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Human leukocyte antigen (HLA) mismatches (MM) between donor and recipient lead to eplet MM (epMM) in lung transplantation (LTX), which can induce the development of de-novo donor-specific HLA-antibodies (dnDSA), particularly HLA-DQ-dnDSA. Aim of our study was to identify risk factors for HLA-DQ-dnDSA development. We included all patients undergoing LTX between 2012 and 2020. All recipients/donors were typed for HLA 11-loci. Development of dnDSA was monitored 1-year post-LTX. EpMM were calculated using HLAMatchmaker. Differences in proportions and means were compared using Chi2-test and Students’ t-test. We used Kaplan-Meier curves with LogRank test and multivariate Cox regression to compare acute cellular rejection (ACR), chronic lung allograft dysfunction (CLAD) and survival. Out of 183 patients, 22.9% patients developed HLA-DQ-dnDSA. HLA-DQ-homozygous patients were more likely to develop HLA-DQ-dnDSA than HLA-DQ-heterozygous patients (p = 0.03). Patients homozygous for HLA-DQ1 appeared to have a higher risk of developing HLA-DQ-dnDSA if they received a donor with HLA-DQB1*03:01. Several DQ-eplets were significantly associated with HLA-DQ-dnDSA development. In the multivariate analysis HLA-DQ-dnDSA was significantly associated with ACR (p = 0.03) and CLAD (p = 0.01). HLA-DQ-homozygosity, several high-risk DQ combinations and high-risk epMM result in a higher risk for HLA-DQ-dnDSA development which negatively impact clinical outcomes. Implementation in clinical practice could improve immunological compatibility and graft outcomes.

Severe rhabdomyolysis frequently results in acute kidney injury (AKI) due to myoglobin accumulation with the need of kidney replacement therapy (KRT). The present study investigated whether the application of Cytosorb® (CS) led to an increased rate of kidney recovery in patients with KRT due to severe rhabdomyolysis. Adult patients with a myoglobin-concentration >10,000 ng/ml and KRT were included from 2014 to 2021. Exclusion criteria were chronic kidney disease and CS-treatment before study inclusion. Groups 1 and 2 were defined as KRT with and without CS, respectively. The primary outcome parameter was independence from KRT after 30 days. Propensity score (PS) matching was performed (predictors: myoglobin, SAPS-II, and age), and the chi2-test was used. 35 pairings could be matched (mean age: 57 vs. 56 years; mean myoglobin: 27,218 vs. 26,872 ng/ml; mean SAPS-II: 77 vs. 76). The probability of kidney recovery was significantly (p = .04) higher in group 1 (31.4 vs. 11.4%, mean difference: 20.0%, odds ratio (OR): 3.6). Considering patients who survived 30 days, kidney recovery was also significantly (p = .03) higher in patients treated with CS (61.1 vs. 23.5%, mean difference: 37.6%, OR: 5.1). In conclusion, the use of CS might positively affect renal recovery in patients with severe rhabdomyolysis. A prospective randomized controlled trial is needed to confirm this hypothesis.

Prolonged mechanical ventilation (PMV) after lung transplantation poses several risks, including higher tracheostomy rates and increased in-hospital mortality. Mechanical power (MP) of artificial ventilation unifies the ventilatory variables that determine gas exchange and may be related to allograft function following transplant, affecting ventilator weaning. We retrospectively analyzed consecutive double lung transplant recipients at a national transplant center, ventilated through endotracheal tubes upon ICU admission, excluding those receiving extracorporeal support. MP and derived indexes assessed up to 36 h after transplant were correlated with invasive ventilation duration using Spearman’s coefficient, and we conducted receiver operating characteristic (ROC) curve analysis to evaluate the accuracy in predicting PMV (>72 h), expressed as area under the ROC curve (AUROC). PMV occurred in 82 (35%) out of 237 cases. MP was significantly correlated with invasive ventilation duration (Spearman’s ρ = 0.252 [95% CI 0.129–0.369], p < 0.01), with power density (MP normalized to lung-thorax compliance) demonstrating the strongest correlation (ρ = 0.452 [0.345–0.548], p < 0.01) and enhancing PMV prediction (AUROC 0.78 [95% CI 0.72–0.83], p < 0.01) compared to MP (AUROC 0.66 [0.60–0.72], p < 0.01). Mechanical power density may help identify patients at risk for PMV after double lung transplantation.

