Transfusion of red blood cells in venoarterial extracorporeal membrane oxygenation: A multicenter retrospective observational cohort study.

BACKGROUND: Evidence-based recommendations for transfusion in patients with venoarterial extracorporeal membrane oxygenation (VA ECMO) are scarce. The current literature is limited to single-center studies with small sample sizes, therefore complicating generalizability. This study aims to create an overview of red blood cell (RBC) transfusion in VA ECMO patients. METHODS: This international mixed-method study combined a survey with a retrospective observational study in 16 centers. The survey inventoried local transfusion guidelines. Additionally, retrospective data of all adult patients with a VA ECMO run >24 h (January 2018 until July 2019) was collected of patient, ECMO, outcome, and daily transfusion parameters. All patients that received VA ECMO for primary cardiac support were included, including surgical (i.e., post-cardiotomy) and non-surgical (i.e., myocardial infarction) indications. The primary outcome was the number of RBC transfusions per day and in total. Univariable logistic regressions and a generalized linear mixed model (GLMM) were performed to assess factors associated with RBC transfusion. RESULTS: Out of 419 patients, 374 (89%) received one or more RBC transfusions. During a median ECMO run of 5 days (1st-3rd quartile 3-8), patients received a median total of eight RBC units (1st-3rd quartile 3-17). A lower hemoglobin (Hb) prior to ECMO, longer ECMO-run duration, and hemorrhage were associated with RBC transfusion. After correcting for duration and hemorrhage using a GLMM, a different transfusion trend was found among the regimens. No unadjusted differences were found in overall survival between either transfusion status or the different regimens, which remained after adjustment for potential confounders. CONCLUSION: RBC transfusion in patients on VA ECMO is very common. The sum of RBC transfusions increases rapidly after ECMO initiation, and is dependent on the Hb threshold applied. This study supports the rationale for prospective studies focusing on indications and thresholds for RBC transfusion.

The interaction of thrombocytopenia, hemorrhage, and platelet transfusion in venoarterial extracorporeal membrane oxygenation: a multicenter observational study.

BACKGROUND: Thrombocytopenia, hemorrhage and platelet transfusion are common in patients supported with venoarterial extracorporeal membrane oxygenation (VA ECMO). However, current literature is limited to small single-center experiences with high degrees of heterogeneity. Therefore, we aimed to ascertain in a multicenter study the course and occurrence rate of thrombocytopenia, and to assess the association between thrombocytopenia, hemorrhage and platelet transfusion during VA ECMO. METHODS: This was a sub-study of a multicenter (N = 16) study on transfusion practices in patients on VA ECMO, in which a retrospective cohort (Jan-2018-Jul-2019) focusing on platelets was selected. The primary outcome was thrombocytopenia during VA ECMO, defined as mild (100-150·109/L), moderate (50-100·109/L) and severe (< 50·109/L). Secondary outcomes included the occurrence rate of platelet transfusion, and the association between thrombocytopenia, hemorrhage and platelet transfusion, assessed through mixed-effect models. RESULTS: Of the 419 patients included, median platelet count at admission was 179·109/L. During VA ECMO, almost all (N = 398, 95%) patients developed a thrombocytopenia, of which a significant part severe (N = 179, 45%). One or more platelet transfusions were administered in 226 patients (54%), whereas 207 patients (49%) suffered a hemorrhagic event during VA ECMO. In non-bleeding patients, still one in three patients received a platelet transfusion. The strongest association to receive a platelet transfusion was found in the presence of severe thrombocytopenia (adjusted OR 31.8, 95% CI 17.9-56.5). After including an interaction term of hemorrhage and thrombocytopenia, this even increased up to an OR of 110 (95% CI 34-360). CONCLUSIONS: Thrombocytopenia has a higher occurrence than is currently recognized. Severe thrombocytopenia is strongly associated with platelet transfusion. Future studies should focus on the etiology of severe thrombocytopenia during ECMO, as well as identifying indications and platelet thresholds for transfusion in the absence of bleeding. TRIAL REGISTRATION: This study was registered at the Netherlands Trial Registry at February 26th, 2020 with number NL8413 and can currently be found at https://trialsearch.who.int/Trial2.aspx?TrialID=NL8413.

PROCALCITONIN GUIDED ANTIBIOTIC STEWARDSHIP: A BALKAN EXPERT CONSENSUS STATEMENT.

