Retraction notice to "Volume replacement with hydroxyethyl starch solution in children" [Br J Anaesth 70 (1993) 661-5].

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief, Professor Hugh Hemmings, based on the recommendations of Justus-Liebig-University Giessen following an internal review of research conducted by Joachim Boldt at the University. This is further described in 'Further Retractions of Articles by Joachim Boldt', https://doi.org/10.1016/j.bja.2020.02.024.

Retraction notice to "Influence of different anticoagulation regimens on platelet function during cardiac surgery" [Br J Anaesth 73 (1994) 639-44].

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief, Professor Hugh Hemmings, based on the recommendations of Justus-Liebig-University Giessen following an internal review of research conducted by Joachim Boldt at the University. This is further described in 'Further Retractions of Articles by Joachim Boldt', https://doi.org/10.1016/j.bja.2020.02.024.

Retraction notice to "Endothelial-related coagulation in cardiac surgery" [Br J Anaesth 74 (1995) 174-9].

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief, Professor Hugh Hemmings, based on the recommendations of Justus-Liebig-University Giessen following an internal review of research conducted by Joachim Boldt at the University. This is further described in 'Further Retractions of Articles by Joachim Boldt', https://doi.org/10.1016/j.bja.2020.02.024.

Preoperative fasting in children: review of existing guidelines and recent developments.

The current guidelines for preoperative fasting recommend intervals of 6, 4, and 2 h (6-4-2) of fasting for solids, breast milk, and clear fluids, respectively. The objective is to minimize the risk of pulmonary aspiration of gastric contents, but also to prevent unnecessarily long fasting intervals. Pulmonary aspiration is rare and associated with nearly no mortality in paediatric anaesthesia. The incidence may have decreased during the last decades, judging from several audits published recently. However, several reports of very long fasting intervals have also been published, in spite of the implementation of the 6-4-2 fasting regimens. In this review, we examine the physiological basis for various fasting recommendations, the temporal relationship between fluid intake and residual gastric content, and the pathophysiological effects of preoperative fasting, and review recent publications of various attempts to reduce the incidence of prolonged fasting in children. The pros and cons of the current guidelines will be addressed, and possible strategies for a future revision will be suggested.

Safety and collection efficiency with a lower transfusion threshold for extracorporeal photopheresis in adult patients with graft-versus-host disease.

BACKGROUND: Extracorporeal photopheresis (ECP) is an established treatment for graft-versus-host disease (GVHD). Various haematocrit thresholds have been used to trigger red blood cells transfusion prior to ECP. Moderate-to-severe GVHD is frequently complicated by anaemia; the safety and collection efficiency with a lower haematocrit for ECP is unknown. METHODS: We prospectively enrolled 26 consecutive adult GVHD patients with haematocrits between 25% and 28·9% who received ECP on the CELLEX system. Preprocedural transfusion was withheld. We monitored the adverse events and transfusions avoided. A complete blood cell count with differential was performed on preprocedural peripheral blood and buffy coat collected. Lymphocyte fold enrichment (LFE) was compared between this cohort and two historical control groups with haematocrits of 29% or higher. RESULTS: Red Blood Cells transfusion was avoided in the lower-haematocrit cohort without adverse events. The median LFE was 4·5 (95%CI, 3·1-5·7) in the lower-haematocrit cohort and 5·2 (95%CI, 4·1-6·5) in the higher-haematocrit CELLEX-treated control group. The median difference was 0·7 (95%CI, -0·3 to 2·0, P = 0·14). It could not be established that the lower-haematocrit cohort was non-inferior to the higher-haematocrit control group with a prespecified non-inferiority margin of 1·3. However, LFE was significantly higher in the lower-haematocrit cohort than the higher-haematocrit UVAR XTS-treated control group (P < 0·01). CONCLUSION: Buffy coat can be collected for ECP using CELLEX in GVHD patients with a haematocrit of 25% or higher, with a collection efficiency superior to that in patients with higher haematocrits but treated using UVAR XTS. No increase in adverse events was observed at these lower haematocrits.

Cerebral oxygenation and hemodynamic measurements during craniosynostosis surgery with near-infrared spectroscopy.

