Long-Term Inhalative Sedation in Children With Pulmonary Diseases.

OBJECTIVES: To describe safety and feasibility of long-term inhalative sedation (LTIS) in children with severe respiratory diseases compared to patients with normal lung function with respect to recent studies that showed beneficial effects in adult patients with acute respiratory distress syndrome (ARDS). DESIGN: Single-center retrospective study. SETTING: 12-bed pediatric intensive care unit (PICU) in a tertiary-care academic medical center in Germany. PATIENTS: All patients treated in our PICU with LTIS using the AnaConDa® device between July 2011 and July 2019. MEASUREMENTS AND MAIN RESULTS: Thirty-seven courses of LTIS in 29 patients were analyzed. LTIS was feasible in both groups, but concomitant intravenous sedatives could be reduced more rapidly in children with lung diseases. Cardiocirculatory depression requiring vasopressors was observed in all patients. However, severe side effects only rarely occured. CONCLUSIONS: In this largest cohort of children treated with LTIS reported so far, LTIS was feasible even in children with severely impaired lung function. From our data, a prospective trial on the use of LTIS in children with ARDS seems justified. However, a thorough monitoring of cardiocirculatory side effects is mandatory.

RESTORE-IMI 1: A Multicenter, Randomized, Double-blind Trial Comparing Efficacy and Safety of Imipenem/Relebactam vs Colistin Plus Imipenem in Patients With Imipenem-nonsusceptible Bacterial Infections.

BACKGROUND: The ß-lactamase inhibitor relebactam can restore imipenem activity against imipenem-nonsusceptible gram-negative pathogens. We evaluated imipenem/relebactam for treating imipenem-nonsusceptible infections. METHODS: Randomized, controlled, double-blind, phase 3 trial. Hospitalized patients with hospital-acquired/ventilator-associated pneumonia, complicated intraabdominal infection, or complicated urinary tract infection caused by imipenem-nonsusceptible (but colistin- and imipenem/relebactam-susceptible) pathogens were randomized 2:1 to 5-21 days imipenem/relebactam or colistin+imipenem. Primary endpoint: favorable overall response (defined by relevant endpoints for each infection type) in the modified microbiologic intent-to-treat (mMITT) population (qualifying baseline pathogen and ≥1 dose study treatment). Secondary endpoints: clinical response, all-cause mortality, and treatment-emergent nephrotoxicity. Safety analyses included patients with ≥1 dose study treatment. RESULTS: Thirty-one patients received imipenem/relebactam and 16 colistin+imipenem. Among mITT patients (n = 21 imipenem/relebactam, n = 10 colistin+imipenem), 29% had Acute Physiology and Chronic Health Evaluation II scores >15, 23% had creatinine clearance <60 mL/min, and 35% were aged ≥65 years. Qualifying baseline pathogens: Pseudomonas aeruginosa (77%), Klebsiella spp. (16%), other Enterobacteriaceae (6%). Favorable overall response was observed in 71% imipenem/relebactam and 70% colistin+imipenem patients (90% confidence interval [CI] for difference, -27.5, 21.4), day 28 favorable clinical response in 71% and 40% (90% CI, 1.3, 51.5), and 28-day mortality in 10% and 30% (90% CI, -46.4, 6.7), respectively. Serious adverse events (AEs) occurred in 10% of imipenem/relebactam and 31% of colistin+imipenem patients, drug-related AEs in 16% and 31% (no drug-related deaths), and treatment-emergent nephrotoxicity in 10% and 56% (P = .002), respectively. CONCLUSIONS: Imipenem/relebactam is an efficacious and well-tolerated treatment option for carbapenem-nonsusceptible infections. CLINICAL TRIALS REGISTRATION: NCT02452047.

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.

Amisulpride for the Rescue Treatment of Postoperative Nausea or Vomiting in Patients Failing Prophylaxis: A Randomized, Placebo-controlled Phase III Trial.

