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Background: Cardiac surgery is associated with a high rate of intraoperative transfusion, requiring pre- ordering or ordering of packed red blood cell (PRBC) before surgery. Our institutional strategy is based on a systematic type and screen (T/S) ordering of 3 PRBCs at the blood bank then stored in a dedicated refrigerator in the operating room for each patient scheduled for cardiac surgery. However, these PRBC units are not always transfused and are therefore at risk of destruction if temperature fluctuations are detected during transport and storage processes. In addition, these orders represent a burden for the blood bank. Therefore, it is relevant to move towards a more tailored PRBC order before cardiac surgery and challenge the systematic ordering protocol. Methods: The Transfusion Understanding Scoring Tool (TRUST) and the Transfusion Risk and Clinical Knowledge (TRACK) Score are designed to stratify blood transfusion needs in cardiac surgery. We retrospectively performed both scores for each patient scheduled for cardiac surgery. Then, we compared their performance to predict PRBC transfusion and determined the optimal threshold to optimize the preoperative PRBC order reflecting the needs of our population managed with our local standards. Results: Receiver operating characteristic (ROC) curves for prediction of PRBC transfusion using the two scores were computed for the whole cohort (n=1249). Both scores performed well (areas under ROC curves: 0.81 and 0.82 (95% CI) using the TRACK Score and the TRUST, respectively). A TRUST < 3 identified a subgroup of patients (53.6%) at low risk of transfusion. The availability of 1 T/S PRBC in the OR would cover the needs of the majority (92.5%) of this group. Conclusions: In our institution, the use of the TRUST preoperatively could offer a more tailored T/S PRBC order for the intraoperative period, especially in the low-risk transfusion group. more...

Postoperative pulmonary complications (PPC) remain a main issue after cardiac surgery. The objective was to report the incidence and identify risk factors of PPC after cardiac surgery. An international multicenter prospective study (42 international centers in 9 countries). A total of 707 adult patients who underwent cardiac surgery under cardiopulmonary bypass. None MEASUREMENTS AND MAIN RESULTS: During a study period of 2 weeks, the investigators included all patients in their respective centers and screened for PPCs. PPC was defined as the occurrence of at least 1 pulmonary complication among the following: atelectasis, pleural effusion, respiratory failure, respiratory infection, pneumothorax, bronchospasm, or aspiration pneumonitis. Among 676 analyzed patients, 373 patients presented with a PPC (55%). The presence of PPC was significantly associated with a longer intensive care length of stay and hospital length of stay. One hundred ninety (64%) patients were not intraoperatively ventilated during cardiopulmonary bypass. Ventilation settings were similar regarding tidal volume, respiratory rate, inspired oxygen. In the regression model, age, the Euroscore II, chronic obstructive pulmonary disease, preoxygenation modality, intraoperative positive end-expiratory pressure, the absence of pre- cardiopulmonary bypass ventilation, the absence of lung recruitment, and the neuromuscular blockade were associated with PPC occurrence. Both individual risk factors and ventilatory settings were shown to explain the high level of PPCs. These findings require further investigations to assess a bundle strategy for optimal ventilation strategy to decrease PPC incidence. more...

Background: Thrombin generation testing has been used to provide information on the coagulation phenotype of patients. The most used technique is the calibrated automated thrombogram (CAT) but it suffers from a lack of standardization, preventing its implementation in routine. The ST Genesia is a new analyzer designed to assess thrombin generation based on the same principle as the CAT. Unlike the CAT system, the ST Genesia is a benchtop, fully automated analyzer, able to perform the analyses individually and not by batch, with strict control of variables such as temperature and volumes, ensuring, theoretically, maximal reproducibility. Objectives: This study aimed at assessing the performance of the STG-DrugScreen application on the ST Genesia analyzer. We also aimed at exploring stability of plasma samples after freezing and defining a reference normal range. Results: Results demonstrated the excellent interexperiment precision of the ST Genesia and confirmed that the use of a reference plasma helps reducing the inter-experiments variability. Stability revealed that plasma samples are stable for at least 11 months at −70°C or lower, except for those containing low molecular weight heparins which have to be tested within 6 months. Freezing had no effect on the majority of thrombin generation parameters except on time to peak. Conclusions: Our results suggest an easy implementation of thrombin generation with the use of ST Genesia in the routine laboratory. This will facilitate the design of multicentric studies and enable the establishment of reliable and evidence-based thresholds, which may improve the management of patients treated with anticoagulants. more...

Introduction: Estimation of residual apixaban plasma concentrations may be requested in the management of emergencies. This study aims at assessing the performance of specific anti-Xa assays calibrated with apixaban on real-life samples with low apixaban plasma concentrations (®-Liquid Anti-Xa assay (STA ® LAX) and the low and normal procedures of the Biophen ®Direct Factor Xa Inhibitors (DiXaI) assay was tested on 134 blood samples, collected from patients on apixaban, wherefrom 74 patients received LMWH after apixaban cessation. The results were compared with the liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) measurements. Results: The Biophen ®DiXaI, Biophen ®DiXaI LOW, and STA ®LAX showed very good correlation with LC-MS/MS measurements in patients without LMWH administration (Spearman r.95,.99, and.98, respectively). Their limits of quantitation were defined at 48, 24, and 12 ng/mL, respectively. The Bland-Altman test measured mean bias (SD) at 5.6 (13.1), −2.5 (5.0), and −0.8 (6.1) ng/ml, respectively. The Spearman r of the Biophen ®DiXaI decreased to 0.64 in presence of low apixaban concentrations. The Spearman r of the Biophen ®DiXaI LOW and STA ®LAX decreased to 0.39 and 0.26, respectively, in presence of LMWH. Conclusions: The accuracy of the low methodologies (Biophen ®DiXaI LOW and STA ®LAX) is slightly improved for low apixaban plasma concentrations, compared with the normal procedure of Biophen ®DiXaI. The interference of LMWH on the low methodologies is measurable, however, less important than the previously reported interference of LMWH on rivaroxaban calibrated specific anti-Xa assays. more...

