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Background: Low T3-(/T4-) syndrome, also known as non-thyroidal Illness Syndrome (NTIS) describes a decrease in free serum thyroid hormones without a concomitant increase in TSH, frequently observed in critically ill patients. However, whether NTIS is only a metabolic adaption to stress in critically ill or plays a crucial role as an independent risk factor for ICU mortality, remains unknown. Our study aimed to evaluate NTIS as an independent risk factor for increased ICU mortality., Methods: All patients admitted to the interdisciplinary intensive care unit (ICU) at the University Hospital of Leipzig between 2008 and 2014 were retrospectively analyzed for thyroidal function. Baseline data, information on additional thyroid function tests, disease progression, hospital and ICU length of stay (LOS) and patient outcome were retrospectively analyzed from the hospitals digital information system. For statistical evaluation, univariate analysis, matched pairs analysis and multivariate logistic regression were conducted., Results: One thousand, seven hundred ninety patients were enrolled in the study, of which 665 showed NTIS. Univariate analysis revealed a positive association of NTIS with ICU- and hospital-LOS, need for mechanical ventilation, incidence of sepsis, acute respiratory distress syndrome, acute liver failure and increased ICU mortality. Results of matched pair analysis confirmed these findings. In multivariate logistic regression, NTIS was associated with an increased ICU-LOS, increased duration of mechanical ventilation, acute kidney injury and liver failure, but showed no independent association with increased ICU-mortality., Conclusion: Duration of mechanical ventilation as well as incidence of acute kidney injury, sepsis and acute liver failure were detected as independent predictors of mortality in patients with NTIS. NTIS itself was no independent predictor of increased ICU-mortality., (© 2023. The Author(s).)

Background: Recent data suggest that anesthesiologic interventions-e.g., the choice of the anesthetic regimen or the administration of blood products-might play a major role in determining outcome after tumor surgery. In contrast to adult patients, only limited data are available regarding the potential association of anesthesia and outcome in pediatric cancer patients., Methods: A retrospective multicenter study assessing data from pediatric patients (0-18 years of age) undergoing surgery for nephroblastoma between 2004 and 2018 was conducted at three academic centers in Europe. Overall and recurrence-free survival were the primary outcomes of the study and were evaluated for a potential impact of intraoperative administration of erythrocyte concentrates, the use of regional anesthesia and the choice of the anesthetic regimen. The length of stay on the intensive care unit, the time to hospital discharge after surgery and blood neutrophil-to-lymphocyte ratio were defined as secondary outcomes., Results: In total, data from 65 patients were analyzed. Intraoperative administration of erythrocyte concentrates was associated with a reduction in recurrence-free survival (hazard ratio (HR) 7.59, 95% confidence interval (CI) 1.36-42.2, p = 0.004), whereas overall survival (HR 5.37, 95% CI 0.42-68.4, p = 0.124) was not affected. The use of regional anesthesia and the choice of anesthetic used for maintenance of anesthesia did not demonstrate an effect on the primary outcomes. It was, however, associated with fewer ICU transfers, a shortened time to discharge and a decreased postoperative neutrophil-to-lymphocyte ratio., Conclusions: The current study provides the first evidence for a possible association between blood transfusion as well as anesthesiologic interventions and outcome after pediatric cancer surgery.

