Rationale and design of the early valve replacement in severe asymptomatic aortic stenosis trial.

BACKGROUND: Aortic valve replacement in asymptomatic severe aortic stenosis is controversial. The Early valve replacement in severe ASYmptomatic Aortic Stenosis (EASY-AS) trial aims to determine whether early aortic valve replacement improves clinical outcomes, quality of life and cost-effectiveness compared to a guideline recommended strategy of 'watchful waiting'. METHODS: In a pragmatic international, open parallel group randomized controlled trial (NCT04204915), 2844 patients with severe aortic stenosis will be randomized 1:1 to either a strategy of early (surgical or transcatheter) aortic valve replacement or aortic valve replacement only if symptoms or impaired left ventricular function develop, or other cardiac surgery becomes nessessary. Exclusion criteria include other severe valvular disease, planned cardiac surgery, ejection fraction <50%, previous aortic valve replacement or life expectancy <2 years. The primary outcome is a composite of cardiovascular mortality or heart failure hospitalization. The primary analysis will be undertaken when 663 primary events have accrued, providing 90% power to detect a reduction in the primary endpoint from 27.7% to 21.6% (hazard ratio 0.75). Secondary endpoints include disability-free survival, days alive and out of hospital, major adverse cardiovascular events and quality of life. RESULTS: Recruitment commenced in March 2020 and is open in the UK, Australia, New Zealand, and Serbia. Feasibility requirements were met in July 2022, and the main phase opened in October 2022, with additional international centers in set-up. CONCLUSIONS: The EASY-AS trial will establish whether a strategy of early aortic valve replacement in asymptomatic patients with severe aortic stenosis reduces cardiovascular mortality or heart failure hospitalization and improves other important outcomes.

Prophylactic corticosteroids for cardiopulmonary bypass in adult cardiac surgery.

BACKGROUND: Cardiac surgery triggers a strong inflammatory reaction, which carries significant clinical consequences. Corticosteroids have been suggested as a potential perioperative strategy to reduce inflammation and help prevent postoperative complications. However, the safety and effectiveness of perioperative corticosteroid use in adult cardiac surgery is uncertain. This is an update of the 2011 review with 18 studies added. OBJECTIVES: Primary objective: to estimate the effects of prophylactic corticosteroid use in adults undergoing cardiac surgery with cardiopulmonary bypass on the: - co-primary endpoints of mortality, myocardial complications, and pulmonary complications; and - secondary outcomes including atrial fibrillation, infection, organ injury, known complications of steroid therapy, prolonged mechanical ventilation, prolonged postoperative stay, and cost-effectiveness. SECONDARY OBJECTIVE: to explore the role of characteristics of the study cohort and specific features of the intervention in determining the treatment effects via a series of prespecified subgroup analyses. SEARCH METHODS: We used standard, extensive Cochrane search methods to identify randomised studies assessing the effect of corticosteroids in adult cardiac surgery. The latest searches were performed on 14 October 2022. SELECTION CRITERIA: We included randomised controlled trials in adults (over 18 years, either with a diagnosis of coronary artery disease or cardiac valve disease, or who were candidates for cardiac surgery with the use of cardiopulmonary bypass), comparing corticosteroids with no treatments. There were no restrictions with respect to length of the follow-up period. All selected studies qualified for pooling of results for one or more endpoints. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were all-cause mortality, and cardiac and pulmonary complications. Secondary outcomes were infectious complications, gastrointestinal bleeding, occurrence of new post-surgery atrial fibrillation, re-thoracotomy for bleeding, neurological complications, renal failure, inotropic support, postoperative bleeding, mechanical ventilation time, length of stays in the intensive care unit (ICU) and hospital, patient quality of life, and cost-effectiveness. We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: This updated review includes 72 randomised trials with 17,282 participants (all 72 trials with 16,962 participants were included in data synthesis). Four trials (6%) were considered at low risk of bias in all the domains. The median age of participants included in the studies was 62.9 years. Study populations consisted mainly (89%) of low-risk, first-time coronary artery bypass grafting (CABG) or valve surgery. The use of perioperative corticosteroids may result in little to no difference in all-cause mortality (risk with corticosteroids: 25 to 36 per 1000 versus 33 per 1000 with placebo or no treatment; risk ratio (RR) 0.90, 95% confidence interval (CI) 0.75 to 1.07; 25 studies, 14,940 participants; low-certainty evidence). Corticosteroids may increase the risk of myocardial complications (68 to 86 per 1000) compared with placebo or no treatment (66 per 1000; RR 1.16, 95% CI 1.04 to 1.31; 25 studies, 14,766 participants; low-certainty evidence), and may reduce the risk of pulmonary complications (risk with corticosteroids: 61 to 77 per 1000 versus 78 per 1000 with placebo/no treatment; RR 0.88, 0.78 to 0.99; 18 studies, 13,549 participants; low-certainty evidence). Analyses of secondary endpoints showed that corticosteroids may reduce the incidence of infectious complications (risk with corticosteroids: 94 to 113 per 1000 versus 123 per 1000 with placebo/no treatment; RR 0.84, 95% CI 0.76 to 0.92; 28 studies, 14,771 participants; low-certainty evidence). Corticosteroids may result in little to no difference in incidence of gastrointestinal bleeding (risk with corticosteroids: 9 to 17 per 1000 versus 10 per 1000 with placebo/no treatment; RR 1.21, 95% CI 0.87 to 1.67; 6 studies, 12,533 participants; low-certainty evidence) and renal failure (risk with corticosteroids: 23 to 35 per 1000 versus 34 per 1000 with placebo/no treatment; RR 0.84, 95% CI 0.69 to 1.02; 13 studies, 12,799; low-certainty evidence). Corticosteroids may reduce the length of hospital stay, but the evidence is very uncertain (-0.5 days, 0.97 to 0.04 fewer days of length of hospital stay compared with placebo/no treatment; 25 studies, 1841 participants; very low-certainty evidence). The results from the two largest trials included in the review possibly skew the overall findings from the meta-analysis. AUTHORS' CONCLUSIONS: A systematic review of trials evaluating the organ protective effects of corticosteroids in cardiac surgery demonstrated little or no treatment effect on mortality, gastrointestinal bleeding, and renal failure. There were opposing treatment effects on cardiac and pulmonary complications, with evidence that corticosteroids may increase cardiac complications but reduce pulmonary complications; however, the level of certainty for these estimates was low. There were minor benefits from corticosteroid therapy for infectious complications, but the evidence on hospital length of stay was very uncertain. The inconsistent treatment effects across different outcomes and the limited data on high-risk groups reduced the applicability of the findings. Further research should explore the role of these drugs in specific, vulnerable cohorts.

