Identifying High-Risk Patients for Severe Pulmonary Complications after Cardiosurgical Procedures as a Target Group for Further Assessment of Lung-Protective Strategies.

OBJECTIVES: It remains unclear whether intraoperative lung-protective strategies can reduce the rate of respiratory complications after cardiac surgery, partly because low-risk patients have been studied in the past. The authors established a screening model to easily identify a high-risk group for severe pulmonary complications (ie, pneumonia or acute respiratory distress syndrome) that may be the ideal target population for the assessment of the potential benefits of such measures. DESIGN: Retrospective observational trial. SETTING: Departments of cardiac surgery and cardiac anesthesia of a university hospital. PARTICIPANTS: Consecutive patients undergoing cardiac surgery on cardiopulmonary bypass and subsequent treatment at a dedicated cardiosurgical intensive care unit between January 2019 and March 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 2,572 patients undergoing surgery, 84 (3.3%) developed pneumonia/acute respiratory distress syndrome that significantly affected the outcome (ie, longer ventilatory support [66% vs 11%], higher reintubation rate [39% vs 3%]), prolonged length of intensive care unit [33 ± 36 vs 4 ± 10 days] and hospital stay [10 ± 15 vs 6 ± 7 days], and higher in-hospital [43% vs 9%] as well as 30-day [7% vs 3%] mortality). The screening model for severe pulmonary complications included left ventricular ejection fraction <52%, EuroSCORE II (European System for Cardiac Operative Risk Evaluation II) >5.9, cardiopulmonary bypass time >123 minutes, left ventricular assist device or aortic repair surgery, and bronchodilatory therapy. A cutoff for the predicted risk of 2.5% showed optimal sensitivity and specificity, with an area under the receiver operating characteristic curve of 0.82. CONCLUSIONS: The authors suggest that future research on intraoperative lung-protective measures focuses on this high-risk population, primarily aiming to mitigate severe forms of postoperative pulmonary dysfunction associated with poor outcomes and increased resource consumption.

Tumour immune microenvironment in resected thymic carcinomas as a predictor of clinical outcome.

BACKGROUND: The spatial distribution of tumour-infiltrating lymphocytes (TILs) is a novel descriptor characterising the tumour immune microenvironment (TIME). The aim of our study was to assess whether a specific TIME of surgically resected thymic carcinoma (TC) can predict tumour invasiveness, recurrence or survival. METHODS: Digital microscopy was performed on 39 TCs immunohistochemically stained to investigate the activation of the immune checkpoint pathway (PD-L1/PD-1), along with density and spatial distribution of TILs phenotypes (CD3+, CD4+, CD8+, FOXP3+, CD56+). The impact of PD-L1 and TIL density considering the intratumoural (iTILs) and stromal (sTILs) distribution on pathological characteristics and clinical outcomes were analysed. RESULTS: In early TC stages, we observed a higher total density of CD3+ (p = 0.05) and CD8+ (p = 0.02) TILs. PD-L1 was expressed in 71.8% of TCs. In advanced TC stages, we observed a lower density of CD3+ (p = 0.04) and CD8+ (p = 0.01) iTILs compared to early stages. Serum concentrations of PD-L1 were significantly higher in TCs compared to healthy controls: 134.43 ± 18.51 vs. 82.01 ± 6.34 pg/ml (p = 0.001), respectively. High densities of stromal CD4+ TILs (54 vs. 32%, p = 0.043) and CD8+ TILs (65 vs. 17%, p = 0.048) were associated with improved freedom from recurrence (FFR) and cause-specific survival (CSS). High density of FoxP3+ TILs were associated with improved FFR (p = 0.03) and CSS (p = 0.003). DISCUSSION: Mapping TIL subpopulations complement the armamentarium for prognostication of TC outcomes. The improved outcome in patients with high density of TILs supports the use of immune checkpoint inhibitors in TC patients.

Non-pulsatile blood flow is associated with enhanced cerebrovascular carbon dioxide reactivity and an attenuated relationship between cerebral blood flow and regional brain oxygenation.