Aims: Septic cardiomyopathy is a severe complication of sepsis and septic shock. This study aimed to evaluate the role of thrombomodulin and its lectin-like domain (LLD-TM) in the development of septic cardiomyopathy and the link between LLD-TM, HMGB-1, and toll-like receptors 2/4 (TLR 2/4) to intracellular mechanisms resulting in reduced cardiac function., Materials and Methods: Sepsis was induced using a polymicrobial peritoneal infection model in wildtype and mice lacking the lectin-like domain of thrombomodulin (TM LeD/LeD ), and severity of disease and cardiac function was compared. Cell cultures of cardiomyocytes were prepared from hearts harvested from wildtype and TM LeD/LeD mice. Cultures of neonatal cardiomyocytes were transfected with complete human thrombomodulin or human thrombomodulin deficient of LLD-TM and when TLR-2 and/or TLR-4 were blocked. All cultures were challenged with inflammatory stimuli., Key Findings: Lack of the LLD-TM results in a significant increase in severity of disease, decreased survival and impaired cardiac function in septic mice. In vivo and in vitro analyses of cardiomyocytes displayed high levels of inflammatory cytokines causing cardio-depression. In vitro results showed a strong correlation between elevated HMGB-1 levels and elevated troponin-1 levels. No connection was found between HMGB-1 and TLR-2 and/or -4 signalling pathways. Phospholamban mediated dysregulation of calcium homeostasis resulted in a general impairment after sepsis induction, but showed no connection to LLD-TM., Significance: Lack of LLD-TM results in an increase in general severity of disease, decreased survival and impaired cardiac function in sepsis. TLR-2 and TLR 4 do not participate as mediating factors in the development of septic cardiomyopathy., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: Cachexia and nutritional problems play a major role in palliative care. Artificial nutrition such as parenteral nutrition is common but its role and indications in terminal patients remain controversial due to lack of data. Therefore, recommendations are vague. Benefits and risks of parenteral nutrition in palliative care as well as the clinical implementation of the guidelines have not been adequately studied yet., Methods: In this single-centre observational study, 72 palliative care patients were followed for 1 month. Patients with and without parenteral nutrition were analysed regarding venous access complications, oedema, weight and health-related quality of life., Results: 93% of all patients showed reduced food intake. 34 (47%) patients received parenteral nutrition. Parenteral nutrition reduced energy deficit but was not associated with quality of life. Complications with the venous accesses for parenteral nutrition were frequent. A relevant proportion of patients with planned parenteral nutrition received no or only a few days of parenteral nutrition. Moreover, patients with parenteral nutrition showed more frequent and pronounced oedema., Conclusion: The benefit-risk balance of palliative parenteral nutrition in end-of-life treatment seems to be questionable. In view of the identified risks, parenteral nutrition in end-of-life care should be initiated with caution., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Despite recent advances and refinements in perioperative management of simultaneous pancreas−kidney transplantation (SPKT) early pancreatic graft dysfunction (ePGD) remains a critical problem with serious impairment of early and long-term graft function and outcome. Hence, we evaluated a panel of classical blood serum markers for their value in predicting early graft dysfunction in patients undergoing SPKT. Methods: From a prospectively collected database medical data of 105 patients undergoing SPKT between 1998 and 2018 at our center were retrospectively analyzed. The primary study outcome was the detection of occurrence of early pancreatic graft dysfunction (ePGD), the secondary study outcome was early renal graft dysfunction (eRGD) as well as all other outcome parameters associated with the graft function. In this context, ePGD was defined as pancreas graft-related complications including graft pancreatitis, pancreatic abscess/peritonitis, delayed graft function, graft thrombosis, bleeding, rejection and the consecutive need for re-laparotomy due to graft-related complications within 3 months. With regard to analyzing ePGD, serum levels of white blood cell count (WBC), C-reactive protein (CRP), procalcitonin (PCT), pancreatic lipase as well as neutrophil−lymphocyte ratio (NLR) and platelet−lymphocyte ratio (PLR) were measured preoperatively and at postoperative days (POD) 1, 2, 3 and 5. Further, peak serum levels of CRP and lipase during the first 72 h were evaluated. Receiver operating characteristics (ROC) curves were performed to assess their predictive value for ePGD and eRGD. Cut-off levels were calculated with the Youden index. Significant diagnostic biochemical cut-offs as well as other prognostic clinical factors were tested in a multivariate logistic regression model. Results: Of the 105 patients included, 43 patients (41%) and 28 patients (27%) developed ePGD and eRGD following SPKT, respectively. The mean WBC, PCT, NLR, PLR, CRP and lipase levels were significantly higher on most PODs in the ePGD group compared to the non-ePGD group. ROC analysis indicated that peak lipase (AUC: 0.82) and peak CRP levels (AUC: 0.89) were highly predictive for ePGD after SPKT. The combination of both achieved the highest AUC (0.92; p < 0.01) in predicting ePGD. Concerning eRGD, predictive accuracy of all analyzed serological markers was moderate (all AUC < 0.8). Additionally, multivariable analysis identified previous dialysis/no preemptive transplantation (OR 2.4 (95% CI: 1.41−4.01), p = 0.021), donor age (OR 1.07 (95% CI: 1.03−1.14), p < 0.010), donor body mass index (OR 1.32 (95% CI: 1.01−1.072), p = 0.04), donors cerebrovascular cause of death (OR 7.8 (95% CI: 2.21−26.9), p < 0.010), donor length of ICU stay (OR 1.27 (95% CI: 1.08−1.49), p < 0.010), as well as CIT pancreas (OR 1.07 (95% CI: 1.03−1.14), p < 0.010) as clinical relevant prognostic predictors for ePGD. Further, a peak of lipase (OR 1.04 (95% CI: 1.02−1.07), p < 0.010), peak of CRP levels (OR 1.12 (95% CI: 1.02−1.23), p < 0.010), pancreatic serum lipase concentration on POD 2 > 150 IU/L (OR 2.9 (95% CI: 1.2−7.13), p = 0.021) and CRP levels of ≥ 180 ng/mL on POD 2 (OR 3.6 (95% CI: 1.54−8.34), p < 0.01) and CRP levels > 150 ng/mL on POD 3 (OR 4.5 (95% CI: 1.7−11.4), p < 0.01) were revealed as independent biochemical predictive variables for ePGD after transplantation. Conclusions: In the current study, the combination of peak lipase and CRP levels were highly effective in predicting early pancreatic graft dysfunction development following SPKT. In contrast, for early renal graft dysfunction the predictive value of this parameter was less sensitive. Intensified monitoring of these parameters may be helpful for identifying patients at a higher risk of pancreatic ischemia reperfusion injury and various IRI- associated postoperative complications leading to ePGD and thus deteriorated outcome.

Perfluorocarbons are oxygen-carrying, dense liquids initially intended for the use in partial or total liquid ventilation of patients with severe acute respiratory distress syndrome but which did not show beneficial effects in clinical studies. However, perfluorocarbons may be used for lung lavage in severe alveolar proteinosis. In acute respiratory distress syndrome, oxygenation may be so severely compromised that the use of nonoxygenated perfluorocarbons may not be possible. We report a case of severe, nonresolving acute respiratory distress syndrome treated with extracorporeal membrane oxygenation to secure oxygenation, using perfluorocarbon in a single instillation to aid the clearance of debris and proteinacous edema., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Extracorporeal Membrane Oxygenation (ECMO) use is increasing despite limited evidence. The aim of this study was to demonstrate heterogeneity of ECMO use and its association with hospital size and annual frequency in Germany., Methods: This is a database analysis of all ECMO cases in Germany from 2010 to 2016 using the German Diagnosis Related Groups (DRG) coding system for ECMO., Results: During the study period, 510 hospitals performed 29,929 ECMO runs (12,572 vvECMO, 11,504 vaECMO, 1993 pECLA) with an increase over time. Mortality ranged between 58% and 66% for vaECMO cases and 66% and 53% for vvECMO cases. 304 (61%) hospitals performed only one ECMO per year. 78%% of all ECMO runs were performed in centres with more than 20 cases per year and more than half of all ECMO runs were performed in hospitals with >1.000 beds. Mortality for vv and vaECMO was highest in very small hospitals (< 200 beds; 70%; 74%) and very large hospitals (>1000 beds; 60%; 62%)., Conclusions: Use of ECMO is still increasing and a substantial proportion of hospitals performs very few ECMO runs. Small hospitals had a significantly higher mortality, but dependence on hospital size and ECMO mortality was irregular., Competing Interests: The authors have declared that no competing interests exist.

