Prevention of post-operative delirium using an overnight infusion of dexmedetomidine in patients undergoing cardiac surgery: a pragmatic, randomized, double-blind, placebo-controlled trial.

BACKGROUND: After cardiac surgery, post-operative delirium (PoD) is acknowledged to have a significant negative impact on patient outcome. To date, there is no valuable and specific treatment for PoD. Critically ill patients often suffer from poor sleep condition. There is an association between delirium and sleep quality after cardiac surgery. This study aimed to establish whether promoting sleep using an overnight infusion of dexmedetomidine reduces the incidence of delirium after cardiac surgery. METHODS: Randomized, pragmatic, multicentre, double-blind, placebo controlled trial from January 2019 to July 2021. All adult patients aged 65 years or older requiring elective cardiac surgery were randomly assigned 1:1 either to the dexmedetomidine group or the placebo group on the day of surgery. Dexmedetomidine or matched placebo infusion was started the night after surgery from 8 pm to 8 am and administered every night while the patient remained in ICU, or for a maximum of 7 days. Primary outcome was the occurrence of postoperative delirium (PoD) within the 7 days after surgery. RESULTS: A total of 348 patients provided informed consent, of whom 333 were randomized: 331 patients underwent surgery and were analysed (165 assigned to dexmedetomidine and 166 assigned to placebo). The incidence of PoD was not significantly different between the two groups (12.6% vs. 12.4%, p = 0.97). Patients treated with dexmedetomidine had significantly more hypotensive events (7.3% vs 0.6%; p < 0.01). At 3 months, functional outcomes (Short-form 36, Cognitive failure questionnaire, PCL-5) were comparable between the two groups. CONCLUSION: In patients recovering from an elective cardiac surgery, an overnight infusion of dexmedetomidine did not decrease postoperative delirium. Trial registration This trial was registered on ClinicalTrials.gov (number: NCT03477344; date: 26th March 2018).

Perioperative individualized hemodynamic optimization according to baseline mean arterial pressure in cardiac surgery patients: Rationale and design of the OPTIPAM randomized trial.

BACKGROUND: Postoperative morbidity and mortality after cardiac surgery with cardiopulmonary bypass (CPB) remain high despite recent advances in both anesthesia and perioperative management. Among modifiable risk factors for postoperative complications, optimal arterial pressure during and after surgery has been under debate for years. Recent data suggest that optimizing arterial pressure to the baseline of the patient may improve outcomes. We hypothesize that optimizing the mean arterial pressure (MAP) to the baseline MAP of the patient during cardiac surgery with CPB and during the first 24 hours postoperatively may improve outcomes. STUDY DESIGN: The OPTIPAM trial (NCT05403697) will be a multicenter, randomized, open-label controlled trial testing the superiority of optimized MAP management as compared with a MAP of 65 mm Hg or more during both the intraoperative and postoperative periods in 1,100 patients scheduled for cardiac surgery with CPB. The primary composite end point is the occurrence of acute kidney injury, neurological complications including stroke or postoperative delirium, and death. The secondary end points are hospital and intensive care unit lengths of stay, Day 7 and Day 90 mortality, postoperative cognitive dysfunction on Day 7 and Day 90, and quality of life at Day 7 and Day 90. Two interim analyses will assess the safety of the intervention. CONCLUSION: The OPTIPAM trial will assess the effectiveness of an individualized target of mean arterial pressure in cardiac surgery with CPB in reducing postoperative morbidity. CLINICAL TRIAL REGISTRATION: NCT05403697.

Effect of Moderate Hypothermia vs Normothermia on 30-Day Mortality in Patients With Cardiogenic Shock Receiving Venoarterial Extracorporeal Membrane Oxygenation: A Randomized Clinical Trial.

