German Patient Blood Management Network: effectiveness and safety analysis in 1.2 million patients.

BACKGROUND: Patient Blood Management (PBM) is a patient-centred, systematic, evidence-based approach to improve patient outcomes by managing and preserving a patient's own blood whilst promoting patient safety and empowerment. The effectiveness and safety of PBM over a longer period have not yet been investigated. METHODS: We performed a prospectively designed, multicentre follow-up study with non-inferiority design. Data were retrospectively extracted case-based from electronic hospital information systems. All in-hospital patients (≥18 yr) undergoing surgery and discharged between January 1, 2010 and December 31, 2019 were included in the analysis. The PBM programme focused on three domains: preoperative optimisation of haemoglobin concentrations, blood-sparing techniques, and guideline adherence/standardisation of allogeneic blood product transfusions. The outcomes were utilisation of blood products, composite endpoint of in-hospital mortality and postoperative complications (myocardial infarction/ischaemic stroke/acute renal failure with renal replacement therapy/sepsis/pneumonia), anaemia rate at admission and discharge, and hospital length of stay. RESULTS: A total of 1 201 817 (pre-PBM: n=441 082 vs PBM: n=760 735) patients from 14 (five university/nine non-university) hospitals were analysed. Implementation of PBM resulted in a substantial reduction of red blood cell utilisation. The mean number of red blood cell units transfused per 1000 patients was 547 in the PBM cohort vs 635 in the pre-PBM cohort (relative reduction of 13.9%). The red blood cell transfusion rate was significantly lower (P<0.001) with odds ratio 0.86 (0.85-0.87). The composite endpoint was 5.8% in the PBM vs 5.6% in the pre-PBM cohort. The non-inferiority aim (safety of PBM) was achieved (P<0.001). CONCLUSIONS: Analysis of >1 million surgical patients showed that the non-inferiority condition (safety of Patient Blood Management) was fulfilled, and PBM was superior with respect to red blood cell transfusion. CLINICAL TRIAL REGISTRATION: NCT02147795.

Follow-Up and Outcome after Coronary Bypass Surgery Preceded by Coronary Stent Implantation.

BACKGROUND: Guidelines on myocardial revascularization define recommendations for percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery. Only little information exists on long-term follow-up and quality of life (QoL) after CABG preceded by PCI. The aim of our study was to evaluate the impact of prior PCI on outcome and QoL in patients with stable coronary artery disease who underwent CABG. METHODS: In our retrospective study, CABG patients were divided in: CABG preceded by PCI: PCI-first (PCF), and CABG-only (CO) groups. The PCF group was further divided in guideline-conform (GCO) and guideline nonconform (GNC) subgroups, according to the SYNTAX score (2014 European Society of Cardiology [ESC]/European Association for Cardio-Thoracic Surgery [EACTS] guidelines). Thirty days mortality, major adverse cardiac events, and QoL using the European Quality-of-Life-5 Dimensions were evaluated. RESULTS: A total of 997 patients were analyzed, of which 784 underwent CABG without (CO), and 213 individuals with prior PCI (PCF). The latter group consisted of 67 patients being treated in accordance (GCO), and 24 in discordance (GNC) to the 2014 ESC/EACTS guidelines. Reinfarction (PCF: 3.8% vs. CO: 1.0%; p = 0.024), re-angiography (PCF: 17.6% vs. CO: 9.0%; p = 0.004), and re-PCI (PCF: 10.4% vs. CO: 3.0%; p < 0.001) were observed more frequently in PCF patients. Also, patients reported better health status in the CO compared to PCF group (CO: 72.48 ± 19.31 vs. PCF: 68.20 ± 17.86; p = 0.01). Patients from the guideline nonconform subgroup reported poorer health status compared to the guideline-conform group (GNC: 64.23 ± 14.56 vs. GCO: 73.42 ± 17.66; p = 0.041) and were more likely to require re-PCI (GNC: 18.8% vs. GCO: 2.4%; p = 0.03). Also, GNC patients were more likely to have left main stenosis (GCO: 19.7% vs. GNC: 37.5%; p < 0.001) and showed higher preinterventional SYNTAX score (GCO: 18.63 ± 9.81 vs. GNC: 26.67 ± 5.07; p < 0.001). CONCLUSION: PCI preceding CABG is associated with poorer outcomes such as reinfarction, re-angiography, and re-PCI, but also worse health status and higher rehospitalization. Nevertheless, results were better when PCI was guideline-conformant. This data should impact the Heart Team decision.

Preoperative cerebral oxygenation in high-risk noncardiac surgical patients: an observational study on postoperative mortality and complications.