Transfusions of blood and blood products are live-saving, but complications may be fatal. Transfusion related lung injury (TRALI) is rare and pathophysiology not yet entirely understood. Diagnosis is difficult due to the usually life-threatening circumstances associated with transfusions and underlying diseases. In this mini-review article, we introduce two cases of TRALI to discuss the problems and controversies associated with different definitions, epidemiology, pathophysiology, blood products, diagnosis, and treatment. Future directions in the field are highlighted., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare

Introduction: Hemoglobin-based oxygen carriers (HBOC) have been developed as an alternative to blood transfusions. Their nitric-oxide-scavenging properties HBOC also induce vasoconstriction. In acute lung injury, an excess of nitric oxide results in a general vasodilation, reducing oxygenation by impairing the hypoxic pulmonary vasoconstriction. Inhaled nitric oxide (iNO) is used to correct the ventilation perfusion mismatch. We hypothesized that the additional use of HBOC might increase this effect. In a rodent model of ARDS we evaluated the combined effect of HBOC and iNO on vascular tone and gas exchange., Methods: ARDS was induced in anaesthetized Wistar rats by saline lavage and aggressive ventilation. Two groups received either hydroxyethylstarch 10% (HES; n = 10) or the HBOC hemoglobin glutamer-200 (HBOC-200; n = 10) via a central venous infusion. Additionally, both groups received iNO. Monitoring of the right ventricular pressure (RVP) and mean arterial pressure (MAP) was performed with microtip transducers. Arterial oxygenation was measured via arterial blood gas analyses., Results: Application of HBOC-200 led to a significant increase of MAP and RVP when compared to baseline and to the HES group. This effect was reversed by iNO. The application of HBOC and iNO had no effect on the arterial oxygenation over time. No difference in arterial oxygenation was found between the groups., Conclusion: Application of HBOC led to an increase of systemic and pulmonary vascular resistance in this animal model of ARDS. The increase in RVP was reversed by iNO. Pulmonary vasoconstriction by hemoglobin glutamer-200 in combination with iNO did not improve arterial oxygenation in ARDS., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

In patients with severely compromised gas exchange, interhospital transportation is frequently necessary due to the need to provide access to specialized care. Risks are inherent during transport, so the anticipated benefits of transportation must be weighed against the possible negative outcome during the transport. The use of specialized teams during transportation can help to reduce adverse events. Diligent planning of the transportation, monitoring and medical staff during transport can decrease adverse events and reduce risks. This article defines the group of patients that may benefit from referral. This article discusses the risks associated with the transportation of patients with severely impaired gas exchange and the risks related to different means of transportation. The decisions required before transportation are described as well as the practical approach starting at the transferring hospital until arrival at the admitting hospital.

Background: The modalities of tracheostomy for critically ill patients are still controversially discussed. Although the use of percutaneous dilatational tracheostomy (PDT) is generally accepted to be a safe procedure, it is still not considered to be suitable for patients requiring a permanent tracheostomy., Methods: This was an observational cohort study investigating long-term outcome parameters of PDT. All patients having received a PDT at the interdisciplinary ICU at the University of Leipzig between October 2008 and August 2009 that survived to discharge were asked for consent to participate ( n = 103). Baseline data, admitting diagnosis, reasons for tracheostomy, and timing for tracheostomy were recorded. Subjects and medical providers were asked for neurological outcome, adverse events, and personal discomfort related to the tracheostomy. The study period was 2 y from the time of tracheostomy., Results: Seventy-one subjects were finally included in the survey. Data of 8 subjects (11%) were incomplete. Reasons for tracheostomy were the need for long-term ventilation (42%), weaning (31%), and neurological deficits (27%). No severe adverse events were registered. Sixty-five percent of all subjects could finally be decannulated. Two subjects remained with their initial tracheostomy, and in 5 subjects (7%) tracheostomy was modified to a surgical tracheostomy. Thirty-seven percent of subjects died during the 2 y. Twenty-five of the surviving subjects (35%) had only minor or moderate neurological and psychological deficits. Complaints were mostly connected to swallowing and breathing., Conclusions: Decannulations after PDT are easily done. Complications after PDT requiring a transformation to a surgical tracheostomy are rare. Elective surgical conversions are not necessary., Competing Interests: The authors have disclosed no conflicts of interest., (Copyright © 2017 by Daedalus Enterprises.)

Background: Prone positioning of patients with acute respiratory distress syndrome (ARDS) has been shown to significantly improve survival rates. Prone positioning reduces collapse of dorsal lung segments with subsequent reduction of alveolar overdistension of ventral lung segments, optimizes lung recruitment and enhances drainage. Patients with ARDS treated by extracorporeal membrane oxygenation (ECMO) can also benefit from prone positioning; however, the procedure is associated with a possible higher risk of serious adverse events., Objective: The aim of this study was to evaluate the safety and feasibility of prone positioning for patients with severe ARDS during ECMO therapy., Material and Methods: This study involved a retrospective analysis of all patients placed in a prone position while being treated by venovenous ECMO (vvECMO) for severe hypoxemia in ARDS as bridge to recovery in the interdisciplinary intensive care unit at the University Hospital Leipzig between January 2009 and August 2013. Baseline data, hospital mortality and serious adverse events were documented. Serious adverse events were defined as dislocation or obstruction of endotracheal tube or tracheal cannula, ECMO cannulas and cardiac arrest. Prone positioning was carried out by at least one doctor and three nurses according to a standardized protocol. Results are given as the median (1st and 3rd quartiles)., Results: A total of 26 patients were treated with vvECMO as bridge to recovery due to severe ARDS. Causes for ARDS were pneumonia (n = 20) and aspiration (n = 2) and four patients had different rare causes of ARDS. The median time on ECMO was 8 days (6;11) and during this period 134 turning events were documented. Patients were proned for a median of 5 (3;7) periods with a median duration of 12 h (8;12). No serious adverse events were recorded. The hospital mortality was 42% and mortality during the ECMO procedure was 35%., Conclusion: Prone positioning significantly reduces the mortality of patients with severe ARDS. In this series of 26 patients with severe ARDS during ECMO therapy no serious adverse events were found during the use of prone positioning.