BACKGROUND: Systemic blood flow in patients on extracorporeal assist devices is frequently not or only minimally pulsatile. Loss of pulsatile brain perfusion, however, has been implicated in neurological complications. Furthermore, the adverse effects of absent pulsatility on the cerebral microcirculation are modulated similarly as CO2 vasoreactivity in resistance vessels. During support with an extracorporeal assist device swings in arterial carbon dioxide partial pressures (PaCO2) that determine cerebral oxygen delivery are not uncommon-especially when CO2 is eliminated by the respirator as well as via the gas exchanger of an extracorporeal membrane oxygenation machine. We, therefore, investigated whether non-pulsatile flow affects cerebrovascular CO2 reactivity (CVR) and regional brain oxygenation (rSO2). METHODS: In this prospective, single-centre case-control trial, we studied 32 patients undergoing elective cardiac surgery. Blood flow velocity in the middle cerebral artery (MCAv) as well as rSO2 was determined during step changes of PaCO2 between 30, 40, and 50 mmHg. Measurements were conducted on cardiopulmonary bypass during non-pulsatile and postoperatively under pulsatile blood flow at comparable test conditions. Corresponding changes of CVR and concomitant rSO2 alterations were determined for each flow mode. Each patient served as her own control. RESULTS: MCAv was generally lower during hypocapnia than during normocapnia and hypercapnia (p < 0.0001). However, the MCAv/PaCO2 slope during non-pulsatile flow was 14.4 cm/s/mmHg [CI 11.8-16.9] and 10.4 cm/s/mmHg [CI 7.9-13.0] after return of pulsatility (p = 0.03). During hypocapnia, non-pulsatile CVR (4.3 ± 1.7%/mmHg) was higher than pulsatile CVR (3.1 ± 1.3%/mmHg, p = 0.01). Independent of the flow mode, we observed a decline in rSO2 during hypocapnia and a corresponding rise during hypercapnia (p < 0.0001). However, the relationship between ΔrSO2 and ΔMCAv was less pronounced during non-pulsatile flow. CONCLUSIONS: Non-pulsatile perfusion is associated with enhanced cerebrovascular CVR resulting in greater relative decreases of cerebral blood flow during hypocapnia. Heterogenic microvascular perfusion may account for the attenuated ΔrSO2/ΔMCAv slope. Potential hazards related to this altered regulation of cerebral perfusion still need to be assessed. TRIAL REGISTRATION: The study was retrospectively registered on October 30, 2018, with Clinical Trial.gov (NCT03732651).

Revisiting aortic valve prosthesis choice in patients younger than 50 years: 10 years results of the AUTHEARTVISIT study.

OBJECTIVES: This population-based cohort study investigated mid-term outcome after surgical aortic valve replacement with a bioprosthetic or mechanical valve prosthesis in patients aged <50 years in a European social welfare state. METHODS: We analysed patient data from the main social insurance carriers in Austria (2010-2020). Subsequent patient-level record linkage with national health data provided patient characteristics and clinical outcome. Survival, reoperation, myocardial infarction, heart failure, embolic stroke or intracerebral haemorrhage, bleeding other than intracerebral haemorrhage and major adverse cardiac events were evaluated as outcomes. RESULTS: A total of 991 patients were analysed. Regarding demographics, no major differences between groups were observed. Multivariable Cox regression revealed no significant difference in overall survival (P = 0.352) with a median follow-up time of 6.2 years. Reoperation-free survival was decreased (hazard ratio = 1.560 [95% CI: 1.076-2.262], P = 0.019) and the risk for reoperation was increased (hazard ratio = 2.770 [95% CI: 1.402-5.472], P = 0.003) in patients who received bioprostheses. Estimated probability of death after reoperation was 0.23 (CL: 0.08-0.35) after 2 years and 0.34 (CL: 0.06-0.53) after 10 years over both groups. Regarding further outcomes, no significant differences between the two groups were observed. CONCLUSIONS: In patients below 50 years of age receiving aortic valve replacement, implantation of bioprostheses when compared to mechanical heart valve prostheses was associated with a significantly higher rate of reoperations and reduced reoperation-free survival. Nevertheless, we could not observe a difference in overall survival. However, long-term follow-up has to evaluate that a significantly lower rate of reoperations may translate in consistently improved long-term survival.