Sepsis as a consequence of infection is a frequent cause of death among critically ill patients. The most common sites of infection are lover respiratory tract, abdominal, urinary tract and catheter-associated blood stream infections. Early empiric, broad-spectrum therapy in those with severe sepsis and/or shock with the aim of reducing mortality may lead to antibiotic overuse, resistance and increased costs. Among numerous serum biomarkers, procalcitonin (PCT) has proved to be one of the most reliable ones in the diagnosis of sepsis. An important means of limiting antibiotic resistance is the antibiotic stewardship program, especially in intensive care units with critically ill patients and prevalence of multiple drug-resistant pathogens. The PCT-guided antibiotic stewardship was first started in Western Europe and Asia-Pacific countries, as well as in the United States. Considering that this method has proven to be effective in reducing antibiotic consumption while improving clinical outcome, a group of experts from the Balkan region decided to make their own recommendations and PCT protocol. When creating this protocol for initiation and duration of antibiotic treatment, they especially reviewed the literature for lower respiratory tract infection and sepsis. In the protocol, they have included the severity of illness, clinical assessment, and PCT levels. Developing a consensus on the clinical algorithm by eminent experts/specialists in various fields of medicine should enable clinicians to use PCT for initiation of antibiotic therapy and monitoring PCT to stop antibiotics earlier. It is crucial that the PCT-guided algorithm becomes an integral part of institutional stewardship program.

RBC Transfusion in Venovenous Extracorporeal Membrane Oxygenation: A Multicenter Cohort Study.

OBJECTIVES: In the general critical care patient population, restrictive transfusion regimen of RBCs has been shown to be safe and is yet implemented worldwide. However, in patients on venovenous extracorporeal membrane oxygenation, guidelines suggest liberal thresholds, and a clear overview of RBC transfusion practice is lacking. This study aims to create an overview of RBC transfusion in venovenous extracorporeal membrane oxygenation. DESIGN: Mixed method approach combining multicenter retrospective study and survey. SETTING: Sixteen ICUs worldwide. PATIENTS: Patients receiving venovenous extracorporeal membrane oxygenation between January 2018 and July 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the proportion receiving RBC, the amount of RBC units given daily and in total. Furthermore, the course of hemoglobin over time during extracorporeal membrane oxygenation was assessed. Demographics, extracorporeal membrane oxygenation characteristics, and patient outcome were collected. Two-hundred eight patients received venovenous extracorporeal membrane oxygenation, 63% male, with an age of 55 years (45-62 yr), mainly for acute respiratory distress syndrome. Extracorporeal membrane oxygenation duration was 9 days (5-14 d). Prior to extracorporeal membrane oxygenation, hemoglobin was 10.8 g/dL (8.9-13.0 g/dL), decreasing to 8.7 g/dL (7.7-9.8 g/dL) during extracorporeal membrane oxygenation. Nadir hemoglobin was lower on days when a transfusion was administered (8.1 g/dL [7.4-9.3 g/dL]). A vast majority of 88% patients received greater than or equal to 1 RBC transfusion, consisting of 1.6 U (1.3-2.3 U) on transfusion days. This high transfusion occurrence rate was also found in nonbleeding patients (81%). Patients with a liberal transfusion threshold (hemoglobin > 9 g/dL) received more RBC in total per transfusion day and extracorporeal membrane oxygenation day. No differences in survival, hemorrhagic and thrombotic complication rates were found between different transfusion thresholds. Also, 28-day mortality was equal in transfused and nontransfused patients. CONCLUSIONS: Transfusion of RBC has a high occurrence rate in patients on venovenous extracorporeal membrane oxygenation, even in nonbleeding patients. There is a need for future studies to find optimal transfusion thresholds and triggers in patients on extracorporeal membrane oxygenation.

Levosimendan Efficacy and Safety: 20 Years of SIMDAX in Clinical Use.