Background: Inhaled carbon monoxide (CO) appears to have beneficial effects on endotoxemia-induced impairment of hypoxic pulmonary vasoconstriction (HPV). This study aims to specify correct timing of CO application, it's biochemical mechanisms and effects on inflammatory reactions., Methods: Mice (C57BL/6; n = 86) received lipopolysaccharide (LPS, 30 mg/kg) intraperitoneally and subsequently breathed 50 ppm CO continuously during defined intervals of 3, 6, 12 or 18 h. Two control groups received saline intraperitoneally and additionally either air or CO, and one control group received LPS but breathed air only. In an isolated lung perfusion model vasoconstrictor response to hypoxia (FiO2 = 0.01) was quantified by measurements of pulmonary artery pressure. Pulmonary capillary pressure was estimated by double occlusion technique. Further, inflammatory plasma cytokines and lung tissue mRNA of nitric-oxide-synthase-2 (NOS-2) and heme oxygenase-1 (HO-1) were measured., Results: HPV was impaired after LPS-challenge (p < 0.01). CO exposure restored HPV-responsiveness if administered continuously for full 18 h, for the first 6 h and if given in the interval between the 3(rd) and 6(th) hour after LPS-challenge (p < 0.05). Preserved HPV was attributable to recovered arterial resistance and associated with significant reduction in NOS-2 mRNA when compared to controls (p < 0.05). We found no effects on inflammatory plasma cytokines., Conclusion: Low-dose CO prevented LPS-induced impairment of HPV in a time-dependent manner, associated with a decreased NOS-2 expression.

Recommendations concerning the management of hemoglobin levels and hematocrit in patients on extracorporeal membrane oxygenation (ECMO) still advise maintenance of a normal hematocrit. In contrast, current transfusion guidelines for critically ill patients support restrictive transfusion practice. We report on a series of patients receiving venovenous ECMO (vvECMO) for acute respiratory distress syndrome (ARDS) treated according to the restrictive transfusion regimen recommended for critically ill patients. We retrospectively analyzed 18 patients receiving vvECMO due to severe ARDS. Hemoglobin concentrations were kept between 7 and 9 g/dL with a transfusion trigger at 7 g/dL or when physiological transfusion triggers were apparent. We assessed baseline data, hospital mortality, time on ECMO, hemoglobin levels, hematocrit, quantities of packed red blood cells received, and lactate concentrations and compared survivors and nonsurvivors. The overall mortality of all patients on vvECMO was 38.9%. Mean hemoglobin concentration over all patients and ECMO days was 8.30 ± 0.51 g/dL, and hematocrit was 0.25 ± 0.01, with no difference between survivors and nonsurvivors. Mean numbers of given PRBCs showed a trend towards higher quantities in the group of nonsurvivors, but the difference was not significant (1.97 ± 1.47 vs. 0.96 ± 0.76 units; P = 0.07). Mean lactate clearance from the first to the third day was 45.4 ± 28.3%, with no significant difference between survivors and nonsurvivors (P = 0.19). In our cohort of patients treated with ECMO due to severe ARDS, the application of a restrictive transfusion protocol did not result in an increased mortality. Safety and feasibility of the application of a restrictive transfusion protocol in patients on ECMO must further be evaluated in randomized controlled trials., (Copyright © 2014 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

The aim of the present study was to characterize a murine model of acute respiratory distress syndrome (ARDS) abiding by the Berlin definition of human ARDS and guidelines for animal models of ARDS. To this end, C57BL/6NCrl mice were challenged with lipopolysaccharide (LPS; 15 mg/kg, i.p.) followed 18 h later by injection of oleic acid (OA; 0.12 mL/kg, i.v.). Controls received saline injection at both time points. Haemodynamics were monitored continuously. Arterial blood gas analyses were performed just before and every 30 min after OA challenge. Ninety minutes after OA challenge, the chest of mice was scanned using micro-computed tomography (CT). Cytokine concentrations were measured in plasma samples. Lungs were harvested 90 min after OA challenge for histology, immunohistochemistry, lung weight measurements and tissue cytokine detection. A histological lung injury score was determined. Eighteen hours after LPS challenge, mice exhibited a severe systemic inflammatory response syndrome. Oxygenation declined significantly after OA injections (Pa o2 /Fi o2 283 ± 73 and 256 ± 71 mmHg at 60 and 90 min, respectively; P < 0.001). Bilateral patchy infiltrates were present on the micro-CT scans. Histology revealed parenchymal damage with accumulation of polymorphonuclear neutrophils, intra-alveolar proteinacous debris and few hyaline membranes. The lung wet : dry ratio indicated damage to the alveolar capillary membrane. Cytokine patterns evidenced a severe local and systemic inflammatory state in plasma and lung tissue. In conclusion, the described two-hit model of ARDS shows a pathological picture of ARDS closely mimicking human ARDS according to the Berlin definition and may facilitate interpretation of prospective experimental results., (© 2014 Wiley Publishing Asia Pty Ltd.)

Objective: To evaluate the risk factors of nosocomial infection during Extracorporeal membrane oxygenation (ECMO) treatment through systematic evaluation and meta-analysis, in order to provide evidence-based basis for clinical treatment and prevention of nosocomial infection during ECMO treatment. Method: Computer search of Cochrane Library, PubMed, Embase, and Web of Science databases was conducted to establish a database of relevant literature published in March 2023. Two researchers independently screened literature, extracted data, and evaluated quality based on inclusion and exclusion criteria, and then analyzed the data using STATA 14.0 software. This plan is registered with PROSPERO as CRD42021271083. Result: A total of 2955 ECMO patients, including 933 nosocomial infected patients, were included in 23 articles. Meta analysis showed that immunosuppression, Heart transplantation, VA-ECMO, CRRT, red blood cell input, ECMO support time, mechanical ventilation time, ICU hospitalization time, and total hospitalization time were the risk factors for nosocomial infection in patients supported by ECMO. Conclusion: ECMO treatment for nosocomial infections in patients is related to multiple factors. In clinical work, medical staff should identify high-risk groups of ECMO nosocomial infections, actively take preventive measures, and reduce the incidence and mortality of nosocomial infections. [ABSTRACT FROM AUTHOR]