Near Infrared Spectroscopy (NIRS) has become widely accepted to evaluate regional cerebral oxygen saturation (rScO2), potentially acting as a surrogate parameter of reduced cerebral oxygen delivery or increased consumption. Low preoperative rScO2 is associated with increased postoperative complications after cardiac surgery. However, its universal potential in pre-anesthesia risk assessment remains unclear. Therefore, we investigated whether low preoperative rScO2 is indicative of postoperative complications and associated with poor outcomes in noncardiac surgical patients. We prospectively enrolled 130 patients undergoing high-risk noncardiac surgery. During pre-anesthesia evaluation, baseline rScO2 was recorded with and without oxygen supplementation. The primary endpoint was 30-day mortality, while secondary endpoints were postoperative myocardial injury, respiratory complications, and renal failure. We further evaluated the impact of body position and preoperative hemoglobin (Hb) concentration on rScO2. Of the initially enrolled 130 patients, 126 remained for final analysis. Six (4.76%) patients died within 30 postoperative days. 95 (75.4%) patients were admitted to the ICU. 32 (25.4%) patients suffered from major postoperative complications. There was no significant association between rScO2 and 30-day mortality or secondary endpoints. Oxygen supplementation induced a significant increase of rScO2. Furthermore, Hb concentration correlated with rScO2 values and body position affected rScO2. No significant association between rScO2 values and NYHA, LVEF, or MET classes were observed. Preoperative rScO2 is not associated with postoperative complications in patients undergoing high-risk noncardiac surgery. We speculate that the discriminatory power of NIRS is insufficient due to individual variability of rScO2 values and confounding factors.

Effects of Different Hemoglobin Levels on Near-Infrared Spectroscopy-Derived Cerebral Oxygen Saturation in Elderly Patients Undergoing Noncardiac Surgery.

Background: Near-infrared spectroscopy (NIRS) is a commonly used technique to evaluate tissue oxygenation and prevent harmful cerebral desaturation in the perioperative setting. The aims of the present study were to assess whether surgery-related anemia can be detected via NIRS of cerebral oxygen saturation and to investigate the effects of different perioperative transfusion strategies on cerebral oxygenation, potentially affecting transfusion decision-making. Study Design and Methods: Data from the ongoing multicenter LIBERAL-Trial (liberal transfusion strategy to prevent mortality and anemia-associated ischemic events in elderly noncardiac surgical patients, LIBERAL) were used. In this single-center sub-study, regional cerebral oxygenation saturation (rSO2) was evaluated by NIRS at baseline, pre-, and post-RBC transfusion. The obtained values were correlated with blood gas analysis-measured Hb concentrations. Results: rSO2 correlated with Hb decline during surgery (r = 0.35, p < 0.0001). Different RBC transfusion strategies impacted rSO2 such that higher Hb values resulted in higher rSO2. Cerebral desaturation occurred at lower Hb values more often. Discussion: Cerebral oxygenation monitoring using NIRS provides noninvasive rapid and continuous information regarding perioperative alterations in Hb concentration without the utilization of patients' blood for blood sampling. Further investigations are required to demonstrate if cerebral rSO2 may be included in future individualized transfusion decision strategies.

Mannitol Is Associated with Less Postoperative Delirium after Aortic Valve Surgery in Patients Treated with Bretschneider Cardioplegia.

BACKGROUND: Heart surgery with extracorporeal circulation (ECC) often leads to postoperative delirium (POD). This is associated with increased morbidity resulting in longer hospital stay and associated costs. The purpose of our study was to analyze the effect of intraoperative mannitol application on POD in patients undergoing elective aortic valve replacement (AVR). MATERIALS AND METHOD: s In our retrospective single-center study, 259 patients underwent elective AVR, using Bretschneider cardioplegic solution for cardiac arrest, between 2014 and 2017. Patients were divided in mannitol (n = 188) and nonmannitol (n = 71) groups. POD was assessed using the confusion assessment method for the intensive care unit (ICU). Statistical significance was assumed at p < 0.05. RESULTS: Baseline patient characteristics did not differ between the groups. Incidence of POD was significantly higher in the nonmannitol group (33.8 vs. 13.8%; p = 0.001). These patients required longer ventilation time (24.1 vs. 17.1 hours; p = 0.021), higher reintubation rate (11.3 vs. 2.7%; p = 0.009), ICU readmission (12.7 vs. 4.8%; p = 0.026), prolonged ICU (112 vs. 70 hours; p = 0.040), and hospital stay (17.8 vs. 12.6 days; p < 0.001), leading to higher expenses (19,349 € vs. 16,606 €, p < 0.001). A 30-day mortality was not affected, but nonmannitol group showed higher Simplified Acute Physiology Score II score (32.2 vs. 28.7; p < 0.001). Mannitol substitution was independently associated with lower incidence of POD (odds ratio: 0.40; 95% confidence interval: 0.18-0.89; p = 0.02). CONCLUSION: Treatment with mannitol during ECC was associated with decreased incidence of POD. This was accompanied by shorter ventilation time, ICU and hospital stay, and lower treatment expenses.

