Wingless-related integration site (WNT) signaling is activated during the inflammatory response upon cardiac surgery: A translational study

ObjectiveCardiac surgery and the use of cardiopulmonary bypass initiate a systemic inflammatory response. Wingless-related integration site (WNT) signaling is part of the innate immunity and has been attributed a major role in the regulation of inflammation. In preclinical research, WNT-5a may sustain an inflammatory response and cause endothelial dysfunction. Our aim was to investigate WNT signaling after cardiac surgery and its association with postoperative inflammation (Clinicaltrials.gov, NCT04058496).MethodsIn this prospective, single-center, observational study, 64 consecutive patients for coronary artery bypass grafting (CABG) ± valve surgery were assigned into three groups: off-pump CABG (n = 28), on-pump CABG (n = 16) and combined valve-CABG surgery (n = 20). Blood samples were acquired before surgery, at intensive care unit (ICU) admission and 4, 8, and 48 h thereafter. Plasma concentrations of WNT-5a and its antagonists Secreted frizzled-related protein 1 (sFRP-1), Secreted frizzled-related protein 5 (sFRP-5), and WNT inhibitory factor 1 (WIF-1) were determined by enzyme-linked immunosorbent assay. In addition, plasma concentrations of six inflammatory cytokines were measured by multiplex immunoassay. Parameters were analyzed for evolution of plasma concentration over time, interactions, intergroup differences, and association with clinical outcome parameters.ResultsAt baseline, WNT-5a, sFRP-1, and WIF-1 were present in a minimal concentration, while sFRP-5 was elevated. A higher baseline value of WNT-5a, sFRP-5, and WIF-1 resulted in higher subsequent values of the respective parameter. At ICU admission, WNT-5a and sFRP-5 reached their maximum and minimum value, respectively. WIF-1 decreased over time and was lowest 8 h after surgery. sFRP-1 changed minimally over time. While WNT-5a returned to the baseline within 48 h, sFRP-5 and WIF-1 did not reach their baseline value at 48 h. Of the investigated WNT system components, only WIF-1 partially reflected the severity of surgery. WNT-5a and WIF-1 had an impact on postoperative fluid balance and noradrenaline requirement.ConclusionWNT-5a, sFRP-5, and WIF-1 are part of the systemic inflammatory response after cardiac surgery. WNT-5a peaks immediately after cardiac surgery and returns to baseline within 48 h, presumably modulated by its antagonist sFRP-5. Based on this translational study, WNT-5a antagonism may be further investigated to assess potentially beneficial effects in patients with a dysregulated inflammation after cardiac surgery

Evidence base for restrictive transfusion triggers in high-risk patients

Liberal versus restrictive red blood cell (RBC) transfusion triggers have been debated for years. This review illustrates the human body's physiologic response to acute anemia and summarizes the evidence from prospective randomized trials (RCTs) for restrictive use of RBC transfusions in high-risk patients. During progressive anemia, the human body maintains the oxygen delivery to the tissues by an increase in cardiac output and peripheral oxygen extraction. Seven RCTs with a total of 5,566 high-risk patients compared a restrictive hemoglobin (Hb) transfusion trigger (Hb < 70 or < 80 g/l) with a liberal Hb transfusion trigger (Hb < 90 or < 100 g/l). Unanimously these studies show non-inferiority, safety, and a significant reduction in RBC transfusions in the restrictive groups. In one RCT mortality was higher in the liberal Hb transfusion group, and in two additional RCTs mortality of subgroups or after risk adjustment was significantly higher in the liberal Hb transfusion trigger groups. Conclusion: Strong RCT evidence suggests the safety of restrictive transfusion triggers. As a consequence, an Hb transfusion trigger of <70 g/l is recommended for high risk patients

Iron deficiency is associated with higher mortality in patients undergoing cardiac surgery: a prospective study

Background Iron deficiency is frequent in patients undergoing cardiac surgery. The relevance of iron deficiency, however, is ill defined. Therefore, our study aimed to investigate the impact of iron deficiency (ferritin <100 μg L−1) with or without concomitant anaemia on clinical outcome after cardiac surgery. Methods In this prospective observational study, 730 patients undergoing elective cardiac surgery were assigned into four groups according to their iron status and anaemia. Mortality, serious adverse events (SAEs), major cardiac and cerebrovascular events (MACCEs), allogenic blood transfusion requirements, and length of hospital stay were assessed during a 90-day follow-up period. The effect of iron deficiency on these outcomes was first calculated in models adjusting for anaemia only, followed by two multivariate models adjusting for anaemia and either the EuroSCORE II or any possible confounders. Results The presence of iron deficiency (ferritin <100 μg L−1) was associated with an increase in 90-day mortality from 2% to 5% in patients without anaemia, and from 4% to 14% in patients with anaemia. Logistic regression resulted in an odds ratio of 3.5 (95% confidence interval: 1.5–8.4); P=0.004. The effect persisted in both multivariate models. Moreover, iron deficiency was associated with an increased incidence of SAEs, MACCEs, transfusion, and prolonged hospital stay. Conclusions Preoperative iron deficiency (ferritin <100 μg L−1) was independently associated with increased mortality, more SAEs, and prolonged hospital stay after cardiac surgery. These findings underline the importance of preoperative iron deficiency screening in the context of a comprehensive patient blood management programme, and highlight its importance as a research topic in cardiac surgery