Surgical or percutaneous coronary revascularization for heart failure: an in silico model using routinely collected health data to emulate a clinical trial.

AIMS: The choice of revascularization with coronary artery bypass grafting (CABG) vs. percutaneous coronary intervention (PCI) in people with ischaemic left ventricular dysfunction is not guided by high-quality evidence. METHODS AND RESULTS: A trial of CABG vs. PCI in people with heart failure (HF) was modelled in silico using routinely collected healthcare data. The in silico trial cohort was selected by matching the target trial cohort, identified from Hospital Episode Statistics in England, with individual patient data from the Surgical Treatment for Ischemic Heart Failure (STICH) trial. Allocation to CABG vs. complex PCI demonstrated random variation across administrative regions in England and was a valid statistical instrument. The primary outcome was 5-year all-cause mortality or cardiovascular hospitalization. Instrumental variable analysis (IVA) was used for the primary analysis. Results were expressed as average treatment effects (ATEs) with 95 confidence intervals (CIs). The target population included 13 519 HF patients undergoing CABG or complex PCI between April 2009 and March 2015. After matching, the emulated trial cohort included 2046 patients. The unadjusted primary outcome rate was 51.1 in the CABG group and 70.0 in the PCI group. IVA of the emulated cohort showed that CABG was associated with a lower risk of the primary outcome (ATE 16.2, 95 CI 20.6 to 11.8), with comparable estimates in the unmatched target population (ATE 15.5, 95 CI 17.5 to 13.5). CONCLUSION: In people with HF, in silico modelling suggests that CABG is associated with fewer deaths or cardiovascular hospitalizations at 5 years vs. complex PCI. A pragmatic clinical trial is needed to test this hypothesis and this trial would be feasible.

Effects of interventions targeting the systemic inflammatory response to cardiac surgery on clinical outcomes in adults.