The metabolic reprogramming of macrophages is a potential therapeutic strategy for sepsis treatment, but the mechanism underlying this reprogramming remains unclear. Since glycolysis can drive macrophage phenotype switching, the rate-limiting enzymes in glycolysis may be key to treating sepsis. Here, we found that, compared with other isoenzymes, the expression of 6-phosphofructokinase, muscle type (PFKM) was the most upregulated in monocytes from septic patients. Recombinant thrombomodulin (rTM) treatment downregulated the protein expression of PFKM in macrophages. Both rTM treatment and Pfkm knockout protected mice from sepsis and reduced the production of the proinflammatory cytokines IL-1β, IL-6, TNF-α, and IL-27, whereas PFKM overexpression increased the production of these cytokines. Mechanistically, rTM treatment inhibited glycolysis in macrophages by decreasing PFKM expression in a hypoxia-inducible factor-1α (HIF-1α)-dependent manner. HIF-1α overexpression increased methyltransferase-like 3 (METTL3) expression, elevated the m6A level on Pfkm, and upregulated the protein expression of PFKM. METTL3 silence attenuated HIF-1α-mediated PFKM expression. These findings provide insight into the underlying mechanism of macrophage reprogramming for the treatment of sepsis. [ABSTRACT FROM AUTHOR]

The prone position is an immediately available and easily implemented procedure that was introduced more than 50 years ago as a method for improvement of gas exchange in patients with acute respiratory distress syndrome (ARDS). In the meantime, a survival advantage could also be shown in patients with severe ARDS, which led to the recommendation of the prone position for treatment of severe ARDS by expert consensus and specialist society guidelines. The continuing coronavirus disease 2019 (COVID-19) pandemic moved the prone position to the forefront of medicine, including the widespread implementation of the prone position for awake, spontaneously breathing nonintubated patients with acute hypoxemic respiratory insufficiency. The survival advantage is possible due to a reduction of the ventilator-associated lung damage. In this article, the physiological effects, data on clinical results, practical considerations and open questions with respect to the prone position are discussed., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

The use of extracorporeal membrane oxygenation (ECMO) is discussed to improve patients' outcome in severe COVID-19 with respiratory failure, but data on ECMO remains controversial. The aim of the study was to determine the characteristics of patients under invasive mechanical ventilation (IMV) with or without veno-venous ECMO support and to evaluate outcome parameters. Ventilated patients with COVID-19 with and without additional ECMO support were analyzed in a retrospective multicenter study regarding clinical characteristics, respiratory and laboratory parameters in day-to-day follow-up. Recruitment of patients was conducted during the first three COVID-19 waves at four German university hospitals of the Ruhr University Bochum, located in the Middle Ruhr Region. From March 1, 2020 to August 31, 2021, the charts of 149 patients who were ventilated for COVID-19 infection, were included (63.8% male, median age 67 years). Fifty patients (33.6%) received additional ECMO support. On average, ECMO therapy was initiated 15.6 ± 9.4 days after symptom onset, 10.6 ± 7.1 days after hospital admission, and 4.8 ± 6.4 days after the start of IMV. Male sex and higher SOFA and RESP scores were observed significantly more often in the high-volume ECMO center. Pre-medication with antidepressants was more often detected in survivors (22.0% vs. 6.5%; p = 0.006). ECMO patients were 14 years younger and presented a lower rate of concomitant cardiovascular diseases (18.0% vs. 47.5%; p = 0.0004). Additionally, cytokine-adsorption (46.0% vs. 13.1%; p < 0.0001) and renal replacement therapy (76.0% vs. 43.4%; p = 0.0001) were carried out more frequently; in ECMO patients thrombocytes were transfused 12-fold more often related to more than fourfold higher bleeding complications. Undulating C-reactive protein (CRP) and massive increase in bilirubin levels (at terminal stage) could be observed in deceased ECMO patients. In-hospital mortality was high (Overall: 72.5%, ECMO: 80.0%, ns). Regardless of ECMO therapy half of the study population deceased within 30 days after hospital admission. Despite being younger and with less comorbidities ECMO therapy did not improve survival in severely ill COVID-19 patients. Undulating CRP levels, a massive increase of bilirubin level and a high use of cytokine-adsorption were associated with worse outcomes. In conclusion, ECMO support might be helpful in selected severe cases of COVID-19. [ABSTRACT FROM AUTHOR]

Background: Blood product transfusions are necessary for critically ill neonates on extracorporeal membrane oxygenation (ECMO). Transfusions are administered in response to unstudied arbitrary thresholds and may be associated with adverse outcomes. The objective of this study was to identify relationships between blood product components and mortality in neonates receiving ECMO support for respiratory indications. Study Design and Methods: A retrospective review of neonates receiving ECMO for respiratory indications from 2002 to 2019 from a single quaternary‐referral neonatal intensive care unit (NICU). Demographic and outcome data and transfusion volume (ml/kg/day) were harvested from the medical record, and baseline mortality risk was assessed using NEO‐RESCUERS scores. The association between volume of red blood cells (RBC), platelet, plasma transfusion rates (ml/kg/day), and mortality on ECMO were assessed after adjustment for NEO‐RESCUERS score. Cox proportional hazards (CPH) competing risk model was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for each variable and mortality outcome. Measurements and Main Results: Among 248 neonates undergoing ECMO for respiratory failure, overall survival was 93%. RBC, platelet, and plasma volume were highly associated with mortality during ECMO in an unadjusted model. After adjusting for NEO‐RESCUERS score, RBC volume was associated with increased mortality risk (HR 1.013, 95% CI 1.004–1.022, p =.0043), but platelet and plasma volume were not associated with mortality. Conclusions: RBC, but not platelet or plasma volume, is associated with mortality in neonates on ECMO. Our findings refute previous studies demonstrating an association between platelet volume and mortality for neonates on ECMO. [ABSTRACT FROM AUTHOR]