IMPORTANCE: The optimal approach to the use of venoarterial extracorporeal membrane oxygenation (ECMO) during cardiogenic shock is uncertain. OBJECTIVE: To determine whether early use of moderate hypothermia (33-34 °C) compared with strict normothermia (36-37 °C) improves mortality in patients with cardiogenic shock receiving venoarterial ECMO. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial of patients (who were eligible if they had been endotracheally intubated and were receiving venoarterial ECMO for cardiogenic shock for <6 hours) conducted in the intensive care units at 20 French cardiac shock care centers between October 2016 and July 2019. Of 786 eligible patients, 374 were randomized. Final follow-up occurred in November 2019. INTERVENTIONS: Early moderate hypothermia (33-34 °C; n = 168) for 24 hours or strict normothermia (36-37 °C; n = 166). MAIN OUTCOMES AND MEASURES: The primary outcome was mortality at 30 days. There were 31 secondary outcomes including mortality at days 7, 60, and 180; a composite outcome of death, heart transplant, escalation to left ventricular assist device implantation, or stroke at days 30, 60, and 180; and days without requiring a ventilator or kidney replacement therapy at days 30, 60, and 180. Adverse events included rates of severe bleeding, sepsis, and number of units of packed red blood cells transfused during venoarterial ECMO. RESULTS: Among the 374 patients who were randomized, 334 completed the trial (mean age, 58 [SD, 12] years; 24% women) and were included in the primary analysis. At 30 days, 71 patients (42%) in the moderate hypothermia group had died vs 84 patients (51%) in the normothermia group (adjusted odds ratio, 0.71 [95% CI, 0.45 to 1.13], P = .15; risk difference, -8.3% [95% CI, -16.3% to -0.3%]). For the composite outcome of death, heart transplant, escalation to left ventricular assist device implantation, or stroke at day 30, the adjusted odds ratio was 0.61 (95% CI, 0.39 to 0.96; P = .03) for the moderate hypothermia group compared with the normothermia group and the risk difference was -11.5% (95% CI, -23.2% to 0.2%). Of the 31 secondary outcomes, 30 were inconclusive. The incidence of moderate or severe bleeding was 41% in the moderate hypothermia group vs 42% in the normothermia group. The incidence of infections was 52% in both groups. The incidence of bacteremia was 20% in the moderate hypothermia group vs 30% in the normothermia group. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial involving patients with refractory cardiogenic shock treated with venoarterial ECMO, early application of moderate hypothermia for 24 hours did not significantly increase survival compared with normothermia. However, because the 95% CI was wide and included a potentially important effect size, these findings should be considered inconclusive. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02754193.

Risk Factors for Developing Severe Acute Kidney Injury in Adult Patients With Refractory Postcardiotomy Cardiogenic Shock Receiving Venoarterial Extracorporeal Membrane Oxygenation.

OBJECTIVES: Postcardiotomy cardiogenic shock occurs in 2-6% of patients undergoing cardiac surgery, and 1% of cardiac surgery patients will require mechanical circulatory support using venoarterial extracorporeal membrane oxygenation. Acute kidney injury is a frequent complication in this population and negatively impacts the survival. We aimed to determine whether the timing of extracorporeal membrane oxygenation implantation influences the renal prognosis of these patients. DESIGN: Retrospective observational cohort study between January 2013 and December 2016. SETTING: An 18-bed surgical ICU in a university hospital. PATIENTS: A total of 4,796 consecutive adult patients who underwent cardiac surgery were included in the study, and 347 (7.2%) were assisted with venoarterial extracorporeal membrane oxygenation for refractory postcardiotomy cardiogenic shock. The patients who died during the first 48 hours after venoarterial extracorporeal membrane oxygenation implantation were excluded. The complete-case analysis included 257 patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the occurrence, within 10 days following the venoarterial extracorporeal membrane oxygenation implantation, of a stage 3 acute kidney injury defined by the Kidney Disease: Improving Global Outcomes group. One hundred sixty-nine patients (65.7%) presented with a Kidney Disease: Improving Global Outcomes stage 3 acute kidney injury; 14 patients (5.4%) died before the end of the follow-up period, without developing the primary outcome. Ninety-two percent of patients with Kidney Disease: Improving Global Outcomes 3 acute kidney injury received renal replacement therapy, for a median duration of 7 days (3-16 d). Late implantation of venoarterial extracorporeal membrane oxygenation was independently associated with an increased risk of Kidney Disease: Improving Global Outcomes stage 3 acute kidney injury (odds ratio, 2.81 [95% CI, 1.31-6.07]; p = 0.008). The other factors associated with Kidney Disease: Improving Global Outcomes stage 3 acute kidney injury were preoperative left ventricular ejection fraction (odds ratio, 1.03 [95% CI, 1.01-1.05]; p = 0.007), intraoperative plasma transfusion (odds ratio, 1.13 [95% CI, 1.02-1.26]; p = 0.022), increased bilirubinemia level (odds ratio, 1.013 [95% CI, 1.001-1.026]; p = 0.032), and increased creatinine levels (odds ratio, 1.012 [95% CI, 1.006-1.018]; p < 0.001) on the day of implantation. CONCLUSIONS: Significant kidney dysfunction is particularly frequent in patients with refractory postcardiotomy cardiogenic shock assisted with venoarterial extracorporeal membrane oxygenation. Early implantation of extracorporeal membrane oxygenation may help prevent acute kidney injury.

