Tranexamic Acid Administration During Liver Transplantation Is Not Associated With Lower Blood Loss or With Reduced Utilization of Red Blood Cell Transfusion.

BACKGROUND: Current clinical guidelines recommend antifibrinolytic treatment for liver transplantation to reduce blood loss and transfusion utilization. However, the clinical relevance of fibrinolysis during liver transplantation is questionable, a benefit of tranexamic acid (TXA) in this context is not supported by sufficient evidence, and adverse effects are also conceivable. Therefore, we tested the hypothesis that use of TXA is associated with reduced blood loss. METHODS: We performed a retrospective cohort study on patients who underwent liver transplantation between 2004 and 2017 at Heidelberg University Hospital, Heidelberg, Germany. Univariable and multivariable linear regression analyses were used to determine the association between TXA administration and the primary end point intraoperative blood loss and the secondary end point intra- and postoperative red blood cell (RBC) transfusions. For further secondary outcome analyses, the time to the first occurrence of a composite end point of hepatic artery thrombosis, portal vein thrombosis, and thrombosis of the inferior vena cava were analyzed using a univariable and multivariable Cox proportional hazards model. RESULTS: Data from 779 transplantations were included in the final analysis. The median intraoperative blood loss was 3000 mL (1600-5500 mL). Intraoperative TXA administration occurred in 262 patients (33.6%) with an average dose of 1.4 ± 0.7 g and was not associated with intraoperative blood loss (regression coefficient B, -0.020 [-0.051 to 0.012], P = .226) or any of the secondary end points (intraoperative RBC transfusion; regression coefficient B, 0.023 [-0.006 to 0.053], P = .116), postoperative RBC transfusion (regression coefficient B, 0.007 [-0.032 to 0.046], P = .717), and occurrence of thrombosis (hazard ratio [HR], 1.110 [0.903-1.365], P = .321). CONCLUSIONS: Our data do not support the use of TXA during liver transplantation. Physicians should exercise caution and consider individual factors when deciding whether or not to administer TXA.

Editor's Choice - Association Between Peri-OPerative Aspirin ResisTance and CardioVascular Outcome (POPART-CVO): a Prospective Non-Interventional Cohort Study.

OBJECTIVE: New onset aspirin resistance during surgery, known as peri-operative aspirin resistance, is observed in up to 30% of vascular surgery patients and is associated with post-operative myocardial damage; questioning aspirin effectiveness towards peri-operative cardiovascular events. The objective of this study was to prospectively evaluate whether peri-operative aspirin resistance in vascular surgery is associated with an adverse cardiovascular outcome. METHODS: Based on a sample size calculation, 194 adult elective vascular or endovascular surgery patients receiving aspirin were analysed in this prospective, single centred, non-interventional cohort study. Platelet function was measured before surgery, one hour after incision, four hours post-operatively, and on the morning of the first and second post-operative days using the Multiplate analyser. The primary outcome was myocardial injury after non-cardiac surgery (MINS). Secondary outcomes included major bleeding, admission to intensive care unit, length of hospital stay, and major adverse cardiac and cerebrovascular events. Subgroup analyses were performed for patients with different cardiovascular risk and for patients who underwent endovascular surgery. RESULTS: Peri-operative aspirin resistance was observed in 27.8% of patients but was not associated with MINS (27.8% vs. 32.1%, aspirin resistance vs. no aspirin resistance, OR 0.812, 95% CI 0.406 - 1.624, p = .56) or with any of the secondary endpoints (all p > .050). In nine of the 10 subgroup analyses, aspirin resistance was not associated with a difference in MINS rate. However, in patients with a low cardiovascular risk profile (RCRI 0-2), MINS occurred more frequently in patients without aspirin resistance (p = .049). CONCLUSION: This study confirmed previous reports demonstrating that peri-operative aspirin resistance is common in patients undergoing vascular or endovascular surgery. However, in patients who continue aspirin throughout the peri-operative period, aspirin resistance is a phenomenon, which does not appear to be related to MINS. Measuring peri-operative platelet function using the Multiplate analyser with the intention to identify and potentially prevent or treat peri-operative aspirin resistance seems to be dispensable.

