Definitions of major bleeding for predicting mortality in critically ill adult patients who survived 24 hours while supported with peripheral veno-arterial extracorporeal membrane oxygenation for cardiogenic shock: a comparative historical cohort study.

PURPOSE: The severity of bleeding events is heterogeneously defined during peripheral veno-arterial extracorporeal membrane oxygenation (pVA-ECMO). We studied three bleeding definitions in pVA-ECMO: the Extracorporeal Life Support Organization (ELSO)-serious bleeding, the Bleeding Academic Research Consortium (BARC), and the universal definition of postoperative bleeding (UPDB) classifications. METHODS: We included consecutive adult patients supported by pVA-ECMO for refractory cardiogenic shock admitted to Lille academic hospitals between January 2013 and December 2019. We assessed the association of bleeding definitions with the primary endpoint of 28-day all-cause mortality with the use of multivariate models accounting for time-dependent and competing variables. We compared models' performances using the Harrell's C-Index and the Akaike information criteria. RESULTS: Twenty-eight-day mortality occurred in 128/308 (42%) 308 patients. The ELSO-serious bleeding (hazard ratio [HR], 1.67; 95% confidence interval [CI], 1.09 to 2.56) and BARC ≥ type 2 (HR, 1.55; 95% CI, 1.01 to 2.37) were associated with 28-day mortality (Harrell's C-index, 0.69; 95% CI, 0.63 to 0.74 for both). Predictors of ELSO-serious bleeding were postcardiotomy, body mass index, baseline platelets count, fibrinogen, and hemoglobin levels. CONCLUSION: Extracorporeal Life Support Organization-serious bleeding and BARC ≥ type 2 are relevant definitions of major bleeding regarding their association with mortality in critically ill patients who survived the first 24 hr while supported with pVA-ECMO for cardiogenic shock. STUDY REGISTRATION: CERAR (IRB 00010254-2022-050, Paris, France); first submitted on 18 April 2022.

RéSUMé: OBJECTIF: La gravité des événements hémorragiques est définie de manière hétérogène pendant une oxygénation par membrane extracorporelle veino-artérielle périphérique (ECMO-VA périphérique). Nous avons étudié trois définitions du saignement sous ECMO-VA périphérique : les classifications des saignements graves selon l'Extracorporeal Life Support Organization (ELSO), celles du Bleeding Academic Research Consortium (BARC) et la définition universelle du saignement postopératoire (UPDB). MéTHODE: Nous avons inclus des patient·es adultes pris·es en charge de manière consécutive par ECMO-VA périphérique à la suite d'un choc cardiogénique réfractaire et admis·es dans les centres hospitaliers universitaires de Lille entre janvier 2013 et décembre 2019. Nous avons évalué l'association des définitions du saignement avec le critère d'évaluation principal de mortalité toutes causes confondues à 28 jours à l'aide de modèles multivariés tenant compte des variables dépendantes du temps et concurrentes. Nous avons comparé les performances des modèles à l'aide de l'indice C de Harrell et du critère d'information d'Akaike. RéSULTATS: La mortalité à 28 jours est survenue chez 128/308 (42 %) patient·es. Le saignement grave selon l'ELSO (rapport de risque [RR], 1,67; intervalle de confiance [IC] à 95 %, 1,09 à 2,56) et une classification BARC ≥ type 2 (RR, 1,55; IC 95 %, 1,01 à 2,37) étaient associés à une mortalité à 28 jours (indice C de Harrell, 0,69; IC 95 %, 0,63 à 0,74 pour les deux). Les prédicteurs d'hémorragie grave selon l'ELSO étaient la postcardiotomie, l'indice de masse corporelle, la numération plaquettaire initiale, le taux de fibrinogène et les taux d'hémoglobine. CONCLUSION: Les définitions du saignement grave de l'Extracorporeal Life Support Organization et une classification BARC ≥ type 2 sont des définitions pertinentes des saignements majeurs en ce qui touche à leur association avec la mortalité chez les personnes gravement malades qui ont survécu aux premières 24 heures alors qu'elles étaient prises en charge par ECMO-VA périphérique à la suite d'un choc cardiogénique. ENREGISTREMENT DE L'éTUDE: CERAR (IRB 00010254-2022-050, Paris, France); soumis pour la première fois le 18 avril 2022.

Cerebral Microbleeds During Transcatheter Aortic Valve Replacement: A Prospective Magnetic Resonance Imaging Cohort.

