Fertility and pregnancy outcomes in women with nonclassic 21-hydroxylase deficiency.

INTRODUCTION: Overall fertility and pregnancy outcomes in patients with nonclassic congenital adrenal hyperplasia (NCCAH) have been poorly studied. It has been suggested that hydrocortisone (HC) may decrease the time to conceive (TTC) and the rate of miscarriage in these patients. OBJECTIVES: To describe fertility and pregnancy outcomes in a large cohort of NCCAH women. The secondary objective was to identify factors that could impact reproductive outcomes, with a particular focus on HC dose and genetic status. DESIGN: Retrospective study in a referral center for congenital adrenal hyperplasia. PATIENTS AND MEASUREMENTS: One hundred seventy-three female patients with NCCAH confirmed by genetic testing, followed in our center between 2010 and 2019. RESULTS: Among the 173 patients, 95 women had a parental project, 86 of whom presented 176 pregnancies, 56% under glucocorticoid (GC) treatment and 44% without, and 76 women obtained 128 live births. Two-thirds of the patients regularized their cycle under GC treatment, with significant decrease of androgens and progesterone levels. This treatment was associated with a shortening of TTC (coef ß = -.196, information coefficient [IC] = [-10.7; -0.91], p = .021). Androgen levels and TTC were positively correlated to the rate of miscarriage (OR = 4.8, IC = [1.15; 20.34], p = .021 for testosterone, OR = 1.4, IC = [1.05; 1.81], p = .02 for androstenedione, and OR = 1.03, IC = [1.01; 1.06], p = .015 for TTC). There was no difference in terms of obstetric outcomes between patients with or without GC treatment. CYP21A2 genotype had no impact on pregnancy outcome or TTC. CONCLUSIONS: Infertility is relative in patients with NCCAH. HC seems beneficial for fertility and pregnancy outcomes, especially for patients with menstrual disorders and high preconceptional androgen levels.

Impact of sex differences on cardiac injury in critically ill patients with COVID-19.

BACKGROUND: COVID-19 infections are associated with accrued inflammatory responses which may result in cardiac injury. Immune response to infection appears different between men and women, suggesting that COVID-19 patients' outcomes may differ according to biological sex. However, the impact of biological sex on the occurrence of cardiac injury during intensive care unit (ICU) stay in COVID-19 patients remain unclear. METHODS: In this multicenter and prospective study, we included consecutive patients admitted to ICU for severe COVID-19 pneumonia, during the first two pandemic waves. Biological, electrocardiogram (ECG) and echocardiographic variables were collected on ICU admission. Cardiac injury was defined by increased troponin above 99th percentile of upper norm value and newly diagnosed ECG and/or echocardiographic abnormalities. The primary endpoint was the proportion of patients with cardiac injury during ICU stay according to biological sex. The impact of biological sex on other subsequent clinical outcomes was also evaluated. RESULTS: We included 198 patients with a median age of 66 (56-73) years, 147 (74%) patients were men and 51 (26%) were women. Overall, 119 (60%) patients had cardiac injury during ICU stay and the proportion of patients with cardiac injury during ICU stay was not different between men and women (60% vs. 61%, p = 1.00). Patients with cardiac injury during ICU stay showed more cardiovascular risk factors and chronic cardiac disease and had a higher ICU mortality rate. On ICU admission, they had a more marked lymphopenia (0.70 (0.40-0.80) vs. 0.80 (0.50-1.10) × 109/L, p < 0.01) and inflammation (C-Reactive Protein (155 (88-246) vs. 111 (62-192) mg/L, p = 0.03); D-Dimers (1293 (709-2523) vs. 900 (560-1813) µg/L, p = 0.03)). Plasmatic levels of inflammatory biomarkers on ICU admission correlated with SAPS-2 and SOFA scores but not with the different echocardiographic variables. Multivariate analysis confirmed cardiovascular risk factors (OR = 2.31; 95%CI (1.06-5.02), p = 0.03) and chronic cardiac disease (OR = 8.58; 95%CI (1.01-73.17), p = 0.04) were independently associated with the occurrence of cardiac injury during ICU stay, whereas biological sex (OR = 0.88; 95%CI (0.42-1.84), p = 0.73) was not. Biological sex had no impact on the occurrence during ICU stay of other clinical outcomes. CONCLUSIONS: Most critically ill patients with COVID-19 were men and experienced cardiac injury during ICU stay. Nevertheless, biological sex had no impact on the occurrence of cardiac injury during ICU stay or on other clinical outcomes. Clinical trial registration NCT04335162.