Preoperative neutrophil to lymphocyte ratio and platelet to lymphocyte ratio are associated with major adverse cardiovascular and cerebrovascular events in coronary heart disease patients undergoing non-cardiac surgery.

BACKGROUND: Preoperative risk prediction in patients at elevated cardiovascular risk shows limited accuracy. Platelet to lymphocyte ratio (PLR) and neutrophil to lymphocyte ratio (NLR) indicate systemic inflammation. Both have been investigated for outcome prediction in the field of oncology and cardiovascular medicine, as well as risk prediction of adverse cardiovascular events in non-surgical patients at increased cardiovascular risk. METHODS: For this post-hoc analysis, we included all 38 coronary heart disease patients from the Leukocytes and Cardiovascular Perioperative Events cohort-1 study scheduled for elective non-cardiac surgery. We evaluated preoperative differential blood counts for association with major adverse cardiovascular and cerebrovascular events (MACCE) defined as the composite endpoint of death, myocardial ischemia, myocardial infarction, myocardial injury after non-cardiac surgery, or embolic or thrombotic stroke within 30 days after surgery. We used Youden's index to calculate cut-off values for PLR and NLR. Additive risk-predictive values were assessed using receiver operating characteristic curve and net reclassification (NRI) improvement analyses. RESULTS: Patients with the composite endpoint MACCE had higher PLR and NLR (309 [206; 380] vs. 160 [132; 203], p = 0.001; 4.9 [3.5; 8.1] vs. 2.6 [2.2; 3.4]), p = 0.001). Calculated cut-offs for PLR > 204.4 and NLR > 3.1 were associated with increased risk of 30-day MACCE (OR 7, 95% CI [1.2; 44.7], p = 0.034; OR 36, 95% CI [1.8; 686.6], p = 0.001). Furthermore, NLR improved risk prediction in coronary heart disease patients undergoing non-cardiac surgery when combined with hs-cTnT or NT-proBNP (NRI total = 0.23, p = 0.008, NRI total = 0.26, p = 0.005). CONCLUSIONS: Both PLR and NLR were associated with perioperative cardiovascular adverse events in coronary heart disease patients. NLR proved to be of additional value for preoperative risk stratification. Both PLR and NLR could be used as inexpensive and broadly available tools for perioperative risk assessment. TRIAL REGISTRATION: NCT02874508, August 22, 2016.

Presepsin for pre-operative prediction of major adverse cardiovascular events in coronary heart disease patients undergoing noncardiac surgery: Post hoc analysis of the Leukocytes and Cardiovascular Peri-operative Events-2 (LeukoCAPE-2) Study.

BACKGROUND: Accurate pre-operative evaluation of cardiovascular risk is vital to identify patients at risk for major adverse cardiovascular and cerebrovascular events (MACCE) after noncardiac surgery. Elevated presepsin (sCD14-ST) is associated with peri-operative MACCE in coronary artery disease (CAD) patients after noncardiac surgery. OBJECTIVES: Validating the prognostic utility of presepsin for MACCE after noncardiac surgery. DESIGN: Prospective patient enrolment and blood sampling, followed by post hoc evaluation of pre-operative presepsin for prediction of MACCE. SETTING: Single university centre. PATIENTS: A total of 222 CAD patients undergoing elective, inpatient noncardiac surgery. INTERVENTION: Pre-operative presepsin measurement. MAIN OUTCOME MEASURES: MACCE (cardiovascular death, myocardial infarction, myocardial ischaemia and stroke) at 30 days postsurgery. RESULTS: MACCE was diagnosed in 23 (10%) patients. MACCE patients presented with increased pre-operative presepsin (median [IQR]; 212 [163 to 358] vs. 156 [102 to 273] pgml, P = 0.023). Presepsin exceeding the previously derived threshold of 184 pg ml was associated with increased 30-day MACCE rate. After adjustment for confounders, presepsin more than 184 pg ml [OR = 2.8 (95% confidence interval 1.1 to 7.3), P = 0.03] remained an independent predictor of peri-operative MACCE. Predictive accuracy of presepsin was moderate [area under the curve (AUC) = 0.65 (0.54 to 0.75), P = 0.023]. While the basic risk model of revised cardiac risk index, high-sensitive cardiac troponin T and N-terminal fragment of pro-brain natriuretic peptide resulted in an AUC = 0.62 (0.48 to 0.75), P = 0.072, addition of presepsin to the model led to an AUC = 0.67 (0.56 to 0.78), P = 0.009 and (ΔAUC = 0.05, P = 0.438). Additive risk predictive value of presepsin was demonstrated by integrated discrimination improvement analysis (integrated discrimination improvement = 0.023, P = 0.022). Net reclassification improvement revealed that the additional strength of presepsin was attributed to the reclassification of no-MACCE patients into a lower risk group. CONCLUSION: Increased pre-operative presepsin independently predicted 30-day MACCE in CAD patients undergoing major noncardiac surgery. Complementing cardiovascular risk prediction by inflammatory biomarkers, such as presepsin, offers potential to improve peri-operative care. However, as prediction accuracy of presepsin was only moderate, further validation studies are needed. TRIAL REGISTRATION: Clinicaltrials.gov: NCT03105427.