BACKGROUND: Cerebral microbleeds (CMBs) have been observed in healthy elderly people undergoing systematic brain magnetic resonance imaging. The potential role of acute triggers on the appearance of CMBs remains unknown. We aimed to describe the incidence of new CMBs after transcatheter aortic valve replacement (TAVR) and to identify clinical and procedural factors associated with new CMBs including hemostatic measures and anticoagulation management. METHODS: We evaluated a prospective cohort of patients with symptomatic aortic stenosis referred for TAVR for CMBs (METHYSTROKE [Identification of Epigenetic Risk Factors for Ischemic Complication During the TAVR Procedure in the Elderly]). Standardized neurologic assessment, brain magnetic resonance imaging, and analysis of hemostatic measures including von Willebrand factor were performed before and after TAVR. Numbers and location of microbleeds on preprocedural magnetic resonance imaging and of new microbleeds on postprocedural magnetic resonance imaging were reported by 2 independent neuroradiologists blinded to clinical data. Measures associated with new microbleeds and postprocedural outcome including neurologic functional outcome at 6 months were also examined. RESULTS: A total of 84 patients (47% men, 80.9±5.7 years of age) were included. On preprocedural magnetic resonance imaging, 22 patients (26% [95% CI, 17%-37%]) had at least 1 microbleed. After TAVR, new microbleeds were observed in 19 (23% [95% CI, 14%-33%]) patients. The occurrence of new microbleeds was independent of the presence of microbleeds at baseline and of diffusion-weighted imaging hypersignals. In univariable analysis, a previous history of bleeding (P=0.01), a higher total dose of heparin (P=0.02), a prolonged procedure (P=0.03), absence of protamine reversion (P=0.04), higher final activated partial thromboplastin time (P=0.05), lower final von Willebrand factor high-molecular-weight:multimer ratio (P=0.007), and lower final closure time with adenosine-diphosphate (P=0.02) were associated with the occurrence of new postprocedural microbleeds. In multivariable analysis, a prolonged procedure (odds ratio, 1.22 [95% CI, 1.03-1.73] for every 5 minutes of fluoroscopy time; P=0.02) and postprocedural acquired von Willebrand factor defect (odds ratio, 1.42 [95% CI, 1.08-1.89] for every lower 0.1 unit of high-molecular-weight:multimer ratio; P=0.004) were independently associated with the occurrence of new postprocedural microbleeds. New CMBs were not associated with changes in neurologic functional outcome or quality of life at 6 months. CONCLUSIONS: One out of 4 patients undergoing TAVR has CMBs before the procedure and 1 out of 4 patients develops new CMBs. Procedural or antithrombotic management and persistence of acquired von Willebrand factor defect were associated with the occurrence of new CMBs. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02972008.

Rational Preparation of Well-Defined Multinuclear Iridium-Aluminum Polyhydride Clusters and Comparative Reactivity.

We report an original alkane elimination approach, entailing the protonolysis of triisobutylaluminum by the acidic hydrides from Cp*IrH4. This strategy allows access to a series of well-defined tri- and tetranuclear iridium aluminum polyhydride clusters, depending on the stoichiometry: [Cp*IrH3Al(iBu)2]2 (1), [Cp*IrH2Al(iBu)]2 (2), [(Cp*IrH3)2Al(iBu)] (3), and [(Cp*IrH3)3Al] (4). Contrary to most transition-metal aluminohydride complexes, which can be considered as [AlHx+3]x- aluminates and LnM+ moieties, the situation here is reversed: These complexes have original structures that are best described as [Cp*IrHx]n- iridate units surrounding cationic Al(III) fragments. This is corroborated by reactivity studies, which show that the hydrides are always retained at the iridium sites and that the [Cp*IrH3]- moieties are labile and can be transmetalated to yield potassium ([KIrCp*H3], 8) or silver (([AgIrCp*H3]n, 10) derivatives of potential synthetic interest. DFT calculations show that the bonding situation can vary in these systems, from 3-center 2-electron hydride-bridged Lewis adducts of the form Ir-H⇀Al to direct polarized metal-metal interaction from donation of d-electrons of Ir to the Al metal, and both types of interactions take place to some extent in each of these clusters.

Early hyperoxia and 28-day mortality in patients on venoarterial ECMO support for refractory cardiogenic shock: a bicenter retrospective propensity score-weighted analysis.