[Nutrition practices in intensive care units: nutritionDay from 2007-2021]. / Ernährungspraxis auf Intensivstationen: nutritionDay 2007­2021.

In intensive care units (ICU), patients who are not able to eat or are considered at nutritional risk typically receive medical nutrition therapy based on partially contradictory guidelines as well as the strategies used in large randomized trials. The aim of this study is to analyze patient data from the nutritionDay project in intensive care to describe current clinical approaches to nutrition support worldwide, in Europe and in the group of German-speaking countries, the DACH (i.e., Germany, Austria, Switzerland) region. From 2007-2021, data of 18,918 adult patients in 1595 ICUs from 63 different countries were included in this cross-sectional study. The aim was to recruit all patients present in ICUs. Median stay in the ICU was 4 days on nutritionDay. Little difference in patient characteristics were observed between worldwide, Europe, and the DACH region. Patient were 64 years old, 40% female, 50% ventilated, 29% sedated, and 10% needed renal replacement therapy. A quarter of the patients died in hospital within 60 days and about half of the patients had been discharged home. Enteral nutrition was given twice as frequently as parenteral nutrition (48% versus 24%). Many patients received oral nutrition (39%) and a substantial number received no nutrition support (10%). Parenteral nutrition was used more frequently in Europe than in other world regions, the lowest use being observed in North America. The amount of nutrition given is very similar in all regions regardless of the nutrition route with about 1500 kcal and 60 g of protein per day. A clear association with body weight was not observed and the variation around the median was very large with half of patients receiving amounts 25% below or above the median. Upon completion of data entry, the nutritionDay project allows each ICU to download a unit report summarizing data that allows comparison with worldwide data in numeric and graphical form to permit easy benchmarking of medical nutrition therapy.

More Nutritional Support on the Wards after a Previous Intensive Care Unit Stay: A nutritionDay Analysis in 136,667 Patients.

ICU (intensive care unit) patients are exposed to nutritional risks such as swallowing problems and delayed gastric emptying. A previous ICU stay may affect nutritional support upon transfer to the ward. The aim was to study the use of enteral (EN), parenteral nutrition (PN), and oral nutritional supplements (ONS) in ward patients with and without a previous ICU stay, also referred to as post- and non-ICU patients. In total, 136,667 adult patients from the nutritionDay audit 2010-2019 were included. A previous ICU stay was defined as an ICU stay during the current hospitalisation before nutritionDay. About 10% of all patients were post-ICU patients. Post-ICU patients were more frequently exposed to risk factors such as a BMI < 18.5 kg/m2, weight loss, decreased mobility, fair or poor health status, less eating and a longer hospital length of stay before nDay. Two main results were shown. First, both post- and non-ICU patients were inadequately fed: About two thirds of patients eating less than half a meal did not receive EN, PN, or ONS. Second, post-ICU patients had a 1.3 to 2.0 higher chance to receive EN, PN, or ONS compared to non-ICU patients in multivariable models, accounting for sex, age, BMI, weight change, mobility, health status, amount eaten on nutritionDay, hospital length of stay, and surgical status. Based on these results, two future goals are suggested to improve nutritional support on the ward: first, insufficient eating should trigger nutritional therapy in both post- and non-ICU patients; second, medical caregivers should not neglect nutritional support in non-ICU patients.

Oxygen Consumption Predicts Long-Term Outcome of Patients with Left Ventricular Assist Devices.

Reduced oxygen consumption (VO2), either due to insufficient oxygen delivery (DO2), microcirculatory hypoperfusion and/or mitochondrial dysfunction, has an impact on the adverse short- and long-term survival of patients after cardiac surgery. However, it is still unclear whether VO2 remains an efficient predictive marker in a population in which cardiac output (CO) and consequently DO2 is determined by a left ventricular assist device (LVAD). We enrolled 93 consecutive patients who received an LVAD with a pulmonary artery catheter in place to monitor CO and venous oxygen saturation. VO2 and DO2 of in-hospital survivors and non-survivors were calculated over the first 4 days. Furthermore, we plotted receiver-operating curves (ROC) and performed a cox-regression analysis. VO2 predicted in-hospital, 1- and 6-year survival with the highest area under the curve of 0.77 (95%CI: 0.6-0.9; p = 0.0004). A cut-off value of 210 mL/min VO2 stratified patients regarding mortality with a sensitivity of 70% and a specificity of 81%. Reduced VO2 was an independent predictor for in-hospital, 1- and 6-year mortality with a hazard ratio of 5.1 (p = 0.006), 3.2 (p = 0.003) and 1.9 (p = 0.0021). In non-survivors, VO2 was significantly lower within the first 3 days (p = 0.010, p < 0.001, p < 0.001 and p = 0.015); DO2 was reduced on days 2 and 3 (p = 0.007 and p = 0.003). In LVAD patients, impaired VO2 impacts short- and long-term outcomes. Perioperative and intensive care medicine must, therefore, shift their focus from solely guaranteeing sufficient oxygen supply to restoring microcirculatory perfusion and mitochondrial functioning.