Timing of ß-Blocker Reintroduction and the Occurrence of Postoperative Atrial Fibrillation after Cardiac Surgery: A Prospective Cohort Study.

BACKGROUND: For cardiac surgery patients under chronic ß-blocker therapy, guidelines recommend their early postoperative reintroduction to decrease the incidence of postoperative atrial fibrillation. The authors hypothesized that the timing of ß-blocker reintroduction affects their effectiveness on the incidence of postoperative atrial fibrillation. METHODS: This multicenter prospective French cohort study included patients on ß-blockers (more than 30 days before surgery) in sinus rhythm without a pacemaker. The primary outcome, time sequence of ß-blocker reintroduction, was analyzed for 192 h after surgery. The secondary outcome, relationship between the occurrence of postoperative atrial fibrillation and timing of ß-blocker reintroduction, was analyzed based on pre- and intraoperative predictors (full and selected sets) according to landmark times (patients in whom atrial fibrillation occurred before a given landmark time were not analyzed). RESULTS: Of 663 patients, ß-blockers were reintroduced for 532 (80%) but for only 261 (39%) patients in the first 48 h after surgery. Median duration before reintroduction was 49.5 h (95% CI, 48 to 51.5 h). Postoperative atrial fibrillation or death (N = 4) occurred in 290 (44%) patients. After performing a landmark analysis to take into account the timing of ß-blocker reintroduction, the adjusted odds ratios (95% CI) for predictor full and selected (increased age, history of paroxysmal atrial fibrillation, and duration of aortic cross clamping) sets for the occurrence of postoperative atrial fibrillation were: adjusted odds ratio (full) = 0.87 (0.58 to 1.32; P = 0.517) and adjusted odds ratio (selected) = 0.84 (0.58 to 1.21; P = 0.338) at 48 h; adjusted odds ratio (full) = 0.64 (0.39 to 1.05; P = 0.076) and adjusted odds ratio (selected) = 0.58 (0.38 to 0.89; P = 0.013) at 72 h; adjusted odds ratio (full) = 0.58 (0.31 to 1.07; P = 0.079) and adjusted odds ratio (selected) = 0.53 (0.31 to 0.91; P = 0.021) at 96 h. CONCLUSIONS: ß-Blockers were reintroduced early (after less than 48 h) in fewer than half of the cardiac surgery patients. Reintroduction decreased postoperative atrial fibrillation occurrence only at later time points and only in the predictor selected set model. These results are an incentive to optimize (timing, doses, or titration) ß-blocker reintroduction after cardiac surgery.

A single-center long-term experience with marginal donor utilization for heart transplantation.

BACKGROUND: To evaluate the early and late outcome of heart transplantation (HT) using marginal (MDs) and optimal donors (ODs). METHODS: Clinical records of recipients transplanted between July 2004 and December 2014 were retrospectively reviewed. MDs were defined as follows: age >55 years, high-dose inotropic support, left ventricular ejection fraction <45%, left ventricular hypertrophy, donor to recipient predicted heart mass ratio <0.86, ischemic time >4 hours. RESULTS: A total of 412 (55%) recipients received an organ from a MD; recipients who received an organ from an OD had less primary graft dysfunction (PGD) (25% vs 38%; P < .001), less acute renal failure (23% vs 34%; P < .001), and higher survival rates (90.2% vs 81.8% at 30 days, 79.5% vs 71.1% at 1 year, 51.8% vs 45.4% at 12 years; P = .01) than recipients who received an organ from a MD. There was no statistically significant difference in 30-day conditional survival between the two groups (survival rates 57.4% vs 55.5% at 12 years; P = .43). PGD, perioperative hemodialysis, and sepsis were independent risk factors of mortality at multivariate analysis. CONCLUSIONS: Utilization of MDs for HT is associated with a higher incidence of PGD and acute renal failure, and a reduction of 30-day survival.