Background Guidelines recommend performing atrial fibrillation (AF) catheter ablation without interruption of a direct oral anticoagulants (DOACs) and to administer unfractionated heparin (UFH) for an activated clotting time (ACT) ≥300 seconds, by analogy with vitamin K antagonist (VKA). Nevertheless, pharmacological differences between DOACs and VKA, especially regarding ACT sensitivity and UFH response, prevent extrapolation from VKA to DOACs. Hypothesis The level of anticoagulation at the time of the procedure in uninterrupted DOAC-treated patients is unpredictable and would complicate intraprocedural UFH administration and monitoring. Methods This prospective study included interrupted DOAC-treated patients requiring AF ablation. Preprocedural DOAC concentration ([DOAC]), intraprocedural UFH administration, and ACT values were recorded. A cohort of DOAC-treated patients requiring flutter catheter ablation was considered to illustrate [DOAC] without DOAC interruption. Results Forty-eight patients underwent AF and 14 patients underwent flutter ablation, respectively. In uninterrupted DOAC-treated patients, [DOAC] ranged from ≤30 to 466 ng/mL. When DOAC were interrupted, from 54 to 218 hours, [DOAC] were minimal (maximum: 36 ng/mL), preventing DOAC-ACT interference. Anyway, ACT values were poorly correlated with UFH doses (R 2 = 0.2256). Conclusions Our data showed that uninterrupted DOAC therapy resulted in an unpredictable and highly variable initial level of anticoagulation before catheter ablation. Moreover, even with DOAC interruption preventing interference between DOAC, UFH, and ACT, intraprocedural UFH monitoring was complex. Altogether, our exploratory results call into question the appropriateness of transposing UFH dose protocols, as well as the relevance of ACT monitoring in uninterrupted DOAC-treated patients. more...

Aims Patients receiving direct oral anticoagulants (DOACs) frequently undergo elective invasive procedures. Their management is challenging. We aimed to determine the optimal duration of DOAC discontinuation that ensures a minimal anticoagulant effect during the procedure. Methods and results This prospective multicentre study included 422 DOAC-treated patients requiring an invasive procedure. Pre-procedural DOAC concentration ([DOAC]) and routine haemostasis assays were performed to determine i/the proportion of patients who achieved a minimal pre-procedural [DOAC] (≤30 ng/mL) according to the duration of DOAC discontinuation, ii/the predictors of minimal [DOAC] and, iii/the ability of routine assays to predict minimal [DOAC]. Lastly, we assessed the predictors of peri-procedural bleeding events. The duration of DOAC discontinuation ranged from 1 to 218 h and pre-procedural [DOAC] from ≤30 to 527 ng/mL. After a 49-72-h discontinuation, 95% of the [DOAC] were ≤30 ng/mL. A 72-h discontinuation predicted concentrations ≤30 ng/mL with 91% specificity. In multivariable analysis, duration of DOAC discontinuation, creatinine clearance more...

INTRODUCTION: Andexanet alfa is a recombinant modified factor Xa protein that has been developed to reverse factor Xa inhibitors. Since May 2018, the FDA has approved its utilization in patients treated with apixaban and rivaroxaban in case of life-threatening or uncontrolled bleeding. On 28 of February 2019, the Committee for Medicinal Products for Human Use adopted a positive opinion, recommending the granting of a conditional marketing authorization for andexanet alfa in Europe. Area covered: The authors provide an overview of andexanet alfa development and its pharmacokinetic and pharmacodynamic properties. The results of the clinical phase III trial ANNEXA as well as current limitations related to andexanet alfa are also discussed. Expert opinion: Although phase I and II studies have proven that andexanet alfa can be effective in reversing the effect of factor Xa inhibitors, its efficacy in major bleeding patients has only been shown for apixaban and rivaroxaban, without any comparator group. Well-designed studies comparing the efficacy and safety of andexanet alfa to other reversal strategies are required to confirm preliminary data. The benefit of andexanet alfa in specific settings needs to be investigated and its use in clinical practice needs to be facilitated by the implementation of international guidelines. more...

The perioperative management of dabigatran is challenging, and recommendations based on activated partial thromboplastin time (aPTT) and thrombin time (TT) are unsatisfactory. Dedicated coagulation tests have limitations at plasma concentrations < 50 ng/ml. Therefore, a more sensitive test, which is available 24/7, is required. It was the aim of this study to investigate the performance of the Hemoclot Thrombin Inhibitors® LOW (HTI LOW) kit, a diluted thrombin time, and the STA® – ECA II (ECA-II) kit, a chromogenic variant of the ecarin clotting time, that were developed to measure low dabigatran concentrations, compared to reference dabigatran analysis by liquid chromatography tandem mass-spectrometry (LC-MS/MS). This study included 33 plasma samples from patients treated with dabigatran etexilate who had plasma concentrations < 200 ng/ml. HTI LOW and ECA-II were performed along with HTI, aPTT (STA®-C. K.Prest® and SynthasIL ®) and TT (STA® – Thrombin). All procedures were performed according to recommendations by the manufacturers. Linear (or curvilinear) correlations and Bland-Altman analyses were calculated. For free dabigatran concentrations < 50 ng/ml, the R2 of linear correlations were 0.69, 0.84 and 0.61, with HTI, HTI LOW and ECA-II, respectively. The R2 for TT, STA®-C. K.Prest® and SynthasIL® were 0.67, 0.42 and 0.15. For HTI, HTI LOW and ECA-II, Bland-Altman analyses revealed mean differences of –6 ng/ml (95 %CI: –25–14 ng/ml), 1 ng/ml (95 %CI: –18–19 ng/ml) and –1 ng/ml (95 %CI: –25–23 ng/ml), demonstrating that tests dedicated to measuring low concentrations are more accurate than HTI. In conclusion, the use of HTI LOW or ECA-II to assess low plasma dabigatran concentrations is supported by our findings. more...