Pulmonary hypertension (PH) is a known and life limiting complication of preterm born young adults with bronchopulmonary dysplasia (BPD), ultimately leading to progressive right ventricular (RV) failure. Prognosis remains poor, especially in patients unresponsive to modern vasoactive pharmacotherapy. Therefore, lung transplantation presents the treatment of choice to avert cardiac failure. With limited donor organ availability and long waiting times, the implantation of a paracorporeal lung assist device (PLAD) is a way to bridge the patient as an alternative to veno-arterial ECMO. Herein, we present the case of a prematurely born 23-year-old female, who developed severe PH due to BPD and consequently experienced therapy refractory RV failure. Urgent PLAD implantation was performed and the patient successfully underwent double-lung transplantation after 215 days of PLAD support. No major PLAD-associated complications occurred and full recovery of RV function could be observed after double-lung transplantation.

Abstract Background Hemadsorption of cytokines is used in critically ill patients with sepsis or septic shock. Concerns have been raised that the cytokine adsorber CytoSorb® unintentionally adsorbs vancomycin. This study aimed to quantify vancomycin elimination by CytoSorb®. Methods Critically ill patients with sepsis or septic shock receiving continuous renal replacement therapy and CytoSorb® treatment during a prospective observational study were included in the analysis. Vancomycin pharmacokinetics was characterized using population pharmacokinetic modeling. Adsorption of vancomycin by the CytoSorb® was investigated as linear or saturable process. The final model was used to derive dosing recommendations based on stochastic simulations. Results 20 CytoSorb® treatments in 7 patients (160 serum samples/24 during CytoSorb®-treatment, all continuous infusion) were included in the study. A classical one-compartment model, including effluent flow rate of the continuous hemodialysis as linear covariate on clearance, best described the measured concentrations (without CytoSorb®). Significant adsorption with a linear decrease during CytoSorb® treatment was identified (p

Abstract Background A cytokine storm is life threatening for critically ill patients and is mainly caused by sepsis or severe trauma. In combination with supportive therapy, the cytokine adsorber Cytosorb® (CS) is increasingly used for the treatment of cytokine storm. However, it is questionable whether its use is actually beneficial in these patients. Methods Patients with an interleukin-6 (IL-6) > 10,000 pg/ml were retrospectively included between October 2014 and May 2020 and were divided into two groups (group 1: CS therapy; group 2: no CS therapy). Inclusion criteria were a regularly measured IL-6 and, for patients allocated to group 1, CS therapy for at least 90 min. A propensity score (PS) matching analysis with significant baseline differences as predictors (Simplified Acute Physiology Score (SAPS) II, extracorporeal membrane oxygenation, renal replacement therapy, IL-6, lactate and norepinephrine demand) was performed to compare both groups (adjustment tolerance:

Abstract There are different methods of artificial liver support for patients with acute liver dysfunction (ALD). However, CytoSorb (CS) might be a new approved option for those patients. Question of interest is whether the elimination performance of CS was comparable to that of advanced organ support (ADVOS). Patients, treated with CS (integrated into high-flux dialysis) or ADVOS and a total bilirubin > 10 mg/dl were included. Laboratory parameters were evaluated before starting therapy (d0) and 12–24 h thereafter (d1). The Wilcoxon-test with associated samples was used for statistical analysis. Thirty-nine patients (33 CS, 6 ADVOS) were included. The median bilirubin at d0 was 16.9 and 17.7 mg/dl and at d1 was 13.2 and 15.9 mg/dl, in the CS and ADVOS group, respectively. There was a significant bilirubin reduction as well in the CS group (p