BACKGROUND: The mortality rate for a patient with a refractory cardiogenic shock on venoarterial (VA) extracorporeal membrane oxygenation (ECMO) remains high, and hyperoxia might worsen this prognosis. The objective of the present study was to evaluate the association between hyperoxia and 28-day mortality in this setting. METHODS: We conducted a retrospective bicenter study in two French academic centers. The study population comprised adult patients admitted for refractory cardiogenic shock. The following arterial partial pressure of oxygen (PaO2) variables were recorded for 48 h following admission: the absolute peak PaO2 (the single highest value measured during the 48 h), the mean daily peak PaO2 (the mean of each day's peak values), the overall mean PaO2 (the mean of all values over 48 h), and the severity of hyperoxia (mild: PaO2 < 200 mmHg, moderate: PaO2 = 200-299 mmHg, severe: PaO2 ≥ 300 mmHg). The main outcome was the 28-day all-cause mortality. Inverse probability weighting (IPW) derived from propensity scores was used to reduce imbalances in baseline characteristics. RESULTS: From January 2013 to January 2020, 430 patients were included and assessed. The 28-day mortality rate was 43%. The mean daily peak, absolute peak, and overall mean PaO2 values were significantly higher in non-survivors than in survivors. In a multivariate logistic regression analysis, the mean daily peak PaO2, absolute peak PaO2, and overall mean PaO2 were independent predictors of 28-day mortality (adjusted odds ratio [95% confidence interval per 10 mmHg increment: 2.65 [1.79-6.07], 2.36 [1.67-4.82], and 2.85 [1.12-7.37], respectively). After IPW, high level of oxygen remained significantly associated with 28-day mortality (OR = 1.41 [1.01-2.08]; P = 0.041). CONCLUSIONS: High oxygen levels were associated with 28-day mortality in patients on VA-ECMO support for refractory cardiogenic shock. Our results confirm the need for large randomized controlled trials on this topic.

Balloon-Expandable Versus Self-Expanding Transcatheter Aortic Valve Replacement: A Propensity-Matched Comparison From the FRANCE-TAVI Registry.

BACKGROUND: No randomized study powered to compare balloon expandable (BE) with self expanding (SE) transcatheter heart valves (THVs) on individual end points after transcatheter aortic valve replacement has been conducted to date. METHODS: From January 2013 to December 2015, the FRANCE-TAVI nationwide registry (Registry of Aortic Valve Bioprostheses Established by Catheter) included 12 141 patients undergoing BE-THV (Edwards, n=8038) or SE-THV (Medtronic, n=4103) for treatment of native aortic stenosis. Long term mortality status was available in all patients (median 20 months; interquartile range, 14 to 30). Patients treated with BE-THV (n=3910) were successfully matched 1:1 with 3910 patients treated with SE-THV by using propensity score (25 clinical, anatomical, and procedural variables) and by date of the procedure (within 3 months). The first coprimary outcome was ≥ moderate occurrence of paravalvular regurgitation or in-hospital mortality, or both. The second coprimary outcome was 2-year all-cause mortality. RESULTS: In propensity-matched analyses, the incidence of the first coprimary outcome was higher with SE-THV (19.8%) compared with BE-THV (11.9%; relative risk, 1.68 [95% CI, 1.46-1.91]; P<0.0001). Each component of the outcome was also higher in patients receiving SE-THV: ≥ moderate paravalvular regurgitation (15.5% versus 8.3%; relative risk, 1.90 [95% CI, 1.63-2.22]; P<0.0001) and in hospital mortality (5.6% versus 4.2%; relative risk, 1.34 [95% CI, 1.07-1.66]; P=0.01). During follow up, all cause mortality occurred in 899 patients treated with SE-THV (2-year mortality, 29.8%) and in 801 patients treated with BE-THV (2-year mortality, 26.6%; hazard ratio, 1.17 [95% CI, 1.06-1.29]; P=0.003). Similar results were found using inverse probability of treatment weighting using propensity score analysis. CONCLUSION: The present study suggests that use of SE-THV was associated with a higher risk of paravalvular regurgitation and higher in-hospital and 2-year mortality compared with use of BE-THV. These data strongly support the need for a randomized trial sufficiently powered to compare the latest generation of SE-THV and BE-THV. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov. Unique identifier: NCT01777828.

Mid-Term Survival and Risk Factors Associated With Myocardial Injury After Fenestrated and/or Branched Endovascular Aortic Aneurysm Repair.

OBJECTIVE: Myocardial injury after non-cardiac surgery (MINS) is an independent predictor of post-operative mortality in non-cardiac surgery patients and may increase health costs. Few data are available for MINS in vascular surgery patients, in general, and those undergoing fenestrated/branched endovascular aortic repairs (F/BEVAR), in particular. The incidence of MINS after F/BEVAR, the associated risk factors, and prognosis have not been determined. The aim of the present study was to help fill these knowledge gaps. METHODS: A single centre, retrospective study was carried out at a high volume F/BEVAR centre in a university hospital. Adult patients who underwent F/BEVAR between October 2010 and December 2018 were included. A high sensitivity troponin T (HsTnT) assay was performed daily in the first few post-operative days. MINS was defined as a HsTnT level ≥ 14 ng/L (MINS14) or ≥ 20 ng/L (MINS20). After assessment of the incidence of MINS, survival up to two years was estimated in a Kaplan-Meier analysis and the groups were compared according to MINS status. A secondary aim was to identify predictors of MINS. RESULTS: Of the 387 included patients, 240 (62.0%) had MINS14 and 166 (42.9%) had MINS20. In multivariable Cox models, both conditions were significantly associated with poor two year survival (MINS14: adjusted hazard ratio [aHR] 2.15, 95% confidence interval [CI] 1.10 - 4.19; MINS20: aHR 2.43, 95% CI 1.36 - 4.34). In a multivariable logistic regression, age, revised cardiac risk index, duration of surgery, pre-operative estimated glomerular filtration rate (eGFR), and haemoglobin level were independent predictors of MINS. CONCLUSION: After F/BEVAR surgery, the incidence of MINS was particularly high, regardless of the definition considered (MINS14 or MINS20). MINS was significantly associated with poor two year survival. The modifiable predictors identified were duration of surgery, eGFR, and haemoglobin level.