Preoperative anaemia and red blood cell transfusion in patients with aneurysmal subarachnoid and intracerebral haemorrhage - a multicentre subanalysis of the German PBM Network Registry.

PURPOSE: Anaemia is common in patients presenting with aneurysmal subarachnoid (aSAH) and intracerebral haemorrhage (ICH). In surgical patients, anaemia was identified as an idenpendent risk factor for postoperative mortality, prolonged hospital length of stay (LOS) and increased risk of red blood cell (RBC) transfusion. This multicentre cohort observation study describes the incidence and effects of preoperative anaemia in this critical patient collective for a 10-year period. METHODS: This multicentre observational study included adult in-hospital surgical patients diagnosed with aSAH or ICH of 21 German hospitals (discharged from 1 January 2010 to 30 September 2020). Descriptive, univariate and multivariate analyses were performed to investigate the incidence and association of preoperative anaemia with RBC transfusion, in-hospital mortality and postoperative complications in patients with aSAH and ICH. RESULTS: A total of n = 9081 patients were analysed (aSAH n = 5008; ICH n = 4073). Preoperative anaemia was present at 28.3% in aSAH and 40.9% in ICH. RBC transfusion rates were 29.9% in aSAH and 29.3% in ICH. Multivariate analysis revealed that preoperative anaemia is associated with a higher risk for RBC transfusion (OR = 3.25 in aSAH, OR = 4.16 in ICH, p < 0.001), for in-hospital mortality (OR = 1.48 in aSAH, OR = 1.53 in ICH, p < 0.001) and for several postoperative complications. CONCLUSIONS: Preoperative anaemia is associated with increased RBC transfusion rates, in-hospital mortality and postoperative complications in patients with aSAH and ICH. TRIAL REGISTRATION: ClinicalTrials.gov , NCT02147795, https://clinicaltrials.gov/ct2/show/NCT02147795.

Fatty Acid Amide Hydrolase Deficiency Is Associated with Deleterious Cardiac Effects after Myocardial Ischemia and Reperfusion in Mice.

Ischemic cardiomyopathy leads to inflammation and left ventricular (LV) dysfunction. Animal studies provided evidence for cardioprotective effects of the endocannabinoid system, including cardiomyocyte adaptation, inflammation, and remodeling. Cannabinoid type-2 receptor (CB2) deficiency led to increased apoptosis and infarctions with worsened LV function in ischemic cardiomyopathy. The aim of our study was to investigate a possible cardioprotective effect of endocannabinoid anandamide (AEA) after ischemia and reperfusion (I/R). Therefore, fatty acid amide hydrolase deficient (FAAH)-/- mice were subjected to repetitive, daily, 15 min, left anterior descending artery (LAD) occlusion over 3 and 7 consecutive days. Interestingly, FAAH-/- mice showed stigmata such as enhanced inflammation, cardiomyocyte loss, stronger remodeling, and persistent scar with deteriorated LV function compared to wild-type (WT) littermates. As endocannabinoids also activate PPAR-α (peroxisome proliferator-activated receptor), PPAR-α mediated effects of AEA were eliminated with PPAR-α antagonist GW6471 i.v. in FAAH-/- mice. LV function was assessed using M-mode echocardiography. Immunohistochemical analysis revealed apoptosis, macrophage accumulation, collagen deposition, and remodeling. Hypertrophy was determined by cardiomyocyte area and heart weight/tibia length. Molecular analyses involved Taqman® RT-qPCR and immune cells were analyzed with fluorescence-activated cell sorting (FACS). Most importantly, collagen deposition was reduced to WT levels when FAAH-/- mice were treated with GW6471. Chemokine ligand-2 (CCL2) expression was significantly higher in FAAH-/- mice compared to WT, followed by higher macrophage infiltration in infarcted areas, both being reversed by GW6471 treatment. Besides restoring antioxidative properties and contractile elements, PPAR-α antagonism also reversed hypertrophy and remodeling in FAAH-/- mice. Finally, FAAH-/--mice showed more substantial downregulation of PPAR-α compared to WT, suggesting a compensatory mechanism as endocannabinoids are also ligands for PPAR-α, and its activation causes lipotoxicity leading to cardiomyocyte apoptosis. Our study gives novel insights into the role of endocannabinoids acting via PPAR-α. We hypothesize that the increase in endocannabinoids may have partially detrimental effects on cardiomyocyte survival due to PPAR-α activation.

Cardiac MRI in Patients with Prolonged Cardiorespiratory Symptoms after Mild to Moderate COVID-19.