Abstract Background Rhabdomyolysis is frequently occurring in critically ill patients, resulting in a high risk of acute kidney injury (AKI) and potentially permanent kidney damage due to increased myoglobin levels. The extracorporeal elimination of myoglobin might be an approach to prevent AKI, but its molecular weight of 17 kDa complicates an elimination with conventional dialysis membranes. Question of interest is, if myoglobin can be successfully eliminated with the cytokine adsorber Cytosorb® (CS) integrated in a high-flux dialysis system. Methods Patients were included between 10/2014 and 05/2020 in the study population if they had an anuric renal failure with the need of renal replacement therapy, if CS therapy was longer than 90 min and if myoglobin level was > 5.000 ng/ml before treatment. The measurement times of the laboratory values were: d-1 = 24–36 h before CS, d0 = shortly before starting CS and d1 = 12–24 h after starting CS treatment. Statistical analysis were performed with Spearman’s correlation coefficient, Wilcoxon test with associated samples and linear regression analysis. Results Forty-three patients were included in the evaluation (median age: 56 years, 77% male patients, 32.6% ECMO therapy, median SAPS II: 80 points and in-hospital mortality: 67%). There was a significant equilateral correlation between creatine kinase (CK) and myoglobin at all measurement points. Furthermore, there was a significant reduction of myoglobin (p = 0.03, 95% confidence interval (CI): − 9030, − 908 ng/ml) during CS treatment, with a median relative reduction of 29%. A higher median reduction of 38% was seen in patients without ongoing rhabdomyolysis (CK decreased during CS treatment, n = 21). In contrast, myoglobin levels did not relevantly change in patients with increasing CK and therefore ongoing rhabdomyolysis (n = 22, median relative reduction 4%). Moreover, there was no significant difference in myoglobin elimination in patients with and without ECMO therapy. Conclusion Blood purification with Cytosorb® during high-flux dialysis led to a significant reduction of myoglobin in patients with severe rhabdomyolysis. The effect might be obscured by sustained rhabdomyolysis, which was seen in patients with rising CK during treatment. Prospective clinical trials would be useful in investigating its benefits in avoiding permanent kidney damage.

Voriconazole (VRC) is used as first line antifungal agent against invasive aspergillosis. Model-based approaches might optimize VRC therapy. This study aimed to investigate the predictive performance of pharmacokinetic models of VRC without pharmacogenetic information for their suitability for model-informed precision dosing. Seven PopPK models were selected from a systematic literature review. A total of 66 measured VRC plasma concentrations from 33 critically ill patients was employed for analysis. The second measurement per patient was used to calculate relative Bias (rBias), mean error (ME), relative root mean squared error (rRMSE) and mean absolute error (MAE) (i) only based on patient characteristics and dosing history (a priori) and (ii) integrating the first measured concentration to predict the second concentration (Bayesian forecasting). The a priori rBias/ME and rRMSE/MAE varied substantially between the models, ranging from −15.4 to 124.6%/−0.70 to 8.01 mg/L and from 89.3 to 139.1%/1.45 to 8.11 mg/L, respectively. The integration of the first TDM sample improved the predictive performance of all models, with the model by Chen (85.0%) showing the best predictive performance (rRMSE: 85.0%; rBias: 4.0%). Our study revealed a certain degree of imprecision for all investigated models, so their sole use is not recommendable. Models with a higher performance would be necessary for clinical use.

Accumulating evidence suggests that a patient subgroup with severe COVID-19 develops a cytokine release syndrome leading to capillary leakage and organ injury. Recent publications addressing therapy of cytokine storms recommended new extracorporeal therapies such as hemoadsorption. This case report describes a 59-year-old SARS-CoV-2-positive patient with severe ARDS. Due to severe hyperinflammation with concomitant hemodynamic instability and progressive renal failure, combination of continuous renal replacement and CytoSorb® hemoadsorption therapy was initiated. Treatment resulted immediately in a control of the hyperinflammatory response. Simultaneously, lung function continued to improve accompanied by profound hemodynamic stabilization. We report the successful utilization of CytoSorb® hemoadsorption in the treatment of a patient with SARS-CoV-2-induced cytokine storm syndrome.