Von Willebrand Factor Multimers during Transcatheter Aortic-Valve Replacement.

BACKGROUND: Postprocedural aortic regurgitation occurs in 10 to 20% of patients undergoing transcatheter aortic-valve replacement (TAVR) for aortic stenosis. We hypothesized that assessment of defects in high-molecular-weight (HMW) multimers of von Willebrand factor or point-of-care assessment of hemostasis could be used to monitor aortic regurgitation during TAVR. METHODS: We enrolled 183 patients undergoing TAVR. Patients with aortic regurgitation after the initial implantation, as identified by means of transesophageal echocardiography, underwent additional balloon dilation to correct aortic regurgitation. HMW multimers and the closure time with adenosine diphosphate (CT-ADP), a point-of-care measure of hemostasis, were assessed at baseline and 5 minutes after each step of the procedure. Mortality was evaluated at 1 year. A second cohort (201 patients) was studied to validate the use of CT-ADP in order to identify patients with aortic regurgitation. RESULTS: After the initial implantation, HMW multimers normalized in patients without aortic regurgitation (137 patients). Among the 46 patients with aortic regurgitation, normalization occurred in 20 patients in whom additional balloon dilation was successful but did not occur in the 26 patients with persistent aortic regurgitation. A similar sequence of changes was observed with CT-ADP. A CT-ADP value of more than 180 seconds had sensitivity, specificity, and negative predictive value of 92.3%, 92.4%, and 98.6%, respectively, for aortic regurgitation, with similar results in the validation cohort. Multivariable analyses showed that the values for HMW multimers and CT-ADP at the end of TAVR were each associated with mortality at 1 year. CONCLUSIONS: The presence of HMW-multimer defects and a high value for a point-of-care hemostatic test, the CT-ADP, were each predictive of the presence of aortic regurgitation after TAVR and were associated with higher mortality 1 year after the procedure. (Funded by Lille 2 University and others; ClinicalTrials.gov number, NCT02628509.).

Central venous-to-arterial PCO2 difference, arteriovenous oxygen content and outcome after adult cardiac surgery with cardiopulmonary bypass: A prospective observational study.

BACKGROUND: Rapid identification and treatment of tissue hypoxia reaching anaerobiosis (dysoxia) may reduce organ failure and the occurrence of major postoperative complications (MPC) after cardiac surgery. The predictive ability of PCO2-based dysoxia biomarkers, central venous-to-arterial PCO2 difference (ΔPCO2) and ΔPCO2 to arteriovenous oxygen content difference ratio, is poorly studied in this setting. OBJECTIVES: We evaluated the ability of PCO2-based tissue dysoxia biomarkers, blood lactate concentration and central venous oxygen saturation measured 2 h after admission to the ICU as predictors of MPC. DESIGN: A prospective, observational cohort study. SETTING: Single-centre, academic hospital cardiovascular ICU. PATIENTS: We included adult patients undergoing cardiac surgery with cardiopulmonary bypass and measured dysoxia biomarkers at ICU admission, and after 2, 6 and 24 h. MAIN OUTCOME MEASURES: The primary endpoint was MPC, a composite of cardiac and noncardiac MPC evaluated in the 48 h following surgery. After univariate analysis of MPC covariates including dysoxia biomarkers measured at 2 h, multivariate logistic regression analyses were performed to identify the association of these biomarkers with MPC for confounders. Areas under the receiver operating characteristic curves were determined for biomarkers which remained independently associated with MPC. RESULTS: MPC occurred in 56.5% of the 308 patients analysed. ΔPCO2, blood lactate concentration and central venous oxygen saturation measured at 2 h, but not ΔPCO2 to arteriovenous oxygen content difference ratio, were significantly associated with MPC. However, only ΔPCO2 was independently associated with MPC after multivariate analysis. The areas under the receiver operating characteristic curves of ΔPCO2 measured at 2 h for MPC prediction was 0.64 (95% CI 0.57 to 0.70, P < 0.001). CONCLUSION: After cardiac surgery with cardiopulmonary bypass, ΔPCO2 measured 2 h after ICU admission was the only dysoxia biomarker independently associated with MPC, but with limited performance. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03107572.