Persistent diaphragm dysfunction after cardiac surgery is associated with adverse respiratory outcomes: a prospective observational ultrasound study.

BACKGROUND: Transient diaphragm dysfunction is common during the first week after cardiac surgery; however, the precise incidence, risk factors, and outcomes of persistent diaphragm dysfunction are not well described. METHODS: In a single-centre prospective cohort study, we included all consecutive patients over 18 yr who underwent elective cardiac surgery. Diaphragm function was evaluated with ultrasound (M-mode) by recording the excursion of both hemidiaphragms at two different time points: preoperatively and after the seventh postoperative day in patients breathing without assistance. Significant diaphragm dysfunction after the seventh day of the index cardiac surgery was defined as a decrease in diaphragm excursion below the lower limit of normal: at rest, < 9 mm for women and < 10 mm for men; after a sniff test, < 16 mm for women and < 18 mm for men. RESULTS: Overall, 122 patients were included in the analysis. The median [interquartile range (IQR)] age was 69 [59-74] years and 96/122 (79%) were men. Ten (8%) patients had diaphragm dysfunction after the seventh postoperative day. We did not identify risk factors for persistent diaphragm dysfunction. Persistent diaphragm dysfunction was associated with a longer median [IQR] duration of noninvasive (8 [0-34] vs 0 [0-0] hr; difference in medians, 8 hr; 95% confidence interval [CI], 0 to 22; P < 0.001) and invasive mechanical ventilation (5 [3-257] vs 3[2-4] hr; difference in medians, 2 hr; 95% CI, 0.5 to 41; P = 0.008); a higher reintubation rate (4/10, 40% vs 1/112, 0.9%; relative risk, 45; 95% CI, 7.1 to 278; P < 0.0001), a higher incidence of pneumonia (4/10 [40%] vs 7/112 [6%]; relative risk, 6; 95% CI, 2 to 16; P < 0.001), and longer median [IQR] length of stay in the intensive care unit (8 [5-29] vs 4 [2-6] days; difference in medians, 4 days; 95% CI, 2 to 12; P = 0.002). CONCLUSION: The incidence of persistent diaphragm dysfunction was 8% in patients undergoing elective cardiac surgery and was associated with adverse respiratory outcomes. STUDY REGISTRATION: ClinicalTrials.gov (NCT04276844); prospectively registered 19 February 2020.

RéSUMé: CONTEXTE: Un dysfonctionnement transitoire du diaphragme est fréquent au cours de la première semaine après une chirurgie cardiaque. Toutefois, l'incidence précise, les facteurs de risque et les devenirs liés à un dysfonctionnement persistant du diaphragme ne sont pas bien décrits. MéTHODE: Dans une étude de cohorte prospective monocentrique, nous avons inclus tous les patients consécutifs de plus de 18 ans qui ont bénéficié d'une chirurgie cardiaque non urgente. La fonction du diaphragme a été évaluée à l'échographie (mode M) en enregistrant l'excursion des deux hémidiaphragmes à deux moments différents : avant l'opération et après le septième jour postopératoire chez les patients respirant sans assistance. Un dysfonctionnement significatif du diaphragme après le septième jour de la chirurgie cardiaque initiale a été défini comme une diminution de l'excursion diaphragmatique en dessous de la limite inférieure de la normale, soit : au repos, < 9 mm pour les femmes et < 10 mm pour les hommes; après un test de reniflement, < 16 mm pour les femmes et < 18 mm pour les hommes. RéSULTATS: Au total, 122 patients ont été inclus dans l'analyse. L'âge médian des patients (écart interquartile [ÉIQ]) était de 69 ans [59-74] ans et 96/122 (79 %) étaient des hommes. Dix (8 %) patients ont présenté un dysfonctionnement du diaphragme après le septième jour postopératoire. Nous n'avons pas identifié de facteurs de risque de dysfonctionnement persistant du diaphragme. Un dysfonctionnement persistant du diaphragme était associé à : une durée médiane [ÉIQ] de ventilation non invasive (8 [0­34] vs 0 [0­0] h; différence dans les médianes, 8 heures; intervalle de confiance [IC] à 95 %, 0 à 22; P < 0,001) et de ventilation mécanique invasive (5 [3­257] vs 3[2­4] h; différence dans les médianes, 2 heures; IC 95 %, 0,5 à 41; P = 0,008) plus longues, un taux de réintubation plus élevé (4/10, 40 % vs 1/112, 0,9 %; risque relatif, 45; IC 95 %, 7,1 à 278; P < 0,0001), une incidence plus élevée de pneumonie (4/10 [40 %] vs 7/112 [6 %]; risque relatif, 6; IC 95 %, de 2 à 16; P < 0,001), et une durée de séjour médiane [ÉIQ] plus longue à l'unité de soins intensifs (8 [5-29] vs 4 [2­6] jours; différence en médianes, 4 jours; IC 95 %, 2 à 12; P = 0,002). CONCLUSION: L'incidence de dysfonctionnement persistant du diaphragme était de 8 % chez les patients bénéficiant d'une chirurgie cardiaque non urgente et était associée à des issues respiratoires indésirables. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov (NCT04276844); enregistrée prospectivement le 19 février 2020.