BACKGROUND: Although antiemetics are commonly used to prevent postoperative nausea or vomiting, the failure rate is appreciable and there is currently no generally accepted standard for rescue treatment of postoperative nausea or vomiting after failed prophylaxis. This prospective, randomized, double-blind, parallel-group, placebo-controlled, multicenter study was designed to test the hypothesis that intravenous amisulpride, a dopamine D2/D3-antagonist, is superior to placebo at treating established postoperative nausea or vomiting after failed prophylaxis. METHODS: A total of 2,285 adult patients undergoing surgery under general inhalational anesthesia and receiving standard antiemetic prophylaxis were enrolled at 23 sites in Canada, France, Germany, and the United States. Of these, 702 patients experienced postoperative nausea or vomiting in the 24-h period after surgery and were randomized to receive a single dose of 5 or 10 mg intravenous amisulpride or matching placebo. The primary endpoint was complete response, defined as no emesis or rescue antiemetic use for 24 h after study drug administration, excluding emesis in the first 30 min. Secondary endpoints included incidence of emesis and rescue medication use, nausea burden, time to treatment failure, and length of stay in postanesthesia care unit and hospital. RESULTS: Complete response occurred in significantly more patients receiving 10 mg amisulpride (96 of 230, 41.7%) than placebo (67 of 235, 28.5%), a 13.2% difference (95% CI, 4.6 to 21.8; odds ratio, 1.80; P = 0.006). A 5-mg dose of amisulpride did not show a significant benefit (80 of 237, 33.8%); the difference from placebo was 5.2% (95% CI, 3.1 to 13.6; odds ratio, 1.24; P = 0.109). The total number of adverse events recorded and proportion of patients with at least one adverse event were comparable between the placebo and amisulpride groups. No clinically relevant toxicities were observed. CONCLUSIONS: A single 10-mg dose of intravenous amisulpride was safe and more effective than placebo at treating established postoperative nausea or vomiting in patients failing postoperative nausea or vomiting prophylaxis.

Randomized, Double-Blind, Placebo-Controlled Study of Intravenous Amisulpride as Treatment of Established Postoperative Nausea and Vomiting in Patients Who Have Had No Prior Prophylaxis.

BACKGROUND: Postoperative nausea and vomiting (PONV) occurs commonly in surgical patients despite widespread prophylactic antiemetic use. Rescue options are currently limited. 5HT3 antagonists are most frequently used for prophylaxis, but if they fail, additional doses are not effective as rescue medication. Intravenous (IV) amisulpride, a well-studied D2/D3 antagonist, has been shown in trials to prevent PONV. This study was designed to determine if amisulpride could be used to treat established PONV in patients at low-to-moderate risk of PONV who had not received any prior prophylaxis. METHODS: Men and women aged over 18 years were permitted to enroll if they were to undergo general inhalational anesthesia, expected to last at least 1 hour, for an outpatient or inpatient surgical procedure. Patients who then suffered PONV were randomized equally to 1 of 3 single-dose IV regimens: placebo or 5 or 10 mg amisulpride. The primary end point was complete response, defined as no emesis in the period 30 minutes to 24 hours after study drug treatment and no use of rescue medication in the entire 24-hour period. RESULTS: One thousand nine hundred eighty-eight patients were enrolled preoperatively, of whom 560 were randomized to a treatment arm. Complete response occurred in 39 of 181 patients (21.5%) in the placebo group compared to 60 of 191 patients (31.4%; P = .016) and 59 of 188 patients (31.4%; P = .016) in the amisulpride 5 and 10 mg groups, respectively. The adverse event profile of amisulpride at either dose was similar to placebo. CONCLUSIONS: IV amisulpride at 5 and 10 mg was safe and efficacious in the treatment of established PONV in surgical patients undergoing general anesthesia with no prior PONV prophylaxis.

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.

GTS-21 reduces microvascular permeability during experimental endotoxemia.