Effect of Levosimendan on Low Cardiac Output Syndrome in Patients With Low Ejection Fraction Undergoing Coronary Artery Bypass Grafting With Cardiopulmonary Bypass: The LICORN Randomized Clinical Trial.

Importance: Low cardiac output syndrome after cardiac surgery is associated with high morbidity and mortality in patients with impaired left ventricular function. Objective: To assess the ability of preoperative levosimendan to prevent postoperative low cardiac output syndrome. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled trial conducted in 13 French cardiac surgical centers. Patients with a left ventricular ejection fraction less than or equal to 40% and scheduled for isolated or combined coronary artery bypass grafting with cardiopulmonary bypass were enrolled from June 2013 until May 2015 and followed during 6 months (last follow-up, November 30, 2015). Interventions: Patients were assigned to a 24-hour infusion of levosimendan 0.1 µg/kg/min (n = 167) or placebo (n = 168) initiated after anesthetic induction. Main Outcomes and Measures: Composite end point reflecting low cardiac output syndrome with need for a catecholamine infusion 48 hours after study drug initiation, need for a left ventricular mechanical assist device or failure to wean from it at 96 hours after study drug initiation when the device was inserted preoperatively, or need for renal replacement therapy at any time postoperatively. It was hypothesized that levosimendan would reduce the incidence of this composite end point by 15% in comparison with placebo. Results: Among 336 randomized patients (mean age, 68 years; 16% women), 333 completed the trial. The primary end point occurred in 87 patients (52%) in the levosimendan group and 101 patients (61%) in the placebo group (absolute risk difference taking into account center effect, -7% [95% CI, -17% to 3%]; P = .15). Predefined subgroup analyses found no interaction with ejection fraction less than 30%, type of surgery, and preoperative use of ß-blockers, intra-aortic balloon pump, or catecholamines. The prevalence of hypotension (57% vs 48%), atrial fibrillation (50% vs 40%), and other adverse events did not significantly differ between levosimendan and placebo. Conclusions and Relevance: Among patients with low ejection fraction who were undergoing coronary artery bypass grafting with cardiopulmonary bypass, levosimendan compared with placebo did not result in a significant difference in the composite end point of prolonged catecholamine infusion, use of left ventricular mechanical assist device, or renal replacement therapy. These findings do not support the use of levosimendan for this indication. Trial Registration: EudraCT Number: 2012-000232-25; clinicaltrials.gov Identifier: NCT02184819.

Extracorporeal Life Support in Out-of-Hospital Refractory Cardiac Arrest.

Out-of-Hospital refractory Cardiac Arrest (OHrCA) has a mortality rate between 90 and 95%. Since 2009, French medical academic societies have recommended the use of extracorporeal life support (ECLS) for OHrCA. According to these guidelines, patients were eligible for ECLS support if vital signs were still present during cardiopulmonary resuscitation (CPR), or if cardiac arrest was secondary to intoxication or hypothermia (≤32°C). Otherwise, patients would receive ECLS if (i) no-flow duration was less than 5 min; (ii) time delays from CPR to ECLS start (low flow) were less than 100 min; and (iii) expiratory end tidal CO2 (ETCO2 ) was more than 10 mm Hg 20 min after initiating CPR. We have reported here our experience with ECLS in OHrCA according to the previous guidelines. We retrospectively analyzed mortality rates of patients supported with ECLS in case of OHrCA. From December 2009 to December 2013, 183 patients were assisted with ECLS, among which 32 cases were of OHrCA. Mean age for the OHrCA patients was 43.6 years. Over two-thirds were male (71.9%). Causes of OHrCA included intoxication, isolated hypothermia <32°C, acute coronary syndrome, pulmonary edema, and other cardiac pathology. Despite adherence to protocols, only two patients (6.2%) with hypothermia and acute myocardium ischemia, respectively, could be discharged from hospital after cardiac recovery. Causes of death were brain death and multiple organ failure. Despite ECLS support setting in accordance with French guidelines in case of refractory OHrCA, mortality rates remained high. French ECLS support recommendations for OHrCA due to presumed cardiac cause should be re-examined through new studies. Low flow duration should be improved by a shorter time of CPR before hospital transfer.

Central venous-to-arterial carbon dioxide difference as a prognostic tool in high-risk surgical patients.