Elevated Presepsin Is Associated With Perioperative Major Adverse Cardiovascular and Cerebrovascular Complications in Elevated-Risk Patients Undergoing Noncardiac Surgery: The Leukocytes and Cardiovascular Perioperative Events Study.

BACKGROUND: Perioperative major adverse cardiovascular and cerebrovascular events (MACCEs) are incompletely understood, and risk prediction is imprecise. Atherogenic leukocytes are crucial in cardiovascular events. However, it is unclear if surgical interventions affect leukocyte counts or activation status. Therefore, we investigated whether noncardiac surgery in patients with elevated cardiovascular risk is associated with changes in atherogenic leukocyte subsets and if these changes are related to perioperative MACCEs. METHODS: We enrolled 40 patients in this single-center prospective observational cohort study. Total leukocytes and subpopulations, including classical, intermediate, and nonclassical monocytes and natural killer and regulatory T cells, were quantified before surgery, at 2 and 6 hours after skin incision, and at postoperative days 1 and 2 (POD1+2). The monocyte activation marker presepsin (sCD14-ST) was measured post hoc to determine differentiation of classical to nonclassical monocytes. We evaluated presepsin for prediction of the composite primary end point MACCE (cardiovascular death, myocardial infarction, myocardial ischemia, and stroke) at 30 days. Its additive value to risk assessment based on high-sensitive cardiac troponin T and N-terminal probrain natriuretic peptide (NT-proBNP) was analyzed. RESULTS: We evaluated 38 patients, of whom 5 (13%) reached MACCE. In the entire cohort, classical monocytes continuously increased and peaked at POD1 (0.35 [0.23-0.43] cells per nanoliter blood [nL] vs 0.45 [0.31-0.66] cells·nL, preoperative [pre-OP] vs POD1, P = .002). Intermediate monocytes doubled by POD1 (0.017 [0.013-0.021] vs 0.036 [0.022-0.043] cells·nL, pre-OP versus POD1, P = .0003). Nonclassical monocytes decreased (0.022 [0.012-0.032] vs 0.012 [0.005-0.023] cells·nL, pre-OP vs 6 hours, P = .003). In our patient population, we did not detect changes in any of the other predefined leukocyte subsets investigated. In patients experiencing a MACCE, classical monocyte expansion was reduced (0.081 [-0.16 to 0.081] cells·nL vs 0.179 [0.081 to 0.292] cells·nL, MACCE versus non-MACCE, P = .016). Patients in the event group presented with elevated pre-OP presepsin (1528 [406-1897] pg·mL vs 123 [82.2-174] pg·mL, MACCE versus non-MACCE, P = .0001). Presepsin was associated with MACCE (area under the curve = 0.964, [0.846-0.998], P = .001). Presepsin above the calculated threshold >184 pg·mL was superior to high-sensitive cardiac troponin T for improvement of NT-proBNP-based risk prediction (28 [74%] vs 22 [58%] correctly classified patients, P = .014). CONCLUSIONS: Noncardiac surgery was associated with an increase in atherogenic leukocyte subsets. In a post hoc analysis, elevated pre-OP presepsin was associated with MACCE and improved NT-proBNP-based risk assessment. After validation in an independent data set, a presepsin cutoff of 184 pg·mL might qualify to complement NT-proBNP-based risk prediction, thereby increasing the proportion of correctly identified high-risk patients.