Predictive risk factors for postoperative pneumonia after heart transplantation.

BACKGROUND: Pneumonia is a frequent complication in patients undergoing heart transplantation (HTx) that increases morbidity and mortality in this population. Nevertheless, the risk factors for postoperative pneumonia (POP) are still unknown. The aim of this study was to investigate the predictive risk factors for POP in HTx recipients. METHODS: In this retrospective study, all patients undergoing HTx between January 2014 and December 2015 were included. All cases of POP occurring until hospital discharge were investigated. The study aimed to determine risk factors using univariate and multivariate Cox regression models. Data are expressed in Odds Ratio [95% CI]. P < 0.05 was necessary to reject the null hypothesis. RESULTS: A total of 175 patients were included without any patients being lost to follow-up, and 89 instances of POP were diagnosed in 59 (34%) patients. Enterobacteriaceae and Pseudomonas aeruginosa were the most common pathogens. In the multivariate analysis, the risk factors were preoperative mechanical ventilation (OR 1.42 [1.12-1.80], P < 0.01) and perioperative blood transfusion (OR 1.42 [95% CI: 1.20-1.70], P < 0.01). POP significantly impacted mortality at 30 days (OR: 4 [1.3-12.4], P = 0.01) and 1 year (OR: 6.8 [2.5-8.4], P < 0.01) and was associated with a longer duration of mechanical ventilation, time to weaning from venoarterial extracorporeal membrane oxygenation and stay in an intensive care unit. Plasma exchanges and intravenous administration of immunoglobulins did not increase the risk of POP. CONCLUSION: After HTx, preoperative mechanical ventilation and blood transfusion were risk factors for POP and were associated with increased mortality. Enterobacteriaceae and Pseudomonas aeruginosa are the most common pathogens of POP.

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.

Levosimendan in the light of the results of the recent randomized controlled trials: an expert opinion paper.

Despite interesting and unique pharmacological properties, levosimendan has not proven a clear superiority to placebo in the patient populations that have been enrolled in the various recent multicenter randomized controlled trials. However, the pharmacodynamic effects of levosimendan are still considered potentially very useful in a number of specific situations.Patients with decompensated heart failure requiring inotropic support and receiving beta-blockers represent the most widely accepted indication. Repeated infusions of levosimendan are increasingly used to facilitate weaning from dobutamine and avoid prolonged hospitalizations in patients with end-stage heart failure, awaiting heart transplantation or left ventricular assist device implantation. New trials are under way to confirm or refute the potential usefulness of levosimendan to facilitate weaning from veno-arterial ECMO, to treat cardiogenic shock due to left or right ventricular failure because the current evidence is mostly retrospective and requires confirmation with better-designed studies. Takotsubo syndrome may represent an ideal target for this non-adrenergic inotrope, but this statement also relies on expert opinion. There is no benefit from levosimendan in patients with septic shock. The two large trials evaluating the prophylactic administration of levosimendan (pharmacological preconditioning) in cardiac surgical patients with poor left ventricular ejection fraction could not show a significant reduction in their composite endpoints reflecting low cardiac output syndrome with respect to placebo. However, the subgroup of those who underwent isolated CABG appeared to have a reduction in mortality. A new study will be required to confirm this exploratory finding.Levosimendan remains a potentially useful inodilator agent in a number of specific situations due to its unique pharmacological properties. More studies are needed to provide a higher level of proof regarding these indications.

Colour Doppler ultrasound after major cardiac surgery improves diagnostic accuracy of the pulmonary infection score in acute respiratory failure: A prospective observational study.