Impact of city police layperson education and equipment with automatic external defibrillators on patient outcome after out of hospital cardiac arrest

INTRODUCTION: Out of hospital cardiac arrest (OHCA) occurs frequently and the outcome is often dismal. Early defibrillation saves lives and brain function in OHCA. The Zurich city police (STAPO) forces were instructed and equipped to provide basic life support (BLS) and to use an AED in 2009. METHODS: Retrospective observational study comparing period 1 (P1) 2004-2009 before equipping and training of the STAPO and period 2 (P2) 2010-2015 after the implementation. Patients suffering from OHCA of cardiac or presumed cardiac origin in the city of Zurich undergoing CPR by EMS in P1 (n=709) and P2 (n=684) were included. Intervention periods and outcome were compared between the periods. Outcome variables were adjusted for patient age and gender, witnessed status, and defibrillation by the EMS, STAPO, layperson or no defibrillation. RESULTS: In P2, CPR was started by the STAPO in a median of 8 (IQR 6-9) minutes after the arrest and thus significantly earlier (median 3min) than by the EMS (p<0.001). STAPO performed the first defibrillation in a median of 9 (IQR 8-10) minutes and thus significantly earlier (median 6min) than the EMS (p<0.001). Outcome improved significantly in P2: proportion of patients with return of spontaneous circulation (ROSC, P2 35.8%, P1 24.0%, OR 1.8, 95% CI 1.4-2.2, p<0.001), hospital admission (P2 32.2%, P1 21.4%, OR 1.7, 95% CI 1.4-2.2, p<0.001) and survival to hospital discharge (P2 13.6%, P1 6.9%, OR 2.1 95% CI 1.5-3.0, p<0.001). If the patient was firstly defibrillated by the STAPO, ROSC (STAPO 74.4%, adj. OR 2.6, 95% CI 1.3-5.4, p=0.010) and hospital admission (STAPO 72.1%, adj. OR 2.8, 95% CI 1.4-5.6, p=0.005) was higher compared to patients firstly defibrillated by the EMS. Survival to hospital discharge (STAPO 30.2%, adj. OR 1.4, 95% CI 0.7-2.9, p=0.38) was unchanged. CONCLUSION: Dispatching BLS trained and AED equipped police forces results in earlier and more successful resuscitation of OHCA victims, leading to higher proportions of patients with ROSC, hospital admission and survival to hospital discharge

Is dilutional coagulopathy induced by different colloids reversible by replacement of fibrinogen and factor XIII concentrates?

BACKGROUND:In this in vitro trial, we assessed the effect on blood coagulation of 60% dilution with different colloids and investigated reversibility by replacement of factor XIII (F XIII), fibrinogen, and the combination of fibrinogen and F XIII.METHODS:Using the blood of 12 volunteers, the following measurements were performed at baseline and after 60% dilution with (hydroxyethyl starch solutions) HES 130/0.42, gelatin, or balanced gelatin solution: blood gas analyses, coagulation factor concentrations (F I, F II, F VII, F VIII, F XIII), impedance aggregometry (Multiplate®), and rotational thromboelastometry (ROTEM(®)). Then F XIII and fibrinogen as well as a combination of both were added, in concentrations corresponding to 6 g fibrinogen and 1250 IU F XIII in adults. ROTEM(®) measurements and determination of factor concentrations were again performed.RESULTS:Colloid dilution led to a significant reduction of fibrinogen polymerization, especially with HES. Platelet function was impaired by all colloids, with gelatin having a significantly greater effect (area under the curve, collagen Test, P ≤ 0.008) than HES and balanced gelatin solution. The substitution of F XIII only did not improve clot formation. Substitution of fibrinogen improved the polymerization of fibrinogen in dilutions with gelatin and balanced gelatin solution (P = 0.002), whereas HES-induced coagulopathy could not be corrected. The combination of fibrinogen and F XIII showed a better effect than the addition of fibrinogen only for certain variables.CONCLUSION:Coagulation and platelet function are impaired by all 3 colloids. However, in vitro gelatin-induced coagulopathy was significantly more reversible than HES-induced coagulopathy