Anesthetic practice during cardiac implantable electronic device implant procedures: A retrospective, single-center study.

Objectives: Data on anesthetic proceedings during cardiac implantable electronic device (CIED) implant procedures are scarce and it remains unclear whether anesthetic care is still required in selected patients. Methods: In this retrospective, single center study we assessed the prevalence of intraoperative anesthetic management comprising anesthetic standby, sedation or general anesthesia as well as anesthetic and procedural complications. We analyzed pre-existing and perioperative risk factors related to procedure-related adverse outcome such as perioperative cardiopulmonary resuscitation (CPR) and 30-day mortality in a uni- and multivariable analysis. Results: In total, PM and ICD insertion were performed in up to 85% and 58% under anesthetic standby, with an increasing tendency over time.Overall, Cardiopulmonary resuscitation (CPR) was required in 59 patients. Acute heart failure (AHF) was the only independent pre-existing risk factor for CPR and for 30-day mortality. Sedation and general anesthesia had a significantly increased odds ratio for CPR compared to anesthetic standby. The risk for CPR significantly decreased during the study period. Conclusions: Over the years anesthetic practice during CIED implant procedures shifted from mixed anesthetic proceedings to mainly standby duties. The prevalence of complications and emergency measures is low, however not uncommon. Accordingly, the presence of an anesthesiologist should be further guaranteed when sedatives were titrated and in AHF patients. However, in patients receiving local anesthetic infiltration only, it seems safe to perform CIED implant procedures without anesthetic standby.

Follistatin-like 1 and Biomarkers of Neutrophil Activation Are Associated with Poor Short-Term Outcome after Lung Transplantation on VA-ECMO.

The investigation of biomarkers associated with undesired outcome following lung transplantation (LuTX) is essential for a better understanding of the underlying pathophysiology, an earlier identification of susceptible recipients and the development of targeted therapeutic options. We therefore determined the longitudinal perioperative course of putative cytokines related to neutrophil activation (chemokine CC motif ligand 4 (CCL-4), interleukin (IL)-23 and Lipocalin 2 (LCN2)) and a cytokine that has been implicated in graft-versus-host disease (Follistatin-like 1 (FSTL1)) in 42 consecutive patients undergoing LuTX. We plotted receiver-operating curves (ROC) to assess the predictive power of the measured cytokines for short-term outcomes namely primary graft dysfunction (PGD), early complications requiring extracorporeal membrane oxygenation (ECMO), and a high postoperative sequential organ failure assessment (SOFA). All cytokines increased immediately after surgery. ROC analyses determined significant associations between CCL4 and a high SOFA score (area under the curve (AUC) 0.74 (95%CI:0.5−0.9; p < 0.05), between LCN2 and postoperative ECMO support (AUC 0.73 (95%CI:0.5−0.9; p < 0.05), and between FSTL1 and PGD (AUC 0.70 (95%CI:0.5−0.9; p < 0.05). The serum concentrations of the neutrophil-derived cytokines LCN2 and CCL4 as well as FSTL1 were all related to poor outcome after LuTX. The specific predictive power, however, still has to be assessed in larger trials. The potential role of FSTL1 as a biomarker in the development of PGD could be of great interest particularly since this protein appears to play a crucial role in allograft tolerance.

Absent Metabolic Transition from the Early to the Late Period in Non-Survivors Post Cardiac Surgery.