BACKGROUND: Organ injury is a common and severe complication of cardiac surgery that contributes to the majority of deaths. There are no effective treatment or prevention strategies. It has been suggested that innate immune system activation may have a causal role in organ injury. A wide range of organ protection interventions targeting the innate immune response have been evaluated in randomised controlled trials (RCTs) in adult cardiac surgery patients, with inconsistent results in terms of effectiveness. OBJECTIVES: The aim of the review was to summarise the results of RCTs of organ protection interventions targeting the innate immune response in adult cardiac surgery. The review considered whether the interventions had a treatment effect on inflammation, important clinical outcomes, or both. SEARCH METHODS: CENTRAL, MEDLINE, Embase, conference proceedings and two trial registers were searched on October 2022 together with reference checking to identify additional studies. SELECTION CRITERIA: RCTs comparing organ protection interventions targeting the innate immune response versus placebo or no treatment in adult patients undergoing cardiac surgery where the treatment effect on innate immune activation and on clinical outcomes of interest were reported. DATA COLLECTION AND ANALYSIS: Searches, study selection, quality assessment, and data extractions were performed independently by pairs of authors. The primary inflammation outcomes were peak IL-6 and IL-8 concentrations in blood post-surgery. The primary clinical outcome was in-hospital or 30-day mortality. Treatment effects were expressed as risk ratios (RR) and standardised mean difference (SMD) with 95% confidence intervals (CI). Meta-analyses were performed using random effects models, and heterogeneity was assessed using I2. MAIN RESULTS: A total of 40,255 participants from 328 RCTs were included in the synthesis. The effects of treatments on IL-6 (SMD -0.77, 95% CI -0.97 to -0.58, I2 = 92%) and IL-8 (SMD -0.92, 95% CI -1.20 to -0.65, I2 = 91%) were unclear due to heterogeneity. Heterogeneity for inflammation outcomes persisted across multiple sensitivity and moderator analyses. The pooled treatment effect for in-hospital or 30-day mortality was RR 0.78, 95% CI 0.68 to 0.91, I2 = 0%, suggesting a significant clinical benefit. There was little or no treatment effect on mortality when analyses were restricted to studies at low risk of bias. Post hoc analyses failed to demonstrate consistent treatment effects on inflammation and clinical outcomes. Levels of certainty for pooled treatment effects on the primary outcomes were very low. AUTHORS' CONCLUSIONS: A systematic review of RCTs of organ protection interventions targeting innate immune system activation did not resolve uncertainty as to the effectiveness of these treatments, or the role of innate immunity in organ injury following cardiac surgery.

Minithoracotomy vs Conventional Sternotomy for Mitral Valve Repair: A Randomized Clinical Trial.

Importance: The safety and effectiveness of mitral valve repair via thoracoscopically-guided minithoracotomy (minithoracotomy) compared with median sternotomy (sternotomy) in patients with degenerative mitral valve regurgitation is uncertain. Objective: To compare the safety and effectiveness of minithoracotomy vs sternotomy mitral valve repair in a randomized trial. Design, Setting, and Participants: A pragmatic, multicenter, superiority, randomized clinical trial in 10 tertiary care institutions in the UK. Participants were adults with degenerative mitral regurgitation undergoing mitral valve repair surgery. Interventions: Participants were randomized 1:1 with concealed allocation to receive either minithoracotomy or sternotomy mitral valve repair performed by an expert surgeon. Main Outcomes and Measures: The primary outcome was physical functioning and associated return to usual activities measured by change from baseline in the 36-Item Short Form Health Survey (SF-36) version 2 physical functioning scale 12 weeks after the index surgery, assessed by an independent researcher masked to the intervention. Secondary outcomes included recurrent mitral regurgitation grade, physical activity, and quality of life. The prespecified safety outcomes included death, repeat mitral valve surgery, or heart failure hospitalization up to 1 year. Results: Between November 2016 and January 2021, 330 participants were randomized (mean age, 67 years, 100 female [30%]); 166 were allocated to minithoracotomy and 164 allocated to sternotomy, of whom 309 underwent surgery and 294 reported the primary outcome. At 12 weeks, the mean between-group difference in the change in the SF-36 physical function T score was 0.68 (95% CI, -1.89 to 3.26). Valve repair rates (≈ 96%) were similar in both groups. Echocardiography demonstrated mitral regurgitation severity as none or mild for 92% of participants at 1 year with no difference between groups. The composite safety outcome occurred in 5.4% (9 of 166) of patients undergoing minithoracotomy and 6.1% (10 of 163) undergoing sternotomy at 1 year. Conclusions and relevance: Minithoracotomy is not superior to sternotomy in recovery of physical function at 12 weeks. Minithoracotomy achieves high rates and quality of valve repair and has similar safety outcomes at 1 year to sternotomy. The results provide evidence to inform shared decision-making and treatment guidelines. Trial Registration: isrctn.org Identifier: ISRCTN13930454.

Trends of repeat revascularization choice in patients with prior coronary artery bypass surgery.

OBJECTIVE: To examine rates and predictors repeat revascularization strategies (percutaneous coronary intervention [PCI] and coronary artery bypass grafting [CABG]) in patients with prior CABG. METHODS: Using the National Inpatient Sample, patients with a history of CABG hospitalized for revascularization by PCI or CABG from January 2004 to September 2015 were included. Regression analyses were performed to examine predictors of receipt of either revascularization strategy as well as in-hospital outcomes. RESULTS: The rate of redo CABG doubled between 2004 (5.3%) and 2015 (10.3%). Patients who underwent redo CABG were more comorbid and experienced significantly worse major adverse cardiovascular and cerebrovascular events (odds ratio [OR]: 5.36 95% CI 5.11-5.61), mortality (OR 2.84 95% CI 2.60,-3.11), bleeding (OR 5.97 95% CI 5.44-6.55) and stroke (OR 2.15 95% CI 1.92-2.41), but there was no difference in cardiac complications between groups. Thoracic complications were high in patients undergoing redo CABG (8%), especially in females. Factors favoring receipt of redo CABG compared to PCI included male sex, age < 80 years, and absence of diabetes and renal failure. CONCLUSION: Reoperation in patients with prior CABG has doubled in the United States over a 12-year period. Patients undergoing redo CABG are more complex and associated with worse clinical outcomes than those receiving PCI.

