Carina Benstoem

Selenium and Its Supplementation in Cardiovascular Disease—What do We Know?

The trace element selenium is of high importance for many of the body’s regulatory and metabolic functions. Balanced selenium levels are essential, whereas dysregulation can cause harm. A rapidly increasing number of studies characterizes the wide range of selenium dependent functions in the human body and elucidates the complex and multiple physiological and pathophysiological interactions of selenium and selenoproteins. For the majority of selenium dependent enzymes, several biological functions have already been identified, like regulation of the inflammatory response, antioxidant properties and the proliferation/differentiation of immune cells. Although the potential role of selenium in the development and progression of cardiovascular disease has been investigated for decades, both observational and interventional studies of selenium supplementation remain inconclusive and are considered in this review. This review covers current knowledge of the role of selenium and selenoproteins in the human body and its functional role in the cardiovascular system. The relationships between selenium intake/status and various health outcomes, in particular cardiomyopathy, myocardial ischemia/infarction and reperfusion injury are reviewed. We describe, in depth, selenium as a biomarker in coronary heart disease and highlight the significance of selenium supplementation for patients undergoing cardiac surgery.

Evaluating outcomes used in cardiothoracic surgery interventional research: a systematic review of reviews to develop a core outcome set.

Background When planning clinical trials, it is a key element to choose appropriate outcomes that ensure the comparability of effects of interventions in ways that minimise bias. We hypothesise that outcome measures in cardiothoracic surgical trials are inconsistent and without standard. Therefore, comparing the relative effectiveness of interventions across studies is problematic. We surmise that cardiothoracic research has focused habitually on the identification of risk factors and on the reduction of adverse outcomes with less consideration of factors that contribute to well being and positive health outcomes (salutogenesis). Methods and Findings We conducted a systematic review of reviews to determine both the type and number of outcomes reported in current cardiothoracic surgery interventional research, in order to identify a list of potential outcomes for a minimum core outcome set (COS). Special focus was placed on outcomes that emphasise salutogenesis. We interpreted salutogenic outcomes as those relating to optimum and/or positive health and well being. We searched Issue 7 (July 2014) of the Cochrane Database of Systematic Reviews. Systematic reviews of randomised trials on non-minimal-invasive off- or on-pump cardiothoracic surgery (elective and emergency, excluding transplants) investigating pre-, intra- or postsurgical interventions related to the outcome of the procedure were eligible for inclusion. We excluded protocols and withdrawn systematic reviews. Two review authors extracted outcome data independently. Unique lists of salutogenically and non-salutogenically focused outcomes were established. 15 systematic reviews involving 371 randomized trials and 58,253 patients were included in this review. Applied definitions of single and composite endpoints varied significantly, and patient-centred, salutogenically focused outcomes were seldom reported. One third of included reviews did not assess patient-centred outcomes at all; all other reviews were unable to perform meta-analyses due to an absence of data or heterogeneity in outcome measures. This compares to 36 non-salutogenically focused outcome domains representing 121 individual non-salutogenically focused outcomes, whereof 50% were assessed only once. Measures of mortality, cerebrovascular complications and hospitalisation were reported most frequently. Two reviews chose a composite endpoint as primary outcome. Pooled analysis of composite endpoints was not possible, as the required data was not reported per patient in all components. Conclusion In cardiothoracic surgical trials, choice and definition of non-salutogenically focused single and composite outcomes are inconsistent. There is an absence of patient centred, salutogenically focused outcome parameters in cardiac trials. We recommend the development of a core outcome set of salutogenically focused and non-salutogenically focused outcomes for cardiothoracic surgical research.