Direct oral anticoagulants (DOAC) are used in several indications for the prevention and treatment of thrombotic events. As highlighted by data from clinical trials and case studies, all DOAC carry the risk of bleeding despite careful selection and patient management. Previous publications have demonstrated the limited knowledge of many physicians concerning the indications for, and correct management of, these anticoagulants. Health institutions should develop risk minimisation strategies and educational materials to prevent major adverse events related to DOAC administration. Major bleeding events are reported in clinical practice and specific antidotes are emerging from Phase III trials. Some antidotes are licensed but their high cost might limit routine use. We therefore illustrate approaches and tools that can help physicians prescribe DOAC appropriately. We focus on screening for modifiable bleeding risk factors and adapting doses according to the individual benefit-risk profile. We also provide recommendations on managing a missed dose, switching, bridging, and resumption. more...

Background The perioperative management of antiplatelet therapy in noncardiac surgery patients who have undergone previous percutaneous coronary intervention (PCI) remains a dilemma. Continuing dual antiplatelet therapy (DAPT) may carry a risk of bleeding, while stopping antiplatelet therapy may increase the risk of perioperative major adverse cardiovascular events (MACE). Methods Occurrence of Bleeding and Thrombosis during Antiplatelet Therapy In Non-Cardiac Surgery (OBTAIN) was an international prospective multicentre cohort study of perioperative antiplatelet treatment, MACE, and serious bleeding in noncardiac surgery. The incidences of MACE and bleeding were compared in patients receiving DAPT, monotherapy, and no antiplatelet therapy before surgery. Unadjusted risk ratios were calculated taking monotherapy as the baseline. The adjusted risks of bleeding and MACE were compared in patients receiving monotherapy and DAPT using propensity score matching. Results A total of 917 patients were recruited and 847 were eligible for inclusion. Ninety-six patients received no antiplatelet therapy, 526 received monotherapy with aspirin, and 225 received DAPT. Thirty-two patients suffered MACE and 22 had bleeding. The unadjusted risk ratio for MACE in patients receiving DAPT compared with monotherapy was 1.9 (0.93–3.88), P=0.08. There was no difference in MACE between no antiplatelet treatment and monotherapy 1.03 (0.31–3.46), P=0.96. Bleeding was more frequent with DAPT 6.55 (2.3–17.96) P=0.0002. In a propensity matched analysis of 177 patients who received DAPT and 177 monotherapy patients, the risk ratio for MACE with DAPT was 1.83 (0.69–4.85), P=0.32. The risk of bleeding was significantly greater in the DAPT group 4.00 (1.15–13.93), P=0.031. Conclusions OBTAIN showed an increased risk of bleeding with DAPT and found no evidence for protective effects of DAPT from perioperative MACE in patients who have undergone previous PCI. more...

Summary Background Enterobacteriaceae are recognized as leading pathogens of healthcare-associated infections. Aim To report the investigation of a nosocomial outbreak of extended-spectrum β-lactamase-producing Enterobacter cloacae affecting cardiothoracic surgery patients in a Belgian academic hospital. Methods Cases were defined based on epidemiological and microbiological investigations, including molecular typing using repetitive element-based polymerase chain reaction and multi-locus sequence typing. Case–control studies followed by field evaluations allowed the identification of a possible reservoir, and the retrospective assessment of human and financial consequences. Findings Over a three-month period, 42 patients were infected or colonized by CTX-M-15-producing E. cloacae strains that belonged to the same clonal lineage. Acquisition mainly occurred in the intensive care unit (N = 23) and in the cardiothoracic surgery ward (N = 16). All but one patient had, prior to acquisition, undergone a cardiothoracic surgical procedure, monitored by the same transoesophageal echocardiography (TOE) probe in the operating room. Despite negative microbiological culture results, the exclusion of the suspected probe resulted in rapid termination of the outbreak. Overall, the outbreak was associated with a high mortality rate among infected patients (40%) as well as significant costs (€266,550). Conclusion The outbreak was indirectly shown to be associated with the contamination of a manually disinfected TOE probe used per-operatively during cardiothoracic surgery procedures, because withdrawal of the putative device led to rapid termination of the outbreak. more...