BACKGROUND: Postoperative pneumonia is a frequent complication after cardiac surgery, and its diagnosis is difficult. Little is known about the diagnostic accuracy of lung ultrasound (LUS) in the detection of pneumonia in cardiac surgical patients. The substitution of chest radiography by colour Doppler LUS (LUS-sCPIS) in the simplified clinical pulmonary infection score (sCPIS) could improve the diagnosis of pneumonia following cardiac surgery. OBJECTIVE: The aim of this study was to compare the diagnostic accuracy of LUS-sCPIS and of sCPIS alone in the detection of postoperative pneumonia after cardiac surgery. DESIGN: A prospective study of diagnostic accuracy. SETTING: A Surgical Intensive Care Unit of a French University Hospital. PATIENTS: Fifty-one patients with acute respiratory failure within 72 h after cardiac surgery were enrolled between January and May 2015. MAIN OUTCOME MEASURE: The two index tests, LUS-sCPIS and sCPIS, were calculated for all patients at the onset of acute respiratory failure. The reference standard for the diagnosis of pneumonia was based on the consensus of three physicians, blind to the sCPIS and LUS-sCPIS data, based on a posthoc review of all the clinical, radiological and microbiological evidence. The diagnostic accuracy of LUS-sCPIS was compared with that of sCPIS in the detection of postoperative pneumonia. RESULTS: Pneumonia was diagnosed in 26 out of 51 patients. The LUS-sCPIS detected the presence of pneumonia with a sensitivity of 92% (95% CI 0.85 to 0.99) and a specificity of 68% (95% CI 0.55 to 0.81). The sCPIS detected the presence of pneumonia with a sensitivity of 35% (95% CI 0.22 to 0.48) and a specificity of 84% (95% CI 0.74 to 0.94). The area under the curve (AUC) of LUS-sCPIS at 0.80 (95% CI 0.69 to 0.91) was higher than the AUC of sCPIS at 0.59 (95% CI 0.47 to 0.71; P = 0.0008). CONCLUSION: Compared with sCPIS, LUS-sCPIS improved diagnostic accuracy in the detection of postoperative pneumonia in patients with acute respiratory failure after cardiac surgery. It could be a useful bedside tool to guide pneumonia management. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03279887.

Bilateral Internal Thoracic Artery Grafting in Women: A Word of Caution.

BACKGROUND: Despite the superior hemodynamic performance of internal thoracic arteries, total arterial revascularization with exclusive bilateral internal thoracic arteries (BITA) is less frequently used especially in specific subsets of patients, including females. We report our experience with total arterial revascularization with exclusive BITA regardless of sex and analyze the impact of female sex on the early and midterm outcomes. METHODS: Total arterial revascularization with exclusive BITA was performed with equal frequency in females (79/99, 80%) and males (392/477, 82%; P = .68) undergoing isolated CABG for 3-vessel disease. Pre, intra and postoperative data were compared between these two groups. RESULTS: Complete revascularization was achieved in 77% of females and 72% of males (P = .08). Early mortality did not differ between the groups (6.3% versus 4.6%, P = .7). The incidence of re-sternotomy for bleeding, postoperative stroke, myocardial infarction, new onset atrial fibrillation, and hemofiltration for renal failure did not differ between the two groups. However, there were significantly more wound revision for combined superficial and deep sternal wound infection in females (26.5% versus 5.1%, P = .0001). Nevertheless, midterm survival, freedom from repeat revascularization, myocardial infarction, stroke, and major adverse cardiovascular and cerebral events at five years were very good and compared favorably between females and males. CONCLUSIONS: Our findings suggest that total arterial myocardial revascularization with exclusive internal thoracic arteries in females carries the same midterm benefits as in males. Early outcomes are comparable except for a higher incidence of wound revision for combined superficial and deep sternal wound infections in females compared to males. Benefits of bilateral internal thoracic artery grafting in females should be weighed against increased risk of early wound revision.

Lateral Membrane-Specific MAGUK CASK Down-Regulates NaV1.5 Channel in Cardiac Myocytes.

RATIONALE: Mechanisms underlying membrane protein localization are crucial in the proper function of cardiac myocytes. The main cardiac sodium channel, NaV1.5, carries the sodium current (INa) that provides a rapid depolarizing current during the upstroke of the action potential. Although enriched in the intercalated disc, NaV1.5 is present in different membrane domains in myocytes and interacts with several partners. OBJECTIVE: To test the hypothesis that the MAGUK (membrane-associated guanylate kinase) protein CASK (calcium/calmodulin-dependent serine protein kinase) interacts with and regulates NaV1.5 in cardiac myocytes. METHODS AND RESULTS: Immunostaining experiments showed that CASK localizes at lateral membranes of cardiac myocytes, in association with dystrophin. Whole-cell patch clamp showed that CASK-silencing increases INa in vitro. In vivo CASK knockdown similarly increased INa recorded in freshly isolated myocytes. Pull-down experiments revealed that CASK directly interacts with the C-terminus of NaV1.5. CASK silencing reduces syntrophin expression without affecting NaV1.5 and dystrophin expression levels. Total Internal Reflection Fluorescence microscopy and biotinylation assays showed that CASK silencing increased the surface expression of NaV1.5 without changing mRNA levels. Quantification of NaV1.5 expression at the lateral membrane and intercalated disc revealed that the lateral membrane pool only was increased upon CASK silencing. The protein transport inhibitor brefeldin-A prevented INa increase in CASK-silenced myocytes. During atrial dilation/remodeling, CASK expression was reduced but its localization remained unchanged. CONCLUSION: This study constitutes the first description of an unconventional MAGUK protein, CASK, which directly interacts with NaV1.5 channel and controls its surface expression at the lateral membrane by regulating ion channel trafficking.