Levosimendan was first approved for clinical use in 2000, when authorization was granted by Swedish regulatory authorities for the hemodynamic stabilization of patients with acutely decompensated chronic heart failure (HF). In the ensuing 20 years, this distinctive inodilator, which enhances cardiac contractility through calcium sensitization and promotes vasodilatation through the opening of adenosine triphosphate-dependent potassium channels on vascular smooth muscle cells, has been approved in more than 60 jurisdictions, including most of the countries of the European Union and Latin America. Areas of clinical application have expanded considerably and now include cardiogenic shock, takotsubo cardiomyopathy, advanced HF, right ventricular failure, pulmonary hypertension, cardiac surgery, critical care, and emergency medicine. Levosimendan is currently in active clinical evaluation in the United States. Levosimendan in IV formulation is being used as a research tool in the exploration of a wide range of cardiac and noncardiac disease states. A levosimendan oral form is at present under evaluation in the management of amyotrophic lateral sclerosis. To mark the 20 years since the advent of levosimendan in clinical use, 51 experts from 23 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, the United Kingdom, and Ukraine) contributed to this essay, which evaluates one of the relatively few drugs to have been successfully introduced into the acute HF arena in recent times and charts a possible development trajectory for the next 20 years.

Preoperative Anaesthesiologic Evaluation of Patient with Known Allergy.

Anaphylaxis is an unanticipated systemic hypersensitivity reaction which can produce deleterious effects, even death, if not treated promptly. Preventive approach implies taking a thorough anamnesis with the emphasis on previously diagnosed allergies. If an allergic reaction occurred during previous surgery, a detailed documentation of administered anaesthetic agents and drugs would be crucial for the following anaesthesiologic management. Preoperative planning and avoiding cross-reactivity with drugs commonly used during anaesthesia are the key points to prevent an anaphylaxis. In case of emergency surgery when the exact identification of allergens is not possible, premedication prophylaxis should be considered. General measures for prevention of anaphylaxis could be undertaken as well, such as the choice of anaesthesiologic drugs and techniques in the operating theatre adequately equipped for the management of predictable anaphylaxis.

Pretransplant and perioperative predictors of early heart transplantation outcomes.

Aim. To identify predictors of 3-month mortality after heart transplantation in a Croatian academic center. Methods. A retrospective review of institutional database identified 117 heart transplantations from January 2008 to July 2014. Two children <14 years were excluded from the study. The remaining 115 patients were dichotomized into survivors and non-survivors adjudicated at 3-months postoperatively, and their demographic, clinical, and longitudinal hemodynamic data were analyzed. Results. 3-month survival after heart transplantation was 86%. Non-survivors were older (59±8 vs 50±14 years, P=0.009), more likely to have previous cardiac surgery (44% vs 19%; odds ratio [OR] 3.28, 95% confidence interval [CI] 1.08-9.90; P=0.029), lower body mass index (BMI) (25±4 vs 28±2 kg/m(2), P=0.001), and be diabetics (44% vs 23%; OR 2.57, 95% CI 0.86-7.66; P=0.083). Creatinine clearance was marginally superior among survivors (59=19 vs 48 ± 20 mL/min, P=0.059). Donor age and sex did not affect outcomes. Non-survivors were more likely to have had ischemic cardiomyopathy (69% vs 32%, P=0.010). Postoperative utilization of epinephrine as a second line inotropic agent was a strong predictor of mortality (63% vs 7%; OR 21.91; 95% CI 6.15-78.06; P<0.001). Serum lactate concentrations were consistently higher among non-survivors, with the difference being most pronounced 2 hours after cardiopulmonary bypass (9.8±3.5 vs 5.2±3.2 mmol/L, P<0.001). The donor hearts exhibited inferior early hemodynamics in non-survivors (cardiac index 3.0±1.0 vs 4.0±1.1 L/min/m(2), P=0.001), stroke volume (49±24 vs 59±19 mL, P=0.063), and left and right ventricular stroke work indices (18±8 vs 30±11 g/beat/m(2), P<0.001 and 5±3 vs 7±4 g/beat/m(2), P=0.060, respectively). Non-survivors were more likely to require postoperative re-sternotomy (50% vs 12%; OR 7.25, 95% CI 2.29-22.92; P<0.001), renal replacement therapy (RRT) (69% vs 9%; OR 22.00, 95% CI 6.24-77.54; P<0.001), and mechanical circulatory assistance (MCS) (44% vs 5%; OR 14.62, 95% CI 3.84-55.62; P<0.001). Binary logistic regression revealed recipient age (P=0.024), serum lactates 2 hours after CPB (P=0.007), and epinephrine use on postoperative day 1 (P=0.007) to be independently associated with 3-month mortality. Conclusion. Pretransplant predictors of adverse outcome after heart transplantation were recipient age, lower BMI, ischemic cardiomyopathy, reoperation and diabetes. Postoperative predictors of mortality were inferior donor heart hemodynamics, epinephrine use, and serum lactate concentrations. Non-survivors were more likely to require re-sternotomy, MCS, and RRT.