Low intraoperative end-tidal carbon dioxide levels are associated with improved recurrence-free survival after elective colorectal cancer surgery.

STUDY OBJECTIVE: Higher levels of carbon dioxide (CO2) increase the invasive abilities of colon cancer cells in vitro. Studies assessing target values for end-tidal CO2 concentrations (EtCO2) to improve surgical outcome after colorectal cancer surgery are lacking. Therefore, we evaluated whether intraoperative EtCO2 was associated with differences in recurrence-free survival after elective colorectal cancer (CRC) surgery. DESIGN: Single center, retrospective analysis. SETTING: Anesthesia records, surgical databases and hospital information system of a tertiary university hospital. PATIENTS: We analyzed 528 patients undergoing elective resection of colorectal cancer at Heidelberg University Hospital between 2009 and 2018. INTERVENTIONS: None. MEASUREMENTS: Intraoperative mean EtCO2 values were calculated. The study cohort was equally stratified into low-and high-EtCO2 groups. The primary endpoint measure was recurrence-free survival until last known follow-up. Groups were compared using Kaplan-Meier analysis. Cox-regression analysis was used to control for covariates. Sepsis, reoperations, surgical site infections and cardiovascular events during hospital stay, and overall survival were secondary outcomes. MAIN RESULTS: Mean EtCO2 was 33.8 mmHg ±1.2 in the low- EtCO2 group vs. 37.3 mmHg ±1.6 in the high-EtCO2 group. Median follow-up was 3.8 (Q1-Q3, 2.5-5.1) years. Recurrence-free survival was higher in the low-EtCO2 group (log-rank-test: p = .024). After correction for confounding factors, lower EtCO2 was associated with increased recurrence-free survival (HR = 1.138, 95%-CI:1.015-1.276, p = .027); the hazard for the primary outcome decreased by 12.1% per 1 mmHg decrease in mean EtCO2. 1-year and 5-year survival was also higher in the low-EtCO2 group. We did not find differences in the other secondary endpoints. CONCLUSIONS: Lower intraoperative EtCO2 target values in CRC surgery might benefit oncological outcome and should be evaluated in confirmative studies.

Perioperative prothrombin complex concentrate and fibrinogen administration are associated with thrombotic complications after liver transplant.

Background: Use of intraoperative prothrombin complex concentrates (PCC) and fibrinogen concentrate administration has been linked to thrombotic events. However, it is unknown if its use is associated with thrombotic events after liver transplant. Methods and analysis: We conducted a post hoc analysis of a prospectively conducted registry database study on patients who underwent liver transplant between 2004 and 2017 at Heidelberg University Hospital, Heidelberg, Germany. Univariate and multivariate analyses were used to determine the association between PCC and fibrinogen concentrate administration and thrombotic complications. Results: Data from 939 transplantations were included in the analysis. Perioperative PCC or fibrinogen administration was independently associated with the primary composite endpoint Hepatic artery thrombosis (HAT), Portal vein thrombosis (PVT), and inferior vena cava thrombosis [adjusted HR: 2.018 (1.174; 3.468), p = 0.011]. PCC or fibrinogen administration was associated with the secondary endpoints 30-day mortality (OR 4.225, p < 0.001), graft failure (OR 3.093, p < 0.001), intraoperative blood loss, red blood cell concentrate, fresh frozen plasma and platelet transfusion, longer hospitalization, and longer length of stay in intensive care units (ICUs) (all p < 0.001). PCC or fibrinogen administration were not associated with pulmonary embolism, myocardial infarction, stroke, or deep vein thrombosis within 30 days after surgery. Conclusion: A critical review of established strategies in coagulation management during liver transplantation is warranted. Perioperative caregivers should exercise caution when administering coagulation factor concentrate during liver transplant surgery. Prospective randomized controlled trials are needed to establish causality for the relationship between coagulation factors and thrombotic events in liver transplantation. Further studies should be tailored to identify patient subgroups that will likely benefit from PCC or fibrinogen administration.