Determinants of diaphragm inspiratory motion, diaphragm thickening, and its performance for predicting respiratory restrictive pattern in Duchenne muscular dystrophy.

INTRODUCTION/AIMS: Respiratory status is a key determinant of prognosis in patients with Duchenne muscular dystrophy (DMD). We aimed to evaluate the determinants of diaphragm ultrasound and its performance in predicting restrictive respiratory patterns in DMD. METHODS: This was a retrospective study of DMD patients followed in our center and admitted for an annual checkup from 2015 to 2018. We included DMD patients who underwent diaphragm ultrasound and pulmonary functional tests. RESULTS: This study included 74 patients with DMD. The right diaphragm thickening fraction (TF) was significantly associated with age (P = .001), Walton score (P = .012), inspiratory capacity (IC) (P = .004), upright forced vital capacity (FVC) (P < .0001), supine FVC (P = .038), and maximal inspiratory pressure (MIP) (P = .002). Right diaphragm excursion was significantly associated with age (P < .0001), steroid use (P = .008), history of spinal fusion (P < .0001), body mass index (BMI) (P = .002), Walton score (P < .0001), IC (P < .0001), upright FVC (P < .0001), supine FVC (P < .0001), and MIP (P < .0001). A right diaphragm TF >28% and a right diaphragm excursion>25.4 mm were associated with an FVC >50% with, respectively, an area under the curve (AUC) of 0.95 (P = .001) and 0.93 (P < .001). A left diaphragm TF >26.8% and a left diaphragm excursion >21.5 mm were associated with an FVC >50% with, respectively, an AUC of 0.95 (P = .011) and 0.97 (P < .001). DISCUSSION: Diaphragm excursion and diaphragm TF can predict restrictive pulmonary insufficiency in DMD.

Anticancer drug-induced life-threatening ventricular arrhythmias: a World Health Organization pharmacovigilance study.

AIMS: With the explosion of anticancer drugs, an emerging concern is the risk for drug-induced sudden death (SD) via ventricular arrhythmias (VA). METHODS AND RESULTS: We used the international pharmacovigilance database VigiBase (n = 18 441 659 reports) to compare drug-induced long QT (diLQT, n = 18 123) and VA (n = 29 193) including torsade de pointes (TdP, n = 8163) reporting for 663 anticancer drugs vs. all other drugs until 01/01/2019. The analysis used the 95% lower-end credibility interval of the information component (IC025), an indicator for disproportionate Bayesian reporting; significant when IC025 >0. There were 2301 reports (13.8% fatal) for 40 anticancer drugs significantly associated with diLQT (with 27 also associated with VA or SD) and 9 drugs associated with VA without diLQT. Half of these (46.9%, 23/49) were associated with SD. Most (41%, 20/49) were kinase inhibitors, 8% (4/49) were hormonal therapies, 6% (3/49) were immunotherapies, 24% (12/49) were cytotoxics, and 20% (10/49) were miscellaneous. In VigiBase, reports of diLQT, TdP, or VA increased from 580 in the period 1967-83 to 15 070 in 2014-18 with the proportion related to anticancer drugs increasing from 0.9% (5/580) to 14.0% (2115/15 070) (P < 0.0001). Concordance between these VigiBase signals and data concerning diLQT and VA/TdP identified in CredibleMeds or US Food and Drug Administration (FDA) labels was moderate (κ = 0.47 and 0.40, P < 0.0001). Twenty-three drugs represent new signals, while 24 flagged by CredibleMeds or FDA had no signal in VigiBase. A three-level SD risk stratification relying on isolated long QT (low risk), associated with VA without SD (moderate risk), and VA with SD (high risk) is proposed. CONCLUSION: This list of liable anticancer drugs may prove useful for physicians and regulatory authorities to re-evaluate cardiac monitoring requirements. CLINICAL TRIAL REGISTRATION: NCT03530215.