Results of extracorporeal life support implementation in routine clinical practice: single center experience.

AIM: To describe our experience in the clinical application of extracorporeal life support (ECLS) and analyze whether ECLS leads to acceptable clinical outcomes in patients with cardiac failure. METHODS: Data from clinical database of University Hospital Center Zagreb, Croatia, on 75 patients undergoing ECLS support from 2009 to 2014 due to cardiac failure were retrospectively analyzed. Outcomes were defined as procedural and clinical outcomes. ECLS as a primary procedure and ECLS as a postcardiotomy procedure due to inability to wean from cardiopulmonary bypass were analyzed. RESULTS: ECLS was used in 75 adult patients, and in 24 (32%) of those procedural success was noted. ECLS was implemented as a primary procedure in 36 patients and as a postcardiotomy procedure in 39 patients. Nine out of 39 (23.08%) patients had postcardiotomy ECLS after heart transplantation. Bleeding complications occurred in 30 (40%) patients, both in primary (11/36 patients) and postcardiotomy group (19/39 patients). ECLS was established by peripheral approach in 46 patients and by central cannulation in 27 patients. In 2 patients, combined cannulation was performed, with an inflow cannula placed into the right atrium and an outflow cannula placed into the femoral artery. Eleven patients treated with peripheral approach had ischemic complications. CONCLUSION: ECLS is a useful tool in the treatment of patients with refractory cardiac failure and its results are encouraging in patients who otherwise have an unfavorable prognosis. Patient outcomes may be further improved by technological advances, more clinical experience in application of the technique, careful patient selection, and multidisciplinary approach in patient management.

Bleeding risk assessment using multiple electrode aggregometry in patients following coronary artery bypass surgery.

Individual variability in the response to antiplatelet therapy (APT), frequently administered preoperatively, has been established by various platelet function assays and could reflect bleeding tendency after coronary artery bypass surgery (CABG). Our hypothesis is that multiple electrode whole-blood aggregometry (MEA) can identify patients at risk for excessive bleeding. We enrolled 211 patients (155 male and 56 female) undergoing isolated CABG in a prospective observational study. Patients were divided into four groups with respect to their preoperative APT management. MEA, using the ASPI and the ADP test, was performed prior to surgery. The primary endpoint was chest tube output (CTO) and the secondary endpoint was perioperative packed red blood cell concentrate (PRBC) administration. Patients were characterized as bleeders if their 24 h CTO exceeded the 75th percentile of distribution. 24 h CTO value of 11.33 ml/kg presented 75th percentile of distribution, thus cut-off value for "bleeder category". The proportion of patients characterized as bleeders was significantly different among the groups in regard to preoperative APT (p = 0.039). Significant differences in both ASPI (p < 0.001) and ADP (p = 0.038) tests were observed between different preoperative APT groups. Significant correlations between the ASPI test (r = -0.170, p = 0.014) and ADP test (r = -0.206, p = 0.003) with 24 h CTO were found. The receiver operating curve revealed an ASPI test value of <20 area under curve (AUC) units (AUC 0.603, p = 0.023) and an ADP test <73 AUC (AUC 0.611, p = 0.009) as a "bleeder" determinant. The proportion of patients transfused with PRBC did not significantly differ among the groups in regard to preoperative APT (p = 0.636). Comparison of the ASPI test values between patients with respect to PRBC administration revealed lower values in the ASPI test in a group of patients transfused with PRBC (mean, 27.88 vs. 40.32 AUC, p = 0.002). Our study showed that MEA is a useful method of predicting CABG patients with excessive postoperative bleeding.

Definition of acetylsalicylic acid resistance using whole blood impedance aggregometry in patients undergoing coronary artery surgery.