INTRODUCTION: No effective pharmacological therapy is currently available to attenuate tissue edema formation due to increased microvascular permeability in sepsis. Cholinergic mediators have been demonstrated to exert anti-inflammatory effects via the α7 nicotinic acetylcholine receptor (α7nAChR) during inflammation. GTS-21, a partial α7nAChR agonist, is an appealing therapeutic substance for sepsis-induced microvascular inflammation due to its demonstrated cholinergic anti-inflammatory properties and its favorable safety profile in clinical trials. This study evaluated the effect of GTS-21 on microvascular permeability and leukocyte adhesion during experimental endotoxemia. METHODS: Male Wistar rats (n=60) were anesthetized and prepared for intravital microscopy (IVM). Sevoflurane inhalation combined with propofol (10mg/kg) and fentanyl (5µg/kg) was used for anesthesia induction, followed by continuous intravenous anesthesia with propofol (10-40mg/kg/h) and fentanyl (10µg/kg/h). The rat mesentery was prepared for evaluation of macromolecular leakage, leukocyte adhesion and venular wall shear rate in postcapillary venules using IVM. Following baseline IVM recording, GTS-21 (1mg/kg) was applied simultaneously with, 1h prior to and 1h after administration of lipopolysaccharide (LPS, 5mg/kg). Test substances (crystalloid solution, LPS, GTS-21) were administered as volume equivalent intravenous infusions over 5min in the respective treatment groups. The consecutive IVMs were performed at 60, 120 and 180min after the baseline IVM. The systemic inflammatory response was evaluated by measuring TNF-α levels after the 180min IVM. RESULTS: Microvascular permeability was significantly reduced in animals treated with GTS-21 simultaneously and 1h after induction of endotoxemia. Leukocyte adhesion, venular wall shear rate and TNF-α levels were not affected by GTS-21 treatment compared to the untreated endotoxemic animals. CONCLUSION: GTS-21 has a protective effect on microvascular barrier function during endotoxemia. Considering its anti-inflammatory efficacy and safety profile, its clinical use might prove beneficial for the treatment of capillary leakage in sepsis therapy.

Intravenous Amisulpride for the Prevention of Postoperative Nausea and Vomiting: Two Concurrent, Randomized, Double-blind, Placebo-controlled Trials.

BACKGROUND: Two essentially identical, randomized, double-blind, placebo-controlled, parallel-group phase III studies evaluated the efficacy of intravenous amisulpride, a dopamine D2/D3 antagonist, in the prevention of postoperative nausea and vomiting in adult surgical patients. METHODS: Adult inpatients undergoing elective surgery during general anesthesia and having at least two of the four Apfel risk factors for postoperative nausea and vomiting were enrolled at 9 U.S. and 10 European sites. A single 5-mg dose of amisulpride or matching placebo was given at induction of anesthesia. The primary endpoint was complete response, defined as no vomiting/retching and no use of antiemetic rescue medication in the 24-h postoperative period. Nausea incidence was a secondary endpoint. RESULTS: Across the two studies, 689 patients were randomized and dosed with study medication, of whom 626 were evaluable per protocol. In the U.S. study, 46.9% (95% CI, 39.0 to 54.9) of patients achieved complete response in the amisulpride group compared to 33.8% (95% CI, 26.2 to 42.0) in the placebo group (P = 0.026). In the European study, complete response rates were 57.4% (95% CI, 49.2 to 65.3) for amisulpride and 46.6% (95% CI, 38.8 to 54.6) for placebo (P = 0.070). Nausea occurred less often in patients who received amisulpride than those who received placebo. There was no clinically significant difference in the safety profile of amisulpride and placebo; in particular, there were no differences in terms of QT prolongation, extrapyramidal side effects, or sedation. CONCLUSIONS: One of the two trials demonstrated superiority, while pooling both in a post hoc change to the plan of analysis supported the hypothesis that amisulpride was safe and superior to placebo in reducing the incidence of postoperative nausea and vomiting in a population of adult inpatients at moderate to high risk of postoperative nausea and vomiting.

Image quality influences the assessment of left ventricular function: an intraoperative comparison of five 2-dimensional echocardiographic methods with real-time 3-dimensional echocardiography as a reference.