Chimeric antigen receptor T-cells safety: A pharmacovigilance and meta-analysis study.

Chimeric-antigen-receptor T cells directed against CD19 (CAR-T) are emerging hematological therapeutics with scarce data on its overall safety profile spectrum. To determine the clinical features and incidence of adverse-drug reactions (ADR) associated with CAR-T. This observational, cross-sectional, pharmacovigilance cohort study examined individual case safety reports from the World Health Organization database VigiBase and meta-analysis of data from CAR-T trials and cohorts in the literature was also performed through March, 2020. The primary objective was to identify ADR associated with approved CAR-T (axicabtagene-ciloleucel; tisagenlecleucel). We conducted a Bayesian disproportionate analysis with the 95% lower credibility-interval of information component (IC025 , significance > 0). We also performed a systematic-review and meta-analysis of CAR-T trials and cohorts in the literature to evaluate ADR incidence. Nine ADR classes were associated with CAR-T: Cytokine release syndrome (CRS, n = 1378, IC025  = 4.24), neurological disorders (n = 963, IC025  = 2.42), hematological disorders (n = 532, IC025  = 3.32), infections (n = 287, IC025  = 2.38), cardiovascular disorders (n = 256, IC025  = 2.81), pulmonary disorders (n = 186, IC025  = 3.80), reno-metabolic disorders (n = 123, IC025  = 1.89), hemophagocytic-lymphohistiocytosis (n = 36, IC025  = 5.01) and hepatic disorders (n = 32, IC025  = 2.49). ADR-related fatalities accounted for 99/1783 (5.5%) of the reports and 262/1783 (14.7%) for all-cause mortality. These ADR-related fatalities were associated with hemophagocytic-lymphohistiocytosis, cerebral vascular disorder, infections, and respiratory failure. In meta-analyses, the most frequent any-grade ADRs were CRS, hematological disorders, and neurological disorders. Fatal ADR were most found with neurological disorders, CRS, and infections. Note, CAR-T infusion may be associated with severe ADR mainly following the week of administration, though rarely fatal. Infections, hemophagocytic-lymphohistiocytosis and end organ failures including neurological or lung involvements require scrutiny.

Quadritherapy vs standard tritherapy immunosuppressant regimen after heart transplantation: A propensity score-matched cohort analysis.

After heart transplant, adding everolimus (EVL) to standard immunosuppressive regimen mostly relies on converting calcineurin inhibitors (CNIs) into EVL. The aim of this study was to describe the effects of combining low-dose EVL and CNIs in maintenance immunosuppression regimen (quadritherapy) and compare it with standard tritherapy associating standard-dose CNIs, mycophenolate mofetil, and corticosteroids. In the 3-year registry cohort of heart transplanted patients, those who received quadritherapy were compared with those who received tritherapy. EVL was added after 3 months posttransplant. Three analyses were performed to control for confounders: propensity score matching, multivariable survival, and inverse probability score weighting analyses. Among 213 patients who were included (75 with quadritherapy), propensity score matching selected 64 unique pairs of patients with similar characteristics. In the matched cohort (n = 128), quadritherapy was associated with fewer deaths (3 [4.7%] vs 17 [21.9%], P = .007) and biopsy-proven acute rejections (15 [23.4%] vs 31 [48.4%], P = .002). These results were confirmed in the overall cohort (n = 213), after multivariable and inverse probability score weighting analyses. Renal function and donor-specific HLA-antibodies remained similar in both groups. Low-dose combination quadritherapy was associated with fewer deaths and rejections, compared with standard immunosuppression tritherapy.

Favorable Outcomes of a Direct Heart Transplantation Strategy in Selected Patients on Extracorporeal Membrane Oxygenation Support.