Intraoperative Fractions of Inspiratory Oxygen Are Associated With Recurrence-Free Survival After Elective Cancer Surgery.

Background: Choice of the fraction of inspiratory oxygen (FiO2) is controversial. The objective of this analysis was to evaluate whether intraoperative FiO2 was associated with recurrence-free survival after elective cancer surgery. Methods and Analysis: In this single-center, retrospective study, we analyzed 1,084 patients undergoing elective resection of pancreatic (n = 652), colorectal (n = 405), or hepatic cancer (n = 27) at Heidelberg University Hospital between 2009 and 2016. Intraoperative mean FiO2 values were calculated. For unstratified analyses, the study cohort was equally divided into a low- and a high-FiO2 group. For cancer-stratified analyses, this division was done within cancer-strata. The primary outcome measure was recurrence-free survival until the last known follow-up. Groups were compared using Kaplan-Meier analysis. A stratified log rank test was used to control for different FiO2 levels and survival times between the cancer strata. Cox-regression analyses were used to control for covariates. Sepsis, reoperations, surgical-site infections, and cardiovascular events during hospital stay and overall survival were secondary outcomes. Results: Median FiO2 was 40.9% (Q1-Q3, 38.3-42.9) in the low vs. 50.4% (Q1-Q3, 47.4-54.7) in the high-FiO2 group. Median follow-up was 3.28 (Q1-Q3, 1.68-4.97) years. Recurrence-free survival was considerable higher in the high-FiO2 group (p < 0.001). This effect was also confirmed when stratified for the different tumor entities (p = 0.007). In colorectal cancer surgery, increased FiO2 was independently associated with increased recurrence-free survival. The hazard for the primary outcome decreased by 3.5% with every 1% increase in FiO2. The effect was not seen in pancreatic cancer surgery and we did not find differences in any of the secondary endpoints. Conclusions: Until definite evidence from large-scale trials is available and in the absence of relevant clinical conditions warranting specific FiO2 values, perioperative care givers should aim for an intraoperative FiO2 of 50% in abdominal cancer surgery as this might benefit oncological outcomes.

Frontline Science: Low regulatory T cells predict perioperative major adverse cardiovascular and cerebrovascular events after noncardiac surgery.

Immune cells drive atherosclerotic lesion progression and plaque destabilization. Coronary heart disease patients undergoing noncardiac surgery are at risk for perioperative major adverse cardiac and cerebrovascular events (MACCE). It is unclear whether differential leukocyte subpopulations contribute to perioperative MACCE and thereby could aid identification of patients prone to perioperative cardiovascular events. First, we performed a hypothesis-generating post hoc analysis of the LeukoCAPE-1 study (n = 38). We analyzed preoperative counts of 6 leukocyte subpopulations in coronary heart disease patients for association with MACCE (composite of cardiac death, myocardial infarction, myocardial ischemia, myocardial injury after noncardiac surgery, thromboembolic stroke) within 30 d after surgery. Regulatory T cells (Tregs) were the only leukocyte subgroup associated with MACCE. We found reduced Tregs in patients experiencing MACCE versus no-MACCE (0.02 [0.01; 0.03] vs. 0.04 [0.03; 0.05] Tregs nl-1 , P = 0.002). Using Youden index, we derived the optimal threshold value for association with MACCE to be 0.027 Tregs nl-1 . Subsequently, we recruited 233 coronary heart disease patients for the prospective, observational LeukoCAPE-2 study and independently validated this Treg cutoff for prediction of MACCE within 30 d after noncardiac surgery. After multivariate logistic regression, Tregs < 0.027 cells nl-1 remained an independent predictor for MACCE (OR = 2.54 [1.22; 5.23], P = 0.012). Tregs improved risk discrimination of the revised cardiac risk index based on ΔAUC (area under the curve; ΔAUC = 0.09, P = 0.02), NRI (0.26), and IDI (0.06). Preoperative Treg levels below 0.027 cells nl-1 predicted perioperative MACCE and can be measured to increase accuracy of established preoperative cardiac risk stratification in coronary heart disease patients undergoing noncardiac surgery.