Introduction Prevalence and 1-year impact of right ventricular systolic dysfunction (RVSD) early after lung transplantation (LTx), in a population without pulmonary hypertension (PHT), is not well documented. In this retrospective study, we hypothesized that, as after heart Tx, occurrence of early RVSD after LTx in those patients (pts) would be associated with impaired 1-year survival.¹ Methods After ICU admission of LTx pts, we routinely perform a comprehensive transoesophageal echocardiographic (TOE) to check pulmonary veins’ patency. After exclusion of pts transplanted for PHT and of pts under ECMO, we retrospectively reviewed RV systolic data acquired during this TOE. At the time of TOE, all pts were mechanically ventilated. RVSD was defined based on visual assessment (RV dilation and/or RV hypokinesia) and RV fractional area change (FAC) Results From January 2004 to March 2018, 166 LTx pts underwent comprehensive TOE in ICU. Indications for LTx were COPD in 117 pts (70.5%), fibrosis in 25 (15.1%), cystic fibrosis in 7 (4.2%), bronchiectasis in 7 pts (4.2%) and other indications in 10 (6.0%). RV visual assessment was reported as abnormal in 56/166 pts (33.7%). RV FAC was reported in 112 pts and was Discussion Based on this retrospective TOE and single-center experience, prevalence of early RVSD after LTx, in a population without PHT, ranges from 34 to 39%, depending on the used criteria (visual assessment or RV FAC). However, occurrence of early RVSD after LTx was not associated with impaired 1-year survival. more...

Dabigatran etexilate (DE), rivaroxaban, and apixaban are nonvitamin K antagonist oral anticoagulants (NOACs) that have been compared in clinical trials with existing anticoagulants (warfarin and enoxaparin) in several indications for the prevention and treatment of thrombotic events. All NOACs presented bleeding events despite a careful selection and control of patients. Compared with warfarin, NOACs had a decreased risk of intracranial hemorrhage, and apixaban and DE (110 mg BID) had a decreased risk of major bleeding from any site. Rivaroxaban and DE showed an increased risk of major gastrointestinal bleeding compared with warfarin. Developing strategies to minimize the risk of bleeding is essential, as major bleedings are reported in clinical practice and specific antidotes are currently not available. In this paper, the following preventive approaches are reviewed: improvement of appropriate prescription, identification of modifiable bleeding risk factors, tailoring NOAC's dose, dealing with a missed dose as well as adhesion to switching, bridging and anesthetic procedures. © 2014 Lessire Sarah et al. more...

The indications for rigid bronchoscopy for interventional pulmonology have increased and include stent placements and transbronchial cryobiopsy procedures. The shared airway between anesthesiologist and pulmonologist and the open airway system, requiring specific ventilation techniques such as jet ventilation, need a good understanding of the procedure to reduce potentially harmful complications. Appropriate adjustment of the ventilator settings including pause pressure and peak inspiratory pressure reduces the risk of barotrauma. High frequency jet ventilation allows adequate oxygenation and carbon dioxide removal even in cases of tracheal stenosis up to frequencies of around 150 min−1; however, in an in vivo animal model, high frequency jet ventilation along with normal frequency jet ventilation (superimposed high frequency jet ventilation) has been shown to improve oxygenation by increasing lung volume and carbon dioxide removal by increasing tidal volume across a large spectrum of frequencies without increasing barotrauma. General anesthesia with a continuous, intravenous, short-acting agent is safe and effective during rigid bronchoscopy procedures. more...

Introduction.We herein report our experience with new fully covered self-expanding metallic stents in the setting of inoperable recurrent benign tracheobronchial stenosis.Methods.Between May 2010 and July 2014, 21 Micro-Tech® FC-SEMS (Nanjing Co., Republic of Korea) were placed in our hospital in 16 patients for inoperable, recurrent (after dilatation), and symptomatic benign airway stenosis. Their medical files were retrospectively reviewed in December 2014, with focus on stent’s tolerance and durability data.Results.Twenty-one stents were inserted: 13 for posttransplant left main bronchus anastomotic stricture, seven for postintubation tracheal stenosis, and one for postlobectomy anastomotic stricture. Positioning was easy for all of them. Stents were in place for a mean duration of 282 days. The most common complications were granulation tissue development (35%), migration (30%), and sputum retention (15%). Fifty-five % of the stents (11/20) had to be removed because of various complications, without difficulty for all of them. None of the patients had life-threatening complications.Conclusion.Micro-Tech FC-SEMS were easy to position and to remove. While the rate of complications requiring stent removal was significant, no life-threatening complication occurred. Further studies are needed to better define their efficacy and safety in the treatment of benign airway disease. more...

Facing coagulation disorders after acute trauma.Trauma is the leading cause of mortality for persons between one and 44 years of age, essentially due to bleeding complications.We screened the PubMed, Scopus and Cochrane Library databases, using specific keywords. Only publications in English were considered.The pathophysiology of trauma-induced coagulopathy (TIC) is complex and includes the classic "lethal triad" (i.e., haemodilution, acidosis, hypothermia) but may also include activation of protein C, endothelial and platelet dysfunction, and fibrinogen depletion. The time between trauma and treatment of the resultant massive bleeding should be as short as possible using techniques for rapid control of bleeding and avoiding aggravating factors (hypothermia, metabolic acidosis and hypocalcaemia). If given within three hours of injury, tranexamic acid (TXA) reduces all causes of mortality in trauma patients and reduces transfusion requirements. In a bleeding patient, crystalloids are preferred to colloids and the ratio of fresh frozen plasma to packed red blood cells should be at least 1:2. Damage control surgery (DCS) should be considered for patients who present with, or are at risk for developing, the "lethal triad", multiple life-threatening injuries or shock, and in mass casualty situations. DCS can also aid in the evaluation of the extent of tissue injuries and the control of haemorrhage and infection. Finally, there is currently no evidence of the added value of laboratory assays in the management of TIC.TIC appears quickly after trauma and should be anticipated and detected as soon as possible. TXA plays a central role in the management of such patients. Each institution should establish a local algorithm for the management of bleeding patients. more...