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.

New Modalities for the Administration of Inhaled Nitric Oxide in Intensive Care Units After Cardiac Surgery or for Neonatal Indications: A Prospective Observational Study.

BACKGROUND: Nitric oxide (NO) has a well-known efficacy in pulmonary hypertension (PH), with wide use for 20 years in many countries. The objective of this study was to describe the current use of NO in real life and the gap with the guidelines. METHODS: This is a multicenter, prospective, observational study on inhaled NO administered through an integrated delivery and monitoring device and indicated for PH according to the market authorizations. The characteristics of NO therapy and ventilation modes were observed. Concomitant pulmonary vasodilator treatments, safety data, and outcome were also collected. Quantitative data are expressed as median (25th, 75th percentile). RESULTS: Over 1 year, 236 patients were included from 14 equipped and trained centers: 117 adults and 81 children with PH associated with cardiac surgery and 38 neonates with persistent PH of the newborn. Inhaled NO was initiated before intensive care unit (ICU) admission in 57%, 12.7%, and 38.9% with an initial dose of 10 (10, 15) ppm, 20 (18, 20) ppm, and 17 (11, 20) ppm, and a median duration of administration of 3.9 (1.9, 6.1) days, 3.8 (1.8, 6.8) days, and 3.1 (1.0, 5.7) days, respectively, for the adult population, pediatric cardiac group, and newborns. The treatment was performed using administration synchronized to the mechanical ventilation. The dose was gradually decreased before withdrawal in 86% of the cases according to the usual procedure of each center. Adverse events included rebound effect for 3.4% (95% confidence interval [CI], 0.9%-8.5%) of adults, 1.2% (95% CI, 0.0%-6.7%) of children, and 2.6% (95% CI, 0.1%-13.8%) of neonates and methemoglobinemia exceeded 2.5% for 5 of 62 monitored patients. Other pulmonary vasodilators were associated with NO in 23% of adults, 95% of children, and 23.7% of neonates. ICU stay was respectively 10 (6, 22) days, 7.5 (5.5, 15) days, and 9 (8, 15) days and ICU mortality was 22.2%, 6.2%, and 7.9% for adults, children, and neonates, respectively. CONCLUSIONS: This study confirms the safety of NO therapy in the 3 populations with a low rate of rebound effect. Gradual withdrawal of NO combined with pulmonary vasodilators are current practices in this population. The use of last-generation NO devices allowed good compliance with recommendations.

Effect of Xenon Anesthesia Compared to Sevoflurane and Total Intravenous Anesthesia for Coronary Artery Bypass Graft Surgery on Postoperative Cardiac Troponin Release: An International, Multicenter, Phase 3, Single-blinded, Randomized Noninferiority Trial.