After major surgery, longitudinal changes in resting energy expenditure (REE) as well as imbalances in oxygen delivery (DO2) and distribution and processing (VO2) may occur due to dynamic metabolic requirements, an impaired macro- and microcirculatory flow and mitochondrial dysfunction. However, the longitudinal pattern of these parameters in critically ill patients who die during hospitalization remains unknown. Therefore, we analyzed in 566 patients who received a pulmonary artery catheter (PAC) their REE, DO2, VO2 and oxygen extraction ratio (O2ER) continuously in survivors and non-survivors over the first 7 days post cardiac surgery, calculated the percent increase in the measured compared with the calculated REE and investigated the impact of a reduced REE on 30-day, 1-year and 6-year mortality in a uni- and multivariate model. Only in survivors was there a statistically significant transition from a negative to a positive energy balance from day 0 until day 1 (Day 0: −3% (−18, 14) to day 1: 5% (−9, 21); p < 0.001). Furthermore, non-survivors had significantly decreased DO2 during the first 4 days and reduced O2ER from day 2 until day 6. Additionally, a lower REE was significantly associated with a worse survival at 30 days, 1 year and 6 years (p = 0.009, p < 0.0001 and p = 0.012, respectively). Non-survivors seemed to be unable to metabolically adapt from the early (previously called the 'ebb') phase to the later 'flow' phase. DO2 reduction was more pronounced during the first three days whereas O2ER was markedly lower during the following four days, suggesting a switch from a predominantly limited oxygen supply to prolonged mitochondrial dysfunction. The association between a reduced REE and mortality further emphasizes the importance of REE monitoring.

Larger pulmonary artery to ascending aorta ratios are associated with decreased survival of patients undergoing pulmonary endarterectomy.

Objectives: The ratio of pulmonary artery (PA) and ascending aorta (AA) diameters has recently been shown to be a useful indicator for disease severity and predictor of outcome in patients with pulmonary hypertension and heart failure. This study aimed at evaluating the applicability of this ratio for perioperative risk assessment of patients with chronic thromboembolic pulmonary hypertension undergoing pulmonary endarterectomy. Methods: In this retrospective cohort study on 149 patients undergoing pulmonary endarterectomy between 2013 and 2020, the preoperative PA to AA ratio was analyzed on axial computed tomography. Variables of pulmonary hemodynamic status were assessed during preoperative right heart catheterization and postoperative Swan-Ganz catheter measurements. Perioperative survival was analyzed by Kaplan-Meier method and log-rank tests. Results: Preoperative computed tomography measurements showed a median AA diameter of 31 mm (range, 19-47 mm), and a median PA diameter of 36 mm (range, 25-55 mm). The calculated median PA to AA ratio was 1.13 (range, 0.79-1.80). PA to AA ratio correlated positively with PA pressure (systolic, r = 0.352 [P < .001]; diastolic, r = 0.406 [P < .001]; mean, r = 0.318 [P < .001]) and inversely with age (r = -0.484 [P < .001]). Univariable Cox regression analysis identified PA diameter (P = .008) as a preoperative parameter predictive of survival. There was a significant difference (log-rank P = .037) in 30-day survival probability for patients with lower PA to AA ratios (<1.136; survival probability, 97.4%) compared with patients with higher ratios (>1.136; survival probability, 88.9%). Conclusions: PA to AA ratio shows a correlation with other variables associated with pulmonary hypertension. In addition, patients with higher PA to AA ratios have lower survival probabilities after PEA. Further analysis of PA to AA ratio on the selection of chronic thromboembolic pulmonary hypertension for different treatment modalities-pulmonary endarterectomy, medical therapy, and or balloon pulmonary angioplasty-is warranted.

Prevalence of Low Muscle Mass in the Computed Tomography at the Third Lumbar Vertebra Level Depends on Chosen Cut-Off in 200 Hospitalised Patients-A Prospective Observational Trial.