OBJECTIVES: Transesophageal echocardiography has become a standard tool for evaluating left ventricular function during cardiac surgery. However, the image quality varies widely between patients and examinations. The aim of this study was to investigate the influence of the image quality on 5 commonly used 2-dimensional methods. METHODS: Transesophageal real-time 3-dimensional echocardiography (3DE) served as a reference. Left ventricular function was evaluated in 63 patients with sufficient real-time 3DE image quality. The image quality was rated using the ratio of the visualized border divided by the total endocardial border. These ratings were used to generate groups of poor (0%-40%), fair (41%-70%), and good (71%-100%) image quality. The ejection fraction (EF), end-diastolic volume, and end-systolic volume were analyzed by the Simpson method of disks (biplane and monoplane), eyeball method, Teichholz method, and speckle-tracking method. Furthermore, the fractional area change was determined. Each correlation with real-time 3DE was evaluated. RESULTS: Correlations of the EF and volumes, respectively, as determined by long-axis view methods increased with improving image quality: the Simpson biplane method was found to be the most accurate method, with good image quality for the EF (r = 0.946) and volumes (end-diastolic volume, r = 0.962; end-systolic volume, r = 0.989). Correlations of the EF and fractional area change by short-axis view methods decreased with improving image quality, with the Teichholz EF found to be most accurate with poor (r = 0.928) in contrast to good (r = 0.699) image quality. CONCLUSIONS: With good image quality, the Simpson biplane method is the most accurate 2-dimensional method for assessing the left ventricular EF. Short-axis view methods, especially the Teichholz method yield better correlations with poor image quality. The eyeball method was unaffected by image quality.

Assessment of left ventricular size and function during cardiac surgery. An intraoperative evaluation of six two-dimensional echocardiographic methods with real time three-dimensional echocardiography as a reference.

Transesophageal echocardiography is recommended to monitor left ventricular (LV) size and function in various operations. Generally, two-dimensional (2D) methods are applied intraoperatively. The aim of this study was to compare the accuracy and feasibility of 6 commonly used 2D methods to assess LV function during surgery. LV function in 120 consecutive patients was evaluated. Real time three-dimensional transesophageal echocardiograpy (3DTEE) served as reference. End-diastolic and end-systolic volumes and ejection fraction (EF) were analyzed with Simpson's method of discs (monoplane [MP] and biplane [BP]), eyeball method, Teichholz' method, and speckle tracking (ST) methods. Furthermore, fractional area change (FAC) and peak systolic pressure rise (dP/dt) were determined. Each 2D method was evaluated regarding correlation and agreement with 3DE, intra- and interobserver variability and the time required for evaluation. Simpson BP showed the strongest correlation and best agreement with 3DE for EF (limits of agreement 3.7 ± 11.6%) and volumes. Simpson MP showed similar agreement with 3DE compared to ST (2.8 ± 14.5% vs. 2.0 ± 15.3% and 3.8 ± 14.4% vs. 1.9 ± 15.6%, respectively). Both the eyeball method and Teichholz' method showed wide limits of agreement (-1.5 ± 18.2% and 5.2 ± 22.1%, respectively). DP/dt did not correlate with 3DE. FAC and ST FAC showed similar agreement. Application of 3DE (429 ± 108 seconds) took the longest time, and the eyeball method took the shortest time (8 ± 5 seconds) for analysis. Simpson BP is the most accurate intraoperative 2D method to evaluate LV function, followed by long-axis MP evaluations. Short-axis views were less accurate but may be suited for monitoring. We do not recommend using dP/dt.

Design of a prospective clinical study on the agreement between the Continuous GlucoseMonitor, a novel device for CONTinuous ASSessment of blood GLUcose levels, and the RAPIDLab® 1265 blood gas analyser: The CONTASSGLU study.

BACKGROUND: Although a device is needed to continuously measure blood glucose levels within an intensive care setting, and several large-scale prospective studies have shown that patients might benefit from intensive insulin, potassium, or glucose therapy during intensive care, no devices are currently available to continuously assess blood glucose levels in critically ill patients. We conceived the study described here to evaluate the clinical use of the Continuous Glucose Monitor (CGM) performed via a central vein, and to determine the impact of phenomena, such as drift and shift, on the agreement between the CGM and a RAPIDLab® 1265 blood gas analyser (BGA). METHODS/DESIGN: In the CONTinuous ASSessment of blood GLUcose (CONTASSGLU) study, up to 130 patients under intensive care will be fitted with the CGM, an ex vivo device that continuously measures blood glucose and lactate levels. Readings from the device taken 8 h after initial placement and calibration will be compared with values measured by a BGA. For this study, we chose the BGA as it is an established standard point-of-care device, instead of the devices used in certified central laboratories. Nevertheless, we will also independently compare the results from the point-of-care BGA with those determined by a central laboratory-based device. Blood samples will be collected from each patient from the same site in which the CGM will measure blood glucose. Consequently, each participant will serve as their own control, and no randomisation is necessary. The 95% limits of agreement and the corresponding confidence intervals will be calculated and compared with a prespecified clinically acceptable relative difference of 20%. DISCUSSION: Several attempts have been made to develop a device to continuously measure blood glucose levels within an intensive care setting or to use the devices that were originally designed for diabetes management, as several of these devices are already available. However, none of these devices were successful in intensive care settings. CONTASSGLU may well bridge this gap by confirming the ability of the CGM to continuously measure blood glucose levels in intensive care settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT01580176.