INTRODUCTION: Focal pressure-related changes in brain perfusion and metabolism are discussed in single-suture craniosynostosis and brachycephalic cases (bicoronal synostosis). Raised intracranial pressure levels could be measured in some cases. In order to find possible loco-regional brain tissue changes during plastic surgery, we investigated oxygenation and perfusion parameters using non-invasive near-infrared spectroscopy (NIRS) probes. METHODS: Twenty-two consecutively operated cases (mean age 7 months) with single-suture craniosynostosis were prospectively investigated using a NIRS probe (LEA(©), O2C, white light 500-800 nm, laser NIR). Measurements for oxygen saturation (SO(2)), relative quantity of hemoglobin (rHb), blood flow, and blood flow velocity of the bilateral frontal, temporal, and parietal cortices were taken transosseously (prior to decompression) and epidurally directly after decompression as well as 15 and 30 min after decompression and before closure. RESULTS: Twenty-two patients with scaphocephaly (11), trigonocephaly (6), anterior plagiocephaly (3), and brachycephaly (2) were investigated. SO(2) was improving in all patient subgroups, showing the highest levels in the fronto-temporal region; rHb improved in scaphocephalic, trigonocephalic, and brachycephalic children. Again, the highest values were found not only in the temporal but also in the frontal region and in brachycephalic patients also in the parietal cortex. CONCLUSION: These preliminary results of a new technology for brain tissue oxygenation and blood flow measurements suggest a regional compromise of cortical metabolism and circulation in patients with craniosynostosis.

Congenital heart surgery: expected versus observed surgical performance according to the Aristotle complexity score.

BACKGROUND: The Aristotle score quantifies the complexity involved in congenital heart surgery. It defines surgical performance as complexity score times hospital survival. We studied how expected and observed surgical performance evolved over time. METHODS: 2312 main procedures carried out between 2006 and 2010 were analyzed. The Aristotle basic score, corresponding hospital survival and related observed surgical performance were estimated. Expected survival was based on the mortality risks published by O'Brien and coauthors. Observed performance divided by expected performance was called the standardized ratio of performance. This should trend towards a figure above 100%. Survival rates and performance are given with 95% confidence intervals. RESULTS: The mean Aristotle basic score was 7.88 ± 2.68. 51 patients died: observed hospital survival was 97.8 % (97.1 %-98.3%). 115 deaths were anticipated: expected survival was 95.2% (93.5%-96.3%). Observed and expected surgical performance reached 7.71 (7.65-7.75) and 7.49 (7.37-7.59), respectively. Therefore the overall standardized ratio of performance was 102.94%. The ratio increased from 2006 (ratio = 101.60%) to 2009 (103.92%) and was 103.42% in 2010. Performance was high for the repair of congenital corrected transposition of the great arteries and ventricular septal defect (VSD) by atrial switch and Rastelli procedure, the Norwood procedure, repair of truncus arteriosus, aortic arch repair and VSD closure, and the Ross-Konno procedure, with corresponding standardized ratios of 123.30%, 116.83%, 112.99%, 110.86% and 110.38%, respectively. With a ratio of 82.87%, performance was low for repair of Ebstein's anomaly. CONCLUSION: The standardized ratio of surgical performance integrates three factors into a single value: procedure complexity, postoperative observed survival, and comparison with expected survival. It constitutes an excellent instrument for quality monitoring of congenital heart surgery programs over time. It allows an accurate comparison of surgical performance across institutions with different case mixes.

Surgical management of congenital heart disease: correlation between hospital costs and the Aristotle complexity score.

BACKGROUND: Hospital costs are expected to correlate with clinical complexity. Do costs for congenital heart surgery correlate with Aristotle complexity scores? METHODS: 442 inpatient stays in 2008 were evaluated. Aristotle scores and levels were determined. Costs were estimated according to the German Institute for Hospital Reimbursement system. Pearson and Spearman R correlation coefficients and corresponding goodness-of-fit regression coefficients R2 were calculated. RESULTS: Mean basic and comprehensive Aristotle scores were 7.60 +/- 2.74 and 9.23 +/- 2.94 points, respectively. Mean expenses per hospital stay amounted to 29,369 +/- 30,823 Euros. Aristotle basic and comprehensive scores and levels were positively correlated with hospital costs. With a Spearman R of 1 and related R2 of 0.9436, scores of the 6 Aristotle comprehensive levels correlated best. Mean hospital reimbursement was 26,412 +/- 17,962 Euros. Compensation was higher than expenses for patients in comprehensive levels 1 to 3, but much lower for those in levels 4 to 6. CONCLUSIONS: Aristotle comprehensive complexity scores were highly correlated with hospital costs. The Aristotle score could be used as a scale to establish the correct reimbursement after congenital heart surgery.

Predicting the pathogenicity of RPE65 mutations.

