 100%, 84.5%, 93.4% of the 953 patients and all decreased from day 1 to day 7. PTX3 monotonically increased with increasing lactate levels. The hsTnT levels were significantly higher when ScvO2 levels were abnormally low (< 70%), suggesting impaired oxygen transport compared with higher ScvO2 levels, suggesting impaired oxygen utilization. NT-proBNP was higher with higher lactate and fluid balance. At ScvO2 levels < 70%, the NT-proBNP was higher than at higher ScvO2 levels. However, even with higher ScvO2, the NT-proBNP was remarkably elevated, suggesting volume expansion. Increased level of NT-proBNP showed the strongest association with 90-day mortality., Conclusions: The selected biomarkers seem related to different mechanisms during sepsis: PTX3 to sepsis severity, hsTnT to impaired oxygen transport, NT-proBNP to sepsis severity, oxygen transport, and aggressive fluid strategy.

Objective: The target of this methodological evaluation was the feasibility of long-term monitoring of changes in lung conditions by time-difference electrical impedance tomography (tdEIT). In contrast to ventilation monitoring by tdEIT, the monitoring of end-expiratory (EELIC) or end-inspiratory (EILIC) lung impedance change always requires a reference measurement., Approach: To determine the stability of the used Pulmovista 500 ® EIT system, as a prerequisite it was initially secured on a resistive phantom for 50 h. By comparing the slopes of EELIC for the whole lung area up to 48 h from 36 pigs ventilated at six positive end-expiratory pressure (PEEP) levels from 0 to 18 cmH 2 O we found a good agreement (range of r 2 = 0.93-1.0) between absolute EIT (aEIT) and tdEIT values. This justified the usage of tdEIT with its superior local resolution compared to aEIT for long-term determination of EELIC., Main Results: The EELIC was between -0.07 Ωm day -1 at PEEP 4 and -1.04 Ωm day -1 at PEEP 18 cmH 2 O. The complex local time pattern for EELIC was roughly quantified by the new parameter, centre of end-expiratory change (CoEEC), in equivalence to the established centre of ventilation (CoV). The ventrally located mean of the CoV was fairly constant in the range of 42%-46% of thorax diameter; however, on the contrary, the CoEEC shifted from about 40% to about 75% in the dorsal direction for PEEP levels of 14 and 18 cmH 2 O., Significance: The observed shifts started earlier for higher PEEP levels. Changes of EELI could be precisely monitored over a period of 48 h by tdEIT on pigs.