Measuring skeletal muscle area (SMA) at the third lumbar vertebra level (L3) using computed tomography (CT) is increasingly popular for diagnosing low muscle mass. The aim was to describe the effect of the CT L3 cut-off choice on the prevalence of low muscle mass in medical and surgical patients. Two hundred inpatients, who underwent an abdominal CT scan for any reason, were included. Skeletal muscle area (SMA) was measured according to Hounsfield units on a single CT scan at the L3 level. First, we calculated sex-specific cut-offs, adjusted for height or BMI and set at mean or mean-2 SD in our population. Second, we applied published cut-offs, which differed in statistical calculation and adjustment for body stature and age. Statistical calculation of the cut-off led to a prevalence of approximately 50 vs. 1% when cut-offs were set at mean vs. mean-2 SD in our population. Prevalence varied between 5 and 86% when published cut-offs were applied (p < 0.001). The adjustment of the cut-off for the same body stature variable led to similar prevalence distribution patterns across age and BMI classes. The cut-off choice highly influenced prevalence of low muscle mass and prevalence distribution across age and BMI classes.

Inflammatory immune response in recipients of transcatheter aortic valves.

Objective: Transcatheter aortic valve implantation (TAVI) is rapidly replacing cardiac surgery due to its minimal invasiveness and practicality. Midterm immunological studies on the biocompatibility of galactose-alpha-1,3-galactose (α-Gal)-carrying bioprosthetic heart valves for TAVI are not available. In this study we investigated whether bioprosthetic heart valves employed for TAVI augment an α-Gal-specific antibody-dependent and antibody-independent immune response 3 months after TAVI implantation. Methods: This prospective observational study included 27 patients with severe aortic valve stenosis undergoing TAVI and 10 patients with severe mitral valve regurgitation treated with a transcatheter MitraClip (Abbott Laboratories, Abbott Park, Ill) procedure. Blood samples were drawn before and 90 days after treatment at a routine checkup. Serum samples were analyzed using enzyme-linked immunosorbent assay. Serum concentrations of α-Gal-specific immunoglobulin (Ig) G, IgG subclasses and IgE, complement factor 3a, NETosis-specific citrullinated H3, and the systemic inflammation markers soluble suppression of tumorigenicity and interleukin 33 were evaluated. Results: Three months after TAVI, we found significantly increased serum concentrations of α-Gal-specific IgG3, complement factor complement factor 3a, citrullinated H3 levels, and soluble suppression of tumorigenicity (P = .002, P = .001, P = .025, and P = .039, respectively). Sensitization of α-Gal-specific IgE antibodies occurred in 55% of all patients after TAVI. Conclusions: Our results indicate that TAVI elicits a midterm, specific humoral immune response against α-Gal and causes an unspecific humoral inflammation compared with patients undergoing MitraClip implantation. This observation will lead to a better understanding of postintervention morbidity and the long-term durability of bioprostheses and indicates that caution is appropriate when designing implantation strategies for younger patients.

Timing of parenteral nutrition in ICU patients: A transatlantic controversy.

BACKGROUND AND AIMS: European and North American guidelines on Parenteral Nutrition (PN) and large Randomized Controlled Trials give divergent advices on nutritional therapeutic strategies for critically ill patients. We therefore investigated differences in therapeutic strategies of clinicians between European and Non-European Intensive Care Units (ICU) regarding start day of PN, preferred route of administration and prescription of total energy targets over the years. METHODS: In this study 16,032 patients from 1389 different ICUs were included. Data collection was performed in 28 different European and Non-European ICUs from 2007 to 2018 via nutritionDay, a worldwide-standardized one-day multinational cross-sectional audit. RESULTS: In this analysis an abrupt delay in PN start days was observed in 2011 (7.64 days (4.31; 19.97); p = 0.001) and 2012 (6.41 days (3.1; 9.72); p = 0.001), which was significantly reversed within the following years until 2018. In European, compared to Non-European countries PN prescription was increased (27% versus 13%). Patients from North-America received significantly less kcal per day compared to Europe (-4.3 kcal kg-1 (-6.9; -1.6); p = 0.001). CONCLUSIONS: Our study provides further evidence on transatlantic discrepancies in nutritional therapy of ICU patients. Regular audits, such as nutritionDay are substantial for self-reflection of clinical daily practice of intensivists. It is time for worldwide consensus in nutritional therapy by developing worldwide guidelines and supporting standardization in nutrition care of critically ill patients.

Transient perioperative inflammation following lung transplantation and major thoracic surgery with elective extracorporeal support: a prospective observational study.