Tobacco use after lung transplantation is associated with adverse outcome. Therefore, active smoking is regarded as a contraindication for lung transplantation and should be excluded prior to placement on the waiting list. The aim of the study was to compare self-reporting with a systematic cotinine based screening approach to identify patients with active nicotine abuse. Nicotine use was systematically assessed by interviews and cotinine test in all lung transplant candidates at every visit in our center. Patients were classified according to the stage prior to transplantation and cotinine test results were compared to self-reports and retrospectively analyzed until June 2019. Of 620 lung transplant candidates, 92 patients (14.8%) had at least one positive cotinine test. COPD as underlying disease (OR 2.102, CI 1.110-3.981; p = 0.023), number of pack years (OR 1.014, CI 1.000-1.028; p = 0.047) and a time of cessation less than one year (OR 2.413, CI 1.410-4.128; p = 0.001) were associated with a positive cotinine test in multivariable regression analysis. The majority of non-COPD patients (n = 13, 72.2%) with a positive test had a cessation time of less than one year. 78 patients (84.7%) falsely declared not consuming any nicotine-based products prior to the test. Finally, all never smokers were test negative. In conclusion, our data demonstrate that active nicotine use is prevalent in transplant candidates with a high prevalence of falsely declaring nicotine abstinence. COPD was the main diagnosis in affected patients. Short cessation time and a high number of pack years are risk factors for continued nicotine abuse.

(1) Background: Respiratory insufficiency with acute respiratory distress syndrome (ARDS) and multi-organ dysfunction leads to high mortality in COVID-19 patients. In times of limited intensive care unit (ICU) resources, chest CTs became an important tool for the assessment of lung involvement and for patient triage despite uncertainties about the predictive diagnostic value. This study evaluated chest CT-based imaging parameters for their potential to predict in-hospital mortality compared to clinical scores. (2) Methods: 89 COVID-19 ICU ARDS patients requiring mechanical ventilation or continuous positive airway pressure mask ventilation were included in this single center retrospective study. AI-based lung injury assessment and measurements indicating pulmonary hypertension (PA-to-AA ratio) on admission CT, oxygenation indices, lung compliance and sequential organ failure assessment (SOFA) scores on ICU admission were assessed for their diagnostic performance to predict in-hospital mortality. (3) Results: CT severity scores and PA-to-AA ratios were not significantly associated with in-hospital mortality, whereas the SOFA score showed a significant association (p < 0.001). In ROC analysis, the SOFA score resulted in an area under the curve (AUC) for in-hospital mortality of 0.74 (95%-CI 0.63–0.85), whereas CT severity scores (0.53, 95%-CI 0.40–0.67) and PA-to-AA ratios (0.46, 95%-CI 0.34–0.58) did not yield sufficient AUCs. These results were consistent for the subgroup of more critically ill patients with moderate and severe ARDS on admission (oxygenation index