OBJECTIVES: Heart transplantation in patients supported by venoarterial extracorporeal membrane oxygenation has been associated with poor prognosis. A specific protocol for extracorporeal membrane oxygenation management encompassing patient selection, implantation strategy, and preoperative and perioperative treatment is applied at our institution. Our aim was to compare posttransplant outcomes of patients supported or not by extracorporeal membrane oxygenation at the time of heart transplantation. DESIGN: A large observational single-center retrospective study was conducted. The primary endpoint was overall survival after heart transplantation. Secondary endpoints included death-censored rejection-free survival and the frequency of extracorporeal membrane oxygenation-related complications. SETTING: One heart transplantation and extracorporeal membrane oxygenation high-volume center. PATIENTS: All consecutive patients over 18 years old with a first noncombined heart transplantation performed between 2012 and 2016 were included. INTERVENTIONS: None (retrospective observational study). MEASUREMENTS AND MAIN RESULTS: Among the 415 transplanted patients, 118 (28.4%) were on extracorporeal membrane oxygenation at the time of transplantation (peripheral, 94%; intrathoracic, 6%). Median time on extracorporeal membrane oxygenation before heart transplantation was 9 days (interquartile range, 5-15 d) and median follow-up post heart transplantation was 20.7 months. Posttransplant survival did not differ significantly between the two groups (1-yr survival = 85.5% and 80.7% in extracorporeal membrane oxygenation vs nonextracorporeal membrane oxygenation patients; hazard ratio, 0.69; 95% CI, 0.43-1.11; p = 0.12, respectively). Donor age, body mass index, creatinine clearance, and ischemic time were independently associated with overall mortality, but not extracorporeal membrane oxygenation at the time of heart transplantation. Rejection-free survival also did not significantly differ between groups (hazard ratio, 0.85; 95% CI, 0.60-1.23; p = 0.39). Local wound infection was the most frequent complication after extracorporeal membrane oxygenation (37% of patients). CONCLUSIONS: With the implementation of a specific protocol, patients bridged to heart transplantation on extracorporeal membrane oxygenation had similar survival compared with those not supported by extracorporeal membrane oxygenation.

Effect of recipient gender and donor-specific antibodies on antibody-mediated rejection after heart transplantation.

Gender-difference regarding antibody-mediated rejection (AMR) after heart transplantation has been described. However, no study accounted for the presence of preformed donor-specific antibodies (pfDSA), a known risk factor of AMR, more common among women than men. In a single-institution 6-year cohort (2010-2015), time to AMR was assessed, comparing men with women by survival analysis with a 1-year death-censored follow-up. All AMRs were biopsy proven. Confounding variables that were accounted for included mean intensity fluorescence (MFI) of pfDSA, recipient age, HLA-, size- and sex-mismatch. 463 patients were included. Overall incidence of AMR was 10.3% at 1 year. After adjusting for confounding variables, independent risk factors of AMR were female recipient gender (adjusted hazard-ratio [adj. HR] = 1.78 [1.06-2.99]), P = .03) and the presence of pfDSA (adj. HR = 3.20 [1.80-5.70], P < .001). This association remained significant when considering pfDSA by their MFI; female recipient gender had an adj. HR = 2.2 (P = .026) and MFI of pfDSA (per 1 MFI-increase) adj. HR = 1.0002 (P < .0001). In this cohort, women were at higher risk of AMR than men and this risk increase was additive to that of pfDSA. These findings may suggest a gender-related difference in the severity of pfDSA.

Respiratory Variability of Pulmonary Velocity-Time Integral As a New Gauge of Fluid Responsiveness For Mechanically Ventilated Patients in the ICU.

OBJECTIVES: To evaluate reliability and feasibility of the respiratory variability of pulmonary velocity-time integral as a new dynamic marker of fluid responsiveness in mechanically ventilated patients. DESIGN: Prospective observational study. SETTING: Medical-surgical ICU of a general hospital. PATIENTS: Fifty mechanically ventilated patients with acute circulatory failure. INTERVENTIONS: Transthoracic echocardiography was performed at inclusion (transthoracic echocardiography baseline). Fluid therapy was prescribed to patients exhibiting one value greater than or equal to 13% among commonly used variables of fluid responsiveness: respiratory variability of aortic velocity-time integral, respiratory variability of inferior vena cava diameter, or pulse pressure variation. MEASUREMENTS AND MAIN RESULTS: Respiratory variability of pulmonary velocity-time integral was assessed at baseline. Respiratory variability of pulmonary velocity-time integral was significantly greater in patients who received fluid therapy (26.9 ± 12.5% vs 6.2 ± 4.3%; p < 0.0001). Respiratory variability of pulmonary velocity-time integral was correlated with respiratory variability of aortic velocity-time integral (r = 0.75; p < 0.0001), respiratory variability of inferior vena cava diameter (r = 0.42; p < 0.01), and pulse pressure variation (r = 0.87; p < 0.0001) at baseline and with the relative increase in cardiac output after fluid therapy (r = 0.44; p = 0.019). Fluid responsiveness was defined as a 10% increase in cardiac output after fluid therapy, assessed by a second transthoracic echocardiography. Respiratory variability of pulmonary velocity-time integral was associated with fluid responsiveness (adjusted odds ratio, 1.58; 95% CI, 1.08-2.32; p = 0.002). Area under the receiver operating characteristics curve was 0.972, and a value of respiratory variability of pulmonary velocity-time integral greater than or equal to 14% yielded a sensitivity of 92% and specificity of 87% to predict fluid responsiveness. Interobserver reproducibility was excellent (intraclass correlation coefficient = 0.94). CONCLUSIONS: Respiratory variability of pulmonary velocity-time integral is a simple and reliable marker of fluid responsiveness for ventilated patients in ICU.