A beneficial effect of acetylsalicylic acid (ASA) on vein graft patency has been described, but some patients experience adverse cardiac events despite appropriate ASA treatment. Study aim was to define ASA resistance using Multiple electrode aggregometry (MEA) preoperatively in group of patients undergoing coronary artery bypass grafting (CABG). Prospective observational trial at University Hospital Center Zagreb enrolled 131 patients scheduled for CABG, and divided them into 4 groups with respect to preoperative antiplatelet therapy (APT). Group 1 received 100 mg ASA per day, Group 2 100 mg ASA + 75 mg clopidogrel per day, Group 3 75 mg clopidogrel per day, and Group 4 did not receive any APT. MEA with ASPI test (sensitive to ASA) and ADP test (sensitive to clopidogrel) was performed prior to surgery. In Group 1, patients were characterized as ASA resistant if their ASPI test value exceeded the 75th percentile distribution. Study enrolled 131 patients. Significant differences both in the ASPI (p < 0.001) and the ADP test (p = 0.038) were observed between patients in different APT groups. In Group (1) ASPI test value of 30 AUC presented 75th percentile of distribution, thus indicating ASA resistance. Group 2 patients had slightly lower ADP test values, but no significant difference occurred (mean 60.05 vs. 63.32 AUC, p = 0.469). In Group 1 and 2, significant correlations between the ADP test and both, platelet count (r = 0.347, p < 0.001) and fibrinogen level (r = 0.364, p < 0.001) were observed. Association between low response to ASA and post-CABG major adverse ischemic events risk increase has been described thus indicating need for ASA resistant patients detection. In patients with preoperative ASPI test exceeding 30 AUC postoperative, ASA dose adjustment or clopidogrel addition according to MEA results should be considered.

Plasma Transfusion and Procoagulant Product Administration in Extracorporeal Membrane Oxygenation: A Secondary Analysis of an International Observational Study on Current Practices.

OBJECTIVES: To achieve optimal hemostatic balance in patients on extracorporeal membrane oxygenation (ECMO), a liberal transfusion practice is currently applied despite clear evidence. We aimed to give an overview of the current use of plasma, fibrinogen concentrate, tranexamic acid (TXA), and prothrombin complex concentrate (PCC) in patients on ECMO. DESIGN: A prespecified subanalysis of a multicenter retrospective study. Venovenous (VV)-ECMO and venoarterial (VA)-ECMO are analyzed as separate populations, comparing patients with and without bleeding and with and without thrombotic complications. SETTING: Sixteen international ICUs. PATIENTS: Adult patients on VA-ECMO or VV-ECMO. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 420 VA-ECMO patients, 59% (n = 247) received plasma, 20% (n = 82) received fibrinogen concentrate, 17% (n = 70) received TXA, and 7% of patients (n = 28) received PCC. Fifty percent of patients (n = 208) suffered bleeding complications and 27% (n = 112) suffered thrombotic complications. More patients with bleeding complications than patients without bleeding complications received plasma (77% vs. 41%, p < 0.001), fibrinogen concentrate (28% vs 11%, p < 0.001), and TXA (23% vs 10%, p < 0.001). More patients with than without thrombotic complications received TXA (24% vs 14%, p = 0.02, odds ratio 1.75) in VA-ECMO, where no difference was seen in VV-ECMO. Of 205 VV-ECMO patients, 40% (n = 81) received plasma, 6% (n = 12) fibrinogen concentrate, 7% (n = 14) TXA, and 5% (n = 10) PCC. Thirty-nine percent (n = 80) of VV-ECMO patients suffered bleeding complications and 23% (n = 48) of patients suffered thrombotic complications. More patients with than without bleeding complications received plasma (58% vs 28%, p < 0.001), fibrinogen concentrate (13% vs 2%, p < 0.01), and TXA (11% vs 2%, p < 0.01). CONCLUSIONS: The majority of patients on ECMO receive transfusions of plasma, procoagulant products, or antifibrinolytics. In a significant part of the plasma transfused patients, this was in the absence of bleeding or prolonged international normalized ratio. This poses the question if these plasma transfusions were administered for another indication or could have been avoided.

The relationship between prolonged cerebral oxygen desaturation and postoperative outcome in patients undergoing coronary artery bypass grafting.