Pharmacological interventions for the prevention of renal injury in surgical patients: a systematic literature review and meta-analysis.

BACKGROUND: The aim of this systematic review was to summarise the results of randomised controlled trials (RCTs) that have evaluated pharmacological interventions for renoprotection in people undergoing surgery. METHODS: Searches were conducted to update a previous review using the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE to August 23, 2019. RCTs evaluating the use of pharmacological interventions for renal protection in the perioperative period were included. The co-primary outcome measures were 30-day mortality and acute kidney injury (AKI). Pooled effect estimates were expressed as risk ratios (RRs) (95% confidence intervals). RESULTS: We included 228 trials enrolling 56 047 patients. Twenty-three trials were considered to be at low risk of bias across all domains. Atrial natriuretic peptides (14 trials; n=2207) reduced 30-day mortality (RR: 0.63 [0.41, 0.97]) and AKI events (RR: 0.43 [0.33, 0.56]) without heterogeneity. These effects were consistent across cardiac surgery and vascular surgery subgroups, and in sensitivity analyses restricted to studies at low risk of bias. Inodilators (13 trials; n=2941) reduced mortality (RR: 0.71 [0.53, 0.94]) and AKI events (RR: 0.65 [0.50, 0.85]) in the primary analysis and in cardiac surgery cohorts. Vasopressors (4 trials; n=1047) reduced AKI (RR: 0.56 [0.36, 0.86]). Nitric oxide donors, alpha-2-agonists, and calcium channel blockers reduced AKI in primary analyses, but not after exclusion of studies at risk of bias. Overall, assessment of the certainty of the effect estimates was low. CONCLUSIONS: There are multiple effective pharmacological renoprotective interventions for people undergoing surgery.

Patient blood management interventions do not lead to important clinical benefits or cost-effectiveness for major surgery: a network meta-analysis.

BACKGROUND: Patient blood management (PBM) interventions aim to improve clinical outcomes by reducing bleeding and transfusion. We assessed whether existing evidence supports the routine use of combinations of these interventions during and after major surgery. METHODS: Five systematic reviews and a National Institute of Health and Care Excellence health economic review of trials of common PBM interventions enrolling participants of any age undergoing surgery were updated. The last search was on June 1, 2019. Studies in trauma, burns, gastrointestinal haemorrhage, gynaecology, dentistry, or critical care were excluded. The co-primary outcomes were: risk of receiving red cell transfusion and 30-day or hospital all-cause mortality. Treatment effects were estimated using random-effects models and risk ratios (RR) with 95% confidence intervals (CIs). Heterogeneity assessments used I2. Network meta-analyses used a frequentist approach. The protocol was registered prospectively (PROSPERO CRD42018085730). RESULTS: Searches identified 393 eligible randomised controlled trials enrolling 54 917 participants. PBM interventions resulted in a reduction in exposure to red cell transfusion (RR=0.60; 95% CI 0.57, 0.63; I2=77%), but had no statistically significant treatment effect on 30-day or hospital mortality (RR=0.93; 95% CI 0.81, 1.07; I2=0%). Treatment effects were consistent across multiple secondary outcomes, sub-groups and sensitivity analyses that considered clinical setting, type of intervention, and trial quality. Network meta-analysis did not demonstrate additive benefits from the use of multiple interventions. No trial demonstrated that PBM was cost-effective. CONCLUSIONS: In randomised trials, PBM interventions do not have important clinical benefits beyond reducing bleeding and transfusion in people undergoing major surgery.

Activation of the innate immune response and organ injury after cardiac surgery: a systematic review and meta-analysis of randomised trials and analysis of individual patient data from randomised and non-randomised studies.

BACKGROUND: It is unclear whether the innate immune response represents a therapeutic target for organ protection strategies in cardiac surgery. METHODS: A systematic review of trials of interventions targeting the inflammatory response to cardiac surgery reporting treatment effects on both innate immune system cytokines and organ injury was performed. The protocol was registered at the International Prospective Register of Systematic Reviews: CRD42020187239. Searches of the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase were performed. Random-effects meta-analyses were used for the primary analysis. A separate analysis of individual patient data from six studies (n=785) explored sources of heterogeneity for treatment effects on cytokine levels. RESULTS: Searches to May 2020 identified 251 trials evaluating 24 interventions with 20 582 participants for inclusion. Most trials had important limitations. Methodological limitations of the included trials and heterogeneity of the treatment effects on cytokine levels between trials limited interpretation. The primary analysis demonstrated inconsistency in the direction of the treatment effects on innate immunity and organ failure or death between interventions. Analyses restricted to important subgroups or trials with fewer limitations showed similar results. Meta-regression, pooling available data from all trials, demonstrated no association between the direction of the treatment effects on inflammatory cytokines and organ injury or death. The analysis of individual patient data demonstrated heterogeneity in the association between the cytokine response and organ injury after cardiac surgery for people >75 yr old and those with some chronic diseases. CONCLUSIONS: The certainty of the evidence for a causal relationship between innate immune system activation and organ injury after cardiac surgery is low.