INTRODUCTION: The purpose of this study was to evaluate the clinical relevance of high values of central venous-to-arterial carbon dioxide difference (PCO2 gap) in high-risk surgical patients admitted to a postoperative ICU. We hypothesized that PCO2 gap could serve as a useful tool to identify patients still requiring hemodynamic optimization at ICU admission. METHODS: One hundred and fifteen patients were included in this prospective single-center observational study during a 1-year period. High-risk surgical inclusion criteria were adapted from Schoemaker and colleagues. Demographic and biological data, PCO2 gap, central venous oxygen saturation, lactate level and postoperative complications were recorded for all patients at ICU admission, and 6 hours and 12 hours after admission. RESULTS: A total of 78 (68%) patients developed postoperative complications, of whom 54 (47%) developed organ failure. From admission to 12 hours after admission, there was a significant difference in mean PCO2 gap (8.7 ± 2.8 mmHg versus 5.1 ± 2.6 mmHg; P = 0.001) and median lactate values (1.54 (1.1-3.2) mmol/l versus 1.06 (0.8-1.8) mmol/l; P = 0.003) between patients who developed postoperative complications and those who did not. These differences were maximal at admission to the ICU. At ICU admission, the area under the receiver operating characteristic curve for occurrence of postoperative complications was 0.86 for the PCO2 gap compared to Sequential Organ Failure Assessment score (0.82), Simplified Acute Physiology Score II score (0.67), and lactate level (0.67). The threshold value for PCO2 gap was 5.8 mmHg. Multivariate analysis showed that only a high PCO2 gap and a high Sequential Organ Failure Assessment score were independently associated with the occurrence of postoperative complications. A high PCO2 gap (≥6 mmHg) was associated with more organ failure, an increase in duration of mechanical ventilation and length of hospital stay. CONCLUSION: A high PCO2 gap at admission in the postoperative ICU was significantly associated with increased postoperative complications in high-risk surgical patients. If the increase in PCO2 gap is secondary to tissue hypoperfusion then the PCO2 gap might be a useful tool complementary to central venous oxygen saturation as a therapeutic target.

Heparin Dosing Regimen Optimization in Veno-Arterial Extracorporeal Membrane Oxygenation: A Pharmacokinetic Analysis.

BACKGROUND: Unfractionated heparin is administered in patients undergoing veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Anticoagulation monitoring is recommended, with an anti-activated factor X (anti-Xa) targeting 0.3 to 0.7 IU/mL. Owing to heparin's heterogeneous pharmacokinetic properties, anti-Xa is unpredictable, generating a challenge in anticoagulation practices. The aim of this study was to build a pharmacokinetic model of heparin accounting for potential confounders, and derive an optimized dosing regimen for a given anti-Xa target. METHODS: Adult patients undergoing VA-ECMO were included between January 2020 and June 2021. Anticoagulation was managed with an initial 100 IU/kg heparin loading dose followed by a continuous infusion targeting 0.2 to 0.7 IU/mL anti-Xa. The data were split into model development and model validation cohorts. Statistical analysis was performed using a nonlinear mixed effects modeling population approach. Model-based simulations were performed to develop an optimized dosing regimen targeting the desired anti-Xa. RESULTS: A total of 74 patients were included, with 1703 anti-Xa observations. A single-compartment model best fitted the data. Interpatient variability for distribution volume was best explained by body weight, C-reactive protein and ECMO indication (post-cardiotomy shock or medical cardiogenic shock), and interpatient variability for elimination clearance was best explained by serum creatinine and C-reactive protein. Simulations using the optimized regimen according to these covariates showed accurate anti-Xa target attainment. CONCLUSION: In adult patients on VA-ECMO, heparin's effect increased with serum creatinine and medical indication, whereas it decreased with body weight and systemic inflammation. We propose an optimized dosing regimen accounting for key covariates, capable of accurately predicting a given anti-Xa target.

Chemical modification of edible sodium caseinate: A new grafting method of oleic acid. Characterization and thermal properties of the conjugate.

Sodium caseinate is a well-known amphiphilic protein derived from natural products currently used for the preparation of edible films. To improve some properties, especially to decrease the hydrophilicity and water solubility of the caseinate, the covalent grafting of a hydrophobic edible fatty acid, namely oleic acid, onto caseinate, appears to be a solution. We describe a new synthesis method for the chemical modification of sodium caseinate involving the synthesis of an acid chloride derivative from oleic acid and a phase transfer catalysis reaction in a biphasic medium. Under these conditions, free amine and alcohol groups of the caseinate are likely to be grafted with a fairly high (>50 %) substitution degree. The caseinate derivative is finely characterized, in particular by DOSY NMR, to assess the formation of a casein/oleic acid grafted compound as well as the absence of residual oleic acid.

David Procedure: A 21-year Experience With 300 Patients.