Background Osteogenesis imperfecta is a genetic disorder of connective tissue causing mostly left-sided heart valves and aortic root pathologies, but a coronary artery involvement reflecting an increased sensitivity to cardiovascular risk factors is also suspected in this patient population. Case presentation We report a 38-year-old patient with an osteogenesis imperfecta and a typical presentation of an acute myocardial infarction. The coronary angiogram showed a coronary 3-vessel disease. The patient underwent a bypass grafting surgery with the internal mammary artery. The sternum was closed using four nitinol clips and had totally stabilized at 4 months with excellent bone healing. Conclusions With the successful clinical outcome in this patient severely affected by its osteogensis imperfecta, we underline the safe use of the LIMA, if precaution is taken towards the sternal bone, and its closure with nitinol clips. more...

Idarucizumab is a specific antagonist for dabigatran etexilate (DE). The recent market authorization of idarucizumab in Europe and the USA may reassure prescribers of DE, as it can increase the safety of the emergency management of patients taking this anticoagulant. However, idarucizumab use should be limited to specific indications to avoid unnecessary risks to patients and costs to healthcare systems. Areas covered: The authors provide an overview of idarucizumab development and its pharmacokinetic and pharmacodynamic properties. The results of the clinical phase III trial RE-VERSE AD and a review of recent case reports of idarucizumab use in emergency contexts are also discussed. Expert opinion: Although idarucizumab has shown clear efficacy in reversing dabigatran-induced coagulopathy, its overall effects on patient outcome have not been proven. Information regarding the clinical context in which patients on DE are admitted for emergency treatment, and accurate laboratory tests of dabigatran plasma level during reversal may inform selection and help with the follow-up of patients who may benefit from idarucizumab. Idarucizumab should be integrated into protocol for the emergency management of patients on DE. Furthermore, the benefit of idarucizumab in specific indications such as acute ischemic stroke should be investigated. more...

Direct oral anticoagulants (DOACs) have been licensed worldwide for several years for various indications. Each year, 10-15% of patients on oral anticoagulants will undergo an invasive procedure and expert groups have issued several guidelines on perioperative management in such situations. The perioperative guidelines have undergone numerous updates as clinical experience of emergency management has increased and perioperative studies including measurement of residual anticoagulant levels have been published. The high inter-patient variability of DOAC plasma levels has challenged the traditional recommendation that perioperative DOAC interruption should be based only on the elimination half-life of DOACs, especially before invasive procedures carrying a high risk of bleeding. Furthermore, recent publications have highlighted the potential danger of heparin bridging use when DOACs are stopped before an invasive procedure. As antidotes are progressively becoming available to manage severe bleeding or urgent procedures in patients on DOACs, accurate laboratory tests have become the standard to guide their administration and their actions need to be well understood by clinicians. This review aims to provide a systematic approach to managing patients on DOACs, based on recent updates of various perioperative guidance, and highlighting the advantages and limits of recommendations based on pharmacokinetic properties and laboratory tests., SCOPUS: re.j, info:eu-repo/semantics/published more...

Introduction Right ventricular (RV) diastolic dysfunction is known to be associated with increased mortality in heart failure or cardiac surgical patients (pts). However, after lung transplantation (LTx), the impact of early RV diastolic dysfunction on 1-year survival, in a population without pulmonary hypertension, is not well documented. Methods We routinely perform a comprehensive transoesophageal echocardiography (TOE) after ICU admission of LTx patients (pts) to check the pulmonary veins’ patency. After exclusion of pts transplanted for pulmonary hypertension and of pts under ECMO, we retrospectively reviewed the diastolic RV parameters acquired during this TOE. At that time, all pts were mechanically ventilated. RV diastolic function was explored by tricuspid peak early and late velocities (E and A waves) (pulsed-wave Doppler (PW) through the tricuspid valve), early diastolic peak velocity (Ea) of the lateral tricuspid annulus (PW-TDI), hepatic venous flow (HVF) pattern (PW Doppler), and characterized as normal or abnormal according to the algorithm validated by Shi et al. One-year survival status was recorded. Continuous variables are presented as median [interquartile range] and analysed with Mann-Whitney U test. Dichotomous variables are presented as numbers (%) and analysed with Chi-Squared test. Results From May 2008 to March 2018, RV diastolic data were available in 69 pts. Indications for LTx were COPD in 51 pts (73.9%), fibrosis in 12 (17.4%), bronchiectasis in 1 pt (1.5%) and other indications in 5 (7.2%). RV diastolic function was categorized as abnormal in 47pts. One-year survival rate was 72.3% (34/47) in the group with early RV diastolic dysfunction and 95.4% (1/22) in the group with normal RV diastolic function (P = 0.027). Discussion Based on these retrospective TOE data in this single-center experience, occurrence of early RV diastolic dysfunction after LTx seems to be associated with impaired 1-year survival. Further prospective data are needed to confirm these preliminary observations. more...

Objectives PIANO (Paediatric study of Intelence As an NNRTI Option; TMC125-C213; NCT00665847) assessed the safety/tolerability, antiviral activity and pharmacokinetics of etravirine plus an optimized background regimen (OBR) in treatment-experienced, HIV-1-infected children (≥ 6 to 95% adherent by questionnaire and 39% by pill count. Forty-one patients experienced virological failure (VF; time-to-loss-of-virological-response non-VF-censored algorithm) (29 nonresponders; 12 rebounders). Of 30 patients with VF with paired baseline/endpoint genotypes, 18 (60%) developed nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations, most commonly Y181C. Mean etravirine area under the plasma concentration–time curve over 12 h (AUC0–12h; 5216 ng h/mL) and C0h (346 ng/mL) were comparable to adult target values. Conclusions Results with etravirine 5.2 mg/kg bid (with OBR) in this treatment-experienced paediatric population and etravirine 200 mg bid in treatment-experienced adults were comparable. Etravirine is an NNRTI option for treatment-experienced paediatric patients. more...