Comparison of intraoperative three-dimensional Doppler color flow mapping to assess mitral regurgitation.

BACKGROUND: Three-dimensional (3D) transesophageal echocardiography (TEE) enables the determination of the vena contracta area (VCA), which is an approved parameter to quantify mitral regurgitation (MR). The aim of this study was to determine the VCA in the operative setting and to compare it to alternative 3D and standard 2D methods, with respect to different etiologies of MR. METHODS: MR in 56 consecutive patients undergoing cardiac surgery was evaluated using 2D and 3D TEE. VCA, vena contracta (VC), and effective regurgitation orifice area (EROA) by 3D and 2D flow convergence methods were determined. The correlations among the methods and the determined areas were evaluated. RESULTS: EROA determination using 3D flow convergence areas correlated strongly with VCA (r = 0.653), however the resulting areas were considerably smaller. VC measurements in the 3D data set correlated slightly less (r = 0.629). EROA, which was determined using 2D flow convergence areas, showed the strongest correlation among the 2D methods (r = 0.406). 2D VC measurements showed weak to no correlation with VCA. Although a correlation was detected when using the biplane method or the midesophageal long-axis view to measure VC, statistical significance was only reached in functional MR and MR due to simple prolapse. CONCLUSIONS: Intraoperative 3D methods to determine MR were feasible and showed improved correlation with VCA compared to 2D measurements. The agreement of 2D methods with VCA declined from functional MR to MR due to prolapse. We recommend the utilization of 3D color Doppler for intraoperative evaluation of MR, especially in patients with complex mitral valve prolapses.

[Patient's participation during the pre-anesthesia visit --"if you have no more questions ..."]. / Patientenbeteiligung im Prämedikationsgespräch - "Falls Sie jetzt keine Fragen mehr haben ..."

Preanesthesia visits are highly complex communicative events with legally demanded participation of the patients. The contribution describes the logical communicative course of this communication type as well as the communicative tasks of the participants. It is shown that physicians in fact offer opportunities for patients' questions but combine them with initiatives for the completion of the interaction; formulations of such offerings are also discouraging patients' questions. Initiative questions of patients during the conversation otherwise indicate where patients are in need for questions.

(1 → 3)-ß-D-Glucan-guided antifungal therapy in adults with sepsis: the CandiSep randomized clinical trial.

PURPOSE: To investigate whether (1 → 3)-ß-d-Glucan (BDG)-guidance shortens time to antifungal therapy and thereby reduces mortality of sepsis patients with high risk of invasive Candida infection (ICI). METHODS: Multicenter, randomized, controlled trial carried out between September 2016 and September 2019 in 18 intensive care units enrolling adult sepsis patients at high risk for ICI. Patients in the control group received targeted antifungal therapy driven by culture results. In addition to targeted therapy, patients in the BDG group received antifungals if at least one of two consecutive BDG samples taken during the first two study days was ≥ 80 pg/mL. Empirical antifungal therapy was discouraged in both groups. The primary endpoint was 28-day-mortality. RESULTS: 339 patients were enrolled. ICI was diagnosed in 48 patients (14.2%) within the first 96 h after enrollment. In the BDG-group, 48.8% (84/172) patients received antifungals during the first 96 h after enrollment and 6% (10/167) patients in the control group. Death until day 28 occurred in 58 of 172 patients (33.7%) in the BDG group and 51 of 167 patients (30.5%) in the control group (relative risk 1.10; 95% confidence interval, 0.80-1.51; p = 0.53). Median time to antifungal therapy was 1.1 [interquartile range (IQR) 1.0-2.2] days in the BDG group and 4.4 (IQR 2.0-9.1, p < 0.01) days in the control group. CONCLUSIONS: Serum BDG guided antifungal treatment did not improve 28-day mortality among sepsis patients with risk factors for but unexpected low rate of IC. This study cannot comment on the potential benefit of BDG-guidance in a more selected at-risk population.