BACKGROUND: The clinical relevance of inflammation induced by elective perioperative extracorporeal membrane oxygenation (ECMO) usage as an integral part of modern lung transplantation (LUTX) remains elusive. The aim of this study was to determine the perioperative cytokine response accompanying major thoracic surgery employing different extracorporeal devices comprising ECMO, cardiopulmonary bypass (CPB), or no extracorporeal circulation in relation to inflammation, clinically tangible as increased sequential organ failure assessment (SOFA) score, called SOFA. METHODS: In this prospective, observational pilot study 42 consecutive patients with end-stage pulmonary disease undergoing LUTX; 15 patients with chronic thromboembolic pulmonary hypertension (CTEPH) undergoing pulmonary endarterectomy and 15 patients with lung cancer undergoing major lung resections were analysed. Cytokine serum concentrations and SOFA were determined before, at end of surgery and in the following postoperative days. RESULTS: LUTX on ECMO and pulmonary endarterectomy (PEA) on CPB triggered an immediate increase in cytokine serum concentrations at end of surgery: IL-6: 66-fold and 71-fold, IL-10: 3-fold and 2.5-fold, ST2/IL-33R: 5-fold and 4-fold and SOFA: 10.5±2.8 and 10.7±1.7, that decreased sharply to baseline levels from postoperative day 1-5. Despite low perioperative mortality (3 patients, 4.1%) extremely high SOFA ≥13 was associated with mortality after LUTX. Delta-SOFA distinguished survivors from non-survivors: -4.5±3.2 vs. -0.3±1.5 (P=0.001). Increased IL-6 serum concentrations were predictive for increased SOFA (sensitivity: 97%, specificity: 80%). Peak cytokine serum concentrations correlated with ECC duration, maximal lactate, transfusion of red-blood-cells, fresh-frozen-plasma, and catecholamine support. CONCLUSIONS: LUTX and PEA on extracorporeal circulation with an excellent outcome triggered an immediate rise and concomitant fall of inflammation as observed in cytokine serum concentrations and SOFA. High absolute SOFA in the presence of an uncomplicated postoperative course may pertain to specific management strategies rather than organ failure.

Potential novel biomarkers for chronic lung allograft dysfunction and azithromycin responsive allograft dysfunction.

Chronic Lung Allograft Dysfunction (CLAD), manifesting as Bronchiolitis Obliterans Syndrome (BOS) or Restrictive Allograft Syndrome (RAS), is the main reason for adverse long-term outcome after Lung Transplantation (LTX). Until now, no specific biomarkers exist to differentiate between CLAD phenotypes. Therefore, we sought to find suitable cytokines to distinguish between BOS, RAS and Azithromycin Responsive Allograft Dysfunction (ARAD); and reveal potential similarities or differences to end-stage fibrotic diseases. We observed significantly increased Lipocalin-2 serum concentrations in RAS compared to BOS patients. In addition, in RAS patients immunohistochemistry revealed Lipocalin-2 expression in bronchial epithelium and alveolar walls. Patients with ARAD showed significantly lower Activin-A serum concentrations compared to Stable-LTX and BOS patients. Further, increased serum concentrations of Lipocalin-2 and Activin-A were predictors of worse freedom-from-CLAD in Stable-LTX patients. These biomarkers serve as promising serum biomarkers for CLAD prediction and seem suitable for implementation in clinical practice.