Intravenous sildenafil citrate and post-cardiac surgery acute kidney injury: a double-blind, randomised, placebo-controlled trial.

BACKGROUND: This study assessed whether i.v. sildenafil citrate prevented acute kidney injury in at-risk patients undergoing cardiac surgery with cardiopulmonary bypass. METHODS: In a double-blind RCT, adults at increased risk of acute kidney injury undergoing cardiac surgery in a single UK tertiary centre were randomised to receive sildenafil citrate 12.5 mg kg-1 i.v. over 150 min or dextrose 5% at the commencement of surgery. The primary outcome was serum creatinine measured at six post-randomisation time points. The primary analysis used a linear mixed-effects model adjusted for the stratification variables, baseline estimated glomerular filtration rate, and surgical procedure. Secondary outcomes considered clinical events and potential disease mechanisms. Effect estimates were expressed as mean differences (MDs) or odds ratios with 95% confidence intervals. RESULTS: The analysis population comprised eligible randomised patients that underwent valve surgery or combined coronary artery bypass graft and valve surgery, with cardiopulmonary bypass, between May 2015 and June 2018. There were 60 subjects in the sildenafil group and 69 in the placebo control group. The difference between groups in creatinine concentration was not statistically significant (MD: 0.88 µmol L-1 [-5.82, 7.59]). There was a statistically significant increase in multiple organ dysfunction scores in the sildenafil group (MD: 0.54 [0.02, 1.07]; P=0.044). Secondary outcomes, and biomarkers of kidney injury, endothelial function, and inflammatory cell activation, were not significantly different between the groups. CONCLUSIONS: These results do not support the use of i.v. sildenafil citrate for kidney protection in adult cardiac surgery. CLINICAL TRIAL REGISTRATION: ISRCTN18386427.

Biomarkers of Inflammation and Lung Recovery in Extracorporeal Membrane Oxygenation Patients With Persistent Pulmonary Hypertension of the Newborn: A Feasibility Study.

OBJECTIVES: Extracorporeal membrane oxygenation is a treatment for Persistent Pulmonary Hypertension of the Newborn with high mortality. HYPOTHESIS: the extracorporeal membrane oxygenation circuit results in inflammatory responses that mitigate against successful weaning. DESIGN: Single-center prospective observational feasibility study. SETTING: PICU. PATIENTS: Twenty-four neonates requiring extracorporeal membrane oxygenation support for Persistent Pulmonary Hypertension of the Newborn. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The reference outcome was death or more than 7 days of extracorporeal membrane oxygenation support. Other outcomes included serial measures of plasma-free hemoglobin and markers of its metabolism, leucocyte, platelet and endothelial activation, and biomarkers of inflammation. Of 24 participants recruited between February 2016 and June 2017, 10 died or required prolonged extracorporeal membrane oxygenation support. These patients were sicker at baseline with higher levels of plasma-free hemoglobin within 12 hours of cannulation (geometric mean ratio, 1.92; 95% CIs, 1.00-3.67; p = 0.050) but not thereafter, versus those requiring less than 7 days extracorporeal membrane oxygenation. Serum haptoglobin concentrations were significantly elevated in both groups. Patients who died or required prolonged extracorporeal membrane oxygenation support demonstrated elevated levels of platelet-leucocyte aggregation, but decreased concentrations of mediators of the inflammatory response: interleukin-8, C-reactive protein, and tumor necrosis factor α. CONCLUSIONS: Clinical status at baseline and not levels of plasma-free hemoglobin or the systemic inflammatory response may determine the requirement for prolonged extracorporeal membrane oxygenation support in neonates.

Rejuvenation of RBCs: validation of a manufacturing method suitable for clinical use.