Role of nutrition support in adult cardiac surgery: a consensus statement from an International Multidisciplinary Expert Group on Nutrition in Cardiac Surgery

Nutrition support is a necessary therapy for critically ill cardiac surgery patients. However, conclusive evidence for this population, consisting of well-conducted clinical trials is lacking. To clarify optimal strategies to improve outcomes, an international multidisciplinary group of 25 experts from different clinical specialties from Germany, Canada, Greece, USA and Russia discussed potential approaches to identify patients who may benefit from nutrition support, when best to initiate nutrition support, and the potential use of pharmaco-nutrition to modulate the inflammatory response to cardiopulmonary bypass. Despite conspicuous knowledge and evidence gaps, a rational nutritional support therapy is presented to benefit patients undergoing cardiac surgery.

Evaluation of Persistent Organ Dysfunction Plus Death As a Novel Composite Outcome in Cardiac Surgical Patients

OBJECTIVES Validated composite outcomes after complicated cardiac surgery are poorly established. Therefore, the authors evaluated a novel composite endpoint, persistent organ dysfunction (POD)+death, which is defined as any need for life-sustaining therapies or death at any time within 28 days from surgery. DESIGN Secondary analysis extracted from a large-scale prospective randomized trial of critically ill cardiac surgery patients. SETTING Multi-institutional, university hospitals. PARTICIPANTS Ninety-five cardiac surgery patients with complicated postoperative courses. INTERVENTIONS Cardiac surgery with cardiopulmonary bypass. MEASUREMENTS AND MAIN RESULTS At 28 days following surgery, the prevalence of POD was 15%, and 23% of patients had died (POD+death = 38%). Patients alive with POD at day 28 exhibited a significantly higher extent of organ injury and longer ICU (33 v 7 days; p<0.001) and hospital lengths of stay (49 v 21 days; p<0.001) compared to patients without POD at day 28. At 3 and 6 months, quality-of-life scores (by Short Form 36 questionnaire) showed a significantly reduced rating for most components in patients with POD at day 28 compared to those without POD. The 6-month mortality rate was 21% among patients alive with POD at day 28 compared to 5% among patients alive without POD (p = 0.05). The calculated number of patients needed per arm to detect a 25% relative risk reduction for mortality alone was 762 compared to 386 per arm for POD+ death. CONCLUSIONS POD+death at day 28 following cardiac surgery may be a valid composite endpoint and offers statistical efficiencies in terms of sample size calculations for cardiac surgical trials.

A core outcome set for all types of cardiac surgery effectiveness trials: a study protocol for an international eDelphi survey to achieve consensus on what to measure and the subsequent selection of measurement instruments

BackgroundCardiovascular disease (CVD) is a major contributor to the burden of disease and the number one cause of death worldwide. From 1990 until today, more people died from coronary heart disease than from any other cause. CVD is regularly treated with minimally or non-minimally invasive off- or on-pump cardiothoracic surgery and several interventions related to the outcome of the surgical procedures have been evaluated in clinical trials, but heterogeneity in outcome reporting hinders comparison of interventions across trials and limits the ability of research synthesis. This problem is encountered with the introduction of core outcome sets (COSs), which should be measured and reported, as a minimum, in all clinical trials for a specific clinical field.Methods/designThis study protocol describes the methods used to develop a COS for all types of cardiac surgery effectiveness trials. We aim to reach consensus on what to measure in an international three-round eDelphi exercise involving adult patients in need or after cardiothoracic surgery, cardiothoracic surgeons, cardiologists, anaesthesiologists, nursing staff and researchers with expertise in this particular field of medical research. Subsequently, outcome measurement instruments (how to measure) will be determined. Recommendations on COS development given by the Core Outcome Measures in Effectiveness Trials (COMET) Initiative and the Outcome Measures in Rheumatology (OMERACT) Initiative were followed.DiscussionThe proposed COS aims to provide methodological guidance for future cardiothoracic surgical trials to ensure the comparability of effects of interventions across studies and enable research synthesis. This does not imply that primary outcomes should always and exclusively be those of the COS. However, to ensure the comparability of results across trials, the outcomes included in this COS should be considered for inclusion besides measuring trial-specific clinical endpoints.