BACKGROUND: Ischemic myocardial damage accompanying coronary artery bypass graft surgery remains a clinical challenge. We investigated whether xenon anesthesia could limit myocardial damage in coronary artery bypass graft surgery patients, as has been reported for animal ischemia models. METHODS: In 17 university hospitals in France, Germany, Italy, and The Netherlands, low-risk elective, on-pump coronary artery bypass graft surgery patients were randomized to receive xenon, sevoflurane, or propofol-based total intravenous anesthesia for anesthesia maintenance. The primary outcome was the cardiac troponin I concentration in the blood 24 h postsurgery. The noninferiority margin for the mean difference in cardiac troponin I release between the xenon and sevoflurane groups was less than 0.15 ng/ml. Secondary outcomes were the safety and feasibility of xenon anesthesia. RESULTS: The first patient included at each center received xenon anesthesia for practical reasons. For all other patients, anesthesia maintenance was randomized (intention-to-treat: n = 492; per-protocol/without major protocol deviation: n = 446). Median 24-h postoperative cardiac troponin I concentrations (ng/ml [interquartile range]) were 1.14 [0.76 to 2.10] with xenon, 1.30 [0.78 to 2.67] with sevoflurane, and 1.48 [0.94 to 2.78] with total intravenous anesthesia [per-protocol]). The mean difference in cardiac troponin I release between xenon and sevoflurane was -0.09 ng/ml (95% CI, -0.30 to 0.11; per-protocol: P = 0.02). Postoperative cardiac troponin I release was significantly less with xenon than with total intravenous anesthesia (intention-to-treat: P = 0.05; per-protocol: P = 0.02). Perioperative variables and postoperative outcomes were comparable across all groups, with no safety concerns. CONCLUSIONS: In postoperative cardiac troponin I release, xenon was noninferior to sevoflurane in low-risk, on-pump coronary artery bypass graft surgery patients. Only with xenon was cardiac troponin I release less than with total intravenous anesthesia. Xenon anesthesia appeared safe and feasible.

Aprotinin vs. tranexamic acid in isolated coronary artery bypass surgery: A multicentre observational study.

BACKGROUND: Aprotinin appears to be more efficacious than lysine analogues to reduce bleeding and transfusion of blood products in high-transfusion-risk cardiac surgical patients. However, in isolated coronary artery bypass graft (CABG) surgery, the results from head-to-head trials remain less conclusive. OBJECTIVE: Our objective was to compare the efficacies and safety of aprotinin and tranexamic acid (TXA) in patients undergoing isolated on-pump CABG. DESIGN: A multicentre before-and-after study pooling individual data from published trials and unpublished data from three other databases. SETTING: Four tertiary care teaching hospitals (Haut-Lévêque Hospital in Bordeaux, Pitié-Salpêtrière Hospital and Bichat-Claude Bernard Hospital in Paris, and Laennec Hospital in Nantes). PATIENTS: We included data of 2496 isolated on-pump CABG surgery patients who received either aprotinin between November 2003 and May 2008 (n = 1267) or TXA between November 2007 and November 2013 (n = 1229). MAIN OUTCOME MEASURES: The primary outcome was total blood loss within 24 h after operation. Secondary outcomes were transfusion of blood products, reoperation for bleeding, renal replacement therapy, ICU length of stay and in-hospital mortality. RESULTS: Adjusted mean (SEM) 24-h blood loss after surgery [483 (11) vs. 634 (11) ml, P < 0.0001] and the proportion of patients requiring intraoperative blood product transfusion (32.7 vs. 46.5%, P = 0.01) were lower in aprotinin-treated patients. No difference was observed with regard to reoperations for bleeding, renal replacement therapy and in-hospital mortality. However, patients receiving aprotinin had a significantly shorter adjusted ICU length of stay. CONCLUSION: In patients undergoing isolated CABG, aprotinin was more effective than TXA in reducing postoperative blood loss, and no safety concerns were identified. The benefits of aprotinin should be considered when evaluating the risk of major blood loss and transfusion in patients scheduled for isolated CABG surgery.

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.

Early High-Volume Hemofiltration versus Standard Care for Post-Cardiac Surgery Shock. The HEROICS Study.

RATIONALE: Post-cardiac surgery shock is associated with high morbidity and mortality. By removing toxins and proinflammatory mediators and correcting metabolic acidosis, high-volume hemofiltration (HVHF) might halt the vicious circle leading to death by improving myocardial performance and reducing vasopressor dependence. OBJECTIVES: To determine whether early HVHF decreases all-cause mortality 30 days after randomization. METHODS: This prospective, multicenter randomized controlled trial included patients with severe shock requiring high-dose catecholamines 3-24 hours post-cardiac surgery who were randomized to early HVHF (80 ml/kg/h for 48 h), followed by standard-volume continuous venovenous hemodiafiltration (CVVHDF) until resolution of shock and recovery of renal function, or conservative standard care, with delayed CVVHDF only for persistent, severe acute kidney injury. MEASUREMENTS AND MAIN RESULTS: On Day 30, 40 of 112 (36%) HVHF and 40 of 112 (36%) control subjects (odds ratio, 1.00; 95% confidence interval, 0.64-1.56; P = 1.00) had died; only 57% of the control subjects had received renal-replacement therapy. Between-group survivors' Day-60, Day-90, intensive care unit, and in-hospital mortality rates, Day-30 ventilator-free days, and renal function recovery were comparable. HVHF patients experienced faster correction of metabolic acidosis and tended to be more rapidly weaned off catecholamines but had more frequent hypophosphatemia, metabolic alkalosis, and thrombocytopenia. CONCLUSIONS: For patients with post-cardiac surgery shock requiring high-dose catecholamines, the early HVHF onset for 48 hours, followed by standard volume until resolution of shock and recovery of renal function, did not lower Day-30 mortality and did not impact other important patient-centered outcomes compared with a conservative strategy with delayed CVVHDF initiation only for patients with persistent, severe acute kidney injury. Clinical trial registered with www.clinicaltrials.gov (NCT 01077349).