BACKGROUND: Rejuvenation of stored red blood cells (RBCs) increases levels of adenosine 5'-triphosphate (ATP) and 2,3-diphosphoglycerate (2,3-DPG) to those of fresh cells. This study aimed to optimize and validate the US-approved process to a UK setting for manufacture and issue of rejuvenated RBCs for a multicenter randomized controlled clinical trial in cardiac surgery. STUDY DESIGN AND METHODS: Rejuvenation of leukoreduced RBC units involved adding a solution containing pyruvate, inosine, phosphate, and adenine (Rejuvesol, Zimmer Biomet), warming at 37°C for 60 minutes, then "manual" washing with saline adenine glucose mannitol solution. A laboratory study was conducted on six pools of ABO/D-matched units made the day after donation. On Days 7, 21, and 28 of 4 ± 2°C storage, one unit per pool was rejuvenated and measured over 96 hours for volume, hematocrit, hemolysis, ATP, 2,3-DPG, supernatant potassium, lactate, and purines added (inosine) or produced (hypoxanthine) by rejuvenation. Subsequently, an operational validation (two phases of 32 units each) was undertaken, with results from the first informing a trial component specification applied to the second. Rejuvenation effects were also tested on crossmatch reactivity and RBC antigen profiles. RESULTS: Rejuvenation raised 2,3-DPG to, and ATP above, levels of fresh cells. The final component had potassium and hemolysis values below those of standard storage Days 7 and 21, respectively, containing 1.2% exogenous inosine and 500 to 1900 µmoles/unit of hypoxanthine. The second operational validation met compliance to the trial component specification. Rejuvenation did not adversely affect crossmatch reactivity or RBC antigen profiles. CONCLUSION: The validated rejuvenation process operates within defined quality limits, preserving RBC immunophenotypes, enabling manufacture for clinical trials.

Body Mass Index and Mortality Among Adults Undergoing Cardiac Surgery: A Nationwide Study With a Systematic Review and Meta-Analysis.

BACKGROUND: In an apparent paradox, morbidity and mortality are lower in obese patients undergoing cardiac surgery, although the nature of this association is unclear. We sought to determine whether the obesity paradox observed in cardiac surgery is attributable to reverse epidemiology, bias, or confounding. METHODS: Data from the National Adult Cardiac Surgery registry for all cardiac surgical procedures performed between April 2002 and March 2013 were extracted. A parallel systematic review and meta-analysis (MEDLINE, Embase, SCOPUS, Cochrane Library) through June 2015 were also accomplished. Exposure of interest was body mass index categorized into 6 groups according to the World Health Organization classification. RESULTS: A total of 401 227 adult patients in the cohort study and 557 720 patients in the systematic review were included. A U-shaped association between mortality and body mass index classes was observed in both studies, with lower mortality in overweight (adjusted odds ratio, 0.79; 95% confidence interval, 0.76-0.83) and obese class I and II (odds ratio, 0.81; 95% confidence interval, 0.76-0.86; and odds ratio, 0.83; 95% confidence interval, 0.74-0.94) patients relative to normal-weight patients and increased mortality in underweight individuals (odds ratio, 1.51; 95% confidence interval, 1.41-1.62). In the cohort study, a U-shaped relationship was observed for stroke and low cardiac output syndrome but not for renal replacement therapy or deep sternal wound infection. Counter to the reverse epidemiology hypotheses, the protective effects of obesity were less in patients with severe chronic renal, lung, or cardiac disease and greater in older patients and in those with complications of obesity, including the metabolic syndrome and atherosclerosis. Adjustments for important confounders did not alter our results. CONCLUSIONS: Obesity is associated with lower risks after cardiac surgery, with consistent effects noted in multiple analyses attempting to address residual confounding and reverse causation.

Vascular endothelial cell changes in postcardiac surgery acute kidney injury.

Acute kidney injury (AKI) is common complication of cardiac surgery; however, the phenotype of this condition is poorly defined. The aim of this study was to characterize changes in endothelial structure and function that underlie postcardiopulmonary bypass (post-CPB) AKI. Adult pigs ( n = 16) were randomized to undergo the following procedures ( n = 8 per group): group 1: sham operation, neck dissection with 2.5 h of general anesthesia; and group 2: CPB, 2.5 h of cardiopulmonary bypass. CPB resulted in the depletion of specific epitopes of glycosaminoglycans side chains of the endothelial glycocalyx: Dolichos biflorus agglutinin: mean difference (MD) [95% confidence interval (CI)], P value: -0.26 (-0.42, -0.09), P = 0.0024, Triticum vulgaris (wheat germ) agglutinin: -0.83 (-1.2, -0.38), P = 0.0005, and Ulex europaeus agglutinin 1: -0.25 (-0.49, -0.009), P = 0.041; endothelial membrane protein: thrombomodulin: -3.13 (-5.6, -0.65), P = 0.02; and adherens junction: VE-cadherin: -1.06 (-1.98, -0.145), P = 0.02. CPB also resulted in reductions in microvascular cortical perfusion: -0.62 (-1.02, -0.22), P = 0.006, and increased renal cortex adenosine levels: 2.32 (0.83, 3.8), P = 0.0059. These changes were accompanied by significant reduction in creatinine clearance at 1.5 h postintervention, MD 95% CI; -51.7 (-99.7, -3.7), P = 0.037, and at 24 h, MD (95% CI): -47.3 (-87.7, -7.6), P = 0.023, and proteinuria immediately postintervention MD (95% CI): 18.79 (2.17, 35.4), P = 0.03 vs. sham. In our experimental CPB model, endothelial injury was associated with loss of autoregulation, increase in microvascular permeability, and reduced glomerular filtration. Interventions that promote endothelial homeostasis may have clinical utility in the prevention of postcardiac surgery AKI.