Performance of existing risk scores around heart transplantation: validation study in a 4-year cohort.

Several risk scores exist to help identify best candidate recipients for heart transplantation (HTx). This study describes the performance of five heart failure risk scores and two post-HTx mortality risk scores in a French single-centre cohort. All patients listed for HTx through a 4-year period were included. Waiting-list risk scores [Heart Failure Survival Score (HFSS), Seattle Heart Failure Model (SHFM), Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC), Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) and Get With The Guidelines-Heart Failure (GWTG-HF)] and post-HTx scores Index for Mortality Prediction After Cardiac Transplantation (IMPACT and CARRS) were computed. Main outcomes were 1-year mortality on waiting list and after HTx. Performance was assessed using receiver operator characteristic (ROC), calibration and goodness-of-fit analyses. The cohort included 414 patients. Waiting-list mortality was 14.0%, and post-HTx mortality was 16.3% at 1-year follow-up. Heart failure risk scores had adequate discrimination regarding waiting-list mortality (ROC AUC for HFSS = 0.68, SHFM = 0.74, OPTIMIZE-HF = 0.72, MAGGIC = 0.70 and GWTG = 0.77; all P-values <0.05). On the contrary, post-HTx risk scores did not discriminate post-HTx mortality (AUC for IMPACT = 0.58, and CARRS = 0.48, both P-values >0.50). Subgroup analysis on patients undergoing HTx after ventricular assistance device (VAD) implantation (i.e. bridge-to-transplantation) (n = 36) showed an IMPACT AUC = 0.72 (P < 0.001). In this single-centre cohort, existing heart failure risk scores were adequate to predict waiting-list mortality. Post-HTx mortality risk scores were not, except in the VAD subgroup.

Intravenous ivabradine versus placebo in patients with low cardiac output syndrome treated by dobutamine after elective coronary artery bypass surgery: a phase 2 exploratory randomized controlled trial.

BACKGROUND: Low cardiac output syndrome (LCOS) is a severe condition which can occur after cardiac surgery, especially among patients with pre-existing left ventricular dysfunction. Dobutamine, its first-line treatment, is associated with sinus tachycardia. This study aims to assess the ability of intravenous ivabradine to decrease sinus tachycardia associated with dobutamine infused for LCOS after coronary artery bypass graft (CABG) surgery. METHODS: In a phase 2, multi-center, single-blind, randomized controlled trial, patients with left ventricular ejection fraction below 40% presenting sinus tachycardia of at least 100 beats per minute (bpm) following dobutamine infusion for LCOS after CABG surgery received either intravenous ivabradine or placebo (three ivabradine for one placebo). Treatment lasted until dobutamine weaning or up to 48 h. The primary endpoint was the proportion of patients achieving a heart rate (HR) in the 80- to 90-bpm range. Secondary endpoints were invasive and non-invasive hemodynamic parameters and arrhythmia events. RESULTS: Nineteen patients were included. More patients reached the primary endpoint in the ivabradine than in the placebo group (13 (93%) versus 2 (40%); P = 0.04). Median times to reach target HR were 1.0 h in the ivabradine group and 5.7 h in the placebo group. Ivabradine decreased HR (112 to 86 bpm, P <0.001) while increasing cardiac index (P = 0.02), stroke volume (P <0.001), and systolic blood pressure (P = 0.03). In the placebo group, these parameters remained unchanged from baseline. In the ivabradine group, five patients (36%) developed atrial fibrillation (AF) and one (7%) was discontinued for sustained AF; two (14%) were discontinued for bradycardia. CONCLUSION: Intravenous ivabradine achieved effective and rapid correction of sinus tachycardia in patients who received dobutamine for LCOS after CABG surgery. Simultaneously, stroke volume and systolic blood pressure increased, suggesting a beneficial effect of this treatment on tissue perfusion. TRIAL REGISTRATION: European Clinical Trials Database: EudraCT 2009-018175-14 . Registered February 2, 2010.