Objectif : Chez les patients severement denutris, un support nutritionnel preoperatoire permet de reduire l’impact pejoratif de la denutrition sur l’evolution postoperatoire. Un pre-requis indispensable est d’identifier cette denutrition. Nous avons voulu savoir si la consultation pre-anesthesique (non obligatoire en Belgique) etait un outil permettant d’atteindre ces objectifs de depistage preoperatoire chez des patients operes d’une chirurgie abdominale. Methode : Notre methode de travail s’est articulee en trois etapes. Apres avoir determine notre situation de depart, nous sommes intervenus en inserant le Nutritionnal risk screening (NRS) 2002 dans notre protocole de consultation informatise et en creant une procedure permettant de coupler notre consultation a celle de dietetique le meme jour. Nous avons ensuite analyse l’efficacite de nos interventions. Resultats : Nous avons recu 87,8 % des patients operes electivement d’une chirurgie abdominale a la consultation pre-anesthesique. Grâce a l’informatisation du NRS 2002, notre depistage nutritionnel est passe de 60,8 % a 86,1 %. Tout patient a risque de denutrition a ete refere le jour meme au service de dietetique pour une evaluation nutritionnelle et un support nutritionnel si necessaire. Cette procedure a reduit au maximum les retours des patients a l’hopital. Le delai moyen de 13 a 15 jours entre la consultation pre-anesthesique et la chirurgie etait suffisant pour mettre en place un support nutritionnel preoperatoire. Conclusion : La consultation pre-anesthesique est ainsi devenue un outil de depistage pour la prise en charge nutritionnelle preoperatoire. more...

The tolerability and immunogenicity of the hepatitis C virus E1 protein as a candidate vaccine was examined in a Phase I, single-arm study. Twenty healthy male volunteers were injected in the deltoid muscle at weeks 0, 3 and 6 with 20 μg recombinant E1 adsorbed on alum. A fourth (booster) dose was administered to 19 subjects at week 26. The candidate therapeutic vaccine was well tolerated. Three vaccine doses induced a clear humoral anti-E1 response that was boosted by a fourth dose. A strong, specific cellular immune response towards E1 was elicited in all vaccine recipients, which included a clear Th1 type response in all but one of the subjects. more...

Rigid bronchoscopy under general anesthesia enables performing diagnostic and/or therapeutic procedures in the tracheobronchial tree. This technique is characterized by specific technical problems, insofar as the anesthesiologist and the operators share the same space, namely the airway. Several potential complications (hemorrhage inside the airway, threat to ventilation ...) may arise. These challenges render the ability to use the variable available techniques essential, as well as knowledge of the complications they could entail, and the ability to rapidly solve them. General anesthesia is usually total intravenous anesthesia, using short acting agents. Ventilation can be spontaneous, but more often insured using high-frequency jet ventilation. The hospital infrastructure and staff must have the expertise to perform this particular procedure, in order to limit the complication rate. more...

The development of recombinant techniques for rapid cloning, expression, and characterization of cDNAs encoding antibody (Ab) subunits has revolutionized the field of antibody engineering. By fusion to heterologous protein domains, chain shuffling, or inclusion of self-assembly motifs, novel molecules such as bispecific Abs can be generated that possess the subset of functional properties designed to fit the intended application. We describe the engineering of Ab fragments produced in bacteria for blocking the CD28-CD80/CD86 costimulatory interaction in order to induce tolerance against transplanted organs. We designed single-chain Fv antibodies, monospecific and bispecific diabodies, and a bispecific tetravalent antibody (BiTAb) molecule directed against the CD80 and/or CD86 costimulatory molecules. These recombinant Ab molecules were expressed in Escherichia coli, followed by purification and evaluation for specific interaction with their respective antigen in an enzyme-linked immunosorbent assay (ELISA). A specific sandwich ELISA confirmed the bispecificity of the bispecific diabodies and the BiTAb. more...

PIANO (Paediatric study of Intelence As an NNRTI Option; TMC125-C213; NCT00665847) assessed the safety/tolerability, antiviral activity and pharmacokinetics of etravirine plus an optimized background regimen (OBR) in treatment-experienced, HIV-1-infected children (≥ 6 to 12 years) and adolescents (≥ 12 to 18 years) over 48 weeks.In a phase II, open-label, single-arm study, 101 treatment-experienced patients (41 children; 60 adolescents) with screening viral load (VL) ≥ 500 HIV-1 RNA copies/mL received etravirine 5.2 mg/kg (maximum dose 200 mg) twice a day (bid) plus OBR.Sixty-seven per cent of patients had previously used efavirenz or nevirapine. At week 48, the most common treatment-related grade ≥ 2 adverse event (AE) was rash (13%); 12% experienced grade 3 AEs. Only two grade 4 AEs occurred (both thrombocytopaenia, not etravirine related). At week 48, 56% of patients (68% children; 48% adolescents) achieved a virological response (VL50 copies/mL; intent-to-treat, noncompleter=failure). Factors predictive of response were adherence 95%, male sex, low baseline etravirine weighted genotypic score and high etravirine trough concentration (C0h ). Seventy-six patients (75%) completed the trial; most discontinuations occurred because of protocol noncompliance or AEs (8% each). Sixty-five per cent of patients were 95% adherent by questionnaire and 39% by pill count. Forty-one patients experienced virological failure (VF; time-to-loss-of-virological-response non-VF-censored algorithm) (29 nonresponders; 12 rebounders). Of 30 patients with VF with paired baseline/endpoint genotypes, 18 (60%) developed nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations, most commonly Y181C. Mean etravirine area under the plasma concentration-time curve over 12 h (AUC0-12h ; 5216 ng h/mL) and C0h (346 ng/mL) were comparable to adult target values.Results with etravirine 5.2 mg/kg bid (with OBR) in this treatment-experienced paediatric population and etravirine 200 mg bid in treatment-experienced adults were comparable. Etravirine is an NNRTI option for treatment-experienced paediatric patients. more...