Lipid peroxidation in acute respiratory distress syndrome and liver failure.

BACKGROUND: Lipid peroxidation processes (LPO) are evident in many organ failures. Due to their toxic properties, they are causative for cellular dysfunction at the site of their origin and far beyond. This study was conducted to investigate differences in LPO pattern of patients with established acute respiratory distress syndrome (ARDS) and patients with end-stage liver failure undergoing liver transplantation (LTX) as two mayor prototypes of organ failure. METHODS: In this prospective, nonrandomized, controlled trial, we examined LPO by measuring malondialdehyde (MDA), and the volatile aldehydes hexanal and propanal as LPO-markers. Eighteen patients with ARDS, 16 subjects undergoing liver transplantation due to liver failure, and 8 healthy controls were included to the study. RESULTS: ARDS patients showed significantly higher levels in MDA concentrations than LTX and controls, respectively. However, MDA levels of patients with end-stage liver failure were equal to those of controls. Blood concentrations of hexanal and propanal, specific by-products of lipid peroxidation, were elevated in both patient groups, but significantly higher only in LTX. Unexpectedly, hexanal and propanal concentrations were significantly higher in LTX than in ARDS patients. In both patient groups, MDA showed no differences between arterial and mixed venous blood, whereas volatile aldehydes were higher in arterial than in mixed venous compartment. CONCLUSIONS: Both ARDS and LTX-patients showed significant evidence of enhanced LPO. However, proportions of MDA and volatile aldehydes differed substantially between the groups. Thus, for the interpretation of LPO markers, disease-specific factors have to be taken into account. Distinctions might be attributable to differences in the effected lipid components or variations in metabolism.

Single-Center Evaluation of Treatment Success Using Two Different Protocols for MRI-Guided Transurethral Ultrasound Ablation of Localized Prostate Cancer.

OBJECTIVES: To assess differences in 24-month oncologic and functional outcomes in men with low to intermediate-risk prostate cancer treated with MRI-guided transurethral ultrasound ablation (TULSA) using intentionally conservative versus intensified treatment parameters. PATIENTS AND METHODS: Patients from a single center involved in two multicenter trials were included in this analysis. This included 14 of 30 patients with Gleason 3 + 3 from a Phase I study using intentionally conservative treatment parameters, and 15 of 115 patients with Gleason ≤ 3 + 4 from a pivotal study using intensified parameters. Follow-up data compared across these cohorts included 12-month biopsy and MRI for all patients, and 24-month PSA, micturition and quality of life (IIEF, IPSS, IPSS-QOL). The prognostic value of baseline parameters and PSA kinetics on 12-month histological recurrence was evaluated by logistic regression. RESULTS: 12-month biopsy revealed clinically significant residual disease in 4 (29%) and 2 (14%) patients from the Phase I and pivotal studies, respectively. PSA nadir was 0.7 ng/ml for Phase I and 0.5 ng/ml for pivotal study patients. Patient age at diagnosis, use of MRI fusion/systematic prostate biopsy, number of obtained cores at initial biopsy, PSA course, and PSA nadir were identified as prognostic factors for treatment success. All but one patient from each cohort maintained erection firmness sufficient for penetration. No cases of pad use were reported at 24 months. There were no Grade 4 or higher adverse events, and no late toxicity related to the procedure. CONCLUSION: Two-year follow-up demonstrated the efficacy of TULSA for the treatment of localized prostate cancer, and the durability of PSA and functional outcomes. Intensifying treatment parameters in the pivotal trial had no impact on safety or functional outcomes through 24 months, while reducing the recurrence rate for clinically significant disease. Careful patient selection by MRI fusion/systematic prostate biopsy and adequate follow-up through routine 12-month biopsy are recommended.