(1) Background: Extracorporeal membrane oxygenation (ECMO) therapy in intensive care units (ICUs) remains the last treatment option for Coronavirus disease 2019 (COVID-19) patients with severely affected lungs but is highly resource demanding. Early risk stratification for the need of ECMO therapy upon admission to the hospital using artificial intelligence (AI)-based computed tomography (CT) assessment and clinical scores is beneficial for patient assessment and resource management; (2) Methods: Retrospective single-center study with 95 confirmed COVID-19 patients admitted to the participating ICUs. Patients requiring ECMO therapy (n = 14) during ICU stay versus patients without ECMO treatment (n = 81) were evaluated for discriminative clinical prediction parameters and AI-based CT imaging features and their diagnostic potential to predict ECMO therapy. Reported patient data include clinical scores, AI-based CT findings and patient outcomes; (3) Results: Patients subsequently allocated to ECMO therapy had significantly higher sequential organ failure (SOFA) scores (p < 0.001) and significantly lower oxygenation indices on admission (p = 0.009) than patients with standard ICU therapy. The median time from hospital admission to ECMO placement was 1.4 days (IQR 0.2–4.0). The percentage of lung involvement on AI-based CT assessment on admission to the hospital was significantly higher in ECMO patients (p < 0.001). In binary logistic regression analyses for ECMO prediction including age, sex, body mass index (BMI), SOFA score on admission, lactate on admission and percentage of lung involvement on admission CTs, only SOFA score (OR 1.32, 95% CI 1.08–1.62) and lung involvement (OR 1.06, 95% CI 1.01–1.11) were significantly associated with subsequent ECMO allocation. Receiver operating characteristic (ROC) curves showed an area under the curve (AUC) of 0.83 (95% CI 0.73–0.94) for lung involvement on admission CT and 0.82 (95% CI 0.72–0.91) for SOFA scores on ICU admission. A combined parameter of SOFA on ICU admission and lung involvement on admission CT yielded an AUC of 0.91 (0.84–0.97) with a sensitivity of 0.93 and a specificity of 0.84 for ECMO prediction; (4) Conclusions: AI-based assessment of lung involvement on CT scans on admission to the hospital and SOFA scoring, especially if combined, can be used as risk stratification tools for subsequent requirement for ECMO therapy in patients with severe COVID-19 disease to improve resource management in ICU settings.

(1) Background: To assess the value of chest CT imaging features of COVID-19 disease upon hospital admission for risk stratification of invasive ventilation (IV) versus no or non-invasive ventilation (non-IV) during hospital stay. (2) Methods: A retrospective single-center study was conducted including all patients admitted during the first three months of the pandemic at our hospital with PCR-confirmed COVID-19 disease and admission chest CT scans (n = 69). Using clinical information and CT imaging features, a 10-point ordinal risk score was developed and its diagnostic potential to differentiate a severe (IV-group) from a more moderate course (non-IV-group) of the disease was tested. (3) Results: Frequent imaging findings of COVID-19 pneumonia in both groups were ground glass opacities (91.3%), consolidations (53.6%) and crazy paving patterns (31.9%). Characteristics of later stages such as subpleural bands were observed significantly more often in the IV-group (52.2% versus 26.1%, p = 0.032). Using information directly accessible during a radiologist’s reporting, a simple risk score proved to reliably differentiate between IV- and non-IV-groups (AUC: 0.89 (95% CI 0.81–0.96), p < 0.001). (4) Conclusions: Information accessible from admission CT scans can effectively and reliably be used in a scoring model to support risk stratification of COVID-19 patients to improve resource and allocation management of hospitals.

Various studies have reported insufficient beta-lactam concentrations in critically ill patients. The extent to which therapeutic drug monitoring (TDM) in clinical practice can reduce insufficient antibiotic concentrations is an ongoing matter of investigation. We retrospectively evaluated routine meropenem and piperacillin measurements in critically ill patients who received antibiotics as short infusions in the first year after initiating a beta-lactam TDM program. Total trough concentrations above 8.0 mg/L for meropenem and above 22.5 mg/L for piperacillin were defined as the breakpoints for target attainment. We included 1832 meropenem samples and 636 piperacillin samples. We found that 39.3% of meropenem and 33.6% of piperacillin samples did not reach the target concentrations. We observed a clear correlation between renal function and antibiotic concentration (meropenem, r = 0.53; piperacillin, r = 0.63). Patients with renal replacement therapy or creatinine clearance (CrCl) of 100 mL/min that achieved the target concentrations with the maximum recommended dosage. Patients with impaired renal function only required TDM if toxic side effects were noted. In contrast, patients with normal renal function required different dosage regimens and TDM-guided therapy to reach the breakpoints of target attainment.