Background Myocardial injury and inflammation at cardiac MRI in patients with COVID-19 have been described in recent publications. Concurrently, a chronic COVID-19 syndrome (CCS) after SARS-CoV-2 infection has been observed and manifests with symptoms such as fatigue and exertional dyspnea. Purpose To explore the relationship between CCS and myocardial injury and inflammation as an underlying cause of the persistent complaints in previously healthy individuals. Materials and Methods In this prospective study from January 2021 to April 2021, study participants without known cardiac or pulmonary diseases prior to SARS-CoV-2 infection who had persistent CCS symptoms such as fatigue or exertional dyspnea after convalescence and healthy control participants underwent cardiac MRI. The cardiac MRI protocol included evaluating the T1 and T2 relaxation times, extracellular volume, T2 signal intensity ratio, and late gadolinium enhancement (LGE). Student t tests, Mann-Whitney U tests, and χ2 tests were used for statistical analysis. Results Forty-one participants with CCS (mean age, 39 years ± 13 [standard deviation]; 18 men) and 42 control participants (mean age, 39 years ± 16; 26 men) were evaluated. The median time between the initial incidence of mild to moderate COVID-19 not requiring hospitalization and undergoing cardiac MRI was 103 days (interquartile range, 88-158 days). Troponin T levels were normal. Parameters indicating myocardial inflammation and edema were comparable between participants with CCS and control participants (T1 relaxation times: 978 msec ± 23 vs 971 msec ± 25 [P = .17]; T2 relaxation times: 53 msec ± 2 vs 52 msec ± 2 [P = .47]; T2 signal intensity ratios: 1.6 ± 0.2 vs 1.6 ± 0.3 [P = .10]). Visible myocardial edema was present in none of the participants. Three of 41 (7%) participants with CCS demonstrated nonischemic LGE, whereas no participants in the control group demonstrated nonischemic LGE (0 of 42 [0%]; P = .07). None of the participants fulfilled the 2018 Lake Louise criteria for the diagnosis of myocarditis. Conclusion Individuals with chronic COVID-19 syndrome who did not undergo hospitalization for COVID-19 did not demonstrate signs of active myocardial injury or inflammation at cardiac MRI. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Lima and Bluemke in this issue.

Elevated body mass index facilitates early postoperative complications after surgery for intracranial meningioma.

Surgical resection represents the primary treatment option for patients suffering from intracranial meningioma. However, early postoperative complications significantly worsen initial favorable postoperative outcomes. Therefore, the ability to preoperatively assess potential risk factors for early postoperative unfavorable events is important to preselect critical patients who might require special attention during clinical management. In the current study, we therefore analyzed our institutional database in order to identify risk factors associated with early postoperative complications after initial meningioma resection. Between 2014 and 2017, 202 patients with intracranial supratentorial meningioma were surgically treated at the authors' institution. Early postoperative complications were defined as any postoperative event requiring further surgical measures within 30 days following initial meningioma resection. A multivariate analysis was performed to identify independent risk factors associated with postoperative complications after surgical meningioma therapy. Overall, 13 out of 202 meningioma patients developed early postoperative complications (6%). The multivariate analysis revealed obesity in terms of elevated body mass index (BMI ≥ 30 kg/m2) (p = 0.03), the presence of atrial fibrillation (p = 0.001) as well as the preoperative Karnofsky Performance Status Scale < 70% (p = 0.004) as independent predictors for early postoperative complications in the course of supratentorial meningioma resection. Obesity is associated with a higher risk of postoperative unfavorable events that require further surgical treatment. Furthermore, the present study identifies several additional risk factors for the development of early postoperative complications after intracranial meningioma resection enabling to preoperatively select for high-risk patients that might require special attention in clinical and surgical management.

[Central Venous Access in Children: Technique and Complications]. / Gefäßzugänge bei Kindern: Technik, Komplikationen und Fallstricke beim zentralen Venenkatheter.

Children with complex diseases often need central venous catheter, not only for intraoperative use, but also for parenteral nutrition, multiple blood draw due to lab examination and to administer drugs that cannot be given via peripheral lines. Whereas the landmark driven vascular access was teached for years, nowadays the routine use of ultrasound based techniques can be called the gold standard. This article highlights standard locations for central venous access like cannulation of the internal jugular vein as well as novel alternatives such as the cannulation of the brachiocephalic vein. The correct insertion depth of central lines is essential to avoid serious complications. Several different formulas are available and can be used. Independent of the used formula, you have to make sure that complications due to incorrect depth of central venous line are a topic of the past. Finally, important tips and tricks to avoid failure and serious complications are discussed.

CpG postconditioning after reperfused myocardial infarction is associated with modulated inflammation, less apoptosis, and better left ventricular function.