Reversal of rocuronium-induced neuromuscular blockade with sugammadex compared with neostigmine during sevoflurane anaesthesia: results of a randomised, controlled trial.

BACKGROUND AND OBJECTIVE: Sugammadex, a modified gamma-cyclodextrin, is a selective relaxant-binding agent designed to reverse the effects of the steroidal neuromuscular blocking agents rocuronium or vecuronium. This study compared the efficacy of sugammadex and neostigmine for reversal of neuromuscular blockade induced by rocuronium for facilitating elective surgery. METHODS: This randomised, multicentre, parallel-group trial included 98 adult patients. Patients received intravenous propofol for induction followed by sevoflurane maintenance anaesthesia. Neuromuscular blockade was monitored using acceleromyography and a train-of-four (TOF) mode of stimulation. Patients were randomly allocated to receive sugammadex 2.0 mg kg(-1) or neostigmine 50 microg kg (-1) (with glycopyrrolate 10 microg kg(-1)) at reappearance of the second response of the TOF (mean 16% twitch height of first response) after the last dose of rocuronium. Safety was evaluated by assessing adverse events, laboratory variables and vital signs. RESULTS: Time to recovery of the TOF ratio of 0.9 after sugammadex compared with neostigmine was significantly shorter (P < 0.0001), being 1.5 versus 18.6 min (geometric means). Predictability of response was greater with sugammadex than neostigmine: with 98% of sugammadex patients versus 11% of neostigmine patients recovering to a TOF ratio of 0.9 within 5 min. There were no clinical events related to residual neuromuscular blockade or reoccurrence of blockade. Serious adverse events were observed in two sugammadex-treated patients and in three neostigmine-treated patients, respectively, but none were considered related to study drugs. CONCLUSION: Sugammadex achieved significantly faster recovery of neuromuscular function after rocuronium to a TOF ratio of 0.9 compared with neostigmine (Clinicaltrials.gov identifier: NCT00451217).

Effects of ketamine on hypoxic pulmonary vasoconstriction in the isolated perfused lungs of endotoxaemic mice.

BACKGROUND AND OBJECTIVE: During sepsis and endotoxaemia, hypoxic pulmonary vasoconstriction (HPV) is impaired. Sedation of septic patients in ICUs is performed with various anaesthetics, most of which have pulmonary dilatory properties. Ketamine is a sympathetic nervous system-activating anaesthetic that preserves cardiovascular stability. The effects of ketamine on the pulmonary vasculature and HPV during sepsis have not been characterized yet. METHODS: Therefore, isolated lungs of mice were perfused with ketamine (0, 0.1, 1.0, and 10 mg kg(-1) body weight min) 18 h following intraperitoneal injection of lipopolysaccharide (LPS); untreated mouse groups served as controls (n = 7 per group, respectively). Pulmonary artery pressure (PAP) and pressure-flow curves during normoxic (FiO(2) = 0.21) and hypoxic (FiO(2) = 0.01) ventilation were obtained. RESULTS: HPV was reduced in endotoxaemic animals when compared with controls (means +/- SD; DeltaPAP control 103 +/- 28% vs. LPS 23 +/- 25%, P < 0.05). Ketamine caused a dose-dependent reduction of HPV in the lungs of control (DeltaPAP 0 mg kg(-1) min(-1) ketamine 103 +/- 28% vs. 10 mg kg(-1) min(-1) ketamine 28 +/- 21%, P < 0.05) and septic animals (DeltaPAP 0 mg kg(-1) min(-1) ketamine 23 +/- 25% vs. 10 mg kg(-1) min(-1) ketamine 0 +/- 4%, P < 0.05). Analysis of pressure-flow curves revealed that ketamine partly reversed the endotoxin-induced changes in basal pulmonary vascular wall properties rather than interfering with the HPV response itself. CONCLUSION: Ketamine modified baseline pulmonary vascular properties, resulting in a reduced HPV responsiveness in untreated mice. Further, ketamine counteracted the LPS-induced changes in pulmonary vascular pressure-flow relationships, but did not affect impaired HPV in this murine endotoxaemia model.