Fractional heat shock protein 27 urine excretion as a short-term predictor in acute exacerbation of chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality and is characterized by episodes of acute exacerbations. Finding a systemic biomarker that reliably predicts outcome after an acute exacerbation remains a major challenge. Heat shock protein 27 (HSP27) has been previously studied in COPD, however, urine excretion trajectory and prognostic value after an exacerbation is unknown. METHODS: In this retrospective post hoc analysis of a prospective study that included 253 COPD patients who were hospitalized for acute exacerbation, 207 patients were analyzed. Urine and serum were sampled at admission, discharge, and 180 days after discharge; urine excretion trajectory was analyzed and correlated with clinicopathological and survival data. RESULTS: HSP27 urine excretion increased after an exacerbation episode [1.8% admission, 1.8% discharge, 2.3% 180 days after discharge (P=0.091)]. In severely ill patients (GOLD IV) this course was even more distinct [1.6% admission, 2.1% discharge, 2.8% 180 days after discharge (P=0.007)]. Furthermore, fractional HSP27 urine excretion at discharge was increased in GOLD IV patients (P=0.031). In Kaplan-Meier and univariable Cox proportional hazard models patients with HSP27 urine excretion below 0.845% showed significantly worse survival at 30, 90 and 180 days after discharge. In a multivariable Cox proportional hazard model including established COPD outcome parameters fractional HSP27 urine excretion remained a significant predictor of survival at 30 and 90 days after discharge. Comparing this model to our already published model that includes HSP27 serum concentration we could show that fractional HSP27 urine excretion performs better in short-term survival. CONCLUSIONS: Our findings provide novel information about fractional HSP27 urine excretion trajectory in acute exacerbation of COPD. Fractional HSP27 urine excretion may be significantly reduced during an episode of acute exacerbation in COPD patients and may be used as a predictor of short-term all-cause mortality.

Heat shock protein 90α in thymic epithelial tumors and non-thymomatous myasthenia gravis.

Background: Thymic epithelial tumors (TETs) are rare malignancies with unique association to the autoimmune disease myasthenia gravis (MG). Heat shock proteins (HSPs) harbor great potential as cancer biomarkers and HSP inhibitors approach clinical cancer therapy. Methods: To explore HSP pathophysiology, we assessed sera (immunoassays) and tissues (immunohistochemistry) of TETs (and thymic tissues) for HSP27, phosphorylated (p)HSP27, HSP70 and HSP90α expression in 114 TETs and 26 non-thymomatous MG patients undergoing extended thymectomy. Results: Serum concentrations of HSP90α were significantly increased in patients with thymic carcinomas, thymomas, thymic neuroendocrine tumors and non-thymomatous MG compared to patients who underwent thymectomy revealing regular thymic morphology or controls. In thymoma patients, high serum HSP90α represented a significantly worse prognostic factor for free-from-recurrence, and complete tumor resection led to decreased levels. The expression of HSP90 in nuclei and cytoplasm of tumor cells and non-neoplastic lymphocytes varied with WHO histological subtype. HSP90 was expressed in centroblasts of thymic germinal centers in MG patients. Higher pHSP27 serum concentrations were observed in seropositive MG and those not treated with steroids. Conclusions: HSP data suggest high potential for HSPs as TET cancer biomarkers or as candidates for targeted therapy. Caution is warranted in TET patients with associated MG overexpressing HSPs.

The inflammatory markers sST2, HSP27 and hsCRP as a prognostic biomarker panel in chronic heart failure patients.

BACKGROUND: The inflammatory markers sST2, HSP27 and hsCRP have already been identified as prognostic markers in chronic heart failure (HF). Though individual biomarkers have proven their value in mortality risk prediction, the role of a multimarker strategy needs further evaluation. MATERIALS AND METHODS: This is an exploratory reanalysis in chronic HF patients. Plasma HSP27, sST2 and hsCRP in outpatients with chronic HF were analysed. Patients were followed for a minimum of twelve months for the endpoint cardiovascular mortality and unplanned HF associated hospitalisation (=event). 15 year overall mortality was assessed retrospectively. The prognostic impact was assessed using a Cox proportional hazard model. RESULTS: 113 chronic HF patients were included. Median follow up time was 614 days and 37 patients (32.7%) experienced an event. A Kaplan-Meier analysis revealed that patients with increased sST2, HSP27 and hsCRP levels have significantly worse prognosis (p < 0.001). The use of a three-biomarker combination was superior in an independent risk prediction of an event (one high vs. two high: HR = 4.5, 95% CI: 1.3-15.5, p = 0.018; and one high vs. all high: HR = 9.8, 95% CI: 2.8-34.3, p < 0.001) as shown in a multivariable cox proportional hazard model. However, the biomarker panel did not predict 15 year overall mortality, in contrast to elevated HSP27 levels (p = 0.012). CONCLUSIONS: The combination of all three markers is an independent predictor of cardiovascular death and unplanned HF associated hospitalisation but not overall mortality. Our findings suggest that adding those markers in combination to well established risk assessment parameters may improve risk stratification.