Postconditioning attenuates inflammation and fibrosis in myocardial infarction (MI). The aim of this study was to investigate whether postconditioning with the cytosine-phosphate-guanine (CpG)-containing Toll-like receptor-9 (TLR9) ligand 1668-thioate (CpG) can modulate inflammation and remodeling in reperfused murine MI. Thirty minutes of left descending coronary artery (LAD) occlusion was conducted in 12-wk-old C57BL/6 mice. Mice were treated with CpG intraperitoneally 5 min before reperfusion. The control group received PBS; the sham group did not undergo ischemia. M-mode echocardiography (3, 7, and 28 days) and Millar left ventricular (LV) catheterization were performed (7 and 28 days) before the hearts were excised and harvested for immunohistochemical (6 h, 24 h, 3 days, 7 days, and 28 days), gene expression (6 h, 24 h, and 3 days; Taqman RT-qPCR), protein, and FACS analysis (24 h and 3 days). Mice treated with CpG showed significantly better LV function after 7 and 28 days of reperfusion. Protein and mRNA expressions of proinflammatory and anti-inflammatory cytokines were significantly induced after CpG treatment. Histology revealed fewer macrophages in CpG mice after 24 h, confirmed by FACS analysis with a decrease in both classically M1- and alternative M2a-monocytes. CpG treatment reduced apoptosis and cardiomyocyte loss and was associated with induction of adaptive mechanisms, e.g., of heme-oxigenase-1 and ß-/α-myosin heavy chain (MHC) ratio. Profibrotic markers collagen type Iα (Col-Ια) and Col-III induction was abrogated in CpG mice, accompanied by fewer myofibroblasts. This led to the formation of a smaller scar. Differential matrix metalloproteinase (MMP)/tissue inhibitor of metalloproteinase (TIMP) expression contributed to attenuated remodeling in CpG, resulting in preserved cardiac function in a Toll-like receptor 1- and TLR9-dependent manner. Our study suggests a cardioprotective mechanism of CpG postconditioning, involving Toll-like receptor-driven modulation of inflammation. This is followed by attenuated remodeling and preserved LV function.NEW & NOTEWORTHY Cytosine-phosphate-guanine (CpG) postconditioning seems to mediate inflammation via Toll-like receptor-1 and Toll-like receptor-9 signaling. Enhanced cytokine and chemokine expressions are partly attenuated by IL-10 and matrix metalloproteinase-8 (MMP8) induction, being associated with lower macrophage infiltration and M1-monocyte differentiation. Furthermore, switch from α- to ß-MHC and balanced MMP/TIMP expression led to lesser cardiomyocyte apoptosis, smaller scar size, and preserved cardiac function. Data of pharmacological postconditioning have been widely disappointing to date. Our study suggests a new pathway promoting myocardial postconditioning via Toll-like receptor activation.

Dynamic changes of angiopoietins and endothelial nitric oxide supply during fluid resuscitation for major gyn-oncological surgery: a prospective observation.

BACKGROUND: Despite goal-directed hemodynamic therapy, vascular function may deteriorate during surgery for advanced abdominal tumor masses. Fluid administration has been shown to be associated with distinct changes in serum levels of functional proteins. We sought to determine how serum total protein and angiopoietin (ANG) levels change during major abdominal tumor surgery. In addition, ex vivo endothelial nitric oxide synthase (eNOS) activation as well as NO bioavailability in vivo were assessed. METHODS: 30 patients scheduled for laparotomy for late-stage ovarian or uterine cancer were prospectively included. Advanced hemodynamic monitoring as well as protocol-driven goal-directed fluid optimization were performed. Total serum protein, ANG-1, -2, and soluble TIE2 were determined pre-, intra-, and postoperatively. Phosphorylation of eNOS was assessed in microvascular endothelial cells after incubation with patient serum, and microvascular reactivity was determined in vivo by near-infrared spectroscopy and arterial vascular occlusion. RESULTS: Cardiac output as well as preload gradually decreased during surgery and were associated with a median total fluid intake of 12.8 (9.7-15.4) mL/kg*h and a postoperative fluid balance of 6710 (4113-9271) mL. Total serum protein decreased significantly from baseline (66.5 (56.4-73.3) mg/mL) by almost half intraoperatively (42.7 (36.8-51.5) mg/mL, p < 0.0001) and remained at low level. While ANG-1 showed no significant dilutional change (baseline: 12.7 (11.9-13.9) ng/mL, postop.: 11.6 (10.8 -13.5) ng/mL, p = 0.06), serum levels of ANG-2 were even increased postoperatively (baseline: 2.2 (1.6-2.6) ng/mL vs. postop.: 3.4 (2.3-3.8) ng/mL, p < 0.0001), resulting in a significant shift in ANG-2 to ANG-1 ratio. Ex vivo phosphorylation of eNOS was decreased depending on increased ANG-2 levels and ANG-2/1 ratio (Spearman r = - 0.37, p = 0.007). In vivo, increased ANG-2 levels were associated with impaired capillary recruitment and NO bioavailability (Spearman r = - 0.83, p = 0.01). CONCLUSIONS: Fluid resuscitation-associated changes in serum vascular mediator profile during abdominal tumor surgery were accompanied by impaired eNOS activity ex vivo as well as reduced NO bioavailability in vivo. Our results may explain disturbed microvascular function in major surgery despite goal-directed hemodynamic optimization.