Efficacy of maintaining low-tidal volume mechanical ventilation as compared to resting lung strategy during coronary artery bypass graft cardiopulmonary bypass surgery: A post-hoc analysis of the MECANO trial.

STUDY OBJECTIVE: To compare a low-tidal-volume with positive end-expiratory pressure strategy (VENT strategy) to a resting-lung-strategy (i.e., no-ventilation (noV) strategy) during cardiopulmonary bypass for coronary artery bypass graft surgery on the incidence of postoperative pulmonary complications. DESIGN: Post-hoc analysis of the MECANO trial which was a prospective single-center, blind, randomized, parallel-group controlled trial. SETTING: Tertiary care cardiac surgery center. PATIENTS: Patients who underwent isolated on-pump coronary bypass surgery were randomized either to VENT or noV group. INTERVENTION: During the cardiopulmonary bypass phase of the cardiac surgery procedure, mechanical ventilation in the VENT group consisted of a tidal volume of 3 mL/kg, a respiratory rate of 5 per minute and a positive end-expiratory pressure of 5 cmH2O. Patients in the noV group received no ventilation during this phase. MEASUREMENTS: Primary composite outcome combining death, early respiratory failure, ventilation support beyond day 2 and reintubation. MAIN RESULTS: In this post-hoc analysis, we retained 725 patients who underwent isolated CABG surgery, from the 1501 patients included in the original study. There were 352 in the VENT group and 373 patients in the noV group. Post-hoc comparison yielded no differences in baseline characteristics between these two groups. The primary outcome occurred less frequently in the VENT group than in the noV group, with 44 (12.5%) and 76 (20.4%) respectively (odds-ratio (OR) = 0.56 (0.37-0.84), p = 0.004). There were fewer early respiratory dysfunctions and prolonged respiratory support in the VENT group (respectively, OR = 0.34 (0.12-0.96) p = 0.033 and OR = 0.51 (0.27-0.94) p = 0.029). Complications related to mechanical ventilation were similar in the two groups. CONCLUSIONS: In this post-hoc analysis, maintaining low-tidal ventilation compared to a resting-lung strategy was associated with fewer pulmonary postoperative complications in patients who underwent isolated CABG procedures.

Prognosis of Right Ventricular Systolic Dysfunction in Patients With Duchenne Muscular Dystrophy.

Background Chronic respiratory failure and heart involvement may occur in Duchenne muscular dystrophy. We aimed to assess the prognostic value of the right ventricular (RV) systolic dysfunction in patients with Duchenne muscular dystrophy. Methods and Results We studied 90 genetically proven patients with Duchenne muscular dystrophy from 2010 to 2019, to obtain respiratory function and Doppler echocardiographic RV systolic function. Prognostic value was assessed in terms of death and cardiac events. The median age was 27.5 years, and median forced vital capacity was at 10% of the predicted value: 83 patients (92%) were on home mechanical ventilation. An RV systolic dysfunction was found in 46 patients (51%). In patients without RV dysfunction at inclusion, a left ventricular systolic dysfunction at inclusion was associated with a higher risk of developing RV dysfunction during follow-up with an odds ratio of 4.5 (P=0.03). RV systolic dysfunction was significantly associated with cardiac events, mainly acute heart failure (62%) and cardiogenic shock (23%). In a multivariable Cox model, the adjusted hazard ratio was 4.96 (95% CI [1.09-22.6]; P=0.04). In terms of death, we found a significant difference between patients with RV dysfunction versus patients without RV dysfunction in the Kaplan-Meier curves (log-rank P=0.045). Conclusions RV systolic dysfunction is frequently present in patients with Duchenne muscular dystrophy and is associated with increased risk of cardiac events, irrespective of left ventricular dysfunction and mechanical ventilation. Registration URL: https://www.clinicaltrials.org; unique identifier: NCT02501083.