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Extracorporeal membrane oxygenation (ECMO) is increasingly being used for patients with severe respiratory failure and has received particular attention during the coronavirus disease 2019 (COVID-19) pandemic. Evidence from two key randomized controlled trials, a subsequent post hoc Bayesian analysis, and meta-analyses support the interpretation of a benefit of ECMO in combination with ultra-lung-protective ventilation for select patients with very severe forms of acute respiratory distress syndrome (ARDS). During the pandemic, new evidence has emerged helping to better define the role of ECMO for patients with COVID-19. Results from large cohorts suggest outcomes during the first wave of the pandemic were similar to those in non-COVID-19 cohorts. As the pandemic continued, mortality of patients supported with ECMO has increased. However, the precise reasons for this observation are unclear. Known risk factors for mortality in COVID-19 and non-COVID-19 patients are higher patient age, concomitant extra-pulmonary organ failures or malignancies, prolonged mechanical ventilation before ECMO, less experienced treatment teams and lower ECMO caseloads in the treating center. ECMO is a high resource-dependent support option; therefore, it should be used judiciously, and its availability may need to be constrained when resources are scarce. More evidence from high-quality research is required to better define the role and limitations of ECMO in patients with severe COVID-19. [ABSTRACT FROM AUTHOR]

Use of extracorporeal membrane oxygenation (ECMO) is increasing among critically ill adults with cardiac and/or respiratory failure. Use of ECMO is associated with hemostatic alterations requiring use of anticoagulation and blood product support. There are limited guidelines to direct transfusion management in the adult patient supported with ECMO. The objective of this article is to describe (1) the role of the transfusion service in providing transfusion support and current understanding of transfusion thresholds, (2) the complexities of monitoring anticoagulation, and (3) the consideration regarding additional factor concentrates and antifibrinolytics within the context of ECMO support. The information provided should assist ECMO care teams in informing transfusion and anticoagulation practice while highlighting key areas for future research and collaboration. [ABSTRACT FROM AUTHOR]

In‐hospital mortality of adult veno‐venous extracorporeal membrane oxygenation (V‐V ECMO) patients remains invariably high. However, little is known regarding timing and causes of in‐hospital death, either on‐ECMO or after weaning. The current review aims to investigate the timing and causes of death of adult patients during hospital admittance for V‐V ECMO, and to define the V‐V ECMO gap, which is represented by the patients that are successfully weaned of ECMO but still die during hospital stay. A systematic search was performed using electronic MEDLINE and EMBASE databases through PubMed. Studies reporting on adult V‐V ECMO patients from January 2006 to December 2020 were screened. Studies that did not report on at least on‐ECMO mortality and discharge rate were excluded from analysis as they could not provide the required information regarding the proposed V‐V ECMO‐gap. Mortality rates on‐ECMO and after weaning, as well as weaning and discharge rates, were analyzed as primary outcomes. Secondary outcomes were the causes of death and complications. Initially, 35 studies were finally included in this review. Merely 24 of these studies (comprising 975 patients) reported on prespecified V‐V ECMO outcomes (on‐ECMO mortality and discharge rate). Mortality on V‐V ECMO support was 27.8% (95% confidence interval (CI) 22.5%‐33.2%), whereas mortality after successful weaning was 12.7% (95% CI 8.8%‐16.6%, defining the V‐V ECMO gap). 72.2% of patients (95% CI 66.8%‐77.5%) were weaned successfully from support and 56.8% (95% CI 49.9%‐63.8%) of patients were discharged from hospital. The most common causes of death on ECMO were multiple organ failure, bleeding, and sepsis. Most common causes of death after weaning were multiorgan failure and sepsis. Although the majority of patients are weaned successfully from V‐V ECMO support, a significant proportion of subjects still die during hospital stay, defining the V‐V ECMO gap. Overall, timing and causes of death are poorly reported in current literature. Future studies on V‐V ECMO should describe morbidity and mortality outcomes in more detail in relation to the timing of the events, to improve patient management, due to enhanced understanding of the clinical course. [ABSTRACT FROM AUTHOR]

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Background: Acute respiratory distress syndrome (ARDS) is multifactorial and can result from sepsis, trauma, or pneumonia, amongst other primary pathologies. It is one of the major causes of death in critically ill patients with a reported mortality rate up to 45%. The present study focuses on the development of a large animal model of smoke inhalation-induced ARDS in an effort to provide the scientific community with a reliable, reproducible large animal model of isolated toxic inhalation injury-induced ARDS.Methods: Animals (n = 21) were exposed to smoke under general anesthesia for 1 to 2 h (median smoke exposure = 0.5 to 1 L of oak wood smoke) after the ultrasound-guided placement of carotid, pulmonary, and femoral artery catheters. Peripheral oxygen saturation (SpO2), vital signs, and ventilator parameters were monitored throughout the procedure. Chest x-ray, carotid, femoral and pulmonary artery blood samples were collected before, during, and after smoke exposure. Animals were euthanized and lung tissue collected for analysis 48 h after smoke inhalation.Results: Animals developed ARDS 48 h after smoke inhalation as reflected by a decrease in SpO2 by approximately 31%, PaO2/FiO2 ratio by approximately 208 (50%), and development of bilateral, diffuse infiltrates on chest x-ray. Study animals also demonstrated a significant increase in IL-6 level, lung tissue injury score and wet/dry ratio, as well as changes in other arterial blood gas (ABG) parameters.Conclusions: This study reports, for the first time, a novel large animal model of isolated smoke inhalation-induced ARDS without confounding variables such as cutaneous burn injury. Use of this unique model may be of benefit in studying the pathophysiology of inhalation injury or for development of novel therapeutics. [ABSTRACT FROM AUTHOR]