Safety metric profiling in surgery for temporal glioblastoma: lobectomy as a supra-total resection regime preserves perioperative standard quality rates.

INTRODUCTION: Supra-total resection in terms of anterior temporal lobectomy (ATL) has gained growing attention with regard to superior long-term disease control for temporal-located glioblastoma. However, aggressive onco-surgical approaches-geared beyond conventional gross total resections (GTR)-may be associated with peri- and postoperative unfavorable events which significantly worsen initial favorable postoperative outcome. In the current study we analyzed our institutional database with regard to patient safety indicators (PSIs), hospital-acquired conditions (HACs) and specific cranial surgery-related complications (CSC) as high standard quality metric profiles in patients that had undergone surgery for temporal glioblastoma. METHODS: Between 2012 and 2018, 61 patients with temporal glioblastoma underwent GTR or temporal lobectomy at the authors' institution. Both groups of differing resection modalities were analyzed with regard to the incidence of PSIs, HACs and CSCs. RESULTS: Overall, we found 6 PSI and 2 HAC events. Postoperative hemorrhage (3 out of 61 patients; 5%) and catheter-associated urinary tract infection (2 out 61 patients; 3%) were identified as the most frequent PSIs and HACs. PSIs were present in 1 out of 41 patients (5%) for the temporal GTR and 2 out of 20 patients for the lobectomy group (p = 1.0). Respective rates for PSIs were 5 of 41 (12%) and 1 of 20 (5%) (p = 0.7). Further, CSCs did not yield significant differences between these two resection modalities (p = 1.0). CONCLUSION: With regard to ATL and GTR as differing onco-surgical approaches these data suggest ATL in terms of an aggressive supra-total resection strategy to preserve perioperative standard safety metric profiles.

Factors influencing early postoperative complications following surgery for symptomatic spinal metastasis: a single-center series and multivariate analysis.

Patients presenting with neurological deficits and/or pain due to spinal metastasis usually require immediate or subacute surgical treatment. Nevertheless, it is unclear whether or not side effects of primary cancer location might influence postoperative complication rate. We therefore analyzed our spinal database to identify factors influencing early postoperative complications after surgery for symptomatic spinal metastases. From 2013 to 2017, 163 consecutive patients suffering from symptomatic spinal metastases were treated at our department. Early postoperative complications were defined as any postoperative event requiring additional medical or surgical treatment within 30 days of spinal surgery. A multivariate regression analysis was performed to identify independent predictors for postoperative complications after surgery for spinal metastasis. Overall, 39 of 163 patients who underwent spinal surgery for spinal metastasis developed early postoperative complications throughout the treatment course (24%). Preoperative ASA score ≥ 3 (p = 0.003), preoperative C-reactive protein level > 10 mg/l (p = 0.008), preoperative Karnofsky Performance Score < 60% (p = 0.03), radiation treatment within 2 months of surgery (p = 0.01), presence of diabetes mellitus (p = 0.008), and preoperative complete neurological impairment (p = 0.04) were significant and independent predictors for early postoperative complications in patients with surgery for spinal metastasis. The ability to preoperatively predict postoperative complication risk is valuable to select critically ill patients at higher risk requiring special attention. Therefore, the present study identified several significant and independent risk factors for the development of early postoperative complication in patients who underwent surgery for spinal metastasis.

Network of Mediators for Vascular Inflammation and Leakage Is Dysbalanced during Cytoreductive Surgery for Late-Stage Ovarian Cancer.

BACKGROUND: Cytoreductive surgery (CS) in late-stage ovarian cancer patients is often challenging due to extensive volume shifts, and high fluid intake may provoke postoperative complications. Expression of vasoactive mediators is altered in cancer patients, which may affect systemic vascular function. We sought to assess how serum levels of vasoactive markers and mediators change during CS in ovarian cancer. METHODS: Following IRB approval and informed consent, pre- and postoperative serum samples were analyzed in 26 late-stage ovarian cancer patients using multiplex protein arrays and ELISA. RESULTS: The proinflammatory cytokines and chemokines IL-6, IL-8, and CCL2 were significantly elevated after 24 hrs compared to the baseline values, with IL-6 and IL-8 being most prominently increased. While ANGPT1 remained unchanged after surgery, its competitive antagonist ANGPT2 was significantly increased. In contrast, serum levels of the ANGPT receptor TIE2 were decreased to 0.6 of the baseline values. While VEGF-D, E-selectin, P-selectin, ICAM-1, and PECAM-1 remained unchanged, serum activity of both thrombomodulin and syndecan-1 was significantly increased following surgery. CONCLUSION: We identified a regulatory network of acute-phase reaction during CS in late-stage ovarian cancer. This suggests that IL-6 exerts positive regulation of other proinflammatory mediators and, by upregulating ANGPT2 and suppressing ANGPT1, induces a serum profile that promotes vascular leakage. This may contribute to the observed hemodynamic alterations during CS procedures.