Effectiveness of Simulation-Based Training on Transesophageal Echocardiography Learning: The SIMULATOR Randomized Clinical Trial.

Importance: Evidence is scarce on the effectiveness of simulation-based training in transesophageal echocardiography (TEE). Objective: To assess the effectiveness of simulation-based teaching vs traditional teaching of TEE knowledge and skills of cardiology fellows. Design, Setting, and Participants: Between November 2020 and November 2021, all consecutive cardiology fellows inexperienced in TEE from 42 French university centers were randomized (1:1; n = 324) into 2 groups with or without simulation support. Main Outcomes and Measures: The co-primary outcomes were the scores in the final theoretical and practical tests 3 months after the training. TEE duration and the fellows' self-assessment of their proficiency were also assessed. Results: While the theoretical and practical test scores were similar between the 2 groups (324 participants; 62.6% male; mean age, 26.4 years) before the training (33.0 [SD, 16.3] points vs 32.5 [SD, 18.5] points; P = .80 and 44.2 [SD, 25.5] points vs 46.1 [SD, 26.1] points; P = .51, respectively), the fellows in the simulation group (n = 162; 50%) displayed higher theoretical test and practical test scores after the training than those in the traditional group (n = 162; 50%) (47.2% [SD, 15.6%] vs 38.3% [SD, 19.8%]; P < .001 and 74.5% [SD, 17.7%] vs 59.0% [SD, 25.1%]; P < .001, respectively). Subgroup analyses showed that the effectiveness of the simulation training was even greater when performed at the beginning of the fellowship (ie, 2 years or less of training) (theoretical test: an increase of 11.9 points; 95% CI, 7.2-16.7 vs an increase of 4.25 points; 95% CI, -1.05 to 9.5; P = .03; practical test: an increase of 24.9 points; 95% CI, 18.5-31.0 vs an increase of 10.1 points; 95% CI, 3.9-16.0; P < .001). After the training, the duration to perform a complete TEE was significantly lower in the simulation group than in the traditional group ( 8.3 [SD, 1.4] minutes vs 9.4 [SD, 1.2] minutes; P < .001, respectively). Additionally, fellows in the simulation group felt more ready and more confident about performing a TEE alone after the training (mean score, 3.0; 95% CI, 2.9-3.2 vs mean score, 1.7; 95% CI, 1.4-1.9; P < .001 and mean score, 3.3; 95% CI, 3.1-3.5 vs mean score, 2.4; 95% CI, 2.1-2.6; P < .001, respectively). Conclusions and Relevance: Simulation-based teaching of TEE showed a significant improvement in the knowledge, skills, and self-assessment of proficiency of cardiology fellows, as well as a reduction in the amount of time needed to complete the examination. These results should encourage further investigation of clinical performance and patient benefits of TEE simulation training.

Abatacept/Ruxolitinib and Screening for Concomitant Respiratory Muscle Failure to Mitigate Fatality of Immune-Checkpoint Inhibitor Myocarditis.

Immune-checkpoint-inhibitor (ICI)-associated myotoxicity involves the heart (myocarditis) and skeletal muscles (myositis), which frequently occur concurrently and are highly fatal. We report the results of a strategy that included identification of individuals with severe ICI myocarditis by also screening for and managing concomitant respiratory muscle involvement with mechanical ventilation, as well as treatment with the CTLA4 fusion protein abatacept and the JAK inhibitor ruxolitinib. Forty cases with definite ICI myocarditis were included with pathologic confirmation of concomitant myositis in the majority of patients. In the first 10 patients, using recommended guidelines, myotoxicity-related fatality occurred in 60%, consistent with historical controls. In the subsequent 30 cases, we instituted systematic screening for respiratory muscle involvement coupled with active ventilation and treatment using ruxolitinib and abatacept. The abatacept dose was adjusted using CD86 receptor occupancy on circulating monocytes. The myotoxicity-related fatality rate was 3.4% (1/30) in these 30 patients versus 60% in the first quartile (P < 0.0001). These clinical results are hypothesis-generating and need further evaluation. SIGNIFICANCE: Early management of respiratory muscle failure using mechanical ventilation and high-dose abatacept with CD86 receptor occupancy monitoring combined with ruxolitinib may be promising to mitigate high fatality rates in severe ICI myocarditis. See related commentary by Dougan, p. 1040. This article is highlighted in the In This Issue feature, p. 1027.