Liberal or restrictive transfusion after cardiac surgery.

BACKGROUND: Whether a restrictive threshold for hemoglobin level in red-cell transfusions, as compared with a liberal threshold, reduces postoperative morbidity and health care costs after cardiac surgery is uncertain. METHODS: We conducted a multicenter, parallel-group trial in which patients older than 16 years of age who were undergoing nonemergency cardiac surgery were recruited from 17 centers in the United Kingdom. Patients with a postoperative hemoglobin level of less than 9 g per deciliter were randomly assigned to a restrictive transfusion threshold (hemoglobin level <7.5 g per deciliter) or a liberal transfusion threshold (hemoglobin level <9 g per deciliter). The primary outcome was a serious infection (sepsis or wound infection) or an ischemic event (permanent stroke [confirmation on brain imaging and deficit in motor, sensory, or coordination functions], myocardial infarction, infarction of the gut, or acute kidney injury) within 3 months after randomization. Health care costs, excluding the index surgery, were estimated from the day of surgery to 3 months after surgery. RESULTS: A total of 2007 patients underwent randomization; 4 participants withdrew, leaving 1000 in the restrictive-threshold group and 1003 in the liberal-threshold group. Transfusion rates after randomization were 53.4% and 92.2% in the two groups, respectively. The primary outcome occurred in 35.1% of the patients in the restrictive-threshold group and 33.0% of the patients in the liberal-threshold group (odds ratio, 1.11; 95% confidence interval [CI], 0.91 to 1.34; P=0.30); there was no indication of heterogeneity according to subgroup. There were more deaths in the restrictive-threshold group than in the liberal-threshold group (4.2% vs. 2.6%; hazard ratio, 1.64; 95% CI, 1.00 to 2.67; P=0.045). Serious postoperative complications, excluding primary-outcome events, occurred in 35.7% of participants in the restrictive-threshold group and 34.2% of participants in the liberal-threshold group. Total costs did not differ significantly between the groups. CONCLUSIONS: A restrictive transfusion threshold after cardiac surgery was not superior to a liberal threshold with respect to morbidity or health care costs. (Funded by the National Institute for Health Research Health Technology Assessment program; Current Controlled Trials number, ISRCTN70923932.).

A Comparison of Red Cell Rejuvenation versus Mechanical Washing for the Prevention of Transfusion-associated Organ Injury in Swine.

BACKGROUND: We evaluated the effects of two interventions that modify the red cell storage lesion on kidney and lung injury in experimental models of transfusion. METHODS: White-landrace pigs (n = 32) were allocated to receive sham transfusion (crystalloid), 14-day stored allogeneic red cells, 14-day red cells washed using the red cells washing/salvage system (CATS; Fresenius, Germany), or 14-day red cells rejuvenated using the inosine solution (Rejuvesol solution; Zimmer Biomet, USA) and washed using the CATS device. Functional, biochemical, and histologic markers of organ injury were assessed for up to 24 h posttransfusion. RESULTS: Transfusion of 14 day red cells resulted in lung injury (lung injury score vs. sham, mean difference -0.3 (95% CI, -0.6 to -0.1; P = 0.02), pulmonary endothelial dysfunction, and tissue leukocyte sequestration. Mechanical washing reduced red cell-derived microvesicles but increased cell-free hemoglobin in 14-day red cell units. Transfusion of washed red cells reduced leukocyte sequestration but did not reduce the lung injury score (mean difference -0.2; 95% CI, -0.5 to 0.1; P = 0.19) relative to 14-day cells. Transfusion of washed red cells also increased endothelial activation and kidney injury. Rejuvenation restored adenosine triphosphate to that of fresh red cells and reduced microvesicle concentrations without increasing cell-free hemoglobin release. Transfusion of rejuvenated red cells reduced plasma cell-free hemoglobin, leukocyte sequestration, and endothelial dysfunction in recipients and reduced lung and kidney injury relative to 14-day or washed 14-day cells. CONCLUSIONS: Reversal of the red cell storage lesion by rejuvenation reduces transfusion-associated organ injury in swine.

An Observational Cohort Feasibility Study to Identify Microvesicle and Micro-RNA Biomarkers of Acute Kidney Injury Following Pediatric Cardiac Surgery.