Human epicardial adipose tissue induces fibrosis of the atrial myocardium through the secretion of adipo-fibrokines.

AIMS: Recent studies have reported a relationship between the abundance of epicardial adipose tissue (EAT) and the risk of cardiovascular diseases including atrial fibrillation (AF). However, the underlying mechanisms are unknown. The aim of this study was to examine the effects of the secretome of human EAT on the histological properties of the myocardium. METHODS AND RESULTS: Samples of EAT and subcutaneous adipose (SAT), obtained from 39 patients undergoing coronary bypass surgery, were analysed and tested in an organo-culture model of rat atria to evaluate the fibrotic properties of human fat depots. The EAT secretome induced global fibrosis (interstitial and peripheral) of rat atria in organo-culture conditions. Activin A was highly expressed in EAT compared with SAT and promoted atrial fibrosis, an effect blocked using neutralizing antibody. In addition, Activin A levels were enhanced in patients with low left-ventricular function. In sections of human atrial and ventricular myocardium, adipose and myocardial tissues were in close contact, together with fibrosis. CONCLUSION: This study provides the first evidence that the secretome from EAT promotes myocardial fibrosis through the secretion of adipo-fibrokines such as Activin A.

Modification of the ß-Adrenoceptor Stimulation Pathway in Zucker Obese and Obese Diabetic Rat Myocardium.

OBJECTIVES: Although metabolic syndrome is associated with increased sympathetic activity that chronically stimulates ß-adrenoceptors, the ß-adrenoceptor signaling pathway has been poorly studied in this situation. We studied the ß-adrenoceptor signaling pathway in Zucker lean, obese, and obese diabetic rats. DESIGN: Experimental, prospective study. SETTING: University medical research laboratory. SUBJECTS: Adult male Zucker lean (control), obese, and obese diabetic rats. INTERVENTIONS: The effects of ß-adrenoceptor stimulation were investigated in vitro in isolated left ventricular papillary muscles in control, obese, and obese diabetic rats. ß1-, ß2-, and ß3-adrenoceptors and multidrug resistance-associated protein 4 were quantified by Western Blotting. Triglyceride, cholesterol, leptin, adiponectin, and C-peptide plasma concentrations were measured. Data are mean ± SD. MEASUREMENTS AND MAIN RESULTS: Hyperlipidemia, high leptin, and C-peptide concentrations were observed in obese and obese diabetic strains, whereas hyperglycemia occurred only in the diabetic strain. The positive inotropic effect of isoproterenol was slightly reduced in obese rats (183% ± 11% of baseline; p = 0.003; n = 7) and markedly reduced in obese diabetic rats (137% ± 18% of baseline; p < 0.001; n = 10) when compared with control rats (210% ± 17% of baseline; n = 9). ß1-adrenoceptors were down-regulated in obese (-41%; p = 0.02) and diabetic (-54%; p = 0.003) when compared with control rats, whereas ß3-adrenoceptors and multidrug resistance-associated protein expression remained unchanged. Direct stimulation of adenylate cyclase with forskolin or administration of 3',5'-cyclic adenosine monophosphate suggests that subtle impairments also occurred beside the down-regulation of ß1-adrenoceptor. CONCLUSIONS: The positive inotropic effect of ß-adrenoceptor stimulation is slightly decreased in Zucker obese rats and was more markedly decreased in Zucker diabetic rats. These decreases are mainly related to ß1-adrenoceptor down-regulation.