58 patients who underwent on-pump coronary artery bypass graft surgery were evaluated for changes in regional cerebral oxygen saturation (rSO2) measured by near infrared spectroscopy (NIRS). If rSO2 during the operation fell to more than 20% under the baseline, standardized interventions were undertaken to maintain rSO2. Despite those interventions, in some cases we observed inability to maintain rSO2 above this threshold. Therefore we divided patients in two subgroups: 1. without prolonged rSO2 desaturation; 2. with prolonged rSO2 desaturation (area under the curve >150 min% for rSO2<20% of baseline and >50 min% for rSO2<50% of absolute value). The data were analyzed to determine whether there were major differences in outcome of these two groups. 18 out of 58 patients (31%) had prolonged rSO2 desaturation during operation. There was significantly higher number of diabetic patients in group with prolonged rSO2 desaturation (p=0.02). Intraoperative data revealed significantly more blood consumption during cardiopulmonary bypass (p=0.007) and the need for inotropes (p=0.04) in desaturation group. Three patients in prolonged desaturation group and no one in another group had stroke, coma or stupor (p=0.03). Logistic regression analysis revealed diabetes mellitus and age as predictors for prolonged rSO2 desaturation. We concluded that prolonged intraoperative rSO2 desaturation is significantly associated with worse neurological outcome in patients - nonresponders to standardized interventions for prevention of rSO2 desaturation.

Early biochemical markers in the assessment of acute kidney injury in children after cardiac surgery.

Our aim was to evaluate biochemical markers in plasma (NGAL, CysC) and urine (NGAL, KIM-1) in children's early onset of acute kidney injury after congenital heart defect surgery using cardiopulmonary bypass. This study prospectively included 100 children with congenital heart defects who developed AKI. Patients with acute kidney injury had significantly higher CysC levels 6 and 12 h after cardiac surgery and plasma NGAL levels 2 and 6 h after cardiac surgery. The best predictive properties for the development of acute kidney injury are the combination (+CysCpl or +NGALu) after 12 h and a combination (+CysCpl and +NGALu) 6 and 24 h after cardiac surgery. We showed that plasma CysC and urinary NGAL could reliably predict the development of acute kidney injury. Measurement of early biochemical markers in plasma and urine, individually and combination, may predict the development of cardiac surgery-associated acute kidney injury in children.

[Preparation of highly HLA-sensitized patient for heart transplantation: first documented case in Croatia]. / Priprema visoko HLA-senzibilizirane bolesnice za transplantaciju srca: prvi slucaj u Republici Hrvatskoj.

The presence of human leukocyte antigen (HLA) poses a significant therapeutic challenge in solid organ transplantation. Sensitized patients (panel reactive antibody, PRA > 10%) receiving a heart transplant are at an increased risk of developing several clinical syndromes that influence short-term, and possibly also long-term patient survival. We present a case of immune system modulation in a highly sensitized patient awaiting heart transplantation. To our knowledge, this is the first case of desensitization therapy in solid organ transplantation done in Croatia. The patient with decompensated primary dilated cardiomyopathy received left ventricular assist device as a bridge to heart transplantation. Pre-transplantation evaluation revealed the presence of fungal pneumonia and high sensitization to HLA antibodies (PRA 97%). Desensitization protocol consisted of mycophenolate mofetil, tacrolimus, intravenous immune globulin and preoperative plasmapheresis along with previously initiated antifungal therapy. We withheld the application of rituximab until after resolution of pneumonia, but our protocol lowered PRA to 6% even without it. Unfortunately, during the next several weeks, a suitable donor was not found and our patient died form multiorgan failure. Avoidance of allosensitization by early referral to transplantation center, early transplantation, and avoidance of transfusions are very important when treating a potential transplant recipient. In this way, waiting time to transplantation, development of posttransplantation complications and mortality are reduced.

[The development of interventional catheterisation in the referral centre for pediatric cardiology of the Republic of Croatia--a retrospective study 1996-2009]. / Razvoj interventne dijagnostike u Referentnom centru za pedijatrijsku kardiologiju RH--retrospektivna studija 1996-2009.