OBJECTIVES: Micro-RNA, small noncoding RNA fragments involved in gene regulation, and microvesicles, membrane-bound particles less than 1 µm known to regulate cellular processes including responses to injury, may serve as disease-specific biomarkers of acute kidney injury. We evaluated the feasibility of measuring these signals as well as other known acute kidney injury biomarkers in a mixed pediatric cardiac surgery population. DESIGN: Single center prospective cohort feasibility study. SETTING: PICU. PATIENTS: Twenty-four children (≤ 17 yr) undergoing cardiac surgery with cardiopulmonary bypass without preexisting inflammatory state, acute kidney injury, or extracorporeal life support. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Acute kidney injury was defined according to modified Kidney Diseases Improving Global Outcomes criteria. Blood and urine samples were collected preoperatively and at 6-12 and 24 hours. Microvesicles derivation was assessed using flow cytometry and NanoSight analysis. Micro-RNAs were isolated from plasma and analyzed by microarray and quantitative real-time polymerase chain reaction. Data completeness for the primary outcomes was 100%. Patients with acute kidney injury (n = 14/24) were younger, underwent longer cardiopulmonary bypass, and required greater inotrope support. Acute kidney injury subjects had different fractional content of platelets and endothelial-derived microvesicles before surgery. Platelets and endothelial microvesicles levels were higher in acute kidney injury patients. A number of micro-RNA species were differentially expressed in acute kidney injury patients. Pathway analysis of candidate target genes in the kidney suggested that the most often affected pathways were phosphatase and tensin homolog and signal transducer and activator of transcription 3 signaling. CONCLUSIONS: Microvesicles and micro-RNAs expression patterns in pediatric cardiac surgery patients can be measured in children and potentially serve as tools for stratification of patients at risk of acute kidney injury.

Nonlinear association of BMI with all-cause and cardiovascular mortality in type 2 diabetes mellitus: a systematic review and meta-analysis of 414,587 participants in prospective studies.

AIMS/HYPOTHESIS: The relationship between BMI and mortality has been extensively investigated in the general population; however, it is less clear in people with type 2 diabetes. We aimed to assess the association of BMI with all-cause and cardiovascular mortality in individuals with type 2 diabetes mellitus. METHODS: We searched electronic databases up to 1 March 2016 for prospective studies reporting associations for three or more BMI groups with all-cause and cardiovascular mortality in individuals with type 2 diabetes mellitus. Study-specific associations between BMI and the most-adjusted RR were estimated using restricted cubic splines and a generalised least squares method before pooling study estimates with a multivariate random-effects meta-analysis. RESULTS: We included 21 studies including 24 cohorts, 414,587 participants, 61,889 all-cause and 4470 cardiovascular incident deaths; follow-up ranged from 2.7 to 15.9 years. There was a strong nonlinear relationship between BMI and all-cause mortality in both men and women, with the lowest estimated risk from 31-35 kg/m2 and 28-31 kg/m2 (p value for nonlinearity <0.001) respectively. The risk of mortality at higher BMI values increased significantly only in women, whilst lower values were associated with higher mortality in both sexes. Limited data for cardiovascular mortality were available, with a possible inverse linear association with BMI (higher risk for BMI <27 kg/m2). CONCLUSIONS/INTERPRETATION: In type 2 diabetes, BMI is nonlinearly associated with all-cause mortality with lowest risk in the overweight group in both men and women. Further research is needed to clarify the relationship with cardiovascular mortality and assess causality and sex differences.

A Phase I study to determine the pharmacokinetic profile, safety and tolerability of sildenafil (Revatio® ) in cardiac surgery: the REVAKI-1 study.

AIMS: Acute kidney injury (AKI) is a common and severe complication of cardiac surgery. There is no effective prevention or treatment. Sildenafil citrate (Revatio® , Pfizer Inc.), a phosphodiesterase type 5 inhibitor, prevents post cardiac surgery AKI in pre-clinical studies, however its use is contraindicated in patients with symptomatic cardiovascular disease. The aim of this study is to assess the safety and pharmacokinetics of intravenous sildenafil in cardiac surgery patients. METHODS: We conducted an open label, dose escalation study with six patients per dose level. The six doses were 2.5 mg, 5 mg or 10 mg as a bolus, either alone or followed by an additional 2 h infusion of 2.5 mg sildenafil. RESULTS: Thirty-six patients entered the trial, of which 33 completed it. The mean age was 69.9 years. One patient died during surgery, two others were removed from the trial before dosing (all at dose level 5 mg + 2.5 mg). The pharmacokinetic profile of sildenafil was similar to previously published studies. For a dose of 10 mg administered as a bolus followed by 2.5 mg administered over 2 h the results were AUC∞ 537 ng h ml-1 , Cmax 189.4 ng ml-1 and t1/2 10.5 h. The drug was well tolerated with no serious adverse events related to drug administration. Higher sildenafil doses stabilized post-surgery nitric oxide bioavailability. CONCLUSIONS: Pharmacokinetics of sildenafil during cardiopulmonary bypass were comparable to those of other patient groups. The drug was well tolerated at therapeutic plasma levels. These results support the further evaluation of sildenafil for the prevention of AKI in cardiac surgery.