FT-IR and FT Raman spectra of eight oligosaccharides have been recorded in the crystalline state. The FT-Raman measurements have been done in the 1500-100 cm−1 range and the FT-IR ones between 1500 and 600 cm−1. Five of these oligosaccharides are oligomers of amylose and four are oligomers of cellulose. The two series present the same monosaccharide composition which is glucose the difference between them being that maltose (the disaccharide analog of amylose) and cellobiose (the disaccharide analog of cellulose) present the different configurations of the glycosidic linkages, α 1–4 and β 1–4 respectively. Features were revealed that appear to be characteristic of details of the stereochemistry and bands associated with the glycosidic linkages were studied. more...

Report a case of a patient, who benefitted from the I-gel, during an elective urological surgery and who presented severe laryngeal hemorrhage at the time of its withdrawal.A 71-year-old male patient had been admitted in the operating room for the insertion of a ureteral stent. He had a history of usual interstitial pneumonia (UIP) requiring corticosteroids and oxygen therapy and a severe obstructive sleep apnea syndrome treated with nasal continuous positive airway pressure (NCPAP). After intravenous induction of anesthesia, a size 5 I-gel (Intersurgical, Wokhingam, UK) was easily inserted in the first attempt. Anesthesia was maintained with sevoflurane. As soon as the procedure ended, the I-Gel was removed. After two minutes, the patient presented a respiratory distress and started spitting significant quantity of blood. Oropharyngeal fiberscopy was performed in emergency and highlighted active bleeding of the left aryepiglottic fold. Hemostasis was obtained by local compression. The patient was transferred to the intensive care unit. He was extubated the following day without complications. No additional procedure was necessary to stop the bleeding.Authors reported the first severe complication associated with the use of size 5 I-gel. Additional studies have to be carried out to specify the advantages and risks associated with the use of this recent material. more...

BACKGROUND Dabigatran etexilate has received its market authorization for various indications worldwide. It was developed to be used in fixed dose regimens without the need of regular monitoring. However, the perioperative management of dabigatran could require an assessment of the drug plasma levels to ensure a safe use of the product, especially in absence of specific antidotes. The EMA stated that dabigatran concentrations under 48 ng/mL should be reached before invasive intervention. The GIHP put the threshold at 30 ng/mL. Therefore, a specific laboratory assay, accurate in the low concentration range, easily available and performable 24h/7 is requested but, until now, all coagulation tests dedicated to the measurement of plasma dabigatran concentrations showed a lower limit of quantitation from 30 to 50 ng/mL. This limits their perioperative utility and the thrombin time (TT) is currently presented as an alternative due to its very high sensitivity to dabigatran. This interesting approach has limitations because TT is affected by several analytical and biological variables that could lead to misinterpretations and expose the patient at riskier hemostatic conditions. In this study, we propose to investigate the performance of two coagulation tests (the Hemoclot Thrombin Inhibitors LOW (HTI LOW) (Hyphen BioMed) and the Ecarin Chromogenic Assay II (ECA-II) (Diagnostica Stago)) specifically developed to measure low plasma dabigatran concentrations and to compare their results with a reference LC-MS/MS. We also assessed the performance of the standard procedure of HTI and TT. MATERIALS AND METHODS Thirty-three plasma samples of patients treated with dabigatran etexilate for stroke prevention in non-valvular atrial fibrillation, were included in the study. Plasma samples were taken randomly and included after a first screening using the HTI to select plasma concentrations For HTI, tested plasma was diluted 1:8 in Owren-Koller® buffer. Fifty μl of tested plasma were mixed with 100 μl of normal pooled plasma and were incubated during 240 sec. One hundred μl of highly purified human thrombin pre-incubated at 37°C was then added to start the reaction. For HTI LOW, the dilution of the sample was reduced to 1:2 and specific calibrators at lower concentrations were used. For ECA-II, tested plasma was diluted 1:5 in Owren-Koller® buffer. Fifty μl of tested plasma were mixed with 140 μl of prothrombin and then 70 µl of chromogenic substrate were added and incubated during 240 sec. Seventy μl of ecarin pre-incubated at 37°C were then added to start the reaction. Thrombin time was performed using Thrombin Time® reagent 1.5NIH (Diagnostica Stago) and the limit of measurement was extended to 300 sec. All of these procedures were performed on a STA-R Evolution® coagulometer (Diagnostica Stago). RESULTS AND DISCUSSION The plasma concentrations ranged from 0 to 200 ng/mL as provided by LC-MS/MS measurements. Among these samples, 17 were between 0 and 50 ng/mL. Linear correlation, Spearman correlation and Bland-Altman analyses versus LC-MS/MS are provided in Figure 1, for assays that express results in ng/mL, i.e. HTI, HTI LOW and ECA-II. For TT, the relation is described by linear correlation. Our results show that HTI LOW performs better than HTI and ECA-II on the whole concentration range providing closer correlation and a lower systematic difference compared to LC-MS/MS. For concentrations below 50 ng/mL HTI LOW and ECA-II reveal similar systematic difference with higher 95% CI for ECA-II and perform better than HTI to estimate plasma concentrations. Thrombin time is less useful than dedicated assays to provide an estimation of the pharmacodynamics of dabigatran. For concentrations above 50 ng/mL it often exceeds the limit of measurement, i.e. 120 sec as defined by the manufacturer, and is influenced by the level of fibrinogen. However, it gives an acceptable correlation for concentration below 50 ng/mL. This may help the biologist to choose which test to use to avoid unnecessary costs and ensure the use of the more accurate dedicated assay to estimate the plasma concentrations. When TT is lower than 120 sec, HTI LOW or ECA-II should be preferred to HTI. CONCLUSION We recommend the use of specific coagulation assays to assess the dabigatran plasma concentrations before invasive procedure. Thrombin time may guide the biologist on the dedicated coagulation test to perform if he uses the HTI platform. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare. more...