Outcome measures in studies on the use of oxytocin for the treatment of delay in labour: a systematic review.

OBJECTIVES to identify primary and secondary outcome measures in randomised trials, and systematic reviews of randomised trials, measuring effectiveness of oxytocin for treatment of delay in the first and second stages of labour, and to identify any positive health-focussed outcomes used. DESIGN eight relevant citation databases were searched up to January 2013 for all randomised trials, and systematic reviews of randomised trials, measuring effectiveness of oxytocin for treatment of delay in labour. Trials of active management of labour or partogram action lines were excluded. 1918 citations were identified. Two reviewers reviewed all citations and extracted data. Twenty-six individual trials and five systematic reviews were included. Primary and secondary outcome measures were documented and analysed using frequency distributions. FINDINGS most frequent primary outcomes were caesarean section (n=15, 46%), length of labour (n=14, 42%), measurements of uterine activity (n=13, 39%) and mode of vaginal birth (n=9, 27%). Maternal satisfaction was identified a priori by one review and included as a secondary outcome by three papers. No further positive health-focussed outcomes were identified. KEY CONCLUSIONS outcomes used to measure the effectiveness of oxytocin for treatment of delay in labour are heterogeneous and tend to focus on adverse events. IMPLICATIONS FOR PRACTICE it is recommended that, in future randomised trials of oxytocin use for delay in labour, some women-centred and health-focussed outcome measures should be used, which may instil a more salutogenic culture in childbirth.

A core outcome set for adult cardiac surgery trials : a consensus study

Background Invasive off- or on-pump cardiac surgery (elective and emergency procedures, excluding transplants are routinely performed to treat complications of ischaemic heart disease. Randomised controlled trials (RCT) evaluate the effectiveness of treatments in the setting of cardiac surgery. However, the impact of RCTs is weakened by heterogeneity in outcome measuring and reporting, which hinders comparison across trials. Core outcome sets (COS, a set of outcomes that should be measured and reported, as a minimum, in clinical trials for a specific clinical field) help reduce this problem. In light of the above, we developed a COS for cardiac surgery effectiveness trials. Methods Potential core outcomes were identified a priori by analysing data on 371 RCTs of 58,253 patients. We reached consensus on core outcomes in an international three-round eDelphi exercise. Outcomes for which at least 60% of the participants chose the response option “no” and less than 20% chose the response option “yes” were excluded. Results Eighty-six participants from 23 different countries involving adult cardiac patients, cardiac surgeons, anaesthesiologists, nursing staff and researchers contributed to this eDelphi. The panel reached consensus on four core outcomes: 1) Measure of mortality, 2) Measure of quality of life, 3) Measure of hospitalisation and 4) Measure of cerebrovascular complication to be included in adult cardiac surgery trials. Conclusion This study used robust research methodology to develop a minimum core outcome set for clinical trials evaluating the effectiveness of treatments in the setting of cardiac surgery. As a next step, appropriate outcome measurement instruments have to be selected.

Xenon triggers pro-inflammatory effects and suppresses the anti-inflammatory response compared to sevoflurane in patients undergoing cardiac surgery