Background: During the COVID-19 pandemic, as the number of available Intensive Care beds in France did not meet the needs, it appeared necessary to transfer a large number of patients from the most affected areas to the less ones. Mass transportation resources were deemed necessary. To achieve that goal, the concept of a Collective Critical Care Ambulance (CCCA) was proposed in the form of a long-distance bus re-designed and equipped to accommodate up to six intensive care patients and allow Advanced Life Support (ALS) techniques to be performed while en route. Methods: The expected benefit of the CCCA, when compared to ALS ambulances accommodating a single patient, was to reduce the resources requirements, in particular by a lower personnel headcount for several patients being transferred to the same destination. A foreseen prospect, comparing to other collective transportation vectors such as airplanes, was the door-to-door capability, minimalizing patients' handovers for safety concerns and time efficiency. With the project of a short-distance transfer of several Intensive Care Unit (ICU) patients together, the opportunity came to test the CCCA under real-life conditions and evaluate safely its technical feasibility and impact in time and resources saving, before it could be proposed for longer distances. Results: Four COVID-19 patients were transported over 37 km. All patients were intubated and under controlled ventilation. One of them was under Norepinephrine support. Mean loading time was 1 min 39 s. Transportation time was 29 min. At destination, the mean unloading time was 1 min 15 s. No serious adverse effect, in particular regarding hemodynamic instability or ventilation disorder, has been observed. No harmful incident has occurred. Conclusions: It was a very instructive test. Collective medical evacuation by bus for critically ill patients under controlled ventilation is suitable and easy to implement. Design, ALS equipment, power autonomy, safety and resources saving, open the way for carrying up to 6 ICU-patients over a long distance. The CCCA could bring a real added-value in an epidemic context and could also be helpful in many other events generating multiple victims such as an armed conflict, a terrorist attack or a natural disaster. [ABSTRACT FROM AUTHOR]

During postnatal adaptation pulmonary surfactant may be inactivated by lipopolysaccharide (LPS). We evaluated the effect of surfactant therapy in combination with antibiotic polymyxin B (PxB) in double-hit model of neonatal lung injury. Surfactant (poractant alfa, Curosurf) was exposed to smooth (S) LPS without/with PxB and tested in captive bubble surfactometer. Preterm rabbits received intratracheally saline (control) or S-LPS and were ventilated with 100% oxygen. After 30 min, LPS-treated animals received no treatment, or surfactant (200 mg/kg) without/with 3% PxB; controls received the same dose of surfactant. Animals were ventilated for further 2 h. In vitro, addition of 5% S-LPS to surfactant increased minimum surface tension (γmin) and addition of 1–3% PxB to surfactant/S-LPS mixture restored γmin to low values. Animals only given S-LPS had lower lung compliance and lung gas volume (LGV) compared to surfactant groups. Treatment with surfactant/PxB, but not with surfactant only, restored LGV. Addition of PxB to the surfactant increased the alveolar expansion. S-LPS interferes with surface activity of the pulmonary surfactant and PxB improves the resistance of surfactant to LPS-induced inactivation. In our neonatal model of respiratory distress syndrome surfactant gives positive response even in simultaneous exposure to S-LPS, when enriched with PxB. [ABSTRACT FROM AUTHOR]

Background: Efficacy and safety of different hemoglobin thresholds for transfusion of red blood cells (RBCs) in adults with an acute respiratory distress syndrome (ARDS) are unknown. We therefore assessed the effect of two transfusion thresholds on short-term outcome in patients with ARDS.Methods: Patients who received transfusions of RBCs were identified from a cohort of 1044 ARDS patients. After propensity score matching, patients transfused at a hemoglobin concentration of 8 g/dl or less (lower-threshold) were compared to patients transfused at a hemoglobin concentration of 10 g/dl or less (higher-threshold). The primary endpoint was 28-day mortality. Secondary endpoints included ECMO-free, ventilator-free, sedation-free, and organ dysfunction-free composites.Measurements and Main Results: One hundred ninety-two patients were eligible for analysis of the matched cohort. Patients in the lower-threshold group had similar baseline characteristics and hemoglobin levels at ARDS onset but received fewer RBC units and had lower hemoglobin levels compared with the higher-threshold group during the course on the ICU (9.1 [IQR, 8.7-9.7] vs. 10.4 [10-11] g/dl, P < 0.001). There was no difference in 28-day mortality between the lower-threshold group compared with the higher-threshold group (hazard ratio, 0.94 [95%-CI, 0.59-1.48], P = 0.78). Within 28 days, 36.5% (95%-CI, 27.0-46.9) of the patients in the lower-threshold group compared with 39.5% (29.9-50.1) of the patients in the higher-threshold group had died. While there were no differences in ECMO-free, sedation-free, and organ dysfunction-free composites, the chance for successful weaning from mechanical ventilation within 28 days after ARDS onset was lower in the lower-threshold group (subdistribution hazard ratio, 0.36 [95%-CI, 0.15-0.86], P = 0.02).Conclusions: Transfusion at a hemoglobin concentration of 8 g/dl, as compared with a hemoglobin concentration of 10 g/dl, was not associated with an increase in 28-day mortality in adults with ARDS. However, a transfusion at a hemoglobin concentration of 8 g/dl was associated with a lower chance for successful weaning from the ventilator during the first 28 days after ARDS onset.Trial Registration: ClinicalTrials.gov NCT03871166. [ABSTRACT FROM AUTHOR]

ARDS, first described in 1967, is the commonest form of acute severe hypoxemic respiratory failure. Despite considerable advances in our knowledge regarding the pathophysiology of ARDS, insights into the biologic mechanisms of lung injury and repair, and advances in supportive care, particularly ventilatory management, there remains no effective pharmacological therapy for this syndrome. Hospital mortality at 40% remains unacceptably high underlining the need to continue to develop and test therapies for this devastating clinical condition. The purpose of the review is to critically appraise the current status of promising emerging pharmacological therapies for patients with ARDS and potential impact of these and other emerging therapies for COVID-19-induced ARDS. We focus on drugs that: (1) modulate the immune response, both via pleiotropic mechanisms and via specific pathway blockade effects, (2) modify epithelial and channel function, (3) target endothelial and vascular dysfunction, (4) have anticoagulant effects, and (5) enhance ARDS resolution. We also critically assess drugs that demonstrate potential in emerging reports from clinical studies in patients with COVID-19-induced ARDS. Several therapies show promise in earlier and later phase clinical testing, while a growing pipeline of therapies is in preclinical testing. The history of unsuccessful clinical trials of promising therapies underlines the challenges to successful translation. Given this, attention has been focused on the potential to identify biologically homogenous subtypes within ARDS, to enable us to target more specific therapies 'precision medicines.' It is hoped that the substantial number of studies globally investigating potential therapies for COVID-19 will lead to the rapid identification of effective therapies to reduce the mortality and morbidity of this devastating form of ARDS. [ABSTRACT FROM AUTHOR]