Perinatal inflammation induces sex-related differences in cardiovascular morbidities in mice.

Sex-related differences in cardiovascular health and disease have been identified, with males having a higher incidence of cardiovascular events but females more likely to develop arrhythmias. Adverse fetal environments are now accepted as a cause for the development of cardiovascular diseases in adulthood, but sex-related differences in response to adverse fetal environments have not been extensively explored. The combination of both in utero and postnatal exposure to inflammation is highly relevant for the infant that is born preterm or has clinical complications at birth or in early postnatal life. We have previously observed cardiac contractile deficiencies and dysregulation of Ca2+-handling proteins in our model of maternal lipopolysaccharide (LPS) and neonatal hyperoxia exposures (LPS/O2). This investigation tested the hypothesis that there are sex-related differences in the adult pathologies after exposure to perinatal inflammation. Using pressure-volume assessments, males exposed to LPS/O2 had more pronounced contractile deficiencies than similarly exposed females, but females tended to have long PR intervals. While both sexes demonstrated decreases in α-myosin heavy chain and connexin 43 after LPS/O2 exposure compared with saline/room air controls, females indicated aberrant increases in microRNA 208a, microRNA 208b, and desmin expression. Our study supports our hypothesis that early life exposure to inflammation results in sex-dependent deficits in cardiovascular function. NEW & NOTEWORTHY Sex-specific differences in cardiovascular disease are recognized, but the mechanisms and origins are not well understood. Adverse maternal environments can influence cardiac development and later cardiovascular disease. This study identifies sex-dependent differences in cardiac disease associated with perinatal inflammation.

Arginase and α-smooth muscle actin induction after hyperoxic exposure in a mouse model of bronchopulmonary dysplasia.

The L-arginine/NO pathway is an important regulator of pulmonary hypertension, the leading cause of mortality in patients with the chronic lung disease of prematurity, bronchopulmonary dysplasia. L-arginine can be metabolized by NO synthase (NOS) to form L-citrulline and NO, a potent vasodilator. Alternatively, L-arginine can be metabolized by arginase to form urea and L-ornithine, a precursor to collagen and proline formation important in vascular remodelling. In the current study, we hypothesized that C3H/HeN mice exposed to prolonged hyperoxia would have increased arginase expression and pulmonary vascular wall cell proliferation. C3H/HeN mice were exposed to 14 days of 85% O2 or room air and lung homogenates analyzed by western blot for protein levels of arginase I, arginase II, endothelial NOS (eNOS), ornithine decarboxylase (ODC), ornithine aminotransferase (OAT), and α-smooth muscle actin (α-SMA). Hyperoxia did not change arginase I or eNOS protein levels. However, arginase II protein levels were 15-fold greater after hyperoxia exposure than in lungs exposed to room air. Greater protein levels of ODC and OAT were found in lungs following hyperoxic exposure than in room air animals. α-SMA protein levels were found to be 7-fold greater in the hyperoxia exposed lungs than in room air lungs. In the hyperoxia exposed lungs there was evidence of greater pulmonary vascular wall cell proliferation by α-SMA immunohistochemistry than in room air lungs. Taken together, these data are consistent with a more proliferative vascular phenotype, and may explain the propensity of patients with bronchopulmonary dysplasia to develop pulmonary hypertension.

Thioredoxin Reductase Inhibition Attenuates Neonatal Hyperoxic Lung Injury and Enhances Nuclear Factor E2-Related Factor 2 Activation.