BACKGROUND: Valve-sparing aortic root replacement with the David procedure is an alternative to the Bentall procedure in patients with aortic root aneurysm. The aim of this study was to describe our long-term experience with this technique and the predictive factors of late failure. METHODS: Between January 1998 and August 2019, 300 consecutive patients underwent a David procedure. Clinical and echocardiographic early- and long-term outcomes were analyzed. Median follow-up was 7.0 years (range, 4.1-11.5), with 98.3% complete. RESULTS: Early mortality was 1%. No early valve-related reoperations occurred. There were 9 cardiac-related deaths and 22 reinterventions (19 valve-related). All patients survived reoperation. In 3 patients reintervention consisted of transcatheter aortic valve implantation. Overall survival rates were 95.3% (95% confidence interval [CI], 92.0-97.2), 91.1% (95% CI, 86.5-94.2), and 82.9% (95% CI, 75.3-88.4) at 5, 10, and 15 years, respectively. Freedom from postoperative aortic insufficiency (AI) grade ≥ 2 was 84.8% (95% CI, 79.9-88.6) and 74.3% (95% CI, 67.4-79.9) at 5 and 10 years, respectively. Freedom from reintervention for aortic valve disease was 97.1% (95% CI, 94.2-98.5), 92.9% (95% CI, 88.2-95.7), and 92.5% (95% CI, 87.1-95.7) at 5, 10, and 15 years, respectively. Preoperative AI ≥ 2 (hazard ratio, 1.782; 95% CI, 1.352-2.350) and a ventriculoaortic junction ≥ 29 mm (hazard ratio, 3.379; 95% CI, 1.726-6.616) were predictive factors for postoperative AI ≥ 2 in a multivariate analysis (P < .001). CONCLUSIONS: Preoperative AI ≥ 2 and a ventriculoaortic junction ≥ 29 mm were identified as risk factors for late postoperative AI ≥ 2.

Subclavian versus femoral arterial cannulations during extracorporeal membrane oxygenation: A propensity-matched comparison.

BACKGROUND: During peripheral extracorporeal veno-arterial membrane oxygenation (VA-ECMO) support, subclavian arterial cannulation provides, in comparison to femoral arterial cannulation, an anterograde flow which may prevent from left ventricular (LV) distention and improve outcomes. We aimed to compare the effectiveness of subclavian cannulation to femoral cannulation in reducing LV overdistension consequences, hemostatic complications and mortality. METHODS: This retrospective study conducted in two intensive care units of the Lille academic hospitals from January 2013 to December 2019 included 372 non-moribund adult patients supported by VA-ECMO. The primary endpoint was a new onset of pulmonary edema (PO) or LV unloading. Secondary endpoints were myocardial recovery, serious bleeding (according to Extracorporeal Life Support Organization definition), thrombotic complications (a composite of stroke, cannulated limb or mesenteric ischemia, intracardiac or aortic-root thrombosis) and 28 day mortality. Differences in outcomes were analyzed using propensity score matching (PSM) and inverse probability of treatment weighting adjustment (IPTW). RESULTS: As compared to femoral cannulation (n = 320 patients), subclavian cannulation (n = 52 patients) did not reduce the occurrence of new onset of PO or LV unloading after PSM [HR 0.99 (95% CI 0.51-1.91)]. There was no other difference in outcomes in PSM cohort. In IPTW adjustment cohort, subclavian cannulation was associated with reduced recovery and increased serious bleeding with four accidental decannulations observed. CONCLUSION: Subclavian artery cannulation was not associated with reduced LV distension related complications, thrombotic complications and 28 day mortality. Rather, it may increase serious bleeding and accidental decannulations, and reduce recovery. Therefore, subclavian cannulation should be limited to vascular accessibility issues.

Assessment of fluid responsiveness during increased intra-abdominal pressure: keep the indices, but change the thresholds.

Dynamic variables of fluid responsiveness are useful guides for fluid management in patients under controlled positive pressure ventilation. In the previous issue of Critical Care, Jacques and colleagues show that these variables remain reliable predictors of fluid responsiveness in a porcine model of intra-abdominal hypertension, but threshold values are higher than during normal intra-abdominal pressure. Their threshold values, however, cannot be applied to clinical practice. This study suggests that intra-abdominal pressure must be measured in critically ill patients, and 'supranormal' values of dynamic variables should be analyzed with caution. The 'fluid responsive part' of an increased dynamic variable in such patients may be estimated by measuring its change during a fluid challenge.

Use of near-infrared spectroscopy during a vascular occlusion test to assess the microcirculatory response during fluid challenge.