The goal of our study was to show an increase in the number of interventional heart catheterisations in the last 14 years in the Referral Centre for Pediatric Cardiology of the Republic of Croatia. From January 1996 to December 2009 2379 children (51% male and 49% female) underwent invasive diagnostic procedures (mean age 4.1+3.8 years, range 1 day-20.5 years). In that period in 22.27% (2379/530) of the children a certain interventional procedure was performed. The number of interventional catheterisations increased from 20/160 (12.5%) in 1996 to 70/224 (31.25%) in 2009. Some interventional procedures were introduced before 1996 (Rashkind BAS, dilatation of pulmonary valve stenosis and myocardial biopsy), while other methods were introduced in the following order: dilatation of critical aortic stenosis in newborns and other ages from 1996, ductus Bottali closure from 1997, interatrial septal defect closure from 2000, native coarctation and recoarctation of the aorta from 2003. Of 530 interventional catheterisations involved in the study during the period of 14 years, there were 140 atrioseptostomias (26.4%), 80 pulmonary valve dilatations (15.1%), 58 aortic valve dilatations in older children (6.8%), 9 dilatations of critical aortic stenosis (1.7%), 58 dilatations of coarctation (10.9%) (of which 32 native and 26 recoarctations), 133 ductus Botalli closures (25.1%) (4 with PFM coils, 68 with Cook coils and 61 with Amplatzer Duct occluder). From 2000 interatrial septal defects were closed in 37 patients, 14 of which were closed with Cardioseal-STARflex system (37.84%) and 23 with Amplatzer device (62.16%). Myocardial biopsy was performed in 37 patients (7%) with 4-5 endomyocardial samples per patient (mainly from the left ventricle) so that we had 120 heart samples in total for further analysis. Hi2-test determined a constant rise in catheterisations in relation to the mean number (p<0.05) except for the years 1997 and 1998 when it was significantly lower than the average. A positive trend in the increase of interventional catheterisations was determined (p<0.005). The share of interventional catheterisations compared to diagnostic catheterisations was found to have statistically significantly increased (p<0.05) from 1996 to 2009. We conclude that in the observed period there is a slight increase in the overall number of catheterisations and a more intense increase of interventional catheterisations, particularly after 1999.

Levosimendan Efficacy and Safety: 20 years of SIMDAX in Clinical Use.

Levosimendan was first approved for clinic use in 2000, when authorisation was granted by Swedish regulatory authorities for the haemodynamic stabilisation of patients with acutely decompensated chronic heart failure. In the ensuing 20 years, this distinctive inodilator, which enhances cardiac contractility through calcium sensitisation and promotes vasodilatation through the opening of adenosine triphosphate-dependent potassium channels on vascular smooth muscle cells, has been approved in more than 60 jurisdictions, including most of the countries of the European Union and Latin America. Areas of clinical application have expanded considerably and now include cardiogenic shock, takotsubo cardiomyopathy, advanced heart failure, right ventricular failure and pulmonary hypertension, cardiac surgery, critical care and emergency medicine. Levosimendan is currently in active clinical evaluation in the US. Levosimendan in IV formulation is being used as a research tool in the exploration of a wide range of cardiac and non-cardiac disease states. A levosimendan oral form is at present under evaluation in the management of amyotrophic lateral sclerosis. To mark the 20 years since the advent of levosimendan in clinical use, 51 experts from 23 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, UK and Ukraine) contributed to this essay, which evaluates one of the relatively few drugs to have been successfully introduced into the acute heart failure arena in recent times and charts a possible development trajectory for the next 20 years.

Intragastric Application of Aspirin, Clopidogrel, Cilostazol, and BPC 157 in Rats: Platelet Aggregation and Blood Clot.

We suggest that the stable gastric pentadecapeptide BPC 157 may rescue thrombocyte function. We focused on the antithrombotic agent aspirin, clopidogrel, and cilostazol application in rats; arachidonic acid, ADP, collagen, and arachidonic acid/PGE1 platelet aggregation (aggregometry) and blood clot viscoelastic properties (thromboelastometry); and the pentadecapeptide BPC 157. Rats received intragastrically for three days once daily treatment with antithrombotic agents-aspirin (10 mg/kg) or clopidogrel (10 mg/kg) or cilostazol (10 mg/kg). Medication (BPC 157 (10 µg/kg) or an equal volume of saline (5 ml/kg)) was given intragastrically, immediately after each antithrombotic agent application. For multiple electrode aggregometry and modified rotational thromboelastometry studies, blood sampling was at 2 h after last application. Adenosine diphosphate (ADP test 6.5 µM), arachidonic acid (ASPI test 0.5 mM), a combination of arachidonic acid and prostaglandin E1 (ASPI test 0.5 mM and PGE1-test 30 nM), and collagen (COL test 3.2 µg/ml) were used as aggregation agonists. Given with aspirin, clopidogrel, or cilostazol in rats, BPC 157 counteracted their inhibitory effects on aggregation activated by arachidonic acid, ADP, collagen, and arachidonic acid/PGE1. Specifically, this includes recovery of the aggregation induced by arachidonic acid (vs. aspirin, vs. clopidogrel, and vs. cilostazol), arachidonic acid/PGE1 (vs. cilostazol), ADP (vs. clopidogrel), or collagen (vs. clopidogrel). Contrarily, there is no effect on the used tests (extrinsic/intrinsic hemostasis system, the fibrin part of the clot) EXTEM, INTEM, and FIBTEM; clotting time; clot formation time; alpha-angle; maximum clot firmness; lysis index after 30 minutes; and maximum lysis. In conclusion, we revealed that BPC 157 largely rescues thrombocyte function.