Oxygen toxicity and antioxidant deficiencies contribute to the development of bronchopulmonary dysplasia. Aurothioglucose (ATG) and auranofin potently inhibit thioredoxin reductase-1 (TrxR1), and TrxR1 disruption activates nuclear factor E2-related factor 2 (Nrf2), a regulator of endogenous antioxidant responses. We have shown previously that ATG safely and effectively prevents lung injury in adult murine models, likely via Nrf2-dependent mechanisms. The current studies tested the hypothesis that ATG would attenuate hyperoxia-induced lung developmental deficits in newborn mice. Newborn C3H/HeN mice were treated with a single dose of ATG or saline within 12 hours of birth and were exposed to either room air or hyperoxia (85% O2). In hyperoxia, ATG potently inhibited TrxR1 activity in newborn murine lungs, attenuated decreases in body weight, increased the transcription of Nrf2-regulated genes nicotinamide adenine dinucleotide phosphate reduced quinone oxidoreductase-1 (NQO1) and heme oxygenase 1, and attenuated alterations in alveolar development. To determine the impact of TrxR1 inhibition on Nrf2 activation in vitro, murine alveolar epithelial-12 cells were treated with auranofin, which inhibited TrxR1 activity, enhanced Nrf2 nuclear levels, and increased NQO1 and heme oxygenase 1 transcription. Our novel data indicate that a single injection of the TrxR1 inhibitor ATG attenuates hyperoxia-induced alterations in alveolar development in newborn mice. Furthermore, our data support a model in which the effects of ATG treatment likely involve Nrf2 activation, which is consistent with our findings in other lung injury models. We conclude that TrxR1 represents a novel therapeutic target to prevent oxygen-mediated neonatal lung injury.

Endothelial permeability following coronary artery bypass grafting: an observational study on the possible role of angiopoietin imbalance.

BACKGROUND: Unresolved inflammation resulting in capillary leakage with endothelial barrier dysfunction is a major contributor to postoperative morbidity and mortality after coronary artery bypass graft (CABG). Angiopoietins (ANGs) are vascular growth factors, also mediating inflammation and disruption of the endothelium, thus inducing capillary leakage. We hypothesized that changes in the relative serum levels of ANG1 and ANG2 influence endothelial barrier function and perioperative morbidity after CABG. METHODS: After approval and informed consent, serum samples (n = 28) were collected pre CABG surgery, 1, 6, and 24 h after aortic de-clamping. ANG1, ANG2, soluble ANG receptor TIE2 (sTIE2), and IL-6 serum concentrations were analyzed by ELISA. Human pulmonary microvascular endothelial cells (HPMECs) were incubated with patient serum and FITC-dextran permeability was assessed. Furthermore, ANG2 secretion of HPMECs was analyzed after incubation with IL-6-containing patient serum. RESULTS: CABG induced an early and sustained increase of ANG2/ANG1 ratio (5-fold after 24 h compared to pre-surgery). These changes correlated with elevated serum lactate levels, fluid balance, as well as the duration of mechanical ventilation. Permeability of HPMECs significantly increased after incubation with post-surgery serum showing a marked shift of ANG2/ANG1 balance (18-fold) compared to serum with a less pronounced increase (6-fold). Furthermore, CABG resulted in increased IL-6 serum content. Pre-incubation with serum containing high levels of IL-6 amplified the ANG2 secretion by HPMECs; however, this was not influenced by blocking IL-6. CONCLUSIONS: CABG affects the balance between ANG1 and ANG2 towards a dominance of the barrier-disruptive ANG2. Our data suggest that this ANG2/ANG1 imbalance contributes to an increased postoperative endothelial permeability, likewise being reflected by the clinical course. The results strongly suggest a biological effect of altered angiopoietin balance during cardiac surgery on endothelial permeability.

Losartan treatment attenuates tumor-induced myocardial dysfunction.

UNLABELLED: Fatigue and muscle wasting are common symptoms experienced by cancer patients. Data from animal models demonstrate that angiotensin is involved in tumor-induced muscle wasting, and that tumor growth can independently affect myocardial function, which could contribute to fatigue in cancer patients. In clinical studies, inhibitors of angiotensin converting enzyme (ACE) can prevent the development of chemotherapy-induced cardiovascular dysfunction, suggesting a mechanistic role for the renin-angiotensin-aldosterone system (RAAS). In the present study, we investigated whether an angiotensin (AT) 1-receptor antagonist could prevent the development of tumor-associated myocardial dysfunction. METHODS AND RESULTS: Colon26 adenocarcinoma (c26) cells were implanted into female CD2F1 mice at 8weeks of age. Simultaneously, mice were administered Losartan (10mg/kg) daily via their drinking water. In vivo echocardiography, blood pressure, in vitro cardiomyocyte function, cell proliferation assays, and measures of systemic inflammation and myocardial protein degradation were performed 19days following tumor cell injection. Losartan treatment prevented tumor-induced loss of muscle mass and in vitro c26 cell proliferation, decreased tumor weight, and attenuated myocardial expression of interleukin-6. Furthermore, Losartan treatment mitigated tumor-associated alterations in calcium signaling in cardiomyocytes, which was associated with improved myocyte contraction velocity, systolic function, and blood pressures in the hearts of tumor-bearing mice. CONCLUSIONS: These data suggest that Losartan may mitigate tumor-induced myocardial dysfunction and inflammation.