INTRODUCTION: Adequate volume expansion (VE) in patients with evidence of hypoperfusion should be aimed not only at achieving an increase in stroke volume (SV) and cardiac index (CI) but also at improved tissue perfusion and oxygenation. Our aim in this study was to assess the dynamic changes in muscle tissue oxygen saturation (StO2) during hypovolaemia and in response to VE. METHODS: We conducted a prospective study of 42 fluid challenges in patients undergoing major abdominal surgery with evidence of hypovolaemia, defined as pulse pressure variation (PPV) >13% and SV variation (SVV) >12%. CI, SV, SVV (FloTrac/Vigileo) and PPV were measured before and after VE. Fluid responsiveness was defined as an increase of SV >15% after a 500-mL colloid infusion over 15 minutes. In all patients, the muscle StO2 and its changes during a standardised vascular occlusion test were analysed using a near-infrared spectroscopy device after anaesthesia induction (which defined the baseline state) and before and after each VE. RESULTS: No patients were preload-responsive after anaesthesia induction. Twenty-nine of forty-two fluid challenges (69%) were positive for VE, with a statistically significant (P < 0.001) difference in SV changes between positive and negative responses to VE. There was a statistically significant difference in PPV and SVV values before VE in the positive and negative fluid responses [PPV: 16% (15% to 18%) vs. 14% (13% to 15%), P = 0.001; and SVV: 14% (13% to 16%) vs. 16% (15% to 16%), P = 0.03 or positive and negative fluid responses, respectively]. Data are presented as medians and 25th and 75th percentiles Before VE there was no significant difference in StO2 values relative to baseline [86% (78% to 88%) vs. 84% (77% to 91%), P = 0.83], without a significant difference (P = 0.36) between positive and negative fluid challenges. Hypovolaemia was associated with a significant reduction (P = 0.004) in StO2 recovery slope, with a significant difference (P = 0.02) between positive and negative fluid challenges. The VE-induced increase in the StO2 recovery slope was 62 ± 49% (P < 0.001) for positive fluid challenges and 26 ± 34% (P = 0.04) for negative fluid challenges. CONCLUSIONS: Hypovolaemia significantly affects the muscle StO2 recovery slope. Restoring effective intravascular volume with fluid loading significantly improves the StO2 recovery slope, despite apparently ineffective changes in systemic haemodynamics.

Evaluation of Anti-Activated Factor X Activity and Activated Partial Thromboplastin Time Relations and Their Association with Bleeding and Thrombosis during Veno-Arterial ECMO Support: A Retrospective Study.

BACKGROUND: We aimed to investigate the relationship between anti-activated Factor X (anti-FXa) and activated Partial Thromboplastin Time (aPTT), and its modulation by other haemostasis co-variables during veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support. We further investigated their association with serious bleeding and thrombotic complications. METHODS: This retrospective single-center study included 265 adults supported by VA-ECMO for refractory cardiogenic shock from January 2015 to June 2019. The concordance of anti-FXa and aPTT and their correlations were assessed in 1699 paired samples. Their independent associations with serious bleeding or thrombotic complications were also analysed in multivariate analysis. RESULTS: The concordance rate of aPTT with anti-FXa values was 50.7%, with 39.3% subtherapeutic aPTT values. However, anti-FXa and aPTT remained associated (ß = 0.43 (95% CI 0.4-0.45) 10-2 IU/mL, p < 0.001), with a significant modulation by several biological co-variables. There was no association between anti-FXa nor aPTT values with serious bleeding or with thrombotic complications. CONCLUSION: During VA-ECMO, although anti-FXa and aPTT were significantly associated, their values were highly discordant with marked sub-therapeutic aPTT values. These results should favour the use of anti-FXa. The effect of biological co-variables and the failure of anti-FXa and aPTT to predict bleeding and thrombotic complications underline the complexity of VA-ECMO-related coagulopathy.

IMPELLA® or Extracorporeal Membrane Oxygenation for Left Ventricular Dominant Refractory Cardiogenic Shock.

Mechanical circulatory support (MCS) devices are effective tools in managing refractory cardiogenic shock (CS). Data comparing veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and IMPELLA® are however scarce. We aimed to assess outcomes of patients implanted with these two devices and eligible to both systems. From 2004 to 2020, we retrospectively analyzed 128 patients who underwent VA-ECMO or IMPELLA® in our institution for refractory left ventricle (LV) dominant CS. All patients were eligible to both systems: 97 patients were first implanted with VA-ECMO and 31 with IMPELLA®. The primary endpoint was 30-day all-cause death. VA-ECMO patients were younger (52 vs. 59.4, p = 0.006) and had a higher lactate level at baseline than those in the IMPELLA® group (6.84 vs. 3.03 mmol/L, p < 0.001). Duration of MCS was similar between groups (9.4 days vs. 6 days in the VA-ECMO and IMPELLA® groups respectively, p = 0.077). In unadjusted analysis, no significant difference was observed between groups in 30-day mortality: 43.3% vs. 58.1% in the VA-ECMO and IMPELLA® groups, respectively (p = 0.152). After adjustment, VA-ECMO was associated with a significant reduction in 30-day mortality (HR = 0.25, p = 0.004). A higher rate of MCS escalation was observed in the IMPELLA® group: 32.3% vs. 10.3% (p = 0.003). In patients eligible to either VA-ECMO or IMPELLA® for LV dominant refractory CS, VA-ECMO was associated with improved survival rate and a lower need for escalation.