Objective: To develop evidence-based clinical practice recommendations regarding transfusion practices in non-bleeding, critically ill adults.Design: A task force involving 13 international experts and three methodologists used the GRADE approach for guideline development.Methods: The task force identified four main topics: red blood cell transfusion thresholds, red blood cell transfusion avoidance strategies, platelet transfusion, and plasma transfusion. The panel developed structured guideline questions using population, intervention, comparison, and outcomes (PICO) format.Results: The task force generated 16 clinical practice recommendations (3 strong recommendations, 13 conditional recommendations), and identified five PICOs with insufficient evidence to make any recommendation.Conclusions: This clinical practice guideline provides evidence-based recommendations and identifies areas where further research is needed regarding transfusion practices and transfusion avoidance in non-bleeding, critically ill adults. [ABSTRACT FROM AUTHOR]

Background: Prone positioning (PP) during veno-venous ECMO is feasible, but its physiological effects have never been thoroughly evaluated. Our objectives were to describe, through electrical impedance tomography (EIT), the impact of PP on global and regional ventilation, and optimal PEEP level. Methods: A monocentric study conducted on ECMO-supported severe ARDS patients, ventilated in pressure-controlled mode, with 14-cmH2O driving pressure and EIT-based "optimal PEEP". Before, during and after a 16-h PP session, EIT-based distribution and variation of tidal impedance, VTdorsal/VTglobal ratio, end-expiratory lung impedance (EELI) and static compliance were collected. Subgroup analyses were performed in patients who increased their static compliance by ≥ 3 mL/cmH2O after 16 h of PP. Results: For all patients (n = 21), tidal volume and EELI were redistributed from ventral to dorsal regions during PP. EIT-based optimal PEEP was significantly lower in PP than in supine position. Median (IQR) optimal PEEP decreased from 14 (12–16) to 10 (8–14) cmH2O. Thirteen (62%) patients increased their static compliance by ≥ 3 mL/cmH2O after PP on ECMO. This subgroup had higher body mass index, more frequent viral pneumonia, shorter ECMO duration, and lower baseline VTdorsal/VTglobal ratio than patients with compliance ≤ 3 mL/cmH2O (P < 0.01). Conclusion: Although baseline tidal volume distribution on EIT may predict static compliance improvement after PP on ECMO, our results support physiological benefits of PP in all ECMO patients, by modifying lung mechanics and potentially reducing VILI. Further studies, including a randomized–controlled trial, are now warranted to confirm potential PP benefits during ECMO. [ABSTRACT FROM AUTHOR]

Purpose: We describe an approach for anticoagulation and transfusions in veno-venous–extracorporeal membrane oxygenation (VV-ECMO), evaluating factors associated with higher transfusion requirements, and their impact on mortality. Methods: Observational study on consecutive adults supported with VV-ECMO for acute respiratory distress syndrome (ARDS). We targeted an activated partial thromboplastin time of 40 to 50 seconds and a hematocrit of 24% to 30%. Univariate and multiple analyses were done to evaluate factors associated with transfusion requirements and the influence of increasing transfusions on mortality during ECMO. Results: In a cohort of 82 VV-ECMO patients (PRedicting dEath for SEvere ARDS on VV-ECMO [PRESERVE] score: 4, Interquartile range [IQR]: 3-5, Respiratory Extracorporeal Membrane Oxygenation Survival Prediction [RESP] score: 2, IQR: 2-4), 76 (92.7%) patients received at least 1 unit of packed red blood cells (PRBCs) during the intensive care unit stay related to ECMO (median PRBC/d 156 mL, IQR: 93-218; median ECMO duration 14 days, IQR: 8-22). A higher requirement of PRBC transfusions was associated with pre-ECMO hematocrit, and with the following conditions during ECMO: platelet nadir, antithrombin III (ATIII), and stage 3 of acute kidney injury (all P <.05). Sixty-two (75.6%) patients survived ECMO. Pre-ECMO hospital stay, PRBC transfusion, and septic shock were associated with mortality (all P <.05). The adjusted odds ratio for each 100mL/d increase in PRBC transfusion was 1.9 (95% confidence interval [CI]: 1.1-3.2, P =.01); for the development of septic shock it was 15.4 (95% CI: 1.7-136.8, P =.01), and for each day of pre-ECMO stay it was 1.1 (95% CI: 1-1.2, P =.04). Conclusion: Implementation of a comprehensive protocol for anticoagulation and transfusions in VV-ECMO for ARDS resulted in a low PRBC requirement, and an ECMO survival comparable to data in the literature. Lower ATIII emerged as a factor associated with increased need for transfusions. Higher PRBC transfusions were associated with ECMO mortality. Further investigations are needed to better understand the right level of anticoagulation in ECMO, and the factors to take into account in order to manage personalized transfusion practice in this select setting. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to determine and compare the incidence of long- and short-term complications of percutaneous dilatation tracheotomies (PDT) and surgical tracheotomies (ST). Design: A single-centre retrospective study. Participants: 305 patients undergoing a tracheotomy (PDT or ST) in the University Medical Center Groningen from 2003 to 2013 were included. Data were gathered from patient files. Main outcome measures: Short-term and long-term complications including tracheal stenosis. Results: The incidence of short- and long-term complications, including tracheal stenosis, was similar in both groups. Analysis of a small high-risk subgroup showed no difference in long-term complications. Conclusions: The rate of short- and long-term complications, including tracheal stenosis, is equal in PDT and ST. PDT is a safe alternative for ST in selected patients. [ABSTRACT FROM AUTHOR]