The structural characterization of five oligomers from the carrageenan family and three oligomers of agarose, has been the aim of the present work. The compounds were chosen so as to study principally the effect of the substitution by a sulphate group on the two main vibrations due to the two glycosidic linkages (the (alpha) 1,3 and the (beta) -1,4). The C-O stretching modes of the two quoted glycosidic linkages have previously been identified in the spectral region between 1120 and 1160 cm -1 , whereas the C-O-C bending mode has been demonstrated to occur at about 730 cm -1 . more...

Direct oral anticoagulants (DOAC) are used in several indications for the prevention and treatment of thrombotic events. As highlighted by data from clinical trials and case studies, all DOAC carry the risk of bleeding despite careful selection and patient management. Previous publications have demonstrated the limited knowledge of many physicians concerning the indications for, and correct management of, these anticoagulants. Health institutions should develop risk minimisation strategies and educational materials to prevent major adverse events related to DOAC administration. Major bleeding events are reported in clinical practice and specific antidotes are emerging from Phase III trials. Some antidotes are licensed but their high cost might limit routine use. We therefore illustrate approaches and tools that can help physicians prescribe DOAC appropriately. We focus on screening for modifiable bleeding risk factors and adapting doses according to the individual benefit-risk profile. We also provide recommendations on managing a missed dose, switching, bridging, and resumption. more...

MAIN RESULTS: The pathophysiology of trauma-induced coagulopathy (TIC) is complex and includes the classic "lethal triad" (i.e., haemodilution, acidosis, hypothermia) but may also include activation of protein C, endothelial and platelet dysfunction, and fibrinogen depletion. The time between trauma and treatment of the resultant massive bleeding should be as short as possible using techniques for rapid control of bleeding and avoiding aggravating factors (hypothermia, metabolic acidosis and hypocalcaemia). If given within three hours of injury, tranexamic acid (TXA) reduces all causes of mortality in trauma patients and reduces transfusion requirements. In a bleeding patient, crystalloids are preferred to colloids and the ratio of fresh frozen plasma to packed red blood cells should be at least 1:2. Damage control surgery (DCS) should be considered for patients who present with, or are at risk for developing, the "lethal triad", multiple life-threatening injuries or shock, and in mass casualty situations. DCS can also aid in the evaluation of the extent of tissue injuries and the control of haemorrhage and infection. Finally, there is currently no evidence of the added value of laboratory assays in the management of TIC.Facing coagulation disorders after acute trauma.PROBLEMS/OBJECTIVES: Trauma is the leading cause of mortality for persons between one and 44 years of age, essentially due to bleeding complications.METHODOLOGY: We screened the PubMed, Scopus and Cochrane Library databases, using specific keywords. Only publications in English were considered.CONCLUSIONS: TIC appears quickly after trauma and should be anticipated and detected as soon as possible. TXA plays a central role in the management of such patients. Each institution should establish a local algorithm for the management of bleeding patients. more...

New treatments are needed for chronic hepatitis C patients in whom viral clearance cannot be achieved. Thirty-five chronic hepatitis C patients (genotype 1) were randomized to receive 20 mug of recombinant HCV E1 (E1) (n = 26) or placebo (n = 9) intramuscularly at weeks 0, 4, 8, 12, and 24. Thirty-four then received open-label E1 vaccine at weeks 50, 53, 56, 59, 62, and 65. Twenty-four patients (12 men, 12 women; mean age, 52 y; 18 interferon-based treatment failures; mean baseline alanine aminotransferase [ALT] level, 118 IU/L) underwent a biopsy before and after 2 courses of E1, 17 months later. Liver histology was scored by 2 blinded pathologists according to the Ishak and Metavir systems. Postinjection reactions were similar to placebo (alum only). Nine of 24 patients (38%) had improvement of 2 points or more, 10 (41%) remained stable, and 5 (21%) showed worsening in total Ishak score. Nine patients (38%) improved both on Ishak and Metavir fibrosis scores. Plasma HCV-RNA levels remained unchanged, whereas ALT levels showed a trend toward a decrease during treatment. All but 3 patients developed a significant de novo E1-specific T-cell response. The increase in anti-E1 antibody levels correlated with the decrease in total Ishak score and with the relative decreases in both Ishak fibrosis score and ALT level (all P < or =.01). In conclusion, E1 therapeutic vaccination is well tolerated and the observed effects warrant further study. more...