To assist in distinguishing disease-causing mutations from nonpathogenic polymorphisms, we developed an objective algorithm to calculate an "estimate of pathogenic probability" (EPP) based on the prevalence of a specific variation, its segregation within families, and its predicted effects on protein structure. Eleven missense variations in the RPE65 gene were evaluated in patients with Leber congenital amaurosis (LCA) using the EPP algorithm. The accuracy of the EPP algorithm was evaluated using a cell-culture assay of RPE65-isomerase activity The variations were engineered into plasmids containing a human RPE65 cDNA and the retinoid isomerase activity of each variant was determined in cultured cells. The EPP algorithm predicted eight substitution mutations to be disease-causing variants. The isomerase catalytic activities of these RPE65 variants were all less than 6% of wild-type. In contrast, the EPP algorithm predicted the other three substitutions to be non-disease-causing, with isomerase activities of 68%, 127%, and 110% of wild-type, respectively. We observed complete concordance between the predicted pathogenicities of missense variations in the RPE65 gene and retinoid isomerase activities measured in a functional assay. These results suggest that the EPP algorithm may be useful to evaluate the pathogenicity of missense variations in other disease genes where functional assays are not available.

Pharmacometric Analysis of the Relationship Between Absolute Lymphocyte Count and Expanded Disability Status Scale and Relapse Rate, Efficacy End Points, in Multiple Sclerosis Trials.

The aim of this work was to assess the relationship between the absolute lymphocyte count (ALC), and disability (as measured by the Expanded Disability Status Scale [EDSS]) and occurrence of relapses, 2 efficacy endpoints, respectively, in patients with remitting-relasping multiple sclerosis. Data for ALC, EDSS, and relapse rate were available from 1319 patients receiving placebo and/or cladribine tablets. Pharmacodynamic models were developed to characterize the time course of the endpoints. ALC-related measures were then evaluated as predictors of the efficacy endpoints. EDSS data were best fitted by a model where the logit-linear disease progression is affected by the dynamics of ALC change from baseline. Relapse rate data were best described by the Weibull hazard function, and the ALC change from baseline was also found to be a significant predictor of time to relapse. Presented models have shown that once cladribine exposure driven ALC-derived measures are included in the model, the need for drug effect components is of less importance (EDSS) or disappears (relapse rate). This simplifies the models and theoretically makes them mechanism specific rather than drug specific. Having a reliable mechanism-specific model would allow leveraging historical data across compounds, to support decision making in drug development and possibly shorten the time to market.

A Pharmacometric Framework for Axitinib Exposure, Efficacy, and Safety in Metastatic Renal Cell Carcinoma Patients.

The relationships between exposure, biomarkers (vascular endothelial growth factor (VEGF), soluble VEGF receptors (sVEGFR)-1, -2, -3, and soluble stem cell factor receptor (sKIT)), tumor sum of longest diameters (SLD), diastolic blood pressure (dBP), and overall survival (OS) were investigated in a modeling framework. The dataset included 64 metastatic renal cell carcinoma patients (mRCC) treated with oral axitinib. Biomarker timecourses were described by indirect response (IDR) models where axitinib inhibits sVEGFR-1, -2, and -3 production, and VEGF degradation. No effect was identified on sKIT. A tumor model using sVEGFR-3 dynamics as driver predicted SLD data well. An IDR model, with axitinib exposure stimulating the response, characterized dBP increase. In a time-to-event model the SLD timecourse predicted OS better than exposure, biomarker- or dBP-related metrics. This type of framework can be used to relate pharmacokinetics, efficacy, and safety to long-term clinical outcome in mRCC patients treated with VEGFR inhibitors. (ClinicalTrial.gov identifier NCT00569946.).

Pharmacometric Modeling of Liver Metastases' Diameter, Volume, and Density and Their Relation to Clinical Outcome in Imatinib-Treated Patients With Gastrointestinal Stromal Tumors.

Three-dimensional and density-based tumor metrics have been suggested to better discriminate tumor response to treatment than unidimensional metrics, particularly for tumors exhibiting nonuniform size changes. In the developed pharmacometric modeling framework based on data from 77 imatinib-treated gastrointestinal patients, the time-courses of liver metastases' maximum transaxial diameters, software-calculated actual volumes (Vactual ) and calculated ellipsoidal volumes were characterized by logistic growth models, in which imatinib induced a linear dose-dependent size reduction. An indirect response model best described the reduction in density. Substantial interindividual variability in the drug effect of all response assessments and additional interlesion variability in the drug effect on density were identified. The predictive ability of longitudinal tumor unidimensional and three-dimensional size and density on overall survival (OS) and progression-free survival (PFS) were compared using parametric time-to-event models. Death hazard increased with increasing Vactual . This framework may guide early clinical interventions based on three-dimensional tumor responses to enhance benefits for patients with gastrointestinal stromal tumors (GIST).