Combination of Photon and Carbon Ion Irradiation with Targeted Therapy Substances Temsirolimus and Gemcitabine in Hepatocellular Carcinoma Cell Lines.

BACKGROUND: This work investigates on putative cytotoxic effects in four different hepatocellular carcinoma (HCC) cell lines after irradiation with photons or carbon ions in combination with new targeted molecular therapy using either Temsirolimus (TEM) or Gemcitabine (GEM). METHODS AND MATERIALS: The HCC cell lines HepG2, Hep3B, HuH7, and PLC were cultured and irradiated with photons or carbon ions at the Heidelberg Ion Beam Therapy Center using the raster-scanning method. For combination experiments, cell lines were first treated with Temsirolimus or GEM before irradiation. Cytotoxicity was measured by a clonogenic survival assay. The evaluation of the experiments and the obtained survival curves were based on the concept of additivity defined by Steel and Peckham. RESULTS: The results for the combination of carbon ions and both tested systemic substances TEM and GEM showed independent toxicities in all four cell lines. Supra-additive effects were observed in PLC cells for photon irradiation combined either with TEM or GEM and in HuH7 cells for the combination of photons with TEM. CONCLUSION: Addition of targeted therapy substances Temsirolimus and GEM to photon irradiation showed additive cytotoxicity in HCC cell lines, whereas independent toxicities where reached by the combination of carbon ions to these substances. It can be assumed that combining 12C with systemic substances only has independent effects because heavy ions cause direct damage because of their high-LET character resulting in complex and clustered double-strand breaks. Nonetheless, further investigations are warranted in order to determine whether addition of systemic therapy allows a reduction of radiation doses in combination therapy. This could possibly lead to better responses and tolerances in patients with HCC.

The relative biological effectiveness for carbon and oxygen ion beams using the raster-scanning technique in hepatocellular carcinoma cell lines.

BACKGROUND: Aim of this study was to evaluate the relative biological effectiveness (RBE) of carbon (12C) and oxygen ion (16O)-irradiation applied in the raster-scanning technique at the Heidelberg Ion beam Therapy center (HIT) based on clonogenic survival in hepatocellular carcinoma cell lines compared to photon irradiation. METHODS: Four human HCC lines Hep3B, PLC, HepG2 and HUH7 were irradiated with photons, 12C and 16O using a customized experimental setting at HIT for in-vitro trials. Cells were irradiated with increasing physical photon single doses of 0, 2, 4 and 6 Gy and heavy ion-single doses of 0, 0.125, 0.5, 1, 2, 3 Gy (12C and 16O). SOBP-penetration depth and extension was 35 mm +/-4 mm and 36 mm +/-5 mm for carbon ions and oxygen ions respectively. Mean energy level and mean linear energy transfer (LET) were 130 MeV/u and 112 keV/um for 12C, and 154 MeV/u and 146 keV/um for 16O. Clonogenic survival was computated and relative biological effectiveness (RBE) values were defined. RESULTS: For all cell lines and both particle modalities α- and ß-values were determined. As expected, α-values were significantly higher for 12C and 16O than for photons, reflecting a steeper decline of the initial slope of the survival curves for high-LET beams. RBE-values were in the range of 2.1-3.3 and 1.9-3.1 for 12C and 16O, respectively. CONCLUSION: Both irradiation with 12C and 16O using the raster-scanning technique leads to an enhanced RBE in HCC cell lines. No relevant differences between achieved RBE-values for 12C and 16O were found. Results of this work will further influence biological-adapted treatment planning for HCC patients that will undergo particle therapy with 12C or 16O.