Effect of ultra-short-term treatment of patients with iron deficiency or anaemia undergoing cardiac surgery: a prospective randomised trial

BACKGROUND Anaemia and iron deficiency are frequent in patients scheduled for cardiac surgery. This study assessed whether immediate preoperative treatment could result in reduced perioperative red blood cell (RBC) transfusions and improved outcome. METHODS In this single-centre, randomised, double-blind, parallel-group controlled study, patients undergoing elective cardiac surgery with anaemia (n=253; haemoglobin concentration (Hb) <120 g/L in women and Hb <130 g/L in men) or isolated iron deficiency (n=252; ferritin <100 mcg/L, no anaemia) were enrolled. Participants were randomly assigned (1:1) with the use of a computer-generated range minimisation (allocation probability 0·8) to receive either placebo or combination treatment consisting of a slow infusion of 20 mg/kg ferric carboxymaltose, 40 000 U subcutaneous erythropoietin alpha, 1 mg subcutaneous vitamin B12, and 5 mg oral folic acid or placebo on the day before surgery. Primary outcome was the number of RBC transfusions during the first 7 days. This trial is registered with ClinicalTrials.gov, number NCT02031289. FINDINGS Between Jan 9, 2014, and July 19, 2017, 1006 patients were enrolled; 505 with anaemia or isolated iron deficiency and 501 in the registry. The combination treatment significantly reduced RBC transfusions from a median of one unit in the placebo group (IQR 0-3) to zero units in the treatment group (0-2, during the first 7 days (odds ratio 0·70 [95% CI 0·50-0·98] for each threshold of number of RBC transfusions, p=0·036) and until postoperative day 90 (p=0·018). Despite fewer RBC units transfused, patients in the treatment group had a higher haemoglobin concentration, higher reticulocyte count, and a higher reticulocyte haemoglobin content during the first 7 days (p≤0·001). Combined allogeneic transfusions were less in the treatment group (0 [IQR 0-2]) versus the placebo group (1 [0-3]) during the first 7 days (p=0·038) and until postoperative day 90 (p=0·019). 73 (30%) serious adverse events were reported in the treatment group group versus 79 (33%) in the placebo group. INTERPRETATION An ultra-short-term combination treatment with intravenous iron, subcutaneous erythropoietin alpha, vitamin B12, and oral folic acid reduced RBC and total allogeneic blood product transfusions in patients with preoperative anaemia or isolated iron deficiency undergoing elective cardiac surgery. FUNDING Vifor Pharma and Swiss Foundation for Anaesthesia Research

Screening for iron deficiency in surgical patients based on noninvasive zinc protoporphyrin measurements

BACKGROUND: Approximately every third surgical patient is anemic. The most common form, iron deficiency anemia, results from persisting iron-deficient erythropoiesis (IDE). Zinc protoporphyrin (ZnPP) is a promising parameter for diagnosing IDE, hitherto requiring blood drawing and laboratory workup. STUDY DESIGN AND METHODS: Noninvasive ZnPP (ZnPP-NI) measurements are compared to ZnPP reference determination of the ZnPP/heme ratio by high-performance liquid chromatography (ZnPP-HPLC) and the analytical performance in detecting IDE is evaluated against traditional iron status parameters (ferritin, transferrin saturation [TSAT], soluble transferrin receptor-ferritin index [sTfR-F], soluble transferrin receptor [sTfR]), likewise measured in blood. The study was conducted at the University Hospitals of Frankfurt and Zurich. RESULTS: Limits of agreement between ZnPP-NI and ZnPP-HPLC measurements for 584 cardiac and noncardiac surgical patients equaled 19.7 μmol/mol heme (95% confidence interval, 18.0-21.3; acceptance criteria, 23.2 μmol/mol heme; absolute bias, 0 μmol/mol heme). Analytical performance for detecting IDE (inferred from area under the curve receiver operating characteristics) of parameters measured in blood was: ZnPP-HPLC (0.95), sTfR (0.92), sTfR-F (0.89), TSAT (0.87), and ferritin (0.67). Noninvasively measured ZnPP-NI yielded results of 0.90. CONCLUSION: ZnPP-NI appears well suited for an initial IDE screening, informing on the state of erythropoiesis at the point of care without blood drawing and laboratory analysis. Comparison with a multiparameter IDE test revealed that ZnPP-NI values of 40 μmol/mol heme or less allows exclusion of IDE, whereas for 65 μmol/mol heme or greater, IDE is very likely if other causes of increased values are excluded. In these cases (77% of our patients) ZnPP-NI may suffice for a diagnosis, while values in between require analyses of additional iron status parameters