[Fibrin gel for treatment of tympanic membrane perforations: an experimental animal model]. / Behandlung von Trommelfellperforationen mit Fibringel: Eine tierexperimentelle Studie.

BACKGROUND: The goal of this study was to evaluate the effects of a fibrin gel on the healing of tympanic membrane perforation in rats. METHODS: Prolonged tympanic membrane perforations in 12 rats were created by application of mitomycin C to the intact tympanic membranes followed by bilateral myringotomy. Repeated applications of a fibrin gel to the perforation site of one tympanic membrane were performed in each animal. Tympanic membranes were observed for a total of 8 weeks. RESULTS: One perforation in each group was already patent at the end of the observation period. The mean healing period of the remaining tympanic membranes was found to be 16.7 days in the fibrin gel group and 19.6 days in the control group. CONCLUSION: A fibrin sheet does not seem to promote the wound healing process of tympanic membranes. However, the sheet might serve as a drug-delivery system for growth factors in the treatment of tympanic membrane perforations, because of its biocompatibility.

PK-PD modeling of individual lesion FDG-PET response to predict overall survival in patients with sunitinib-treated gastrointestinal stromal tumor.

Pharmacometric models were developed to characterize the relationships between lesion-level tumor metabolic activity, as assessed by the maximum standardized uptake value (SUVmax) obtained on [(18)F]-fluorodeoxyglucose (FDG) positron emission tomography (PET), tumor size, and overall survival (OS) in 66 patients with gastrointestinal stromal tumor (GIST) treated with intermittent sunitinib. An indirect response model in which sunitinib stimulates tumor loss best described the typically rapid decrease in SUVmax during on-treatment periods and the recovery during off-treatment periods. Substantial interindividual and interlesion variability were identified in SUVmax baseline and drug sensitivity. A parametric time-to-event model identified the relative change in SUVmax at one week for the lesion with the most pronounced response as a better predictor of OS than tumor size. Based on the proposed modeling framework, early changes in FDG-PET response may serve as predictor for long-term outcome in sunitinib-treated GIST.

[Structure and process quality of inpatient urologic rehabilitation]. / Struktur- und Prozessqualität der stationären urologischen Rehabilitation.

Inpatient rehabilitation and "Anschlussheilbehandlung" (rehabilitation soon after operation or acute intervention) are effective and economic for long-term improvement of urologic patients. Only therapy guided by urologic specialists during rehabilitation and afterwards guarantees the possibility of excellent results. Especially QOL and functional deficits are improved markedly by urologic rehabilitation. Therefore, inpatient urologic rehabilitation should be initiated more often in the future.

Influence of aprotinin on the thrombomodulin/protein C system in pediatric cardiac operations.

Thirty consecutive children scheduled for pediatric cardiac operation with cardiopulmonary bypass were included in the study. Before the operation, the patients were randomly divided into two groups: with aprotinin (n = 15, 30,000 U/kg after induction of anesthesia, 30,000 U/kg added to the prime of the cardiopulmonary bypass or without aprotinin (n = 15). Thrombomodulin, (free) protein S, protein C, and thrombin/antithrombin III complex were measured from arterial blood samples taken after induction of anesthesia (at baseline, before aprotinin) and before, during, and after cardiopulmonary bypass until the first postoperative day. Standard coagulation parameters (antithrombin III, fibrinogen, platelet count, and partial thromboplastin time) were without differences between the groups. Thrombomodulin plasma concentrations were within normal range ( < 40 micrograms/L) and were similar in both groups at baseline. During cardiopulmonary bypass and until 5 hours after cardiopulmonary bypass, however, thrombomodulin plasma levels were significantly lower in the children treated with aprotinin. No further differences were observed on the first postoperative day. Protein C and protein S plasma levels did not differ between the two groups. Thrombin/antithrombin III-complex plasma concentrations increased significantly during cardiopulmonary bypass, however, without showing differences between children with (225 +/- 49 micrograms/L) and without (149 +/- 31 micrograms/L) aprotinin treatment. Blood loss and the need for homologous blood and blood products did not differ significantly between the two groups. We concluded that administration of aprotinin resulted in reduced thrombomodulin plasma levels in pediatric patients undergoing cardiac operation without altering protein C/protein S plasma concentration. The exact role of aprotinin in endothelium-derived coagulation should be further studied.

Does platelet size correlate with function in patients undergoing cardiac surgery?