Impact of remote ischemic preconditioning preceding coronary artery bypass grafting on inducing neuroprotection.

BACKGROUND: Neurological complications after coronary artery bypass grafting (CABG) reduce quality of life, increase mortality, and inflate resource utilization. The risk of postoperative neurological complications parallels the increasing risk burden of the contemporary patient population. We evaluated the efficacy of remote ischemic preconditioning (RIPC) on inducing neuroprotection. METHODS: Seventy patients undergoing first-time CABG were randomly assigned to RIPC or a sham procedure. Structural brain magnetic resonance imaging (MRI) was complemented with functional connectivity MRI to gain a whole-brain global connectivity analysis. Paired neurocognitive and MRI data were acquired pre- and postoperatively. The primary end point was a composite of new ischemic brain lesions and neurocognitive impairment. Secondary end points included brain connectivity profiles, pooled ischemic volumes, and individual components of the primary outcome. The Shapiro-Wilk test was used to determine whether a data set followed a normal distribution. The Fisher exact test was used to calculate the measures of association for categorical variables, whereas continuous data were tested with either the Mann-Whitney U test or the Student t test. RESULTS: There was no between-group difference in the incidence of the primary end point (9 [27%] in the RIPC group vs 8 [24%] in the control group, odds ratio, 1.17 [95% confidence interval, 0.34-4.06]; P = 1.0). Although RIPC did not reduce the incidence of brain ischemia (8/33 [24%] vs 7/33 [21%]; P = 1.0), the pooled ischemic volume was lower in the RIPC group (157 [interquartile range, 125-231] vs 777 [interquartile range, 564-965] mm3; P = .004). Postoperative neurocognition was marginally superior in the RIPC group as evidenced by a lower absolute number of abnormal neurocognitive tests in the RIPC group (7/99 [7%] vs 16/99 [16%]; odds ratio, 0.40 [95% confidence interval, 0.14-1.09]; P = .074). Robust reductions of functional connectivity profiles for the associative thalamus were documented in both groups, irrespective of RIPC (RIPC group, t = 3.31; P < .01; and the control group, t = 3.52; P < .01). CONCLUSIONS: Silent brain ischemia occurs frequently after CABG. RIPC did not reduce the incidence of the primary outcome. However, RIPC significantly reduced the pooled volume of ischemic brain lesions. Surgery adversely affected global brain connectivity, with RIPC conferring no demonstrable protection. The association of RIPC with superior neurocognitive test scores failed to cross the threshold for significance.

Short-Term Therapies for Treatment of Acute and Advanced Heart Failure-Why so Few Drugs Available in Clinical Use, Why Even Fewer in the Pipeline?

Both acute and advanced heart failure are an increasing threat in term of survival, quality of life and socio-economical burdens. Paradoxically, the use of successful treatments for chronic heart failure can prolong life but-per definition-causes the rise in age of patients experiencing acute decompensations, since nothing at the moment helps avoiding an acute or final stage in the elderly population. To complicate the picture, acute heart failure syndromes are a collection of symptoms, signs and markers, with different aetiologies and different courses, also due to overlapping morbidities and to the plethora of chronic medications. The palette of cardio- and vasoactive drugs used in the hospitalization phase to stabilize the patient's hemodynamic is scarce and even scarcer is the evidence for the agents commonly used in the practice (e.g. catecholamines). The pipeline in this field is poor and the clinical development chronically unsuccessful. Recent set backs in expected clinical trials for new agents in acute heart failure (AHF) (omecamtiv, serelaxine, ularitide) left a field desolately empty, where only few drugs have been approved for clinical use, for example, levosimendan and nesiritide. In this consensus opinion paper, experts from 26 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Israel, Italy, The Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, Turkey, U.K. and Ukraine) analyse the situation in details also by help of artificial intelligence applied to bibliographic searches, try to distil some lesson-learned to avoid that future projects would make the same mistakes as in the past and recommend how to lead a successful development project in this field in dire need of new agents.