IntroductionCardiac surgery encompasses various stimuli that trigger pro-inflammatory mediators, reactive oxygen species and mobilization of leucocytes. The aim of this study was to evaluate the effect of xenon on the inflammatory response during cardiac surgery.MethodsThis randomized trial enrolled 30 patients who underwent elective on-pump coronary-artery bypass grafting in balanced anaesthesia of either xenon or sevoflurane. For this secondary analysis, blood samples were drawn prior to the operation, intra-operatively and on the first post-operative day to measure the pro- and anti-inflammatory cytokines interleukin-6 (IL-6), interleukin-8/C-X-C motif ligand 8 (IL-8/CXCL8), and interleukin-10 (IL-10). Chemokines such as C-X-C motif ligand 12/ stromal cell-derived factor-1α (CXCL12/SDF-1α) and macrophage migration inhibitory factor (MIF) were measured to characterize xenon’s perioperative inflammatory profile and its impact on migration of peripheral blood mononuclear cells (PBMC).ResultsXenon enhanced the postoperative increase of IL-6 compared to sevoflurane (Xenon: 90.7 versus sevoflurane: 33.7 pg/ml; p = 0.035) and attenuated the increase of IL-10 (Xenon: 127.9 versus sevoflurane: 548.3 pg/ml; p = 0.028). Both groups demonstrated a comparable intraoperative increase of oxidative stress (intra-OP: p = 0.29; post-OP: p = 0.65). While both groups showed an intraoperative increase of the cardioprotective mediators MIF and CXCL12/SDF-1α, only MIF levels decreased in the xenon group on the first postoperative day (50.0 ng/ml compared to 23.3 ng/ml; p = 0.012), whereas it remained elevated after sevoflurane anaesthesia (58.3 ng/ml to 53.6 ng/ml). Effects of patients’ serum on chemotactic migration of peripheral mononuclear blood cells taken from healthy volunteers indicated a tendency towards enhanced migration after sevoflurane anaesthesia (p = 0.07).ConclusionsCompared to sevoflurane, balanced xenon anaesthesia triggers pro-inflammatory effects and suppresses the anti-inflammatory response in cardiac surgery patients even though the clinical significance remains unknown.Trial registrationThis clinical trial was approved by the European Medicines Agency (EudraCT-number: 2010-023942-63) and at ClinicalTrials.gov (NCT01285271; first received: January 24, 2011).

Evaluation of the cardioprotective potential of extracellular vesicles – a systematic review and meta-analysis

Cardiovascular diseases are the main cause of death worldwide, demanding new treatments and interventions. Recently, extracellular vesicles (EVs) came in focus as important carriers of protective molecules such as miRNAs and proteins which might contribute to e.g. improved cardiac function after myocardial infarction. EVs can be secreted from almost every cell type in the human body and can be transferred via the bloodstream in almost every compartment. To provide an all-encompassing overview of studies investigating these beneficial properties of EVs we performed a systematic review/meta-analysis of studies investigating the cardioprotective characteristics of EVs. Forty-three studies were investigated and catalogued according to the EV source. We provide an in-depth analysis of the purification method, size of the EVs, the conducted experiments to investigate the beneficial properties of EVs as well as the major effector molecule encapsulated in EVs mediating protection. This study provides evidence that EVs from different cell types and body fluids provide cardioprotection in different in vivo and in vitro studies. A meta-analysis was performed to estimate the underlying effect size. In conclusion, we demonstrated that EVs from different sources might serve as a promising tool for treating cardiovascular diseases in the future.

Vitamin C to Improve Organ Dysfunction in Cardiac Surgery Patients—Review and Pragmatic Approach

The pleiotropic biochemical and antioxidant functions of vitamin C have sparked recent interest in its application in intensive care. Vitamin C protects important organ systems (cardiovascular, neurologic and renal systems) during inflammation and oxidative stress. It also influences coagulation and inflammation; its application might prevent organ damage. The current evidence of vitamin C’s effect on pathophysiological reactions during various acute stress events (such as sepsis, shock, trauma, burn and ischemia-reperfusion injury) questions whether the application of vitamin C might be especially beneficial for cardiac surgery patients who are routinely exposed to ischemia/reperfusion and subsequent inflammation, systematically affecting different organ systems. This review covers current knowledge about the role of vitamin C in cardiac surgery patients with focus on its influence on organ dysfunctions. The relationships between vitamin C and clinical health outcomes are reviewed with special emphasis on its application in cardiac surgery. Additionally, this review pragmatically discusses evidence on the administration of vitamin C in every day clinical practice, tackling the issues of safety, monitoring, dosage, and appropriate application strategy.