OBJECTIVE: Platelet dysfunction secondary to cardiopulmonary bypass (CPB) is one of the major reasons for nonsurgical post-operative bleeding in cardiac surgery. Whether platelet size is an indicator for platelet function was investigated in patients undergoing coronary artery bypass grafting. DESIGN: Prospective study. SETTING: Intra-operative, cardiac surgery operations. PATIENTS: 80 consecutive patients undergoing coronary artery bypass grafting. Excluding criteria were pre-operative coagulation disorders and medication with anticoagulants within the last 10 days before the operation day. MEASUREMENTS AND RESULTS: Platelet function was assessed by aggregometry using a turbidimetric method (inductors: ADP 2.0 mumol/l, collagen 4 micrograms/l, epinephrine 25 mumol/l). Mean platelet volume (MPV) was measured by an electrical conductivity method. Measurements were carried out before, during, and after CPB until the 1st post-operative day on intensive care unit (ICU). Platelet size decreased significantly during CPB (max. -25% after weaning from bypass) and returned to baseline values on the 1st post-operative day. Platelet count (ranging from 93 - 304 x 10(9)/l) did not correlate significantly with MPV or aggregation variables. Maximum aggregation and maximum gradient of aggregation induced by ADP and collagen were significantly decreased by CPB with the most pronounced reduction at the end of CPB (ranging from -25% to -45%). Analyses of co-variance revealed a significant correlation between changes in MPV and changes in aggregation variables (ADP, collagen). CONCLUSIONS: Platelet volume is easy to measure even in the operation room or in ICU and may indicate abnormalities in platelet function in the post-bypass period of cardiac surgery patients.

Thrombomodulin in pediatric cardiac surgery.

In 30 consecutive children with congenital heart disease scheduled for pediatric cardiac operations, thrombomodulin, protein C, free protein S, and thrombin-antithrombin complex were measured by enzyme-linked immunosorbent assay after the induction of anesthesia (baseline value), and then before, during, and after cardiopulmonary bypass until the first postoperative day. The patients were divided prospectively into two groups: children weighing less than 10 kg (group 1; n = 15) and those weighing more than 10 kg (group 2; n = 15). At baseline, the plasma concentration of thrombomodulin was significantly higher in the children in group 1 than in those in group 2 (83.1 +/- 11.0 ng/mL versus 29.2 +/- 12.1 ng/mL). During cardiopulmonary bypass, the thrombomodulin level was reduced in both groups without showing any significant group differences. Five hours after cardiopulmonary bypass and on the first postoperative day, the thrombomodulin level exceeded normal values only in the children weighing less than 10 kg. In both groups, the protein C levels were already below normal at the beginning of the study. The baseline protein S concentration was higher in the smaller children (80% +/- 18%) than in the larger children (66% +/- 11%). It was reduced by cardiopulmonary bypass in both groups; however, postoperatively it did not return to normal in group 1 (45.1% +/- 10%). Plasma levels of the thrombin-antithrombin complex were similar in both groups, with a marked increase at the end of cardiopulmonary bypass, and returned to near-normal levels by 5 hours after bypass.(ABSTRACT TRUNCATED AT 250 WORDS)

Circulating adhesion molecules in cardiac operations: influence of high-dose aprotinin.

Cardiac operations using cardiopulmonary bypass (CPB) are associated with a systemic inflammatory response most likely attributable to the release of various inflammatory mediators and activation of complement or coagulation cascade. In addition, (circulating) adhesion molecules, such as endothelial leukocyte adhesion molecule (ELAM-1), vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1), appear to be of central importance in the CPB-related inflammatory process. In this situation, antiproteases, such as aprotinin, may help to prevent damage of endothelial integrity. In a prospective study, 40 consecutive patients undergoing elective cardiac operation were randomly divided into two groups (with 20 patients in each group): in group 1 "high-dose" aprotinin was used (2 million IU of aprotinin before CPB, 500,000 IU/h until end of operation, 2 million IU added to the prime) (with aprotinin), and in group 2 no aprotinin was given (without aprotinin). Circulating adhesion molecules (cICAM-1, cELAM-1, and cVCAM-1) were measured from arterial blood samples using ELISA after induction of anesthesia (baseline), during CPB, at the end of the operation, 5 hours after CPB, and on the first postoperative day. The two groups were comparable concerning their biometric profile and CPB data. Baseline values of circulating adhesion molecules were within normal range and similar in both groups. During CPB, hemodilution resulted in a decrease in all circulating adhesion molecules. On the first postoperative day, cICAM-1 (with aprotinin, 215 +/- 32 ng/mL; without aprotinin, 230 +/- 40 ng/mL) and cELAM-1 (with aprotinin, 28 +/- 6 ng/mL; without aprotinin, 31 +/- 6 ng/mL) returned to baseline values.(ABSTRACT TRUNCATED AT 250 WORDS)